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ETHICS APPROVAL | ONCOLOGY | All procedures were approved by the University of North Carolina at Chapel Hill Oncology Protocol Review Committee (LCCC1707) and Institutional Review Board (#16‐3409) and performed in accordance with ethical standards of the 1964 Helsinki Declaration and its later amendments. | PMC10469755 | |
CLINICALTRIALS.GOV IDENTIFIER | NCT03569605. | PMC10469755 | ||
ACKNOWLEDGMENTS | cancer | CANCER, RECRUITMENT | We are grateful for the valuable contributions of study team members, including Dr. Donald Rosenstein, Dr. Kristen Polzien, Dr. Lindsey Camp, Karen Hatley, Erin Coffman, and Susanna Choi. We thank Dr. Eliza Park, Dr. Andrew Smitherman, Lauren Lux, Dr. Allison Lazard, and community‐based organizations that helped with study recruitment. We gratefully acknowledge the young adult cancer survivors who participated in the study. | PMC10469755 |
DATA AVAILABILITY STATEMENT | The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions. | PMC10469755 | ||
REFERENCES | PMC10469755 | |||
Background | diphtheria, tetanus, poliomyelitis | DIPHTHERIA, TETANUS, POLIOMYELITIS, PERTUSSIS | Vaccination schedules differ from country to country. In France, the diphtheria, tetanus, pertussis, poliomyelitis (dTcaP) booster vaccine coverage for adults aged 25 has been lower than those recommended. We evaluated the impact of an awareness campaign undertaken by the French national health insurance system in 2021. | PMC10463893 |
Methods | A randomized, controlled study with adults residing in the Ardennes region was conducted to evaluate the effect on vaccine coverage of the booster vaccine reminder campaign carried out via letter and/or email and/or SMS. The randomization unit was the municipal administrative area (canton). Ten cantons were grouped into the intervention group (INT) and nine were the control group (CON). Outcomes were the booster vaccine delivery and the consultation of a general practitioner (GP) within 12 months (since the French national health insurance running the campaign suggested patients to consult their GP). | PMC10463893 | ||
Results | A total of 1,975 adults were included (INT: 67.3% vs. CON: 32.7%). Of them, 331 received a booster vaccine (INT: 17.4% vs. CON: 15.5%; p = 0.29), and 1,442 consulted a GP (INT: 73.7% vs. CON: 76.8%; p = 0.14). Those who consulted a GP had more frequent vaccine delivery (INT: 19.1% vs. CON: 10.5%; p < 0.0001). | PMC10463893 | ||
Conclusions | This study found that the awareness campaign run by the French national health insurance did not improve the uptake of the dTcaP booster and that there was a low rate of vaccinated adults aged 25 years. A GP consultation was associated with dTcaP booster vaccine delivery which may show that there is a need of involving GPs in vaccination follow-ups. Patients recognize GPs as providers of credible information and they may play a key role in individualized preventive healthcare actions. Systematic consultations with GPs for follow-up could be proposed to insured adults aged 25 years in the future. | PMC10463893 | ||
Keywords | PMC10463893 | |||
Background | diphtheria, tetanus, poliomyelitis | DIPHTHERIA, PERTUSSIS, TETANUS, POLIOMYELITIS, INFLUENZA | Vaccination schedules differ from country to country and are followed according to local recommendations. According to literature, the best scheduling model in Europe for the diphtheria, tetanus, pertussis and poliomyelitis (DTPP) vaccination in children as well as the influenza vaccination for people over 65 years is still unestablished [The initial vaccination in the DTPP schedule is mandatory with two injections of the diphtheria, tetanus, pertussis, poliomyelitis vaccine for children (DTCaP) at two and four months of age followed by boosters at 11 months and six years. A booster dose of the vaccine for adults (dTcaP) is then recommended for people aged 12, 25, 45 and 65 years old followed by a dose every 10 years thereafter. This scheduling is displayed in the health notebook that is systematically distributed to the parents of every child born in France. To date, long-term vaccination proposal campaigns do not exist, and vaccination uptake is based on the medical relationship between practitioners and patients. Moreover, vaccines must be prescribed by a medical practitioner and are reimbursed at 65% by the health insurance.The public health policy in France sets to achieve at least 95% vaccination recommendation coverage (all vaccines except for influenza) at the appropriate ages [The effectiveness of awareness campaigns for adults is often questionable and presents a public health concern. In a systematic review, vaccination reminders and follow-up interventions via telephone call, email, letter or SMS for people in different age groups and countries found increased vaccination coverage by an average of 8% [ | PMC10463893 |
Methods | PMC10463893 | |||
Study design | A prospective, randomized, controlled study was conducted in the Ardennes region in 2021. Participants included were those aged 25 years in 2020, residing in the region in June 2021 and who had not had a dTcaP booster vaccine dispensed from a pharmacy between January 1, 2019 and June 1, 2021. Those that were not affiliated with the general French health insurance system were excluded. | PMC10463893 | ||
Study variables | The randomization unit was a municipal administrative area known as the canton. Among the 19 cantons in the Ardennes region, participants were pooled out of 10 cantons that were randomly selected to constitute the intervention group (INT) and of nine cantons that made up the control group (CON). The choice of the canton as the randomization unit made it possible to limit contamination bias.Participants (aged 25 in 2020) in the INT group received information regarding the dTcaP booster vaccine (Fig.
Information of the awareness campaign for the dTcaP booster vaccine disseminated by the French national health insurance to French adults aged 25 years (intervention group) residing in the Ardennes region on June 1, 2021 | PMC10463893 | ||
Data collection | Data was collected on the dispensing of the dTcaP booster vaccine by pharmacies and pro-pharmacies within 12 months that the information by the CPAM had been disseminated. Outcomes included the dTcaP booster vaccine delivery (which was assessed using the Club Inter Pharmaceutic (CIP) codes corresponding to the vaccine in the CPAM database) and a consultation with a GP at least once within 12 months after the start of the awareness campaign for those who had already received the dTcaP booster vaccine. A GP consultation was an endpoint because the French national health insurance running the awareness campaign suggested that patients consult with their GP. | PMC10463893 | ||
Ethical considerations | MAY | Data processing was carried out in compliance with the French regulations, in particular the General Data Protection Regulation (GDPR) 2016/679 of the European Parliament and the Council of April 27, 2016 applicable since May 25, 2018 as well as the Data Protection Act of January 6, 1978 (amended in 2018). Participants’ non-opposition to the use of their data was collected. The study was registered in the public directory of the Health Data Hub (No. F20210521141129) and was approved by the Ethics Committee of the | PMC10463893 | |
Statistical analysis | Data were described using numbers and percentages (%). The analysis of the outcomes consisted of a comparison between the percentage of dTcaP booster vaccine delivery and the percentage of GP visits in both the INT and CON groups using Chi-square tests. The significance level was set at 0.05. Statistical analysis was performed using SAS software (Version 9.4, SAS Inc., Cary, NC, USA). | PMC10463893 | ||
Results | Among the 2,653 adults included in this study, a total of 678 (25.6%) received a dTcaP booster vaccine from a pharmacy or pro-pharmacy in 2021. The remaining 1,975 eligible adults were identified by the local CPAM Pole (INT: 67.3% vs. CON: 32.7%) (Fig.
Study flow chart. *municipal administrative areas, CPAM; The dTcaP booster vaccine delivery between June 2021 and June 2022 occurred for 331 (16.7%) adults and no significant difference concerning the rate of vaccination was found between the two groups (INT: 17.4% vs. CON: 15.5%; p = 0.29) (Table
Outcomes of an awareness campaign initiated by the French national health insurance for the dTcaP booster vaccine for adults aged 25 years in the 19 cantons of the Ardennes region*Ten cantons were randomly selected to constitute the intervention group (INT) and nine cantons made up the control group (CON). †at least once within 12 months after the start of the awareness campaign. CPAM; | PMC10463893 | ||
Discussion | This study found that the awareness campaign run by the CPAM did not improve the uptake of the dTcaP booster for adults aged 25 years. These findings may be inconsistent with existing literature on the effectiveness of patient reminders for vaccinations [Since this study was conducted in 2021, the effects of the COVID-19 pandemic may have limited the uptake of the dTcaP booster vaccine and corresponds with Rachlin et al., that found a 3% decrease for routine practices of other vaccinations in 2021 [As a health insurer, the CPAM is not entirely recognized among the French population for its preventive approaches, therefore, the awareness campaign may not have corresponded to the expectations of the participants. Some participants may not have paid sufficient attention to the information disseminated in the awareness campaign. In 2020, Plichon et al. studied the impact of the framing of a message and the arguments presented to explain changes in attitude towards vaccinations, intention to be vaccinated or to recommend a vaccination to relatives [The rate of vaccinated adults during the study period was low (16.7%). Over the last few years, vaccine hesitancy associated with negative feelings about the safety of vaccines has developed in France. According to Larson et al., in 2016 among 67 countries, 45.2% of the French population were skeptical about vaccine safety [Consultations with a GP was significantly associated with the uptake of the dTcaP booster vaccine. Patients recognize GPs as providers of credible information and they play a key role in individualized preventive healthcare actions, in which their influence on the acceptance of vaccines in children has already been shown [Regarding the strengths and limitations of this study, the originality of testing the impact of an awareness campaign on a large population via a randomized methodology posed a strength. However, we did not directly question the participants to identify the reasons why participants did not have the booster vaccine in the follow-up. For the INT group, we were unable to ascertain if information from the CPAM campaign was actually received and read, nor to assess their satisfaction with its content. The absence of an individual data collection on participants’ follow-up and healthcare pathways also did not allow us to take into consideration any possible confounding factors such as the professional setting (where some may have received a vaccination through an occupational medicine specialist), or to identify a routine follow-up provided by the GP. | PMC10463893 | ||
Conclusions | Vaccination coverage of the dTcaP booster vaccine for 25-year-olds was low in the Ardennes region in France in 2021 and the awareness campaign run by the CPAM did not improve vaccine uptake. A GP consultation was associated with dTcaP booster vaccine delivery which may show that there is a need of involving GPs in vaccination follow-ups. Systematic consultations with GPs for follow-ups could be proposed to insured adults aged 25 years in the future. | PMC10463893 | ||
Acknowledgements | The authors would like to thank Sarina Yaghobian and Marty Brucato from AcaciaTools for their reviewing and proofreading services. | PMC10463893 | ||
Authors’ contributions | CC, AH, BV, and AB participated in the design and helped interpret the results of the study as well as co-authored the article. AH, B-NP and SS participated in interpreting the results and contributed to the article’s writing. MC conducted the data collection, participated in the interpretation of the results, and co-authored the article. CB participated in the study’s design, supervised the study’s conduct, performed the statistical analysis of the data, participated in the interpretation of the results, and participated in the writing of the article. | PMC10463893 | ||
Funding | None. | PMC10463893 | ||
Data availability | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10463893 | ||
Declarations | PMC10463893 | |||
Ethics approval and consent to participate | The study was conducted according to the Declaration of Helsinki guidelines and was approved by the Ethics Committee of | PMC10463893 | ||
Consent for publication | Not applicable. | PMC10463893 | ||
Competing interests | The authors declare no competing interests. | PMC10463893 | ||
References | PMC10463893 | |||
Subject terms | toxicities, cancer | ADVERSE EVENTS, CANCER, ADVERSE EVENT, SOLID TUMORS | This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/mThe majority of cancer patients do not respond to single agent immune checkpoint blockade and several combinatorial approaches have now been tested. Here the authors report the results of a phase I dose escalation trial of nivolumab (anti-PD1) in combination with IFN-γ in patients with advanced solid tumors. | PMC10374608 |
Introduction | osteopetrosis, death, cancers | CANCERS, CHRONIC GRANULOMATOUS DISEASE, SOLID TUMORS, OSTEOPETROSIS, DISEASES | Systemic immune checkpoint blockade (ICB) with drugs targeting the programmed death one (PD-1) pathway has revolutionized oncology. ICB offers the potential for some patients to experience durable anti-tumor responses; however, the majority of patients do not respond to single-agent ICBCytokines have been used for decades as anti-cancer therapeutics with mixed success. Interferon-gamma (IFN-γ) is the only type II interferon and is FDA-approved for the treatment of two rare pediatric diseases, osteopetrosis and chronic granulomatous disease. In the 1980s-90s it was evaluated as a single agent for use against a variety of different cancers and demonstrated limited activityHere we report the results of a phase I dose escalation trial of the combination of IFN-γ and the anti-PD-1 targeted mAb nivolumab in patients with advanced solid tumors (NCT02614456). The trial establishes a recommended phase two dose of IFN-γ at 50 mcg/m | PMC10374608 |
Results | PMC10374608 | |||
Evaluable patients | Of the 26 patients accrued, all were evaluable for the primary safety analysis, and 23 were evaluable for exploratory efficacy analysis. Three patients in the 25 mcg/m | PMC10374608 | ||
Safety | All-grade, TNBC, DLTs, arthralgias | ADVERSE EVENTS, ADVERSE EVENT | Adverse events are summarized in Table All-grade adverse events occurring in >2 patientsAll grade adverse events occurring in > 2 patients attributed as at least possibly related to either drug and stratified by dose level and grade (* denotes dose limiting toxicity).There were three DLTs on the trial, one in the 75 mcg/mTwo AEs of interest occurred during the trial. In the 50 mcg/mWe also looked at irAEs that would be normally associated with treatment with nivolumab; however, there were no grade ≥ 3 irAEs and no patients received steroids for management of any irAE. The only AE of any grade attributable as an irAE occurred in one patient. This was a patient with TNBC who experienced a complete response (CR) on trial and completed the 3 months of IFN-γ and the entire year of nivolumab. While on nivolumab alone, the patient experienced grade 2 arthralgias that started three months after completing IFN-γ. This was managed with anti-inflammatory supportive medications initially, later maintained on a tricyclic antidepressant. | PMC10374608 |
Efficacy | Twenty-three patients were evaluable for post-hoc exploratory efficacy analysis (Fig. | PMC10374608 | ||
Tumor biopsy analysis | tumor | SECONDARY, TUMOR | Planned secondary analyses of baseline tumor biopsies were compared to on-treatment biopsies collected after IFN-γ induction but prior to the administration of nivolumab. Of 21 patients with biopsy specimens evaluable for comparison of PD-L1 expression, TPS was >1% at baseline in 52% of patients (Supplementary Table | PMC10374608 |
Peripheral blood flow cytometry | As pre-specified we performed exploratory immune phenotyping of peripheral blood by multi-parametric flow cytometry to quantify subsets of monocytes and T cells, as well as their expression of various biomarkers. Across all four cohorts, while the frequency of classical monocytes remained relatively unchanged throughout the course of treatment (Fig. | PMC10374608 | ||
Impacts of IFN-γ and PD-1 blockade on monocytes. | Counts of (Several treatment-related changes were also observed in the peripheral T-cell populations. First, patients with longer duration of therapy tended to have higher numbers of CD4 | PMC10374608 | ||
Cytokine analysis | In an exploratory post-hoc analysis performed to assess the relative paucity of irAEs, we noted a statistically significant increase in plasma concentrations of six chemokines from baseline compared to both C1D1 and C2D15. These included known IFN-γ inducible chemokines CXCL9, CXCL10, and CXCL11 (Fig. | PMC10374608 | ||
Changes in IFNγ-associated chemokines after induction and addition of nivolumab. | Box plots displaying distribution of chemokine concentrations at three time points on study: baseline, C1D1, C2D15. | PMC10374608 | ||
Discussion | ascites, cancers, pleural effusion, DLTs, tumor, pleural or peritoneal disease, pleural disease, TNBC, RCC, esophagogastric carcinoma, tumors | PLEURAL EFFUSION, ASCITES, CANCERS, OVARIAN CANCER, TUMOR, PROLIFERATION, DISEASE, PLEURAL DISEASE, SOLID TUMOR, EFFUSIONS, PLEURAL EFFUSIONS, EVENTS, TUMORS, RCC | IFN-γ signaling plays an integral role in regulating immune activation and senescence in the TME, induces the expression of PD-L1 and is an essential component of an effective anti-tumor response with PD-1 pathway targeted agentsOverall, the combination was well tolerated. An increased burden of flu-like symptoms was present in most patients, slightly worse at higher doses of IFN-γ, but were generally grade 1-2 and tolerable with supportive care. We did see an unexpected number of patients develop new ascites or pleural effusions, but it is unclear whether this is attributable to IFN-γ. Prior trials of single-agent IFN-γ have not previously reported such a concern. The majority of patients who developed new fluid collections had cancers associated with ascites (i.e., ovarian cancer), or had baseline pleural or peritoneal disease that may have foreshadowed this possibility. One patient developed a pleural effusion after IFN-γ induction without baseline pleural disease that improved upon subsequent anti-cancer therapy without positive fluid cytology. Further trials that involve IFN-γ should consider incorporating planned prospective fluid analysis in patients that develop new ascites or effusions.Exploratory analyses of efficacy in this trial were modest, with one patient with metastatic TNBC and no prior immunotherapy exposure achieving a durable CR. Although two patients achieved stable disease despite progression on prior ICB, the sample size is too small to make any conclusions. One clear limitation of this trial is the heterogeneous population, with multiple diagnoses that have subsequently demonstrated poorly immunogenic tumors or modest single agent benefit from PD-1 targeted drugs, thus potentially hampering any benefit from IFN-γ. Additionally, the four dose cohorts are small, limiting efforts to assess differences in IFN-γ dose ranges, although more patients with clinical benefit were treated in the two lower dosed cohorts. Based on a combination of increased low-grade AEs and DLTs starting at 75 mcg/mNotably, in an exploratory post-hoc observation, there appeared to be a paucity of irAEs amongst patients in this study. The relative incidence of grade ≥ 3 irAE development with nivolumab is about 10-15%. With 26 treated patients, we would have predicted 3-4 events, and yet only one patient developed any manifestations attributable as an irAE, and this only after discontinuing IFN-γ. Several factors may have contributed to this, for example 46.2% patients had received prior ICB without any irAEs and thus may have been less likely to develop an irAE. Additionally, 16 of 23 patients evaluable for efficacy (69.6%) progressed within the first 100 days of therapy, and simply may not have been exposed long enough to nivolumab. It is also possible this was merely by chance. However, it is reasonable to speculate whether the IFN-γ may have altered the immune milieu in such a way to restrain irAE development. Support for this hypothesis exists with the results of the post-hoc exploratory cytokine analysis, which showed a statistically significant increase in CXCL9, CXCL10, and CXCL11. These three chemokines are known to be directly induced by IFN-γ signaling and bind to a common receptor (CXCR3). Primarily, they are responsible for regulating immune cell migration, differentiation, and activation and thus are important regulators of immune responses in the TME; however, they have also been implicated in promoting tumor proliferation and metastasesA number of notable findings were revealed in pre-planned exploratory PBMC flow cytometry studies and biopsy tissue assessments. IFN-γ induction significantly increased the frequency of intermediate monocytes (CD14Additionally, patients with the lowest frequency of circulating CD4There were several limitations to this trial that may have impacted the results. The heterogeneous population and small cohort sizes limits comparisons of efficacy and correlatives and dose comparisons. Future trials of larger cohorts in specific cancers, such as RCC, TNBC, or esophagogastric carcinoma, might allow for better assessment of efficacy and a better understanding of the impacts of IFN-γ at the TME in these tumors. The choice of subcutaneous every other day administration may not have been optimal and may have limited the impact of IFN-γ on the TME and ultimately on efficacy. Lastly, advances and standardization in PD-L1 testing that were not available when this study was designed and conducted may have affected the analytic yield.In summary, the combination of IFN-γ and nivolumab in previously treated advanced solid tumor patients was safe and based on clinical and correlative findings we recommend 50 mcg/m | PMC10374608 |
Methods | PMC10374608 | |||
Study design | tumor, DLTs, toxicity, toxicities, Chase Cancer | FOX, TUMOR, DISEASE PROGRESSION | The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki and was approved by the Fox Chase Cancer Center (FCCC) Institutional Review Board. This was a single-center, investigator-initiated phase I trial. The study was pre-registered at clinicaltrials.gov and first posted November 25, 2015 (Patients in each cohort were assessed for dose-limiting toxicities (DLTs) as specified in the protocol (provided in the supplementary material) over the first six weeks of the combination phase, not including the one-week IFN-γ induction since that time period would not have reflected DLTs from the combination. If two or more DLTs occurred in any cohort, that dose of IFN-γ would be deemed intolerable and the prior completed dose would be considered the maximum tolerated dose (MTD). Patients that were not evaluable for DLT because they went off trial for disease progression or withdraw of consent without receiving 75% of IFN-γ doses were replaced, but were included in overall safety analysis. Based on a complete assessment of toxicity, as well as correlative factors, the study team had authority to denote the MTD as the recommended phase two dose (RP2D), or if warranted for safety and/or scientific reasons, a lower dose could also be chosen as the RP2D.Patients were seen every two weeks once they entered the combination phase, then every three weeks during the single agent phase. RECIST version 1.1 was used to assess objective tumor response, with assessments performed after the combination phase and then every 9 weeksAll patients provided written informed consent and were not compensated for study participation. The first patient was enrolled 12/29/2015 and the last patients was enrolled 2/12/2018. A steering committee consisting of select study investigators and staff met after each dose cohort to review safety data and decide whether to proceed to the next dose, and the study conduct was also reviewed regularly by an independent FCCC data safety monitoring board. The study was conducted at and sponsored by Fox Chase Cancer Center and all data was evaluated independently. Funding for study conduct and IFN-γ administration was provided by Horizon Pharma, LLC. The original design included plans for expansion cohorts to assess preliminary efficacy as measured by response rate in specific cancers of interest; however, the funding organization elected to halt further trial conduct after the Phase I portion. The original plan can be found in the full protocol in the supplement, but no changes to analysis or design of the phase I portion were made. | PMC10374608 |
Study population | DISEASE | Eligible patients were ≥ 18 years of age, and could have any metastatic solid tumor type where there was demonstrated evidence of potential efficacy to anti-PD-1 pathway targeted therapy at the time of study design. All genders were eligible and patients self-reported. All patients needed to have received at least one prior systemic anti-cancer therapy; prior ICB was allowed, as long as the reason for discontinuation was not an irAE. A site of disease amenable to a fresh biopsy was required for inclusion. A two-week washout period for previous systemic therapy was required, and patients could not have a prior history or concomitant autoimmune condition. | PMC10374608 | |
Study objectives | tumor, esophagogastric carcinoma | SECONDARY, TUMOR, METASTATIC CANCER | The primary endpoint of the study was the safety of the combination and to establish a RP2D. A final RP2D was to be established by the study steering committee at the conclusion of all accrued dose cohorts. Initial secondary efficacy endpoints included PFS, OS (median and at 1 year), and ORR for patients in the planned expansion cohorts of esophagogastric carcinoma and in patients with metastatic cancers refractory to prior PD-1 targeted treatment. We also planned to investigate the relationship between PD-L1 expression on tumor cells and on immune cells in the tumor microenvironment before and after treatment initiation. The expansion cohorts were not pursued due to perceived limited efficacy by the funding body, and a decision was made to perform exploratory post-hoc analyses to evaluate efficacy in the dose escalation patients. Pre-planned exploratory objectives included investigating changes in PD-L1 expression in tumor biopsy samples and in peripheral blood in relation to response, as well as the effect of IFN-γ administration on changes in known IFN-γ markers. Post-hoc, we elected to perform an exploratory cytokine analysis from plasma at various time points to associate with incidence of irAEs. | PMC10374608 |
Pre-specified exploratory correlative assessments | tumor, Tumor | PATHOLOGY, TUMOR, INFILTRATION, TUMOR | All patients were required to undergo a baseline tumor biopsy within 28 days prior to starting trial treatment, and then underwent a second tumor biopsy of the same site after the IFN-γ induction phase but before receiving nivolumab. Tumor specimens were to be evaluated by immunohistochemistry for PD-L1 expression and immune cell infiltration as pre-planned exploratory analysis. Biopsy samples underwent routine pathology review to determine cellularity and tumor presence via hematoxylin and eosin stain. PD-L1 expression was determined via immunohistochemistry (IHC) utilizing VENTANA PD-L1 (SP263) and calculated using the tumor proportion score (TPS) | PMC10374608 |
Post-hoc correlative analyses | In a post-hoc analysis prompted by clinical observations during the trial, cytokines in plasma were analyzed by the FCCC High Throughput Screening Facility utilizing the Human Chemokine Panel 40-plex (Bio-Plex Pro, Bio-Rad cat # 171AK99MR2) following manufacturer’s protocols and plates were read on a Bio-Plex 100/200 (Bio-Rad Laboratories, Hercules CA). Plasma underwent cryopreservation at −80 °C via standard operating procedures and was later used for batch cytokine analysis. The instrument was driven with Bio-Plex Manager (version 6.1.0727) software and data was analyzed and exported utilizing Bio-Plex Data Pro software (version 1.2.03). | PMC10374608 | ||
Statistical analysis | death | REGRESSION | PFS and OS in all evaluable patients were calculated using Kaplan-Meier curves. PFS was the interval to progression or death in those evaluable for efficacy. Duration of treatment was defined as the date from first dose of IFN-γ to progression, death, or completion of all treatments. The ORR was calculated using RECIST v 1.1. Planned exploratory correlative analysis of the difference in immune parameters at various treatment time points was done using a Wilcoxon test where consecutive samples from the same patient constituted a pair. Correlations to duration of treatment were performed using a Cox proportional hazards regression and tests for dose dependence were done using a Kruskal–Wallis test. For the post-hoc cytokine analysis, a two-sided Wilcoxon test was used to compare cytokine levels and in order to account for multiple hypotheses, the Benjamini–Hochberg false discovery rate (FDR) was computed, separately, for each comparison performed (baseline vs. C1D1, baseline vsC1D15, C1D1 vs C1D15). Cytokines with FDR corrected | PMC10374608 |
Reporting summary | Further information on research design is available in the | PMC10374608 | ||
Supplementary information |
Supplementary InformationPeer Review FileReporting Summary | PMC10374608 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-40028-z. | PMC10374608 | ||
Acknowledgements | Cancer | CANCER | The authors thank Irina Shchaveleva, Chun Zhou, and Judy Fang from the FCCC Immune Monitoring/Cell Sorting Facility for technical support. Jeffrey Sherman, Jeffrey Nieves, and Amy Grahn for support from Horizon Pharma. The NCI Cancer Center Support Grant (CA06927; FCCC) for support of core facilities utilized (Immune Monitoring/Cell Sorting, High Throughput Screening, and Biostatistics & Bioinformatics Facilities) and philanthropic funds from the FCCC In Vino Vita fundraiser, FCCC Bucks County and Mainline Boards of Associates, C.W.A. Local 13000 Jim Willer Golf Tournament, and the FCCC Dragon Boat Team. Employees of Horizon Therapeutics did not contribute to or influence study design, data collection, or data analysis. Full support for clinical trial provided by Horizon Therapeutics, PLC. | PMC10374608 |
Author contributions | T.M., J.O. | PATHOLOGY | M.Z. is the corresponding author, conceptualized and designed the study, was the principal investigator of the clinical trial, coordinated data analysis and wrote and edited the manuscript. E.R.P. provided oversight for trial design and conduct, participated in data analysis and provided editorial support. K.S.C. coordinated primary correlative analysis plans, oversaw the flow cytometry analysis, and provided writing and editorial support. A.W.F. performed the flow cytometry work and analysis and provided writing and editorial support. K.C., T.M., J.O. coordinated trial activities and helped with data collection and analysis. RK oversaw trial conduct, coordinated specimen collection and analysis, provided writing and editorial support. H.B., C.S.D., E.D., D.M.G., A.J., L.M., E.O. participated in patient accrual and provided editorial support. K.D., K.R. provided statistical analysis for clinical and correlative data and provided writing and editorial support. R.K.A. oversaw collection and processing of all correlative specimens and provided data analysis. E.A.D. prepared and analyzed all pathology specimens. E.C., M.E. performed multiplex and cytokine analyses and provided data analysis support and editorial support. All authors had an opportunity to review and approve the final submitted manuscript and | PMC10374608 |
Peer review | PMC10374608 | |||
Data availability | Source data are provided with this paper. The minimum dataset necessary to interpret, verify and extend this research has been provided within the source data file wherever applicable. Per ICMJE guidelines de-identified participant data has been provided within the source data file. The study protocol has been provided as supplementary material. | PMC10374608 | ||
Competing interests | Chase Cancer | FOX | M.Z.: Institutionally directed research funding from Horizon Therapeutics and Bristol-Myers Squibb; Advisory Board Honorarium from Horizon Therapeutics. K.S.C.: Advisory Board Honorarium from Horizon Therapeutics, institutionally-directed research funding from Bristol-Myers Squibb. E.R.P.: Advisory Board Honorarium from Horizon Therapeutics. H.B.: research support (clinical trials) from BMS, Lilly, Amgen; Advisory Board/Consultant for BMS, Lilly, Genentech, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, Astra Zeneca, Novartis, Genmab, Regeneron, BioNTech, Amgen, Axiom, PharmaMar, Takeda, Mirati, Daiichi, Guardant, Natera, Oncocyte, Beigene, iTEO, Jazz, Janssen, Da Volterra, Puma, BerGenBio, Bayer, Iobiotech; Data and Safety Monitoring Board for University of Pennsylvania (CAR T Program), Takeda, Incyte, Novartis, Springworks; employment at Fox Chase Cancer Center; Scientific Advisory Board for Sonnetbio (stock options), Inspirna (formerly Rgenix, stock options), Nucleai (stock options); honoraria from Amgen, Pfizer, Daiichi, Regeneron; travel support from Amgen, BMS, Merck, Lilly, EMD-Serono, Genentech, Regeneron. The remaining authors declare no competing interests. | PMC10374608 |
References | PMC10374608 | |||
Purpose: | hearing preservation |
Editor-in-Chief: Ryan W. McCreeryEditor: Andrea Warner-CzyzCochlear implant (CI) recipients with hearing preservation experience significant improvements in speech recognition with electric–acoustic stimulation (EAS) as compared to with a CI alone, although outcomes across EAS users vary. The individual differences in performance may be due in part to default mapping procedures, which result in electric frequency-to-place mismatches for the majority of EAS users. This study assessed the influence of electric mismatches on the early speech recognition for EAS users. | PMC10166189 | |
Method: | Twenty-one participants were randomized at EAS activation to listen exclusively with a default or place-based map. For both groups, the unaided thresholds determined the acoustic cutoff frequency (i.e., > 65 dB HL). For default maps, the electric filter frequencies were assigned to avoid spectral gaps in frequency information but created varying magnitudes of mismatches. For place-based maps, the electric filter frequencies were assigned to avoid frequency-to-place mismatches. Recognition of consonant–nucleus–consonant words and vowels was assessed at activation and 1, 3, and 6 months postactivation. | PMC10166189 | ||
Results: | For participants with default maps, electric mismatch at 1500 Hz ranged from 2 to −12.0 semitones ( | PMC10166189 | ||
Conclusions: | The present sample of EAS users experienced better initial performance when electric mismatches were small or eliminated. These data suggest the utility of methods that reduce electric mismatches, such as place-based mapping procedures. Investigation is ongoing to determine whether these differences persist with long-term EAS use. | PMC10166189 | ||
Supplemental Material: | hearing preservation |
Adult cochlear implant (CI) recipients with hearing preservation experience significant improvements in speech recognition with electric–acoustic stimulation (EAS) as compared to preoperative performance or postactivation with a CI alone, although performance across EAS users remains widely variable (Maps that align the filter frequencies to the cochlear place frequencies, referred to here as Default mapping procedures for EAS devices do not incorporate variability in AID of the electrode contacts, which can result in electric frequency-to-place mismatches that negatively influence acute speech recognition (EAS users may experience better early speech recognition with maps derived from a place-based mapping procedure that eliminates electric frequency-to-place mismatches by incorporating the AID of electrode contacts for individual CI recipients. For example, the place-based mapping procedure used in this report calculated the AID of each electrode contact from the postoperative computed tomography (CT) imaging and estimated the cochlear place frequency. The filter frequencies for specific channels were assigned to match the place frequencies of the corresponding electrode contacts. While this approach eliminates electric mismatches, it can result in spectral gaps that default mapping procedures avoid. Spectral gaps generally result in poorer performance for EAS users (This report assessed the influence of electric frequency-to-place mismatches on the speech recognition outcomes of EAS users within the first 6 months of device use. The study sample included EAS users who were randomized to listen exclusively with either a default map (variable magnitudes of electric mismatch across individuals) or a place-based map (no electric mismatch). The hypotheses were that early speech recognition outcomes would be better for EAS users with smaller electric mismatches and that the negative influence of larger electric mismatches would persist over the initial months of EAS listening experience. | PMC10166189 | |
Method | Preliminary data were reviewed from an ongoing, prospective investigation of performance with default versus place-based maps for CI recipients. The study site institutional review board approved the procedures, and participants provided consent. Participants were randomized to listen exclusively with either a default or place-based map. Procedures were completed at device activation (2–4 weeks postoperatively) and at 1, 3, and 6 months postactivation. Both the research audiologist who completed the assessments and the participants were blinded to the assigned map. | PMC10166189 | ||
Participants | Adult CI recipients were considered for inclusion if they underwent cochlear implantation at the study site, received a MED-EL lateral wall electrode array, were 18–80 years of age at the time of surgery, and presented with an unaided hearing threshold of ≤ 65 dB HL at 125 Hz in the implanted ear at device activation. Potential participants who failed the Mini-Mental State Examination ( | PMC10166189 | ||
Procedure | Unaided detection thresholds in the implanted ear were measured behaviorally using pure-tone stimuli presented over insert earphones at each interval. A low-frequency pure-tone average (LFPTA) was calculated from the unaided detection thresholds at 125, 250, and 500 Hz.Participants were fit with the ear-level Sonnet2For participants randomized to listen with a default map, the electric filter frequencies were generated by the clinical software. The software assigned the low-frequency filter associated with the most apical electrode contact as the frequency where the unaided detection threshold exceeded 65 dB HL (the acoustic cutoff frequency). The remaining mid- to high-frequency information was logarithmically distributed across the active channels.For participants randomized to listen with a place-based map, the electric filter frequencies were assigned to align low- to mid-frequency information with the cochlear place frequencies. Postoperative CT imaging was obtained for all cases using a Morita cone-beam CT scanner, and the image was uploaded to the OTOPLAN software (CAScination AG and MED-EL Corporation). Two reviewers manually identified cochlear anatomical landmarks (e.g., modiolus and round window) and individual electrode contacts for each CT image; those landmarks were used by the software to calculate the AID for each electrode contact, as previously described (Speech recognition was assessed using tasks of vowel and word recognition. Vowel recognition tasks have been shown to be sensitive measures of the influence of electric mismatches on speech recognition with a CI alone ( | PMC10166189 | ||
Electric Frequency-to-Place Mismatch | Electric frequency-to-place mismatch was quantified as the semitone deviation between the electric center frequency and the SG place frequency for the electrode contact closest to the 1500-Hz cochlear place (~267°). The 1500-Hz place frequency was selected because it has been shown to be an important region for frequency alignment in CI simulations evaluating speech recognition ( | PMC10166189 | ||
Data Analysis | Linear mixed models (LMMs) implemented in R using the | PMC10166189 | ||
Results | REGRESSION | The data included 21 participants (11 female) who were randomized to listen with either a default map (Demographic information for electric–acoustic stimulation users listening with either a default map or a place-based map.
Unaided air-conduction pure-tone detection thresholds for each participant at initial activation and 1, 3, and 6 months postactivation. Individual thresholds are indicated by symbol shape and fill, as defined in
Speech recognition as a function of electric frequency-to-place mismatch at 1500 Hz at initial activation and 1, 3, and 6 months postactivation. Performance was assessed for vowel recognition (left column) and consonant–nucleus–consonant (CNC) words recognition (right column), scored as the percent correct. Individual performance is indicated by symbol shape and fill, as defined in Regression coefficients from the linear mixed models that evaluated the main effects of interval (1, 3, and 6 months), absolute electric frequency-to-place mismatch at 1500 Hz, angular insertion depth (AID) of E1, and the interaction of interval and electric mismatch on speech recognition (rationalized arcsine units) for participants with default maps.
In a second set of analyses, these LMMs were expanded to include the data from the participants with place-based maps. Regression coefficients from the linear mixed models that evaluated the main effects of interval (1, 3, and 6 months), absolute electric frequency-to-place mismatch at 1500 Hz, angular insertion depth (AID) of E1, and the interaction of interval and electric mismatch on speech recognition (rationalized arcsine units) for participants with default maps and participants with place-based maps.
Additional analyses were conducted to evaluate other factors thought to affect performance in EAS users (i.e., LFPTA and age). No significant main effects were observed when the models that included the data from all participants were expanded to include LFPTA ( | PMC10166189 | |
Discussion | vowel and word recognition | SEPARATION | This report prospectively evaluated the early speech recognition for EAS users as a function of electric mismatch. Participants listened exclusively with either default maps (median electric mismatch: −5 semitones) or place-based maps that eliminated electric mismatches for low- to mid-frequency information. Poorer speech recognition was observed for EAS users with larger magnitudes of electric mismatch. For example, models including all participants predict poorer performance at 6 months postactivation for individuals listening to maps with 6 semitones of electric mismatch as compared to maps with no electric mismatch by 21 and 22 RAUs for vowel and word recognition, respectively. These data suggest that electric frequency-to-place mismatches may influence the speech recognition outcomes of adult EAS users—at least within the initial 6 months of device use. The preliminary patterns of performance for EAS users with place-based maps suggest the utility of methods that minimize or eliminate electric mismatches to support early speech recognition.The early effects of electric frequency-to-place mismatches for EAS users corroborate the previously observed performance differences for participants with normal hearing listening to EAS simulations. In both paradigms, we observe better performance with place-based maps than for spectrally shifted maps (One factor to consider when evaluating the present place-based mapping procedure is that it may result in a spectral gap between the acoustic and electric outputs. Default mapping procedures limit spectral gaps by assigning a single frequency to the acoustic cutoff and electric low-frequency filter. The poorer performance with spectral gaps for EAS users and listeners for EAS simulations (Another factor to consider is electric-on-acoustic masking. For CI recipients with electrode contacts that reside close to or within the region of functional acoustic hearing, the electric current spread from apical electrode contact(s) may introduce substantial masking of the low-frequency acoustic cues (These preliminary data indicate that electric frequency-to-place mismatches influence the early performance of EAS users, although there are limitations worth consideration. This report estimated the cochlear place frequency using the SG frequency-to-place function described by Another limitation is the modest sample size of the current study, which is not sufficient to assess the relationship between electric mismatches, AID of E1, and other device and mapping variables that have been observed to influence the speech recognition of CI recipients, such as angular separation between the electrode contacts ( | PMC10166189 |
Conclusions | These preliminary data suggest that EAS users experience better speech recognition when electric frequency-to-place mismatches are minimal and that the negative effects of larger magnitudes of electric mismatches are observed up to 6 months of listening experience. Methods to minimize electric mismatches, such as place-based mapping procedures, may support better early speech recognition for the population of patients similar to the participants in the present experiment. Ongoing work will evaluate the patterns of speech recognition and acclimatization to varying magnitudes of electric frequency-to-place mismatches with long-term device use. | PMC10166189 | ||
Data Availability Statement | The present preliminary data are available by e-mailing Margaret T. Dillon ( | PMC10166189 | ||
Supplementary Material | PMC10166189 | |||
Descriptive statistics of the vowel recognition and consonant–nucleus–consonant (CNC) word recognition (percent correct) for participants with default maps and participants with place-based maps at each interval. | Click here for additional data file. | PMC10166189 | ||
Acknowledgments | Deafness | DISORDERS, BROWN | The work was supported in part by a research grant provided to the university from MED-EL Corporation. Funding was also provided by the National Institute on Deafness and Other Communication Disorders (R21DC018389 awarded to Margaret Dillon and Kevin Brown, and T32DC005360 awarded to Paul Manis). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Samantha Scharf, AuD, and Kelly Anderson, BS, assisted with participant assessment. Alyssa Flippo, AuD, provided insight on the review of the acoustic output. | PMC10166189 |
Footnote | Twelve semitones equal one octave. In the statistical models, electric mismatch was converted to an absolute value, removing the distinction between basal and apical shifts. | PMC10166189 | ||
References | PMC10166189 | |||
1. Introduction | tumor, Glioblastoma, aggressive cancer, BrICS-LIT, metabolic abnormalities | TUMOR, INFILTRATION, DISEASE, GLIOBLASTOMA, BRAIN TUMOR, AGGRESSIVE CANCER, BRAIN, TUMOR PROGRESSION, TUMOR RECURRENCE | Glioblastoma (GBM) is a fatal disease, with poor prognosis exacerbated by difficulty in assessing tumor extent with imaging. Spectroscopic MRI (sMRI) is a non-contrast imaging technique measuring endogenous metabolite levels of the brain that can serve as biomarkers for tumor extension. We completed a three-site study to assess survival benefits of GBM patients when treated with escalated radiation dose guided by metabolic abnormalities in sMRI. Escalated radiation led to complex post-treatment imaging, requiring unique approaches to discern tumor progression from radiation-related treatment effect through our quantitative imaging platform. The purpose of this study is to determine true tumor recurrence timepoints for patients in our dose-escalation multisite study using novel methodology and to report on median progression-free survival (PFS). Follow-up imaging for all 30 trial patients were collected, lesion volumes segmented and graphed, and imaging uploaded to our platform for visual interpretation. Eighteen months post-enrollment, the median PFS was 16.6 months with a median time to follow-up of 20.3 months. With this new treatment paradigm, incidence rate of tumor recurrence one year from treatment is 30% compared to 60–70% failure under standard care. Based on the delayed tumor progression and improved survival, a randomized phase II trial is under development (EAF211).Glioblastoma (GBM) is a highly aggressive cancer that originates in glial cells in the brain, with a very poor prognosis for every age group. The disease has a median survival of 15–16 months [Standard-of-care therapy for GBM patients is guided by a combination of T1-weighted contrast-enhanced MRI (T1w-CE) and T2-weighted fluid-attenuated inversion recovery MRI (FLAIR). T1w-CE indicates areas of high-grade tumor where gadolinium-based contrast agents can accumulate due to breakdown of the blood–brain barrier and is used to guide surgical resection. However, T1w-CE MRI usually underestimates the extent of tumor infiltration [We recently completed a multi-institutional, single-arm pilot clinical trial for newly-diagnosed GBM patients where brain regions with a Cho/NAA ≥ 2x normal were treated with an escalated radiation dose of 75 Gy [To address these challenges, we developed novel quantitative and visualization tools to track patients after initial treatment, minimize the effects of confounding treatment changes, pinpoint tumor recurrence timepoints, and perform PFS analysis. These tools use a combination of a quantitative imaging platform and structured reporting methods. The Brain Imaging Collaboration Suite Longitudinal Imaging Tracker (BrICS-LIT) is a custom-built web application for the purpose of longitudinal MRI imaging follow-up of brain tumor patients [ | PMC9964256 |
2. Materials and Methods | PMC9964256 | |||
2.1. Clinical Trial Treatment Protocol | IDH | After newly diagnosed GBM patients completed surgery, sMRI scans were acquired along with standard imaging to guide radiation treatment. At each participating site, a Siemens 3T scanner was used to perform an echo planar sMRI pulse sequence with GRAPPA parallelization with either a 32- or 20-channel head coil. The scan was acquired with an echo time of 50 ms, repetition time of 1551 ms, and flip angle of 71 degrees, leading to a scan time of 15 min and a nominal voxel size of 108 μL [In For the cohort of 30 patients who received treatment, 2 had an IDH mutation, 9 were MGMT hypermethylated, 11 had a gross total resection (defined by whether their pre-RT T1w-CE lesion volumes were less than 1 mL), and 19 had a subtotal surgical resection [ | PMC9964256 | |
2.2. Follow-Up | BrICS-LIT, tumor | PATHOLOGY, TUMOR, BRAIN TUMOR | After patients completed RT, they returned for follow-up imaging every 2–3 months. At University of Miami and Emory University, follow-up occurred every 2 months, while patients at Johns Hopkins University had follow-up visits at 3-month intervals. Standard clinical follow-up was performed using the institution standard brain tumor protocol. T2 FLAIR and T1w-CE MRIs from each follow-up visit were uploaded to BrICS-LIT [In Often, if an enhancing lesion grows suspiciously fast, patients will undergo additional surgeries during this follow-up period. Many patients on this trial had second or even third surgeries to remove an enhancing lesion that was suspicious for tumor. After those surgeries, clinical pathologists at each respective site assessed tissue samples for presence of tumor and reported findings in pathology reports. | PMC9964256 |
2.3. Tumor Recurrence Determination | BrICS-LIT, tumor, necrosis | DISEASE PROGRESSION, TUMOR, PROLIFERATION, TUMOR PROGRESSION, NECROSIS, PATHOLOGY, TUMOR RECURRENCE | With BrICS-LIT, we graphed lesion volumes and BT-RADS scores over each patient’s follow-up period to observe long-term trends. As tumor-mimicking treatment effects such as pseudo-progression and radiation necrosis are commonly associated with high-dose radiation, we sought to use BrICS-LIT and clinical pathology reports to determine true tumor recurrence dates on a case-by-case basis. The following criteria were established across all patients to label the date of first disease progression. First, if the patient received any follow-up surgery and biopsy, then their pathology report served as the ground truth for tumor progression. If the re-resection or biopsy specimens contained over 20% tumor as described in the pathology report, the previous date was labeled as progression. When the pathology report did not include a percentage but mentioned positive tumor presence, the previous follow-up was labeled as progression. While other factors included in pathology reports such as mitosis or elevated proliferation index could have been used as cutoff points for progression, these factors were not present in every report we received. Therefore, we used a defined cutoff based on information that every report shared. This cutoff was set a priori and not changed in the analysis. For patients who did not receive re-resection, follow-up imaging was evaluated by comparing volumetric changes of contrast-enhancing and FLAIR lesions over time. Dates where significant increases in segmented tumor volume leading to BT-RADS scores of 3c and 4 were further examined using RT dose map overlays. By overlaying an RT dose map over follow-up anatomic imaging, we could look for cases where an enhanced lesion continued to expand and significantly spread outside of the high-dose target (appearing red in the overlaid dose maps). If the enhancing lesion spread outside the high-dose radiation field, the corresponding follow-up date was defined as the tumor recurrence date. Otherwise, if the enhancing lesion volume stabilized within the high-dose region of the brain, the enhancement was attributed to radiation necrosis. Every case where the enhancing lesion extended past the high-dose radiation target was verified and agreed upon by a neuro-radiologist and the patient’s treating radiation oncologist. | PMC9964256 |
2.4. Survival Analysis | All survival outcomes were assessed using the lifelines Python survival analysis library [ | PMC9964256 | ||
3. Results | PMC9964256 | |||
3.1. Survival Analysis | deaths | TUMOR PROGRESSION | Eighteen months after completing enrollment, the median PFS time was 16.6 months (As mentioned previously, fourteen out of nineteen patients with tumor progression had confirmed progression before their deaths. The criteria we outlined for determining progression were applied to this subgroup with additional details in | PMC9964256 |
4. Discussion | tumor, toxicity, toxicities, edema, necrosis, BrICS-LIT, IDH | DISEASE PROGRESSION, TUMOR, RECURRENCE, EDEMA, TUMOR PROGRESSION, NECROSIS, PATHOLOGY, TUMOR RECURRENCE | In this study we describe the use of novel imaging visualization tools and structured reporting to analyze the results to date of our 30-patient clinical trial utilizing dose-escalated radiation guided by Cho/NAA sMRI maps. With standard-of-care therapy including standard RT with concurrent and adjuvant TMZ, GBM prognosis remains poor with a median OS that is consistently limited to about 16 months and an incidence of recurrence at one year from start of treatment of 60–70% [While escalated radiation shows promising results, most patients on the trial exhibited pseudo-progression and radiation necrosis that lasted far longer than patients on standard radiation therapies. In standard clinical practice, T1w-CE imaging is the mainstay for defining tumor recurrence. However, under high-dose irradiation, post-treatment radiation effects often mimic those of tumor recurrence on clinical images, prompting labeling of disease progression before true tumor recurrence. Multiple patients on the trial were recommended for additional surgeries due to the apparent increase in contrast enhancing volume on T1w-CE imaging; however, these lesions were often in-field of the high-dose target and were later confirmed to be either pseudo-progression or radiation necrosis via pathology reports. The pathology reports for the first patient from our results section showed zero and minimal tumor both one year and two years after completion of RT. It was common to see pathology reports five to even nine months after completion of RT finding minimal tumor in samples biopsied. Our dependence on pathology reports from biopsy for in-field recurrence determination is a limitation for our criteria, especially in cases where there were not additional surgical interventions at critical timepoints.While we acknowledge that quantitative tools such as BrICS-LIT do not necessarily solve the problem of differentiating tumor from necrosis, they were helpful in tracking the patient’s disease-state during follow-up. Using our LIT database, radiation dose maps, and post-surgery pathology reports, we performed a retrospective analysis showing a ten month improvement of PFS compared to standard therapy using sMRI-guided dose escalation. With BrICS-LIT, we can graph lesion volumes and structured reporting scores throughout the patient’s follow-up period. Rather than manually inspecting independent images and qualitatively assessing the patient across their latest few follow-up dates, with BrICS-LIT we can use segmentation algorithms to calculate lesion volumes and make comparisons quantitatively. If, for example, enhancing lesion volume is increasing at an exponential rate, there is good reason to be suspicious for tumor progression. However, if the lesion volume stays within-field and remains stable over several months, the enhancing lesion could be mostly radiation necrosis unless proven otherwise through biopsy. A limitation of this study is that we did not use MRI perfusion-weighted imaging or other advanced imaging to further differentiate imaging findings. While some studies have shown benefits in using MRI perfusion to characterize indeterminate cases, there is wide variation in how it is applied, including at the three trial sites on this study, which would lead to variations in interpretation [Future plans involve fully automating lesion segmentation in both FLAIR and T1w-CE MRIs as well as generating suggestive, structured reporting scores for each follow-up visit. While escalating the radiation dosage to 75 Gy led to minimal clinical toxicity for patients on this trial, there was one patient who had grade 3 toxicities as a result of their radiation, with edema on FLAIR imaging pushing across the midline of their brain. Additionally, there were a handful of cases where 75 Gy was not sufficient to control tumor as at least seven cases had in-field recurrence. External factors such as MGMT hypermethylation and IDH mutation likely contribute to how patients respond to different amounts of radiation [ | PMC9964256 |
5. Conclusions | glioblastoma, BrICS-LIT, necrosis | RECURRENCE, TUMOR PROGRESSION, NECROSIS, GLIOBLASTOMA, PATHOLOGY, TUMOR RECURRENCE | With a median time to follow-up of 20.3 months for censored patients, guiding escalated radiation dose to glioblastoma patients through spectroscopic MRI led to a median PFS of 16.6 months with a one-year incidence of recurrence from treatment of 30%, half that of standard therapy. These results are extremely encouraging and suggest the need for sMRI to be a part of standard clinical practice. While escalated radiation doses over larger treatment volumes show promising results towards improving survival, differentiating between true tumor recurrence and radiation-related necrosis even one year after completion of radiation therapy remains a challenge.By developing quantitative web applications such as BrICS-LIT, we have managed to segment lesions and calculate structured reporting scores for each patient during the follow-up phase of their treatment with the hope of more easily delineating recurrence. Through radiation map overlays, graphing lesion volumes for observable trends, and patient pathology reports, we present our methodology for calculating the tumor progression date. Through the quantitative data we have collected in BrICS-LIT, we plan to develop automated, optimized radiation treatment plans that operate at a voxel-level granularity, with the hope of delaying recurrence for as long as possible. | PMC9964256 |
Author Contributions | Conceptualization, E.A.M., M.G., P.B.B., S.S.G., E.S., H.H., M.H., L.R.K., H.-K.G.S., H.S. and B.D.W.; Methodology, K.K.R., V.H., P.B.B., S.S.G., E.S., H.-K.G.S., H.S. and B.D.W.; Software, K.K.R., S.S.G., E.S., H.S. and B.D.W.; Validation, E.A.M., M.d.l.F., M.H., H.-K.G.S., H.S. and B.D.W.; Formal analysis, K.K.R., V.H., J.R., E.A.M., M.d.l.F., H.S. and B.D.W.; Resources, B.D.W.; Data curation, K.K.R., V.H., J.R., E.A.M., M.G., P.B.B., A.S.G., E.M.D., M.H., L.R.K., H.-K.G.S., H.S. and B.D.W.; Writing—original draft, K.K.R. and H.S.; Writing—review & editing, K.K.R., V.H., J.R., E.A.M., M.G., P.B.B., S.S.G., A.G.T., A.S.G., E.S., H.H., M.d.l.F., E.M.D., M.H., L.R.K., H.-K.G.S. and B.D.W.; Visualization, K.K.R., A.G.T. and B.D.W. All authors have read and agreed to the published version of the manuscript. | PMC9964256 | ||
Institutional Review Board Statement | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Emory University (IRB00094188 on 4/14/2017). | PMC9964256 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9964256 | ||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. | PMC9964256 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9964256 | ||
References | tumor | TUMOR, RESIDUAL TUMOR, BRAIN, TUMOR PROGRESSION, CAVITY | A comparison between the ratio map of choline to N-acetylaspartate (Cho/NAA) and T1-weighted contrast-enhanced (T1w-CE) imaging for three patients on the trial. For each patient, the top left image contains the Cho/NAA ratio map superimposed on the T1w image along with a contour encompassing all voxels with a Cho/NAA ≥ 2x normal. That contour is overlaid on the T1w-CE image on the top right image which shows enhancement from residual tumor and recent surgery. The bottom left image shows a 3D volume rendering of the volume of tissue that received 75 Gy of radiation guided by the Cho/NAA ≥ 2x contour, while the bottom right image shows a 3D volume rendering of the residual contrast enhancing lesion, which normally receives 60 Gy of radiation along with resection cavity in standard therapies. In all cases, the Cho/NAA ≥ 2x contour was significantly larger than the contrast-enhancing lesion.A view of the Brain Imaging Collaboration Suite Longitudinal Imaging Tracker (BrICS-LIT). The top row consists of T2-weighted fluid-attenuated inversion recovery (FLAIR) MRIs and the middle row of T1w-CE MRIs co-registered and interpolated to an atlas for easier comparison. Studies are longitudinally arranged from newest (left column) to oldest (right column). Segmented lesions are overlaid in the top two rows, while the radiation dose map is overlaid on the T1w-CE MRI in the bottom row to intuitively determine the radiation dose received of the suspected recurring tumor.Kaplan–Meier estimator for PFS; median PFS: 16.6 months with a median time to follow-up of 20.3 months.With our web platform, clinicians assessed ((Compiled genetic and PFS data for 14 of the 19 patients with confirmed tumor progression. | PMC9964256 |
Purpose | We assessed the efficiency of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) incorporated biomimetic calcium phosphate on β-tricalcium phosphate (β-TCP) (rhBMP-2/BioCaP/β-TCP) on bone formation in a model of socket preservation using cone beam computed tomography (CBCT) scanning and histological examination. | PMC10579201 | ||
Methods | tooth | Forty patients undergoing minimally invasive single-root tooth extraction for dental implantation were randomized to three groups according to the material used for socket preservation: filling with rhBMP-2/BioCaP/β-TCP, β-TCP, or natural healing (kept unfilled) (controls). The alveolar sockets (including the control group) were covered by two-layer collagen membranes and sutured. Two CBCT scans were taken, one immediately after socket preservation procedure (baseline) and another 6 weeks later. Gray values (GVs) obtained from CBCT were recorded. During insertion of the dental implant, biopsies were taken and analyzed histologically for new bone formation, residual material, and unmineralized bone tissue at the core of the biopsy. | PMC10579201 | |
Results | ± | The mean (± standard deviation) changes of GVs of the CBCT scans at the central area of filled materials were as follows: 373.19 ± 157.16 in the rhBMP-2/BioCaP/β-TCP group, 112.26 ± 197.25 in the β-TCP group, and -257 ± 273.51 in the control group. The decrease of GVs in the rhBMP-2/BioCaP/β-TCP group as compared with the β-TCP group was statistically significant ( | PMC10579201 | |
Graphical Abstract | PMC10579201 | |||
Keywords | PMC10579201 | |||
Introduction | tooth loss, tumors, neoplasm, trauma | ATROPHIC, NEOPLASM, TUMORS, DISEASES, HYDROXYAPATITE | Sufficient alveolar bone is a prerequisite for successful placement of dental implants. However, atrophic maxilla or mandible is a common finding in clinical practice due to tooth loss, trauma, tumors, neoplasm resection, or bone metabolism diseases [Different materials, such as autografts, allografts, and xenografts have been used for filling the socket and retaining the alveolar bone volume [Synthesized bone substitutes are useful options as they can avoid these aforementioned shortcomings. Different synthesized bone substitute materials have been used in implant dentistry for socket preservation, such as hydroxyapatite (HA), tricalcium phosphate (TCP), biphasic calcium phosphate (BCP) or a combination of these materials. Calcium phosphate (CaP) bioceramics are mostly used as bone substitutes in clinical practice, and low dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) (approved by the FDA) [Cone beam computed tomography (CBCT) is widely used in implant dentistry with grey values (GVs) scale to measure density, volume, and contour of bone [Therefore, the objective of this study was to determine the efficiency of rhBMP-2/BioCaP/β-TCP in socket preparation using CBCT studies and histological examination of biopsies for assessing bone formation. | PMC10579201 |
Methods | PMC10579201 | |||
Patient selection and study design | fasting blood glucose, Obese, inflammation, periodontitis, allergy, tooth, diabetes | UNCONTROLLED HYPERTENSION, PERIAPICAL PERIODONTITIS, OBESE, INFLAMMATION, PERIODONTITIS, ALLERGY, DIABETES | The study was approved by the Clinical Research Ethics Committees of the Academic Center for Dentistry of Amsterdam (code ACTA 202061), Vrije Universiteit Amsterdam, The Netherlands, and Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine (code SH9H-2019-T231-4), China. This trial was conducted following the international standard for clinical investigations with medical devices (ISO 14155:2020). Written informed consent was obtained from all participants.A total of 40 patients were recruited in this study (15 in rhBMP-2/BioCaP/β-TCP group, 15 in β-TCP group, and 10 in the natural healing group). All patients met the selection criteria shown in Tables Inclusion criteria• Patients over the age of 18 years• The study includes patients who have undergone the extraction of a single-root tooth based on appropriate indications for tooth extraction• Patients whose tooth extraction site has been classified as either EDS-1 or EDS-2 according to the classification system developed by N. Caplanis et al. [• After the tooth extraction, implant surgery will be the follow-up treatment for these patients• Before participating in the trial, all subjects provided their voluntary and informed consent to participate in the studyExclusion criteria• Patients with conditions considered absolute contraindications for oral implant treatment based on the criteria established by Debby Hwang et al. [• Patients with uncontrolled local inflammation in the extracted or adjacent teeth, including uncontrolled periodontitis (periodontal probing depth > 4 mm) and acute periapical periodontitis• Patients with uncontrolled diabetes, where fasting blood glucose is still ≥ 8.8 mmol/L despite drug use• Patients with severe uncontrolled hypertension (blood pressure > 180/100 mmHg)• Obese patients with a body mass index (BMI) > 28 kg/m• Patients who have continuously used antibiotics or chronic anti-inflammatory therapy (≥ three times per week) within the first four weeks after surgery• Patients who smoke or use tobacco equivalent/chewing tobacco more than ten cigarettes daily• Patients who have an allergy to the investigational product• Female patients who are pregnant or nursing or refuse to take any contraception• Patients whose compliance could be improved by the investigator• Patients who have participated in or are participating in clinical trials of other medical devices or drugs within the 30 days before Day 0Schematic of clinical trial procedure. Intra-oral photographs of socket preservation and dental implant surgery. | PMC10579201 |
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