article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Major progress has occurred in multiple myeloma (MM) treatment in recent years, but this is not seen in low- and middle-income countries.\n\n\n\nWe retrospectively assessed the efficacy and safety of cyclophosphamide, thalidomide, and dexamethasone (cyclophosphamide 400 mg/m2 for 5 days, thalidomide 100 mg once daily, if tolerated, and dexamethasone 40 mg once weekly; in 28-day cycles) in patients with newly diagnosed MM treated at our institution between April 2008 and December 2012. Survival outcomes were estimated by the Kaplan-Meier method.\n\n\n\nFifty-nine patients were found to meet the selection criteria. Median age was 56 years (27-78). Fifty-nine percent (n = 35) were male. International Staging System three was found in 24%. The median number of treatment cycles was 11 (range 4-12). After a median of 81-month follow-up (range 5-138 months), the overall response rate was 69.5%. The complete response and very good partial response were 5% and 32%, respectively. Median progression-free survival (PFS) was 35 months (95% CI, 18 to 41). The 3-year PFS was 47.4% (95% CI, 34.5 to 59.6) and 5-year PFS was 24.9% (95% CI, 14.4 to 36.9). The median of overall survival (OS) was 81 months (95% CI, 33 to not reached). The 3-year OS was 63.4% (95% CI, 49.2 to 74.6), and 5-year OS was 57.5% (95% CI, 43.2 to 69.4). The most common adverse event was neutropenia (grade 3 and 4, 30.5%). Out of 23 patients eligible for stem-cell transplantation, 10 (43.5%) proceeded with autologous transplantation. Treatment-related deaths occurred in four patients (6.7%).\n\n\n\nCyclophosphamide, thalidomide, and dexamethasone achieves good response rates with tolerable toxicity, especially in patients age 65 years or younger representing a feasible approach for patients with MM in low-income health care settings.",
"affiliations": "Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Oncológico Miraflores, Lima, Peru.",
"authors": "Vasquez|Jule|J|0000-0001-6477-4660;Ruiz|Rossana|R|0000-0001-5199-6686;Aliaga|Karina|K|0000-0002-1495-4396;Valencia|Fernando|F|0000-0003-2475-0570;Villena|Marco|M|;Quintana|Shirley|S|0000-0002-1879-2486;Vidaurre|Tatiana|T|0000-0003-1995-4560;Casanova|Luis|L|",
"chemical_list": "D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1200/GO.20.00665",
"fulltext": "\n==== Front\nJCO Glob Oncol\nJCO Glob Oncol\ngo\ngo\nGO\nJCO Global Oncology\n2687-8941\nWolters Kluwer Health\n\n34297605\nGO.20.00665\n10.1200/GO.20.00665\nORIGINAL REPORTS\nHematologic Malignancies\nCyclophosphamide, Thalidomide, and Dexamethasone as Initial Therapy for Patients With Newly Diagnosed Multiple Myeloma in a Middle-Income Country: 7-Year Follow-Up\nhttps://orcid.org/0000-0001-6477-4660\nVasquez Jule MD 1\nhttps://orcid.org/0000-0001-5199-6686\nRuiz Rossana MD 1\nhttps://orcid.org/0000-0002-1495-4396\nAliaga Karina MD 1\nhttps://orcid.org/0000-0003-2475-0570\nValencia Fernando MD 1\nVillena Marco MD 1\nhttps://orcid.org/0000-0002-1879-2486\nQuintana Shirley MD 1\nhttps://orcid.org/0000-0003-1995-4560\nVidaurre Tatiana MD 1\nCasanova Luis MD 2\n1 Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru\n2 Instituto Oncológico Miraflores, Lima, Peru\nJule Vasquez, MD, Instituto Nacional de Enfermedades Neoplasicas, 2520 East Angamos, Lima 15038, Peru; e-mail: jvasquez@inen.sld.pe.\n2021\n23 7 2021\n7 GO.20.006654 1 2021\n3 5 2021\n28 6 2021\n© 2021 by American Society of Clinical Oncology\n2021\nAmerican Society of Clinical Oncology\nhttps://creativecommons.org/licenses/by/4.0/ Licensed under the Creative Commons Attribution 4.0 License: http://creativecommons.org/licenses/by/4.0/\n\nPURPOSE\n\nMajor progress has occurred in multiple myeloma (MM) treatment in recent years, but this is not seen in low- and middle-income countries.\n\nMATERIALS AND METHODS\n\nWe retrospectively assessed the efficacy and safety of cyclophosphamide, thalidomide, and dexamethasone (cyclophosphamide 400 mg/m2 for 5 days, thalidomide 100 mg once daily, if tolerated, and dexamethasone 40 mg once weekly; in 28-day cycles) in patients with newly diagnosed MM treated at our institution between April 2008 and December 2012. Survival outcomes were estimated by the Kaplan-Meier method.\n\nRESULTS\n\nFifty-nine patients were found to meet the selection criteria. Median age was 56 years (27-78). Fifty-nine percent (n = 35) were male. International Staging System three was found in 24%. The median number of treatment cycles was 11 (range 4-12). After a median of 81-month follow-up (range 5-138 months), the overall response rate was 69.5%. The complete response and very good partial response were 5% and 32%, respectively. Median progression-free survival (PFS) was 35 months (95% CI, 18 to 41). The 3-year PFS was 47.4% (95% CI, 34.5 to 59.6) and 5-year PFS was 24.9% (95% CI, 14.4 to 36.9). The median of overall survival (OS) was 81 months (95% CI, 33 to not reached). The 3-year OS was 63.4% (95% CI, 49.2 to 74.6), and 5-year OS was 57.5% (95% CI, 43.2 to 69.4). The most common adverse event was neutropenia (grade 3 and 4, 30.5%). Out of 23 patients eligible for stem-cell transplantation, 10 (43.5%) proceeded with autologous transplantation. Treatment-related deaths occurred in four patients (6.7%).\n\nCONCLUSION\n\nCyclophosphamide, thalidomide, and dexamethasone achieves good response rates with tolerable toxicity, especially in patients age 65 years or younger representing a feasible approach for patients with MM in low-income health care settings.\n==== Body\npmcINTRODUCTION\n\nMultiple myeloma (MM) is a hematologic malignancy accounting for roughly 10% of all blood cancers.1 New cases of MM in United States are more than 30,000 per year.2 In Peru, the incidence is estimated at 1.82 × 100,000 for both sexes.3 Major changes have happened on the MM treatment from the first case described in 1844,4 since steroids, chemotherapy, transplant, proteasome inhibitors, and immunomodulators5-9 to newer treatments such as monoclonal antibodies.10\n\nCONTEXT\n\nKey Objective\n\nMultiple myeloma (MM) is one of the hematologic malignancies that has incorporated the largest number of novel treatments as part of its therapeutical arsenal in recent years. However, the benefit of modern therapies is not fully available for countries with limited resources.\n\nKnowledge Generated\n\nThis study provides new data about long-term outcomes in terms of the efficacy, safety, and survival of patients with MM treated with cyclophosphamide, thalidomide, and dexamethasone as first-line treatment. Patient younger than 65 years are those who have the best benefit with this regimen.\n\nRelevance\n\nThese findings can be applied to low- and middle-income countries struggling to have access to novel treatments such as bortezomib, lenalidomide, and daratumumab and could be used both for eligible and noneligible patients with MM for autologous transplantation.\n\nIn low- and middle-income countries, limited resources in health care make it difficult to have availability of novel drugs. The cost of the myeloma drugs is expensive. Regimens such as bortezomib, thalidomide, and dexamethasone (VTD) or bortezomib, lenalidomide, and dexamethasone (VRD) can cost $100,000 US dollar (USD) or more per year.11 In this scenario, a traditional treatment such as cyclophosphamide, thalidomide, and dexamethasone (CTd) is a more affordable alternative for newly diagnosed patients.12,13\n\nThe aim of this study was to determine the clinical efficacy, safety, and survival outcomes of transplant-eligible and -ineligible patients with MM treated with CTd as first line of treatment in a country with limited resources.\n\nMATERIALS AND METHODS\n\nPatients and Staging\n\nWe evaluated patients with newly diagnosed MM treated at the National Cancer Institute (Instituto Nacional de Enfermedades Neoplásicas) in Lima, Perú, between April 2008 and December 2012. The diagnosis of MM was based on the WHO 2008 criteria.14 Staging was based on International Staging System.15 The inclusion criteria were as follows: Diagnosis of MM at Instituto Nacional de Enfermedades Neoplásicas and have received at least four cycles of CTd; for protocol, the evaluation of the treatment response was after 4, 8, and 12 cycles. Exclusion criteria were MM treated previously, patients with another cancer, patients with HIV infection, diagnosis of plasma cell leukemia, and incomplete medical records. This study obtained the written informed consent from all patients and also had the approval of the Institutional Review Board.\n\nDuring the study period, 181 patients were evaluated, of which 93 patients received CTd, 19 thalidomide dexamethasone, six vincristine, doxorubicin, and dexamethasone (VAD), four cyclophosphamide dexamethasone, five other chemotherapy agents, and seven only radiotherapy; 22 did not meet criteria because of previous treatment; and 25 did not receive any treatment because of loss to follow-up.\n\nIn the CTd cohort, 24 received only three or less cycles (25%), and 10 (11%) received four or more cycles, but without assessment of the treatment response or had other exclusion criteria; finally, 59 (64%) patients fulfilled the selection criteria.\n\nTreatment and Response Criteria\n\nTreatment was based on CTd (cyclophosphamide 400 mg/m2 orally for 5 days, thalidomide 100 mg the first week increasing to 200 mg if tolerated and dexamethasone 40 mg weekly, 28-day cycles). All patients received acetylsalicylic acid 100 mg/d as prophylaxis for deep venous thrombosis.16 Toxicity was evaluated according to Common Terminology Criteria for Adverse Events version 4.0. Treatment-related mortality (TRM) was defined as death occurring in the absence of progressive cancer and having received CTd in the last 30 days before death.\n\nResponse rates were evaluated according to international response criteria after 4, 8, and 12 cycles.17\n\nStatistical Analysis\n\nA descriptive analysis of the information was made through frequencies, percentages, and summary measures. Overall survival (OS) was defined as the time from the date of diagnosis to the date of last control or death. Progression-free survival (PFS) was defined as the time from the date of treatment initiation to the date of last control, progression recurrence, or death. OS and PFS were estimated using the Kaplan-Meier method, and differences were tested with the log-rank test. In the analysis of the information, Stata 15 (StataCorp, TX) was used.\n\nRESULTS\n\nPatient Characteristics\n\nThe clinical and pathologic characteristics of the patients are shown in Table 1. The median age was 56 years (27-78). The majority were male (59%). In addition, there was a predominance of early stages.\n\nTABLE 1 Clinical and Pathologic Characteristics\n\nToxicity and Response Treatment\n\nThe most common adverse event was neutropenia (44.1%). Neutropenia grades 3 and 4 account for 18.6% and 11.9%, respectively. Also, severe infection was 8.4% and deep vein thrombosis was 6.8%. The toxicities are detailed in Table 2.\n\nTABLE 2 Treatment-Related Toxicity\n\nRegarding the total response rate, it was 69.5%, with a low strict complete response of 1.7%; the other types of responses are detailed in Table 3.\n\nTABLE 3 Treatment Response\n\nPFS and OS\n\nThe median of follow-up was 41 months (range 5-138 months). The median PFS was 35 months (95% CI, 18 to 41) as shown in Figure 1. The 3-year PFS was 47.4% (95% CI, 34.5 to 59.6), and 5-year PFS was 24.9% (95% CI, 14.4 to 36.9).\n\nFIG 1 OS of 59 patients with multiple myeloma. OS, overall survival.\n\nThe median of OS was 81 months (95% CI, 33 to not reached). The 3-year OS was 63.4% (95% CI, 49.2 to 74.6), and 5-year OS was 57.5% (95% CI, 43.2 to 69.4) as shown in Figure 2.\n\nFIG 2 PFS of 59 patients with multiple myeloma. PFS, progression-free survival.\n\nTreatment-Related Mortality\n\nTreatment-related deaths occurred in four patients (6.7%) who were age 62, 64, 74, and 76 years. The median age was 69 years (range 62-76 years), 50% patients were male, 50% achieved at least PR, the median of cycles was 9 (range 6-12), 50% had grade 3 neutropenia, 50% had grade 3 thrombocytopenia, 50% had grade 2 neurotoxicity, three patients died because of pneumonia, and one because of ischemic cerebrovascular disease.\n\nTransplantation of Hematopoietic Progenitors\n\nThe stem-cell transplant program started in our institution in 2012, that is, 4 years after our first patient has received CTd. As an institutional policy, only patients age 65 years and younger were transplanted. Since the late 2011, 33 patients received at least four cycles of CTd, but only 23 patients were eligible for Autologous Stem Cell Transplantation (ASCT) according to the age inclusion criteria. Only 10 (43.5%) patients proceeded with ASCT as a consolidation after induction. The main reason why patients did not proceed onto ASCT was progressive disease (six patients, 46%) followed by limiting comorbidities (three patients, 23%) and failure to collect cells (two patients, 15%). Forty percent (4 patients) of the 10 transplanted patients are on maintenance with thalidomide. The median age was 55 years (range 47-60 years), and 88% were male. The median of treatment cycles was 12 (range, 10-12).\n\nDISCUSSION\n\nThe findings from this study suggest that CTd may be a feasible treatment in a middle-income country such as Peru. The CTd regimen achieves durable responses with tolerable toxicity. The treatment of MM has evolved in our country; until 2006, the most used treatment was VAD.18 Thalidomide was available in our institution at the end of 2007 as a salvage treatment. Considering the good outcomes for thalidomide reported in international studies, it was used as part of our front-line treatment since 2008.19,20\n\nStudies have shown that thalidomide plus dexamethasone is superior to VAD in terms of response rate and survival.21,22 However, these outcomes were modest compared with those reported in a triplet regimen that included cyclophosphamide, such as CTD,12,13 and ThaCyDex23,24 either in front-line or salvage treatment. The above treatments can be considered not standards in high-income countries where VRD is the first-line treatment in most clinical scenarios. The high cost of this novel regimen, more than $200,000 USD per year, makes it unaffordable in Peru.11 Our regimen CTd is an outpatient treatment, but more importantly, a feasible therapy. In Table 4, we can see that the cost of treatment for 1 year of $1,860 USD is almost a sixth cheaper than VTD in Peru, but 60 times than in the United States. Compared to VRD, our treatment is 50 times cheaper in Peru, but 90 times than in the United States. As shown, the administration and the cost of CTd is appropriate for public institutions in Peru.\n\nTABLE 4 Cost of Multiple Myeloma Treatment\n\nA good regimen also has to be safe and effective. The overall response rate obtained in our study was 69%, which is similar to the 63.8% reported by Morgan's study in patients noneligible for ASCT, however this outcome was worse compared to patients eligible for transplant who had an overall response rate of 82.5%. The treatment regimen in each study was every 21 days and 28 days, respectively. In addition, the dose of cyclophosphamide in both studies was 500 mg weekly. The study presented by Hungria et al25 reports even higher overall responses (89.7%). Regarding complete response rates, our study reported 6.8%, which is different from Hungria's study and Morgan's study, which reported 20.7% and 13%, respectively.13,25 In Hungria's study, cyclophosphamide was given at 50 mg daily with dexamethasone at high doses (40 mg days 1-4 and 15-18), which is different from the low-dose dexamethasone used in our study (40 mg per week). In our study, cyclophosphamide was given at 400 mg/m2 for 5 consecutive days with a total dose higher to the above studies. This different approach tried to improve the intensity of the chemotherapy in the first week instead of weekly as in Morgan's study or in a metronomic way as in Hungria's study. This dose was used uniformly regardless of the eligibility for transplant. The response rates are lower than most recent treatments such as lenalidomide-dexamethasone (RD),26 bortezomib, cyclophosphamide, and dexamethasone,27 VTD,28 and VRD,29 which have shown high total response rates that range from 70% to 100%. Thalidomide was given 100 mg daily during the first week, and then was increased to 200 mg; all patients received the full dose of thalidomide since the second week.\n\nThe hematologic toxicity in our study was 30% for grades 3 and 4, which is high compared with Morgan's study13 for transplant candidates where it was only 4.5% for the same grades; we believe that it could be because of the different way of administering cyclophosphamide in our case: 400 mg/m2 × 5 days making a total of 2,000 mg/m2, whereas in Morgan's study, 500 mg/weekly making a total of 2,000 mg total dose, meaning an increase of 50% on average. Regarding infections, our work reports 30.5% of infections and Morgan's study reports 20% of grades 3 and 4, which can also be related to the difference in dose. If we focus on peripheral neuropathy, the percentages of grades 3 and 4 are similar in both studies with 3.4% in ours and 3.8% in Morgan's study.\n\nIn terms of survival, it is similar with other CTd treatment studies. The PFS in our study was 34 months, which is higher than that in Morgan's study with 27 months,13 but similar to those patients who received ASCT in the same study. We believe that a probable cause of this initial difference is that in our work, a more intensive induction regimen was used, but this little advantage is lost when high dose of melphalan is administered as conditioning in transplantation. In our study, the median OS was 81 months with a long-term follow-up (5-138 months). In Morgan's study the median OS was not reached with a shorter follow-up (0-73 months); however, they showed that OS was comparable in both treatment groups, CTd and cyclophosphamide, vincristine, doxorubicin, and dexamethasone, where the latter had a median OS of 63 months13 Modern treatments such as RD,26 VTD,28 and VRD29 have OS at 2 years of 87%, 95%, and 97%, respectively, much higher than the nearly 70% in our study (Fig 1). In terms of PFS, RD, VTD, and VRD reported 50%, 50%, and 70%, respectively. By contrast, in our study, the PFS at 2 years was 60%, but with a rapid decrease at 5 years to 25% (Fig 2).\n\nThe TRM of our study was 6.7%, discretely below that of Morgan's study13 with 8.5%; in addition, among the causes of TRM, infection was observed as the main cause in both studies. We could observe that the deaths of the patients occurred particularly in advanced age (older than 65 years), in females, and in those who received at least six courses of CTd, probably because of low marrow reserve and advanced age. This group of patients may benefit from a 50% reduction in the cyclophosphamide dose.\n\nPatients eligible for ASCT who received transplant in our study were 43.5%, which is different from Morgan's study, which had 67.4% patients eligible. Factors such as progressive disease because of a delay in the preparation process for transplant and lost to follow-up were the main causes of not having a transplant. In our study, the median age was 55 years, similar to that of Morgan's study with 58 years. The failure to collect was 15% in our study, but for the small number of patients, this may be a nonsignificant result, which is different from Morgan's study with 1.96%. In our study only, 40% of patients are on maintenance with thalidomide, which is something that should be corrected.\n\nThe main strength of this study is that CTd represents a low-cost regimen, which can be affordable in any low-income country compared with more modern cancer drugs.30 In addition, CTd regimen let us avoid the use of outpatient chemotherapy rooms. This oral regimen can be used in patients who are both transplant-eligible and transplant-ineligible. The use of this regimen is not only intended for patients from low-income countries since it is shown that it can be used in combination with novel agents such as carfilzomib, as demonstrated by the CYKLONE study.31 We will have to wait for more studies to determine its real value in this era of new agents.\n\nThe main limitation of our study is the small number of patients because the cases are from a single institution. Although 181 patients with newly diagnosed MM were admitted in our institution in the study period, only 93 received the standard treatment, 12% were non eligible because of being non-naïve to treatment, and 14% were lost to follow-up. The latter can be the result of both the lack of access to the continuity of cancer care, or that the patients were referred only for diagnosis, considering that our institution is the referral cancer center in Peru. When focusing on the patients who finally received CTd, 25% of the patients were not able to receive at least four cycles. This is mainly because of the discontinuation of treatment for economic issues rather than toxicities as was reported in a Peruvian study, where the abandonment rate was 18%.32 Another major limitation of the study is that cytogenetic and fluorescent in situ hybridization studies to categorize patients according to the risk are not available in our institution.\n\nIn conclusion, the CTd regimen achieves good response rates with tolerable toxicity, especially in patients age 65 years or younger. In older patients, it is reasonable to reduce full doses. This regimen represents an affordable and effective approach for patients with MM in the scenario of low-income health care with an acceptable toxicity profile.\n\nPRIOR PRESENTATION\n\nAUTHOR CONTRIBUTIONS\n\nConception and design: Jule Vasquez, Rossana Ruiz, Karina Aliaga, Marco Villena, Shirley Quintana, Tatiana Vidaurre, Luis Casanova\n\nFinancial support: Jule Vasquez, Marco Villena, Shirley Quintana, Luis Casanova\n\nAdministrative support: Jule Vasquez, Karina Aliaga, Marco Villena\n\nProvision of study materials or patients: Jule Vasquez, Karina Aliaga, Fernando Valencia, Marco Villena, Luis Casanova\n\nCollection and assembly of data: All authors\n\nData analysis and interpretation: Jule Vasquez, Rossana Ruiz, Karina Aliaga, Marco Villena, Shirley Quintana, Tatiana Vidaurre, Luis Casanova\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\n\nThe following represents disclosure information provided by the authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/go/authors/author-center.\n\nOpen Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).\n\nPresented at 2016 ASCO Annual Meeting, general poster session, June 3-7, Chicago, IL.\n\nJule Vasquez\n\nHonoraria: Janssen, Roche\n\nConsulting or Advisory Role: Janssen\n\nResearch Funding: Roche\n\nTravel, Accommodations, Expenses: Janssen\n\nMarco Villena\n\nConsulting or Advisory Role: AbbVie\n\nLuis Casanova\n\nTravel, Accommodations, Expenses: Roche\n\nNo other potential conflicts of interest were reported.\n\nJule Vasquez\n\nHonoraria: Janssen, Roche\n\nConsulting or Advisory Role: Janssen\n\nResearch Funding: Roche\n\nTravel, Accommodations, Expenses: Janssen\n\nMarco Villena\n\nConsulting or Advisory Role: AbbVie\n\nLuis Casanova\n\nTravel, Accommodations, Expenses: Roche\n\nNo other potential conflicts of interest were reported.\n==== Refs\nREFERENCES\n\n1. Kyle RA Rajkumar SV : Multiple myeloma. N Engl J Med 351 :1860-1873, 2004 15509819\n2. Siegel RL Miller KD Jemal A : Cancer statistics, 2016. CA Cancer J Clin 66 :7-30, 2016 26742998\n3. Payet E ; Perez P Poquioma E , et al : Registro de Cáncer de Lima Metropolitana 2004-2005. Estudio de Incidencia y Mortaidad, Volume IV . Lima, Peru, Departamento de Epidemiología y estadística del Cáncer, Instituto Nacional de Enfermedades Neoplásicas, 2013\n4. Solly S : Remarks on the pathology of mollities ossium; with cases. Med Chir Trans 27 :435-498.8, 1844\n5. Gregory WM Richards MA Malpas JS : Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: An overview of published trials. J Clin Oncol 10 :334-342, 1992 1531068\n6. Anderson H Scarffe JH Ranson M , et al : VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 71 :326-330, 1995 7841049\n7. Rajkumar SV Blood E Vesole D , et al : Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24 :431-436, 2006 16365178\n8. Gay F Hayman SR Lacy MQ , et al : Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: A comparative analysis of 411 patients. Blood 115 :1343-1350, 2010 20008302\n9. Cavo M Tacchetti P Patriarca F , et al : Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: A randomised phase 3 study. Lancet 376 :2075-2085, 2010 21146205\n10. Palumbo A Chanan-Khan A Weisel K , et al : Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375 :754-766, 2016 27557302\n11. Rajkumar SV : Value and cost of myeloma therapy. Am Soc Clin Oncol Ed Book 38 :662-666, 2018\n12. Morgan GJ Davies FE Gregory WM , et al : Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood 118 :1231-1238, 2011 21652683\n13. Morgan GJ Davies FE Gregory WM , et al : Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC myeloma IX randomized trial results. Haematologica 97 :442-450, 2012 22058209\n14. Steven H Campo E Harris L , et al : WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Multiple Myeloma (ed 4). Lyon, France, International Agency for Research on Cancer (IARC), 2008, pp 200-202\n15. Greipp PR San Miguel J Durie BG , et al : International staging system for multiple myeloma. J Clin Oncol 23 :3412-3420, 2005 15809451\n16. Palumbo A Rajkumar SV Dimopoulos MA , et al : Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 22 :414-423, 2008 18094721\n17. Durie BG Harousseau JL Miguel JS , et al : International uniform response criteria for multiple myeloma. Leukemia 20 :1467-1473, 2006 16855634\n18. Vasquez J Casanova L : Respuesta al Tratamiento de Primera Línea de los Pacientes con Mieloma Múltiple, Instituto Nacional De Enfermedades Neoplásicas 2002-2006. Revista Acta Cancerológica, Volumen 42 , Enero-Junio 2013, pp 7-16\n19. Richardson P Anderson K : Thalidomide and dexamethasone: A new standard of care for initial therapy in multiple myeloma. J Clin Oncol 24 :334-336, 2006 16365174\n20. Rajkumar SV Hayman S Gertz MA , et al : Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20 :4319-4323, 2002 12409330\n21. Cavo M Zamagni E Tosi P , et al : Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 106 :35-39, 2005 15761019\n22. Vogl DT Liu SV Chong EA , et al : Post-transplant outcomes of induction therapy for myeloma: Thalidomide and dexamethasone versus doxorubicin, vincristine, and dexamethasone prior to high-dose melphalan with autologous stem cell support. Am J Hematol 82 :1071-1075, 2007 17696204\n23. Garcia-Sanz R Gonzalez-Fraile MI Sierra M , et al : The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma. Hematol J 3 :43-48, 2002 11960395\n24. Garcia-Sanz R Gonzalez-Porras JR Hernandez JM , et al : The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 18 :856-863, 2004 14973508\n25. Hungria VT Crusoe EQ Maiolino A , et al : Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible. Ann Hematol 95 :271-278, 2016 26518211\n26. Rajkumar SV Jacobus S Callander NS , et al : Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol 11 :29-37, 2010 19853510\n27. Reeder CB Reece DE Kukreti V , et al : Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial. Leukemia 23 :1337-1341, 2009 19225538\n28. Moreau P Avet-Loiseau H Facon T , et al : Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood 118 :5752-5758, 2011; quiz 982 21849487\n29. Richardson PG Weller E Lonial S , et al : Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116 :679-686, 2010 20385792\n30. Aguiar PM Lima TM Storpirtis S : Systematic review of the economic evaluations of novel therapeutic agents in multiple myeloma: What is the reporting quality? J Clin Pharm Ther 41 :189-197, 2016 27009796\n31. Mikhael JR Reeder CB Libby EN , et al : Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol 169 :219-227, 2015 25683772\n32. Vasquez L Diaz R Chavez S , et al : Factors associated with abandonment of therapy by children diagnosed with solid tumors in Peru. Pediatr Blood Cancer 65 :e27007, 2018 29431252\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2687-8941",
"issue": "7()",
"journal": "JCO global oncology",
"keywords": null,
"medline_ta": "JCO Glob Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003520:Cyclophosphamide; D003907:Dexamethasone; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012189:Retrospective Studies; D013792:Thalidomide",
"nlm_unique_id": "101760170",
"other_id": null,
"pages": "1199-1205",
"pmc": null,
"pmid": "34297605",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "20895811;21849487;20385792;14973508;29431252;11960395;16365174;16365178;26742998;18094721;19225538;30231405;20008302;22058209;21652683;12409330;15809451;15761019;21146205;25683772;17696204;15509819;27557302;1531068;26518211;7841049;27009796;19853510;16855634",
"title": "Cyclophosphamide, Thalidomide, and Dexamethasone as Initial Therapy for Patients With Newly Diagnosed Multiple Myeloma in a Middle-Income Country: 7-Year Follow-Up.",
"title_normalized": "cyclophosphamide thalidomide and dexamethasone as initial therapy for patients with newly diagnosed multiple myeloma in a middle income country 7 year follow up"
} | [
{
"companynumb": "PE-CELGENEUS-PER-20210707467",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Myasthenia gravis is a chronic autoimmune disorder caused by antibodies directed against the neuromuscular junction. Some patients may have an associated thymoma, which confers a worse prognosis. Eculizumab, a monoclonal antibody that inhibits the activation of terminal complement, has recently been approved for the treatment of refractory generalized myasthenia gravis. This is an early case report of thymoma-associated refractory myasthenia gravis successfully treated with eculizumab in a real-world setting.",
"affiliations": "Neurometabolic Diseases Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain, and Neurology Department, Bellvitge University Hospital, Barcelona, Spain.;Neurology Department, Bellvitge University Hospital, Barcelona, Spain.;Neurology Department, Bellvitge University Hospital, Barcelona, Spain.;Neurology Department, Bellvitge University Hospital, Barcelona, Spain.;Neurology Department, Bellvitge University Hospital, Barcelona, Spain.;Neurology Department, Neuromuscular Unit, Bellvitge University Hospital, n/n Feixa Llarga street, L'Hospitalet de Llobregat, Barcelona, 08906, Spain.",
"authors": "Vélez-Santamaría|Valentina|V|https://orcid.org/0000-0001-7782-2473;Nedkova|Velina|V|;Díez|Laura|L|;Homedes|Christian|C|;Alberti|M Antonia|MA|;Casasnovas|Carlos|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1756286420932035",
"fulltext": "\n==== Front\nTher Adv Neurol Disord\nTher Adv Neurol Disord\nTAN\nsptan\nTherapeutic Advances in Neurological Disorders\n1756-2856 1756-2864 SAGE Publications Sage UK: London, England \n\n10.1177/1756286420932035\n10.1177_1756286420932035\nCase Report\nEculizumab as a promising treatment in thymoma-associated myasthenia gravis\nhttps://orcid.org/0000-0001-7782-2473Vélez-Santamaría Valentina Neurometabolic Diseases Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain, and Neurology Department, Bellvitge University Hospital, Barcelona, Spain\n Nedkova Velina Neurology Department, Bellvitge University Hospital, Barcelona, Spain\n Díez Laura Neurology Department, Bellvitge University Hospital, Barcelona, Spain\n Homedes Christian Neurology Department, Bellvitge University Hospital, Barcelona, Spain\n Alberti M. Antonia Neurology Department, Bellvitge University Hospital, Barcelona, Spain\n Casasnovas Carlos Neurology Department, Neuromuscular Unit, Bellvitge University Hospital, n/n Feixa Llarga street, L’Hospitalet de Llobregat, Barcelona, 08906, Spain\n carloscasasnovas@bellvitgehospital.cat\n1 7 2020 \n2020 \n13 17562864209320359 3 2020 14 5 2020 © The Author(s), 20202020SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Myasthenia gravis is a chronic autoimmune disorder caused by antibodies directed against the neuromuscular junction. Some patients may have an associated thymoma, which confers a worse prognosis. Eculizumab, a monoclonal antibody that inhibits the activation of terminal complement, has recently been approved for the treatment of refractory generalized myasthenia gravis. This is an early case report of thymoma-associated refractory myasthenia gravis successfully treated with eculizumab in a real-world setting.\n\ncase reportcomplement inhibitoreculizumabmyasthenia gravisrefractorythymomacover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nMyasthenia gravis (MG) is a chronic autoimmune disorder caused by antibodies against receptors and proteins at the neuromuscular junction. Acetylcholine receptor antibodies are found in 85% of patients with MG,1 typically of immunoglobulin subclasses IgG1 and IgG3, and induce a complement-mediated attack. This, in turn, causes morphological and functional changes in the postsynaptic membrane, and impairs neuromuscular synaptic transmission leading to fatigable muscle weakness.2 MG can be classified into subgroups by pathogenic antibody specificity, thymus histology, and clinical features (e.g. extent of involvement and age of onset).3 Moreover, about 15% of patients have an associated thymoma and about 30% of patients with thymoma develop MG, making it the most frequent autoimmune disorder linked to thymoma. These cases of thymoma-associated MG have a worse prognosis than other subgroups and more often become refractory.4 In most cases, MG can be treated successfully with an individualized combination of immunosuppressive therapy, acetylcholinesterase inhibitors, and thymectomy, plus treatment of acute exacerbations; however, issues persist with the small group of patients that have treatment-refractory MG.5 Their substantial disease burden has motivated the search for new therapeutic targets.6\n\nEculizumab is a recombinant, humanized monoclonal antibody that inhibits terminal complement activation, thereby preventing damage to the neuromuscular junction. It was only recently approved for the treatment of refractory MG.7 We report a case of refractory thymoma-associated MG treated with eculizumab.\n\nCase report\nA 25-year-old woman was transferred to our hospital with a 2-month history of binocular diplopia, severe dysphagia, nasal voice, and weakness of her proximal arm. Examination of the orbicularis oculi with single-fiber electromyography showed increased jitter, blood testing revealed acetylcholine receptor antibody positivity (>20.0 nmol/L; reference range: 0.00–1.00) with negative results for anti-muscle-specific receptor tyrosine kinase, anti-lipoprotein receptor-related protein-4 (LRP4), anti-titin and anti-ryanodine antibodies, and chest computed tomography showed a large anterior mediastinal mass suggestive of thymoma. Treatment was therefore started with pyridostigmine (360 mg/day), oral prednisone (50 mg/day with progressive decrease to 10 mg/day), intravenous immunoglobulins (2 g/kg each time; two rounds), and plasma exchange (two rounds). However, due to the persistence of bulbar symptoms and the suspected thymoma, she was referred to our MG clinic. Examination at the clinic revealed mild ptosis of the right eye, but normal ocular movement without diplopia. Her voice was nasal and became completely unintelligible after 45 s. She also had difficulty chewing and fatigable weakness in her cervical and proximal arm and leg muscles, corresponding to Myasthenia Gravis Foundation of America class IIIb. Other autoimmune diseases were excluded based on negative results for antinuclear antibodies, anti-extractable nuclear antigen panel, rheumatoid factor, antithyroid peroxidase, and antithyroglobulin antibodies, plus the presence of normal creatine kinase levels and normal needle electromyography results. Thymectomy was performed through a left anterolateral thoracotomy, and the subsequent histology showed a completely encapsulated stage I tumor (Masaoka–Koga classification), consistent with a type B1 thymoma with small areas of B2 (<10%).\n\nUnfortunately, the symptoms of MG deteriorated after thymectomy and the patient required immunoglobulins (0.4 g/kg over 5 days) and plasma exchange, as well as an increased dose of prednisone (25 mg/day). We therefore started treatment with tacrolimus (4 mg daily with weekly monitoring of blood levels; reference range: 5.0–20.0 µg/L). She experienced a new exacerbation without a clear trigger 3 months later with tacrolimus levels of 7.7 µg/L. She then had persistent bulbar symptoms and generalized weakness of variable severity, and over the next 18 months, she needed regular intravenous immunoglobulin and plasma exchange almost every 2 weeks.\n\nDue to lack of response, tacrolimus was discontinued after 6 months, and rituximab 375 mg/m2 was administered weekly for 4 weeks and then monthly for 2 months. Although the patient experienced a slight improvement with rituximab, she required admissions for septicemia due to methicillin-resistant Staphylococcus aureus and for large vessel thrombosis. Cyclophosphamide was then started at 1000 mg, and continued at 500 mg every 4 weeks for 6 months). Azathioprine was started 3 months later, with the daily dose gradually increased to 100 mg/day, with no related cytopenia or hepatic toxicity.\n\nWe then performed both 18 fluorodeoxyglucose positron emission tomography to identify any thymic remnants and a second thymectomy, but neither gave positive results. Finally, treatment with eculizumab (initial phase: 900 mg via intravenous infusion every week for 4 weeks, and then 1200 mg via intravenous infusion every 14 days) was approved in August 2018.\n\nWe used the quantitative myasthenia gravis (QMG) and the myasthenia gravis activities of daily living (MG-ADL) scales to document the response to treatment with eculizumab. The patient gave written informed consent for data collection and publication.\n\nOn initiating eculizumab her QMG and MG-ADL scores were 23 and 12, respectively. During the 18 months before starting eculizumab administration, her QMG scores had ranged between 15 and 32 (median: 22; SD 6.1) and her MG-ADL scores had ranged between 6 and 20 (median: 9; SD 1.5). Eculizumab notably improved her motor symptoms by week 8 of therapy, lowering both the QMG and the MG-ADL scores to 9 (median: 12; SD 4.5) and 3 (median: 3; SD 0.5), respectively (Figure 1). Improvement was particularly marked for those items related to bulbar symptoms.\n\nFigure 1. QMG (blue line) and MG-ADL (red line) scores under the different immunosuppressant treatments.\n\nMG-ADL, myasthenia gravis activities of daily living; QMG, quantitative myasthenia gravis.\n\nThe patient continues to receive eculizumab every 2 weeks, prednisone was safely tapered, and the intravenous immunoglobulin infusions have been spaced. At week 48 after eculizumab initiation, the QMG score was 7 and the MG-ADL score was 2, with 1200 mg every 14 days eculizumab, 100 mg/day azathioprine, and 5 mg/day prednisone. Crucially, she has not presented with any serious side effects attributable to eculizumab.\n\nDiscussion\nWe present a case of thymoma-associated MG refractory to treatment with maximum safe and adequate doses of several immunosuppressive drugs. The patient had suffered frequent life-threatening MG crises and had needed frequent rescue therapies, resulting in severe side effects, including infection and thrombosis. Thus, her MG was considered highly refractory and suitable for eculizumab, which resulted in good clinical response.\n\nThymomas are strongly associated with refractory MG, conferring worse prognosis and often requiring more aggressive therapeutic strategies. This is partially due to certain well-recognized features of the thymus cytoarchitecture and environment that lead to a defective self-tolerance and an increase in mature T-cell escape into the circulation. These features include a disorganized cortex with no recognizable medulla, absent B or myoid cells, no major histocompatibility complex class II molecule expression, defective AIRE expression, and failure of FOXP3+ regulatory T-cell generation. The roles of autoantigen expression, autoimmunization, and T-cell selection remain unclear.8\n\nAn optimized therapeutic strategy is essential for refractory MG, and it seems rational to use concomitant drugs that act on different pathways of the immune response. When eculizumab was started, besides the mandatory thymectomy, our patient was receiving combined treatment with corticoids and azathioprine (to inhibit T-cell proliferation and IL-2 production), the monoclonal antibody rituximab (to deplete B lymphocytes), and various short-term immunomodulatory therapies (to reduce circulating autoantibodies).9 The complement pathway, specifically the activation and formation of the membrane attack complex, is an additional therapeutic target because of the role of complement in destroying the neuromuscular junction.10\n\nThe efficacy of eculizumab in treating refractory generalized MG that is acetylcholine receptor antibody-positive was demonstrated in the phase III, randomized, double-blind, placebo-controlled REGAIN study. However, patients with a history of thymoma or thymic neoplasm were excluded from that trial and there are no data on its use in this subgroup. In our patient, administering eculizumab to act on a completely different target, while still treating with other immunosuppressants that act on ‘classic’ pathways, we achieved a clear improvement that has been maintained for a year. The patient has experienced no more crises requiring admission, her corticosteroid use has been reduced, the intervals between intravenous immunoglobulin doses have increased, and her quality of life has improved markedly. Furthermore, she has experienced no serious side effects due to eculizumab, which appears to be better tolerated than previous immunosuppressants.\n\nIn conclusion, although more data are required to determine the role of eculizumab in future therapeutic algorithms for MG, it is clear that new therapies such as this are urgently needed to remedy the considerable disease burden in these patients. This report supports that eculizumab is a promising treatment in thymoma-associated MG.\n\nAuthors’ Note:\nCarlos Casasnovas is also affiliated to Neurometabolic Diseases Group, Bellvitge Institute for Biomedical Research; Center for Biomedical Research in Network on Rare Diseases, CIBERER - ISC III.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: CERCA Program/ Generalitat de Catalunya.\n\nORCID iD: Valentina Vélez-Santamaría \nhttps://orcid.org/0000-0001-7782-2473\n==== Refs\nReferences\n1 \nPhillips WD Vincent A. \nPathogenesis of myasthenia gravis: update on disease types, models, and mechanisms\n. F1000Res \n2016 ; 5 : 1513 .\n2 \nCetin H Vincent A. \nPathogenic mechanisms and clinical correlations in autoimmune myasthenic syndromes\n. Semin Neurol \n2018 ; 38 : 344 –354\n.30011414 \n3 \nGilhus NE Verschuuren JJ. \nMyasthenia gravis: subgroup classification and therapeutic strategies\n. Lancet Neurol \n2015 ; 14 : 1023 –1036\n.26376969 \n4 \nMaggi L Andreetta F Cavalcante P , et al\nThymoma-associated myasthenia gravis: outcome, clinical and pathological correlations in 197 patients on a 20-year experience\n. J Neuroimmunol \n2008 ; 201–202 : 237 –244\n.\n5 \nSuh J Goldstein JM Nowak RJ. \nClinical characteristics of refractory myasthenia gravis patients\n. Yale J Biol Med \n2013 ; 86 : 255 –260\n.23766745 \n6 \nEngel-Nitz NM Boscoe A Silvestri NJ , et al\nBurden of illness in patients with treatment refractory myasthenia gravis\n. Muscle Nerve . Epub ahead of print 27 \n2 \n2018 DOI: 10.1002/mus.26114 .\n7 \nHoward JF JrUtsugisawa K Benatar M , et al; REGAIN Study Group. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study\n. Lancet Neurol \n2017 ; 16 : 976 –986\n.29066163 \n8 \nMarx A Willcox N Ströbel P , et al\nThymoma and paraneoplastic myasthenia gravis\n. Autoimmunity \n2010 ; 43 : 413 –427\n.20380583 \n9 \nBinks S Vincent A Palace J. \nMyasthenia gravis: a clinical-immunological update\n. J Neurol \n2016 ; 263 : 826 –834\n.26705120 \n10 \nDhillon S. \nEculizumab: a review in generalized myasthenia gravis\n. Drugs \n2018 ; 78 : 367 –376\n.29435915\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1756-2856",
"issue": "13()",
"journal": "Therapeutic advances in neurological disorders",
"keywords": "case report; complement inhibitor; eculizumab; myasthenia gravis; refractory; thymoma",
"medline_ta": "Ther Adv Neurol Disord",
"mesh_terms": null,
"nlm_unique_id": "101480242",
"other_id": null,
"pages": "1756286420932035",
"pmc": null,
"pmid": "32655688",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29066163;27408701;20380583;30011414;26376969;26705120;29435915;29486521;18722676;23766745",
"title": "Eculizumab as a promising treatment in thymoma-associated myasthenia gravis.",
"title_normalized": "eculizumab as a promising treatment in thymoma associated myasthenia gravis"
} | [
{
"companynumb": "ES-ROCHE-2641679",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC.\n\n\n\nChemotherapy naive mCRPC patients received docetaxel 75 mg/m2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed.\n\n\n\nEighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change.\n\n\n\nThe addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen.",
"affiliations": "Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI. Electronic address: vaishamu@karmanos.org.",
"authors": "Thakur|Manish K|MK|;Heilbrun|Lance|L|;Dobson|Kimberlee|K|;Boerner|Julie|J|;Stark|Karri|K|;Li|Jing|J|;Smith|Daryn|D|;Heath|Elisabeth|E|;Fontana|Joseph|J|;Vaishampayan|Ulka|U|",
"chemical_list": "D000077143:Docetaxel; D013004:Somatostatin; C517782:pasireotide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clgc.2018.01.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "16(3)",
"journal": "Clinical genitourinary cancer",
"keywords": "Clinical trial; Neuroendocrine; Pasireotide; SOM230",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011241:Prednisone; D064129:Prostatic Neoplasms, Castration-Resistant; D013004:Somatostatin; D016896:Treatment Outcome",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "e695-e703",
"pmc": null,
"pmid": "29534939",
"pubdate": "2018-06",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "18829513;25199761;18494832;18182665;18309951;21483004;22454414;17977644;17404365;23169519;19191785;24727321;22995653;14751362;24211163;23294853;26742998;14666719;22389870",
"title": "Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer.",
"title_normalized": "phase i trial of the combination of docetaxel prednisone and pasireotide in metastatic castrate resistant prostate cancer"
} | [
{
"companynumb": "US-INGENUS PHARMACEUTICALS, LLC-INF201803-000251",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugad... |
{
"abstract": "BACKGROUND\nNext generation sequencing (NGS) allows the detection of minor variant HIV drug resistance mutations (DRMs). However data from new NGS platforms after Prevention-of-Mother-to-Child-Transmission (PMTCT) regimen failure are limited.\n\n\nOBJECTIVE\nTo compare major and minor variant HIV DRMs with Illumina MiSeq and Life Technologies Ion Personal Genome Machine (PGM) in infants infected despite a PMTCT regimen.\n\n\nMETHODS\nWe conducted a cross-sectional study of NGS for detecting DRMs in infants infected despite a zidovudine (AZT) and Nevirapine (NVP) regimen, before initiation of combination antiretroviral therapy. Sequencing was performed on PCR products from plasma samples on PGM and MiSeq platforms. Bioinformatic analyses were undertaken using a codon-aware version of the Smith-Waterman mapping algorithm and a mixture multinomial error filtering statistical model.\n\n\nRESULTS\nOf 15 infants, tested at a median age of 3.4 months after birth, 2 (13%) had non-nucleoside reverse transcriptase inhibitor (NNRTI) DRMs (K103N and Y181C) by bulk sequencing, whereas PGM detected 4 (26%) and MiSeq 5 (30%). NGS enabled the detection of additional minor variant DRMs in the infant with K103N. Coverage and instrument quality scores were higher with MiSeq, increasing the confidence of minor variant calls.\n\n\nCONCLUSIONS\nNGS followed by bioinformatic analyses detected multiple minor variant DRMs in HIV-1 RT among infants where PMTCT failed. The high coverage of MiSeq and high read quality improved the confidence of identified DRMs and may make this platform ideal for minor variant detection.",
"affiliations": "Division of Medical Virology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zilj Drive, Parow 7500, South Africa.;Department of Medicine, University of California, San Diego, Stein Clinical Research Building #325 (mail code 0679), 9500 Gilman Drive, La Jolla, CA 92093, USA; San Diego Veterans Affairs Healthcare System, (Mail Code 8208), 150 W. Washington Street #100, San Diego, CA 92103, USA.;Department of Medicine, University of California, San Diego, Stein Clinical Research Building #325 (mail code 0679), 9500 Gilman Drive, La Jolla, CA 92093, USA.;Department of Genetics, Stellenbosch University, Private Bag X1, 7602 Matieland, South Africa.;Institute for Microbial Biotechnology and Metagenomics, New Life Sciences Building, 2nd Floor, Core 2, University of the Western Cape, Modderdam Road, P/Bag X17, Bellville 7530, South Africa.;Department Paediatrics and Child Health, Stellenbosch University and Tygerberg Children's Hospital, Francie van Zijl Drive, Parow 7500, South Africa.;Department Paediatrics and Child Health, Stellenbosch University and Tygerberg Children's Hospital, Francie van Zijl Drive, Parow 7500, South Africa; Children's Infectious Diseases Clinical Research Unit (KIDCRU) Ward J8, Tygerberg Hospital, Francie van Zijl Drive, Parow 7500, South Africa.;University of California, San Diego, AVRC, 220 Dickinson, Suite A, San Diego, CA 92103, USA.;Department of Medicine, University of California, San Diego, Stein Clinical Research Building #325 (mail code 0679), 9500 Gilman Drive, La Jolla, CA 92093, USA.;Division of Medical Virology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zilj Drive, Parow 7500, South Africa; National Health Laboratory Service, Tygerberg, Francie van Zijl Drive, Parow 7500, South Africa. Electronic address: guvz@sun.ac.za.",
"authors": "Fisher|Randall G|RG|;Smith|Davey M|DM|;Murrell|Ben|B|;Slabbert|Ruhan|R|;Kirby|Bronwyn M|BM|;Edson|Clair|C|;Cotton|Mark F|MF|;Haubrich|Richard H|RH|;Kosakovsky Pond|Sergei L|SL|;Van Zyl|Gert U|GU|",
"chemical_list": "D019380:Anti-HIV Agents; D012367:RNA, Viral",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "62()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "HIV-1 drug resistance; Minor variant antiretroviral drug resistance mutations; Nevirapine; Next generation sequencing; Non-nucleoside reverse transcriptase inhibitor resistance; Prevention of mother to child transmission",
"medline_ta": "J Clin Virol",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D019295:Computational Biology; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D059645:Mutation Rate; D012367:RNA, Viral; D012189:Retrospective Studies; D019562:Viral Load",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "48-53",
"pmc": null,
"pmid": "25542470",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20377404;23420840;22179227;23687292;20190870;24785949;20102271;18295909;25034127;22716976;23264671;23300238;22615779;22293443;21655292;23432488;18683370;24797459;24151309;21632754;20539818;19859531;20942667;23397353;20334564",
"title": "Next generation sequencing improves detection of drug resistance mutations in infants after PMTCT failure.",
"title_normalized": "next generation sequencing improves detection of drug resistance mutations in infants after pmtct failure"
} | [
{
"companynumb": "ZA-CIPLA LTD.-2015ZA00312",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPosterior reversible encephalopathy syndrome (PRES) has been associated with the use of several medications, including chemotherapeutic agents.\nA 65-year-old woman was diagnosed with adenocarcinoma of the ovary, after sixth-line treatment with topotecan, at the beginning of the fourth cycle, she was admitted to the emergency room for presenting tonic-clonic seizures, visual disturbance, and hypertension. A 66-year-old woman was diagnosed with bilateral breast cancer; due to disease progression, treatment with paclitaxel and gemcitabine was started, 1 month after the last dose of chemotherapy, she was admitted to the emergency room for suffering severe headache, altered mental status, tonic-clonic seizures, and hypertension. A 60-year-old patient diagnosed with breast cancer on the left side, underwent second-line chemotherapy with gemcitabine, carboplatin, and bevacizumab, and 1 month after the last dose of chemotherapy, she was also admitted to the emergency room due to altered mental status, vomiting, tonic-clonic seizures, and hypertension.\n\n\nMETHODS\nThey were diagnosed as PRES based on physical examination, laboratory findings, and imaging techniques that revealed diffuse lesions and edema within the parieto-occipital regions.\n\n\nMETHODS\nThey received support treatment with blood pressure (BP) control, seizures were controlled with a single anti-epileptic agent, and chemotherapeutic agents from the onset of PRES to its resolution were discontinued.\n\n\nRESULTS\nAll these patients improved after medical treatment was started.\n\n\nCONCLUSIONS\nMedical personnel and therapeutic establishments need to be made aware about this chemotherapy-induced neurologic complication.",
"affiliations": "Neuro-oncology Unit, Instituto Nacional de Cancerología.;Neuro-oncology Unit, Instituto Nacional de Cancerología.;Neuro-oncology Unit, Instituto Nacional de Cancerología.;Neuro-oncology Unit, Instituto Nacional de Cancerología.;Neurosurgery ISSSTE Hospital Regional 1° de Octubre.;Imaging Department.;Internal Medicine Fundación Clínica Médica Sur.;Research Unit, Instituto Nacional de Cancerología, Mexico City, Mexico.",
"authors": "Cacho-Díaz|Bernardo|B|;Lorenzana-Mendoza|Nydia A|NA|;Salmerón-Moreno|Karen|K|;Reyes-Soto|Gervith|G|;Castillo-Rangel|Carlos|C|;Corona-Cedillo|Roberto|R|;Escobar-Ceballos|Salvador|S|;Garza-Salazar|Jaime G de la|JG|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000015691",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31083272MD-D-18-0912210.1097/MD.0000000000015691156915300Research ArticleClinical Case ReportChemotherapy-induced posterior reversible encephalopathy syndrome Three case reportsCacho-Díaz Bernardo MDa∗Lorenzana-Mendoza Nydia A. MDaSalmerón-Moreno Karen MDaReyes-Soto Gervith MDaCastillo-Rangel Carlos MDbCorona-Cedillo Roberto MDcEscobar-Ceballos Salvador MDdde la Garza-Salazar Jaime G. MD, PhDeNA. a Neuro-oncology Unit, Instituto Nacional de Cancerologíab Neurosurgery ISSSTE Hospital Regional 1° de Octubrec Imaging Departmentd Internal Medicine Fundación Clínica Médica Sure Research Unit, Instituto Nacional de Cancerología, Mexico City, Mexico.∗ Correspondence: Bernardo Cacho-Díaz, Neuro-oncology Unit, Instituto Nacional de Cancerología, San Fernando 22 Col, Sección XVI, Mexico City 14080, Mexico (e-mail: bernardocacho@doctor.com).5 2019 13 5 2019 98 19 e156917 12 2018 10 4 2019 22 4 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nPosterior reversible encephalopathy syndrome (PRES) has been associated with the use of several medications, including chemotherapeutic agents.\n\nPatient concerns:\nA 65-year-old woman was diagnosed with adenocarcinoma of the ovary, after sixth-line treatment with topotecan, at the beginning of the fourth cycle, she was admitted to the emergency room for presenting tonic-clonic seizures, visual disturbance, and hypertension. A 66-year-old woman was diagnosed with bilateral breast cancer; due to disease progression, treatment with paclitaxel and gemcitabine was started, 1 month after the last dose of chemotherapy, she was admitted to the emergency room for suffering severe headache, altered mental status, tonic-clonic seizures, and hypertension. A 60-year-old patient diagnosed with breast cancer on the left side, underwent second-line chemotherapy with gemcitabine, carboplatin, and bevacizumab, and 1 month after the last dose of chemotherapy, she was also admitted to the emergency room due to altered mental status, vomiting, tonic-clonic seizures, and hypertension.\n\nDiagnosis:\nThey were diagnosed as PRES based on physical examination, laboratory findings, and imaging techniques that revealed diffuse lesions and edema within the parieto-occipital regions.\n\nInterventions:\nThey received support treatment with blood pressure (BP) control, seizures were controlled with a single anti-epileptic agent, and chemotherapeutic agents from the onset of PRES to its resolution were discontinued.\n\nOutcomes:\nAll these patients improved after medical treatment was started.\n\nLessons:\nMedical personnel and therapeutic establishments need to be made aware about this chemotherapy-induced neurologic complication.\n\nKeywords\ncancerchemotherapyneuro-oncologyposterior reversible encephalopathy syndromeOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPosterior reversible encephalopathy syndrome (PRES) was first described in 1996 by Hinchey et al based on observations in 15 patients with a consistent and reversible pattern of neurological symptoms and neuroimaging findings.[1] PRES represents a clinical radiographic disorder characterized by the presence of subcortical vasogenic edema and white matter predominance lesions in most cases involving the parieto-occipital regions; these symptoms are commonly reversible.[2,3] Although there are no guidelines to direct the assessment, literature indicates that clinical judgement is essential.[2] Diagnosis might be considered in the presence of: transient neurological symptoms with a clinical context of hypertensive crisis, autoimmune disorders, pregnancy-related complications, renal failure, and the use of cytotoxic drugs; along with fully reversible brain edema.[2,4] Clinical manifestations and signs are not specific, however, leading symptoms described are: headache, seizures, altered mental status, and visual impairment; that are usually accompanied by the presence of hypertension.[2,5]\n\nWe present 3 cases of chemotherapy-associated PRES.\n\n1.1 Case 1\nA 65-year-old woman was diagnosed with disseminated endometrioid adenocarcinoma of the ovary. Her past medical history was unremarkable. She was initially treated with right hemicolectomy and oophorectomy followed by 3 cycles of paclitaxel and carboplatin (Taxol/Carbo). Three months later, she underwent interval laparotomy and treatment with 3 more cycles of Taxol/Carbo. After a disease-free period of 23 months, progression localized to the pancreas led to the administration of 3 cycles of Taxol/Carbo. One month later, she relapsed with portal vein and celiac trunk metastatic lesions and was shifted to third-line chemotherapy with 8 cycles of liposomal Adriamycin and underwent cytoreductive laparotomy, achieving a disease-free period of 11 months. Then, she received fourth-line chemotherapy with methotrexate because of disease progression to the liver. She received fifth-line chemotherapy with gemcitabine. Positron emission tomography–computed tomography (PET-CT) demonstrated disease progression, leading to the administration of sixth-line treatment with topotecan (4 mg, total dose). Two days after beginning the fourth cycle, the patient was admitted to the emergency room because of tonic–clonic seizures and visual disturbance. Her blood pressure (BP) was 162/73 mm Hg, and blood tests showed no abnormal findings other than hyperglycemia (174 mg/dL). Physical examination revealed no abnormal findings. She had no medical history of hypertension or diabetes. Brain magnetic resonance imaging (MRI) revealed parieto-occipital hyperintensities on T2-WI and fluid-attenuated inversion recovery as well as restricted diffusion (Fig. 1). Seizures were treated with diazepam and phenytoin (690 mg/d) and strict metabolic and BP control. She was discharged on the 2nd day because of clinical resolution of her symptoms. A new brain MRI was taken 9 days later showing disappearance of the lesions (Fig. 2) leading to the diagnosis of PRES. Although no antihypertensive was prescribed, she did receive levetiracetam (1 g/12 h) for the next 16 months without any report of new seizures; also, she underwent another 3 cycles of topotecan without recurrence of PRES, and finally, eighth-line chemotherapy with Taxol/Carbo was administered with partial response. After 24 months of the diagnosis, she continues treatment under vigilant monitoring by the neuro-oncology unit.\n\nFigure 1 Case 1, MRI showed parieto-occipital hyperintensities on FLAIR (A–D) and T2-WI (E–H).\n\nFigure 2 Case 1, 10 days later after treatment initiation, MRI showed resolution of parieto-occipital lesions on FLAIR (A–C) and T2-WI (D–F).\n\n1.2 Case 2\nA 66-year-old woman was diagnosed with bilateral breast cancer classified as infiltrating ductal carcinoma hormone sensitive (Luminal A). Her past medical history was unremarkable. She received first-line treatment with neoadjuvant fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC) prior to surgery; she was, subsequently, consolidated with 4 cycles of vinorelbine (NVB) plus Adriamycin, followed by adjuvant radiotherapy and tamoxifen. One month later, she was diagnosed with uterine cervix carcinoma 1B1, for which she underwent radical hysterectomy. Two years later, she presented with a new mass in the right breast. Core needle biopsy showed infiltrating ductal carcinoma that was treated with neoadjuvant docetaxel plus carboplatin prior to surgery and radiotherapy, and at that time, she received anastrozole treatment. Three years later, her treatment was changed to capecitabine and exemestane because of liver metastases. Four months later, new liver metastases were documented, and NVB was added to capecitabine for another 4 months. Her treatment was changed to docetaxel plus capecitabine leading to partial response. As the patient showed progressive disease, treatment with paclitaxel (120 mg, total dose) and gemcitabine (1200 mg, total dose) was started. One month after the last dose of chemotherapy, she was admitted to the emergency room because of severe headache, altered mental status, tonic–clonic seizures (2 episodes), and hypertension (150/90 mm Hg). Physical examination revealed no abnormal findings. Blood tests showed a lactate dehydrogenase level (LDH) of 819, serum creatinine level of 2.47, and hyperglycemia (184 mg/dL). CT revealed diffuse hypodensities and edema within the parieto-occipital regions (Fig. 3). During hospitalization, she was treated with 840 mg of phenytoin, IV steroids, hydration, and the antihypertensive drug nicardipine (20 mg/12 h). Two days after the event, she remained asymptomatic and was discharged on the 6th day with prescription for long-active nifedipine (20 mg/12 h) and phenytoin (100 mg/8 h); 2 weeks later, MRI and blood tests showed resolution of the abnormalities (Fig. 3), leading to the diagnosis of PRES. Because of development of rash, phenytoin was stopped after 1 month. The patient died after 3 months of diagnosis due to cancer progression (outside the CNS).\n\nFigure 3 Case 2, CT showed hypodensities in the subcortical parieto-occipital white matter (A–C). Two weeks after treatment initiation, MRI FLAIR showed resolution of the lesions (D–F).\n\n1.3 Case 3\nA 60-year-old patient diagnosed with breast cancer on the left side, classified as infiltrating ductal carcinoma triple negative, was treated with 4 cycles of FAC Ch. Then, she received placlitaxel prior to radical mastectomy. Her past medical history was unremarkable. Eight months later, she presented with headache and nominal aphasia leading to the diagnosis of brain metastasis. The patient underwent radiosurgery and second-line chemotherapy with gemcitabine (1000 mg, total dose), carboplatin (350 mg, total dose), and bevacizumab (1320 mg, total dose). She required steroid to ameliorate the gemcitabine-induced rash, after the last dose of chemotherapy, she presented with altered mental status, vomiting (10 episodes), and tonic–clonic seizure (1 episode) and was admitted to the emergency room.\n\nHer BP was 150/100 mm Hg. Blood test showed metabolic acidosis, lactate levels of 4.8 mmol/L, platelet count of 106,000 per mL, and hyperglycemia (198 mg/dL). Physical examination revealed no abnormal findings. She was treated with 5 mg of diazepam, IV steroid, hydration, diuretic (20 mg/24 h of furosemide), and antihypertensive drugs. MRI revealed diffuse hyperintensities and edema within the parieto-occipital regions, leading to the diagnosis of PRES probably secondary to bevacizumab treatment (Fig. 4). Diazepam was changed to levetiracetam (1 g/12 h) and after the 2nd day of the event, she showed complete resolution of symptoms and was discharged. Because the patient had completed the last chemotherapy regimen, she received third-line chemotherapy with ixabepilone and underwent radiosurgery to treat brain metastasis progression. The patient died 1 year after the diagnosis of PRES because of complications caused by liver, brain, and soft tissue metastases.\n\nFigure 4 Case 3, MRI showed parieto-occipital hyperintensities on FLAIR (A–D). These were completely resolved a few days after treatment.\n\n2 Discussion\nPRES has been increasingly recognized within the cancer population. Chemotherapeutic agents that have previously been described to be associated with PRES include taxanes, platinum derivatives, vinca alkaloids, antimetabolites, anthracyclines, angiogenic inhibitors, folate antagonists, and immunosuppressants.[6–8] Leading theory of the pathophysiological changes in PRES states that rapidly developing hypertension exceeds the upper limit of cerebral blood flow autoregulation and causes hyperperfusion, breaking the blood–brain barrier and allowing the interstitial extravasation of plasma and macromolecules.[2] On the grounds that patients with cancer are exposed to several treatment regimens that include a combination of various cytotoxic agents, it is difficult to identify a direct association between PRES and any of the chemotherapeutic agents in these cases; nonetheless, it has been noted that an intense treatment can increase the risk of PRES as well as the mortality rates.[9]\n\nOn hospital admission, our patients presented with common symptoms of PRES, including high BP, altered mental status, and seizures. Their neuroimaging findings involving both the hemispheres at parieto-occipital regions were documented as well. Chemotherapeutic agents from the onset of PRES to its resolution were discontinued. All patients showed complete clinical and radiologic resolution of PRES. Despite the risk of PRES recurrence, the potential causative agent was reintroduced to one of the patients who was carefully monitored, as suggested previously.[10]\n\nPRES in case 1 was associated with topotecan, an alkaloid derivative of camptothecin commonly used in the treatment of ovarian, cervical, and recurrent lung cancer, which works through the inhibition of the topoisomerase I complex.[11] One of the main toxic effects of topotecan is the depletion of bone marrow, resulting in neutropenia, thrombocytopenia, and anemia.[12] Topotecan can cross the blood–brain barrier; therefore, its use as brain metastases treatment was studied in a phase III trial, but the drug did not show any survival advantage.[13] Topotecan has been associated with aseptic meningitis, seizures, and chronic encephalopathy when administered intrathecally.[14] We are not aware of any previous report describing topotecan as an agent associated with PRES; however, the association of PRES with another inhibitor of topoisomerase I has been reported (irinotecan 180 mg/m2).[15]\n\nCases 2 and 3 received agents that are more frequently described in the setting of PRES. Although rare, PRES with paclitaxel (80 to 135 mg/m2), an agent that arrests cells in G2 and M phases of the cell cycle,[16,17] and gemcitabine (1000 mg/m2), an analogue of cytarabine,[18] has been described, even though these drugs do not cross the blood–brain barrier. Combination with other drugs, such as cisplatin, or cancer brain damage may facilitate the penetration of paclitaxel within the endothelium.[16–18] In case 2, the gemcitabine–paclitaxel regimen was associated with PRES. The underlying mechanism is unclear, but acute kidney injury-induced hypertension might cause and/or facilitate endothelial damage.[19] This patient had transient elevation in LDH levels. LDH is an enzyme frequently used as a marker of tissue damage and its elevation has been proposed as a prognostic factor of PRES.[20]\n\nFinally, endothelial alteration induced by the inhibition of vascular endothelial growth factor suggests an important role of bevacizumab as a cause of PRES. The most common reported side effect of bevacizumab is hypertension resulting from nitric oxide release, which disrupts the blood–brain barrier and leads to PRES. A favorable prognosis in patients with bevacizumab-induced PRES has been suggested, and some have proposed the term benign reversible encephalopathy syndrome instead of PRES. [21,22]\n\nIn conclusion, PRES is a reversible disorder that can be induced by several chemotherapeutic agents. There is no specific treatment for PRES other than eliminate or treat the precipitating cause. Prognosis is usually favorable; most patients achieved clinical recovery in 2 to 8 days.10% to 20% of patients are reported with persistent neurological sequelae.[2]\n\nAcknowledgments\nThe authors thank Enago (www.enago.com) for the English language review.\n\nAuthor contributions\nConceptualization: Bernardo Cacho-Díaz.\n\nData curation: Nydia A Lorenzana-Mendoza, Roberto Corona-Cedillo, Salvador Escobar-Ceballos.\n\nMethodology: Bernardo Cacho-Díaz.\n\nResources: Nydia A Lorenzana-Mendoza, Carlos Castillo-Rangel.\n\nSupervision: Bernardo Cacho-Díaz, Carlos Castillo-Rangel.\n\nValidation: Bernardo Cacho-Díaz, Gervith Reyes-Soto, Jaime G de la Garza-Salazar.\n\nVisualization: Roberto Corona-Cedillo.\n\nWriting – original draft: Nydia A Lorenzana-Mendoza, Salvador Escobar-Ceballos.\n\nWriting – review & editing: Karen Salmerón-Moreno, Gervith Reyes-Soto, Jaime G de la Garza-Salazar.\n\nBernardo Cacho-Díaz orcid: 0000-0001-9289-5312.\n\nNydia A. Lorenzana-Mendoza orcid: 0000-0001-5456-6999.\n\nAbbreviations: BP = blood pressure, Ch = chemotherapy, CNS = central nervous system, FAC = cyclophosphamide, LDH = lactate dehydrogenase, MRI = magnetic resonance imaging, NVB = vinorelbine, PET-CT = positron emission tomography–computed tomography, PRES = posterior reversible encephalopathy syndrome.\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nInstitutional ethics and scientific committee approved this research (INCAN/CI/837/17).\n\nAll procedures performed in studies involving humans were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nInformed and written consent was obtained from the patients for publication of this case report and accompanying images.\n\nThis article does not contain any studies with animals performed by any of the authors.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Hinchey J Chaves C Appignani B \nA reversible posterior leukoencephalopathy syndrome . N Engl J Med \n1996 ;334 :494–500 .8559202 \n[2] Fugate JE Rabinstein AA \nPosterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions . Lancet Neurol \n2015 ;14 :914–25 .26184985 \n[3] Singer S Grommes C Reiner AS \nPosterior reversible encephalopathy syndrome in patients with cancer . Oncologist \n2015 ;20 :806–11 .26032137 \n[4] Bartynski WS \nPosterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema . AJNR Am J Neuroradiol \n2008 ;29 :1043–9 .18403560 \n[5] Hefzy HM Bartynski WS Boardman JF \nHemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features . AJNR Am J Neuroradiol \n2009 ;30 :1371–9 .19386731 \n[6] Bhatt A Farooq MU Majid A \nChemotherapy related posterior reversible leukoencephalopathy syndrome . Nat Clin Pract \n2009 ;5 :163–9 .\n[7] Chen YH Huang CH \nReversible posterior leukoencephalopathy syndrome induced by vinorelbine . Clin Breast Cancer \n2012 ;12 :222–5 .22424944 \n[8] Ozcan C Wong SJ Hari P \nReversible posterior leukoencephalopathy syndrome and bevacizumab . N Engl J Med \n2006 ;354 :980–2 .\n[9] Kamiya-Matsuoka C Paker AM Chi L \nPosterior reversible encephalopathy syndrome in cancer patients: a single institution retrospective study . J Neuroonco \n2016 ;128 :75–84 .\n[10] Taillibert S Le Rhun E Chamberlain MC \nChemotherapy-related neurotoxicity . Curr Neurol Neurosci Rep \n2016 ;16 :81.27443648 \n[11] Lorusso D Pietragalla A Mainenti S \nReview role of topotecan in gynaecological cancers: current indications and perspectives . Crit Rev Oncol Hematol \n2010 ;74 :163–74 .19766512 \n[12] Dunton CJ \nManagement of treatment-related toxicity in advanced ovarian cancer . Oncologist \n2002 ;7 suppl 5 :11–9 .12324629 \n[13] Neuhaus T Ko Y Muller RP \nA phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer . Br J Cancer \n2009 ;100 :291–7 .19127261 \n[14] Stone JB DeAngelis LM \nCancer-treatment-induced neurotoxicity—focus on newer treatments . Nat Rev Clin Oncol \n2016 ;13 :92–105 .26391778 \n[15] Plavetić ND Rakušić Z Ozretić D \nFatal outcome of posterior “reversible” encephalopathy syndrome in metastatic colorectal carcinoma after irinotecan and fluoropyrimidine chemotherapy regimen . World J Surg Oncol \n2014 ;12 :264.25142792 \n[16] Onujiogu N Lengyel E Yamada SD \nReversible posterior leukoencephalopathy syndrome following intravenous paclitaxel and intraperitoneal cisplatin chemotherapy for fallopian tube cancer . Gynecol Oncol \n2008 ;111 :537–9 .18554701 \n[17] Muallaoğlu S Koçer M Güler N \nAcute transient encephalopathy after weekly paclitaxel infusion . Med Oncol \n2012 ;29 :1297–9 .21618057 \n[18] Larsen FO Hansen SW \nSevere neurotoxicity caused by gemcitabine treatment . Acta Oncol \n2004 ;43 :590–1 .15370618 \n[19] Canney M Kelly D Clarkson M \nPosterior reversible encephalopathy syndrome in end-stage kidney disease: not strictly posterior or reversible . Am J Nephrol \n2015 ;41 :177–82 .25871433 \n[20] Gao B Liu FL Zhao B \nAssociation of degree and type of edema in posterior reversible encephalopathy syndrome with serum lactate dehydrogenase level: initial experience . Eur J Radiol \n2012 ;81 :2844–7 .22209526 \n[21] Sawaya R Radwan W Hammoud S \nBenign reversible encephalopathy syndrome after bevacizumab therapy for metastatic ovarian cancer . Med Oncol \n2014 ;31 :831.24385223 \n[22] Seet RCS Rabinstein AA \nClinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment . QJM \n2012 ;105 :69–75 .21865314\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "98(19)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001921:Brain; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms; D054038:Posterior Leukoencephalopathy Syndrome",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e15691",
"pmc": null,
"pmid": "31083272",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chemotherapy-induced posterior reversible encephalopathy syndrome: Three case reports.",
"title_normalized": "chemotherapy induced posterior reversible encephalopathy syndrome three case reports"
} | [
{
"companynumb": "MX-TEVA-2019-MX-1066934",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "OBJECTIVE\nThe relationship between the time spent at extreme International Normalized Ratios (INRs) and the time in the therapeutic range (TTR) with bleeding and thrombosis in warfarin-treated patients was examined.\n\n\nMETHODS\nConsecutive patients treated with warfarin for atrial fibrillation or for venous thrombosis who were managed by the anticoagulation management service or adult internal medicine clinic of a large, tertiary care, integrated health system between June 1, 2011, and October 9, 2012, were eligible for study inclusion. Data collected for the outcomes analysis included INRs and dates; current use of aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, or nonsteroidal antiinflammatory drugs; and any clinically significant bleeding or thrombosis events identified.\n\n\nRESULTS\nIn the 837 patients who met the inclusion criteria, 636.5 patient-years of therapy were provided, of which 14.4 patient-years (2.26% of time) were spent at INRs of <1.5; 2.9 patient-years of therapy (0.45% of time) were spent at INRs of >4.5. The patient population had a mean individual TTR of 65%. The percentage of time at an INR of >4.5 was positively associated with an increased risk of major bleeding (p = 0.0085). The percentage of time spent with an INR of <1.5 was not associated with a significant increase in the risk of thrombosis.\n\n\nCONCLUSIONS\nThe percentage of time spent with an INR of >4.5 was associated with an increased risk of major bleeding in patients receiving warfarin for atrial fibrillation or for venous thrombosis at two outpatient clinics. The relationships between thrombosis risk and the TTR or the time spent at an INR of <1.5 were not significant, but the thromboembolic event rate was unusually low, as was the time spent at an INR of <1.5.",
"affiliations": "Ashley L. Barta, Pharm.D., is Clinical Pharmacist, Sanford USD Medical Center, Sioux Falls, SD; when this project was conducted she was Postgraduate Year 1 Resident, Sanford USD Medical Center. Edith A. Nutescu, Pharm.D., is Associate Professor, Department of Pharmacy Systems Outcomes and Policy, and Co-Director, Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago College of Pharmacy, Chicago. Paul A. Thompson, Ph.D., is Director, Methodology and Data Analysis Center, and Professor, Department of Pediatrics, Sanford School of Medicine, Sanford Research, Sioux Falls. Henry I. Bussey, Pharm.D., is President and Senior Editor, ClotCare.org, San Antonio, TX, and President, Genesis Clinical Research, San Antonio. Michael P. Gulseth, Pharm.D., BCPS, FASHP, is Program Director for Anticoagulation Services, Sanford USD Medical Center, and Adjunct Assistant Professor, College of Pharmacy, South Dakota State University, Sioux Falls.;Ashley L. Barta, Pharm.D., is Clinical Pharmacist, Sanford USD Medical Center, Sioux Falls, SD; when this project was conducted she was Postgraduate Year 1 Resident, Sanford USD Medical Center. Edith A. Nutescu, Pharm.D., is Associate Professor, Department of Pharmacy Systems Outcomes and Policy, and Co-Director, Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago College of Pharmacy, Chicago. Paul A. Thompson, Ph.D., is Director, Methodology and Data Analysis Center, and Professor, Department of Pediatrics, Sanford School of Medicine, Sanford Research, Sioux Falls. Henry I. Bussey, Pharm.D., is President and Senior Editor, ClotCare.org, San Antonio, TX, and President, Genesis Clinical Research, San Antonio. Michael P. Gulseth, Pharm.D., BCPS, FASHP, is Program Director for Anticoagulation Services, Sanford USD Medical Center, and Adjunct Assistant Professor, College of Pharmacy, South Dakota State University, Sioux Falls.;Ashley L. Barta, Pharm.D., is Clinical Pharmacist, Sanford USD Medical Center, Sioux Falls, SD; when this project was conducted she was Postgraduate Year 1 Resident, Sanford USD Medical Center. Edith A. Nutescu, Pharm.D., is Associate Professor, Department of Pharmacy Systems Outcomes and Policy, and Co-Director, Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago College of Pharmacy, Chicago. Paul A. Thompson, Ph.D., is Director, Methodology and Data Analysis Center, and Professor, Department of Pediatrics, Sanford School of Medicine, Sanford Research, Sioux Falls. Henry I. Bussey, Pharm.D., is President and Senior Editor, ClotCare.org, San Antonio, TX, and President, Genesis Clinical Research, San Antonio. Michael P. Gulseth, Pharm.D., BCPS, FASHP, is Program Director for Anticoagulation Services, Sanford USD Medical Center, and Adjunct Assistant Professor, College of Pharmacy, South Dakota State University, Sioux Falls.;Ashley L. Barta, Pharm.D., is Clinical Pharmacist, Sanford USD Medical Center, Sioux Falls, SD; when this project was conducted she was Postgraduate Year 1 Resident, Sanford USD Medical Center. Edith A. Nutescu, Pharm.D., is Associate Professor, Department of Pharmacy Systems Outcomes and Policy, and Co-Director, Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago College of Pharmacy, Chicago. Paul A. Thompson, Ph.D., is Director, Methodology and Data Analysis Center, and Professor, Department of Pediatrics, Sanford School of Medicine, Sanford Research, Sioux Falls. Henry I. Bussey, Pharm.D., is President and Senior Editor, ClotCare.org, San Antonio, TX, and President, Genesis Clinical Research, San Antonio. Michael P. Gulseth, Pharm.D., BCPS, FASHP, is Program Director for Anticoagulation Services, Sanford USD Medical Center, and Adjunct Assistant Professor, College of Pharmacy, South Dakota State University, Sioux Falls.;Ashley L. Barta, Pharm.D., is Clinical Pharmacist, Sanford USD Medical Center, Sioux Falls, SD; when this project was conducted she was Postgraduate Year 1 Resident, Sanford USD Medical Center. Edith A. Nutescu, Pharm.D., is Associate Professor, Department of Pharmacy Systems Outcomes and Policy, and Co-Director, Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago College of Pharmacy, Chicago. Paul A. Thompson, Ph.D., is Director, Methodology and Data Analysis Center, and Professor, Department of Pediatrics, Sanford School of Medicine, Sanford Research, Sioux Falls. Henry I. Bussey, Pharm.D., is President and Senior Editor, ClotCare.org, San Antonio, TX, and President, Genesis Clinical Research, San Antonio. Michael P. Gulseth, Pharm.D., BCPS, FASHP, is Program Director for Anticoagulation Services, Sanford USD Medical Center, and Adjunct Assistant Professor, College of Pharmacy, South Dakota State University, Sioux Falls. michael.gulseth@sanfordhealth.org.",
"authors": "Barta|Ashley L|AL|;Nutescu|Edith A|EA|;Thompson|Paul A|PA|;Bussey|Henry I|HI|;Gulseth|Michael P|MP|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp140752",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "72(14)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D015331:Cohort Studies; D016903:Drug Monitoring; D005260:Female; D006470:Hemorrhage; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013927:Thrombosis; D013997:Time Factors; D014859:Warfarin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1188-94",
"pmc": null,
"pmid": "26150568",
"pubdate": "2015-07-15",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Relationship between time spent at extreme International Normalized Ratios and time in therapeutic range with bleeding and thrombosis in warfarin-treated patients.",
"title_normalized": "relationship between time spent at extreme international normalized ratios and time in therapeutic range with bleeding and thrombosis in warfarin treated patients"
} | [
{
"companynumb": "US-JNJFOC-20160226158",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate is highly effective against acquisition of HIV infection, and only two cases of infection with a multidrug-resistant virus have been reported under adequate long-term adherence, as evidenced by tenofovir diphosphate concentrations in dried blood spots. We report a case of wild-type HIV-1 infection despite consistent use of emtricitabine and tenofovir disoproxil fumarate.\n\n\n\nThe patient participated in the Amsterdam PrEP project, a demonstration project of daily and event-driven PrEP. We did extensive testing for HIV, including plasma HIV RNA and nested PCR on bulk peripheral blood mononuclear cells (PBMCs) and sigmoid biopsies after seroconversion.\n\n\n\nA 50-year-old man who has sex with men and had been on daily emtricitabine and tenofovir disoproxil fumarate for 8 months presented with fever, urinary tract infection caused by Escherichia coli, anal lymphogranuloma venereum infection, and a positive fourth-generation HIV test. We found an atypical seroconversion pattern, with initially only gp160 antibodies detected in the western blot. HIV RNA could not be detected in plasma, and nested PCR for HIV RNA and DNA on bulk PBMCs and sigmoid biopsies were negative. PrEP was discontinued; 3 weeks later HIV RNA was detected in plasma. No drug-resistant mutations were detected. Tenofovir diphosphate concentrations in dried blood spots were stable and high.\n\n\n\nTo our knowledge, this is the first detailed case report suggesting wild-type HIV-1 infection despite good adherence, evidenced by repeatedly high concentrations of tenofovir diphosphate in dried blood spots. PrEP providers need to be aware that infection can occur despite good adherence. Regular HIV testing and awareness of atypical patterns of seroconversion is highly recommended.\n\n\n\nZonMw, National Institute for Public Health and the Environment, Internal GGD research funds, Aidsfonds, Stichting AmsterdamDiner Foundation, Gilead Sciences, Janssen Pharmaceutica, M A C AIDS Fund, and ViiV Healthcare.",
"affiliations": "Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, Netherlands; Department of Infectious Diseases, Clinic for Sexually Transmitted Infections, Public Health Service of Amsterdam, Amsterdam, Netherlands. Electronic address: ehoornenborg@ggd.amsterdam.nl.;Department of Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Academic Medical Center, University of Amsterdam, Netherlands.;Department of Infectious Diseases, Clinic for Sexually Transmitted Infections, Public Health Service of Amsterdam, Amsterdam, Netherlands.;Department of Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Academic Medical Center, University of Amsterdam, Netherlands.;Department of Medical Microbiology, Experimental Virology, Academic Medical Center, University of Amsterdam, Netherlands.;Department of Medical Microbiology, Clinical Virology, Academic Medical Center, University of Amsterdam, Netherlands.;Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Netherlands.;Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.;Department of Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Academic Medical Center, University of Amsterdam, Netherlands; Department of Global Health and Amsterdam Institute for Global Health and Development, Academic Medical Center, University of Amsterdam, Netherlands; HIV Monitoring Foundation, Amsterdam, Netherlands.;Department of Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Academic Medical Center, University of Amsterdam, Netherlands; Department of Dermatology, Academic Medical Center, University of Amsterdam, Netherlands; National Institute of Public Health and the Environment, Center for Infectious Disease Control, Bilthoven, Netherlands.;Department of Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Academic Medical Center, University of Amsterdam, Netherlands.;Department of Infectious Diseases, Amsterdam Infection and Immunity Institute (AI&II), Academic Medical Center, University of Amsterdam, Netherlands; Department of Global Health and Amsterdam Institute for Global Health and Development, Academic Medical Center, University of Amsterdam, Netherlands.",
"authors": "Hoornenborg|Elske|E|;Prins|Maria|M|;Achterbergh|Roel C A|RCA|;Woittiez|Lycke R|LR|;Cornelissen|Marion|M|;Jurriaans|Suzanne|S|;Kootstra|Neeltje A|NA|;Anderson|Peter L|PL|;Reiss|Peter|P|;de Vries|Henry J C|HJC|;Prins|Jan M|JM|;de Bree|Godelieve J|GJ|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D010755:Organophosphates; D012367:RNA, Viral; C583447:tenofovir diphosphate; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2352-3018(17)30132-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3018",
"issue": "4(11)",
"journal": "The lancet. HIV",
"keywords": null,
"medline_ta": "Lancet HIV",
"mesh_terms": "D000225:Adenine; D019380:Anti-HIV Agents; D000068679:Emtricitabine; D015658:HIV Infections; D006679:HIV Seropositivity; D015497:HIV-1; D018451:Homosexuality, Male; D006801:Humans; D008219:Lymphogranuloma Venereum; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D010755:Organophosphates; D065129:Pre-Exposure Prophylaxis; D012367:RNA, Viral; D000068698:Tenofovir; D063106:Transgender Persons; D014552:Urinary Tract Infections",
"nlm_unique_id": "101645355",
"other_id": null,
"pages": "e522-e528",
"pmc": null,
"pmid": "28919303",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquisition of wild-type HIV-1 infection in a patient on pre-exposure prophylaxis with high intracellular concentrations of tenofovir diphosphate: a case report.",
"title_normalized": "acquisition of wild type hiv 1 infection in a patient on pre exposure prophylaxis with high intracellular concentrations of tenofovir diphosphate a case report"
} | [
{
"companynumb": "NL-MYLANLABS-2018M1028120",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
},
... |
{
"abstract": "This 44-year-old healthy white male was referred to our office for the treatment of a recurrent basal cell carcinoma clinically involving the left inferior forehead extending down to the left glabellar region of the face. The preoperative size of the tumor was 1.5 x 1.5 cm (Figure 1). The lesion had been present since 1998 and had undergone previous liquid nitrogen treatment and, subsequently, excisional surgery. The patient had no significant medical history, and the only medication he had been taking was ibuprofen as needed. The patient did not smoke, nor did he have a history of diabetes. After discussing the various treatment options with the patient, he opted to undergo Mohs micrographic surgery. After two stages, the tumor was fully removed, and the defect measured 2.0 3 2.3 cm (Figure 2). The postoperative defect extended through the frontalis muscle superiorly and the procerus muscle inferomedially, down to the periosteum. The left corrugator supercilli muscle was spared from removal. How would you manage this wound?",
"affiliations": "Northern Indiana Dermatology and Skin Surgery Center, Portage, IN, USA.",
"authors": "Desai|Ruchik S|RS|;Donnelly|Heidi B|HB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/1524-4725.2006.32016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-0512",
"issue": "32(1)",
"journal": "Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]",
"keywords": null,
"medline_ta": "Dermatol Surg",
"mesh_terms": "D000328:Adult; D002280:Carcinoma, Basal Cell; D005153:Facial Neoplasms; D005546:Forehead; D006801:Humans; D008297:Male; D019651:Reconstructive Surgical Procedures; D012878:Skin Neoplasms; D016038:Skin Transplantation; D013524:Surgical Flaps",
"nlm_unique_id": "9504371",
"other_id": null,
"pages": "112-4",
"pmc": null,
"pmid": "16393611",
"pubdate": "2006-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Repair of a glabellar and inferior forehead defect.",
"title_normalized": "repair of a glabellar and inferior forehead defect"
} | [
{
"companynumb": "US-RANBAXY-2014US-91544",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Background. Somatic type malignancy (STM) occurs in 2% of all germ cell tumours (GCTs). The prognosis is unfavourable and the origin is poorly understood. Pathogenetic hypotheses involve direct transformation of teratoma, origin from totipotent cancer cells, or derivation from yolk sac tumour elements. Case Presentation. A 31-year-old patient was cured from testicular seminoma clinical stage IIc by orchiectomy and cisplatin-based chemotherapy. Nine years later, he experienced a late relapse with a mass sized 5 × 6 cm located at the former metastatic site. As no remission occurred after chemotherapy with three cycles of cisplatin, ifosfamide and etoposide, the mass was surgically resected. Histologically, the specimen consisted of neurofibroma with areas of malignant peripheral nerve sheath tumour and spots with mature bone formation. FISH analysis disclosed isochromosome 12p in the majority of evaluated cells suggesting somatic type malignancy (STM) of GCT. The patient is well 1 year after surgery. Conclusion. The pathogenesis of this STM remains enigmatic. The origin from GCT was evidenced by documentation of isochromosome 12p. Unrecognized teratomatous elements in the primary and totipotent cancer cells surviving the first chemotherapy could be hypothesized to represent the origin. STM developing from seminoma cells would be another novel hypothesis.",
"affiliations": "Department of Urology, Albertinen-Krankenhaus Hamburg, Süntelstrasse 11a, 22457 Hamburg, Germany.;Department of Urology, Albertinen-Krankenhaus Hamburg, Süntelstrasse 11a, 22457 Hamburg, Germany.;Department of Diagnostic Radiology, Albertinen-Krankenhaus Hamburg, Süntelstrasse 11a, 22457 Hamburg, Germany.;Institute of Pathology, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.;Institute of Pathology, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.;Institute of Pathology, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.",
"authors": "Dieckmann|Klaus-Peter|KP|0000-0002-3821-7956;Anheuser|Petra|P|;Gehrckens|Ralf|R|;Wilczak|Waldemar|W|;Sauter|Guido|G|;Höflmayer|Doris|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/2457023",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2017/2457023Case ReportPure Testicular Seminoma Relapsing Late with Somatic Type Malignancy http://orcid.org/0000-0002-3821-7956Dieckmann Klaus-Peter \n1\n\n*\nAnheuser Petra \n1\nGehrckens Ralf \n2\nWilczak Waldemar \n3\nSauter Guido \n3\nHöflmayer Doris \n3\n1Department of Urology, Albertinen-Krankenhaus Hamburg, Süntelstrasse 11a, 22457 Hamburg, Germany2Department of Diagnostic Radiology, Albertinen-Krankenhaus Hamburg, Süntelstrasse 11a, 22457 Hamburg, Germany3Institute of Pathology, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany*Klaus-Peter Dieckmann: dieckmannkp@t-online.deAcademic Editor: Didier Frappaz\n\n2017 7 3 2017 2017 245702315 1 2017 27 2 2017 Copyright © 2017 Klaus-Peter Dieckmann et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Somatic type malignancy (STM) occurs in 2% of all germ cell tumours (GCTs). The prognosis is unfavourable and the origin is poorly understood. Pathogenetic hypotheses involve direct transformation of teratoma, origin from totipotent cancer cells, or derivation from yolk sac tumour elements. Case Presentation. A 31-year-old patient was cured from testicular seminoma clinical stage IIc by orchiectomy and cisplatin-based chemotherapy. Nine years later, he experienced a late relapse with a mass sized 5 × 6 cm located at the former metastatic site. As no remission occurred after chemotherapy with three cycles of cisplatin, ifosfamide and etoposide, the mass was surgically resected. Histologically, the specimen consisted of neurofibroma with areas of malignant peripheral nerve sheath tumour and spots with mature bone formation. FISH analysis disclosed isochromosome 12p in the majority of evaluated cells suggesting somatic type malignancy (STM) of GCT. The patient is well 1 year after surgery. Conclusion. The pathogenesis of this STM remains enigmatic. The origin from GCT was evidenced by documentation of isochromosome 12p. Unrecognized teratomatous elements in the primary and totipotent cancer cells surviving the first chemotherapy could be hypothesized to represent the origin. STM developing from seminoma cells would be another novel hypothesis.\n==== Body\n1. Background\nGerm cell tumours (GCTs) have the potential to differentiate into many directions [1, 2]. The most surprising morphologic variant is the somatic type malignancy (STM) formerly called malignant transformation. Friedman and Moore were the first to document cases with “neuroepithelioma” and sarcoma arising within teratomatous germ cell tumours [3]. Pathologically, STMs encompass a wide spectrum of histologic appearances [4] with sarcoma of all subtypes comprising 50% and carcinomas of various subtypes comprising about 20% of cases followed by primitive neuroectodermal tumours (PNET) ranking third with 10% [5, 6]. The remainder is made up of rare malignancies including haematologic neoplasms and undifferentiated tumours [4, 7].\n\nMorphologically, STMs appear like typical primary neoplasms with no obvious histological resemblance to germ cell tumours. However, modern FISH (fluorescence in situ hybridization) techniques have revealed that most of the STMs have retained isochromosome 12p which is characteristic for GCTs despite their morphologic dissimilarity [8].\n\nSTMs are rare events that are encountered in about 3% of metastasized cases with GCT [5, 9, 10]. Prognosis is usually unfavourable because cisplatin-based chemotherapy is not efficacious in these histologic variants [11]. Surgical excision represents the mainstay of treatment in these cases. After the first report on a small series of STM with documentation of clinical outcome in 1985 [12], no more than six systematic clinicopathological evaluations and several small case series have been reported to date encompassing around 500 cases with STM [5, 9, 10, 13–18]. Accordingly, the knowledge regarding incidence, biological behavior, and clinical management is still limited at present. We here report the case of a patient with STM that is exceptional because of its clinical and histologic features.\n\n2. Case Description\nA 31-year-old white man of European ancestry who was on insulin treatment for diabetes mellitus type 1 since childhood presented with right-sided back pain. Computed tomography (CT) disclosed a 7 × 11 cm retroperitoneal mass compressing the vena cava and additional mediastinal lymphadenopathy of 2.1 cm in size. Further clinical evaluation revealed a right-sided testicular mass and a thrombosis of the vena cava with extension of the intravascular clotting into both iliac veins (Figure 1). The serum level of beta human chorionic gonadotropin (bHCG) was increased to 36.6 U/L (upper limit of norm, 2.5 U/L); alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) were within normal limits. The management consisted of antithrombotic treatment and inguinal orchiectomy. Histologic evaluation revealed pure testicular seminoma (Figure 2). Subsequently, the patient received chemotherapy with 3 courses of cisplatin, etoposide, and bleomycin. Upon restaging, the bHCG serum level had normalized and the mediastinal mass had disappeared, while the retroperitoneal mass had shrunk to 3 × 3 cm. One year thereafter, the residual mass had completely disappeared. With respect to the thrombotic occlusion of the vena cava, multiple collateral veins had evolved in the retroperitoneum. Later, during follow-up, the patient developed hypogonadism with the need for testosterone replacement therapy. Nine years after initial treatment, the patient presented with abdominal pain. Abdominal CT revealed an oval mass sized 5 × 6 cm located in the retroperitoneum caudal to the left renal vein and between vena cava and abdominal aorta (Figure 3). No other neoplastic deposits were observed. The serum levels of bHCG, AFP, and LDH were within normal limits. The findings were considered to represent a late relapse of seminoma mainly because the newly evolved mass was located right at the site of the initial metastasis 9 years priorly. Accordingly, the patient received a chemotherapy regimen consisting of three cycles of cisplatin, ifosfamide, and etoposide. Upon restaging with CT, no significant change of the retroperitoneal mass was noted. Therefore, surgical excision was performed. Despite the complex intraabdominal venous collateral network, a complete surgical excision of the mass was accomplished. Postoperative recovery was uneventful, and, 6 months thereafter, the patient is in good condition and is pursuing his work again.\n\nCut section of the specimen revealed a firm white-greyish mass with several bone-like appearing tiny spots and a clearly demarcated rim (Figure 4). Histological evaluation disclosed loosely whorled and short intersecting fascicles composed of cells with round to oval nuclei, with small nucleoli and a small-to-moderate amount of mostly clear cytoplasm. Along the edge, some mature bone formation was observed. Noteworthy, in several areas of the specimen, the cells were more crowded, the nuclei showed atypia, and mitotic activity was observed. Immunohistochemical stains with glial fibrillary astrocytic protein (GFAP) demonstrated positive cytoplasmic staining; S100 showed focal nuclear and cytoplasmic positive staining. Germ cell tumour markers (Oct3/4, PLAP, SALL4, Glypican 3, and CD30), pancytokeratin (AE1/AE3), and neurofilament muscle specific markers (Desmin) as well as CD34, CD117, SOX10, MDM2, and EMA were all negative. The proliferation marker Ki-67 was positive in less than 5% of cells. Given the overall rather benign neurogenic differentiation with focal increased cellularity, nuclear atypia, and mitotic activity, the diagnosis of neurofibroma with transition into a low-grade malignant peripheral nerve sheath tumour (MPNST) was made (Figures 5(a) and 5(b)). No components of seminoma or other germ cell tumours were detected in the completely embedded specimen. Fluorescence in situ hybridization (FISH) examination revealed excess genetic material of chromosome 12p (isochromosome 12p) (Figure 6). This finding was considered as evidence for a somatic type malignancy occurring on the basis of a germ cell tumour metastasis in the retroperitoneum rather than a primary soft tissue tumour.\n\n3. Discussion\nClinically, the case presented here is noteworthy because of several features that are uncommon but otherwise characteristic in patients with testicular GCT, and professionals caring for testis cancer patients should be aware of these. One feature is the excessive thrombosis of the vena cava extending into both iliac veins. As documented in the present patient, such events are pathogenetically associated with abdominal metastases compressing the vena cava, reducing blood flow velocity, and thus precipitating intravascular clotting [19–21]. Another peculiarity is the relapse of disease occurring as late as nine years after primary treatment. Late relapses of GCT are rare but may occur in about 2% of patients and chemotherapy is thought to be associated with these events [22, 23].\n\nHowever, the most striking feature of the present case is the histology of the resected retroperitoneal mass. As outlined before, somatic type malignancies encompass a wide variety of malignant neoplastic histologies with sarcoma and carcinoma representing the most prevalent types [6]. Among the less frequently encountered histologies are PNET, haematologic neoplasms, and undifferentiated tumours [4]. Malignant peripheral nerve sheath tumours as seen in our patient are among the least common variants with only 4 cases reported so far [6, 13].\n\nThe pathogenesis of STM is poorly understood. The traditional theory forwarded by Mostofi and Sobin suggested mesenchymal elements within teratomas to give rise to malignant transformation [24]. In fact, STM is located in direct vicinity to teratoma in most of the cases either in primary testicular tumours or in metastatic deposits, and, accordingly, the old name teratoma with malignant transformation was coined. However, whether STM directly originates from teratoma remained unknown. Thus, a competing pathogenetic theory was forwarded postulating STM to originate from primitive totipotent germ cells [25]. Recently, the derivation of STM from the blastematous stroma of yolk sac tumours was suggested [26]. Finally, the rather frequent finding of STM in metastases surgically resected after chemotherapy [27, 28] suggested a selection process of chemotherapy-resistant cell populations to be another pathogenetic factor.\n\nOur case is unique because neither teratoma nor yolk sac tumour had been documented at the time of first presentation. The primary tumour consisted of pure seminoma and reevaluation of the histologic sections did not reveal the presence of nonseminomatous elements. The occurrence of STM in a metastasis from pure testicular seminoma has never been reported before. Malagón et al. briefly mentioned a case of primary mediastinal seminoma containing components of a malignant nerve sheath tumour [29]; however, that particular constellation is probably different from primary testicular seminoma biologically. In our patient, evidence for the origin of the neurofibroma with transition to the MPNST from the previous GCT derived from the documentation of isochromosome 12p with FISH technique. Isochromosome 12p is characteristic of GCT [30] and it is retained in most of the STMs deriving from GCT, though lack of isochromosome 12p may not exclude the diagnosis of GCT [31]. In addition, the finding of mature bone within the tumour could be interpreted as residual teratoma component, thus arguing in favour of the GCT origin.\n\nThree hypotheses would explain the findings in our patient. The first hypothesis assumes that the primary testicular seminoma as well as the metastasis at first presentation would have contained some foci of teratoma or even yolk sac tumour that escaped histological detection due to their small size. The minuscule foci of teratoma persisted at the site of the metastasis after chemotherapy despite radiological complete remission and gave rise to the full-blown STM at the time of clinical late relapse. The second hypothesis would suggest development of somatic type malignancy from seminoma cells. This pathway had not been conceived before and the transition from fully differentiated seminoma cells to completely dissimilar nongerm cell histologies would be rather enigmatic. The third hypothesis would suggest the presence of totipotent germ cells at the site of the primary metastasis that survived the first chemotherapy and gave rise to differentiation into teratoma and the STM. However, in the aggregate, no particular proof of any specific pathway can be given and the pathogenesis of the STM in our patient with seminoma remains indeterminate.\n\n4. Conclusion\nDevelopment of somatic type malignancy from germ cell tumours is a rare event and its pathogenesis is still poorly understood. The present case supports the contention that conventional chemotherapy is ineffective in STM and that surgery is the mainstay of cure. The present case is unique because of the unprecedented origin of STM from pure seminoma generating one novel pathogenetic hypothesis of STM.\n\nAcknowledgments\nThanks are due to Dr. B. Feyerabend, Hamburg, who provided technical assistance in reviewing the histological slides obtained during the first treatment of the patient.\n\nAbbreviations\nGCT:Germ cell tumour\n\nSTM:Somatic type malignancy\n\nPNET:Primitive neuroectodermal tumours\n\nFISH:Fluorescence in situ hybridization\n\nCT:Computerized tomography\n\nbHCG:Beta human chorionic gonadotropin\n\nAFP:Alpha fetoprotein\n\nLDH:Lactate dehydrogenase\n\nMPNST:Malignant peripheral nerve sheath tumour.\n\nEthical Approval\nThis report was approved by the Institutional Ethical Committee of Albertinen-Krankenhaus Hamburg (2016, Fallbericht Urologie).\n\nConsent\nThis patient provided written informed consent to the publication of this report.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Abdominal computerized tomography showing a large mass in the upper retroperitoneum compressing the vena cava. Thrombotic occlusion of vena cava with extension of intravascular clotting into both iliac veins.\n\nFigure 2 Histological section of the orchiectomy specimen showing pure seminoma. Haematoxylin-eosin stain, original ×100.\n\nFigure 3 Abdominal CT scan showing a 5 × 6 cm mass with several calcifications between abdominal aorta and vena cava below the left renal vein: location is identical with metastatic site at first presentation.\n\nFigure 4 Cut section of the retroperitoneal mass after surgical excision: firm white-greyish mass and a clearly demarcated rim.\n\nFigure 5 (a) Histological section of the resected abdominal mass: representative images of the tumour, composed of dispersed cells with no atypia, sometimes with a background of collagen fibers, resembling neurofibroma. Haematoxylin-eosin stain, original ×50. (b) Histological section of the resected abdominal mass: More hypercellular areas with moderate nuclear atypia, resembling a malignant peripheral nerve sheath tumour (MPNST). Haematoxylin-eosin stain, original ×50.\n\nFigure 6 FISH analysis of resected abdominal mass: dual color probe (ZytoLight KRAS/CEN 12), demonstrating polysomy and isochromosome 12p (CEN 12: red; KRAS: green); magnification 1000x.\n==== Refs\n1 Howitt B. E. Berney D. M. Tumors of the testis: morphologic features and molecular alterations Surgical Pathology Clinics 2015 8 4 687 716 10.1016/j.path.2015.07.007 2-s2.0-84961634127 26612222 \n2 Moch H. Cubilla A. L. Humphrey P. A. Reuter V. E. Ulbright T. M. The 2016 WHO classification of tumours of the urinary system and male genital organs—Part A: renal, penile, and testicular tumours European Urology 2016 70 93 105 10.1016/j.eururo.2016.02.029 2-s2.0-84971574471 26935559 \n3 Friedman N. B. Moore R. A. Tumors of the testis: a report on 922 cases Military Surgeon 1946 99 573 593 20276801 \n4 Mikuz G. Colecchia M. Teratoma with somatic-type malignant components of the testis. A review and an update Virchows Archiv 2012 461 1 27 32 10.1007/s00428-012-1251-x 2-s2.0-84864285113 22622519 \n5 Motzer R. J. Amsterdam A. Prieto V. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors Journal of Urology 1998 159 1 133 138 10.1016/s0022-5347(01)64035-7 2-s2.0-0031986550 9400455 \n6 Necchi A. Colecchia M. Nicolai N. Towards the definition of the best management and prognostic factors of teratoma with malignant transformation: a single-institution case series and new proposal BJU International 2011 107 7 1088 1094 10.1111/j.1464-410x.2010.09705.x 2-s2.0-79953232043 20868391 \n7 Zeh N. Wild P. J. Bode P. K. Retroperitoneal teratoma with somatic malignant transformation: a papillary renal cell carcinoma in a testicular germ cell tumour metastasis following platinum-based chemotherapy BMC Urology 2013 13, article 9 10.1186/1471-2490-13-9 2-s2.0-84873701028 \n8 Looijenga L. H. J. Zafarana G. Grygalewicz B. Role of gain of 12p in germ cell tumour development APMIS 2003 111 1 161 170 10.1034/j.1600-0463.2003.11101201.x 2-s2.0-0038222516 12752258 \n9 Lutke Holzik M. F. Hoekstra H. J. Mulder N. H. Suurmeijer A. J. H. Sleijfer D. T. Gietema J. A. Non-germ cell malignancy in residual or recurrent mass after chemotherapy for nonseminomatous testicular germ cell tumor Annals of Surgical Oncology 2003 10 2 131 135 10.1245/ASO.2003.05.024 2-s2.0-0038622012 12620907 \n10 García-Labastida L. Gómez-Macías G. S. Flores-Gutiérrez J. P. Secondary malignant transformation of testicular teratomas: case series and literature review Actas Urologicas Espanolas 2014 38 9 622 627 10.1016/j.acuro.2014.02.014 2-s2.0-84908271376 24909334 \n11 El Mesbahi O. Terrier-Lacombe M.-J. Rebischung C. Theodore C. Vanel D. Fizazi K. Chemotherapy in patients with teratoma with malignant transformation European Urology 2007 51 5 1306 1312 10.1016/j.eururo.2006.10.021 2-s2.0-33947202102 17081678 \n12 Ahmed T. Bosl G. J. Hajdu S. I. Teratoma with malignant transformation in germ cell tumors in men Cancer 1985 56 4 860 863 10.1002/1097-0142(19850815)56:4<860::aid-cncr2820560426>3.0.co;2-3 2-s2.0-0021990296 2990657 \n13 Comiter C. V. Kibel A. S. Richie J. P. Nucci M. R. Renshaw A. A. Prognostic features of teratomas with malignant transformation: a clinicopathological study of 21 cases The Journal of Urology 1998 159 3 859 863 10.1016/s0022-5347(01)63754-6 2-s2.0-0031931448 9474169 \n14 Guo C. C. Punar M. Contreras A. L. Testicular germ cell tumors with sarcomatous components: an analysis of 33 cases The American Journal of Surgical Pathology 2009 33 8 1173 1178 10.1097/pas.0b013e3181adb9d7 2-s2.0-68249093368 19561445 \n15 Rice K. R. Magers M. J. Beck S. D. W. Management of germ cell tumors with somatic type malignancy: pathological features, prognostic factors and survival outcomes Journal of Urology 2014 192 5 1403 1409 10.1016/j.juro.2014.05.118 2-s2.0-84908134885 24952240 \n16 Giannatempo P. Pond G. R. Sonpavde G. Treatment and clinical outcomes of patients with teratoma with somatic-type malignant transformation: an international collaboration Journal of Urology 2016 196 95 100 10.1016/j.juro.2015.12.082 2-s2.0-84969534998 26748165 \n17 Cabral F. C. Krajewski K. M. Rosenthal M. H. Hirsch M. S. Howard S. A. Teratoma with malignant transformation: report of three cases and review of the literature Clinical Imaging 2014 38 5 589 593 10.1016/j.clinimag.2014.04.011 2-s2.0-84906046340 24908364 \n18 Fujimura T. Yamada Y. Nasu M. Hamasaki K. Minowada S. Kitamura T. Different transformation of mature teratoma in a patient with mixed germ cell tumor of the testis International Journal of Urology 2005 12 6 588 590 10.1111/j.1442-2042.2005.01097.x 2-s2.0-23244466233 15985085 \n19 Piketty A.-C. Fléchon A. Laplanche A. The risk of thrombo-embolic events is increased in patients with germ-cell tumours and can be predicted by serum lactate dehydrogenase and body surface area British Journal of Cancer 2005 93 8 909 914 10.1038/sj.bjc.6602791 2-s2.0-27144536603 16205699 \n20 Honecker F. Koychev D. Luhmann A. D. Venous thromboembolic events in germ cell cancer patients undergoing platinum-based chemotherapy Onkologie 2013 36 11 663 668 10.1159/000355652 2-s2.0-84888340593 24192771 \n21 Solari L. Krönig M. Ihorst G. High rates of thromboembolic events in patients with germ cell cancer undergoing cisplatin-based polychemotherapy Urologia Internationalis 2016 96 4 399 405 10.1159/000445126 2-s2.0-84963582713 27074038 \n22 Dieckmann K.-P. Albers P. Classen J. Late relapse of testicular germ cell neoplasms: a descriptive analysis of 122 cases The Journal of Urology 2005 173 3 824 829 10.1097/01.ju.0000154013.96349.36 2-s2.0-13744261967 15711278 \n23 Ehrlich Y. Rosenbaum E. Baniel J. Late relapse of testis cancer Current Urology Reports 2013 14 5 518 524 10.1007/s11934-013-0355-4 2-s2.0-84886793544 23839244 \n24 Mostofi F. K. Sobin L. H. Histological Typing of Testis Tumors 1977 Geneva, Switzerland World Health Organization \n25 Ulbright T. M. Loehrer P. J. Roth L. M. Einhorn L. H. Williams S. D. Clark S. A. The development of non-germ cell malignancies within germ cell tumors. A clinicopathologic study of 11 cases Cancer 1984 54 9 1824 1833 10.1002/1097-0142(19841101)54:960;1824::aid-cncr282054091062;3.0.co;2-j 2-s2.0-0021147174 6090001 \n26 Magers M. J. Kao C.-S. Cole C. D. ‘Somatic-type’ malignancies arising from testicular germ cell tumors: a clinicopathologic study of 124 cases with emphasis on glandular tumors supporting frequent yolk sac tumor origin American Journal of Surgical Pathology 2014 38 10 1396 1409 10.1097/pas.0000000000000262 2-s2.0-84908554551 24921638 \n27 Ahlgren A. D. Simrell C. R. Triche T. J. Ozols R. Barsky S. H. Sarcoma arising in a residual testicular teratoma after cytoreductive chemotherapy Cancer 1984 54 9 2015 2018 10.1002/1097-0142(19841101)54:9<2015::aid-cncr2820540939>3.0.co;2-b 2-s2.0-0021198856 6478436 \n28 Rice K. R. Beck S. D. W. Pedrosa J. A. Masterson T. A. Einhorn L. H. Foster R. S. Surgical management of late relapse on surveillance in patients presenting with clinical stage I testicular cancer Urology 2014 84 4 886 891 10.1016/j.urology.2014.05.054 2-s2.0-84921967970 25260450 \n29 Malagón H. D. Valdez A. M. C. Moran C. A. Suster S. Germ cell tumors with sarcomatous components: a clinicopathologic and immunohistochemical study of 46 cases American Journal of Surgical Pathology 2007 31 9 1356 1362 10.1097/pas.0b013e318033c7c4 2-s2.0-34548238872 17721191 \n30 Bosl G. J. Ilson D. H. Rodriguez E. Motzer R. J. Reuter V. E. Chaganti R. S. K. Clinical relevance of the I(12p) chromosome in germ cell tumors Journal of the National Cancer Institute 1994 86 5 349 355 10.1093/jnci/86.5.349 2-s2.0-0028327321 8308927 \n31 Summersgill B. Goker H. Osin P. Establishing germ cell origin of undifferentiated tumors by identifying gain of 12p material using comparative genomic hybridization analysis of paraffin-embedded samples Diagnostic Molecular Pathology 1998 7 5 260 266 10.1097/00019606-199810000-00005 2-s2.0-0032421515 9990484\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2017()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "2457023",
"pmc": null,
"pmid": "28367345",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "25260450;24908364;23839244;12752258;24192771;24921638;26612222;22622519;6090001;15711278;27074038;17081678;6478436;24952240;26748165;15985085;16205699;26935559;24909334;12620907;23402579;9474169;9990484;9400455;20276801;20868391;2990657;19561445;17721191;8308927",
"title": "Pure Testicular Seminoma Relapsing Late with Somatic Type Malignancy.",
"title_normalized": "pure testicular seminoma relapsing late with somatic type malignancy"
} | [
{
"companynumb": "DE-ACCORD-050460",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "The effect of body mass index (BMI) and chemotherapy dose reduction on pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for locoregional breast cancer remains unclear. Contemporary studies have reported largely on trial populations and used dose-capping.\n\n\n\nPatient registries at the University of Iowa were queried to identify patients with operable breast cancer who received NAC. Dose reductions were calculated for taxanes (T), anthracyclines (A) and non-A-T chemotherapy. Clinical-pathologic characteristics, chemotherapy dose reductions, and adverse events were compared between normal (BMI <25) and overweight/obese patients (BMI ≥25). Additionally, the synergistic effect of BMI and chemotherapy dose reduction on pCR was assessed.\n\n\n\nOf 171 eligible patients, 112 were overweight/obese. Chemotherapy dosing was capped in 2 patients; all others initiated full weight-based treatment. Overweight/obese patients required more frequent taxane (44.6% vs. 25.4%; P = .01) and any chemotherapy dose reductions (50.9% vs. 33.9%; P = .03). pCR was attained in 29.2% of patients. In a multivariable model, the interaction term for BMI as a continuous variable and any chemotherapy dose reduction was significant independent of the clinical stage and tumor receptor status (P = .04). For obese patients, any chemotherapy dose reduction was significantly associated with increased odds of not attaining pCR.\n\n\n\nDuring NAC, overweight/obese patients more often have chemotherapy dose reductions. Chemotherapy dose reduction in obese patients was a powerful predictor of not attaining pCR. This was not seen for normal or overweight patients. Opportunities might exist to improve pCR rates in this higher-risk group.",
"affiliations": "Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA.;Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA.;Division of Health Services Research, Department of Pharmacy Practice and Science, College of Pharmacy, University of Iowa, Iowa City, IA.;Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA.;Department of Internal Medicine, University of Iowa, Iowa City, IA.;Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA. Electronic address: alex-thomas@uiowa.edu.",
"authors": "Raman|Rachna|R|;Mott|Sarah L|SL|;Schroeder|Mary C|MC|;Phadke|Sneha|S|;El Masri|Jad|J|;Thomas|Alexandra|A|",
"chemical_list": "D018943:Anthracyclines; D000970:Antineoplastic Agents; D043823:Taxoids",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2016.06.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "16(6)",
"journal": "Clinical breast cancer",
"keywords": "BMI; Chemotherapy dosing; Dose capping; Neoadjuvant therapy; Taxane; Weight-based dosing; pCR",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D015992:Body Mass Index; D001943:Breast Neoplasms; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009765:Obesity; D050177:Overweight; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "480-486",
"pmc": null,
"pmid": "27431461",
"pubdate": "2016-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "26936608;24074777;24530096;22257523;22903527;23980075;20067334;18757321;12637460;11321664;16606972;24298066;25767600;25034931;25902916;22848477;15956006;23446808;23034147;15897552;22778026;20308670;22473167;23165161;26626021;22276820;16182899;25677740;22508812;24960521;9719081;20308671;22766518;8918498",
"title": "Effect of Body Mass Index- and Actual Weight-Based Neoadjuvant Chemotherapy Doses on Pathologic Complete Response in Operable Breast Cancer.",
"title_normalized": "effect of body mass index and actual weight based neoadjuvant chemotherapy doses on pathologic complete response in operable breast cancer"
} | [
{
"companynumb": "US-JNJFOC-20161219944",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Langerhans cell histiocytosis (LCH) is an infrequent disease, characterized by oligoclonal proliferation of immature myeloid-derived cells. However, the exact pathogenesis remains unknown. In rare cases, LCH is present in patients with concomitant myeloid proliferative neoplasms. Here, we describe a 69-year-old male, who presented with a maculopapular rash covering truncus, face, and scalp. A cutaneous ulcerating lesion on the right cheek led to a biopsy showing LCH. Lesional cells were BRAF V600E and JAK2 V617F mutated. A bone marrow aspirate showed no infiltration of Langerhans cells, but alterations consistent with primary myelofibrosis (PMF) and a polymerase chain reaction test were positive for JAK2 V617F. Our case highlights an uncommon condition of two hematological malignancies present in the same patient. The identification of the BRAF V600E mutation supports previous findings of this mutation in LCH. Interestingly, a JAK2 V617F mutation was found in both LCH and PMF cells, indicating a possible clonal relationship between the two malignancies.",
"affiliations": "Department of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, Aarhus N 8200, Denmark.;Department of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, Aarhus N 8200, Denmark.;Department of Pathology, Copenhagen University Hospital, Blegdamsvej 3B, København N 2200, Denmark.;Department of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, Aarhus N 8200, Denmark.;Department of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, Aarhus N 8200, Denmark.;Department of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, Aarhus N 8200, Denmark.",
"authors": "Holst|Johanne Marie|JM|https://orcid.org/0000-0003-1100-4747;Enemark|Marie Beck|MB|https://orcid.org/0000-0003-4086-5183;Plesner|Trine Lindhardt|TL|;Pedersen|Martin Bjerregaard|MB|;Ludvigsen|Maja|M|https://orcid.org/0000-0001-5089-3271;d'Amore|Francesco|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6623706",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560\n2090-6579\nHindawi\n\n10.1155/2021/6623706\nCase Report\nCoexisting BRAF-Mutated Langerhans Cell Histiocytosis and Primary Myelofibrosis with Shared JAK2 Mutation\nhttps://orcid.org/0000-0003-1100-4747\nHolst Johanne Marie johahols@rm.dk\n1 2\nhttps://orcid.org/0000-0003-4086-5183\nEnemark Marie Beck 1 2\nPlesner Trine Lindhardt 3\nPedersen Martin Bjerregaard 1\nhttps://orcid.org/0000-0001-5089-3271\nLudvigsen Maja 1 2\nd'Amore Francesco 1 2\n1Department of Hematology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, Aarhus N 8200, Denmark\n2Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 82, Aarhus N 8200, Denmark\n3Department of Pathology, Copenhagen University Hospital, Blegdamsvej 3B, København N 2200, Denmark\nAcademic Editor: Stephen E. Langabeer\n\n2021\n16 4 2021\n2021 662370623 11 2020\n30 3 2021\n7 4 2021\nCopyright © 2021 Johanne Marie Holst et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nLangerhans cell histiocytosis (LCH) is an infrequent disease, characterized by oligoclonal proliferation of immature myeloid-derived cells. However, the exact pathogenesis remains unknown. In rare cases, LCH is present in patients with concomitant myeloid proliferative neoplasms. Here, we describe a 69-year-old male, who presented with a maculopapular rash covering truncus, face, and scalp. A cutaneous ulcerating lesion on the right cheek led to a biopsy showing LCH. Lesional cells were BRAFV600E and JAK2V617F mutated. A bone marrow aspirate showed no infiltration of Langerhans cells, but alterations consistent with primary myelofibrosis (PMF) and a polymerase chain reaction test were positive for JAK2V617F. Our case highlights an uncommon condition of two hematological malignancies present in the same patient. The identification of the BRAFV600E mutation supports previous findings of this mutation in LCH. Interestingly, a JAK2V617F mutation was found in both LCH and PMF cells, indicating a possible clonal relationship between the two malignancies.\n\nAarhus University\n==== Body\n1. Introduction\n\nLangerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of immature myeloid-derived cells similar to Langerhans cells [1–3]. The disease is rare and affects adults at a rate of approximately 1-2 cases per million [3, 4]. It may present as localized to a single site or occur as more disseminated disease with multiorgan involvement. The clinical course is highly related to disease stage and type of organ involvement with high survival rates in unifocal disease as opposed to multisystem disease, particularly if resistant to therapy [1]. The pathogenesis of LCH is poorly understood, but the neoplastic cells are believed to originate from immature myeloid-derived dendritic cells, similar to epidermal Langerhans cells [1, 3]. Approximately 50% of LCH cases harbor BRAFV600E mutations in LCH cells resulting in constitutive Ras/Raf/MEK/ERK signaling and increased mitogen-activated protein kinase (MAPK) activity [4–7]. LCH has previously been reported associated with other hematological disorders, including cases of myeloid proliferative neoplasia (MPN) [8, 9]. Here, we present a rare case presentation of BRAFV600E-mutated LCH and coexisting primary myelofibrosis (PMF) both sharing a Janus kinase 2 (JAK2)V617F mutation.\n\n2. Case Presentation\n\nA 69-year-old man was admitted to our department after skin biopsies from the ear and right cheek (Figure 1(a)) had revealed a histopathological picture morphologically and immunohistochemically consistent with LCH (Figure 2). Due to a painless, nonitching maculo-papular rash on face, scalp, and truncus (Figure 1(b)), he was treated with phototherapy (i.e., UVB) and topical steroids by a local dermatologist for approximately one year. During the last three months prior to admission, a 2.5 cm × 2.5 cm ulcerative cutaneous lesion had developed on his cheek. He had symptomatic generalized pruritus and fatigue but no night sweats, weight loss, or bone pain. Neither peripheral lymph adenopathy nor hepatosplenomegaly were found. Blood counts showed mild anemia with hemoglobin of 12.9 g/dL, a total leucocyte count of 14.5 × 109/L, and platelets of 451 × 109/L. During the following year, the patient continued to have anemia, sustained leukocytosis, and a varying level of thrombocytes. At diagnosis, serum-bilirubin, serum-aminotransferase, serum-lactate dehydrogenase, and serum-creatinine levels were normal.\n\nImmunohistochemically, a biopsy from the skin and ear showed a tumor cell population with a strong expression of S100 and CD1a (CD207) and moderate expression of CD68 (Figures 2(b) and 2(c)). The proliferation rate of the neoplastic cells was 40% (Ki-67). Both BRAFV600E mutation and JAK2V617F mutation (variant allele frequency (VAF) 0.08%) were detected in the sample using a quantitative polymerase chain reaction (qPCR) assay with a sensitivity of 1% and 0.01%, respectively.\n\nA trephine biopsy showed no evidence of LCH in the bone marrow, but the histomorphology was consistent with a chronic myeloproliferative neoplasia of PMF type (Figure 3). The bone marrow was hypercellular with an elevated number of clustered atypic megakaryocytes (large hyperlobulated in varying shapes and with large hyperchromatic nuclei). Increased reticulin and early-stage collagen fibrosis were seen. A JAK2V617F mutation (VAF 0.2%) was identified, while other common MPN-associated mutations in genes such as CALR or MPL were not found. No BRAF mutation was identified in the bone marrow.\n\nIn order to determine the extent of disease dissemination, a combined positron emission tomography-computed tomography (PET/CT) scan was performed. It revealed increased focal 18F-FDG uptake localized to the right cheek lesion, a cutaneous lesion in the occipital area, a cervical lymph node, the soft tissue anterior to the pubic bone (Figure 4(a)), and several foci in pelvic bones (Figure 4(b)). Thus, the patient suffered from multifocal LCH. The CT scan revealed an edematous appearance of both kidneys surrounded by adipose tissue similar to the appearance described in patients with Erdheim–Chester disease (Figure 3(c)). However, a kidney biopsy showed no infiltration of LCH.\n\nThe patient had a medical history of multiple cardiovascular events on an atherosclerotic background including coronary bypass grafting, bypass surgery of the leg, and a cerebral insult with moderate cognitive sequelae. His medication consisted of tamsulosin, clopidogrel, and simvastatin. He was a nonsmoker and had no history of alcohol abuse.\n\nHis family history included several cases of cancer, including a brother with chronic lymphoid leukemia and a niece treated for acute lymphocytic leukemia.\n\nThe patient was treated with IV cytarabine (100 mg/m2), which had to be prematurely discontinued due to infectious complications. The patient was mainly affected by the LCH skin alterations, and as the disease progressed, subsequently, the patient was treated with the oral BRAF-inhibitor vemurafenib for three months. This considerably improved his skin alterations (Figure 1(c)). Nine treatments of topical application of mechlorethamine were performed in the same period. Following a planned lower-extremity thrombectomy, the patient developed an acute coronary infarction. Sadly, he died of infectious complications one year after the initial diagnosis of LCH and PMF.\n\n3. Discussion\n\nHere, we describe the clinical, histopathological, and molecular findings in a patient who was diagnosed with two rare coexisting cancers of hematopoietic origin, i.e., LCH and PMF. While a BRAF mutation seemed limited to the LCH-associated lesions, a JAK2V617F mutation was found in both the cutaneous LCH lesion and in the LCH-void, but PMF involved bone marrow. The latter observation may suggest a possible pathogenetic relationship between the two malignant conditions in this patient. To our knowledge, the occurrence of coexisting LCH and PMF has only been described once before [10]. In that report, LCH and PMF were demonstrated to share the JAK2V617F mutation by performing a molecular genetic analysis on laser microdissected single LCH and PMF cells, suggesting a possible clonal relationship between the two cell populations.\n\nLCH is characterized by proliferating clonal neoplastic cells with surface markers similar to those of normal Langerhans cells found in the skin [1–3]. However, the origin of the malignant cell population in LCH has been questioned [11], and a comparison of global gene and protein expression patterns between LCH cells and epidermal Langerhans cells shows surprisingly low overall correlation [12]. Furthermore, numerous of the overexpressed genes in LCH cells are known to be associated with myeloid-derived dendritic cells. Some previous reports have found LCH associated with other hematopoietic disorders, including myelo- and lymphoproliferative malignancies [8, 9, 13, 14]. It has therefore been hypothesized that mutations in common hematopoietic precursor cells may explain the development of occasional co-occurrence of two hematological diseases [8, 15]. Interestingly, Milne et al. found BRAFV600E mutations present both in myeloid progenitors and CD34+ cells from LCH patients [16]. Our finding of a shared JAK2 mutation in the LCH and PMF lesions of our patient supports the hypothesis of common pathogenetic steps, possibly at the hematopoietic progenitor cell level, leading to the development of both diseases. Both BRAF and JAK2 are genes whose regulatory impact lies upstream of the MAPK and Pi3K pathways [5, 17]. Hence, the occurrence of a shared JAK2 mutation may suggest a concurrent development of LCH and PMF from clonally related hematopoietic progenitor cell populations.\n\nThe qPCR was performed on DNA extracted from bone marrow and skin biopsies with a substantial contribution from nonneoplastic cells. This may in part explain the low allelic frequencies of JAK2 mutations identified in the samples. Presence of blood cells in the LCH skin biopsy resulting in identification of the same JAK2 mutation in the LCH skin biopsy may therefore also represent a possible pitfall.\n\nBoth LCH and PMF are associated with chronic inflammation, and this may contribute to the pathophysiology in both diseases [1, 18–20]. With this case, we show interesting possible insight into the pathogenesis of LCH with the association of both the MAPK and JAK-STAT pathways, which are both involved in various immunologic and inflammatory responses. Furthermore, the identification of BRAFV600E and constitutive MAPK and Ras/Raf/MEK/ERK signaling has contributed to the establishment of LCH as a malignant process [4, 21]. BRAF signaling is involved in various cellular functions, such as proliferation, apoptosis, angiogenesis, and survival. Accordingly, BRAF mutations have been associated with various cancers, e.g., hairy cell leukemia and metastatic melanoma [4, 22, 23]. The BRAF enzyme inhibitor vemurafenib represents an attractive novel treatment option in BRAFV600E-mutated cancers [24]. Also, our patient had a remarkable clinical benefit from the treatment with vemurafenib leading to considerable improvement of the original facial skin alterations. The short observation period on vemurafenib treatment due to the patient's death following complications after a planned vascular surgery procedure does not allow us to evaluate whether vemurafenib also was beneficial on PMF.\n\n4. Conclusion\n\nIn conclusion, here we describe a patient with coexisting BRAFV600E-mutated LCH and PMF sharing a JAK2V617F mutation. Whether a possible molecular relationship between LCH and MPN exists—and if the diseases, in some cases, share common pathologic driving events—will require further investigations on a larger number of cases, and, if possible, investigated with careful single-cell analysis.\n\nAcknowledgments\n\nThis work was supported by grants from Aarhus University, iLymph, SEB pension, the Danish Lymphoma Group, and the Ølufgaard P. N. Kristensen Foundation.\n\nData Availability\n\nOriginal clinical pathological data are obtained from the patient's medical record with written informed consent as well as approval from the Danish Data Protection Agency (record no. 1-16-02-420-15) and the Danish National Committee on Health Research Ethics (record no. 1609521).\n\nConsent\n\nWritten consent was obtained from the patient.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\n\nJohanne Marie Holst and Marie Beck Enemark contributed equally and share first authorship.\n\nFigure 1 (a) Tumor localized to the cheek of the patient. (b) Painless, nonitching maculopapular rash on the patient's truncus. (c) Normalization of the skin after BRAF-inhibitor treatment.\n\nFigure 2 Skin sample at the time of diagnosis showing histopathological and immunohistochemical features consistent with Langerhans cell histiocytosis. (a) Haematoxylin and eosin staining (100x), and immunohistochemical staining for (b) S100 (100x) and (c) CD1a (100x).\n\nFigure 3 Giemsa staining of the bone marrow sample showing histopathological features consistent with primary myelofibrosis (200x).\n\nFigure 4 Elevated 18F-FDG uptake localized corresponding to (a) the right cheek, cutaneous portion of the back head (occipital) and in one lymph node at the neck and (b) several foci in the pelvic bones, and a soft tissue process ahead of right os pubis showing increased 18F-FDG activities. (c) The CT scan showing pathological edematous appearance of the kidney surrounded by adipose tissue.\n==== Refs\n1 Durham B. H. Molecular characterization of the histiocytoses: neoplasia of dendritic cells and macrophages Seminars in Cell & Developmental Biology 2019 86 62 76 10.1016/j.semcdb.2018.03.002 2-s2.0-85043979049 29526544\n2 Allen C. E. Merad M. McClain K. L. Langerhans-cell histiocytosis New England Journal of Medicine 2018 379 9 856 868 10.1056/nejmra1607548 2-s2.0-85052884670\n3 Emile J.-F. Abla O. Fraitag S. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages Blood 2016 127 22 2672 2681 10.1182/blood-2016-01-690636 2-s2.0-84971328245 26966089\n4 Papo M. Cohen-Aubart F. Trefond L. Systemic histiocytosis (Langerhans cell histiocytosis, erdheim-chester disease, destombes-rosai-dorfman disease): from oncogenic mutations to inflammatory disorders Current Oncology Reports 2019 21 7 p. 62 10.1007/s11912-019-0810-6 2-s2.0-85066502934\n5 Tran G. Huynh T. N. Paller A. S. Langerhans cell histiocytosis: a neoplastic disorder driven by Ras-ERK pathway mutations Journal of the American Academy of Dermatology 2018 78 3 579 590 10.1016/j.jaad.2017.09.022 2-s2.0-85032330403 29107340\n6 Zinn D. J. Chakraborty R. Allen C. E. Langerhans cell histiocytosis: emerging insights and clinical implications Oncology (Williston Park, N. Y.) 2016 30 2 122 139\n7 Kobayashi M. Tojo A. Langerhans cell histiocytosis in adults: advances in pathophysiology and treatment Cancer Science 2018 109 12 3707 3713 10.1111/cas.13817 2-s2.0-85055869507 30281871\n8 Kiavash K. Malone J. C. Langerhans cell histiocytosis associated with underlying hematolymphoid disorders in adults: report of 2 cases and review of the literature The American Journal of Dermatopathology 2018 40 8 588 593 10.1097/dad.0000000000001072 2-s2.0-85056281774 30035752\n9 Iwasaki T. Takahashi I. Nagashima T. Cutaneous Langerhans cell histiocytosis in elderly with chronic myelomonocytic leukemia The Journal of Dermatology 2014 41 3 262 265 10.1111/1346-8138.12417 2-s2.0-84896325494 24628074\n10 Bonometti A. Bagnoli F. Fanoni D. JAK2-mutated Langerhans cell histiocytosis associated with primary myelofibrosis treated with ruxolitinib Human Pathology 2018 73 171 175 10.1016/j.humpath.2017.10.017 2-s2.0-85041834501 29107666\n11 Merad M. Ginhoux F. Collin M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells Nature Reviews Immunology 2008 8 12 935 947 10.1038/nri2455 2-s2.0-56749152272\n12 Allen C. E. Li L. Peters T. L. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells The Journal of Immunology 2010 184 8 4557 4567 10.4049/jimmunol.0902336 2-s2.0-77952765452 20220088\n13 Feldman A. L. Berthold F. Arceci R. J. Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis The Lancet Oncology 2005 6 6 435 437 10.1016/s1470-2045(05)70211-4 2-s2.0-19944371212 15925822\n14 Edelbroek J. R. Vermeer M. H. Jansen P. M. Langerhans cell histiocytosis first presenting in the skin in adults: frequent association with a second haematological malignancy British Journal of Dermatology 2012 167 6 1287 1294 10.1111/j.1365-2133.2012.11169.x 2-s2.0-84870171240\n15 Yohe S. L. Chenault C. B. Torlakovic E. E. Asplund S. L. McKenna R. W. Langerhans cell histiocytosis in acute leukemias of ambiguous or myeloid lineage in adult patients: support for a possible clonal relationship Modern Pathology 2014 27 5 651 656 10.1038/modpathol.2013.181 2-s2.0-84899973583 24186134\n16 Milne P. Bigley V. Bacon C. M. Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults Blood 2017 130 2 167 175 10.1182/blood-2016-12-757823 2-s2.0-85024099686 28512190\n17 Perner F. Perner C. Ernst T. Heidel F. H. Roles of JAK2 in aging, inflammation, hematopoiesis and malignant transformation Cells 2019 8 8 10.3390/cells8080854\n18 Halbritter F. Farlik M. Schwentner R. Epigenomics and single-cell sequencing define a developmental hierarchy in Langerhans cell histiocytosis Cancer Discovery 2019 9 10 1406 1421 10.1158/2159-8290.cd-19-0138 2-s2.0-85072849016 31345789\n19 Ruberti S. Bianchi E. Bianchi E. Involvement of MAF/SPP1 axis in the development of bone marrow fibrosis in PMF patients Leukemia 2018 32 2 438 449 10.1038/leu.2017.220 2-s2.0-85039974173 28745329\n20 Koschmieder S. Mughal T. I. Hasselbalch H. C. Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both Leukemia 2016 30 5 1018 1024 10.1038/leu.2016.12 2-s2.0-84959486080 26854026\n21 Badalian-Very G. Vergilio J.-A. Degar B. A. Recurrent BRAF mutations in Langerhans cell histiocytosis Blood 2010 116 11 1919 1923 10.1182/blood-2010-04-279083 2-s2.0-77956904045 20519626\n22 Davies H. Bignell G. R. Cox C. Mutations of the BRAF gene in human cancer Nature 2002 417 6892 949 954 10.1038/nature00766 2-s2.0-18444374405 12068308\n23 Tiacci E. Trifonov V. Schiavoni G. BRAFMutations in hairy-cell leukemia New England Journal of Medicine 2011 364 24 2305 2315 10.1056/nejmoa1014209 2-s2.0-79959293462\n24 Haroche J. Cohen-Aubart F. Emile J.-F. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with brafv600e-mutated erdheim-chester disease Journal of Clinical Oncology 2015 33 5 411 418 10.1200/jco.2014.57.1950 2-s2.0-84922354803 25422482\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2021()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "6623706",
"pmc": null,
"pmid": "33953993",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26854026;31115724;31398915;21663470;12068308;24628074;28745329;30281871;29107666;26966089;20220088;15925822;29107340;31345789;30035752;24186134;26888790;19029989;25422482;22835048;28512190;20519626;29526544;30157397",
"title": "Coexisting BRAF-Mutated Langerhans Cell Histiocytosis and Primary Myelofibrosis with Shared JAK2 Mutation.",
"title_normalized": "coexisting braf mutated langerhans cell histiocytosis and primary myelofibrosis with shared jak2 mutation"
} | [
{
"companynumb": "DK-PFIZER INC-2021697935",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nIncreasing evidence from experimental studies and clinical observations suggests that drugs with anticholinergic properties can cause physical and mental impairment. The aim of the present study was to evaluate the relationship between the use of drugs with anticholinergic activity and negative outcomes in older nursing home residents.\n\n\nMETHODS\nWe used data from the database of the U.L.I.S.S.E project (Un Link Informatico sui Servizi Sanitari Esistenti per l'Anziani), a prospective multicenter observational study. Patients from 31 facilities in Italy were assessed at baseline and at 6 and 12 months by trained personnel, using the Minimum Data Set for Nursing Home (MDS-NH). The only exclusion criterion was age younger than 65 years. The Anticholinergic Risk Scale (ARS), a list of commonly prescribed drugs with potential anticholinergic effects, was used to calculate the anticholinergic load.\n\n\nRESULTS\nA total population of 1490 patients was analyzed; almost half of the sample (48%) was using drugs with anticholinergic properties. The population of patients with ARS 1 or higher had a higher comorbidity index (P < .003) and greater cognitive impairment (CPS 5-6) (P < .007). They were more likely to suffer from heart failure, Parkinson disease, depression, anxiety, and schizophrenia. In multivariate analysis, a higher score in the ARS scale was associated with a greater likelihood of functional decline (described as the loss of ≥1 ADL point) (odds ratio [OR] 1.13; confidence interval [CI] 1.03-1.23), to a higher rate of falls (OR 1.26; CI 1.13-1.41), and to a higher incidence of delirium (OR 1.16; CI 1.02-1.32) during a 1-year follow-up.\n\n\nCONCLUSIONS\nThe use of medications with anticholinergic properties is common among older nursing home residents. Our results suggest that among older nursing home residents the use of anticholinergic drugs is associated with important negative outcomes, such as functional decline, falls, and delirium.",
"affiliations": "Department of Gerontology, Geriatrics and Physiatry, Catholic University of Sacred Heart, Roma, Italy. Electronic address: Francesco.landi@rm.unicatt.it.;Geriatrics and Geriatric Emergency Care, IRCCS-INRCA, Ancona, Italy.;Department of Gerontology, Geriatrics and Physiatry, Catholic University of Sacred Heart, Roma, Italy.;Department of Gerontology, Geriatrics and Physiatry, Catholic University of Sacred Heart, Roma, Italy.;Department of Clinical and Experimental Medicine, Section of Internal Medicine, Gerontology, and Clinical Nutrition, University of Ferrara, Ferrara, Italy.;Department of Biomedical Sciences and Public Health, Unit of Hygiene, Preventive Medicine and Public Health, Università Politecnica delle Marche, Ancona, Italy.;Epidemiology Department, Regional Health Authority of Umbria, Italy; Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia Medical School, Perugia, Italy.;Scientific Direction, IRCCS-INRCA, Ancona, Italy.;Geriatrics and Geriatric Emergency Care, IRCCS-INRCA, Ancona, Italy.",
"authors": "Landi|Francesco|F|;Dell'Aquila|Giuseppina|G|;Collamati|Agnese|A|;Martone|Anna Maria|AM|;Zuliani|Giovanni|G|;Gasperini|Beatrice|B|;Eusebi|Paolo|P|;Lattanzio|Fabrizia|F|;Cherubini|Antonio|A|",
"chemical_list": "D018680:Cholinergic Antagonists",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-8610",
"issue": "15(11)",
"journal": "Journal of the American Medical Directors Association",
"keywords": "Anticholinergic medications; delirium; falls; functional decline",
"medline_ta": "J Am Med Dir Assoc",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D000369:Aged, 80 and over; D018680:Cholinergic Antagonists; D016208:Databases, Factual; D003693:Delirium; D005260:Female; D016330:Frail Elderly; D006801:Humans; D007558:Italy; D008297:Male; D009735:Nursing Homes; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100893243",
"other_id": null,
"pages": "825-9",
"pmc": null,
"pmid": "25282629",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Anticholinergic drug use and negative outcomes among the frail elderly population living in a nursing home.",
"title_normalized": "anticholinergic drug use and negative outcomes among the frail elderly population living in a nursing home"
} | [
{
"companynumb": "IT-JNJFOC-20141108792",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "A 64-year-old male with a history of stabile chronic obstructive pulmonary disease (COPD) presented with increasing dyspnea and sputum for the last two months. Complete blood count showed WBC 14x103/ml, Hgb: 14.2 g/dL and eosinophilia. Blood biochemistry was normal. Chest x-ray showed hyperlucency while thorax computed tomography (CT) revealed obstructive lung disease and bronchiectasis. Pulmonary function tests demonstrated severe obstructive lung disease and a negative bronchoreversibility with a moderately reduced diffusing capacity/alveolar volume (DLCO/VA). ABG gases revealed significant hypoxemia. Sputum culture was negative. Total IgE was 1140 ng/ml. Aspergillus RAST, precipitins and aspergillusgalactomannan antigen were positive. CF genetic screening tests gave negative results. Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction that occurs due to bronchial aspergillus colonization. It is most common in patients with asthma and cystic fibrosis. We present a COPD case with an acute exacerbation due to Aspergillus fumigatus that lead to an aberrant clinical profile unresponsive to conventional treatment. Clinicians should consider Aspergillus fumigatus as an etiologic agent in an atypical and severe COPD exacerbation.",
"affiliations": "Department of Pulmonary Medicine, Cerrahpasa Medical Faculty, Istanbul Cerrahpasa University. tetikkurt@gmail.com.",
"authors": "Tetikkurt|Cuneyt|C|;Kubat|Bahar|B|;Tetikkurt|Seza|S|;Karakas|Gulsum|G|",
"chemical_list": "D007073:Immunoglobulin E",
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2020.1155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1122-0643",
"issue": "90(1)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
"keywords": null,
"medline_ta": "Monaldi Arch Chest Dis",
"mesh_terms": "D001228:Aspergillosis; D001229:Aspergillosis, Allergic Bronchopulmonary; D001232:Aspergillus fumigatus; D001987:Bronchiectasis; D018450:Disease Progression; D004417:Dyspnea; D004802:Eosinophilia; D006801:Humans; D007073:Immunoglobulin E; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D013183:Sputum; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9307314",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31986874",
"pubdate": "2020-01-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An atypical acute exacerbation of COPD due to Aspergillus fumigatus.",
"title_normalized": "an atypical acute exacerbation of copd due to aspergillus fumigatus"
} | [
{
"companynumb": "TR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-013418",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "Analyze the cumulative evidence for pregnancy outcomes after maternal exposure to tocilizumab, an anti-interleukin-6-receptor monoclonal antibody used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. At present, published experience on tocilizumab use during pregnancy is very limited.\n\n\n\nWe have analyzed all pregnancy-related reports documented in the Roche Global Safety Database until December 31, 2014 (n = 501).\n\n\n\nAfter exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were found to have been exposed to tocilizumab shortly before or during pregnancy, with pregnancy outcomes being reported in 288 pregnancies (72.2%). Of these 288 pregnancies, 180 were prospectively reported resulting in 109 live births (60.6%), 39 spontaneous abortions (21.7%), 31 elective terminations of pregnancy (17.2%), and 1 stillbirth. The rate of malformations was 4.5%. Co-medications included methotrexate in 21.1% of the prospectively ascertained cases. Compared to the general population, an increased rate of preterm birth (31.2%) was observed. Retrospectively reported pregnancies (n = 108) resulted in 55 live births (50.9%), 31 spontaneous abortions (28.7%), and 22 elective terminations (20.4%). Three infants/fetuses with congenital anomalies were reported in this group. No increased risks for adverse pregnancy outcomes were observed after paternal exposure in 13 pregnancies with known outcome.\n\n\n\nNo indication for a substantially increased malformation risk was observed. Considering the limitations of global safety databases, the data do not yet prove safety, but provide information for physicians and patients to make informed decisions. This is particularly important after inadvertent exposure to tocilizumab, shortly before or during early pregnancy.",
"affiliations": "Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. Electronic address: maria.hoeltzenbein@charite.de.;Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.;Genentech, Inc., A Member of the Roche Group, South San Francisco, California, United States.;National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, Trondheim University Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Rheumatology, Ålesund Hospital, Ålesund, Norway.;Genentech, Inc., A Member of the Roche Group, South San Francisco, California, United States.;Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.;National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, Trondheim University Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.",
"authors": "Hoeltzenbein|Maria|M|;Beck|Evelin|E|;Rajwanshi|Richa|R|;Gøtestam Skorpen|Carina|C|;Berber|Erhan|E|;Schaefer|Christof|C|;Østensen|Monika|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.semarthrit.2016.05.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "46(2)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Malformation; Maternal exposure; Pregnancy; Rheumatoid arthritis; Spontaneous abortion; Tocilizumab",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D016208:Databases, Factual; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D018811:Maternal Exposure; D008727:Methotrexate; D008875:Middle Aged; D011247:Pregnancy; D011256:Pregnancy Outcome; D011358:Product Surveillance, Postmarketing; D018570:Risk Assessment; D055815:Young Adult",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "238-245",
"pmc": null,
"pmid": "27346577",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data.",
"title_normalized": "tocilizumab use in pregnancy analysis of a global safety database including data from clinical trials and post marketing data"
} | [
{
"companynumb": "PHHY2016DE177403",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Prolonged prothrombin time is observed in patients taking warfarin (WF) with a fluoropyrimidine, such as S-1. When WF is combined with S-1, the prothrombin time-international normalized ratio (PT-INR) and dose adjustment of WF should be closely monitored. To date, no clinical data have been reported in terms of the relation between temporal variation of PT-INR and its therapeutic range. In this study, we retrospectively collected patients' clinical data including PT-INR. We identified 21 patients receiving WF therapy before the start of S-1 treatment. Patient characteristics were male/female: 18/3, median age: 69 (range 48-81) years old, cancer of gastric/lung/pancreatic/other: 8/5/4/4, and history of deep vein thrombosis (DVT)/atrial fibrillation (AF)/cerebral infarction (CI)/other: 11/6/2/2. The PT-INR of 16 patients exceeded normal upper limits after taking S-1 with WF. The median time to exceed the PT-INR upper therapeutic range is 25 (range 3-77) days. Patients receiving WF anticoagulant therapy concomitant with S-1 should have their PT-INR closely monitored and WF doses adjusted accordingly.",
"affiliations": "Division of Pharmacy, National Cancer Center Hospital East.",
"authors": "Yamamoto|Kaori|K|;Suzuki|Shinya|S|;Ikegawa|Kiwako|K|;Nomura|Hisanaga|H|;Fuse|Nozomu|N|;Saito|Shinichiro|S|",
"chemical_list": "D000925:Anticoagulants; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D014859:Warfarin; D010094:Oxonic Acid",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010094:Oxonic Acid; D011517:Prothrombin Time; D012189:Retrospective Studies; D005641:Tegafur; D014859:Warfarin",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "65-8",
"pmc": null,
"pmid": "26809527",
"pubdate": "2016-01",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Evaluation of Drug Interaction between S-1 and Warfarin.",
"title_normalized": "evaluation of drug interaction between s 1 and warfarin"
} | [
{
"companynumb": "JP-TEVA-668335ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Allogeneic stem cell transplantation (allo-SCT) can be a curative treatment for patients with a hematologic malignancy due to alloreactive T cell responses recognizing minor histocompatibility antigens (MiHA). Yet tumor immune escape mechanisms can cause failure of T cell immunity, leading to relapse. Tumor cells display low expression of costimulatory molecules and can up-regulate coinhibitory molecules that inhibit T cell functionality on ligation with their counter-receptors on the tumor-reactive T cells. The aim of this explorative study was to evaluate immune checkpoint expression profiles on T cell subsets and on cytomegalovirus (CMV)- and/or MiHA-reactive CD8+ T cells of allo-SCT recipients using a 13-color flow cytometry panel, and to correlate these expression patterns to clinical outcomes. MiHA-reactive CD8+ T cells exhibited an early differentiated CD27++/CD28++ phenotype with low KLRG-1 and CD57 expression. These T cells also displayed increased expression of PD-1, TIM-3, and TIGIT compared with total effector memory T cells and CMV-specific CD8+ T cells in healthy donors and allo-SCT recipients. Remarkably, high coexpression of PD-1, TIGIT, and KLRG-1 on MiHA-reactive CD8+ T cells was associated with relapse after allo-SCT. Taken together, these findings indicate that MiHA-specific CD8+ T cells of relapsed patients have a distinctive coinhibitory expression signature compared with patients who stay in remission. This phenotype may serve as a potential monitoring tool in patients. Moreover, these findings suggest that PD-1 and TIGIT play important roles in regulating T cell-mediated tumor control, providing a rationale for immunotherapy with blocking antibodies to treat relapse after allo-SCT.",
"affiliations": "Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Oncology and Hematologic Malignancies, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Oncology and Hematologic Malignancies, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Willemijn.Hobo@Radboudumc.nl.",
"authors": "Hutten|Tim J A|TJA|;Norde|Wieger J|WJ|;Woestenenk|Rob|R|;Wang|Ruo Chen|RC|;Maas|Frans|F|;Kester|Michel|M|;Falkenburg|J H Frederik|JHF|;Berglund|Sofia|S|;Luznik|Leo|L|;Jansen|Joop H|JH|;Schaap|Nicolaas|N|;Dolstra|Harry|H|;Hobo|Willemijn|W|",
"chemical_list": "C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; C534712:TIGIT protein, human; D015534:Trans-Activators",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2017.11.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "24(4)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Allo-SCT; MiHA; PD-1; TIGIT and T cells",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D064591:Allografts; D018414:CD8-Positive T-Lymphocytes; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019337:Hematologic Neoplasms; D006801:Humans; D007156:Immunologic Memory; D037181:Lectins, C-Type; D008297:Male; D009363:Neoplasm Proteins; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D012008:Recurrence; D033581:Stem Cell Transplantation; D015534:Trans-Activators",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "666-677",
"pmc": null,
"pmid": "29197680",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Increased Coexpression of PD-1, TIGIT, and KLRG-1 on Tumor-Reactive CD8+ T Cells During Relapse after Allogeneic Stem Cell Transplantation.",
"title_normalized": "increased coexpression of pd 1 tigit and klrg 1 on tumor reactive cd8 t cells during relapse after allogeneic stem cell transplantation"
} | [
{
"companynumb": "NL-ROCHE-2125197",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Little is known about the obstetrical management of patients with Takayasu arteritis (TA) who have undergone extra-anatomic vascular bypass (EAVB). We describe two cases of EAVB. Case 1 underwent EAVB due to renovascular hypertension associated with stenosis of the abdominal aorta, and Case 2 due to amaurosis fugax episodes associated with stenosis of the brachiocephalic and left common carotid arteries. Pregnancy outcomes were favorable for both cases, though the original symptoms recurred during the third trimester in each case, possibly due to increased blood flow to the pregnant uterus. Neither bypass occlusion nor anastomotic aneurysm formation was observed. Pregnancy outcomes of patients with EAVB due to TA are favorable, although pregnancies of patients with TA who have cardiovascular complications are associated with an increased risk of maternal and fetal morbidity. The obstetrical management of these patients, however, should include monitoring for complications related to the EAVB.",
"affiliations": "Department of Perinatal and Women's Medicine, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Perinatal and Women's Medicine, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Vascular Surgery, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Perinatal and Women's Medicine, Tokyo Medical and Dental University, Tokyo, Japan.",
"authors": "Miyasaka|Naoyuki|N|;Egawa|Makiko|M|http://orcid.org/0000-0002-1609-1360;Isobe|Mitsuaki|M|;Inoue|Yoshinori|Y|;Kubota|Toshiro|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.13139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "42(12)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "Takayasu disease; anticoagulation; complications; extra-anatomic bypass graft; pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D006973:Hypertension; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D013625:Takayasu Arteritis; D014656:Vascular Surgical Procedures; D055815:Young Adult",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1864-1869",
"pmc": null,
"pmid": "27718287",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Obstetrical management of patients with extra-anatomic vascular bypass grafts due to Takayasu arteritis.",
"title_normalized": "obstetrical management of patients with extra anatomic vascular bypass grafts due to takayasu arteritis"
} | [
{
"companynumb": "JP-BAYER-2017-011955",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "LT from ABO-I donors requires preconditioning regimens to prevent postoperative catastrophic AMR. NAC for HBL is known to cause myelosuppression leading to a reduction in the number and function of lymphocytes. We investigated this chemotherapy-induced myelosuppression in HBL patients listed for LT from ABO-I donors with reference to the kinetics of B, T cells, and anti-ABO blood type isoagglutinin titers. Between 2005 and 2015, of the 319 patients who underwent LDLT at our institute, 12 were indicated for unresectable HBL. Three patients with unresectable HBL who underwent LDLT from ABO-I donors are included in this study. Immunosuppression consisted of a standard regime of tacrolimus and low-dose steroids as in ABO compatible/identical LDLT. No additional preoperative therapies for B-cell depletion were used. Absolute lymphocyte counts, lymphocyte subsets (including CD20+ B cells, CD3+CD4+ T cells and CD3+CD8+ T cells), and anti-ABO blood type isoagglutinin titers were measured before LDLT and postoperatively. The median age at diagnosis was 19 months (range, 3-31 months). The median follow-up was seven months (range, 6-15 months). The median interval from the last NAC to LDLT was 33 days (range, 25-52 days). The median interval from LDLT to adjuvant chemotherapy was 28 days (range, 22-36 days). The counts of CD20+ B cells before LDLT were depleted to median 5 cells/mm(3) (range, 0-6 cells/mm(3)). There was a transient rebound in the CD20+ B cell counts on day seven (maximum of 82 cells/mm(3)) followed by a decline starting at 14 days after LDLT that was sustained for the duration of adjuvant chemotherapy. Anti-ABO blood type isoagglutinin titers were lowered to between 1:1 and 1:16 before LDLT and remained low for the duration of follow-up in this study. All of the three patients remained in good health without either acute cellular or AMR after LDLT. The B-cell depletion that occurs after cisplatin-based chemotherapy for HBL may help accomplish safe ABO-I LDLT in children without the use of additional conditioning regimens for prevention of AMR.",
"affiliations": "Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.;Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan.;Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.",
"authors": "Kanazawa|Hiroyuki|H|;Fukuda|Akinari|A|;Mali|Vidyadhar Padmakar|VP|;Rahayatri|Tri Hening|TH|;Hirata|Yoshihiro|Y|;Sasaki|Kengo|K|;Uchida|Hajime|H|;Shigeta|Takanobu|T|;Sakamoto|Seisuke|S|;Matsumoto|Kimikazu|K|;Kasahara|Mureo|M|",
"chemical_list": "D000017:ABO Blood-Group System; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D017252:CD3 Complex; D000069283:Rituximab; D002945:Cisplatin; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12675",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "20(3)",
"journal": "Pediatric transplantation",
"keywords": "ABO blood type incompatible; SIOPEL; chemotherapy; hepatoblastoma; living donor liver transplantation",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000017:ABO Blood-Group System; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D001402:B-Lymphocytes; D001787:Blood Group Incompatibility; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D017024:Chemotherapy, Adjuvant; D002675:Child, Preschool; D002945:Cisplatin; D003586:Cytomegalovirus Infections; D005260:Female; D018197:Hepatoblastoma; D006801:Humans; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D007223:Infant; D008113:Liver Neoplasms; D016031:Liver Transplantation; D019520:Living Donors; D016131:Lymphocyte Subsets; D008297:Male; D012306:Risk; D000069283:Rituximab; D016559:Tacrolimus; D019172:Transplantation Conditioning; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "401-7",
"pmc": null,
"pmid": "27012966",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Chemotherapy-induced B-cell depletion in hepatoblastoma patients undergoing ABO-incompatible living donor liver transplantation.",
"title_normalized": "chemotherapy induced b cell depletion in hepatoblastoma patients undergoing abo incompatible living donor liver transplantation"
} | [
{
"companynumb": "JP-JNJFOC-20161202319",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nTo assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis.\n\n\nMETHODS\nThirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity.\n\n\nRESULTS\nAll 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis.\n\n\nCONCLUSIONS\nPatients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity.",
"affiliations": "Department of Pediatric Nephrology, Leuven University Hospital, Leuven, Belgium. martine.besouw@uzleuven.be",
"authors": "Besouw|Martine T P|MT|;Schneider|Jerry|J|;Janssen|Mirian C|MC|;Greco|Marcella|M|;Emma|Francesco|F|;Cornelissen|Elisabeth A|EA|;Desmet|Koen|K|;Skovby|Flemming|F|;Nobili|François|F|;Lilien|Marc R|MR|;De Paepe|Anne|A|;Malfait|Fransiska|F|;Symoens|Sofie|S|;van den Heuvel|Lambertus P|LP|;Levtchenko|Elena N|EN|",
"chemical_list": "D015415:Biomarkers; D027682:Cation Transport Proteins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D000079923:Copper Transporter 1; D005819:Genetic Markers; D020011:Protective Agents; D012076:Renal Agents; C490079:SLC31A1 protein, human; D003543:Cysteamine; D003300:Copper; D003094:Collagen; D002570:Ceruloplasmin; D008249:Protein-Lysine 6-Oxidase; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "163(3)",
"journal": "The Journal of pediatrics",
"keywords": "FS; Fanconi syndrome",
"medline_ta": "J Pediatr",
"mesh_terms": "D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D027682:Cation Transport Proteins; D002570:Ceruloplasmin; D002648:Child; D002675:Child, Preschool; D003094:Collagen; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003300:Copper; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D003543:Cysteamine; D003554:Cystinosis; D005198:Fanconi Syndrome; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D020011:Protective Agents; D008249:Protein-Lysine 6-Oxidase; D012076:Renal Agents; D017422:Sequence Analysis, DNA; D055815:Young Adult",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "754-60",
"pmc": null,
"pmid": "23651769",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Copper deficiency in patients with cystinosis with cysteamine toxicity.",
"title_normalized": "copper deficiency in patients with cystinosis with cysteamine toxicity"
} | [
{
"companynumb": "DK-MYLANLABS-2015M1005051",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CYSTEAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor. A 47 year old male presented with symptoms of sour taste in his mouth, occasional nausea, indigestion and 15-pound weight loss over two months. He had an unremarkable upper gastrointestinal endoscopy. Imaging showed a large liver mass in the left hepatic lobe that was resected and then reported as UESL. He went on to develop lung metastases and was initially treated with doxorubicin and ifosfamide followed by switching of therapy to gemcitabine and docetaxel due to progression of disease. He had a good response after two cycles and went on to receive four more cycles, achieving stable disease. We can therefore conclude that the combination of gemcitabine and docetaxel is a potential therapeutic option for patients with UESL.",
"affiliations": "Department of Oncology/Hematology, Creighton University School of Medicine , Omaha, NE.;Division of Oncology/Hematology, Department of Medicine, University of Nebraska Medical Center , Omaha, NE, USA.;Division of Oncology/Hematology, Department of Medicine, University of Nebraska Medical Center , Omaha, NE, USA.;Division of Oncology/Hematology, Department of Medicine, University of Nebraska Medical Center , Omaha, NE, USA.",
"authors": "Kallam|Avyakta|A|;Krishnamurthy|Jairam|J|;Kozel|Jessica|J|;Shonka|Nicole|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.4081/rt.2015.6009",
"fulltext": "\n==== Front\nRare TumorsRare TumorsRTRare Tumors2036-36052036-3613PAGEPress Publications, Pavia, Italy 10.4081/rt.2015.6009Case ReportUndifferentiated Embryonal Sarcoma of Liver Kallam Avyakta 1Krishnamurthy Jairam 2Kozel Jessica 2Shonka Nicole 21 Department of Oncology/Hematology, Creighton University School of Medicine, Omaha, NE2 Division of Oncology/Hematology, Department of Medicine, University of Nebraska Medical Center, Omaha, NE, USADivision of Oncology/Hematology, Department of Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198, USA. +1.402.559.5168 - +1.402.559.6520. nshonka@unmc.eduContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n30 12 2015 29 12 2015 7 4 600912 5 2015 22 6 2015 ©Copyright A. Kallam et al.2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor. A 47 year old male presented with symptoms of sour taste in his mouth, occasional nausea, indigestion and 15-pound weight loss over two months. He had an unremarkable upper gastrointestinal endoscopy. Imaging showed a large liver mass in the left hepatic lobe that was resected and then reported as UESL. He went on to develop lung metastases and was initially treated with doxorubicin and ifosfamide followed by switching of therapy to gemcitabine and docetaxel due to progression of disease. He had a good response after two cycles and went on to receive four more cycles, achieving stable disease. We can therefore conclude that the combination of gemcitabine and docetaxel is a potential therapeutic option for patients with UESL.\n\nKey words\nembryonalliversarcoma\n==== Body\nIntroduction\nUndifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor. Initially described as malignant mesenchymoma, mesenchymal sarcoma or fibromyxosarcoma, it was termed as UESL by Stocker et al. in 1978.1 UESL refers to a heterogeneous group of tumors derived from mesenchymal tissues. It is usually seen in the pediatric population with peak incidence noted in children between 6 and 10 years of age. It is extremely rare in adults with less than 70 cases of UESL having been reported in patients above 15 years of age.2,3 While some studies have reported a slight female predominance in the adult population, others have not.4-6\n\nCase Report\nWe present the case of a 47 year old male who presented with symptoms of sour taste in his mouth, occasional nausea, indigestion, as well as a 15-pound weight loss over two months. Initial physical examination and labs were unremarkable. He went to the local emergency room for evaluation after he had symptomatic tachycardia while exercising. He was admitted for further evaluation and had an upper gastrointestinal endoscopy which was unrevealing. This was followed by imaging of his liver which revealed a 15×13×11 cm liver mass in the left hepatic lobe.\n\nFollowing this, he underwent a computed tomography (CT) scan of his chest, abdomen, and pelvis that also revealed the aforementioned liver lesion without any evidence of metastatic disease. Two weeks later, he underwent left lobectomy and resection of the liver mass.\n\nThe tumor showed pleomorphic spindled tumor cells arranged in fascicles with large zones of necrosis, a marked mitotic rate, interspersed foam cells, and focal areas that were more epitheloid and discohesive, with others that contained osteoclast-like giant cells. Immunohistochemistry revealed positive CD68 and caldesmon, with trace or weakly positive SMA, ALK-1, CD8/18 and AE1/AE3. All others were negative.\n\nFinal pathology was consistent with high grade spindle cell sarcoma with mild fibroblastic differentiation (Figure 1). As the liver represented the only site of disease, this was determined to represent a primary undifferentiated (embryonal) liver sarcoma. Tumor dimensions were 16×15.5×11.2 cm with a positive margin. Two of 2 celiac lymph nodes removed at the time of surgery were positive. Fluorescence in situ hybridization (FISH) was done for an Anaplastic Lymphoma kinase (ALK) gene rearrangement and was negative which ruled out inflammatory fibrosarcoma.\n\nThere was a delay in his care due the time it took for his pathologic diagnosis to be completed and as he moved back into this country and hence, two months later, CT showed significantly progressing disease and lung metastases. He was admitted to begin chemotherapy with dox-orubicin (25 mg/m2 IV for days 1 to 3) and ifosfamide (2.5 g/m2 for days 1 to 5). He received a total of two cycles after which he had significant progression of disease (Figure 2A) and was switched to gemcitabine (900 mg/m2 IV on days 1 and 8) and docetaxel (100 mg/m2 IV on day 8). He had a good response after two cycles (Figure 2B) and went on to receive four more cycles, achieving stable disease. His course was complicated by Pneumocystis jiroveci pneumonia after his primary physician placed him on steroids to aid his appetite without giving prophylactic antibiotics. After the 6th cycle of chemotherapy, he was admitted to a local hospital for worsening pneumonia. Due to a rapid decline in his performance status, he elected for hospice care. He died three weeks later.\n\nDiscussion and Conclusions\nAlthough, the precise etiology of UESL is unclear, it is thought to be associated with multiple genetic mutations. Multiple cytogenetic studies have shown overexpression of p53 in more than 80% of these tumor cells, thus suggesting a role of p53 pathway in the pathogenesis of this tumor.7 These studies have shown UESL to be associated with inac-tivation of the TP53 gene through the loss of heterozygosity and pathogenic mutation of the remaining allele leading to over expression. Studies have also shown UESL to have t(11;19)(q11;q13.3/13.4). Interestingly, UESL has known to share similar histological features and cytogenetic alterations as mesangial hamartoma of the liver, which is a benign tumor noted in pediatric population. This lead to the postulation that mesangial hamartoma could potentially progress to UESL with development of additional mutations.8 Patients with UESL can present with a variety of nonspecific symptoms such as nausea, vomiting, abdominal pain, jaundice, weight loss and fatigue.4 Painless abdominal distension secondary to the hepatic mass as well as spontaneous rupture of the tumor leading to intraperitoneal hemorrhage in rapidly growing tumors has been reported.9 For unclear reasons, the right lobe is known to be more commonly involved than the left lobe, although simultaneous involvement of both the lobes have also been reported.4,5 Laboratory tests are of limited use as liver function can be normal or mildly deranged.5 Serum alpha-feto protein usually remains normal but may be elevated in some cases.7,10\n\nCT scan or magnetic resonance imaging (MRI) reveals a large space occupying lesion with mixed solid-cystic features.11 These tumors are large with sizes ranging from 10 to 35 cm.5,12 The differential diagnosis for UESL include infectious etiologies such as an amebic liver abscess, intrahepatic hydatid cyst, polycystic liver disease, Caroli’s disease, simple bile duct cyst, biliary cystadenoma, hamartoma, cystadenocarcinoma, bilioma.13 PET scan and hydatid serologies can be done to narrow the differential diagnosis. Biopsy is often diagnostic. A pseudo-capsule with foci of extra capsular infiltration surrounds the tumor. UESL is composed of stellate and spindle shaped cells, set in myxoid matrix and areas of hyper cellularity. Moderate nuclear hyperchromasia and pleomorphism can also be seen. PAS positive, diastase resistant eosinophilic globules are typically seen within the cytoplasm.14 Variable immuno-reactivity to desmin, vementin, cytokeratin, alpha1 antitrypsin, alpha 1 anti-chymotrypsin, CD34 antibodies has also been reported.2,12,15\n\nUESL is a highly aggressive neoplasm with poor prognosis. While initial studies reported a median survival of less than 1 year after initial diagnosis more recent studies have reported the median survival to be closer to 2.5 years.1,2 The long term disease free survival was noted to be very poor even in patients who underwent complete surgical resection of the tumor. However, several recent reports have shown that the tumor can also be potentially curable.16-18 Surgical resection followed by chemotherapy remains the treatment of choice for patients with UESL, resulting in an improved overall survival.2,19 Neo-adjuvant or adjuvant systemic chemotherapy with combinations of doxorubicin, cisplatin or cyclophosphamide is often used and may improve survival.17,20 Combination chemotherapy regimens such as cisplatin with cyclophosphamide, doxorubicin or actinomycin D and/or vincristine have been used and have shown to be effective.2 Radiotherapy has been used rarely.21 In cases of recurrence, radical excision if feasible is recommended.3 With the use of adjuvant chemotherapy, survival of greater than 10 years has also been reported. In patients with unresectable tumors and patients with spontaneous tumor rupture, prognosis is extremely poor.12 Liver transplantations have been performed in the pediatric population with UESL with mixed results.22,23 This has however, not been reported in adults. Our case is unique since to the best of our knowledge, this is the first reported success of the combination of gemcitabine and docetaxel in UESL.\n\nFigure 1. Hematoxylin and eosin stain at 400× magnification.\n\nFigure 2. Computed tomography imaging before (A) and after (B) receiving gemcitabine and docetaxel.\n==== Refs\nReferences\n1. Stocker JT Ishak KG \nUndifferentiated (embryonal) sarcoma of the liver. Report of 31 cases . Cancer \n1978 ;42 :336 -48 .208754 \n2. Lenze F Birkfellner T Lenz P \nUndifferentiated embryonal sarcoma of the liver in adults . Cancer \n2008 ;112 :227482 .\n3. Nishio J Iwasaki H Sakashita N \nUndifferentiated (embryonal) sarcoma of the liver in middle-aged adults: smooth muscle differentiation determined by immunohistochemistry and electron microscopy . Hum Pathol \n2003 ;34 :246 -52 .12673559 \n4. Dai C Xu F Shu H \nUndifferentiated (embryonal) sarcoma of liver in adult: a case report . World J Gastroenterol \n2005 ;11 : 926 -9 .15682496 \n5. Li XW Gong SJ Song WH \nUndifferentiated liver embryonal sarcoma in adults: a report of four cases and literature review . World J Gastroenterol \n2010 ;16 : 4725 -32 .20872975 \n6. Yang L Chen LB Xiao J Han P \nClinical features and spiral computed tomography analysis of undifferentiated embryonic liver sarcoma in adults . J Digest Dis \n2009 ;10 :305 -9 .\n7. Lepreux S Rebouissou S Le Bail B \nMutation of TP53 gene is involved in car-cinogenesis of hepatic undifferentiated (embryonal) sarcoma of the adult, in contrast with wnt or telomerase pathways: an immunohistochemical study of three cases with genomic relation in two cases . J Hepatol \n2005 ;42 :424 -9 .15710230 \n8. Lauwers GY Grant LD Donnelly WH \nHepatic undifferentiated (embryonal) sarcoma arising in a mesenchymal hamartoma . Am J Surg Pathol \n1997 ;21 :1248 -54 .9331300 \n9. Yedibela S Reck T Ott R \n[Undifferen tiated, embryonal sarcoma as a rare cause of spontaneous liver rupture in adults] . Chirurg \n2000 ;71 :101 -5 . [Article in German] 10663012 \n10. Zaheer W Allen SL Ali SZ \nPrimary multicystic undifferentiated embryonal sarcoma of the liver in an adult presenting with peripheral eosinophilia . Ann Clin Lab Sci \n1994 ;24 :495 -500 .7847778 \n11. Kalra N Vyas S Das PJ \nUndifferentiated embryonal sarcoma of liver in an adult masquerading as complicated hydatid cyst . Ann Hepatol \n2011 ; 10 :81 -3 .21301015 \n12. Pachera S Nishio H Takahashi Y \nUndifferentiated embryonal sarcoma of the liver: case report and literature survey . J Hepatobiliary Pancreat \n2008 ;15 :536 -44 .\n13. Mortele KJ Ros PR \nCystic focal liver lesions in the adult: differential CT and MR imaging features . Radiographics \n2001 ;21 :895 -910 .11452064 \n14. Agaram N P Baren A Antonescu CR \nPediatric and adult hepatic embryonal sarcoma: a comparative ultrastructural study with morphologic correlations . Ultrastruct Pathol \n2006 ;30 :403 -8 .17182431 \n15. Buetow PC Buck JL Pantongrag-Brown L \nUndifferentiated (embryonal) sarcoma of the liver: Pathologic basis of imaging findings in 28 cases . Radiology \n1997 ;203 :779 -83 .9169704 \n16. Leuschner I , ed. Spindle cell rhab-domyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis . Soft tissue tumors . New York : Springer ; 1995 pp 261 -272 .\n17. Bisogno G Pilz T Perilongo G \nUndifferentiated sarcoma of the liver in childhood . Cancer \n2002 ;94 :252 -7 .11815984 \n18. Gonzalez-Crussi F \nUndifferentiated (embryonal) liver sarcoma of childhood: evidence of leiomyoblastic differentiation . Fetal Pediatr Pathol \n1983 ;1 :281 -90 .\n19. O’Sullivan MJ Swanson PE Knoll J \nUndifferentiated embryonal sarcoma with unusual features arising within mes-enchymal hamartoma of the liver: report of a case and review of the literature . Pediatr Develop Pathol \n2001 ;4 :482 -9 .\n20. Kim D Kim K Jung S \nUndifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy . J Pediatr Surg \n2002 ;37 :1419 -23 .12378446 \n21. Geel J Loveland J Pitcher G \nManagement of undifferentiated embryonal sarcoma of the liver in children: a case series and management review . S Afr Med J \n2013 ;103 :728 -31 .24079623 \n22. Husted T Neff G Thomas M \nLiver transplantation for primary or metastatic sarcoma to the liver . Am J Transplant \n2006 ;6 :392 -7 .16426326 \n23. Dower NA Smith LJ \nLiver transplantation for malignant liver tumors in children . Med Pediatr Oncol \n2000 ;34 :136 -40 .10657876\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-3605",
"issue": "7(4)",
"journal": "Rare tumors",
"keywords": "embryonal; liver; sarcoma",
"medline_ta": "Rare Tumors",
"mesh_terms": null,
"nlm_unique_id": "101526926",
"other_id": null,
"pages": "6009",
"pmc": null,
"pmid": "26788276",
"pubdate": "2015-12-29",
"publication_types": "D002363:Case Reports",
"references": "18836810;11452064;12378446;16426326;6687281;10657876;11779051;9169704;208754;7882713;7847778;20872975;19906110;24079623;18361435;15710230;9331300;11815984;17182431;15682496;10663012;12673559;21301015",
"title": "Undifferentiated Embryonal Sarcoma of Liver.",
"title_normalized": "undifferentiated embryonal sarcoma of liver"
} | [
{
"companynumb": "US-SA-2016SA024499",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Helicobacter cinaedi is a rare pathogen but known to cause bacteremia, cellulitis and enterocolitis. Recently, cases of involving various organs are increasingly reported such as endocarditis, meningitis, and kidney cyst infection. We report a case of intrauterine H. cinaedi infection leading preterm birth and neonatal sepsis. A 29-year-old pregnant women who was no underlying disease hospitalized due to threatened preterm labor at 22 weeks of gestation. Clinical findings showed uterine tenderness, fever, leukocytosis and elevated C-reactive protein. H. cinaedi was isolated from amniotic fluid obtained by transabdominal amniocentesis. We diagnosed as intrauterine H. cinaedi infection and administered intravenous ampicillin followed by oxytocin to terminate pregnancy. A live 446 g male infant was delivered. The patient was no signs of infection throughout postpartum course and discharged on post-delivery day 5. The neonate was admitted in neonatal intensive care unit and administered ampicillin and amikacin. H. cinaedi was isolated from umbilical cord blood culture. He has no signs of infection on day 5 but died from uncontrollable hyperglycemia and ketoacidosis on 15 days of age. H. cinaedi can cause intrauterine infection during pregnancy and lead preterm labor and neonatal sepsis.",
"affiliations": "Department of Obstetrics and Gynecology, University of Miyazaki, Japan. Electronic address: yohei_maki@med.miyazaki-u.ac.jp.;Department of Obstetrics and Gynecology, University of Miyazaki, Japan.;Department of Obstetrics and Gynecology, University of Miyazaki, Japan.;Department of Obstetrics and Gynecology, University of Miyazaki, Japan.;Department of Obstetrics and Gynecology, University of Miyazaki, Japan.;Department of Obstetrics and Gynecology, University of Miyazaki, Japan.",
"authors": "Maki|Yohei|Y|;Furukawa|Seishi|S|;Kodama|Yuki|Y|;Sumiyoshi|Kaeko|K|;Kino|Emi|E|;Sameshima|Hiroshi|H|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "22(6)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Helicobacter cinaedi; Intrauterine infection; Neonatal sepsis",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000328:Adult; D016470:Bacteremia; D005260:Female; D016998:Helicobacter; D016481:Helicobacter Infections; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008826:Microbial Sensitivity Tests; D000071074:Neonatal Sepsis; D007752:Obstetric Labor, Premature; D011247:Pregnancy; D014591:Uterine Diseases",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "414-6",
"pmc": null,
"pmid": "26806147",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Preterm labor and neonatal sepsis caused by intrauterine Helicobacter cinaedi infection.",
"title_normalized": "preterm labor and neonatal sepsis caused by intrauterine helicobacter cinaedi infection"
} | [
{
"companynumb": "PHHY2016JP074887",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYTOCIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "An infant presented with global developmental delay and infantile spasms. EEG was suggestive of hypsarrhythmia. She was started on sodium valproate, clonazepam and adrenocorticotropic hormone injection. After an initial improvement the child developed vomiting, altered sensorium and increase in frequency of seizures suggestive of encephalopathy. Valproate-induced hyperammonaemia or hepatic encephalopathy was considered and the drug was withheld following which there was a dramatic improvement. Paradoxically, the liver function tests and serum ammonia were normal. However, a complete reversal of encephalopathy, on withdrawal of the drug, strongly suggested an adverse drug reaction (ADR) due to valproic acid. Marginal elevation of serum valproic acid prompted us to use the Naranjo ADR probability score to confirm the diagnosis. This case highlights the fact that valproate toxicity can manifest with normal liver function and serum ammonia levels. This is the youngest reported case with this rare form of valproate-induced encephalopathy.",
"affiliations": "Department of Pediatrics, ESI-PGIMSR, Chennai, Tamil Nadu, India.",
"authors": "Sivathanu|Shobhana|S|;Sampath|Sowmya|S|;Veerasamy|Madhubala|M|;Sunderkumar|Satheeshkumar|S|",
"chemical_list": "D000927:Anticonvulsants; D002998:Clonazepam; D014635:Valproic Acid; D000641:Ammonia; D000324:Adrenocorticotropic Hormone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000324:Adrenocorticotropic Hormone; D000641:Ammonia; D000927:Anticonvulsants; D002998:Clonazepam; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D008111:Liver Function Tests; D020258:Neurotoxicity Syndromes; D013036:Spasms, Infantile; D014635:Valproic Acid",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24810446",
"pubdate": "2014-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11952778;16277730;15839456;11720147;16787750;14651674;11903461;10636156;16010067;7249508",
"title": "Encephalopathy in an infant with infantile spasms: possible role of valproate toxicity.",
"title_normalized": "encephalopathy in an infant with infantile spasms possible role of valproate toxicity"
} | [
{
"companynumb": "IN-WATSON-2015-00730",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aberrant expression of the anaplastic lymphoma kinase (ALK) gene in ALK-positive (ALK+) anaplastic large cell lymphoma (ALCL) is usually due to t(2;5)/NPM-ALK. However, rarely, aberrant ALK expression can also result from a rearrangement of the ALK gene with various partner genes. Central nervous system (CNS) metastasis is very rare in ALK+ALCL. Patients with CNS involvement show an inferior prognosis.\n\n\nMETHODS\nHere, we present the case of an 8-year-old girl diagnosed with ALK+ALCL. She presented with fever, skin nodules, leg swelling, and abdominal pain over the preceding 6 mo. She had extensive involvement and showed an extraordinary rare translocation, t(2;17)/CLTC-ALK, as demonstrated by RNA-seq. She underwent chemotherapy as per ALCL99, followed by vinblastine (VBL) maintenance treatment, and achieved complete remission. However, she developed CNS relapse during VBL monotherapy. The patient achieved a durable second remission with high-dose chemotherapy (including methotrexate 8 g/m2) and continuous treatment with alectinib and VBL.\n\n\nCONCLUSIONS\nAlectinib showed significant and durable CNS effects in this patient. However, more cases are needed to prove the efficacy and safety of alectinib for pediatric ALK+ALCL patients.",
"affiliations": "Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Chigene (Beijing) Translational Medical Research Center Co., Ltd., Beijing 101111, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. zhenghuyong@vip.sina.com.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.",
"authors": "Yang|Jing|J|;Li|Jun|J|;Gu|Wei-Yue|WY|;Jin|Ling|L|;Duan|Yan-Long|YL|;Huang|Shuang|S|;Zhang|Meng|M|;Wang|Xi-Si|XS|;Liu|Yi|Y|;Zhou|Chun-Ju|CJ|;Gao|Chao|C|;Zheng|Hu-Yong|HY|;Zhang|Yong-Hong|YH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v8.i9.1685",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2307-8960",
"issue": "8(9)",
"journal": "World journal of clinical cases",
"keywords": "Alectinib; Anaplastic; CLTC/ALK; Case report; Central nervous system; Lymphoma; Pediatric",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "1685-1692",
"pmc": null,
"pmid": "32420302",
"pubdate": "2020-05-06",
"publication_types": "D002363:Case Reports",
"references": "11090048;25205428;12112524;15208656;28699160;29512859;20679620;11369626;30529198;31331844;19738127;12750159;29925295;21855232;30992232;10807789;31226541;19521280;30245054",
"title": "Central nervous system relapse in a pediatric anaplastic large cell lymphoma patient with CLTC/ALK translocation treated with alectinib: A case report.",
"title_normalized": "central nervous system relapse in a pediatric anaplastic large cell lymphoma patient with cltc alk translocation treated with alectinib a case report"
} | [
{
"companynumb": "CN-ROCHE-2611603",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Previous studies from western countries have reported that active hepatocellular carcinoma (HCC) was associated with direct-acting antiviral (DAA) treatment failure. We sought to examine this issue in an Asian cohort.\n\n\n\nA retrospective cohort study was conducted on hepatitis C virus (HCV)-infected patients with advanced fibrosis who were treated with DAAs at our hospital between January 2017 and June 2018.\n\n\n\nWe treated 1021 HCV-infected patients during this period. A total of 976 of those patients were enrolled in a per-protocol analysis, including 556 (57.2%) who had genotype 1b infections, and 314 (32.3%) who had genotype 2 infections. The mean age of all 976 patients was 65.5 years, and 44.5% were male. 781 of the patients had no HCC, 172 had inactive HCC, and 23 had active HCC. Non-sustained virologic response (SVR) was noted in 10 (1.3%) patients without HCC, 5 (2.9%) patients with inactive HCC, and 4 (13.0%) patients with active HCC. After adjustment for confounders, active HCC (versus inactive HCC and non-HCC) was associated with non-SVR (adjusted odds ratio [AOR] = 24.5 (95% confidence interval [CI] = 4.4-136.9), P<0.001). Next, we excluded the 23 patients with active HCC from the multivariate analysis. After adjustment for confounders, inactive HCC (versus non-HCC) was not associated with non-SVR (AOR = 3.1 (95% CI = 0.94-9.95), P = 0.06).\n\n\n\nActive HCC was associated with non-SVR, while inactive HCC was not. We thus suggest the deferral of DAA treatment until after the complete radiological response of HCCs to treatment.",
"affiliations": "Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.",
"authors": "Yen|Yi-Hao|YH|;Chen|Chien-Hung|CH|;Hung|Chao-Hung|CH|;Wang|Jing-Houng|JH|;Lu|Sheng-Nan|SN|;Kee|Kwong-Ming|KM|;Hu|Tsung-Hui|TH|0000-0002-9172-1967",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0222605",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0222605PONE-D-19-19092Research ArticleMedicine and Health SciencesOncologyCancers and NeoplasmsCarcinomasHepatocellular CarcinomaMedicine and Health SciencesOncologyCancers and NeoplasmsGastrointestinal TumorsHepatocellular CarcinomaMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesHepatocellular CarcinomaMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesCirrhosisMedicine and Health SciencesOncologyCancer TreatmentBiology and life sciencesOrganismsVirusesRNA virusesFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis C virusBiology and Life SciencesGeneticsHeredityGenetic MappingVariant GenotypesBiology and Life SciencesDevelopmental BiologyFibrosisMedicine and Health SciencesSurgical and Invasive Medical ProceduresDigestive System ProceduresLiver TransplantationMedicine and Health SciencesSurgical and Invasive Medical ProceduresTransplantationOrgan TransplantationLiver TransplantationMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsNauseaMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsNauseaActive hepatocellular carcinoma is an independent risk factor of direct-acting antiviral treatment failure: A retrospective study with prospectively collected data Active hepatocellular carcinoma is an independent risk factor of direct-acting antiviral treatment failureYen Yi-Hao ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSupervisionValidationVisualizationWriting – original draftWriting – review & editingChen Chien-Hung SupervisionHung Chao-Hung SupervisionWang Jing-Houng SupervisionLu Sheng-Nan SupervisionKee Kwong-Ming Supervisionhttp://orcid.org/0000-0002-9172-1967Hu Tsung-Hui Supervision*Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, TaiwanLin Wenyu EditorHarvard Medical School, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: dr.hu@msa.hinet.net3 10 2019 2019 14 10 e02226057 7 2019 3 9 2019 © 2019 Yen et al2019Yen et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background & aims\nPrevious studies from western countries have reported that active hepatocellular carcinoma (HCC) was associated with direct-acting antiviral (DAA) treatment failure. We sought to examine this issue in an Asian cohort.\n\nMethods\nA retrospective cohort study was conducted on hepatitis C virus (HCV)-infected patients with advanced fibrosis who were treated with DAAs at our hospital between January 2017 and June 2018.\n\nResults\nWe treated 1021 HCV-infected patients during this period. A total of 976 of those patients were enrolled in a per-protocol analysis, including 556 (57.2%) who had genotype 1b infections, and 314 (32.3%) who had genotype 2 infections. The mean age of all 976 patients was 65.5 years, and 44.5% were male. 781 of the patients had no HCC, 172 had inactive HCC, and 23 had active HCC. Non-sustained virologic response (SVR) was noted in 10 (1.3%) patients without HCC, 5 (2.9%) patients with inactive HCC, and 4 (13.0%) patients with active HCC. After adjustment for confounders, active HCC (versus inactive HCC and non-HCC) was associated with non-SVR (adjusted odds ratio [AOR] = 24.5 (95% confidence interval [CI] = 4.4–136.9), P<0.001). Next, we excluded the 23 patients with active HCC from the multivariate analysis. After adjustment for confounders, inactive HCC (versus non-HCC) was not associated with non-SVR (AOR = 3.1 (95% CI = 0.94–9.95), P = 0.06).\n\nConclusion\nActive HCC was associated with non-SVR, while inactive HCC was not. We thus suggest the deferral of DAA treatment until after the complete radiological response of HCCs to treatment.\n\nhttp://dx.doi.org/10.13039/501100011892Kaohsiung Chang Gung Memorial HospitalCMRPG8H1331Yen Yi-Hao This study was supported by Grant CMRPG8H1331 from the Kaohsiung Chang Gung Memorial Hospital, Taiwan. Grant Recipient is Yi-Hao Yen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nThe availability of direct-acting antivirals (DAAs) has led to an increase in the number of patients receiving hepatitis C virus (HCV) treatment, including patients with hepatocellular carcinoma (HCC) [1]. The primary reason for treating HCV in patients with known HCC is similar to that for treating it in patients without HCC: to ameliorate the liver necroinflammation and fibrosis progression that can ultimately lead to the clinical consequences of cirrhosis [2].\n\nA recent systematic review and meta-analysis reported that sustained virologic response (SVR) rates were lower in HCC patients treated with DAAs than in non-HCC patients treated with DAAs, especially in those with active HCC. However, the heterogeneity was high. Furthermore, the studies reviewed in the meta-analysis were all from western countries [1].\n\nThe aim of the present study was to examine whether active HCC was associated with DAA treatment failure in an Asian cohort.\n\nPatients and methods\nPatients\nWe performed a retrospective study that enrolled all HCV-infected patients with advanced fibrosis who were treated with DAAs at Kaohsiung Chang Gung Memorial Hospital between January 2017 and June 2018. The National Health Insurance Administration (NHIA) of Taiwan has provided reimbursements for DAAs since January 2017 for HCV-infected patients with advanced fibrosis. Advanced fibrosis was defined as the presence of any one of the following: transient elastography (TE) with a liver stiffness measurement (LSM) ≥ 9.5Kpa [3], a Fibrosis-4 (FIB-4) score ≥ 3.25 [4], a liver biopsy showing advanced fibrosis (METAVIR fibrosis score ≥ 3) [5], ultrasound-identified liver cirrhosis with splenomegaly, or endoscopy showing gastroesophageal varices.\n\nThe treatment regimens used for enrolled patients included daclatasvir+asunaprevir (DCV+ASV) for 24 weeks in genotype 1b patients without resistance-associated variants (RAVs) [6]; ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) combined with ribavirin (RBV) for 12 weeks in genotype 1a patients without cirrhosis; 3D combined with RBV for 24 weeks in genotype 1a patients with cirrhosis; 3D for 12 weeks without RBV in genotype 1b patients; elbasvir/grazoprevir (GZR/EBR) for 12 weeks without RBV in treatment-naïve genotype 1a patients without RAVs; GZR/EBR with RBV for 12 weeks in treatment-experienced genotype 1a patients without RAVs; 16 weeks of GZR/EBR combined with RBV for genotype 1a patients with non-structure protein 5A (NS5A) RAVs; 12 weeks of GZR/EBR without RBV in treatment-naïve genotype 1b patients; 12 weeks of GZR/EBR with RBV in treatment-experienced genotype 1b patients; 12 weeks of GZR/EBR without RBV in treatment-naïve genotype 4 patients; 16 weeks of GZR/EBR with RBV in treatment-experienced genotype 4 patients; sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks without RBV in genotype 1, 4, 5, and 6 patients; SOF/LDV for 12 weeks with RBV in treatment-experienced, liver decompensation (Child–Turcotte–Pugh (CTP)B or C), or post-liver transplant patients; and SOF and RBV for 12 weeks for genotype 2 patients. In the case of suboptimal response to that last regimen [7], patients had the option to self-pay for and add DCV to the regimen. For our analysis, we classified the various regimens as either adequate or inadequate based upon HCV therapy guidelines [7]. Accordingly, SOF and RBV for 12 weeks for genotype 2 patients was defined as an inadequate regimen [7].\n\nThe presence of HCC in a patient was confirmed by histological or image analysis based on the recommendations of current guidelines [8–11].\n\nAs per the request of the NHIA, the treating physicians were required to input pre-treatment data (that is, ultrasound and lab data within 6 months of DAA initiation), as well as lab data at week 4 of the treatment, at the end of the treatment, and at week 12 of the follow-up period, into the national registry system. They were also required to input the reason (that is, intolerance, death, or other) for any premature discontinuation of treatment for patients who had such discontinuation, as well as the reason (that is, death or other) for not providing SVR12 data for any patients lacking such data. Due to the high costs of DAAs, the treating physicians were penalized if they did not input these data into the national registry system. Furthermore, all the patients signed an informed consent form provided by the NHIA which told them that they were required to comply with NHIA regulations; otherwise, their reimbursements for the DAA treatment would be canceled. As a result, there was ultimately only one patient who was still alive and without SVR data at the week 12 follow-up in this cohort. This 66-year-old female patient received a resection for HCC during the DAA treatment and then refused a follow-up appointment due to fatigue when a nurse contacted by phone (Table 1, case number 43).\n\n10.1371/journal.pone.0222605.t001Table 1 Patients who were excluded from per protocol analysis.\nPremature discontinue due to intolerance\tPatient number\tGender\tAge, years\tCTP\tHCCs\teGFR\n(ml/min/1.732)\tRegimen\tReason of premature discontinue treatment\tDuration of treatment (weeks)\tSVR status\t\n\t1\tM\t57\tA6\tN\t106\tDCV/ASV\tFever, diarrhea.\t16\tSVR\t\n\t2\tF\t82\tA5\tY\t52\tDCV/ASV\tPost TACE syndrome\t18\tSVR\t\n\t3\tF\t60\tA5\tN\t69\t3D\tLegs edema, dypsnea\t1\tNon-SVR\t\n\t4\tF\t84\tA5\tY\t80\t3D\tHyperbilirubinemia, bilirubin (direct/total): 2.1/3.8 mg/dl\t1\tNon-SVR\t\n\t5\tF\t84\tA5\tN\t42\tSOF/RBV\tFatigue\t4\tUnknown\t\n\t6\tF\t83\tA5\tY\t67\tGZR/EBR\tNausea\t4\tUnknown\t\n\t7\tM\t84\tA5\tY\t50\tSOF/RBV\tNausea\t8\tSVR\t\n\t8\tM\t82\tA6\tY\t28\tSOF/LDV+RBV\tFatigue\t4\tUnknown\t\n\t9\tM\t81\tA5\tN\t60\tSOF/RBV\tEpigastralgia\t4\tUnknown\t\n\t10\tF\t81\tA5\tY\t50\t3D\tNausea\t3\tUnknown\t\n\t11\tF\t81\tA5\tN\t62\t3D\tNausea\t2\tNon-SVR\t\n\t12\tF\t80\tA5\tN\t54\t3D\tNausea\t2\tNon-SVR\t\n\t13\tF\t79\tA6\tN\t100\tGZR/EBR\tDelirium\t6\tSVR\t\n\t14\tF\t75\tA5\tY\t82\t3D\tHyperbilirubinemia, bilirubin (direct/total): 3.3/5.8 mg/dl\t1\tNon-SVR\t\n\t15\tM\t75\tA5\tY\t97\tGZR/EBR\tProstate cancer with bone metastasis, wish hospice care\t4\tNon-SVR\t\n\t16\tF\t75\tA5\tN\t55\t3D\tPalpitation\t3\tNon-SVR\t\n\t17\tF\t74\tA5\tN\t54\tSOF/RBV\tPalpitation\t2\tNon-SVR\t\n\t18\tF\t74\tA5\tN\t10\t3D\tRenal function downhill\t1\tNon-SVR\t\n\t19\tF\t74\tA5\tN\tESRD\tGZR/EBR\tDizziness, nausea\t4\tSVR\t\n\t20\tM\t74\tA5\tY\t59\t3D\tPost TACE syndrome\t10\tUnknown\t\n\t21\tF\t70\tA5\tY\t154\tSOF/RBV\tHypertension, poor control\t2\tNon-SVR\t\n\t22\tF\t69\tA5\tN\tESRD\t3D\tDelirium\t2\tNon-SVR\t\n\t23\tF\t69\tA5\tY\t90\t3D\tLegs edema\t11\tSVR\t\n\t24\tM\t68\tA5\tN\t57\tSOF/RBV\tSyncope\t8\tNon-SVR\t\n\t25\tM\t68\tA5\tY\t15\tGZR/EBR\tAST/ALT: 540/264 (U/L)\t2\tNon-SVR\t\n\t26\tF\t66\tA5\tN\t97\t3D\tPalpitation, depression, fatigue\t3\tNon-SVR\t\n\t27\tF\t64\tA5\tN\t93\t3D\tStroke\t4\tUnknown\t\n\t28\tM\t64\tA5\tN\t85\t3D\tLegs edema\t10\tSVR\t\n\t29\tF\t58\tA5\tN\tESRD\t3D\tNausea, vomiting\t4\tNon-SVR\t\n\t30\tM\t63\tA5\tN\t78\t3D\tLiver decompensation (new onset of ascites)\t8\tNon-SVR\t\n\t31\tM\t38\tA5\tN\t126\tGZR/EBR\tUlcer bleeding\t10\tNon-SVR\t\n\t32\tM\t59\tA5\tN\t8\t3D\tLiver decompensation, (new onset of ascites, variceal bleeding)\t2\tNon-SVR\t\nDied during treatment\nOr before follow up week 12\tPatient number\tGender\tAge, years\tCTP\tHCCs\teGFR\n (ml/min/1.732)\tRegimen\tCause of death\tDuration of treatment (weeks)\tSVR status\t\n\t33\tF\t68\tA5\tY\t56\t3D\tinfluenza B infection/respiratory failure\t10\tUnknown\t\n\t34\tF\t91\tA5\tN\t65\tDCV/ASV\tSeizure/aspiration pneumonia\t3\tUnknown\t\n\t35\tM\t66\tA5\tY\t76\tDCV/ASV\tAcute myocardial infarction\t14\tUnknown\t\n\t36\tF\t59\tA5\tN\t55\tSOF/RBV\tOvary cancer with peritoneal carcinomatosis\t6\tUnknown\t\n\t37\tF\t78\tA5\tY\t58\t3D\tNausea, poor intake, pre-renal azotemia\t1\tUnknown\t\n\t38\tM\t63\tC11\tN\t164\tSOF/LDV+RBV\tNecrotizing fascitis\t5\tUnknown\t\n\t39\tF\t87\tA6\tY\t73\tSOF/RBV\tHCCs with extrahepatic spread\t12\tUnknown\t\n\t40\tM\t66\tA5\tY\t15\tSOF/RBV\tStaphylococcus aureus sepsis, decompensated cirrhosis\t12\tUnknown\t\n\t41\tF\t77\tA5\tY\t77\tGZR/EBR\tvariceal bleeding\t12\tUnknown\t\n\t42\tF\t79\tB7\tY\t41\tSOF/LDV/RBV\tDecompensated cirrhosis, pneumonia\t12\tUnknown\t\nMiscellaneous\tPatient number\tGender\tAge, years\tCTP\tHCCs\teGFR\n (ml/min/1.732)\tRegimen\tReasons of exclusion\tTreatment duration (weeks)\tSVR status\t\n\t43\tF\t66\tA5\tY\t70\tGZR/EBR\tRefuse follow due to fatigue after resection for HCC\t12\tUnknown\t\n\t44\tM\t54\tA5\tY\t76\tSOF/LDV/RBV\tHCC combined cholangiocarcinoma\t12\tSVR\t\n\t45\tF\t62\tA5\tN\t110\tDCV/ASV\tDid not check pre-treatment RAVs, virologic relapse with RAVs (L31V, P58S, Y93H in NS5A).\t24\tRelapse\t\nSVR, sustained virologic response; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir; GZR/EBR, grazoprevir plus elbasvir; DCV, daclatasvir; ASV, Asunaprevir; RBV, ribavirin; HCC, hepatocellular carcinoma; eGFR, estimated Glomerular filtration rate; TACE, Transcatheter arterial chemoembolization; AST, aspartate aminotransferase; ALT, alanine aminotransferase; RAVs, resistant associated variants; NS5A, non-structure protein 5A;ESRD, end stage renal disease\n\nWe excluded 32 patients with premature discontinuation of treatment due to intolerance, as well as ten patients who died during treatment or before follow-up week 12. We also excluded 1 patient who was alive at follow-up week 12 but refused to make a follow-up appointment, 1 patient with HCC combined with cholangiocarcinoma, and 1 patient treated with DCV+ASV who was mistakenly not given a pre-treatment RAV test but was found to have RAVs (L31V, P58S, and Y93H in the HCV NS5A region) at the time of virologic relapse. Among the 45 excluded patients, 21 were patients with HCC (Table 1). Finally, a total of 976 patients were enrolled in this study.\n\nDetermination of the presence of an active tumor was based on the recommendations of current guidelines [8–11]. All other data was collected at the time of the initiation of DAA treatment and included the tumor size, tumor number, Barcelona Clinic Liver Cancer (BCLC) stage [10], and the treatment modalities received for HCC.\n\nAll the procedures used in the study were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. This study was approved by the Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital (IRB number: 201801814B0). The requirement for informed consent was waived by the IRB. The data were analyzed anonymously.\n\nDefinition of SVR\nSerum HCV RNA levels were determined by COBAS TaqMan HCV Test (TaqMan HCV; Roche Molecular Systems Inc., Branchburg, N.J., lower limit of detection: 15 IU/ml). SVR was defined as undetectable HCV RNA 12 weeks after the end of therapy [12]. The genotyping of HCV was performed by primer-specific real-time PCR with the cobas® HCV GT assay (Roche Molecular Systems, Pleasanton, CA, USA).\n\nStatistical analysis\nThe baseline characteristics of the patients were summarized as mean (± standard deviation), median (interquartile range), or frequency (percentage). The distributions of the baseline characteristics according to the HCC and SVR status were estimated using the chi-squared or Fisher's exact test for categorical variables, and estimated using the independent two-sample t-test for continuous variables. Covariates in the multivariable model were chosen a priori for clinical importance. The potential confounders included age, gender, platelet count, prior history of interferon-based treatment, CTP class, and DAA regimen. Each p-value was two-sided and was considered statistically significant if the p-value less than 0.05. All analyses were performed using Stata version 14.0. (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP.).\n\nResults\nThe baseline characteristics of and a comparison between the patients in the active HCC, inactive HCC and non-HCC groups in this cohort are shown in Table 2. There were 976 patients in the cohort, 781 of the patients had no HCC, 172 had inactive HCC, and 23 had active HCC. In this cohort with advanced fibrosis, only 28 (2.9%) patients had decompensated cirrhosis (defined by CTP class B or C). Genotype 1b and 2 patients accounted for 870 (89.1%) of the patients in the entire cohort, while 61 patients were genotype 1a and 40 were genotype 6. Meanwhile, none of the patients in the cohort were genotype 3 patients because reimbursements were not being provided for the regimen for genotype 3 during this period. Compared to the inactive HCC and non-HCC patients, the patients with active HCC had higher alpha-fetoprotein (AFP), aspartate aminotransferase-to-platelet ratio index (APRI), and FIB-4 levels; and had lower albumin and platelet levels, a lower SVR rate and higher proportion of patients with ascites.\n\n10.1371/journal.pone.0222605.t002Table 2 Baseline characteristics of HCV patients who underwent treatment with DAA stratified by HCC status.\nCharacteristics\tEntire cohort,\nN = 976\tNon-HCC,\nN = 781\tInactive HCC,\nN = 172\tActive HCC,\nN = 23\tP\t\nAge (years)\t65.5 ± 10.1\t64.5 ± 10.3\t70.2 ± 7.9\t65.9 ± 8.4\t<0.001\t\nMale\t435 (44.6%)\t341 (43.7%)\t80 (46.5%)\t14 (60.9%)\t0.224\t\nBMI (kg/m2)\t25 ± 4.0\t25 ± 4.0\t24.7 ± 4.0\t25.5 ± 3.4\t0.521\t\nTreatment regimen, n (%)\t\t\t\t\t-\t\n Daclatasvir+Asunaprevir, n (%)\t93 (9.5%)\t75 (9.6%)\t15 (8.7%)\t3 (13.0%)\t\t\n Harvoni, n (%)\t120 (12.3%)\t94 (12.0%)\t26 (15.1%)\t0 (0%)\t\t\n Harvoni+Rib, n (%)\t47 (4.8%)\t37 (4.7%)\t8 (4.7%)\t2 (8.7%)\t\t\n Sofosbuvir+Rib, n (%)\t266 (27.3%)\t217 (27.8%)\t45 (26.2%)\t4 (17.4%)\t\t\n Sofosbuvir+Rib+Daclatasvir, n (%)\t49 (5.0%)\t31 (4.0%)\t14 (8.1%)\t4 (17.4%)\t\t\n Viekirax+Dasabuvir, n (%)\t252 (25.8%)\t209 (26.8%)\t37 (21.5%)\t6 (26.1%)\t\t\n Viekirax+Dasabuvir+Rib, n (%)\t32 (3.3%)\t29 (3.7%)\t3 (1.7%)\t0 (0%)\t\t\n Zepatier, n(%)\t117 (12.0%)\t89 (11.4%)\t24 (14.0%)\t4 (17.4%)\t\t\nCreatinine (mg/dL)\t1.1 ± 1.4\t1.1 ± 1.4\t1.2 ± 1.4\t1.3 ± 1.8\t0.300\t\nAFP (ng/ml)*\t5.9 (3.4–12.5)\t5.6 (3.2–10.9)\t7.6 (4–15.1)\t92.2 (10–297.1)\t<0.001\t\nAlbumin (mg/dL)\t4.2 ± 0.4\t4.2 ± 0.4\t4.0 ± 0.4\t3.7 ± 0.4\t<0.001\t\nAST (IU/L)*\t61 (43–97)\t60 (42–94)\t65 (43.5–95)\t116 (60–178)\t<0.001\t\nALT (IU/L)*\t69 (42–116)\t68 (41–116)\t67 (43–110.5)\t104 (65–145)\t0.250\t\nTotal bilirubin (mg/dL)\t1.0 ± 0.6\t1.0 ± 0.6\t1.0 ± 0.5\t1.2 ± 0.7\t0.145\t\nPlatelet (109/L)*\t131 (98–172)\t137 (102–177)\t115.5 (85–145)\t88 (60–99)\t<0.001\t\nINR\t1.1 ± 0.3\t1.1 ± 0.3\t1.1 ± 0.1\t1.1 ± 0.1\t0.820\t\nHCV genotype\t\t\t\t\t0.275\t\n 1b\t556 (57.2%)\t441 (56.5%)\t100 (58.1%)\t15 (65.2%)\t\t\n 2\t314 (32.3%)\t247 (31.6%)\t59 (34.3%)\t8 (34.8%)\t\t\n Others\t102 (10.5%)\t89 (11.4%)\t13 (7.6%)\t0 (0%)\t\t\nHCV RNA (log IU/ml)\t13.4 ± 2.1\t13.5 ± 2.1\t13.2 ± 2.1\t13.4 ± 1.9\t0.276\t\nInterferon experienced, n(%)\t274 (28.1%)\t224 (28.7%)\t46 (26.7%)\t4 (17.4%)\t0.500\t\nFinal SVR, code = 1, n(%)\t957 (98.1%)\t770 (98.6%)\t167 (97.1%)\t20 (87.0%)\t0.003\t\nAscites, n(%)\t11 (1.1%)\t9 (1.2%)\t0 (0%)\t2 (8.7%)\t0.016\t\nDecompensation, n(%)\t28 (2.9%)\t22 (2.8%)\t4 (2.3%)\t2 (8.7%)\t0.222\t\nHBsAg positive, n(%)\t57 (5.8%)\t56 (7.2%)\t1 (0.6%)\t0 (0%)\t<0.001\t\nLT, n(%)\t9 (0.9%)\t8 (1.0%)\t1 (0.6%)\t0 (0%)\t1.000\t\nHCV-HIV coinfection, n(%)\t3 (0.3%)\t3 (0.4%)\t0 (0%)\t0 (0%)\t1.000\t\nAPRI\t1.9 ± 1.8\t1.8 ± 1.6\t2.2 ± 2.0\t4.8 ± 3.9\t<0.001\t\nFIB-4\t5.0 ± 4.4\t4.5 ± 3.7\t6.3 ± 4.9\t11.7 ± 11.2\t<0.001\t\nP-value is estimated using chi-squared, Fisher’s exact or one-way ANOVA test.\n\nData are presented as mean, standard deviation or number (%).\n\n*AFP, AST, ALT and Platelet are presented as median (interquartile range)\n\nSVR, sustained virologic response; BMI, body mass index; AFP, alpha-fetoprotein\n\nSOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir; GZR/EBR, grazoprevir plus elbasvir; DCV, daclatasvir; ASV, Asunaprevir; RBV, ribavirin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; LT, liver transplantation; HIV, human immunodeficiency virus; HCC, hepatocellular carcinoma; APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis-4 index\n\nHCC patient characteristics\nThere were 195 patients with HCC. The mean age of these patients was 69.7 years, their median AFP level was 8.3 ng/ml at HCV treatment initiation, and 25.6% of the patients were treatment-experienced. Genotype 1b was the predominant genotype among these patients (59%), while the tumor characteristics of the HCC group at diagnosis are shown in Table 3. The average tumor size at HCC diagnosis was 2.6 ± 1.6 cm, and the majority of patients with a tumor present were at BCLC stage 0 or A (83.1%). Only 8 patients (4.1%) underwent liver transplantation (LT) with a pre-transplantation diagnosis of HCC, while recurrent HCC was not noted in any of those patients post-LT. Hepatic resection was performed in 57 (29.2%) patients, 143 (73.3%) patients received radiofrequency ablation (RFA), and 81 (41.5%) patients received transcatheter arterial chemoembolization (TACE).\n\n10.1371/journal.pone.0222605.t003Table 3 Tumor characteristics of patients with HCC who underwent treatment with DAA.\nHCC tumor characteristics\tHCC group (n = 195)\t\nSize (cm)\t2.6 ± 1.6\t\nNumber\t\t\n 1, N (%)\t141 (72.3%)\t\n 2–3, N (%)\t39 (20.0%)\t\n 4 or more, N (%)\t7 (3.6%)\t\n Unknown\t8 (4.1%)\t\nBCLC\t\t\n 0, N (%)\t52 (26.7%)\t\n A, N(%)\t110 (56.4%)\t\n B, N(%)\t23 (11.8%)\t\n C, N(%)\t5 (2.6%)\t\n Unknown\t5 (2.6%)\t\nTreatment received\t\t\n Resection, N (%)\t57 (29.2%)\t\n Liver transplant, N (%)\t7 (3.6%)\t\n RFA, N (%)\t143 (73.3%)\t\n TACE, N (%)\t81 (41.5%)\t\n Others, N (%)\t6 (3.1%)\t\nHCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Clinic; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization.\n\nPatients may have received multiple therapies\n\nCharacteristics of patients with active HCCs\nThe characteristics of the patients with active HCC are shown in Table 4. Twenty-three patients had active HCC at the initiation of DAA treatment. Among those patients, the tumor stage at the initiation of DAA treatment was BCLC stage B in 4 patients, BCLC stage C in 2 patients, and BCLC stage 0 or A in the remaining 17 patients. Only 3 of the patients did not achieve SVR, and 2 of those patients, both of whom had BCLC stage 0 (Table 4, case numbers 5 and 7), were treated with SOF/DCV/RBV. The third patient, who had BCLC stage C, was treated with SOF+RBV. He received concurrent sorafenib and DAA treatment (Table 4, case number 18).\n\n10.1371/journal.pone.0222605.t004Table 4 Clinical characteristics of patients with active HCCs.\nPatient\nnumber\tSex\tAge, years\tCTP\tAFP (ng/ml)\tPlatelet count (109/L)\tSVR\tRegimen\tGenotype\tInterferon experienced\tTumor number\tTumor size (cm)\tBCLC\t\n1\tM\t65\tA6\t1098\t72\tSVR\tSOF/DCV/RBV\t2\tN\t1\t2.2\tA\t\n2\tM\t68\tA6\t341\t143\tSVR\tGZR/EBR\t1b\tN\t>10\t2.3\tB\t\n3\tM\t52\tA6\t8.6\t149\tSVR\t3D\t1b\tN\t3\t1.9\tA\t\n4\tM\t70\tB9\t209\t91\tSVR\tSOF/LDV/RBV\t1b\tN\t1\t1.5\t0\t\n5\tF\t72\tA5\t7.8\t131\tNon-SVR\tSOF/DCV/RBV\t2\tN\t1\t1.1\t0\t\n6\tM\t66\tA5\t6.4\t90\tSVR\tSOF/RBV\t2\tN\t1\t1.3\t0\t\n7\tF\t71\tA6\t150\t40\tNon-SVR\tSOF/DCV/RBV\t2\tN\t1\t1.6\t0\t\n8\tF\t58\tA5\t92\t86\tSVR\tGZR/EBR\t1b\tY\t1\t2\t0\t\n9\tF\t76\tA6\t27\t60\tSVR\tGZR/EBR\t1b\tN\t4\t1.7\tB\t\n10\tM\t66\tA5\t416\t133\tSVR\t3D\t1b\tN\t1\t1.6\t0\t\n11\tF\t60\tB8\t120\t60\tSVR\tSOF/LDV/RBV\t1b\tN\t1\t2.3\tC (Post RFA, no viable tumor in liver. A seeding tumor at abdominal wall).\t\n12\tF\t48\tA5\t204\t30\tSVR\t3D\t1b\tN\t1\t1.6\t0\t\n13\tF\t66\tA5\t10\t91\tSVR\tSOF/RBV\t2\tN\t2\t1\tA\t\n14\tM\t70\tA5\t463\t88\tSVR\tGZR/EBR\t1b\tN\t1\t2\tA\t\n15\tF\t58\tA5\t31\t88\tSVR\t3D\t1b\tY\t2\t1.8\tA\t\n16\tM\t74\tA5\t77\t92\tSVR\tDCV/ASV\t1b\tN\t2\t1.4\tA\t\n17\tM\t67\tA5\t122\t61\tSVR\tDCV/ASV\t1b\tN\t5\t1.1\tB\t\n18\tM\t61\tA6\t10\t55\tNon-SVR\tSOF/RBV\t2\tN\t1\t2.3\tC (Left portal vein tumor thrombus)\t\n19\tF\t79\tA5\t10\t112\tSVR\tSOF/DCV/RBV\t2\tN\t2\t1.5\tA\t\n20\tM\t59\tA5\t44\t58\tSVR\tSOF/RBV\t2\tN\t2\t1.5\tA\t\n21\tM\t72\tA5\t1044\t63\tSVR\tDCV/ASV\t1b\tY\t>5\t3\tB\t\n22\tM\t75\tA5\t15\t76\tSVR\t3D\t1b\tY\t1\t1.8\t0\t\n23\tM\t52\tA5\t297\t99\tSVR\t3D\t1b\tN\t1\t1.5\t0\t\nHCCs, hepatocellular carcinomas; CTP, Child–Turcotte–Pugh; LSM, liver stiffness measurement by transient elastography; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir; GZR/EBR, grazoprevir plus elbasvir; DCV, daclatasvir; ASV, Asunaprevir; RBV, ribavirin; BCLC, Barcelona Clinic Liver Cancer; RFA, radiofrequency ablation\n\nNon-SVR rate by regimen\nThe HCV treatment regimens used for all the patients are shown in Table 2. SOF/RBV for 12 weeks was the most common regimen (27%), followed by 3D for 12 weeks (25.8%), LDV/SOF (12.3%) for 12 weeks, and GZR/EBR (12.0%) for 12 weeks. Thirty-two (3.3%) patients were treated with 3D+RBV (the treatment duration was 12 weeks in 12 patients, 24 weeks in 20 patients); all of those patients were genotype 1a and all achieved SVR. No patients received more than 12 weeks of GZR/EBR treatment.\n\nThe patients with HCC were compared to those without HCC regarding specific DAA regimens (Fig 1). For patients treated with DCV/ASV, non-SVR was noted in 1 HCC patient (5.6%), while all of the non-HCC patients achieved SVR. For patients treated with LDV/SOF, all of the HCC patients achieved SVR, while non-SVR was noted in one (1.1%) of the non-HCC patients. For patients treated with LDV/SOF+RBV and 3D+RBV, all of the patients (including all of the HCC and non-HCC patients) achieved SVR. For patients treated with SOF+DCV+ RBV, non-SVR was noted in 3 (16.7%) HCC patients, while all of the non-HCC patients achieved SVR. For patients treated with SOF/RBV, non-SVR was noted in 4 HCC patients (8.2%), while non-SVR was noted in 8 (3.7%) of the non-HCC patients. For patients treated with 3D, all of the HCC patients achieved SVR, while non-SVR was noted in 1 (0.5%) of the non-HCC patients. For patients treated with GZR/EBR, all of the HCC patients achieved SVR, while non-SVR was noted in 1 (1.1%) of the non-HCC patients.\n\n10.1371/journal.pone.0222605.g001Fig 1 Non-SVR rate of DAA therapy by treatment regimen received.\nSOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir; GZR/EBR, grazoprevir plus elbasvir; DCV, daclatasvir; ASV, Asunaprevir;\n\nThe comparison of SVR rates between patients with and without HCC stratified by genotype and treatment regimen were shown in S1 Table. The SVR rates were not significantly different between patients with and without HCC stratified by genotype and treatment regimen except in genotype 2 patients treated with SOF+DCV+RBV for 12 weeks.\n\nClinical characteristic of patients with non-SVR\nThe clinical characteristic of the patients with non-SVR are shown in Table 5. Twelve patients were treated with SOF and RBV for 12 weeks. Among these patients, 5 patients had an LSM >13ka (the cutoff value of METAVIR F4) [13–15], and 2 patients had active HCC. Seven patients were treated with a regimen other than SOF and RBV. Among these patients, 4 patients had an LSM >13 kPa, and 2 patients had active HCC.\n\n10.1371/journal.pone.0222605.t005Table 5 Characteristics of patients with non-SVR.\nPatient\nnumber\tSex\tAge, years\tCTP\tHCCs\tLSM (kPa)\tPlatelet count (109/L)\tSplenomegaly\tRegimen\tGenotype\tInterferon experienced\t\n1\tF\t51\tA5\tN\t11.5\t186\tN\tGZR/EBR\t1b\tN\t\n2\tM\t60\tA5\tY, inactive, post liver transplant\tNA\t270\tN\tSOF/RBV\t2\tN\t\n3\tF\t72\tA5\tN\tNA\t100\tY\tSOF/RBV\t2\tY\t\n4\tM\t61\tA5\tY, active\t21.5\t55\tY\tSOF/RBV\t2\tN\t\n5\tM\t52\tA5\tN\t21.5\t246\ts/p splenectomy\tSOF/RBV\t2\tN\t\n6\tF\t72\tA6\tY, active\tNA\t40\tY\tSOF/RBV/DCV\t2\tN\t\n7\tM\t61\tA5\tY, inactive\t27\t105\tN\tSOF/RBV/DCV\t2\tY\t\n8\tF\t73\tA5\tY, active\t22\t131\tN\tSOF/RBV/DCV\t2\tN\t\n9\tF\t80\tA5\tN\t45\t121\tN\tSOF/RBV\t2\tN\t\n10\tM\t82\tA5\tY, active\t40\t130\tY\tSOF/RBV\t2\tN\t\n11\tM\t59\tA5\tN\t27\t127\tY\tSOF/LDV\t6\tN\t\n12\tF\t64\tA5\tN\t27\t62\tY\tSOF/RBV\t2\tN\t\n13\tF\t67\tA5\tN\t12\t132\tN\tSOF/RBV\t2\tY\t\n14\tF\t65\tA5\tN\t7.8\t152\tN\tSOF/RBV\t2\tN\t\n15\tM\t59\tA5\tY, inactive\t15.5\t158\tN\tSOF/RBV\t2\tY\t\n16\tM\t66\tA5\tN\t21.3\t170\tN\t3D\t1b\tY\t\n17\tM\t58\tA5\tY, inactive\tNA\t118\tY\tSOF/RBV\t2\tN\t\n18\tM\t63\tA5\tN\t7.8\t82\tY\tSOF/RBV\t2\tY\t\n19\tF\t55\tA6\tY, inactive\tNA\t227\tN\tDCV/ASV\t1b\tN\t\nHCCs, hepatocellular carcinomas; CTP, Child–Turcotte–Pugh; LSM, liver stiffness measurement by transient elastography; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir; GZR/EBR, grazoprevir plus elbasvir; DCV, daclatasvir; ASV, Asunaprevir; RBV, ribavirin; NA, not available; Y, yes; N, No\n\nUnivariate predictors of non-SVR\nThe univariate predictors of non-SVR are shown in Table 6. The proportion of patients with genotype 2, proportion of patients with a history of HCC, proportion of patients with active HCC, and proportion of patients who were treated with the inadequate regimen (SOF+RBV) were higher in the non-SVR group; AST levels were higher in the non-SVR group.\n\n10.1371/journal.pone.0222605.t006Table 6 Univariate predictors of non-SVR.\nCharacteristics\tSVR, N = 957\tNon-SVR, N = 19\tP\t\nAge (years)\t65.5 ± 10.1\t64.4 ± 8.5\t0.48\t\nMale\t425 (44.4%)\t10 (52.6%)\t0.61\t\nBMI (kg/m2)\t25.0 ± 4.0\t25.6 ± 5.1\t0.55\t\nTreatment regimen, n (%)\t\t\t0.01\t\n DCV/ASV, n (%)\t92 (9.6%)\t1 (5.3%)\t\t\n SOF/LDV, n (%)\t119 (12.4%)\t1 (5.3%)\t\t\n SOF/LDV+RBV, n (%)\t47 (4.9%)\t0 (0.0%)\t\t\n SOF+RBV, n (%)\t254 (26.5%)\t12 (63.2%)\t\t\n SOF+DCV+RBV, n (%)\t46 (4.8%)\t3 (15.8%)\t\t\n 3D, n (%)\t251 (26.2%)\t1 (5.3%)\t\t\n 3D+RBV, n (%)\t32 (3.3%)\t0 (0.0%)\t\t\n GZR/EBR+RBV, n (%)\t-\t-\t\t\n GZR/EBR, n(%)\t114 (11.9%)\t3 (15.8%)\t\t\nCreatinine (mg/dl)\t1.1 ± 1.4\t0.8 ± 0.2\t0.41\t\nAFP (ng/ml)\t5.9 (3.4–12.5)\t6.5 (4.2–24.2)\t0.92\t\nAlbumin (mg/dl)\t4.2 ± 0.4\t4.1 ± 0.5\t0.34\t\nAST (IU/L)\t61 (43–95)\t83 (44–162)\t0.03\t\nALT (IU/L)\t68 (42–114)\t101 (52–145)\t0.16\t\nTotal bilirubin (mg/dl)\t1.0 ± 0.6\t1.0 ± 0.5\t0.72\t\nPlatelet (109/L)\t131 (98–172)\t130 (100–170)\t0.97\t\nINR\t1.1 ± 0.3\t1.1 ± 0.1\t0.77\t\nHCV genotype\t\t\t<0.001\t\n 1b\t553 (57.8%)\t3 (15.8%)\t\t\n 2\t299 (31.2%)\t15 (78.9%)\t\t\n Others\t101 (10.6%)\t1 (5.3%)\t\t\nHCV RNA (log IU/ml)\t13.4 ± 2.1\t13.9 ± 2.6\t0.35\t\nInterferon experienced, n(%)\t268 (28.0%)\t6 (31.6%)\t0.73\t\nAscites, n(%)\t11 (1.1%)\t0 (0.0%)\t0.81\t\nDecompensation, n(%)\t28 (2.9%)\t0 (0.0%)\t0.45\t\nHBsAg positive, n(%)\t55 (5.7%)\t2 (10.5%)\t0.31\t\nLT, n(%)\t14 (1.5%)\t1 (5.3%)\t0.16\t\nHCV-HIV coinfection, n(%)\t3 (0.3%)\t0 (0.0%)\t0.94\t\nHCC, n(%)\t187 (19.5%)\t8 (42.1%)\t0.02\t\nActive HCC, n(%)\t20 (2.1%)\t3 (15.8%)\t0.009\t\nSVR, sustained virologic response; BMI, body mass index; AFP, alpha-fetoprotein\n\nSOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir; GZR/EBR, grazoprevir plus elbasvir; DCV, daclatasvir; ASV, Asunaprevir; RBV, ribavirin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; LT, liver transplantation; HIV, human immunodeficiency virus; HCC, hepatocellular carcinoma.\n\nMultivariable predictors of non-SVR\nThe multivariable predictors of non-SVR are shown in Table 7, the data for which were provided through Model A of our per-protocol (PP) analysis. There were 781 patients without HCC, 172 patients with inactive HCC, and 23 patients with active HCC enrolled in the multivariate analysis. Non-SVR was noted in 5 (2.9%) patients with inactive HCC, 4 (13.0%) patients with active HCC, and 10 (1.3%) patients without HCC. After adjustment for confounders, active HCC (versus inactive HCC and non-HCC) was associated with non-SVR (adjusted odds ratio [AOR]: 24.5 (95% confidence interval [CI]: 4.4–136.9), P<0.001).\n\n10.1371/journal.pone.0222605.t007Table 7 Multivariable predictors of non-SVR.\nCovariate\tModel A\tModel B\tModel C\t\nOR\t95% CI\tP\tOR\t95% CI\tP\tOR\t95% CI\tP\t\nAge (per year)\t0.98\t0.93–1.02\t0.35\t0.96\t0.91–1.01\t0.12\t1.03\t1.00–1.07\t0.05\t\nGender, male vs. female\t1.24\t0.47–3.25\t0.67\t1.47\t0.51–4.28\t0.48\t0.79\t0.43–1.44\t0.44\t\nDecompensated cirrhosis, yes vs. no\t-\t\t\t-\t\t\t1.88\t0.40–8.84\t0.43\t\nPlatelet, <100 vs. ≥100 (109/L)\t0.38\t0.09–1.55\t0.18\t0.41\t0.09–1.90\t0.26\t0.68\t0.34–1.36\t0.28\t\nHCC*, yes vs. no\t24.47\t4.37–136.93\t<0.001\t3.07\t0.94–9.95\t0.06\t2.82\t1.53–5.20\t0.001\t\nTreatment regimen, SOF+RBV vs. others\t6.79\t2.44–18.84\t<0.001\t8.5\t2.76–26.21\t<0.001\t1.66\t0.91–3.04\t0.100\t\nInterferon experienced, yes vs.no\t1.96\t0.70–5.52\t0.20\t2.17\t0.74–6.32\t0.16\t1.05\t0.54–2.04\t0.88\t\nModel A: per protocol analysis. HCC*: active HCC versus inactive HCC and non-HCC. All patients with decompensated cirrhosis achieved SVR\n\nModel B: per protocol analysis. HCC*: inactive HCC versus non-HCC. All patients with decompensated cirrhosis achieved SVR\n\nModel C: intention to treat analysis, HCC*: HCC versus non-HCC\n\nHCC, hepatocellular carcinoma; SVR, sustained virologic response; SOF, sofosbuvir; RBV, ribavirin.\n\nIn Model B of our PP analysis, we excluded the 23 patients with active HCC; there were thus 781 patients without HCC and 172 patients with a history of inactive HCC enrolled into this multivariate analysis. After adjustment for confounders, a history of inactive HCC was not associated with non-SVR (AOR: 3.1(95% CI = 0.94–9.95), P = 0.062).\n\nModel C consisted of an intention to treat (ITT) analysis. We excluded 1 patient with HCC combined with cholangiocarcinoma and 1 patient with virologic relapse due to malpractice (Table 1, case numbers 44 and 45). We then enrolled 43 patients who were initially excluded from the PP analysis (Table 1, case numbers 1–43) into this analysis. Overall, there were 215 patients with HCC and 804 patients without HCC included in the analysis. Non-SVR was noted in 24 (11.2%) of the patients with HCC and 28 (3.5%) of the patients without HCC. After adjustment for confounders, HCC (AOR: 2.8(95% CI: 1.5–5.2), P = 0.001) was associated with non-SVR.\n\nDiscussion\nSeveral factors are reportedly associated with DAA treatment failure, including cirrhosis, inadequate drug regimens, and adherence [16–21]. Regarding cirrhosis, Prenner et al. conducted a retrospective study on cirrhotic patients who were treated with DAAs. In that study, cirrhosis was defined by one of the following: liver biopsy, TE >12.5 kPa, acoustic radiation force impulse (ARFI) >2.0 m/s, magnetic resonance elastography >5 kPa, or FibroSURETM testing [22]. Among these non-invasive tests, only TE is available in our hospital. However, TE can be inaccurate in HCC patients with tumors located at the right lobe of the liver or who have undergone right hepatectomy. Few patients underwent liver biopsy in our cohort, and histology results were available mainly for those who underwent resection for HCC. Therefore, we did not include cirrhosis as a covariate in the multivariate analysis. Instead, we used substages and substage indicators of cirrhosis such as platelet count <100 (109/L)(surrogate marker of clinical significant portal hypertension)[23] and decompensated cirrhosis as covariates in the multivariate analysis. Regarding inadequate regimens, SOF/RBV for 12 weeks is an inadequate regimen for genotype 2 patients with cirrhosis [7]. Therefore, SOF/RBV versus other regimens was included as a covariate in the multivariate analysis. Regarding adherence, we used a PP analysis in this study.\n\nActive HCC was associated with non-SVR by the PP analysis. The possible mechanisms include the possibilities that HCC may lead to distortion of the liver architecture and decreased DAA delivery and that HCC may function as a reservoir for HCV replication [24, 25].\n\nA history of inactive HCC was not associated with non-SVR according to the PP analysis conducted in our study. In contrast, a previous study reported that a history of inactive HCC was associated with DAA treatment failure. However, the authors of that study did not mention whether their result was based on an ITT or PP analysis [26].\n\nFurthermore, we performed an ITT analysis. We enrolled 43 patients who were initially excluded from the PP analysis (Table 1, case numbers 1–43) into this ITT analysis. Among those 43 patients, 20 were patients with HCC, and non-SVR was noted in 17 of these patients with HCC. Of the remaining 195 patients with HCC who completed DAA treatment, non-SVR was noted in only 8 patients. Therefore, HCC was associated with DAA treatment failure mainly due to the intolerance of DAA treatments.\n\nRegarding specific DAA regimens in HCC patients, the non-SVR rate was highest in the patients treated with SOF+DCV+RBV for 12 weeks. Three (16.7%) patients were non-SVR after being treated with this regimen (Table 5, case numbers 6–8), two of the non-SVR patients had active HCC, and all of the non-SVR patients had clinically significant portal hypertension defined by either platelet count < 100 (109/L) and splenomegaly or LSM> 20kPa [23, 27]. Real-world data from Taiwan have shown high SVR rates with this regimen in genotype 2 patients with advanced fibrosis (98.5% and 100%, respectively) [28, 29]. Therefore, the higher non-SVR rate with this regimen in our study was due to advanced cirrhosis and active HCC. The non-SVR rate was the second highest in patients treated with SOF/RBV for 12 weeks. Four (8.2%) patients were non-SVR after being treated with this regimen. 100% SVR was noted in HCC patients treated with LDV/SOF, 3D, and GZR/EBR, although the numbers of such patients were limited.\n\nPrenner et al. conducted a retrospective cohort study that enrolled cirrhotic patients treated with DAA in a LT center [22]. In their multivariable analysis, active HCC at the time of DAA initiation was associated with non-SVR. That result was compatible with our study. However, there were also some differences between Prenner’s study and our study. Firstly, more advanced liver disease was noted in Prenner’s study; all of the patients were cirrhotic and 26% of the patients had decompensated cirrhosis. In contrast, while all of the patients in our study had advanced fibrosis, only 2.9% had decompensated cirrhosis. Secondly, a higher proportion of patients were treated with inadequate regimens such as SOF/simeprevir for 12 weeks (46%) in Prenner’s study. In contrast, an inadequate regimen (SOF/RBV for 12 weeks) was used to treat only 27.3% of the patients in our study. This difference could explain the higher non-SVR rate in Prenner’s (14.7%) study compared with our study (1.9%).\n\nIn another study, Beste, et al. examined SVR rates among veterans with and without HCC. In that study, the rate of SVR was 91.9% in non-HCC patients, 74.5% in HCC patients, and 93.4% in patients with a pre-LT diagnosis of HCC who underwent LT. This data was abstracted from a corporate data warehouse, with each diagnosis of HCC being obtained using the International Classification of Diseases (ICD) codes. Therefore, the number of patients with active HCC could not be evaluated in that study. Meanwhile, the patients in the HCC group who were treated with DAAs after LT had similar failure rates to those without HCC. Based on these findings, Beste, et al. recommended that the deferral of DAA treatment until the post-LT setting may be considered among HCC patients listed for LT [30]. However, due to the extreme shortage of deceased donors in Taiwan, the deferral of DAA treatment until the post-LT setting in not feasible in Taiwan.\n\nIn terms of clinical application, the findings of our study include several key points: first, the patients with HCC were older and had more advanced liver disease, and the association of HCC with non-SVR was mainly due to the HCC patients being more intolerant of DAA treatment. Second, active HCC was associated with non-SVR in the PP analysis, while inactive HCC was not. We thus recommend that DAA treatment be commenced after a complete radiological response to HCC treatment has been achieved. Although liver decompensation is the major driver of death in HCV-related HCC patients [31], no evidence supports the conclusion that patients with active HCC gain a survival benefit after DAA treatment. Current guidelines also recommend DAA treatment in those who have undergone curative treatment for HCC [12].\n\nThe strength of this study is that it was a retrospective study with prospectively collected data. Due to the high cost of DAAs, the patients and physicians in Taiwan were informed that they must comply with the regulations of the NHIA. Therefore, only one patient who was alive at follow-up week 12 with an unknown SVR outcome was noted in this cohort, and there was no missing data for the cohort enrolled in the PP analysis. Secondly, we comprehensively examined the possible mechanisms for HCC with DAA treatment failure. According to our ITT analysis, HCC was associated with non-SVR due to the HCC patients being more intolerant of DAA treatment. According to our PP analysis, active HCC was associated with non-SVR, while inactive HCC was not.\n\nOur study had several limitations. Firstly, around 40% of the patients in our cohort received first generation all-oral DAA regimens (DCV/ASV, SOF/RBV, SOF/DCV/RBV), which are no longer recommended by current guidelines [12]. Future studies with the currently recommended DAA therapies will thus be needed to confirm the findings of the present study. Secondly, the most important cofounder associated with non-SVR is the presence of cirrhosis [12]. However, TE is not feasible in patients with HCC. Therefore, we recommend that ARFI, which has a high diagnostic accuracy, be used to evaluate cirrhosis in patients with or without HCC in future studies [32]. Thirdly, the reimbursements from the NHIA in Taiwan allow us to aggressively treat HCV-infected patients, including patients with active HCC or a limited life expectancy. The findings of this study thus may not be generalizable to other countries that only treat patients as recommended by the guideline [12].\n\nIn conclusion, in this study, the patients with HCC were older and had more advanced liver disease, which led them to be relatively intolerant of DAA treatment and caused a lower SVR rate. Furthermore, active HCC was associated with non-SVR, while inactive HCC was not, so we suggest the deferral of DAA treatment until after complete radiological response to HCC treatment has been achieved.\n\nSupporting information\nS1 Data raw data.\n(XLSX)\n\nClick here for additional data file.\n\n S1 Table The comparison of SVR rates between patients with and without HCC stratified by genotype and treatment regimen.\n(DOCX)\n\nClick here for additional data file.\n\n 10.1371/journal.pone.0222605.r001Decision Letter 0 Lin Wenyu Academic Editor© 2019 Wenyu Lin2019Wenyu LinThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Submission Version0\n28 Jul 2019\n\n\nPONE-D-19-19092\n\nActive hepatocellular carcinoma is an independent risk factor of direct-acting antiviral treatment failure: a retrospective study with prospectively collected data\n\nPLOS ONE\n\nDear Dr Hu,\n\nThank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised by two reviewers during the review process.\n\nWe would appreciate receiving your revised manuscript by Sep 11 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.\n\nIf you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.\n\nTo enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols\n\nPlease include the following items when submitting your revised manuscript:\n\nA rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.\n\nA marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.\n\nAn unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.\n\n\n\nPlease note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.\n\nWe look forward to receiving your revised manuscript.\n\nKind regards,\n\nWenyu Lin, PhD\n\nAcademic Editor\n\nPLOS ONE\n\nJournal Requirements:\n\nWhen submitting your revision, we need you to address these additional requirements.\n\nPlease ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at\n\nhttp://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf\n\n1. Thank you for including the following funding information within the acknowledgements section of your manuscript; \"This study was supported by Grant CMRPG8H1331 from the Chang Gung Memorial\n\nHospital-Kaohsiung Medical Center, Taiwan. The funders had no role in study design,\n\ndata collection and interpretation, or the decision to submit the work for publication.\"\n\nWe note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.\n\nPlease remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:\n\n\"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript\"\n\n[Note: HTML markup is below. Please do not edit.]\n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. \n\nReviewer #1: Partly\n\nReviewer #2: Yes\n\n**********\n\n2. Has the statistical analysis been performed appropriately and rigorously? \n\nReviewer #1: I Don't Know\n\nReviewer #2: Yes\n\n**********\n\n3. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n4. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n5. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: The study aimed to investigate the association of active hepatocellular carcinoma (HCC) with DAA treatment failure. There are some problems in this study and below are my comments:\n\n1. There are many active HCV related HCC patients (hundreds) in the hospital, but the authors only enroll 23 patients with active HCCs.DAA is not recommened for HCV with active HCC if life span was expected to be less than 6 months, how do the authors select which active HCC patients with HCV receive DAA. The selection bias may impact the result of the study.\n\n2. The authors should compare the difference of baseline characters in non-HCC, inactive HCC and active HCC patients and revised in Table 2.\n\n3. The study had as high as 41.5% of HCC patients received TACE before DAA Tx. TACE usually resulted in a low complete response rates in HCC patients. This in unexpected, how do the authors explain the high percentage of TACE here?\n\n4. In table 6, the percentage of SVR vs non-SVR should be revised in several variates including tx regimen, genotype, HCC, active HCC etc.\n\n5. In table 6, the authors should also include cirrhosis status ( not only decomepnsated) and fibrosis stage ( eg,using FIB-4) into univariate analysis and if significant, add into multivariate analyais.\n\n6. Decompensated cirrhosis is believed to be associated with lower SVR in many studies, but why pts with decompensated cirrhosis have 100% SVR in this study.\n\n7. In table 7. Some were analyzed in per protocol tx some in intention to treat, both per protocol and intention to treat should be analyzed in different group of patients.\n\n8. In table 7, why genotype which is significant in univariate analysis is not included in multivariate analysis. Only 26.5% of patients received SOF/RBV, why the authors chose SOF/RBV vs non SOF/RBV in multivariate analysis in stead of SOF based vs non-SOF based regimen.\n\n9. 172 had inactive HCC, and 23 had active HCC in this study. But in table 7, there were 215 patients with HCC and 804 patients without HCC included in the analysis. How do the authors explain the difference.\n\nReviewer #2: The author thoroughly analyzed the prediction power of active HCC on the success of anti-virus treatment. The data is well organized and presented in an logic way. There are no major concern about the paper, just a few suggestions that might be helpful\n\n1 Any immunological reason that cause failure of DAAs? most of the HCC patients are very weak and through intense treatment, would the author supply more data about their immune system?\n\n2 Would the comparison be carried between non-HCC and HCC with same serum type and same treatment? This might be more precise to define the prediction power of HCC, exclude confounding problem caused by serum type and treatment regime.\n\n**********\n\n6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #1: No\n\nReviewer #2: No\n\n[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files to be viewed.]\n\nWhile revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.\n\n10.1371/journal.pone.0222605.r002Author response to Decision Letter 0 Submission Version1\n6 Aug 2019\n\n\nReviewer #1: The study aimed to investigate the association of active hepatocellular carcinoma (HCC) with DAA treatment failure. There are some problems in this study and below are my comments:\n\n1. There are many active HCV related HCC patients (hundreds) in the hospital, but the authors only enroll 23 patients with active HCCs. DAA is not recommened for HCV with active HCC if life span was expected to be less than 6 months, how do the authors select which active HCC patients with HCV receive DAA. The selection bias may impact the result of the study.\n\nResponse: Thank you so much for your comments. The National Health Insurance Administration (NHIA) of Taiwan has provided reimbursements for DAAs since January 2017 for HCV-infected patients with advanced fibrosis. Advanced fibrosis was defined as the presence of any one of the following: transient elastography (TE) with a liver stiffness measurement (LSM) ≥ 9.5Kpa [3], a Fibrosis-4 (FIB-4) score ≥ 3.25 [4], a liver biopsy showing advanced fibrosis (METAVIR fibrosis score ≥ 3) [5], ultrasound-identified liver cirrhosis with splenomegaly, or endoscopy showing gastroesophageal varices. Please see page 5, 1st paragraph. Patients with active HCC were not excluded from reimbursement if they had advanced fibrosis. \n\n2. The authors should compare the difference of baseline characters in non-HCC, inactive HCC and active HCC patients and revised in Table 2.\n\nResponse: Thank you so much for your comments. We have compare the difference of baseline characters in non-HCC, inactive HCC and active HCC patients and revised in Table 2. Compared to the inactive HCC and non-HCC patients, the patients with active HCC had higher alpha-fetoprotein (AFP), aspartate aminotransferase-to-platelet ratio index (APRI), and FIB-4 levels; and had lower albumin and platelet levels, a lower SVR rate and higher proportion of patients with ascites. Please see page 19, last 5 lines.\n\n3. The study had as high as 41.5% of HCC patients received TACE before DAA Tx. TACE usually resulted in a low complete response rates in HCC patients. This in unexpected, how do the authors explain the high percentage of TACE here?\n\nResponse: Thank you so much for your comments. In our daily practice, patients may have received multiple therapies. We performed radiofrequency ablation for patients received TACE with incomplete radiological response. \n\n4. In table 6, the percentage of SVR vs non-SVR should be revised in several variates including tx regimen, genotype, HCC, active HCC etc.\n\nResponse: Thank you so much for your comments. We have provided the percentage of SVR vs non-SVR in several variates including tx regimen, genotype, HCC, active HCC in table 6.\n\n5. In table 6, the authors should also include cirrhosis status ( not only decomepnsated) and fibrosis stage ( eg,using FIB-4) into univariate analysis and if significant, add into multivariate analyais.\n\nResponse: Thank you so much for your comments. Prenner et al. conducted a retrospective study on cirrhotic patients who were treated with DAAs. In that study, cirrhosis was defined by one of the following: liver biopsy, TE >12.5 kPa, acoustic radiation force impulse (ARFI) >2.0 m/s, magnetic resonance elastography >5 kPa, or FibroSURETM testing [22]. Among these non-invasive tests, only TE is available in our hospital. However, TE can be inaccurate in HCC patients with tumors located at the right lobe of the liver or who have undergone right hepatectomy. Few patients underwent liver biopsy in our cohort, and histology results were available mainly for those who underwent resection for HCC. Therefore, we did not include cirrhosis as a covariate in the multivariate analysis. Please see page 46, 1st paragraph.\n\nIn our previous studies enrolled more than 1700 treatment-naïve chronic hepatitis C patients who underwent liver biopsy prior to interferon therapy. Using liver biopsy as reference, the diagnostic accuracy of AST to Platelet Ratio Index (APRI) and FIB-4 to predict advanced fibrosis (≥F3) and cirrhosis (F4) are suboptimal (area under receiver operating characteristic curve (AUROC) around 0.70) [1], the diagnostic accuracy of \n\nultrasound-identified cirrhosis is poor (AUROC=0.66) [2]. \n\nFurther, the use of APRI and FIB-4 entails a risk of overestimating the fibrosis stage due to the impact of necroinflammatory activity on transaminases. In our previous study, we stratified the enrolled patients into the categories of AST≤37 IU/L (N=132), 37<AST≤74 IU/L, (N=501), 74<AST≤148 IU/L (N=737), and AST>148 IU/L (N=346). The upper limit for normal AST in our hospital is 37 IU/L. The cutoff values of FIB-4 to predict ≥F3 are 1.4, 2.2, 3.2, and 5.2 in the categories of AST≤37 IU/L, 37<AST≤74 IU/L, 74<AST≤148 IU/L, and AST>148 IU/L. Significant variations in the cutoff values of FIB-4 to predict ≥F3 were noted in patients stratified by AST level [1].\n\nReference: \n\n1. Yen YH, Kuo FY, Kee KM, Chang KC, Tsai MC, Hu TH, et al. APRI and FIB-4 in the evaluation of liver fibrosis in chronic hepatitis C patients stratified by AST level. PLoS One. 2018 Jun 28;13(6):e0199760.\n\n2. Yen YH, Kuo FY, Chen CH, Hu TH, Lu SN, Wang JH, et al. Ultrasound is highly specific in diagnosing compensated cirrhosis in chronic hepatitis C patients in real world clinical practice. Medicine (Baltimore). 2019 Jul;98(27):e16270. \n\n6. Decompensated cirrhosis is believed to be associated with lower SVR in many studies, but why pts with decompensated cirrhosis have 100% SVR in this study.\n\nResponse: Thank you so much for your comments. The lower SVR rates in patients with decompensated cirrhosis as compared to patients with compensated cirrhosis in other studies were due to treatment discontinuations rather than virological failures [1]. In our study, two patients with decompensated cirrhosis received DAA treatment died during treatment or before follow up week 12, the SVR outcome of both patients were unknown. Please see table 1, case number 38 and 42. Twenty-eight patients with decompensated cirrhosis completed the treatment course and follow up and all patients achieved SVR. \n\nReference: 1. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. 2018;69:461-511\n\n7. In table 7. Some were analyzed in per protocol tx some in intention to treat, both per protocol and intention to treat should be analyzed in different group of patients.\n\nResponse: Thank you so much for your comments.\n\nMultivariable Predictors of Non-SVR were shown in Table 7. Covariates in the multivariable model were chosen a priori for clinical importance. The potential confounders included age, gender, platelet count, prior history of interferon-based treatment, CTP class, and DAA regimen. Please see page 18, 2nd paragraph, line 5-8. \n\nSeveral factors are reportedly associated with DAA treatment failure, including cirrhosis, inadequate drug regimens, and adherence [16-21]. Regarding cirrhosis, Prenner et al. conducted a retrospective study on cirrhotic patients who were treated with DAAs. In that study, cirrhosis was defined by one of the following: liver biopsy, TE >12.5 kPa, acoustic radiation force impulse (ARFI) >2.0 m/s, magnetic resonance elastography >5 kPa, or FibroSURETM testing [22]. Among these non-invasive tests, only TE is available in our hospital. However, TE can be inaccurate in HCC patients with tumors located at the right lobe of the liver or who have undergone right hepatectomy. Few patients underwent liver biopsy in our cohort, and histology results were available mainly for those who underwent resection for HCC. Therefore, we did not include cirrhosis as a covariate in the multivariate analysis. Instead, we used substages and substage indicators of cirrhosis such as platelet count <100 (109/L)［surrogate marker of clinical significant portal hypertension］[23] and decompensated cirrhosis as covariates in the multivariate analysis. Regarding inadequate regimens, SOF/RBV for 12 weeks is an inadequate regimen for genotype 2 patients with cirrhosis [7]. Therefore, SOF/RBV versus other regimens was included as a covariate in the multivariate analysis. Regarding adherence, we used a PP analysis in this study. Please see page 46. \n\n8. In table 7, why genotype which is significant in univariate analysis is not included in multivariate analysis. Only 26.5% of patients received SOF/RBV, why the authors chose SOF/RBV vs non SOF/RBV in multivariate analysis in stead of SOF based vs non-SOF based regimen.\n\nResponse: Thank you so much for your comments. Covariates in the multivariable model were chosen a priori for clinical importance. The potential confounders included age, gender, platelet count, prior history of interferon-based treatment, CTP class, and DAA regimen. Please see page 18, 2nd paragraph, line 5-8. Genotype is significant in univariate analysis of non-SVR is due to most of the non-SVR cases were genotype 2 patients who received inadequate regimen (i.e. SOF/RBV 12 weeks in cirrhotic patients). In contrast, SOF/DCV/RBV is not in inadequate regimen. Therefore, we did not chose SOF based vs non-SOF based regimen in multivariate analysis. \n\n9. 172 had inactive HCC, and 23 had active HCC in this study. But in table 7, there were 215 patients with HCC and 804 patients without HCC included in the analysis. How do the authors explain the difference.\n\nResponse: Thank you so much for your comments.\n\nthe data for which were provided through Model A of our per-protocol (PP) analysis. There were 781 patients without HCC, 172 patients with inactive HCC, and 23 patients with active HCC enrolled in the multivariate analysis. Please see page 42, first paragraph. \n\nModel C consisted of an I ntention to treat (ITT) analysis. We excluded 1 patient with HCC combined with cholangiocarcinoma and 1 patient with virologic relapse due to malpractice (Table 1, case numbers 44 and 45). We then enrolled 43 patients who were initially excluded from the PP analysis (Table 1, case numbers 1-43) into this analysis. Overall, there were 215 patients with HCC and 804 patients without HCC included in the analysis. Please see page 42 last paragraph and page 43 first paragraph.\n\nReviewer #2: The author thoroughly analyzed the prediction power of active HCC on the success of anti-virus treatment. The data is well organized and presented in an logic way. There are no major concern about the paper, just a few suggestions that might be helpful\n\n1 Any immunological reason that cause failure of DAAs? most of the HCC patients are very weak and through intense treatment, would the author supply more data about their immune system?\n\nResponse: Thank you so much for your comments.\n\nFrom genome-wide associated studies, single-nucleotide polymorphisms (SNPs) near the interleukin (IL) 28B locus have also shown association with treatment response with pegylated interferon and ribavirin therapy in patients with genotype 1 hepatitis C [1]. Slightly higher SVR rates have been seen in patients with the favorable IL28B genotype CC compared with those with TT in interferon-free DAA trials [2]; however, appropriately powered studies designed to assess this are still lacking. Our study is a retrospective study using chart review, we do not have data about their immune system.\n\nReferences: \n\n1. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399–401.\n\n2. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A,et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in nonresponders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014;384:1756–65.\n\n2 Would the comparison be carried between non-HCC and HCC with same serum type and same treatment? This might be more precise to define the prediction power of HCC, exclude confounding problem caused by serum type and treatment regime.\n\n Response: Thank you so much for your comments. The comparison of SVR rates between patients with and without HCC stratified by genotype and treatment regimen were shown in supplementary table 1. The SVR rates were not significantly different between patients with and without HCC stratified by genotype and treatment regimen except in genotype 2 patients treated with SOF+DCV+RBV for 12 weeks.\n\nAttachment Submitted filename: Response to Reviewers.docx\n\nClick here for additional data file.\n\n 10.1371/journal.pone.0222605.r003Decision Letter 1 Lin Wenyu Academic Editor© 2019 Wenyu Lin2019Wenyu LinThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Submission Version1\n4 Sep 2019\n\n\n[EXSCINDED]\n\nActive hepatocellular carcinoma is an independent risk factor of direct-acting antiviral treatment failure: a retrospective study with prospectively collected data\n\nPONE-D-19-19092R1\n\nDear Dr. Hu,\n\nWe are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.\n\nWithin one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.\n\nShortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the \"Update My Information\" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.\n\nIf your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.\n\nWith kind regards,\n\nWenyu Lin, PhD\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments (optional):\n\nThe authors have adequately addressed the comments raised by two reviewers. The manuscript is suitable to publish in Plos One.\n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your \"Accept\" recommendation.\n\nReviewer #2: All comments have been addressed\n\n**********\n\n2. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. \n\nReviewer #2: Yes\n\n**********\n\n3. Has the statistical analysis been performed appropriately and rigorously? \n\nReviewer #2: Yes\n\n**********\n\n4. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #2: Yes\n\n**********\n\n5. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #2: Yes\n\n**********\n\n6. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #2: the author well addressed all concerns rised by the reveiwers, data is solid and logically organized, the manuscripts meets publication criterias, should be suggested to publish.\n\n**********\n\n7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #2: No\n\n10.1371/journal.pone.0222605.r004Acceptance letter Lin Wenyu Academic Editor© 2019 Wenyu Lin2019Wenyu LinThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n10 Sep 2019\n\n\nPONE-D-19-19092R1 \n\nActive hepatocellular carcinoma is an independent risk factor of direct-acting antiviral treatment failure: a retrospective study with prospectively collected data \n\nDear Dr. Hu:\n\nI am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. \n\nIf your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.\n\nFor any other questions or concerns, please email plosone@plos.org. \n\nThank you for submitting your work to PLOS ONE.\n\nWith kind regards,\n\nPLOS ONE Editorial Office Staff\n\non behalf of\n\nDr. Wenyu Lin \n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n1 Ji F , Yeo YH , Wei MT , Ogawa E , Enomoto M , Lee DH , et al\nSustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: A systematic review and meta-analysis . J Hepatol . 2019 \n2 Cabibbo G , Celsa C , Cammà C , Craxì A . Should we cure hepatitis C virus in patients with hepatocellular carcinoma while treating cancer? \nLiver Int . 2018 ;38 :2108 –2116 . 10.1111/liv.13918 \n29935096 \n3 Wang JH , Changchien CS , Hung CH , Eng HL , Tung WC , Kee KM ,et al\nFibroScan and ultrasonography in the prediction of hepatic fibrosis in patients with chronic viral hepatitis . J Gastroenterol . 2009 ;44 :439 –46 . 10.1007/s00535-009-0017-y \n19308312 \n4 Sterling RK , Lissen E , Clumeck N , Sola R , Correa MC , Montaner J , et. al\nDevelopment of a simple noninvasive index to predict significant fibrosis patients with HIV/HCV co-infection . Hepatology \n2006 ;43 :1317 –1325 . 10.1002/hep.21178 \n16729309 \n5 Bedossa P , Poynard T . An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group . Hepatology . 1996 ; 24 : 289 –293 . 10.1002/hep.510240201 \n8690394 \n6 Karino Y , Toyota J , Ikeda K , Suzuki F , Chayama K , Kawakami Y , et al\nCharacterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir . J Hepatol . 2013 ;58 :646 –654 . 10.1016/j.jhep.2012.11.012 \n23178977 \n7 EASL recommendations on treatment of chronic hepatitis C 2016 . J Hepatol \n2017 ;66 :153e94 .27667367 \n8 Heimbach JK , Kulik LM , Finn RS , Sirlin CB , Abecassis MM , Roberts LR , et al\nAASLD guidelines for the treatment of hepatocellular carcinoma . Hepatology \n2018 ; 67 : 358 –80 . 10.1002/hep.29086 \n28130846 \n9 Omata M , Cheng AL , Kokudo N , Kudo M , Lee JM , Jia J , et al\nAsia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update . Hepatol Int \n2017 ;11 :317 –70 . 10.1007/s12072-017-9799-9 \n28620797 \n10 European Association for the Study of the Liver . EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma . J Hepatol . 2018 ;69 :182 –236 . 10.1016/j.jhep.2018.03.019 \n29628281 \n11 Kudo M , Matsui O , Izumi N , Iijima H , Kadoya M , Imai Y; Liver Cancer Study Group of Japan. Surveillance and diagnostic algorithm for hepatocellular carcinoma proposed by the Liver Cancer Study Group of Japan: 2014 update . Oncology . 2014 ;87 \nSuppl 1 :7 –21 .\n12 European Association for the Study of the Liver . EASL Recommendations on Treatment of Hepatitis C 2018 . J Hepatol . 2018 ;69 :461 –511 \n10.1016/j.jhep.2018.03.026 \n29650333 \n13 Afdhal NH , Bacon BR , Patel K , Lawitz EJ , Gordon SC , Nelson DR , et al\nAccuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study . Clin Gastroenterol Hepatol \n2015 ;13 :772 –779 , e771–e773\n10.1016/j.cgh.2014.12.014 \n25528010 \n14 Degos F , Perez P , Roche B , Mahmoudi A , Asselineau J , Voitot H , et al\nDiagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study) . J Hepatol \n2010 ;53 :1013 –1021 . 10.1016/j.jhep.2010.05.035 \n20850886 \n15 Zarski JP , Sturm N , Desmorat H , Melin P , Raabe JJ , Bonny C , et al\nNoninvasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study . Liver Int \n2010 ;30 :1049 –1058 . 10.1111/j.1478-3231.2010.02265.x \n20492512 \n16 Majumdar A , Kitson MT , Roberts SK . Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis . Aliment Pharmacol Ther . 2016 ;43 :1276 –1292 \n10.1111/apt.13633 \n27087015 \n17 Karino Y , Toyota J , Ikeda K , Suzuki F , Chayama K , Kawakami Y , et al\nCharacterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir . J Hepatol . 2013 ;58 :646 –654 . 10.1016/j.jhep.2012.11.012 \n23178977 \n18 Schneider MD , Sarrazin C . Antiviral therapy of hepatitis C in 2014: do we need resistance testing? \nAntiviral Res . 2014 ;105 :64 –71 . 10.1016/j.antiviral.2014.02.011 \n24583028 \n19 Pawlotsky JM . Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus . Hepatology . 2011 ;53 :1742 –1751 . 10.1002/hep.24262 \n21374691 \n20 Perez AB , Chueca N , Garcia F . Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long? \nGerms . 2017 ;7 :40 \n10.18683/germs.2017.1107 \n28331841 \n21 Pawlotsky JM . Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens . Gastroenterology . 2016 ;151 :70 –86 . 10.1053/j.gastro.2016.04.003 \n27080301 \n22 Prenner SB , VanWagner LB , Flamm SL , Salem R , Lewandowski RJ , Kulik L . Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals . J Hepatol . 2017 ;66 :1173 –1181 . 10.1016/j.jhep.2017.01.020 \n28161470 \n23 Bruix J , ShermanM. Management of hepatocellular carcinoma: an update . Hepatology \n2011 ; 53 :1020 –1022 \n10.1002/hep.24199 \n21374666 \n24 Kushner T , Dieterich D ,Saberi B . Direct-acting antiviral treatment for patients with hepatocellular carcinoma . Curr Opin Gastroenterol \n2018 ;34 :132 –139 . 10.1097/MOG.0000000000000431 \n29517502 \n25 Chtioui H . OATP1B1 and DAA treatment for hepatitis C in patients with hepatocellular carcinoma . Hepatology \n2017 ;66 :2091 \n26 Sugiura A , Joshita S , Umemura T , Yamazaki T , Fujimori N , Kimura T , et al\nPast history of hepatocellular carcinoma is an independent risk factor of treatment failure in patients with chronic hepatitis C virus infection receiving direct-acting antivirals . J Viral Hepat . 2018 ;25 :1462 –1471 . 10.1111/jvh.12973 \n30044517 \n27 Garcia-Tsao G , Abraldes JG , Berzigotti A , Bosch J . Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases . Hepatology . 2017 ;65 :310 –335 . 10.1002/hep.28906 \n27786365 \n28 Liu CH , Su TH , Liu CJ , Hong CM , Yang HC , Tseng TC ,et al\nSofosbuvir-based direct acting antiviral therapies for patients with hepatitis C virus genotype 2 infection . J Gastroenterol Hepatol . 2019 \n1 \n29 \n10.1111/jgh.14615 \n30693965 \n29 Cheng PN , Chiu YC , Chien SC , Chiu HC . Real-world effectiveness and safety of sofosbuvir plus daclatasvir with or without ribavirin for genotype 2 chronic hepatitis C in Taiwan . J Formos Med Assoc . 2019 ;118 :907 –913 . 10.1016/j.jfma.2018.09.016 \n30316677 \n30 Beste LA , Green PK , Berry K , Kogut MJ , Allison SK , Ioannou GN . Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma . J Hepatol . 2017 ;67 :32 –39 . 10.1016/j.jhep.2017.02.027 \n28267622 \n31 Cabibbo G , Petta S , Barbara M , Attardo S , Bucci L , Farinati F , et al Italian Liver Cancer (ITA.LI.CA) group. Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma . J Hepatol . 2017 ;67 :65 –71 . 10.1016/j.jhep.2017.01.033 \n28192185 \n32 Hu X , Qiu L , Liu D , Qian L . Acoustic Radiation Force Impulse (ARFI) elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: a systematic review and meta-analysis . Med Ultrason \n2017 ;19 :23 –31 . 10.11152/mu-942 \n28180193\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "14(10)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D005260:Female; D006526:Hepatitis C; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D000072230:Sustained Virologic Response; D017211:Treatment Failure",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0222605",
"pmc": null,
"pmid": "31581209",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20492512;20850886;28267622;29650333;29935096;30693965;27786365;27087015;28192185;28180193;8690394;27667367;21374691;28620797;27080301;25427729;28960433;25528010;24583028;29628281;29517502;23178977;30044517;31096005;28130846;19308312;28161470;30316677;21374666;28331841;16729309",
"title": "Active hepatocellular carcinoma is an independent risk factor of direct-acting antiviral treatment failure: A retrospective study with prospectively collected data.",
"title_normalized": "active hepatocellular carcinoma is an independent risk factor of direct acting antiviral treatment failure a retrospective study with prospectively collected data"
} | [
{
"companynumb": "TW-KADMON PHARMACEUTICALS, LLC-KAD201910-000736",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadd... |
{
"abstract": "Lung abscess is defined as the necrosis of lung tissue with cavity formation due to varied etiology. The treatment of lung abscesses is medical involving antibiotics and chest physiotherapy. The failure of medical line of management requires an invasive surgical or percutaneous approach for drainage and control of infection. While the literature is ample regarding the surgical approach, it is rather scarce on the percutaneous approach. The percutaneous drainage has been most studied with computed tomography guidance. With our case series we describe to the treatment of lung abscesses non-responsive to medical management, by a bedside minimally invasive ultrasound or fluoroscopy guided percutaneous drainage approach.",
"affiliations": "Department of Clinical Medicine and Surgery, Section of Respiratory Disease, University Federico II, Monaldi Hospital, Naples. alessandromatarese@yahoo.it.",
"authors": "Matarese|Alessandro|A|;Tamburrini|Mario|M|;Desai|Unnati|U|;Zuccon|Umberto|U|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2020.1214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1122-0643",
"issue": "90(1)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
"keywords": null,
"medline_ta": "Monaldi Arch Chest Dis",
"mesh_terms": "D004322:Drainage; D006801:Humans; D008169:Lung Abscess; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "9307314",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32138472",
"pubdate": "2020-03-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Percutaneous lung abscess drainage: revisiting the old gold standard.",
"title_normalized": "percutaneous lung abscess drainage revisiting the old gold standard"
} | [
{
"companynumb": "IT-AUROBINDO-AUR-APL-2020-037829",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": null,
... |
{
"abstract": "Non-remitting patients with hematologic myeloid malignancies have poor prognosis. To overcome this problem, we investigated the use of reduced-intensity preconditioning umbilical cord blood transplantation (RICBT) combined with recombinant G-CSF (rG-CSF) with high-dose Ara-C, fludarabine, melphalan, and 4 Gy of TBI in a phase I/II study in patients with non-remitting myeloid hematologic malignancies. Thirteen patients were enrolled, including 12 with non-remitting AML and one patient with blastic crisis CML (CML-BC). The patients' median age was 45 years, with a median comorbidity index of 4. All patients received 4/6 serological HLA-antigen matched unrelated umbilical cord blood. All patients were engrafted within 30 days after RICBT (median, 20 days; range, 14-29) and achieved complete remission without prior hematopoiesis. Common grade III non-hematologic toxicities included eight cases of transient mucositis (62%) and six cases of febrile neutropenia (46%). Transplant-related mortality was 7.7%. The 1-year overall survival was 28.6% in cases without post-RICBT treatment and 83.3% in cases with post-RICBT treatment. These data suggest that in active AML and CML-BC, the combination of rG-CSF with high-dose Ara-C and fludarabine/melphalan/4 Gy TBI with a reduced-intensity preconditioning regimen is well tolerated, secures engraftment and has significant anti-leukemia activity. In addition, performing post-RICBT treatment may provide high-quality long-term survival and remission.",
"affiliations": "Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.;Division of Hematology, The First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.",
"authors": "Gotoh|M|M|;Yoshizawa|S|S|;Katagiri|S|S|;Suguro|T|T|;Asano|M|M|;Kitahara|T|T|;Akahane|D|D|;Okabe|S|S|;Tauchi|T|T|;Ito|Y|Y|;Ohyashiki|K|K|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2014.66",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "49(7)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D036101:Cord Blood Stem Cell Transplantation; D003561:Cytarabine; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D055815:Young Adult",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "955-60",
"pmc": null,
"pmid": "24732960",
"pubdate": "2014-07",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "17700155;11850858;19545742;21205990;19802028;17637692;9746770;16573743;17607586;11719394;17038536;18410901;17151364;21886171;17036221;17119111;17569820;20651401;17988995;15812397;15173064;7581076;10637248;15994282;16275591;17382251;1887253;11157478;12580971;23208313;23673863;10556959;20530795;10373073;2684307;19159415;11704792;15282535;16443557;11110676;14976039;16003230;20424188;17690701;19709082;18162238;18195683;19797728",
"title": "A novel reduced-intensity umbilical cord blood transplantation using a recombinant G-CSF combined with high-dose Ara-C for active myeloid malignancies.",
"title_normalized": "a novel reduced intensity umbilical cord blood transplantation using a recombinant g csf combined with high dose ara c for active myeloid malignancies"
} | [
{
"companynumb": "JP-CELGENEUS-087-50794-14075087",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": nul... |
{
"abstract": "Plasmapheresis for the treatment of hypertriglyceridemia has previously been performed in patients with sudden onset severe hypertriglyceridemia and acute pancreatitis; however, only a few reports of this procedure have been published. We report here on a case showing severe hypertriglyceridemia during asparaginase (Asp) treatment for acute lymphocytic leukemia (ALL), and give an overview of a lipid-lowering apheresis therapy. To prevent the complication of pancreatitis due to hypertriglyceridemia, we performed plasma exchange (PE) three times using fresh frozen plasma. PE remarkably reduced both serum triglyceride and total cholesterol levels from 5430 mg/dL to 403 mg/dL and from 623 mg/dL to 204 mg/dL, respectively. The causes of severe hyperlipidemia in this patient were considered to include: the Asp treatment for ALL, and a genetic background with a heterozygote of familial lipoprotein lipase (LPL) defect syndrome, because the patient's plasma LPL level after intravenous heparin injection was low at 137 ng/mL. Hence, PE using fresh frozen plasma may be useful not only to remove lipoproteins, but also to supply defective factors, such as LPL, in similar cases.",
"affiliations": "Division of Nephrology, Kanazawa Medical University, Uchinada, Japan. yam99845@yahoo.co.jp",
"authors": "Nakagawa|Masaru|M|;Kimura|Syogo|S|;Fujimoto|Keiji|K|;Atumi|Hirokatsu|H|;Imura|Jyunko|J|;Chikazawa|Yoshihiro|Y|;Imamura|Hidetsugu|H|;Okuyama|Hiroshi|H|;Yamaya|Hideki|H|;Fukushima|Toshihiro|T|;Nakagawa|Atsushi|A|;Asaka|Mitsuhiro|M|;Yokoyama|Hitoshi|H|",
"chemical_list": "D000970:Antineoplastic Agents; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase; D001215:Asparaginase",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1744-9987.2008.00647.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1744-9979",
"issue": "12(6)",
"journal": "Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy",
"keywords": null,
"medline_ta": "Ther Apher Dial",
"mesh_terms": "D000970:Antineoplastic Agents; D001215:Asparaginase; D002784:Cholesterol; D006801:Humans; D015228:Hypertriglyceridemia; D008071:Lipoprotein Lipase; D008297:Male; D010956:Plasmapheresis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D012720:Severity of Illness Index; D014280:Triglycerides; D055815:Young Adult",
"nlm_unique_id": "101181252",
"other_id": null,
"pages": "509-13",
"pmc": null,
"pmid": "19140851",
"pubdate": "2008-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case report of an adult with severe hyperlipidemia during acute lymphocytic leukemia induction therapy successfully treated with plasmapheresis.",
"title_normalized": "a case report of an adult with severe hyperlipidemia during acute lymphocytic leukemia induction therapy successfully treated with plasmapheresis"
} | [
{
"companynumb": "JP-JAZZ-2019-JP-010762",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo describe the case of a woman exposed to angiotensin-II receptor blockers (ARBs) in the preconceptional period and to systematically review the literature on the safety of these drugs when used by pregnant women.\n\n\nMETHODS\nThe case was identified at the Korean Motherisk Program (Seoul). For the systematic review, we searched the PubMed for case reports, case series, and post-marketing surveys.\n\n\nRESULTS\nA hypertensive woman was exposed to irbesartan prior to conception. The embryo had delayed development of upper and lower extremities and decreased digital groove. A karyotype identified a 45,XO Turner syndrome. The patient had a spontaneous abortion. Including the case reported here, 64 published cases were identified in total; 57.8% had favorable and 42.2% had unfavorable outcomes. Duration of treatment during pregnancy among women who had adverse fetal outcomes was 26.3 +/- 10.5 weeks (mean +/- SD), compared with 17.3 +/- 11.6 weeks in those who had favorable outcomes (p = 0.04).\n\n\nCONCLUSIONS\nExposure to ARBs for a period longer than the first trimester of pregnancy appears to be associated with a high risk for adverse fetal outcomes.",
"affiliations": "PharmaREASONS. Toronto, Ontario, Canada.",
"authors": "Velázquez-Armenta|Elvia Yadira|EY|;Han|Jung Yeol|JY|;Choi|June Seek|JS|;Yang|Kwang Moon|KM|;Nava-Ocampo|Alejandro A|AA|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan",
"country": "England",
"delete": false,
"doi": "10.1080/10641950601147937",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-1955",
"issue": "26(1)",
"journal": "Hypertension in pregnancy",
"keywords": null,
"medline_ta": "Hypertens Pregnancy",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D005260:Female; D006801:Humans; D000077405:Irbesartan; D047489:Preconception Injuries; D011247:Pregnancy; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D013777:Tetrazoles; D013997:Time Factors; D014424:Turner Syndrome",
"nlm_unique_id": "9421297",
"other_id": null,
"pages": "51-66",
"pmc": null,
"pmid": "17454218",
"pubdate": "2007",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Angiotensin II receptor blockers in pregnancy: a case report and systematic review of the literature.",
"title_normalized": "angiotensin ii receptor blockers in pregnancy a case report and systematic review of the literature"
} | [
{
"companynumb": "CA-RANBAXY-2012US-52842",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Metaplastic breast carcinoma is a rare entity characterized by rapid growth and heterogeneous histological features. It comprises less than 1% of all breast cancers, and no definitive treatment has yet been identified. CASE REPORT We describe here a patient who presented with acute hypercalcemia and was found to have a large ulcerated breast mass. Once the patient's hypercalcemia was stabilized, she underwent complete surgical resection that revealed a large, cavitary, necrotic mass measuring over 11 cm. The final surgical pathology revealed metaplastic carcinoma with extensive squamous differentiation and ductal carcinoma in situ. At the request of her family, no additional treatment was pursued. CONCLUSIONS While there is not a significant body of data on the pathogenesis of metaplastic breast carcinoma, it is typically hormone receptor negative and has a variable response to chemotherapy. Surgical excision is the most commonly pursued treatment.",
"affiliations": "Rush Medical College, Chicago, IL, USA.;Department of Surgery, Rush University Medical Center, Chicago, IL, USA.;Department of Pathology, Rush University Medical Center, Chicago, IL, USA.;Department of Pathology, Rush University Medical Center, Chicago, IL, USA.;Division of Surgical Oncology, Rush University Medical Center, Chicago, IL, USA.",
"authors": "Hardy|Brendan M|BM|;Cortina|Chandler S|CS|;Javidiparsijani|Sara|S|;Ghai|Ritu|R|;Madrigrano|Andrea|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.912427",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3089068910.12659/AJCR.912427912427ArticlesHypercalcemia in Metaplastic Squamous Cell Carcinoma of the Breast Hardy Brendan M. EF1Cortina Chandler S. AEF2Javidiparsijani Sara BD3Ghai Ritu D3Madrigrano Andrea A4\n1 Rush Medical College, Chicago, IL, U.S.A.\n2 Department of Surgery, Rush University Medical Center, Chicago, IL, U.S.A.\n3 Department of Pathology, Rush University Medical Center, Chicago, IL, U.S.A.\n4 Division of Surgical Oncology, Rush University Medical Center, Chicago, IL, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Brendan M. Hardy, e-mail: Brendan.m.hardy@gmail.com2019 20 3 2019 20 366 369 31 7 2018 19 10 2018 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 71\n\nFinal Diagnosis: Metaplastic squamous cell carcinoma of the breast\n\nSymptoms: Altered mental status • necrotic breast mass\n\nMedication: —\n\nClinical Procedure: Mastectomy\n\nSpecialty: Oncology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nMetaplastic breast carcinoma is a rare entity characterized by rapid growth and heterogeneous histological features. It comprises less than 1% of all breast cancers, and no definitive treatment has yet been identified.\n\nCase Report:\nWe describe here a patient who presented with acute hypercalcemia and was found to have a large ulcerated breast mass. Once the patient’s hypercalcemia was stabilized, she underwent complete surgical resection that revealed a large, cavitary, necrotic mass measuring over 11 cm. The final surgical pathology revealed meta-plastic carcinoma with extensive squamous differentiation and ductal carcinoma in situ. At the request of her family, no additional treatment was pursued.\n\nConclusions:\nWhile there is not a significant body of data on the pathogenesis of metaplastic breast carcinoma, it is typically hormone receptor negative and has a variable response to chemotherapy. Surgical excision is the most commonly pursued treatment.\n\nMeSH Keywords:\nBreastCarcinoma, Squamous CellMetaplasia\n==== Body\nBackground\nMetaplastic breast carcinoma (MBC) is a rare disease comprising less than 1% of all breast tumors [1]. The literature on MBC is limited to case studies and retrospective observational studies, and due to its variable pathology and low incidence, there is no consensus regarding treatment [2]. Recently revised National Comprehensive Cancer Network (NCCN) guidelines identified metaplastic histology as a negative prognostic factor when it accounts for >10% of a tumor. However, specific treatment guidelines are not provided, so common therapy modalities have historically paralleled those utilized for invasive ductal carcinoma (IDC) [3,4]. Despite this common approach, MBC is generally regarded as more aggressive than IDC due to its rapid growth and propensity to spread hematogenously [4]. In the past, there have also been reports of chemoresistance, but recent literature has shown that multimodal treatment is associated with improved outcomes [4].\n\nCase Report\nA 71-year-old female with a past medical history of dementia, hypertension, and hyperlipidemia presented to the emergency department with a 4-day history of progressive altered mental status accompanied by polyuria and polydipsia. She had mild hypotension, was unable to open her eyes, and responded only to painful stimuli. On further physical examination, she was found to have a large, firm, right retroareolar breast mass which was suspicious for a neoplasm. The mass had associated skin dimpling, nipple retraction, and bloody nipple discharge but with no evidence of axillary or supraclavicular lymphadenopathy.\n\nThe patient’s family accompanied her and reported that her last mammogram 6 years prior showed no abnormalities. While her family discovered the breast mass approximately 2 weeks before admission, the patient was unable to communicate when the mass was initially noticed. She had no previous surgeries or family history of malignancy. Medications included hydrochlorothiazide, carvedilol, losartan, atorvastatin, and mirtazapine.\n\nLaboratory work revealed a marked leukocytosis of 29.3 K/uL with neutrophil predominance, calcium of 15.3 mg/dL, potassium of 3.0 mmol/L, ionized calcium of 1.9 mmol/L, parathyroid hormone (PTH) level of 13.6 pg/mL, and PTH related-peptide of 31 pg/mL. Electrocardiogram showed a decreased QTc interval. A computerized tomography (CT) of her head was negative for any acute changes, but chest CT showed peripherally enhancing necrotic nodules in the right breast without signs of axillary lymphadenopathy. Both urinalysis and urine culture confirmed the presence of an Escherichia coli urinary tract infection which was treated with ceftriaxone.\n\nThe patient’s mental status improved with intravenous fluids, zoledronic acid, and treatment of her urinary tract infection. Hydrochlorothiazide was also discontinued and replaced with losartan, as thiazides can cause hypercalcemia. After one week of treatment, both her calcium and ionized calcium down trended to 7.1 mg/dL and 1.2 mmol/L, respectively. During this time, head CT was repeated with intravenous contrast and bone scan was performed confirming no evidence of metastatic disease.\n\nOnce the patient was medically stable, a multidisciplinary discussion was held with the patient, her family, the surgical oncology team, and the medical oncology team to develop a treatment plan for her likely breast cancer. Considering the patient’s age, dementia, and prior wishes, the family initially elected for isolated drainage of the mass rather than definitive surgical excision.\n\nThe initial operation revealed a necrotic mass draining serosanguinous fluid which was debrided from the surrounding breast tissue. The incision was left open and treated with a wet-to-dry dressing. Initial pathology showed a hormone-receptor negative invasive carcinoma with extensive squamous differentiation and necrosis, and ductal carcinoma in-situ (DCIS). The pathology was discussed with the patient and her family several days later and because of difficulties in wound care and the clear evidence of cancer, the decision for complete right mastectomy for wound palliation was reached. Final surgical pathology after mastectomy revealed metaplastic carcinoma with extensive squamous differentiation and DCIS. Per the wishes of the patient and her family, no further treatment was pursued.\n\nThe gross specimen was a large, ulcerative, cavitary, necrotic mass measuring 11.3×11×10.2 centimeters. The edges of the ulcer were indurated, and the nipple was ulcerated as well. The cut surfaces showed a white and tan infiltrative, nodular, ulcerative mass with irregular borders and finger-like projections in the breast extending all the way underneath the area of the nipple.\n\nMicroscopically, the specimen showed invasive, poorly differentiated carcinoma composed of nests of large pleomorphic cells with large nuclei, abundant dense eosinophilic cytoplasm, and keratin pearls showing marked squamous differentiation (Figure 1). There were numerous mitotic figures, marked stromal desmoplasia, and large areas of necrosis. There was also a small focus of high grade in situ carcinoma (Figure 2). By immunohistochemistry, the tumor cells were negative for estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor type 2 (HER2/neu). The cells showed nuclear p63 staining consistent with squamous differentiation. The Ki-67 proliferation index was high and unfavorable at >20%.\n\nDiscussion\nMetaplastic breast carcinoma is a rare disease that was first recognized as a distinct pathologic entity in the 21st century. Wargotz and Norris developed a classification system that divides the disease into 5 subtypes: squamous cell, carcinosarcoma, spindle cell, matrix-producing, and MBC with osteoclastic giant cells [1]. The most common form identified thus far is the spindle cell subtype [2]. Data and research on MBC are limited due to its rarity and recent designation as a distinct pathological entity [4].\n\nMBC commonly presents as a rapidly growing mass that is consistently larger than other breast cancers on initial examination [2]. Mean age at presentation is 53 to 61 years, and the majority of cases are hormone receptor negative [1,3,5]. In comparison to IDC, MBC typically presents as a more poorly differentiated tumor with less lymph node involvement [2,3]. Histology demonstrates infiltrating squamous carcinoma, eosinophilic cytoplasm, and some rare keratin pearl formation. The tumors are often cystic structures with lining composed of squamous cell carcinoma [1,2].\n\nImaging methods used to identify more common forms of breast cancer are also useful in identifying MBC. Magnetic resonance imaging (MRI) frequently shows an irregular mass with spiculated margins and T2 hyperintensity. Mammographic appearance is described as a high-density mass with irregular and/or spiculated margins. Sonographic appearance is described as complex echogenicity with solid and cystic components [2,6].\n\nWhile treatment for MBC mirrors that of IDC, optimal treatment strategies have not been thoroughly researched. Options are usually limited to surgery and chemoradiation; however, traditional chemoradiation regimens used for IDC have had mixed results against MBC [4,7,8]. MBC does not preclude breast conservation therapy (BCT), but the larger tumor size often requires mastectomy. BCT should be considered in appropriate patients, as there is no difference in disease-free survival when comparing BCT to mastectomy [7].\n\nThe American Joint Committee on Cancer’s (AJCC) staging manual was recently updated to integrate HER2, PR, and ER status into the staging of breast cancer patients. These biomarkers must be included for case reporting in US cancer registries or the cancer is considered unstaged. While it is unclear exactly how the changes in staging criteria will affect treatment and outcomes, a preliminary study reported that 35% of women with stages I to III invasive breast cancer under the old AJCC staging guidelines would be restaged under the new criteria [9]. In the case of our patient, the tumor was T4bN0M0. Under the 7th edition AJCC staging guidelines, the tumor is stage IIIB, but under the 8th edition guidelines the tumor is stage IIIC. Although the increased stage suggests a decrease in overall survival, treatment was directed largely by the family’s wishes and would not have changed [9].\n\nConclusions\nThis case highlights a rare form of breast cancer discovered in the setting of altered mental status due to hypercalcemia. Although there are no definitive treatment guidelines for MBC, a multidisciplinary approach must be developed by surgeons, medical oncologists, radiation oncologists, and the patient to best treat this disease. In this case, unique patient circumstances required a constant open dialogue between the patient, providers, and the patient’s family. Further case reports, cases series, and prospective trials are needed to define treatment guidelines for this unique type of breast cancer.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Microscopic examination showing invasive poorly differentiated carcinoma with keratin pearls and marked squamous differentiation.\n\nFigure 2. Microscopic examination showing a focus of high grade in situ carcinoma.\n==== Refs\nReferences:\n1. Wargotz ES Norris HJ Metaplastic carcinomas of the breast. IV. Squamous cell carcinoma of ductal origin Cancer 1990 65 272 76 2153044 \n2. Schwartz TL Mogal H Papageorgiou C Metaplastic breast cancer: Histologic characteristics, prognostic factors and systemic treatment strategies Exp Hematol Oncol 2013 2 31 24499560 \n3. Pezzi CM Patel Parekh L Cole K Characteristics and treatment of metaplastic breast cancer: Analysis of 892 cases from the National Cancer Data Base Ann Surg Oncol 2007 14 166 73 17066230 \n4. Ong CT Campbell BM Thomas SM Metaplastic breast cancer treatment and outcomes in 2500 patients: A retrospective analysis of a national oncology database Ann Surg Oncol 2018 25 8 2249 60 29855830 \n5. Lai H Tseng L Chang T The prognostic significance of metaplastic carcinoma of the breast (MCB) – a case-controlled comparison study with infiltrating ductal carcinoma Breast 2013 22 968 73 23787124 \n6. Velasco M Santamaría G Ganau S MRI of metaplastic carcinoma of the breast Am J Roentgenol 2005 184 1274 78 15788609 \n7. Shah DR Tseng WH Martinez SR Treatment options for metaplastic breast cancer ISRN Oncol 2012 2012 706162 22778998 \n8. Luini A Aguilar M Gatti G Metaplastic carcinoma of the breast, an unusual disease with worse prognosis: The experience of the European Institute of Oncology and review of the literature Breast Cancer Res and Treat 2007 101 349 53 17009109 \n9. Plichta JK Ren Yi Thomas SM Implications for breast cancer restaging based on the 8th edition AJCC Staging Manual Ann Surg 2018 [Epub ahead of print]\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D001943:Breast Neoplasms; D002294:Carcinoma, Squamous Cell; D005260:Female; D006801:Humans; D006934:Hypercalcemia",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "366-369",
"pmc": null,
"pmid": "30890689",
"pubdate": "2019-03-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15788609;17009109;17066230;2153044;22778998;23787124;24499560;29855830;30312199",
"title": "Hypercalcemia in Metaplastic Squamous Cell Carcinoma of the Breast.",
"title_normalized": "hypercalcemia in metaplastic squamous cell carcinoma of the breast"
} | [
{
"companynumb": "US-MYLANLABS-2019M1083593",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": "3",
... |
{
"abstract": "We present here the first reported case of a non-syndromic cleft lip and palate (NSCLP) in an HIV-exposed newborn of a mother on antiretroviral therapy (ART) in Indonesia. Genetic testing was performed to confirm a suspected genetic condition. Genomic DNA was extracted from the blood, and genetic variations of the interferon regulatory factor 6 (IRF6) rs642961 (Mspl) (G>A) and transforming growth factor alpha (TGFA) BamHI (rs11466297, A>C) and RsaI (rs3732248, C>T) were performed by PCR-RFLP and IRF6 gene analysis by PCR sequencing. Genotyping of DNA sequence variants in the IRF6 gene showed both parents had genotype GA, while the child had genotype GG (genotype wild type). There was no difference observed in the TGFA BamHI gene variant between the child and her mother and father that were wild-type polymorphisms (normal), while the Rsa1 polymorphisms of them were heterozygotes. A genetic variant of IRF6 might be a protective factor for NSCLP, while Rsa1 gene variant (A) allele can be considered to be the risk factor associated with NSCLP development. This case report also highlights the possible etiologic role of ART in NSCLP; therefore, early control of adverse effects of ART might be an important factor in decreasing the incidence of the congenital anomalies in HIV-infected children.",
"affiliations": "Department of Oral Medicine, Faculty of Dentistry, Universitas Padjadjaran, Bandung, Indonesia.;Department of Oral Biology, Faculty of Dentistry, Universitas Padjadjaran, Bandung, Indonesia.;Department of Orthodontics, Faculty of Dentistry, Universitas Padjadjaran, Bandung, Indonesia.",
"authors": "Sufiawati|Irna|I|;Maskoen|Ani Melani|AM|;Soemantri|Eky Setiawan Soeria|ESS|",
"chemical_list": "D044966:Anti-Retroviral Agents; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; C587886:TGFA protein, human; D016211:Transforming Growth Factor alpha",
"country": "Denmark",
"delete": false,
"doi": "10.1111/odi.13403",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1354-523X",
"issue": "26 Suppl 1()",
"journal": "Oral diseases",
"keywords": "\nTGFA\n; HIV; IRF6; non-syndromic cleft lip and palate",
"medline_ta": "Oral Dis",
"mesh_terms": "D044966:Anti-Retroviral Agents; D002971:Cleft Lip; D002972:Cleft Palate; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections; D006801:Humans; D007231:Infant, Newborn; D050835:Interferon Regulatory Factors; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D016211:Transforming Growth Factor alpha",
"nlm_unique_id": "9508565",
"other_id": null,
"pages": "165-168",
"pmc": null,
"pmid": "32862534",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Genetic variation of IRF6 and TGFA genes in an HIV-exposed newborn with non-syndromic cleft lip palate.",
"title_normalized": "genetic variation of irf6 and tgfa genes in an hiv exposed newborn with non syndromic cleft lip palate"
} | [
{
"companynumb": "ID-VIIV HEALTHCARE LIMITED-ID2020GSK184896",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
... |
{
"abstract": "A 62-year-old man presented to our institute with diarrhoea and dysuria on a background of subtotal colectomy and end ileostomy and biological therapy for Crohn's disease. He was diagnosed with urinary tract infection and acute kidney injury (AKI). Renal ultrasound suggested left hydronephrosis, with renal protocol computed tomography (CT) showing a large pelvic mass. Magnetic resonance imaging (MRI) of the pelvis demonstrated a rectal tumour invading the bladder and compressing both ureters. He underwent cystoscopy, flexible sigmoidoscopy and positron emission tomography-CT and was diagnosed with stage IV non-Hodgkin's diffuse large B-cell lymphoma. He was treated primarily with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin and prednisolone chemotherapy regimen. He had ongoing urosepsis before admission for pelvic exenteration. He underwent cystoprostatectomy, excision of rectal stump and formation of ileal conduit. Histology showed no signs of residual malignancy. One year later, the patient was admitted to the intensive care unit with aspiration pneumonia, urosepsis and AKI. Despite maximal therapy, he developed multiorgan failure and passed away.",
"affiliations": "Department of Paediatric Surgery, Our Lady's Children's Hospital, Dublin, Ireland hardyadams01@gmail.com.;Department of General & Vascular Surgery, Tallaght Hospital, Dublin, Ireland.;Department of Surgery, University Hospital Limerick, Limerick, Ireland.;Department of Surgery, Tallaght University Hospital, Dublin, Ireland.",
"authors": "Hardy|Adam Joseph|AJ|;Stoica|Ionica|I|;Kearney|David Edward|DE|;O'Riordain|Diarmuid S|DS|",
"chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228818",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(4)",
"journal": "BMJ case reports",
"keywords": "cancer intervention; colon cancer; inflammatory bowel disease; malignant disease and immunosuppression; surgical oncology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001691:Biological Therapy; D003131:Combined Modality Therapy; D003424:Crohn Disease; D003520:Cyclophosphamide; D003937:Diagnosis, Differential; D004317:Doxorubicin; D017809:Fatal Outcome; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012004:Rectal Neoplasms; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32303524",
"pubdate": "2020-04-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diffuse large B-cell lymphoma of the rectum in a patient with Crohn's disease.",
"title_normalized": "diffuse large b cell lymphoma of the rectum in a patient with crohn s disease"
} | [
{
"companynumb": "IE-ALVOGEN-2020-ALVOGEN-115434",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "We reported a HIV-infected patient, diagnosed as PJP with G6PD deficiency. Pneumocystis jiroveci pneumonia (PJP) is the most common opportunistic infection in subjects with human immunodeficiency virus (HIV) infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is the first line regimen for Pneumocystis jirovecii pneumonia. However, patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency should avoid this agent to prevent hemolysis. Although there is evidence of echinocandins used successfully in animal studies, and few articles describing the clinical use of caspofungin, the clinical experience of anidulafungin as an alternative regimen to the treatment of PJP is rare in the HIV-infected patients.\n\n\n\nThe patient was successfully treated with anidulafungin for 3 weeks and was led to a successful outcome.",
"affiliations": "Department of Pharmacy, Taichung Hospital, Ministry of Health Welfare, Taichung, Taiwan. ayumi1023@gmail.com.",
"authors": "Chang|H-C|HC|;Yang|W-T|WT|;Chen|T-C|TC|",
"chemical_list": "D000935:Antifungal Agents; D000077612:Anidulafungin",
"country": "Italy",
"delete": false,
"doi": "10.26355/eurrev_201812_16666",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1128-3602",
"issue": "22(24)",
"journal": "European review for medical and pharmacological sciences",
"keywords": null,
"medline_ta": "Eur Rev Med Pharmacol Sci",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000077612:Anidulafungin; D000935:Antifungal Agents; D023241:Antiretroviral Therapy, Highly Active; D005955:Glucosephosphate Dehydrogenase Deficiency; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D011020:Pneumonia, Pneumocystis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9717360",
"other_id": null,
"pages": "8961-8964",
"pmc": null,
"pmid": "30575940",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pneumocystis jirovecii pneumonia in a human immunodeficiency virus-infected patient with G6PD deficiency-successful treatment with anidulafungin.",
"title_normalized": "pneumocystis jirovecii pneumonia in a human immunodeficiency virus infected patient with g6pd deficiency successful treatment with anidulafungin"
} | [
{
"companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-277183",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN"
},
"dru... |
{
"abstract": "BACKGROUND\nCardiac metastasis of urothelial carcinoma is a very rare but clinically important complication. Most cardiac metastases are asymptomatic; symptoms from cardiac metastasis were seen in advanced stage and many of these cases were reported to have a poor prognosis. So it is important to find asymptomatic cardiac metastasis and to start chemotherapy early in order to improve the patient's prognosis.\n\n\nMETHODS\nA 73-year-old Asian man was referred to our hospital because of a right ventricular tumor. He had a history of left ureteral cancer 9 years ago. In screening echocardiography for paroxysmal atrial fibrillation, a low echogenic tumor was detected in his right ventricular apex, and characteristic ST segment elevation was detected in electrocardiography. An (18)F-fluorodeoxyglucose positron emission tomography revealed abnormal uptake in his right ventricular apex tumor and prostate, and a biopsy of the prostatic tumor showed urothelial carcinoma cells. He received systemic gemcitabine, paclitaxel and cisplatin chemotherapy for the urothelial carcinoma, and the cardiac tumor size was reduced temporarily. Finally, he died of multiple organ failure 16 months after his first admission, but his survival period was relatively longer than previous reports.\n\n\nCONCLUSIONS\nWe experienced a case of a metastatic cardiac tumor from urothelial carcinoma. We found asymptomatic cardiac metastasis by screening echocardiography and electrocardiography. Our patient received systemic chemotherapy and his survival period was relatively longer than previous reports. Electrocardiography and echocardiography may be useful to find asymptomatic cardiac metastasis of neoplasms.",
"affiliations": "Department of Cardiology, Neurology and Aging Science, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi, 783-8505, Japan. nakashimayasuteru@yahoo.co.jp.;Department of Cardiology, Neurology and Aging Science, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi, 783-8505, Japan.;Department of Cardiology, Neurology and Aging Science, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi, 783-8505, Japan.;Department of Cardiology, Neurology and Aging Science, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi, 783-8505, Japan.;Department of Urology, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi, 783-8505, Japan.;Department of Urology, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi, 783-8505, Japan.;Department of Cardiology, Neurology and Aging Science, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi, 783-8505, Japan. kitaokah@kochi-u.ac.jp.",
"authors": "Nakashima|Yasuteru|Y|;Tanioka|Katsutoshi|K|;Kubo|Toru|T|;Yamasaki|Naohito|N|;Yamasaki|Ichiro|I|;Syuin|Taro|T|;Kitaoka|Hiroaki|H|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0740-3",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 74010.1186/s13256-015-0740-3Case ReportMetastatic cardiac tumor from urothelial carcinoma detected by transthoracic echocardiography: a case report Nakashima Yasuteru nakashimayasuteru@yahoo.co.jp Tanioka Katsutoshi Kubo Toru Yamasaki Naohito Yamasaki Ichiro Syuin Taro Kitaoka Hiroaki kitaokah@kochi-u.ac.jp Department of Cardiology, Neurology and Aging Science, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi 783-8505 Japan Department of Urology, Kochi Medical School, Kochi University, Oko-cho, Nankoku-city, Kochi 783-8505 Japan 16 11 2015 16 11 2015 2015 9 25716 4 2015 20 10 2015 © Nakashima et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nCardiac metastasis of urothelial carcinoma is a very rare but clinically important complication. Most cardiac metastases are asymptomatic; symptoms from cardiac metastasis were seen in advanced stage and many of these cases were reported to have a poor prognosis. So it is important to find asymptomatic cardiac metastasis and to start chemotherapy early in order to improve the patient’s prognosis.\n\nCase presentation\nA 73-year-old Asian man was referred to our hospital because of a right ventricular tumor. He had a history of left ureteral cancer 9 years ago. In screening echocardiography for paroxysmal atrial fibrillation, a low echogenic tumor was detected in his right ventricular apex, and characteristic ST segment elevation was detected in electrocardiography. An 18F-fluorodeoxyglucose positron emission tomography revealed abnormal uptake in his right ventricular apex tumor and prostate, and a biopsy of the prostatic tumor showed urothelial carcinoma cells. He received systemic gemcitabine, paclitaxel and cisplatin chemotherapy for the urothelial carcinoma, and the cardiac tumor size was reduced temporarily. Finally, he died of multiple organ failure 16 months after his first admission, but his survival period was relatively longer than previous reports.\n\nConclusions\nWe experienced a case of a metastatic cardiac tumor from urothelial carcinoma. We found asymptomatic cardiac metastasis by screening echocardiography and electrocardiography. Our patient received systemic chemotherapy and his survival period was relatively longer than previous reports. Electrocardiography and echocardiography may be useful to find asymptomatic cardiac metastasis of neoplasms.\n\nKeywords\nCardiac metastasisEchocardiographyUrothelial carcinomaissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nCardiac metastasis from urothelial carcinoma is very uncommon. To the best of our knowledge, only a small number of cases were reported and most of the cases had poor prognosis. We present a case of a metastatic cardiac tumor from urothelial cell carcinoma that was incidentally detected by screening echocardiography. We treated the patient with systemic chemotherapy and succeeded in temporarily reducing the tumor size. The patient had 16 months of survival from diagnosis of cardiac metastasis, which is a longer period than other cases reported in the literature.\n\nCase presentation\nA 73-year-old Asian man was referred to our hospital because of a right ventricular tumor. He had a history of left ureteral cancer, and he had undergone nephroureterectomy of his left kidney 9 years ago and transurethral resection of a bladder tumor (TUR-Bt) for intravesical recurrence. After four histories of TUR-Bt, no evidence of cancer recurrence was found for a period of 6 years. However, echocardiography for cardiac screening of paroxysmal atrial fibrillation revealed a low echogenic tumor in his right ventricle (RV), and he was admitted to our hospital for further examination.\n\nThe results of a physical examination were almost within normal limits, and laboratory tests showed mild chronic kidney disease (creatinine level of 1.22 mg/dl and blood urea nitrogen level of 21 mg/dl) and a mildly elevated brain natriuretic peptide level (178 pg/ml). In electrocardiography (ECG), mild ST-segment elevation and T wave inversion were revealed in V1–3 (Fig. 1). Transthoracic echocardiography revealed a 35×35 mm low echogenic tumor that was invading the myocardium of the apex of his RV, and the border of the tumor was poorly defined. There was a small amount of pericardial effusion and no detectable valvular abnormality (Fig. 2a, b).Fig. 1 Electrocardiography at first admission for cardiac evaluation. Heart rate was 75/minute with normal axis. However, mild ST elevation and T inversion were detected in V1–3\n\nFig. 2 Transthoracic echocardiography. a, b Echocardiography before chemotherapy (a, diastolic phase; b, systolic phase): a low echogenic tumor was detected in the right ventricle apex wall (white arrowheads). c, d Echocardiography after two courses of chemotherapy (c, diastolic phase; d, systolic phase): right ventricle apex tumor had become smaller (white arrowheads)\n\n\n\n\nWe suspected the tumor to be a metastasis from urothelial cancer based on its echocardiographical features and the patient’s past history. We tried to detect the primary lesion by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and it showed abnormal FDG uptake in his RV apex tumor and prostate (Fig. 3a). Pelvis magnetic resonance imaging (MRI) revealed another lesion invading his prostate, and a biopsy of the prostate lesion showed carcinoma cells suspected to be from the urothelial carcinoma with squamous differentiation. Although the tumor was localized on his RV apical wall, and the risk of RV apical wall perforation due to cardiac biopsy was therefore considered to be relatively high, we recommended surgical or transvenous biopsy of the RV tumor for definite diagnosis of a metastatic cardiac tumor. However, he did not wish to undergo a biopsy.Fig. 3 The patient’s 18F-fluorodeoxyglucose positron emission tomography. a His 18F-fluorodeoxyglucose positron emission tomography before chemotherapy: abnormal uptake was detected in the right ventricle apex tumor and prostate tumor (white arrowheads). b His 18F-fluorodeoxyglucose positron emission tomography after chemotherapy: uptake in the right ventricle apex tumor and prostate tumor was reduced\n\n\n\nWe decided to perform systemic chemotherapy for the urothelial carcinoma and cardiac lesion. The patient received gemcitabine, paclitaxel and cisplatin therapy (GTC) for the urothelial carcinoma. After two courses of GTC therapy (75 and 50 % dose), the tumors of the prostate and RV apex wall became smaller, and FDG uptake of the tumors was also reduced as shown by follow-up FDG-PET (Figs. 2c, d and 3b). We suspected the RV tumor to be a metastatic cardiac tumor from urothelial carcinoma without pathological analysis because chemotherapy for the urothelial carcinoma was also effective for the RV tumor.\n\nHowever, a new pubic bone metastasis was also revealed by follow-up FDG-PET. Radiation therapy was then performed for pubic bone metastasis (3 Gy×18 times, total 54 Gy). After the radiation therapy, chemotherapy was continued but the regime was changed to gemcitabine and cisplatin (GC) because of renal dysfunction. However, after three cycles of GC chemotherapy (50 % dose each), lung metastasis and adrenal gland metastasis were also detected, and chemotherapy itself was discontinued because of renal dysfunction, bone marrow suppression, and poor performance status.\n\nFinally, he died from multiple organ failure 16 months after his first admission. An autopsy was not performed because permission could not be obtained from his family.\n\nDiscussion\nAccording to a recent review, cardiac metastasis from a malignant neoplasm is not rare. In past autopsy studies, the incidences of cardiac metastasis were estimated to range from 1.7 to 14 % in patients with cancer and from 0.7 to 3.5 % in the general population [1]. By contrast, the incidence of primary cardiac malignant neoplasm ranged from only 0.001 to 0.28 % [2]. In addition, the incidence of cardiac metastasis is expected to increase because of the improvement of prognosis for patients with cancer that is associated with advances in cancer therapeutic strategies [1].\n\nBussani et al. reported a large series of autopsy cases in 2007 [2]. They examined the cases of 18,751 in-hospital deceased patients, and they found one or more malignant neoplasms in 7289 patients. They also found cardiac metastasis in 662 of the patients (9.1 % of all), and the most common cancers among cardiac metastases were lung cancer (39.2 % of cardiac metastasis cases from lung cancer), breast cancer (10.0 %), mesothelioma (9.4 %) and lymphoma/leukemia (10.0 %). It was also shown that mesothelioma, melanoma and lung cancer have a relatively high potential for cardiac metastasis [2].\n\nBy contrast, cardiac metastasis from urothelial carcinoma is very rare. According to the autopsy study from Bussani et al. only 12 of 307 patients with urothelial carcinoma had cardiac metastasis [2]. In fact, to the best of our knowledge, only a small number of cases of symptomatic cardiac metastasis from urothelial carcinoma have been reported in the English literature. The reason for the rarity of cardiac metastasis from urothelial carcinoma is unclear. However, it may be due to the metastatic pathway of urothelial carcinoma. Malignant tumors metastasize to the heart by four alternative pathways: direct extension, hematogenous spread, lymphatic spread, and intracavitary extension from the inferior vena cava [3]. In epithelial malignancies, including urothelial carcinoma, distal metastasis occurred mainly by the lymphatic pathway [3]. However, in the heart, lymphatic flow is directly from the endocardium to the epicardium, and lymphatics drain from the heart to the mediastinum. It is therefore speculated that tumor cells cannot easily reach the heart without lymphatic flow stagnating due to tumor emboli [2]. This mechanism of the lymphatic system may play an important role in the rarity of cardiac metastasis from urothelial carcinoma.\n\nThe prognosis of cardiac metastasis from urothelial carcinoma is poor. Hattori et al. showed in a review of 14 cases that most patients died shortly after the original diagnosis or first visit [4]. Systemic chemotherapy or surgical resection of the tumor resulted in a prognosis of relatively long survival in only a few patients [5–8]. In our case, cardiac metastasis was detected by screening echocardiography for paroxysmal atrial fibrillation before the patient had any complaint, and systemic chemotherapy for urothelial carcinoma resulted in relatively long survival. Thus, early detection of cardiac metastasis and prostatic recurrence of carcinoma may have been important for the relatively long survival of our patient.\n\nIn addition, in our case, ECG showed characteristic abnormality (mild ST elevation and T inversion in V1–3). The exact cause of this ECG abnormality is unknown, but myocardial injury of the RV apex wall attributed to the metastatic tumor may have resulted in the ECG abnormality. A similar ECG abnormality was reported by Na et al. in a case of mimicking ST-segment elevation in myocardial infarction [9]. This case suggested that new onset ECG abnormality might provide a clue for the diagnosis of cardiac metastasis.\n\nConclusions\nWe experienced a case of a metastatic cardiac tumor from urothelial carcinoma. He received systemic chemotherapy and his survival period was relatively longer than previous reports. In metastasis to the heart, most patients are asymptomatic, and it is therefore important to detect ECG or echocardiographical abnormality, recognize cardiac metastasis, and start appropriate treatment as early as possible.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nYN wrote the report. KT, TK, NY and HK treated the patient in our cardiology department, and IY and TS treated the patient with chemotherapy. YN, KT, TK, NY and HK contributed to the revision. All authors read and approved the final manuscript.\n\nAcknowledgements\nAll authors have no disclosures in preparation of this manuscript.\n==== Refs\nReferences\n1. Al-Mamgani A Baartman L Baaijens M de Pree I Incrocci L Levendag PC Cardiac metastases Int J Clin Oncol. 2008 13 369 72 10.1007/s10147-007-0749-8 18704641 \n2. Bussani R De-Giorgio F Abbate A Silvestri F Cardiac metastases J Clin Pathol. 2007 60 27 34 10.1136/jcp.2005.035105 17098886 \n3. Burke A, Virmani R. Tumors of the heart and great vessels. Atlas of tumor pathology. 3rd ed. Washington DC: Armed forces institute of pathology; 1996. p. 195–209.\n4. Hattori S Miyajima A Maeda T Takeda T Morita S Kosaka T Metastatic urothelial carcinoma to pericardia manifested by dyspnea from cardiac tamponade during systemic chemotherapy: case report and literature review Can Urol Assoc J. 2012 6 E184 8 10.5489/cuaj.11130 23093641 \n5. Doshi TV Doshi JV Makaryus JN Makaryus AN A rare case of successfully treated cardiac metastasis from transitional cell bladder cancer Am J Ther. 2013 20 307 10 21436764 \n6. Shields AM Pomplun S Deshpande R Whitaker DC Right ventricular metastasis of transitional cell carcinoma of the renal pelvis: successful single stage surgical treatment Interact Cardiovasc Thorac Surg. 2011 12 297 300 10.1510/icvts.2010.256230 21051378 \n7. Spiliotopoulos K Argiriou M Argyrakos T Haritopoulos K Kanakakis K Sakellaridis T Solitary metastasis of urothelial carcinoma of the urinary bladder to the heart: an unusual clinical manifestation J Trorac Cardiovasc Surg. 2008 136 1377 8 10.1016/j.jtcvs.2007.11.046 \n8. Mountzios G Bamias A Dalianis A Danias P Pantelidaki E Nanas J Endocardial metastases as the only site of relapse in a patient with bladder carcinoma: a case report and review of the literature Int J Cardial. 2010 140 e4 7 10.1016/j.ijcard.2008.11.012 \n9. Na JO Choi CU Lim HE Cardiac metastasis of bladder cancer presented as mimicking ST segment elevation myocardial infarction Eur Heart J 2011 32 40 10.1093/eurheartj/ehq313 20729226\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "9()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002295:Carcinoma, Transitional Cell; D003841:Deoxycytidine; D004452:Echocardiography; D017809:Fatal Outcome; D006338:Heart Neoplasms; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure; D017239:Paclitaxel; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D019459:Urothelium",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "257",
"pmc": null,
"pmid": "26567955",
"pubdate": "2015-11-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19026837;21051378;23093641;18704641;20729226;17098886;21436764;19046610",
"title": "Metastatic cardiac tumor from urothelial carcinoma detected by transthoracic echocardiography: a case report.",
"title_normalized": "metastatic cardiac tumor from urothelial carcinoma detected by transthoracic echocardiography a case report"
} | [
{
"companynumb": "JP-ACCORD-036061",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Alternaria spp may cause opportunistic mycoses in the skin after cutaneous inoculation or through blood dissemination in immune-suppressed patients. Here, we describe a case of cutaneous infection with Alternaria spp in a 62-year-old man, presenting with multifocal papules and erythematous nodules involving distal limbs bilaterally. The absence of inflammatory bowel disease was confirmed by a gastroenterologist. The patient was under treatment for uveitis of unknown origin with immunosuppressive doses of cyclosporin and prednisolone for approximately 3 months. The diagnosis was based on clinical signs, demonstration of fungal elements in skin biopsies and deep fungal culture. Complete clinical remission was achieved by oral and systemic treatment with antifungal drugs. However, because cessation of the immunosuppressive medication was not possible, his clinical history was characterised by multiple flares requiring each time oral and intravenous antifungal treatment.",
"affiliations": "Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.;Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.;Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.;Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.",
"authors": "Satta|Rosanna|R|;Dore|Maria Pina|MP|;Pes|Giovanni Mario|GM|http://orcid.org/0000-0003-3265-2823;Biondi|Gabriele|G|",
"chemical_list": "D000935:Antifungal Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223857",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "dermatology; infectious diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000284:Administration, Oral; D000528:Alternaria; D060487:Alternariosis; D000935:Antifungal Agents; D003937:Diagnosis, Differential; D006801:Humans; D007049:Iatrogenic Disease; D007165:Immunosuppression Therapy; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29739763",
"pubdate": "2018-05-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22682192;25370461;22871097;25291955;18727797;21752048;25908651;15793517;24483780",
"title": "Iatrogenic immunosuppression may favour Alternaria skin lesion flares.",
"title_normalized": "iatrogenic immunosuppression may favour alternaria skin lesion flares"
} | [
{
"companynumb": "IT-EDENBRIDGE PHARMACEUTICALS, LLC-IT-2018EDE000182",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE"
... |
{
"abstract": "Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor derived from mesenchymal tissue. Although standard chemotherapy for SHT/HPC has not been established, temozolomide plus bevacizumab (TMZ+Bev) therapy for SFT/HPC has been reported. The effectiveness and safety of TMZ+Bev (temozolomide 150 mg/m2 orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle), which was administered from December 2013 until April 2019 to four patients with SFT/HPC, were retrospectively analyzed. Four patients with SFT/HPC received TMZ+Bev. The age of the patients ranged from 41 to 75 years. Two were male, and the primary tumor sites were the meninges in three patients and the pleura in one. One achieved partial response; the others, stable disease (SD). The progression-free survival time ranged from 9.4 to 29.6 months according to RECIST v1.1. One patient died 59 months after using TMZ+Bev, and the others survived for 17 to 64 months. All patients experienced Grade 3 or higher lymphopenia, and three had Grade 3 or higher leukopenia and neutropenia. One patient subsequently received doxorubicin; another, pazopanib. TMZ+Bev therapy for SFT/HPC is safe and effective for maintaining long-term SD.",
"affiliations": "Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Brain and Mind Research Center, Nagoya University, Nagoya, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.;Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.;Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.;Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.",
"authors": "Maeda|Osamu|O|;Ohka|Fumiharu|F|;Maesawa|Satoshi|S|;Matsuoka|Ayumu|A|;Shimokata|Tomoya|T|;Mitsuma|Ayako|A|;Urakawa|Hiroshi|H|;Nakamura|Shota|S|;Shimoyama|Yoshie|Y|;Nakaguro|Masato|M|;Wakabayashi|Toshihiko|T|;Ando|Yuichi|Y|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D000077204:Temozolomide",
"country": "Japan",
"delete": false,
"doi": "10.18999/nagjms.82.4.631",
"fulltext": "\n==== Front\nNagoya J Med Sci\nNagoya J Med Sci\nNagoya Journal of Medical Science\n0027-7622 2186-3326 Nagoya University \n\n10.18999/nagjms.82.4.631\nOriginal Paper\nSolitary fibrous tumor/hemangiopericytoma treated with temozolomide plus bevacizumab: a report of four cases and literature review\nMaeda Osamu 1 Ohka Fumiharu 2 Maesawa Satoshi 3 Matsuoka Ayumu 1 Shimokata Tomoya 1 Mitsuma Ayako 1 Urakawa Hiroshi 1 Nakamura Shota 4 Shimoyama Yoshie 5 Nakaguro Masato 5 Wakabayashi Toshihiko 2 Ando Yuichi 1 \n1 Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan\n\n2 Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n3 Brain and Mind Research Center, Nagoya University, Nagoya, Japan\n\n4 Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n5 Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan\nCorresponding Author: Osamu Maeda, MD, PhD\n\nDepartment of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan\n\nTel: +81-52-744-1903, Fax: +81-52-744-1903, E-mail: maeda-o@med.nagoya-u.ac.jp\n\n\n11 2020 \n82 4 631 644\n14 1 2020 19 3 2020 This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).ABSTRACT\nSolitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor derived from mesenchymal tissue. Although standard chemotherapy for SHT/HPC has not been established, temozolomide plus bevacizumab (TMZ+Bev) therapy for SFT/HPC has been reported. The effectiveness and safety of TMZ+Bev (temozolomide 150 mg/m2 orally on days 1–7 and days 15–21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle), which was administered from December 2013 until April 2019 to four patients with SFT/HPC, were retrospectively analyzed. Four patients with SFT/HPC received TMZ+Bev. The age of the patients ranged from 41 to 75 years. Two were male, and the primary tumor sites were the meninges in three patients and the pleura in one. One achieved partial response; the others, stable disease (SD). The progression-free survival time ranged from 9.4 to 29.6 months according to RECIST v1.1. One patient died 59 months after using TMZ+Bev, and the others survived for 17 to 64 months. All patients experienced Grade 3 or higher lymphopenia, and three had Grade 3 or higher leukopenia and neutropenia. One patient subsequently received doxorubicin; another, pazopanib. TMZ+Bev therapy for SFT/HPC is safe and effective for maintaining long-term SD.\n\nKey Words\nsolitary fibrous tumorhemangiopericytomatemozolomidebevacizumabchemotherapy\n==== Body\nINTRODUCTION\nSolitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) are rare mesenchymal neoplasms that may occur in any organ, including the pleura and central nervous system (CNS). Nuclear atypia, hypercellularity, more than 4 mitoses/10 HPFs, and necrosis are associated with aggressive clinical behavior.1 Extracranial metastatic disease of CNS SFT/HPC can occur in the bone, lung, and liver.2 Rarely, patients present with hyperglycemia (Doege-Potter Syndrome),3,4 which is associated with the production of a form of insulin-like growth factor, IGF-2.5,6\n\nClassically, SFT is characterized by CD34-positive spindle cells in a collagenous background with an elaborate vasculature that includes staghorn blood vessels.7 However, approximately 5 to 10% of SFTs are negative for CD34 expression. In addition, Ki-67 is a nuclear protein that is expressed in proliferating cells and is thus a surrogate indicator of the cellular proliferation rate. Ki-67 expression is reported to be related to the disease-free survival time of patients with SFT of the pleura.8\n\nIn the World Health Organization Classification of Tumors of Soft Tissue and Bone 2013, the subcategory of HPC was removed from the classification of extrapleural SFT because HPC included tumors that represented cellular examples of SFT, as well as other distinct tumor types that may histologically resemble SFT.9 On the other hand, neuropathologists retained the term HPC given its historical understanding and distinct clinicopathologic correlations, such as high recurrence rates and long-term risk of systemic metastasis.10\n\nRecently, both SFT and HPC have become to be considered variants of a single pathologic entity characterized by the presence of an NGFI-A Binding Protein 2 (NAB2) and Signal Transducer and Activator of Transcription 6 (STAT6) fusion protein.11-13 Therefore, in the World Health Organization Classification of Tumors of the Central Nervous System 2016, the combined term SFT/HPC was created to describe such lesions.10 Nuclear STAT6 signals in immunohistochemistry are reported to be useful for distinguishing HPC/SFT from other mesenchymal neoplasms.14-16\n\nAlthough various chemotherapeutic agents were tried to treat SFT/HPC, most of them showed insufficient effectiveness. Park et al reported the efficacy of combination chemotherapy with temozolomide plus bevacizumab (TMZ+Bev).17 Temozolomide is an imidazotetrazine derivative of the alkylating agent dacarbazine and is approved for the treatment of malignant glioma and Ewing sarcoma in Japan, and bevacizumab is an antibody that targets vascular endothelial growth factor (VEGF) and inhibits angiogenesis. In the present study, we analyzed the clinical course of patients with SFT/HPC who received TMZ+Bev in our hospital.\n\nPATIENTS AND METHODS\nPatientsl\nThis study was a retrospective analysis of the clinical course of patients with SFT/HPC who received TMZ+Bev from December 2013 until April 2019 at Nagoya University Hospital. Because the administration of these two drugs for this disease is not approved and is off-label in Japan, we conducted this study after approval of the institutional review board. This retrospective observational study was approved by the Ethics Review Board of Nagoya University Hospital (approval number 2019-0053).\n\nDiagnosis of SFT/HPC\nHistopathological diagnoses of SFT/HPC were made by expert pathologists using HE staining and immunohistochemical analyses for markers including CD34 and Ki-67. Additional immunohistochemical analysis of STAT6 was performed to confirm the diagnosis.\n\nChemotherapy\nAll patients received temozolomide 150 mg/m2 orally on days 1–7 and days 15–21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and Choi criteria.18 The toxicity profile was evaluated according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).\n\nRESULTS\nThe histopathological findings of SFT/HPC in all four patients revealed malignant characteristics including high cell density and/or mitosis (Fig. 2A, 4A, 6A and 8A). Strong nuclear staining with an anti-STAT6 antibody was observed in the tumors of all four cases (Fig. 2D, 4D, 6D and 8D). All four patients received TMZ+Bev. Patient characteristics and therapeutic effectiveness are summarized in Table 1, and adverse events are described in Table 2. The clinical course of each patient is as follows.\n\nFig. 1 Case 1\n\nFig. 1A: Magnetic resonance imaging (MRI) of brain tumor at tentorium cerebelli.\n\nFig. 1B and 1C: Computed tomography (CT) of lung metastases.\n\nFig. 1D and 1E: CT of pancreatic metastases.\n\nFig. 2 Histopathology of Case 1.\n\nFig. 2A: Growth of swollen spindle cells with necrosis and mitosis.\n\nFig. 2B: Partial CD34 positivity is observed.\n\nFig. 2C: The Ki-67 index is 20%.\n\nFig. 2D: Strong nuclear staining with anti-STAT6 antibody can be observed.\n\nTable 1 Patient characteristics and effectiveness of TMZ+Bev\n\n\t\t\t\tBest overall\n\nresponse\t\tProgression-free\n\nsurvival (months)\t\tOverall \nsurvival \n(months)\tPrognosis\t\nAge\tSex\tPrimary organ\tMetastases\tChoi\tRECIST\t\tChoi\tRECIST\t\t\n41\tM\tmeninges\tpancreas, lung\tSD\tSD\t\t26.4\t29.6\t\t64.4+\talive\t\n47\tF\tmeninges\tpelvis, bone\tSD\tSD\t\t8.9\t18.6\t\t20.7+\talive\t\n52\tF\tmeninges\tliver, lung\tSD\tSD\t\t9.4\t9.4\t\t59.0\tdied\t\n75\tM\tpleura\tlymph nodes, \nspleen, liver\tPR\tPR\t\t15.8\t15.8\t\t17.3+\talive\t\nTable 2 Adverse events of the four patients who received TMZ+Bev\n\n\tGrade 1\tGrade 2\tGrade 3\tGrade 4\t\nLeukopenia\t1\t\t3\t\t\nNeutropenia\t1\t\t3\t\t\nLymphopenia\t\t\t3\t1\t\nThrombocytopenia\t3\t1\t\t\t\nAnemia\t2\t\t1\t\t\nHemolysis\t\t\t1\t\t\nAnorexia\t2\t\t\t\t\nNausea\t2\t\t\t\t\nVomiting\t1\t\t\t\t\nDiarrhea\t2\t\t\t\t\nStomatitis\t1\t\t\t\t\nSkin rash\t\t1\t\t\t\nFatigue\t1\t\t\t\t\nProteinuria\t2\t2\t\t\t\nHypoalbuminemia\t4\t\t\t\t\nAST increased\t2\t\t\t\t\nALT increased\t3\t\t\t\t\nγ GTP increased\t2\t\t\t\t\nALP increased\t2\t\t\t\t\nLDH increased\t2\t\t\t\t\nCase 1\nA 41-year-old man underwent surgery for brain tumor nine years ago. He received stereotactic radiation therapy for local recurrence (Fig. 1A). Metastases in the lung (Fig. 1B, 1C) and pancreas (Fig. 1D, 1E) were diagnosed, and TMZ+Bev was started. Three months after starting TMZ+Bev, he underwent surgical resection for a recurrent brain tumor (Fig. 2). Although the disease progressed in nine months before starting TMZ+Bev, the patient maintained stable disease (SD) for over 24 months. He experienced autoimmune hemolytic anemia, which resolved after corticosteroid administration and was not exacerbated despite restarting TMZ+Bev after two months of cessation. Therefore, the cause of the hemolytic anemia was unlikely to be related to TMZ+Bev. Because his metastatic tumors grew very slowly and the adverse effects were tolerable, TMZ+Bev was continued for over five years.\n\nCase 2\nA 47-year-old woman underwent surgery and radiation therapy for brain tumors 22 years ago (Fig. 3A). She experienced buttock pain, and multiple bone metastases including in the right pelvis (Fig. 3B) and vertebrae (Fig. 3C) were diagnosed five years ago. Biopsy from the right pelvis was performed to confirm that the metastasis was SFT/HPC (Fig. 4). She underwent palliative radiation therapy (30 Gy in 10 fractions) for metastases in the 6th to 8th thoracic vertebrae. TMZ+Bev was initiated, and the patient maintained SD for approximately nine months and 19 months according to the Choi criteria and RECIST, respectively. Metastatic progression occurred gradually, and thus, TMZ+Bev was continued for 20 months. She experienced minimal adverse effects.\n\nFig. 3 Case 2\n\nFig. 3A: MRI of brain tumor at the right occipital lobe.\n\nFig. 3B: CT of metastasis at the right ilium.\n\nFig. 3C: CT of metastasis at the seventh thoracic vertebra.\n\nFig. 4 Histopathology of Case 2.\n\nFig. 4A: Dense growth of spindle-shaped cells with a round nuclear shape.\n\nFig. 4B: Slight CD34 positivity can be observed.\n\nFig. 4C: The Ki-67 index is 15%.\n\nFig. 4D: Strong nuclear staining with anti-STAT6 antibody can be observed.\n\nCase 3\nA 52-year-old woman underwent surgery and radiation therapy for brain tumors 18 years ago. She was diagnosed with liver metastasis five years ago (Fig. 5A) and underwent partial hepatectomy (Fig. 6). Four months ago, local recurrence (Fig. 5B) and metastases in the liver (Fig. 5C) and the lung (Fig. 5D) were diagnosed and progressed over approximately three months. TMZ+Bev was initiated, and the patient maintained SD for nine months. One year and nine months after the start of TMZ+BEV, liver metastasis progressed. Although pazopanib was administered, it was not effective. TMZ+Bev was restarted, but the disease continued to progress. She died four years and eleven months after the initial administration of TMZ+Bev.\n\nFig. 5 Case 3\n\nFig. 5A: Liver metastases before hepatectomy.\n\nFig. 5B: Recurrence of brain tumor contact to the falx cerebri and the tentorium cerebelli.\n\nFig. 5C: Recurrence of liver metastasis.\n\nFig. 5D: Lung metastases.\n\nFig. 6 Histopathology of Case 3.\n\nFig. 6A: Growth of spindle-shaped cells with oval nuclei.\n\nFig. 6B: CD34 positivity can be observed.\n\nFig. 6C:The Ki-67 index is 3–4%.\n\nFig. 6D: Strong nuclear staining with anti-STAT6 antibody can be observed.\n\nCase 4\nA 75-year-old man underwent surgery for a left pleural tumor one year and one month ago (Fig. 7A, 8). Metastases in lymph nodes (Fig. 7B), the spleen (Fig. 7D) and the liver (Fig. 7E) were diagnosed, and TMZ+Bev was initiated. The paratracheal lymph nodes (Fig. 7B) and subcarinal lymph nodes shrank (Fig. 7C), and splenic metastasis (Fig. 7D) was undetectable after TMZ+Bev treatment. The liver metastases (Fig. 7E) were unchanged. He achieved partial response (PR) five months after the initiation of TMZ+Bev. However, liver metastasis progressed 16 months after the initial administration TMZ+Bev (Fig. 7F). He received doxorubicin as a second-line chemotherapy regimen.\n\nFig. 7 Case 4\n\nFig. 7A: Left intrathoracic tumor before surgery.\n\nFig. 7B and 7C: Paratracheal lymph node metastases before (B) and after (C) TMZ+Bev.\n\nFig. 7D: Splenic metastasis before TMZ+Bev\n\nFig. 7E: Liver metastases before TMZ+Bev\n\nFig. 7F: Liver metastases progressed 16 months after the initiation of TMZ+Bev.\n\nFig. 8 Histopathology of Case 4.\n\nFig. 8A: Growth of spindle-shaped cells with oval nuclei.\n\nFig. 8B: CD34 positivity can be observed.\n\nFig. 8C: The Ki-67 index is 3–4%.\n\nFig. 8D: Strong nuclear staining with anti-STAT6 antibody can be observed.\n\nDISCUSSION\nOut of four patients who received TMZ+Bev, one (Case 4) achieved PR. According to the CT and/or MRI findings for postoperative surveillance before TMZ+Bev, the metastatic progression of two patients (Cases 1 and 3) seemed to be suppressed because the time to progression was prolonged after the administration of TMZ+Bev. Because the toxicities due to TMZ+Bev were tolerable, the treatment can be continued for years in some cases.\n\nAlthough only one patient achieved PR, all four patients maintained SD for a long duration. The reason for the discrepancy is not clear. The number of cases in this study is too small to analyze the issue. However, one possible explanation is the heterogeneity of the characteristics. The size of tumor, duration between diagnosis and the initiation of TMZ+Bev, and locations of the primary lesion and metastases were different for the patients. Tumor shrinkage and the duration of effectiveness might depend on such characteristics. In addition, no patients in the present study showed a significant decrease in the tumor density on contrast-enhanced CT. Although we analyzed the CT images according to previously reported methods, the conditions including the selection of the regions of interest (ROI), the timing of the scan and the method of injection of the contrast media might not be exactly the same as in the institutions that reported the effectiveness according to the Choi criteria.\n\nThe precise pharmacological mechanisms of TMZ+Bev have not been fully elucidated.17 Bevacizumab may enhance the cytotoxic activity of temozolomide. The VEGF–VEGF receptor pathway could be a potential key therapeutic target in HPC/SFT. As described below, tyrosine kinase inhibitors, of which the VEGF receptor is a target, have also demonstrated evidence of activity in HPC/SFT.\n\nRecent reports of SFT/HPC adopt both RECIST and Choi criteria to evaluate the treatment efficacy. Choi criteria are developed as an evaluation method of treatment efficacy for gastrointestinal stromal tumors (GISTs) with imatinib, which measures tumor diameter and tumor density in computed tomography (CT) with contrast enhancement and is reported to have good correlation according to [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET).18 Of the four patients presented here, none showed a significant decrease in density on contrast-enhanced CT.\n\nThere is no established standard chemotherapy regimen for SFT/HPC. Previous reports of chemotherapy for SFT/HPC are summarized in Table 3.\n\nTable 3 Previous reports of chemotherapy regimens for SFT/HPC\n\n\tResponse\t\t\t\t\t\n\tNumber\n\nof\n\npatients\t\tEvaluation\tNumber\n\nof\n\nevaluable\n\npatients\tPR (%)\t\tSD (%)\t\tPD (%)\t\tPFS\n\n(months)\tOS\n\n(months)\tReference\t\nChemotherapy regimen\t\nanthracycline-based *1\t17\t\tRECIST\t17\t1\t(5.9)\t\t13\t(76.5)\t\t3\t(17.6)\t\t4.2\t14.6\t19\t\ndoxorubicin-based *2\t15\t\tRECIST\t15\t0\t(0)\t\t14\t(93.3)\t\t1\t(6.7)\t\t4.6\t22.8\t20\t\ngemcitabine-based *3\t2\t\tRECIST\t2\t0\t(0)\t\t1\t(50)\t\t1\t(50)\t\t\t\t\t\npaclitaxel\t1\t\tRECIST\t1\t0\t(0)\t\t1\t(100)\t\t0\t(0)\t\t\t\t\t\nanthracycline-based *4\t30\t\tRECIST\t30\t6\t(20)\t\t8\t(26.7)\t\t17\t(56.7)\t\t4\t–\t21\t\nbevacizumab monotherapy\t7\t\tRECIST\t7\t2\t(28.6)\t\t4\t(57.1)\t\t1\t(14.3)\t\t9\t32.8\t22\t\ntemozolomide plus\n\nbevacizumab\t14\t\tRECIST\t14\t2\t(14.3)\t\t12\t(85.7)\t\t0\t(0)\t\t10.8\t24.3\t17\t\n\tChoi\t14\t11\t(78.6)\t\t2\t(14.3)\t\t1\t(7.1)\t\t9.7\t\ndacarbazine\t8\t\tRECIST\t8\t3\t(37.5)\t\t4\t(50)\t\t1\t(12.5)\t\t7\t–\t23\t\ntrabectedin\t11\t\tRECIST\t11\t1\t(9.1)\t\t8\t(72.7)\t\t2\t(18.2)\t\t11.6\t22.3\t25\t\npazopanib\t13\t\tRECIST\t13\t1\t(7.7)\t\t8\t(61.5)\t\t2\t(15.4)\t\t4.7\t13.3\t26\t\n\t\t\tChoi\t11\t5\t(45.5)\t\t4\t(36.4)\t\t2\t(18.2)\t\t\t\t\t\npazopanib\t36\t\tRECIST\t36\t2\t(5.6)\t\t21\t(58.3)\t\t12\t(33.3)\t\t5.6\tnot reached\t27\t\n\tChoi\t35\t18\t(51.4)\t\t9\t(25.7)\t\t8\t(22.9)\t\t5.6\t\nsorafenib\t5\t\tRECIST\t5\t0\t(0)\t\t–\t\t\t–\t\t\t–\t19.7\t28\t\nsunitinib\t35\t\tRECIST\t31\t2\t(6.5)\t\t16\t(51.6)\t\t13\t(41.9)\t\t6\t16\t29\t\n\tChoi\t29\t14\t(48.3)\t\t5\t(17.2)\t\t10\t(34.5)\t\t7\t\naxitinib\t17\t\tRECIST\t17\t1\t(5.9)\t\t14\t(82.4)\t\t2\t(11.8)\t\t9.4\t25.3\t30\t\n\t\t\tChoi\t17\t7\t(41.2)\t\t6\t(35.3)\t\t4\t(23.5)\t\t5.1\t\t\t\n*1: Doxorubicin (Dox) monotherapy for 14 patients, ifosfamide (Ifos) + epirubicin (Epi) for 1 patient, Ifos + Dox for 1 patient and dacarbazine (DTIC) + Ifos + Dox for 1 patient.\n\n*2: Dox + Ifos for 12 patients, Dox + DTIC for 1 patient, Dox + cisplatin for 1 patient and Dox monotherapy for 1 patient.\n\n*3: Gemcitabine (Gem) monotherapy for 1 patient and Gem + docetaxel for 1 patient.\n\n*4: Epi + Ifos for 22 patients, Dox for 7 patients and Epi for 1 patient.\n\nConstantinidou et al reported that conventional anthracycline-based chemotherapy has limited efficacy.19 Of 24 patients, 17 received anthracycline-based chemotherapy, three received axitinib, two received TMZ+Bev, one received trabectedin and one received an experimental drug. The overall survival (OS) time from the time of diagnosis for these 24 patients was 46 months.\n\nAccording to a report by Park et al,20 of 21 patients, 4 received more than 1 regimen of chemotherapy for a total of 25 treatments. Of 18 patients who received first-line chemotherapy, no patients achieved complete response (CR) or PR, and 16 (89%) experienced SD. Five patients maintained SD for at least 6 months after first-line treatment. The median OS time from diagnosis was 10.3 years.\n\nStacchiotti et al reported 42 patients treated with chemotherapy.21 Among the 31 patients who received anthracycline-based chemotherapy, 30 patients could be evaluated. The overall PFS time was 4 months, and 20% of patients were progression-free at 6 months.\n\nThe effectiveness of bevacizumab monotherapy was reported by Agulnik et al22 Of the seven patients, two (29%) experienced PR, while only one (14%) experienced PD at the first evaluation. Combination treatment with TMZ+Bev was reported by Park et al17 for the first time. Of 14 patients, 11 (79%) achieved PR according to Choi criteria, with a median time to response of 2.5 months. The most frequently observed toxic effect was myelosuppression. Both dacarbazine and temozolomide are triazene compounds. The effectiveness of dacarbazine has also been reported.23\n\nEribulin and trabectedin, cytotoxic drugs that are used for soft tissue sarcoma, have been reported as treatment agents for SFT/HPC. Of 128 patients treated with eribulin,24 there was one patient with SFT in whom drug activity was reported. The efficacy of trabectedin was reported in eleven patients with advanced SFT.25 Moreover, it has been used as second-line therapy in 8 patients (73%) and as at least third-line therapy in another 3 (27%).\n\nAs there are angiogenesis inhibitors other than bevacizumab, the efficacy of several small molecule compounds has been reported. In a prospective study with 13 patients treated with pazopanib as a first-line treatment for metastatic disease,26 the median OS time was 13.3 months, and the median PFS time was 4.7 months. Using the Choi criteria, 5 achieved PR (46%) and 4 maintained SD (36%). In a phase II trial of pazopanib,27 36 were enrolled (34 with malignant SFT and two with dedifferentiated SFT). Of the 35 patients evaluated, 18 (51%) achieved PR, and nine (26%) experienced SD according to the Choi criteria. The administration of sorafenib has also been reported.28 Two of five patients achieved disease control with sorafenib for 9 months, while disease progression occurred within the month preceding their inclusion. For sunitinib,29 of 31 patients, two achieved PR, and 16 experienced SD. A <30% decrease in size was observed in three patients. Fourteen of 29 patients evaluated according to the Choi criteria achieved PR. The median PFS by RECIST was 6 months. In two of six patients, sunitinib resistance was overcome by increasing the dose to 50 mg/day. The use of axitinib has also been reported.30 Of 17 patients, the best responses according to the Choi criteria were PR in seven patients and SD in six patients. The best responses according to RECIST were PR in one patient and SD in 14 patients. The median Choi-PFS time was 5.1 months. The median Choi-PFS times were 14.8 and 2.8 months for responsive and nonresponsive patients, respectively. The median OS time was 25.3 months.\n\nAs described above, various chemotherapies for SFT/HPC have been reported. These chemotherapeutic regimens can be divided into three groups. One is traditional chemotherapy with cytotoxic agents for soft tissue sarcoma such as doxorubicin, ifosfamide, and taxanes. Another is temozolomide + bevacizumab or bevacizumab monotherapy. The third is tyrosine kinase inhibitors including pazopanib, sorafenib and sunitinib. Since traditional cytotoxic chemotherapies have limited effectiveness, other options have been developed.\n\nThere are some limitations in the present study. First, because the incidence of SFT/HPC is very rare, the number of cases is small. Second, since this is a retrospective analysis, the treatment plan was dependent on each physician. Third, the tumors’ primary lesions were located in the meninges and thorax. Since tumors with different primary lesions might have different biological characteristics, the therapeutic effect and clinical courses of various tumors might not be the same.\n\nCONCLUSION\nTMZ+Bev for SFT/HPC is safe, effective and can be continued long-term. An optimized treatment strategy for SFT/HPC should be established.\n\nCONFLICTS OF INTEREST\nYuichi Ando received research funding from Chugai Pharmaceutical Co., Ltd., outside the submitted work. The other authors have no conflicts of interest to disclose.\n\nAbbreviations\nBevBevacizumab\n\nCRComplete response\n\nHPCHemangiopericytoma\n\nOSOverall survival\n\nPDProgressive disease\n\nPFSProgression-free survival\n\nPRPartial response\n\nRECIST criteriaResponse Evaluation Criteria in Solid Tumors\n\nSDStable disease\n\nSFTSolitary fibrous tumor\n\nSTAT6Signal Transducer and Activator of Transcription 6\n\nTMZTemozolomide\n==== Refs\nREFERENCES\n1. Vallat-Decouvelaere AV, Dry SM, Fletcher CD. Atypical and malignant solitary fibrous tumors in extrathoracic locations: evidence of their comparability to intra-thoracic tumors. Am J Surg Pathol. 1998;22(12):1501–1511.\n2. Metellus P, Bouvier C, Guyotat J, et al. Solitary fibrous tumors of the central nervous system: clinicopathological and therapeutic considerations of 18 cases. Neurosurgery. 2007;60(4):715–722; discussion 722. DOI: 10.1227/01.NEU.0000255418.93678.AD\n3. Chamberlain MH, Taggart DP. Solitary fibrous tumor associated with hypoglycemia: an example of the Doege-Potter syndrome. J Thorac Cardiovasc Surg. 2000;119(1):185–187.\n4. Balduyck B, Lauwers P, Govaert K, Hendriks J, De Maeseneer M, Van Schil P. Solitary fibrous tumor of the pleura with associated hypoglycemia: Doege-Potter syndrome: a case report. J Thorac Oncol. 2006;1(6):588–590.\n5. de Groot JW, Rikhof B, van Doorn J, et al. Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases. Endocr Relat Cancer. 2007;14(4):979–993. DOI: 10.1677/ERC-07-0161\n6. Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab. 2014;99(3):713–722. DOI: 10.1210/jc.2013-3382\n7. Cheah AL, Billings SD, Goldblum JR, Carver P, Tanas MZ, Rubin BP. STAT6 rabbit monoclonal antibody is a robust diagnostic tool for the distinction of solitary fibrous tumour from its mimics. Pathology. 2014;46(5):389–395. DOI: 10.1097/PAT.0000000000000122\n8. Franzen D, Diebold M, Soltermann A, et al. Determinants of outcome of solitary fibrous tumors of the pleura: an observational cohort study. BMC Pulm Med. 2014;14:138. DOI: 10.1186/1471-2466-14-138\n9. Doyle LA. Sarcoma classification: an update based on the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone. Cancer. 2014;120(12):1763–1774. DOI: 10.1002/cncr.28657\n10. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–820. DOI: 10.1007/s00401-016-1545-1\n11. Chmielecki J, Crago AM, Rosenberg M, et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet. 2013;45(2):131–132. DOI: 10.1038/ng.2522\n12. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet. 2013;45(2):180–185. DOI: 10.1038/ng.2509\n13. Mohajeri A, Tayebwa J, Collin A, et al. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosomes Cancer. 2013;52(10):873–886. DOI: 10.1002/gcc.22083\n14. Schweizer L, Koelsche C, Sahm F, et al. Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol. 2013;125(5):651–658. DOI: 10.1007/s00401-013-1117-6\n15. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol. 2014;27(3):390–395. DOI: 10.1038/modpathol.2013.164\n16. Fritchie KJ, Jin L, Rubin BP, et al. NAB2-STAT6 Gene Fusion in Meningeal Hemangiopericytoma and Solitary Fibrous Tumor. J Neuropathol Exp Neurol. 2016;75(3):263–271. DOI: 10.1093/jnen/nlv026\n17. Park MS, Patel SR, Ludwig JA, et al. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor. Cancer. 2011;117(21):4939–4947. DOI: 10.1002/cncr.26098\n18. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25(13):1753–1759. DOI: 10.1200/JCO.2006.07.3049\n19. Constantinidou A, Jones RL, Olmos D, et al. Conventional anthracycline-based chemotherapy has limited efficacy in solitary fibrous tumour. Acta Oncol. 2012;51(4):550–554. DOI: 10.3109/0284186X.2011.626450\n20. Park MS, Ravi V, Conley A, et al. The role of chemotherapy in advanced solitary fibrous tumors: a retrospective analysis. Clin Sarcoma Res. 2013;3(1):7. DOI: 10.1186/2045-3329-3-7\n21. Stacchiotti S, Libertini M, Negri T, et al. Response to chemotherapy of solitary fibrous tumour: a retrospective study. Eur J Cancer. 2013;49(10):2376–2383. DOI: 10.1016/j.ejca.2013.03.017\n22. Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013;24(1):257–263. DOI: 10.1093/annonc/mds237\n23. Stacchiotti S, Tortoreto M, Bozzi F, et al. Dacarbazine in solitary fibrous tumor: a case series analysis and preclinical evidence vis-a-vis temozolomide and antiangiogenics. Clin Cancer Res. 2013;19(18):5192–5201. DOI: 10.1158/1078-0432.CCR-13-0776\n24. Schöffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol. 2011;12(11):1045–1052. DOI: 10.1016/S1470-2045(11)70230-3\n25. Khalifa J, Ouali M, Chaltiel L, et al. Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group. BMC Cancer. 2015;15:700. DOI: 10.1186/s12885-015-1697-8\n26. Maruzzo M, Martin-Liberal J, Messiou C, et al. Pazopanib as first line treatment for solitary fibrous tumours: the Royal Marsden Hospital experience. Clin Sarcoma Res. 2015;5:5. DOI: 10.1186/s13569-015-0022-2\n27. Martin-Broto J, Stacchiotti S, Lopez-Pousa A, et al. Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2019;20(1):134–144. DOI: 10.1016/S1470-2045(18)30676-4\n28. Valentin T, Fournier C, Penel N, et al. Sorafenib in patients with progressive malignant solitary fibrous tumors: a subgroup analysis from a phase II study of the French Sarcoma Group (GSF/GETO). Invest New Drugs. 2013;31(6):1626–1627. DOI: 10.1007/s10637-013-0023-z\n29. Stacchiotti S, Negri T, Libertini M, et al. Sunitinib malate in solitary fibrous tumor (SFT). Ann Oncol. 2012;23(12):3171–3179. DOI: 10.1093/annonc/mds143\n30. Stacchiotti S, Simeone N, Lo Vullo S, et al. Activity of axitinib in progressive advanced solitary fibrous tumour: Results from an exploratory, investigator-driven phase 2 clinical study. Eur J Cancer. 2019;106:225–233. DOI: 10.1016/j.ejca.2018.10.024\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0027-7622",
"issue": "82(4)",
"journal": "Nagoya journal of medical science",
"keywords": "bevacizumab; chemotherapy; hemangiopericytoma; solitary fibrous tumor; temozolomide",
"medline_ta": "Nagoya J Med Sci",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006393:Hemangiopericytoma; D006801:Humans; D008297:Male; D008579:Meningioma; D008875:Middle Aged; D009367:Neoplasm Staging; D010043:Outcome and Process Assessment, Health Care; D010997:Pleural Neoplasms; D000077982:Progression-Free Survival; D012074:Remission Induction; D054364:Solitary Fibrous Tumors; D000077204:Temozolomide",
"nlm_unique_id": "0412011",
"other_id": null,
"pages": "631-644",
"pmc": null,
"pmid": "33311794",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9850176;25664166;30578023;23575898;24030747;23761323;24005614;22711763;24423303;22023088;22910841;24648013;27157931;25115286;21480200;17415209;17409923;23663788;18045950;10612786;23313954;23313952;26472661;17470865;30528807;26883114;24977739;23888069;21937277;23566418",
"title": "Solitary fibrous tumor/hemangiopericytoma treated with temozolomide plus bevacizumab: a report of four cases and literature review.",
"title_normalized": "solitary fibrous tumor hemangiopericytoma treated with temozolomide plus bevacizumab a report of four cases and literature review"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-320128",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "An Asian man presented to the Foot and Ankle Clinic with a 5-month history of right ankle pain of gradual onset. He had a non-fluctuant swelling around the Achilles tendon insertion with a tender palpable lump. Radiograph demonstrated Haglund's deformity and also possible calcification at the attachment of the Achilles tendon for which he had an injection of a local anaesthetic and a steroid to treat the insertional Achilles tendinitis. A few months later, he developed acute anorexia, abdominal distension secondary to ascites and groin lymphadenopathy. Histology of the lymph node biopsy revealed granulomatous lymphadenitis consistent with tuberculosis (TB) and started on quadruple agent anti-TB treatment. The sample was not cultured. He developed constant ooze from his groin lymph node biopsy site and also fluctuance around the Achilles tendon and heel. Pus from the heel stained positive for auramine indicating TB calcaneum with subsequent culture for acid fast bacilli (AFB) confirming diagnosis of TB calcaneum.",
"affiliations": "Bone Tumour Unit, Royal National Orthopaedic Hospital, Stanmore, UK. elizabethgillott@hotmail.com",
"authors": "Gillott|Elizabeth|E|;Ray|Pinak|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002111:Calcaneus; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D011859:Radiography; D014376:Tuberculosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23709539",
"pubdate": "2013-05-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9571457;18785421;16624213;21519128;10615974;15249832;11964626;11964638;17340138;8894337;10954440;1483611;22735321;8314185;12512406",
"title": "Tuberculosis of the calcaneum masquerading as Haglund's deformity: a rare case and brief literature review.",
"title_normalized": "tuberculosis of the calcaneum masquerading as haglund s deformity a rare case and brief literature review"
} | [
{
"companynumb": "GB-RANBAXY-2015R1-92113",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nUntreated invasive aspergillosis (IA) is lethal, yet diagnosis is often delayed. Recognising the risk factors can lead to earlier diagnosis. We present a case of an invasive pulmonary aspergillosis in a patient with cirrhosis, who had been treated with corticosteroids for 2.5 weeks for alcoholic hepatitis. He was successfully treated with liposomal amphotericin B and caspofungin (first in combination, then caspofungin monotherapy).\n\n\nOBJECTIVE\nTo evaluate the role of aspergillosis in cirrhosis.\n\n\nMETHODS\nA literature search on aspergillosis in cirrhosis and liver failure patients was conducted in PubMed/Medline (2002-dec 2012), according to pre-set selection criteria.\n\n\nRESULTS\n20 out of 330 articles were retrieved, representing 43 patients with cirrhosis and/or liver failure who had an aspergillosis infection. Most Aspergillus (A.) infections were due to A. fumigatus and the lungs were the most frequent organ involved (42/43). 58% of the patients used steroids and mortality was 53.5%. The most frequent used antifungal was caspofungin.\n\n\nCONCLUSIONS\nDiagnosis of IA is difficult and there might be a delay in diagnosis since cirrhosis is not recognised as one of the classical risk factors. Mortality was 53.5%, but this is lower than in previous decades. Since voriconazole is hepatotoxic, treatment with caspofungin and/or amphotericin is preferable.\n\n\nCONCLUSIONS\nEarly recognition of aspergillosis in a cirrhosis/liver failure patient is crucial and should prompt direct treatment.",
"affiliations": "Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium. sarah.jeurissen@ugent.be;Department of General Internal Medicine and Infectious Diseases, Ghent University, Ghent, Belgium.;Department of General Internal Medicine and Infectious Diseases, Ghent University, Ghent, Belgium.;Department of Internal Medicine, Hospital \"AZ Gezondheidszorg\", Oostkust, campus \"OLV Ter Linden\", Knokke, Belgium.;Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.;Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.;Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.",
"authors": "Jeurissen|S|S|;Vogelaers|D|D|;Sermijn|E|E|;Van Dycke|K|K|;Geerts|A|A|;Van Vlierberghe|H|H|;Colle|I|I|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; C068538:liposomal amphotericin B; D000666:Amphotericin B; D000077336:Caspofungin",
"country": "England",
"delete": false,
"doi": "10.2143/ACB.3408",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "68(5)",
"journal": "Acta clinica Belgica",
"keywords": null,
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D000077336:Caspofungin; D054714:Echinocandins; D006801:Humans; D016867:Immunocompromised Host; D055744:Invasive Pulmonary Aspergillosis; D055666:Lipopeptides; D008104:Liver Cirrhosis, Alcoholic; D008297:Male; D012307:Risk Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "368-75",
"pmc": null,
"pmid": "24579244",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Invasive aspergillosis in patients with cirrhosis, a case report and review of the last 10 years.",
"title_normalized": "invasive aspergillosis in patients with cirrhosis a case report and review of the last 10 years"
} | [
{
"companynumb": "BE-PFIZER INC-2020178548",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CASPOFUNGIN"
},
"drugadditional": null,
... |
{
"abstract": "A 69-year-old female living donor kidney transplant recipient presented with right facial painful edema. The patient's body mass index was 14 (kilograms per meter squared), and her creatinine clearance was 15 mL/min. A computed tomography detected a subcutaneous mass under the nasolabial fold in contact with the maxillary bone. A biopsy from an ipsilateral oral mucosal ulcer returned the diagnosis of Epstein-Barr virus-positive mucocutaneous ulcer. Within 2 weeks, the lesion perforated the tissue. The mass and the affected bone were removed, and histopathology detected inflammation with many microorganisms. The opportunistic pathogen Streptococcus anginosus was isolated from wound cultures. Immunosuppressives were restricted, antibiotics were administered, and the patient started hemodialysis. Rituximab was applied for the lymphoproliferative disease. The lesion healed, allowing for surgical restoration. Two years later, the patient has remained free of local pathology and with improved nutritional and functional status. Epstein-Barr virus-positive muco cutaneous ulcers should be considered in the differential diagnosis of oral and facial lesions of immunocompromised patients and may be complicated with bacterial infections.",
"affiliations": "From the Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece.",
"authors": "Eleftheriadis|Theodoros|T|;Rountas|Christos|C|;Golfinopoulos|Spyridon|S|;Liakopoulos|Vassilios|V|;Stefanidis|Ioannis|I|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2021.0053",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "19(8)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": null,
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "868-870",
"pmc": null,
"pmid": "34085910",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Kidney Transplant Recipient With a Perforated Cheek: Oral Epstein-Barr Virus-Positive Mucocutaneous Ulcer Complicated With an Opportunistic Bacterial Infection.",
"title_normalized": "a kidney transplant recipient with a perforated cheek oral epstein barr virus positive mucocutaneous ulcer complicated with an opportunistic bacterial infection"
} | [
{
"companynumb": "GR-TEVA-2022-GR-2018922",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1"... |
{
"abstract": "This is a case of a 23-year-old African American male with a history of paranoid schizophrenia that developed neutropenia on a clozapine-topiramate therapy. Clozapine had well addressed the patient's psychotic symptoms, while topiramate was used as a weight-lowering agent. The patient had fairly stable leukocyte counts for eight months on clozapine 300 mg and topiramate 100 mg daily. Doubling the dosage of topiramate led to severe neutropenia after two months. Reviewing the patient's laboratory reports showed a gradual decline of neutrophils occurring at a lower dosage, followed by a rapid decline after an increased dosage. In this case, we report that not only did topiramate act as the neutropenic agent, but also it might have done so in a dose-dependent manner.",
"affiliations": "Department of Psychiatry, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 8103, Lubbock, TX 79430, USA.;Department of Psychiatry, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 8103, Lubbock, TX 79430, USA.;Department of Psychiatry, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 8103, Lubbock, TX 79430, USA.;Department of Psychiatry, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 8103, Lubbock, TX 79430, USA.",
"authors": "Sharma|Pravesh|P|;Davis|Jeffrey|J|;Rachamallu|Vivekananda|V|;Aligeti|Manish|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/6086839",
"fulltext": "\n==== Front\nCase Rep PsychiatryCase Rep PsychiatryCRIPSCase Reports in Psychiatry2090-682X2090-6838Hindawi Publishing Corporation 10.1155/2016/6086839Case ReportConcomitant Use of Topiramate Inducing Neutropenia in a Schizophrenic Male Stabilized on Clozapine Sharma Pravesh \n*\nDavis Jeffrey Rachamallu Vivekananda Aligeti Manish Department of Psychiatry, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 8103, Lubbock, TX 79430, USA*Pravesh Sharma: pravesh.sharma@ttuhsc.eduAcademic Editor: Toshiya Inada\n\n2016 24 1 2016 2016 608683915 11 2015 31 12 2015 Copyright © 2016 Pravesh Sharma et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This is a case of a 23-year-old African American male with a history of paranoid schizophrenia that developed neutropenia on a clozapine-topiramate therapy. Clozapine had well addressed the patient's psychotic symptoms, while topiramate was used as a weight-lowering agent. The patient had fairly stable leukocyte counts for eight months on clozapine 300 mg and topiramate 100 mg daily. Doubling the dosage of topiramate led to severe neutropenia after two months. Reviewing the patient's laboratory reports showed a gradual decline of neutrophils occurring at a lower dosage, followed by a rapid decline after an increased dosage. In this case, we report that not only did topiramate act as the neutropenic agent, but also it might have done so in a dose-dependent manner.\n==== Body\n1. Introduction\nAtypical antipsychotics have been preferred over first-generation or typical antipsychotics due to their decreased extrapyramidal side effects [1]. However, they are also associated with metabolic syndrome, particularly weight gain, and clozapine has been shown to have the greatest impact on weight gain among all atypical antipsychotics [2]. A common method of countering this effect is treatment with topiramate [3]. In a 12-week naturalistic, open study to understand the benefits of topiramate in individuals suffering from schizophrenia and treated with clozapine, topiramate augmentation led to a 2.5% decrease in body weight (P = 0.015). A meta-analysis of nine studies examining its use in nonpsychiatric patients for treatment of obesity found a 6.5% rate of weight loss at 6 months [4]. Clozapine has also been well known to cause leukopenia, particularly neutropenia. Regular laboratory interventions are mandated when a patient is started on clozapine as per guidelines [5]. Typically, topiramate is not considered a neutropenic agent, but the effects of cotherapy on decrease in leukocytes have not been thoroughly studied or reported.\n\n2. Case Report\nMr. S, a 23-year-old African American male with the diagnosis of paranoid schizophrenia, was hospitalized in our inpatient psychiatric hospital approximately 15 months ago. The patient had failed trials of several typical and atypical antipsychotics. Leading up to the admission, he was having religious delusions, ideas of reference, and thoughts of cutting his arm (he had lacerated his arm prior to that admission). He was displaying thought blocking and poverty of speech. His laboratory data, including complete blood count, basal metabolic profile, and thyroid function tests, were within normal limits. His urine drug screen was negative except for cannabinoids and blood alcohol level was less than 5 milligram per deciliter. Based on that, he was started on clozapine. He was discharged with a dosage of 200 mg of clozapine daily and was instructed to return to outpatient psychiatry clinic in a week. During that appointment, the patient continued to exhibit psychotic symptoms and also had gained considerable weight (345.7 pounds, body mass index of 42.7 kg/m2). Subsequently, clozapine was increased to 250 mg per day for one week and to 300 mg per day thereafter. In addition, topiramate was initiated at 25 mg per day for one week and 50 mg per day for the following two weeks and then finally increased to 100 mg per day until the following appointment. Mr. S continued clozapine 300 mg daily and topiramate 100 mg daily for the following eight months, during which his WBC and ANC were within the normal range. After eight months on this regimen, his weight continued to increase (370.2 pounds, body mass index of 48.28 kg/m2) but clinically he was doing well and he denied symptoms of psychosis and reported euthymic mood. In lieu of this, topiramate was increased to 200 mg per day, with no change in clozapine dosage. After 13 days, it caused a temporary spike in WBC to 7,000/μL and neutrophils to 3,500/μL, following which it showed an abrupt decline in leukocyte (neutrophil) count: 5,200/μL (2,200/μL) on the 27th day, 5300/μL (2,100/μL) on the 40th day, and 4,500/μL (1,700/μL) on the 54th day. On the 57th day, the pharmacy denied a refill for clozapine due to the lowered neutrophils. The patient's ANC count further plummeted to 1200/μL, while WBC count was 4,200/μL. A day later, the patient's laboratory results showed 5,200 WBC/μL and 1,900 neutrophils/μL (Figure 1). Considering that and assuming that clozapine was the cause of agranulocytosis, he was admitted to our psychiatric inpatient facility for medication management and monitoring of laboratory measurements. The patient was not experiencing any significant psychotic symptoms at that time.\n\nAt the time of admission, the patient had not been taking clozapine for two days as the pharmacy refused to refill it. During the hospital course, topiramate was tapered off, the patient was started on olanzapine 10 mg daily, and lithium was started to aid in mood stabilization and to help control WBC/ANC levels by virtue of its ability to potentially cause leukocytosis [6]. The patient tolerated the transition from clozapine to olanzapine and lithium. He denied hearing voices and other symptoms of psychosis. After starting lithium, WBC spiked to 7,800/μL and ANC to 4,800 μL. At time of discharge, Mr. S had 5,800 WBC/μL and 2,600 neutrophils/μL, with similar values two days later at outpatient follow-up.\n\n3. Discussion\nA review of the patient's medical records was focused on WBC and ANC values in relation to medication dosing and changes. A literature search was also performed using the PubMed database. The parameters of the search included all English language publications (excluding review articles) between 1990 and 2015 which contained the words topiramate or topiramate in combination with the words leukopenia, neutropenia, or agranulocytosis. This returned a total of three results, including two case reports describing topiramate-induced leukopenia or neutropenia, only one of which involved concurrent clozapine therapy.\n\nThere is empirical evidence of leukopenia or neutropenia resulting from clozapine and from a combination of clozapine and other psychotropic drugs [7, 8], but a search of topiramate-induced leukopenia or neutropenia is scarce. The search produced two reported cases. In one case a patient with a two-year history of being on clozapine developed leukopenia after the addition of topiramate due to concerns about weight gain. Consequently, topiramate was stopped while clozapine was restarted. The patient's leukocyte count then returned to the normal limits [9].\n\nA second case report described a patient with intractable partial epilepsy who developed agranulocytosis after topiramate was added to a phenytoin and acetazolamide regimen. Topiramate was decreased and eventually discontinued causing WBC to return to the normal limits [10].\n\nOur case suggests a dose-dependent effect of topiramate when used with another leukopenic agent. Mr. S showed an upward trend in WBC and ANC during the 6 weeks prior to reaching the combination of clozapine 300 mg and topiramate 100 mg. At these doses, WBC and ANC levels gradually declined and then decreased more rapidly after topiramate was increased to 200 mg. Clozapine is mostly metabolized by CYPIA2. However, drugs that inhibit CYP2D6 are reported to elevate clozapine plasma level. There is little data about the interaction between topiramate and antipsychotic drugs. It is worth noting that topiramate has no effect on CYPIA2 and CYP2D6, which are the main metabolizing enzymes of clozapine [11].\n\n4. Conclusion\nCare should be taken when considering adding topiramate concurrently with any neutropenic agent. While the benefits of weight control may be desired, patients and their families should be counseled that the addition of topiramate to clozapine might cause decreased leukocytes or neutrophils, even if the patient has not previously had neutropenia while on clozapine. Nevertheless, if topiramate is started, the dose should be increased slowly and laboratory values monitored carefully. As established in our case report, this may be a dose-dependent effect. Dosage changes should be spaced apart enough to monitor the trends in leukocyte counts and special care should be taken when considering an increase of topiramate to 200 mg daily. An increase in frequency of complete blood count tests might be considered to provide closer attention to and changes in trends.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthors' Contribution\nAll authors contributed equally to the preparation and writing of this case report.\n\nFigure 1\n==== Refs\n1 American Diabetes Association Consensus development conference on antipsychotic drugs and obesity and diabetes Diabetes Care 2004 27 2 596 601 10.2337/diacare.27.2.596 14747245 \n2 Newcomer J. W. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review CNS Drugs 2005 19 supplement 1 1 93 2-s2.0-18744366088 15998156 \n3 Tschoner A. Engl J. Laimer M. Metabolic side effects of antipsychotic medication International Journal of Clinical Practice 2007 61 8 1356 1370 10.1111/j.1742-1241.2007.01416.x 2-s2.0-34447341958 17627711 \n4 Hahn M. K. Remington G. Bois D. Cohn T. Topiramate augmentation in clozapine-treated patients with schizophrenia: clinical and metabolic effects Journal of Clinical Psychopharmacology 2010 30 6 706 710 10.1097/jcp.0b013e3181fab67d 2-s2.0-78649362141 21105286 \n5 Novartis Pharmaceuticals Canada Inc Clozaril (Clozapine Tablets) 2015 Dorval, Canada Novartis Pharmaceuticals Canada Inc \n6 Mattai A. Fung L. Bakalar J. Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children Human Psychopharmacology 2009 24 7 584 589 10.1002/hup.1056 2-s2.0-72849112157 19743394 \n7 Demler T. L. Trigoboff E. Are clozapine blood dyscrasias associated with concomitant medications? Innovations in Clinical Neuroscience 2011 8 4 35 41 2-s2.0-79958291428 21637633 \n8 Gerson S. L. Lieberman J. A. Friedenberg W. R. Lee D. Marx J. J. Jr. Meltzer H. Polypharmacy in fatal clozapine-associated agranulocytosis The Lancet 1991 338 8761 262 263 10.1016/0140-6736(91)90410-q 2-s2.0-0025827142 \n9 Behar D. Schaller J. L. Topiramate leukopenia on clozapine European Child and Adolescent Psychiatry 2004 13 1 51 52 10.1007/s00787-004-0323-0 2-s2.0-1442349768 14991432 \n10 Minakawa E. N. Matsumoto R. Kinoshita M. Topiramate induced agranulocytosis BMJ Case Reports 2009 10.1136/bcr.11.2008.1273 \n11 Besag F. M. C. Berry D. Interactions between antiepileptic and antipsychotic drugs Drug Safety 2006 29 2 95 118 10.2165/00002018-200629020-00001 2-s2.0-32244439673 16454538\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6838",
"issue": "2016()",
"journal": "Case reports in psychiatry",
"keywords": null,
"medline_ta": "Case Rep Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101583308",
"other_id": null,
"pages": "6086839",
"pmc": null,
"pmid": "26904343",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "1676820;19743394;14991432;14747245;16454538;21105286;15998156;21637633;21686380;17627711",
"title": "Concomitant Use of Topiramate Inducing Neutropenia in a Schizophrenic Male Stabilized on Clozapine.",
"title_normalized": "concomitant use of topiramate inducing neutropenia in a schizophrenic male stabilized on clozapine"
} | [
{
"companynumb": "US-JNJFOC-20160303654",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "We present the case of a patient with a deep vein thrombosis (DVT) who failed rivaroxaban therapy. Our patient initially presented with left lower extremity edema, erythema, and pain. He was subsequently started on rivaroxaban therapy for a combined treatment period of 12 months, during and after which he persisted to have evidence of a DVT. The patient's prescribed drug regimen was changed from rivaroxaban to warfarin, which demonstrated a rapid resolution of the DVTs as determined by ultrasound assessment of our patient's lower extremity veins. Rivaroxaban, a factor Xa inhibitor, is a well-known oral anticoagulant that is used for a variety of indications and has become a mainstay in the treatment of deep vein thrombosis. With the introduction and emergence of this medication in the clinic, postmarketing reports of efficacy or lack thereof are important to review. In conclusion, we anticipate that it is likely that there are other patients with DVTs who may not respond to rivaroxaban and for whom alternative anticoagulation therapies should be explored.",
"affiliations": "College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.;College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.;The Cardiovascular Institute of Greater Los Angeles, Tarzana, CA, USA.;Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.;Providence Tarzana Medical Center, Tarzana, CA, USA.;Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.;College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.",
"authors": "Yaghoubian|Jonathan M|JM|0000-0001-8732-1154;Adashek|Jacob|J|;Yaghoubian-Yazi|Bahareh|B|;Nagar|Menachem|M|;Toomari|Nojan|N|;Pietras|Richard J|RJ|0000-0002-2846-3192;Ben-Zur|Uri M|UM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/3628127",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2017/3628127Case ReportIncomplete Resolution of Deep Vein Thromboses during Rivaroxaban Therapy http://orcid.org/0000-0001-8732-1154Yaghoubian Jonathan M. \n1\n\n*\nAdashek Jacob \n1\nYaghoubian-Yazi Bahareh \n2\nNagar Menachem \n3\nToomari Nojan \n4\nhttp://orcid.org/0000-0002-2846-3192Pietras Richard J. \n5\nBen-Zur Uri M. \n1\n\n2\n\n4\n\n1College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA\n2The Cardiovascular Institute of Greater Los Angeles, Tarzana, CA, USA\n3Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel\n4Providence Tarzana Medical Center, Tarzana, CA, USA\n5Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA*Jonathan M. Yaghoubian: jyaghoubian@westernu.eduAcademic Editor: Tayfun Sahin\n\n2017 30 7 2017 2017 362812714 4 2017 15 6 2017 Copyright © 2017 Jonathan M. Yaghoubian et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present the case of a patient with a deep vein thrombosis (DVT) who failed rivaroxaban therapy. Our patient initially presented with left lower extremity edema, erythema, and pain. He was subsequently started on rivaroxaban therapy for a combined treatment period of 12 months, during and after which he persisted to have evidence of a DVT. The patient's prescribed drug regimen was changed from rivaroxaban to warfarin, which demonstrated a rapid resolution of the DVTs as determined by ultrasound assessment of our patient's lower extremity veins. Rivaroxaban, a factor Xa inhibitor, is a well-known oral anticoagulant that is used for a variety of indications and has become a mainstay in the treatment of deep vein thrombosis. With the introduction and emergence of this medication in the clinic, postmarketing reports of efficacy or lack thereof are important to review. In conclusion, we anticipate that it is likely that there are other patients with DVTs who may not respond to rivaroxaban and for whom alternative anticoagulation therapies should be explored.\n==== Body\n1. Introduction\nRivaroxaban (Xarelto®) is a novel oral anticoagulant that inhibits platelet activation and fibrin clot formation via direct, selective, and reversible inhibition of factor Xa in both the intrinsic and extrinsic coagulation pathways. Factor Xa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, factor II, and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin. At this time, factor Xa inhibitors are emerging as a popular alternative to the use of vitamin K antagonists (VKA) or warfarin therapy because factor Xa inhibitors do not require international normalized ratio (INR) testing nor specific dietary restrictions. The indications for rivaroxaban therapy include reduction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, treatment of deep vein thrombosis (DVT), treatment of pulmonary embolism (PE), reduction in the risk of recurrence of DVT and of PE after a 6-month trial for the treatment for DVT and/or PE, or prophylaxis of DVT (which may lead to PE in patients undergoing knee replacement or hip replacement surgery) [1]. Major contraindications include active pathological bleeding and severe hypersensitivity reaction such as anaphylaxis [1]. Rivaroxaban is currently widely recommended as a mainstay treatment for DVT [2]. A minimum of three months of anticoagulation with medications such as rivaroxaban are recommended in those with unprovoked DVT or recurrent DVT or provoked with minor risk factors for DVT [2]. If treatment is successful and the thrombus resolves, some patients may still require indefinite treatment [2]. Unfortunately, when factor Xa inhibitors fail, the alternatives in an outpatient setting are to change therapy to low molecular weight heparin and/or warfarin therapies [2]. Indeed, the standard for both prevention and treatment for over 60 years has been vitamin k antagonists like warfarin (Coumadin®, Jantoven®, and Marevan®), phenprocoumon, and acenocoumarol; however, VKA therapy is inconvenient due in part to its increased risk of adverse events such as bleeding, dietary restrictions, and the need for regular blood monitoring, thereby making it a less desirable option [2].\n\nIn addition to not requiring dietary restrictions nor frequent INR evaluations, rivaroxaban has other advantages such as rapid absorption and almost 100% bioavailability when taken with food (at specific doses) [3] and has been shown, in some studies, to be noninferior to enoxaparin/VKA—the current standard of care for venous thromboembolism [4]. On the other hand, rivaroxaban's disadvantages have been documented as well. The major disadvantages include internal bleeding, particularly gastrointestinal bleeding [5], as well as documented cases in which thromboembolisms do not completely resolve [6, 7].\n\n2. Case Presentation\nThe patient in this case report is a 65-year-old white male, with a past medical history significant for mild depression and subclinical hypothyroidism, who presented in 2015 with a primary complaint of 3 days of left lower extremity pain, erythema, and edema. At the time of the visit, he also complained of dizziness of 2-day duration which was not related to changes of position. The severity of this symptom was mild to moderate, and no other associated symptoms were noted. He reported being very sedentary and experienced some tingling of the right foot. The patient denied chest pain, shortness of breath, palpitations, or syncope. He did not monitor his blood pressure at home, nor did he follow any exercise or diet programs. He has no known drug allergies, and his drug regimen at initial presentation included escitalopram 20 milligrams every other day for mild depression (which was being tapered off), as well as fiber supplements and daily multivitamins. Overall, the patient was noted to have multiple risk factors for coronary artery disease including male gender, age, sedentary lifestyle, stress, and tobacco use.\n\nOn physical examination, the patient was reported as a well-developed, well-nourished male with a BMI of 23.1 and body weight of 79.4 kilograms. The patient's neck was supple with no jugular venous distention. A left carotid bruit was audible, carotid pulses were +2/2, and there was a normal carotid artery upstroke bilaterally. His lungs were clear to auscultation bilaterally without wheezes or rhonchi. His cardiovascular exam revealed a regular heart rate and rhythm. His cardiac point of maximal impulse was at the left fifth intercostal space in the mid-clavicular line. Normal cardiac S1 and S2 sounds were noted with physiologic splitting of S2. No murmurs, thrills, rubs, gallops, or clicks were appreciated. Pulses in the extremities were 2+ throughout bilaterally at the time of presentation, and no cyanosis or clubbing was noted. Mild varicose veins in the distal lower extremities bilaterally were noted. Evidence of left lower extremity pain, erythema, and edema were noted. An abridged mental status exam revealed a cooperative patient well oriented to time, place, and person, without evidence of psychotic features. The patient's recall was within normal limits.\n\nGiven these findings, the patient underwent an ultrasound study that confirmed a left femoral vein thrombus, and he was started on rivaroxaban therapy. In accord with current recommendations for rivaroxaban therapy, the patient was started on rivaroxaban at 15 milligrams PO twice daily for 3 weeks and then continued at 20 milligrams PO daily for 6 months. Upon initiation of rivaroxaban, aspirin 81 milligrams PO daily was added to his regimen. DVT presence was monitored, and rivaroxaban therapy was eventually discontinued after a total of one year (per protocol [2]) and aspirin was continued for an additional 2 months. When serial follow-up ultrasounds continued to show persistent thrombi in the femoral and popliteal veins, he was then restarted on rivaroxaban therapy for another 2 months at 20 mg daily. After this second challenge with rivaroxaban, a repeat ultrasound again showed a persistent DVT. The patient was then bridged to warfarin therapy, continuing rivaroxaban at 20 mg daily and adding warfarin 5 mg daily with an INR goal of 2.0–3.0. Thereafter, his INR goals were met by adjusting his warfarin dose weekly. After 5 days of bridging, rivaroxaban was discontinued.\n\nThe patient was maintained on warfarin 7.5 milligrams alternating with 5 milligrams on alternate days PO (dosing varies by week per INR) in addition to escitalopram, fiber supplementation, and multivitamins, as mentioned earlier. This regimen was well tolerated by the patient and without complication.\n\nIn review, after initiation of rivaroxaban therapy, the patient continued to be symptomatic; therefore, we continued to monitor his DVTs to assess his progression. A Siemens ACUSON Cypress ultrasound system was used to perform ultrasonography of his lower extremity which revealed thrombus in his left mid-superficial femoral vein (SFV). The ultrasound assessments began six days after initiation of rivaroxaban therapy (Figures 1(a)–1(d)) and then again at 9 months. Then, after one year of rivaroxaban and aspirin treatment, followed by 2 months of aspirin therapy alone, another ultrasound was performed which continued to demonstrate thrombus presence. Finally, after bridging to warfarin therapy, another ultrasound was performed which demonstrated vast improvements (see Figures 2(a)–2(e)).\n\nFigures 1(a)–1(d) demonstrated our initial/baseline ultrasound findings which correspond to six days following initiation of rivaroxaban therapy. The right mid-SFV appeared patent without compression (Figure 1(a)) and fully collapsed upon compression (Figure 1(b)), indicating no presence of thrombi. The left SFV measured 8.3 millimeters, before compression with the ultrasound transducer (Figure 1(c)), and manual compression of the vessel measured 8.2 millimeters (Figure 1(d)), indicating the presence of a thrombus.\n\nOver a period of approximately one year of treatment with rivaroxaban, the ultrasound measurements demonstrated a general downward trend in the size of the thrombi which were followed over approximately one year of treatment with rivaroxaban, but a complete resolution in half of the vessels followed was not detected. The left common femoral vein (CFV) DVT resolved at the 9th-month mark (Figure 2(a)), and the left proximal SFV thrombosis resolved at the one-year mark (Figure 2(b)). The more distal thrombi (left mid-SFV and distal SFV) waxed and waned, but these were generally stable at the one-year assessment. When the patient was switched to warfarin treatment, there was an approximately 13% improvement in the left distal SFV and a 20% improvement of the left mid-SFV in a period of just 16 days (Figures 2(c) and 2(d)). The most drastic change in percent occlusion was of the left popliteal vein, which underwent a rapid and complete resolution of the thrombosis within 16 days of warfarin treatment after a slow but steady decline in the size of the thrombus with rivaroxaban therapy alone (Figure 2(e)).\n\n3. Discussion and Conclusion\nThis case is of interest because a widely used and approved pharmacologic treatment of DVT did not perform as expected in this patient. A thorough literature review revealed little in the way of reports of rivaroxaban failure in the treatment of DVT, although a few case reports in which potential rivaroxaban failure is noted have emerged recently [6, 7]. Postmarketing surveillance is clearly an important factor in the further development, safety, and efficacy of any novel drug. Since the initial FDA approval of rivaroxaban in July 2011, this drug has been indicated for many uses and is widely recommended in current clinical practice [8].\n\nHeparin and vitamin K antagonist have at times been shown to fail in the treatment of thrombi [9–11]. The recent addition of factor Xa inhibitors to anticoagulant agents is not without fault (i.e., failure, bleeding, and lack of reversal agents), as demonstrated in this case report and other papers [6, 7, 12]. The risk factors for failure of anticoagulation therapy are vast and vary from patient to patient; pharmacodynamics, pharmacokinetics, metabolism, and elimination all have a hand in how a drug interacts in a given patient and are further discussed below [13–15]. The patient discussed in our case does not seem to have any of these risk factors as noted from his normal liver function tests and creatinine clearance.\n\nAnother lab value of interest is the D-dimer level. The patient's D-dimer value was elevated to 4160 ng/ml fibrinogen equivalent units or FEU (normal is less than 500 ng/ml FEU) upon initiation of rivaroxaban treatment. The D-dimer level was noted to decrease over time with rivaroxaban alone; however, the value never normalized (even after more than one year of treatment). Over approximately 5 months of warfarin therapy alone, the D-Dimer values steadily normalized (190 ng/ml FEU).\n\nAlthough factor Xa inhibitors are quite popular, there are cases emerging of its rare adverse effects (i.e., exsanguination), especially in patients with hypertension, heart failure, coronary heart disease, and impaired renal and/or hepatic function and those with certain types of cancers [16]. Animal models are exposing other mechanisms that affect the efficacy of rivaroxaban; in one mouse model, rivaroxaban's anticoagulant effect was augmented by angiotensin II [17].\n\nThe pathophysiology for the potential failure of rivaroxaban therapy in the treatment of DVT is poorly understood. However, drug metabolism may play a significant role. The physiologic metabolism of rivaroxaban is severalfold, including oxidative degradation of the morpholinone moiety as the major pathway and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring as the minor pathways, all of which occur within hepatocytes and liver microsomes [13]. Any change in the metabolism of any of these pathways would lead to a change in the efficacy of the drug itself. Furthermore, the main metabolite of rivaroxaban is excreted both renally and fecally via the biliary system, and malfunctioning of these pathways could also lead to a change in the efficacy of rivaroxaban. Rivaroxaban is also well known to be metabolized by the cytochrome P450 isoenzyme CYP3A4 and binds to P-glycoprotein, hence leading to risks of pharmacokinetic interactions that may alter its anticoagulant properties [14]. Furthermore, it is notable that rivaroxaban has a terminal half-life of only 5–9 hours, yet it is generally recommended to be taken at 20 mg PO once a day after an initial dosing period at 15 mg PO twice daily. In view of such relatively rapid elimination, high, early peaks of rivaroxaban could increase the risk of bleeding and low troughs could result in suboptimal anticoagulation. It will be important to determine if a better rivaroxaban dosing regimen is required to address its unique pharmacokinetic profile [15]. One study suggests a method that measures rivaroxaban's activity level in individual patients, which can be used to compare clinical variable and patient outcomes, leading to a more customizable treatment plan and dosing regimen [18].\n\nWith regard to this case report on thrombus resolution after warfarin therapy, further work-up is warranted to discover the lack of the expected response to primary rivaroxaban treatment; these diagnostics may include a thrombophilia panel and rivaroxaban serum levels to determine genetic risk factors and compliance, respectively. The patient did not present with any apparent hepatic or renal insufficiency based on normal liver function tests and creatinine levels on initial examination, as mentioned previously. Renal function has been shown to have a hand in the dosing of factor Xa inhibitors [19]. Factors that may be affecting this drug's efficacy could be lack of proper compliance, various hypercoagulable states, or certain mutations that can cause undesirable metabolism of rivaroxaban [20]. Selective serotonin reuptake inhibitors have been known to cause platelet aggregation/hypercoagulable states and potentially lead to thrombus formation and even cause pulmonary embolism [21].\n\nBecause of the threat of a pulmonary embolism from a DVT, it is important to have considered other factors/features that may be related to thrombi. A negative D-dimer lab value can help exclude the possibility of a PE [22]; in the case of our patient, initially, his D-dimer value was elevated, as noted above, and normalized after some time with warfarin therapy alone; this was not unexpected, as the protective effects of warfarin in the case of DVT/pulmonary embolism have been well documented [23].\n\nAnother feature of DVTs to consider is whether the thrombi noted in our patient are persistent or recurrent. Due to the location, initial size, and downtrending progression of the thrombi, we strongly believe that our patient had persistent thrombi. Assessing for persistent versus recurrent thrombi would be quite difficult as a thrombus can form in as little as 4 hours [24].\n\nAlthough extremes of body weight (<50 kg or >120 kg) are not reported to significantly influence rivaroxaban's effects, the International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of rivaroxaban (and other direct oral anticoagulants) in patients with a BMI >40 kg/m2 or body weight >120 kg due to the lack of clinical data in this population (ISTH) [25].\n\nIn clinical practice, it may be best to choose between available anticoagulant drugs on a case-by-case basis [26]. It will be important to take into account patient preferences, monitoring constraints and difficulty controlling the INR, the risk of bleeding, drug interactions, and the cost of treatment [27]. In light of this case report, we acknowledge novel oral anticoagulants, such as rivaroxaban, to be an important contribution to many formularies as they have been beneficial to the vast majority of patients who require anticoagulation; this case report is merely intended to highlight a noted anomaly to be taken into consideration for future practice.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Lower extremity ultrasound findings upon initial evaluation. (a) Uncompressed right superficial femoral vein patent. (b) Compressed right superficial femoral vein completely collapsed. (c) Uncompressed left superficial femoral vein at 8.3 mm. (d) Compressed left superficial femoral vein at 8.2 mm.\n\nFigure 2 Left lower extremity vein percent occlusion. (a) Progression of vein occlusion of left CFV. (b) Progression of vein occlusion of left proximal SFV. (c) Progression of vein occlusion of left mid-SFV. (d) Progression of vein occlusion of left distal SFV. (e) Progression of vein occlusion of left popliteal vein.\n==== Refs\n1 Rivaroxaban: new drug. After hip or knee replacement surgery: LMWH is safer Prescrire International 2009 18 151 153 10.1097/01.NPR.0000413489.82497.39 19743567 \n2 XARELTO®, https://www.xareltohcp.com/dvt-pe/dvt-pe.html \n3 Voukalis C. Lip G. Y. Shantsila E. Non-vitamin K oral anticoagulants versus vitamin K antagonists in the treatment of venous thromboembolic disease Expert Opinion on Pharmacotherapy 2016 17 15 2033 2047 10.1080/14656566.2016.1232393 27667112 \n4 Cohen A. T. Dobromirski M. The use of rivaroxaban for short- and long-term treatment of venous thromboembolism Thrombosis and Haemostasis 2012 107 6 1035 1043 10.1160/th11-12-0859 22371186 \n5 Deutsch D. Boustière C. Ferrari E. Albaladejo P. Morange P. Benamouzig R. Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures Therapeutic Advances in Gastroenterology 2017 10 6 495 505 28567119 \n6 Rankin J. Nagar M. Crosby J. Toomari N. Pietras R. Ben-Zur U. M. Possible failure of novel direct-acting oral anticoagulants in management of pulmonary embolism: A case report Journal of Medical Case Reports 2016 10 1, article no. 346 2-s2.0-85000910558 10.1186/s13256-016-1135-9 \n7 Rudd K. M. Winans A. R. M. Panneerselvam N. Possible rivaroxaban failure during the postpartum period Pharmacotherapy 2015 35 11 e164 e168 2-s2.0-84948124331 10.1002/phar.1662 26598101 \n8 U.S. Food and Drug Administration FDA approves Xarelto to reduce risk of blood clots after hip, knee replacements [FDA News Release] 2011, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm261839.htm \n9 King A. B. Duffy OA. E. Kumar A. B. Heparin Resistance and Anticoagulation Failure in a Challenging Case of Cerebral Venous Sinus Thrombosis Neurohospitalist 2016 6 3 118 121 10.1177/1941874415591500 27366296 \n10 Maurin N. Heparin resistance and antithrombin deficiency Medizinische Klinik 2009 104 6 441 449 2-s2.0-67650757729 10.1007/s00063-009-1093-8 19533051 \n11 Osinbowale O. Malki M. A. Schade A. Bartholomew J. R. An algorithm for managing warfarin resistance. Clinic Journal of Medicine 2009 76 12 724 730 \n12 Milling T. J. Frontera J. Exploring indications for the Use of direct oral anticoagulants and the associated risks of major bleeding American Journal of Managed Care 2017 23, supplement 4 S67 S80 10.1136/bmj.j2216 28581331 \n13 Weinz C. Schwarz T. Kubitza D. Mueck W. Lang D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans Drug Metabolism and Disposition 2009 37 5 1056 1064 10.1124/dmd.108.025569 2-s2.0-66449099711 19196845 \n14 Frost C. Song Y. Barrett Y. C. A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban Clinical Pharmacology: Advances and Applications 2014 6 179 187 10.2147/CPAA.S61131 25419161 \n15 Moore T. J. Optimal dosing of rivaroxaban is undefined BMJ 2016 355 i5549 10.1136/bmj.i5549 2-s2.0-84992549256 \n16 Salemis N. S. Rivaroxaban-induced chest wall spontaneous expanding hematoma Drug Discoveries & Therapeutics 2017 11 1 47 50 10.5582/ddt.2016.01064 28123155 \n17 Yang D. Shao J. Hu R. Chen H. Xie P. Liu C. Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice Scientific Reports 2017 7 1, article 369 10.1038/s41598-017-00473-5 \n18 Nandor S. Laszlo G. Tamas T. Bela M. Gabor S. Successful direct thrombin inhibitor treatment of a left atrial appendage thrombus developed under rivaroxaban therapy Orvosi Hetilap 2016 157 4 154 156 2-s2.0-84961367005 10.1556/650.2016.30350 26772828 \n19 Yong W. K. Sang H. L. Tae K. C. Ki H. Y. Shin Y. S. A case of pulmonary embolism associated with escitalopram Psychiatry Investigation 2007 4 1 52 54 2-s2.0-34247230257 \n20 Louw S. Saragas N. P. Ferrao P. N. Chirwa T. F. Jacobson B. F. Correlation between rivaroxaban (Xarelto) plasma activity, patient clinical variables and outcomes in a South African centre South African Medical Journal 2016 106 10 1017 1020 2-s2.0-84989821203 10.7196/SAMJ.2016.v106i10.10584 27725023 \n21 Schwartz J. B. Potential Effect of Substituting Estimated Glomerular Filtration Rate for Estimated Creatinine Clearance for Dosing of Direct Oral Anticoagulants Journal of the American Geriatrics Society 2016 64 10 1996 2002 2-s2.0-84992051998 10.1111/jgs.14288 27549687 \n22 Perrier A. Desmarais S. Goehring C. D-dimer testing for suspected pulmonary embolism in outpatients American Journal of Respiratory and Critical Care Medicine 1997 156 2 492 496 10.1164/ajrccm.156.2.9702032 2-s2.0-0030754108 9279229 \n23 Kabrhel C. Courtney D. M. Camargo C. A. Jr. Factors associated with positive D-dimer results in patients evaluated for pulmonary embolism Academic Emergency Medicine 2010 17 6 589 597 2-s2.0-77953563102 10.1111/j.1553-2712.2010.00765.x 20624138 \n24 Venous Thromboembolism (Blood Clots) 2017, https://www.cdc.gov/ncbddd/dvt/facts.html 10.1007/978-981-10-0965-5 \n25 Martin K. Beyer-Westendorf J. Davidson B. L. Huisman M. V. Sandset P. M. Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH Journal of Thrombosis and Haemostasis 2016 14 6 1308 1313 2-s2.0-84974728198 10.1111/jth.13323 27299806 \n26 Powell J. R. Are new oral anticoagulant dosing recommendations optimal for all patients? JAMA 2015 313 10 1013 1014 10.1001/jama.2015.59 25756434 \n27 Kearon C. Ageno W. Cannegieter S. C. Cosmi B. Geersing G.-J. Kyrle P. A. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH Journal of Thrombosis and Haemostasis 2016 14 7 1480 1483 2-s2.0-84990179336 10.1111/jth.13336 27428935\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2017()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "3628127",
"pmc": null,
"pmid": "28828188",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "19743567;27912791;25419161;27725023;19533051;28337024;26598101;27428935;27756735;20624138;28567119;19952297;27549687;25756434;19196845;28123155;27299806;9279229;27366296;27667112;28581331;22371186;26772828",
"title": "Incomplete Resolution of Deep Vein Thromboses during Rivaroxaban Therapy.",
"title_normalized": "incomplete resolution of deep vein thromboses during rivaroxaban therapy"
} | [
{
"companynumb": "US-MYLANLABS-2018M1074594",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "1",
... |
{
"abstract": "The local injection of triamcinolone acetonide (TA) is effective in preventing pyloric stenosis and deformity following large endoscopic submucosal dissection (ESD). However, because of its long-acting nature, TA can induce long-term local immunosuppression and subsequent adverse events. We report a case of a cytomegalovirus (CMV) ulcer that formed only at the TA local injection site. A 68-year-old man underwent ESD to treat early gastric cancer that formed over the pylorus. The lesion extended to the duodenum, and an artificial ulcer covered more than two-thirds of the circumference of the pylorus. To prevent pyloric stenosis, TA was locally injected into the ulcer floor. On day 12, a deeper ulcer 10 mm in diameter was discovered in the center of the post-ESD ulcer. Biopsies revealed large cells with intranuclear inclusion bodies, which stained positive for the anti-CMV antibody. Local TA injections are useful, however, CMV ulcer might occur as adverse events.",
"affiliations": "Departments of Gastroenterology and Neurology, Kagawa Medical University School of Medicine, Kagawa 761-0793, Japan. hiro4884@med.kagawa-u.ac.jp",
"authors": "Mori|Hirohito|H|;Fujihara|Shintaro|S|;Nishiyama|Noriko|N|;Kobara|Hideki|H|;Oryu|Makoto|M|;Kato|Kiyohito|K|;Rafiq|Kazi|K|;Masaki|Tsutomu|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D013256:Steroids; D014222:Triamcinolone Acetonide",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v19.i7.1143",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "19(7)",
"journal": "World journal of gastroenterology",
"keywords": "Adverse events; Cytomegalovirus-associated ulcer; Local immunosuppression; Local triamcinolone acetonide injection; Pyloric stenosis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D003586:Cytomegalovirus Infections; D005773:Gastroscopy; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007267:Injections; D008297:Male; D011707:Pyloric Stenosis; D012307:Risk Factors; D013256:Steroids; D013276:Stomach Ulcer; D013997:Time Factors; D014222:Triamcinolone Acetonide; D014945:Wound Healing",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "1143-6",
"pmc": null,
"pmid": "23467493",
"pubdate": "2013-02-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18647984;22696191;21492854;17096062;17524403;11373417;21359522;11156645;16713746;6382655;18322872;18373177;16013003;22136782",
"title": "Cytomegalovirus-associated gastric ulcer: a side effect of steroid injections for pyloric stenosis.",
"title_normalized": "cytomegalovirus associated gastric ulcer a side effect of steroid injections for pyloric stenosis"
} | [
{
"companynumb": "JP-SANOFI-AVENTIS-2013SA025230",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditio... |
{
"abstract": "A 44-year-old male patient with a single vessel ischaemic heart disease was referred to the lipid clinic for management of hypercholesterolaemia after an episode of admission with thrombocytopenic purpura secondary to atorvastatin. Atorvastatin was discontinued and his platelet counts improved gradually with steroids. He is now established on a different statin with no further episodes of thrombocytopenia. Though a drug challenge was never done, an idiosyncratic reaction to the initial statin seems to be the most likely cause.",
"affiliations": "Clinical Biochemistry, Pathology Department, Hull Royal Infirmary, Hull, UK. deepan@doctors.org.uk",
"authors": "Narayanan|Deepa|D|;Kilpatrick|Eric S|ES|",
"chemical_list": "D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2010()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000924:Anticholesteremic Agents; D000069059:Atorvastatin; D006538:Heptanoic Acids; D006801:Humans; D006937:Hypercholesterolemia; D008297:Male; D011696:Purpura, Thrombocytopenic; D011758:Pyrroles",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22750917",
"pubdate": "2010-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18386006;19329822;9788465;16633945;9704662;9521221;12002257;11386889;8495082;18577855;11207170;9218924",
"title": "Atorvastatin-related thrombocytopenic purpura.",
"title_normalized": "atorvastatin related thrombocytopenic purpura"
} | [
{
"companynumb": "GB-RANBAXY-2013RR-73085",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,
... |
{
"abstract": "Metastases to the pituitary gland are rare; cancers that most commonly metastasize to the pituitary are breast and lung cancers. No specific computed tomography or magnetic resonance imaging features reliably distinguish primary pituitary masses from metastases. A combination of a detailed clinical assessment together with specialist endocrine and neuroradiology support is essential to make the rare diagnosis of a pituitary metastasis. We present the case of a man with metastatic lung cancer, initially presenting as hypopituitarism. Subtle features in the history, together with neuroimaging findings atypical for pituitary adenomas, provided clues that the diagnosis was one of the pituitary metastases. Treatment of diabetes insipidus (DI) with replacement antidiuretic hormone (ADH) was complicated by extreme difficulties in achieving a satisfactory sodium and water balance. This was the result of coexistent DI and syndrome of inappropriate ADH secretion perpetuated by the patient's primary lung cancer, a phenomenon not previously described in the literature.",
"affiliations": "Department of Cardiovascular Sciences , University Hospitals of Leicester NHS Trust, Glenfield General Hospital , Leicester , UK.;Nottingham University Hospitals NHS Trust, Queen's Medical Centre , Nottingham, Nottinghamshire , UK.;Department of Endocrinology , University Hospitals of Leicester NHS Trust , Leicester , UK.;Department of Radiology , University Hospitals of Leicester NHS Trust , Leicester , UK.;Department of Endocrinology , University Hospitals of Leicester NHS Trust , Leicester , UK.",
"authors": "Gulsin|Gaurav Singh|GS|;Jacobs|Madeleine Louisa Bryson|ML|;Gohil|Shailesh|S|;Thomas|Adam|A|;Levy|Miles|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omw044",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omw044omw044200Case ReportsCompeting interests in a lung cancer with metastasis to the pituitary gland: syndrome of inappropriate ADH secretion versus diabetes insipidus Gulsin Gaurav Singh 1*Jacobs Madeleine Louisa Bryson 2Gohil Shailesh 3Thomas Adam 4Levy Miles 31 Department of Cardiovascular Sciences, University Hospitals of Leicester NHS Trust, Glenfield General Hospital, Leicester, UK2 Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, Nottinghamshire, UK3 Department of Endocrinology, University Hospitals of Leicester NHS Trust, Leicester, UK4 Department of Radiology, University Hospitals of Leicester NHS Trust, Leicester, UK* Correspondence address. Department of Cardiovascular Sciences, University Hospitals of Leicester NHS Trust, Glenfield General Hospital, Groby Road, Leicester LE3 9QP, UK. Tel: +44 116 258 3244; E-mail: gaurav.gulsin@nhs.net1 2016 01 6 2016 2016 6 125 129 2 3 2016 29 4 2016 10 5 2016 © The Author 2016. Published by Oxford University Press.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comMetastases to the pituitary gland are rare; cancers that most commonly metastasize to the pituitary are breast and lung cancers. No specific computed tomography or magnetic resonance imaging features reliably distinguish primary pituitary masses from metastases. A combination of a detailed clinical assessment together with specialist endocrine and neuroradiology support is essential to make the rare diagnosis of a pituitary metastasis. We present the case of a man with metastatic lung cancer, initially presenting as hypopituitarism. Subtle features in the history, together with neuroimaging findings atypical for pituitary adenomas, provided clues that the diagnosis was one of the pituitary metastases. Treatment of diabetes insipidus (DI) with replacement antidiuretic hormone (ADH) was complicated by extreme difficulties in achieving a satisfactory sodium and water balance. This was the result of coexistent DI and syndrome of inappropriate ADH secretion perpetuated by the patient's primary lung cancer, a phenomenon not previously described in the literature.\n==== Body\nINTRODUCTION\nPost-mortem studies have shown that the pituitary gland is a rare site for metastases of malignant tumours. Only 1–3.6% of malignant tumours have been found to metastasize to the pituitary [1]. Of those tumours which do spread to the pituitary, breast cancer in women and lung cancer in men are commonest, although others (prostate, renal cell carcinoma, gastrointestinal, lymphoma, leukaemia, thyroid cancer and plasmacytoma) are also reported to cause pituitary metastases [1]. Rarer still are symptomatic manifestations of pituitary metastases. One series found only 7% of pituitary metastases to be symptomatic [2]. Most frequently patients present with symptoms of diabetes insipidus (DI) or anterior pituitary dysfunction, ophthalmoplegia or visual disturbances, or headaches [1, 3].\n\nWe present a case of a man with metastatic lung cancer, which initially presented as a pituitary mass causing hypopituitarism. Subtle features in the patient's history, together with neuroimaging findings atypical for pituitary adenomas, provided clues that the diagnosis in the patient was one of the pituitary metastases and not a primary pituitary tumour. Treatment of DI with replacement antidiuretic hormone (ADH) was complicated by extreme difficulties in achieving a satisfactory sodium and water balance. Initially, the patient presented with hypernatraemia as a result of pure water loss from a new presentation of DI, probably unmasked by commencing hydrocortisone replacement. Subsequently, he developed hypotonic hyponatraemia which was initially felt to be due to over-treatment with desmopressin. However, several days after stopping the desmopressin, his hyponatraemia worsened. Because the half-life of desmopressin is only 2–3 h, we hypothesized that there must be endogenous inappropriate ADH secretion. Therefore, the difficulties in stabilizing his sodium were probably the result of coexistent DI unmasked by commencing steroids, as a well as syndrome of inappropriate ADH secretion caused by the patient's primary lung cancer, a phenomenon not previously described in the literature.\n\nCASE REPORT\nA 77-year-old male smoker presented to our medical assessment unit with a 1-day history of confusion, insomnia and reduced appetite. There was no other past medical or drug history of relevance. Initial examination revealed normal vital signs, but marked confusion [Abbreviated Mental Test (AMT) score of 4/10, where a score of <8 is suggestive of confusion]. There was no focal neurological deficit, visual field defect or ophthalmoplegia. Initial blood tests were unremarkable other than a mild elevation in his urea and creatinine (Table 1). An urgent computed tomography (CT) brain scan was performed, revealing an enhancing (1.5 × 1.7 cm) suprasellar mass (Fig. 1A). There was also oedema of the overlying optic tract (Fig. 1B), a finding most unusual for primary pituitary adenoma. Further laboratory testing showed hypopituitarism in keeping with anterior pituitary dysfunction (Table 2). Hormone replacement therapy with levothyroxine and hydrocortisone was commenced. There was subsequent improvement in the patient's clinical condition. After discussion with the neurosurgical team, the patient was considered unsuitable for surgical intervention due to his age. He was discharged home with urgent endocrine outpatient follow-up.\nTable 1: Results of admission blood tests at first presentation.\n\nNa\t135 mmol/l\t\nK\t4.6 mmol/l\t\nUrea\t8.7 mmol/l\t\nCreatinine\t151 umol/l\t\nAlbumin\t36 g/l\t\nALP\t51 iu/l\t\nALT\t15 iu/l\t\nBilirubin\t10 umol/l\t\nWCC\t8.0 × 109/l\t\nHb\t129 g/l\t\nPlt\t172 × 109/l\t\nThere is a mild elevation of serum urea and creatinine.\n\n\nTable 2: Results of pituitary profile blood tests.\n\nFree thyroxine\t4.8 pmol/l\t\nTSH\t0.99 miu/l\t\nLH\t<0.5\t\nFSH\t<0.5\t\nProlactin\t95 miu/l\t\nTestosterone\t<0.3\t\nCortisol\t44 nmol/l\t\nSHBG\t32 nmol/l\t\nThere is panhypopituitarism, with low thyroid function tests, sex hormones and cortisol levels.\n\n\nFigure 1: CT head scan images. An enhancing mass is seen in the pituitary fossa (Arrow, A). There is also overlying optic tract oedema (Arrow, B), not typically seen with pituitary adenomas.\n\n\n\nFive days after discharge, the patient re-presented to hospital, this time with worsening confusion, reduced mobility, thirst, polyuria and polyphagia. His wife remarked that she had to conceal food from the patient in light of his new symptoms of increased appetite. These unusual changes in symptoms were not in keeping with those features ordinarily experienced by patients with a pituitary adenoma. The symptoms of hunger and confusion, in particular, raised suspicions that there was involvement of surrounding brain tissue, particularly of the hypothalamus. Examination now revealed a clinically dehydrated man with an AMT score of 2/10. His 24-h fluid intake was 1600 ml, with an output of 4000 ml. There was still no focal neurological deficit. Repeat blood tests showed mild hypernatraemia, raised serum osmolality and a further elevation of the patient's urea (Table 3), in keeping with his dehydration. Repeat thyroid function testing revealed an improvement in serum free thyroxine (9.0 pmol/l, reference range 9.0–25.0 pmol/l). After intravenous fluid rehydration, an urgent magnetic resonance imaging (MRI) brain scan was organized. This showed the known pituitary mass, but now larger with marked hypothalamic extension (Fig. 2). A chest X-ray also uncovered a suspicious left pseudo-nodular shadow at the level of the aortic arch (Fig. 3) and a subsequent CT thorax confirmed a left lung mass lesion with impingement into the left main pulmonary artery (Fig. 4).\nTable 3: Results of blood tests taken at patient's second presentation to hospital.\n\nNa\t148 mmol/l\t\nK\t4.4 mmol/l\t\nUrea\t11.0 mmol/l\t\nCreatinine\t104 umol/l\t\nSerum osm.\t308 mmol/kg\t\nUrine osm.\tUnavailable\t\nThere is mild hypernatraemia, raised serum urea and creatinine, and an elevated serum osmolality.\n\n\nFigure 2: MRI brain scan, coronal (A) and sagittal (B) views are shown. The known pituitary mass is seen (red arrow), but now with marked hypothalamic extension (yellow arrow). The pituitary and hypothalamic masses were deemed to be continuous after detailed review by a specialist neuroradiologist, although this is not easily apparent on any one image.\n\n\nFigure 3: Patient's chest radiograph. There is a pseudo-nodular shadow visible at the left lung hilum (arrow).\n\n\nFigure 4: Patients CT scan thorax. A left-sided pulmonary mass is visible (A, red arrow). There is invasion into the left main pulmonary artery (B, blue arrow).\n\n\n\nThe case was discussed at our local pituitary and lung cancer multidisciplinary team meetings, where a diagnosis of a primary lung cancer with metastasis to the pituitary was made, complicated by cranial DI. The atypical features in the patient's clinical history and neuroimaging were the key factors that contributed to the diagnosis of pituitary metastases than a typical pituitary adenoma. Only symptomatic treatment was considered appropriate for the patient's ongoing management. Replacement ADH therapy in the form of demopressin was commenced with serial blood tests performed for monitoring of serum sodium and paired serum/urine osmolalities (Table 3). There was initial improvement in the patient's biochemistry following ADH replacement, after which increased doses were required to maintain an adequate sodium and water balance. This was followed by a substantial fall in serum sodium and osmolality, which persisted even after discontinuing ADH replacement (Table 4). Although initially it was felt that over-treatment with desmopressin was the likely cause of the hypotonic hyponatraemia, sodium levels continued to fall to a nadir of 122 mmol/l 5 days after stopping desmopressin (Table 4). Because the half-life of desmopressin is 2–3 h, it was felt that there must be endogenous secretion of ADH from a source other than his pituitary gland. Because of his underlying new diagnosis of lung cancer, it was felt that the likely diagnosis was the syndrome of inappropriate ADH secretion (SIADH) from this tumour. The challenging sodium and water balance in this case represented the interplay between coexisting DI as a consequence of a pituitary metastasis and SIADH from a lung primary.\nTable 4: Serial blood tests results following commencement of ADH replacement therapy (desmopressin).\n\nDay\t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t15\t19\t20\t21\t\nNa (mmol/l)\t149\t147\t142\t148\t146\t137\t137\t152\t145\t144\t139\t130\t127\t122\t122\t122\t\nSerum osmolality (mmol/kg)\t314\t313\t293\t\t298\t283\t284\t319\t305\t398\t290\t\t261\t\t249\t255\t\nUrine osmolality (mosmol/kg)\t\t594\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nUrine in/out (ml)\t\t\t\t1600/4000\t\t\t\t2100/3300\t\t\t\t\t\t\t\t\t\nUrea (mmol/l)\t5.5\t\t\t\t6.6\t7.8\t7.1\t11.3\t10.6\t8.7\t8.6\t7.9\t6\t6.9\t6.9\t6.2\t\nCreatinine (umol/l)\t87\t\t\t\t84\t80\t86\t130\t110\t95\t85\t82\t73\t67\t74\t77\t\nEstimated GFR (MDRD, ml/min)\t78\t\t\t\t82\t86\t79\t49\t60\t71\t80\t84\t>90\t>90\t>90\t90\t\nDesmopressin dose\t10 mcg BD\t10 mcg BD\t10 mcg BD\t10 mcg BD\t10 mcg BD\t10 mcg BD\t10 mcg BD\t30 mcg BD\t30 mcg BD\t30 mcg BD\t10 mcg BD\tStopped\tStopped\tStopped\tStopped\tStopped\t\nDespite an initial improvement in the patient's sodium and osmolalities with desmopressin, the patient later developed hyponatraemia that persisted even after discontinuing therapy. Note that from Days 11 to 21, the patient's hyponatraemia worsened despite receiving no replacement ADH therapy. Renal function remained relatively unaffected throughout. BD, twice daily..\n\n\n\nSadly, the patient's clinical and biochemical conditions deteriorated. After review by the palliative care team, it was decided that serial blood test monitoring be discontinued and palliative care be initiated. The patient was discharged home, where he died soon after.\n\nDISCUSSION\nMetastases to the pituitary gland are rare; three large post-mortem series' reported prevalence rates of 1–3.6% [4–6]. Those cancers which most commonly metastasize to the pituitary gland are breast cancers in women and lung cancers in men [2, 7], as seen in this case.\n\nThe vast majority of pituitary metastases are clinically silent, with only 7% reported as symptomatic in one series [2]. When symptoms do occur, these are usually those of DI (polydipsia and polyuria), headaches, visual field defects and ophthalmoplegia [6–8].\n\nNeuroimaging is essential for the diagnosis of pituitary lesions. No specific CT or MRI features can reliably distinguish primary pituitary masses from pituitary metastases. Thickening of the pituitary stalk, extension to surrounding areas and loss of signal from the posterior pituitary have been claimed to be suggestive of pituitary metastases [1]. In this case, overlying optic tract oedema and hypothalamic extension of the pituitary mass were indicative of an atypical pituitary mass. Clearly, the combination of a detailed clinical history together with specialist endocrine and neuro-radiology support is essential to make the rare diagnosis of a pituitary metastasis.\n\nA combined diagnosis of DI and SIADH, as in the case presented here, was not reached without careful consideration of other possible diagnoses. In cases of hypopituitarism, it has been reported that low cortisol levels seen in ACTH deficiency can mask symptoms of DI [9, 10]. Cortisol has a direct inhibitory effect on endogenous ADH secretion; hence, ACTH deficiency increases tonic ADH activity, reducing the capacity for excretion of free water. When patients are rendered steroid replete, the ability to excrete free water is restored, and this may have been the reason our patient presented with classical features of DI soon after starting hydrocortisone.\n\nThe unique aspect of our case was the development of hypotonic hyponatraemia 5 days after stopping desmopressin. Because his hyponatraemia continued to worsen long after the presumed clearance of desmopressin, we felt that the likely cause was endogenous ADH secretion from his lung cancer. This provided a management dilemma because it would usually be counter-intuitive to fluid restrict a patient that has recently developed DI due to the risk of severe dehydration and hypernatraemia. However, we felt that he had dual biochemical pathology and that the initial predominant biochemical ‘lesion’ was ADH deficiency, which subsequently became over-ridden by rising levels of ADH from his aggressive lung tumour, leading to endogenous hypotonic hyponatraemia.\n\nOther possible causes of hypotonic hyponatraemia apart from SIADH include adrenal insufficiency and total body salt depletion, but we felt these were clinically unlikely because the patient was on supra-physiological doses of hydrocortisone with no clinical signs of hypoadrenalism or hypovolaemia. In the workup of hyponatraemia, it is usually very important to measure urine sodium, a level of >30 mmol/l suggesting total body salt loss or low effective arterial volume. In our patient, urine sodium was not measured, which was an omission, but salt depletion was unlikely given that he presented with hypernatraemia from DI-associated pure water loss only a few days earlier, and at the time of hyponatraemia, the patient was clinically euvolemic with no signs of low arterial volume.\n\nIn summary, we present a very interesting case of lung cancer with pituitary metastasis, which proved a challenging management dilemma as regards his sodium. With the recently published European Guidelines [11], there has been increased prominence of the recommended systematic approach to managing hyponatraemia. This case brings out several interesting aspects of sodium homeostasis including the effect of corticosteroids on ADH, and the likely co-existence of ADH and SIADH in the same patient, which provides a good basis for the discussion of sodium pathophysiology.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nFUNDING\nNone.\n\nETHICAL APPROVAL\nNone required.\n\nCONSENT\nThe patient presented in this report is deceased; therefore, no consent was obtained.\n\nGUARANTOR\nG.S.G is the guarantor of this work.\n==== Refs\nREFERENCES\n1 Fassett DR , Couldwell WT \nMetastases to the pituitary gland . Neurosurg Focus \n2004 ;16 :1 –4 .15254983 \n2 Teears RJ , Siverman EM \nClinicopathologic review of 88 cases of carcinoma metastatic to the pituitary gland . Cancer \n1974 ;36 :478 –80 .\n3 Komninos J , Vlassopoulou V , Protopapa D , Korfias S , Kontogeorgos G , Sakas DE et al \nTumours metastatic to the pituitary gland: case report and literature review . J Clin Endocrinol Metab \n2004 ;89 :574 –80 .14764764 \n4 Abrams HL , Spiro R , Golstein N \nMetastases in carcinoma: analysis of 1000 autopsied cases . Cancer \n1950 ;3 :74 –85 .15405683 \n5 Kovacs K \nMetastatic cancer of the pituitary gland . Oncology \n1973 ;27 :533 –42 .4355105 \n6 Max MB , Deck MD , Rottenberg DA \nPituitary metastasis: incidence in cancer patients and clinical differentiation from pituitary adenoma . Neurology \n1981 ;31 :998 –1002 .7196526 \n7 Morita A , Meyer FB , Laws ER \nSymptomatic pituitary metastases . J Neurosurg \n1998 ;89 :69 –73 .9647174 \n8 Branch CL , Laws ER \nMetastatic tumours of the sella turcica masquerading as primary pituitary tumours . J Clin Endocrinol Metab \n1987 ;65 :469 –74 .3624409 \n9 Huang CH , Chou K , Lee P \nA case of lymphocytic hypophysitis with masked diabetes insipidus unveiled by glucocorticoid replacement . Am J Kidney Dis \n2005 ;45 :197 –200 .15696461 \n10 Ohta M , Kimura T , Ota K \nGlucocorticoid-induced central diabetes insipidus in a case of malignant lymphoma . Tohuku J Exp Med \n2006 ;163 :245 –54 .\n11 Spasovski G , Vanholder R , Allolio B , Annane D , Ball S , Bichet D et al \nClinical practice guideline on diagnosis and treatment of hyponatraemia . Eur J Endocrinol \n2014 ;170 :G1 –47 .24569125\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2016(6)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "125-9",
"pmc": null,
"pmid": "27274855",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports",
"references": "4355105;3624409;15191337;9647174;15696461;7196526;1882385;14764764;24569125;15405683",
"title": "Competing interests in a lung cancer with metastasis to the pituitary gland: syndrome of inappropriate ADH secretion versus diabetes insipidus.",
"title_normalized": "competing interests in a lung cancer with metastasis to the pituitary gland syndrome of inappropriate adh secretion versus diabetes insipidus"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1955188",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 16-year-old boy with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (HLH) underwent allogeneic hematopoietic stem cell transplantation after conditioning with fludarabine, melphalan, total body irradiation, and rabbit antithymocyte globulin (ATG). A severe, persistent infusion reaction occurred after the initial administration of ATG. Investigations showed a rapid increase in the levels of liver enzymes and ferritin, and the reactivation of HLH was confirmed by marked hemophagocytosis in the bone marrow. Treatment with pulse glucocorticoid therapy resulted in the improvement of HLH. This is the first case of HLH reactivation triggered by ATG. Physicians should therefore be cautious of HLH reactivation, especially when a severe and prolonged infusion reaction occurs.",
"affiliations": "Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Pathology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.",
"authors": "Matsuda|Kensuke|K|;Toyama|Kazuhiro|K|;Toya|Takashi|T|;Ikemura|Masako|M|;Nakamura|Fumihiko|F|;Kurokawa|Mineo|M|",
"chemical_list": "D000961:Antilymphocyte Serum; D007155:Immunologic Factors; C512542:thymoglobulin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9226-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2922525210.2169/internalmedicine.9226-17Case ReportReactivation of Hemophagocytic Lymphohistiocytosis Triggered by Antithymocyte Globulin Matsuda Kensuke 1Toyama Kazuhiro 2Toya Takashi 1Ikemura Masako 3Nakamura Fumihiko 1Kurokawa Mineo 12\n1 Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan\n2 Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Japan\n3 Department of Pathology, Graduate School of Medicine, The University of Tokyo, JapanCorrespondence to Dr. Mineo Kurokawa, kurokawa-tky@umin.ac.jp\n\n8 12 2017 15 2 2018 57 4 583 586 22 3 2017 25 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 16-year-old boy with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (HLH) underwent allogeneic hematopoietic stem cell transplantation after conditioning with fludarabine, melphalan, total body irradiation, and rabbit antithymocyte globulin (ATG). A severe, persistent infusion reaction occurred after the initial administration of ATG. Investigations showed a rapid increase in the levels of liver enzymes and ferritin, and the reactivation of HLH was confirmed by marked hemophagocytosis in the bone marrow. Treatment with pulse glucocorticoid therapy resulted in the improvement of HLH. This is the first case of HLH reactivation triggered by ATG. Physicians should therefore be cautious of HLH reactivation, especially when a severe and prolonged infusion reaction occurs. \n\nantithymocyte globulinEpstein-Barr virushemophagocytic lymphohistiocytosisinfusion reaction\n==== Body\nIntroduction\nSecondary hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory disorder that develops as a result of various infections and malignancies. The massive activation of macrophages and cytokine release are induced by uncontrolled infection and malignancies. The resultant immune dysregulation is believed to play a pivotal role in the pathogenesis of HLH (1). The most common cause of secondary HLH is Epstein-Barr virus (EBV) infection. The incidence of EBV-associated HLH (EBV-HLH) is especially high in Asia (2), which is explained by the high prevalence of EBV infection in Asian people and host immunogenetic factors. The clinical features of HLH include fever, hepatosplenomegaly, cytopenias, hyperferritinemia, elevated transaminases, high serum soluble interleukin-2 receptor (sIL-2R), and hemophagocytosis. The initial treatment for HLH is usually immunosuppressive therapy composed of corticosteroids with or without cyclosporine A (CsA) and etoposide (ETP) (3). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment.\n\nAntithymocyte globulin (ATG) is a polyclonal antibody drug that is used in immunosuppressive therapy of HLH (4). ATG induces the lysis of T-cells and other target cells in a complement-dependent fashion and restores immune dysregulation, mainly through the depletion of T-cells (5,6). Similarly to other antibody drugs, infusion reactions are a frequent adverse effect of ATG. An infusion reaction is an infusion-related side effect that manifests as transient fever, tachycardia, and rash (7). Although the pathogenesis of infusion reaction has not yet been well elucidated, previous reports have revealed that complement activation play a key role in infusion reactions (7). We herein describe a case of EBV-HLH reactivation which was triggered by an infusion reaction in a patient who was treated with ATG.\n\nCase Report\nA 16-year-old boy presented to our institute with persistent fever following an episode of initial exposure to EBV. A physical examination revealed hepatosplenomegaly. Laboratory analyses revealed the following findings: hemoglobin, 132 g/L; platelet count, 41×109/L; aspartate aminotransferase, 2,893 U/L; serum triglycerides, 3.0 mmol/L; serum ferritin, 89,400 μg/L; and serum sIL-2R, 18,917 U/mL (Figure a). The patient's anti-viral capsid antigen (VCA)-immunoglobulin G (IgG) titer was 1:40; there was no increase in the levels of VCA-IgM and EBV nucleoside antigen antibodies. The whole blood EBV-DNA load was 1,310 copies per μg DNA. Bone marrow aspiration revealed hemophagocytosis by activated macrophages. Based on these findings, he was diagnosed with EBV-HLH. A pathological examination of the bone marrow aspirate revealed the accumulation of CD3-positive atypical lymphocytes, which were found to be positive for EBV-RNA by in situ hybridization (EBER-ISH). The treatment of HLH was initiated with dexamethasone and CsA, which resulted in defervescence and the normalization of the platelet count and liver enzyme levels. The addition of weekly intravenous ETP was required due to the recurrence of HLH during the attenuation of dexamethasone and CsA. The patient finally underwent bone marrow transplantation from a matched unrelated donor following reduced-intensity conditioning (RIC) with fludarabine (30 mg/m2/day, day -6 to -2), melphalan (140 mg/m2, day -2), total body irradiation (4 Gy, day -1), and rabbit ATG (ThymoglobulinⓇ, 1.25 mg/kg/day, day -5, -4), as shown in Figure b. ATG was added to the RIC regimen with the aim of achieving T-cell depletion. Dexamethasone, CsA, and ETP were discontinued on days -11, -7, and -20, respectively. On day -5, premedication with methylprednisolone (1 mg/kg) was delivered prior to the initial ATG infusion; nevertheless, the patient developed high fever and tachycardia, which was consistent with a severe infusion reaction (grade 3 according to CTCAE version 4.0). The fever persisted through the following day, and laboratory analyses revealed an increase in the patient's aspartate aminotransferase (568 U/L) and ferritin (5,510 μg/L) levels. Bone marrow aspiration revealed marked hemophagocytosis, leading to the diagnosis of recurrent HLH. Pulse glucocorticoid therapy with methylprednisolone was initiated, which resulted in the clinical improvement of HLH. Bone marrow transplantation was performed as scheduled. Tacrolimus and short-term methotrexate were administered as prophylaxis against graft versus host disease (GVHD). On day 18, the patient developed grade 2 acute GVHD (skin, stage 0; liver, stage 1; gut, stage 1), which was successfully treated with methylprednisolone (2 mg/kg, daily). Simultaneous cytomegalovirus antigenemia was ameliorated with foscarnet (intravenous) from day 15 to 23. No other infections were recorded. Neutrophil engraftment with complete donor chimerism was achieved on day 22. On day 222, the patient's whole blood was negative for EBV-DNA. He has been relapse-free for 24 months since transplantation.\n\nFigure. The clinical course. a: The overall clinical course from the onset of symptoms until bone marrow transplantation. b: The detailed clinical course from transplantation conditioning until neutrophil engraftment. Acute graft versus host disease (GVHD; grade II) was successfully treated with mPSL (2 mg/kg, daily). DEX: dexamethasone, CsA: cyclosporine A, ETP: etoposide, ATG: antithymocyte globulin, BMT: bone marrow transplantation, Lym: lymphocyte, Flu: fludarabine (30 mg/m2/day, day -6 to -2), Mel: melphalan (140 mg/m2, day -2), TBI: total body irradiation (4 Gy, day -1), mPSL: methyl-prednisolone, AST: aspartate aminotransferase, LDH: lactate dehydrogenase\n\nDiscussion\nThis is the reported case of EBV-HLH reactivation immediately after the administration of ATG. Infusion reaction-related symptoms are usually transient and disappear after the end of administration. In this case, however, the inflammatory symptoms persisted after the administration of ATG, despite the administration of an appropriate dosage of anti-inflammatory drugs. The increase in the transaminase and ferritin levels on the following day suggested the recurrence of HLH. Bone marrow aspiration showed marked hemophagocytosis.\n\nThe mechanism of action of ATG is mainly dependent on T-cell depletion through complement-dependent cell lysis (5,6). Complement activation induces the release of various chemical mediators, and results in an infusion reaction (7). Macrophage activation and the release of cytokines, which are strongly associated with the pathogenesis of HLH, are also mediated by complement activation (8). Thus, the relationship between the infusion reaction and the recurrence of HLH may be partly explained by the induction of complement activation following the administration of ATG. In this case, it is possible that ATG exerts its effect through complement activation, and that complement activation not only yielded an infusion reaction but also resulted in the recurrence of HLH. Previous reports on the induction of HLH by rituximab and infliximab may support this notion because these drugs have the potential to cause infusion reactions (9,10).\n\nIt is also possible that the recurrence of HLH was induced by other causes. First, the recurrence of HLH might occur due to the discontinuation of combination therapy with DEX, CsA and ETP. However, there have been no reports on HLH reactivation shortly before transplantation under these circumstances. Furthermore, the patient had no symptoms and none of the patient's laboratory results suggested of the recurrence of HLH before the administration of ATG. Thus, a more reasonable explanation is that ATG triggered the recurrence of HLH. Second, the recurrence of HLH might be related to EBV reactivation because ATG is a well-known risk factor for viral reactivation (11). The latency period in our case was too short to support this notion. ATG-related EBV reactivation has thus far only been reported after transplantation in patients with lymphoproliferative disorder, with a median latency period of 71 days. Third, other preconditioning drugs, such as fludarabine could have influenced the recurrence of HLH.\n\nIn this case, although HLH was controlled after pulse glucocorticoid therapy, it is possible that the conditioning regimen, which included fludarabine, melphalan, and total body irradiation, also suppressed the progression of HLH because these treatments may have immunosuppressive effects.\n\nIn conclusion, physicians should be aware of the possibility of the immediate reactivation of HLH in patients who are treated with ATG, especially when a severe infusion reaction is seen.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nChandrakasan S , Filipovich AH \nHemophagocytic lymphohistiocytosis advances in pathophysiology, diagnosis, and treatment . J Pediatr \n163 : 1253 -1259 , 2013 .23953723 \n2. \nIshii E , Ohga S , Imashuku S , et al \nNationwide survey of hemophagocytic lymphohistiocytosis in Japan . Int J Hematol \n86 : 58 -65 , 2007 .17675268 \n3. \nImashuku S \nTreatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010 . J Pediatr Hematol Oncol \n33 : 35 -39 , 2011 .21088619 \n4. \nJordan MB , Filipovich AH \nHematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step . Bone Marrow Transplant \n42 : 433 -437 , 2008 .18679369 \n5. \nMohty M \nMechanisms of action of antithymocyte globulin: T-cell depletion and beyond . Leukemia \n21 : 1387 -1394 , 2007 .17410187 \n6. \nAyuk FA , Fang L , Fehse B , et al \nAntithymocyte globulin induces complement-dependent cell lysis and caspase-dependent apoptosis in myeloma cells . Exp Hematol \n33 : 1531 -1536 , 2005 .16338496 \n7. \nvan der Kolk LE , Grillo-López AJ , Baars JW , et al \nComplement activation plays a key role in the side-effects of rituximab treatment . Br J Haematol \n115 : 807 -811 , 2001 .11843813 \n8. \nKhan MA , Assiri AM , Broering DC \nComplement and macrophage crosstalk during process of angiogenesis in tumor progression . J Biomed Sci \n22 : 58 , 2015 .26198107 \n9. \nRamos-Casals M , Brito-Zerón P , López-Guillermo A , et al \nAdult haemophagocytic syndrome . Lancet \n383 : 1503 -1516 , 2014 .24290661 \n10. \nBrito-Zerón P , Bosch X , Pérez-de-Lis M , et al \nInfection is the major trigger of hemophagocytic syndrome in adult patients treated with biological therapies . Semin Arthritis Rheum \n45 : 391 -399 , 2016 .26277577 \n11. \nUhlin M , Wikell H , Sundin M , et al \nRisk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation . Haematologica \n99 : 346 -352 , 2014 .24056821\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Epstein-Barr virus; antithymocyte globulin; hemophagocytic lymphohistiocytosis; infusion reaction",
"medline_ta": "Intern Med",
"mesh_terms": "D000293:Adolescent; D000961:Antilymphocyte Serum; D020031:Epstein-Barr Virus Infections; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007155:Immunologic Factors; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D019172:Transplantation Conditioning",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "583-586",
"pmc": null,
"pmid": "29225252",
"pubdate": "2018-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16338496;17410187;26198107;18679369;11843813;17675268;24056821;23953723;21088619;24290661;26277577",
"title": "Reactivation of Hemophagocytic Lymphohistiocytosis Triggered by Antithymocyte Globulin.",
"title_normalized": "reactivation of hemophagocytic lymphohistiocytosis triggered by antithymocyte globulin"
} | [
{
"companynumb": "JP-SA-2018SA053893",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"d... |
{
"abstract": "Neuroendocrine tumors (NETs) are a heterogeneous group of tumors developing from neural crest cells, with numerous sites of origin, commonly the gastrointestinal and genitourinary tracts. NETs of the genitourinary tract are more common in women. Small cell carcinoma of the prostate or testicular carcinoid are the NETs in male. In this article, we present a rare case of NET of the scrotum. Our patient was a 47-year-old male with a history of complicated pilonidal cysts resulting in chronic scrotal wounds. Biopsy of a large nonhealing scrotal wound revealed a high-grade neuroendocrine carcinoma with features most suggestive of small cell carcinoma. Presenting with advanced disease at diagnosis, he was started on systemic therapy and unfortunately progressed through multiple lines of treatment, including CAPTEM (capecitabine and temozolomide). Unfortunately, due to multiple logistical reasons, the patient was unable to receive the then off-label immunotherapy based on DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial. He, unfortunately, succumbed to his disease within months of diagnosis.",
"affiliations": "SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.",
"authors": "Akhtar|Komal|K|;Vyas|Vrinda|V|;Ashok Kumar|Prashanth|P|0000-0001-6236-2822;Corines|James|J|;de la Roza|Gustavo|G|;Basnet|Alina|A|",
"chemical_list": "D000069287:Capecitabine; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1177/23247096211008717",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n33834875\n10.1177/23247096211008717\n10.1177_23247096211008717\nCase Report\nPrimary Neuroendocrine Tumor of the Scrotum: An Uncommon Site for a Rare Tumor\nAkhtar Komal MD 1\nVyas Vrinda MBBS 1\nhttps://orcid.org/0000-0001-6236-2822\nAshok Kumar Prashanth MBBS 1\nCorines James DO 1\nde la Roza Gustavo MD 1\nBasnet Alina MD 1\n1 SUNY Upstate Medical University, Syracuse, NY, USA\nKomal Akhtar, MD, Division of Hematology-Oncology, SUNY Upstate Medical University, 750 E Adams Street, Syracuse, NY 13210, USA. Email: akhtark@upstate.edu\n9 4 2021\nJan-Dec 2021\n9 2324709621100871721 2 2021\n21 2 2021\n14 3 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nNeuroendocrine tumors (NETs) are a heterogeneous group of tumors developing from neural crest cells, with numerous sites of origin, commonly the gastrointestinal and genitourinary tracts. NETs of the genitourinary tract are more common in women. Small cell carcinoma of the prostate or testicular carcinoid are the NETs in male. In this article, we present a rare case of NET of the scrotum. Our patient was a 47-year-old male with a history of complicated pilonidal cysts resulting in chronic scrotal wounds. Biopsy of a large nonhealing scrotal wound revealed a high-grade neuroendocrine carcinoma with features most suggestive of small cell carcinoma. Presenting with advanced disease at diagnosis, he was started on systemic therapy and unfortunately progressed through multiple lines of treatment, including CAPTEM (capecitabine and temozolomide). Unfortunately, due to multiple logistical reasons, the patient was unable to receive the then off-label immunotherapy based on DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial. He, unfortunately, succumbed to his disease within months of diagnosis.\n\nneuroendocrine tumor\nscrotal malignancy\nscrotal carcinoma\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nNeuroendocrine tumors (NETs) are a heterogeneous group of relatively rare tumors, comprising ~2% of all malignancies, with a prevalence of <200 000 in the United States. They arise from neural crest cells and, hence, can have various sites of origin.1 They are more commonly found in the lungs and gastrointestinal tract, but are rare in the genitourinary tract.2,3 They are more common in women.3 Most male genital tract NETs are prostatic small cell carcinomas or testicular carcinoids. Small cell carcinoma is extremely rare in the scrotum, penis, and penile urethra.3\n\nNETs are divided into 2 groups based on clinical behavior, histology, and proliferation rate: well-differentiated (low grade to intermediate grade) and poorly differentiated (high grade) NETs.2 We report a case of poorly differentiated NET of the scrotal skin with rapidly progressive clinical course at this rare site.\n\nCase Presentation\n\nThe patient was a 47-year-old male with a complicated urological history due to recurrent pilonidal sinus requiring multiple perineal surgeries. It eventually led to the development of a fungating perineal wound and an urethro-cutaneous fistula, for which a urethroplasty was done. Perineal skin pathology obtained at the time of urethroplasty showed inflammation and fibrosis, but no evidence of malignancy. Two months post urethroplasty, the patient noted worsening scrotal swelling. A computed tomography scan of the pelvis with contrast revealed enlarged bilateral inguinal lymph nodes measuring 2.3 and 3.0 cm. Bilateral hydroceles were present, but there was no clear evidence of a discrete mass. He was managed conservatively with close follow-up. A few months later, he presented to the emergency department with painful and indurated swelling of the scrotum. Repeat computed tomography scan done at this time showed a mass measuring around 13 × 6.8 cm at the base of the penis with moderate bilateral pelvic and bilateral inguinal lymphadenopathy, consistent with metastatic disease (Figure 1).\n\nFigure 1. Computed tomography pelvis with contrast showing bilateral pelvic and groin lymphadenopathy with penile base mass and scrotal edema.\n\nThis prompted an urological evaluation with surgical exploration. Extensive wound debridement was performed, and a biopsy of the scrotal mass obtained. The biopsy showed a poorly differentiated malignant neoplasm with extensive necrosis infiltrating adipose tissue. The tumor was composed of cohesive sheets of hyperchromatic cells with scant cytoplasm, nuclear molding, and dispersed chromatin (Figure 2A and B). Immunohistochemistry staining was positive for synaptophysin (Figure 2C), chromogranin (Figure 2D), and CAM5.2, but negative for CK7, CK20, CDX2, uroplakin II, GATA3, p63, and CK5/6. Additional immunostains showed the tumor cells to be positive for INSM1, while being negative for WT-1, desmin, CK7, and Merkel cell polyomavirus. Ki-67 showed a high labeling index of ~80%. This histopathology and immunophenotype profile supported the diagnosis of a high-grade NET, with features consistent with small cell carcinoma, arising from scrotal skin. Next-generation testing on the tumor sample revealed no targetable mutations, no microsatellite instability (low) and a tumor mutation burden (TMB) of 9. The histopathology was second reviewed at a high-volume center as well.\n\nFigure 2. (A) Shows a malignant neoplasm with multiple areas of necrosis (black arrowheads) infiltrating adipose tissue (red arrow). (B) Shows poorly differentiated, hyperchromatic tumor cells with scant cytoplasm (left) adjacent to an area of necrosis (right). (C and D) demonstrate tumor cells staining positive for synaptophysin and chromogranin, respectively, consistent with a diagnosis of high-grade neuroendocrine carcinoma.\n\nChemotherapy has been the historical treatment of choice for high-grade NET. Hence, the patient was treated with 4 cycles of carboplatin and etoposide over a duration of 3 months. Unfortunately, restaging scans showed progression prompting a change in treatment to cisplatin and irinotecan, of which he received 3 cycles over 3 months. The patient’s treatment course was complicated by neutropenia; in the interim also showing disease progression, with worsening abdominal lymphadenopathy, this time with metastatic skin deposits for which he was offered palliative radiotherapy with weekly cisplatin over 2 weeks. Subsequent scans noted further progression in the scrotum, penis, and bulky retroperitoneal lymphadenopathy. Attempts to use immunotherapy were unsuccessful due to insurance issues as at that time, this was considered off-label. He was switched to third-line treatment with capecitabine and temozolomide (CAPTEM), around 7 months after his diagnosis, of which he was able to tolerate 2 cycles with continued rapid progression necessitating a hospitalization for symptom control. He was evaluated by the palliative care team and ultimately transitioned to hospice care, passing away within months after diagnosis.\n\nDiscussion\n\nScrotal carcinomas are a rare entity, occurring mostly as either basal cell or squamous cell histology. NETs of the scrotum are even rarer. NETs are a heterogeneous group of tumors, classified according to the originating site, histopathology proliferation index, and mitotic rate count. Extrapulmonary NETs are less common and are broadly classified into well-differentiated and poorly differentiated histological subtypes. Poorly differentiated subtypes confer a poor prognosis, characterized by a high mitotic index, high proliferation index, which rarely secrete amines or hormones and often present with local metastases. Our patient had an aggressive disease course, progressing through multiple lines of chemotherapy. Use of dual immune checkpoint blockade was considered based on the data from the DART trial, using ipilimumab and nivolumab, which revealed an overall response rate of 44% in patient with high-grade carcinoma (independent of tumor site), with one patient reaching an unconfirmed complete response. The 6-month progression-free survival was 31%, with a medial overall survival of 11 months among those with high-grade tumors. The proposed hypothesis was that high-grade neuroendocrine cancers could have a higher tumor mutational burden, allowing for a better response to immunotherapy.4 Unfortunately, immunotherapy could not be used due to insurance issues.\n\nWe treated him with temozolamide and capecitabine, based on data from the CAPTEM studies done previously. CAPTEM have been known to be active in the first-line setting for advanced pancreatic neuroendocrine neoplasms.3 A meta-analysis to study safety and efficacy of treating patients with advanced NETs with CAPTEM showed the combination to be both effective and relatively safe in a variety of different malignancies.5,6 In addition, the high objective response rates, achieved with CAPTEM makes it natural choice for patients who are heavily pretreated and “chemo resistant” until this regimen.5-7\n\nA comparison of our case and cases published since 2019 has been summarized in Table 1.\n\nTable 1. A Summary Comparing Our Case to Cases Reported on Scrotal NETs Since 2019.\n\nCase\tOur current case\t\n Age in years\t47\t\n Sex\tMale\t\n Presenting symptoms/signs\tScrotal swelling, recurrent abscess\t\n Imaging\tGroin lymphadenopathy, mass in the base of penis\nLung nodules\t\n Histopathology\tCohesive sheets of hyperchromatic cells with scant cytoplasm, nuclear molding, and dispersed chromatin in an infiltrative pattern with extensive necrosis\t\n Immunohistochemistry\tSynaptophysin: +\t\nChromogranin: +\t\nCAM5.2: +\t\nINSM1: +\t\nCK7: −\t\nCK20: −\t\nCDX2: −\t\nUroplakin II: −\t\nGATA3: −\t\np63: −\t\nCK5/6: −\t\nWT1: −\t\nDesmin: −\t\nKi67: 80%\t\n Next-generation sequencing\tMSI: − stable\t\nTMB: 9\t\nNo other targetable mutation\t\n Treatment\t*Carboplaton/etoposide, 4 cycles—progression\t\n*Cisplatin/irinotecan, 3 cycles—progression, neutropenia\t\n*Capecitabine/temozolomide, 2 cycles\t\n Outcome\tDied within months since diagnosis.\t\nCase\tMunshi et al8\t\n Age in years\t33\t\n Sex\tMale\t\n Presenting symptoms/signs\tRight testicular mass, infertility\t\n Imaging\tWell-defined lobulated intratesticular soft tissue mass lesion\t\n Histopathology\tTumor cells with granular eosinophilic cytoplasm, rounded nuclei, and salt and pepper chromatin\t\n Immunohistochemistry\tSynaptophysin: +\t\nChromogranin: +\t\nCKAE1/AE3: +\t\nCD56: −\t\nCD99: −\t\nKi67: 0%\t\n Next-generation sequencing\tN/A\t\n Treatment\tFocal excision\t\n Outcome\tNo recurrence on follow-up reported\t\nCase\tKim et al9\t\n Age in years\t54\t\n Sex\tMale\t\n Presenting symptoms/signs\tRight testicular mass\t\n Imaging\tRight solid heterogeneous testicular mass, right groin lymph nodes\nBilateral pulmonary nodules\t\n Histopathology\tEpithelioid cells with granular, focally rhabdoid cytoplasm, vacuoles, and hyaline globules arranged in nested and focally trabecular growth pattern\t\n Immunohistochemistry\tSynaptophysin: +\t\n\tVimentin: +\t\n\tChromogranin: −\t\n\tCAM5.2: +\t\n\tCD56: +\t\n\tCD10: +\t\n\tβ-catenin: +\t\n\tS100: +\t\n\tPankeratin: −\t\n\tCK7: −\t\n\tCK20: −\t\n\tInhibin: −\t\n\tEMA: −\t\n\tCalretinin: −\t\n\tMART1: −\t\n\tKi67: 2%\t\n Next-generation sequencing\tN/A\t\n Treatment\tRadical orchiectomy\t\n Outcome\tNot reported\t\nAbbreviations: MSI, microsatellite instability; N/A, not available; NETs, neuroendocrine tumors; TMB, tumor mutation burden.\n\nNeuroendocrine carcinomas represent a heterogeneous tumor entity, with scrotal NETs being quite rare. Early diagnosis and treatment are of paramount importance, because of the aggressiveness of some tumor types.\n\nOur sincere thanks to the Department of Hematology and Oncology at the Upstate University Hospital for all the support and guidance.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Patient identifiers have been removed. Hence informed consent has not been obtained.\n\nORCID iD: Prashanth Ashok Kumar https://orcid.org/0000-0001-6236-2822\n==== Refs\nReferences\n\n1 Basu B Sirohi B Corrie P. Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin. Endocr Relat Cancer. 2010;17 :R75-R90.\n2 Schott M Klöppel G Raffel A Saleh A Knoefel WT Scherbaum WA. Neuroendocrine neoplasms of the gastrointestinal tract. Dtsch Arztebl Int. 2011;108 : 305-312.21629514\n3 Maricić A Katunarić M Sutalo N , et al . Primary large-cell neuroendocrine carcinoma of the scrotum. Wien Klin Wochenschr. 2010;122 :360-362.20559878\n4 Patel SP Othus M Chae YK , et al . A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in patients with nonpancreatic meuroendocrine tumors. Clin Cancer Res. 2020;26 :2290-2296.31969335\n5 Lu Y Zhao Z Wang J , et al . Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: a meta-analysis. Medicine (Baltimore). 2018;97 :e12784.\n6 Ramirez RA Beyer DT Chauhan A , et al . The role of capecitabine/temozolomide in metastatic neuroendocrine tumors. Oncologist. 2016;21 :671-675.27226359\n7 Peixoto RD Noonan KL Pavlovich P Kennecke HF Lim HJ. Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs. J Gastrointest Oncol. 2014;5 :247-252.25083296\n8 Munshi SA Saada H Mujtaba S Elkoushy MA. Primary testicular neuroendocrine tumor with azoospermia: extending indications for testicle-sparing surgery. Urol Case Rep. 2019;23 :78-81.30705829\n9 Kim JK Baumgarten A Walter O Patel T. Paraganglioma of the testicle: a case presentation and review of the literature. Urol Case Rep. 2019;24 :100847.31211058\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "neuroendocrine tumor; scrotal carcinoma; scrotal malignancy",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D012611:Scrotum; D000077204:Temozolomide",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211008717",
"pmc": null,
"pmid": "33834875",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30313101;20559878;27226359;31211058;20008097;30705829;31969335;21629514;25083296",
"title": "Primary Neuroendocrine Tumor of the Scrotum: An Uncommon Site for a Rare Tumor.",
"title_normalized": "primary neuroendocrine tumor of the scrotum an uncommon site for a rare tumor"
} | [
{
"companynumb": "US-CHEMI SPA-2110696",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Isoniazid (INH) is an integral component of treatment of tuberculosis. An acute overdose is potentially fatal and is characterised by the clinical triad of repetitive seizures unresponsive to the usual anticonvulsants, metabolic acidosis with a high anion gap and coma. A case of isoniazid induced seizures after therapeutic dose of 600 mg. as a part of CAT I thrice weekly intermittent anti-tuberculosis regimen for pulmonary tuberculosis is reported. The frequency of the usage of Isoniazid as antituberculosis therapy requires that physicians be aware of such toxicity.",
"affiliations": "Department of Tuberculosis and Respiratory Diseases, LRS Institute of Tuberculosis and Respiratory Diseases, New Delhi. mmpuri@rediffmail.com",
"authors": "Puri|M M|MM|;Kumar|Lokender|L|;Vishwakarma|P D|PD|;Behera|D|D|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-5707",
"issue": "59(2)",
"journal": "The Indian journal of tuberculosis",
"keywords": null,
"medline_ta": "Indian J Tuberc",
"mesh_terms": "D000368:Aged; D000995:Antitubercular Agents; D004359:Drug Therapy, Combination; D006801:Humans; D007538:Isoniazid; D008297:Male; D012640:Seizures; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "0373027",
"other_id": null,
"pages": "100-2",
"pmc": null,
"pmid": "22838208",
"pubdate": "2012-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures with single therapeutic dose of isoniazid.",
"title_normalized": "seizures with single therapeutic dose of isoniazid"
} | [
{
"companynumb": "IN-ALKEM LABORATORIES LIMITED-IN-ALKEM-2022-05206",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugad... |
{
"abstract": "OBJECTIVE\nSingle-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696).\n\n\nMETHODS\nPatients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) > or = 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m(2) weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m(2) added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral alpha .05, 355 events were needed and 400 patients planned.\n\n\nRESULTS\nFour hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS > or = 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity.\n\n\nCONCLUSIONS\nThe addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer.",
"affiliations": "Medical and Experimental Oncology Unit, Oncology Institute Giovanni Paolo II, Bari, Italy.",
"authors": "Colucci|Giuseppe|G|;Labianca|Roberto|R|;Di Costanzo|Francesco|F|;Gebbia|Vittorio|V|;Cartenì|Giacomo|G|;Massidda|Bruno|B|;Dapretto|Elisa|E|;Manzione|Luigi|L|;Piazza|Elena|E|;Sannicolò|Mirella|M|;Ciaparrone|Marco|M|;Cavanna|Luigi|L|;Giuliani|Francesco|F|;Maiello|Evaristo|E|;Testa|Antonio|A|;Pederzoli|Paolo|P|;Falconi|Massimo|M|;Gallo|Ciro|C|;Di Maio|Massimo|M|;Perrone|Francesco|F|;|||;|||;|||",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2009.25.4433",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "28(10)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "1645-51",
"pmc": null,
"pmid": "20194854",
"pubdate": "2010-04-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study.",
"title_normalized": "randomized phase iii trial of gemcitabine plus cisplatin compared with single agent gemcitabine as first line treatment of patients with advanced pancreatic cancer the gip 1 study"
} | [
{
"companynumb": "IT-PFIZER INC-2020448644",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We describe the case of a 23-year-old white female, 10-12 weeks pregnant, with a history of intravenous drug use and a recently diagnosed pneumonia, who was found deceased in her bed after a night of sleep. Although postmortem serum toxicology tested positive for alprazolam, tetrahydrocannabinol, and morphine, the ultimate cause of death was determined to be cardiac tamponade secondary to an isolated abscess in the ascending aorta. The patient had several risk factors for aortic rupture and cardiac tamponade including intravenous drug use, pneumonia, and pregnancy. However, an autopsy of the patient showed an isolated abscess of the ascending aorta without evidence of infective endocarditis, coronary artery rupture, aortic aneurysm, or aortic dissection making this an unusual case of cardiac tamponade. The aim of this case report is to encourage providers to obtain a tissue culture of any aortic abscesses so that the organisms involved can be identified. The identification of such organisms may help guide antimicrobial treatment in similar presentations in the future.",
"affiliations": "Western Michigan University Homer Stryker M.D. School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49007, USA.;Western Michigan University Homer Stryker M.D. School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49007, USA. John.Livingstone@med.wmich.edu.",
"authors": "Shattuck|Brandy|B|;Livingstone|John|J|http://orcid.org/0000-0002-9711-7218",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12024-017-9856-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-769X",
"issue": "13(2)",
"journal": "Forensic science, medicine, and pathology",
"keywords": "Abscess; Aortic; Intravenous; Isolated; Pregnant; Tamponade",
"medline_ta": "Forensic Sci Med Pathol",
"mesh_terms": "D000038:Abscess; D001011:Aorta; D001019:Aortic Rupture; D002305:Cardiac Tamponade; D005260:Female; D006801:Humans; D011014:Pneumonia; D011247:Pregnancy; D011248:Pregnancy Complications; D015819:Substance Abuse, Intravenous; D055815:Young Adult",
"nlm_unique_id": "101236111",
"other_id": null,
"pages": "226-229",
"pmc": null,
"pmid": "28315148",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27278541;9175336;26202654;7590550;25563772;24200396;26889448;10685714;25301923;20625143;18609201;25609416;23629391;21353789;1582323;26718232;27607875;27352336;6447812;8745179;22919449;26905825;19395500",
"title": "A case of cardiac tamponade due to an isolated abscess in the ascending aorta of a pregnant woman with a history of intravenous substance abuse.",
"title_normalized": "a case of cardiac tamponade due to an isolated abscess in the ascending aorta of a pregnant woman with a history of intravenous substance abuse"
} | [
{
"companynumb": "US-PFIZER INC-2017229226",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "Transient 5-oxoprolinuria is a phenomenon that is well recognised in adults. We illustrate an unusual paediatric case of transient 5-oxoprolinuria presenting during an episode of severe sepsis with concomitant paracetamol use. The 15-month-old patient had an extremely high anion gap metabolic acidosis. Adequate resuscitation failed to correct the biochemical disturbance, and high levels of 5-oxoproline were identified. A combination of haemofiltration, replenishment of glutathione stores with N-acetylcysteine and cessation of paracetamol administration resulted in the resolution of the acidosis. Subsequent testing following treatment of the sepsis revealed no ongoing 5-oxoprolinuria.\n\n\nCONCLUSIONS\nTransient 5-oxoprolinuria has been previously reported in the adult population during episodes of severe sepsis and various pharmaceutical interventions. This case illustrates that it is a phenomenon that should be considered in paediatric patients where a very high anion gap metabolic acidosis exists that cannot be explained by the biochemical indices.\n\n\nBACKGROUND\n• 5-oxoprolinuria in the paediatric population is usually secondary to an inborn error of metabolism. • Transient 5-oxoprolinuria is well recognised in adults during episodes of severe glutathione depletion.\n• Transient 5-oxoprolinuria is a phenomenon rarely reported in the paediatric population. • It highlights the importance of investigating a high anion gap such that unusual diagnoses are not missed.",
"affiliations": "Sheffield Children's NHS Foundation Trust, Sheffield Children's Hospital, Western Bank, Sheffield, S10 2TH, UK. Sarah.hulley@nhs.net.;Sheffield Children's NHS Foundation Trust, Sheffield Children's Hospital, Western Bank, Sheffield, S10 2TH, UK. Jeff.perring@sch.nhs.uk.;Sheffield Children's NHS Foundation Trust, Sheffield Children's Hospital, Western Bank, Sheffield, S10 2TH, UK. Nigel.manning@sch.nhs.uk.;Sheffield Children's NHS Foundation Trust, Sheffield Children's Hospital, Western Bank, Sheffield, S10 2TH, UK. Simon.olpin@sch.nhs.uk.;Sheffield Children's NHS Foundation Trust, Sheffield Children's Hospital, Western Bank, Sheffield, S10 2TH, UK. Sufin.yap@sch.nhs.uk.",
"authors": "Hulley|Sarah L|SL|;Perring|Jeff|J|;Manning|Nigel|N|;Olpin|Simon|S|;Yap|Sufin|S|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D005981:Glutathione Synthase; D011761:Pyrrolidonecarboxylic Acid",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-015-2585-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6199",
"issue": "174(12)",
"journal": "European journal of pediatrics",
"keywords": "5-oxoproline; Anion gap; Metabolic acidosis; Paracetamol; Pyroglutamate",
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D000082:Acetaminophen; D000136:Acid-Base Equilibrium; D000138:Acidosis; D000592:Amino Acid Metabolism, Inborn Errors; D018712:Analgesics, Non-Narcotic; D005260:Female; D005981:Glutathione Synthase; D006801:Humans; D007223:Infant; D011761:Pyrrolidonecarboxylic Acid; D018805:Sepsis",
"nlm_unique_id": "7603873",
"other_id": null,
"pages": "1685-8",
"pmc": null,
"pmid": "26122794",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24111553;16922670;10890623;22256446;17699243;25129617;2567460;9474033;17594793;2246862;15983968;9665429;18809984",
"title": "Transient 5-oxoprolinuria: unusually high anion gap acidosis in an infant.",
"title_normalized": "transient 5 oxoprolinuria unusually high anion gap acidosis in an infant"
} | [
{
"companynumb": "GB-JNJFOC-20151202001",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Pyridostigmine is an acetylcholinesterase inhibitor commonly used in the treatment of myasthenia gravis. We describe a patient who developed a rash after recently being started on pyridostigmine and give a general review of leukocytoclastic vasculitis.\n\n\n\nA 91-year-old man was diagnosed with ocular myasthenia gravis. He was started on pyridostigmine, and 2 weeks later he developed a rash. The rash was biopsied and found to be secondary to leukocytoclastic vasculitis; the pyridostigmine was stopped, loratadine was started, and the rash resolved.\n\n\n\nLeukocytoclastic vasculitis is commonly caused by a hypersensitivity reaction to medications, or it can be associated with certain medical conditions. We present a brief review of the most common medications and medical conditions known to cause this reaction, but to our knowledge this is the first description of pyridostigmine causing this reaction.",
"affiliations": "Medical Student in Internal Medicine at the University of Otago School of Medicine in Dunedin, New Zealand. singu331@student.otago.ac.nz.;Pathology Registrar at the University of Otago School of Medicine in Dunedin, New Zealand. tim.hodgson@sclabs.co.nz.;Consultant in Medicine at The Dunedin Hospital; an Honorary Clinical Senior Lecturer at the University of Otago School of Medicine in Dunedin, New Zealand; Clinical Assistant Professor of Medicine at Stanford University School of Medicine; and a Hospitalist at the Santa Clara Medical Center in CA. davidclarkemd@mac.com.",
"authors": "Singh|Gunveen|G|;Hodgson|Tim|T|;Clarke|David E|DE|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D017336:Loratadine; D011729:Pyridostigmine Bromide",
"country": "United States",
"delete": false,
"doi": "10.7812/TPP/15-240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-5767",
"issue": "21()",
"journal": "The Permanente journal",
"keywords": null,
"medline_ta": "Perm J",
"mesh_terms": "D000369:Aged, 80 and over; D002800:Cholinesterase Inhibitors; D006801:Humans; D017336:Loratadine; D008297:Male; D009157:Myasthenia Gravis; D011729:Pyridostigmine Bromide; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "9800474",
"other_id": null,
"pages": "15-240",
"pmc": null,
"pmid": "28080955",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24250337;8169261;22449668;17415507;8867537;11816242;16490843;6703752",
"title": "Leukocytoclastic Vasculitis Secondary to Pyridostigmine (Mestinon): Report of a Possible First Case.",
"title_normalized": "leukocytoclastic vasculitis secondary to pyridostigmine mestinon report of a possible first case"
} | [
{
"companynumb": "NZ-IMPAX LABORATORIES, INC-2017-IPXL-00995",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BENDROFLUMETHIAZIDE"
},
"dr... |
{
"abstract": "Thrombotic microangiopathies (TMA) include a variety of vascular disorders characterized by the presence of microthrombi, coagulopathy by platelet activation and consumption, and systemic damage. The most frequent secondary causes are infections and some medications. However, the presence of chemotherapeutic agents is not so common, and the induction of TMA by oxaliplatin is poorly understood, with few published case reports. We present the case of a patient with a history of gallbladder carcinoma, in whom findings compatible with TMA were documented, and with a temporal and sole relation to oxaliplatin.",
"affiliations": "Internal Medicine Department, Fundación Cardioinfantil, Bogotá, Colombia.;Internal Medicine Department, Fundación Cardioinfantil, Bogotá, Colombia.",
"authors": "Fuentes-Lacouture|María Cynthia|MC|;Barrera-Garavito|Edgar Camilo|EC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000510307",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000510307\ncro-0013-1191\nCase Report\nOxaliplatin-Induced Thrombotic Microangiopathy in a Patient with Stage IV Gallbladder Carcinoma: Primary Association or Multiple Hits?\nFuentes-Lacouture María Cynthia * Barrera-Garavito Edgar Camilo Internal Medicine Department, Fundación Cardioinfantil, Bogotá, Colombia\n*María Cynthia Fuentes-Lacouture, Internal Medicine Department, Fundación Cardioinfantil - Universidad del Rosario, Calle 163a # 13B −60, Bogotá D.C. (Colombia), cynthiafuentes27@gmail.com\nSep-Dec 2020 \n29 9 2020 \n29 9 2020 \n13 3 1191 1195\n19 7 2020 19 7 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Thrombotic microangiopathies (TMA) include a variety of vascular disorders characterized by the presence of microthrombi, coagulopathy by platelet activation and consumption, and systemic damage. The most frequent secondary causes are infections and some medications. However, the presence of chemotherapeutic agents is not so common, and the induction of TMA by oxaliplatin is poorly understood, with few published case reports. We present the case of a patient with a history of gallbladder carcinoma, in whom findings compatible with TMA were documented, and with a temporal and sole relation to oxaliplatin.\n\nKeywords\nThrombotic microangiopathiesOxaliplatinNeoplasmChemotherapy\n==== Body\nIntroduction\nThrombotic microangiopathies (TMA) are disorders characterized by intravascular destruction of red blood cells, thrombocytopenia due to activation and consumption, and formation of microthrombi in the systemic vasculature, causing ischemic organ damage [1]. It can be classified as primary or secondary, with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome being the most representative of the former. Secondary causes are often related to acute infections, including HIV infection, and drug-induced ones. Among the latter, some chemotherapeutic agents have been characterized by inducing this clinical picture, such as gemcitabine [2]. However, there are few reports about the relationship with oxaliplatin, and apparently none reported at the moment with capecitabine. We present the case of a patient treated with the capecitabine and oxaliplatin (CapeOX) for metastatic gallbladder carcinoma, in whom criteria for chemotherapy-induced TMA were documented.\n\nCase Description\nA 64-year-old female patient consulted the emergency department due to a 5-day history of asthenia and severe abdominal pain associated with 1 episode of dark stools. She had a history of hypertension, type 2 diabetes mellitus, and stage IV T4N1M1 gallbladder carcinoma, with metastatic liver disease, for which she had received chemotherapy initially with gemcitabine and cisplatin; however, due to disease progression she was on CapeOx therapy (capecitabine and oxaliplatin), the last dose 20 days ago. On physical examination, she was pale and jaundiced. The abdominal examination revealed a palpable, 10-cm diameter stone mass located in the right hypochondrium with extension to the epigastrium.\n\nThe initial laboratory results showed metabolic acidemia with severe hyperlactatemia; complete blood count revealed leukocytes of 41,600 cell/mm3, with neutrophilia, macrocytic anemia, and severe thrombocytopenia with counts below 30,000 cell/mm3. Kidney function was preserved. Sepsis of abdominal origin was suspected as the first possibility, and antibiotics therapy was started at ICU. An abdominal CT scan revealed a solid hypodense mass in liver segment VI, in close contact and loss of cleavage plane with gallbladder, measuring 100 × 86 mm. Because of dark stools and anemia, endoscopic studies of gastrointestinal tract were requested, which were negative for active or recent bleeding. Despite antibiotic management, the patient status worsened, and anemia and thrombocytopenia persisted, requiring continuous transfusion support. Peripheral blood smear was positive for schistocytes. Lactate dehydrogenase level was 978 U/L, indirect bilirubin 1.5 mg/dL, and reticulocyte was elevated, and haptoglobin level was less than 8 mg/dL, confirming hemolytic anemia. The patient was additionally suffering from neurological disorders, caused by mutism and disorientation.\n\nAdditional workup showed coagulation abnormalities with consumed fibrinogen. With a plasmic score of 5 points, the diagnosis of TMA was considered taking into account the International Working Group criteria. TMA was suspected to be in association with oxaliplatin and active neoplastic disease. Management with plasmapheresis was proposed; however, in the face of advanced neoplastic disease and secondary complications, it was deferred. The patient died 17 days after admission.\n\nDiscussion\nTMA are diseases of the vascular system that cause multi-organic involvement. They are characterized by the presence of microangiopathic anemia, thrombocytopenia, and organ damage [1]. Despite a clear pathophysiology with compromised vasculature, the causes and triggers differ between subgroups and classification, and are thus divided into primary and secondary or acquired. Among the primaries, we are familiar with thrombocytopenic thrombotic purpura, with an incidence of 3 in 1,000,000 inhabitants [3], and hemolytic uremic syndrome.\n\nHowever, secondary TMA represents the vast majority of cases, reaching 94% of cases in a retrospective study carried out by Bayer et al. [4]. In this study, it was found that pregnancy, infections, medications, and malignancy were the principal triggers.\n\nAmong drugs associated with TMA, there is a strong association with gemcitabine and calcineurin inhibitors [4, 5], frequently used as chemotherapy and immunosuppressants in solid-organ transplant recipients, respectively. In the case of malignancies, the majority of cases represent adenocarcinomas, with another large part being secondary to hematologic diseases. The incidence of TMA reported among these entities ranges between 3 and 12% [6].\n\nRegarding gemcitabine-induced TMA, a variable time course between the administration of the drug and the development of symptoms has been described, with a mean time at onset of 7.4 months after the administration of gemcitabine. Nevertheless, some authors have tried to identify risk factors for its development, with a median cumulative dose of 20,000 mg/m2or 21.9 doses being one of the main factors associated with its development [7].\n\nIn this case, our patient had a previous diagnosis of gallbladder carcinoma, for which she had previously received gemcitabine therapy, and was currently under management with oxaliplatin because of disease progression. Despite not having ADAMTS13 measurement, with a plasmic score of 5 there was an intermediate risk for the development of TMA, and in the appropriate clinical context and without any other explanation for the patient's manifestations, this diagnosis was considered as a first possibility.\n\nThere are some case reports in the literature in which the administration of oxaliplatin-based chemotherapy has been associated with the appearance of TMA [8], in which pathophysiology is still unknown. However, in the three similar reports found in the literature (Table 1), standard treatment with steroids and free frozen plasma or plasma exchange was administered, with 2 of the 3 cases achieving complete remission.\n\nWe found no reports in which patients had previous exposure to gemcitabine, with subsequent administration of oxaliplatin, as in our case. This leads us to question the possibility that previous exposure to this drug has favored endothelial changes in our patient that could have facilitated the development of this fatal complication, promoting the theory of “multiple hits” necessary for the development of secondary TMA [4], taking into account the possible immune-mediated mechanism of oxaliplatin-induced TMA, associated with a previous exposure to gemcitabine, which is known to induce TMA through a toxic mechanism secondary to endothelial damage [9].\n\nRegardless of the pathophysiology, it is important to recognize early signs of this disease, due to its high mortality rate in case of not administering appropriate treatment. Despite the implication of a qualitative or quantitative deficiency of the enzyme ADAMTS13 in the pathophysiology of the disease, the clinicopathological findings of hemolytic anemia and thrombocytopenia in the context of certain diseases or exposure to medications or infections should lead to suspicion of this entity [5].\n\nOnce the diagnosis is established, it is necessary to start immediate therapy, which is generally based on plasma exchange, with which mortality can change from 90 to 20% [3, 5]. Additionally, the use of high-dose steroids is recommended concomitantly with plasmapheresis, although it is important to note that some patients may improve with plasma exchange as single therapy [10].\n\nFinally, TMA is a fatal entity, which occurs in patients on specific medications. Its causal association with the use of oxaliplatin is still enigmatic, with few reports in the literature on this association.\n\nConclusion\nThe clinical and paraclinical suspicion of TMA is crucial for the early initiation of therapies that can change the natural history of this not so rare complication. Despite the fact that we clearly know some diseases and medications that are associated with it, there are some circumstances such as in this case where its diagnosis should be considered, despite not having a clear association. There are case reports of oxaliplatin in which there is an evident association with the development of TMA, this being one of them. However, to our knowledge, this is the first case report in which there was previous exposure to a drug related to the development of TMA (gemcitabine), with subsequent administration of oxaliplatin, supporting the possible “multiple-hits” model.\n\nStatement of Ethics\nThe manuscript has been sufficiently de-identified to protect the patient. However, informed consent was obtained for the publication of the case.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding was received.\n\nNone of the authors have disclosures relevant to this manuscript.\n\nAuthor Contributions\nAll authors contributed to the editing of the manuscript.\n\nM.C.F.-L. wrote the manuscript. E.C.B.-G. performed text review and corrections based on clinical experience.\n\nTable 1 Clinical characteristics and outcomes of patients with TMA secondary to oxaliplatin in published case reports\n\n\tBaretta Z et al., 2013\tNiu J and Mims MP, 2012\tDahabreh I et al., 2006\t\nSex\tMale\tFemale\tMale\t\nAge\t73\t68\t52\t\nNeoplasia\tIIIB colon adenocarcinoma\tRectal adenocarcinoma\tSigmoid adenocarcinoma\t\nTiming\tFourth cycle\tSecond cycle\tFourth cycle\t\nTreatment\tSteroids, frozen plasma infusion\tSteroids, plasma exchange\tSteroids, frozen plasma infusion\t\nOutcome\tDeath\tComplete remission\tComplete remission\n==== Refs\nReferences\n1 Tsai HM Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome Am J Med 2013 126 (3) 200 9 23410558 \n2 Scully M Hunt BJ Benjamin S Liesner R Rose P Peyvandi F et al Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies Br J Haematol 2012 158 (3) 323 35 22624596 \n3 Deford CC Reese JA Schwartz LH Perdue JJ Kremer Hovinga JA Lämmle B et al Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura Blood 2013 122 (12) 2023 142 23838348 \n4 Bayer G Von Tokarski F Thoreau B Bauvois A Barbet C Cloarec S et al Etiology and Outcomes of Thrombotic Microangiopathies Clin J Am Soc Nephrol 2019 14 (4) 557 66 30862697 \n5 Arnold DM Patriquin CJ Nazy I Thrombotic microangiopathies: a general approach to diagnosis and management CMAJ 2017 189 (4) E153 9 27754896 \n6 Gordon LI Kwaan HC Cancer- and drug-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome Semin Hematol 1997 34 (2) 140 7 9109216 \n7 Walter RB Joerger M Pestalozzi BC Gemcitabine-associated hemolytic-uremic syndrome Am J Kidney Dis 2002 40 (4) E16 12324937 \n8 Baretta Z Falci C Piva E Conte P Fatal Oxaliplatin-Induced Thrombotic Thrombocytopenic Purpura: A Case Report Clin Colorectal Cancer 2013 12 (4) 294 6 24188688 \n9 Hassane I Corinne I Vincent L Lucille M Isabelle T Olivier R Gemcitabine-induced thrombotic microangiopathy: a systematic review Nephrol Dial Transplant 2006 21 (11) 3038 45 16968717 \n10 George JN How I treat patients with thrombotic thrombocytopenic purpura: 2010 Blood 2010 116 (20) 4060 9 20686117\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(3)",
"journal": "Case reports in oncology",
"keywords": "Chemotherapy; Neoplasm; Oxaliplatin; Thrombotic microangiopathies",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1191-1195",
"pmc": null,
"pmid": "33173484",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "24188688;30862697;16968717;22624596;23838348;23410558;20686117;12324937;9109216;27754896",
"title": "Oxaliplatin-Induced Thrombotic Microangiopathy in a Patient with Stage IV Gallbladder Carcinoma: Primary Association or Multiple Hits?",
"title_normalized": "oxaliplatin induced thrombotic microangiopathy in a patient with stage iv gallbladder carcinoma primary association or multiple hits"
} | [
{
"companynumb": "CO-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-267901",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"dru... |
{
"abstract": "Spinal cord stimulators (SCSs) have been used for decades to treat chronic pain. SCSs are often used to treat patients with chronic back pain caused by failed back surgery syndrome, patients with complex regional pain syndrome, or individuals who are not candidates for surgery. SCSs are a relative contraindication in patients with another electrical pulse device. We present 3 patients who received SCS despite having another implant in place. There was no interaction between devices. The first case was a patient with failed back surgery syndrome who had an implantable cardiac defibrillator and an SCS implant. The second case was a nonsurgical candidate with a pacemaker who received an SCS to help with lower back pain due to an occupational injury. The third case was a patient with complex regional pain syndrome and a bladder stimulator with a previous SCS who received a revision to help manage the pain. In all these patients, pain scores significantly improved after the trial.",
"affiliations": "Department Anesthesiology, University of Cincinnati, Cincinnati, OH, USA; Department Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Electronic address: alaaawny@hotmail.com.;University of Cincinnati College of Medicine, Cincinnati, OH, USA.;Department Anesthesiology, University of Cincinnati, Cincinnati, OH, USA.",
"authors": "Abd-Elsayed|Alaa|A|;Grandhi|Ravi|R|;Sachdeva|Harsh|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jclinane.2016.08.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "35()",
"journal": "Journal of clinical anesthesia",
"keywords": "Electrical interference; Electrical pulse devices; Spinal cord stimulator",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D059350:Chronic Pain; D004599:Electric Stimulation Therapy; D005260:Female; D006801:Humans; D017116:Low Back Pain; D008297:Male; D008875:Middle Aged; D010138:Pacemaker, Artificial; D019736:Prostheses and Implants; D062187:Spinal Cord Stimulation",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "475-478",
"pmc": null,
"pmid": "27871577",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lack of electrical interference between spinal cord stimulators and other implanted electrical pulse devices.",
"title_normalized": "lack of electrical interference between spinal cord stimulators and other implanted electrical pulse devices"
} | [
{
"companynumb": "US-APOTEX-2017AP017128",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": null,
... |
{
"abstract": "About 3% of all cancer patients suffer from cancer of unknown primary origin. These patients present with metastatic disease for which a primary site cannot be detected at the time of diagnosis. Sophisticated diagnostic techniques and operational procedures have failed to improve the diagnostic efficacy in this group of patients. Consequently, a limited diagnostic procedure with basic laboratory tests and imaging studies is sufficient for the diagnosis of this syndrome. The use of immunohistochemistry, as well as serum tumor markers of high specificity that may help to identify other tumors, is highly suggested. Although the prognosis for the majority of these patients still remains poor, several subsets of favorable outcome to treatment have been recognized. Nevertheless, promising in vitro data and new drugs on trials, paralleled with a better knowledge of the underlying pathogenetic molecular mechanisms, offer a more optimistic look to the future therapeutic management of these patients.",
"affiliations": "Department of Medicine/Oncology Unit, Ioannina University Hospital, Ioannina 45110, Greece.",
"authors": "Briasoulis||E|;Pavlidis||N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "2(3)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": null,
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "142-152",
"pmc": null,
"pmid": "10388044",
"pubdate": "1997",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cancer of Unknown Primary Origin.",
"title_normalized": "cancer of unknown primary origin"
} | [
{
"companynumb": "FI-MYLANLABS-2019M1088817",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "Background: A recent phase 2 study reported success using combination of ibrutinib and venetoclax for relapsed/refractory mantle cell lymphoma (MCL). We report a case of MCL with hyperleukocytosis that developed fatal hyperkalemia after a single low initiation dose of venetoclax.Case report: A 72-year-old man with known MCL was admitted for hyperkalemia and anemia (Hgb = 6.6 g/dL, K+ =9.6 mmol/L). Repeated K+ measurements and clinical evaluation were consistent with pseudohyperkalemia. The patient's lymphocyte count had risen from 15.2 to 466.8 K/uL in the preceding 1.5 months despite 8 cycles of ibrutinib. Based on the results of a recent phase 2 study Venetoclax was added; after a single very low initiation dose of venetoclax the patient developed fatal hyperkalemia.Discussion: The proliferation of new therapies is making difficult to perform randomized clinical trials large enough to capture potential risks of new therapies in specific scenarios. Fatal hyperkalemia resulted from use of a recently recommended combination regimen for refractory/relapsed MCL in a phase 2 study, despite dose escalation and TLS prophylaxis suggesting increased risk of this regimen for patients with hyperleukocytosis.",
"affiliations": "Department of Internal Medicine, Veterans Administration Health Care System, Minneapolis, MN, USA.;Pathology and Laboratory Medicine, Veterans Administration Health Care System, Minneapolis, MN, USA.;Hematology Oncology, Veterans Administration Health Care System, Minneapolis, MN, USA.;Pathology and Laboratory Medicine, Veterans Administration Health Care System, Minneapolis, MN, USA.",
"authors": "Verma|Aman|A|;Mbughuni|Michael|M|;Mariash|Evan|E|;Mesa|Hector|H|http://orcid.org/0000-0003-1833-4642",
"chemical_list": "D019086:Bridged Bicyclo Compounds, Heterocyclic; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; C551803:ibrutinib; D000225:Adenine; C579720:venetoclax",
"country": "England",
"delete": false,
"doi": "10.1080/1120009X.2019.1687995",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "31(7-8)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Lymphoma; adverse drug event; ibrutinib; leukocytosis; mantle-cell; venetoclax",
"medline_ta": "J Chemother",
"mesh_terms": "D000225:Adenine; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006801:Humans; D006947:Hyperkalemia; D007964:Leukocytosis; D020522:Lymphoma, Mantle-Cell; D008297:Male; D009364:Neoplasm Recurrence, Local; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "428-431",
"pmc": null,
"pmid": "31738653",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyperleukocytosis increases risk of fatal hyperkalemia with new ibrutinib/venetoclax regimen for refractory mantle cell lymphoma.",
"title_normalized": "hyperleukocytosis increases risk of fatal hyperkalemia with new ibrutinib venetoclax regimen for refractory mantle cell lymphoma"
} | [
{
"companynumb": "US-ABBVIE-19K-163-3013468-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti-diarrheal treatment in case of important digestive adverse events.",
"affiliations": "INSERM UMR866, Dijon, France. fghiringhelli@cgfl.fr.;Department of Medical Oncology, Centre Georges François Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France.;Department of Pathology, Centre Georges François Leclerc, Dijon, France.;Department of Medical Oncology, Centre Georges François Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France.;INSERM UMR866, Dijon, France. sladoire@cgfl.fr.",
"authors": "Ghiringhelli|François|F|;Vincent|Julie|J|;Beltjens|Françoise|F|;Bengrine|Leila|L|;Ladoire|Sylvain|S|",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000077146:Irinotecan; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-015-0295-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "33(6)",
"journal": "Investigational new drugs",
"keywords": "Adverse event; Aflibercept; Colitis; Colorectal cancer",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D046728:Colitis, Microscopic; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "1263-6",
"pmc": null,
"pmid": "26490656",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21789126;12177445;25877855;15175435;15864388;12177446;25088940;24440672;22949147;19406901;19628950;20142801;26269669",
"title": "Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients.",
"title_normalized": "fluorouracil leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients"
} | [
{
"companynumb": "FR-MYLANLABS-2016M1002329",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "Opioids are frequently used to manage chronic non-cancer pain despite the lack of evidence of benefit and clear evidence of opioid-related harms. Patients undergoing high-dose opioid therapy are at risk of multiple complications, such as opioid toxicity, including fatal overdose and opioid dependence.\n\n\n\nThis article provides an overview of the pharmacology of buprenorphine and reviews current evidence for the use of high-dose sublingual buprenorphine-naloxone in the pharmacological management of patients at high risk of complications from chronic opioid use.\n\n\n\nBuprenorphine-naloxone is well tolerated by patients with chronic pain, and has the potential to improve pain scores and affective symptoms. This is exemplified in a case study based on these authors' experience in an addiction medicine setting. As the rates of pharmaceutical opioid prescribing and related harms continue to increase in Australia, buprenorphine-naloxone is a viable option to manage high-risk chronic pain patients who are unable to reduce or cease their opioid use.",
"affiliations": "MBBS, FRACP, FAChAM, Addiction Medicine Specialist, Western Health and Melbourne Health, Vic.;MBBS, FAChAM, Clinical Director, Turning Point, Vic.;BSc (Hons), MBChB, PhD, FRANZCP, FAChAM, Director, Turning Point, Eastern Health, Vic; Professor of Addiction Studies, Monash University, Vic.",
"authors": "Chong|Joan|J|;Frei|Matthew|M|;Lubman|Dan I|DI|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine",
"country": "Australia",
"delete": false,
"doi": "10.31128/AJGP-07-19-4994",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "49(6)",
"journal": "Australian journal of general practice",
"keywords": null,
"medline_ta": "Aust J Gen Pract",
"mesh_terms": "D000286:Administration, Sublingual; D000701:Analgesics, Opioid; D001315:Australia; D002047:Buprenorphine; D059350:Chronic Pain; D005260:Female; D006801:Humans; D008875:Middle Aged; D059408:Pain Management; D013995:Time; D016896:Treatment Outcome",
"nlm_unique_id": "101718099",
"other_id": null,
"pages": "339-343",
"pmc": null,
"pmid": "32464722",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Managing long-term high-dose prescription opioids in patients with non-cancer pain: The potential role of sublingual buprenorphine.",
"title_normalized": "managing long term high dose prescription opioids in patients with non cancer pain the potential role of sublingual buprenorphine"
} | [
{
"companynumb": "AU-TEVA-2021-AU-1942048",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "1",
"... |
{
"abstract": "Anticoagulation monitoring during transition from direct oral anticoagulants (DOAC) to heparin infusions is a significant challenge. Factor Xa inhibitors influence the heparin calibrated antifactor Xa assay. The University of Virginia (UVA) Medical Center utilized a corrected antifactor Xa assay (c-AXA) during this transition period, which removes DOAC-mediated antifactor Xa activity (d-AXA) and reflects heparin-specific activity. Currently, the duration of this influence is not well described.\n\n\n\nThis study had two aims: to determine if the initial d-AXA is predictive of the duration of DOAC influence and to further characterize this influence among different patient populations.\n\n\n\nThis retrospective study included adult patients admitted to UVA Medical Center between September 2016 and March 2017, with c-AXA measurements, who received apixaban or rivaroxaban within 48 hours before heparin initiation. A Pearson correlation test, Kaplan-Meier Survival Analysis, and multivariate linear regression were used to assess the relationship between initial d-AXA and duration of influence.\n\n\n\nSixty-eight patients met inclusion criteria and were maintained on either apixaban (85%) or rivaroxaban (15%) before heparin initiation. The initial d-AXA ranged from 0.11 to 3.27 IU/ml. The mean duration of influence was 69.3 ± 46.2 hours, with a median duration of 62.7 hours. No strong correlation was identified between initial d-AXA and duration of influence (R2 = 0.124). Presence of interacting medications significantly increased duration of influence (p=0.012). No significant difference in duration of influence existed between patients with normal renal function and those with dynamic renal function (p=0.84), or with body mass index (BMI) greater than 40 kg/m2 (p=0.16).\n\n\n\nThe initial d-AXA was not predictive of duration of influence in patients transitioning from DOACs to heparin infusion; however, the median duration of influence suggests influence may be present for longer than currently stated in the literature, especially in those taking interacting medications.",
"affiliations": "Department of Pharmacy, Tufts Medical Center, Boston, Massachusetts, USA.;Department of Pharmacy, University of Virginia Medical Center, Charlottesville, Virginia, USA.;Department of Pharmacy, University of Virginia Medical Center, Charlottesville, Virginia, USA.;Department of Pathology, University of Virginia Medical Center, Charlottesville, Virginia, USA.;Department of Pharmacy, University of Colorado Health, Aurora, Colorado, USA.",
"authors": "Plum|Michelle D|MD|0000-0002-4471-2419;Hedrick|John N|JN|;Hockman|Rebecca|R|;Bazydlo|Lindsay|L|;Palkimas|Surabhi|S|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.2444",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "40(9)",
"journal": "Pharmacotherapy",
"keywords": "anticoagulation; antifactor Xa assay; direct factor Xa inhibitors; hematology; heparin monitoring; laboratory interference; pharmacokinetics",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D001780:Blood Coagulation Tests; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors; D005260:Female; D006493:Heparin; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "880-888",
"pmc": null,
"pmid": "32677060",
"pubdate": "2020-09",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "The Relationship between the Initial Anti-factor Xa Measurement and the Duration of Direct Oral Anticoagulant Influence in Patients Transitioning to Heparin.",
"title_normalized": "the relationship between the initial anti factor xa measurement and the duration of direct oral anticoagulant influence in patients transitioning to heparin"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-094260",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nBeta-lactam antibiotic (BLA) therapy is frequently needed to treat infective endocarditis (IE). Hypersensitive reactions to BLA restrict BLA therapy in allergic patients. In the current case, we aim to describe the utility of desensitization (DS) in this context. Although the evidence is limited, DS is recommended.\n\n\nMETHODS\nThis case report deals with a 79-year-old woman with a clinical suspicion of allergy to BLA and a methicillin-sensitive Staphylococcus aureus (MSSA) IE. A cloxacillin DS protocol was developed to enable treatment with cloxacillin.\n\n\nCONCLUSIONS\nAlternative antibiotic treatments may be less effective or not available in MSSA IE. In this case report, DS allowed optimal cloxacillin treatment.",
"affiliations": "Consorci Sanitari del Maresme, Pharmacy, Mataro, Spain.;Consorci Sanitari del Maresme, Pharmacy, Mataro, Spain.;Consorci Sanitari del Maresme, Pharmacy, Mataro, Spain.;Consorci Sanitari del Maresme, Pharmacy, Mataro, Spain.;Consorci Sanitari del Maresme, Intensive Care Unit, Mataro, Spain.;Consorci Sanitari del Maresme, Intensive Care Unit, Mataro, Spain.",
"authors": "Marin|S|S|;Campins|L|L|;Miarons|M|M|;Pérez-Cordón|L|L|;Reina-Aguilar|C|C|;Solsona|M|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D010406:Penicillins; D003023:Cloxacillin",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12751",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "cloxacillin; desensitization; drug hypersensitivity; endocarditis; immunologic",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D003023:Cloxacillin; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D004697:Endocarditis, Bacterial; D005260:Female; D006801:Humans; D010406:Penicillins; D018805:Sepsis; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "921-924",
"pmc": null,
"pmid": "30030968",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful desensitization to cloxacillin in a patient with sepsis, with infective endocarditis and clinical suspicion of hypersensitivity to penicillins, a case report.",
"title_normalized": "successful desensitization to cloxacillin in a patient with sepsis with infective endocarditis and clinical suspicion of hypersensitivity to penicillins a case report"
} | [
{
"companynumb": "PHHY2018ES162134",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Hepatitis E virus (HEV) is an increasingly recognised pathogen, affecting several hundred thousand individuals in western countries each year. Importantly, the majority of immunocompromised individuals are not able to clear HEV but develop a chronic course of infection. In the case of lymphoma, which is an inherent immunosuppressive disease per se, chemotherapy can even further exacerbate the immunosuppressive status. As the mechanism of HEV chronification is barely understood, it is important to gain knowledge about the influence of chemotherapeutic drugs on the HEV replication cycle to guide rational clinical management of HEV infection in such patients. In this case report, a 70 year old man was diagnosed with lymphoplasmacytic lymphoma. As we observed the occurrence of chronic HEV after treatment with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in vivo, we investigated the influence of BTK signaling and ibrutinib treatment in the HEV replication cycle in vitro. First, we detected an HEV-induced mobilisation of BTK in human liver cells during HEV replication. A moderate antiviral effect against HEV replicating isolates including genotypes 1 and 3 was observed, suggesting that ibrutinib did not support HEV replication in a direct manner. Combinatory treatments of ibrutinib with ribavirin indicated that ibrutinib did not influence the antiviral effect of ribavirin. Taken together, chemotherapy targeting cellular factors for the treatment of lymphomas may be a neglected risk factor for the chronification of HEV. For ibrutinib, despite the upregulation of its target BTK during HEV replication, we observed neither a proviral effect on HEV replication nor an influence on the antiviral effect of ribavirin, suggesting that the chronification of HEV may be favoured by its immunosuppressive effect.",
"affiliations": "Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, 48149 Münster, Germany.;Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.;Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Münster, Germany.;Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Münster, Germany.;Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.;Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, Germany.;Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, 48149 Münster, Germany.;Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, Germany. eike.steinmann@ruhr-uni-bochum.de.;Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany. Behrendt.Patrick@mh-hannover.de.",
"authors": "Schlevogt|Bernhard|B|;Kinast|Volker|V|0000-0002-6984-678X;Reusch|Julia|J|;Kerkhoff|Andrea|A|;Praditya|Dimas|D|0000-0003-1607-850X;Todt|Daniel|D|0000-0002-3564-1014;Schmidt|Hartmut H|HH|;Steinmann|Eike|E|;Behrendt|Patrick|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/pathogens8030129",
"fulltext": "\n==== Front\nPathogensPathogenspathogensPathogens2076-0817MDPI 10.3390/pathogens8030129pathogens-08-00129Case ReportChronic Hepatitis E Virus Infection during Lymphoplasmacytic Lymphoma and Ibrutinib Treatment Schlevogt Bernhard 1†https://orcid.org/0000-0002-6984-678XKinast Volker 23†Reusch Julia 4Kerkhoff Andrea 4https://orcid.org/0000-0003-1607-850XPraditya Dimas 23https://orcid.org/0000-0002-3564-1014Todt Daniel 3Schmidt Hartmut H. 1Steinmann Eike 3*Behrendt Patrick 256*1 Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, 48149 Münster, Germany2 Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany3 Department for Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, Germany4 Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Münster, Germany5 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany6 German Centre for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, 30625 Hannover, Germany* Correspondence: eike.steinmann@ruhr-uni-bochum.de (E.S.); Behrendt.Patrick@mh-hannover.de (P.B.); Tel.: +49-234-32-23189 (E.S.); +49-(0)511-220027-137 (P.B.)† Equally contribution.\n\n22 8 2019 9 2019 8 3 12918 7 2019 17 8 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Hepatitis E virus (HEV) is an increasingly recognised pathogen, affecting several hundred thousand individuals in western countries each year. Importantly, the majority of immunocompromised individuals are not able to clear HEV but develop a chronic course of infection. In the case of lymphoma, which is an inherent immunosuppressive disease per se, chemotherapy can even further exacerbate the immunosuppressive status. As the mechanism of HEV chronification is barely understood, it is important to gain knowledge about the influence of chemotherapeutic drugs on the HEV replication cycle to guide rational clinical management of HEV infection in such patients. In this case report, a 70 year old man was diagnosed with lymphoplasmacytic lymphoma. As we observed the occurrence of chronic HEV after treatment with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib in vivo, we investigated the influence of BTK signaling and ibrutinib treatment in the HEV replication cycle in vitro. First, we detected an HEV-induced mobilisation of BTK in human liver cells during HEV replication. A moderate antiviral effect against HEV replicating isolates including genotypes 1 and 3 was observed, suggesting that ibrutinib did not support HEV replication in a direct manner. Combinatory treatments of ibrutinib with ribavirin indicated that ibrutinib did not influence the antiviral effect of ribavirin. Taken together, chemotherapy targeting cellular factors for the treatment of lymphomas may be a neglected risk factor for the chronification of HEV. For ibrutinib, despite the upregulation of its target BTK during HEV replication, we observed neither a proviral effect on HEV replication nor an influence on the antiviral effect of ribavirin, suggesting that the chronification of HEV may be favoured by its immunosuppressive effect.\n\nhepatitis E virusibrutinibBruton’s tyrosine kinasechronificationlymphoplasmacytic lymphomaimmunosuppression\n==== Body\n1. Introduction\nHepatitis E virus (HEV) is increasingly recognised as an important pathogen, affecting several hundred thousand individuals in western countries each year [1]. Although HEV usually is a self-limiting disease, immunocompromised individuals are at risk to develop a chronic course of infection [2], with rapid progression to fibrosis, cirrhosis or even the development of liver failure [3]. The mechanism of HEV chronification is barely understood so far and treatment options in chronically infected patients are limited to the reduction of immunosuppression [2], pegylated interferon-α [4] and the off-label therapeutic ribavirin. Ribavirin showed efficacy in about 85% but is accompanied in part by severe side effects [5,6]. Chronic infections have also been reported in patients with underlying haematological malignancies [7]. Corresponding treatment often includes drugs inhibiting the host cell cycle. The knowledge about their influence on the viral replication cycle is of utmost importance to guide rational clinical management of HEV infection in such patients.\n\n2. Material and Methods\n2.1. Cell Culture\nHepG2 cells were cultured on rat collagen-coated (SERVA Electrophoresis GmbH, Heidelberg, Germany) culture plates in Dulbecco’s Modified Eagle Medium (4.5 g/L glucose, Gibco, Thermo Fisher Scientific, Waltham, MA, USA) containing 10% fetal calf serum (FCS, Gibco, Thermo Fisher Scientific, Waltham, MA, USA), 2 mM L-glutamine (Gibco, Thermo Fisher Scientific, Waltham, MS, USA), 0.1 mM non-essential amino acid (Invitrogen), 10 U/mL penicillin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and 10 μg/mL streptomycin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) at 37 °C. \n\n2.2. Compounds and Reagents\nRibavirin was purchased from Sigma Aldrich, St. Louis, MO, USA. Ibrutinib was purchased from MedChemExpress (Sollentuna, Sweden). All compounds were stored and diluted according to the manufacturer’s recommendations.\n\n2.3. HEV Plasmids and In Vitro Transcription\nThree plasmid constructs harbouring a subgenomic HEV sequence coupled to a Gaussia luciferase, Firefly luciferase or GFP reporter gene were used to generate HEV in vitro transcripts as previously described [8]. One of the constructs derives from the gt1 Sar55/S17 strain (based on clone pSK E2, GenBank accession no.AF444002), two derive from the Kernow-C1 p6 genome (gt3; GenBank accession no.JQ679013) and one derives from the G3-HEV83-2-27 genome (gt3; GenBank accession no.AB740232) and was a kind gift from the laboratory of Takaji Wakita. Capping of all constructs was performed using Ribo m7G CapAnalog (Promega, Madison, WI, USA). \n\n2.4. HEV Replication Assay\nFirst, 5 × 106 HepG2 cells in 400 μL Cytomix containing 2 mM ATP and 5 mM glutathione were mixed with 5 μg of HEV RNA. Electroporation was carried out with a Gene Pulser system (Bio-Rad, Munich, Germany). Afterwards, cells were cultured in DMEM on collagen-coated plates. Compounds were added for 48 h and viral replication was determined by measuring luciferase activity.\n\n2.5. Luciferase Assay\nSupernatant of cells (Gaussia luciferase) or suspension containing lysed cell (Firefly luciferase), were added to a 96-well white, flat-bottom microplate followed by the detection of luminescence using a microplate reader (CentroXS3 LB960, Berthold technologies, Bad Wildbad, Germany). Coelenterazine (Gaussia luciferase) or D-Luciferin (Firefly luciferase) was used as a substrate.\n\n2.6. Viability Assay\nCell viability was determined by performing an MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay (Sigma-Aldrich, Munich, Germany), according to the manufacturer’s suggestions.\n\n2.7. Antibody-Based Microarray\nMobilisation of signalling molecules upon HEV replication was analysed by performing an antibody-based microarray (Kinex™ KAM-900P, Kinexus, Vancouver, BC, Canada). In brief, HepG2 cells were transfected with 5 µg subgenomic HEV-p6-GFP transcripts, 5 µg transferRNA (Sigma Aldrich, St. Louis, MO, USA) served as a control. Cells were harvested 12 and 48 h post electroporation, according to the manufacturer’s protocol, and shipped to Kinexus for microarray analysis. The whole data set will be published elsewhere (Kinast et al., manuscript in preparation).\n\n2.8. Statistical Methods\nFor data analysis, GraphPad Prism 8 software was used.\n\n2.9. Ethics\nThe study was approved by the ethics committee of the medical council of Westfalen-Lippe in Münster, Germany (record 2010-192-f-S), and it conforms to the ethical guidelines of the 1975 Declaration of Helsinki. The patient gave written informed consent to participate in this study.\n\n3. Case\nA 70 year old man was diagnosed with lymphoplasmacytic lymphoma. IgM was markedly elevated (717 mg/dL, normal: 40–230 mg/dL) and bone marrow infiltration was 40%. A typical MYD88-mutation was identified (c.794T > C). Throughout the entire course of the disease, the patient suffered from severe, progressive pancytopenia requiring constant transfusion of platelets and red blood cells. As initial treatment, the patient received four courses of bortezomib and dexamethasone (Figure 1A). However, pancytopenia did not improve. Follow-up bone marrow biopsies showed neither haematological reconstitution nor progressive or refractory lymphoma. As critical cytopenia persisted, the patient received a single infusion of rituximab without any improvement of bone marrow function. Concomitantly, the patient developed acute hepatitis E (genotype 3c) with peak alanine amino-transferase (ALT) at 1579 U/L (normal: 10–50 U/L). Apart from zoonotic transmission, HEV could have also been transmitted by repeated blood transfusions. Other viral infections causing hepatitis were excluded. Abdominal ultrasound showed no hepatic abnormality. Due to persistent cytopenia, treatment was escalated with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib over 3 weeks, again with no effects on pancytopenia (Figure 1A). ALT levels initially declined, but then remained elevated at greater 100 U/L. Stimulation of bone marrow with granulocyte macrophage colony-stimulating factor (GM-CSF) was not successful. As HEV-RNA levels in blood (20,000,000 IU/mL) and faeces were positive for more than 3 months, chronic hepatitis E was diagnosed. CD19-positive B-cells were massively diminished in peripheral blood. As viral infections can cause pancytopenia, treatment with ribavirin was initiated despite concerns due to poor bone marrow function. Therefore, the dosage of ribavirin was slowly increased up to 1000 mg daily. Within 2 months of therapy, HEV-RNA decreased to 33 IU/mL followed by the normalisation of transaminases. Unfortunately, treatment had to be paused because of a severe exanthema associated with ribavirin. Despite the improvement of liver function, there was no recovery of pancytopenia, arguing against HEV-associated pancytopenia. After stopping ribavirin, the viral load increased again which was followed by an increase in transaminases and bilirubin (Figure 1A). The patient was able to restart ribavirin but died a few weeks later due to pulmonal mycosis caused by severe prolonged pancytopenia.\n\nWe observed the occurrence of chronic hepatitis E in the patient after ibrutinib treatment, concurrent with observations in French patients [9,10]. Due to the B-cell signalling inhibitory potential of ibrutinib, infections with hepatotropic viruses could be favoured, as has already been suggested for hepatitis B virus [11]. Therefore, we investigated the influence of BTK signalling and ibrutinib treatment in the HEV replication cycle in vitro in the hepatoma cell line HepG2. Although HepG2 cells may not always reflect the in vivo situation, they are a well-characterised, suitable and robust model to study liver-related diseases. First, we analysed the modulation of BTK during HEV replication (Figure 1B). We identified both an upregulation and phosphorylation of BTK as well as a phosphorylation of CREB (cAMP responsive element binding protein 1) in HEV replicating cells compared with mock transfected cells (Figure 1C), indicating an HEV-induced mobilisation of BTK in human liver cells. Next, we investigated the effect of an HEV infection by ibrutinib treatment on different HEV replicating isolates including genotypes 1 and 3. An antiviral effect against all tested HEV replicons upon treatment with 3.33 µM ibrutinib was observed without cytotoxicity (Figure 1D), suggesting that ibrutinib did not support HEV replication in a direct manner but rather had antiviral activity. Combinatory treatments of ibrutinib with ribavirin indicated that ibrutinib did not influence the antiviral effect of ribavirin (Figure 1E). Therefore, the clinical course of the patient cannot be explained by a direct effect of the drug but might be caused by the concomitant medication (e.g., rituximab), the influence of ibrutinib on cellular immunity or due to the underlying aplasia.\n\n4. Conclusions\nLymphomas are inherent immunosuppressive diseases and chemotherapy can further exacerbate the immunosuppressive status of lymphoma patients. Chemotherapy targeting cellular factors for the treatment of lymphomas may be a neglected risk factor for the chronification of HEV. Therefore, for reasonable clinical decision-making, it is important to gain further knowledge about the influence of applied drugs on the HEV replication cycle. For ibrutinib, despite the upregulation of its target BTK during HEV replication, we observed neither a proviral effect on HEV replication nor an influence on the antiviral effect of ribavirin. Therefore, a possible proviral influence of this drug on HEV infection in vivo—as suggested by our case—may be favoured by its immunosuppressive effect.\n\nAcknowledgments\nWe are grateful to Suzanne Emerson for the hepatitis E virus p6 clone and Sar55 and to Takaji Wakita for the 83-2-27 clone. Moreover, we thank all members of the Institute of Experimental Virology, TWINCORE, the Department for Molecular and Medical Virology, Ruhr University Bochum and Oksana Nadzemova for helpful support, suggestions and discussions.\n\nAuthor Contributions\nB.S., J.R., A.K. and H.H.S. acquired clinical data. B.S., J.R., A.K., H.H.S. and P.B. organised the clinical data. B.S., J.R., A.K., H.H.S. and P.B. analysed the clinical data. V.K. and D.P. performed in vitro experiments. B.S., V.K., J.R., A.K., D.T., H.S., E.S. and P.B. performed formal analysis. V.K. visualised the data. A.K., D.T., H.H.S., E.S. and P.B. supervised the study. B.S., V.K., E.S. and P.B. wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.\n\nFunding\nThis work was supported by a grant from the German Federal Ministry of Health with regard to a decision of the German Bundestag by the Federal Government (CHED-project grant No: ZMVI1-2516-AUK-701 /BMG: 321-4471-02/157).\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 (A) Clinical course of index patient. Depicted are the courses of alanine amino-transferase (ALT; light gray line), bilirubine (medium gray line) and hepatitis E virus (HEV)-RNA in serum (black line) over the monitored time. Arrows and black horizontal bars indicate courses and period of application of medication, respectively. (B) Bruton’s tyrosine kinase. Depicted is a simplified scheme of Bruton’s tyrosine kinase (BTK), the downstream substrates of activated BTK and their associated signalling cascades. (C) Heatmap of altered expression levels and phosphorylation status of BTK and its downstream substrates in HEV-p6 replicating HepG2 cells, determined by an antibody microarray. (D) Effect of ibrutinib on HEV-p6 replication. Depicted is the dose-dependent inhibition of different HEV replicating isolates including genotypes 1 and 3 in HepG2 cells upon ibrutinib treatment for 48 h. Reduction in replication was determined via reporter luciferase read-out and normalised to the untreated control. Cell viability was monitored via MTT assay. Depicted are the mean values of three independent experiments. (E) Combinatory effect of ibrutinib and ribavirin on HEV-p6 replication. Heatmap indicates the potential differences between the actual experimental effects and the theoretical additive effects at various concentrations of the two compounds 48 h post electroporation. Depicted are the values of one representative experiment.\n==== Refs\nReferences\n1. Faber M. Willrich N. Schemmerer M. Rauh C. Kuhnert R. Stark K. Wenzel J.J. Hepatitis E virus seroprevalence, seroincidence and seroreversion in the German adult population J. Viral Hepat. 2018 25 752 758 10.1111/jvh.12868 29377436 \n2. Kamar N. Selves J. Mansuy J.-M. Ouezzani L. Péron J.-M. Guitard J. Cointault O. Esposito L. Abravanel F. Danjoux M. Hepatitis E Virus and Chronic Hepatitis in Organ-Transplant Recipients N. Engl. J. Med. 2008 358 811 817 10.1056/NEJMoa0706992 18287603 \n3. Behrendt P. Steinmann E. Manns M.P. Wedemeyer H. The impact of hepatitis E in the liver transplant setting J. Hepatol. 2014 61 1418 1429 10.1016/j.jhep.2014.08.047 25195557 \n4. Kamar N. Rostaing L. Abravanel F. Garrouste C. Esposito L. Cardeau-Desangles I. Mansuy J.M. Selves J. Peron J.M. Otal P. Pegylated Interferon-α for Treating Chronic Hepatitis E Virus Infection after Liver Transplantation Clin. Infect. Dis. 2010 50 e30 e33 10.1086/650488 20113176 \n5. Kamar N. Izopet J. Tripon S. Bismuth M. Hillaire S. Dumortier J. Radenne S. Coilly A. Garrigue V. D’Alteroche L. Ribavirin for Chronic Hepatitis E Virus Infection in Transplant Recipients N. Engl. J. Med. 2014 370 1111 1120 10.1056/NEJMoa1215246 24645943 \n6. Todt D. Meister T.L. Steinmann E. Hepatitis E virus treatment and ribavirin therapy: Viral mechanisms of nonresponse Curr. Opin. Virol. 2018 32 80 87 10.1016/j.coviro.2018.10.001 30384328 \n7. Von Felden J. Alric L. Pischke S. Aitken C. Schlabe S. Spengler U. Giordani M.T. Schnitzler P. Bettinger D. Thimme R. The Burden of Hepatitis E among Patients with Hematological Malignancies: A Retrospective European Cohort Study J. Hepatol. 2019 10.1016/j.jhep.2019.04.022 31108159 \n8. Drave S.A. Debing Y. Walter S. Todt D. Engelmann M. Friesland M. Wedemeyer H. Neyts J. Behrendt P. Steinmann E. Extra-hepatic replication and infection of hepatitis E virus in neuronal-derived cells J. Viral Hepat. 2016 23 512 521 10.1111/jvh.12515 26891712 \n9. Protin C. Abravanel F. Laurent G. Tavitian S. Oberic L. Izopet J. Martin-Blondel G. Ysebaert L. Alric L. Hepatitis E virus infection and ribavirin treatment in patients with chronic lymphocytic leukemia receiving ibrutinib J. Hepatol. 2017 66 S250 10.1016/S0168-8278(17)30807-3 \n10. Boudin L. Patient M. Tsogou P.T.N. Roméo E. Bladé J.-S. De Jauréguiberry J.-P. Successful treatment with ribavirine for chronic hepatitis E in chronic lymphocytic leukemia treated with Ibrutinib Bull. Cancer 2019 106 84 85 10.1016/j.bulcan.2018.11.011 30579570 \n11. Ngoma P.D.J. Kabamba B. Dahlqvist G. Sempoux C. Lanthier N. Shindano T. Neste E.V.D. Horsmans Y. Occult HBV reactivation induced by ibrutinib treatment: A case report Acta Gastro-Enterol. Belg. 2015 78 424 426\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-0817",
"issue": "8(3)",
"journal": "Pathogens (Basel, Switzerland)",
"keywords": "Bruton’s tyrosine kinase; chronification; hepatitis E virus; ibrutinib; immunosuppression; lymphoplasmacytic lymphoma",
"medline_ta": "Pathogens",
"mesh_terms": null,
"nlm_unique_id": "101596317",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31443360",
"pubdate": "2019-08-22",
"publication_types": "D002363:Case Reports",
"references": "26891712;25195557;24645943;30384328;29377436;20113176;30579570;18287603;26712054;31108159",
"title": "Chronic Hepatitis E Virus Infection during Lymphoplasmacytic Lymphoma and Ibrutinib Treatment.",
"title_normalized": "chronic hepatitis e virus infection during lymphoplasmacytic lymphoma and ibrutinib treatment"
} | [
{
"companynumb": "DE-CELLTRION INC.-2019DE027051",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Iatrogenic demyelination is a distinct clinical subtype of central nervous system inflammatory disorders. The Janus kinase inhibitor, tofacitinib, is an oral disease-modifying antirheumatic drug that has shown contradictory effects on multiple sclerosis in animal models. In this report, we describe a novel case of reversible multifocal CNS demyelination in a patient with seropositive rheumatoid arthritis on tofacitinib. Although the mechanism is not completely understood, activation of T17 cells by tofacitinib and the subsequent increased production of interleukin-17 could be the cause. Moreover, a link between TNF-α and JAK/STAT pathways has been suggested, which may further explain the occurrence of iatrogenic demyelination in this case.",
"affiliations": "Department of Neurology, Ibn Sina Hospital, Kuwait.;Department of Neurology, Ibn Sina Hospital, Kuwait. Electronic address: dr.ismail.ibrahim2012@gmail.com.;Department of Neurology, Ibn Sina Hospital, Kuwait; Health Sciences Centre, Kuwait University, Department of Medicine, Kuwait.;Case Western Reserve University School of Medicine, Cleveland, OH, United States; Multiple Sclerosis and Neuroimmunology Program, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.",
"authors": "Massoud|Fathi|F|;Ismail|Ismail Ibrahim|II|;Al-Hashel|Jasem Y|JY|;Abboud|Hesham|H|",
"chemical_list": "D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2020.102568",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "46()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Demyelination; Iatrogenic; Janus kinase inhibitor; Multiple sclerosis; Tofacitinib",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000818:Animals; D003711:Demyelinating Diseases; D006801:Humans; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102568",
"pmc": null,
"pmid": "33296970",
"pubdate": "2020-11",
"publication_types": "D016422:Letter",
"references": null,
"title": "CNS demyelination during tofacitinib therapy: First report.",
"title_normalized": "cns demyelination during tofacitinib therapy first report"
} | [
{
"companynumb": "KW-PFIZER INC-2020510701",
"fulfillexpeditecriteria": "1",
"occurcountry": "KW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOFACITINIB CITRATE"
},
"drugadditional": "1",... |
{
"abstract": "BACKGROUND\nHepatitis B (HBV) reactivation induced by chemotherapy is a problem currently encountered in the management of malignancies. HBV reactivation occurs particularly in patients who were not checked for HBV status, and therefore have not undergone antiviral prophylaxis. HBV reactivation may ultimately lead to fulminant liver failure (FLF). Liver transplantation (OLT), the only remaining effective treatment option, is generally denied for subjects with a recent history of malignancy.\n\n\nMETHODS\nWe described retrospectively three cases of FLF caused by HBV reactivation in two men and one woman undergoing rituximab-containing chemotherapy for malignant lymphomas: follicular, diffuse large B-cell and lymphoplasmacytic types. The two men reactivated after eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone and the one woman after 13 cycles of rituximab monotherapy; their hematologic disease was in remission. All three patients were hepatitis B surface antigen (HBsAg)-positive with high HBV DNA levels. Neither man had been screened for HBV before chemotherapy; the woman had been treated with lamivudine (LAM) experiencing an HBV flare-up due to emergence of LAM resistance. All patients fulfilled King's College criteria for urgent OLT upon admission to the transplant center and underwent an urgent OLT. Their hemato-oncologic prognosis was considered to be favorable. All three patients are alive (54, 46, and 37 months post-transplantation), tumor-free and HBsAg negative on a standard HBV prophylaxis regimen: hepatitis B immunoglobulin and LAM + adefovir or tenofovir.\n\n\nCONCLUSIONS\nBefore chemotherapy appropriate prophylaxis for HBV reactivation should always be administered to at-risk patients. However, if reactivation with FLF occurs, OLT should not be generally denied. The prognosis of the hematologic malignancy should be assessed; OLT should be considered for patients in remission with a favorable long-term prognosis, for our data suggest acceptable survival.",
"affiliations": "Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. Electronic address: jan.sperl@ikem.cz.",
"authors": "Sperl|J|J|;Frankova|S|S|;Kieslichova|E|E|;Oliverius|M|M|;Janousek|L|L|;Honsova|E|E|;Trunecka|P|P|;Spicak|J|J|",
"chemical_list": "D000970:Antineoplastic Agents; D004279:DNA, Viral",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "45(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D004279:DNA, Viral; D005260:Female; D006515:Hepatitis B virus; D006801:Humans; D016031:Liver Transplantation; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014775:Virus Activation",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2834-7",
"pmc": null,
"pmid": "24034061",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Urgent liver transplantation for chemotherapy-induced HBV reactivation: a suitable option in patients recently treated for malignant lymphoma.",
"title_normalized": "urgent liver transplantation for chemotherapy induced hbv reactivation a suitable option in patients recently treated for malignant lymphoma"
} | [
{
"companynumb": "CZ-CONCORDIA PHARMACEUTICALS INC.-E2B_00011737",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN HEPATITIS B VIRUS IMMUNE GLOBULIN"
... |
{
"abstract": "Case of disseminated Nocardia beijingensis, initially diagnosed and treated by health department as tuberculosis, presented with worsening symptoms and new lesions. Adjustment to antinocardial treatment resulted in significant clinical and radiographic improvement. Maintain a high index of suspicion for Nocardia in patients diagnosed with tuberculosis with worsening lesions despite therapy.",
"affiliations": "Division of Infectious Diseases and Global Health, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Infectious Diseases and Global Health, University of Florida College of Medicine, Gainesville, Florida, USA.;Malcolm Randall Veterans Health Administration Medical Centre, Gainesville, Florida, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Infectious Diseases and Global Health, University of Florida College of Medicine, Gainesville, Florida, USA.",
"authors": "Bertrán-López|Jovanna|J|;Abbott|Andrew|A|;Archibald|Lennox K|LK|;Benninger|Lauryn|L|;Lascano|Jorge|J|;Kalyatanda|Gautam|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa186",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n32548208\n10.1093/ofid/ofaa186\nofaa186\nID Teaching Cases\nAcademicSubjects/MED00290\nDisseminated Nocardia beijingensis Masquerading as Pulmonary Tuberculosis in a Patient With Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome\nBertrán-López Jovanna 1 Abbott Andrew 1 Archibald Lennox K 2 Benninger Lauryn 3 Lascano Jorge 3 Kalyatanda Gautam 1 1 \nDivision of Infectious Diseases and Global Health, University of Florida College of Medicine, Gainesville, Florida, USA\n2 \nMalcolm Randall Veterans Health Administration Medical Centre, Gainesville, Florida, USA\n3 \nDivision of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida, USA\nCorrespondence: Jovanna Bertran-Lopez, MD, MPH, 1120 NW 14th Street, Suite 863, Miami FL 33136 (jovanna.bertran@gmail.com).\n6 2020 \n21 5 2020 \n21 5 2020 \n7 6 ofaa18628 2 2020 12 5 2020 15 5 2020 10 6 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nCase of disseminated Nocardia beijingensis, initially diagnosed and treated by health department as tuberculosis, presented with worsening symptoms and new lesions. Adjustment to antinocardial treatment resulted in significant clinical and radiographic improvement. Maintain a high index of suspicion for Nocardia in patients diagnosed with tuberculosis with worsening lesions despite therapy.\n\ndisseminated NocardiaHIV/AIDSNocardia beijingensistuberculosis\n==== Body\nNocardiae are Gram-positive, branching, filamentous, aerobic and weakly acid-fast bacteria that are ubiquitous in soil and aqueous environments. Nocardiosis usually manifests in 2 major forms: cutaneous and pulmonary. The cutaneous form occurs via direct inoculation of the microorganism into the skin. The pulmonary form of the disease usually results from inhalation of aerosolized bacteria resulting in establishment of a pulmonary focus leading to an acute bronchopneumonia. Pulmonary nocardiosis is more often seen in immunocompromised persons, such as those with disorders of cell-mediated immunity, on immunosuppressive therapy or persons with conditions that otherwise compromise the immune system. The brain is one of the most common secondary sites of infection.\n\n\nNocardia infections are suppurative with destruction of healthy tissues and production of local or multifocal abscesses [1, 2]. In the United States, there are approximately 500–1000 new cases of nocardiosis yearly; 60% of these cases are associated with pre-existing compromised immune systems [1, 3]. Therapy differs depending on the clinical syndrome and species [1]. In this study, we present a case of Nocardia beijingensis in a patient who was initially diagnosed and treated for tuberculosis (TB) but later found to have disseminated nocardiosis.\n\nCASE REPORT\nA 45-year-old pine straw baler, originally from Mexico and with no known medical history, presented to his primary care physician with hiccups that had progressed to hemoptysis during the previous 2 months. Additional symptoms included subjective fevers, night sweats, and a 40-pound weight loss. He was referred to a pulmonology clinic after a chest radiograph revealed a spiculated left hilar soft tissue mass. A computed tomography (CT) scan of the thorax showed pulmonary cavitary lesions with mediastinal and hilar lymphadenopathy (Figure 1). Because the patient’s symptoms and imaging findings were suggestive of pulmonary TB, he was referred to the Health Department where he was commenced on first-line, anti-tuberculous therapy with isoniazid, rifampin, pyrazinamide, and ethambutol. A human immunodeficiency virus (HIV) test was positive; Mycobacterium tuberculosis (MTB) nucleic acid amplification test (NAA) was negative for TB. Two weeks after starting anti-tuberculous therapy, the patient presented to the emergency department with complaints of masses in the left supraclavicular region and the scalp. On physical examination, he had tachycardia, mild confusion, and cachectic physique. There were fluctuant masses without surrounding erythema in the occipital and parietal scalp and the supraclavicular region (Figures 2 and 3). Baseline laboratory test results revealed a normochromic, normocytic anemia with hemoglobin of 8.1 g/dL, CD4 count of 49 cells/µL, and an HIV viral load of 100 000 copies/mL (Supplementary Table 1).\n\nFigure 1. Initial computed tomography thorax showing cavitary pulmonary lesions.\n\nFigure 2. Left supraclavicular mass on presentation.\n\nFigure 3. Parietal scalp lesion on presentation.\n\nComputed tomography imaging of the head and neck showed multiple soft tissue lesions about the calvarium with adjacent osseous destruction and intracranial extension with an epidural component and areas of vasogenic edema with associated ring-enhancing features in the right temporal lobe that were concerning for cerebritis and abscess formation (Figure 4). There was also a large necrotic mass in the left supraclavicular area. The left supraclavicular and scalp abscess were aspirated, and specimens were sent for bacterial and acid-fast bacilli (AFB) culture. The differential diagnosis at that juncture included nocardiosis, MTB, immune reconstitution inflammatory syndrome (IRIS) from anti-tuberculous therapy, and disseminated fungal infection. Microscopy revealed branching, beaded Gram-positive rods (Figure 5). A lumbar puncture was performed, and analysis of the cerebrospinal fluid was unremarkable. Repeat MTB NAA was negative. Other tests for Blastomyces antibody, Aspergillus galactomannan, cryptococcal antigen, and antibody for Toxoplasma immunoglobulin (Ig)G and IgM were all negative. Cerebrospinal fluid analyses for AFB and fungal and routine bacterial cultures, cryptococcal antigen, and Toxoplasma polymerase chain reaction were all negative (Supplementary Table 2).\n\nFigure 4. Initial computed tomography of the head revealing a lesion in the right temporal lobe.\n\nFigure 5. Gram stain of left supraclavicular mass.\n\n\nNocardia sp was confirmed on culture so treatment for TB was therefore discontinued and replaced with trimethoprim-sulfamethoxazole (TMP/SMX), imipenem, and amikacin while awaiting final speciation and susceptibility test results. After 2 weeks of treatment, antiretroviral therapy (ART) with bictegravir/emtricitabine/tenofovir alafenamide was started. Hsp65 deoxyribonucleic acid sequencing by the Florida Health Department identified the Nocardia isolate as N beijingensis that was susceptible to amikacin, azithromycin, ceftriaxone, ciprofloxacin, imipenem, linezolid, minocycline, and TMP/SMX, but resistant to amoxicillin-clavulanate.\n\nThree weeks after discharge, the patient presented to another hospital acutely with seizures, which were thought to be secondary to the imipenem. His antibiotic regimen was therefore changed—imipenem was discontinued and ceftriaxone was started. A repeat CT scan of the head demonstrated increased ring enhancement and edema around multiple parenchymal lesions. He also had bilateral supraclavicular swelling. Due to the concern of nonadherence to prescribed antibiotics, the patient was re-admitted to hospital and the new antibiotic regimen was initiated. Intravenous antibiotics were continued for approximately 8 weeks, during which time he showed both radiological and clinical improvement (Supplementary Figures 1–4). After completion of IV therapy, he was transitioned to oral minocycline and TMP/SMX.\n\nDISCUSSION\n\nNocardia beijingensis was first isolated in 2001 from the soil in Beijing, the capital of the People’s Republic of China [4]. Although initially described as a human pathogen in Asia in 2004, subsequent case reports have depicted disease in humans in Australia, Europe, United States, and Latin America [5]. Few cases of infection caused by this species of Nocardia have been reported in the Western Hemisphere; the first case report was published by Crozier et al [6] in 2014 in an immunocompetent host presenting with a hilar mass.\n\n\nNocardia species are well recognized causes of infections in both immunocompromised and immunocompetent hosts. Disseminated nocardiosis, as in our patient, most frequently begins in the respiratory tract via inhalation of spores that can be found in the soil and organic matter [7]. Secondary sites of infection include the brain, bone, skin, lung, eyes, and lymphatics; multiorgan involvement can occur [1]. Our patient’s initial pulmonary findings followed by involvement of the central nervous system (CNS), calvarium, scalp, and the supraclavicular region underscore this pattern of disease progression. Based on his history, we believe that our patient acquired the original infection through occupational exposure while gathering pine straw from the ground here in the United States.\n\nUncontrolled HIV and other immunosuppressed states can contribute to disseminated Nocardia disease. Disseminated nocardiosis is more common in immunosuppressed patients, as was described in a retrospective study of Nocardia cases at a large teaching hospital in Michigan [8]. Overall, the incidence of nocardiosis among patients with acquired immune deficiency syndrome is relatively low (0.1% to 0.4%) compared with other opportunistic diseases [9]. However, this is approximately 140 times the incidence of the general population, and a review of all cases of nocardiosis from 1999 to 2004 from a tertiary hospital in Miami reported that 76% were also infected with HIV [9, 10]. The reasons for the relatively low overall incidence of the disease compared with other opportunistic infections in populations with HIV infection is not well understood and is likely multifactorial [7]. The degree of dysfunction of cell-mediated immunity, cellular immune dysfunction that is not present in all patients with HIV, a noncellular immune response active against Nocardia, underdiagnosis or underreporting, and Pnemocystis jiroveci pneumonia prophylaxis with TMP/SMX have been postulated as reasons behind the low incidence [7, 11].\n\nThe clinical presentation of pulmonary nocardiosis can be mistaken for pulmonary TB [12]. In 1888, Edmond Nocard, a 19th century veterinarian and biologist, described the disease as a pseudo-TB; recent studies have shown no significant difference in the presenting symptoms between pulmonary TB and pulmonary nocardiosis [13–15]. Radiographic changes include consolidation, nodules (often cavitary), masses, and interstitial involvement; upper lobe involvement—a classic finding of pulmonary TB—is commonly seen in pulmonary nocardiosis and may lead to incorrect inferences [3]. Moreover, the presence of either pulmonary TB or pulmonary nocardiosis does not necessarily rule out the other, especially in patients with significant immunosuppression, such as those with HIV infection. Thus, concomitant Nocardia sp and MTB pulmonary infections can occur [16]. In our patient, coinfection was excluded as multiple cultures for mycobacteria and MTB NAA testing remained negative.\n\nDue to the mentioned similarity with TB, the diagnosis of pulmonary nocardiosis may be delayed, which can increase the risk of poor outcomes and higher morbidity and mortality rates [9, 11, 17]. Compounding the problem is the fact that pulmonary nocardiosis masquerades as TB more frequently than expected. Studies in China, Ghana, and Tanzania have reported 4.5% to 18% of patients presenting with pulmonary findings concerning for TB, who in fact have pulmonary infection caused by Nocardia spp [13, 15, 18, 19]. When evaluating the etiology of pulmonary lesions, the African studies have shown a pulmonary TB-to-nocardiosis ratio among patients with HIV ranging anywhere from 9:1 to 90:1 depending on the country and methodology [20]. However, these studies were conducted in countries with a higher incidence of TB than the United States. Based on our literature review in PubMed with terms Nocardia and TB, there have been no studies in the United States that have ascertained the prevalence of Nocardia in patients with suspected pulmonary TB. In addition, there have been relatively few US case reports in the HIV era of patients with Nocardia being mistakenly diagnosed and treated for TB. Furthermore, approximately 1%–2% of all brain lesions could be due to Nocardia [21]. For all these reasons, we believe that, for patients being evaluated for TB, there should be a high index of suspicion for Nocardia, especially if there are concomitant pulmonary and brain lesions or worsening symptoms without a confirmed diagnosis of TB.\n\nTreatment of disseminated nocardiosis is based mainly on retrospective reviews and expert opinion with recommendations for a 3-drug regimen in severe disease with a total duration of at least 12 months to prevent relapse [2, 22]. Trimethoprim-sulfamethoxazole is considered the backbone of therapeutic regimens for Nocardia spp infection because most species are susceptible. Notable exceptions include Nocardia otitidiscaviarum, which is commonly resistant, and Nocardia nova and Nocardia farcinica, which are occasionally resistant [22]. The selection of antibiotics for empiric combination therapy should be based on the species of Nocardia if known. Susceptibilities should be requested, and therapy should be adjusted based on the organism’s profile. Trimethoprim-sulfamethoxazole, linezolid, and carbapenems have good CNS penetration and are used in disseminated disease and brain lesions [2].\n\nPatient’s clinical course was complicated by seizure and a CT head with an increase in ring enhancement and edema of the brain lesions while on empiric therapy with TMP/SMX, imipenem, and amikacin. Seizure is a well recognized, albeit uncommon, adverse effect of imipenem [23]. The patient was switched to ceftriaxone based on susceptibilities before repeat CT scanning of the head was performed. However, the increasing ring enhancement and edema of the brain lesions later seen on repeat imaging was concerning for IRIS or nonadherence with therapy. Immune reconstitution inflammatory syndrome is rarely reported with Nocardia treatment, but with his recent initiation of ART in the preceding weeks, this was high on the differential [24]. By the time the patient was re-admitted and a second CT scan was performed, the lesions had begun to improve, and his seizures had resolved; accordingly, steroid therapy was not started. The patient completed 8 weeks of intravenous therapy with ceftriaxone, amikacin, and TMP/SMX with a good clinical response and was transitioned to oral minocycline and TMP/SMX. Outpatient follow up 5 months later showed radiologic improvement and complete clinical resolution of symptoms and lesions (Supplement Figures 1−4). The Infectious Diseases Service at our facility continued to follow the patient during and after he completed 1 year of antimicrobial therapy. Since completing therapy, he has not had any clinical signs of disease recurrence. At the present time, his only medications are antiretroviral therapy (bictegravir/emtricitabine/tenofovir alafenamide) and prophylactic TMP/SMX, with an undetectable HIV viral load and most recent CD4 count of 130.\n\nCONCLUSIONS\nOur patient’s case highlights several crucial learning points regarding Nocardia including acknowledging the lack of available data within the United States in regard to the incidence and prevalence of Nocardia, particularly N beijingensis, in people with HIV having suspected pulmonary TB. A comprehensive list of differential diagnoses and meticulous diagnostic evaluation of these patients is of paramount importance to prevent the morbidity and mortality associated with a delayed or missed diagnosis. Prompt diagnosis and treatment will allow these patients to have a favorable clinical outcome.\n\nSupplementary Data\nSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\nofaa186_suppl_Supplementary_Figure_1 Click here for additional data file.\n\n ofaa186_suppl_Supplementary_Figure_2 Click here for additional data file.\n\n ofaa186_suppl_Supplementary_Figure_3 Click here for additional data file.\n\n ofaa186_suppl_Supplementary_Figure_4 Click here for additional data file.\n\n ofaa186_suppl_Supplementary_Tables Click here for additional data file.\n\n Acknowledgments\nWe thank the patient and his family for permitting the publication of his case and their cooperation with care during the past months.\n\n\nPotential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1. \nBeaman BL , Beaman L \nNocardia species: host-parasite relationships\n. Clin Microbiol Rev 1994 ; 7 :213 –64\n.8055469 \n2. \nAnagnostou T , Arvanitis M , Kourkoumpetis TK , et al. \nNocardiosis of the central nervous system: experience from a general hospital and review of 84 cases from the literature\n. Medicine (Baltimore) 2014 ; 93 :19 –32\n.24378740 \n3. \nYaşar Z , Acat M , Onaran H , et al. \nAn unusual case of pulmonary nocardiosis in immunocompetent patient\n. Case Rep Pulmonol 2014 ; 2014 :963482 .25506020 \n4. \nWang L , Zhang Y , Lu Z , et al. \n\nNocardia beijingensis sp. nov., a novel isolate from soil\n. Int J Syst Evol Microbiol 2001 ; 51 :1783 –8\n.11594609 \n5. \nKageyama A , Poonwan N , Yazawa K , et al. \n\nNocardia beijingensis, is a pathogenic bacterium to humans: the first infectious cases in Thailand and Japan\n. Mycopathologia 2004 ; 157 :155 –61\n.15119850 \n6. \nCrozier JA , Andhavarapu S , Brumble LM , Sher T \nFirst report of Nocardia beijingensis infection in an immunocompetent host in the United States\n. J Clin Microbiol 2014 ; 52 :2730 –2\n.24829230 \n7. \nMcNeil MM , Brown JM \nThe medically important aerobic actinomycetes: epidemiology and microbiology\n. Clin Microbiol Rev 1994 ; 7 :357 –417\n.7923055 \n8. \nSteinbrink J , Leavens J , Kauffman CA , Miceli MH \nManifestations and outcomes of nocardia infections: comparison of immunocompromised and nonimmunocompromised adult patients\n. Medicine (Baltimore) 2018 ; 97 :e12436 .30290600 \n9. \nAmbrosioni J , Lew D , Garbino J \nNocardiosis: updated clinical review and experience at a tertiary center\n. Infection 2010 ; 38 :89 –97\n.20306281 \n10. \nCastro JG , Espinoza L \nNocardia species infections in a large county hospital in Miami: 6 years experience\n. J Infect 2007 ; 54 :358 –61\n.16979760 \n11. \nPintado V , Gómez-Mampaso E , Cobo J , et al. \nNocardial infection in patients infected with the human immunodeficiency virus\n. Clin Microbiol Infect 2003 ; 9 :716 –20\n.12925115 \n12. \nKhadka P , Basnet RB , Rijal BP , Sherchand JB \nPulmonary nocardiosis masquerading renascence of tuberculosis in an immunocompetent host: a case report from Nepal\n. BMC Res Notes 2018 ; 11 :488 .30016976 \n13. \nDong G , Chu P , Guo J , et al \nNontuberculous mycobacterial and Nocardia\n\n infections mimicking pulmonary tuberculosis: a retrospective study of a general hospital patient population in China\n. J Med Microbiol 2019 . doi:10.1099/jmm.0.000961 \n14. \nShariff M , Gunasekaran J \nPulmonary nocardiosis: review of cases and an update\n. Can Respir J 2016 ; 2016 :7494202 .27445562 \n15. \nHoza AS , Mfinanga SGS , Moser I , König B \nIsolation, biochemical and molecular identification of Nocardia species among TB suspects in northeastern, Tanzania; a forgotten or neglected threat?\nBMC Infect Dis 2017 ; 17 :407 .28595598 \n16. \nEkrami A , Khosravi AD , Samarbaf Zadeh AR , Hashemzadeh M \nNocardia co-infection in patients with pulmonary tuberculosis\n. Jundishapur J Microbiol 2014 ; 7 :e12495 .25741428 \n17. \nUttamchandani RB , Daikos GL , Reyes RR , et al. \nNocardiosis in 30 patients with advanced human immunodeficiency virus infection: clinical features and outcome\n. Clin Infect Dis 1994 ; 18 :348 –53\n.8011814 \n18. \nAlnaum HM , Elhassan MM , Mustafa FY , Hamid ME \nPrevalence of Nocardia species among HIV-positive patients with suspected tuberculosis\n. Trop Doct 2011 ; 41 :224 –6\n.21878441 \n19. \nSakyi SA , Danquah KO , Ephraim RD , et al. \nEvaluating the contribution of Nocardia spp. and Mycobacterium tuberculosis to pulmonary infections among HIV and non-HIV patients at the Komfo Anokye Teaching Hospital, Ghana\n. Can J Infect Dis Med Microbiol 2018 ; 2018 :2910198 .30581513 \n20. \nJones N , Khoosal M , Louw M , Karstaedt A \nNocardial infection as a complication of HIV in South Africa\n. J Infect 2000 ; 41 :232 –9\n.11120610 \n21. \nSherbuk J , Saly D , Barakat L , Ogbuagu O \nUnusual presentation of disseminated Nocardia abscessus infection in a patient with AIDS\n. BMJ Case Rep 2016 ; 2016 . doi:10.1136/bcr-2016-215649 \n22. \nWilson JW \nNocardiosis: updates and clinical overview\n. Mayo Clin Proc 2012 ; 87 :403 –7\n.22469352 \n23. \nCannon JP , Lee TA , Clark NM , et al. \nThe risk of seizures among the carbapenems: a meta-analysis\n. J Antimicrob Chemother 2014 ; 69 :2043 –55\n.24744302 \n24. \nSoman R , Koparkar V , Almeida A , et al. \nParadoxical response in cerebral nocardiosis in a renal transplant recipient\n. J Assoc Physicians India 2018 ; 66 :91 –2\n.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(6)",
"journal": "Open forum infectious diseases",
"keywords": "HIV/AIDS; Nocardia beijingensis; disseminated Nocardia; tuberculosis",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa186",
"pmc": null,
"pmid": "32548208",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "30581513;20306281;25741428;27440848;24744302;31321940;15119850;7923055;12925115;16979760;21878441;28595598;24378740;27445562;31021740;11120610;22469352;11594609;24829230;30290600;8055469;25506020;30016976;8011814",
"title": "Disseminated Nocardia beijingensis Masquerading as Pulmonary Tuberculosis in a Patient With Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome.",
"title_normalized": "disseminated nocardia beijingensis masquerading as pulmonary tuberculosis in a patient with human immunodeficiency virus acquired immune deficiency syndrome"
} | [
{
"companynumb": "US-009507513-2010USA000774",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMIKACIN"
},
"drugadditional": null,
... |
{
"abstract": "Certain drugs can cause kidney stones but as far as we are aware, ceftazidime-related urinary calculi have not been previously reported. We report here a case of an 8-year-old boy who developed hydronephrosis secondary to urinary calculi after receiving ceftazidime 2.0 g by intravenous infusion daily for two weeks. Previously, his left kidney showed no signs of disease. A retrograde double J ureteral stent was inserted, ceftazidime terminated, fluids increased and urine alkalised. On day 25, the patient showed no signs of kidney stones or hydronephrosis. Clinicians should be aware of the possibility of ceftazidime-related urinary calculi particularly if patients are receiving long-term treatment.",
"affiliations": "Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.;Department of Urology, Second People's Hospital of Yichang, Second People's Hospital of China Three Gorges University, Yichang, Hubei, China.",
"authors": "Gao|Pan|P|https://orcid.org/0000-0003-4314-7929;Liu|Zonglai|Z|;Yang|Han|H|;He|Ziqiu|Z|;Zhang|Zhi|Z|;Guo|Xiong|X|;Zhang|Hongbo|H|;Ai|Wei|W|;Du|Dan|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002442:Ceftazidime",
"country": "England",
"delete": false,
"doi": "10.1177/0300060520921667",
"fulltext": "\n==== Front\nJ Int Med Res\nJ. Int. Med. Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520921667\n10.1177_0300060520921667\nCase Report\nCeftazidime-related urinary calculi in a young boy: a case report\nhttps://orcid.org/0000-0003-4314-7929Gao Pan Liu Zonglai Yang Han He Ziqiu Zhang Zhi Guo Xiong Zhang Hongbo Ai Wei Du Dan Department of Urology, Second People’s Hospital of Yichang, Second People’s Hospital of China Three Gorges University, Yichang, Hubei, China\nDan Du, Department of Urology, Second People’s Hospital of Yichang, Second people’s Hospital of China Three Gorges University, 21 Xiling One Road, Yichang, 443000, Hubei Province, China. Email: 2976539511@qq.com\n30 4 2020 \n4 2020 \n48 4 03000605209216679 12 2019 1 4 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Certain drugs can cause kidney stones but as far as we are aware, ceftazidime-related urinary calculi have not been previously reported. We report here a case of an 8-year-old boy who developed hydronephrosis secondary to urinary calculi after receiving ceftazidime 2.0 g by intravenous infusion daily for two weeks. Previously, his left kidney showed no signs of disease. A retrograde double J ureteral stent was inserted, ceftazidime terminated, fluids increased and urine alkalised. On day 25, the patient showed no signs of kidney stones or hydronephrosis. Clinicians should be aware of the possibility of ceftazidime-related urinary calculi particularly if patients are receiving long-term treatment.\n\nCeftazidimecalculikidney stonesdouble J stentedited-statecorrected-prooftypesetterts2\n==== Body\nIntroduction\nCeftazidime is a third-generation cephalosporin antibiotic and is commonly used in clinical practice.1 The drug has broad spectrum antimicrobial coverage, a long half-life, is generally well tolerated and is on the World Health Organization (WHO) list of essential medicines 1,2 We report a case of a young boy who developed severe hydronephrosis secondary to urinary calculi following treatment with ceftazidime.\n\nCase report\nAn 8-year-old boy presented to our hospital with severe hydronephrosis in his right kidney. A day before admission, the patient experienced right lower back pain accompanied by nausea, vomiting, fever, polyuria, dysuria and haematuria. Ultrasound examination of the right kidney showed severe hydronephrosis and magnetic resonance imaging (MRI) showed severe hydrops. There were no obvious abnormalities in the patient’s left kidney (Figure 1). Before this event, the patient had been physically healthy and had no prior history of high blood pressure, diabetes, immunodeficiency or recent foreign travel\n\nFigure 1. Magnetic resonance imaging (MRI) scan of the patient on admission. The solid arrow indicates the severe hydrops in the right kidney. No abnormalities were observed in the left kidney.\n\nInitially, the patient was thought to have ureteropelvic junction stenosis and so transperitoneal pyeloplasty using the Anderson-Hynes technique was performed.3 During the laparoscopy it was confirmed that there was right ureteropelvic junction obstruction. Post-surgery, the patient was prescribed a daily intravenous infusion of ceftazidime 2.0 g for two weeks. At the end of this period, a computed tomography (CT) scan of the lower abdomen and pelvis showed that the hydronephrosis of the right kidney had significantly reduced and the ureteral stent was in a good position. However, the previous healthy left kidney showed some high-density shadows in both the ureter and kidney, and hydronephrosis had developed (Figures 2 and 3).\n\nFigure 2. A computed tomography scan (CT) of the patient two weeks after receiving ceftazidime 2.0 g by intravenous infusion daily. The arrows indicate the hydronephrosis and the high-density shadow that had developed in the left kidney.\n\nFigure 3. A computed tomography scan (CT) of the patient two weeks after receiving ceftazidime 2.0 g by intravenous infusion daily. The arrow indicates the high-density shadow in the left ureter.\n\nA retrograde double J ureteral stent was inserted on the left side and intravenous ceftazidime was terminated. The patient’s liquid intake was increased and he was given potassium sodium hydrogen citrate granules to alkalise his urine. Six days later, a CT scan showed that the left ureteral stones had decreased in size and had returned to the renal pelvis and the hydronephrosis had reduced significantly (Figure 4).\n\nFigure 4. A computed tomography (CT) scan of the patient six days after a retrograde double J ureteral stent was inserted, ceftazidime terminated, fluids increased and urine alkalised. The arrow indicates that the left ureteral stones had decreased in size and had returned to the renal pelvis and hydronephrosis had significantly reduced.\n\nTwenty-five days after the left kidney catheterization, a subsequent CT scan showed that the kidney stones and hydronephrosis had disappeared completely and so the stent was removed (Figure 5). Six months after the operation, a CT scan showed no signs of kidney stones or hydronephrosis in the left kidney.\n\nFigure 5. A computed tomography (CT) scan of the patient 25 days after surgery. The arrow indicates that the left kidney stones and hydronephrosis had disappeared completely.\n\nThis case report did not require ethics committee approval. Written authorisation was obtained from the patient's family before publication of this article.\n\nDiscussion\nDrug-related calculi account for approximately 1–2% of all kidney stones.4 Although the exact mechanisms of drug-induced calculi are unknown, two main hypotheses have been suggested; one relates to solubility of the drug (i.e., low solubility results in high urine concentration which leads to crystal formation in the urinary tract) and the other to metabolic effects of the drug which induce calculi formation.4,5\n\nAlthough there have been several reports suggesting cephalosporins have the potential to induce urolithiasis,6–11 as far as we are aware there have been no previous reports of ceftazidime-related urinary calculi. Our patient had no left kidney ureteral calculi or hydronephrosis on admission and with the exception of intravenous infusion of 500 ml 0.5% glucose on the day after surgery, ceftazidime was the only drug given to the patient. Therefore, we suggest that the formation of the urinary calculi in this patient was linked to ceftazidime.\n\nOn discovering the left urinary calculi and hydronephrosis we placed a ureteral stent which enabled urinary drainage, avoided aggravation of renal hydronephrosis and improved renal function. In addition, the patient’s fluid intake was increased and his urine was alkalised. The left urinary calculi gradually dissolved and on the 25th day after surgery, the stones and secondary hydronephrosis had disappeared. At the six-month follow-up, the patient showed no signs of urinary calculi or hydronephrosis.\n\nOur case study suggests that clinicians should consider the possibility of ceftazidime-related urinary calculi when a patient who is receiving the antibiotic presents with symptoms of low back pain or abnormal kidney function. For management, we suggest insertion of a retrograde double J ureteral stent followed by increased fluid intake and urinary alkalinisation.\n\nDeclaration of conflicting interests\nThe authors declare that there are no conflicts of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD\nPan Gao https://orcid.org/0000-0003-4314-7929\n==== Refs\nReferences\n1 Tuon FF Rocha JL Formigoni-Pinto MR. \nPharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review\n. Infection \n2018 ; \n46 : 165 –181\n.29110143 \n2 World Health Organization (2019 ). World Health Organization model list of essential medicines: 21st list 2019 . \nGeneva : \nWorld Health Organization \nhttps://www.who.int/medicines/publications/essentialmedicines/en/.\n3 Valdivia Uría JG Sánchez Elipe MA Sánchez Zalabardo M. \nLaparoscopic pyeloplasty\n. Arch Esp Urol \n2002 ; \n55 : 679 –686\n.12224166 \n4 Daudon M Jungers P. \nDrug-induced renal calculi: epidemiology, prevention and management\n. Drugs \n2004 ; \n64 : 245 –275\n.14871169 \n5 Daudon M Frochot V Bazin D , et al\nDrug-induced kidney stones and crystalline nephropathy: pathophysiology, prevention and treatment\n. Drugs \n2018 ; \n78 : 163 –201\n.29264783 \n6 Mazhari R Kimmel PL. \nHematuria: an algorithmic approach to finding the cause\n. Cleve Clin J Med \n2002 ; \n69 : 870, 872–874, 876 passim.\n7 Lim IW Stride PJ Horvath RL. \nA case of cephalothin-associated urolithiasis\n. Clin Pharmacol \n2011 ; \n3 : 1 –3\n.22287851 \n8 Kimata T Kaneko K Takahashi M , et al\nIncreased urinary calcium excretion caused by ceftriaxone: possible association with urolithiasis\n. Pediatr Nephrol \n2012 ; \n27 : 605 –609\n.22038204 \n9 Chutipongtanate S Thongboonkerd V. \nCeftriaxone crystallization and its potential role in kidney stone formation\n. Biochem Biophys Res Commun \n2011 ; \n406 : 396 –402\n.21329669 \n10 Imafuku A Sawa N Sekine A , et al\nRisk factors of ceftriaxone-associated biliary pseudolithiasis in adults: influence of renal dysfunction\n. Clin Exp Nephrol \n2018 ; \n22 : 613 –619\n.29027036 \n11 Avci Z Koktener A Uras N , et al\nNephrolithiasis associated with ceftriaxone therapy: a prospective study in 51 children\n. Arch Dis Child \n2004 ; \n89 : 1069 –1072\n.15499067\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "48(4)",
"journal": "The Journal of international medical research",
"keywords": "Ceftazidime; calculi; double J stent; kidney stones",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D002648:Child; D006801:Humans; D007669:Kidney Calculi; D008279:Magnetic Resonance Imaging; D008297:Male; D014057:Tomography, X-Ray Computed; D014545:Urinary Calculi",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "300060520921667",
"pmc": null,
"pmid": "32351152",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21329669;12430972;15499067;14871169;29110143;22287851;29027036;29264783;22038204;12224166",
"title": "Ceftazidime-related urinary calculi in a young boy: a case report.",
"title_normalized": "ceftazidime related urinary calculi in a young boy a case report"
} | [
{
"companynumb": "CN-B.BRAUN MEDICAL INC.-2083902",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTAZIDIME"
},
"drugadditional": null,... |
{
"abstract": "Treatment options for patients with aggressive chronic inflammatory demyelinating neuropathy are limited and include the anti-CD20 antibody rituximab and the immunosuppressive regime cyclophosphamide. We aimed to investigate retrospectively the efficacy of bortezomib, a proteasome inhibitor tackling highly metabolically active cell types such as plasma cells, in a case series of 10 treatment refractory CIDP patients. All patients reported showed a deterioration of the clinical CIDP scores under first-line treatment or escalating treatment with cyclophosphamide or rituximab. One or two cycles of bortezomib treatment (each cycle with 1.3 mg/m2 administered s.c. on days 1, 4, 8, and 11) stabilized the majority of the patients (n = 6) during treatment and even improved clinical and electrophysiological parameters of four patients up to 1 year later. No relevant side-effects were reported. Two patients received autologous peripheral blood stem cell transplantation after bortezomib, which led to fatal infections. We conclude that bortezomib could be an attractive escalating treatment option with a good side-effect profile for patients with treatment refractory CIDP.",
"affiliations": "Department of Neurology, St. Josef-Hospital, Ruhr University, Gudrunstr. 56, 44791, Bochum, Germany. Kalliopi.Pitarokoili@ruhr-uni-bochum.de.;Department of Neurology, St. Josef-Hospital, Ruhr University, Gudrunstr. 56, 44791, Bochum, Germany.;Department of Neurology, St. Josef-Hospital, Ruhr University, Gudrunstr. 56, 44791, Bochum, Germany.;Department of Hematology and Oncology, St. Josef Hospital, Ruhr University, Bochum, Germany.;Department of Neurology, St. Josef-Hospital, Ruhr University, Gudrunstr. 56, 44791, Bochum, Germany.;Department of Neurology, St. Josef-Hospital, Ruhr University, Gudrunstr. 56, 44791, Bochum, Germany.",
"authors": "Pitarokoili|Kalliopi|K|http://orcid.org/0000-0002-2483-4929;Yoon|Min-Suk|MS|;Kröger|Ilka|I|;Reinacher-Schick|Anke|A|;Gold|Ralf|R|;Schneider-Gold|Christiane|C|",
"chemical_list": "D018951:Antigens, CD20; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D000069286:Bortezomib",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-017-8599-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "264(9)",
"journal": "Journal of neurology",
"keywords": "B cells; Bortezomib; Chronic inflammatory demyelinating polyneuropathy; Nerve conduction studies; Proteasome inhibitor; Treatment",
"medline_ta": "J Neurol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "2010-2020",
"pmc": null,
"pmid": "28836002",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": "15326250;9217150;12088688;15525302;11971045;27422265;19886739;1186294;1262904;27211850;27017186;21040140;7496785;15710853;25889583;24523485;10209187;15703014;19455715;26843559;18178525;20133204;20639381;23771584;22261118;4022350;25561275;9533779;27557302;18322240;19628298;24740168;18217957;10852542;19564582;21233415;27760868;25875484;17382963;12084892;18542049;21179602;16914929;13572689;24525285;9855536;26401517;27533122",
"title": "Severe refractory CIDP: a case series of 10 patients treated with bortezomib.",
"title_normalized": "severe refractory cidp a case series of 10 patients treated with bortezomib"
} | [
{
"companynumb": "DE-TAKEDA-2017MPI007752",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3... |
{
"abstract": "BACKGROUND\n18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a useful tool for identifying high-risk features in patients with newly diagnosed multiple myeloma (NDMM). This study evaluated the role of autologous stem cell transplantation (ASCT) in patients presenting with positive results on PET/CT scans.\n\n\nMETHODS\nThe medical records of 210 patients who underwent PET/CT at diagnosis were retrospectively reviewed. Eligible patients for transplantation proceeded to upfront ASCT with high-dose chemotherapy (HDT) after induction therapy with novel agents.\n\n\nRESULTS\nThe presence of a number of focal lesions (FL) >3 and extramedullary disease (EMD) occurred in 111 and 35 patients, respectively. ASCT was performed in 54 patients. Among patients with FL > 3, those treated with ASCT showed a prolonged 2-year progression-free survival (PFS) and overall survival (OS) rates compared to those not treated with ASCT (PFS, 60.2% vs. 23.5%, P < 0.001; OS, 91.7% vs. 63.6%, P = 0.005). In patients with FL ≤ 3, treatment by ASCT was associated with a higher 2-year PFS rate than no treatment by ASCT (74.0% vs. 54.9%, P = 0.040). The OS of patients treated with ASCT was not significantly longer than that of patients not treated with ASCT (P = 0.115). In multivariate analysis, FL > 3, Revised International Staging System (R-ISS), and upfront ASCT were independent prognostic factors for PFS and OS.\n\n\nCONCLUSIONS\nPresenting FL > 3 on baseline PET/CT represents a high-risk feature in patients with NDMM. Frontline ASCT with HDT prolonged the survival of patients with FL > 3.",
"affiliations": "Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea.;Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.;Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.;Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, Hwasun, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.;Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea. Electronic address: jhmoon@knu.ac.kr.",
"authors": "Cho|Hee Jeong|HJ|;Baek|Dong Won|DW|;Kim|Ju-Hyung|JH|;Lee|Jungmin|J|;Chung|Yu Kyung|YK|;Jung|Sung-Hoon|SH|;Song|Ga-Young|GY|;Ahn|Seo-Yeon|SY|;Ahn|Jae-Sook|JS|;Yang|Deok-Hwan|DH|;Lee|Je-Jung|JJ|;Kim|Hyeoung-Joon|HJ|;Hong|Chae Moon|CM|;Jeong|Shin Young|SY|;Min|Jung-Joon|JJ|;Sohn|Sang-Kyun|SK|;Moon|Joon Ho|JH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2021.08.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": null,
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "18F-FDG PET/CT; Autologous stem cell transplantation; Focal lesions; Long-term outcomes; Newly diagnosed multiple myeloma",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": null,
"nlm_unique_id": "101525386",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34598908",
"pubdate": "2021-08-31",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Favorable Long-Term Outcomes with Autologous Stem Cell Transplantation for High-Risk Multiple Myeloma Patients with a Positive Result On 18F-FDG PET/CT at Baseline.",
"title_normalized": "favorable long term outcomes with autologous stem cell transplantation for high risk multiple myeloma patients with a positive result on 18f fdg pet ct at baseline"
} | [
{
"companynumb": "KR-AMGEN-KORSP2022041274",
"fulfillexpeditecriteria": "2",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "4",
... |
{
"abstract": "Recurrent toxic shock syndrome (TSS) is uncommon. A certain level of clinical suspicion is indicated with a complex sepsis presentation in the postoperative kidney transplant patient. We present a case of presumed recurrent postoperative TSS in a living kidney transplant recipient. The patient was a 19-year-old Caucasian female with a 4-year prior single episode of toxin-mediated sepsis and chronic kidney disease (CKD) secondary to autosomal recessive Alport's syndrome (confirmed via renal biopsy and genetic testing). She received a human leukocyte antigen (HLA) 2A 2B 1DR MM, CMV -D/-R kidney from her 21-year-old friend. The patient received Campath and IV steroid induction after total cold ischemic time of 170 minutes with 40 minutes of revascularization. On postoperative day (POD) 5, she required re-exploration with reimplantation and stenting of the transplanted ureter. The patient subsequently spiked a fever of 101.6° with a generalized rash prompting collection of blood cultures which demonstrated no growth. Infectious Disease was consulted due to persistent fevers despite IV antibiotics. On POD 12, the patient returned to the operating room (OR) for evacuation of hematoma after decline in Hgb to 5.8 and CT confirmed perinephric hematomas. Kidney biopsy showed no rejection and donor specific antibodies (DSAs) were unremarkable. The patient underwent 1 treatment of empiric plasmapheresis for possible non-HLA antibodies followed by initiation of clindamycin. The patient's condition improved, and she was discharged home with a normal creatinine. Recurrent TSS is rare but should be added to the differential diagnoses of immuno-compromised patients undergoing kidney transplantation with a history of prior toxin-mediated sepsis.",
"affiliations": "Morsani College of Medicine, University of South Florida, Tampa, FL, USA.;Department of Transplant Surgery, Tampa General Medical Group, Tampa, FL, USA.;7829Office of Clinical Research, Tampa General Hospital, Tampa, FL, USA.;Department of Transplant Surgery, Tampa General Medical Group, Tampa, FL, USA.",
"authors": "Aslam|Sadaf|S|;Buggs|Jacentha|J|;Rogers|Ebonie|E|;Bowers|Victor|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0003134820945217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-1348",
"issue": "87(1)",
"journal": "The American surgeon",
"keywords": "kidney transplant; recurrent; toxic shock syndrome",
"medline_ta": "Am Surg",
"mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D009394:Nephritis, Hereditary; D010956:Plasmapheresis; D011183:Postoperative Complications; D012008:Recurrence; D051436:Renal Insufficiency, Chronic; D012772:Shock, Septic; D055815:Young Adult",
"nlm_unique_id": "0370522",
"other_id": null,
"pages": "89-91",
"pmc": null,
"pmid": "32812781",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent Postoperative Toxic Shock Syndrome in a Living Kidney Transplant Recipient.",
"title_normalized": "recurrent postoperative toxic shock syndrome in a living kidney transplant recipient"
} | [
{
"companynumb": "US-BAYER-2021A238652",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Our aim was to describe the clinical and microbiological features of four cases of severe vancomycin-susceptible methicillin-resistant Staphylococcus aureus (MRSA) infections in which the vancomycin non-susceptibility development and daptomycin resistance occurred under therapy with teicoplanin (three cases) and daptomycin switched to vancomycin (one case). Clinical data were retrospectively reviewed. On nine clinical epidemiologically unrelated daptomycin-susceptible (DAP-S) and daptomycin-resistant (DAP-R) MRSA, we performed: (i) DAP-VAN-TEC-CFX-RIF minimum inhibitory concentrations (MICs); (ii) glycopeptide resistance detection (GRD) by δ-hemolysis; (iii) glycopeptide population analysis; (iv) molecular characterization by PFGE-MLST-SCCmec-agr-typing; (v) rpoB and mprF single nucleotide polymorphisms (SNPs); (vi) dltA-mprF-atl-sceD expression by real-time quantitative polymerase chain reaction (qPCR). Three out of the four patients did not survive despite salvage treatment; two died with active MRSA infection and one died because of Stenotrophomonas maltophilia sepsis. The fourth patient, in which a reversion to a DAP-S phenotype occurred, survived with daptomycin plus trimethoprim/sulfamethoxazole and oxacillin treatment, and endovascular device removal. Daptomycin resistance development was preceded by a stable heterogeneous vancomycin-intermediate S. aureus (hVISA) or VISA phenotype acquisition, while in one case, daptomycin resistance was preceded by an unstable daptomycin heteroresistance (hDAP) behavior reverting to DAP-S during vancomycin plus rifampin therapy followed by high doses of daptomycin. All DAP-R strains showed hVISA or DAP-R traits, including mutations and/or up-regulation of genes involved in cell wall turnover and cell membrane perturbation. In our study, daptomycin resistance arose during glycopeptide therapy. The emergence of DAP-R isolates was preceded by a stable VISA or hVISA phenotype or by instability reverting to a DAP-S heteroresistant phenotype. Daptomycin, as first-line therapy for the treatment of severe MRSA infections, should be used at optimal dosage combined with other agents such as beta-lactams, to prevent daptomycin resistance occurrence.",
"affiliations": "National Institute for Infectious Diseases \"L. Spallanzani\", Rome, Italy.;Department of Biomedical and Biotechnological Sciences, MMAR Laboratory, University of Catania, Catania, Italy. v.cafiso@unict.it.;Department of Biomedical and Biotechnological Sciences, MMAR Laboratory, University of Catania, Catania, Italy.;Department of Microbiology, San Camillo-Forlanini Hospital, Rome, Italy.;Department of Microbiology, San Camillo-Forlanini Hospital, Rome, Italy.;National Institute for Infectious Diseases \"L. Spallanzani\", Rome, Italy.;Department of Biomedical and Biotechnological Sciences, MMAR Laboratory, University of Catania, Catania, Italy.",
"authors": "Capone|A|A|;Cafiso|V|V|;Campanile|F|F|;Parisi|G|G|;Mariani|B|B|;Petrosillo|N|N|;Stefani|S|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017334:Teicoplanin; D014640:Vancomycin; D017576:Daptomycin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-016-2581-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "35(4)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": null,
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017576:Daptomycin; D024881:Drug Resistance, Bacterial; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D020869:Gene Expression Profiling; D006461:Hemolysis; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D058885:Multilocus Sequence Typing; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D017334:Teicoplanin; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "625-31",
"pmc": null,
"pmid": "26815434",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21393156;21746940;21173172;19073304;22302374;24840624;22403425;22026752;24183798;19671586;25226591;11157898;19778764;19552801;22253738;17854479;20200036;11972351;25447803;25600843;20837752;26143590;23215859",
"title": "In vivo development of daptomycin resistance in vancomycin-susceptible methicillin-resistant Staphylococcus aureus severe infections previously treated with glycopeptides.",
"title_normalized": "in vivo development of daptomycin resistance in vancomycin susceptible methicillin resistant staphylococcus aureus severe infections previously treated with glycopeptides"
} | [
{
"companynumb": "IT-WATSON-2016-11715",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Several risk factors for severe COVID-19 specific for patients with inflammatory rheumatic and musculoskeletal diseases (RMDs) have been identified so far. Evidence regarding the influence of different RMD treatments on outcomes of SARS-CoV-2 infection is still poor.\n\n\n\nData from the German COVID-19-RMD registry collected between 30 March 2020 and 9 April 2021 were analysed. Ordinal outcome of COVID-19 severity was defined: (1) not hospitalised, (2) hospitalised/not invasively ventilated and (3) invasively ventilated/deceased. Independent associations between demographic and disease features and outcome of COVID-19 were estimated by multivariable ordinal logistic regression using proportional odds model.\n\n\n\n2274 patients were included. 83 (3.6%) patients died. Age, male sex, cardiovascular disease, hypertension, chronic lung diseases and chronic kidney disease were independently associated with worse outcome of SARS-CoV-2 infection. Compared with rheumatoid arthritis, patients with psoriatic arthritis showed a better outcome. Disease activity and glucocorticoids were associated with worse outcome. Compared with methotrexate (MTX), TNF inhibitors (TNFi) showed a significant association with better outcome of SARS-CoV-2 infection (OR 0.6, 95% CI0.4 to 0.9). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) (OR 2.2, 95% CI 1.3 to 3.9), Janus kinase inhibitor (JAKi) (OR 1.8, 95% CI 1.1 to 2.7) and rituximab (OR 5.4, 95% CI 3.3 to 8.8) were independently associated with worse outcome.\n\n\n\nGeneral risk factors for severity of COVID-19 play a similar role in patients with RMDs as in the normal population. Influence of disease activity on COVID-19 outcome is of great importance as patients with high disease activity-even without glucocorticoids-have a worse outcome. Patients on TNFi show a better outcome of SARS-CoV-2 infection than patients on MTX. Immunosuppressants, rituximab and JAKi are associated with more severe course.",
"affiliations": "Epidemiology Unit, German Rheumatism Research Center Berlin, Berlin, Germany Anne.Regierer@drfz.de.;Department of Rheumatology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany.;Epidemiology Unit, German Rheumatism Research Center Berlin, Berlin, Germany.;Department for Rheumatology and Clinical Immunology, University of Schleswig-Holstein at Kiel, Kiel, Germany.;Department of Rheumatology, Clinical Immunology and Osteology, Immanuel Hospital Berlin-Wannsee Branch, Berlin, Germany.;Medicine V, University of Heidelberg, Heidelberg, Germany.;IDIR, University of Jena, Jena, Germany.;Policlinic for Rheumatology and Hiller Research Unit for Rheumatology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.;Krankenhaus St. Josef, Wuppertal, Germany.;Division of Rheumatology and Clinical Immunology, Internal Medicine IV, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany.;Epidemiology Unit, German Rheumatism Research Center Berlin, Berlin, Germany.;Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, KEM Kliniken Essen-Mitte, Essen, Germany.;Rheumatology and Clinical Immunology, Giessen University, Bad Nauheim, Germany.",
"authors": "Regierer|Anne Constanze|AC|0000-0003-2456-4049;Hasseli|Rebecca|R|0000-0002-2982-8253;Schäfer|Martin|M|0000-0001-6487-3634;Hoyer|Bimba F|BF|0000-0002-5252-1719;Krause|Andreas|A|;Lorenz|Hanns-Martin|HM|;Pfeil|Alexander|A|0000-0002-2709-6685;Richter|Jutta|J|;Schmeiser|Tim|T|;Schulze-Koops|Hendrik|H|0000-0002-1681-491X;Strangfeld|Anja|A|0000-0002-6233-022X;Voll|Reinhard E|RE|;Specker|Christof|C|0000-0003-2504-3229;Mueller-Ladner|Ulf|U|",
"chemical_list": "D000075242:Janus Kinase Inhibitors; D000079424:Tumor Necrosis Factor Inhibitors; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1136/rmdopen-2021-001896",
"fulltext": "\n==== Front\nRMD Open\nRMD Open\nrmdopen\nrmdopen\nRMD Open\n2056-5933\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nrmdopen-2021-001896\n10.1136/rmdopen-2021-001896\nInfections\n1506\n2474\nOriginal researchTNFi is associated with positive outcome, but JAKi and rituximab are associated with negative outcome of SARS-CoV-2 infection in patients with RMD\nhttp://orcid.org/0000-0003-2456-4049\nRegierer Anne Constanze 1\nhttp://orcid.org/0000-0002-2982-8253\nHasseli Rebecca 2\nhttp://orcid.org/0000-0001-6487-3634\nSchäfer Martin 1\nhttp://orcid.org/0000-0002-5252-1719\nHoyer Bimba F 3\nKrause Andreas 4\nLorenz Hanns-Martin 5\nhttp://orcid.org/0000-0002-2709-6685\nPfeil Alexander 6\nRichter Jutta 7\nSchmeiser Tim 8\nhttp://orcid.org/0000-0002-1681-491X\nSchulze-Koops Hendrik 9\nhttp://orcid.org/0000-0002-6233-022X\nStrangfeld Anja 1\nVoll Reinhard E 1011\nhttp://orcid.org/0000-0003-2504-3229\nSpecker Christof 1213\nMueller-Ladner Ulf 14\n1 Epidemiology Unit, German Rheumatism Research Center Berlin, Berlin, Germany\n2 Department of Rheumatology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany\n3 Department for Rheumatology and Clinical Immunology, University of Schleswig-Holstein at Kiel, Kiel, Germany\n4 Department of Rheumatology, Clinical Immunology and Osteology, Immanuel Hospital Berlin-Wannsee Branch, Berlin, Germany\n5 Medicine V, University of Heidelberg, Heidelberg, Germany\n6 IDIR, University of Jena, Jena, Germany\n7 Policlinic for Rheumatology and Hiller Research Unit for Rheumatology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany\n8 Krankenhaus St. Josef, Wuppertal, Germany\n9 Division of Rheumatology and Clinical Immunology, Internal Medicine IV, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany\n10 Department of Rheumatology and Clinical Immunology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany\n11 Centre of Chronic Immunodeficiency, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany\n12 Department of Rheumatology and Clinical Immunology, KEM Kliniken Essen-Mitte, Essen, Germany\n13 Rheumatology, Heinrich Heine University Düsseldorf, Dusseldorf, Germany\n14 Rheumatology and Clinical Immunology, Giessen University, Bad Nauheim, Germany\nCorrespondence to Dr Anne Constanze Regierer; Anne.Regierer@drfz.de\n2021\n19 10 2021\n19 10 2021\n7 3 e00189625 8 2021\n24 9 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nIntroduction\n\nSeveral risk factors for severe COVID-19 specific for patients with inflammatory rheumatic and musculoskeletal diseases (RMDs) have been identified so far. Evidence regarding the influence of different RMD treatments on outcomes of SARS-CoV-2 infection is still poor.\n\nMethods\n\nData from the German COVID-19-RMD registry collected between 30 March 2020 and 9 April 2021 were analysed. Ordinal outcome of COVID-19 severity was defined: (1) not hospitalised, (2) hospitalised/not invasively ventilated and (3) invasively ventilated/deceased. Independent associations between demographic and disease features and outcome of COVID-19 were estimated by multivariable ordinal logistic regression using proportional odds model.\n\nResults\n\n2274 patients were included. 83 (3.6%) patients died. Age, male sex, cardiovascular disease, hypertension, chronic lung diseases and chronic kidney disease were independently associated with worse outcome of SARS-CoV-2 infection. Compared with rheumatoid arthritis, patients with psoriatic arthritis showed a better outcome. Disease activity and glucocorticoids were associated with worse outcome. Compared with methotrexate (MTX), TNF inhibitors (TNFi) showed a significant association with better outcome of SARS-CoV-2 infection (OR 0.6, 95% CI0.4 to 0.9). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) (OR 2.2, 95% CI 1.3 to 3.9), Janus kinase inhibitor (JAKi) (OR 1.8, 95% CI 1.1 to 2.7) and rituximab (OR 5.4, 95% CI 3.3 to 8.8) were independently associated with worse outcome.\n\nConclusion\n\nGeneral risk factors for severity of COVID-19 play a similar role in patients with RMDs as in the normal population. Influence of disease activity on COVID-19 outcome is of great importance as patients with high disease activity—even without glucocorticoids—have a worse outcome. Patients on TNFi show a better outcome of SARS-CoV-2 infection than patients on MTX. Immunosuppressants, rituximab and JAKi are associated with more severe course.\n\nCOVID-19\nantirheumatic agents\nglucocorticoids\nJustus-Liebig-University Giessen special-featureunlocked\n==== Body\npmcKey messages\n\nWhat is already known about this subject?\n\nAlso in rheumatic and musculoskeletal diseases (RMDs) age, male sex and specific comorbidities are general risk factors for severity of SARS-CoV-2 infection.\n\nRMD disease activity and glucocorticoids are specific risk factors.\n\nWhat does this study add?\n\nRMD treatment is associated with SARS-CoV-2 infection severity.\n\nWhile patients under TNFi treatment show better outcome, those under immunosuppressants, Janus kinase inhibitor (JAKi) and rituximab show worse outcome.\n\nHow might this impact on clinical practice or further developments?\n\nPatients with RMD under treatment with immunosuppressants, JAKi and rituximab need special guidance during the pandemic.\n\nIntroduction\n\nSince the beginning of the SARS-CoV-2 pandemic, increasing evidence about COVID-19 in inflammatory rheumatic and musculoskeletal diseases (RMDs) has been gained. In the general population, age, male sex and certain chronic diseases such as cardiovascular disease (CVD) have been identified as risk factors for severity of COVID-19.1 2 In patients with RMD, similar risk factors have been described. In addition, for those patients also RMD-specific risk factors play a role.3–6 Disease activity of the underlying RMD, for example, is of utmost importance for the outcome of COVID-19.4 6\n\nSince immunomodulatory treatment can influence the outcome of infectious diseases significantly, the impact of the RMD treatment is also of great interest for patients with RMD suffering from SARS-CoV-2 infection. On the one hand, certain immunomodulatory drugs have been proven beneficial in the course of a SARS-CoV-2 infection7; on the other hand, immunomodulatory drugs can be detrimental.8 Moreover, timing and dosing of the treatment appears to be crucial. For example, dexamethasone is a standard treatment for severe COVID-197 at present, but a long-term glucocorticoid treatment due to RMD is associated with a worse outcome of SARS-CoV-2 infection.4 6 The same might be true for Janus kinase inhibitor (JAKi) treatment.9\n\nThe impact of TNFi on SARS-CoV-2 infection is not completely understood. Use of TNFi in comparison to ‘no disease-modifying anti-rheumatic drug (DMARD)’ was associated with a lower risk of hospitalisation in the first analysis of the data from the Global Rheumatology Alliance (GRA).3 However, it was not significantly associated with lower risk of mortality in a more recent analysis of the GRA in which MTX was used as reference category.4 Potential beneficial effects of TNFi have also been described in patients with COVID-19 with inflammatory bowel disease.10\n\nDue to the lack of interventional studies in patients with RMDs and SARS-CoV-2 infection, the effects of RMD treatment have been evaluated in observational studies only. In this analysis from the German COVID19-RMD registry, we analysed the risk factors for the severity of SARS-CoV-2 infection in patients with RMD, specifically focusing on the impact of RMD treatment.\n\nMethods\n\nData source\n\nThe German COVID-19 registry for patients with RMDs was founded in March 2020 by the German Society for Rheumatology, together with the Justus-Liebig-University Giessen. Rheumatologists voluntarily entered the data into a web-based registry with implemented plausibility checks (https://www.covid19-rheuma.de; for more details, see Hasseli et al11).\n\nSARS-CoV-2 infection outcome parameters\n\nThe primary outcome of interest was the mutually exclusive ordinal COVID-19 severity outcome:\n\n(1) neither hospitalised, ventilated nor deceased; (2) hospitalised with or without non-invasive ventilation, but neither invasively ventilated nor deceased; and (3) invasively ventilated or deceased. At the time of analysis, all patients were required to have a resolved clinical course.\n\nStatistical analyses\n\nPatient characteristics are shown descriptively, stratified by the three categories of the ordinal outcome. Independent associations between demographic and disease features and the ordinal COVID-19 outcome were estimated by multivariable ordinal logistic regression using the proportional odds model and were reported as OR and 95% CI. In the proportional odds model, an increase in severity is assumed to be equal across categories: the increase from ‘neither hospitalised, ventilated nor deceased’ to ‘hospitalised with or without non-invasive ventilation, but neither invasively ventilated nor deceased’ is treated in the same way as the increase from the latter category to ‘invasively ventilated or deceased’. Potential deviations from this assumption were assessed graphically and did not show relevant deviation (data not shown). Covariates included in the model were age, sex, key comorbidities (hypertension alone or CVD alone, hypertension combined with CVD, chronic lung disease, chronic kidney disease (CKD) and diabetes), RMD or diagnostic group, rheumatic disease treatment prior to COVID-19 diagnosis (without glucocorticoids), as well as the combined status of disease activity as per the physician’s global assessment (severe/high or moderate disease activity vs minimal/low disease activity or remission), and the prednisolone-equivalent glucocorticoid use (1–10 mg/day and >10 mg/day). The combined status of disease activity and glucocorticoid use represents both their main effects and interaction (in an additive sense) and is analysed to disentangle the effects of both factors.\n\nAll patients with confirmed SARS-CoV-2 infection were included in the main analyses. Patients with missing primary outcome (n=2) or missing values for age, sex and DMARDs (n=2) were excluded from analysis. Smoking status was missing in many cases. Therefore, we have not included smoking in the analysis. Missing values for glucocorticoid therapy and disease activity were derived by multiple imputation using full conditional specification.12 Results of the ordinal logistic regression analyses for 10 imputed data sets were pooled by Rubin’s rules.\n\nFor patients listed as having more than one RMD or being treated with more than one of the medications of interest, we created a hierarchy based on clinical expertise to categorise patients. We used the same hierarchy as in Strangfeld et al.4 This process produces disjoint categories, allowing a clear reference group for interpretation of the regression models and avoiding collinearities. Patients with more than one of the following diseases were grouped according to the following hierarchy: systemic lupus erythematosus >vasculitis>other CTD >rheumatoid arthritis (RA) >psoriatic arthritis (PsA)>(other) spondyloarthritis (SpA) >other non-inflammatory joint diseases (IJDs)/non-CTD rheumatic disease; where ‘X>Y’ means that disease X has priority over disease Y and an individual who has both disease X and disease Y is counted as patient with disease X. Similarly, patients receiving multiple csDMARDs or immunosuppressants (except glucocorticoids) were grouped according to the following hierarchy: immunosuppressants>sulfasalazine>antimalarials>leflunomide>methotrexate. Patients receiving a bDMARD/tsDMARD alone or in combination were considered solely in the bDMARD/tsDMARD group. Patients with an IJD other than RA, PsA or SpA (n=6); patients treated with more than one bDMARD/tsDMARD (n=1); and patients receiving interleukin-1 inhibitors (n=27) or belimumab (n=11) were excluded from analysis due to low numbers.\n\nRegression coefficients were considered statistically significant for p values <0.05. All analyses were conducted in SAS V.9.4 or R V.4.0.4.\n\nResults\n\nPatient characteristics\n\nBaseline characteristics of the patients are shown in table 1. Of the 2274 patients included, 1771 (78%) did not require hospitalisation. Eighty-three patients died, resulting in a case fatality rate of 3.6%.\n\nTable 1 Patient characteristics\n\nParameter\tNot hospitalised, no death\tHospitalised, no invasive ventilation or death\tInvasive ventilation or death\tTotal\t\nN\t1771 (77.9)\t374 (16.4)\t129 (5.7)\t2274\t\nGeneral\t\t\t\t\t\nAge (years)\t55 (18)\t67 (19)\t71 (19)\t57 (19)\t\n 66–75\t226 (12.8)\t90 (24.1)\t38 (29.5)\t354 (15.6)\t\n >75\t137 (7.7)\t112 (29.9)\t47 (36.4)\t296 (13)\t\nMale sex\t546 (30.8)\t130 (34.8)\t67 (51.9)\t743 (32.7)\t\nEver smoker\t115 (96.6)\nn=119\nMissing=1652\t21 (100)\nn=21\nMissing=353\t9 (100)\nn=9\nMissing=120\t145 (97.3)\nn=149\nMissing=2125\t\nIJDs\t\t\t\t\t\nRheumatoid arthritis\t781 (44.1)\t193 (51.6)\t76 (58.9)\t1050 (46.2)\t\nSpondyloarthritis\t251 (14.2)\t28 (7.5)\t6 (4.7)\t285 (12.5)\t\nPsoriatic arthritis\t287 (16.2)\t19 (5.1)\t9 (7)\t315 (13.9)\t\nJIA (poly, oligo, not systemic)\t6 (0.3)\t0\t0\t6 (0.3)\t\nAll IJDs\t1313 (74.1)\t238 (63.6)\t90 (69.8)\t1641 (72.2)\t\nCTDs/vasculitis\t\t\t\t\t\nSLE\t91 (5.1)\t12 (3.2)\t2 (1.6)\t105 (4.6)\t\nCTDs (other than SLE)\t134 (7.6)\t29 (7.8)\t13 (10.1)\t176 (7.7)\t\nVasculitides\t145 (8.2)\t81 (21.7)\t29 (22.5)\t255 (11.2)\t\nAll CTD/vasculitides\t364 (20.6)\t121 (32.4)\t43 (33.3)\t528 (23.2)\t\nOther RMDs\t\t\t\t\t\nTotal\t151 (8.5)\t32 (8.6)\t11 (8.5)\t194 (8.5)\t\nDisease activity\tn=1751\nMissing=20\tn=355\nMissing=19\tn=109\nMissing=20\tn=2215\nMissing=59\t\nRemission\t939 (53.6)\t165 (46.5)\t37 (33.9)\t1141 (51.5)\t\nMinimal/low disease activity\t603 (34.4)\t112 (31.5)\t44 (40.4)\t759 (34.3)\t\nModerate disease activity\t169 (9.7)\t57 (16.1)\t12 (11)\t238 (10.7)\t\nSevere/high disease activity\t40 (2.3)\t21 (5.9)\t16 (14.7)\t77 (3.5)\t\nComorbidities\t\t\t\t\t\nHypertension\t524 (29.6)\t186 (49.7)\t83 (64.3)\t793 (34.9)\t\nCardiovascular disease\t121 (6.8)\t97 (25.9)\t51 (39.5)\t269 (11.8)\t\nChronic lung disease\t168 (9.5)\t72 (19.3)\t43 (33.3)\t283 (12.4)\t\nChronic kidney disease\t64 (3.6)\t71 (19)\t35 (27.1)\t170 (7.5)\t\nObesity (BMI ≥30)\t355 (20)\t87 (23.3)\t31 (24)\t473 (20.8)\t\nDiabetes\t137 (7.7)\t67 (17.9)\t31 (24)\t235 (10.3)\t\nCancer\t50 (2.8)\t25 (6.7)\t10 (7.8)\t85 (3.7)\t\nNumber of comorbidities\t0 (1)\t1.5 (2)\t2 (3)\t1 (2)\t\n No comorbidity\t896 (50.6)\t74 (19.8)\t15 (11.6)\t985 (43.3)\t\n ≥3 comorbidities\t135 (7.6)\t94 (25.1)\t53 (41.1)\t282 (12.4)\t\nDMARD therapies\t\t\t\t\t\ncsDMARDs\t639 (36.1)\t125 (33.4)\t37 (28.7)\t801 (35.2)\t\n Methotrexate (monotherapy)\t381 (21.5)\t84 (22.5)\t22 (17.1)\t487 (21.4)\t\n Leflunomide\t76 (4.3)\t15 (4)\t9 (7)\t100 (4.4)\t\n Sulfasalazine\t51 (2.9)\t12 (3.2)\t4 (3.1)\t67 (2.9)\t\n Antimalarial\t131 (7.4)\t14 (3.7)\t2 (1.6)\t147 (6.5)\t\nImmunosuppressants\t60 (3.4)\t36 (9.6)\t8 (6.2)\t104 (4.6)\t\nbDMARDs\t653 (36.9)\t102 (27.3)\t41 (31.8)\t796 (35)\t\nTNF inhibitors\t439 (24.8)\t43 (11.5)\t6 (4.7)\t488 (21.5)\t\nAbatacept\t21 (1.2)\t8 (2.1)\t1 (0.8)\t30 (1.3)\t\nB cell-targeted bDMARDs\t46 (2.6)\t29 (7.8)\t27 (20.9)\t102 (4.5)\t\n Rituximab\t37 (2.1)\t28 (7.5)\t26 (20.2)\t91 (4)\t\n Belimumab\t9 (0.5)\t1 (0.3)\t1 (0.8)\t11 (0.5)\t\nIL-6 inhibitors\t47 (2.7)\t9 (2.4)\t3 (2.3)\t59 (2.6)\t\nIL-1 inhibitors\t21 (1.2)\t3 (0.8)\t3 (2.3)\t27 (1.2)\t\nIL-17, IL-23, IL-12/23 inhibitors\t79 (4.5)\t10 (2.7)\t1 (0.8)\t90 (4)\t\ntsDMARDs\t108 (6.1)\t33 (8.8)\t14 (10.9)\t155 (6.8)\t\n JAK inhibitors\t101 (5.7)\t32 (8.6)\t14 (10.9)\t147 (6.5)\t\n Apremilast\t7 (0.4)\t1 (0.3)\t0\t8 (0.4)\t\nNo DMARD therapies\t311 (17.6)\t79 (21.1)\t29 (22.5)\t419 (18.4)\t\nFurther therapies\t\t\t\t\t\nGlucocorticoids (#)\t485 (27.5)\nn=1759\nMissing=12\t198 (52.9)\nn=373\nMissing=1\t78 (60.5)\nn=129\nMissing=0\t761 (33.6)\nn=2261\nMissing=13\t\n 0 mg/day<glucocorticoids\n≤10 mg/day\t453 (25.8)\t179 (48)\t60 (46.5)\t692 (30.6)\t\n Glucocorticoids>10 mg/day\t24 (1.4)\t18 (4.8)\t18 (14)\t60 (2.7)\t\nNSAIDs\t395 (22.9)\n(n=1736\nMissing=47\t59 (16.3)\n(n=120\nMissing=2\t12 (9.9)\nn=83\nMissing=0\t466 (21.1)\nn=2208\nMissing=66\t\nData are N (column %) for categorical variables or mean (SD) for continuous variables. Table includes all patients with a non-missing outcome and non-missing values for age, sex and DMARDs (four patients excluded). Data refer to patients with non-missing values for the respective variable; total N for patients with non-missing values is given in parentheses for variables with missing values; the total number of missing values is also given in parentheses, for the applicable variables. # denotes patients with a missing glucocorticoid dosage. For csDMARD therapies and immunosuppressants, only patients not simultaneously receiving a bDMARD/tsDMARD are included. For csDMARDs, patients are included who correspond to the specific therapy when applying the hierarchy described in the Methods section.\n\nbDMARD, biological disease-modifying antirheumatic drug; BMI, body mass index; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CTD, connective tissue disease; DMARD, disease-modifying anti-rheumatic drug; IJD, inflammatory joint disease; IL, interleukin; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; N, number; NSAID, non-steroidal anti-inflammatory drug; RMDs, rheumatic and musculoskeletal diseases; SLE, systemic lupus erythematosus; TNF, tumour necrosis factor; tsDMARD, targeted synthetic disease-modifying antirheumatic drug.\n\nThe mean age of all patients was 57 years; 67% were female. The most common RMD was RA with 46%, followed by PsA (14%), SpA (13%) and vasculitides (11%).\n\nEighty-six per cent of patients had a PCR-confirmed diagnosis of SARS-CoV-2 infection; 8% had only an antibody-confirmed diagnosis; the remaining patients had an unknown/other type of diagnosis (two patients were diagnosed based on symptoms only). For all patients, the outcome of SARS-CoV-2 infection was known.\n\nRMD treatments\n\nAt the time of SARS-CoV-2 infection, 18% did not receive any DMARD treatment (see table 1). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) were used in 5%, csDMARDs in 35%, bDMARDs in 35% and tsDMARDs in 7%. Methotrexate was the most common csDMARD, and TNFi was the most common bDMARD. Rituximab was used in 91 patients (4%), and JAKi was used in 147 patients (6.5%).\n\nSARS-CoV-2 infection outcome analysis\n\nAge above 65 years was associated with higher COVID-19 severity with an OR of 2.6 (95% CI 2.0 to 3.6) and above 75 years with an OR of 3.6 (95% CI 3.0 to 5.0) (table 2 and figure 1A). Male sex was also associated with greater severity (OR 1.7, 95% CI 1.3 to 2.1).\n\nFigure 1 (A–E) Results of the multivariable ordinal logistic regression using the proportional odds model and reported as OR and 95% CI for each regressor variable. Associations with SARS-CoV-2 infection severity are shown with (A) general factors, (B) comorbidities, (C) RMD diagnosis, (D) RMD disease activity and glucocorticoids, (E) RMD treatment (immunosuppressants: mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin). The reference categories are as follows: (A) ≤65 years, ≤65 years, female sex; (B) the non-presence of the specific comorbidity; (C) rheumatoid arthritis; (D) remission/low disease activity, no glucocorticoids; and (E) methotrexate monotherapy. Missing values were imputed via multiple imputation. N=2222. Compared with table 1, the following numbers of patients were excluded: 27 patients receiving IL-1 inhibitors, 11 patients receiving belimumab, 8 patients receiving apremilast, 6 patients with non-systemic JIA, one patient receiving multiple bMARDs/tsDMARDs. bDMARD, biological disease-modifying antirheumatic drug; CVD, cardiovascular disease; CTD, connective tissue diseases; DMARD, disease-modifying anti-rheumatic drugs; DA, disease activity; GC, Glucocorticoids; IL, interleukin; JAK, Janus kinase; TNF, tumour necrosis factor; tsDMARD, targeted synthetic disease-modifying anti-rheumatic drugs.\n\nTable 2 Results of the multivariable ordinal logistic regression using the proportional odds model\n\nOrdinal regression (proportional odds model)\tOR\t95% CI\t\nGeneral\t\n Age ≤65 years\t1.0\tReference\t\n 65 years<age≤75\t2.6\t2.0 to 3.6\t\n Age >75\t3.6\t3.0 to 5.0\t\n Male sex (vs female)\t1.7\t1.3 to 2.1\t\nComorbidities\t\n Hypertension alone or CVD alone\t1.5\t1.2 to 2.0\t\n Hypertension and CVD\t2.4\t1.7 to 3.6\t\n Chronic lung disease\t2.0\t1.5 to 2.6\t\n Chronic kidney disease\t1.8\t1.2 to 2.5\t\n Diabetes mellitus\t1.3\t0.9 to 1.8\t\nRheumatic disease\t\n Rheumatoid arthritis\t1.0\tReference\t\n Systemic lupus erythematosus\t0.5\t0.2 to 1.1\t\n Vasculitides\t1.1\t0.7 to 1.5\t\n Other connective tissue diseases\t0.9\t0.6 to 1.5\t\n Psoriatic arthritis\t0.5\t0.3 to 0.7\t\n Spondyloarthritides\t0.8\t0.5 to 1.3\t\n Other rheumatic diseases (not IJDs/CTDs/vasculitis)\t1.0\t0.6 to 1.8\t\nMedication*\t\n Methotrexate (monotherapy)\t1.0\tReference\t\n No DMARD therapy\t0.9\t0.7 to 1.4\t\n Leflunomide\t0.8\t0.5 to 1.4\t\n Antimalarials\t0.7\t0.4 to 1.3\t\n Sulfasalazine\t1.1\t0.6 to 2.1\t\n Immunosuppressants\t2.2\t1.3 to 3.9\t\n TNF inhibitors\t0.6\t0.4 to 0.9\t\n Abatacept\t1.3\t0.5 to 3.0\t\n Rituximab\t5.4\t3.3 to 8.8\t\n IL-6 inhibitors\t0.7\t0.3 to 1.5\t\n IL-17/IL-23/IL-12+23 inhibitors\t0.9\t0.4 to 1.9\t\n JAK inhibitors\t1.8\t1.1 to 2.7\t\nDisease activity and glucocorticoids\t\n Remission/low DA, no GCs\t1.0\t(Reference)\t\n Remission/low DA, GCs 1–10 mg/day\t1.6\t1.2 to 2.0\t\n Remission/low DA, GCs>10 mg/day\t4.6\t1.9 to 11.4\t\n Moderate/high DA, no GCs\t2.0\t1.3 to 3.1\t\n Moderate/high DA, GCs 1–10 mg/day\t2.4\t1.5 to 3.7\t\n Moderate/high DA, GCs >10 mg/day\t5.3\t2.5 to 10.9\t\nOrdinal outcome of COVID-19 severity was defined as (1) not-hospitalised, (2) hospitalised but not invasively ventilated and (3) invasively ventilated/deceased.\n\nMissing values imputed via multiple imputation. Effects significant at level α=0.05 are marked in bold. N=2222. Compared with table 1, the following numbers of patients were excluded: 27 patients receiving IL-1 inhibitors, 11 patients receiving belimumab, 8 patients receiving apremilast, 6 patients with non-systemic JIA, 1 patient receiving multiple bDMARDs/tsDMARDs.\n\n*Patients receiving multiple csDMARDs or immunosuppressants (except glucocorticoids) were grouped according to the following hierarchy: immunosuppressants>sulfasalazine>antimalarials>leflunomide>methotrexate. Patients receiving a bDMARD/tsDMARD alone or in combination were considered solely in the bDMARD/tsDMARD group.\n\nbDMARD, biological disease-modifying antirheumatic drug; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CTD, connective tissue disease; CVD, cardiovascular disease; DA, disease activity; DMARD, disease-modifying antirheumatic drug; GC, glucocorticoid; IJD, inflammatory joint disease; IL, interleukin; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; TNF, tumour necrosis factor; tsDMARD, targeted synthetic disease-modifying antirheumatic drug.\n\nArterial hypertension, CVD, chronic lung disease (including chronic obstructive pulmonary disease, asthma and interstitial lung diseases), and CKD showed significant associations with COVID-19 severity (table 2 and figure 1B). The strongest association was found for patients having both comorbidities, arterial hypertension and CVD (OR 2.4, 95% CI 1.7 to 3.6).\n\nWith respect to the underlying RMD entity, PsA was associated with less severe COVID-19 course in comparison to RA (OR 0.5, 95% CI 0.27 to 0.74) (table 2 and figure 1C).\n\nSince disease activity and the use of glucocorticoids are usually linked, both factors were analysed jointly. The results are shown in table 2 and figure 1D. Remission/low disease activity with low dose GCs (1–10 mg/d) showed a significant association with worse outcome (OR 1.6, 95% CI: 1.2 to 2.0) compared with remission/low disease activity without GCs. This effect increased with higher GC doses (OR 4.6, 95% CI 1.9 to 11.4). Moderate/high disease activity but no GCs were also associated with a worse outcome compared with remission/low disease activity with no GCs (OR 1.99, 95% CI 1.28 to 3.11). Moderate/high disease activity with low-dose GC were associated with a worse COVID-19 outcome with an OR of 2.4 (95% CI 1.5 to 3.7), and in case of moderate/high disease activity with high-dose GC, this was even more prominent with an OR of 5.3 (95% CI 2.53 to 10.9).\n\nFor the analysis of the impact of RMD treatment on the outcome of SARS-CoV-2 infection, MTX monotherapy was used as reference (table 2 and figure 1E). Treatment with immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) was associated with a higher COVID-19 severity (OR 2.2, 95% CI 1.3 to 3.9). JAKis were also associated with a significantly worse severity (OR 1.8, 95% CI 1.1 to 2.7). The strongest association with worse outcome of COVID-19 was found for rituximab with an OR of 5.4 (95% CI 3.3 to 8.8). In contrast, TNFi showed a significant association with a better outcome of SARS-CoV-2 infection with an OR of 0.6 (95% CI 0.4 to 0.9).\n\nDiscussion\n\nThis analysis adds evidence that medication for RMD has a considerable impact on the course of SARS-CoV-2 infection. Two main results could be retrieved from this analysis: (1) TNFi is not associated with a more severe course of SARS-CoV-2 infection in patients with RMD and, (2) in contrast, immunosuppressants, JAKis and rituximab are associated with a more severe course. Moreover, it could be confirmed that general risk factors like age, male sex and certain chronic conditions are also associated with greater severity of SARS-CoV-2 infection in patients with underlying RMD.1 2\n\nRMD-specific risk factors have been described. The impact of disease activity and GC use are of utmost importance. Disease activity and the use of GC are usually linked. Analysing these effects separately from each other is very difficult because of the known confounding by indication in the setting of observational data. In a correspondence to the COVID-19 mortality analysis of the GRA data set,4 this interaction was shown.13 Here, we present similar results. However, in this analysis, GC use was associated with worse outcome even in patients in remission or low disease activity.\n\nIn this analysis, PsA was associated with a better COVID-19 course compared with RA. In the COVID-19 mortality analysis, PsA was not significantly associated but also showed an OR of less than 1.0 (0.75, 95% CI 0.53 to 1.07). Whether the positive association seen in our analysis is due to true differences between the diseases or unmeasured confounders is not clear. However, the risk of severe infection in bDMARD-treated patients with psoriasis compared with patients with RA is much lower, which might be a signal of different susceptibility for severe infections.14\n\nA very important finding of our analysis is the potential beneficial effect of TNFi. This association was not seen in an earlier mortality analysis, although TNFi showed also an OR of less than 1.0 (0.9; 95% CI: 0.5 to 1.4).4 This discrepancy might be due to the large heterogeneity in the GRA data set with large differences between the countries regarding the outcomes. In the analysis by Sparks et al. TNFi were used as reference medication and therefore, due to methodological reasons, the impact of TNFi could not be estimated in this study.5 There are also clinical trials using TNFi in different settings of COVID-19.15\n\nIn the GRA analysis concerning the risk of mortality, sulfasalazine was significantly associated with mortality.4 In our analysis, sulfasalazine was not associated with COVID-19 severity, which may be due to more homogenous data with regard to healthcare system-related factors.\n\nRegarding the influence of rituximab, there is growing evidence for an association with a worse outcome. This has been shown in various settings in RMDs.4 5 16–18 In our analysis, we confirmed these results. The influence of B-cell depletion/anti-CD20 antibodies like rituximab on COVID-19 outcome has also been studied in other diseases in which these treatments are used.19 20 For example, observational studies from multiple sclerosis showed a similar association of rituximab with severe COVID-19 outcome as in RMD.21\n\nData addressing an influence of JAKis on COVID-19 outcome are still limited. Thus, our analysis adds important knowledge showing an association of JAKi as RMD treatment with a more severe course of COVID-19. A negative association with COVID-19 outcome was also seen in the RA analysis of the GRA data set.5 In an analysis from Sweden, an increased risk of COVID-19-related hospitalisation as well as COVID-19-related death has been described for patients under therapy with JAKis.16 In contrast, owing to their anti-inflammatory potential, JAKis have been approved for the short-term treatment of severe COVID-19.9 22 Here, the timing and duration of the treatment seems to play a role, with negative impact in patients with RMD pretreated with JAKis and potential benefits when initiated to treat severe SARS-CoV-2 infection. A pathophysiological explanation could be that type I interferon response is crucial in the initial phase of infection for a good outcome of SARS-CoV2 infection.23 Therefore, inhibition of the type I interferon pathway by JAKi in the early phase of infection might contribute to more severe COVID-19.\n\nThe strengths of this analysis in comparison to the GRA data lie in the fact that our data are more homogenous as they were collected in a single country within one healthcare system and similar treatments and chances of care for all included patients.\n\nHowever, there also are study limitations. Missing data on known confounders like RMD disease duration and number of RMD pretreatments limit the interpretation. Especially for rituximab and JAKi, it is known that they are often used in non-responder to MTX/TNFi.24 25 Therefore, the negative impact of those therapies on COVID-19 severity needs to be interpreted carefully. Similarly, we do not have detailed data on RTX dosage and—even more important—time of last infusion to be able to calculate the number of days between RTX treatment and date of SARS-CoV-2 infection. Furthermore, we do not know if the RMD treatment was paused due to acute SARS-CoV-2 infection. Although most patients continue their RMD treatment in the pandemic as stated in the treatment recommendations, in the case of an acute symptomatic infection especially in hospitalised patients, it is recommended to pause the immunomodulating treatment.26–28 Differential effects of the RMD treatment might therefore also be explained by different half-lives of these drugs.\n\nIn conclusion, risk factors for higher severity of SARS-CoV-2 infection known for the general population, such as age, male sex and certain chronic conditions, play a similar role in patients with RMDs. In addition, further risk factors need to be taken into account, for example, the influence of higher disease activity with an increased risk of worse outcome even without using GCs on the one hand and association of chronically administered GCs with a similar worse outcome on the other. Regarding RMD medication, our data show that treatment with TNFi was associated with better outcome of SARS-CoV-2 infection than MTX. Moreover, treatment with immunosuppressants, JAKi and rituximab was associated with worse outcome of SARS-CoV-2 infection. These associations may be attributed to residual and unmeasured confounding due to higher burden of comorbidity or cumulative effect of therapies. Taken together, while it is crucial to control RMD disease activity, the medication used to achieve this control needs to be carefully chosen.\n\nThe authors thank all physicians and personnel involved in the documentation of the cases in our registry: Dr Fredrik Albach, Dr Annette Alberding, Dr Tobias Alexander, Professor Dr Rieke Alten, Dr Susanne Amann, Dr Christopher Amberger, Dr Michaela Amberger, Dr Bianka Andermann, Nils Anders, Ioana Andreica, Dr Jan Andresen, Dr Nikolaos Andriopoulos, Dr Peer Aries, Professor Dr Martin Aringer, Dr Uta Arndt, Sarah Avemarg, Professor Dr Marina Backhaus, Professor Dr Christoph Baerwald, Dr Erich Bärlin, Dr Nora Bartholomä., Dr Hans Bastian, Dr Michael Bäuerle, Dr Jutta Bauhammer, Dr Christine Baumann, Professor Dr Heidemarie Becker, Dr Klaus Becker, Dr Michaela Bellm, Dr Sylvia Berger, Dr Gerhard Birkner, Professor Dr Norbert Blank, Daniel Blendea, Dr Hans Bloching, Dr Stephanie Böddeker, Dr Susanne Bogner, Dr Martin Bohl-Bühler, Sebastian Böltz, Dr Ilka Bösenberg, Nicole Böttcher, PD Dr Jan Brandt-Jürgens, Dr Matthias Braun, Dr Matthias Braunisch, Dr Jan Phillip Bremer, Dr Matthias Broll, Dr Andreas Bruckner, Dr Veronika Brumberger, Dr. Martin Brzank, Dr. Sahra Büllesfeld, Sandra Burger, Dr Gamal Chehab, Dr Michaela Christenn, Dr Anne Claußnitzer, Professor Dr Kirsten de Groot, Dr Elvira Decker, Dr Frank Demtröder, Dr Jacqueline Detert, Dr Rainer Dörfler, Dr Ines Dornacher, Dr Elke Drexler, Dr Edmund Edelmann, Dr Roman Eder, Dr Christina Eisterhues, Dr Andreas Engel, Dr Joachim Michael Engel, Dr Brigitte Erbslöh-Möller, Dr Miriam Feine, PD Dr Martin Feuchtenberger, Professor Dr Dr Christoph Fiehn, PD Dr Rebecca Fischer-Betz, Professor Dr Martin Fleck, Dr Stefanie Freudenberg, Dr Christian Fräbel, Dr Petra Fuchs, Dr Regina Gaissmaier, Dr Ino Gao, Oliver Gardt, Dr Georg Gauler, Dr Katrin Geißler, Dr Joachim Georgi, Dr Jasmin Gilly, Yannik Gkanatsas, Dr Cornelia Glaser, Agnes Gniezinski-Schwister, Dr Rahel Gold, Dr Norman Görl, Dr Karl-Heinz Göttl, Dr Beate Göttle, Dr Anett Gräßler, Dr Ricardo Grieshaber-Bouyer, Dr Gisela Grothues, Dr Mathias Grünke, Dr Elizabeth Guilhon de Araujo, Dr Florian Günther, Mirjam Haag, Dr Linda Haas, Dr Anna Haas-Wöhrle, Dr Denitsa Hadjiski, PD Dr Hildrun Haibel, Till Ole Hallmann-Böhm, Dr Urs Hartmann, Dr Charlotte S. Hasenkamp, Dr Maura-Maria Hauf, Dr Matthias Hauser, Dr Nicole Heel, Dr Liane Hein, Dr Reinhard Hein, Dr Claudia Hendrix, Professor Dr Jörg Henes, Dr Karen Herlyn, Dr Walter Hermann, Professor Dr Peter Herzer, Dr Andrea Himsel, Dr Guido Hoese, PD Dr Paula Hoff, Marie-Therese Holzer, Dr Johannes Hornig, Melanie Huber, Dr Georg Hübner, Dr Georg Hübner, Ole Hudowenz, PD Dr Axel Hueber, Dr Verena Hupertz, Dr Elke Iburg, Dr Annette Igney-Oertel, Dr Steffen Illies, PD Dr Annett M. Jacobi, Ilona Jandova, Dipl.-Med. Christiane Jänicke, Dr Sebastian T. Jendrek, Dr Anne Johannes, Dr Aaron Juche, Dr Sarah Kahl, Dr Ludwig Kalthoff, Dr Wiebke Kaluza-Schilling, Dr Eleni Kampylafka, Dr Antje Kangowski, Dr Andreas Kapelle, Dr Kirsten Karberg, Dr Dorothee Kaudewitz, Dr Bernd Oliver Kaufmann, Professor Dr Gernot Keyßer, Dr Nayereh Khoshraftar-Yazdi, Dr Matthias Kirchgässner, Dr Matthias Kirrstetter, Dr Birgit Kittel, Dr Christoph Kittel, Julia Kittler, Dr Arnd Kleyer, Dr Claudia Klink, Dr Barbara Knau, Professor Dr Christian Kneitz, Anna Knothe, Dr Katrin Köchel, Dr Benjamin Köhler, Dr Peter Korsten, Dr Magdolna Kovacs, Dr Dietmar Krause, Dipl.-Med. Gabi Kreher, Dr Rene Kreutzberger, Dr Eveline Krieger-Dippel, Professor Dr Klaus Krüger, Dr Brigitte Krummel-Lorenz, Dr Martin Krusche, Dr Holger Kudela, Dr Christoph Kuhn, Dr Kerstin Kujath, Dr Reiner Kurthen, Dr Rolf Kurzeja, Peter Kvacskay, Professor Dr Peter Lamprecht, Sabine Langen, Dr Heiko Lantzsch, Dr Petra Lehmann, Dr Nicolai Leuchten, PD Dr Christian Löffler, Dr Dorothea Longerich-Scheuß, Dr Gitta Lüdemann, Dr Thomas Lutz, Vanessa Maerz, Dr Hartmut Mahrhofer, Dr Ingeborg Maier, Professor Dr Karin Manger, Professor Dr Elisabeth Märker-Hermann, Dr Anette Märtz, Dr Anette Märtz, Hanin Matar, Dr Johannes Mattar, Dr Sebastian Maus, Dr Ursula Mauß-Etzler, Dr Regina Max, Dr Florian Meier, Dr Adelheid Melzer, Carlos Meneses, Dr Hans-Jürgen Menne, Dr Helga Merwald-Fraenk, Dr Claudia Metzler, Dr Sabine Mewes, Dr Harriet Morf, Dr Harald Mörtlbauer, Dr Markus Mortsch, Dr Burkhard Muche, PD Dr Niels Murawski, Dr Antoine Murray, Dr Jana Naumann, Dr Anabell Nerenheim, Dr Joachim Neuwirth, Phuong Nguyen, Dr Stine Niehus, Dr Martin Nielsen, Dr Matthias Noehte, Dr Dirk Nottarp, Dr Dieter Nüvemann, Dr Wolfgang Ochs, Dr Sarah Ohrndorf, Dr Jürgen Olk, Dr Silke Osiek, Dr Filiz Özden, Dr Bettina Panzer, Dr Alina Patroi, Dr Ulrich Pfeiffer, Dr Dorothea Pick, Dr Marta Piechalska, Dr Matthias Pierer, I. Pohlenz, Dr Mikhail Protopopov, Dr Almut Pulla, Dr Michael Purschke, Dr Judith Rademacher, Dr Wolf Raub, PD Dr Jürgen Rech, Dr Sabine Reckert, Dr Sabine Reckert, Dr Anke Reichelt de Tenorio, Dr Christiane Reindl, Dr Annja Reisch, Professor Dr Gabriela Riemekasten, PD Dr Markus Rihl, Dr Viale Rissom, Dr Karin Rockwitz, Dr Maike Rösel, Dr Markus Röser, Dr Christoph Rossmanith, PD Dr Ekkehard Röther, Dr Fabian Röther, Dr Maria Roth-Szadorski, Professor Dr Martin Rudwaleit, Dr Petra Saar, Jasemine Saech, Dr Oliver Sander, Dr Eva Sandrock, Dr Ertan Saracbasi-Zender, Dr Michael Sarholz, Dr Christoph Schäfer, Dr Kerstin Schäfer, Dr Martin Scheel, Dr Stefan Schewe, Dr Hermine Schibinger, Magnus Schiebel, Dr Andreas Schieweck-Güsmer, Dr Susanne Schinke, Dr Ulrike Schlenker, Dr Daniel Schlittenhardt, PD Dr Marc Schmalzing, Dr Verena Schmitt, Dr Matthias Schmitt-Haendle, Dr Sebastian Schnarr, Dr Dieter Schöffel, Dr Michaela Scholz, Dr Jutta Schönherr, Dr Ulrich Schoo, Dr Judith Schreiber, Anna-Sophie Schübler, Dr Florian Schuch, Dr Ilka Schwarze, Dr Carola Schwerdt, Dr Eva Seipelt, Dr Matthias Sekura, Dr Jörg Sensse, Dr Nyamsuren Sentis, Dr Christine Seyfert, Ondrej Sglunda, Dr Naheed Sheikh, Dr Iris Sievert, Dr David Simon, Marta Sluszniak, Dr Katharina Sokoll, Dr Sigrid Sonn, Dr Susanna Späthling-Mestekemper, Dr Lydia Spengler, Gerald Stapfer, Dr Nicolai Steinchen, Dr Mirko Steinmüller, Karen Steveling, Dr Karin Stockdreher, Dr Helga Streibl, Professor Dr Johannes Strunk, Dr Mechthild Surmann, Dr Ingo H. Tarner, Dr Stefanie Tatsis, Dr Astrid Thiele, Dr Jan Thoden, Dr Anika Tuleweit, Professor Dr Peter Vaith, Dr Inka Vallbracht-Ackermann, Dr Susanne Veerhoff, Dr Susanne Veerhoff, Professor Dr Nils Venhoff, Dr Anita Viardot, Lisa Vinnemeier-Laubenthal, Dr Markus Voglau, Dr Marcus von Deimling, Dr Cay-Benedict von der Decken, Dr Heike von Löwis, Dr Marisa Walther, Dr Sven Weidner, Dr Martin Weigelt, Professor Dr Stefan Weiner, Dr Jutta Weinerth, Dr Angela Weiß, Dr Martin Welcker, Dr Stephanie Werner, Dr Dirk Wernicke, Dr Franziska Wiesent, Professor Dr Peter Willeke, Dr Lea Winau, Dr Hans Wisseler, Dr Matthias Witt, Dr Stefan Wolf, Dr Nina Wysocki, Dr Panagiota Xanthouli, Dr Monika Zaus, Dr Markus Zeisbrich, Dr Silke Zinke\n\nData availability statement\n\nData are available upon reasonable request. Applications to access the data should be made to the COVID-19 steering committee of the German Society for Rheumatology.\n\nEthics statements\n\nPatient consent for publication\n\nNot applicable.\n\nEthics approval\n\nThe study was approved by the ethics committee of the Justus-Liebig-University Giessen (#52–50) and is registered at EuDRACT (2020-001958-21#). For the present analysis, we included data from 30 March 2020 to 9 April 2021.\n\nTwitter: @rheuma_doktorin, @ChSpecker\n\nACR and RH contributed equally.\n\nContributors: ACR, RH, MS and UM-L had access to the study data, developed the figures and tables, and vouched for the data and analyses. MS performed the statistical analyses and contributed to data quality control, data analysis and data interpretation. ACR, RH, BFH, AK, HM-L, AP, JR, TS, AS, HS-K, REV, CS and UM-L contributed to data collection, data quality control, data analysis and data interpretation. All authors contributed to the intellectual content during the drafting and revision of the work and approved the final version to be published. ACR and RH act as guarantors.\n\nFunding: The registry is funded, in part, by the German Society for Rheumatology. RH is funded, in part, by a JLU Career grant of the Justus-Liebig-University Giessen, Germany.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020;323 :1239–42. 10.1001/jama.2020.2648 32091533\n2 Docherty AB, Harrison EM, Green CA, et al . Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369 :m1985. 10.1136/bmj.m1985 32444460\n3 Gianfrancesco M, Hyrich KL, Al-Adely S, et al . Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 global rheumatology alliance physician-reported registry. Ann Rheum Dis 2020;79 :859–66. 10.1136/annrheumdis-2020-217871 32471903\n4 Strangfeld A, Schäfer M, Gianfrancesco MA, et al . Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 global rheumatology alliance physician-reported registry. Ann Rheum Dis 2021;80 :930–42. 10.1136/annrheumdis-2020-219498 33504483\n5 Sparks JA, Wallace ZS, Seet AM, et al . Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: results from the COVID-19 global rheumatology alliance physician registry. Ann Rheum Dis 2021;80 :1137–46. 10.1136/annrheumdis-2021-220418 34049860\n6 Hasseli R, Mueller-Ladner U, Hoyer BF, et al . Older age, comorbidity, glucocorticoid use and disease activity are risk factors for COVID-19 hospitalisation in patients with inflammatory rheumatic and musculoskeletal diseases. RMD Open 2021;7 :e001464. 10.1136/rmdopen-2020-001464 33479021\n7 RECOVERY Collaborative Group, Horby P, Lim WS, et al . Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384 :693–704. 10.1056/NEJMoa2021436 32678530\n8 Singh B, Ryan H, Kredo T, et al . Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19. Cochrane Database Syst Rev 2021;2 :CD013587. 10.1002/14651858.CD013587.pub2 33624299\n9 Kalil AC, Patterson TF, Mehta AK, et al . Baricitinib plus Remdesivir for hospitalized adults with Covid-19. N Engl J Med 2021;384 :795–807. 10.1056/NEJMoa2031994 33306283\n10 Ungaro RC, Brenner EJ, Gearry RB, et al . Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut 2021;70 :725–32. 10.1136/gutjnl-2020-322539 33082265\n11 Hasseli R, Mueller-Ladner U, Schmeiser T, et al . National Registry for patients with inflammatory rheumatic diseases (IRD) infected with SARS-CoV-2 in Germany (recovery): a valuable mean to gain rapid and reliable knowledge of the clinical course of SARS-CoV-2 infections in patients with IRD. RMD Open 2020;6 :e001332. 10.1136/rmdopen-2020-001332 32878994\n12 van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res 2007;16 :219–42. 10.1177/0962280206074463 17621469\n13 Schäfer M, Strangfeld A, Hyrich KL, et al . Response to: 'Correspondence on 'Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician reported registry'' by Mulhearn et al. Ann Rheum Dis 2021. 10.1136/annrheumdis-2021-220134. [Epub ahead of print: 01 Mar 2021].\n14 García-Doval I, Hernández MV, Vanaclocha F, et al . Should tumour necrosis factor antagonist safety information be applied from patients with rheumatoid arthritis to psoriasis? Rates of serious adverse events in the prospective rheumatoid arthritis BIOBADASER and psoriasis BIOBADADERM cohorts. Br J Dermatol 2017;176 :643–9. 10.1111/bjd.14776 27258623\n15 Robinson PC, Liew DFL, Liew JW, et al . The potential for repurposing anti-TNF as a therapy for the treatment of COVID-19. Med 2020;1 :90–102. 10.1016/j.medj.2020.11.005 33294881\n16 Bower H, Frisell T, Di Giuseppe D, et al . Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population: a nationwide Swedish cohort study. Ann Rheum Dis 2021. 10.1136/annrheumdis-2021-219845. [Epub ahead of print: 23 Feb 2021].\n17 Avouac J, Drumez E, Hachulla E, et al . COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study. Lancet Rheumatol 2021;3 :e419–26. 10.1016/S2665-9913(21)00059-X 33786454\n18 Felten R, Duret PM, Bauer E, et al . OP0282 Rituximab associated with severe COVID-19 among patients with inflammatory arthritides: a 1-year multicenter study in 1116 succesive patients receiving biologic agents. Ann Rheum Dis 2021;80 :170–1. 10.1136/annrheumdis-2021-eular.1521\n19 Jakubíková M, Týblová M, Tesař A, et al . Predictive factors for a severe course of COVID-19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival. Eur J Neurol 2021;28 :3418–25. 10.1111/ene.14951 34080271\n20 Duléry R, Lamure S, Delord M, et al . Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy. Am J Hematol 2021;96 :934–44. 10.1002/ajh.26209 33909916\n21 Simpson-Yap S, De Brouwer E, Kalincik T, et al . Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis. Neurology 2021. 10.1212/WNL.0000000000012753. [Epub ahead of print: 05 Oct 2021].\n22 Guimarães PO, Quirk D, Furtado RH, et al . Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021;385 :406–15. 10.1056/NEJMoa2101643 34133856\n23 Zhang Q, Bastard P, Liu Z, et al . Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020;370 :eabd4570. 10.1126/science.abd4570 32972995\n24 Listing J, Kekow J, Manger B, et al . Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFα inhibitors and rituximab. Ann Rheum Dis 2015;74 :415–21. 10.1136/annrheumdis-2013-204021 24291654\n25 Finckh A, Tellenbach C, Herzog L, et al . Comparative effectiveness of antitumour necrosis factor agents, biologics with an alternative mode of action and tofacitinib in an observational cohort of patients with rheumatoid arthritis in Switzerland. RMD Open 2020;6 :e001174. 10.1136/rmdopen-2020-001174 32385143\n26 Hasseli R, Müller-Ladner U, Keil F, et al . The influence of the SARS-CoV-2 lockdown on patients with inflammatory rheumatic diseases on their adherence to immunomodulatory medication - a cross sectional study over 3 months in Germany. Rheumatology 2021. 10.1093/rheumatology/keab230. [Epub ahead of print: 11 Mar 2021].\n27 Hausmann JS, Kennedy K, Simard JF, et al . Immediate effect of the COVID-19 pandemic on patient health, health-care use, and behaviours: results from an international survey of people with rheumatic diseases. Lancet Rheumatol 2021;3 :e707–14. 10.1016/S2665-9913(21)00175-2 34316727\n28 Schulze-Koops H, Krüger K, Hoyer BF, et al . Updated recommendations of the German Society for rheumatology for the care of patients with inflammatory rheumatic diseases in times of SARS-CoV-2-methodology, key messages and justifying information. Rheumatology 2021;60 :2128–33. 10.1093/rheumatology/keab072 33502500\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2056-5933",
"issue": "7(3)",
"journal": "RMD open",
"keywords": "COVID-19; antirheumatic agents; glucocorticoids",
"medline_ta": "RMD Open",
"mesh_terms": "D000086382:COVID-19; D006801:Humans; D000075242:Janus Kinase Inhibitors; D000069283:Rituximab; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "101662038",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34670840",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "32091533;33479021;33082265;34049860;33786454;32972995;33648957;34133856;33306283;34610987;34556483;27258623;33704418;32471903;33624299;33909916;33502500;32678530;32878994;32385143;33294881;33622688;24291654;17621469;34316727;32444460;33504483;34080271",
"title": "TNFi is associated with positive outcome, but JAKi and rituximab are associated with negative outcome of SARS-CoV-2 infection in patients with RMD.",
"title_normalized": "tnfi is associated with positive outcome but jaki and rituximab are associated with negative outcome of sars cov 2 infection in patients with rmd"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2022030749",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"drugadditional": "3",
... |
{
"abstract": "We report a case of a primary malignant lymphoma of the trigeminal nerve that was associated with facial pain. A 65-year-old man was examined at another hospital for unilateral facial pain. Carbamazepine was prescribed, but his symptoms did not improve. Magnetic resonance imaging (MRI) revealed swelling of the trigeminal nerve and a mass lesion in Meckel's cave. The patient was referred to our hospital at this point. Gadolinium-enhanced MRI and F18-Fluorodeoxyglucose-position emission tomography suggested a likely malignant tumour and a biopsy was performed. Histopathological examination showed diffuse a large B cell lymphoma. The patient was treated with high-dose methotrexate (HD-MTX) and radiotherapy. Despite responding well to initial treatment, the patient relapsed, with lymphoma observed throughout the body. He died of pneumonia 18 months after the initial diagnosis. Facial pain is a symptom that is commonly managed in general practice. If symptoms do not improve, repeated imaging studies, including contrast MRI, is warranted. This is the first reported case of primary neurolymphomatosis (NL) of the trigeminal nerve associated with facial pain alone. Furthermore, HD-MTX and radiotherapy may be considered for the management of primary NL of a cranial nerve.",
"affiliations": "Department of Neurosurgery, Asahikawa Medical University, Hokkaido, Japan.;Department of Neurosurgery, Asahikawa Medical University, Hokkaido, Japan.;Department of Neurosurgery, Asahikawa Medical University, Hokkaido, Japan.;Department of Neurosurgery, Asahikawa Medical University, Hokkaido, Japan.",
"authors": "Sato|Hirotaka|H|;Hiroshima|Satoru|S|;Anei|Ryogo|R|;Kamada|Kyousuke|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/02688697.2019.1568391",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-8697",
"issue": null,
"journal": "British journal of neurosurgery",
"keywords": "HD-MTX; Neurolymphomatosis; radiotherapy; trigeminal neuralgia",
"medline_ta": "Br J Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "8800054",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "30741017",
"pubdate": "2019-02-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Primary neurolymphomatosis of the trigeminal nerve.",
"title_normalized": "primary neurolymphomatosis of the trigeminal nerve"
} | [
{
"companynumb": "NVSC2020JP095426",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
"d... |
{
"abstract": "A 71-year-old woman with advanced ascending colon cancer was admitted to our hospital. Abdominal computed tomography( CT)revealed locally advanced sigmoid colon cancer with suspected invasion of the liver and duodenum. The clinical stage of the disease was cT4bN3M1a, cStage Ⅳa, with wild-type RAS and UGT1A1 expression. An ileostomy was performed because of bowel obstruction. The patient received 6 courses of FOLFOXIRI plus bevacizumab(Bev). The only adverse event was Grade 3 neutropenia. Laparoscopic right hemicolectomy with lymph node dissection was performed. The pathological diagnosis was the absence of viable, Grade 3 carcinoma cells. This result suggested that preoperative FOLFOXIRI plus Bev chemotherapy is useful for the treatment of locally advanced colon cancer.",
"affiliations": "Dept. of Gastroenterological Surgery, Osaka Police Hospital.",
"authors": "Naito|Atsushi|A|;Kagawa|Yoshinori|Y|;Kawai|Kenji|K|;Takeno|Atsushi|A|;Takeda|Yutaka|Y|;Ohtsuka|Masahisa|M|;Suzuki|Yozo|Y|;Imasato|Mitsunobu|M|;Fujie|Yujiro|Y|;Nakaba|Hiroyuki|H|;Akamatsu|Hiroki|H|;Murata|Kohei|K|",
"chemical_list": "D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D044682:Colon, Ascending; D003110:Colonic Neoplasms; D004386:Duodenum; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008099:Liver; D009944:Organoplatinum Compounds",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "298-300",
"pmc": null,
"pmid": "32381968",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Complete Pathological Response in a Patient with Advanced Ascending Colon Cancer That Invaded the Liver and Duodenum after FOLFOXIRI plus Bevacizumab Chemotherapy.",
"title_normalized": "a case of complete pathological response in a patient with advanced ascending colon cancer that invaded the liver and duodenum after folfoxiri plus bevacizumab chemotherapy"
} | [
{
"companynumb": "JP-PFIZER INC-2020196113",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Propofol related infusion syndrome (PRIS) is a rare, but extremely dangerous complication of propofol administration. Unexplained anion-gap metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, elevated liver enzymes, and potentially fatal cardiac arrhythmias are characteristic of PRIS. Risk factors for the develop- ment of PRIS include dose and duration of propofol infusion, severe illness, and concomitant administration of catecholamine and glucocorticoids. PRIS causing hyperkalemia is a well-known clinical entity. Although the development of PRIS depends on the duration and total amount of drug infused, repeated boluses of propofol, commonly used for rapid sequence intubation and conscious sedation, can potentially precipitate fatal hyperkalemia. This is of particular concern in advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) patients. We report a case of a propofol induced hyperkalemia causing near fatal cardiac arrhythmia in a dialysis dependent ESRD patient. We report successful revival from cardiac arrest by intensive calcium regimen and hemodialysis. This case highlights underrecognized problem of propofol-induced hy- perkalemia, which can be of particular concerns in advanced CKD and ESRD.",
"affiliations": null,
"authors": "Virmani|Sarthak|S|;Onuchic|Ana|A|;El-Ali|Ibrahim M|IM|;Trivedi|Ruchir D|RD|",
"chemical_list": "D018686:Anesthetics, Intravenous; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-6178",
"issue": "80(8)",
"journal": "Connecticut medicine",
"keywords": null,
"medline_ta": "Conn Med",
"mesh_terms": "D018686:Anesthetics, Intravenous; D001145:Arrhythmias, Cardiac; D004562:Electrocardiography; D006323:Heart Arrest; D006801:Humans; D006947:Hyperkalemia; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D010346:Patient Care Management; D015742:Propofol; D006435:Renal Dialysis; D016896:Treatment Outcome",
"nlm_unique_id": "0372745",
"other_id": null,
"pages": "491-493",
"pmc": null,
"pmid": "29782787",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Propofol Induced Hyperkalemia and Its Management in End Stage Renal Disease Patients.",
"title_normalized": "propofol induced hyperkalemia and its management in end stage renal disease patients"
} | [
{
"companynumb": "US-TEVA-2018-US-938905",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nThe report aims to present a case of endometrial cancer with unusual initial presentation. A literature review is conducted to speculate symptoms presented by endometrial cancer other than vaginal bleeding.\n\n\nMETHODS\nA 43-year-old, para 1, lean female suffered from copious watery vaginal discharge that was odorless and colorless for 8 months without any signs of abnormal vaginal bleeding. Preliminary surveys in private clinics with per vaginal examination and Papanicolaou smear were normal. Urinary incontinence was mistakenly impressed. When the patient turned to our center for help as symptoms aggravated, transvaginal sonography revealed hydrometra with papillary endometrium lesions. Hysteroscopy survey with endometrial biopsy revealed endometrial adenocarcinoma.\n\n\nCONCLUSIONS\nThis is a case of endometrial cancer with unusual presentation. Transvaginal sonography and hysteroscopy are easy and sensitive screening tools that should be readily offered to patients with suspicious symptoms.",
"affiliations": "Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan; Department of Obstetrics and Gynecology, Graduate School of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.;Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan; Department of Obstetrics and Gynecology, Graduate School of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan. Electronic address: jengcj@gmail.com.",
"authors": "Ker|Chin-Ru|CR|;Jeng|Cherng-Jye|CJ|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.tjog.2020.05.036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-4559",
"issue": "59(4)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "Abnormal vaginal discharge; Endometrial cancer; Hysteroscopy; Transvaginal sonography; Urinary incontinence",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D003937:Diagnosis, Differential; D016889:Endometrial Neoplasms; D005260:Female; D006801:Humans; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography; D014549:Urinary Incontinence; D019522:Vaginal Discharge",
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "590-593",
"pmc": null,
"pmid": "32653135",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Endometrial adenocarcinoma initially mistaken as urinary incontinence.",
"title_normalized": "endometrial adenocarcinoma initially mistaken as urinary incontinence"
} | [
{
"companynumb": "TW-PFIZER INC-2020343899",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "A 45-year-old man was transferred to our hospital because of advanced gastric cancer and peritoneal dissemination. After he received an S-1 plus cisplatin( CDDP) regimen for 6 courses, the primary lesion and ascites had disappeared. However, the primary lesion recurred, and he underwent treatment with 16 courses of an S-1 plus docetaxel regimen. He subsequently developed peripheral neuropathy, and was switched to the irinotecan (CPT-11) regimen. As he experienced appetite loss, it was impossible to continue the chemotherapy. Therefore, he underwent a salvage surgery and an R0 resection was performed. However, 9 months after the surgery, he experienced paraaortic lymph node recurrence and peritoneal dissemination. The patient died 13 months after the surgery.",
"affiliations": "Dept. of Gastrointestinal Surgery, Kanagawa Cancer Center.",
"authors": "Shirai|Junya|J|;Cho|Haruhiko|H|;Fujikawa|Hirohito|H|;Iwasaki|Kenichi|K|;Ogata|Takashi|T|;Yoshikawa|Takaki|T|;Tsuburaya|Akira|A|;Sujishi|Ken|K|;Yamada|Takanobu|T|;Osaragi|Tomohiko|T|;Yoneyama|Katsuya|K|;Kasahara|Akio|A|;Yamamoto|Yuji|Y|;Rino|Yasushi|Y|;Masuda|Munetaka|M|",
"chemical_list": "D004338:Drug Combinations; D043823:Taxoids; C079198:S 1 (combination); D005641:Tegafur; D000077143:Docetaxel; D010094:Oxonic Acid",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "40(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004338:Drug Combinations; D017809:Fatal Outcome; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid; D010534:Peritoneal Neoplasms; D016879:Salvage Therapy; D013274:Stomach Neoplasms; D043823:Taxoids; D005641:Tegafur",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2194-6",
"pmc": null,
"pmid": "24394057",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of gastric cancer with intensive peritoneal dissemination treated with long-term chemotherapy and surgery.",
"title_normalized": "a case of gastric cancer with intensive peritoneal dissemination treated with long term chemotherapy and surgery"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-110241",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"druga... |
{
"abstract": "In this case report we aimed to present a patient with granulocytic sarcomaa, neutropenic fever, ARDS and Pneumocystis jirovecii pneumoniae that was hospitalized in our intensive care unit. The patient recovered and then developed vancomycin resistant enterococci (VRE) bacteremia due to port catheter during follow up. The patient had risk factors for VRE bacteremia and he was administered linezolide without removing the catheter. He was discharged with recovery.",
"affiliations": "Turgutlu State Hospital, Department of Chest Diseases, Manisa, Turkey.;Izmir University School of Medicine, Department of Chest Diseases, Izmir, Turkey.;Izmir University School of Medicine, Department of Chest Diseases, Izmir, Turkey.;Izmir University School of Medicine, Department of Medical Microbiology, Izmir, Turkey.;Ege University School of Medicine, Department of Infectious Diseases and Clinical Microbiology, Izmir, Turkey.;Ege University School of Medicine, Department of Chest Diseases, Izmir, Turkey.",
"authors": "Emre|Julide Celdir|JC|;Baysak|Aysegul|A|;Oz|Adnan Tolga|AT|;Ece|Gulfem|G|;Arda|Bilgin|B|;Bacakoglu|Feza|F|",
"chemical_list": null,
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2014.17.49.3246",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-17-4910.11604/pamj.2014.17.49.3246Case ReportVancomycın resıstant enterococcus bacteremıa ın a patıent wıth Pneumocystis jiroveci pneumonıa, granulocystıc sarcoma and acute respıratory dıstress syndrome Emre Julide Celdir 1Baysak Aysegul 2&Oz Adnan Tolga 2Ece Gulfem 3Arda Bilgin 4Bacakoglu Feza 51 Turgutlu State Hospital, Department of Chest Diseases, Manisa, Turkey2 Izmir University School of Medicine, Department of Chest Diseases, Izmir, Turkey3 Izmir University School of Medicine, Department of Medical Microbiology, Izmir, Turkey4 Ege University School of Medicine, Department of Infectious Diseases and Clinical Microbiology, Izmir, Turkey5 Ege University School of Medicine, Department of Chest Diseases, Izmir, Turkey& Corresponding author: Aysegul Baysak, Izmir University School of Medicine, Department of Chest Diseases, Izmir, Turkey23 1 2014 2014 17 4920 8 2013 24 11 2013 © Julide Celdir Emre et al.2014The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.In this case report we aimed to present a patient with granulocytic sarcomaa, neutropenic fever, ARDS and Pneumocystis jirovecii pneumoniae that was hospitalized in our intensive care unit. The patient recovered and then developed vancomycin resistant enterococci (VRE) bacteremia due to port catheter during follow up. The patient had risk factors for VRE bacteremia and he was administered linezolide without removing the catheter. He was discharged with recovery.\n\nGranulocystic sarcomaPneumocystis jiroveci pneumoniaevancomycin resistant enterococci(VRE)\n==== Body\nIntroduction\nGranulocytic sarcoma is a rare extramedullary tumor that originates from granulocytic cells. Granulocytic sarcoma may develop during acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative disorders. It is usually detected on skin,bones, soft tissue and periost layer. It is common in children and adolescents and equally shown in both genders. This is a sign of bad prognosis [1]. Surgical excision, combined chemotherapy, and radiotherapy are treatment models [2]. Allogenic or autologous bone marrow transplantation are additional treatment to systemic chemotherapy in case of coexistence of acute leukemia and granulocytic sarcomae [1]. Recently immunosuppressed cases have increased due to an increment in cytotoxic and corticosteroid treatment (organ transplantation, systemic disorders, etc.) [3, 4]. Neutropenia is defined as neutrophil count less than 500/mm3or decreasing under 500/mm3 in 24-48 hours. Febril neutropenia, is defined as fever higher than 38.3°C or higher than 38°C during one hour [3]. Pulmonary complications are ictu causes of morbidity and mortality in immunosuppressed cases. In these cases mortality develops depending on underlying disorders, infectious agent and type of complication. Early diagnosis, and treatment are important and multidiciplinary approach is needed. Prematures, children with primary immunodefiency, hematological malignities, organ transplantation, immunosuppresive treatment are under risk of P.jirovecii infection other than AIDS. Pneumocystis jiroveci pneumoniae is a clinical icture with diffuse interstitial infiltration. Besides normal pulmonary X-ray, cystic form with increased risk of spontanous pneumothorax, paranchymal consolidation, multiple nodules, pleural fluid, and enlargement of lymph nodes may be other radiological images [5]. Enterococcal infections have increased due to increment in third generation cephalosporin use in 1970s. First isolation of VRE was in 1978 and then globally spreaded and became one of the most important reason of hospital infection. Enterecoccus feacalis and Enterecoccus faecium are the most common strains [6]. In this case report we aimed to present a patient with granulocytic sarcomae, neutropenic fever, acute respiratory distress syndrome (ARDS) and Pneumocystis jiroveci pneumoniae that was hospitalized in our intensive care unit.\n\nPatient and observation\nNineteen year old male patient had left arm pain two months ago and afterwards he was diagnosed as granulocytic sarcoma. On the seventh day of his chemotherapy neutropenic fever developed. He was administered piperacillin/tazobactam, amikacin; but fever continued and teicoplanin was initiated. Then the antibiotics were stopped and amphothericin B and meropenem was begun. On the twentyfifith day of the chemotherapy regime neutropenic state ended. He developed fever, dyspnea and hypotension on the 27th day. His physical examination showed cyanosis, dyspnea, increased respiratory sound at the upper and middle lung level bilaterally. The arterial blood gas analysis revealed severe hypoxemia (PaO2/FiO2: 82.5) and he was entubated. The patient was transffered to intensive care unit and mechanical ventilation support was applied. The chest X-ray revealed bilaterally increased non-homogeneous density on all zones (Figure 1). High Resolution computerized tomography indicated frost glass appearance (Figure 2). No growth was reported on microbiological cultures. Pneumocytis jiroveci pneumoniae was not detected on broncho alveolar lavage sample by Giemsa stain and trimethoprim/sulfamethoxazole (TMP/SMX) 80mg/day was iniated. Clinical and radiological recovery was obtained (Figure 3). Mechanical ventilation support was stopped on the nineth day. Fever increased on twelveth day. Vancomycin resistant Enterecoccus feacalis was detected on blood culture taken from the port catheter and evaluated as hospital infection. Strict infection control measures were taken and the patient was administered linezolide. Peripheral and catheter blood cultures were drawn in 48-72 hours before the removal of the port catheter. The patient was discharged on the twentyfourth day with recovery.\n\nFigure 1 The chest X-ray image revealed bilaterally increased non-homogeneous density on all zones\n\nFigure 2 High resolution computerized tomography (HRCT) image of the patient\n\nFigure 3 Radiological recovery of the patient on chest X-ray\n\nDiscussion\n\nP. Jiroveci pneumoniae is a clinical picture in individuals with cellular immundeficiency and fever, cough, progressive hypoxemia and dyspnea develops. The clinical status of the patient may be severe. Diffuse interstitial and perihilar infiltration are typical on chest X-ray [7]. Fever and dyspneae may appear a few days earlier. P. jirovecicannot be detected on culture. The diagnosis can be done by direct microscopic examination of the lower respiratory tract samples with Giemsa and Wright stain and PCR. In our case report we could not show P. jiroveci on bronchoscopic samples and ampiric treatment was initiated considering hypoxemia and radiological image.\n\nThe treatment of P. jiroveci pneumoniae requires TMP/SMX (15 mg/kg/day) for 14-21 days as the first line agent. In cases with mild to severe hypoxemia (PaO2 < 70 mmHg) corticosteroid treatment potentiates oxygenation and decreases mortality. The recommended treatment requires 40 mg/day twice for 5 days, 40 mg/day for five days and 20 mg methylprednisolone for 11 days [3]. In our case TMP-SMX and methylprednisolone were iniated and clinical and radiological recovery were obtained. Also dyspnea healed.\n\nEnterococci are a part of the gastrointestinal system and vaginal flora and infections are commonly due to endogeneous flora. The bacterial isolate is transferred to patients by contamianted hands and fomites. Recently there is an increment in nosocomial infections due to enterococci. VRE infections particulary increased in patients with underlying disorders. E. Faecium strains show 47% vancomycin resistance [8, 9]. The risk factors for VRE infection are immunsuppression, long duration of hospitalization, and broad spectrum antibiotic. Our patient had all of these risk factors. VRE was reported on port catheter which was used to administer chemotherapy [9]. Linezolid is the only member of synthetic oxyzolidone family and is active in-vitro against resistant Gram positive cocci such as vancomycin resistant Enterococcus faecalis and Enterococcus faecium and methicilin resistant Staphylococcus aureus [9, 10]. The approval was declared in our country in 2005. Our case was treated with linezolide without removing the catheter.\n\nConclusion\nChemotherapy and other treatment modalities have increased survey; but long duration of hospitalization, and broad spectrum antibiotic use increase the risk of resistant infections. Appropiate microbiological culture and multidiciplinary approach can decrease mortality.\n\nCompeting interests\nThe authors declare no competing interest.\n\nAuthors’ contributions\nCeldir Emre and Oz were doctors responsible for this patient. Ece carried out microbiologycal analysis. Arda was the doctor from the department of Infectious Diseases who monitors us with this case. Celdir Emre, Baysak and Ece were major contributors to writing the manuscript and to the conception and design as well as drafting the article for publication. Bacakoglu supervised the redaction of this article. All the authors have read and approved the final version of the manuscript\n==== Refs\nReferences\n1 Finnegan DPJ Jones FGC McMullin MF Acute myeloid leukemia with concurrent myeloid sarcomaa treated with autologous bone marrow transplantion:two illustrative cases and a literature review Hematol Oncol. 2005 23 3,4 133 135 16273593 \n2 Dutta Roy S Stafford JS Scally J Selvachandran SN Granulocytic sarcomaa of the breast antedating acute myelogenous leukemia Breast. 2004 13 3 242 246 15177430 \n3 Türk Toraks Dernegi Bagisikligi Baskilanmis Eriskinlerde Gelisen Pnömoni Tani ve Tedavi Rehberi 2009 \n4 Rano A Agusti C Sibila O Torres A Pulmonary infections in non-HIV immunocompromised patients Curr Opin Pulm Med. 2005 11 3 213 7 15818182 \n5 Franquet T Gimenez A Hidalgo A Imaging of opportunistic fungal infections in immunocompromised patients Eur J Radiol. 2004 51 2 130 8 15246518 \n6 Akalin Erdal Geçmisten Gelecege Yogun Bakim Infeksiyonlari Yogun Bakim Dergisi 2007 7 1 5 8 \n7 De Pauw BE Verweij PE Mandell GL Bennett JE Dolin R Infections in patients with hematologic malignancies Principles and Practice of Infectious Diseases 2005 Elsevier Inc 3432 41 \n8 Tasbakan IM Vankomisine dirençli enterekok olgular? ANKEM Derg 2010 24 Ek 2 82 4 \n9 Usluer Gaye Linezolid ANKEM Derg 2010 24 Ek 2 114 8 \n10 Ulusoy Sercan Yogun bakim ünitesinde Gram-pozitif mikroorganizmalar ve direnç sorunu Yogun bakim Derg 3.2 2003 118 128\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "17()",
"journal": "The Pan African medical journal",
"keywords": "(VRE); Granulocystic sarcoma; Pneumocystis jiroveci pneumoniae; vancomycin resistant enterococci",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D016470:Bacteremia; D016984:Enterococcus faecium; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012128:Respiratory Distress Syndrome; D023981:Sarcoma, Myeloid; D065507:Vancomycin-Resistant Enterococci; D055815:Young Adult",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "49",
"pmc": null,
"pmid": "25018799",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15177430;15246518;15818182;16273593",
"title": "Vancomycin resistant enterococcus bacteremia in a patient with Pneumocystis jiroveci pneumonia, granulocystic sarcoma and acute respiratory distress syndrome.",
"title_normalized": "vancomycin resistant enterococcus bacteremia in a patient with pneumocystis jiroveci pneumonia granulocystic sarcoma and acute respiratory distress syndrome"
} | [
{
"companynumb": "TR-MYLANLABS-2015M1015695",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TEICOPLANIN"
},
"drugadditional": null,
... |
{
"abstract": "Stereotactic body radiation therapy (SBRT) is considered the standard of care for treatment of inoperable early stage non-small cell carcinoma of the lung. SBRT delivers a very high dose of ionizing radiation to a relatively small region encompassing the tumor and spares a significant portion of the remaining lung from high doses. However, the conformal high dose comes at the expense of treating a larger volume of normal lung to lower doses. In general, this has been deemed to be acceptable with an overall lower risk of radiation pneumonitis. However, in the face of predisposing factors, the higher doses delivered by this technique may lead to an increase in radiation pneumonitis. We report on two patients being treated with SBRT in which severe radiation pneumonitis developed in spite of our radiation dosimetry being significantly below the acceptable limit for lung toxicity. Both patients developed a \"fulminant\" form of radiation pneumonitis with radiographic abnormalities well beyond the treated volume. In one patient, the disease proved fatal. Both patients were on amiodarone at the time SBRT was administered. Given the rarity of fulminant radiation pneumonitis, especially with the relatively small fields treated by SBRT, we suspect that amiodarone enhanced the pulmonary toxicity.",
"affiliations": "Radiation Oncology, Carl Kirkland Cancer Center, 620 W. Forest Ave, Jackson, TN 38301, USA.;Carl Kirkland Cancer Center, 620 W. Forest Ave., Jackson, TN 38301, USA.",
"authors": "Georgiou|Anastasios|A|https://orcid.org/0000-0002-3984-6498;Farmer|Adam|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/8754951",
"fulltext": "\n==== Front\nCase Rep PulmonolCase Rep PulmonolCRIPUCase Reports in Pulmonology2090-68462090-6854Hindawi 10.1155/2019/8754951Case ReportSevere and Fatal Multilobar Nonclassic Radiation Pneumonitis following Stereotactic Body Radiation Therapy (SBRT) for Treatment of Inoperable Non-Small-Cell Lung Cancer: A Report of Two Cases and Possible Enhancement by Concurrent Amiodarone https://orcid.org/0000-0002-3984-6498Georgiou Anastasios algeorgiou@msn.com\n1\nFarmer Adam \n2\n\n1Radiation Oncology, Carl Kirkland Cancer Center, 620 W. Forest Ave, Jackson, TN 38301, USA\n2Carl Kirkland Cancer Center, 620 W. Forest Ave., Jackson, TN 38301, USAAcademic Editor: Akif Turna\n\n2019 4 8 2019 2019 875495113 4 2019 29 6 2019 Copyright © 2019 Anastasios Georgiou and Adam Farmer.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Stereotactic body radiation therapy (SBRT) is considered the standard of care for treatment of inoperable early stage non-small cell carcinoma of the lung. SBRT delivers a very high dose of ionizing radiation to a relatively small region encompassing the tumor and spares a significant portion of the remaining lung from high doses. However, the conformal high dose comes at the expense of treating a larger volume of normal lung to lower doses. In general, this has been deemed to be acceptable with an overall lower risk of radiation pneumonitis. However, in the face of predisposing factors, the higher doses delivered by this technique may lead to an increase in radiation pneumonitis. We report on two patients being treated with SBRT in which severe radiation pneumonitis developed in spite of our radiation dosimetry being significantly below the acceptable limit for lung toxicity. Both patients developed a “fulminant” form of radiation pneumonitis with radiographic abnormalities well beyond the treated volume. In one patient, the disease proved fatal. Both patients were on amiodarone at the time SBRT was administered. Given the rarity of fulminant radiation pneumonitis, especially with the relatively small fields treated by SBRT, we suspect that amiodarone enhanced the pulmonary toxicity.\n==== Body\n1. Introduction\nStereotactic body radiation therapy (SBRT) is now considered the standard of care for treatment of inoperable early stage non-small cell carcinoma of the lung [1]. SBRT delivers a very high dose of ionizing radiation to a relatively small region encompassing the tumor and spares a significant portion of the remaining lung from high doses. This can be achieved by a variety of techniques with Volumetric Modulated Arc Therapy (VMAT), an advanced form of Intensity Modulate Radiation Therapy (IMRT) that dynamically delivers a precisely-sculpted 3D dose distribution with a 360-degree rotation of the linear-accelerator gantry in a single or multi-arc treatment, being an accepted form of delivery of the dose. However, the conformal high dose comes at the expense of treating a larger volume of normal lung to lower doses [2]. In the absence of predisposing factors, the use of VMAT may result in a decrease in the risk of radiation pneumonitis [3, 4]. However, even with the use of highly conformal techniques, patients with predisposing factors such as contralateral pneumonectomy [5], immunosuppression[6], administration of concurrent chemotherapy [7], and interstitial lung disease[8, 9] may be at increased risk for radiation pneumonitis.\n\nWe present two patients treated with VMAT based SBRT who developed severe bilateral pulmonary infiltrates highly suggestive of radiation pneumonitis. Of the two patients, one rapidly deteriorated and the process proved fatal. In both cases, the degree of radiographic abnormality was out of proportion to the expected pattern of radiation pneumonitis especially since both patients received SBRT. The doses to the normal surrounding lung were well within the accepted limits. However, given the striking radiographic abnormalities that were noted in all lung fields, even those receiving very little radiation exposure, a review was made to identify any previously unknown predisposing factors.\n\nWith the exception of both patients being on amiodarone, a known pulmonary toxin, other contributing etiologies were ruled out as best as possible. A review of the literature led to a finding that amiodarone is also a photosensitizer. Furthermore, there have been a few older case reports in which amiodarone was suspected of enhancing radiation mucositis. To our knowledge, there are no reports of amiodarone enhanced radiation pulmonary toxicity. However, this may be due to the fact that up until recently, the majority of patients have been treated with techniques giving much lower radiation doses to large volumes of the lung and with much lower doses per fraction than those administered via SBRT.\n\n2. Case Presentation\nThe authors note that written informed consent was obtained agreeing to publication of the following two cases.\n\n2.1. Patient 1\nAn 81-year-old female presented with increasing cough and a chest x-ray revealed a right lower lung mass. Subsequent work-up with CT scans, PET scan, and needle core-biopsy yielded a diagnosis of a clinical stage T1cN0M0 adenocarcinoma of the lung. Her past medical history was pertinent in that she had chronic atrial fibrillation for which she had undergone cardiac ablation and placement of a permanent pacemaker. Pulmonary function studies revealed an FEV1 of 0.97 liters which was 56% of predicted. Her medications included allopurinol 300mg daily, atenolol 50mg daily, diltiazem extended release 180mg daily, furosemide 40mg daily, rivaroxaban 15mg daily and, amiodarone 200mg twice daily. The patient had been on amiodarone for at least three years and after first-line therapy for atrial fibrillation had been ineffective.\n\nAfter presentation at a multi-disciplinary lung cancer conference, it was decided that she was not a surgical candidate. Therefore, she was treated with a total of 50Gy in 5 fractions of SBRT using two co-planar arcs (Figure 1). The Dose-Volume Histogram (DVH) for the treatment plan showed total lung minus target dose within accepted guidelines (Figure 2).\n\nOne month later, she presented with mild dyspnea and a nonproductive cough. She denied fevers, chills, hemoptysis, weight loss, or chest pain. Her physical examination did reveal coarse rales in the right lung field. A chest x-ray at that time revealed a new right upper lung infiltrate at the treated site (Figure 3). Her laboratory work was unremarkable with no elevation of the white blood cell count. A diagnosis of radiation pneumonitis was made and she was placed on prednisone 20 milligrams b.i.d.\n\nUnfortunately, she presented 5 days later to the emergency room with increasing dyspnea and nonproductive cough. A chest x-ray now revealed bilateral pulmonary infiltrates (Figure 4). There had been marked worsening of the infiltrates in the right lung. The patient's respiratory status declined and she required intubation and mechanical ventilation\n\nA nuclear medicine ventilation/perfusion scan revealed a low probability for pulmonary emboli. A CT scan of the chest revealed diffuse bilateral pulmonary infiltrates in all lobes of both lungs (Figure 5).\n\nUrine tests for Streptococcus Pneumonia antigen, Histoplasma antibody, Blastomycosis antibody, and Legionella antigen were negative. Serum tests for Cryptococcal antigen, Histoplasma antibody, Coccidioides antibody, Blastomycosis antibody, and Aspergillus antibody were negative. Blood cultures and urine cultures were negative. A respiratory viral panel was negative.\n\nShe was treated with intravenous methylprednisolone. Empiric intravenous antibiotic and antifungal therapy was started with doxycycline, meropenem, vancomycin, and caspofungin. Her rivaroxaban was discontinued in preparation for fiber-optic bronchoscopy once the risk of bleeding during the procedure had subsided. Her amiodarone was not discontinued.\n\nIn spite of maximal support, she succumbed to her disease within 72 hours after her initial presentation with the suspected radiation induced changes and prior to evaluation with bronchoscopy.\n\n2.2. Patient 2\nA 69-year-old gentleman initially presented with left-sided chest pain and upper abdominal pain. A CT scan of the chest was performed that revealed a 4.3 cm mass in the posterior left lower lung. A needle core biopsy revealed a moderately differentiated squamous cell carcinoma. Staging studies included a PET and MRI of the brain. This gentleman's disease was staged as a clinical T2N0M0 lung cancer.\n\nThis gentleman's past medical history was significant for a prior stroke in the left middle cerebral artery region leaving him with right-sided weakness. He had significant coronary artery disease and had undergone prior coronary artery bypass grafting. His medications included aspirin 81mg daily, tamsulosin 0.4mg, levothyroxine 100mcg daily, lisinopril 20mg daily, lovastatin 40mg daily, clopidogrel 75mg daily, hydrochorothiazide 25mg- triamterene 37.5mg daily, and amiodarone 200mg daily. Amiodarone had been started two years prior due to ventricular arrhythmia.\n\nAfter discussion with his cardiologist and pulmonologist, this gentleman was referred for radiation therapy. Consequently, he received a total dose of 50Gy in 5 fractions using SBRT thru two coplanar arcs (Figure 6). The Dose-Volume Histogram (DVH) for the treatment plan showed total lung minus target dose within accepted guidelines (Figure 7).\n\nA CT scan of the chest performed 3 months after completion of therapy revealed a significant decrease in the size of the left lower lung mass with no evidence to suggest progression of disease. A PET scan performed 6 months later revealed complete resolution of the previously identified hypermetabolic mass in the left lower lung.\n\nNine months after his treatment, he presented with acute onset of confusion. He was noted to have significant hypoxemia on room air that required high-flow nasal cannula at 6 liters/minute. His arterial blood gases showed a pH of 7.45, pCO2 of 31, PO2 56. His white count was normal. A nuclear medicine ventilation perfusion scan was performed that revealed no evidence of pulmonary emboli.\n\nA CT scan of the chest was performed that revealed volume loss in both lungs with coarse subpleural interstitial changes in the upper and lower lobes (Figure 8). Bibasilar atelectasis and pneumonitis greater in the left lung base were noted.\n\nUrine tests for Streptococcus Pneumoniae and Legionella were negative. A respiratory viral panel was negative. Blood and urine cultures were negative. Fiber-optic bronchoscopy was performed and biopsies from the left lower lung region revealed mild inflammation. The biopsied portions of pulmonary parenchyma showed interstitial fibroblastic proliferation with fibrinous material. The pathologist commented these findings might be observed in the case of organizing/fibrous pneumonia. The bronchial brushings from left lower lung showed significant atypia favoring squamous cell carcinoma. However the bronchial washings were negative for malignancy.\n\nHe was treated empirically with intravenous levofloxacin and steroids. His amiodarone was discontinued. His pulmonary status slowly improved and he was able to avoid intubation. Given his debilitated state, the patient chose surveillance.\n\nA CT scan of the chest performed 3 months after his hospitalization revealed no evidence to suggest progression of cancer (Figure 9). There was improvement in the previously noted interstitial and posttreatment changes throughout the lung fields.\n\nThis gentleman is alive 18 months later after his initial presentation with dyspnea and the images taken in Figure 6. He remains dyspneic but a follow CT of the chest shows continued improvement in the infiltrates and consolidation. In retrospect, in spite of the cytology report favoring malignancy, it is doubtful that this gentleman had recurrence of disease. The findings on the cytology most likely represent significant atypia secondary to treatment effect. Either untreated lymphangitic carcinomatosis or local recurrence leads to a very poor survival with no expectation that the radiographic abnormalities would improve.\n\n3. Discussion\nGiven the rarity of bilateral fulminant radiation pneumonitis, a review was undertaken to evaluate for any common predisposing factors in the two cases. It was noted that both patients were on amiodarone which is a known pulmonary toxin. A possible interaction between VMAT based SBRT lung cancer treatment and amiodarone warrants further scrutiny in light of the following issues.\n\n3.1. Fulminant Sporadic Radiation Pneumonitis\nRadiation pneumonitis is a known complication after radiation therapy for treatment of lung malignancy. The classical presentation usually occurs within 6 months of treatment with most cases occurring within 1 to 3 months after completion of thoracic radiotherapy. It is usually associated with symptoms of a nonproductive cough and dyspnea. Radiographs of the chest usually reveal pulmonary infiltrates within the irradiated portion of the lungs [10].\n\nHowever, a more fulminant form of radiation pneumonitis has been reported in the literature. This has been referred to as “sporadic” radiation pneumonitis [6, 11]. This form is considered rare and therefore descriptions are confined to case reports. Unlike the more classic pattern, there are significant pulmonary infiltrates found throughout portions of the lung fields receiving either no or very little exposure to radiation therapy. This form of radiation pneumonitis may be an immune related phenomenon similar to a hypersensitivity reaction.\n\nGiven its rarity, the authors doubt that both of our reported cases of possible fulminant radiation pneumonitis are a coincidence without any common factors.\n\n3.2. Amiodarone Toxicity\nAmiodarone is a known pulmonary toxin. The most significant factors for amiodarone pulmonary toxicity are age of the patient, duration of therapy, and dose [12]. The onset of the disease consists of progressive generalized weakness, cough, and dyspnea. In its most severe form, amiodarone pulmonary toxicity can present as an Acute Respiratory Distress Syndrome (ARDS) with rapid onset of progressive diffuse pneumonitis and respiratory failure [13, 14].\n\nIt is well documented that amiodarone can lead to cutaneous photosensitivity [15–19]. Although the wavelength of ultraviolet light thought to cause photosensitivity reactions [20] is usually considered to be nonionizing, it should be noted that there is no absolute threshold distinguishing nonionizing from ionizing radiation in this portion of the electromagnetic spectrum.\n\nIn addition to its well-known pulmonary toxicity and lesser known toxicity of photosensitivity, amiodarone has been suspected of enhancing the mucosal side effects of therapeutic radiation. Several case reports are noted in the literature in which amiodarone was suspected of leading to severe mucosal and cutaneous toxicity out of proportion to that expected from radiation therapy for treatment of head and neck cancer [21–24].\n\nIt is noted that the patient with fatal pneumonitis was on amiodarone 200mg twice daily whereas the surviving second patient was on a lower dose of 200mg daily.\n\n3.3. Dose Constraints for VMAT Based Treatment of Lung Cancer\nFor lung cancer patients, the use of VMAT allows the treating oncologist to better meet the traditional (emphasis added) dose constraints on lung volume [25]. Recently, there has been concern that new dose constraints needed for VMAT based therapy given a possible increase in fatal radiation pneumonitis [26]. In this regard, radiation oncologists and medical physicists have recognized that SBRT treatment via VMAT does lead to an increase in the volume of lung receiving low doses of ionizing radiation. However, in the two cases presented above, the radiographic changes were multilobar and included portions of the lungs that were clearly outside the coplanar fields used. Therefore, VMAT cannot be considered as the sole contributor to the wider effect seen in these two patients. However, in the presence of amiodarone, it is plausible that larger lung volumes exposed to low dose ionizing radiation through the use of VMAT may trigger an immune mediated response.\n\nA review was made of the dose distribution in both patients. The radiation exposure to the normal lung was well within the accepted traditional limits for radiation induced pneumonitis.\n\n4. Conclusion\nIn summary, given that the use of VMAT (or by analogy IMRT type of external beam treatment) exposes a larger volume of the normal lung to low doses of radiation therapy, coupled with amiodarone being a known pulmonary toxin and possible radiation-sensitizer, a plausible argument can be made that this combination of factors may lead to severe pulmonary toxicity. Given the increasing use of SBRT, the possibility of amiodarone induced severe radiation pneumonitis in patients being treated with this modality needs to be further investigated and documented. By reporting these two cases, our hope is that awareness of this possible interaction by pulmonologists and radiation oncologists will lead to scrutiny of past and future cases of severe fulminant radiation pneumonitis to further delineate any association between SBRT and amiodarone.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 SBRT plan for Patient 1 showing conformal radiation dose delivery to the right pulmonary mass.\n\nFigure 2 DVH showing total lung minus target dose for patient 1.\n\nFigure 3 A chest X-ray showing the development of lung infiltrates in and around the treated right lung mass occurring one month following completion of SBRT.\n\nFigure 4 A chest X-ray, taken 5 days after the chest X-ray depicted in Figure 3, revealing rapid progression of lung infiltrates in multiple lobes.\n\nFigure 5 CT scan images above the plane, thru the plane, and below the plane of SBRT treatment showing diffuse infiltrates ((a), (b), and (c) images respectively).\n\nFigure 6 SBRT plan for Patient 2 showing conformal radiation dose delivery to the left pulmonary mass.\n\nFigure 7 DVH showing total lung minus target dose for patient 2.\n\nFigure 8 CT images above and at the plane of SBRT treatment showing lung infiltrates and dense consolidation in the left lower lung ((a) and (b) images respectively).\n\nFigure 9 CT images 3 months after the initial presentation of pneumonitis. Images are at approximately the same level as those shown in Figure 6. There has been considerable clearing of the infiltrates and dense consolidation.\n==== Refs\n1 Videtic G. M. Donington J. Giuliani M. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline Practical Radiation Oncology 2017 7 5 295 301 10.1016/j.prro.2017.04.014 28596092 \n2 Vogelius I. S. Westerly D. C. Cannon G. M. MRT may increase pneumonitis risk relative to 3D-CRT in patients receiving combined chemotherapy and radiation therapy: a modeling study of dose dumping International Journal of Radiation Oncology • Biology • Physics 2011 80 3 893 899 10.1016/j.ijrobp.2010.12.073 \n3 Yom S. S. Liao Z. Liu H. H. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small cell lung acncer patients treated with concurrent chemotherapy and Intensity-Modulated Radiotherapy International Journal of Radiation Oncology • Biology • Physics 2007 68 1 94 102 10.1016/j.ijrobp.2006.12.031 \n4 Chun S. G. Hu C. Choy H. Impact of Intensity-Modulated Radiation Therapy technique for locally advanced non-small-cell lung cancer: A secondary analysis of the NRG Oncology RTOG 0617 randomized control trial International Journal of Radiation Oncology, Biology, Physics 2017 35 1 56 62 10.1200/JCO.2016.69.1378 \n5 Allen A. Czerminska M. Janne P. Fatal pneumonitis associated with Intensity-Modulated Radiation Therapy for mesothelioma International Journal of Radiation Oncology, Biology, Physics 2006 65 3 640 645 \n6 Westhoff P. De Ruysscher D. Schramel F. Fatal bilateral pneumonitis after loco-regional thoracic chemo-radiation in a transplanted patient under immunosuppressive therapy Anticancer Reseach 2014 34 12 7315 7317 \n7 Hu Y. Li J. Su X. Fatal pneumonitis associated with postoperative intensity-modulated radiotherapy in lung cancer: Case report and review Oncology Letters 2013 5 2 714 716 10.3892/ol.2012.1053 23420543 \n8 Glick D. Lyen S. Kandel S. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival in patients treated with stereotactic body radiation therapy (SBRT) Clinical Lung Cancer 2018 19 2 e219 e226 10.1016/j.cllc.2017.06.021 29066051 \n9 Tsurugai Y. Takeda A. Sanuki N. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias Radiotherapy & Oncology 2017 125 2 310 316 10.1016/j.radonc.2017.08.026 28919004 \n10 Wall R. J. Schnapp L. M. Radiation pneumonitis Respiratory Care 2006 51 11 1255 1260 2-s2.0-37349097115 17067408 \n11 Osborn V. W. Leaf A. Lee A. Bilateral diffuse grade 5 radiation pneumonitis after intensity modulated radiation therapy for localized lung cancer World Journal of Clinical Oncology 2017 8 3 285 288 10.5306/wjco.v8.i3.285 28638799 \n12 Papiris S. A. Triantafillidou C. Kolilekas L. Markoulaki D. Manali E. D. Amiodarone: Review of pulmonary effects and toxicity Drug Safety 2010 33 7 539 558 10.2165/11532320-000000000-00000 20553056 \n13 Schwaiblmair M. Berghaus T. Haeckel T. Amiodarone-induced pulmonary toxicity: an under-recongized and severe adverse effect? Clinical Research in Cardiology 2010 99 11 693 700 10.1007/s00392-010-0181-3 2-s2.0-78649645682 20623129 \n14 Singh V. K. Acute respiratory distress syndrome complicated by amiodarone induced pulmonary fibrosis: don’t let your guard down Journal of Clinical and Diagnostic Research 2017 11 4 UD01 UD02 10.7860/JCDR/2017/24710.9674 \n15 Shah N. Warnakulasuriya S. Case Report: Amiodarone-induced peri-oral photosensitivity Journal of Oral Pathology & Medicine 2004 33 1 56 58 10.1111/j.1600-0714.2004.00069.x 14675142 \n16 Boyle J. Amiodarone-induced cutaneous photosensitivity British Journal of Dermatology 1986 115 2 253 254 10.1111/j.1365-2133.1986.tb05732.x 3741790 \n17 Yones S. S. O'Donoghue N. B. Palmer R. A. Menage H. d. Hawk J. L. Persistent severe amiodarone-induced photosensitivity Clinical and Experimental Dermatology 2005 30 5 500 502 10.1111/j.1365-2230.2005.01820.x 16045677 \n18 Walter J. Bradner H. Curtis G. Amiodarone photosensitivity Archives of Dermatology 1984 120 1591 1594 6508331 \n19 Ferguson J. Addo H. Jones S. Johnson B. Frain-Bell W. A study of cutaneous photosensitivity induced by amiodarone British Journal of Dermatology 1985 113 5 537 549 10.1111/j.1365-2133.1985.tb02377.x 4063190 \n20 Diffey B. Chalmers R. Muston H. Photobiology of amiodarone: preliminary in vitro and in vivo studies Clinical and Experimental Dermatology 1984 9 3 248 255 10.1111/j.1365-2230.1984.tb00791.x 6733954 \n21 Hercbergs A. Early onset acute radiation toxicity and amiodarone International Journal of Radiation Oncology • Biology • Physics 1989 16 2 p. 525 10.1016/0360-3016(89)90355-6 \n22 Demange L. Marechal F. Nguyen T. D. Could amiodarone increase acute cutaneous and mucosal toxicity of radiotherapy? International Journal of Radiation Oncology • Biology • Physics 1987 13 2 p. 289 10.1016/0360-3016(87)90142-8 \n23 Topham C. Brierley J. Tomlinson H. Toxicity and amiodarone International Journal of Radiation Oncology • Biology • Physics 1988 14 5 p. 1056 10.1016/0360-3016(88)90037-5 \n24 De Neve W. Fortan L. Storme G. Increased acute mucosal and cutaneous radiation toxicity in two patients taking amiodarone International Journal of Radiation Oncology • Biology • Physics 1992 22 1 p. 224 10.1016/0360-3016(92)91008-B \n25 Murshed H. Liui H. H. Liao Z. Dose and volume reduction for normal lung using intensity-modulated radiotherapy in for advanced-stage non-small-cell lung cancer International Journal of Radiation Oncology, Biology, Physics 2004 58 1258 1267 \n26 Khalil A. A. Hoffmann L. Moeller D. S. Farr K. P. Knap M. M. New dose constraint reduces radiation-induced fatal pneumonitis in locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy Acta Oncologica 2015 54 9 1343 1349 10.3109/0284186X.2015.1061216 2-s2.0-84955437540 26198657\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6854",
"issue": "2019()",
"journal": "Case reports in pulmonology",
"keywords": null,
"medline_ta": "Case Rep Pulmonol",
"mesh_terms": null,
"nlm_unique_id": "101585355",
"other_id": null,
"pages": "8754951",
"pmc": null,
"pmid": "31467761",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "14675142;15001271;16045677;16751058;17067408;1727124;17321067;20553056;20623129;21477946;23420543;25503166;26198657;28034064;28571241;28596092;28638799;28919004;29066051;2921159;3360650;3741790;3818397;4063190;6508331;6733954",
"title": "Severe and Fatal Multilobar Nonclassic Radiation Pneumonitis following Stereotactic Body Radiation Therapy (SBRT) for Treatment of Inoperable Non-Small-Cell Lung Cancer: A Report of Two Cases and Possible Enhancement by Concurrent Amiodarone.",
"title_normalized": "severe and fatal multilobar nonclassic radiation pneumonitis following stereotactic body radiation therapy sbrt for treatment of inoperable non small cell lung cancer a report of two cases and possible enhancement by concurrent amiodarone"
} | [
{
"companynumb": "US-PFIZER INC-2019389499",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Indolent T-cell lymphoproliferative disorder (T-LPD) of the gastrointestinal (GI) tract is a new provisional entity in the 2016 revision of the World Health Organization classification. The disease has an indolent course and progression to aggressive T-cell lymphoma has rarely been reported. We describe a case of a 37-year-old male with indolent T-LPD of the GI tract who 3 years later developed aggressive T-cell lymphoma and died of progressive disease. An infiltrate of indolent T-LPD in the GI tract and aggressive lymphoma diagnosed from the liver biopsy had similar immunophenotype, but cellular infiltrate in the liver showed more atypia compared with the GI biopsies of indolent T-LPD. Moreover, T-cell gene rearrangement studies showed an identical clonal rearrangement in indolent T-LPD and aggressive lymphoma. Patients with indolent T-LPD of the GI tract need a long-term follow-up, as some of them may develop more aggressive lymphoma.",
"affiliations": "1 University of Michigan, Ann Arbor, MI, USA.;2 University of Pittsburgh, Pittsburgh, PA, USA.;3 St. John Hospital and Medical Center, Detroit, MI, USA.;4 National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;5 City of Hope National Medical Center, Duarte, CA, USA.",
"authors": "Perry|Anamarija M|AM|https://orcid.org/0000-0002-5700-2141;Bailey|Nathanael G|NG|https://orcid.org/0000-0002-6747-680X;Bonnett|Michelle|M|;Jaffe|Elaine S|ES|https://orcid.org/0000-0003-4632-0301;Chan|Wing C|WC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1066896918785985",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1066-8969",
"issue": "27(1)",
"journal": "International journal of surgical pathology",
"keywords": "aggressive T-cell lymphoma; gastrointestinal tract; indolent T-cell lymphoproliferative disorder; non-Hodgkin lymphoma; progression",
"medline_ta": "Int J Surg Pathol",
"mesh_terms": "D000328:Adult; D018450:Disease Progression; D017809:Fatal Outcome; D005767:Gastrointestinal Diseases; D006801:Humans; D016399:Lymphoma, T-Cell; D008232:Lymphoproliferative Disorders; D008297:Male",
"nlm_unique_id": "9314927",
"other_id": null,
"pages": "102-107",
"pmc": null,
"pmid": "29986618",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8765187;23861889;24862568;24009234;17676338;15046193;15185856;29592893;27402301;8780585;24316103;24439229;8826934;10517900;8313332",
"title": "Disease Progression in a Patient With Indolent T-Cell Lymphoproliferative Disease of the Gastrointestinal Tract.",
"title_normalized": "disease progression in a patient with indolent t cell lymphoproliferative disease of the gastrointestinal tract"
} | [
{
"companynumb": "US-MYLANLABS-2019M1012790",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTricyclic antidepressive agents are widely used in suicide attempts and present a variety of deleterious effects. Rhabdomyolysis is a rare complication of such poisoning.\n\n\nMETHODS\nA 55-year-old woman ingested 120 pills of 25 mg clomipramine in a suicide attempt two days before admission. After gastric lavage in another emergency department on the day of intake, 80 pills were removed. On admission to our department, she was disoriented, complaining of a dry mouth and tremors at the extremities. An electrocardiogram showed a sinus rhythm with narrow QRS complexes. Laboratory results showed high creatine phosphokinase (CK = 15,094 U/l on admission; normal range = 26 to 140 U/l), hypocalcemia, slightly increased serum transaminases and mild metabolic acidosis. The patient's medical history included depression with previous suicide attempts, obsessive-compulsive disorder, hypothyroidism and osteoporosis. She presented cardiac arrest with pulseless electric activity for seven minutes and afterwards, without sedation, showed continuous side-to-side eye movement. She developed refractory hypotension, with need for vasopressors. Ceftriaxone and clindamycin administration was started because of a hypothesis of bronchoaspiration. The patient remained unresponsive even without sedation, with continuous side-to-side eye movement and a decerebrate posture. She died two months later. Rhabdomyolysis is a very rare complication of poisoning due to tricyclic drugs. It had only previously been described after an overdose of cyclobenzaprine, which has a toxicity profile similar to tricyclic drugs.\n\n\nCONCLUSIONS\nAlthough arrhythmia is the most important complication, rhabdomyolysis should be investigated in cases of clomipramine poisoning.",
"affiliations": "Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil.;Emergency Department, Universidade Federal de São Paulo, São Paulo, Brazil.",
"authors": "Santana|Nathalie Oliveira de|NO|;Góis|Aécio Flávio Teixeira de|AF|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D003402:Creatine Kinase; D002997:Clomipramine",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1516-3180",
"issue": "131(6)",
"journal": "Sao Paulo medical journal = Revista paulista de medicina",
"keywords": null,
"medline_ta": "Sao Paulo Med J",
"mesh_terms": "D000929:Antidepressive Agents, Tricyclic; D002997:Clomipramine; D003402:Creatine Kinase; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D012206:Rhabdomyolysis; D013406:Suicide, Attempted",
"nlm_unique_id": "100897261",
"other_id": null,
"pages": "432-5",
"pmc": null,
"pmid": "24346784",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rhabdomyolysis as a manifestation of clomipramine poisoning.",
"title_normalized": "rhabdomyolysis as a manifestation of clomipramine poisoning"
} | [
{
"companynumb": "BR-MYLAN-2014M1001223",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOXETINE\\FLUOXETINE HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "Trimethoprim-sulfamethoxazole (TMP-SMZ) is one of the most commonly used antibiotics. Although many of its adverse effects are well recognized, TMP-SMZ related hepatotoxicity is considered rare and is usually characterized by cholestasis or mixed hepatocellular-holestatic reactions. In this study, we describe the case of a previously healthy young man with acute fulminant liver failure caused by TMP-SMZ. The patient presented with complaints of 'flu-like' symptoms with myalgia and fever after taking TMP-SMZ for 7 d for otitis externa. The patient subsequently developed fever, worsening jaundice, and a rash on his neck and chest. Liver enzymes peaked on day 3 with alanine aminotransferase (ALT) 11,549, aspartate aminotransferase (AST) 23,289, alkaline phosphatase 245, and total bilirubin 10.3 mg/dL, with a conjugated bilirubin of 8.3 mg/dL, prothrombin time (PT) 60.5 s, partial normalized ratio (PTT) 49 s, and international normalized ratio (INR) 7.5. Of note, acetaminophen level on admission was undetectable. Serology for hepatitis A, B, C, cytomegalovirus, HIV, toxoplasmosis, and blood cultures were all negative. The patient developed hepatic encephalopathy with hallucination on day 4. Laboratory tests revealed a serum ammonia level of 190 U, serum creatinine kinase (CK) 10,466 (42 on admission), serum creatinine 8.2 mg/dL (1.2 on admission), and significant metabolic acidosis. Renal ultrasound was unremarkable. The patient was started on hemodialysis for acute renal failure. Meanwhile, liver transplantation assessment was also initiated. On day 8 post-admission (15 d after taking TMP-SMZ), the patient received a successful orthotopic liver transplant.",
"affiliations": "Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. fzaman@lsuhsc.edu",
"authors": "Zaman|Fahim|F|;Ye|Gang|G|;Abreo|Kenneth D|KD|;Latif|Shahnila|S|;Zibari|Gazi B|GB|",
"chemical_list": "D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Denmark",
"delete": false,
"doi": "10.1034/j.1399-0012.2003.00040.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "17(5)",
"journal": "Clinical transplantation",
"keywords": null,
"medline_ta": "Clin Transplant",
"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D006801:Humans; D008099:Liver; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "461-4",
"pmc": null,
"pmid": "14703931",
"pubdate": "2003-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure.",
"title_normalized": "successful orthotopic liver transplantation after trimethoprim sulfamethoxazole associated fulminant liver failure"
} | [
{
"companynumb": "US-PFIZER INC-2015331988",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nTo analyze the clinical characteristics and treatment of noninfectious scleritis in Japanese patients, focusing on the efficacy of methotrexate (MTX).\n\n\nMETHODS\nRetrospective.\n\n\nMETHODS\nA retrospective study of patients with noninfectious scleritis treated at Hiroshima University from February 2016 to May 2020 was performed. The patients' clinical features, associated systemic diseases, treatments, and visual outcomes were studied. The efficacy of MTX was also analyzed.\n\n\nRESULTS\nThe study comprised 57 patients (88 eyes) with noninfectious scleritis, of whom 31 had bilateral involvement and the majority had anterior diffuse scleritis (n = 45). The commonest ocular complication was anterior chamber cells (38.6%), followed by ocular hypertension (28.1%). Associated systemic diseases were observed in 24.6% of the patients. Systemic immunosuppressive treatment was required in 78.9% of the patients, and 45.6% of the patients needed corticosteroid-sparing immunosuppressive treatment. Treatment success was achieved in 88.2% of the patients. Decreased vision was observed in 9.8% of the patients with ≥ 3-month follow-up. Seventeen patients were treated with MTX; the median maximum dose was 16 mg/week (range 8-16 mg). The scleritis was well controlled in almost 80% of the patients treated with MTX and systemic corticosteroids ≤ 5 mg. MTX adverse effects occurred in 47.1% of the MTX-treated patients; they were either tolerable or improved with dose adjustment in most cases.\n\n\nCONCLUSIONS\nOur study suggests the significance of prompt initiation of corticosteroid-sparing immunosuppressive treatment in treating patients with refractory scleritis or those intolerant of systemic corticosteroids. Moreover, MTX may be used effectively and safely for the treatment of noninfectious scleritis in Japanese patients.",
"affiliations": "Department of Ophthalmology and Visual Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, 734-8551, Japan.;Department of Ophthalmology and Visual Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, 734-8551, Japan. yharada@hiroshima-u.ac.jp.;Department of Ophthalmology and Visual Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, 734-8551, Japan.",
"authors": "Hiyama|Tomona|T|;Harada|Yosuke|Y|;Kiuchi|Yoshiaki|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10384-020-00778-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5155",
"issue": "65(1)",
"journal": "Japanese journal of ophthalmology",
"keywords": "Corticosteroid-sparing treatment; Japanese; Methotrexate; Scleritis; Uveitis",
"medline_ta": "Jpn J Ophthalmol",
"mesh_terms": "D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D008727:Methotrexate; D012189:Retrospective Studies; D015423:Scleritis; D016896:Treatment Outcome; D014792:Visual Acuity",
"nlm_unique_id": "0044652",
"other_id": null,
"pages": "97-106",
"pmc": null,
"pmid": "33107015",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical characteristics and efficacy of methotrexate in Japanese patients with noninfectious scleritis.",
"title_normalized": "clinical characteristics and efficacy of methotrexate in japanese patients with noninfectious scleritis"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1935719",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "This study was conducted to evaluate complications (minor and major) that occurred in patients who underwent modern cerebral angiography.\nA retrospective assessment of 644 consecutive cerebral angiographic cases was undertaken with specific emphasis on complications.\nThe most common complication of diagnostic cerebral angiography was groin hematoma seen in 10 (1.55%) patients. One patient had complications arising from the development of a femoral artery pseudoaneurysm. Neurologic complications occurred in 4 (0.62%) cases. Three (0.47%) cases had transient complications which resolved completely within 24 h. One patient (0.16%) was left with permanent hemiplegia. There were 6 (5%) cases of contrast-induced nephropathy out of the 120 cases in whom subarachnoid hemorrhage had occurred and who possessed complete data of kidney function tests. Five of them were reversible, and one was permanent. One patient (0.16%) died from air emboli.\nNeurologic complications following cerebral angiography are rare but must be minimized by careful case selection and training. Although the risk is small, complications such as permanent disability or even death cannot be completely obviated.",
"affiliations": "Department of Neurosurgery, Neurovascular Diseases Research Center, Second Affiliated Hospital Anhui Medical University, Hefei, Anhui Province, People's Republic of China.;Department of Neurosurgery, Neurovascular Diseases Research Center, Second Affiliated Hospital Anhui Medical University, Hefei, Anhui Province, People's Republic of China.;Department of Neurosurgery, Neurovascular Diseases Research Center, Second Affiliated Hospital Anhui Medical University, Hefei, Anhui Province, People's Republic of China.;Department of Neurosurgery, Neurovascular Diseases Research Center, Second Affiliated Hospital Anhui Medical University; Department of Neurosurgery, Neurovascular Diseases Research Center and Skull Base Tumor Research Center, Anhui Medical University, 678 Fu Road, Hefei, Anhui Province, People's Republic of China.",
"authors": "Shen|Jie|J|;Karki|Mohan|M|;Jiang|Tao|T|;Zhao|Bing|B|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0028-3886.237018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3886",
"issue": "66(4)",
"journal": "Neurology India",
"keywords": "Cerebral angiography; contrast-induced nephropathy; neurologic complications",
"medline_ta": "Neurol India",
"mesh_terms": "D002533:Cerebral Angiography; D006801:Humans; D012189:Retrospective Studies",
"nlm_unique_id": "0042005",
"other_id": null,
"pages": "1154-1158",
"pmc": null,
"pmid": "30038108",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Complications associated with diagnostic cerebral angiography: A retrospective analysis of 644 consecutive cerebral angiographic cases.",
"title_normalized": "complications associated with diagnostic cerebral angiography a retrospective analysis of 644 consecutive cerebral angiographic cases"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201809147",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "Cardiotoxicity is one of the most feared side effects of chemotherapy with enhanced morbidity and mortality in survivors. Arrhythmia, heart failure, myocardial ischemia, hypertension, and thromboembolism are commonly reported as side effects. Hereby, we are reporting a case of severe mitral regurgitation as a complication of chemotherapy.",
"affiliations": "Department of Cardiology, Najafabad Branch, Islamic Azad University, Isfahan, Iran.;Department of Nephrology, Isfahan Kidney Diseases Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.;Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Mirdamadi|Ahmad|A|;Naeini|Afsoon Emami|AE|;Behjati|Mohaddeseh|M|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jrms.JRMS_471_17",
"fulltext": "\n==== Front\nJ Res Med SciJ Res Med SciJRMSJournal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences1735-19951735-7136Medknow Publications & Media Pvt Ltd India JRMS-22-13110.4103/jrms.JRMS_471_17Case ReportSevere mitral regurgitation, an unusual manifestation of chemotherapy-induced cardiotoxicity Mirdamadi Ahmad Naeini Afsoon Emami 1Behjati Mohaddeseh 2Department of Cardiology, Najafabad Branch, Islamic Azad University, Isfahan, Iran1 Department of Nephrology, Isfahan Kidney Diseases Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran2 Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, IranAddress for correspondence: Dr. Mohaddeseh Behjati, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. E-mail: behjati@med.mui.ac.ir2017 26 12 2017 22 13117 6 2017 09 8 2017 23 9 2017 Copyright: © 2017 Journal of Research in Medical Sciences2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Cardiotoxicity is one of the most feared side effects of chemotherapy with enhanced morbidity and mortality in survivors. Arrhythmia, heart failure, myocardial ischemia, hypertension, and thromboembolism are commonly reported as side effects. Hereby, we are reporting a case of severe mitral regurgitation as a complication of chemotherapy.\n\nCardiotoxicitychemotherapymitral regurgitation\n==== Body\nINTRODUCTION\nCardiotoxic side effects related to chemotherapy limit dosing and impose cancer survivor to enhanced morbidity and mortality.[1] Current established guidelines for screening of chemotherapy-related cardiotoxicity are mainly based on a serial assessment of the left ventricular ejection fraction.[2] Cardiac tissue is damaged by variety of ways during cancer treatment.[3] The speculated mechanism of valvular regurgitation could be secondary to chemotherapy-induced reduced ejection fraction, but insufficient data favors this mechanism as the whole. Degenerative valvular regurgitation disproportionate to decrease in the left ventricular ejection fraction and valvular or myocardial damage should be considered in survivors of chemotherapy survivors.[4]\n\nCASE REPORT\nOur case was a 48-year-old woman who underwent chemotherapy for treatment of invasive ductal carcinoma of the breast. She was under close observation of cardiologist from the beginning of therapy. Her chemotherapy started by Adriamycin and Cyclophosphamide. After 4 courses of this therapy, 4 courses of combination therapy by Pertuzumab/Trastuzumab and Taxotel started. Combination therapy followed by surgery and then radiotherapy. Pathologic examination of removed tissue specimen revealed no residual malignant cell, but she faced myocardial dysfunction during chemotherapy. Furthermore, she suffered from severe mitral regurgitation during her therapy. Precise evaluation of mitral valve showed no obvious cause for this severe mitral regurgitation and severe mitral regurgitation was not secondary to left ventricular dilation or mitral valve annulus dilation. Aggravation of mitral regurgitation was so obvious that lead to consideration for its management. The patient was evaluated for mitral valve repair or mitral valve clip. In the worst period of heart injury, left ventricular ejection fraction decreased to 30%–35%. In this state, chemotherapy was discontinued. Medical therapy that had initiated from the first days of chemotherapy, increased and aggressive medical treatment for heart failure continued. In the peak time of myocardial dysfunction, left ventricular end diastolic volume was 130 ml. After several months of dilemma for how to approach mitral regurgitation, cardiac condition started to recovery. Mitral regurgitation improved much better than cardiac contraction during a year after that. Finally, mitral regurgitation severity decreased to mild degree and left ventricular end diastolic volume decreased to 80 ml. Two-dimensional (2D) and 3D echocardiography images before and after recovery are depicted in Figures 1 and 2, respectively.\n\nFigure 1 Severe mitral regurgitation and increased left ventricle volumes induced by chemotherapy\n\nFigure 2 Decreased severity of mitral regurgitation and decreased left ventricle volumes after cessation of chemotherapy\n\nDISCUSSIONS\nHereby, we presented a case of severe mitral regurgitation during chemotherapy which improved significantly by cessation of chemotherapy, in addition to appropriate cardiac treatment. Severe mitral regurgitation is a yet unreported manifestation of chemotherapy-induced cardiotoxicity which needs prompt attention. Fortunately, mitral regurgitation was reversible similar to left ventricular dysfunction, and we did not need an interventional and invasive strategy to manage it. Since each chemotherapy agent has an impact on cardiovascular system, cardio-oncology knowledge should be joined from the beginning of patient management.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 McGowan JV Chung R Maulik A Piotrowska I Walker JM Yellon DM Anthracycline chemotherapy and cardiotoxicity Cardiovasc Drugs Ther 2017 31 63 75 28185035 \n2 Jiji RS Kramer CM Salerno M Non-invasive imaging and monitoring cardiotoxicity of cancer therapeutic drugs J Nucl Cardiol 2012 19 377 88 22351492 \n3 Ewer M Benjamin R Yeh E Kufe DW Pollock RE Weichselbaum RR Weichselbaum R Bast R Gansler T Cardiac complications of cancer treatment Holland-Frei Cancer Medicine 2003 6th ed Hamilton, ON BC Decker \n4 Murbraech K Wethal T Smeland KB Holte H Loge JH Holte E Valvular dysfunction in lymphoma survivors treated with autologous stem cell transplantation: A National cross-sectional study JACC Cardiovasc Imaging 2016 9 230 9 26897666\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1735-1995",
"issue": "22()",
"journal": "Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences",
"keywords": "Cardiotoxicity; chemotherapy; mitral regurgitation",
"medline_ta": "J Res Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101235599",
"other_id": null,
"pages": "131",
"pmc": null,
"pmid": "29387118",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "22351492;26897666;28185035",
"title": "Severe mitral regurgitation, an unusual manifestation of chemotherapy-induced cardiotoxicity.",
"title_normalized": "severe mitral regurgitation an unusual manifestation of chemotherapy induced cardiotoxicity"
} | [
{
"companynumb": "IR-SAKK-2018SA171809AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "A 30-year-old man with a 20-year history of well-controlled type 1 diabetes mellitus and no microvascular complications traveled from near sea level to an altitude of 3000 m within 6 hours. At altitude, his blood glucose levels began to rise, necessitating increased insulin delivery. Typical symptoms of acute mountain sickness (AMS) developed, and he became increasingly hyperglycemic and unwell. Upon presentation to an emergency clinic, diabetic ketoacidosis (DKA) was diagnosed and was managed with insulin, intravenous fluids with potassium, and acetazolamide orally. No other potential causes for diabetic ketoacidosis were identified. Hyperglycemia, ketosis, and acidosis resolved with treatment as expected, but an increased insulin requirement was noted for the next 48 hours, until returning to expected levels when acetazolamide was discontinued. This case describes an episode of mild diabetic ketoacidosis potentially precipitated by moderate to severe acute mountain sickness, and an apparent hyperglycemic effect of acetazolamide. Individuals with type 1 diabetes traveling to altitude and their physicians should be vigilant for this complication and should be aware of the effects of conventional first-line therapies for acute mountain sickness on insulin requirement, glycemic control, and preexisting microvascular diabetes complications.",
"affiliations": "Department of Endocrinology, North Shore Hospital, Takapuna, Auckland, New Zealand. Electronic address: steven@endocrinology.co.nz.",
"authors": "Miller|Steven C M|SC|",
"chemical_list": "D001786:Blood Glucose; D007328:Insulin; D000086:Acetazolamide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-6032",
"issue": "26(2)",
"journal": "Wilderness & environmental medicine",
"keywords": "AMS; DKA; T1DM; acetazolamide; acute mountain sickness; dexamethasone; diabetic ketoacidosis; type 1 diabetes mellitus",
"medline_ta": "Wilderness Environ Med",
"mesh_terms": "D000086:Acetazolamide; D000328:Adult; D000532:Altitude Sickness; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D006801:Humans; D007328:Insulin; D008297:Male",
"nlm_unique_id": "9505185",
"other_id": null,
"pages": "185-8",
"pmc": null,
"pmid": "25899916",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diabetic ketoacidosis and acute mountain sickness: case report and review of treatment options in type 1 diabetes mellitus.",
"title_normalized": "diabetic ketoacidosis and acute mountain sickness case report and review of treatment options in type 1 diabetes mellitus"
} | [
{
"companynumb": "NZ-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-109450",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"d... |
{
"abstract": "Maternally inherited diabetes and deafness is a rare genetic disease mainly caused by a point mutation in mitochondrial deoxyribonucleic acid. Lipoprotein lipase gene mutations are associated with familial dyslipidemias, which are difficult to manage. We reported for the first time a case that had both maternally inherited diabetes and severe hyperlipidemia caused by lipoprotein lipase gene mutation (C.347(exon3)G>C) that was resistant to fenofibrate and atorvastatin. We were able to manage the patient's hyperlipidemia with bezafibrate, and her diabetes was well controlled with insulin. In conclusion, genetic testing is helpful in identifying rare and interesting cases when clinicians suspect inheritable diseases. Additionally, when one fibrate drug is ineffective in treating hyperlipidemia, it might be worthwhile trying another fibrate.",
"affiliations": "Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China.",
"authors": "Zhang|Xiaojuan|X|;Chen|Yongyong|Y|;Tong|Nanwei|N|https://orcid.org/0000-0002-5395-3660;Shao|Qing|Q|;Zhou|Yueyang|Y|;Mu|Tong|T|;Yang|Xiaoling|X|;Zhang|Yuwei|Y|https://orcid.org/0000-0003-2281-5000",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1111/jdi.13651",
"fulltext": "\n==== Front\nJ Diabetes Investig\nJ Diabetes Investig\n10.1111/(ISSN)2040-1124\nJDI\nJournal of Diabetes Investigation\n2040-1116\n2040-1124\nJohn Wiley and Sons Inc. Hoboken\n\n34460997\n10.1111/jdi.13651\nJDI13651\nCase Report\nCase Reports\nMaternally inherited diabetes and deafness coexists with lipoprotein lipase gene mutation‐associated severe hyperlipidemia that was resistant to fenofibrate and atorvastatin, but sensitive to bezafibrate: A case report\nMIDD coexists with LPL gene mutation\nZhang et al.\nZhang Xiaojuan 1\nChen Yongyong 1 2\nTong Nanwei https://orcid.org/0000-0002-5395-3660\n1\nShao Qing 1\nZhou Yueyang 1\nMu Tong 1\nYang Xiaoling 1\nZhang Yuwei https://orcid.org/0000-0003-2281-5000\n1 doczhangyw@scu.edu.cn\n\n1 Department of Endocrinology and Metabolism West China Hospital of Sichuan University Chengdu China\n2 Department of Endocrinology and Metabolism The Fifth People's Hospital of Chongqing Chongqing China\n* *Correspondence\nYuwei Zhang\nTel.: +86‐28‐8542‐3369\nFax: +86‐28‐85423369\nE‐mail address: doczhangyw@scu.edu.cn\n\n22 9 2021\n2 2022\n13 2 10.1111/jdi.v13.2 397401\n20 8 2021\n02 6 2021\n25 8 2021\n© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nMaternally inherited diabetes and deafness is a rare genetic disease mainly caused by a point mutation in mitochondrial deoxyribonucleic acid. Lipoprotein lipase gene mutations are associated with familial dyslipidemias, which are difficult to manage. We reported for the first time a case that had both maternally inherited diabetes and severe hyperlipidemia caused by lipoprotein lipase gene mutation (C.347(exon3)G>C) that was resistant to fenofibrate and atorvastatin. We were able to manage the patient’s hyperlipidemia with bezafibrate, and her diabetes was well controlled with insulin. In conclusion, genetic testing is helpful in identifying rare and interesting cases when clinicians suspect inheritable diseases. Additionally, when one fibrate drug is ineffective in treating hyperlipidemia, it might be worthwhile trying another fibrate.\n\nThe pedigree chart of the patient’s family. The arrow denotes proband (the patient) who has a point mutation in the lipoprotein lipase gene (heterozygous, C.347(exon3)G>C) and a point mutation in mitochondrial deoxyribonucleic acid (tRNA3243A>G).\n\nHypertriglyceridemia\nLipoprotein lipase\nMaternally inherited diabetes and deafness\nInnovation Spark Project of Sichuan University2018SCUH0084 Sichuan Regional Innovation Cooperation Project20QYCX0100 Data Center of Management Science, National Natural Science Foundation of China ‐ Peking University 10.13039/501100016022 82070660 source-schema-version-number2.0\ncover-dateFebruary 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.1 mode:remove_FC converted:15.02.2022\nJ Diabetes Investig 2022; 13 : 397–401\n==== Body\npmcINTRODUCTION\n\nMaternally inherited diabetes and deafness is a rare genetic disease mainly caused by a point mutation in mitochondrial deoxyribonucleic acid (tRNA3243A>G). It is extremely rare when it coexists with another genetic disease. Lipoprotein lipase (LPL) is a rate‐limiting enzyme that hydrolyzes cleavage of the triglyceride core of lipoproteins, which is essential for TG clearance and modulation of lipid metabolism. LPL gene mutations result in disturbance in TG clearance and disorders in lipid metabolism. They are associated with several types of familial dyslipidemias 1 , 2 , 3 . Here, we report a case with severe hyperlipidemia who carries a point mutation in the LPL gene (heterozygous, C.347(exon3)G>C) (rs775728208) and a point mutation in mitochondrial deoxyribonucleic acid (tRNA3243A>G).\n\nCASE REPORT\n\nA 31‐year old female patient with low body mass index (14.5 kg/m2) was found to have elevated blood glucose 5 years earlier in a medical checkup. Her blood glucose was not well controlled until insulin was started 3 years earlier. Several of her family members from her mother’s descent had diabetes and hyperlipidemia (Figure 1). The patient’s grandmother died from diabetic ketoacidosis at the age of 33 years. Her aunt died from diabetic nephropathy at the age of 47 years. The patient’s mother, her aunt and cousin had mild hyperlipidemia that was being well managed with statins. The patient’s blood lipid profile on admission was 16.8 mmol/L (1486.73 mg/dL) for triglycerides (TG) and 9.91 mmol/L (382.53 mg/dL) for total cholesterol (TC). Abdominal ultrasonography showed splenomegaly. Her visual and auditory acuities were within the normal limits. The results of C‐peptide release test are shown in Table 1. Insulin autoantibody, protein tyrosine phosphatase antibody, islet cell antibody and glutamic acid decarboxylase antibody were negative.\n\nFigure 1 Pedigree chart of the patient's family. The arrow denotes proband (the patient). LPL, lipoprotein lipase gene.\n\nTable 1 75‐g glucose load oral glucose tolerance test and C‐peptide release test\n\n\t0 min\t30 min\t60 min\t120 min\t\nGlucose (mmol/L)\t9.51\t13.97\t19.18\t21.73\t\nGlucose (mg/dL)\t171.18\t251.46\t345.24\t391.14\t\nC‐peptide (nmol/L)\t0.413 (0.48–0.78)\t1.157 (2.01–3.23)\t1.68 (3.52–4.76)\t1.27 (1.34–2.50)\t\nJohn Wiley & Sons, Ltd\n\nAs a matter of fact, severe hyperlipidemia was identified in the patient 2.5 years earlier in a medical checkup. She was put on a low‐fat diet and was additionally treated with fenofibrate. However, minimal effects were observed. Two years earlier, she stopped taking lipid‐lowering medications during the fourth week of pregnancy and suffered from acute pancreatitis as a result of chylomicronemia, an extremely high TG level (>33.3 mmol/L; 2,946.92 mg/dL) and a TC level of 16.94 mmol/L (653.88 mg/dL) at the 26th week of her pregnancy. During hospitalization, her baby was delivered spontaneously at week 26+3, but died 2 days after birth. Daily fenofibrate combined with atorvastatin was prescribed to her after delivery. Although her blood TC level was reduced to 3.94 mmol/L (152.08 mg/dL) with combined treatment, her blood TG stayed >10 mmol/L (884.96 mg/dL).\n\nWe suspected the patient had genetic diseases related to glucose and lipid metabolism. Therefore, blood samples from the patient and her mother were collected for genetic testing. Her diabetes continued to be treated with insulin, but we changed her lipid‐lowering drug to bezafibrate. The patient’s TC level was successfully reduced to 2.5 mmol/L (96.5 mg/dL), and her TG level dropped to 2.3 mmol/L (203.54 mg/dL) after bezafibrate treatment for 3 months. The genetic testing results showed that the patient had a point mutation in the LPL gene (heterozygous, C.347(exon3)G>C; rs775728208; Figure 2) and a point mutation in the mitochondrial gene (TRNL1, tRNA3243A>G; Figure 3). Her mother was reported to have the same heterozygous point mutation in the LPL gene (Figure 2).\n\nFigure 2 Lipoprotein lipase gene (LPL) gene analysis of the patient and her mother. The arrow denotes the variation site.\n\nFigure 3 Mitochondrial gene analysis of the patient. TRNL, mitochondrially encoded transfer ribonucleic acid leucine; mtDNA, mitochondrial deoxyribonucleic acid.\n\nDISCUSSION\n\nThe clinical manifestations of maternally inherited diabetes and deafness and its severity are different from patient‐to‐patient, because different amounts of mutated mitochondrial deoxyribonucleic acid are inherited 4 . The patient had insulin‐dependent diabetes, low body mass index and splenomegaly, but no impairments in visual and auditory acuities. Several of her family members developed severe diabetes complications and died at an early age, some of them had hyperlipidemia that was easy to control. It is not clear whether maternally inherited diabetes and deafness could affect lipid metabolism. Given the patient presented with severe hyperlipidemia that was resistant to fenofibrate and atorvastatin, her clinical manifestations and her family history, a suspicion of genetic disease involving both glucose and lipid metabolism was raised. There is evidence showing that fibrates are not effective enough in familial dyslipidemia because of LPL gene mutations 5 . Interestingly, although fenofibrate failed to reduce blood TG levels in this patient, bezafibrate dramatically decreased her blood TG level to near normal. Brisson et al. 6 reported that LPL‐P207L mutation attenuated the effects of fenofibrate in reducing TG levels. Likewise, Gao et al. 7 showed that some rare synonymous LPL gene variants could decrease the TG reduction effects of fenofibrate. In contrast, some LPL gene mutations, such as LPL D9N and LPL N291S, did not show a significant influence on the lipid‐lowering effect of bezafibrate 8 . Therefore, it is possible that the LPL gene mutation seen in this patient attenuated fenofibrate effects, but preserved the role of bezafibrate in reducing blood TG.\n\nFibrates are known to activate peroxisome proliferator‐activated receptor (PPAR) α to modulate lipoprotein gene expression, and upregulate LPL protein expression and activity, therefore promoting TG clearance. Bezafibrate is a non‐selective PPAR activator, whereas fenofibrate only activates PPARα 9 . PPARβ is associated with fatty acid oxidation and energy consumption 9 . A previous case report showed that pioglitazone, a PPARγ agonist, greatly augmented the TG‐lowering effects of fenofibrate and atorvastatin 10 , which suggests the augmentation effects of PPARγ agonists on reducing TG. The effect of bezafibrate on PPARβ and PPARγ might contribute to the lipid‐lowering action of bezafibrate.\n\nThis is the first case reporting a patient carrying a mutation in the LPL gene (heterozygous, C.347(exon3)G>C)(rs775728208) and a mutation in the mitochondrial gene (TRNL1, tRNA3243A>G). The patient’s hypertriglyceridemia was resistant to fenofibrate and atorvastatin, but sensitive to bezafibrate, which gives clinicians a clue that when one fibrate drug is ineffective, it might be worthwhile trying another one.\n\nDISCLOSURE\n\nThe authors declare no conflict of interest.\n\nApproval of the research protocol: N/A.\n\nInformed Consent: Written informed consent was obtained from all the participants.\n\nApproval date of Registry and the Registration No. of the study/trial: N/A.\n\nAnimal Studies: N/A.\n\nACKNOWLEDGMENTS\n\nThe authors thank the patient and her family for their consent. This work is supported by Sichuan Regional Innovation Cooperation Project (20QYCX0100), Innovation Spark Project of Sichuan University (2018SCUH0084) and National Natural Science Foundation of China (82070660) to Y Zhang.\n==== Refs\nREFERENCES\n\n1 Musambil M , Al‐Rubeaan K , Al‐Qasim S , et al. Primary hypertriglyceridemia: a look back on the clinical classification and genetics of the disease. Curr Diabetes Rev 2020; 16 : 521–531.31057121\n2 Taghizadeh E , Ghayour‐Mobarhan M , Ferns GA , et al. A novel variant in LPL gene is associated with familial combined hyperlipidemia. BioFactors 2020; 46 : 94–99.31599081\n3 Evans D , Arzer J , Aberle J , et al. Rare variants in the lipoprotein lipase (LPL) gene are common in hypertriglyceridemia but rare in Type III hyperlipidemia. Atherosclerosis 2011; 214 : 386–390.21159338\n4 Robinson KN , Terrazas S , Giordano‐Mooga S , et al. The role of heteroplasmy in the diagnosis and management of maternally inherited diabetes and deafness. Endocr Pract 2020; 26 : 241–246.31682520\n5 Moulin P , Dufour R , Averna M , et al. Identification and diagnosis of patients with familial chylomicronemia syndrome (FCS): expert panel recommendations and proposal of an \"FCSscore\". Atherosclerosis 2018; 275 : 265–272.29980054\n6 Brisson D , Ledoux K , Bossé Y , et al. Effect of apolipoprotein E, peroxisome proliferator‐activated receptor alpha and lipoprotein lipase gene mutations on the ability of fenofibrate to improve lipid profiles and reach clinical guideline targets among hypertriglyceridemia patients. Pharmacogenetics 2002; 12 : 313–320.12042669\n7 Gao F , Ballantyne C , Ma L , et al. Rare LPL gene variants attenuate triglyceride reduction and HDL cholesterol increase in response to fenofibric acid therapy in individuals with mixed dyslipidemia. Atherosclerosis 2014; 234 : 249–253.\n8 García‐Otín AL , Civeira F , Aristegui R , et al. Allelic polymorphism ‐491A/T in apo E gene modulates the lipid‐lowering response in combined hyperlipidemia treatment. Eur J Clin Investig 2002; 32 : 421–428.12059987\n9 Tenenbaum A , Fisman EZ . Balanced pan‐PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention? Cardiovasc Diabetol 2012; 11 : 140.23150952\n10 Chyzhyk V , Kozmic S , Brown AS , et al. Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence. J Clin Lipidol 2019; 13 : 89–99.30352774\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2040-1116",
"issue": null,
"journal": "Journal of diabetes investigation",
"keywords": "Hypertriglyceridemia; Lipoprotein lipase; Maternally inherited diabetes and deafness",
"medline_ta": "J Diabetes Investig",
"mesh_terms": null,
"nlm_unique_id": "101520702",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34460997",
"pubdate": "2021-08-30",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Maternally inherited diabetes and deafness coexists with lipoprotein lipase gene mutation-associated severe hyperlipidemia that was resistant to fenofibrate and atorvastatin, but sensitive to bezafibrate: A case report.",
"title_normalized": "maternally inherited diabetes and deafness coexists with lipoprotein lipase gene mutation associated severe hyperlipidemia that was resistant to fenofibrate and atorvastatin but sensitive to bezafibrate a case report"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-329349",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN NOS"
},
"dru... |
{
"abstract": "An elderly woman admitted in our geriatric inpatient unit suffered from disturbing outbursts of crying and, less frequently, episodes of laughing. The patient was diagnosed with pseudobulbar affect related to a mixed neurodegenerative disorder. This condition is often underdiagnosed and undertreated, despite being relatively frequent in patients with neurodegenerative disorders. This case report describes the treatment of pseudobulbar affect in this patient. The only available treatment in Canada for this condition, antidepressants, was not effective for our patient. Dextromethorphan/quinidine is a good accepted alternative, but the combination is not marketed in Canada. To manage this problem, we used compounded quinidine capsules and dextromethorphan cough syrup. The crying of our patient improved significantly and rapidly after the initiation of this treatment. This case will help professionals to review their central role in treating this complex and disabling condition.",
"affiliations": "Department of Pharmacy, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada.;Department of Geriatric Medicine, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada.;Department of Neurosciences, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.;Department of Geriatric Medicine, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada.",
"authors": "Villeneuve|Yannick|Y|https://orcid.org/0000-0001-9186-774X;Cruz-Santiago|Diana|D|;Masson|Helene|H|;Clerc|Doris|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X20921076",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20921076\n10.1177_2050313X20921076\nCase Report\nTreatment of pseudobulbar affect in a mixed neurodegenerative disorder with compounded quinidine capsules and dextromethorphan cough syrup\nhttps://orcid.org/0000-0001-9186-774XVilleneuve Yannick 1 Cruz-Santiago Diana 23 Masson Helene 4 Clerc Doris 5 1 Department of Pharmacy, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada\n2 Department of Geriatric Medicine, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada\n3 Department of Family and Emergency Medicine, Université de Montréal, Montreal, Quebec, Canada\n4 Department of Neurosciences, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada\n5 Department of Geriatric Medicine, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada\nYannick Villeneuve, Department of Pharmacy, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, H3W 1W5, Canada. Email: yannick.villeneuve.ccsmtl@ssss.gouv.qc.ca\n3 6 2020 \n2020 \n8 2050313X2092107631 8 2019 27 3 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).An elderly woman admitted in our geriatric inpatient unit suffered from disturbing outbursts of crying and, less frequently, episodes of laughing. The patient was diagnosed with pseudobulbar affect related to a mixed neurodegenerative disorder. This condition is often underdiagnosed and undertreated, despite being relatively frequent in patients with neurodegenerative disorders. This case report describes the treatment of pseudobulbar affect in this patient. The only available treatment in Canada for this condition, antidepressants, was not effective for our patient. Dextromethorphan/quinidine is a good accepted alternative, but the combination is not marketed in Canada. To manage this problem, we used compounded quinidine capsules and dextromethorphan cough syrup. The crying of our patient improved significantly and rapidly after the initiation of this treatment. This case will help professionals to review their central role in treating this complex and disabling condition.\n\nPseudobulbar affectcryinglaughingneurodegenerative disordergeriatricscompounded quinidine capsulesdextromethorphan cough syrupalternative Nuedexta®cover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nPseudobulbar affect (PBA) is a condition associated with excessive crying or laughing in situations that would normally not trigger this type of reaction. The reaction is either disproportionate or incongruent to the situation.1–3 This condition is relatively frequent in neurological disorders,4 but, according to a panel consensus, it is often underdiagnosed and undertreated.5 PBA can also be misdiagnosed with a psychiatric condition because of the presentation.6 One accepted treatment of PBA, dextromethorphan/quinidine (DM/Q) combination, is not available in Canada. This case report describes the treatment with compounded quinidine capsules and dextromethorphan cough syrup in a patient diagnosed with PBA related to a mixed neurodegenerative disorder. The role of the pharmacist was important in this case because it supported the medical team in having access to DM/Q and monitoring its efficacy and security. This case will help professionals review their central role in treating this complex and disabling condition.\n\nCase presentation\nAn 86-year-old woman admitted in our geriatric inpatient unit exhibited frequent episodes of involuntary, uncontrolled, particularly disturbing outbursts of crying and, less frequently, uncontrolled episodes of laughing. She also had episodes of wandering at night. The situation was becoming untenable and could not be managed by her husband anymore. Past medical history was positive for hypertension, osteoporosis, gait abnormality, nocturnal urinary incontinence, and Alzheimer’s disease (AD) with related behavioral problems. Her medications included amlodipine (2.5 mg daily), venlafaxine (75 mg daily), quetiapine (25 mg at bedtime), and calcium/vitamin D (500 mg/400 units daily). Parkinsonism was present on physical examination.\n\nThe initial workup included biochemical and laboratory investigation to exclude metabolic, inflammatory, hormonal, and toxic causes for dementia. All results were within normal limits. This patient had an obvious adverse impact on activities of daily living and, as she had a progressive and severe multi-domain cognitive decline, she could not perform an MMSE (Mini-Mental State Examination). Brain computerized tomography (CT) scan performed 4 years earlier showed mild cerebral atrophy and leukoaraiosis in the white matter regions of the brain (Figure 1). An electromyogram was performed to rule out motoneuron disease, which was negative. Magnetic resonance imaging (MRI) revealed nonspecific subcortical signal abnormalities of the white matter associated with subcortical ischemic changes and a left-sided cerebellar lacuna (Figure 2). Brain positron emission tomography (PET) with fluoro-2-deoxy-d-glucose (FDG) was in favor of a mixed neurodegenerative disorder, showing an altered metabolic pattern suggestive of AD dementia or/and dementia with Lewy bodies (DLB). DLB could explain the parkinsonism symptoms observed in the patient. She was seen by a psychiatrist who diagnosed dysregulation of affective expression without evidence of significant depressive or anxious symptoms. Following evaluation by a neurologist, PBA secondary to a mixed neurodegenerative disorder was considered the likely diagnosis. Imaging with dopamine transporter agents would have been helpful to obtain a more precise diagnosis, but it is not available at our center.\n\nFigure 1. CT brain showing mild cerebral atrophy and leukoaraiosis in the white matter regions of the brain.\n\nFigure 2. MRI brain showing (a) nonspecific subcortical signal abnormalities of the white matter associated with subcortical ischemic changes and (b) a left-sided cerebellar lacuna.\n\nVenlafaxine was stopped to try different medications. Table 1 describes the medication trials received by the patient during her hospitalization in order to reduce her crying and laughing symptoms. DM/Q was determined to be the most effective medication. A mild improvement was observed by the husband following 3 days of treatment. After 1 week, the effect was more apparent, as crying episodes were less frequent and of shorter duration. After 2 weeks, the crying episodes were reduced by 50% and wandering at night was less disturbing. At that point, the patient was discharged home with DM/Q and then 1 year later moved to a nursing home, where she died a few weeks after admission.\n\nTable 1. Medication trials during hospitalization.\n\nMedication\tDosage\tEffect\tDischarge\t\nCrying and laughing\t\n Mirtazapine\t30 mg daily\tNo effect\tNo\t\n Paroxetine\t15 mg daily\tNo effect\tNo\t\n Fluoxetine\t10 mg daily\tNo effect on PBA\nAkathisia\tNo\t\n Sertraline\t50 mg daily\tNo effect\tYes\t\n DM/Q\t20/10 mg daily × 1 week, then twice daily\tClinical global impression improved ⩾50% at discharge\tYes\t\n Oxazepam\t5 mg twice daily as needed\tHelping partially\tYes\t\nParkinsonism\t\n Levodopa/carbidopa\t50 mg twice daily\tWorsened behavior\tNo\t\nPBA: pseudobulbar affect; DM/Q: dextromethorphan/quinidine.\n\nDiscussion\nThe pathophysiology of PBA is not well established; the best hypothesis remains a disruption of the cortico–pontine–cerebellar circuit, resulting in a lack of emotional control.1,6 Several neurotransmitters are implicated in PBA, mostly serotonin and glutamate.1 This condition is associated with different neurological disorders such as stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), AD or Parkinson’s disease (PD).4 In one study, among several neurological disorders, the mean prevalence of PBA was 36.7%, and TBI was the most prevalent etiology at 52.4%.4 In our case, PBA was secondary to a mixed neurodegenerative disorder (possibly AD or/and DLB), which correlates with the scientific literature. Patients affected by PBA have an increased risk of social and relationship problems as well as psychiatric symptoms.1,6 The medical team initially considered relocating the patient to a nursing home because her husband was overwhelmed by the situation. Eventually, the DM/Q combination greatly helped in reducing her symptoms and allowed her to return home.\n\nThe most recent diagnostic criteria for PBA published by Miller et al.1 are listed in Table 2. The Center for Neurologic Study–Lability Scale (CNS-LS) is also helpful for PBA screening. Table 3 shows the self-report items of the CNS-LS developed by Moore et al.7 Each item must be evaluated on a scale of 1 to 5: 1 (never), 2 (rarely), 3 (occasionally), 4 (frequently), and 5 (most of the time).7 The CNS-LS is strictly validated for screening PBA in ALS and MS.2 Therefore, using this scale for neurological disorders other than ALS and MS, as was the case in our patient, requires caution. The CNS-LS cutoff point to detect PBA is 13 or more for ALS and 17 or more for MS.2 The case description and the neurologist evaluation confirmed that our patient had the four essential criteria seen in Table 2 to diagnose PBA.\n\nTable 2. Diagnostic criteria for PBA proposed by Miller et al.1\n\n\nEssential criteria\n\t\nPatient experiences episodes of involuntary or exaggerated emotional expression that result from a brain disorder, including episodes of laughing, crying, or related emotional displays.\t\nEpisodes represent a change in the patient’s usual emotional reactivity, are exaggerated or incongruent with the patient’s subjective emotional state, and are independent or in excess of the eliciting stimulus.\t\nEpisodes cause clinically significant distress or impairment in social or occupational functioning.\t\nThe symptoms cannot be attributed to another neurological or psychiatric disorder or to the effects of a substance.\t\n\nSupportive criteria\n\t\nPatient may experience accompanying autonomic changes (e.g. flushing of the face) and pseudobulbar signs (e.g. increased jaw jerk, exaggerated gag reflex, tongue weakness, dysarthria, and dysphagia).\t\nPatients may exhibit a proneness to anger.\t\nPBA: pseudobulbar affect.\n\nTable 3. Self-report items of the CNS-LS developed by Moore et al.7\n\n\nLaughter subscale\n\t\nI find that even when I try to control my laughter I am often unable to do so.\t\nI find that I am easily overcome by laughter.\t\nThere are times when I won’t be thinking of anything happy or funny at all, but then I’ll suddenly be overcome by funny or happy thoughts.\t\nOthers have told me that I seem to become amused very easily or that I seem to become amused about things that really aren’t funny.\t\n\nTearfulness subscale\n\t\nI find myself crying very easily.\t\nThere are times when I feel fine 1 min, and then I’ll become tearful the next over something small or for no reason at all.\t\nI find that even when I try to control my crying I am often unable to do so.\t\nCNS-LS: Center for Neurologic Study–Lability Scale.\n\nTable 4 summarizes the differential diagnosis of PBA. PBA can be misdiagnosed with psychiatric conditions, contributing to potentially unnecessary treatment and a risk of increasing adverse drug reactions or drug interactions.6 Two of the main features that help differentiate PBA from a psychiatric condition are the duration and the congruence of emotion.1,6 In PBA, the distress episode lasts from 1 s to a few minutes,8 and it is either disproportionate or incongruent to the situation.1,6 In contrast, the mood changes observed in a psychiatric condition persist in time and are usually congruent to the situation.1,6 The treatment of PBA is challenging as a depressive episode can coexist as frequently as 50% in patients with PBA.6 The psychiatric evaluation of our patient was helpful to eliminate comorbid psychiatric conditions.\n\nTable 4. Differential diagnostic of PBA.1,6\n\nPsychiatric conditions\t\n Depression\t\n Bipolar disorder\t\n Posttraumatic stress disorder\t\nRare conditions\t\n Essential crying\t\n Witzelsucht\t\n Epilepsy\t\nToxic effect of drugs\t\n Substance abuse\t\n Chemotherapy\t\n Other\t\n Euphoria in MS\t\nPBA: pseudobulbar affect; MS: multiple sclerosis.\n\nTreatment of PBA is described in Table 5. Published studies assessing the benefits of antidepressants in PBA are small, difficult to compare, and included patients where the underlying disorder was usually stroke.1 Response to antidepressants in PBA seems faster and occurs at lower doses than in psychiatric conditions.2 The only approved treatment of PBA by the Food and Drug Administration (FDA) and the European Union (EU) is DM/Q.9 The active drug dextromethorphan is an N-methyl-d-aspartate receptor antagonist and a sigma-1 receptor agonist.3,9 Quinidine is only necessary to increase the concentration of dextromethorphan by inhibiting the cytochrome P450 2D6 (CYP2D6).3,9 DM/Q was first studied in MS and ALS,2,3,9 but recently in the PRISM II trial,8 DM/Q was effective in patients with dementia and PBA. Our patient could be compared to the PRISM II study as their population included different types of dementia. There is no head-to-head study comparing antidepressants and DM/Q, but the clinical experience of one clinician seems to suggest that DM/Q could be associated with a better response in PBA.2 We could argue the same with our case, as the outcome was considerably better with DM/Q compared to several antidepressants. Her crying episodes improved significantly and rapidly after the initiation of DM/Q, so we did not need to monitor the effectiveness of the medication with the evolution of CNS-LS score.\n\nTable 5. Double-blind studies in the treatment of PBA.2\n\nMedication\tDose\t\nAmitriptyline\tMean dosage of 57.8 mg daily, but the maximum dosage used is 75 mg daily\t\nNortriptyline\t20 mg daily × 1 week, 50 mg daily × 2 weeks, 70 mg daily × 1 week, then 100 mg daily\t\nCitalopram\t⩾65 years old: 20 mg daily\n<65 years old: 10 mg daily\t\nFluoxetine\t20 mg daily\t\nSertraline\t50 mg daily but may increase to 100 mg daily after 4 weeks at 50 mg daily\t\nDM/Q\t• FDA: 20/10 mg daily × 1 week, then twice daily3\n\n• EU: Same as FDA, but if the response is not achieved after 3 weeks at 20/10 mg twice daily, then may increase to 30/10 mg twice daily9\t\nDM/Q: dextromethorphan/quinidine; FDA: Food and Drug Administration; EU: European Union.\n\nThe most frequent adverse drug reactions from short-term trial of DM/Q are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, elevated gamma-glutamyltransferase, and flatulence.3 An electrocardiogram (ECG) is recommended after the first dose of DM/Q to monitor the QT interval,3 even though, according to the European Medicines Agency, there is a low risk of QT prolongation for patients without cardiac disease.9 The QT interval of our patient was normal after the first dose of DM/Q. Recognizing quinidine is a CYP2D6 inhibitor, drug interactions must be considered, especially if the interaction involves a drug that prolongs QT interval.3,9 Moreover, quinidine is metabolized by CYP3A4; CYP3A4 inducers or CYP3A4 inhibitors must therefore be avoided.9 CYP3A4 inhibitors could increase the risk of QT prolongation.9 The use of an antidepressant with DM/Q should be approached with caution due to a possible risk of pharmacokinetic or pharmacodynamic interactions (QT prolongation, serotonin syndrome), depending on the antidepressant.10 Finally, quinidine is a P-glycoprotein inhibitor.3,9 The sertraline could have been reassessed for our patient when we noticed the effectiveness of DM/Q, but the medical team decided to keep it as they did not want to risk any deterioration. Indeed, the goal of care was to provide comfort, which was much improved compared to her state upon admission. We considered the risk of interaction low, and the combination was well tolerated.\n\nSince DM/Q is not available in Canada, we had to find an alternative for our patient. First, we used the expertise of a pharmaceutical laboratory to make compounded 10 mg quinidine capsules. As we did not know whether the patient would need 20 or 30 mg of dextromethorphan, we determined that a dextromethorphan cough syrup was an easy available option to facilitate the titration. However, we stopped at 20 mg, as it achieved a good effectiveness. Interestingly, we found two case reports with positive response for PBA in which DM/Q was changed to dextromethorphan cough syrup plus fluoxetine, considering fluoxetine is also a CYP2D6 inhibitor.11,12 This treatment combination was not considered for our patient as she had presented akathisia induced by fluoxetine.\n\nConclusion\nPBA is a common finding in neurological disorders and it must not be confused with a psychiatric condition. Good patient care is essential to minimize the disruptive consequences of PBA on the patient and his or her family. A subset of patients will not respond to antidepressants for treating PBA; in this case, DM/Q is a good alternative. This case report could help pharmacists and other professionals considering compounded quinidine capsules and dextromethorphan cough syrup as an alternative to the marketed DM/Q combination when it is not available. The pharmacist can play an important role in supporting the medical team in the treatment and monitoring of patients with this condition.\n\nThe authors thank Audrey Attia for her support with the literature search, Theresa Feeser for editing the manuscript, and Dr David Landry for selecting CT/MRI images. All of the authors approved the final version and agreed to be accountable for all aspects of the work.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed consent: Written informed consent was obtained from a legally authorized representative for anonymized patient information to be published in this article.\n\nORCID iD: Yannick Villeneuve \nhttps://orcid.org/0000-0001-9186-774X\n==== Refs\nReferences\n1 \nMiller A Pratt H Schiffer RB. \nPseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments\n. Expert Rev Neurother \n2011 ; 11 (7 ): 1077 –1088\n.21539437 \n2 \nPioro EP. \nCurrent concepts in the pharmacotherapy of pseudobulbar affect\n. Drugs \n2011 ; 71 (9 ): 1193 –1207\n.21711063 \n3 \nCruz MP. \nNuedexta for the treatment of pseudobulbar affect: a condition of involuntary crying or laughing\n. P T \n2013 ; 38 (6 ): 325 –328\n.23946627 \n4 \nBrooks BR Crumpacker D Fellus J , et al\nPRISM: a novel research tool to assess the prevalence of pseudobulbar affect symptoms across neurological conditions\n. PLOS ONE \n2013 ; 8 (8 ): e72232 .23991068 \n5 \nArciniegas DB Lauterbach EC Anderson KE , et al\nThe differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting\n. CNS Spectr \n2005 ; 10 (5 ): 1 –14\n; quiz 15–16.\n6 \nSauve WM. \nRecognizing and treating pseudobulbar affect\n. CNS Spectr \n2016 ; 21 (S1): 34 –44\n.28044945 \n7 \nMoore SR Gresham LS Bromberg MB , et al\nA self report measure of affective lability\n. J Neurol Neurosurg Psychiatry \n1997 ; 63 (1 ): 89 –93\n.9221973 \n8 \nDoody RS D’Amico S Cutler AJ , et al\nAn open-label study to assess safety, tolerability, and effectiveness of dextromethorphan/quinidine for pseudobulbar affect in dementia: PRISM II results\n. CNS Spectr \n2016 ; 21 (6 ): 450 –459\n.26471212 \n9 \nYang LP Deeks ED \nDextromethorphan/quinidine: a review of its use in adults with pseudobulbar affect\n. Drugs \n2015 ; 75 (1 ): 83 –90\n.25420446 \n10 \nSchoedel KA Morrow SA Sellers EM. \nEvaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect\n. Neuropsychiatr Dis Treat \n2014 ; 10 : 1161 –1174\n.25061302 \n11 \nButler MI Williams D Cotter DR. \nCough suppressant and fluoxetine in the treatment of pseudobulbar affect: a case report\n. J Clin Psychopharmacol \n2016 ; 36 (5 ): 525 –526\n.27496344 \n12 \nMcGrane I VandenBerg A Munjal R. \nTreatment of pseudobulbar affect with fluoxetine and dextromethorphan in a woman with multiple sclerosis\n. Ann Pharmacother \n2017 ; 51 (11 ): 1035 –1036\n.28691510\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "8()",
"journal": "SAGE open medical case reports",
"keywords": "Pseudobulbar affect; alternative Nuedexta®; compounded quinidine capsules; crying; dextromethorphan cough syrup; geriatrics; laughing; neurodegenerative disorder",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X20921076",
"pmc": null,
"pmid": "32547756",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "28691510;28044945;26471212;21711063;23946627;21539437;25420446;9221973;27496344;25061302;15962457;23991068",
"title": "Treatment of pseudobulbar affect in a mixed neurodegenerative disorder with compounded quinidine capsules and dextromethorphan cough syrup.",
"title_normalized": "treatment of pseudobulbar affect in a mixed neurodegenerative disorder with compounded quinidine capsules and dextromethorphan cough syrup"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-252169",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drug... |
{
"abstract": "Several sophisticated techniques and many chemotherapy drugs have improved life expectancy of oncologic patients allowing us to observe late complications which present many years after the initial treatment.\nWe present a unique case of a patient affected by acute lymphoblastic leukemia at the age of 6 years, treated with whole brain radiotherapy and intrathecal chemotherapy, developing meningiomatosis and leptomeningeal alterations as late complications and the interaction of these two entities caused a peculiar form of hydrocephalus without ventricular dilation. The diagnosis of pseudotumor cerebri was excluded due the postradio/chemotherapy development of meningiomatosis, not present in a previously head magnetic resonance imaging, that exerted compression to the Sylvian aqueduct causing intracranial hypertension with papillary stasis without ventricles enlargement due to brain stiffness. Moreover, a peculiar intraoperative rubbery consistency of brain parenchyma was detected strengthening this complex diagnosis.\nAt the best of our knowledge, this is the first report of obstructive hydrocephalus without ventricles dilation caused by brain stiffness related to late alterations of oncologic treatments. This report could be a guide for further complex patients diagnoses and for improving treatments efficacy.",
"affiliations": "Department of Neurosurgery, Cannizzaro Hospital, Via Messina 829, Catania.;Department of Neurosurgery, Hospital \"San Gerardo,\" Via G. B. Pergolesi 33, Monza, Italy.;Department of Neurosurgery, Cannizzaro Hospital, Via Messina 829, Catania.;Department of Neurosurgery, Cannizzaro Hospital, Via Messina 829, Catania.;Department of Amethyst Radiotherapy Center, San Giovanni Calibita Fatebenefratelli Hospital, Tiber Island, Rome.;Department of Neurosurgery, Cannizzaro Hospital, Via Messina 829, Catania.;Department of Neurosurgery, Cannizzaro Hospital, Via Messina 829, Catania.;Neurosurgery Unit, Highly Specialized Hospital and of National Importance \"Garibaldi\", Piazza Santa Maria di Gesù 5, Catania, Italy.;Department of Neurosurgery, Cannizzaro Hospital, Via Messina 829, Catania.;Neurosurgery Unit, Highly Specialized Hospital and of National Importance \"Garibaldi\", Piazza Santa Maria di Gesù 5, Catania, Italy.",
"authors": "Umana|Giuseppe Emmanuele|GE|;Raudino|Giuseppe|G|;Alberio|Nicola|N|;Inserra|Francesco|F|;Giovinazzo|Giuseppe|G|;Fricia|Marco|M|;Chiriatti|Stefano|S|;Nicoletti|Giovanni Federico|GF|;Cicero|Salvatore|S|;Scalia|Gianluca|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.25259/SNI_145_2020",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097 2152-7806 Scientific Scholar USA \n\nSNI-11-219\n10.25259/SNI_145_2020\nCase Report\nSlit-like hypertensive hydrocephalus: Report of a late, complex, and multifactorial complication in an oncologic patient\nUmana Giuseppe Emmanuele 1umana.nch@gmail.com Raudino Giuseppe 2giuraudino@hotmail.it Alberio Nicola 1n.alberio@tin.it Inserra Francesco 1inserrafrancesco@hotmail.com Giovinazzo Giuseppe 3g.v.giovinazzo@gmail.com Fricia Marco 1marco.fricia@aoec.it Chiriatti Stefano 1stefanochiriatti@libero.it Nicoletti Giovanni Federico 4gfnicoletti@alice.it Cicero Salvatore 1cicerosalvatore@yahoo.it Scalia Gianluca 4gianluca.scalia@outlook.it 1 Department of Neurosurgery, Cannizzaro Hospital, Via Messina 829, Catania,\n2 Department of Neurosurgery, Hospital “San Gerardo,” Via G. B. Pergolesi 33, Monza, Italy,\n3 Department of Amethyst Radiotherapy Center, San Giovanni Calibita Fatebenefratelli Hospital, Tiber Island, Rome,\n4 Neurosurgery Unit, Highly Specialized Hospital and of National Importance “Garibaldi”, Piazza Santa Maria di Gesù 5, Catania, Italy.\n* Corresponding author: Giuseppe Emmanuele Umana, MD, MSc, AACS, Department of Neurosurgery, Cannizzaro Hospital, Trauma Center, Gamma Knife Center, Via Messina, 829, Catania - 95126, Italy. mana.nch@gmail.com\n2020 \n01 8 2020 \n11 21931 3 2020 07 7 2020 Copyright: © 2020 Surgical Neurology International2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background: \nSeveral sophisticated techniques and many chemotherapy drugs have improved life expectancy of oncologic patients allowing us to observe late complications which present many years after the initial treatment.\n\nCase Description: \nWe present a unique case of a patient affected by acute lymphoblastic leukemia at the age of 6 years, treated with whole brain radiotherapy and intrathecal chemotherapy, developing meningiomatosis and leptomeningeal alterations as late complications and the interaction of these two entities caused a peculiar form of hydrocephalus without ventricular dilation. The diagnosis of pseudotumor cerebri was excluded due the postradio/chemotherapy development of meningiomatosis, not present in a previously head magnetic resonance imaging, that exerted compression to the Sylvian aqueduct causing intracranial hypertension with papillary stasis without ventricles enlargement due to brain stiffness. Moreover, a peculiar intraoperative rubbery consistency of brain parenchyma was detected strengthening this complex diagnosis.\n\nConclusion: \nAt the best of our knowledge, this is the first report of obstructive hydrocephalus without ventricles dilation caused by brain stiffness related to late alterations of oncologic treatments. This report could be a guide for further complex patients diagnoses and for improving treatments efficacy.\n\nHydrocephalusIntrathecal chemotherapyMeningiomatosisRadiotherapySlit ventricle\n==== Body\nINTRODUCTION\nLife expectancy of oncologic patients, both adults and pediatric, has progressively improved with the development of modern treatments and diagnostics. Several sophisticated techniques and many chemotherapy drugs fit with the single patient’s needs. A positive consequence of these improvements is the emergence of long-term survivors. This has led to very long follow-ups that can teach us important lessons, as now we have the chance to observe late complications which present many years after the initial treatment.\n\nWe present a unique case of a patient affected by acute lymphoblastic leukemia at the age of 6 years, treated with whole brain radiotherapy (WBRT) and intrathecal chemotherapy, who developed cerebral meningiomatosis and leptomeningeal alterations as late complications, and the interaction of these two entities caused a peculiar form of hydrocephalus without ventricular dilation.\n\nCASE DESCRIPTION\nClinical presentation\nA 35-year-old female was admitted to our institution because she had been suffering from progressive headaches for about 10 years – referred as debilitating in the past 6 months – which worsen with emotions like rage or concern, associated with blurred vision and tinnitus. Mini-mental state examination (MMSE) gave a score of 23.\n\nMedical history\nHer clinical history was positive for acute lymphoblastic leukemia, diagnosed in 1990 and treated with AIEOP 8703 protocol (cobalt radiotherapy [RT] in pediatric age and intrathecal chemotherapy with IV vincristine, IV daunorubicin, prednisone, methotrexate intrathecal, and IM L-asparaginase). In 1995, she was declared in complete remission. A right oophorectomy at the age of 9, caused by ovarian torsion, was also reported. In 2000, she underwent brain magnetic resonance imaging (MRI) that did not find pathological alterations. In 2011, she underwent in vitro fertilization, which unfortunately failed.\n\nPreoperative imaging and instrumental assessment\nThe patient underwent in-depth investigation that documented cerebral meningiomatosis, characterized by 5 meningiomas, <3 cm each, located at the right cerebral middle fossa, at the border of the right tentorium, at the torcula, at the middle third of the superior sagittal sinus (SSS), and at the left Sylvian fissure; a T2-weighted brain MRI sequence documented a typical bilateral enlargement of optic nerve sheath, related to intracranial hypertension; of notice, ventricles were not enlarged, but they presented slit-like aspect [Figure 1]. Considering that the tentorial meningioma was compressing the Sylvian aqueduct, an MRI with cerebrospinal fluid (CSF) flowmetry was performed revealing an irregular pattern at the level of Sylvian aqueduct [Figure 2]; cerebral MR venography showed normal venous flow at the level of the SSS, due to the fact that the meningiomas were of little size and in T1-weighted gadolinium-enhanced images, there was no invasion of the SSS. Initially, the patient underwent medical therapy based on acetazolamide, without clinical benefit. Then, the patient underwent a 72 h spinal CSF drainage connected to LiquoGuard® system that showed elevated intracranial pressure (ICP) values, ranging between 13 and 21 mmHg/24 h with a mean value of 17 mmHg. Subsequently, she reported a transitory relief of symptoms with a corresponding decrease in ICP equal to a mean value of 13 mmHg. The patient was then addressed to the ophthalmologist, who documented a bilateral papillary stasis. At the beginning, a diagnosis of pseudotumor cerebri was made but it was object of controversies during multidisciplinary oncologic discussions. We repeated brain MRI scan, fundus oculi examination, and we performed PET scan with gallium to confirm the meningiomatosis hypothesis, with the plan to perform Gamma Knife treatment to control at least some of the meningiomas.\n\nFigure 1: Gadolinium T1-weighted magnetic resonance imaging images showing postcontrast enhancement of five meningiomas, <3 cm each, located at the right cerebral middle fossa, at the border of the right tentorium, at the torcula, at the middle third of the superior sagittal sinus , and at the left Sylvian fissure (a). T2-weighted sequences documented typical bilateral enlargement of optic nerve sheath, related to intracranial hypertension; of notice, ventricles were not enlarged, conversely, they present slit-like aspect (b). T2-weighted Turbo spin echo brain magnetic resonance imaging sequences showing normal representation of cisterns and sulci that rule out the hypothesis of pseudotumor cerebri (c).\n\nFigure 2: Brain magnetic resonance imaging with cerebrospinal fluid flowmetry revealed an irregular pattern at the level of the Sylvian aqueduct, resulting in its reduced diameter due to compression by the right tentorial meningioma\n\nClinical considerations and management\nIn our opinion, the patient was not affected by pseudotumor cerebri due to the normal global brain anatomy with good representation of the cisterns and sulci and the very high ICP values. Our hypothesis was that the absence of hydrocephalus was related to previous RT and intrathecal chemotherapy in pediatric age and that the tentorial meningioma causes compression of the Sylvian aqueduct; we elaborated two options for a multimodal treatment strategy: (a) surgical resection of the tentorial meningioma and Gamma Knife treatment to control the other lesions, with ventriculoperitoneal shunt (VPS) to be considered in a second surgical time after clinical postoperative evaluation and (b) VPS to resolve intracranial hypertension and radiosurgery to control mainly the tentorial meningioma and avoid further growth with associated compression of the brainstem. In agreement with the patient, we decided to perform the latter option. First, she underwent Gamma Knife treatment of the tentorial meningioma because the presence of the ventricular catheter could cause artifacts and negatively affect the accuracy of radiosurgery planning. The following day, with the guidance of the neuronavigation, we introduced the ventricular catheter at the right Kocher’s point and connected the distal catheter with a single route, without the typical skin interruption at the cervical level, to the peritoneum in the epigastric-suprahepatic site. A programmable valve with virtual off option was implanted and set at the 5th setting (145 mmH2O).\n\nPostoperative imaging and clinical follow-up\nThe postoperative period was uneventful, a postoperative brain computed tomography scan [Figure 3] showed correct catheter positioning and stability of the ventricular diameters. The patient had a fast recovery with resolution of headache, visual disturbance, and tinnitus. A postoperative fundus oculi and optical coherence tomography scan documented an improvement of papillary stasis and a significant improvement in the thickness of the optic nerve fibers.\n\nFigure 3: Postoperative head computed tomography scan showed correct catheter positioning and stability of the ventricular diameters.\n\nAfter a 6-month follow-up, she is doing well, without clinical disturbance. MMSE gave a score of 25. She will continue to be followed for the other meningiomas and the VPS function with brain MRI every year and further Gamma Knife treatment of the lesions.\n\nDISCUSSION\nIt is known that RT in children affected by cancer can cause structural changes in the brain, linked to cognitive late effects [3,18,20] These effects can clinically manifest as cognitive, behavioral, social, or hormonal deficits, months, or years after RT.[1,8] There are several reports of significant reductions in total white matter volume after cranial RT in cancer survivors.[16,18] Radiation injury causes cellular changes, including alterations in neuronal cytoarchitecture,[17] loss of oligodendrocyte and oligodendrocyte precursor cell populations,[2,17] and impaired neurogenesis.[6,14] In mice, brain structure changes after RT are consistent with observations in human survivors.[15] During the developmental period, the entity of radiation damage to one brain region is difficult to assess globally, as the brain is an exceedingly interconnected organ, with interdependence mediated not only by neuronal connections but also related to cellular migration, vascular supply, physical restrictions, and other factors. As a result, radiation damage to one brain area can cause a global perturbation of the brain development.\n\nThe aim of intrathecal chemotherapy is to increase central nervous system drug exposure through direct CSF introduction, while reducing systemic drug toxicity.[7,11]\n\nIntrathecal chemotherapy can cause potentially tragic effects. Chemical arachnoiditis, characterized by headache, back pain, vomiting, fever, meningism, and CSF pleocytosis, is common and potentially serious consequences.[5,13] Far worse symptoms also have been described, such as cauda equina syndrome, seizures, paraplegia, papilledema, encephalitis, cranial nerve palsies, and myelopathy.[5,19]\n\nGállego Pérez-Larraya et al.[9] reported that 28% of patients affected by non-Hodgkin lymphoma and treated with intrathecal liposomal cytarabine developed moderate or severe neurotoxicity. In our opinion, the patient was not affected by pseudotumor cerebri due to good representation of the cisterns and sulci despite the presence of multiple meningiomas. Our hypothesis was that the tentorial meningioma caused compression to the Sylvian aqueduct, but this hypothesis was debated, as there was no ventricular dilation. After multidisciplinary oncological discussion, we focused on the clinical history, characterized by WBRT and intrathecal chemotherapy in pediatric age. We hypothesized that the RT could have caused the development of meningiomatosis; WBRT in pediatric age could have altered the normal compliance of the brain parenchyma, justifying its resistance to intracranial hypertension, which prevented the development of the typical radiological finding of the hydrocephalus, but not the indirect signs of the duplication of optic nerve sheaths on the brain MRI and stasis papillae at the fundus oculi examination. RT and the combination of intrathecal chemotherapy resulted in reactive ependymitis, with increased ventricular stiffness as well as reduced compliance. Clearly, the meninges had also been affected with an increase of pial stiffness. Our theory was confirmed during surgery by the fact that after dural opening, on coagulation of the brain parenchyma, usually made to avoid bleeding during catheter introduction, presented the peculiar characteristic of a rubbery consistence, and it was not possible to proceed further with bipolar forceps, forcing the surgeon to use a #11 scalpel to incise the parenchyma which was then coagulated, although it was bleeding less. At the best of our knowledge, this is the first report of such a condition, which we can define as slit-like hydrocephalus causing intracranial hypertension as a rare multifactorial complication of RT and intrathecal chemotherapy in pediatric age, Sylvian aqueduct compression caused by meningioma in a patient affected by meningiomatosis, which is in itself a challenging condition to manage, due to the young age of the patient. The present report, although unique, presents two main limitations linked to the documentation of the cerebral stiffness. First, we thought to perform a brain biopsy during the shunt procedure to evaluate histopathological alterations, but the patient did not give her consent to such an invasive sampling. Second, we discussed about the possibility to perform magnetic resonance elastography (MRE), which is an emerging technique to evaluate brain stiffness in neurodegenerative pathologies, to study meningiomas consistency and patients affected by hydrocephalus. However, MRE is an experimental technology, and there are conflicting data about the brain areas to evaluate and obtain pathognomonic results of brain stiffness.[4,10,12,21] Moreover, the patient was treated 29 years before our observation, and it was impossible to have MRE data to compare with the brain consistency before the radiochemotherapy treatments. Finally, we do not have the possibility to perform MRE in our region, but we are planning to provide it and to follow-up the patient with MRE to study eventual further brain stiffness modification.\n\nCONCLUSION\nWith the present report, we suggest an in-depth and complex diagnosis to justify a very rare case characterized by concomitant pathologies, multifactorial direct and indirect effects of the disease, and late radio/chemotherapy side effects. At the best of our knowledge, this is the first report of obstructive hydrocephalus without ventricles dilation caused by brain stiffness related to oncologic treatments. To achieve these complex diagnostic conclusions, we conducted a multidisciplinary and multicentric debate. This report could be a guide for further complex patients diagnoses and for improving treatments efficacy. MRE could represent a useful tool, if available, but further implementation and validation of the technique are required.\n\nHow to cite this article: Umana GE, Raudino G, Alberio N, Inserra F, Giovinazzo G, Fricia M, et al. Slit-like hypertensive hydrocephalus: Report of a late, complex, and multifactorial complication in an oncologic patient. Surg Neurol Int 2020;11:219.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Armstrong GT Liu Q Yasui Y Huang S Ness KK Leisenring W Long-term outcomes among adult survivors of childhood central nervous system malignancies in the childhood cancer survivor study J Natl Cancer Inst 2009 101 946 58 19535780 \n2 Atkinson S Li YQ Wong CS Changes in oligodendrocytes and myelin gene expression after radiation in the rodent spinal cord Int J Radiat Oncol Biol Phys 2003 57 1093 100 14575841 \n3 Beera KG Li YQ Dazai J Stewart J Egan S Ahmed M Altered brain morphology after focal radiation reveals impact of off-target effects: Implications for white matter development and neurogenesis Neuro Oncol 2018 20 788 98 29228390 \n4 Bertalan G Klein C Schreyer S Steiner B Kreft B Tzschätzsch H Biomechanical properties of the hypoxic and dying brain quantified by magnetic resonance elastography Acta Biomater 2020 101 395 402 31726251 \n5 Bleyer WA The clinical pharmacology of methotrexate: New applications of an old drug Cancer 1978 41 36 51 342086 \n6 Boström M Kalm M Karlsson N Erkenstam NH Blomgren K Irradiation to the young mouse brain caused long-term, progressive de pletion of neurogenesis but did not disrupt the neurovascular niche J Cereb Blood Flow Metab 2013 33 935 43 23486289 \n7 Byrnes DM Vargas F Dermarkarian C Kahn R Kwon D Hurley J Complications of intrathecal chemotherapy in adults: Single-institution experience in 109 consecutive patients J Oncol 2019 2019 4047617 31186634 \n8 Dennis M Spiegler BJ Hetherington CR Greenberg ML Neuropsychological sequelae of the treatment of children with medulloblastoma J Neurooncol 1996 29 91 101 8817420 \n9 Gàllego Pérez-Larraya JG Palma JA Carmona-Iragui M Fernández-Torrón R Irimia P Rodríguez-Otero P Neurologic complications of intrathecal liposomal cytarabine administered prophylactically to patients with non-Hodgkin lymphoma J Neurooncol 2011 103 603 9 20953897 \n10 Kalra P Raterman B Mo X Kolipaka A Magnetic resonance elastography of brain: Comparison between anisotropic and isotropic stiffness and its correlation to age Magn Reson Med 2019 82 671 9 30957304 \n11 Kerr JZ Berg S Blaney SM Intrathecal chemotherapy Crit Rev Oncol Hematol 2001 37 227 36 11248578 \n12 Kurt M Wu L Laksari K Ozkaya E Suar ZM Lv H Optimization of a multifrequency magnetic resonance elastography protocol for the human brain J Neuroimaging 2019 29 440 6 31056818 \n13 Kwong YL Yeung DY Chan JC Intrathecal chemotherapy for hematologic malignancies: Drugs and toxicities Ann Hematol 2009 88 193 201 19050889 \n14 Monje ML Mizumatsu S Fike JR Palmer TD Irradiation induces neural precursor-cell dysfunction Nat Med 2002 8 955 62 12161748 \n15 Nieman BJ de Guzman AE Gazdzinski LM Chakravarty MM Pipitone J Strother D White and gray matter abnormalities after cranial radiation in children and mice Int J Radiat Oncol Biol Phys 2015 93 882 91 26530758 \n16 Palmer SL Reddick WE Glass JO Gajjar A Goloubeva O Mulhern RK Decline in corpus callosum volume among pediatric patients with medulloblastoma: Longitudinal MR imaging study AJNR Am J Neuroradiol 2002 23 1088 94 12169462 \n17 Parihar VK Limoli CL Cranial irradiation compromises neuronal architecture in the hippocampus Proc Natl Acad Sci USA 2013 110 12822 7 23858442 \n18 Reddick WE Glass JO Palmer SL Wu S Gajjar A Langston JW Atypical white matter volume development in children following craniospinal irradiation Neuro Oncol 2005 7 12 9 15701278 \n19 Resar LM Phillips PC Kastan MB Leventhal BG Bowman PW Civin CI Acute neurotoxicity afer intrathecal cytosine arabinoside in two adolescents with acute lymphoblastic leukemia of B-cell type Cancer 1993 71 117 23 8416707 \n20 Riggs L Bouffet E Laughlin S Laperriere N Liu F Skocic J Changes to memory structures in children treated for posterior fossa tumors J Int Neuropsychol Soc 2014 20 168 80 24460980 \n21 Takamura T Motosugi U Sasaki Y Kakegawa T Sato K Glaser KJ Influence of age on global and regional brain stiffness in young and middle-aged adults J Magn Reson Imaging 2019 51 727 33 31373136\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "11()",
"journal": "Surgical neurology international",
"keywords": "Hydrocephalus; Intrathecal chemotherapy; Meningiomatosis; Radiotherapy; Slit ventricle",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "219",
"pmc": null,
"pmid": "32874722",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "19050889;26530758;14575841;8416707;15701278;29228390;23858442;30957304;8817420;23486289;12169462;24460980;19535780;31373136;31056818;20953897;31186634;11248578;31726251;342086;12161748",
"title": "Slit-like hypertensive hydrocephalus: Report of a late, complex, and multifactorial complication in an oncologic patient.",
"title_normalized": "slit like hypertensive hydrocephalus report of a late complex and multifactorial complication in an oncologic patient"
} | [
{
"companynumb": "IT-TEVA-2020-IT-1857876",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
"drugadditional": null,
... |
{
"abstract": "Ingestion of viscous lidocaine in children can lead to potentially lethal neurologic and cardiac effects. We report the case of a 2-year-old boy who developed posterior reversible encephalopathy syndrome 2 days after unobserved ingestion of about 500 mg viscous lidocaine (40 mg/kg of bodyweight). Initially, the child presented with convulsive status epilepticus and subsequent cardiac arrest necessitating cardiopulmonary resuscitation for eight minutes. After 2 days of full recovery, the child presented with progressive disorientation, dizziness, and visual neglect. Lasting for 2 days, these symptoms finally disappeared completely. Combined with the findings on cerebral magnetic resonance imaging, this episode was interpreted as posterior reversible encephalopathy syndrome. Two weeks after the ingestion, no neurologic and visual abnormalities were found. Viscous lidocaine is prescribed routinely for dentition or other painful lesions in the oral cavity in children. Despite the potential hazardousness of the drug, packaging of viscous lidocaine is not childproof. Therefore, physicians have to instruct the parents carefully to minimize the risk of overuse or accidental ingestion. In general, the use of viscous lidocaine should be limited.",
"affiliations": "From the Departments of *Pediatric Surgery, †Pediatric Anesthesiology and Critical Care Medicine, and ‡Pediatrics, Women's and Children's Hospital Linz, Austria.",
"authors": "Kargl|Simon|S|;Hornath|Franz|F|;Rossegg|Ulrike|U|;Biebl|Ariane|A|;Pumberger|Wolfgang|W|;Schmitt|Klaus|K|;Furtner|Dieter|D|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000091",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "30(3)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000779:Anesthetics, Local; D016887:Cardiopulmonary Resuscitation; D002675:Child, Preschool; D004349:Drug Packaging; D004435:Eating; D006323:Heart Arrest; D006801:Humans; D008012:Lidocaine; D008297:Male; D054038:Posterior Leukoencephalopathy Syndrome; D013226:Status Epilepticus",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "185-7",
"pmc": null,
"pmid": "24589808",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Status epilepticus, cardiac resuscitation, and posterior reversible encephalopathy syndrome after ingestion of viscous lidocaine: a plea for more childproof packaging of pharmaceuticals.",
"title_normalized": "status epilepticus cardiac resuscitation and posterior reversible encephalopathy syndrome after ingestion of viscous lidocaine a plea for more childproof packaging of pharmaceuticals"
} | [
{
"companynumb": "AT-WATSON-2015-01262",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Cutaneous mucormycosis is a rare, often fatal fungal infection that most commonly affects patients with underlying immunosuppression but also can occur in premature neonates. We report the case of an extremely premature boy (<25 weeks) who developed primary cutaneous mucormycosis shortly after birth. Although surgical debridement has been a mainstay of treatment in combination with antifungal therapy, our patient was successfully treated with amphotericin B alone-the management only reported in three other cases to date. We present this case to highlight that prompt initiation of treatment with amphotericin B alone may be an appropriate alternative to surgical intervention, particularly in patients with non-angioinvasive disease who are poor surgical candidates.",
"affiliations": "University of Virginia School of Medicine, Charlottesville, Virginia, USA.;Department of Dermatology, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Dermatology, University of Virginia Health System, Charlottesville, Virginia, USA.;Department of Dermatology, University of Virginia Health System, Charlottesville, Virginia, USA.",
"authors": "Vittitow|Stephany L|SL|https://orcid.org/0000-0003-1360-5837;Rusu|Corina A|CA|;Abubakar|Maryam O|MO|;Burnsed|Jennifer|J|;Gru|Alejandro A|AA|https://orcid.org/0000-0002-2573-8074;Zlotoff|Barrett J|BJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": null,
"journal": "Pediatric dermatology",
"keywords": "amphotericin B; conservative treatment; infant newborn diseases; mucormycosis; premature birth",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8406799",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34888931",
"pubdate": "2021-12-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Primary cutaneous mucormycosis in a premature neonate treated conservatively with amphotericin B.",
"title_normalized": "primary cutaneous mucormycosis in a premature neonate treated conservatively with amphotericin b"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2022US023964",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPICILLIN"
},
"drugadditional": "3",
... |
{
"abstract": "Anti-neutrophil cytoplasmic antibodies (ANCA) play an important role in the pathogenesis of pauci-immune renal vasculitis. However, in 10% of the cases, ANCA are absent. We present a case of a 64-year-old man with a chronic untreated hepatitis C virus infection and Middle Eastern thalassemia who was ANCA-negative when he was hospitalized due to acute kidney injury and accounts for an uncommon presentation of renal vasculitis. The patient had earlier reported to have undergone local lobectomy and adjuvant chemotherapy (carboplatin/pemetrexed) for lung adenocarcinoma a month prior. IL-6 has been reported to be involved in the pathophysiological cascade causing pauci-immune glomerulonephritis amongst non-small cell lung cancer patients. Previous studies with subgroup analysis have demonstrated that ANCA negativity has been associated with more chronic glomerular lesions and less crescent formation, which tends to have a critical outcome in the renal system. However, our patient underwent kidney biopsy exhibiting active crescentic glomerulonephritis, pauci-immune type with 5 cellular crescents amongst 15 glomeruli. To our knowledge, this is the third reported case of ANCA-negative vasculitis with typical presentation on biopsy in non-small cell lung cancer patients.",
"affiliations": "New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA.;JSS Medical College, Mysuru, India.;New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA.;New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA.;New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA.",
"authors": "Kancharla|Pragnan|P|;Surapaneni|B K|BK|;Goldfinger|M|M|;Hennrick|K|K|;Ozeri|David J|DJ|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000490101",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000490101cro-0011-0372Case ReportParaneoplastic Seronegative Pauci-Immune Glomerulonephritis Associated with Lung Adenocarcinoma Responds to Rituximab: A Case Report Kancharla Pragnan a*Surapaneni B.K. bGoldfinger M. aHennrick K. aOzeri David J. aaNew York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USAbJSS Medical College, Mysuru, India*Pragnan Kancharla, MD, New York-Presbyterian Brooklyn Methodist Hospital, 506 6th Street, Brooklyn, NY 11215 (USA), E-Mail pragnan1992@gmail.comMay-Aug 2018 13 6 2018 13 6 2018 11 2 372 377 14 5 2018 14 5 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Anti-neutrophil cytoplasmic antibodies (ANCA) play an important role in the pathogenesis of pauci-immune renal vasculitis. However, in 10% of the cases, ANCA are absent. We present a case of a 64-year-old man with a chronic untreated hepatitis C virus infection and Middle Eastern thalassemia who was ANCA-negative when he was hospitalized due to acute kidney injury and accounts for an uncommon presentation of renal vasculitis. The patient had earlier reported to have undergone local lobectomy and adjuvant chemotherapy (carboplatin/pemetrexed) for lung adenocarcinoma a month prior. IL-6 has been reported to be involved in the pathophysiological cascade causing pauci-immune glomerulonephritis amongst non-small cell lung cancer patients. Previous studies with subgroup analysis have demonstrated that ANCA negativity has been associated with more chronic glomerular lesions and less crescent formation, which tends to have a critical outcome in the renal system. However, our patient underwent kidney biopsy exhibiting active crescentic glomerulonephritis, pauci-immune type with 5 cellular crescents amongst 15 glomeruli. To our knowledge, this is the third reported case of ANCA-negative vasculitis with typical presentation on biopsy in non-small cell lung cancer patients.\n\nKeywords\nParaneoplastic seronegative pauci-immune glomerulonephritisLung adenocarcinoma\n==== Body\nIntroduction\nRapidly progressive glomerulonephritis is a clinical syndrome presenting with rapid deterioration of the renal function with characteristic features of nephritic syndrome, such as proteinuria and hematuria. Crescent formation is the pathological finding in these cases and represents a nonspecific response to severe injury to the glomerular capillary wall as observed in kidney biopsy. Pauci-immune rapidly progressive glomerulonephritis, a type of rapidly progressive glomerulonephritis, is a necrotizing glomerulonephritis with few or no immune deposits by immunofluorescence and electron microscopy. Pauci-immune renal vasculitis with focal glomerular necrosis and crescent formation is usually associated with anti-neutrophil cytoplasmic antibodies (ANCA). However, it is noteworthy that in 10% of the cases, ANCA are absent, and this accounts for an uncommon presentation of renal vasculitis [1].\n\nCase Report\nA 64-year-old Caucasian man with a past medical history of chronic hepatitis C virus infection presented to the emergency room with acute kidney injury. He had recently been treated for localized non-small cell adenosquamous lung cancer and undergone lobectomy and adjuvant chemotherapy with carboplatin and pemetrexed, receiving his last dose 1 month prior to hospital presentation. On examination, the patient was afebrile with a blood pressure of 139/85, a heart rate of 82, a respiratory rate of 16, and a 98% saturation on room air. He was noted to be edematous with diffuse purpuric and petechial skin lesions. Initial laboratory findings were significant for normocytic anemia, with a hemoglobin level of 6.7 g/dL, WBC of 13.1 K/μL, serum creatinine of 11.60 mg/dL, BUN of 118, potassium of 4.7 and a proBNP of 90,193 pg/mL. Urinalysis showed slightly cloudy, red-colored urine with 100 mg/dL protein, 385 RBC/HPF, and 4 hyaline casts/LPF. Spot urine protein:creatinine ratio estimated 4.5 g of proteinuria per 24 h.\n\nOn admission, hemodialysis was initiated for volume overload and the patient received blood transfusion for his anemia. Serologies including ANA, anti-DNA, hepatitis B, cryoglobulin, HIV, anti-GBM antibody, anti-myeloperoxidase antibody, and anti-proteinase 3 antibody were negative and complement levels were normal. Renal ultrasound revealed no evidence of chronic renal disease, atrophy or hydronephrosis. Renal biopsy (Fig. 1, 2, 3) sent to the Weill Cornell Medical College revealed active crescentic glomerulonephritis (CrGN), of the pauci-immune type. CT scan-guided renal biopsy revealed very small metastatic bone lesions to the sacrum and T4 vertebrae, confirmed on repeat imaging 3 months later. The patient was treated with 1 g of SoluMedrol daily for 3 days, 2 cycles of plasmapheresis and induction therapy using rituximab 375 mg/m2, and oral prednisone. His renal function subsequently improved and his purpuric rash resolved. He died 6 months later from progression of metastatic lung cancer.\n\nDiscussion\nPauci-immune glomerulonephritis is a devastating form of acute kidney injury. It is rare with an incidence of 3.1 cases per million per year in the United States. However, rates are significantly higher in Caucasian males and individuals older than 65 years [2, 3]. They usually present with clinical pictures varying from asymptomatic hematuria to more severe forms that require rapid intervention. Laboratory testing usually reveals hematuria, proteinuria, and elevation in serum creatinine with active urinary sediment [4]. Clinically, patients complain of constitutional symptoms such as low-grade fever, fatigue, weight loss as well as other symptoms such as myalgia and arthralgia, which often precede the presentation of the disease [4, 5].\n\nIn a study of 85 patients with a diagnosis of pauci-immune CrGN reported by Chen et al. [6], it was noted that 28 patients (32.9%) were ANCA-negative (mean age 39.7 years) with a younger age of onset compared to ANCA-positive patients (mean age 57.6 years). The prevalence of fever, weight loss, muscle pain, and arthralgia was found to be lower in ANCA-negative patients compared to that in ANCA-positive pauci-immune CrGN patients. Furthermore, there was less prevalence of pulmonary involvement in ANCA-negative (10.7 vs. 36.8%; χ2 = 6.33, p < 0.05) compared to ANCA-positive patients and less ophthalmic, otic or nasal involvement (3.6 vs. 24.6%; χ2 = 4.34, p < 0.05) in the former. However, proteinuria and the prevalence of nephrotic syndrome are more common in patients that are ANCA-negative (p < 0.01 and p < 0.001, respectively). Renal survival was also worse in ANCA-negative patients compared to ANCA-positive patients (p < 0.05). Hung et al. [7] reported in their subgroup analysis of pauci-immune glomerulonephritis that ANCA-negative subjects had more chronic glomerular lesions compared to ANCA-positive patients who had more acute glomerular lesions. The chronicity of the renal disease in ANCA-negative patients is likely responsible for their poor treatment response and worse renal prognosis.\n\nThe pathogenesis of ANCA-negative pauci-immune CrGN still remains unclear. There are several theories that attempt to explain the phenomenon of ANCA-negative pauci-immune CrGN. Roth et al. [8] observed that purified immunoglobulins from ANCA-negative patients did not react with their sera but reacted with MPO antigens. It was reported that a ceruloplasmin fragment bound to the epitope of MPO reduced anti-MPO autoantibody detection by 30–50%. Hence, circulatory fragments of ceruloplasmin have been known to mask ANCA positivity, resulting in ANCA-negative vasculitis [9]. A second possibility is that in ANCA-negative pauci-immune CrGN, there are low levels of antibodies that are not detected by currently available assays. Finally, the third possibility is that a new undetected antigen, which is therefore testing negative in prevailing assays, drives the etiology of ANCA-negative pauci-immune CrGN.\n\nIn our case, the recent diagnosis of metastatic non-small cell lung adenocarcinoma suggests that our patient's ANCA-negative pauci-immune CrGN may be a paraneoplastic manifestation of his malignancy. A literature review from PubMed showed two additional cases of ANCA-negative pauci-immune CrGN associated with stage 4 non-small cell lung cancer. One of them was treated with steroids but died of renal failure and intestinal bleeding 2 weeks after the diagnosis and the other was treated with steroids, cyclophosphamide and azathioprine with death occurring 8 months after diagnosis [10, 11]. Morikawa et al. [10] reported a large amount of neutrophil infiltration in the glomerulus, with crescent formation, and significantly elevated serum levels of IL-6, TGF-β, and IL-8 with IL-6 producing adenosquamous lung cancer playing a key role in the pathogenesis of ANCA-negative pauci-immune glomerulonephritis.\n\nInterestingly, in our case and the previous two reported cases of patients with non-small cell lung cancer who developed ANCA-negative pauci-immune CrGN, there was antecedent chemotherapy. Can the temporal relationship of carboplatin and pemetrexed infusion and the development of ANCA-negative pauci-immune CrGN suggest autoimmune syndrome induced by adjuvants (ASIA)? ASIA describes autoimmune syndromes that are triggered by a substance that modulates the immune system such as a vaccine [12]. Cytotoxic chemotherapy can also be considered an adjuvant as it can modulate the immune system in the following ways: (1) it alters the normal balance of self-tolerance [13], (2) high cell turnover and cell destruction activates the immune system through increased synthesis of cytokines [14], and (3) chemotherapy itself generates autoantibodies [15].\n\nConclusion\nWe presented a case of ANCA-negative pauci-immune CrGN temporally related to non-small cell lung cancer. Our case highlights the importance of having a broad differential in renal failure patients post-chemotherapy. This rare manifestation prompts the following questions: (1) Are IL-6-producing adenocarcinomas capable of inducing ANCA-negative pauci-immune CrGN? (2) Is chemotherapy a potential trigger of ANCA-negative pauci-immune CrGN in non-small cell lung cancer? (3) How should ANCA-negative pauci-immune CrGN associated with non-small cell lung cancer be treated?\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare\n\nDisclosure Statement\nThe authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this case report. The authors do not have any conflicts of interest to disclose.\n\nFig. 1 PAS histochemistry (medium magnification) demonstrating an uninvolved glomerulus (left) and a glomerulus with segmental crescent formation (right). Asterisk marks the focus of crescent formation.\n\nFig. 2 PAS histochemistry (high magnification) demonstrating an involved glomerulus with segmental crescent formation (lower half of glomerulus).\n\nFig. 3 EM demonstrating subendothelial electron-dense deposits. RBCs annotated with blue asterisks. Some dense deposits highlighted with blue arrows. No subepithelial electron-dense deposits are seen.\n==== Refs\nReferences\n1 Eisenberger U Fakhouri F Vanhille P Beaufils H Mahr A Guillevin L ANCA-negative pauci-immune renal vasculitis: histology and outcome Nephrol Dial Transplant 2005 7 20 (7) 1392 9 15855209 \n2 Falk RJ ANCA-associated renal disease Kidney Int 1990 11 38 (5) 998 1010 2266686 \n3 Hogan SL Falk RJ Chin H Cai J Jennette CE Jennette JC Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis Ann Intern Med 2005 11 143 (9) 621 31 16263884 \n4 Falk RJ Hogan S Carey TS Jennette JC The Glomerular Disease Collaborative Network: Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis Ann Intern Med 1990 11 113 (9) 656 63 2221646 \n5 Pendergraft WF 3rd Preston GA Shah RR Tropsha A Carter CW Jr Jennette JC Autoimmunity is triggered by cPR-3(105–201), a protein complementary to human autoantigen proteinase-3 Nat Med 2004 1 10 (1) 72 9 14661018 \n6 Chen M Yu F Wang SX Zou WZ Zhao MH Wang HY Antineutrophil cytoplasmic autoantibody-negative Pauci-immune crescentic glomerulonephritis J Am Soc Nephrol 2007 2 18 (2) 599 605 17215440 \n7 Hung PH Chiu YL Lin WC Chiang WC Chen YM Lin SL Poor renal outcome of antineutrophil cytoplasmic antibody negative Pauci-immune glomerulonephritis in Taiwanese J Formos Med Assoc 2006 10 105 (10) 804 12 17000453 \n8 Roth AJ Ooi JD Hess JJ van Timmeren MM Berg EA Poulton CE Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis J Clin Invest 2013 4 123 (4) 1773 83 23549081 \n9 Shah S Havill J Rahman MH Geetha D. A historical study of American patients with anti-neutrophil cytoplasmic antibody negative pauci-immune glomerulonephritis Clin Rheumatol 2016 4 35 (4) 953 60 26445939 \n10 Morikawa T Yoshida A Kobayashi S Shibata M Hamada M Kishida M AP-VAS 2012 case report: a case of ANCA-negative pauci-immune crescentic glomerulonephritis associated with IL-6-producing adenosquamous cell carcinoma of the lung CEN Case Rep 2013 11 2 (2) 158 64 28509297 \n11 Baldeo C Ali R Hritani A Poenariu A ANCA-Negative Pauci-Immune Crescentic Glomerulonephritis Linked with Non-Small Cell Carcinoma of the Lung Case Rep Nephrol Dial 2015 7 5 (2) 168 72 26266249 \n12 Watad A David P Brown S Shoenfeld Y Autoimmune/Inflammatory Syndrome Induced by Adjuvants and Thyroid Autoimmunity Front Endocrinol (Lausanne) 2017 1 7 150 28167927 \n13 Amft N D'Cruz D Postchemotherapy connective tissue diseases – more than just rheumatism? Lupus 1996 8 5 (4) 255 6 8869893 \n14 Wandl UB Nagel-Hiemke M May D Kreuzfelder E Kloke O Kranzhoff M Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders Clin Immunol Immunopathol 1992 10 65 (1) 70 4 1382910 \n15 Abu-Shakra M Buskila D Ehrenfeld M Conrad K Shoenfeld Y Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies Ann Rheum Dis 2001 5 60 (5) 433 41 11302861\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(2)",
"journal": "Case reports in oncology",
"keywords": "Lung adenocarcinoma; Paraneoplastic seronegative pauci-immune glomerulonephritis",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "372-377",
"pmc": null,
"pmid": "30022938",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "26445939;28167927;26266249;28509297;2266686;2221646;17000453;8869893;15855209;14661018;1382910;17215440;11302861;16263884;23549081",
"title": "Paraneoplastic Seronegative Pauci-Immune Glomerulonephritis Associated with Lung Adenocarcinoma Responds to Rituximab: A Case Report.",
"title_normalized": "paraneoplastic seronegative pauci immune glomerulonephritis associated with lung adenocarcinoma responds to rituximab a case report"
} | [
{
"companynumb": "US-PFIZER INC-2018268577",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": null,
... |
{
"abstract": "Tigecycline, the first glycylcycline-class drug, is a broad-spectrum antibiotic with activity against multi-drug resistant (MDR) organisms. We describe a case of sustained and severe hypoglycemia in a patient treated with tigecycline for pneumonia due to MDR Klebsiella pneumoniae.\n\n\n\nA 74-year-old man was admitted for treatment of pneumonia. At admission he had prediabetes. In the hospital he developed renal failure. On day 3, the patient experienced severe shortness of breath. He was intubated and transferred to the intensive care unit (ICU) for ventilator support. In the ICU the antibiotic regimen was cefoperazone and sulbactam (1 g every 12 h). Continuous Renal Replacement Therapy was started on that day. Test for anti-neutrophil cytoplasmic antibodies (ANCA) was positive, and so the nephrologist and rheumatologist agreed on a diagnosis of ANCA-associated vasculitis, with renal and pulmonary involvement and acute renal failure. Plasmapheresis, and high-dose methylprednisolone treatment were started on day 6, and there was obvious improvement in the patient's condition. The steroid regimen was gradually tapered to oral prednisone (35 mg every day) on day 19. Afterwards, the patient's pneumonia worsened. Sputum culture showed Klebsiella pneumoniae sensitive to only tigecycline. Tigecycline treatment (100 mg every 12 h) was administered on day 20. Hypoglycemia started about 37 h after the first dose of tigecycline. Infusion of 50% glucose through the femoral vein was required for over 20 h to maintain normal blood glucose concentrations. Tigecycline was stopped, but the hypoglycemia resolved only after a further 34 h. The insulin and C-peptide levels were found to be markedly elevated during the hypoglycemia. The Naranjo scale score of 7 indicated that the likelihood of tigecycline causing severe hypoglycemia was \"probable.\"\n\n\n\nThis is the first report of sustained severe hypoglycemia due to tigecycline. Oversecretion of insulin appears to have been the cause of the hypoglycemia in our patient. The mechanism needs to be investigated.",
"affiliations": "Department of Endocrinology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, 3 East Qing Chun Road, Zhejiang, 310016, Hangzhou, China.;Department of Endocrinology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, 3 East Qing Chun Road, Zhejiang, 310016, Hangzhou, China.;Department of Endocrinology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, 3 East Qing Chun Road, Zhejiang, 310016, Hangzhou, China.;Department of Endocrinology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, 3 East Qing Chun Road, Zhejiang, 310016, Hangzhou, China. srrshnfm@zju.edu.cn.",
"authors": "Chen|Yixin|Y|;Li|Lin|L|;Zhang|Nan|N|;Li|Hong|H|0000-0003-4158-1860",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-019-0321-y",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 32110.1186/s40360-019-0321-yCase ReportTigecycline-induced sustained severe hypoglycemia: a case report Chen Yixin yixin29@zju.edu.cn Li Lin 3312012@zju.edu.cn Zhang Nan 3198047@zju.edu.cn http://orcid.org/0000-0003-4158-1860Li Hong 13588706366srrshnfm@zju.edu.cn 0000 0004 1759 700Xgrid.13402.34Department of Endocrinology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, 3 East Qing Chun Road, Zhejiang, 310016 Hangzhou China 19 8 2019 19 8 2019 2019 20 5015 1 2019 9 7 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTigecycline, the first glycylcycline-class drug, is a broad-spectrum antibiotic with activity against multi-drug resistant (MDR) organisms. We describe a case of sustained and severe hypoglycemia in a patient treated with tigecycline for pneumonia due to MDR Klebsiella pneumoniae.\n\nCase presentation\nA 74-year-old man was admitted for treatment of pneumonia. At admission he had prediabetes. In the hospital he developed renal failure. On day 3, the patient experienced severe shortness of breath. He was intubated and transferred to the intensive care unit (ICU) for ventilator support. In the ICU the antibiotic regimen was cefoperazone and sulbactam (1 g every 12 h). Continuous Renal Replacement Therapy was started on that day. Test for anti-neutrophil cytoplasmic antibodies (ANCA) was positive, and so the nephrologist and rheumatologist agreed on a diagnosis of ANCA-associated vasculitis, with renal and pulmonary involvement and acute renal failure. Plasmapheresis, and high-dose methylprednisolone treatment were started on day 6, and there was obvious improvement in the patient’s condition. The steroid regimen was gradually tapered to oral prednisone (35 mg every day) on day 19. Afterwards, the patient’s pneumonia worsened. Sputum culture showed Klebsiella pneumoniae sensitive to only tigecycline. Tigecycline treatment (100 mg every 12 h) was administered on day 20. Hypoglycemia started about 37 h after the first dose of tigecycline. Infusion of 50% glucose through the femoral vein was required for over 20 h to maintain normal blood glucose concentrations. Tigecycline was stopped, but the hypoglycemia resolved only after a further 34 h. The insulin and C-peptide levels were found to be markedly elevated during the hypoglycemia. The Naranjo scale score of 7 indicated that the likelihood of tigecycline causing severe hypoglycemia was “probable.”\n\nConclusion\nThis is the first report of sustained severe hypoglycemia due to tigecycline. Oversecretion of insulin appears to have been the cause of the hypoglycemia in our patient. The mechanism needs to be investigated.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s40360-019-0321-y) contains supplementary material, which is available to authorized users.\n\nKeywords\nTigecyclineHypoglycemiaMulti-drug resistant organismissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nTigecycline is the first glycylcycline-class antibiotic to be available in parenteral form. It has been approved by the US Food and Drugs Administration (FDA) for treatment of complicated skin and intra-abdominal infections and community-acquired bacterial pneumonia. Tigecycline is a broad-spectrum antibiotic, with proven activity against multidrug-resistant (MDR) organisms. In clinical trials the most frequently reported adverse reactions were nausea, vomiting, and diarrhea. Hypoglycemic events were rare (< 2%) [1]; severe hypoglycemia has never been reported.\n\nWe describe a case of sustained severe hypoglycemia in a patient treated with tigecycline for pneumonia caused by MDR Klebsiella pneumoniae. Our description followed of the case followed the CARE guidelines and the CARE checklist was provided as an additional file (Additional file 1).\n\nCase presentation\nA 78-year-old man with complaints of cough and trouble breathing for 1 month was admitted to the ward of the Respiratory Medicine Department of Sir Run Run Shaw Hospital on the 12th January 2018. He had been seen earlier in the outpatient clinic on 23th December 2017. At that visit a chest computed tomography (CT) scan had demonstrated pneumonia; echocardiogram had shown thickening of the left ventricular wall, with ejection fraction of 65.8%; and the serum creatinine had been 76 μmol/L, indicating normal renal function. He had been treated with levofloxacin (0.5 g every day) for 1 week in the outpatient department. As there was no improvement, levofloxacin was substituted with moxifloxacin (0.4 g every day) and he was advised hospitalization for further therapy.\n\nAt admission, the patient was conscious and well oriented. A digital electronic sphygmomanometer showed blood pressure of 144/74 mmHg and heart rate of 96 beats/min. The respiratory rate was 18 breaths/min and the temperature was 36.3 °C. There were no rales or wheezes heard in the chest. Mild ankle edema was present. Physical examination was otherwise normal.\n\nThe patient had history of hypertension for over 10 years and was on nifidipine, with good control of blood pressure. He had no history of diabetes. However glycated hemoglobin (HbA1c) was 6.2%, suggesting impaired glucose metabolism. His gallbladder had been removed 30 years ago. He was married and had two children. All family members were in good health.\n\nAfter admission, antibiotic treatment was started with piperacillin and tazobactam (4.5 g every 8 h). His serum creatinine level rose sharply, and on the day 2 of admission it was 506 μmol/L. It continued to rise over the following days. A nephrology consultant suggested two possibilities: allergic interstitial nephritis and renal vasculitis, and advised tests for autoantibodies. Blood was drawn and sent to the laboratory.\n\nOn day 3, however, the patient experienced severe shortness of breath. He was intubated and transferred to the intensive care unit (ICU) for ventilator support. In the ICU the antibiotic regimen was changed to cefoperazone and sulbactam (1 g every 12 h). Continuous Renal Replacement Therapy (CRRT) was started on that day.\n\nOn day 5, test for anti-neutrophil cytoplasmic antibodies (ANCA) was positive, and so the nephrologist and rheumatologist agreed on a diagnosis of ANCA-associated vasculitis, with renal and pulmonary involvement and acute renal failure.\n\nPlasmapheresis, and intravenous methylprednisolone treatment (500 mg every day for 3 days) were started on day 6, and there was obvious improvement in the patient’s condition. On day 7, he was taken off the ventilator and transferred to the nephrology department. Hemodialysis and antibiotic therapy were continued. The steroid regimen was gradually tapered to oral prednisone (35 mg every day) on day 19.\n\nOver the next few days the patient’s pneumonia worsened. He complained of increasing chest tightness, and there was progressive increase in the levels of inflammatory markers C-reactive protein and procalcitonin. Chest CT revealed increase in lung consolidation and inflammation. On day 15 cefoperazone and sulbactam were substituted with meropenem (0.5 g every 12 h). By this time his blood glucose had increased as a result of the methylprednisolone treatment. His postprandial glucose concentration after dinner was 15 mmol/L. He was started on repaglinide (0.5 mg with dinner) on day 16. On day 18 the results of sputum cultures showed infection with Candida albicans and multi-resistant Klebsiella pneumoniae sensitive only to tigecycline. Voriconazole (400 mg every 12 h) was started on day 18, and meropenem was replaced with off-label tigecycline (100 mg every 12 h) on day 20. Meanwhile, on day 19, the dose of repaglinide was increased to 1 mg with dinner (Fig. 1). The patient’s chest tightness was partly relieved, and serum procalcitonin decreased sharply, indicating response to the new antibiotic.\nFig. 1 The patient’s glycemic profile on days 15–19. Repaglinide was administered (0.5 mg with dinner) on day 16. The dose was doubled on day 19\n\n\n\nOn day 22 the patient experienced a typical hypoglycemic attack after breakfast, manifesting with palpitations, tremor, sweating, and hunger. Glucometer showed blood glucose to be 2.8 mmol/L. The symptoms were promptly relieved with 20 g of oral glucose, and the blood glucose rose to 10.4 mmol/L. No hypoglycemic event occurred the next day (Fig. 2). On day 24, however, the patient suffered another hypoglycemic attack. This time, it was severe and sustained. Glucometer showed blood glucose to be 2.0 mmol/L. The patient was confused and irritable. He was administered 40 mL 50% glucose intravenously, following which blood glucose rose to 8.7 mmol/L. However, three further hypoglycemic episodes occurred on the same day. Each time the blood glucose concentration was restored to normal with intravenous 50% glucose. Repaglinide was stopped on day 24. The nephrologist consulted us on day 25 to discuss the course of further treatment. After evaluation of the patient’s drug history and clinical manifestations, we decided that tigecycline was the likely cause of the hypoglycemia and stopped the drug (Fig. 3). However, the hypoglycemia persisted. Oral glucose, repeated doses of intravenous 50% glucose solution, and infusion with 16.7% glucose (50 mL 10% glucose + 10 mL 50% glucose) solution could not maintain normal blood glucose concentrations. Therefore, femoral vein cannulation was performed and 50% glucose solution was infused (Fig. 4). With this, the blood glucose concentration was maintained at 3.6–7.4 mmol/L over the next 20 h. At 6 PM on day 26 the blood glucose showed an obvious rise and remained above 10 mmol/L through the rest of the night, indicating that the hypoglycemia had probably been corrected. Intravenous 50% glucose infusion was stopped on day 27 (Fig. 5). There were no further episodes of hypoglycemia.\nFig. 2 The patient’s glycemic profile on days 20–23. Intravenous tigecycline (100 mg every 12 h) was started on day 20. The first hypoglycemic attack was on day 22\n\n\nFig. 3 The patient’s glycemic profile on days 24–25. The patient had four hypoglycemic episodes on day 24. A sustained and more severe hypoglycemic attack occurred on day 25. The last dose of tigecycline was administered at 8 AM on day 25\n\n\nFig. 4 The patient’s glycemic profile on days 25–26. The hypoglycemia continued. Continuous 50% glucose infusion through the femoral vein was started on the night of day 25\n\n\nFig. 5 The patient’s glycemic profile on days 26–27. The blood glucose showed an obviously rise at 6 PM on day 26 and remained above 10 mmol/L from then on, indicating probable resolution of the hypoglycemia. The 50% glucose infusion was discontinued on day 27\n\n\n\nDuring the episodes of hypoglycemia, insulin and C-peptide levels were also measured along with blood glucose; both were found to be elevated whenever hypoglycemia occurred. Figures 1, 2, 3, 4, 5 show the patient’s glycemic profile from day 15 to day 27. Table 1 lists the pertinent laboratory values.\nTable 1 Results of Laboratory Tests during Hospital Stay\n\nLaboratory test (normal value)\tDay 25\tDay 26\tDay 28\t\nGlucose (4.16–5.83 mmol/L)\t2.87\t5.06\t4.06\t\nInsulin (1.90–23.00 μIU/mL)\t33.07\t30.99\t3.7\t\nC-peptide (250–600 pmol/L)\t> 13333\t> 13333\t2189\t\nSerum cortisol at 8 AM (6.70–22.60 μg/dL)\t\t6.44\t\t\nSerum ACTH at 8 AM (10–80 ng/L)\t\t5\t\t\nTSH (0.35–4.94 mIU/L)\t\t2.65\t\t\nInsulin autoantibody (negative)\t\tNegative\t\t\nACTH Adrenocorticotropic hormone, TSH Thyroid-stimulating hormone\n\n\n\nOn day 28, polymyxin B and imipenem were started for treatment of the pneumonia. However, the patient’s condition deteriorated and he died shortly after.\n\nDiscussion and conclusion\nHypoglycemic attacks are not a common adverse reaction in patients receiving tigecycline: only 11 cases have been reported between 2004 and 2009. In 2014, in a phase III study comparing tigecycline and ertapenem in diabetic foot patients with and without osteomyelitis, 34 of 477 patients had hypoglycemic attacks in the tigecycline group [2]. The attacks were much more common in diabetic patients who were also taking glucose-lowering treatment.\n\nOur patient was unusual in that he suffered prolonged and severe hypoglycemia; such a reaction has not been reported before. The first episode occurred about 37 h after the first dose of tigecycline. Two days later, the hypoglycemia recurred, and this time it was sustained. Tigecycline was stopped, but the hypoglycemia was not relieved until 34 h after the last dose of tigecycline. According to the prescription information from the FDA [1], the single-dose half-life of 100 mg of tigecycline is 27 h. The duration of the hypoglycemia in our patient was consistent with the pharmacokinetics of tigecycline.\n\nOur patient had received repaglinide before the hypoglycemic event. However, this drug cannot cause such sustained hypoglycemia as it has a short half-life of only about 1 h [3]. In fact, diabetic patients usually need multiple doses of repaglinide each day to ensure blood glucose control. Moreover, 90% of the metabolites of repaglinide are excreted through the bile, and so the clearance rate is unaffected by renal failure.\n\nInterestingly, in our patient, insulin and C-peptide levels were markedly elevated even though blood glucose was low, indicating that overproduction of insulin was the main cause of the hypoglycemia. Three days after tigecycline was stopped there was a sharp decline in the insulin and C-peptide levels. Thus, it appears that tigecycline stimulates the secretion of insulin. However, the mechanism of action is not yet clear. In our patient, impaired renal function would have resulted in delayed clearance of insulin and thus led to prolongation of hypoglycemia.\n\nOur patient had autoimmune disease, as indicated by the positive test for ANCA. This led us to consider insulin autoimmune syndrome as a possible cause of the hypoglycemia. However, this possibility was ruled out by the negative insulin autoantibody test and the fact that tigecycline contains no sulfhydryl group (Fig. 6).\nFig. 6 Chemical structure of tigecycline. Tigecycline contains no sulfhydryl group\n\n\n\nThe Naranjo Adverse Drug Reaction Probability Scale [4] showed a probable relationship (score of 7) between the patient’s severe hypoglycemia and tigecycline treatment (Table 2). Because of ethical considerations we could not restart treatment with tigecycline despite its antibiotic efficacy in this patient.\nTable 2 The Patient’s Scores for the Naranjo Adverse Drug Reaction Probability Scale Questions\n\nTo assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.\t\n\tYes\tNo\tDo not know\tScore\t\nI. Are there previous conclusive reports on this reaction?\t+ 1\t0\t0\t+ 1\t\n2. Did the adverse event appear after the suspected drug was administered?\t+ 2\t−1\t0\t+ 2\t\n3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?\t+ 1\t0\t0\t+ 1\t\n4. Did the adverse reaction reappear when the drug was re-administered?\t+ 2\t−1\t0\t0\t\n5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?\t−1\t+ 2\t0\t+ 2\t\n6. Did the reaction reappear when a placebo was given?\t−1\t+ 1\t0\t0\t\n7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?\t+ 1\t0\t0\t0\t\n8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?\t+ 1\t0\t0\t0\t\n9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\t+ 1\t0\t0\t0\t\n10. Was the adverse event confirmed by any objective evidence?\t+ 1\t0\t0\t+ 1\t\n\t\t\tTotal score\t7\t\n\n\nTo summarize, we report a patient who suffered prolonged and severe hypoglycemia while on treatment with tigecycline. The hypoglycemia resolved only 34 h after stoppage of the drug. The Naranjo scale score of 7 indicated that a “probable” relationship exists between tigecycline administration and the severe hypoglycemia. Insulin and C-peptide levels showed a close inverse relationship with blood glucose, indicating that oversecretion of insulin was the likely cause of the prolonged hypoglycemia. Further investigations are needed to clarify the underlying mechanisms. To our knowledge, this is the first report of sustained severe hypoglycemia due to tigecycline.\n\nAdditional file\n\nAdditional file 1: The CARE checklist. (XLSX 11 kb)\n\n \n\n\nAbbreviations\nANCAAnti-neutrophil cytoplasmic antibodies\n\nCTComputed tomography\n\nFDAFood and Drugs Administration\n\nHbA1cGlycated hemoglobin\n\nICUIntensive care unit\n\nMDRMulti-drug resistant\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nYC contributed to the patient’s clinical care and writing of the report. HL contributed to manuscript conception and the revision of the report. LL contributed to the data collection and data interpretation. NZ contributed to the patient’s clinical care and data collection. All authors read and approved the final manuscript.\n\nFunding\nNo sources of funding are declared for this study.\n\nAvailability of data and materials\nThe dataset analyzed during the current study are available in the Mendeley. (10.17632/3ym3x4ckyn.1).\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent to publish was obtained from the patient’s wife to report individual patient data in any form. A copy of the written consent is available for review.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Wyeth Pharmaceuticals Inc. TYGACIL® (tigecycline) FOR INJECTION for intravenous use Prescribing Information. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.\n2. Lauf L Ozsvár Z Mitha I Phase 3 study comparing tigecycline and ertapenem in patients with diabetic foot infections with and without osteomyelitis Diagn Microbiol Infect Dis 2014 78 4 469 480 10.1016/j.diagmicrobio.2013.12.007 24439136 \n3. Novo Nordisk Inc. PRANDIN® (repaglinide) tablets, for oral use Prescribing Information. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.\n4. Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 10.1038/clpt.1981.154 7249508\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-6511",
"issue": "20(1)",
"journal": "BMC pharmacology & toxicology",
"keywords": "Hypoglycemia; Multi-drug resistant organism; Tigecycline",
"medline_ta": "BMC Pharmacol Toxicol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D006801:Humans; D007003:Hypoglycemia; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D018410:Pneumonia, Bacterial; D000078304:Tigecycline",
"nlm_unique_id": "101590449",
"other_id": null,
"pages": "50",
"pmc": null,
"pmid": "31426870",
"pubdate": "2019-08-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24439136;7249508",
"title": "Tigecycline-induced sustained severe hypoglycemia: a case report.",
"title_normalized": "tigecycline induced sustained severe hypoglycemia a case report"
} | [
{
"companynumb": "CN-PFIZER INC-2019385048",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
},
"drugadditional": null,
... |
{
"abstract": "Nocturnal leg cramps are painful, involuntary muscle contractions commonly seen in elderly. While mostly harmless, they can severely impair quality of life and often disrupt sleep. Adverse drug effects may be responsible for a fraction of nocturnal leg cramps but often go unrecognized, resulting in additional prescribing intended to deal with adverse effects that might be better addressed by reduction, substitution, or discontinuation of the offending agent.\n\n\n\nAn 87 year old female presented as outpatient in family medicine with nocturnal leg cramps which had been present for five years and increasingly burdened her quality of life. She had been using quinine 200 mg once daily for symptomatic relief but the cramps kept returning with increasing intensity. During clinical examination we found neither structural nor neurological or metabolic disorders that explained her symptoms. When doing a medication analysis, we found that she was taking a statin together with quinine. Quinine is a cytochrome P450 isoenzyme 3A4 inhibitor, the very enzyme which is involved in the metabolism of most statins. Therefore the use of both substances simultaneously increases blood levels of the statin thereby increasing the risk of side effects including symptomatic myopathy and myalgia. After discontinuing both medications, the patient was, and remained, symptom free.\n\n\n\nThis case report describes a possible medication interaction that has rarely been noted in literature.",
"affiliations": "Institute of General Practice and Family Medicine Bonn, University Clinic Bonn, Siegmund-Freud Str. 25, 53127, Bonn, Germany. johannes.just@ukb.uni-bonn.de.;Institute of General Practice and Family Medicine Bonn, University Clinic Bonn, Siegmund-Freud Str. 25, 53127, Bonn, Germany.;Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.",
"authors": "Just|Johannes M|JM|;Weckbecker|Klaus|K|;Just|Katja S|KS|",
"chemical_list": "D003580:Cytochromes; D011803:Quinine; D019821:Simvastatin",
"country": "England",
"delete": false,
"doi": "10.1186/s12877-016-0337-8",
"fulltext": "\n==== Front\nBMC GeriatrBMC GeriatrBMC Geriatrics1471-2318BioMed Central London 33710.1186/s12877-016-0337-8Case ReportQuinine induced simvastatin toxicity through cytochrome inhibition - a case report Just Johannes M. 0049 - (0)228 - 28711156johannes.just@ukb.uni-bonn.de 1Weckbecker Klaus Klaus.weckbecker@ukb.uni-bonn.de 1Just Katja S. katja.just@bfarm.de 21 Institute of General Practice and Family Medicine Bonn, University Clinic Bonn, Siegmund-Freud Str. 25, 53127 Bonn, Germany 2 Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany 1 10 2016 1 10 2016 2016 16 16812 5 2016 15 9 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNocturnal leg cramps are painful, involuntary muscle contractions commonly seen in elderly. While mostly harmless, they can severely impair quality of life and often disrupt sleep. Adverse drug effects may be responsible for a fraction of nocturnal leg cramps but often go unrecognized, resulting in additional prescribing intended to deal with adverse effects that might be better addressed by reduction, substitution, or discontinuation of the offending agent.\n\nCase presentation\nAn 87 year old female presented as outpatient in family medicine with nocturnal leg cramps which had been present for five years and increasingly burdened her quality of life. She had been using quinine 200 mg once daily for symptomatic relief but the cramps kept returning with increasing intensity. During clinical examination we found neither structural nor neurological or metabolic disorders that explained her symptoms. When doing a medication analysis, we found that she was taking a statin together with quinine. Quinine is a cytochrome P450 isoenzyme 3A4 inhibitor, the very enzyme which is involved in the metabolism of most statins. Therefore the use of both substances simultaneously increases blood levels of the statin thereby increasing the risk of side effects including symptomatic myopathy and myalgia. After discontinuing both medications, the patient was, and remained, symptom free.\n\nConclusion\nThis case report describes a possible medication interaction that has rarely been noted in literature.\n\nKeywords\nGeriatricsAdverse drug eventAdverse drug reactionAged 80, and overDrug interactionCytochrome P-450 Enzyme Systemno fundingissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nNocturnal leg cramps are painful involuntary muscle contractions, typically in the legs or feet. They occur during prolonged rest and often disrupt sleep. They are common among older persons and some individuals experience multiple painful awakenings per night [1, 2].\n\nIn a study group of 365 patients with a mean age of 78.5 years, the prevalence of leg cramps was 50 %. Of these 50 %, a fifth had had cramps for longer than 10 years plus two fifth never reported them to their practitioner [1]. Already decades ago, quinine has been suggested with beneficial effects in nocturnal leg cramps [3]. Even though efficacy was reported, data is inconsistent [4] and risk for adverse drug events such as pancytopenia should be considered [5]. In Germany quinine may be used for leg cramps. However, in the US it is not approved for that indication and the U.S. Food and Drug Administration (FDA) as well as the German Federal Institute for Drugs and Medical Devices published warning statements especially due to the risk of thrombocytopenia [6, 7].\n\nEspecially older people are more likely to receive a statin prescription. Between 2011 and 2012, 47.1 % of Americans aged 75 and older used a prescription cholesterol-lowering medication in the past 30 days [8]. Statins are known to potentially induce myopathy which can lead to discontinuation of treatment. Patient and drug-related factors such as age, genetics, comorbidities and metabolism, drug-drug interactions, drug transport respectively, can alter the probability [9]. Statins are metabolized by cytochrome P450 3A4 (CYP3A4) isoenzyme. Drugs inhibiting CYP3A4 can therefore interact with statins such as protease inhibitors, cyclosporine, verapamil, amiodarone, macrolide antibiotics and fibrates, which can increase the probability for adverse drug events (ADEs) as in this case of statin-induced myalgia [10]. A case-report on quinine-induced acute renal failure was published. The renal failure resulted in a combination of hemolytic uremic syndrome and rhabdomyolysis with disseminated intravascular coagulation with concordant use of atorvastatin and quinine [11]. In addition, the drug label of quinine sulfate provided by the FDA recommends a reduced dosage of quinine in renal failure due to decreased clearance. Furthermore, the FDA indicates that quinine is an inhibitor of CYP3A4 and therefore patients receiving co-medication, especially CYP3A4 substrates, should be monitored carefully for increased risk of ADEs [12].\n\nADEs may be responsible for a fraction of nocturnal leg cramps but often go unrecognized, resulting in additional prescribing intended to deal with adverse effects that might be better addressed by reduction, substitution, or discontinuation of the offending agent [13].\n\nIn the case of statin induced myopathy and myalgia, additional prescription of quinine might not only be useless but harmful by elevating statin blood levels through cytochrome induction thereby increasing its harmful side effects [11].\n\nWe obtained informed consent from the patient. This case report was structured using the CARE Statement Guideline on reporting case reports [14]. For a visual representation see “timeline”.\n\nCase presentation\nInformation\nThis 87 year old female pensioner presented for the treatment of recurrent nocturnal leg cramps to our family medicine practice. She reported a history of intense, painful sensations in the leg who were associated with sudden muscle hardness. The symptoms regularly appeared in both calves similarly during the night but never during daytime. They had been occurring regularly for five years with a low to intermediate pain intensity. Since three weeks symptoms had been worsening and the patient now described an “intense pain”. She had been treated with quinine by her former family doctor in the past and therefore began to self-medicate with quinine 200 mg once daily from her own stocks achieving only short term symptomatic relief. She asked the consulting doctor to give her another quinine prescription.\n\nThe patient had moved here about a year ago and had been a patient of our practice since. She was in very good general condition (Barthel-ADL Score 100 points) and enjoyed good quality of life despite the leg cramps. There was no history of neurologic disorders, hypoglycaemia, diabetes, alcoholism or hypothyroidism. Information on earlier diagnostics concerning the leg cramps was not available.\n\nHer past medical history and medication is displayed in Table 1.Table 1 Patient’s characteristics\n\nAge\t87 years\t\nSymptoms\tNocturnal leg cramps of moderate intensity since years. Since three weeks intensity of symptoms increased despite the use of quinine for symptomatic relief\t\nMedical history\tmyocardial infarction in 2002 with consecutive coronary artery bypass graft (CABG)\narterial hypertension\nchronic kidney disease III\nknee replacement left + right.\t\nMedication\taspirin 100 mg 1-0-0\nbisoprolol 2,5 mg 1-0-0\nramipril 5 mg 1-0-0\nsimvastatin 40 mg 0-0-1\nvitamin D3 1000 IU 1-0-0\ntorasemide 5 mg 1-0-0\nfentanyl patch 12,5 μg once every 3 days.\nSelf-medication: quinine200 mg once daily\t\n\n\nClinical findings\nWe conducted a clinical examination based on uptodate’s guideline on nocturnal leg cramps [15].\n\nThe 87 old female patient presented in good physical condition. Inspection and palpation of the musculoskeletal system showed no physical abnormalities like muscle atrophy or hypertrophy, bone abnormalities, muscle tenderness or stiffness. Skin examination of the lower extremities was unremarkable despite scars from knee replacement on both sides. Strong arterial pulses were palpable in all relevant locations. Examination of the sensory as well as motor system yielded no pathological findings.\n\nStructural disorders such as flat feet, genu recurvatum, and the hypermobility syndrome were ruled out.\n\nDiagnostic assessment\nLaboratory testing and other studies are usually not required in diagnosing nocturnal leg cramps [15].\n\nStill we took a blood sample including Creatinine, GFR, Vitamin B12 and folic acid. Renal function had deteriorated compared to prior laboratory findings (Creatinine from 0.91 (range 0.51–0.95) to 1.42, GFR from 64 to 38) (see Fig. 1). The values for tested vitamins were within normal limits. As the blood sample had to be stored for analysis on the following day (outpatient, office setting), we could not analyse creatinine kinase (CK) values. Nocturnal leg cramps are most commonly idiopathic in nature [15]. In this case, past medical history, physical examination and laboratory findings yielded no pathological results. A graphic display is given in the timeline.Fig. 1 Timeline: no legend\n\n\n\nIn preparing the demanded quinine prescription, we conducted a medication interaction analysis. The analysis showed a warning for the combination of quinine and HMG-CoA reductase inhibitors. Quinine is a CYP3A4 inhibitor, the very enzyme which is involved in the metabolism of most statins [16]. Thereby it may increase blood levels of simvastatin by reducing its first-pass metabolism. One case report documents renal failure, rhabdomyolysis, haemolytic uremic syndrome and disseminated intravascular coagulation after ingestion of quinine along with atorvastatin [11].\n\nCramps qualify as symptomatic myopathy which is associated with statin therapy and is dose, blood level and cytochrome metabolism dependent [10, 17]. Therefore we considered the combination of the statin and quinine or the statin alone as the most likely cause of the nocturnal leg cramps.\n\nTherapeutic intervention\nBased on these reports we discussed the possible medication interaction with the patient and gave her a resume of the positive effects of the statin. Shared decision making led to an immediate discontinuation of simvastatin and quinine.\n\nFollow up and outcomes\nWe reviewed the patient two and three weeks after the discontinuation of her medication. After three weeks she reported to having been “cramp free” for one week for the first time in years, while renal function was improved (Creatinine 1.03, GFR 55) (see Fig. 1). We scheduled a consultation two months and six months later in which the patient continued to be without cramps.\n\nDiscussion\nThis report shows a case of leg cramps as a possible result of both unnoticed medication side effects as well as medication interaction through cytochrome inhibition.\n\nThe discontinuation of both quinine and simvastatin led to a complete and sustained remission of symptoms. Furthermore, renal function improved. With respect to the patient’s age and strain we abstained confirming the diagnosis of a drug-drug interaction by using a challenge-dechallenge-rechallenge testing protocol which is a limitation to this study. In addition we did not want to re-administer quinine which is not first-line therapy in nocturnal leg cramps and is not licensed for the use in leg cramps in the US. Unfortunately simvastatin and CK levels could not be obtained during initial blood sampling due to limitations in laboratory analysis which is a limitation to this study.\n\nDiscontinuing the lipid-lowering therapy may lead to an increase in mortality [18]. One observational study found that statin use was independently associated with a reduction in the risk of all-cause mortality (adjusted hazard ratio 0.89; 95 % CI 0.81–0.98; p = 0.02) [19]. Therefore, despite limited high-quality evidence, class I recommendations have been made that all patients undergoing CABG should receive statin therapy unless contraindicated [20]. On the other hand, in patients who develop intolerable muscle symptoms statin treatment can be stopped [21]. As the patient already reached old age with overall good quality of life which was greatly impaired by the nocturnal leg cramps, discussing the case with the patient, she chose to discontinue statin therapy.\n\nThereby, adhered to the Good Palliative–Geriatric Practice algorithm, to assess the possibility to discontinue medication in the elderly in accordance with a 4- step medication decision making model [22, 23]. Following our patient’s decisions, we were not able to proof the diagnosis of a drug-drug interaction by using a challenge-dechallenge-rechallenge testing protocol which is another limitation to this study. A simple side effect of simvastatin without cytochrome related medication interaction is an alternative explanation for this case.\n\nConclusion\nThis case report should remind physicians first, that symptomatic myopathy induced by statins may present with cramp like symptoms and second, symptomatic myopathy is dose related with quinine and other CYP3A4 inhibitors having the potential to increase statin blood levels and thereby symptom intensity.\n\nAbbreviations\nADEsAdverse drug events\n\nCABGCoronary artery bypass graft\n\nCYPCytochrome P450\n\nFDAFood and Drug Administration\n\nWe thank the patient involved for giving us consent to publication of the data.\n\nFunding\nWe received no funding for this case report.\n\nAvailability of data and materials\nAll clinical data relevant to the case has been included in the main body of the text.\n\nAuthors’ contribution\nJJ was the responsible practitioner, carried out the literature research and drafted the manuscript. KW supervised the clinical process and reviewed the manuscript critically. KJ participated in the literature search and in drafting the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Abdulla AJ Jones PW Pearce VR Leg cramps in the elderly: prevalence, drug and disease associations Int J Clin Pract 1999 53 7 494 496 10692732 \n2. Naylor JR Young JB A general population survey of rest cramps Age Ageing 1994 23 5 418 420 10.1093/ageing/23.5.418 7825490 \n3. Moss HK Herrmann LG Use of quinine for relief of \"night cramps\" in the extremities: Preliminary report JAMA 1940 115 16 1358 1359 10.1001/jama.1940.72810420002011a \n4. Man-Son-Hing M Wells G Lau A Quinine for nocturnal leg cramps J Gen Intern Med 1998 13 9 600 606 10.1046/j.1525-1497.1998.00182.x 9754515 \n5. Man-Son-Hing M Wells G Meta-analysis of efficacy of quinine for treatment of nocturnal leg cramps in elderly people BMJ (Clinical research ed) 1995 310 6971 13 17 10.1136/bmj.310.6971.13 \n6. FDA Drug Safety Communication. New risk management plan and patient Medication Guide for Qualaquin (quinine sulfate). [http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm218202.htm]\n7. Chinin gegen nächtliche Wadenkrämpfe (Limptar® N). Bescheid des BfArM zu Änderungen der Produktinformation, einschließlich Einschränkung der Indikation, u.a. wegen des Risikos für schwere Blutbildveränderungen (Thrombozytopenien) im Rahmen eines nationalen Stufenplanverfahrens. [http://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RV_STP/a-f/chinin-stp.html]\n8. Prescription Cholesterol-lowering Medication Use in Adults Aged 40 and Over: United States, 2003–2012. [http://www.cdc.gov/nchs/data/databriefs/db177.pdf]\n9. Abd TT Jacobson TA Statin-induced myopathy: a review and update Expert Opin Drug Saf 2011 10 3 373 387 10.1517/14740338.2011.540568 21342078 \n10. Joy TR Hegele RA Narrative review: statin-related myopathy Ann Intern Med 2009 150 12 858 868 10.7326/0003-4819-150-12-200906160-00009 19528564 \n11. Lim AK Ho L Levidiotis V Quinine-induced renal failure as a result of rhabdomyolysis, haemolytic uraemic syndrome and disseminated intravascular coagulation Intern Med J 2006 36 7 465 467 10.1111/j.1445-5994.2006.01104.x 16780456 \n12. Highlights of prescribing information: Qualanin®. [http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021799s024lbl.pdf]. Accessed 3 Mar 2016.\n13. Rochon PA Gurwitz JH Optimising drug treatment for elderly people: the prescribing cascade BMJ (Clinical research ed) 1997 315 7115 1096 1099 10.1136/bmj.315.7115.1096 \n14. Gagnier J Kienle G Altman DG Moher D Sox H Riley DS The CARE guidelines: consensus-based clinical case report guideline development J Clin Epidemiol 2013 67 1 46 51 10.1016/j.jclinepi.2013.08.003 24035173 \n15. Nocturnal leg cramps. [http://www.uptodate.com/contents/nocturnal-leg-cramps]. Accessed 3 Mar 2016.\n16. Michalets EL Update: clinically significant cytochrome P-450 drug interactions Pharmacotherapy 1998 18 1 84 112 9469685 \n17. Kasiske BL Wanner C O'Neill WC An assessment of statin safety by nephrologists Am J Cardiol 2006 97 8A 82C 85C 10.1016/j.amjcard.2005.12.015 16581334 \n18. Kulik A Ruel M Lipid-lowering therapy and coronary artery bypass graft surgery: what are the benefits? Curr Opin Cardiol 2011 26 6 508 517 10.1097/HCO.0b013e32834b9fb1 21934497 \n19. Philip F Blackstone E Kapadia SR Impact of statins and beta-blocker therapy on mortality after coronary artery bypass graft surgery Cardiovascular Diagn. Ther. 2015 5 1 8 16 \n20. McIlroy DR Myles PS Does the use of statins improve outcomes in coronary artery bypass graft surgery? Expert Rev Cardiovasc Ther 2015 13 12 1285 1288 10.1586/14779072.2015.1099434 26473309 \n21. McKenney JM Davidson MH Jacobson TA Guyton JR Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force Am J Cardiol 2006 97 8A 89C 94C 10.1016/j.amjcard.2006.02.030 16581336 \n22. Garfinkel D Mangin D Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy Arch Intern Med 2010 170 18 1648 1654 10.1001/archinternmed.2010.355 20937924 \n23. Holmes HM Hayley DC Alexander GC Sachs GA Reconsidering medication appropriateness for patients late in life Arch Intern Med 2006 166 6 605 609 10.1001/archinte.166.6.605 16567597\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2318",
"issue": "16(1)",
"journal": "BMC geriatrics",
"keywords": "Adverse drug event; Adverse drug reaction; Aged 80, and over; Cytochrome P-450 Enzyme System; Drug interaction; Geriatrics",
"medline_ta": "BMC Geriatr",
"mesh_terms": "D000369:Aged, 80 and over; D003580:Cytochromes; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D009120:Muscle Cramp; D011788:Quality of Life; D011803:Quinine; D019821:Simvastatin",
"nlm_unique_id": "100968548",
"other_id": null,
"pages": "168",
"pmc": null,
"pmid": "27716084",
"pubdate": "2016-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9366745;25774344;16567597;21342078;25536410;24035173;20937924;16581336;9754515;7827545;16581334;10692732;26473309;7825490;16780456;19528564;9469685;21934497",
"title": "Quinine induced simvastatin toxicity through cytochrome inhibition - a case report.",
"title_normalized": "quinine induced simvastatin toxicity through cytochrome inhibition a case report"
} | [
{
"companynumb": "DE-DRREDDYS-USA/GER/17/0087487",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "Histoplasma capsulatum infection is a rare complication in the allogeneic stem cell transplant patients. Minimal guidance exists on how to appropriately manage histoplasmosis in these patients. We report a patient who developed Histoplasma pneumonia while receiving voriconazole prophylaxis at a therapeutic trough level. The patient experienced significant clinical improvement after initiation of itraconazole pharmacotherapy. We recommend a lower threshold for evaluation for histoplasmosis in allogeneic hematopoietic stem cell transplant recipients who live in endemic regions, regardless of their antifungal prophylactic regimen.",
"affiliations": "Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.;Department of Pharmacy, Division of Hematology-Oncology, University of Kentucky, Lexington, KY, USA.;Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.",
"authors": "Agrawal|Vaibhav|V|https://orcid.org/0000-0002-6383-3777;Brinda|Bryan J|BJ|;Farag|Sherif S|SS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/8124137",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/8124137\nCase Report\n\nHistoplasma capsulatum Infection in an Allogeneic Hematopoietic Stem Cell Transplant Patient Receiving Voriconazole Prophylaxis\nhttps://orcid.org/0000-0002-6383-3777Agrawal Vaibhav agrawal1@iu.edu\n1\n\n2\n Brinda Bryan J. \n3\n Farag Sherif S. \n1\n\n2\n \n1Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN, USA\n\n2Bone Marrow and Blood Stem Cell Transplantation Program, Indiana University, Indianapolis, IN, USA\n\n3Department of Pharmacy, Division of Hematology-Oncology, University of Kentucky, Lexington, KY, USA\nAcademic Editor: Tomás J. González-López\n\n\n2020 \n12 2 2020 \n2020 812413721 11 2019 20 1 2020 Copyright © 2020 Vaibhav Agrawal et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nHistoplasma capsulatum infection is a rare complication in the allogeneic stem cell transplant patients. Minimal guidance exists on how to appropriately manage histoplasmosis in these patients. We report a patient who developed Histoplasma pneumonia while receiving voriconazole prophylaxis at a therapeutic trough level. The patient experienced significant clinical improvement after initiation of itraconazole pharmacotherapy. We recommend a lower threshold for evaluation for histoplasmosis in allogeneic hematopoietic stem cell transplant recipients who live in endemic regions, regardless of their antifungal prophylactic regimen.\n==== Body\n1. Introduction\nWithin the United States, most cases of Histoplasma capsulatum infection have been reported in the Ohio and Mississippi River valleys. While an otherwise asymptomatic H. capsulatum infection can occur in patients with competent immune systems, it is far more clinically concerning in those who are immunosuppressed [1]. Typical signs and symptoms of H. capsulatum infection include fever, chills, myalgias, dry cough, and chest discomfort. In immunocompromised patients, the disease may become disseminated and if untreated, is usually fatal with a reported mortality rate of 67% in allogeneic hematopoietic stem cell transplant recipients [2]. Itraconazole and amphotericin are the first-line therapies for treatment of histoplasmosis; however, other antifungal agents such as voriconazole and posaconazole are thought to be active and have been utilized as salvage therapy [3]. Here, we present a unique case of H. capsulatum infection in a matched-unrelated donor stem cell transplant patient who was receiving voriconazole prophylaxis.\n\n2. Case Presentation\nA 55-year-old male who was a long-term resident of Indiana with a history of allogenic peripheral stem cell transplantation presented to the bone marrow transplant clinic for routine follow-up. He initially was diagnosed with stage IVB diffuse large B-cell lymphoma in August 2009 and was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and achieved complete remission. He relapsed in April 2010 and was treated with rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (R-ESHAP) and underwent an autologous peripheral stem cell transplant in July 2010 with the myeloablative preparative regimen of carmustine, etoposide, cytarabine, and melphalan (BEAM). In July 2015, he developed therapy-related myelodysplastic syndrome after his autologous transplant and underwent initial cytoreduction with 5-azacytidine followed by a matched-unrelated donor allogeneic peripheral blood stem cell transplantation in June 2016 at another institution. The patient developed acute graft-versus-host disease (GVHD) involving the skin and gut approximately one month after transplantation, which responded to corticosteroids as well as continuation of calcineurin inhibitor. He continued to be treated intermittently with courses of corticosteroids for presumed chronic GVHD of the liver until day 282 after transplant when he switched his care to our institution. At this point, he was found to have no evidence of active GVHD except for a mild elevation of alkaline phosphatase; corticosteroids were therefore tapered and discontinued on day 329 after transplant. He was also found to have anemia and thrombocytopenia, which was shown to be due to thrombotic microangiopathy, and calcineurin inhibitor therapy was also discontinued and the patient was placed on mycophenolate mofetil to prevent any exacerbations of chronic GVHD.\n\nOn day +365 after transplant, he presented to the clinic with a cough productive of whitish sputum, fatigue, weakness, and intermittent fevers with chills. A chest X-ray showed no radiographic abnormalities, and a respiratory viral panel was positive for parainfluenza virus type 3. Blood cultures were negative. No abnormalities were noted in his blood counts or complete metabolic panel. His anti-infectious regimen at the time included prophylaxis with atovaquone 1500 mg daily for prevention of pneumocystis pneumonia, valacyclovir 500 mg daily for prevention of zoster infections, and voriconazole 200 mg twice daily for prevention of fungal infections in the setting of his increased risk secondary to long-term steroid exposure. Initial recommendations were to proceed with supportive care therapeutic strategies for his parainfluenza virus type 3. He returned to the clinic two weeks later and while reporting general improvement in his respiratory symptoms, he continued to experience chills and sweating at night without any documented fever. No antibacterial therapy was prescribed at this time, and continued therapeutic intervention with supportive care was recommended. Five days later, he returned to the clinic with complaints of wheezing, green-yellow sputum production, low-grade fevers, continued fatigue, and nausea. Blood cultures, sputum cultures, and serum cytomegalovirus were all negative. He received nebulized albuterol and a prescription for clarithromycin. A computed tomography (CT) scan of the chest was performed that revealed diffuse peribronchial wall thickening with tree in bud nodularity in the lower lobes, two pulmonary nodules within the left apex each measuring 3 mm, and a 5 mm nodule within the right lower lobe. A repeat respiratory viral panel showed the persistence of both parainfluenza virus 3 and now newly detected respiratory syncytial virus A.\n\nAs the patient was not clinically improving and continued to report low-grade fever a week later, bronchoscopy was performed. Bronchoalveolar lavage (BAL) fluid showed pink and cloudy secretions with 6% monocytes, 93% granulocytes, and 1% eosinophils. Calcofluor-white and Gram stains were negative for Aspergillus and blastomycosis, as well as for Histoplasma. A positive antigen for Histoplasma was detected in the bronchoalveolar lavage sample using MiraVista diagnostic testing, but below the limit of quantification (reported as above the limit of detection but <0.4 ng/mL). A urine Histoplasma test was negative. At this time, a voriconazole serum trough level was 2.4 mcg/mL (goal 1–5.5 mcg/mL). He was also evaluated in a consultative visit by Infectious Disease to affirm this diagnosis of histoplasmosis. With concern for the patient's worsening clinical condition in his immunocompromised state and the lack of access to molecular testing at the time to support the result of antigen testing, recommendations were made to discontinue voriconazole and commence treatment with itraconazole 200 mg twice daily by mouth and mycophenolate mofetil was discontinued.\n\nThe patient returned to the clinic two weeks later and reported resolution of fever, improved well-being, and significant reduction in the frequency and productive nature of his cough. An itraconazole trough level was therapeutic at 0.5 mcg/mL (goal > 0.5 mcg/mL). Over the next two months, the patient reported resolution of all symptoms. He continues on therapeutic itraconazole with the plan of continuing lifelong suppressive therapy after one year of treatment.\n\n3. Discussion\n\nHistoplasma infection is a rare complication in stem cell transplant recipients with very few cases reported to date, and minimal guidance exists on how to appropriately manage this infection in this patient population [3–7].\n\nInfection by Histoplasma capsulatum has been reported to occur frequently in the endemic areas of the United States in the Midwest and Central states along the Ohio and Mississippi River valleys. It is the most prevalent endemic mycosis in the United States. In the immunocompetent individual, histoplasmosis generally manifests as an asymptomatic and self-limited presentation with symptoms that are often typical of cough or nonspecific flu-like symptoms. It is reported that fewer than five percent of exposed individuals develop the symptomatic disease of progressive disseminated histoplasmosis, with common risk factors including an immunocompromised state, immunosuppressive medications, or prior solid organ transplantation [8]. In the absence of treatment, and in cases of presentation in immunocompromised individuals, severe complications can arise, including potentially fatal fibrosing mediastinitis, respiratory failure, and progressive fibrosis of lymph nodes [9]. Disseminated histoplasmosis is characterized by the progressive spread of infection to extrapulmonary sites of multiple organs and is fatal unless adequate and timely treatment is administered.\n\nIn most patients, histoplasmosis presents as a subacute pulmonary infection and is commonly mistaken as a community-acquired pneumonia or viral infection and is often only considered after there is no initial response to antibacterial therapy [10]. Symptoms typically resolve within a few weeks, but there may be persistent fatigue and asthenia that lasts for several months [11]. While most infections are self-limited, it is estimated that progressive disseminated infection occurs more commonly in immunocompromised patients.\n\nThe relationship between an individual's underlying immune function and histoplasmosis severity was elucidated in the early years of the acquired immunodeficiency syndrome (AIDS) epidemic, whereby an increased incidence in symptomatic histoplasmosis was noted [12]. Symptomatic H. capsulatum infection is usually accompanied by hematogenous dissemination, which in the normal host is controlled by T-cell-mediated immunity. Immunocompromised patients are unable to mount adequate immune responses and consequently become symptomatic during the period of acute dissemination [1, 9, 13].\n\nEndemically exposed hematopoietic stem cell transplant (HSCT) recipients may be at increased risk for disseminated histoplasmosis, especially when graft-versus-host disease is managed with long-term corticosteroid therapy [1]. Reactivation of latent Histoplasma, rather than a newly acquired infection, is the apparent cause of disseminated histoplasmosis in immunosuppressed patients, particularly in patients from endemic areas [14]. Nevertheless, post-transplantation histoplasmosis is rare even in endemic areas. In solid organ transplant recipients, the largest single-center series reported an incidence of 1 case per 1000 person-years [15]. In a prospectively collected series of solid organ and HSCT patients diagnosed with endemic mycoses, only three of 16,200 HSCT recipients of histoplasmosis were identified (0.02%) of which only one patient underwent an allogeneic transplant [16]. Overall, there have been an estimated seven cases of histoplasmosis reported in the allogenic HSCT population, of which four patients with reported outcomes died [2, 4, 5, 7, 17, 18]. Furthermore, there have been no previously reported cases of histoplasmosis in patients where antifungal prophylaxis with agents that have clinical activity against Histoplasma were used as was in our reported case.\n\nCulture of blood, respiratory samples, or bone marrow remains the accepted gold standard for diagnosis, but cultures take weeks to produce result and are often influenced by the extent of disease burden [19]. The presence of organisms in the bone marrow aspirate and biopsy is often the earliest diagnostic approach for early detection in the immunocompromised patient, especially given that the fungus may not be evident in culture for two to three weeks from the initial infection [20]. Serologic studies have not reported to be helpful in diagnosis of histoplasmosis in a prior study of immunocompromised patients, but the sensitivity of detection specifically in the bone marrow transplant population has yet to be studied [21]. Though a definitive diagnosis of histoplasmosis necessitates culture or histopathologic confirmation, a probable diagnosis can still be made in a patient with increased risk secondary to immunocompromised status, compatible clinical picture, and mycological evidence [22].\n\nThe diagnostic yield of BAL in confirming the diagnosis of a bacterial or fungal pulmonary infection is often difficult, particularly with the exposure to antibiotic or antifungal prophylaxis. Cytopathologic evaluation of the BAL fluid is relatively noninvasive and has a sensitivity of around 50% for acute pulmonary histoplasmosis; when combined with BAL Histoplasma antigen testing, the sensitivity increases to about 97% [23]. Antigen testing is generally accepted as the leading modality to diagnose histoplasmosis. The Histoplasma antigen was reformulated into an enzyme immunoassay (EIA) in 1989, and the third generation MiraVista H. capsulatum Galactomannan EIA became available in 2007. The MiraVista EIA Histoplasma antigen test was found to be the highest in patients with disseminated histoplasmosis (91.8%) and the lowest in patients with subacute histoplasmosis (30%) [24]. Detecting the urine antigen has additionally proven to be slightly more sensitive than the serum across all manifestations of histoplasmosis. In a large retrospective multicenter reviewing the incidence of histoplasmosis in a solid organ transplant population, urine Histoplasma antigen detection was the most sensitive diagnostic method with 93% positivity and detection of antibody the least sensitive, positive in 36% of cases [24]. The sensitivity of BAL antigen testing is generally accepted as being superior to both urine and serum (93% vs. 79% and 56%, respectively) [22]. In nondisseminated histoplasmosis, the antigen burden is lower and thus the sensitivity of antigen testing is lower, but combing the results of urine and antigen serum has demonstrated improvement in the sensitivity of detecting pulmonary histoplasmosis [25].\n\nMolecular diagnostic methods have the advantage of higher analytic specificity and shorter turnaround times as compared to other diagnostic methodologies, especially when considering the time needed for colony growth in culture-based diagnosis [26]. There are currently no FDA-approved molecular assays for Histoplasma directly applicable to clinical specimens, though laboratory-based PCR assays using a variety of molecular targets have been developed. In prior studies focused in hematology-oncology patients that often have prolonged cytopenias, addition of molecular analysis testing has increased the efficacy of bronchoalveolar lavage in the diagnosis of respiratory infections [27]. In a study of 107 consecutive hospitalized patients with hematologic malignancies and bone marrow transplant recipients who underwent BAL for evaluation of pulmonary infiltrates, the addition of PCR-based Aspergillus DNA detection to improve the diagnostic capacity of invasive Aspergillus infection decreased mortality from 80 to 35.6% (P=0.003) [28].\n\nAlthough systemic candidiasis and aspergillosis are more commonly reported as major causes of fungal infections in HSCT recipients, disseminated histoplasmosis presents a threat to the HSCT recipient from an endemic area. Furthermore, the diagnosis of histoplasmosis is especially challenging because empiric or prophylactic antifungal treatment is often administered after HSCT, and this may possibly lead to an underestimation of histoplasmosis. The significant mortality associated with post-transplant histoplasmosis and nonspecific clinical presentation further emphasizes the importance of maintaining a low threshold for considering the diagnosis of histoplasmosis. This accounts for the distinct diagnosis used between definitions of invasive fungal disease in clinical practice compared to clinical research definitions [29].\n\nThe Infectious Disease Society of America (IDSA) last published guidelines for the management of histoplasmosis in 2007 [3, 23]. In general, for patients with mild-to-moderate pulmonary histoplasmosis, treatment is not recommended. However, if patients have symptoms for greater than one month, as in the case of our patient, therapeutic itraconazole should be employed for at least one year. While there is no specific recommendation for treatment of histoplasmosis in immunocompromised patients, including recipients of allogeneic HSCT who are receiving immunosuppressive medications, the guidelines recommend that patients who are not immunocompetent should receive suppressive therapy with itraconazole if immunosuppression cannot be reversed. Furthermore, they specifically recommend prophylaxis with itraconazole in HIV patients with CD4 counts <150 cells/mm3 in endemic areas where the incidence is above 10 cases per 100 patient-years. Indiana, where the patient lived prior to his allogeneic stem cell transplant, is among the states that are endemic for histoplasmosis [30]. Past infection, determined by the skin test reactivity assay, occurs in 50–80% of Indiana residents [31].\n\nVoriconazole has been reported to be successful in the treatment of a small number of patients with varying forms of Histoplasma infection [31–33]. The drug has demonstrated in vitro activity against H. capsulatum, but isolates that became resistant to fluconazole were noted to have elevated minimum inhibitory concentration (MIC) values to voriconazole in patients with AIDS, suggesting that resistance may develop during treatment with voriconazole [34]. IDSA recommends that voriconazole only be utilized as a second-line alternative to itraconazole for treatment of histoplasmosis. In addition, no specific prophylaxis is recommended.\n\nMonitoring of voriconazole blood levels has been advocated as a means to ensure adequate drug exposure in treating patients with invasive mycoses. Freifeld et al. examined nine patients with disseminated histoplasmosis who failed treatment with amphotericin or itraconazole and received voriconazole as secondary therapy where serum trough levels were determined [32]. All patients were deemed to have clinically improved while receiving voriconazole 200 mg twice daily. Of the 20 samples obtained from these patients, serum voriconazole levels ranged from undetectable to 8 mcg/mL. In addition, archived H. capsulatum isolates from AIDS patients who had either primary or relapsed histoplasmosis were employed for MIC testing via a modified Clinical and Laboratory Standards Institute (CLIA) assay. The median MIC for primary and relapsed isolates was 0.015 mCg/mL and 0.03 mCg/mL, respectively. Despite two patients having voriconazole levels below the MIC values, no patient relapsed. The authors proposed a threshold voriconazole trough value of 0.125 mCg/mL for the treatment of histoplasmosis [32]. Notably our patient's trough level was higher at 2.4 mCg/mL.\n\nTo our knowledge, this is the first case of histoplasmosis reported in an allogeneic stem cell transplant recipient who was receiving voriconazole as antifungal prophylaxis at the appropriate serum drug levels for Aspergillus prophylaxis. The detection of Histoplasma, despite therapeutic voriconazole levels, is unique to our case. The reason for infection despite seemingly adequate coverage with voriconazole is unclear but may be related to relative resistance, though voriconazole may have contributed to his borderline positive antigen result seen on broncheoalveolar fluid antigen testing. We cannot exclude the possibility that the organism present either was intrinsically resistant or developed resistance to voriconazole due to prolonged drug exposure.\n\nWhile voriconazole is not a well-validated treatment or prophylactic modality for Histoplasma infections, we would recommend caution in using this agent for either approach. Though molecular-based diagnostic methods have the potential to improve the diagnostic sensitivity of Histoplasma infections on this unique population, we recommend timely evaluation and high clinical suspicion with the current culture and serologic-based diagnostic methodology. We also recommend a lower threshold for evaluation for histoplasmosis in allogeneic transplant recipients who live in endemic regions, regardless of their antifungal prophylactic regimen.\n\nDisclosure\nVaibhav Agrawal and Bryan J. Brinda are co-first authors.\n\nConflicts of Interest\nThe authors of this article do not have any conflicts of interest to disclose.\n\nAuthors' Contributions\nVA, SF, and BJB contributed to the research and collection of information and participated in the drafting of the report. All authors critically revised the document for intellectual content and approved the final version.\n==== Refs\n1 Kauffman C. A. Diagnosis of histoplasmosis in immunosuppressed patients Current Opinion in Infectious Diseases 2008 21 4 421 425 10.1097/qco.0b013e328306eb8d 2-s2.0-49049107208 18594296 \n2 Natarajan M. Swierzbinski M. J. Maxwell S. Pulmonary Histoplasma infection after allogeneic hematopoietic stem cell transplantation: case report and review of the literature Open Forum Infectious Diseases 2017 4 2 p. ofx041 10.1093/ofid/ofx041 2-s2.0-85030663277 \n3 Wheat L. J. Freifeld A. G. Kleiman M. B. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America Clinical Infectious Diseases 2007 45 7 807 825 10.1086/521259 2-s2.0-34848865974 17806045 \n4 Haydoura S. Wallentine J. Lopansri B. Ford C. D. Saad D. Burke J. P. Disseminated histoplasmosis in allogeneic bone marrow transplant: a diagnosis not to be missed Transplant Infectious Disease 2014 16 5 822 826 10.1111/tid.12261 2-s2.0-84907931623 24981307 \n5 Peterson M. W. Pratt A. D. Nugent K. M. Pneumonia due to Histoplasma capsulatum in a bone marrow transplant recipient Thorax 1987 42 9 698 699 10.1136/thx.42.9.698 2-s2.0-0023619936 3317978 \n6 Tomblyn M. Chiller T. Einsele H. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective Biology of Blood and Marrow Transplantation 2009 15 10 1143 1238 10.1016/j.bbmt.2009.06.019 2-s2.0-69849102119 19747629 \n7 Walsh T. J. Catchatourian R. Cohen H. Disseminated histoplasmosis complicating bone marrow transplantation American Journal of Clinical Pathology 1983 79 4 509 511 10.1093/ajcp/79.4.509 2-s2.0-0020540082 6340463 \n8 Wheat L. J. Connolly-Stringfield P. Kohler R. B. Frame P. T. Gupta M. R. Histoplasma capsulation polysaccharide antigen detection in diagnosis and management of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome The American Journal of Medicine 1989 87 4 396 400 10.1016/s0002-9343(89)80820-4 2-s2.0-0024449978 2801730 \n9 Kauffman C. A. Histoplasmosis: a clinical and laboratory update Clinical Microbiology Reviews 2007 20 1 115 132 10.1128/cmr.00027-06 2-s2.0-33846535287 17223625 \n10 Hage C. A. Knox K. S. Wheat L. J. Endemic mycoses: overlooked causes of community acquired pneumonia Respiratory Medicine 2012 106 6 769 776 10.1016/j.rmed.2012.02.004 2-s2.0-84859790523 22386326 \n11 Goodwin R. A. Loyd J. E. Des Prez R. M. Histoplasmosis in normal hosts Medicine 1981 60 4 231 266 10.1097/00005792-198107000-00001 2-s2.0-0019408832 7017339 \n12 Wheat L. J. Connolly-Stringfield P. A. Baker R. L. Disseminated histoplasmosis in the acquired immune deficiency syndrome Medicine 1990 69 6 361 374 10.1097/00005792-199011000-00004 2233233 \n13 Porta A. Maresca B. Host response and Histoplasma capsulatum /macrophage molecular interactions Medical Mycology 2000 38 6 399 406 10.1080/mmy.38.6.399.406 11204877 \n14 Davies S. F. Khan M. Sarosi G. A. Disseminated histoplasmosis in immunologically suppressed patients. Occurrence in a nonendemic area The American Journal of Medicine 1978 64 1 94 100 10.1016/0002-9343(78)90183-3 2-s2.0-0017862135 623139 \n15 Cuellar-Rodriguez J. Avery Rk Fau - Lard M. Lard M Fau - Budev M. Histoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area Clinical Infectious Diseases 2009 49 5 710 716 19635026 \n16 Kauffman C. A. Freifeld A. G. Andes D. R. Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET) Transplant Infectious Disease 2014 16 2 213 224 10.1111/tid.12186 2-s2.0-84897961656 24589027 \n17 Honarpisheh H. H. Curry J. L. Richards K. Cutaneous histoplasmosis with prominent parasitization of epidermal keratinocytes: report of a case Journal of Cutaneous Pathology 2016 43 12 1155 1160 10.1111/cup.12792 2-s2.0-84987617468 27516534 \n18 Hot A. Maunoury C. Poiree S. Diagnostic contribution of positron emission tomography with [18F] fluorodeoxyglucose for invasive fungal infections Clinical Microbiology and Infection 2011 17 3 409 417 10.1111/j.1469-0691.2010.03301.x 2-s2.0-79751480817 20636432 \n19 Couppié P. Aznar C. Carme B. Nacher M. American histoplasmosis in developing countries with a special focus on patients with HIV: diagnosis, treatment, and prognosis Current Opinion in Infectious Diseases 2006 19 5 443 449 10.1097/01.qco.0000244049.15888.b9 2-s2.0-33748347475 16940867 \n20 Cooperberg A. A. Schwartz J. The diagnosis of disseminated histoplasmosis from marrow aspiration Annals of Internal Medicine 1964 61 2 289 295 10.7326/0003-4819-61-2-289 2-s2.0-26044441813 14204863 \n21 Kauffman C. A. Israel K. S. Smith J. W. White A. C. Schwarz J. Brooks G. F. Histoplasmosis in immunosuppressed patients The American Journal of Medicine 1978 64 6 923 932 10.1016/0002-9343(78)90445-x 2-s2.0-0018102991 350045 \n22 Azar M. M. Hage C. A. Clinical perspectives in the diagnosis and management of histoplasmosis Clinics in Chest Medicine 2017 38 3 403 415 10.1016/j.ccm.2017.04.004 2-s2.0-85020090342 28797485 \n23 Hage C. A. Davis T. E. Fuller D. Diagnosis of histoplasmosis by antigen detection in BAL fluid Chest 2010 137 3 623 628 10.1378/chest.09-1702 2-s2.0-77949517290 19837826 \n24 Hage C. A. Ribes J. A. Wengenack N. L. A multicenter evaluation of tests for diagnosis of histoplasmosis Clinical Infectious Diseases 2011 53 5 448 454 10.1093/cid/cir435 2-s2.0-80051970256 21810734 \n25 Guarner J. Brandt M. E. Histopathologic diagnosis of fungal infections in the 21st century Clinical Microbiology Reviews 2011 24 2 247 280 10.1128/cmr.00053-10 2-s2.0-79955063463 21482725 \n26 Simon S. Veron V. Boukhari R. Blanchet D. Aznar C. Detection of Histoplasma capsulatum DNA in human samples by real-time polymerase chain reaction Diagnostic Microbiology and Infectious Disease 2010 66 3 268 273 10.1016/j.diagmicrobio.2009.10.010 2-s2.0-77349101312 20159374 \n27 Oren I. Hardak E. Zuckerman T. Does molecular analysis increase the efficacy of bronchoalveolar lavage in the diagnosis and management of respiratory infections in hemato-oncological patients? International Journal of Infectious Diseases 2016 50 48 53 10.1016/j.ijid.2016.07.011 2-s2.0-84989886957 27484225 \n28 Hardak E. Yigla M. Avivi I. Fruchter O. Sprecher H. Oren I. Impact of PCR-based diagnosis of invasive pulmonary aspergillosis on clinical outcome Bone Marrow Transplantation 2009 44 9 595 599 10.1038/bmt.2009.65 2-s2.0-70749134843 19308034 \n29 Donnelly J. P. Chen S. C. Kauffman C. A. Revision and update of the consensus definitions of invasive fungal disease from the European organization for research and treatment of cancer and the mycoses study group education and research consortium Clinical Infectious Diseases 2019 10.1093/cid/ciz1008 \n30 Vail G. M. Young R. S. Wheat L. J. Filo R. S. Cornetta K. Goldman M. Incidence of histoplasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area Transplant Infectious Disease 2002 4 3 148 151 10.1034/j.1399-3062.2002.01016.x 2-s2.0-0036758557 12421460 \n31 Freifeld A. Proia L. Andes D. Voriconazole use for endemic fungal infections Antimicrobial Agents and Chemotherapy 2009 53 4 1648 1651 10.1128/aac.01148-07 2-s2.0-65649147960 19139290 \n32 Freifeld A. Arnold S. Ooi W. Relationship of blood level and susceptibility in voriconazole treatment of histoplasmosis Antimicrobial Agents and Chemotherapy 2007 51 7 2656 2657 10.1128/aac.01583-06 2-s2.0-34447285720 17438046 \n33 Li R.-K. Ciblak M. A. Nordoff N. In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum Antimicrobial Agents and Chemotherapy 2000 44 6 1734 1736 10.1128/aac.44.6.1734-1736.2000 2-s2.0-0034037292 10817743 \n34 Wheat L. J. Connolly P. Smedema M. Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed fluconazole Journal of Antimicrobial Chemotherapy 2006 57 6 1235 1239 10.1093/jac/dkl133 2-s2.0-33749189082 16627592\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2020()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "8124137",
"pmc": null,
"pmid": "32099699",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "20636432;7017339;28797485;3317978;31802125;17438046;19837826;17806045;19139290;10817743;27484225;28470019;2801730;19308034;16940867;16627592;22386326;18594296;350045;24589027;14204863;6340463;11204877;21810734;19747629;27516534;24981307;623139;19635026;17223625;12421460;21482725;2233233;20159374",
"title": "Histoplasma capsulatum Infection in an Allogeneic Hematopoietic Stem Cell Transplant Patient Receiving Voriconazole Prophylaxis.",
"title_normalized": "histoplasma capsulatum infection in an allogeneic hematopoietic stem cell transplant patient receiving voriconazole prophylaxis"
} | [
{
"companynumb": "US-ACCORD-174717",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "DiGeorge syndrome or 22q11.2 deletion syndrome is one of the most common genetic microdeletion syndromes in humans. In addition to physical manifestations, DiGeorge syndrome is associated with a high prevalence of psychiatric disorders, such as intellectual disability, schizophrenia and attention-deficit/hyperactivity disorder. Usually, the diagnosis of DiGeorge syndrome is made in early childhood. This article reports on the late diagnosis of a patient with panic disorder and comorbid major depression at the age of 51. Since genetic testing was not available before the 1990s, there might be many over 40-year-old patients, who remained undiagnosed. Psychiatric symptoms exhibit distinctive developmental trajectories and many of these exhibit an increase in incidence during adulthood. Hence, undiagnosed adult DiGeorge patients might present in psychiatric services. As in this case, a correct diagnosis of DiGeorge syndrome in adults may help to improve treatment and outcome.",
"affiliations": "Department of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. christoph.kraus@meduniwien.ac.at.;Department of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.;Department of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.;Department of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.",
"authors": "Kraus|Christoph|C|http://orcid.org/0000-0002-7144-2282;Vanicek|Thomas|T|;Weidenauer|Ana|A|;Khanaqa|Tav|T|;Stamenkovic|Mara|M|;Lanzenberger|Rupert|R|http://orcid.org/0000-0003-4641-9539;Willeit|Matthäus|M|;Kasper|Siegfried|S|http://orcid.org/0000-0001-8278-191X",
"chemical_list": null,
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-018-1335-y",
"fulltext": "\n==== Front\nWien Klin WochenschrWien. Klin. WochenschrWiener Klinische Wochenschrift0043-53251613-7671Springer Vienna Vienna 133510.1007/s00508-018-1335-yShort ReportDiGeorge syndrome Relevance of psychiatric symptoms in undiagnosed adult patientshttp://orcid.org/0000-0002-7144-2282Kraus Christoph christoph.kraus@meduniwien.ac.athttp://www.meduniwien.ac.at/psychiatrie 1Vanicek Thomas 1Weidenauer Ana 1Khanaqa Tav 2Stamenkovic Mara 1http://orcid.org/0000-0003-4641-9539Lanzenberger Rupert 1Willeit Matthäus 1http://orcid.org/0000-0001-8278-191XKasper Siegfried 11 0000 0000 9259 8492grid.22937.3dDepartment of Psychiatry and Psychotherapy, Clinical Department of General Psychiatry, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria 2 0000 0004 1936 9756grid.10253.35Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany 18 4 2018 18 4 2018 2018 130 7 283 287 23 1 2018 19 3 2018 © The Author(s) 2018Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Summary\nDiGeorge syndrome or 22q11.2 deletion syndrome is one of the most common genetic microdeletion syndromes in humans. In addition to physical manifestations, DiGeorge syndrome is associated with a high prevalence of psychiatric disorders, such as intellectual disability, schizophrenia and attention-deficit/hyperactivity disorder. Usually, the diagnosis of DiGeorge syndrome is made in early childhood. This article reports on the late diagnosis of a patient with panic disorder and comorbid major depression at the age of 51. Since genetic testing was not available before the 1990s, there might be many over 40-year-old patients, who remained undiagnosed. Psychiatric symptoms exhibit distinctive developmental trajectories and many of these exhibit an increase in incidence during adulthood. Hence, undiagnosed adult DiGeorge patients might present in psychiatric services. As in this case, a correct diagnosis of DiGeorge syndrome in adults may help to improve treatment and outcome.\n\nKeywords\n22q11 deletion syndromePanic disorderDepressionPsychiatric geneticsAnxiety disordersMedical University of ViennaOpen access funding provided by Medical University of Vienna.\n\nissue-copyright-statement© Springer-Verlag GmbH Austria, part of Springer Nature 2018\n==== Body\nIntroduction\nThe 22q11 deletion syndrome (DS), also known as DiGeorge or velocardiofacial syndrome, is one of the most common microdeletion syndromes in humans. It occurs in 1 in every 3000–6000 births and is equally distributed between males and females [1, 2]. The median age at diagnosis in children with congenital heart disease in a Swedish sample from 1991–2000 was 3.9 years [1]. Since lifetime support and early management of disease complications enhance quality of life in DiGeorge syndrome patients [3], early diagnosis is crucial. Genetic tests were not available until the mid-1990ies in Austria, therefore a substantial number of patients might be undiagnosed. Based on population data (Statistics Austria, www.statistik.at) and incidence rates, approximately 1800 patients with 22q11 DS aged older than 18 years could exist, for whose sake a correct diagnosis would be an important step towards targeted treatment.\n\nIn infants, DiGeorge syndrome typically presents with the triad immunodeficiency (~75% of patients), congenital cardiac anomalies (~75%) and hypocalcaemia due to hypoparathyroidism (~50%). However, a large number of further symptoms are known, which comprise palatal abnormalities (~75%), gastrointestinal problems such as reflux disease or dysmotility (~30%), genitourinary anomalies such as renal agenesis (~30%), hernia (~1%), neuronal tube defects, polydactyly, anomalies in the spine, face, ear, nose, eyelids or eyes (e.g. hypertelorism), malignancies or seizures, early-onset Parkinson disease (~30%) and psychiatric disorders (~60%) (see [4] for detailed pathophysiological mechanisms and comprehensive review). Variability in phenotype and severity is high, the clinical presentation is heterogeneous and therefore, the diagnosis in non-typically presenting patients is easily overlooked.\n\nDiGeorge syndrome constitutes an increased risk for psychiatric diseases, such as intellectual disability, schizophrenia, attention deficit hyperactivity disorder or anxiety disorders (Table 1). Given the heterogeneity of symptoms and the unavailability of genetic testing in primary care settings or smaller community hospitals, patients might remain undiagnosed. Patients, who lack easily recognizable manifestations, such as cardiac defects, immunodeficiency and facial malformations might grow old without the need for substantial medical interventions. But undiagnosed patients exhibit an increased likelihood for psychiatric symptoms with progressing age. This is why the medical community must be informed of the case reported here to consider this genetic syndrome in clinical practice.Table 1 Cumulative incidence (in %) for psychiatric diseases on 22q11.2 deletions and controls\n\nDisease\tICD-10\tControls\tCases\tCases/controls\t\nAny psychiatric disorder\tF00–F99\t10.05 (9.40–10.74)\t30.32 (22.69–40.51)\t3.0\t\nSchizophrenia and related disorders\tF20–F29\t1.37 (1.12–1.67)\t7.23 (3.04–17.16)\t5.3\t\nMood disorders\tF30–F39\t3.14 (2.77–3.57)\t5.87 (2.17–15.88)\t1.9\t\nNeurotic, stress-related, and somatoform disorders\tF40–F48\t4.68 (4.24–5.15)\t7.03 (3.09–15.99)\t1.5\t\nIntellectual disability\tF70–F79\t0.73 (0.57–0.93)\t15.08 (9.90–22.98)\t20.7\t\nPervasive developmental disorders\tF84\t1.40 (1.19–1.64)\t11.65 (7.08–19.18)\t8.3\t\nChildhood autism\tF84.0\t0.40 (0.29–0.53)\t3.40 (1.40–8.26)\t8.5\t\nBehavioral and emotional disorders with onset usually occurring in childhood and adolescence\tF90–F98\t3.43 (3.10–3.80)\t8.69 (4.76–15.87)\t2.5\t\nFigures represent percentages and are taken from [5]\n\nNumbers in brackets represent 95% confidence intervals\n\nICD-10 international classification of diseases and related health problems, 10th revision\n\n\n\nThe pathophysiology of DiGeorge syndrome consists of microdeletions of 1.5–3 million base pairs on the long arm of chromosome 22 [2], which is one of the most structurally complex regions in the genome [4]. There are approximately 90 genes in a typical 3Mb 22q11.2 locus, which are hemizygously deleted. Several mouse models or single gene knockouts provide good translational evidence for 22q11 deletion syndrome [2]. Once diagnosis is suspected, genetic testing is necessary to determine the molecular pathophysiology of DiGeorge syndrome. Fluorescence in situ hybridization (FISH) with specific probes is able to probe the critical region of chromosome 22. Nowadays, FISH is increasingly being replaced by more modern tests, such as microarrays, SNP arrays or multiplex PCR methods.\n\nCase presentation\nPsychiatric history\nA 51-year-old man was admitted to our university hospital in September 2016 with panic attacks, dyspnea and chronic obstructive pulmonary disease (COPD) grade IV. During panic attacks, the patient experienced a feeling of heart-race (but heart frequency remained below 100/min), cramps in the upper extremities and fear of death. In addition, the patient suffered from chronic abdominal pain (over all quadrants). Therefore, he had previously been admitted many times to hospitals near his hometown at medical and surgical departments. Since no organic causes for the symptoms were identified, the patient was referred to a local psychiatric department where he was admitted as an inpatient seven times between 2014 and 2016. The patient increasingly developed subtle memory and concentration deficits, depressed mood, and ruminations, predominantly about his deteriorating health. Because he relinquished hopes of recovery from abdominal pain, for the first time in his life in 2016, he made a suicide attempt by taking an unknown amount of trazodone and triazolam tablets. He was discharged from the psychiatric ward of the community hospital after stabilization of acute suicidal thoughts 1 week before being admitted to our hospital.\n\nIn the initial psychiatric examination, perception, memory and concentration were reduced. The thought flow was reduced, he exhibited depressed mood and ruminations, the patient felt sick, hopeless, and had increased feelings of guilt (mainly for seeking help from his family during panic attacks). His affect was reduced, there was inner tension with concomitant low levels of energy and increased motor activity. His mood deteriorated during the day with ruminating thoughts during the evenings and nights. Consequently, he had difficulties falling asleep, sleeping through the night, decreased total sleep time, early morning awakening and fatigue during the day. Occasionally, he exhibited anxiety, with a feeling of rapid heartbeat, panic and fear of death. These panic attacks were sometimes associated with dyspnea. The psychiatric examination was otherwise normal. In particular, there was no suicidal ideation or suicidality. Hence, a diagnosis of panic disorder with comorbid major depression (MD) with a current severe episode was made.\n\nThe patient was unemployed, had previously worked as a waiter and lived alone in a small town (<5000 inhabitants). He had no current partner or children. The patient was supported by the department’s social worker. He maintained social contact with his sister and two brothers, all of whom were psychiatrically healthy and highly functioning. The patient was described as a life-time worry-child by his sister. She also described a single short psychotic episode in 2013 with delusions of grandiosity.\n\nNeurocognitive testing (carried out after improvement of the severe depressive episode) showed crystallized intelligence at an average, fluid intelligence at low average level (Multiple Choice Vocabulary Intelligence Test, MWT-B: 94; Basic Intelligence Functions, IBF, IQ: 82), there were no clinical signs of rapid onset dementia. An electroencephalogram (EEG) exhibited scattered theta waves over all leads, cranial magnetic resonance imaging (MRI) was not tolerated by the patient due to claustrophobic reactions.\n\nOn admission, the daily psychopharmacological therapy consisted of olanzapine 10 mg and trazodone 150 mg. At our hospital, sertraline was established as an antidepressant and anti-anxiety medication and dosed up to 250 mg. Serum concentration of sertraline was 50 ng/ml at 250 mg p.o.q.d. (reference value: 10–150 ng/ml at 250 mg). Due to better augmentative and side-effect profiles, olanzapine was changed to amisulpride and left at 50 mg at night. As additional anti-anxiety therapy, pregabaline was slowly titrated to 300 mg, thereby taking advantage of low potential of respiratory depression. With this combinatory antidepressant and anti-anxiety treatment, the patient achieved marked improvement of mood within 4 weeks. Anxiety and inner tension levels dropped, there were no further panic attacks during the stay in hospital.\n\nAdditionally, the patient was treated in psychotherapeutic groups at our ward but participation in physiotherapy and occupational therapy was poor. His favorite pastime at our ward was playing cards on his laptop. A successful relocation to a nursing home in Vienna was initiated by the social worker team.\n\nMedical history\nIn the initial medical examination, the patient weighed 80 kg at 179 cm, had mild edema in both legs, noisy breathing (mild wheezing) and reported diffuse but severe abdominal pain that had started 6 months ago. Previously performed examinations (gastroscopy, coloscopy, X‑ray) did not find a somatic cause for the pain. Thus, psychogenic causes were assumed. The patient reported moderate amounts of alcohol consumption and smoked approximately 20 cigarettes a day (23 pack years). Penicillin and contrast agent allergies were known. All other examinations were normal.\n\nThe patient had a medical history of heart surgery for septal defect at 6 years of age (6), correction of polydactyly (two additional thumbs, age 6 years), appendectomy (8 years), polypectomy in the nose (10 years) and colon (51 years) were diagnosed and treated.\n\nA 12-lead electrocardiogram (ECG) after admission was normal. Blood laboratory tests showed combined hypercholesterolemia (triglycerides [TG] 81 mg/dl, cholinesterase [CHE] 334 mg/dl, low-density lipoprotein [LDL] 249.89 mg/dl, slightly elevated liver enzymes, gamma-glutamyl transferase [GGT] 103 U/l, glutamic-pyruvic transaminase [GPT] 55 U/l) were not reproducible by further testing. Creatine kinase (CK) was moderately elevated throughout the hospital stay (190–362 U/l), whereby psychogenic muscular tension was considered as the most likely reason. Arterial blood gases (pCO2: 51.4%, pO2: 50.6%, pH 7.4) in combination with obstructive breathing, severely reduced forced expiratory volume in 1 s (FEV1) (17%) and moderate vascular shadows in chest X‑rays confirmed previously known COPD. Cardiac sonography showed a pronounced septal shift with inspiratory left-sided shift, a borderline right ventricular function and elevated pulmonary artery pressure (36 mm Hg).\n\nFurther internal medical consultations recommended gastroscopy whereby an antrum gastritis, duodenitis with several small ulcerous lesions and a reflux esophagitis were diagnosed and treated with pantoprazole 80 mg/day. Further radiological testing, e.g. computed tomography-angiography (CTA) with contrast agent and cortisone treatment (allergy) was performed for suspected abdominal claudication. The examination demonstrated high-grade obstruction of the celiac artery but with good collateral arteries and no signs of reduced perfusion of abdominal organs. Obstruction was confirmed with abdominal duplex sonography, whereby reduced flow profiles in the splenic artery and common hepatic artery were demonstrated. Additionally, in the CT, renal cysts in both kidneys in part hemorrhagic were found. A possible stenosis of the ligamentum arcuatum was evaluated with MR angiography (MRA), but due to phobic reactions and lack of compliance during breathing provocation, two attempts did not yield sufficient data for full evaluation of stenosis of the ligamentum arcuatum. After frequent consultations with abdominal surgeons, gastroenterologists and interventional radiologists, explorative surgery was not performed and a conservative approach was chosen. The abdominal pain significantly decreased after initiating antidepressive and anti-anxiety treatment with sertraline and pregabaline. Treatment of gastritis with adequate proton pump inhibitor dosage may also have contributed to improvement of pain. In a telephone call 3 months after discharge, the patient stated he was pain-free.\n\nGenetic testing\nDue to early onset heart septum defect, polydactyly, slightly reduced cognitive performance, mild microcephaly and facial abnormities as well as psychiatric diagnoses, a geneticist was consulted. A microarray of genomic DNA with SNP Array Cytoscan HD (Affymetrix, Santa Clara, CA, USA) was performed and a 3.2 Mb deletion in region 22q11.21 was detected. This microdeletion was confirmed by molecular cytogenetics (with HIRA 22q11 Kreatech FISH probes, Leica Biosystems, Wetzlar, Germany).\n\nDiscussion\nThis case history highlights a late diagnosis of 22q11 deletion syndrome (DS). Although early signs such as polydactyly and congenital heart disease were present, genetic testing was only performed after psychiatric manifestation of the disease in middle age. Panic disorder and a severe depressive episode with suicidal ideation were successfully treated with sertraline and antidepressant augmentation with the atypical antipsychotic amisulpride. Antidepressant and anti-anxiety psychopharmacological therapy resembled conventional antidepressant therapy. By combining anxiolytics with a non-sedative anxiolytic (pregabaline), significant improvement of panic disorder was achieved and abdominal pain was also alleviated. If arterial obstruction was a consequence of an abdominal malformation, high blood lipids or smoking, remains open in this case. Furthermore, no certain association between pulmonary obstruction and 22q11 DS is known; however, the patient exhibited nicotine addiction (~23 pack years), which constitutes an additional risk factor for atherosclerosis and could explain COPD-IV. In our patient, typical signs and symptoms were present at an early age. Since the patient did not report significant health problems in this life period, delayed diagnosis might be explainable by the lack of earlier medical consultation.\n\nDiGeorge syndrome and psychiatry\nConcerning neuropsychiatric symptoms catechol-O-methyl transferase (COMT) deletions result in increased vulnerability for neuropsychiatric disorders. DiGeorge syndrome patients exhibit an approximately 3‑fold increased risk for psychiatric disorders, as shown by a recent study in a large Danish cohort [5]. In this study the mean age at diagnosis for psychiatric disorders was 12.4 years for individuals with deletions. The risk was highly elevated (~20.7 times) for intellectual disabilities, markedly elevated for schizophrenia and psychotic spectrum disorder, and still substantially elevated for mood and anxiety disorders (see Table 1). Notably, numbers tend to vary between epidemiological studies due to design and selection of patients [6]. Incidence rates of psychiatric disorders in DiGeorge syndrome are highlighted in Fig. 1. There are developmental trajectories with anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder peaking in childhood and early youth, while incidence of psychotic disorders increases throughout the lifetime. Strikingly, anxiety disorders exhibit high prevalence rates in DiGeorge syndrome patients, which fits to our patient’s psychiatric history; however, 1–2% of patients diagnosed with schizophrenia have DiGeorge syndrome. Thus, there is consensus that genetic screening is currently not recommended in schizophrenia [7].Fig. 1 Developmental trajectories of psychiatric diseases among patients with DiGeorge syndrome. ASD autism sprectrum disorder, ADHD attention-deficit/hyperactivity disorder. (Figure corresponds to Fig. 2B in [1] and is reproduced with permission from Elsevier)\n\n\n\nDue to deletions of major neurotransmitter gatekeeping enzymes, such as COMT, which degrades dopamine (and to a lesser extent serotonin), neuronal development is impaired in DiGeorge syndrome [1]. Although pathogenetic processes in DiGeorge syndrome are still poorly understood, there is evidence for reductions in neuronal gray matter and alterations of transmitter release [1]. Deletions of important neurotransmitter gatekeeping enzymes provide an excellent model for the discovery of genomic risk factors for neuropsychiatric disorders. The combination of relatively high incidence, developmental disease trajectories, clinical manifestations, environmental stress/life events and animal models could serve as a powerful model for translational research in neuropsychiatric disorders.\n\nThere are few specific recommendations for the treatment of DiGeorge syndrome patients [3]. Combinations of psychopharmacological and psychotherapeutic treatments are recommended for the respective psychiatric disorders, but apart from an increased risk for seizures (approximately 5–7-fold compared to healthy subjects) [8], only few specific recommendations are available. Importantly, lifetime concomitant psychosocial treatments are crucial to improve patient outcomes [3].\n\nConclusion\nThis short report highlights the importance of knowledge on this relatively frequent genetic condition. Diagnosing DiGeorge syndrome early in life improves the chances to timely treat psychiatric disorders. On the other hand, a substantial number of adult undiagnosed patients might present with psychiatric symptoms. The neurodevelopment of DiGeorge syndrome is linked to the lack of important neurotransmitter genes such as COMT, which degrades monoaminergic transmitters such as dopamine and serotonin. Moreover, 22q11 DS offers interesting opportunities for translational studies on monoaminergic alterations in neuropsychiatric disorders. Genetic testing for DiGeorge syndrome should be done in psychiatric patients with intellectual disabilities, developmental disorders and schizophrenia if cardiac malformations, immunodeficiency, hypoparathyroidism or malformations are present. Once the diagnosis is confirmed, symptomatic psychopharmacological treatment should be initiated but there should also be a focus on psychosocial treatment to improve patient outcomes.\n\nFunding\nOpen access funding provided by Medical University of Vienna.\n\nCompliance with ethical guidelines\nConflict of interest\nThe following statements do not relate to any aspects of the current report. S. Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AstraZeneca, Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Dr. Willmar Schwabe GmbH and Servier. R. Lanzenberger received travel grants and/or conference speaker honoraria from AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, AOP Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, and Roche Austria GmbH. T. Vanicek received travel grants and compensation for workshop participation from Pfizer and Eli Lilly and speaker honoraria from Eli Lilly. C. Kraus has received travel grants from Roche Austria GmbH and AOP Orphan Pharmaceuticals AG. M. Willeit received speaker honoraria from Janssen-Cilag Pharma GmbH. A. Weidenauer, T. Khanaqa, M. Stamenkovic, and M. Willeit declare that they have no competing interests.\n\nEthical standards\nThis article does not contain any studies with human participants or animals performed by any of the authors. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.\n==== Refs\nReferences\n1. Jonas RK Montojo CA Bearden CE The 22q11.2 deletion syndrome as a window into complex neuropsychiatric disorders over the lifespan Biol Psychiatry 2014 75 351 360 10.1016/j.biopsych.2013.07.019 23992925 \n2. Scambler PJ The 22q11 deletion syndromes Hum Mol Genet 2000 9 2421 2426 10.1093/hmg/9.16.2421 11005797 \n3. Fung WL Butcher NJ Costain G Practical guidelines for managing adults with 22q11.2 deletion syndrome Genet Med 2015 17 599 609 10.1038/gim.2014.175 25569435 \n4. McDonald-McGinn DM Sullivan KE Marino B 22q11.2 deletion syndrome Nat Rev Dis Primers 2015 1 15071 10.1038/nrdp.2015.71 27189754 \n5. Hoeffding LK Trabjerg BB Olsen L Risk of psychiatric disorders among individuals with the 22q11.2 deletion or duplication: a Danish nationwide, register-based study JAMA Psychiatry 2017 74 282 290 10.1001/jamapsychiatry.2016.3939 28114601 \n6. Schneider M Debbane M Bassett AS Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome Am J Psychiatry 2014 171 627 639 10.1176/appi.ajp.2013.13070864 24577245 \n7. Kaltenboeck A Friedrich F Hinterbuchinger B Diagnosis of 22q11.2 deletion syndrome in the context of newly developed psychosis Neuropsychiatr 2016 30 223 226 10.1007/s40211-016-0203-0 27822729 \n8. Kao A Mariani J McDonald-McGinn DM Increased prevalence of unprovoked seizures in patients with a 22q11.2 deletion Am J Med Genet A 2004 129A 29 34 10.1002/ajmg.a.30133 15266612\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0043-5325",
"issue": "130(7-8)",
"journal": "Wiener klinische Wochenschrift",
"keywords": "22q11 deletion syndrome; Anxiety disorders; Depression; Panic disorder; Psychiatric genetics",
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D001289:Attention Deficit Disorder with Hyperactivity; D003398:Craniosynostoses; D004062:DiGeorge Syndrome; D006801:Humans; D008297:Male; D008382:Marfan Syndrome; D008875:Middle Aged; D012559:Schizophrenia",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "283-287",
"pmc": null,
"pmid": "29671046",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28114601;27189754;27822729;15266612;23992925;11005797;24577245;25569435",
"title": "DiGeorge syndrome : Relevance of psychiatric symptoms in undiagnosed adult patients.",
"title_normalized": "digeorge syndrome relevance of psychiatric symptoms in undiagnosed adult patients"
} | [
{
"companynumb": "AT-MYLANLABS-2018M1081279",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAZOLAM"
},
"drugadditional": "3",
... |
{
"abstract": "Any highly infectious and rapidly spreading disease is a primary concern for immunocompromised solid organ transplant recipients. The number of data about the spectrum of clinical illness, the treatment modalities, and the outcomes of COVID-19 in this vulnerable population is scant and still remains empirical. Herein, we report the first COVID-19 case of a heart transplant recipient in Turkey who presented with fever, postnasal discharge, and myalgias for two days. The possibility of lung involvement was ruled out by thoracic computed tomography. Despite stable vital signs, we reduced the intensity of immunosuppressive therapy and maintained home self-isolation promptly. We also commenced a five-day course of hydroxychloroquine 200 mg q12h initially. After confirmation of real-time reverse-transcriptase-polymerasechain- reaction testing of the nasopharyngeal swab positive for COVID-19, the patient was hospitalized. After a loading dose of favipiravir 1,600 mg b.i.d., the patient received a five-day course of favipiravir 600 mg q12h. He was discharged with cure after 23 days of hospital isolation and treatment. In conclusion, treatment process can be affected by the daily electrocardiography, hand-held portable echocardiography, myocardial injury markers, and pulse oximeter for selfmonitoring in the follow-up of previous heart transplant recipients suffering from COVID-19. The lack of treatment protocols in the solid organ transplant recipients with COVID-19 infection and the controversies about the protective effect of immunosuppression invite a global and update discussion.",
"affiliations": "Department of Infectious Diseases and clinical Microbiology, Ankara University School of Medicine, Ankara, Turkey.;Department of Cardiovascular Surgery, Ankara University School of Medicine, Ankara, Turkey.;Department of Cardiovascular Surgery, Ankara University School of Medicine, Ankara, Turkey.;Department of Cardiology, Ankara University School of Medicine, Ankara, Turkey.;Department of Cardiovascular Surgery, Ankara University School of Medicine, Ankara, Turkey.;Department of Cardiology, Ankara University School of Medicine, Ankara, Turkey.;Department of Infectious Diseases and clinical Microbiology, Ankara University School of Medicine, Ankara, Turkey.;Department of Cardiovascular Surgery, Ankara University School of Medicine, Ankara, Turkey.",
"authors": "Çınar|Güle|G|;Sarıcaoğlu|Cahit|C|;İnan|Bahadır|B|;Dinçer|İrem|İ|;Çakıcı|Mehmet|M|;Sayın|Tamer|T|;Azap|Alpay|A|;Akar|Ahmet Rüçhan|AR|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5606/tgkdc.dergisi.2020.20291",
"fulltext": "\n==== Front\nTurk Gogus Kalp Damar Cerrahisi Derg\nTurk Gogus Kalp Damar Cerrahisi Derg\ntjtcs_pmc\nTurkish Journal of Thoracic and Cardiovascular Surgery\n1301-5680 2149-8156 Bayçınar Medical Publishing \n\n10.5606/tgkdc.dergisi.2020.20291\nCase Report\nHeart transplant recipient survivor from COVID-19: The first case of Turkey\nÇınar Güle 1 Sarıcaoğlu Cahit 2 İnan Bahadır 2 Dinçer İrem 3 Çakıcı Mehmet 2 Sayın Tamer 3 Azap Alpay 1 Akar Ahmet Rüçhan 2 \n1 \nDepartment of Infectious Diseases and clinical Microbiology, Ankara University School of Medicine, Ankara, Turkey\n\n\n2 \nDepartment of Cardiovascular Surgery, Ankara University School of Medicine, Ankara, Turkey\n\n\n3 \nDepartment of Cardiology, Ankara University School of Medicine, Ankara, Turkey\n\nAhmet Rüçhan Akar, MD. Ankara Üniversitesi Tıp Fakültesi Kalp ve Damar Cerrahisi Anabilim Dalı, 06590 Çankaya, Ankara, Türkiye. Tel: +90 312 - 595 60 84\nakarruchan@gmail.com.\n\n10 2020 \n21 10 2020 \n28 4 674 679\n10 6 2020 11 8 2020 Copyright © 2020, Turkish Society of Cardiovascular Surgery2020Turkish Society of Cardiovascular SurgeryThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Any highly infectious and rapidly spreading disease is a primary concern for immunocompromised solid organ transplant recipients. The number of data about the spectrum of clinical illness, the treatment modalities, and the outcomes of COVID-19 in this vulnerable population is scant and still remains empirical. Herein, we report the first COVID-19 case of a heart transplant recipient in Turkey who presented with fever, postnasal discharge, and myalgias for two days. The possibility of lung involvement was ruled out by thoracic computed tomography. Despite stable vital signs, we reduced the intensity of immunosuppressive therapy and maintained home self-isolation promptly. We also commenced a five-day course of hydroxychloroquine 200 mg q12h initially. After confirmation of real-time reverse-transcriptase-polymerasechain- reaction testing of the nasopharyngeal swab positive for COVID-19, the patient was hospitalized. After a loading dose of favipiravir 1,600 mg b.i.d., the patient received a five-day course of favipiravir 600 mg q12h. He was discharged with cure after 23 days of hospital isolation and treatment. In conclusion, treatment process can be affected by the daily electrocardiography, hand-held portable echocardiography, myocardial injury markers, and pulse oximeter for selfmonitoring in the follow-up of previous heart transplant recipients suffering from COVID-19. The lack of treatment protocols in the solid organ transplant recipients with COVID-19 infection and the controversies about the protective effect of immunosuppression invite a global and update discussion.\n\nCOVID-19heart transplantationsimmunocompromised\n==== Body\nIntroduction\nThe coronavirus disease 2019 (COVID-19) outbreak for solid organ transplant (SOT) recipients is exceptionally complex and dynamic.[1-3] The limited data on the impact of the COVID-19 infection on SOT recipients lead to several assumptions. Firstly, SOT recipients are at a higher risk of morbidity and mortality from COVID-19, due to their current immunosuppressed state.[1] However, others a rgue that host-inflammatory response appears to be milder, possibly due to the concomitant use of immunomodulatory drugs in SOTs.[4,5] Secondly, advanced age, presence of comorbidities such as hypertension, coronary artery disease, heart failure, obesity, and diabetes are the primary risk factors of myocardial injury during COVID-19 infection.[6,7] Indeed, heart transplant recipients have usually numerous comorbidities. \n\nThe Republic of Turkey, Ministry of Health (Tr MoH) reported the first COVID-19 case on March 11th, 2020 and the first death due to COVID-19 on March 16th, 2020 in Turkey.[8] As of June 4th, 2020, the number of patients with COVID-19 in Turkey exceeds 166,422 with a total of 4,609 fatalities.[8] Currently, there are only few reports about the outcomes of heart transplant patients with COVID-19 infection in the literature.[4,9]\n\nCase Report\nOn April 6th, 2020, a 64-year-old man (weight 78 kg; height 170 cm, and body surface area 1.89 m2) presented to the outpatient clinic with the symptoms of COVID-19 infection complaining of intermittent fever (maximal temperature: 38.2°C), postnasal discharge, and myalgias. He denied cough, sore throat, shortness of breath, gastrointestinal symptoms, or anosmia. He had a history of orthotopic heart transplantation bridged from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for post-infarction refractory cardiogenic shock in December 2013. The marginal donor was a 58-year-old male with a history of hypertension and left ventricular hypertrophy. His post-transplant course was unremarkable except for hypertension, with no episodes of rejection. On further discussion with the patient, he stated that his wife was a pharmacist and COVID-19-positive for two days. Nasopharyngeal and oropharyngeal swabs tested negative for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) by real-time reverse-transcriptase-polymerase-chainreaction (RT-PCR) assay. No compliant finding with COVID-19 was detected on chest radiograph or computed tomography (CT) (Figure 1). Electrocardiography showed sinus rhythm, 76 bpm with the previously confirmed right bundle branch block. The complete blood count analysis revealed mild leukopenia and lymphopenia. C-reactive protein (CRP) was mildly elevated to 6.1 mg/L (normal range: 0 to 5 mg/L) (Table 1). Considering the history of his close contact, we commenced on hydroxychloroquine 200 mg q12h, selfisolated in a separate home from his wife - the treatment targeted for symptomatic relief at this stage under close follow-up with self-measured pulse oximeter. \n\nFigure 1 (a) A posteroanterior chest radiograph. (b. c) Thoracic computed tomography scans on April 6th, 2020 (Day 2) showing no COVID-19-related abnormalities.\n\n\n\nTable 1 Laboratory test results\nMeasure\tReference range\tIllness\nDay 2\tIllness\nDay 4,\nHospital\nDay 1\tIllness\nDay 6,\nHospital\nDay 3\tIllness\nDay 7,\nHospital\nDay 4\tIllness\nDay 8,\nHospital\nDay 5\t\nWhite-cell count (per L)\t4.5-llxlO9\t4.46\t3.89\t3.06\t2.08\t3.52\t\nLymphocyte count (per L)\t1.5-4X109\t0.83\t0.70\t0.90\t0.98\t1.23\t\nPlatelet count (per L)\t150-400X109\t123\t127\t122\t118\t120\t\nC-reactive protein (mg/L)\t0-5\t6.1\t5.2\t5.2\t5.1\t4.8\t\nNeutrophil lymphocyte ratio\t1-2.8\t3.3\t3.94\t2\t0.86\t1.61\t\nD-dimer (ng/mL)\t0-243\t68\t74\t67\t65\t59\t\nFerritin (ng/mL)\t23-336\t-\t33\t-\t52.4\t52.6\t\nTroponin (pg/mL)\t0-14\t12.7\t-\t9.6\t9.6\t9.2\t\nNT-proBNP (pg/mL)\t0-125\t-\t-\t185\t126\t117\t\nFibrinogen (g/L)\t2-3.93\t-\t-\t-\t3.5\t3.62\t\nProcalcitonin (ng/ml)\t0.05-0.5\t0.063\t-\t-\t-\t0.033\t\nLactatedehydrogenase (U/L)\t0-248\t185\t203\t188\t169\t502\t\nLactate (mmol/L)\t0.5-2.2\t-\t-\t-\t-\t-\t\nCyclosporinlevelat 2nd h (ng/mL)\t400-600\t-\t509\t786\t-\t-\t\nMaximal body temperature (°C)\t \t37.2\t38.3\t37.8\t36.7\t36.7\t\nNT-proBNP: N-terminal pro-brain natriuretic peptide.\t\n\n\n\nThe repeated RT-PCR assay of a nasopharyngeal swab on April 7th, 2020 tested positive for SARS-CoV-2 and the patient was hospitalized and isolated. On arrival, the body temperature was 36.8°C with a pulse rate of 82 bpm, a blood pressure of 130/80 mmHg, a respiratory rate of 20 breaths/min, and an oxygen saturation of 97% on room air. Auscultation of the chest revealed natural breathing sounds. He did not require oxygen supplementation. According to the blood chemistry tests, mild leukopenia and lymphopenia persisted. Laboratory results showed normal renal and hepatic function. His immunosuppressive regimen consisted of cyclosporine A 100 mg q12h and mycophenolic acid 360 mg q12h. The dose of cyclosporine was adjusted as 75 mg q12h to achieve a cyclosporine level between 400 and 600 ng/mL at 2h. Other medications were pantoprazole 40 mg per day, acetylsalicylic acid 100 mg per day, candesartan 8 mg per day, and pravastatin sodium 20 mg per day. \n\nFollowing hospitalization, hydroxychloroquine therapy was discontinued. After a loading dose of favipiravir 1,600 mg b.i.d., 600 mg q12h maintenance dose was initiated under the recommendations of the Coronavirus Scientific Advisory Board of the Tr MoH. Prophylactically, subcutaneous enoxaparin sodium 0.4 mL was commenced q12. Daily electrocardiogram monitoring was performed with particular attention to QT prolongation, and no additional findings were detected. Handheld portable echocardiography revealed a mildly dilated left atrium, hypertrophic myocardium, and abnormal interventricular septal movement with normal left ventricular function. The need for oxygen did not arise. Favipiravir treatment was completed in five days and discontinued thereafter. On Day 23 of the disease, two PCR tests-24-h apart-were negative for COVID-19. The patient was discharged on mycophenolate sodium 360 mg b.i.d. and cyclosporine 100 mg b.i.d. \n\nA written informed consent was obtained from the patient.\n\nDiscussion\nOur report of the first confirmed case of COVID-19 in a heart transplant recipient in Turkey illustrates a mild form of the disease, but with unique challenges. At the time of the diagnosis of this case, no formal guidelines were available for the optimal treatment of COVID-19 infection and for the management of immunosuppression in heart transplant recipients. The SOT recipients are at an increased risk of acquisition of COVID-19 infection and progression to severe disease.[10] Furthermore, multiple off-label and investigational drugs may interact with immunosuppressive regimens. Some have severe cardiac side effects. However, data have been rapidly accumulated on this subject.[1,2] \n\nThe initial report from China, with two heart transplant recipients with COVID-19, revealed both severe and mild forms of the disease.[4] One patient progressed to respiratory failure, which required the administration of intravenous human gamma globulin and a five-day course of methylprednisolone 80 mg/day; however, both patients survived eventually. \n\nOn the contrary, others support corticosteroidsparing immunosuppression with dose reduction in antiproliferative therapy.[11] In case of significant lymphopenia on clinical presentation, Hsu et al.[12] suggested withholding mycophenolate mofetil. The authors continued tacrolimus and prednisone in a dual heart and kidney transplant recipient. Recently, donor-specific Class II antibodies were detected in a pediatric heart transplant with COVID-19 infection.[9] The authors administered intravenous immunoglobulin for desensitization with no adverse outcomes. To date, the most extensive case series, including 28 recipients with a heart transplant who had confirmed COVID-19 infection was reported from New York, US by Latif et al.[3] Twenty-two p atients ( 79%) w ere a dmitted t o hospital, seven patients (25%) required mechanical ventilation, and evidence of myocardial injury was present in 13 (77%) patients. The case fatality rate was 25% in this heart transplant cohort with COVID-19. The authors discontinued mycophenolate mofetil in 16 (70%) patients and reduced the dose of calcineurin inhibitors in six patients (26%). \n\nSimilarly, we preferred dose reduction in our case instead of cessation of immunosuppression or corticosteroid/immunoglobulin administration. Another issue in heart transplant recipients with COVID-19 infection is the monitoring of cardiac injury biomarkers, daily electrocardiography, and echocardiographic monitoring, which are all critical. After our first case, we suggest that heart transplant recipients who have mild COVID-19 symptoms and no evidence of myocardial injury can be isolated at home to avoid in-person contact. Pulse oximeter selfmonitoring may be a useful adjunct for the decision for hospitalization during close daily follow-up. Handheld echocardiography may be also a useful adjunct in monitoring cardiac injury, as well as the biochemical markers during the COVID-19 crisis. Availability at the COVID-19 clinic, examination at the bedside, and the ease of equipment disinfection are the potential advantages. \n\nIn vitro assays have shown that hydroxychloroquine exerts antiviral activity against certain viruses, such as influenza A and B viruses.[13] Several studies have reported that it can also inhibit SARS-CoV-2 in vitro, suggesting that it may have utility in fighting against COVID-19.[14] However, hydroxychloroquine is known to be associated with significant side effects, including QTc interval prolongation, Torsades de Pointes, and ventricular arrhythmias.[15] Even fatal arrhythmias have been also reported.[15] Therefore, the use of hydroxychloroquine should be avoided in patients with congenital long QT syndrome, persistent corrected QT measurements >500 msec, bradycardia, history of ventricular arrhythmias, uncorrected hypokalemia and hypomagnesemia, recent myocardial infarction, or uncompensated heart failure and for patients receiving other drugs which prolong the QT interval and those with heart diseases.[16] \n\nAlthough a decision to administer favipiravir was based on the recommendations of the Coronavirus Scientific Advisory Board of the Tr MoH, caution is still required. Favipiravir was originally developed and licensed as an anti-influenza drug in Japan.[17] Favipiravir triphosphate is a purine nucleoside analog, which functions as a competitive inhibitor of ribonucleic acid (RNA)-dependent RNA polymerase. It is a prodrug which is ribosylated and phosphorylated intracellularly to form its active metabolite, favipiravir ribofuranosyl-5´-triphosphate (favipiravir-RTP).[17] Recent in vitro and human studies have repositioned favipiravir as an experimental agent against SARS-CoV-2. A randomized-controlled trial (ChiCTR200030254) showed that COVID-19 patients treated with favipiravir had a higher recovery rate (71.43%) than those treated with umifenovir (55.86%), and the fever and cough relief time was significantly shorter in the favipiravir group.[18] In an in vitro study, SARS-CoV-2 was inhibited by favipiravir in Vero E6 cells with an EC50 of 61.88 µMol.[19] In another study including patients without severe disease (i.e., oxygen saturation >93%), the use of favipiravir was associated with faster viral clearance rates (mean clearance time: 4 vs. 11 days, respectively) and a more frequent radiographic improvement (on Day 14, 91% vs. 62%, respectively) compared to lopinavir-ritonavir.[20] In the light of these findings, the COVID-19 guidelines of the Tr MoH recommend favipiravir for COVID-19 patients who are unable to tolerate the first-line therapy with hydroxychloroquine or who have comorbid conditions (i.e., immunosuppression). \n\nIn conclusion, the results of ongoing randomizedcontrolled trials are critical to gain a better understanding of this subject. Also, subgroup analysis for solid organ transplant recipients is of paramount importance. In the current COVID-19 era, further collaborative, multi-center, and large-scale heart transplant analyses are urgently warranted.\n\nConflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.\n\nFinancial Disclosure: The authors received no financial support for the research and/or authorship of this article.\n\nAcknowledgments We would like to thank all the deceased donors and their families. We also acknowledge the work of all the healthcare workers working toward fighting against COVID- 19 worldwide.\n==== Refs\n1 Siddiqi HK Mehra MR COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal J Heart Lung Transplant 2020 39 405 407 32362390 \n2 Michaels MG La Hoz RM Danziger-Isakov L Blumberg EA Kumar D Green M Coronavirus disease 2019: Implications of emerging infections for transplantation Am J Transplant 2020 20 1768 1772 32090448 \n3 Latif F Farr MA Clerkin KJ Habal MV Takeda K Naka Y Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease 2019 JAMA Cardiol 2020 e202159 \n4 Li F Cai J Dong N First cases of COVID-19 in heart transplantation from China J Heart Lung Transplant 2020 39 496 497 32362394 \n5 Aslam S Mehra MR COVID-19: Yet another coronavirus challenge in transplantation J Heart Lung Transplant 2020 39 408 409 32253113 \n6 Shi S Qin M Shen B Cai Y Liu T Yang F Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China JAMA Cardiol 2020 5 802 810 32211816 \n7 Bonow RO Fonarow GC O'Gara PT Yancy CW Association of coronavirus disease 2019 (COVID-with myocardial injury and mortality JAMA Cardiol 2020 5 751 753 32219362 \n8 The Republic of Turkey, Ministry of Health COVID Database Avaliable at: https://covid19.saglik.gov.tr/TR-66935/genelkoronavirus-tablosu.html . [Access: June 09, 2020]. \n9 Russell MR Halnon NJ Alejos JC Salem MM Reardon LC COVID-19 in a pediatric heart transplant recipient: Emergence of donor-specific antibodies J Heart Lung Transplant 2020 39 732 733 32430156 \n10 DeFilippis EM Farr MA Givertz MM Challenges in Heart Transplantation in the Era of COVID-19 Circulation 2020 141 2048 2051 32314596 \n11 Johnson KM Belfer JJ Peterson GR Boelkins MR Dumkow LE Managing COVID-19 in renal transplant recipients: a review of recent literature and case supporting corticosteroid-sparing immunosuppression Pharmacotherapy 2020 40 517 524 32339304 \n12 Hsu JJ Gaynor P Kamath M Fan A Al-Saffar F Cruz D COVID-19 in a high-risk dual heart and kidney transplant recipient Am J Transplant 2020 20 1911 1915 32315122 \n13 Zou L Dai L Zhang X Zhang Z Zhang Z Hydroxychloroquine and chloroquine: a potential and controversial treatment for COVID-19 Arch Pharm Res 2020 43 765 772 32740801 \n14 Liu J Cao R Xu M Wang X Zhang H Hu H Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Cell Discov 2020 6 16 16 32194981 \n15 Jankelson L Karam G Becker ML Chinitz LA Tsai MC QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review Heart Rhythm 2020 17 1472 1479 32438018 \n16 Giudicessi JR Noseworthy PA Friedman PA Ackerman MJ Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19) Mayo Clin Proc 2020 95 1213 1221 32359771 \n17 Shiraki K Daikoku T Favipiravir, an anti-influenza drug against life-threatening RNA virus infections Pharmacol Ther 2020 209 107512 107512 32097670 \n18 Chen C Zhang Y Huang J Yin P Cheng Z Wu J Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial medRxiv 2020 \n19 Wang M Cao R Zhang L Yang X Liu J Xu M Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Cell Res 2020 30 269 271 32020029 \n20 Cai Q Yang M Liu D Chen J Shu D Xia J Experimental treatment with favipiravir for COVID-19: An open-label control study Engineering (Beijing) 2020 [Online ahead of print]\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1301-5680",
"issue": "28(4)",
"journal": "Turk gogus kalp damar cerrahisi dergisi",
"keywords": "COVID-19; heart transplantation; simmunocompromised",
"medline_ta": "Turk Gogus Kalp Damar Cerrahisi Derg",
"mesh_terms": null,
"nlm_unique_id": "100887967",
"other_id": null,
"pages": "674-679",
"pmc": null,
"pmid": "33403142",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "32339304;32402056;32219362;32194981;32362394;32253113;32362390;32090448;32097670;32359771;32020029;32438018;32346491;32211816;32315122;32314596;32430156;32740801",
"title": "Heart transplant recipient survivor from COVID-19: The first case of Turkey.",
"title_normalized": "heart transplant recipient survivor from covid 19 the first case of turkey"
} | [
{
"companynumb": "TR-ACCORD-215162",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Lymphoproliferative disorders presenting simultaneously with or subsequent to the occurrence of chronic myeloid leukemia (CML) have rarely been reported. Herein, we report 8 cases of a variety of lymphoproliferative conditions associated with CML at different times during the course of the disease. All 8 patients were treated with tyrosine kinase inhibitors at some point during the course of their illness. The literature regarding the uncommon association of these apparently unrelated disorders is reviewed as well as the possible underlying mechanisms that could be associated with this phenomenon.",
"affiliations": "Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ont., Canada.",
"authors": "Alshehry|Nawal F|NF|;Al-Huneini|Mohammed|M|;Lipton|Jeffrey H|JH|;Michelis|Fotios V|FV|",
"chemical_list": "D000970:Antineoplastic Agents; D011505:Protein-Tyrosine Kinases",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000375150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "134(3)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "161-7",
"pmc": null,
"pmid": "25968918",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Lymphoproliferative Disorders in Patients with Chronic Myeloid Leukemia: A Single-Center Case Series.",
"title_normalized": "lymphoproliferative disorders in patients with chronic myeloid leukemia a single center case series"
} | [
{
"companynumb": "PHHY2015CA058864",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NILOTINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "We present a 20-year-old female patient with papillophlebitis in the right eye. Minimal expansion of the blind spot and nasal peripheral defects in the right eye visual field were detected. The patient was using ethinyl estradiol-cyproterone acetate for ovarian cyst and menstrual irregularity. An improvement in the patient's visual field began within a week after cessation of ethinyl estradiol-cyproterone acetate. Ophthalmoscopic findings resolved completely in the sixth week. This situation suggests that female sex hormones or thromboembolic process caused by them may be responsible for the pathogenesis of papillophlebitis. But the exact mechanism in the pathogenesis of papillophlebitis is still controversial.",
"affiliations": "a Department of Ophthalmology and.;a Department of Ophthalmology and.;a Department of Ophthalmology and.;b Department of Internal Medicine, Division of Hematology, Medical Faculty , Ondokuz Mayis University , Samsun , Turkey.;a Department of Ophthalmology and.",
"authors": "Eski Yücel|Ozlem|O|;Güngor|Inci|I|;Gül|Adem|A|;Turgut|Mehmet|M|;Aritürk|Nursen|N|",
"chemical_list": "D003278:Contraceptives, Oral, Hormonal; D004338:Drug Combinations; D004997:Ethinyl Estradiol; D017373:Cyproterone Acetate; C032640:Cyproterone acetate, ethinyl estradiol drug combination",
"country": "England",
"delete": false,
"doi": "10.3109/09513590.2015.1056139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0951-3590",
"issue": "31(8)",
"journal": "Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology",
"keywords": "Big blind spot syndrome; ethinyl estradiol-cyproterone acetate; female sex hormone; papillophlebitis",
"medline_ta": "Gynecol Endocrinol",
"mesh_terms": "D003278:Contraceptives, Oral, Hormonal; D017373:Cyproterone Acetate; D004338:Drug Combinations; D004997:Ethinyl Estradiol; D005260:Female; D006801:Humans; D008599:Menstruation Disturbances; D010048:Ovarian Cysts; D010211:Papilledema; D055815:Young Adult",
"nlm_unique_id": "8807913",
"other_id": null,
"pages": "601-3",
"pmc": null,
"pmid": "26291803",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Papillophlebitis associated with the use of oral contraceptive: a case report.",
"title_normalized": "papillophlebitis associated with the use of oral contraceptive a case report"
} | [
{
"companynumb": "PHHY2015TR136697",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYPROTERONE\\ETHINYL ESTRADIOL"
},
"drugadditional": n... |
{
"abstract": "Second-line antiretroviral therapy (ART) based on ritonavir-boosted protease inhibitors (bPIs) represents the only available option after first-line failure for the majority of individuals living with human immunodeficiency virus (HIV) worldwide. Maximizing their effectiveness is imperative.\n\n\n\nThis cohort study was nested within the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) cluster-randomized trial in rural KwaZulu-Natal, South Africa. We prospectively investigated risk factors for virological failure (VF) of bPI-based ART in the combined study arms. VF was defined by a plasma viral load >1000 copies/mL ≥6 months after initiating bPI-based ART. Cumulative incidence of VF was estimated and competing risk regression was used to derive the subdistribution hazard ratio (SHR) of the associations between VF and patient clinical and demographic factors, taking into account death and loss to follow-up.\n\n\n\nOne hundred one participants contributed 178.7 person-years of follow-up. Sixty-five percent were female; the median age was 37.4 years. Second-line ART regimens were based on ritonavir-boosted lopinavir, combined with zidovudine or tenofovir plus lamivudine or emtricitabine. The incidence of VF on second-line ART was 12.9 per 100 person-years (n = 23), and prevalence of VF at censoring was 17.8%. Thirteen of these 23 (56.5%) virologic failures resuppressed after a median of 8.0 months (interquartile range, 2.8-16.8 months) in this setting where viral load monitoring was available. Tuberculosis treatment was associated with VF (SHR, 11.50 [95% confidence interval, 3.92-33.74]; P < .001).\n\n\n\nSecond-line VF was frequent in this setting. Resuppression occurred in more than half of failures, highlighting the value of viral load monitoring of second-line ART. Tuberculosis was associated with VF; therefore, novel approaches to optimize the effectiveness of PI-based ART in high-tuberculosis-burden settings are needed.\n\n\n\nNCT01509508.",
"affiliations": "Department of Infection and Immunity, University College London, United Kingdom.;Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa.;Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa.;Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa.;Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa.;Geneva University Hospital, HIV Unit, Department of Internal Medicine, Switzerland.;INSERM U1219-Centre Inserm Bordeaux Population Health, Université de Bordeaux, France.;Department of Infection and Immunity, University College London, United Kingdom.;Department of Infection and Immunity, University College London, United Kingdom.",
"authors": "Collier|Dami|D|;Iwuji|Collins|C|;Derache|Anne|A|;de Oliveira|Tulio|T|;Okesola|Nonhlanhla|N|;Calmy|Alexandra|A|;Dabis|Francois|F|;Pillay|Deenan|D|;Gupta|Ravindra K|RK|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cix015",
"fulltext": "\n==== Front\nClin Infect DisClin. Infect. DiscidClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America1058-48381537-6591Oxford University Press US 2832939310.1093/cid/cix015cix015Major ArticleEditor's ChoiceVirological Outcomes of Second-line Protease Inhibitor–Based Treatment for Human Immunodeficiency Virus Type 1 in a High-Prevalence Rural South African Setting: A Competing-Risks Prospective Cohort Analysis Collier Dami \n1\n\na\nIwuji Collins \n2\n\n3\n\na\nDerache Anne \n2\n\n4\nde Oliveira Tulio \n2\n\n5\nOkesola Nonhlanhla \n2\nCalmy Alexandra \n6\nDabis Francois \n7\n\n8\nPillay Deenan \n1\n\n2\nGupta Ravindra K. \n1\n\n2\nfor the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) Study Group \nb\n1 Department of Infection and Immunity, University CollegeLondon, United Kingdom2 Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa3 Research Department of Infection and Population Health, University CollegeLondon, United Kingdom4 Sorbonne Universités, University Pierre and Marie Curie Université Paris 06, Inserm, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France5 University of KwaZulu-Natal, Durban, South Africa6 Geneva University Hospital, HIV Unit, Department of Internal Medicine, Switzerland7 INSERM U1219—Centre Inserm Bordeaux Population Health, Université de Bordeaux, France8 Université de Bordeaux, ISPED, Centre INSERM U1219-Bordeaux Population Health, Francea D. C. and C. I. contributed equally to this work.\n\nb Members of the ANRS 12249 TasP Study Group are listed in the Appendix.\n\nCorrespondence: R. K. Gupta, Department of Infection and Immunity, University College London, 90 Gower St, London WC1E 6BT, UK (ravindra.gupta@ucl.ac.uk).\n\n15 4 2017 13 3 2017 13 3 2017 64 8 1006 1016 09 8 2016 12 1 2017 © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Summary\nA community based, second-line treatment cohort of 102 subjects was followed monthly in community clinics with a total of 178 patient-years of follow-up; second-line virological failure was frequent in this setting.\n\nAbstract\nBackground.\nSecond-line antiretroviral therapy (ART) based on ritonavir-boosted protease inhibitors (bPIs) represents the only available option after first-line failure for the majority of individuals living with human immunodeficiency virus (HIV) worldwide. Maximizing their effectiveness is imperative.\n\nMethods.\nThis cohort study was nested within the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) cluster-randomized trial in rural KwaZulu-Natal, South Africa. We prospectively investigated risk factors for virological failure (VF) of bPI-based ART in the combined study arms. VF was defined by a plasma viral load >1000 copies/mL ≥6 months after initiating bPI-based ART. Cumulative incidence of VF was estimated and competing risk regression was used to derive the subdistribution hazard ratio (SHR) of the associations between VF and patient clinical and demographic factors, taking into account death and loss to follow-up.\n\nResults.\nOne hundred one participants contributed 178.7 person-years of follow-up. Sixty-five percent were female; the median age was 37.4 years. Second-line ART regimens were based on ritonavir-boosted lopinavir, combined with zidovudine or tenofovir plus lamivudine or emtricitabine. The incidence of VF on second-line ART was 12.9 per 100 person-years (n = 23), and prevalence of VF at censoring was 17.8%. Thirteen of these 23 (56.5%) virologic failures resuppressed after a median of 8.0 months (interquartile range, 2.8–16.8 months) in this setting where viral load monitoring was available. Tuberculosis treatment was associated with VF (SHR, 11.50 [95% confidence interval, 3.92–33.74]; P < .001).\n\nConclusions.\nSecond-line VF was frequent in this setting. Resuppression occurred in more than half of failures, highlighting the value of viral load monitoring of second-line ART. Tuberculosis was associated with VF; therefore, novel approaches to optimize the effectiveness of PI-based ART in high-tuberculosis-burden settings are needed.\n\nClinical Trials Registration.\nNCT01509508.\n\nHIVantiretroviral therapyvirological failuresecond lineprotease inhibitorWellcome Trusthttp://dx.doi.org/10.13039/100004440British Infection Associationhttp://dx.doi.org/10.13039/501100004664Wellcome Senior FellowshipWT108082AIA\n==== Body\nDespite clinical and public health gains following antiretroviral therapy (ART) rollout, treatment failure of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART is common [1–4], with up to 3 million human immunodeficiency virus (HIV)–infected patients estimated to receive second-line, boosted protease inhibitor (bPI)–based ART by 2020 [5]. Treatment failure on second-line ART is a major concern given poor, if any, access to further regimens in high-burden settings.\n\nData from observational studies of second-line bPI-based ART treatment outcomes in sub-Saharan Africa suggest a 14%–32% prevalence of virological failure (VF) [6–12], with randomized trials from comparable settings reporting lower prevalence of VF at 17%–19% at 48 weeks and longer durations of follow-up [13–16]. These studies were largely conducted in urban or periurban areas. Although associations have been reported between second-line VF and poor adherence [6, 8, 10, 17, 18] and delayed switch [7, 9], socioeconomic and demographic factors such as education level, employment, and data on household members have not been studied together. Furthermore, the potentially critical association between concomitant tuberculosis (TB) [17] and second-line bPI failure is inconclusive.\n\nPreviously published cohort studies have used a Kaplan-Meier survival analysis and standard Cox regression models that can result in inflated estimates due to competing events. Competing risk regression analysis overcomes this limitation by accounting for events, such as death, that preclude the subject from experiencing the study outcome. This is particularly important in sub-Saharan Africa where mortality remains significant following ART initiation due to advanced disease stage as well as loss to follow-up [19]. Here we have applied competing risk methods to comprehensively and prospectively investigate risk factors for VF of bPI-based second-line ART in a rural population of South Africa. In this setting ART was readily available and follow-up optimum according to local standards, including real-time viral load monitoring.\n\nMATERIALS AND METHODS\nStudy Setting and Study Design\nThis cohort study was nested within the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) trial (ClinicalTrials.gov identifier: NCT01509508), an ongoing cluster-randomized trial evaluating the impact of immediate vs deferred ART initiation (according to South African guidelines) on HIV incidence [20] (see Supplementary Materials). The trial started recruiting in March 2012 in Hlabisa subdistrict, Umkhanyakude district, Northern KwaZulu-Natal, where the antenatal prevalence of HIV is 44%, one of the highest in South Africa [21, 22]. This rural setting is also one of the poorest districts in South Africa with very high unemployment rates.\n\nThis analysis is based on the treatment outcomes documented prospectively in the subgroup of patients on second-line bPI-based treatment within the TasP trial. Participants from all clusters irrespective of trial arm were included in this cohort. Participants were aged >15 years, resident in Hlabisa subdistrict, and included from the date of initiation of second-line treatment till the earliest of the date last seen in clinic, death, or loss to follow-up. No participants initiating bPI ART after May 2015 were included to allow at least 6 months’ follow-up for the primary outcome to occur. The participants’ outcomes were recorded until November 2015.\n\nOutcome and Prespecified Explanatory Variables\nThe primary outcome was VF defined as a VL >1000 copies/mL on at least 1 occasion ≥6 months after commencing second-line treatment. Any death occurring during the trial period was recorded and follow-up time was censored at the date of death. Loss to follow-up was defined as ≥3 consecutive missed clinic appointments. Follow-up time was censored at the last clinic visit. For all the other participants who remained in the trial with virological suppression (VL < 1000 copies/mL), follow-up was censored as the latest of either the date of the last laboratory test or last clinic visit.\n\nClinic Procedures and Laboratory Methods\nAt presentation to the trial clinics, all consenting HIV-infected participants were asked to complete the study questionnaires and underwent clinical examination by trial nurses. CD4 count was measured in TasP clinics using a commercial point-of-care CD4 test (Alere PIMA device tool, Alere Inc, Waltham, Massachusetts). VL was measured using The Abbott m2000 RealTime System with HIV type 1 (HIV-1) VL determination from human plasma of HIV-1–infected individuals in the range of 40–10000000 copies/mL (Abbott Molecular Inc, Des Plaines, Illinois). The viral load assay was CE (Conformité Européene) marked and performed at the Africa Centre laboratory; the laboratory participated in Quality Control for Molecular Diagnostics (QCMD) for VL quality assurance testing. Both CD4 and viral load were measured at baseline, and at months 3 and 6 after ART initiation and every 6 months thereafter. Full-genome deep sequencing was performed after 2 consecutive VL measurements >1000 copies/mL at least 6 months apart following second-line VF, as per adapted protocol from Gall et al [23]. In brief, 4 overlapping fragments, spanning approximately 9 kb of the HIV genome, were amplified and purified as per adapted protocol from Gall et al [23]. The library preparation was done on equimolar pooled amplicons, using the Nextera XT Library preparation kit, followed by sequencing on the Illumina MiSeq platform. Next-generation sequencing (NGS) data were analyzed on Geneious software and a threshold of 2% was used for minority variants detection, with a minimum coverage of 1000 reads. In the case of a single VL >1000 copies/mL, Sanger sequencing was done following Manasa et al’s protocol [24]. The external quality assurance for Sanger sequencing was with QCMD. Drug resistance mutations were identified according to the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu/) [25]. We reported mutations where they were detected above 2% frequency. Safety monitoring blood samples were also taken as per protocol [20].\n\nStatistical Analysis\nParticipant characteristics were reported using frequency and percentage for categorical variables and median and interquartile range (IQR) for continuous variables. The incidence of second-line failure per 100 person-years was estimated with its 95% confidence interval (CI).\n\nWe estimated the cumulative incidence function of VF on second-line treatment, taking into account death and loss to follow-up as competing risks. Competing risk regression was used to estimate the subdistribution hazard ratio (SHR) of the associations between VF and participant clinical and demographic factors, accounting for the competing risks of death and loss to follow-up, according to the model of Fine and Gray [26]. In the final multivariable model, mutually adjusted estimates of the SHRs were determined by including those factors with evidence of an association in the univariable analysis and a P value of <.1. Although age and sex were not significantly associated with VF in the univariable analysis, they were kept in the final model as they were a priori specified confounders. Analysis was done using Stata software version 13.\n\nEthical Committee Approval\nEthics approval was granted by the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (BFC 104/11) and the Medicines Control Council of South Africa. The study was also authorized by the KwaZulu-Natal Department of Health in South Africa. Written informed consent was obtained from all participants.\n\nRESULTS\nOne hundred one participants were included in this analysis. Sixteen (15.8%) individuals were already on second-line treatment at enrollment into the trial for a median of 2.7 years (IQR, 1.1–3.9 years). Three of these participants had VF at the baseline clinic visit. Seven (6.9%) participants had not initiated ART at enrollment into the trial. The remaining 78 (77.2%) were on first-line NNRTI-based ART for a median duration of 4.9 years (IQR, 3.2–6.7 years) at the time of enrollment; 41 (52.6%) of these had VF at the baseline clinic visit in the TasP trial, necessitating a switch to bPI along with 2 nucleoside reverse transcriptase inhibitors (NRTIs). Median duration on bPI for the 85 patients was 0.6 years (IQR, 0.3–0.9 years).\n\nThe majority of participants were female (65.4%) and the median age at initiation of second-line treatment was 37.4 years (IQR, 31.6–45.3 years). There was a high level of unemployment (91.9%) in this cohort of participants residing in a rural setting (Table 1). Thirteen individuals (12.9%) were diagnosed with TB during the study period.\n\nTable 1. Demographic and Clinical Characteristics of Study Participants\n\nCharacteristic\tNo. (%)\t\nSex (n = 101)\t\n Female\t66 (65.4)\t\nAge at initiating bPI-based ART, y, median (IQR) (n = 101)\t37.4 (31.6–45.3)\t\nRelationship status (n = 100)\t\n Single\t76 (76.0)\t\n Married\t17 (17.0)\t\n Widowed\t7 (7.0)\t\nEmployed (n = 87)\t\n Yes\t7 (8.1)\t\nEducation level (n = 101)\t\n Primary or less\t46 (45.5)\t\n Some secondary\t30 (29.7)\t\n Completed secondary\t25 (24.8)\t\nHousehold asset ownership index score (n = 100)\t\n Low\t37 (37.0)\t\n Medium\t52 (52.0)\t\n High\t11 (11.0)\t\nOther HIV-positive household member (n = 101)\t\n Yes\t68 (67.3)\t\nDistance to national highway, km, median (IQR) (n = 101)\t2.5 (1.4–5.6)\t\nDistance to clinic, km, median (IQR) (n = 101)\t1.2 (0.8–1.9)\t\nClinical characteristics\t\n Duration of HIV diagnosis, y, median (IQR) (n = 95)\t5.1 (2.7–7.6)\t\n Duration on NNRTI-based first-line ART, y, median (IQR) (n = 101)\t4.6 (2.2–6.4)\t\n Duration on bPI-based second-line ART, y, median (IQR) (n = 101)\t2.0 (1.4–2.5)\t\n On bPI before recruitment to TasP (n = 101)\t\n Yes\t16 (15.8)\t\n CD4 within 6 mo prior to switch to bPI, cells/mm3, median (IQR) (n = 31)\t180 (107–343)\t\n Viral load within 6 mo of switch to bPI, copies/mL (n = 61)\t\n <1000\t18 (29.5)\t\n >1000\t43 (70.5)\t\n Nadir CD4 count prior to first-line ART, cells/mm3, median (IQR) (n = 94)\t95.5 (17.0–191.0)\t\n Tuberculosis treatment within 6 mo of PI failure (n = 94)\t5 (5.3)\t\n No. of clinic visits/y, median (IQR) (n = 101)\t12.7 (10.4–14.0)\t\n WHO stage (n = 90) at cohort baseline\t\n 1\t47 (53.2)\t\n 2\t18 (20.0)\t\n 3\t23 (25.6)\t\n 4\t2 (2.2)\t\n Median pill count, % (n = 92)\t\n 0–96\t25 (27.2)\t\n ≥97\t67 (72.8)\t\n First-line regimen\t\n ZDV/d4T + 3TC/FTC + NVP/EFV\t54 (53.5)\t\n TDF + 3TC/FTC + NVP/EFV\t47 (46.5)\t\n Second-line regimen\t\n ZDV/TDF + 3TC/FTC + LPV/r\t101 (100.0)\t\nData are presented as No. (%) unless otherwise indicated.\n\nAbbreviations: 3TC, lamivudine; ART, antiretroviral therapy; bPI, ritonavir-boosted protease inhibitor; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; HIV, human immunodeficiency virus; IQR, interquartile range; LPV/r, lopinavir/ritonavir; NNRTI, nonnucleoside reverse transcriptase inhibitor; NVP, nevirapine; TasP, treatment as prevention; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization; ZDV, zidovudine.\n\nVirological Failure and Associated Risk Factors\nThe 101 participants contributed 178.7 person-years of follow-up to the analysis. The overall incidence of VF on second-line ART was 12.9 per 100 person-years. At administrative censoring, 76 participants were alive and in care, 1 had died, and 1 was lost to follow-up before any VF was documented, and 23 participants had VF at least 6 months after initiating bPI second-line ART (Supplementary Figure 1). Following intensification of adherence counseling, 13 of the 23 participants (56.5%), including the 3 patients with bPI VF at the baseline clinic visit, resuppressed with a VL <1000 copies/mL after a median of 8.0 months (IQR, 2.8–16.8 months) (Supplementary Figure 2). Eight of these 13 participants subsequently rebounded with a VL >1000 copies/mL. The prevalence of VF in patients alive and on bPI ART at the time of administrative censoring was 17.8% (18/101).\n\nIn the univariable analysis, second-line VF was associated with concomitant TB treatment within 6 months of failure (SHR, 15.9 [95% CI, 6.2–40.6]; P < .0001) and a lower level of adherence (median pill count <97%) (SHR, 2.4 [95% CI, 1.0–5.7]; P = .04). In the multivariable analysis, the association of TB treatment with VF on bPI second-line treatment remained (SHR, 11.5 [95% CI, 3.9–33.7]; P < .001), whereas the association with median pill count was no longer present (Table 2).\n\nTable 2. Subdistribution Hazard Ratios (SHRs) of Clinical and Demographic Characteristics and Association With Virological Failure on Second-line Ritonavir-Boosted Protease Inhibitor–Based Treatment: Univariable Analysis Followed by Multivariable Model of Mutually Adjusted SHRs\n\nCharacteristic\tUnivariable Model\tMultivariable Model\t\nEvents/Follow-up Timea\tRate (95% CI)b\tSHR (95% CI)\t\nP Value\tSHR (95% CI)\t\nP Value\t\nSex\t\n Female\t15/1.29\t11.59 (6.99–19.22)\t1\t.90\t1\t.79\t\n Male\t8/0.51\t15.72 (7.87-31.45)\t1.06 (.45–2.49)\t\t0.85 (.18–1.64)\t\t\nAge at initiating bPI-based ART, y\t\n 16–35\t11/0.78\t14.18 (7.85–25.61)\n\t1\t.61\t1\t.98\t\n ≥35\t12/1.03\t11.68 (6.63–20.56)\t0.81 (.36–1.82)\t\t1.02 (.33–3.04)\t\t\nRelationship status\t\n Single\t18/1.34\t13.48 (8.49–21.39)\t1\t.55\t\t\t\n Married\t3/0.34\t8.68 (2.80–26.90)\t0.72 (.19–2.67)\t\t\t\t\n Widowed\t2/0.10\t20.20 (5.05–80.75)\t1.72 (.53–5.59)\t\t\t\t\nEducation level\t\n Primary or less\t11/0.84\t13.13 (7.27–23.71)\t1\t.93\t\t\t\n Some secondary\t6/0.43\t13.85 (6.22–30.83)\t1.16 (.47–2.84)\t\t\t\t\n Completed secondary\t6/0.53\t11.28 (5.07–25.10)\t1.18 (.41–3.38)\t\t\t\t\nEmployed\t\n No\t16/1.29\t12.41 (7.60–20.26)\t1\t.87\t\t\t\n Yes\t1/0.09\t10.65 (1.50–75.62)\t0.86 (.16–4.79)\t\t\t\t\nHousehold asset ownership index score\t\n Low\t7/0.69\t10.20 (4.86–21.39)\t1\t.87\t\t\t\n Medium\t14/0.92\t15.18 (8.99–25.63)\t1.14 (.44–2.93)\t\t\t\t\n High\t2/0.17\t11.55 (2.89–46.20)\t1.42 (.37–5.47)\t\t\t\t\nOther HIV-positive household member\t\n No\t8/0.56\t14.29 (7.14–28.57)\t1\t.70\t\t\t\n Yes\t15/1.24\t12.07 (7.27–20.12)\t1.17 (.52–2.61)\t\t\t\t\nDistance to national highway, km\t\n <2\t14/0.69\t20.35 (12.05–34.36)\t1\t.16\t\t\t\n 2–16\t9/1.12\t8.07 (4.20–15.51)\t0.54 (.23–1.27)\t\t\t\t\nDistance to clinic, km\t\n <1\t10/0.76\t13.23 (7.12–24.58)\t1\t\t\t\t\n 1–2\t8/0.61\t13.11 (6.55–26.20)\t1.78 (.70–4.52)\t\t\t\t\n 2–4\t5/0.44\t11.45 (4.77–27.52)\t0.81 (.27–2.41)\t.34\t\t\t\nClinical characteristics\t\n Nadir CD4 prior to first-line ART, cells/mm3\t\n <100\t8/0.48\t16.78 (8.39–33.56)\t1\t.37\t\t\t\n ≥100\t10/0.93\t10.72 (5.77–19.92)\t0.66 (.26–1.66)\t\t\t\t\n Tuberculosis treatment within 6 mo of PI failure\t\n No\t17/1.62\t10.47 (6.51–16.84)\t1\t<.0001c\t1\t<.001c\t\n Yes\t4/0.03\t116.23 (43.62–309.68)\t15.86 (6.21–40.56)\t\t11.50 (3.92–33.74)\t\t\n No. of visits per year\t\n 0–11\t17/0.91\t18.76 (11.67–30.18)\t1\t.75\t\t\t\n 12–22\t6/0.90\t6.69 (3.01–14.89)\t0.85 (.30–2.34)\t\t\t\t\n WHO stage\t\n 1\t7/0.80\t8.79 (4.19–18.44)\t1\t.26\t\t\t\n 2\t7/0.26\t27.12 (12.93–56.89)\t2.03 (.86–4.81)\t\t\t\t\n 3/4\t7/0.50\t13.94 (6.64–29.24)\t1.37 (.42–4.51)\t\t\t\t\n Median pill count, %\t\n ≥97\t12/1.30\t27.14 (14.12–52.16)\t1\t.04c\t1\t.28\t\n 0–96\t9/0.33\t9.20 (5.23–16.20)\t2.41 (1.02–5.65)\t\t1.83 (0.61–5.50)\t\t\n Duration between HIV diagnosis and baseline. y\t\n 0–3\t8/0.66\t12.21 (6.11–24.42)\t1\t.87\t\t\t\n 4–7\t8/0.64\t12.41 (6.21–24.82)\t0.80 (.31–2.05)\t\t\t\t\n 8–20\t5/0.36\t13.75 (5.73–33.05)\t1.01 (.32–3.17)\t\t\t\t\n On PI before recruitment to TasP\t\n No\t16/1.31\t12.22 (7.49–19.95)\t1\t.13\t\t\t\n Yes\t7/0.49\t14.17 (6.76–29.73)\t1.97 (.81–4.75)\t\t\t\t\n Duration on first-line regimen, y\t\n <3\t7/0.61\t11.50 (5.48–24.12)\t1\t.35\t\t\t\n 3–5\t7/0.73\t9.58 (4.67–20.09)\t0.69 (.24–1.94)\t\t\t\t\n 6–12\t9/0.46\t19.42 (10.11–37.33)\t1.38 (.50–3.84)\t\t\t\t\n Duration on second-line regimen, y\t\n <2\t8/0.56\t14.18 (7.09–28.36)\t1\t.72\t\t\t\n 2–3\t9/0.70\t12.87 (6.70–24.73)\t0.99 (.38–2.56)\t\t\t\t\n 3–10\t6/0.54\t11.12 (5.00–24.75)\t1.47 (.49–4.40)\t\t\t\t\nData are presented as No. (%) unless otherwise indicated.\n\nAbbreviations: ART, antiretroviral therapy; bPI, ritonavir-boosted protease inhibitor; CI, confidence interval; HIV, human immunodeficiency virus; PI, protease inhibitor; SHR, subdistribution hazard ratio; TasP, treatment as prevention; WHO, World Health Organization.\n\na Follow-up time in 100 person-years.\n\nb Rate per 100 person-years.\n\nc Associations with some evidence against the null.\n\nThirteen participants were diagnosed with TB and received antituberculosis treatment during the study observation period; 4 of them were treated within 6 months of VF; 1 participant, within 6 months of censoring, did not experience VF; the remaining 8 participants were diagnosed and treated for TB at time points distant from their study exit and did not exhibit VF after initiation of antituberculosis treatment.\n\nDrug Resistance\nGenotypes were available at first-line NNRTI ART failure in 9 participants and at bPI ART failure in 6 participants of the 23 with VF failure of second-line ART (Table 3). The reasons for missing genotypes were as follows: 4 patients receiving care in Department of Health clinics and therefore no sample was available; resuppression in 10 patients and therefore no viremic confirmatory sample available for genotyping; and no confirmatory sample in 2. Three of 5 patients exposed to tenofovir in their first-line regimen developed high-level tenofovir resistance with the K65R mutation, and 2 had accessory tenofovir mutations A62V, V75I, or F77L in the reverse transcriptase gene. In one of these individuals, K65R was detected only by NGS (at 12% frequency; Table 3). All first-line failures had major NNRTI resistance and 5 of 9 had high-level lamivudine/emtricitabine resistance (M184V/I). An additional drug resistance–associated variant (at <20% frequency) conferring NNRTI resistance was detected in patient 6 (K103N at 12%). NGS did not detect minority variants in the protease gene in any of the 9 patients with second-line failure.\n\nTable 3. Resistance Mutations Identified by Next-Generation Sequencing\n\nParticipant ID\tFirst-line Regimen\tSecond-line Regimen\tDuration on bPI, y\tTime-point\tPI Mutations\tNRTI Mutations\tNNRTI Mutations\t\n1\td4T, 3TC, EFV\tTDF, 3TC, LPV/r\t2.0\tFirst-line failure\t—\tM184V\tK103N, P225H, K238T\t\nSecond-line failure\t—\t—\t\nP225H\n10%, K238T8%\t\n2\tTDF, FTC, EFV\tZDV, 3TC, LPV/r\t2.3\tFirst-line failure\t—\t—\t—\t\nSecond-line failure\t—\t—\t—\t\n3\tTDF, 3TC, EFV\tTDF, 3TC, LPV/r\t1.1\tFirst-line failure\t—\tA62V, K65R, V75I, Y115F\tE138Q, G190E\t\nSecond-line failure*\t—\t—\t—\t\n4\td4T, 3TC, NVP\nd4T, 3TC, EFV\tTDF, 3TC, LPV/r\t1.7\tFirst-line failure\t—\tM184V\tK103N, P255H\t\nSecond-line failure\t—\t—\t—\t\n5\td4T, 3TC, EFV\tTDF, 3TC, LPV/r\t1.9\tFirst-line failure\t—\tT69N, K70N\tV106M, E138G6%, G190A, F227L\t\nSecond-line failure\t—\t—\t\t\n6\tTDF, 3TC, EFV\tZDV, 3TC, LPV/r\t2.1\tFirst-line failure\t—\t—\t\nK103N\n12%, V106M, G190A\t\nSecond-line failure\t—\t\t\t\n7\td4T, 3TC, EFV\nZDV, 3TC, EFV\tTDF, 3TC, LPV/r\t1.6\tFirst-line failure\t—\tM41L, L74I, V75L, M184V, T215Y\tV106M, V179D\t\nSecond-line failure\t—\t\t—\t\n8\td4T, 3TC, EFV\nTDF, 3TC, EFV\tZDV, 3TC, LPV/r\t2.0\tFirst-line failure\t—\tM41L, A62V, K65R, K70T2%, V75I, M184V\tK103N, V106M, E138G, F227L6%\t\nSecond-line failure\t\nM46I, I54V, L76V, V82A\n\t\nT215Y\n\t\nE138G\n5%\n\t\n9\td4T, 3TC, NVP\nTDF, FTC, EFV\tTDF, 3TC, LPV/r\t1.5\tFirst-line failure\t—\t\nK65R\n12%, M184V\tK103N, Y188L/F15%, K238T\t\nSecond-line failure\t—\t\t\t\nFirst-line failure time-point indicates mutations present at first-line NNRTI virological failure. Second-line failure time-point indicates mutations acquired or lost where there are second-line bPI failure sequencing data available. These are presented in boldface type where they are newly acquired and where a mutation is lost. Minority variants detected between 2% and 20% are reported in italic type with their respective frequencies in subscript. Sequences with an asterisk (*) indicate population sequencing data derived by Sanger methodology. Dash (—) indicates no mutations.\n\nAbbreviations: 3TC, lamivudine; bPI, ritonavir-boosted protease inhibitor; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; ID, Identity Document; LPV/r, lopinavir/ritonavir; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine.\n\nAt second-line bPI ART failure, only 1 of 8 (12.5%) participants had acquired major PI mutations: M46I, I54V, L76V, and V82A. This individual received rifampicin containing TB treatment started at the same time as double-dose bPI.\n\nDISCUSSION\nWe determined the incidence rate for VF on second-line ART and associated risk factors in rural KwaZulu-Natal within the TasP trial. The incidence rate of VF was 12.9 per 100 person-years (95% CI, 8.6–19.4), and prevalence was 17.8% at the end of the observation period. A meta-analysis of studies conducted in resource-limited settings reported a pooled prevalence of VF of 23.1% (range, 11.4%–39.9%) after 12 months of treatment with bPI ART [6], although our prevalence estimate was based on a follow-up period of <1 year in those initiated on second-line ART within TasP. More recent randomized trials reported a lower prevalence of VF, between 14% and 19% at 48 and 96 weeks of treatment [13–15, 27]. However, the lower prevalence within trials may not be generalizable to the “real world” because trial participants are closely monitored.\n\nThere are considerable differences between studies in the definition of VF (from VL >50 to >1000 copies/mL), and guidelines are not clear on a definition of second-line failure that should trigger a switch of treatment regimen. We therefore chose a pragmatic definition of a single VL >1000 copies/mL, particularly as the follow-up time was relatively short for patients in TasP who switched to second-line ART within the trial. We found that many patients with VF on bPI ART resuppressed to VL <1000 copies/mL following a period of intense adherence counseling. This phenomenon has been reported in patients treated with first-line ART in both South Africa [28] and other parts of sub-Saharan Africa [29], and demonstrates that the efficacy of second-line treatment could be optimized if regular VL monitoring is widely available, adding to the impetus for development of point-of-care VL testing in tandem with effective adherence counseling.\n\nThe association between TB treatment and VF of NNRTI-based first-line ART has previously been reported [17]. Here we found evidence of an association between TB treatment and VF of second-line treatment. Our study design did not allow us to infer causality between TB treatment and VF, as some patients were never virologically suppressed even before the rifampicin treatment. TB disease itself could be a marker of virological and clinical failure; indeed, the 2010 World Health Organization (WHO) clinical criteria for treatment failure include a new diagnosis of TB [30]. In patients failing during the rifampicin treatment, the mechanism leading to VF may be due to drug interactions between PIs and rifampicin. Rifampicin, a potent cytochrome P450 3A4 inducer, significantly reduces the serum levels of PIs, and concurrent use can lead to VF [31, 32]. To compensate for this phenomenon, double-dosed bPI has been proposed—from twice-daily 400 mg/100 mg to 800 mg/200 mg of lopinavir/ritonavir, as is in this clinical setting [33]. However, the success of such a strategy may be limited by intolerance to the higher doses of PIs [34–36]. Nonadherence to treatment may also contribute to failure as the inherent polypharmacy required to treat both conditions may be a challenge for patients.\n\nPoor adherence has been shown to be associated with VF in other studies [6, 8, 10, 17, 18]; however, we found no association between adherence measured by pill count and VF. This might in part be due to the fact that adherence was high in this trial context, although announced pill count is susceptible to pill dumping by participants and therefore not be a particularly good marker for adherence: indeed, 88% of participants on first-line NNRTI ART had an overall adherence of ≥95% at 6 months [37].\n\nWe found multiple major NRTI and NNRTI mutations at first-line failure in the participants who had genotype testing (9 participants), consistent with data from resource-limited settings [2, 38]. Though numbers were small, NGS increased detection of significant tenofovir resistance (K65R mutation) by around 50%, consistent with previous NGS studies in this setting [39]. We found acquired major protease mutations in only 1 (11%) failing bPI ART, consistent with other data from South Africa [8, 18, 40–42]. NGS did not increase the detection rate of mutations in protease. The high genetic barrier of bPI to resistance development could be a reason for this. It is worth noting that standard genotype tests based on pol sequencing ignore the influence of mutations in other genes such as gag [43–47] and env [48] on PI resistance. Notably, the individual with major protease resistance had received double-boosted PI treatment, and coupled with previous reports of multiple major protease resistance mutations in children treated with double-dose PI [49, 50], further work regarding this approach is warranted.\n\nThe main methodological strength of this study is the application of regression methods, which account for the presence of competing risks to estimate the rate of VF on second-line treatment and the association between covariates of interest and VF. Other cohort studies reporting outcomes on second-line treatment and factors associated with VF have used standard Kaplan-Meier survival analysis and Cox regression models, which can lead to biased or inflated estimates of association. As this analysis was done on prospectively collected data within a trial context with preset procedures rather than routine data, we also minimized the common problem of missing data and information bias.\n\nThere are some limitations of the study. First, although the sample size is small, the prevalence of VF on bPI we found is in line with other published studies. The inclusion of whole-genome sequencing data, albeit from 9 patients, is unique to this cohort. Second, the study was nested in a randomized community trial and as such the patients may not be truly reflective of the general HIV population, given the intense monitoring and provision of counseling and adherence interventions that may impact their attitude toward health and promote more successful treatment outcomes. We did not measure drug levels to assess pharmacokinetic drug–drug interactions or adherence before a clinical visit. Finally, 16 (15.8%) patients were included who were already on second-line ART at enrollment, for a median of 2.7 years, representing a potential bias.\n\nThere was also heterogeneity in the patient population. We included all participants from the parent study irrespective of study arm, though study arm had no effect on outcome, largely due to poor linkage to care in this setting (Dabis et al, 21st International AIDS Conference 2016, Durban, abstract FRAC0105LB). We included newly diagnosed as well as ART-experienced patients, as both present for first-line therapy under “real-world” programmatic conditions, sometimes with evidence of drug resistance to thymidine analogues arising from prior ART [51] or with evidence of transmitted drug resistance [52].\n\nIn conclusion, this study found that second-line PI-based VF was common in this population accessing ART in rural South Africa under trial circumstances but recruited at the population level. Further research is needed to understand the mechanisms behind VF of bPI ART in TB-coinfected patients. Novel approaches to optimize second-line ART in resource-limited settings are still urgently needed as this population is likely to grow rapidly, owing to the WHO 2015 guidelines to test and treat all people living with HIV [53].\n\nSupplementary Material\nSupplementary Data Click here for additional data file.\n\n Notes\n\nAuthor contributions D. C., R. K. G., F. D., D. P., and C. I. designed the study; R. G., D. C., N. O., C. I., F. D., A. C., and D. P. collected and analyzed the data; D. C. and R. G. wrote the first draft; A. D. and T. de O. performed experiments and analyzed data.\n\n\nDisclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the International Initiative for Impact Evaluation (3ie) or the Bill & Melinda Gates Foundation. The funders had no role in the design, analysis, and interpretation of the study or the decision to submit for publication.\n\n\nFinancial support. The French National Agency for AIDS and Viral Hepatitis Research (ANRS) is the sponsor and co-funder of the trial. Research discussed in this publication has been co-funded by 3ie with support from the Bill & Melinda Gates Foundation. The Deutsche Gesellschaft für Internationale Zusammenarbeit co-funded the first part of the trial. The trial is conducted with the support of Merck & Co and Gilead Sciences, which provided the Atripla drug supply. The Africa Health Research Institute for Population Health receives core funding from the Wellcome Trust, which provides the platform for the population- and clinic-based research at the Centre. D. C. is funded by a British Infection Association fellowship and R. G. is funded by a Wellcome Senior Fellowship (WT108082AIA).\n\n\nPotential conflicts of interest All authors: No potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n\nAPPENDIX\nAppendix Table 1. ANRS 12249 Treatment as Prevention Study Group (as of March 2016)\n\nName\tRole\tAffiliation\t\nInvestigators\t\n François Dabis\tCo-PI (France)\t- Université. Bordeaux, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n- INSERM, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n Deenan Pillay\tCo-PI (South Africa)\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n- Faculty of Medical Sciences, University College London, United\nKingdom (UK)\t\n Marie-Louise Newell\tCo-PI (United Kingdom)\t- Africa Centre for Population Health University of KwaZulu- Natal, South Africa\t\n-Faculty of Medicine, University of Southampton, UK\t\nCoordinators\t\n Collins Iwuji\tTrial Coordinator and HIV Clinician (South Africa)\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n- Research Department of Infection and Population Health, University College London, UK\t\n Joanna Orne-Gliemann\tTrial Coordinator (France)\t- Univ. Bordeaux, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n- INSERM, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\nStudy team\t\n Kathy Baisley\tStatistics\t- Department of Global Health and Development, London School of Tropical Medicine and Hygiene\t\n- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n Till Bärnighausen\tHealth economics\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n- Dept of Global Health & Population, Harvard School of Public Health, Harvard Univ. Boston, USA\t\n Eric Balestre\tEpidemiology and Biostatistics\t- Univ. Bordeaux, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n- INSERM, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n Sylvie Boyer\tHealth economics\t- INSERM, UMR912 (SESSTIM), Marseille, France\t\n- Aix Marseille Université, UMR_S912, IRD, Marseille, France\t\n- ORS PACA, Observatoire Régional de la Santé Provence- Alpes-Côte d’Azur, Marseille, France\t\n Alexandra Calmy\tAdult Medicine\t- Service des maladies infectieuses, Hôpital Universitaire de Geneve, Genève, Switzerland\t\n Vincent Calvez\tVirology\t- Department of virology, Hôpital Pitié-Salpétrière, Paris, France\t\n Anne Derache\tVirology\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n Hermann Donfouet\tStatistics/Economist\t- INSERM, UMR912 (SESSTIM), Marseille, France\t\n- Aix Marseille Université, UMR_S912, IRD, Marseille, France\t\n- ORS PACA, Observatoire Régional de la Santé Provence- Alpes-Côte d’Azur, Marseille, France\t\n Rosemary Dray-Spira\tSocial sciences\t- INSERM U1018, CESP, Epidemiology of Occupational and Social Determinants of Health, Villejuif, France\t\n- University of Versailles Saint-Quentin, UMRS 1018, Villejuif, France\t\n Jaco Dreyer\tData management\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n Andrea Grosset\tStatistics\t- INSERM, UMR912 (SESSTIM), 13006, Marseille, France\t\n- Aix Marseille Université, UMR_S912, IRD, Marseille, France\t\n- ORS PACA, Observatoire Régional de la Santé Provence- Alpes-Côte d’Azur, Marseille, France\t\n Kobus Herbst\tData management\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n John Imrie\tSocial sciences\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n- Centre for Sexual Health and HIV Research, Research Department of Infection and Population, Faculty of Population Health Sciences, University College London, London, UK\t\n Joseph Larmarange\tSocial sciences\t- CEPED (Centre Population & Développement-UMR 196- Paris Descartes/INED/IRD), IRD (Institut de Recherche pour le Développement), Paris, France.\t\n- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n France Lert\tSocial Sciences\t- INSERM U1018, CESP, Epidemiology of Occupational and Social Determinants of Health, Villejuif, France\t\n- University of Versailles Saint-Quentin, UMRS 1018, Villejuif, France\t\n Thembisa Makowa\tField operations\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n Anne-Geneviève Marcelin\tVirology\t- Department of virology, Hôpital Pitié-Salpétrière, Paris, France\t\n Nuala McGrath\tEpidemiology/Social sciences\t- Faculty of Medicine and Faculty of Human, Social and Mathematical Sciences, University of Southampton, UK\n- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n- Research Department of Infection and Population Health, University College London, UK\t\n Nonhlanhla Okesola\tNurse manager\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n Tulio de Oliveira\tBioinformatics\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n Delphine Perriat\tEpidemiology/social sciences\t- Univ. Bordeaux, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n- INSERM, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n Melanie Plazy\tEpidemiology/social sciences\t- Univ. Bordeaux, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n- INSERM, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n Camelia Protopopescu\tStatistics/Economist\t- INSERM, UMR912 (SESSTIM), Marseille, France\t\n- Aix Marseille Université, UMR_S912, IRD, Marseille, France\t\n- ORS PACA, Observatoire Régional de la Santé Provence- Alpes-Côte d’Azur, Marseille, France\t\n Luis Sagaon-Teyssier\tHealth economics\t- INSERM, UMR912 (SESSTIM), Marseille, France\t\n- Aix Marseille Université, UMR_S912, IRD, Marseille, France\t\n- ORS PACA, Observatoire Régional de la Santé Provence- Alpes-Côte d’Azur, Marseille, France\t\n Bruno Spire\tHealth economics\t- INSERM, UMR912 (SESSTIM), 13006, Marseille, France\t\n- Aix Marseille Université, UMR_S912, IRD, Marseille, France\t\n- ORS PACA, Observatoire Régional de la Santé Provence- Alpes-Côte d’Azur, Marseille, France\t\n Frank Tanser\tEpidemiology and Biostatistics\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\n Rodolphe Thiébaut\tEpidemiology and Biostatistics\t- Univ. Bordeaux, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n- INSERM, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n Thierry Tiendrebeogo\tEpidemiology and Biostatistics\t- Univ. Bordeaux, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n- INSERM, ISPED, Centre Inserm U1219 Bordeaux Population Health, Bordeaux, France\t\n Thembelihle Zuma\tPsychology/Social sciences\t- Africa Centre for Population Health, University of KwaZulu- Natal, South Africa\t\nScientific advisory board\t\t\t\n Chair: Bernard Hirschel (Switzerland)\t\t\t\nInternational experts\t\t\t\n Xavier Anglaret (Ivory Coast)\t\t\t\n Hoosen Cooavdia (South Africa)\t\t\t\n Alpha Diallo (France)\t\t\t\n Bruno Giraudeau (France)\t\t\t\n Jean-Michel Molina (France)\t\t\t\n Lynn Morris (South Africa)\t\t\t\n François Venter (South Africa)\t\t\t\n Sibongile Zungu (South Africa)\t\t\t\nCommunity representatives\t\t\t\n Eric Fleutelot (France)\t\t\t\n Eric Goemaere (South Africa)\t\t\t\n Calice Talom (Cameroon)\t\t\t\nSponsor representatives (ANRS)\t\t\t\n Brigitte Bazin\t\t\t\n Claire Rekacewicz\t\t\t\nPharmaceutical company representatives\t\t\t\n Golriz Pahlavan-Grumel (MSD)\t\t\t\n Alice Jacob (Gilead)\t\t\t\nData safety and monitoring board\t\t\t\n Chair: Patrick Yeni (France)\t\t\t\n Sinead Delany-Moretlwe (South Africa)\t\t\t\n Nathan Ford (South Africa)\t\t\t\n Catherine Hankins (Netherlands)\t\t\t\n Helen Weiss (UK)\n==== Refs\nReferences\n1. \nBoender TS Sigaloff KC McMahon JH \nLong-term virological outcomes of first-line antiretroviral therapy for HIV-1 in low- and middle-income countries: a systematic review and meta-analysis . Clin Infect Dis 2015 ; 61 :1453 –61 .26157050 \n2. \nGupta RK Hill A Sawyer AW \nVirological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis . Lancet Infect Dis 2009 ; 9 :409 –17 .19555900 \n3. \nHamers RL Sigaloff KC Wensing AM ; PharmAccess African Studies to Evaluate Resistance (PASER) \nPatterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: implications for second-line ART strategies . Clin Infect Dis 2012 ; 54 :1660 –9 .22474222 \n4. \nManasa J Lessells RJ Skingsley A ; Southern African Treatment and Resistance Network \nHigh-levels of acquired drug resistance in adult patients failing first-line antiretroviral therapy in a rural HIV treatment programme in KwaZulu-Natal, South Africa . PLoS One 2013 ; 8 :e72152 .23991055 \n5. \nEstill J Ford N Salazar-Vizcaya L \nThe need for second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical modelling study . Lancet HIV 2016 ; 3 : e132 –9 .26939736 \n6. \nAjose O Mookerjee S Mills EJ Boulle A Ford N \nTreatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis . AIDS 2012 ; 26 :929 –38 .22313953 \n7. \nFox MP Ive P Long L Maskew M Sanne I \nHigh rates of survival, immune reconstitution, and virologic suppression on second-line antiretroviral therapy in South Africa . J Acquir Immune Defic Syndr 2010 ; 53 :500 –6 .19838128 \n8. \nJohnston V Cohen K Wiesner L \nViral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch . J Infect Dis 2014 ; 209 :711 –20 .23943851 \n9. \nLevison JH Orrell C Losina E Lu Z Freedberg KA Wood R \nEarly outcomes and the virological effect of delayed treatment switching to second-line therapy in an antiretroviral roll-out programme in South Africa . Antivir Ther 2011 ; 16 :853 –61 .21900717 \n10. \nMurphy RA Sunpath H Castilla C \nSecond-line antiretroviral therapy: long-term outcomes in South Africa . J Acquir Immune Defic Syndr 2012 ; 61 :158 –63 .22692090 \n11. \nSchoffelen AF Wensing AM Tempelman HA Geelen SP Hoepelman AI Barth RE \nSustained virological response on second-line antiretroviral therapy following virological failure in HIV-infected patients in rural South Africa . PLoS One 2013 ; 8 :e58526 .23505529 \n12. \nSigaloff KC Hamers RL Wallis CL ; PharmAccess African Studies to Evaluate Resistance (PASER) \nSecond-line antiretroviral treatment successfully resuppresses drug-resistant HIV-1 after first-line failure: prospective cohort in sub-Saharan Africa . J Infect Dis 2012 ; 205 :1739 –44 .22448003 \n13. \nPaton NI Kityo C Hoppe A ; EARNEST Trial Team \nAssessment of second-line antiretroviral regimens for HIV therapy in Africa . N Engl J Med 2014 ; 371 :234 –47 .25014688 \n14. \nCiaffi L Koulla-Shiro S Sawadogo A ; 2LADY Study Group \nEfficacy and safety of three second-line antiretroviral regimens in HIV-infected patients in Africa . AIDS 2015 ; 29 :1473 –81 .26244387 \n15. \nAmin J Boyd MA Kumarasamy N ; SECOND-LINE \nCorrection: raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection . PLoS One 2015 ; 10 :e0140623 .26451848 \n16. \nHakim JT Kityo CM Walker S \nSecond-line treatment in sub-Saharan Africa: week 144 follow-up of the earnest trial . Top Antiviral Med 2015 ; 23 :232 .\n17. \nEl-Khatib Z Ekstrom AM Ledwaba J \nViremia and drug resistance among HIV-1 patients on antiretroviral treatment: a cross-sectional study in Soweto, South Africa . AIDS 2010 ; 24 :1679 –87 .20453629 \n18. \nLathouwers E De Meyer S Dierynck I \nVirological characterization of patients failing darunavir/ritonavir or lopinavir/ritonavir treatment in the ARTEMIS study: 96-week analysis . Antivir Ther 2011 ; 16 :99 –108 .21311113 \n19. \nGupta A Nadkarni G Yang WT \nEarly mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis . PLoS One 2011 ; 6 :e28691 .22220193 \n20. \nIwuji CC Orne-Gliemann J Tanser F ; ANRS 12249 TasP Study Group \nEvaluation of the impact of immediate versus WHO recommendations-guided antiretroviral therapy initiation on HIV incidence: the ANRS 12249 TasP (treatment as prevention) trial in Hlabisa sub-district, KwaZulu-Natal, South Africa: study protocol for a cluster randomised controlled trial . Trials 2013 ; 14 :230 .23880306 \n21. \nNational Department of Health . The 2013 National Antenatal Sentinel HIV Prevalence Survey South Africa . Pretoria : National Department of Health , 2015 .\n22. \nHoulihan CF Bland RM Mutevedzi PC \nCohort profile: Hlabisa HIV treatment and care programme . Int J Epidemiol 2011 ; 40 :318 –26 .20154009 \n23. \nGall A Ferns B Morris C \nUniversal amplification, next-generation sequencing, and assembly of HIV-1 genomes . J Clin Microbiol 2012 ; 50 :3838 –44 .22993180 \n24. \nManasa J Danaviah S Pillay S \nAn affordable HIV-1 drug resistance monitoring method for resource limited settings . J Vis Exp 2014 . doi:10.3791/51242 .\n25. \nRhee SY Gonzales MJ Kantor R Betts BJ Ravela J Shafer RW \nHuman immunodeficiency virus reverse transcriptase and protease sequence database . Nucleic Acids Res 2003 ; 31 :298 –303 .12520007 \n26. \nFine JP Gray RJ \nA proportional hazards model for the subdistribution of a competing risk . J Am Stat Assoc 1999 ; 94 : 496 –509 .\n27. \nBoyd MA Kumarasamy N Moore CL ; SECOND-LINE Study Group \nRitonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study . Lancet 2013 ; 381 :2091 –9 .23769235 \n28. \nHoffmann CJ Charalambous S Sim J \nViremia, resuppression, and time to resistance in human immunodeficiency virus (HIV) subtype C during first-line antiretroviral therapy in South Africa . Clin Infect Dis 2009 ; 49 :1928 –35 .19911963 \n29. \nGupta RK Goodall RL Ranopa M ; DART Virology Group and Trial Team \nHigh rate of HIV resuppression after viral failure on first-line antiretroviral therapy in the absence of switch to second-line therapy . Clin Infect Dis 2014 ; 58 :1023 –6 .24352348 \n30. \nWorld Health Organization . Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach: 2010 revision . Geneva, Switzerland : WHO , 2010 .\n31. \nBurger DM Agarwala S Child M Been-Tiktak A Wang Y Bertz R \nEffect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers . Antimicrob Agents Chemother 2006 ; 50 :3336 –42 .17005814 \n32. \nla Porte CJ Colbers EP Bertz R \nPharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers . Antimicrob Agents Chemother 2004 ; 48 :1553 –60 .15105105 \n33. \nNational Department of Health . National consolidated guidelines for the prevention of mother-to-child transmission of HIV (PMTCT) and the management of HIV in children, adolescents and adults . South Africa: National Department of Health 2014 \nhttp://www.hst.org.za/publications/national-consolidated-guidelines-prevention-mother-child-transmission-hiv-pmtct-and-man. Accessed 1 August 2016.\n34. \nMurphy RA Marconi VC Gandhi RT Kuritzkes DR Sunpath H \nCoadministration of lopinavir/ritonavir and rifampicin in HIV and tuberculosis co-infected adults in South Africa . PLoS One 2012 ; 7 :e44793 .23028623 \n35. \nNijland HM L’homme RF Rongen GA \nHigh incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets . AIDS 2008 ; 22 :931 –5 .18453852 \n36. \nSunpath H Winternheimer P Cohen S \nDouble-dose lopinavir-ritonavir in combination with rifampicin-based anti-tuberculosis treatment in South Africa . Int J Tuberc Lung Dis 2014 ; 18 :689 –93 .24903940 \n37. \nIwuji C Dray-Spira R Calmy A ,\n \n\nDoes a universal test and treat strategy impact ART adherence in rural South Africa? ANRS 12249 TasP cluster-randomized trial . J Int AIDS Soc 2015 ; 18 : 16 –7 .\n38. \nTenoRes Study Group . Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study . Lancet Infect Dis 2016 ; 16 : 565 –75 .26831472 \n39. \nCasadellà M Noguera-Julian M Sunpath H \nTreatment options after virological failure of first-line tenofovir-based regimens in South Africa: an analysis by deep sequencing . AIDS 2016 ; 30 :1137 –40 .26807968 \n40. \nLevison JH Orrell C Gallien S \nVirologic failure of protease inhibitor-based second-line antiretroviral therapy without resistance in a large HIV treatment program in South Africa . PLoS One 2012 ; 7 :e32144 .22427821 \n41. \nWallis CL Mellors JW Venter WD Sanne I Stevens W \nProtease inhibitor resistance is uncommon in HIV-1 subtype C infected patients on failing second-line lopinavir/r-containing antiretroviral therapy in South Africa . AIDS Res Treat 2011 ; 2011 :769627 .21490784 \n42. \nBoender TS Hamers RL Ondoa P \nProtease inhibitor resistance in the first 3 years of second-line antiretroviral therapy for HIV-1 in sub-Saharan Africa . J Infect Dis 2016 ; 214 :873 –83 .27402780 \n43. \nFun A Wensing A Verheyen J Nijhuis M \nHuman immunodeficiency virus Gag and protease: partners in resistance . Retrovirology 2012 ; 9 :63 .22867298 \n44. \nGupta RK Kohli A McCormick AL Towers GJ Pillay D Parry CM \nFull-length HIV-1 Gag determines protease inhibitor susceptibility within in vitro assays . AIDS 2010 ; 24 :1651 –5 .20597164 \n45. \nParry CM Kohli A Boinett CJ Towers GJ McCormick AL Pillay D \nGag determinants of fitness and drug susceptibility in protease inhibitor-resistant human immunodeficiency virus type 1 . J Virol 2009 ; 83 :9094 –101 .19587031 \n46. \nSutherland KA Mbisa JL Ghosn J \nPhenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag-protease genes . J Antimicrob Chemother 2014 ; 69 :3340 –8 .25096075 \n47. \nSutherland KA Ghosn J Gregson J \nHIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir . J Antimicrob Chemother 2015 ; 70 :243 –8 .25228587 \n48. \nRabi SA Laird GM Durand CM \nMulti-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance . J Clin Invest 2013 ; 123 :3848 –60 .23979165 \n49. \nLange CM Hué S Violari A \nSingle genome analysis for the detection of linked multiclass drug resistance mutations in HIV-1-infected children after failure of protease inhibitor-based first-line therapy . J Acquir Immune Defic Syndr 2015 ; 69 :138 –44 .25923117 \n50. \nGiandhari J Basson AE Coovadia A \nGenetic changes in HIV-1 Gag-protease associated with protease inhibitor-based therapy failure in pediatric patients . AIDS Res Hum Retroviruses 2015 ; 31 :776 –82 .25919760 \n51. \nGregson J Kaleebu P Marconi VC \nOccult drug resistance to thymidine analogues and multidrug resistant HIV-1 following failure of first line tenofovir-based antiretroviral regimens in sub-Saharan Africa: a retrospective multi-centre cohort study . Lancet Infect Dis 2016 ; doi:10.1016/S1473–3099(16)30469–8.\n52. \nGupta RK Jordan MR Sultan BJ \nGlobal trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis . Lancet 2012 ; 380 :1250 –8 .22828485 \n53. \nWorld Health Organization . Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis to ART . Available at: http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1. Accessed 1 August 2016.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1058-4838",
"issue": "64(8)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HIV; antiretroviral therapy; protease inhibitor; second line; virological failure",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents; D005260:Female; D005838:Genotype; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011446:Prospective Studies; D012424:Rural Population; D013019:South Africa; D016896:Treatment Outcome; D014376:Tuberculosis; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1006-1016",
"pmc": null,
"pmid": "28329393",
"pubdate": "2017-04-15",
"publication_types": "D016428:Journal Article",
"references": "25228587;23028623;21490784;17005814;12520007;26807968;22828485;23769235;22993180;22867298;25096075;26157050;26939736;23991055;19838128;22448003;19555900;22474222;18453852;15105105;22692090;20597164;24747156;21900717;23880306;22313953;19911963;21311113;24903940;24352348;25923117;20453629;23943851;25014688;26244387;20154009;25919760;22220193;23505529;26451848;27402780;27914856;22427821;26831472;23979165;19587031",
"title": "Virological Outcomes of Second-line Protease Inhibitor-Based Treatment for Human Immunodeficiency Virus Type 1 in a High-Prevalence Rural South African Setting: A Competing-Risks Prospective Cohort Analysis.",
"title_normalized": "virological outcomes of second line protease inhibitor based treatment for human immunodeficiency virus type 1 in a high prevalence rural south african setting a competing risks prospective cohort analysis"
} | [
{
"companynumb": "GB-VIIV HEALTHCARE LIMITED-ZA2017140674",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional"... |
{
"abstract": "Ibrutinib is a Burton tyrosine kinase inhibitor (BTKi) approved for the treatment of several hematologic malignancies. Analyze skin adverse events (SAE). All the patients treated with Ibrutinib featuring cutaneous adverse events were selected. Twenty five patients were retrieved with a median interval between Ibrutinib start and SAE time of onset of 120 days. Most common SAE observed involved hairs and nails. Eczematous reaction and leucocytoclastic vasculitis were also detected. One patient had a long-history Ibrutinib treatment and experienced numerous cutaneous adverse events. Infective disease such as superficial mycosis and impetigo were rarely present in our series. Despite the development of cutaneous SAE, all the patients continued their concomitant drugs without the onset of any further SAE. Our data suggest Ibrutinib-associated rash should be distinguished in early and late events and a careful dermatologic management of patients should be scheduled.",
"affiliations": "Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Haematopathology, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Haematopathology, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Hematology, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.;Division of Hematology, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia.;Division of Dermatology Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italia.",
"authors": "Pileri|Alessandro|A|0000-0002-1025-7171;Guglielmo|Alba|A|;Agostinelli|Claudio|C|;Evangelista|Valeria|V|0000-0002-1412-2776;Bertuzzi|Clara|C|;Alessandrini|Aurora|A|;Bruni|Francesca|F|;Starace|Michela|M|;Massi|Alice|A|;Broccoli|Alessandro|A|;Patrizi|Annalisa|A|;Zinzani|Pier Luigi|PL|;Piraccini|Bianca Maria|BM|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.14190",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "33(6)",
"journal": "Dermatologic therapy",
"keywords": "adverse-events; ibrutinib; skin",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000225:Adenine; D006801:Humans; D009369:Neoplasms; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e14190",
"pmc": null,
"pmid": "32790083",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cutaneous adverse-events in patients treated with Ibrutinib.",
"title_normalized": "cutaneous adverse events in patients treated with ibrutinib"
} | [
{
"companynumb": "IT-ABBVIE-20K-083-3542860-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "3",
... |
{
"abstract": "Nearly all men with prostate cancer who are treated with androgen deprivation therapy develop disease progression. There is considerable evidence to suggest that CXCL 13 released by tumor cells leads to B-cell infiltration into the prostate cells. This B-cell infiltration has been postulated to play a role in development of disease progression following androgen-deprivation therapies. We present a case of a patient who achieved remission of metastatic castrate-resistant prostate cancer after receiving rituximab and bendamustine for the treatment of follicular lymphoma. The findings in this report suggest that further investigation is warranted for utilizing B-cell targeted therapy in delaying progression of castrate-resistant prostate cancer.",
"affiliations": "1 Department of Internal Medicine, UConn Health, Farmington, CT, USA.;2 UConn School of Pharmacy, Farmington, CT, USA.;2 UConn School of Pharmacy, Farmington, CT, USA.;1 Department of Internal Medicine, UConn Health, Farmington, CT, USA.",
"authors": "Bindal|Poorva|P|;Jalil|Sharif Aa|SA|;Holle|Lisa M|LM|;Clement|Jessica M|JM|",
"chemical_list": "D000726:Androgen Antagonists; D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218790338",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(6)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Castrate resistant; Rituximab; prostate cancer",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000726:Androgen Antagonists; D000074322:Antineoplastic Agents, Immunological; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D000069283:Rituximab",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1509-1511",
"pmc": null,
"pmid": "30092742",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Potential role of rituximab in metastatic castrate-resistant prostate cancer.",
"title_normalized": "potential role of rituximab in metastatic castrate resistant prostate cancer"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-217088",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BICALUTAMIDE"
},
"dr... |
{
"abstract": "Differentiation syndrome (DS), formerly known as retinoic acid syndrome, is a relatively common and potentially severe complication seen in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and/or arsenic trioxide. The full-blown syndrome consists of unexplained fever, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, hypotension, and renal failure. Most measures currently used for management of DS have very little evidence-based support, and therefore, many remain controversial. Despite the lack of evidence supporting DS prophylaxis, several groups have adopted a preventive strategy with corticosteroids, especially for patients with leukocyte levels higher than from 5 to 10 × 10(9)/L. DS diagnosis should be suspected in the presence of any of the above-mentioned signs and symptoms, and preemptive treatment with dexamethasone should be started immediately. Other supportive measures can also be crucial for the correct management of DS, especially in those patients with life-threatening complications. Temporary discontinuation of all-trans retinoic acid or arsenic trioxide is indicated only for patients in very poor clinical condition or with severe renal or pulmonary dysfunction, sometimes requiring admission to the intensive care unit. Recognition of specific biomarkers and a better understanding of DS pathogenesis can be helpful for the development of specific therapies to counteract DS in a timely manner.",
"affiliations": "University Hospital La Fe; and.",
"authors": "Sanz|Miguel A|MA|;Montesinos|Pau|P|",
"chemical_list": "D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2013-10-512640",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "123(18)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000077237:Arsenic Trioxide; D001152:Arsenicals; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D010087:Oxides; D011292:Premedication; D013577:Syndrome; D014212:Tretinoin",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2777-82",
"pmc": null,
"pmid": "24627526",
"pubdate": "2014-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia.",
"title_normalized": "how we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia"
} | [
{
"companynumb": "ES-MYLANLABS-2015M1019265",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
... |
{
"abstract": "Delirium occurs frequently in critically ill children, and children with neuroblastoma may be at particular risk. Early diagnosis and treatment may improve short- and long-term outcomes. In this case series, we present four critically ill children with neuroblastoma who were diagnosed with delirium in the post-operative period. In all four patients, the diagnosis of delirium facilitated targeted intervention and improvement. Heightened awareness by pediatric oncologists, surgeons, and intensivists may lead to earlier diagnosis and improvement in clinical outcomes.",
"affiliations": "Division of Pediatric Critical Care Medicine, Weill Cornell Medical College, New York, New York.",
"authors": "Traube|Chani|C|;Augenstein|Julie|J|;Greenwald|Bruce|B|;LaQuaglia|Michael|M|;Silver|Gabrielle|G|",
"chemical_list": "D018680:Cholinergic Antagonists; D003987:Dibenzothiazepines; D009294:Narcotics; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.24917",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(6)",
"journal": "Pediatric blood & cancer",
"keywords": "critical care; delirium; neuroblastoma; pediatrics",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D001569:Benzodiazepines; D002675:Child, Preschool; D018680:Cholinergic Antagonists; D003693:Delirium; D003987:Dibenzothiazepines; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009294:Narcotics; D009447:Neuroblastoma; D010149:Pain, Postoperative; D011183:Postoperative Complications; D000069348:Quetiapine Fumarate; D012307:Risk Factors; D012983:Soft Tissue Neoplasms; D058495:Sotos Syndrome",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1121-3",
"pmc": null,
"pmid": "24376154",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neuroblastoma and pediatric delirium: a case series.",
"title_normalized": "neuroblastoma and pediatric delirium a case series"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-099695",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.