With the advent of the immunotherapy era, the combination of radiotherapy and immunotherapy has become a critical strategy to enhance patient outcomes. In addition to its direct cytotoxicity, radiotherapy modulates the immune response within the tumor and its surrounding microenvironment by stimulating the body's anti-tumor immune response. This interplay provides the rationale for combining radiotherapy with immunotherapy. This review will summarize the immunomodulatory mechanisms of radiation therapy, evaluate the clinical efficacy and safety of combining radiotherapy with immunotherapy, and outline its current applications, challenges, and future potential. In the future, the combination of radiotherapy and immunotherapy holds immense potential in esophageal cancer treatment. Through additional prospective clinical trials exploring optimal combinations, timing, and biomarkers, we can further refine treatment strategies and enhance patient survival.

Central nervous system (CNS) metastases from Wilms tumor (WT) are exceedingly rare. Intracerebral hemorrhage secondary to metastatic WT is even less common, and the management of such cases is further complicated when patients are receiving a direct oral anticoagulant (DOAC) like Rivaroxaban, for which pediatric reversal guidelines are lacking.

We report on the case of a 5-year-old boy with relapsed stage IV Wilms tumor who presented with rapidly progressive neurological deterioration caused by brain metastases with extensive intraparenchymal and intraventricular hemorrhage while receiving Rivaroxaban due to prior thrombosis. An emergent craniotomy and tumor resection was safely performed after emergent reversal of anticoagulation with Rivaroxaban using Andexanet alfa, administered in this pediatric patient with off-label consent in the setting of a life-threatening intracranial hemorrhage requiring emergent neurosurgical intervention. No excessive intraoperative bleeding was noted. Treatment for relapsed WT according to the SIOP-UMBRELLA-Protocol was initiated. Three weeks after Andexanet alfa treatment, a thrombotic event in the left iliac veins occurred, requiring anticoagulation with unfractionated heparin.

This case highlights the therapeutic challenges of managing intracranial hemorrhage in a pediatric patient requiring emergent neurosurgical debulking in the setting of Rivaroxaban anticoagulation. To our knowledge, this is the second case reporting on Rivaroxaban reversal through Andexanet alfa in children. Early multidisciplinary intervention, meticulous neurosurgical management and continuation of oncologic therapy can lead to favorable outcomes even in such complex presentations.

Human papillomavirus (HPV) is a well-established oncogenic virus implicated in the development of several epithelial cancers, most notably cervical, anogenital, and oropharyngeal carcinomas. In contrast, neuroendocrine neoplasms (NENs)-a heterogeneous group of malignancies arising from neuroendocrine cells across various organ systems-have not traditionally been linked to HPV infection. In this study, we performed extensive genomic and transcriptomic profiling to compare HPV-positive NENs to HPV-positive non-NENs across anatomical sites, aiming to uncover biologically and clinically actionable differences.

HPV16- and HPV18-positive tumors were identified from 101,343 solid tumors profiled at Caris Life Sciences (Phoenix, AZ) with DNA and RNA sequencing. Prevalence of pathogenic mutations and copy number amplifications were calculated. Fisher's exact/χ² tests were applied appropriately with p-values adjusted for multiple comparisons (p < 0.05).

HPV positivity was most frequent in cervical carcinomas (70%, 1200/1716). Importantly, 6% (96/1620) of NENs from all tissues were positive for HPV16 or HPV18. Among HPV-positive NENs, 93% were high-grade compared to 54% observed in HPV-negative NENs (p < 0.001), highlighting a strong association between HPV and tumor aggressiveness in this subset. Analysis of HPV-associated sites (cervix, anorectal region, and head and neck) revealed that HPV-positive NENs possess distinct genomic and transcriptomic landscapes compared to HPV-positive non-NENs. Notably, interferon signaling was significantly suppressed in HPV-positive NENs, suggesting a unique tumor-immune microenvironment.

Our findings indicate that HPV-positive NENs form a distinct subset with unique genomic features, including reduced interferon signaling, compared to HPV-positive non-NENs. Thus, future studies focused on evaluating HPV status, along with genomic and transcriptomic characteristics, may uncover biologically and clinically actionable distinctions for this rare yet clinically significant tumor subgroup.

Not applicable.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.

Brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A-AVD) improves outcomes in advanced-stage classic Hodgkin lymphoma, but patients with a positive early interim PET have inferior prognosis. We evaluated whether very early [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG)-PET-guided treatment adaptation after one cycle of A-AVD improves activity while limiting exposure to intensive chemotherapy.

This single-arm, multicentre, phase 2 trial was conducted at 16 centres in seven countries (the Netherlands, Spain, Denmark, Belgium, Portugal, Slovakia, and Poland). Adults aged 18-60 years with previously untreated advanced-stage classic Hodgkin lymphoma, WHO performance status 0-2, and adequate organ function received one cycle of A-AVD (brentuximab vedotin 1·2 mg/kg intravenously, doxorubicin 25 mg/m² intravenously, vinblastine 6 mg/m² intravenously, and dacarbazine 375 mg/m² intravenously, all on days 1 and 15), followed by centrally reviewed [¹⁸F]FDG-PET-CT (PET1). PET1-negative (Deauville score 1-3) patients received five additional A-AVD cycles; PET1-positive (Deauville score 4-5) patients switched to six cycles of BrECADD (brentuximab vedotin 1·8 mg/kg intravenously on day 1; etoposide 150 mg/m² intravenously on days 2-4; cyclophosphamide 1250 mg/m² intravenously on day 2; doxorubicin 40 mg/m² intravenously on day 2; dexamethasone 40 mg orally on days 2-5; dacarbazine 250 mg/m² intravenously on days 3-4). The primary endpoint was 2-year modified progression-free survival (mPFS), defined as the proportion of patients alive and free of progression, relapse, or death from treatment start, with initiation of new systemic therapy for persistent disease counted as an event. Analyses were prespecified and conducted in the evaluable population (registered and eligible patients, who commenced the allocated treatment according to PET1 results after 1 cycle of A-AVD). The safety population consists of all patients who started A-AVD treatment (ie, received at least one dose of study therapy). This is the primary analysis of a completed trial. This trial is registered on ClinicalTrials.gov (NCT03517137) and EudraCT 2017-000498-35).

From Aug 1, 2019, to Aug 31, 2021, we enrolled 150 patients (81 males [54%] and 69 females [46%]; median age 32 years [IQR 23-39]) who received one cycle of A-AVD, after which 90 (60%) of them had a negative PET1 and 60 (40%) a positive result. 145 were evaluable for efficacy; the median follow-up at the clinical cutoff (Sept 1, 2023; database lock Dec 11, 2023) was 30·1 months (IQR 24·6-36·4). 16 patients experienced an mPFS event. The estimated 2-year mPFS was 89·5% (80% CI 85·7-92·4). The most common grade 3-4 adverse event was neutropenia (53 [35%] of 150) followed by anaemia (18 [12%]) and peripheral sensory neuropathy (nine [6%]). Serious adverse events occurred in 45 (30%) of 150 patients. No deaths occurred.

Very early PET-guided intensification with BrECADD yields high activity in advanced-stage classic Hodgkin lymphoma while sparing most patients intensive chemotherapy.

Takeda Oncology.

In histoplasmosis-endemic regions, pulmonary nodules often raise concern for malignancy. Distinguishing benign infectious granulomas from neoplastic lesions while limiting invasiveness is a major diagnostic challenge.

We report a case series of 11 patients diagnosed with nodular pulmonary histoplasmosis at the University Hospital of Guadeloupe, a French West Indies institution located in an endemic area. Clinical, radiologic, microbiologic, and histopathologic data were retrospectively reviewed.

All 11 patients presented with solid pulmonary nodules associated with mediastinal and/or hilar lymphadenopathy, mimicking locally advanced lung cancer. Among the nine patients who underwent 18F-FDG PET/CT, all but one showed hypermetabolic activity in the nodule. Five patients were immunocompromised, and notably, four of the eleven patients were treated for rheumatoid arthritis. Diagnosis was established through surgical resection in five cases, percutaneous or lymph node biopsy in another five, and bronchoalveolar lavage (BAL) alone in one patient. Serologic testing was positive in all five patients tested, and H. capsulatum PCR on BAL was positive in two of the four cases tested. Exposure history and clinical context supported the diagnosis in several cases, but noninvasive tests alone were generally insufficient to exclude malignancy.

This series illustrates the diagnostic difficulty of pulmonary nodules in histoplasmosis-endemic areas and the frequent need for invasive procedures. The development of improved, noninvasive diagnostic strategies is essential to avoid unnecessary surgery while ensuring timely cancer diagnosis.

Uterine sarcomas are rare heterogeneous neoplasms, comprising only a small percentage of uterine malignancies. There is a diverse array of uterine sarcoma sub-types, each with distinct molecular, clinical, and behavioral features. In recent years, there has been significant advancement in all facets of the multi-disciplinary management of uterine sarcomas. Despite this, several challenges regarding optimization of treatment remain. Pre-operative diagnosis can be difficult, as imaging and biopsy may not reproducibly distinguish uterine sarcomas from benign entities. Early-stage uterine sarcomas are potentially curable with surgery; however, there remains a high risk of recurrence, and the use of adjuvant treatment is controversial. There is also a lack of high-quality data to guide best practices for fertility-sparing surgery in younger patients. Optimal management requires multi-disciplinary discussion by clinicians experienced in sarcoma management at specialized sarcoma centers, as initial management may have a profound impact on patient outcomes. In this review, we summarize and address many of these challenges facing patients with early-stage uterine sarcoma, and provide a comprehensive update on the clinical features, the molecular and genomic pathogenesis, and the current diagnostic and treatment landscape for these patients.

Antibody-drug conjugates (ADC) have emerged as an important part of systemic treatment across disease sites. To date, there is no robust pooled prevalence estimate of nausea and vomiting induced by ADCs. Establishing such estimates is essential to determine if ADC-induced nausea and vomiting (ADCINV) represents a clinically significant problem warranting further research into antiemetic prophylaxis. Our aim is to report the prevalence of reported ADCINV across literature.

A systematic search of Medline, Embase, Cochrane CENTRAL and Web of Science was conducted from database inception until September 24, 2025. Articles were included if they reported nausea and/or vomiting due to ADCs used in cancer treatment, in the abstract. Pooled prevalence was reported. Subgroup analysis was conducted by ADC. Meta-regression was conducted by age and sex. Quality assessment was conducted. Type I error was set at 0.05.

A total of 209 studies with 15,493 patients were included. Thirty-nine percent (95%CI, 36-42%) of patients experience any nausea, and 26% (95%CI, 23-29%) experience any vomiting. Younger patients are more likely to experience nausea; each 10-year increase in age is associated with a 12% decrease in nausea rates. Higher emetogenic ADCs include trastuzumab deruxtecan, sacituzumab govitecan, brentuximabvedotin and patritumab deruxtecan. Lower emetogenic agents include disitimab vedotin, telisotuzumab vedotin and rovalpituzumab tesirine.

This is the first study to report prevalence of ADCINV across ADCs. It is a prevalent adverse effect akin to chemotherapy-induced nausea and vomiting that should be viewed as clinically relevant and further investigated to help develop optimal strategies related to antiemetics.

Breast cancer is a common malignant tumor with limited treatment options and poor prognosis. SNRPB2, a core spliceosomal component involved in pre-mRNA splicing, is dysregulated in multiple cancers, but its role in breast cancer remains incompletely understood.

We analyzed SNRPB2 expression in breast cancer using TCGA, CPTAC, and HPA databases, and assessed its prognostic value via Kaplan-Meier plotter. The biological function of SNRPB2 was evaluated through in vitro cell line assay, and the underlying molecular mechanisms were determined via RNA-seq, RT-qPCR, and additional GEO datasets. Our findings demonstrated that SNRPB2 was significantly overexpressed in breast cancer tissues and correlated with malignant progression and poor prognosis. Knockdown of SNRPB2 induced G2/M cell cycle arrest in cancer cells, decreased expression of numerous genes related to cell cycle and immune modulation, and triggered alterations in multiple alternative splicing events. Mechanistically, SNRPB2 knockdown might promote cancer cell cycle arrest by regulating HMGA2 splicing and expression, while simultaneously suppressing the expression of immune-related genes such as CSF1, CSF1R, IL6, and CX3CL1. Immune infiltration analysis revealed that SNRPB2 expression correlated with increased infiltration of activated inflammatory cells and myeloid-derived suppressor cells.

SNRPB2 potentially plays a dual role in promoting breast cancer progression and shaping the immunosuppressive microenvironment, partly through HMGA2 splicing modulation and immune-regulatory gene suppression. These findings suggest that SNRPB2 may represent a promising therapeutic target for breast cancer.

Tumor is a major disease that seriously threatens human health, and its occurrence and progression involve complex interactions between the genome, epigenome, and environmental factors. Epigenetic modifications-such as DNA methylation, histone modifications, non-coding RNA regulation, and mRNA modifications-play key roles in tumor progression, metastasis, and drug resistance. Natural medicines offer multi-target and holistic regulatory effects, showing unique advantages in cancer therapy. Emerging evidence suggests that natural medicines and its active components can exert anti-tumor activities by modulating epigenetic mechanisms. This review summarizes natural medicines-mediated epigenetic regulation against tumors. It details how natural medicines influences DNA methylation by suppressing DNA methyltransferases (DNMTs) and altering tumor suppressor gene promoter methylation. The modulation of histone modifications through targeting histone deacetylases (HDACs), histone lysine methyltransferases (HKMTs), and histone lysine demethylases (HKDMs) is also discussed. Furthermore, the review covers natural medicines's regulation of non-coding RNAs (e.g., lncRNAs, miRNAs, circRNAs) and their downstream pathways, as well as its role in mRNA modifications, notably N6-methyladenosine (m6A). Overall, this work highlights the epigenetic potential of natural medicines in tumor therapy, enhancing the mechanistic understanding of its anti-tumor effects and supporting natural medicines modernization and precision oncology. However, challenges remain due to natural medicines complexity and tumor epigenetic heterogeneity, calling for deeper investigation and clinical validation.