BACKGROUND: Immunotherapy has transformed the management of some solid tumor types, but its impact has been limited to the subset of cancer patients who have "hot" or immunogenic tumors. Num2erous studies are based on st...BACKGROUND: Immunotherapy has transformed the management of some solid tumor types, but its impact has been limited to the subset of cancer patients who have "hot" or immunogenic tumors. Num2erous studies are based on strategies for turning "cold," or immune-unresponsive, tumors into a "hot" state. The gut microbiome has emerged as a potential co-therapy for standard immune checkpoint inhibitors (ICIs) to achieve this goal. Recent approaches have primarily focused on the use of probiotics, microbial consortia, or fecal microbiota transplantations in combination with anti-PD-1 and anti-CTLA-4 antibodies. METHODS: This review highlights the current status of microbiome modulation and its potential impact on clinical practice. Probiotics, such as CMB588, and microbial consortia have been selected following successful preclinical studies. These taxa may initiate T cell infiltration and are commonly found in the microbial profiles of individuals who have previously responded to immunotherapy. RESULTS: Several trials with these therapies have had success and noted minimal safety concerns compared to monotherapy treatments. Fecal microbiota transplantation (FMT), originally used to treat Clostridium difficile infections, has also demonstrated promising results in increasing immune checkpoint inhibitor (ICI) efficacy across various cancer types and is being utilized in multiple ongoing trials. CONCLUSION: These therapeutics form the foundation for exciting possibilities in immunotherapy and improving patient outcomes.
OncoEducate is a clinician-supervised generative artificial intelligence (AI) application designed to deliver standardized, regimen-level, plain-language education at the point of care. We developed a templated handout g...OncoEducate is a clinician-supervised generative artificial intelligence (AI) application designed to deliver standardized, regimen-level, plain-language education at the point of care. We developed a templated handout generator using a locked prompt and predefined content structure that incorporates diagnosis, treatment regimen, and treatment intent, with clinician review prior to patient distribution. We then conducted a prospective, two-phase pilot at a single academic cancer center. In Phase I, six clinicians evaluated AI-generated handouts for nine commonly used palliative-intent genitourinary (GU) oncology regimens using 7-point Likert-scale items. In Phase II, patients with advanced kidney, prostate, or urothelial cancers initiating palliative-intent therapy received clinician-reviewed handouts and completed follow-up surveys at the next office or infusion visit or by telephone when in-person completion was not feasible. Clinicians rated handouts as useful (median 6/7) and accessible (median 6.5/7), with median accuracy ratings of 6-7/7 across domains. During an 8-week period, 20 of 21 approached patients enrolled (95%). Patients rated handouts as informative and readable (median 7/7 for both), and 65% correctly identified treatment intent as palliative. These findings support the feasibility and acceptability of clinician-reviewed, templated AI-generated handouts in routine GU oncology care, justifying larger randomized studies to evaluate clinical impact.
BACKGROUND: It is unclear whether moderate-intensity aerobic exercise is feasible and safe for inpatients with non-hematological cancer receiving one cycle of chemotherapy. OBJECTIVES: To evaluate adherence, compliance,...BACKGROUND: It is unclear whether moderate-intensity aerobic exercise is feasible and safe for inpatients with non-hematological cancer receiving one cycle of chemotherapy. OBJECTIVES: To evaluate adherence, compliance, acceptability, adverse events, and clinical stability during a short-term moderate-intensity aerobic training in non-hematological inpatients undergoing one cycle of chemotherapy. METHODS: This feasibility and safety study included adults with non-hematological cancer inpatients receiving one cycle of chemotherapy. Patients participated in four consecutive days of moderate-intensity aerobic training using a cycle ergometer, during which vital signs and perceived exertion were monitored. Following the intervention, patients were assessed for the acceptability of intervention. Adherence rates, compliance, and adverse events related to the training were also recorded. RESULTS: Twenty patients (mean age 61 ± 15 years, mean BMI 25 ± 8 kg/m2; 75% with digestive cancers, 50% physically active) were analyzed. Adherence to the intervention was 92%, compliance was 68.6%, and acceptability was reported at 100%. Vital signs and perceived exertion remained stable throughout all training sessions (heart rate P = .99, peripheral O2 saturation P = .54, mean arterial blood pressure P = .79, sensation of dyspnea P = .97). Two patients reported adverse events during training (vomiting and extreme fatigue), while three experienced adverse effects post-training (tremor, nausea, and back pain). CONCLUSIONS: Short-term moderate-intensity aerobic training for inpatients with non-hematological cancer undergoing one cycle of chemotherapy is feasible and safe.
T-cell engagers (TCEs) are a diverse class of bispecific and multispecific molecules that co-bind CD3 on T cells and tumor-associated antigens to form an immune synapse and induce targeted T-cell-mediated cytotoxicity. W...T-cell engagers (TCEs) are a diverse class of bispecific and multispecific molecules that co-bind CD3 on T cells and tumor-associated antigens to form an immune synapse and induce targeted T-cell-mediated cytotoxicity. While TCEs have demonstrated remarkable efficacy in hematologic malignancies, translation into solid tumors has been more challenging. Recent advances seen with tebentafusp in metastatic uveal melanoma and tarlatamab in small-cell lung cancer have validated the approach and driven a rapidly expanding pipeline targeting other tumor associated antigens such as STEAP1, MUC16, and PRAME among others. Unique challenges in solid tumors include antigen heterogeneity and density thresholds, on-target/off-tumor toxicities, and physical and immunologic barriers within the tumor microenvironment. To address these, next-generation engineering strategies, such as half-life extension, protease- or context-dependent masking, multispecificity, and "armed" constructs incorporating cytokine or co-stimulatory payloads, are being developed to enhance intratumoral activity while limiting systemic toxicities. Combination regimens with checkpoint blockade, chemotherapy, targeted therapies, and oncolytic platforms are also being actively investigated to overcome immune resistance and improve durability of response. Collectively, next-generation TCEs guided by rational target selection, context-dependent activation, and biomarker-driven patient stratification, are poised to broaden the reach of immunotherapy in solid tumors. In this review, we synthesize the recent advances that aim to expand the therapeutic window of TCEs for the treatment of solid tumors.
BACKGROUND: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms with distinct histopathological, immunophenotypic, and molecular features. Described in the early 1990s, they include angiomyolipo...BACKGROUND: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms with distinct histopathological, immunophenotypic, and molecular features. Described in the early 1990s, they include angiomyolipoma, lymphangioleiomyomatosis, and clear cell "sugar" tumors, and can arise in various sites, most often the kidney, uterus, lung, and soft tissues. While usually indolent, some exhibit aggressive behavior with invasion, recurrence, and metastasis. METHODS: A comprehensive literature review was conducted to summarize the current understanding of PEComa biology, diagnostic approaches, risk stratification systems, and therapeutic strategies. Emphasis was placed on studies defining the molecular landscape, treatment outcomes with mTOR inhibitors, and emerging prognostic tools. RESULTS: Molecularly, most PEComas harbor loss-of-function mutations in the TSC1 or TSC2 genes, resulting in constitutive mTOR signaling pathway activation, a central driver of tumorigenesis and a key therapeutic target. A distinct subset is defined by TFE3 gene rearrangements, exhibiting unique clinicopathologic features and suggesting an alternative, mTOR-independent oncogenic mechanism. Accurate diagnosis requires integration of morphology, immunohistochemistry, and molecular testing, while risk stratification is guided by established histologic criteria and emerging prognostic models. Surgical resection remains the standard of care for localized disease, whereas mTOR inhibitors constitute the cornerstone of systemic therapy for advanced or unresectable PEComas. Additional approaches, including immune checkpoint inhibitors, locoregional therapies, and chemotherapy, may be considered in selected cases. CONCLUSIONS: This review summarizes PEComa biology, diagnosis, prognosis, and treatment, emphasizing the need for international collaboration to improve risk stratification and personalized therapies.
Koot A, Ottevanger P, Hermens R
… +14 more, Aarts A, Walraven J, Bonenkamp H, de Wilt J, Nieuwenhuijzen G, van der Veen A, Keemers M, Zandee W, Blanken C, van Aken M, Donders R, Stalmeier P, Netea-Maier R, COMBO study group
BACKGROUND: : Over the last decades optimal treatment for patients with differentiated thyroid cancer (DTC) is debated. Two treatment decisions for patients who could benefit from more individualized approaches and share...BACKGROUND: : Over the last decades optimal treatment for patients with differentiated thyroid cancer (DTC) is debated. Two treatment decisions for patients who could benefit from more individualized approaches and shared decision making (SDM), are the extent of surgery decision in patients with low-risk DTC, and the decision to start or delay the treatment with Tyrosine Kinase Inhibitors (TKIs) in patients with advanced DTC. Our aim is to examine the effect of a Patient Decision Aid (PtDA) on observed SDM, while physicians were trained in SDM. METHODS: In this multicenter RCT (2020-2024), all physicians (n = 26) received a 5-hour SDM training. Patients (n = 86) with DTC were randomized to receive a PtDA or care as usual. The primary outcome was the observed SDM as rated by blinding observers with the observing patient involvement in decision making (OPTION5) scale from audio-recorded consultations. Secondary outcomes included well-being measures, information-related measures, and decision-related measures. RESULTS: Mean OPTION5 scores were 52 (range 0-100) for the PtDA and 54 (range 0-100) for the usual care group. The PtDA did not improve observed SDM, nor the secondary outcomes. Results of the Beta testing (n = 33) showed that the PtDA was readable (n = 30) and helpful for decision making (n = 28). All patients recommended using the PtDA. CONCLUSION: In this RCT, with high baseline SDM quality provided by trained physicians, PtDAs did not further improve SDM quality. Nevertheless, since all patients recommended the PtDA, future studies should establish the potential benefit of PtDAs, particularly as SDM training is usually not provided. TRIAL REGISTRATION: ClinicalTrials.gov NCT03905369.
BACKGROUND: IDH1 mutations are causal in tumor development and progression; however, their association with disease characteristics, prognosis, and therapy response in patients with resected intrahepatic cholangiocarcino...BACKGROUND: IDH1 mutations are causal in tumor development and progression; however, their association with disease characteristics, prognosis, and therapy response in patients with resected intrahepatic cholangiocarcinoma (ICC) remains controversial. MATERIALS AND METHODS: In this cohort study, we recruited 803 patients who underwent curative resection for ICC at a single hospital in China. We performed whole-exome sequencing and Sanger sequencing to identify IDH1 mutations. We used the Kaplan-Meier method and log-rank test to compare overall survival (OS) and disease-free survival (DFS). RESULTS: A total of 5 different subtypes of IDH1 somatic mutation affecting 94 (11.7%) patients were identified. R132C was the most frequent mutant allele in this cohort, followed by R132L and R132G. Across all patients considered, those that received adjuvant chemotherapy had significantly superior OS and DFS compared with those that did not receive adjuvant chemotherapy. In the whole ICC cohort, patients with IDH1 mutations showed no significant difference in OS compared with patients with wild-type IDH1. When we looked at patients that either received or did not receive adjuvant chemotherapy separately, univariate and multivariable analyses revealed that IDH1 mutations were significantly associated with superior OS among patients that received adjuvant chemotherapy, whereas they were marginally associated with worse OS among patients that did not receive adjuvant chemotherapy. CONCLUSION: We characterized the distribution of IDH1 mutations in a large cohort of patients with ICC from China. The presence of IDH1 mutations was associated with better survival and decreased risk of recurrence in patients with resected ICC that received adjuvant chemotherapy.
BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Medulloblastoma has intrinsic characteristics that pose significant challenges to effective immunotherapy. Nevertheless, several clinical...BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Medulloblastoma has intrinsic characteristics that pose significant challenges to effective immunotherapy. Nevertheless, several clinical trials have explored immunotherapeutic strategies in patients diagnosed with medulloblastoma. This systematic review aimed to synthesize all immunotherapy modalities investigated in medulloblastoma patients and reported clinical outcomes. METHODS: A systematic search was conducted in PubMed, Scopus, Web of Science, and ClinicalTrials.gov from inception to 30 June 2025 using the terms "immunotherapy" and ("brain tumor," "pediatric brain tumor," or "medulloblastoma"). Original articles, clinical trials, and conference abstracts evaluating any immunotherapeutic intervention in patients with medulloblastoma were included. Risk of bias was assessed using JBI critical appraisal tools. RESULTS: Fifty-six studies met the inclusion criteria, encompassing at least 183 patients with medulloblastoma. Nearly half were Phase I trials (24/56, 43%), and 18% (10/56) were non-trial designs. Among the 29 studies reporting clinical outcomes, adoptive cellular therapies in combination regimens (7/29, 24%) and immune checkpoint inhibitors (6/29, 21%) were most frequently evaluated. Overall, clinical benefit was limited. Median overall survival ranged from 1.29 to 47 months, and median progression-free survival from 0.79 to 11 months. Progressive disease was reported in 40 patients, partial responses in 13, and complete responses in three patients. CONCLUSIONS: Despite increasing trial activity, immunotherapy has shown modest efficacy in patients with medulloblastoma. Interpretation is limited by small cohorts, heterogeneity, and inconsistent reporting of outcomes. Future studies should prioritize rational antigen selection, molecular subgroup stratification, and improved trial design.
Rieke DT, Schwartz S, Ochsenreither S
… +14 more, Chapuy B, Amthauer H, Deubzer HE, Lehmann A, Keilholz U, Wardelmann E, Vokuhl C, Eggert A, Fröhling S, Horst D, Capper D, Keller U, Dragomir MP, Schallenberg S
Metastatic cancers of unknown primary (CUP) pose significant diagnostic and therapeutic challenges. We present the case of a 63-year old male patient with a CUP showing neuroendocrine differentiation, metastasized to the...Metastatic cancers of unknown primary (CUP) pose significant diagnostic and therapeutic challenges. We present the case of a 63-year old male patient with a CUP showing neuroendocrine differentiation, metastasized to the iliac bone, bone marrow, supraclavicular and retroperitoneal lymph nodes. Immunohistochemical and molecular profiling revealed strong pan-neurotrophic tyrosine kinase (Trk) expression without NTRK-gene fusion, corroborating the neural cell origin. Following molecular tumor board (MTB) discussion, genome-wide methylation profiling suggested the diagnosis of a neuroblastoma but results were below diagnostic thresholds. Subsequent imaging and laboratory findings confirmed an INRGSS stage M neuroblastoma, a rare finding in older adults. Despite multimodal therapy, including polychemotherapy and immunotherapy according to pediatric GPOH neuroblastoma guidelines, disease progression necessitated an experimental approach. Comprehensive molecular analysis and MTB discussion revealed several potential treatment targets, leading to subsequent treatment including dinutuximab beta, nivolumab, cabozantinib, I-131-mIBG radionuclide therapy and alpelisib, unfortunately, all followed by disease progression. This case demonstrates the potential of comprehensive molecular analysis including methylation profiling for diagnosis and treatment guidance in rare tumors. Additional research is urgently required to improve outcomes in elderly patients with neuroblastoma.
BACKGROUND: Guidelines recommend biopsy of first breast cancer recurrence. Our group recently showed that only half of patients in Washington diagnosed with metastatic breast cancer (MBC) between 2008 and 2017 underwent...BACKGROUND: Guidelines recommend biopsy of first breast cancer recurrence. Our group recently showed that only half of patients in Washington diagnosed with metastatic breast cancer (MBC) between 2008 and 2017 underwent biopsy. METHODS: Oncologists in our group identified patients in which a lung malignancy was diagnosed in patients with a breast cancer history. RESULTS: We identified eight illustrative cases. Lung findings were typically identified on a CT obtained for staging or radiation planning. In five cases, patients were treated curatively for two early-stage malignancies. In two cases, patients with MBC were found to have early-stage lung adenocarcinomas. In one case, MBC and metastatic lung cancer were diagnosed synchronously. CONCLUSIONS: While imaging can raise suspicion for breast cancer recurrence, relying on radiologic appearance to infer that a lesion (1) is malignant and (2) represents spread of the known primary risks treating both the primary tumor and the newly detected condition inappropriately.
Jani CT, Tran E, Jaeger E
… +11 more, Dong J, Husni N, Stoppler MC, Hockenberry AJ, Mercer J, Pal S, Agarwal N, Choueiri TK, Rose B, Bagrodia A, McKay RR
INTRODUCTION: Circulating tumor DNA (ctDNA) sequencing complements tissue-based next-generation sequencing (NGS), offering noninvasive and serial testing. We explore the mutational landscape of renal cell carcinoma (RCC)...INTRODUCTION: Circulating tumor DNA (ctDNA) sequencing complements tissue-based next-generation sequencing (NGS), offering noninvasive and serial testing. We explore the mutational landscape of renal cell carcinoma (RCC) using matched tissue and ctDNA data to assess complementarity and clinical significance of molecular alterations. METHODS: From the Tempus multimodal database, we retrospectively analyzed de-identified data from patients with RCC with concurrent tissue (Tempus xT) and ctDNA testing (Tempus xF). Patients with xT and xF matched samples (collected ±90 days of one another) were included. We evaluated socio-demographic and clinical characteristics and selected pathogenic somatic short variants (PSSVs) and copy number variants (CNV). Analyses were restricted to the 104 genes shared by all assays. RESULTS: Among 392 patients, 66% (n = 259) had metastatic disease. The median time from tissue to blood collection was 21 days. The most common tissue sites were kidney (49%, n = 189) and bone (11%, n = 43). Frequently altered tissue-tested genes were: VHL (59%), PBRM1 (32%), and SETD2 (23%). Most frequently altered genes in ctDNA were TP53 (23%), VHL (18%), BAP1 (6%), and PBRM1 (5%); notably, 176 patients did not have any pathogenic or likely pathogenic variants detected in the 104 genes analyzed. Complementary ctDNA and tissue testing detected 6% more alterations than tissue testing alone, with greater concordance in metastatic cases. CONCLUSION: ctDNA testing offers complementary insights to tissue NGS in RCC, particularly in metastatic disease, suggesting the potential utility of ctDNA in advanced RCC. Longitudinal analysis may enhance delineation of biomarkers of response and resistance at mutation and ctDNA fraction levels.
BACKGROUND: This study aimed to examine the number of FDA-approved cancer pharmacotherapies and analyse pivotal study characteristics over time, including sample sizes. METHODS: We developed a web scraper to collate a co...BACKGROUND: This study aimed to examine the number of FDA-approved cancer pharmacotherapies and analyse pivotal study characteristics over time, including sample sizes. METHODS: We developed a web scraper to collate a cohort of FDA-approved cancer pharmacotherapies from 1953 until 31 December 2024. For each pharmacotherapy, details of pivotal studies leading to approval were recorded, including protocol and final sample size, study design, therapy type, and quality assessment using Cochrane Risk of Bias tools. We used regression analyses and discretization to identify trends in sample size. Type I error was set at 0.05.(Study protocol pre-registration: https://doi.org/10.17605/OSF.IO/KVA23). RESULTS: We identified 255 pharmacotherapies, supported by 306 pivotal studies; 125 (49%) were targeted pharmacotherapies, 61 (24%) chemotherapies, 47 (18%) immunotherapies, 21 (8%) hormonal therapies, and 1 (0.4%) other. The median sample size was 290 (IQR = 427); sample sizes increased in the 1990s (median = 407) and remained stable thereafter. Stratified analysis demonstrated smaller sample sizes for phase 1 and 2 studies before 1980, with no change in phase 3 studies. For 165 studies reporting protocol sample sizes, studies from 2020-2024 (median = 147.5) were smaller than those from 2010-2019 (median = 320). CONCLUSIONS: The increase in sample sizes during the 1990s may reflect new policies and legislation. Subsequent stability in sample size could be due to modern trial designs (eg, basket/umbrella studies, surrogate endpoints) that require smaller sample sizes. The recent decrease in protocol sample sizes may herald a similar decline for future studies but requires post-market surveillance to verify credibility.
INTRODUCTION: Molecular tumor boards (MTBs) integrate clinical, pathological, and molecular data to prioritize therapy options. Because MTB-guided treatment starts at varying time points after MTB discussion, vulnerabili...INTRODUCTION: Molecular tumor boards (MTBs) integrate clinical, pathological, and molecular data to prioritize therapy options. Because MTB-guided treatment starts at varying time points after MTB discussion, vulnerabilities to immortal time bias occur if treatment delay is ignored. METHODS: Retrospective survival analysis of 949 consecutive individuals discussed at the University Cancer Center Hamburg MTB (2016-2022). Index date (t0) was the first MTB discussion. Therapy initiation was modeled as a time-dependent exposure using Mantel-Byar methods and visualized with Simon-Makuch plots. Therapy strata were priority 1 targeted, priority 2 targeted, and non-targeted therapy. RESULTS: Among solid tumors (n = 854), targeted therapy was implemented in 24% and was off-label in 51%. ORR/DCR were 30.8%/61% for priority 1, 11.4%/36.4% for priority 2, and 37.5%/52.1% for non-targeted therapy (P = .017). The progression-free survival ratio (MTB-directed therapy vs immediately preceding line) exceeded 1.3 in 63% of targeted therapy recipients. From the MTB date, median survivalMTB was 16.5 months (priority 1), 15.5 months (priority 2), and 11.0 months (non-targeted). In Mantel-Byar analysis, progression-free survivalSimonMakuch favored priority 1 (P = .002) with 1-year rates of 28%, 12%, and 15% for priority 1, priority 2, and non-targeted therapy, respectively. One-year overall survivalSimonMakuch was 52%, 34%, and 42%. In a time-dependent Cox model, priority 1 was associated with lower risk of death versus no targeted post-MTB therapy (hazard ratio 0.80, 95% confidence interval 0.64-0.99, P = .038). CONCLUSIONS: After correction for immortal time bias, implementation of the top-priority MTB recommendation was associated with improved disease control and survival signals, although confounding and selection effects remain key limitations.