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DATA AVAILABILITY STATEMENT | Data are available upon request. | PMC9939110 | ||
REFERENCES | PMC9939110 | |||
Background | tissue loss, CLI | CRITICAL LIMB ISCHEMIA | Critical limb ischemia (CLI) is associated with increased risk of tissue loss, leading to significant morbidity and mortality. Therapeutic angiogenesis using cell-based treatments, notably mesenchymal stem cells (MSCs), is essential for enhancing blood flow to ischemic areas in subjects suffering from CLI. The objective of this study was to evaluate the feasibility of using placenta-derived mesenchymal stem cells (P-MSCs) in patients with CLI. | PMC10324209 |
Methods | CLI | This phase I dose-escalation study investigated P-MSCs in nine CLI patients who were enrolled into each of the two dosage groups (20 × 10 | PMC10324209 | |
Results | All dosages of P-MSCs, including the highest tested dose of 60 × 10 | PMC10324209 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13287-023-03390-9. | PMC10324209 | ||
Keywords | PMC10324209 | |||
Introduction | DLTs, CLI, PAD, lower-extremity ischemia, toxicities, gangrene, atherosclerotic, pain, extracranial carotids, non-atherosclerotic | PERIPHERAL ARTERY DISEASE, ARTERIAL DISORDERS, GANGRENE, PAD, CRITICAL LIMB ISCHEMIA | Peripheral artery disease (PAD), except for aortic and coronary involvement, includes all arterial disorders. It is mainly associated with extracranial carotids, upper extremity arteries, renal and mesenteric arteries, and lower limb arteries [Critical limb ischemia (CLI), the most severe form of PAD, results in ischemic rest pain, unhealed wounds, gangrene, and limb amputations. Endovascular revascularization or open surgery is the current standard treatment for improving blood flow to affected limbs [Vascular regeneration processes, such as angiogenesis and arteriogenesis, occur in ischemic lesions in healthy tissues. Yet, this phenomenon does not occur in CLI [In preclinical studies employing animal models of lower-extremity ischemia, autologous and allogeneic MSCs produced from various sources, including bone marrow, adipose tissue, and prenatal sources, have been beneficial [MSCs improve the endurance of pre-existing blood vessels in co-culture with ECs in a dose-dependent manner [The placenta is a highly vascular tissue that receives several angiogenesis-stimulating impulses. This feature makes it an ideal milieu for signals that promote angiogenesis. Placenta-derived mesenchymal stem cells (P-MSCs) exhibit morphological features nearly identical to those of other MSCs, which are detected in the vascular niche of the placenta [P-MSCs are an excellent example of fetal stem cells that have been suggested as substitutes for medical applications [Similar to other MSCs, P-MSCs exhibit a limited level of HLA-A, HLA-B, and HLA-C molecules, which reduces their immunogenicity and increases their suitability for transplantation. P-MSCs cause pro-inflammatory M1 cells to transform into anti-inflammatory M2 cells. He S.et al. showed that placental mesenchymal cells (PDA-002) injected into a mouse model of HLI increased M2 anti-inflammatory macrophages in ischemic tissue. They also induce the cytokine profile and gene expression of Th2 lymphocytes. These findings indicate that the increase in angiogenesis of PDA-002 cells occurs through an immunomodulatory mechanism in which T lymphocytes play a key role in the differentiation and reprogramming of macrophages toward the M2 type [Additionally, P-MSCs expressing HLA-G inhibit T cell development [In this study, owing to the distinguishing features of P-MSCs in regenerating ischemic tissue and regaining tissue function through immunomodulation and angiogenesis, the therapeutic benefit of P-MSCs was utilized for subjects with CLI. This is a report of a dose-escalation phase 1 study (IRCT ID: IRCT20210221050446N1) to evaluate the tolerability and identify the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of intramuscular P-MSC delivery in nine atherosclerotic and non-atherosclerotic patients with CLI. | PMC10324209 |
Materials and methods | PMC10324209 | |||
Patient recruitment and study design | arterial occlusion, diabetus mellitus, CLI, toxicity, diabetic foot, thromboangiitis | ARTERIAL OCCLUSION, DISEASE, HYPERCHOLESTEROLEMIA, DIABETIC FOOT, THROMBOANGIITIS, BUERGER DISEASE, TAO | Individuals with CLI who participated in the inpatient and outpatient vascular surgery services at Taleghani Hospital, whose primary treating vascular surgeons determined that they were not eligible for surgical or endovascular intervention but were considered suitable candidates, were offered to participate in this trial. Nine patients with CLI were included in the trial: two with diabetic foot and seven with TAO (Table Demographic and baseline disease conditionHC: Hypercholesterolemia; ESH: ex smoke habit; BD: Buerger disease; AS: active smoker; DM: diabetus mellitus; TAO: thromboangiitis obliteransThe enrolled CLI patients had complete arterial occlusion without run-off of the lower extremities, as verified by conventional diagnostic angiography. Table Eligibility criteria for patients enrolled in the studyBased on the trial entrance order, eligible patients were randomized into one of the two P-MSC dosing cohorts. A 3 + 3 dose escalation approach was adopted, with three–six patients in each P-MSC dose cohort: 20 × 10A DLT was described in this study as a grade 2 toxicity or any grade 3 toxicity expected to be attributable to P-MSC administration that did not resolve during the 14 days. The highest P-MSC dosage for which the prevalence of DLTs was less than or equal to one case was regarded as the MTD. If two or more subjects developed a DLT during the 14 days of administration, the MTD was considered to have been exceeded. | PMC10324209 |
Preparation of P-MSCs | P-MSCs were harvested from placental tissue acquired from a full-term delivery with written informed consent from a healthy mother and delivered fresh tissue. After successful vaginal birth at a maternity hospital, the placenta was obtained from informed, healthy women (Additional file According to the current GMP (Good Manufacturing Practice) standards, all steps were carried out in a GMP-grade clean room facility. The fresh placenta was rinsed with PBS, divided into small pieces, and washed with 0.9% sodium chloride solution to remove any remaining blood before incubation for three hours at 37 °C with GMP-grade collagenase NB6 at 1 mg/mL (SERVA Electrophoresis GmbH). Following the addition of 0.9% sodium chloride solution, the mixture was shaken and centrifuged.The supernatant was withdrawn and the cell pellet was cultured on MSC complete medium with 10% pharmaceutical grade Australian origin fetal bovine serum (ATOCEL). Primary cultures were kept in a 37 °C humidified 5% COAccording to the International Society of Cell Therapy (ISCT), confirmatory tests were carried out, including flow cytometry (CD34, CD45, CD29, CD90, and CD105) (Additional file | PMC10324209 | ||
Implant procedure | allergies, pain | ALLERGIES | P-MSCs were administered under spinal anesthesia (3 patients) or IV sedation (6 patients) to relieve pain. P-MSC treatment was administered at two time points, eight weeks apart. The total amount of the suspension was injected intramuscularly using a 30 G needle to a depth of 1–1.5 cm and an area of 10 × 6 cm (30–40 sites with 0.5–1.0 ml of P-MSCs per site) on each occasion. The injections were distributed as follows: the knee to the ankle was divided into five equal parts in four lines (the anterior, anterolateral, and superficial posterior compartments of the leg), and six points were identified at the dorsum of the foot, and the surroundings of the wound (if there was a wound).Patients received 100 mg hydrocortisone before injection to avoid side effects such as allergies. Oxygen saturation was measured 30 min before and 6 h after the injection of P-MSCs throughout the dosage. | PMC10324209 |
Outcome measurement and follow-up | ABI, tumor necrosis, TNF-α, CLI, pain, Cancer | ADVERSE EVENT, TUMOR NECROSIS, ADVERSE EVENTS, LIMB ISCHEMIA, ULCERS, ULCERATION, CANCER | To assess the safety and effectiveness of P-MSC injections in the enrolled participants, we assessed medical records, electrocardiogram (ECG) results, vital signs (respiration, heart rate, blood pressure, oxygen saturation, and body temperature), blood chemistry, physical examination reports, digital photographs of wounds, and angiography at baseline and at the months follow-up.The primary safety evaluations that followed repeated doses of perinatal tissue MSC transplantation in no-option CLI patients, including tracking and documenting all possible adverse events (AEs) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 5.0), were the main outcomes of the study.In addition to the usual safety laboratory measures, the levels of a few pro-inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were assessed to determine the immunological response to P-MSC transplantation (ELISA R&D, USA). Flow cytometry was used to compare the lymphocyte profiles before and after P-MSC administration in terms of CD4, CD8, and CD25 levels.In this study, in addition to investigating the safety of placental mesenchymal stem cell administration, efficacy endpoints were also investigated, including an increase in the ankle-brachial pressure index (ABI), maximal walking distance, vasculogenesis, relief of rest pain, healing of ulceration, and prevention of major amputation in the target limb.The visual analog scale (VAS) was used to evaluate pain, ranging from 0 for the best (totally resolved) to 10 for the most painful condition. Wound healing was evaluated using digital photographs of the ulcers. Objective criteria for limb ischemia included ABI measurements (Clinical trial methodology for intramuscular administration of P-MSC. | PMC10324209 |
Statistical analysis | Individual data are described using frequency graphs and tables. Categorical data were summarized as counts and percentages. All data from participants who withdrew prematurely from the study were included in any analysis where possible. The data were transferred to a statistical package for analysis (GraphPad Prism 9.0; GraphPad Software, La Jolla, CA, USA). The Wilcoxon nonparametric paired test was used to compare inflammatory cytokine levels, lymphocyte profiles, blood chemistry, and collateral grades on conventional angiography between the baseline and 6 months after the intervention. One-way ANOVA or Friedman test was applied to compare the variables (VAS rating scores, ABI, maximal walking distance, and quality of life) between different times before and after the intervention. Differences were considered statistically significant at | PMC10324209 | ||
Results | PMC10324209 | |||
Characteristic of patients | CLI | From April 2022 to August 2022, 15 patients with CLI were recruited for the clinical trial to determine their eligibility for study enrolment. Of these, 11 patients received treatment with P-MSCs, and eight patients completed the trial. Three patients were excluded from the study because of clinical worsening (Fig. Flowchart: 15 patients recruited in the study and allocated to two groups (low-dose group = 3; high-dose group = 8)Comparison of clinical outcome on baseline and 6 months after implantation of P-MSCs | PMC10324209 | |
Safety evaluation of P-MSC therapy | TNF-α, tumor necrosis, CLI, diarrhea, pruritus | DISEASE PROGRESSION, MINOR, ADVERSE EVENT, TUMOR NECROSIS | The MTD was not reached after P-MSC treatment, as no cases of DLT or AEs leading to discontinuation of P-MSC treatment were reported in this trial. Intramuscular injection of all doses of P-MSCs, including the maximum tested dose of 60 × 10Two patients experienced moderate post-injection diarrhea a day after cell therapy. In addition, two patients developed minor pruritus. The diarrhea improved on its own, and pruritus disappeared after one day of antihistamine therapy. There was one adverse event due to disease progression that was unrelated to the cell treatment; one patient received below-knee amputation of the treated leg three months after cell administration. During the follow-up phase, the physical evaluation and vital signs did not change from baseline.All patients underwent routine hematological and biochemical testing, both before and after cell treatment. The results demonstrated that the test improved over time. Among which FBs (fast blood sugar) showed a significant decrease (The immunological profiles (IL-1, IFN-γ, and TNF-α) (CD4, CD8, and CD25) of patients with CLI were evaluated before and 6 months after P-MSC administration in this study. The results demonstrated a statistically significant reduction in IL-1 and IFN-γ serum levels over a 6-month follow-up period after P-MSC therapy (Change in patients’ serum inflammatory cytokines levels on days 0 (baseline) and 6 months after the first infusion. Analysis of biomarkers on before (baseline) and 6 months after the first infusion demonstrated a significant reduction in IL-1, and interferon-γ (IFN-γ) in all patients with CLI. Serum levels of tumor necrosis factor alpha (TNF-α) decreased in four cases, but the differences were not statistically significant. *Patient samples were analyzed using flow cytometry for CD4, CD8, and CD25 markers before and after treatment with P-MSCs (Fig. Measured markers of CD4 and CD8 and CD25 on patients with CLI at screening and 6-month follow-up after P-MSC implantation | PMC10324209 |
Secondary outcome measures of P-MSC therapy | PMC10324209 | |||
Angiogenesis | placenta-derived mesenchymal stem cells (P-MSC). | We evaluated arterial angiography data 6 months after cell injection and classified the degree of collateral vessel development as + 0 (no collateral circulation), + 1 (slight collateral circulation), + 2 (moderate collateral circulation), and + 3 (high collateral circulation) [Changes in collateral artery development on angiography 6 months following implantation of placenta-derived mesenchymal stem cells (P-MSC). | PMC10324209 | |
Pain relief and physical functioning | pain | At the beginning of the trial and at the 1-, 3-, and 6-month follow-up visits, the rest pain was assessed using VAS (Table Efficacy parameters: As shown in Fig. In six patients, the treadmill test performed to determine the maximum walking distance improved significantly (The VascuQoL-6 survey was used to subjectively assess changes in leg symptoms and benefits after cell infusion (Fig. | PMC10324209 | |
Ulcer healing and Limb salvage | amputation, Gangrene, gangrene, ulcers, amputations, ulcer/gangrene, TAO, necrosis, ulcer, gangrenes, sores | THROMBOANGIITIS OBLITERANS, MINOR, WOUND INFECTION, GANGRENE, ULCERS, GANGRENE, NECROSIS, ISCHEMIC NECROSIS, SUPERINFECTION, ULCER, GANGRENES, TAO | Ten extremities completed the 6-month follow-up study. At baseline, nine limbs had non-healing sores, necrosis, and gangrene. Throughout the 6-month follow-up period, one limb demonstrated significant healing of the ulcer, and two limbs with ulcers and gangrenes did not progress and remained entirely dry. We performed minor amputations in one patient before cell treatment and five patients after P-MSC implantation, whose wounds healed after amputation, and the total ulcer surface measurement was largely reduced (Fig. Representation of the treated limbs showing the progression of ischemic ulcer/gangrene throughout 6-month follow-up. Patient 3: a 41-year-old man with thromboangiitis obliterans (TAO), Rutherford IV presented with non-healing ulcers on the ankle and lateral midfoot healed completely at 6 months after P-MSC implantation. Patient 4: a 55-year-old man with TAO presented with gangrene of the first and second toes, and a history of amputation of the 3th and 4th toes showed clear healing of ischemic necrosis on foot after amputation at 6 months after P-MSC implantation. Patient 7: A 66-year-old men, TAO with Rutherford-III, initially advanced gangrene and wound infection who diagnosed as needing major amputation, get minor amputation after cellular therapy and whole ulcer surface measurement was largely decreased at 6 months after P-MSC implantation. Patient 9: a 62-year-old man with Rutherford IV (TAO) presented with non-healing ulcers at dorsum of the foot and gangrene of the toe, showed clear healing of ulcer. Gangrene did not progress during the 6-month follow-upAt the six-month follow-up, the amputation rate in this trial was 40% (4 of 10 limbs). Of the nine patients, four underwent amputation, three of whom were diagnosed as needing major amputation. Referring clinicians concur that the first therapeutic approach is no longer effective following P-MSC therapy. Hence, they underwent minor amputation. Only one patient underwent major amputation (due to superinfection at the gangrene site) on day 70 after cell therapy and was excluded from the trial before the end of follow-up. | PMC10324209 |
Discussion | Pain, non-atherosclerotic PAD, CLI, amputation, amputations, pain, ill, major amputations, ulcer | LIMB ISCHEMIA, DISEASE, MINOR, SECONDARY, ISCHEMIC ULCERS, ULCERATION, ULCER, COMPLICATIONS | In ischemic lesions in CLI patients, normal vascular regeneration mechanisms, including angiogenesis and arteriogenesis, do not take place [No clinical research has documented the safety and effectiveness of utilizing P-MSCs to treat patients with non-atherosclerotic PAD. Therefore, in this primary clinical trial, we assessed the safety, feasibility, and tolerability of prenatal MSCs as potential treatments for patients with CLI. Our findings demonstrated that, following cell injection, physical function and clinical complications improved significantly in all participants. Most of the recovered patients had a dramatic response—2 to 3 month after the first MSC injection that persisted during the 6-month follow-up assessment. Despite the small patient population, the efficacy outcomes for some patients with advanced disease stages are highly encouraging.In this dose-escalation phase I experiment, two cell doses (20 million and 60 million MSCs) were tested until the MTD was established, as the optimal number of cells required for angiogenesis remains unknown. Few studies on cell doses have been conducted, and such studies will be critical for optimizing the administration of enlarged populations of stem cells or marker-selected stem cell populations MTD was established. MTD was not achieved following P-MSC therapy because no occurrences of DLT or AEs leading to P-MSC treatment discontinuation were recorded in this experiment. All dosages of P-MSCs, including the highest tested dose of 60 × 10We selected appropriate patient populations for the transplantation of stem cells in this clinical study, as there is a great deal of diversity in the capacity of patients to establish significant vascular repairs [We utilized IM injection in this trial because it effectively conveys a large number of cells to ischemic sites, as reported in preexisting cell-based treatments for CLI [Although this trial was not powered for effectiveness criteria measures, we found clinically substantial improvements in limb blood circulation and severity of limb ischemia. This was demonstrated by a substantial improvement in rest pain, blood flow, and maximum walking distance after P-MSC implantation. Pain scores showed a decreasing trend after treatment with P-MSCs in both dose groups, up to a decrease of 4.5 units. ABI, which is considered a marker of tissue perfusion, increased over the first trimester. However, this increasing trend was not significant in the second trimester after the injection (mean baseline ABI: 1.04; 3-month mean ABI: 1.12; 6-month mean ABI: 1.08.4, In this trial, all patients showed improved symptoms on the QoL questionnaire and reduced analgesic usage. Interestingly, one patient experienced dramatic improvement in the injected leg despite major amputation before the end of the follow-up period. It is worth emphasizing that all patients acknowledged and were informed of the significant clinical benefits of the treated limb.In this clinical trial, angiographic evaluation was performed before and after cell infusion and revealed that collateral vessel formation scores were elevated. However, these changes were not significant (One of the main outcomes of effectiveness in this study was the prevention of major limb amputation. We were able to avoid or perform minor amputations rather than major amputations in the patients with CLI. In the study by Gupta et al., the number of ulcer healings and amputations was comparable in both groups (placebo and BM-MSC). It is possible that allogeneic BM-MSC treatment did not provide significant benefit to severely ill patients who were facing amputation owing to the advanced form of their condition [In addition, considerable improvement or complete healing was observed in all patients with ischemic ulcers. Even when we had to perform minor amputations in a few patients before or after P-MSC implantation, the wounds healed after amputation, and the measurement of the total wound area was greatly reduced.Our study had a number of caveats and limitations. This study was not powerful enough to determine whether high doses of P-MSCs were more effective than low doses of P-MSCs.ABI improvement was the primary outcome of several stem cell studies on CLI; however, there was no noticeable difference between baseline and follow-up. Yet, other secondary endpoints, such as amputation-free interval extension, wound healing, and rest pain, showed substantial improvements [In this trial, the collateral vessel formation scores changes were not significant. Part of the reason is the small number of patients in this study. The other part could be the low resolution of the angiography method used in this clinical trial. It should be mentioned that there is a need for more accurate methods to check the collateralization, such as magnetic resonance angiography (MRA) and digital subtraction angiography (DSA), which can show the formation of new vessels with higher accuracy [Because the number of injected limbs was insufficient to conduct a statistical analysis, data on the amputation-free survival rate and ulcer healing were reported descriptively.Despite the immunomodulatory and anti-inflammatory characteristics of MSCs, there are emerging concerns regarding their tumorigenic potential owing to their innate predisposition to migrate to injured tissues and inflammatory regions [In this study, we followed the patients for 6 months in terms of clinical and preclinical outcomes, which seems to be short, since some criteria such as the results of angiogenesis, ABI, relief of rest pain, healing of ulceration, and prevention of major amputation in the target limb may change in the long term. In other words, most of the results will be more accurate during a more thorough follow-up. | PMC10324209 |
Conclusions | CLI | CRITICAL LIMB ISCHEMIA | In conclusion, our observations from this early clinical trial indicate that intramuscular treatment with high doses of P-MSCs is safe and well tolerated. Despite our encouraging results, we cannot claim that MSC treatment is beneficial and safe for patients with CLI. To fill this knowledge gap regarding the therapeutic properties of MSCs for critical limb ischemia, additional large randomized clinical trials are necessary. | PMC10324209 |
Acknowledgements | We deeply appreciate the efforts by Mahmood Bozorgmehr and Faezeh Maghsood for their assistance with data analysis. | PMC10324209 | ||
Author contributions | MH, ZSH | This article is a part of the Ph.D. thesis by ZSH at Shahid Beheshti University of Medical Sciences, Tehran, Iran. MS proposed the initial idea. MS designed and supervised the in vitro section, and MH supervised the clinical section of the study. ZSH designed and carried out all laboratory jobs and data analysis, and manuscript writing. ZSH, SHK, and MH took care of the patients and performed the follow-up checks. SHK, SSHN, and MV consulted in the study design. All authors read and approved the final manuscript. | PMC10324209 | |
Funding | This work was carried out under the grant of School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran, with the ID number of 61342 and ethical code of IRCT20210221050446N1. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. | PMC10324209 | ||
Availability of data and materials | All data generated or analyzed during this study are included in this published article. | PMC10324209 | ||
Declarations | PMC10324209 | |||
Ethics approval and consent to participate | CLI | CRITICAL LIMB ISCHEMIA | This project under the title “Safety assessment for transplantation of adaptive human placental mesenchymal stem cells in patients with Critical limb ischemia (CLI): clinical trial phase 1” was approved by Ethical Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.REC.1400.025) (Approval date: 12/12/2021, consent to participate date: 19/04/2022). Written informed consent was obtained from each patient or the patient’s legally authorized surrogate before the conduct of study-specific procedures. All procedures were conducted in accordance with the relevant approved regulations, guidelines, and the Declaration of Helsinki. The trial was registered as IRCT20210221050446N1 at the Iranian Registry of clinical trials. | PMC10324209 |
Consent for publication | Not relevant. | PMC10324209 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10324209 | ||
References | PMC10324209 | |||
Background | bullous disorder, pemphigoid | BULLOUS DISORDER, PEMPHIGOID | Edited by: Vinay Keshavamurthy, Post Graduate Institute of Medical Education and Research (PGIMER), IndiaReviewed by: Yuval Tal, Hadassah Medical Center, Israel; Daisuke Tsuruta, Osaka City University, JapanBullous pemphigoid (BP) is a common subepidermal bullous disorder that lacks adequate treatment alternatives. Dupilumab, an anti-interleukin (IL) 4 receptor α antibody blocking Th2 molecules IL-4 and 13, has been used off-label and shown to be effective in refractory BP cases. | PMC10399451 |
Methods | hyperpigmentation, eczematous lesion, pruritus, urticarial, various disease severities | HYPERPIGMENTATION, ERUPTIONS, REMISSION, URTICARIAL, DISEASE | BP patients with various disease severities and comorbidities were included in this case series. All patients received dupilumab alone or in combination with immunosuppressants in a real-world setting. Complete remission (CR) was defined as the absence of pruritus symptoms and previous BP eruptions, with only hyperpigmentation patches and without newly occurring lesions for at least 4 weeks. Disease relapse was classified as the appearance of three or more new lesions within 1 month or at least one large urticarial or eczematous lesion that did not resolve within a week. | PMC10399451 |
Findings | Pruritus, eosinophilia | PRURITUS, ERUPTIONS, EOSINOPHILIA | Ten individuals were enrolled in this case series. Pruritus symptoms and BP eruptions improved significantly in nine patients (90%). Seven patients (70%) attained CR, including all mild-to-moderate (100%) cases and three of six (50%) severe BP cases. At the dupilumab monotherapy stage, eosinophilia was observed in two severe cases. One patient out of seven (14.3%) relapsed after 1 year of follow-up after CR. | PMC10399451 |
Conclusion | Eosinophilia, mild-to-moderate disease | EOSINOPHILIA | Treatment of BP with diverse comorbidities with anti-IL-4 receptor α antibody provides further credentials to a prospective randomized study. More impressive efficacy and safety profiles were observed in patients with mild-to-moderate disease after 1 year of follow-up. Eosinophilia may occur in patients receiving dupilumab monotherapy. | PMC10399451 |
Introduction | autoimmune subepidermal bullous disorder, Dupilumab, atopic dermatitis, Bullous pemphigoid, pruritus, AD | BULLOUS PEMPHIGOID, ATOPIC DERMATITIS, PATHOGENESIS | Bullous pemphigoid (BP) is a common autoimmune subepidermal bullous disorder that primarily affects older people, with tense bullae and pruritus as its characteristic clinical manifestations (The importance of T helper 2 (Th2) cells and the Th2 molecule milieu in the pathogenesis of BP has been demonstrated. Dupilumab is an interleukin (IL)-4 receptor α antagonist that blocks both the IL-4 and IL-13 pathways and has demonstrated efficacy in atopic dermatitis (AD) treatment ( | PMC10399451 |
Methods | blisters, pruritus, ONFH, MP | INFILTRATION, OSTEONECROSIS OF THE FEMORAL HEAD, BULLOUS PEMPHIGOID, DISEASE, ADVERSE EFFECTS, BULLOUS PEMPHIGOID, DISEASE | Patients from the Department of Dermatology, Peking Union Medical College Hospital (PUMCH), were recruited in the case series. All patients were diagnosed with BP using at least three of the following methods: (i) hematoxylin and eosin staining demonstrating subepidermal blisters and eosinophil infiltration; (ii) direct immunofluorescence staining showing a linear deposition of IgG/IgM or complements at the basement membrane zone (BMZ); (iii) serum detection of IgG autoantibodies against BP180 (BPAG2) via an enzyme-linked immunosorbent assay; and (iv) indirect immunofluorescence showing circulating IgG antibodies binding to the BMZ. All patients in our case series have an average follow-up duration of more than 1 year.Patients who had taken medications (such as furosemide, spironolactone, amiodarone, gliptins, anti-PD-1, and anti-PD-L1) (We evaluated the clinical response and adverse effects of dupilumab in ten Chinese BP patients with varying comorbidities and severities. An initial dose of 600 mg was administered subcutaneously (SC), followed by 300 mg SC every 2 weeks in cases 2-9, and 300 mg every week in case 10 because of a serious disease condition. Owing to the severity of the disease and a more stable financial situation, the patient in case 1 initially received three doses of 600 mg preload dose every 2 weeks, followed by 300 mg every 2 weeks. Furthermore, nine of ten (90%) patients also received immunosuppressive therapy, such as a tapering course of methylprednisolone and Demographics of BP patients treated with dupilumab.BP, bullous pemphigoid; F, female; M, male; TwHF, Tripterygium wilfordii Hook F; MP, methylprednisolone; IVIG, intravenous immunoglobulin; ONFH, osteonecrosis of the femoral head; BPDAI, The Bullous Pemphigoid Disease Area Index (total maximum score of 372); BPDAI pruritus component (total maximum score of 30).*BPDAI cutoff values of 20–57 were used to define mild, moderate, and severe BP ( | PMC10399451 |
Results | itching, bullae, hypertension, erythema, herpes, reduction in skin lesion, eosinophilic leukemia, parasite infection, eosinophilia, pruritus, hyperkalemia, blisters, herpes zoster, coronary heart disease, skin lesions, allergic diseases | VIRUS, OEDEMA OF THE LOWER LIMBS, RECURRENCE, HYPERTENSION, DISEASE, ERYTHEMA, HERPES, KIDNEY INSUFFICIENCY, EOSINOPHILIC LEUKEMIA, EOSINOPHILIA, CARDIAC INSUFFICIENCY, ERUPTIONS, REMISSION, ADVERSE EVENT, HERPES ZOSTER, CORONARY HEART DISEASE, SKIN LESIONS |
Nine patients (90%) receiving dupilumab therapy showed notable improvements in their pruritus symptoms and BP eruptions. Seven patients (70% of the total) obtained CR. On average, it took 8.3 weeks (58 days) for seven patients to achieve CR. In our case series, 100% of mild-to-moderate cases attained CR. Of the severe BP patients (cases 1, 6, 7, 8, 9, and 10 in which BPDAI exceeded 57) (In case 1, the patient initially received three courses of a higher dose of 600 mg SC every 2 weeks, followed by 300 mg SC every 2 weeks. In the interim, 40 mg of TwHF was also administered. The fact that the daily dose of methylprednisolone in case 1 was 16 mg, which is far below the recommended prescribing regimen of 0.75–1 mg/kg for severe patients (Clinical presentation before and after therapy in case 1. Erythematous patches and tense bullae appear on the trunk, extremities, and hands before treatment A 98-year-old male patient with intolerable pruritus for at least 1 month presented to our department in case 6. He suffered from hypertension and coronary heart disease in an inferior general condition. BP symptoms improved after treatment with topical corticosteroids, minocycline, and niacinamide for 3 weeks. However, he swiftly developed new blisters and experienced intractable itching. Owing to contraindications with oral corticosteroids and extremely old age, dupilumab monotherapy was introduced. Prior to dupilumab administration, the eosinophil count and anti-BP180 antibody concentration were 5.9% and 16 U/ml, respectively. However, there were no laboratory results after treatment because he was unable to visit the hospital during the COVID-19 pandemic. We made contact via the PUMCH online communication system during the follow-up period. Two days after the first injection, his pruritus significantly improved, and he could fall asleep soundly. After five courses of dupilumab monotherapy, he reported CR and no new lesions. Overall, the patient received a total of seven courses of dupilumab monotherapy and was completely symptom free. During the 1-year follow-up period, there were no reports of disease flare-ups.In case 7, a younger patient initially received 40 mg of methylprednisolone per day, but more than 50 new blisters developed after 3 days of treatment, and he suffered from severe pruritus. The initial loading dose of 600 mg of dupilumab by injection was prescribed. He reported a significant improvement in previously identified skin lesions and pruritus symptoms the next day. Following two injections of dupilumab, he was nearly free of blisters and had smaller erythematous regions. Additionally, a substantial decrease in eosinophil counts was observed (from 20% before therapy to 0.1% after the first course of dupilumab). The patient reported no new blister formation and complete symptom alleviation after three injections of dupilumab. Anti-BP180 antibody titers decreased from over 150 U/L to 113 U/L after 12 weeks. Additionally, dupilumab markedly facilitated methylprednisolone tapering (from an initial dose of 40 mg/day to 10 mg/day in 6 months).Case 8 patient reported a reduction in the edema of the lower limbs and feet after the first injection of dupilumab. However, she continued to develop new blisters on the right upper extremity. The percentage of eosinophils significantly increased from 38.8% before treatment to 65.2% and 67.7% 1 and 2 weeks after the first injection, respectively. She experienced intense pruritus and impatience. We introduced the immunosuppressant TwHF at a dosage of 40 mg daily after two courses of dupilumab. Additionally, topical corticosteroids were applied to her newly formed blisters. The patient reported a marked reduction in skin lesion counts and pruritus after TwHF introduction. Additionally, eosinophil levels decreased to 31%. However, 2 days after the fourth injection of dupilumab, she described a relapse characterized by the appearance of new erythema on her face. A compound betamethasone injection (containing 7 mg of betamethasone) was prescribed. After 4 days of betamethasone injections, her skin lesions improved significantly, and her eosinophil count returned to normal levels. Until the present time, the patient has reported CR of skin lesions and pruritus with a normal eosinophil count. We did not rule out the roles of TwHF and betamethasone and classified the patient as being in partial remission even though the patient ultimately attained satisfactory results. During the 44 weeks of treatment with dupilumab plus TwHF and topical corticosteroid, we observed a significant decrease in total IgE (from 1,090 IU/ml after three injections to 33.9 IU/ml) and anti-BP180 (from 115 U/ml before dupilumab initiation to 20 U/ml). After 44 weeks of combination treatment, we chose to discontinue dupilumab. At her most recent clinic visit (six months subsequent to CR), she was still maintaining CR with 40 mg of TwHF daily. No recurrence of the disease was reported. It was noteworthy that the patient had herpes zoster 3 months previously, and treatment with dupilumab did not result in a recurrence of the herpes virus.Case 9 showed a modest improvement in pruritus and bullae after two courses of dupilumab. However, the eosinophil count was markedly increased to 38.7%, 37.6%, and 42.4% 3 days, 1 week, and 2 weeks after the first injection, respectively. We had to reinitiate conventional systemic immunosuppressive therapies. Intravenous methylprednisolone (40 mg daily) was administered 1 week after two injections of dupilumab. Four days later, she experienced a perceptible reduction in itching, and no new blisters appeared. We tapered methylprednisolone to 20 mg daily while prescribing 60 mg of TwHF daily. After three administrations of dupilumab, methylprednisolone dosage was reduced by 16 mg daily. However, the patient reported a relapse of BP four days after methylprednisolone tapering. She suffered intolerable pruritus and the rapid development of over 30 new lesions. The daily dose of methylprednisolone was increased to 32 mg so that she ultimately achieved disease control. While receiving anti-IL-4 receptor therapy, cardiac insufficiency, kidney insufficiency, and hyperkalemia did not worsen in this case. This patient was classified as having no improvement because disease control was achieved by increasing the dosage of conventional systemic immunosuppressive therapies. In cases 8 and 9, the eosinophil count was substantially elevated following dupilumab monotherapy. In both patients, parasite infection, allergic diseases, and eosinophilic leukemia were ruled out. We proposed that eosinophilia following the initiation of dupilumab could be an adverse event in both cases.Case 10 was referred to our dermatology department due to resistance to traditional BP treatment. We implemented a systemic combination therapy consisting of 300 mg of dupilumab SC every 2 weeks and 40 mg of TwHF daily. After 2 weeks of combination therapy, the patient reported a persistent increase in the number of bullae (In the case series, four mild-to-moderate patients (BPDAI not exceeding 57) ( | PMC10399451 |
Discussion and overview of literature | Eosinophilia, bullae, hypereosinophilia, inflammation, asthma, AD, MP | RECURRENCE, EOSINOPHILIA, BULLOUS PEMPHIGOID, PROLIFERATION, HYPEREOSINOPHILIA, DISEASE, DISEASE, INFLAMMATION, ADVERSE EVENT, BULLOUS PEMPHIGOID, ASTHMA, CHRONIC EOSINOPHILIC PNEUMONIA, REMISSION, SEPARATION, PATHOLOGY, PATHOGENESIS, COMPLICATIONS | BP, the most prevalent autoantibody-mediated cutaneous blistering disorder, is characterized by pruritic vesicles or bullae and primarily affects older people. Pathogenic B and T cells, autoantibodies, and inflammatory cytokines/chemokines are significant in the characteristic pathology of BP (The pathogenesis and emerging therapeutic strategies in bullous pemphigoid. The existence of IgG antibodies and the complement element C3, which attacks the BMZ, characterizes BP. Immune complex production triggers the activation of complement, which results in the migration of eosinophils, mast cells, and neutrophils, as well as the secretion of proteases and inflammatory markers, thereby inducing dermal-epidermal split. The pattern of distribution of the subsets of T cells is atypical. The Th2, Tfh, and Th17 groupings are elevated, whereas the Treg cell count is diminished. By means of the release of IL-17, aberrant Th17 cell types enhance the pro-inflammatory immune reaction, stimulate neutrophils, magnify the inflammatory process, and promote tissue injury. Th2 cells and Th2 cell-released IL-4 stimulates B cell growth, antibody synthesis, and class-switching of immunoglobulins. The improper functioning of Treg cells promotes the activation of autoreactive CD4+ T lymphocytes and the creation of autoantibodies. Enhanced Tfh proliferation facilitates the production of autoantibodies in BP by B cells. Possible targets range from CD20+ lymphocytes with rituximab to the Th2 axis with dupilumab, and omalizumab or the IL-17/IL-23 axis, as well as the inhibition of particular complement or inflammatory mediators.A potent inhibitor of Th2-related chemokines (such as CCL17, CCL18, CCL22, and CCL26) in AD patients, dupilumab, an IL-4 receptor antagonist blocking both IL-4 and IL-13 signaling pathways, significantly improves the molecular signature of AD and exhibits a satisfactory efficacy and safety profile (Our current case series indicates that anti-IL-4 receptor α therapy in combination with immunosuppressive medications is well tolerated even in older BP patients with severe cardiovascular, metabolic, endocrine, infectious, and renal complications or other poor general conditions. Moreover, all mild and moderate patients in our case series achieved CR, and no disease flare-up was noted during the 1-year follow-up period, pointing to excellent efficacy profiles and a low recurrence rate in mild-to-moderate patients receiving dupilumab combined with methylprednisolone and/or TwHF. In these patients, dupilumab therapy also greatly aided the tapering of immunosuppressive medication. In comparison with rituximab (average of 148 days to CR), seven patients in this case series experienced CR 58 days earlier on average, which suggests early effectiveness in dupilumab-treated individuals (When conventional treatments had not yet been prescribed, we discovered a substantial rise of eosinophil counts in two patients with severe BP receiving dupilumab monotherapy. Eosinophilia was documented as an adverse event in 52 patients (4.1%) who received dupilumab for asthma treatment, and 59 patients (9.0%) for AD and mainly were laboratory results without clinical symptoms (only 0.2% of patients receiving asthma treatment were associated with eosinophil-related severe clinical adverse results [aggravation of hypereosinophilia and chronic eosinophilic pneumonia]) (BP is currently a therapeutic challenge, as the validated treatments are corticosteroids and corticosteroid-sparing immunosuppressants, the efficacy of which is counterbalanced by their low safety profile with long-term use. The most recent findings on the pathogenesis of BP have provided an impetus for additional research aimed at identifying novel target treatments for refractory cases, with the intent of ensuring long-term effective and safe treatments for BP patients. Possible targets range from CD20+ lymphocytes with rituximab to the Th2 axis with dupilumab, and omalizumab or the IL-17/IL-23 axis, as well as the inhibition of particular complement or inflammatory mediators. The evidence of these new therapeutic targets and specific investigational compounds is shown in Novel Biologics in the treatment of BP.BP, bullous pemphigoid; IL, interleukin, Pred, prednisone; IVIG, intravenous immunoglobulin; TCS, topical corticosteroid; NA, not available; TwHF, Tripterygium wilfordii Hook F; MP, methylprednisolone; BPDAI, The Bullous Pemphigoid Disease Area Index; MMF, mycophenolate mofetil; AZA, azathioprine; MTX, methotrexine.Eosinophil accumulation and eosinophilic spongiosis are prevalent features of BP, and numerous published data support the essential pathogenic function of eosinophils in BP. In the presence of eosinophil-related cytokines and chemokines, IL-5-activated eosinophils migrate to the BMZ, resulting in derma-epidermal separation (Several lines of research point to an essential role of the IL-17/IL-23 pathway in the pathogenesis of BP. Increased concentrations of IL-17A+ lymphocytes with CD4 expression have been identified in the peripheral blood of patients with BP, and genes encoding the IL-17/23 pathways have been found to be amplified among individuals with BP (Preliminary evidence has demonstrated a prolonged period of remission, steroid-sparing activity, and a satisfactory safety record in patients with severe BP treated with rituximab. Moreover, the evidence supporting the use of omalizumab as an additional agent in the treatment of BP is accumulating. Omalizumab and rituximab are currently administered as additional therapeutic modalities in BP treatment (Limitations exist in this study. We cannot conclude the appropriate dosage and the interval of dupilumab for BP treatment because of the small sample size, short follow-up period, lack of a control group, single-center research, and a retrospective study design. Instead of dupilumab monotherapy, the majority of BP patients received immunosuppressive treatments concurrently. Further clinical trials are needed to deal with these unresolved issues.Our current case series on anti-IL-4 receptor α therapy in treating BP combined with immunosuppressants provides further credentials to a prospective randomized study. A deep understanding of Th2 inflammation and anti-Th2 therapy may yield the clinical development of better-targeted therapies in BP patients. | PMC10399451 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10399451 | ||
Ethics statement | This study was approved by the ethics committee of Peking Union Medical College Hospital (ethics document number: JS-3132). The patients/participants provided their written informed consent to participate in this study. | PMC10399451 | ||
Author contributions | DISEASE, BULLOUS PEMPHIGOID | S-HW wrote the manuscript with significant contributions from Y-GZ. S-ZL and YS assessed the Bullous Pemphigoid Disease Area Index. Y-GZ collected clinical pictures and revised the article critically. All authors contributed to the article and approved the submitted version. | PMC10399451 | |
Acknowledgments | PMC10399451 | |||
Conflict of interest | Y-GZ served as a speaker for Sanofi, but this was not associated with this study.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10399451 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10399451 | ||
References | PMC10399451 | |||
Supplementary Information | endometrial cancer | ENDOMETRIAL CANCER | Second-line treatment of endometrial cancer is an unmet medical need. Lurbinectedin showed promising antitumor activity in a phase I study in combination with doxorubicin in advanced endometrial cancer. This phase 2 Basket trial evaluated lurbinectedin 3.2 mg/mThe online version contains supplementary material available at 10.1007/s10637-023-01383-2. | PMC10560193 |
Keywords | PMC10560193 | |||
Introduction | cancer, endometrial cancer, TCGA, Endometrial cancer | CANCER, ENDOMETRIAL CANCER, ENDOMETRIAL CANCER | Endometrial cancer is the sixth most common cause of cancer in females with 417,000 cases every year [Lurbinectedin (ZEPZELCAThis report focuses on the outcomes of the endometrial cancer cohort. In addition, retrospective biomarker analysis based on TCGA and PromiSe molecular subtypes was explored. This cohort was evaluated because promising antitumor activity was previously found in a phase I study for a combination of doxorubicin plus lurbinectedin in patients with advanced endometrial cancer [ | PMC10560193 |
Methods | The study protocol was approved by the Independent Local Ethics Committee of each participating center and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulations for clinical trials. Signed informed consent was obtained from all patients prior to any study-specific procedure. Additionally, patients were invited to participate in a translational study designed to identify molecular predictors of response or resistance to lurbinectedin, through an independent informed consent. The trial is registered at | PMC10560193 | ||
Patient selection | Tumors, endometrial cancer | DISEASE, ENDOMETRIAL CANCER, ENDOMETRIAL CARCINOMA, TUMORS | Seventy-three patients with endometrial cancer were treated at 19 investigational sites in Belgium (n = 3), France (n = 17), Germany (n = 2), Spain (n = 23), Switzerland (n = 2), the United Kingdom (n = 9), and the USA (n = 17). Eligibility criteria included patients ≥ 18 years old with pathologically proven diagnosis of endometrial carcinoma; pretreated with one prior adjuvant/advanced chemotherapy-containing line (including platinum or not); measurable disease as per the Response Criteria in Solid Tumors (RECIST) v.1.1 [ | PMC10560193 |
Lurbinectedin treatment | All patients were treated with lurbinectedin 3.2 mg/m | PMC10560193 | ||
Efficacy and safety assessments | tumor, Toxicity, Cancer | ADVERSE EVENT, TUMOR, ADVERSE EVENTS, DISEASE, CANCER | The primary objective of this study was to assess the antitumor activity of lurbinectedin in terms of ORR, primary endpoint, assessed by the investigators. Radiological tumor evaluation was performed every six weeks (two cycles) until Cycle 6, and every nine weeks (three cycles) thereafter. Objective response was to be confirmed at least four weeks later. Secondary efficacy endpoints included disease control rate (ORR or stable disease), duration of response (DoR), progression-free survival (PFS), and OS.Safety was evaluated in all patients who received at least one lurbinectedin infusion, complete or incomplete, by assessment of adverse events (AEs), clinical laboratory test results, physical examinations and vital signs. Laboratory tests were done weekly during Cycles 1 and 2, and on Day 1 of subsequent cycles. AEs were recorded and coded with the Medical Dictionary for Regulatory Activities (MedDRA), v.21.0. AEs and laboratory values were graded according to the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), v. 4.0. All patients were followed until recovery from any lurbinectedin-related AE. | PMC10560193 |
Translational study | cancer, tumor, tumors | CANCER, TUMOR, TUMORS, PATHOGENESIS | Fifty of 73 treated patients (68.5%) had available archived formalin-fixed paraffin-embedded tumor samples and consented to participate in an optional translational study. In order to characterize patients’ tumors, a next generation sequencing (NGS) custom gene panel was performed, targeting 151 genes involved in cancer pathogenesis and DNA-repair (see Supplemental | PMC10560193 |
Statistical methods | REGRESSION, RECRUITMENT | Up to 50 evaluable patients were to be recruited to test the null hypothesis that 10% or less patients get a response (p ≤ 0.10) Initially, 15 patients were to be included in a first stage. If one confirmed response occurred in the first 15 evaluable patients, recruitment had to continue up to 25 evaluable patients. Two of the first 15 patients had confirmed partial response (PR) to lurbinectedin treatment and, therefore, recruitment continued. Due to the signs of activity also observed in combination with doxorubicin [Descriptive statistics were used. Non-continuous variables are described in frequency tables using counts and percentages. Continuous variables are described by median, minimum and maximum. Binomial exact estimates and its 95% confidence interval (CI) were calculated for the evaluation of the main endpoint (ORR). The Kaplan-Meier method was used to analyze DoR, PFS and OS. For the translational sub-study analysis, the correlation between mutational status and OS or PFS was evaluated by a Cox regression analysis and Kaplan-Meier curves represented. SAS and R software were used to generate statistical outputs. | PMC10560193 | |
Results | PMC10560193 | |||
Lurbinectedin treatment | neutropenia, leukopenia, febrile neutropenia, hematological toxicity, anemia | LEUKOPENIA, NEUTROPENIA, ANEMIA, FEBRILE NEUTROPENIA | A total of 378 cycles were administered to the 73 treated patients. The median number of cycles per patient was 4 (range, 1–22 cycles), with 31.5% of patients having received ≥ 6 cycles. The median relative dose intensity was 97.7% (range, 64.9–102.9%). Twenty patients had treatment-related dose delays, being hematological toxicity the most common reason: grade 2–4 neutropenia in 13 patients and grade 3 anemia in two patients. Lurbinectedin dose was reduced due to treatment-related reasons in 6.9% of cycles in 20 patients, being hematological toxicity the most common cause: grade 2-4 neutropenia in eight patients and eight cycles; grade 3/4 febrile neutropenia in two patients and two cycles; and grade 3 leukopenia in one patient and one cycle. Of note, the protocol stated that in case of grade 4 neutropenia, lurbinectedin dose had to be reduced instead of continuing at the same dose with granulocyte colony-stimulating factor (G-CSF) prophylaxis. | PMC10560193 |
Discussion | carcinosarcoma, endometrial cancer, tumor, endometrioid tumors, endometrial carcinoma | CARCINOSARCOMA, ENDOMETRIAL CANCER, TUMOR, ENDOMETRIAL CARCINOMA, ENDOMETRIOID TUMOR | This cohort from a phase 2 exploratory Basket study included 73 patients with pretreated endometrial cancer who received therapy with single-agent lurbinectedin. ORR according to RECIST v.1.1 was 11.3% (95%CI, 5.0–21.0%). Responses were mostly observed in patients with endometrioid tumors and the median of prior lines was one. These results (eight objective responses) were lower than the threshold of ≥ 10 confirmed responses established in the statistical hypothesis for this endometrial carcinoma cohort. However, although the cohort did not meet the planned hypothesis, hints of antitumor activity were observed, with two patients achieving complete response and six patients with partial responses in a quite heterogeneous cohort that included patients with different number of prior lines administered (up to four previous lines), different histology subtypes (e.g., carcinosarcoma, endometrial stromal sarcoma), and not characterized molecularly at study entry according to current guidelines [Studies in small cohorts of patients of lurbinectedin in combination with other drugs have shown to increase the single-agent activity in pretreated endometrial cancer. For instance, in combination with doxorubicin (ORR = 42% and median DoR = 7.5 months) [Retrospective tumor molecular and genomic profiling have shown different lurbinectedin response depending on the presence of mutations on particular genes, protein levels and specific molecular subtypes, with better PFS and OS in the Lurbinectedin administered at 3.2 mg/mIn conclusion, the current efficacy results suggest that antitumor activity of lurbinectedin could be improved in patients with pretreated endometrial cancer when administered in combination with other agents and in populations with previous molecular classification. Immunotherapy added to chemotherapy has shown promising results in the first-line treatment of endometrial cancer [ | PMC10560193 |
Acknowledgements | Cancer | CANCER | We gratefully acknowledge the patients, their families and the investigator teams. Vivek Subbiah is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center. Vivek Subbiah acknowledges support of The Jacquelyn A. Brady Fund. | PMC10560193 |
Author contributions | Pierre | Rebecca Kristeleit: Investigation, Resources, Writing – review & editing. Alexandra Leary: Investigation, Resources, Writing – review & editing. Jean Pierre Delord: Investigation, Resources, Writing – review & editing. Victor Moreno: Investigation, Resources, Writing – review & editing. Ana Oaknin: Investigation, Resources, Writing – review & editing. Daniel Castellano: Investigation, Resources, Writing – review & editing. Geoffrey I. Shapiro: Investigation, Resources, Writing – review & editing. Cristian Fernández: Conceptualization, Methodology, Writing – Original Draft, Writing – review & editing, Supervision. Carmen Kahatt: Conceptualization, Methodology, Writing – review & editing, Supervision. Vicente Alfaro: Methodology, Writing – Original Draft, Writing – review & editing. Mariano Siguero: Methodology, Formal analysis, Writing – review & editing. Ali Zeaiter: Methodology, Writing – review & editing, Supervision. Ahmad Awada: Investigation, Resources, Writing – review & editing. Anna Santaballa: Investigation, Resources, Writing – review & editing. Khalil Zaman: Investigation, Resources, Writing – review & editing. Jalid Sehouli: Investigation, Resources, Writing – review & editing. Vivek Subbiah: Conceptualization, Investigation, Resources, Writing – Original Draft, Writing – review & editing. | PMC10560193 | |
Funding | Anderson Cancer, Cancer | CANCER | The study was funded by Pharma Mar S.A, including partial funding by grants from the Centro para el Desarrollo Tecnológico Industrial (CDTI) during the conduct of the study (grant number IDI-20150006). VS is supported by a US National Institutes of Health (NIH) grant (no. R01CA242845 and R01CA273168); MD Anderson Cancer Center Department of Investigational Cancer Therapeutics is supported by the Cancer Prevention and Research Institute of Texas (no. RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (no. 1U01 CA180964), NCATS (Center for Clinical and Translational Sciences) Grant (no. UL1 TR000371), and the MD Anderson Cancer Center Support Grant (no. P30 CA016672). | PMC10560193 |
Data availability | Individual participant data are not publicly available since this requirement was not anticipated in the study protocol considering that this trial started patient enrolment in 2015. Clinical trial summary results were placed in the European Clinical Trials Database (EudraCT; | PMC10560193 | ||
Declarations | PMC10560193 | |||
Ethical approval | All procedures performed were in accordance with the ethical standards of the institutional and/or national research committees, and with the Declaration of Helsinki or comparable ethical standards. | PMC10560193 | ||
Informed consent | Written informed consent was obtained from all patients included in the study. | PMC10560193 | ||
Competing interests | Cancer | ONCOLOGY, EVENTS, CANCER, EMD | Alexandra Leary has grants or contracts from Agenus, Astra Zeneca, BMS, GSK, Iovance, MSD, OSE Immuno, Roche as principal investigator in clinical trials and from ARCAGY-GYENCO, AZ, Sanofi for translational research; has payment as invited speaker from Astra Zeneca, Clovis, GSK, Kephren publishing, Medscape; payment for consultancy from GLG and Orion, and payment for writing engagement from Onko+; has participation in Advisory Boards from Ability Pharma, Apmonia, Astra Zeneca, Blueprint, Clovis, GSK, Merck Serono, MSD, Tesaro and Zentaris; has participation in a steering committee from MSD; was IDMC member or chair for Clovis and Pfizer; and participated in an Academic Research Project for LX Repair and Owkin. Ana Oaknin has grants or contracts from Abbvie Deutschland Gmbh & Co Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, Astrazeneca AB, Beigene USA, Inc., Belgian Gynaecological Oncology Group (BGOG), Bristol‐Myers Squibb International Corporation (BMSM Clovis Oncology, Corcept Therapeutics, Eisai, F. Hoffmann‐La Roche, Grupo Español de Investigación en Cáncer de Ovario (GEICO), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Healthcare, Merck Sharp & dohme, Millennium Pharmaceuticals, Mundipharma Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem; has payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ESMO, Edizioni Minerva Medica SpA and Doctaforum Servicios S.L.; has support for attending meetings and/or travel from AstraZeneca; Clovis Oncology; PharmaMar, and Roche; and participation on a Data Safety Monitoring Board or Advisory Board from Agenus, AstraZeneca, Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann‐La Roche, GlaxoSmithKline, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs, and Sutro Biopharma, Inc., as well as participation to non‐remunerated activities and non‐remunerated leadership roles for GCIC and GEICO. Daniel Castellano have payment for Advisory Board or Expert Opinion from Pfizer, Roche, BMS, MSD, Astellas, Astra Zeneca, Novartis, Gilead, Ipsen, Pierre Fabre, Sanofi, Eisai, Janssen and GSK. Geoffrey. I. Shappiro has payment to Dana-Farber Cancer Institute from PharmaMar for conduct of the clinical trial; has sponsored research agreement with payment to DFCI from Merck KGaA/EMD-Serono, Merck & Co. and Lilly; has funding for investigator-initiated clinical trials to DFCI from Pfizer; consulting fees from XinThera, Inc.; has patent issued to Cyclacel Pharmaceuticals and Geoffrey I. Shapiro for dosage regimen for sapacitabine and seliciclib, and pending to Liam Cornell and Geoffrey I. Shapiro for compositions and methods for predicting response and resistance to CDK4/6 inhibition; and has participation on advisory boards for Pfizer, Eli Lilly, Merck KGaA/EMD-Serono, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Bayer, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalks, CytomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, and Janssen. Cristian Fernández, Carmen Kahatt, Vicente Alfaro, Mariano Siguero, Daniel Rueda and Ali Zeaiter have personal fees for salary as full time employee from PharmaMar S.A. Cristian Fernández, Carmen Kahatt, Vicente Alfaro, Daniel Rueda and Ali Zeaiter are stock ownership of PharmaMar S.A. Ahmad Awada has advisory role with Amgen, AstraZeneca, Bayer, Daiichi, EISAI, Genomic Health, Hengrui, Innate, Ipsen, Leo Pharma, Lilly, Merck, MSD, Novartis, Pfizer and Seattle Genetics; has speaker fees with Amgen, AstraZeneca, Bayer, Daiichi, EISAI, Genomic Health, Ipsen, Leo Pharma, Lilly, Merck, MSD, Novartis, Pfizer and Seattle Genetics; and has research grants to his Institute by BSM and Roche. Vivek Subbiah received grants from PharmaMar, Eli Lilly/LOXO Oncology, Blueprint Medicines Corporation, Turning PointTherapeutics and Boston Pharmaceuticals; and grants fromHelsinn Pharmaceuticals during the conduct of the study; in addition, Vivek Subbiah received a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study; research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, PharmaMar and Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Relay therapeutics, Roche and Medimmune; travel funds from PharmaMar, Incyte, ASCO, ESMO; and other support from Medscape, all outside the submitted work. The remaining authors made no disclosures. | PMC10560193 |
References | PMC10560193 | |||
Background | malaria | MALARIA | A better understanding of vector distribution and malaria transmission dynamics at a local scale is essential for implementing and evaluating effectiveness of vector control strategies. Through the data gathered in the framework of a cluster randomized controlled trial (CRT) evaluating the In2Care (Wageningen, Netherlands) Eave Tubes strategy, the distribution of the | PMC10288776 |
Methods | infection | MAY, INFECTION | From May 2017 to April 2019, adult mosquitoes were collected monthly using human landing catches (HLC) in twenty villages in Gbêkê region. Mosquito species wereidentified morphologically. Monthly entomological inoculation rates (EIR) were estimated by combining the HLC data with mosquito sporozoite infection rates measured in a subset of | PMC10288776 |
Results | Overall, | PMC10288776 | ||
Conclusion | malaria | MALARIA, DISEASE | These results demonstrate that the intensity of malaria transmission is extremely high in Gbêkê region, especially during the rainy season. The study highlights the risk factors of transmission that could negatively impact current interventions that target indoor control, as well as the urgent need for additional vector control tools to target the population of malaria vectors in Gbêkê region and reduce the burden of the disease. | PMC10288776 |
Keywords | PMC10288776 | |||
Background | diagnosisof, AIDS, malaria, Tuberculosis, deaths | MALARIA, AIDS, TUBERCULOSIS, MAY, MALARIA | Malaria is still a major public health problem in sub-Saharan Africa despite improvements in the diagnosisof the pathogens and large-scale deployment of vector control tools, such as long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS). According to the World Malaria Report 2021, a slight upward trend in malaria incidence was observed in 2020, after stagnation, between 2015 and 2019 [Today, the greatest burden of malaria occurs across in the World Health Organization (WHO) African region, with an estimated 228 million malaria cases and 602,000 malaria deaths [In Côte d’Ivoire, malaria transmission is perennial, albeit with a sharp increase during the wet season [Vector control by the national malaria control programme (NMCP) is based on sustaining high LLIN access and use, via universal coverage campaigns supplemented with continuous distribution from antenatal care campaigns and the expanded programme for immunization; targeted IRS in high transmission areas since 2020 and treatment. Since 2010, the NMCP, with the support of the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund), started scaling up mass distribution of LLINs to achieved universal coverage. Unfortunately, the large scale use of pyrethroid insecticides in public health as well as in agriculture has resulted in mosquitoes building up high resistance to the insecticide [In the Gbêkê region, central Côte d’Ivoire the In2Care (Wageningen, Netherlands) Eave Tubes, a new tool for the targeted delivery of insecticides against mosquitoes, attempting to enter houses through the eaves have been evaluated in a large-scale cluster randomized trial (CRT) between May 2017 and April 2019 [ | PMC10288776 |
Methods | PMC10288776 | |||
Study area and trial design | malaria | MALARIA | The study was carried out in the Gbêkê region in central Côte d’Ivoire. This region is characterized by wet savannah with a single annual rainy season (April to November) followed by a long dry season (December to March). There was an average annual rainfall of 1223 mm and an average temperature of 26.3 C during the study period. It is highly malaria endemic area with year-round transmission, and malaria cases are almost entirely attributable to The eave tube study design was a two-armed, cluster-randomized controlled trial with 20 villages (clusters) per arm. Villages in the control arm received universal coverage of LLINs, while the villages in the intervention arm received universal coverage of LLINs plus the screening plus eave tube (SET) intervention free of charge [ | PMC10288776 |
Mosquito sampling | MAY | Each month between May 2017 and April 2019, mosquitoes were sampled using human landing catches (HLC) both indoors and outdoors for one night at four randomly selected houses in the 20 study villages (Fig. A map of study area, showing sampling villagesMonthly rainfall and temperature data during the study period was obtained from the National Weather Service of Bouake airport. The data consist of monthly mean of the daily rainfall and temperature in the region. | PMC10288776 | |
Determining | A random subset of 59,901 captured | PMC10288776 | ||
Data analysis | Human landing catch captures were done monthly and then the data were pooled every two months for analysis. The human biting rate (HBR, the number of Anopheles vectors collected per person per night), the sporozoite rate (SR, the number of vectors positive for sporozoites over the number of vectors tested) and the entomological inoculation rate (EIR, is the number of infective bites per person per night). EIR was calculated by multiplying the HBR by the SR as described by Sternberg et alA separate rate was determinedfor HBR, SR and EIR for each species.Statistical analysis for the comparison of HBR, SRs and EIR between species, seasons (rainy/dry), year and collection positions (indoor/outdoor) were performed using R software version 4.1.2, and figures with GraphPad Prism 7 software.To assess the difference in HBR and EIR, a generalized linear mixed model (GLMM) fitting a negative binomial distribution was applied using the | PMC10288776 | ||
Results | PMC10288776 | |||
Species composition and vector distribution | malaria | MALARIA, MAY | A total of 157,645 mosquitoes belonging to four genera were collected over 4,880 sampling person-nights using HLC methods (Table Diversity and abundance of mosquito species from 20 villages in Gbêkê region from May 2017 to April 2019Overall, Entomological outcomes by season and collection location for SR: Sporozoite rate, EIR: mean entomological inoculation rate, [95% CI]: 95% Confidence intervalThe relative abundance and species composition of the malaria vectors varied from one village to another (Table Distribution of malaria vector and N. infected: Number infected; SR: Sporozoite rate; [95% CI]: 95% Confidence intervalA map of | PMC10288776 |
Dynamics of malaria transmission | PMC10288776 | |||
Seasonal abundance and biting patterns of Anopheles mosquitoes | malaria | MALARIA | The monthly abundance of human-biting Monthly abundances of human-biting Anopheles species in Gbêkê regionDuring the sampling period, more vectors (of the Mean density of Abundance of malaria vectors varied from one year to the other (Table Entomological outcomes for [95% CI]: 95% Confidence intervalHourly catches of Anopheles vector at different hours of the night in Gbêkê region | PMC10288776 |
Parity and sporozoite infection rate | We dissected 71,951 Anopheles for determination of parous rate. Overall, A total of 14,490 When considering the collection years, the sporozoite rate of | PMC10288776 | ||
Entomological inoculation rate (EIR) | malaria | MALARIA | In Gbêkê region, malaria transmission occurred all year long (Fig. Monthly variation of entomological inoculation rate for Anopheles species from may 2017 to april 2019 | PMC10288776 |
Discussion | malaria | MALARIA | This study was conducted to characterize The study of malaria transmission revealed that three common African This study demonstrated that the malaria vector species and abundance and malaria transmission intensity in the Gbêkê region varied significantly according to the season. High risk of malaria transmission was recorded in Gbêkê region probably due to the presence of several vectors harbouring the Hourly mosquito captures showed that malaria vector populations began host searching at around 06:00 pm –07:00 pm, peaked at 00:00 am–03:00 am and then declined to negligible levels by 06:00 am–07:00 am. The biting time does not indicate a shift in host seeking towards dusk or dawn when people are unprotected by their bed netsThis study has allowed a better understanding of malaria transmission dynamics and vector biting behaviour in Gbêkê region following the universal coverage of LLINs. The study highlights the risk factors of transmission that could negatively impact current interventions that target indoor control. Considering an aim of malaria elimination in Côte d’Ivoire and particulary in the Gbêkê region, it is increasingly urgent to research and develop novel vector control tools or complementary strategies particularly designed to suppress its very large malaria vector populations and the behaviour of vector populations. | PMC10288776 |
Conclusions | MALARIA | Malaria transmission in the Gbêkê area was mainly due to | PMC10288776 | |
Acknowledgements | We thank all participants of the study, especially technicians at the VCPEC-IPR for their technical assistance. We are also, grateful to the villagers of all sites for their kind collaboration. | PMC10288776 | ||
Author contributions | RN, AAK, EDS, MBT, JC and LPAA conceived and designed the study. LPAA, RZW, EDS, IZT, WAO, FHAY and SC participated in the data collection, laboratory and data management work. RN, AAK, EDS and LPAA supervised the study. SC and LPAA analysed the data. SC and AAK wrote the manuscript. All authors revised the manuscript. All authors read and approved the final manuscript. | PMC10288776 | ||
Funding | This study was made possible by the support of the Pennsylvania State University from the Bill & Melinda Gates Foundation (OPP1131603). | PMC10288776 | ||
Availability of data and materials | The datasets used and/or analysed during the current study are available At Intitut Pierre Richet/Institut national de santé Publique and will be made available on reasonable request. | PMC10288776 | ||
Declarations | PMC10288776 | |||
Ethics approval and consent to participate | malaria, yellow fever | MALARIA, YELLOW FEVER | The trial was reviewed and approved by the Côte d’Ivoire Ministry of Health ethics committee (039/MSLS/CNER-dkn). We also obtained written and verbal informed consent from all trial participants. Mosquito collectors were immunized against yellow fever and medical supervision was provided during the trial. Confirmed malaria cases were treated free of charge for illness according to national policies. | PMC10288776 |
Consent for publication | Not applicable. | PMC10288776 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10288776 | ||
References | PMC10288776 | |||
Subject terms | The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for | PMC10673712 | ||
Introduction | ovarian cancer, HRD | OVARIAN CANCER | Homologous recombination deficiency (HRD) associated with inactivation of mainly PARPi have been extensively tested in patients with ovarian cancer. Six phase III clinical trials have demonstrated that maintenance with a PARPi, with or without bevacizumab (bev), following platinum-based therapy in patients with newly diagnosed advanced ovarian cancer (AOC) improved progression-free survival (PFS) for BRCAmut and for BRCAwt HRD cases [The European HRD ENGOT initiative (EHEI) is a unique collaboration of European academic laboratories aiming to provide new reliable biomarkers for HRD in AOC to select patients who benefit from PARPi ± bev in the first-line maintenance [ | PMC10673712 |
Kaplan–Meier Estimates of Progression-free Survival and Overall survival according to ShallowHRDv2 or Mychoicetest in PAOLA-1 trial. | tumors, scars | TUMORS | Kaplan–Meier estimates of (Importantly, The main advantage of detecting HRD by genomic scars is to identify tumors deficient for HRR pathway in the absence of | PMC10673712 |
Discussion | tumor, HRD | TUMOR | Assessment of HRD status is mandatory to balance benefit and risks of PARPi maintenance in newly diagnosed AOC patients. We report here clinical validation of Analysis of the discordant cases between The clinical value of HRD testing may not be restricted to the question of ola in AOC. Contrary to ola, which has not been authorized in first line for HRP cases (alone or in combination with bev), niraparib has obtained an “all-comers” approval. However, the subgroup analysis of the PRIMA trial showed a smaller magnitude of benefit with niraparib in the HRP subgroup, as determined by MyChoice (HR: 0.68 versus 0.40 in HRP and HRD, respectively, with median PFS of 8.1 and 5.4 months with or without niraparib in the HRP subgroup, respectively), limiting the clinical benefit for patients in this situation [Other teams also participated in the EHEI and the new tests detecting HRD have been validated on tumor samples from the PAOLA-1 trial [In conclusion, academic decentralized | PMC10673712 |
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