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Introduction: Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking., Methods: This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected., Results: 711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %., Conclusion: Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and Qbiotics. JK has received research funding from LEO Pharma, honorium from BMS, Amgen, Janssen; and educational funding from MSD, Janssen and Astra Zeneca. RRT has served on advisory boards for BMS, MSD, Amgen, Pierre-Fabre, Astra Zeneca and Roche. CL has received research funding from BMS, Roche, consulting fees from BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Amgen, Merck Serono, Roche and Iflax; speaking fees from Amgen, BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Incyte, Pfizer, Roche; and travel funding from BMS, MSD, Novartis, Pierre-Fabre, Roche, Sanofi and served on advisory boards for BMS, Pierre Fabre, Sanofi, Novartis, MSD, Magen, Merck Serono, Roche and Inflax. CA has received travel funding from BMS, Roche and Amgen and speaking fees from Novartis. RJS has served on advisory boards for Merck, Novartis, Pfizer, and Replimune and receives grant funding from Merck. CR has served on advisory boards for Pierre Fabre, Sanofi, BMS, MSD, Novartis, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; involved in steering committees for Novartis, Regeneron, Pfizer and IO Biotech and a consultant IDMC for Ultimovacs; received speaking fees from Pierre Fabre, Sanofi, BMS, MSD and Novartis and travel funding from Pierre Fabre. JM has intermittent project focused consultant or advisory relationships with Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Johnson & Johnson, and Pierre Fabre and has received travel support from L′ Oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. MSC has served on advisory boards or as a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi and received honoraria from BMS, MSD, and Novartis. DBJ has served on advisory boards or as a consultant for AstraZeneca, BMS, The Jackson Laboratory, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. BN has received financial compensation from Novartis, Roche, BMS, MSD, and Pierre-Fabre for service on advisory boards and speaking engagements; and institutional research funding from Pfizer, Novartis, Roche and Merck-Serono. VR has received honoraria from AstraZeneca and has received travel and education funding from MSD and Novartis. PAA has served as a consultant for BMS, MSD, Roche-Genentech, Ventana, Novartis, Amgen and Array and received research funding from BMS, Roche-Genentech and Ventana. JW has served as a consultant for Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, EMD Serono, and Bristol Myers Squibb; has had equity roles in Biond, Evaxion, OncoC4, and Instill Bio; received institutional research support from Bristol Myers Squibb, Merck, GSK, Moderna, Pfizer, Novartis, and AstraZeneca; served in scientific advisory roles with CytomX, Incyte, ImCheck, Biond, Sellas, Instill Bio, OncoC4, and NexImmune; and holds patent agreements with Moffitt Cancer Center and Biodesix. PR has received honoraria from BMS, MSD, Novartis, Pierre-Fabre, Merck and Sanofi; and served in an advisory capacity for MSD, BMS, Sanofi, Pierre-Fabre, Blueprint Medicines and Philogen. GAM has received institutional research funding through Roche-Genentech, MSD, Roche, and BMS and other funding through Novartis and BMS. SH has served as a consultant for Amgen, Genmab, Xencor, Astellas Pharma, Regeneron, and Nektar. AA has served as a consultant for BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi; received speaking fees from Pierre Fabre, Novartis, MSD, BMS, Roche, Merck, Sanofi; institutional funding from Pierre-Fabre, Novartis, Roche, BMS, MSD, Merck and Sanofi; and travel funding from BMS, MSD, Novartis, Pierre-Fabre. AH has served on an advisory board for BMS, MSD and Novartis. RD has received honoraria from Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, touchIME, T3 Pharmaceuticals, Pfizer; served as a consultant for Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, touchIME, MaxiVax, Regeneron, Pfizer, T3 Pharmaceuticals and received institutional research funding from Roche, BMS, Novartis, MSD and Amgen. CUB has served as a consultant for AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Third Rock Ventures; received institutional research funding from SC, Bristol-Myers Squibb, NanoString Technologies, and Novartis; provided expert testimony for Freshfields Bruckhaus Deringer; received travel funding from BMS; and has ownership interest in Immagene and Signature Oncology. GVL has received honoraria from BMS, Pierre-Fabre and received served as a consultant for Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal AG (Sandoz Company), Highlight Therapeutics, Innovent Biologics USA Inc, Merck Sharp & Dohme, Novartis, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Provectus, QBiotics, Regeneron, and AstraZeneca. The remaining authors have nothing to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In 2012, the Strategic Advisory Group of Experts on Immunization (SAGE) recommended introduction of at least one inactivated poliovirus vaccine (IPV) dose in essential immunization programs. We evaluated systemic humoral and intestinal mucosal immunity of a sequential IPV-bivalent oral poliovirus vaccine (bOPV) schedule compared with a co-administration IPV + bOPV schedule in an open-label, randomized, controlled, non-inferiority, inequality trial in Dhaka, Bangladesh. Healthy infants aged 6 weeks were randomized to either: (A) IPV and bOPV at 6 and bOPV at 10 and 14 weeks (IPV + bOPV-bOPV-bOPV); or (B) IPV at 6 and bOPV at 10 and 14 weeks (IPV-bOPV-bOPV). Of 456 participants enrolled and randomly assigned during May-August 2015, 428 (94%) were included in the modified intention-to-treat analysis (arm A: 211, arm B: 217). Humoral immune responses did not differ at 18 weeks between study arms: type 1 (98% versus 96%; p = 0.42), type 2 (37% versus 39%; p = 0.77), and type 3 (97% versus 93%; p = 0.07). Virus shedding one week after the bOPV challenge dose in arm B was non-inferior to arm A (type 1 difference = -3% [90% confidence interval: -6 - 0.4%]; type 3 difference: -3% [-6 to -0.2%]). Twenty-six adverse events including seven serious adverse events were reported among 25 participants including one death; none were attributed to study vaccines. An IPV-bOPV-bOPV sequential schedule induced comparable systemic humoral immunity to all poliovirus types and types 1 and 3 intestinal mucosal immunity as an IPV + bOPV-bOPV-bOPV co-administration schedule., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Khalequ Zaman, Asma Binte Aziz, Mohammad Yunus, Warda Haque b reports financial support was provided by Centers for Disease Control and Prevention. Cynthia J Snider’s spouse previously owned stock in Sanofi Pasteur, (Published by Elsevier Ltd.)

Background: Vaccination constitutes an attractive control measure for hepatitis E virus (HEV), a major cause of maternal and perinatal mortality globally. Analysis of pregnant participants in an effectiveness trial of the HEV vaccine HEV239 showed possible HEV239-associated fetal losses. We aimed to conduct a detailed analysis of this safety signal., Methods: In a double-blind, cluster-randomised trial, 67 villages in Matlab, Bangladesh, were randomly allocated (1:1) to two vaccine groups, in which non-pregnant women aged 16-39 years received either HEV239 (HEV239 group) or Hepa-B (a hepatitis B vaccine; control group). We implemented weekly surveillance for pregnancy detection, and follow-up of pregnancies once every 2 weeks, using physician-confirmed diagnoses to evaluate fetal loss outcomes (miscarriage [spontaneous abortion], stillbirth, and elective termination). Data from a parallel system of reproductive health surveillance in Matlab were used to clarify study diagnoses when necessary. Miscarriage was assessed only among participants whose first positive pregnancy test and vaccination date (for whichever dose was closest to the date of last menstrual period [LMP]) were before 20 weeks' gestation. We defined the following analysis periods of interest: from 90 days before the LMP until the pregnancy outcome (the proximal period); from the LMP date until the pregnancy outcome (the pregnancy period); from 90 days before the LMP until the LMP date (90 days pre-LMP period); and from enrolment until 90 days before the LMP (the distal period). Both Poisson and Cox regression models were used to assess the associations between receipt of HEV239 and fetal loss outcomes. The trial was registered with ClinicalTrials.gov (NCT02759991)., Findings: Among the 19 460 non-pregnant participants enrolled in the trial, 5011 were identified as having pregnancies within 2 years following vaccination and met the criteria for analysis (2407 in the HEV239 group and 2604 in the control group). Among participants vaccinated in the proximal period and evaluated for miscarriage, miscarriage occurred in 54 (8·9%) of 607 in the HEV239 group and 32 (4·5%) of 719 in the control group (adjusted relative risk [aRR] 2·0 [95% CI 1·3-3·1], p=0·0009). Similarly, the risk of miscarriages was increased in the HEV239 group versus the control group among participants inadvertently vaccinated during pregnancy (22 [10·5%] miscarriages among 209 participants in the HEV239 group vs 14 [5·3%] of 266 in the control group; aRR 2·1 [95% CI 1·1-4·1], p=0·036) and among those vaccinated within 90 days pre-LMP (32 [8·0%] of 398 vs 18 [4·0%] of 453; 1·9 [1·1-3·2], p=0·013). No increased risk of miscarriage was observed in those who received HEV239 in the distal period (93 [5·6%] of 1647 vs 80 [4·5%] of 1773; 1·3 [0·8-1·9], p=0·295). Stillbirth and elective termination showed no increased risk among women administered HEV239 versus those administered Hepa-B in any of the analysis periods., Interpretation: HEV239 given shortly before or during pregnancy was associated with an elevated risk of miscarriage. This association poses a possible safety concern for programmatic use of HEV239 in women of childbearing age., Funding: Research Council of Norway and Innovax., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Hepatitis E virus (HEV) leads to high mortality in pregnant women in low-income countries. We aimed to evaluate the safety of a HEV vaccine and its effectiveness in preventing hepatitis E during pregnancy., Methods: In this phase 4, double-blind, cluster-randomised trial, 67 villages in Matlab, Bangladesh, were randomised 1:1 to receive HEV239 (a recombinant HEV vaccine) or a control vaccine (Hepa-B, a hepatitis B vaccine), using block randomisation with random number tables and blocks of size eight, stratified by cluster population size. Eligible non-pregnant women (aged 16-39 years) were vaccinated intramuscularly on day 0, at 1 month, and at 6 months, and followed up for 2 years after the last immunisation. The primary endpoint was hepatitis E in the pregnant, per-protocol population (those who received all three doses within 2 days of the scheduled dates), while safety was a secondary endpoint, assessed in the intention-to-treat (ITT) population (participants who received at least one dose). Solicited adverse events were recorded for the first 7 days after each dose, and unsolicited events until 2 years after a participant's final dose. Pregnancy-related safety outcomes were assessed in the pregnant ITT population. This study is registered with ClinicalTrials.gov (NCT02759991)., Findings: Between Oct 2, 2017, and Feb 28, 2019, 19 460 participants were enrolled and received either HEV239 (9478 [48·7%] participants, 33 clusters) or Hepa-B (9982 [51·3%] participants, 34 clusters), of whom 17 937 (92·2%) participants received three doses and 17 613 (90·5%) were vaccinated according to protocol (8524 [48·4%] in the HEV239 group and 9089 [51·6%] in the control group). No pregnant participants were confirmed to have hepatitis E in either treatment group. HEV239 showed a mild safety profile, similar to Hepa-B, with no difference in the proportion of solicited adverse events between groups and no severe solicited events. Pain was the most common local symptom (1215 [12·8%] HEV239 recipients and 1218 [12·2%] Hepa-B recipients) and fever the most common systemic symptom (141 [1·5%] HEV239 recipients and 145 [1·5%] Hepa-B recipients). None of the serious adverse events or deaths were vaccine related. Among pregnant participants, the HEV239 group had a higher risk of miscarriage (136 [5·7%] of 2407 pregnant participants) compared with the control group (102 [3·9%] of 2604; adjusted odds ratio 1·54 [95% CI 1·15-2·08])., Interpretation: The effectiveness of HEV239 in pregnant women remains uncertain. HEV239 was safe and well tolerated in non-pregnant women, but findings regarding miscarriage warrant further investigation., Funding: Research Council of Norway; Innovax., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Rotavirus gastroenteritis is accountable for an estimated 128 500 deaths among children younger than 5 years worldwide, and the majority occur in low-income countries. Although the clinical trials of rotavirus vaccines in Bangladesh revealed a significant reduction of severe rotavirus disease by around 50%, the vaccines are not yet included in the routine immunization program. The present study was designed to provide data on rotavirus diarrhea with clinical profiles and genotypes before (2017-2019) and during the COVID-19 pandemic period (2020-2021). Fecal samples were collected from 2% of the diarrheal patients at icddr,b Dhaka hospital of all ages between January 2017 and December 2021 and were tested for VP6 rotavirus antigen using ELISA. The clinical manifestations such as fever, duration of diarrhea and hospitalization, number of stools, and dehydration and so on were collected from the surveillance database (n = 3127). Of the positive samples, 10% were randomly selected for genotyping using Sanger sequencing method. A total of 12 705 fecal samples were screened for rotavirus A antigen by enzyme immunoassay. Overall, 3369 (27%) were rotavirus antigen-positive, of whom children <2 years had the highest prevalence (88.6%). The risk of rotavirus A infection was 4.2 times higher in winter than in summer. Overall, G3P[8] was the most prominent genotype (45.3%), followed by G1P[8] (32.1%), G9P[8] (6.8%), and G2P[4] (6.1%). The other unusual combinations, such as G1P[4], G1P[6], G2P[6], G3P[4], G3P[6], and G9P[6], were also present. Genetic analysis on Bangladeshi strains revealed that the selection pressure (dN/dS) was estimated as <1. The number of hospital visits showed a 37% drop during the COVID-19 pandemic relative to the years before the pandemic. Conversely, there was a notable increase in the rate of rotavirus positivity during the pandemic (34%, p < 0.00) compared to the period before COVID-19 (23%). Among the various clinical symptoms, only the occurrence of watery stool significantly increased during the pandemic. The G2P[4] strain showed a sudden rise (19%) in 2020, which then declined in 2021. In the same year, G1P[8] was more prevalent than G3P[8] (40% vs. 38%, respectively). The remaining genotypes were negligible and did not exhibit much fluctuation. This study reveals that the rotavirus burden remained high during the COVID-19 prepandemic and pandemic in Bangladesh. Considering the lack of antigenic variations between the circulating and vaccine-targeted strains, integrating the vaccine into the national immunization program could reduce the prevalence of the disease, the number of hospitalizations, and the severity of cases., (© 2024 Wiley Periodicals LLC.)

Breast cancer is diagnosed in nearly 3 million people worldwide. Radiation therapy is an integral component of disease management for patients with breast cancer, and is used after breast-conserving surgery or a mastectomy to reduce the risk of a local recurrence. The following review describes the methods used to personalize radiation therapy by optimizing patient selection, using advanced treatment techniques to lessen the radiation dose to normal organs, and using hypofractionation in order to shorten the duration of radiation treatment.

Introduction: Elective pelvic nodal irradiation for patients with muscle-invasive bladder cancer (MIBC) undergoing trimodal therapy (TMT ) is controversial. In patients with node-negative (N0) MIBC, the benefit of elective whole-pelvis concurrent chemoradiation (WP-CCR) compared to bladder-only (BO )-CCR has not been demonstrated. Using real-world data from the National Cancer Database (NCDB ), we sought to compare the overall survival (OS ) between BO-CCR and WP-CCR for MIBC., Methods: Using the 2020 NCDB Participant User File, we identified cases of MIBC diagnosed between 2017 and 2019. We selected patients with clinical T2-T4aN0M0 disease receiving CCR as first-line treatment. CCR was defined as transurethral resection of bladder tumor followed by ≥40 Gy radiation to the bladder with concurrent single- or multiple-agent chemotherapy. Based on elective nodal irradiation status, patients were stratified as having received BO-CCR vs. WP-CCR. OS analysis was performed using summary three-month conditional landmark, inverse probability treatment weighting (IPTW)-adjusted Kaplan-Meier estimates, and Cox regression., Results: A total of 604 patients receiving CCR for MIBC were identified: 367 (60.8%) BO-CCR and 237 (39.2%) WP-CCR. Before IPTW, the groups were imbalanced in terms of baseline characteristics. The median followup of the weighted population was 42.3 months (interquartile range 18.1-49.1 months). In IPTW-adjusted Cox proportional hazards regression analysis, WP-CCR was associated with a significant OS benefit compared to BO-CCR (adjusted hazard ratio 0.72, 95% confidence interval 0.54-0.96, p=0.026)., Conclusions: In the setting of CCR for N0 MIBC, this retrospective NCDB analysis revealed that WP-CCR was associated with a benefit in OS compared to BO-CCR.

Glioblastoma is the most common primary brain tumor with an estimated 14,000 Americans diagnosed with this disease annually. This disease is treated with maximal surgical resection followed by adjuvant radiation therapy. Radiation therapy was initially delivered to the whole brain and with no concurrent or adjuvant systemic therapy. Advances in imaging and treatment delivery have allowed for partial brain irradiation to minimize radiation dose to normal structures, as well as sparing structures important for memory such as the hippocampus, decreasing morbidity and toxicity. While there is no consensus on the optimal radiation volume needed to successfully treat glioblastoma, there is consensus that the tumor bed with margin is preferable to treatment of the whole brain. Additionally, advances in knowledge regarding tumor biology have demonstrated the benefit of concurrent and adjuvant chemotherapy, as well as demonstrated that methylation of genes in the tumor can predispose greater responsiveness to chemotherapy. The following review describes the advancements in specific radiation techniques that have been used to improve the therapeutic ratio for management of glioblastoma and methods used to personalize radiation treatment for patients based on genomic markers as well as clinical factors. The review also describes future investigations that are currently taking place in order to enable a further improvement of clinical outcomes for patients with glioblastoma.