Although combining programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in neoadjuvant therapy is effective for deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) gastric or esophagogastric junction (EGJ) adenocarcinoma, few T4 stage patients have been studied. The effectiveness and safety of this dual immunotherapy for T4 locally advanced dMMR/MSI-H gastric/EGJ adenocarcinoma is largely unknown. Patients with T4 locally advanced dMMR/MSI-H gastric/EGJ adenocarcinoma treated with dual immune checkpoint inhibitors as neoadjuvant therapy were identified from a prospectively maintained gastric/EGJ adenocarcinoma database. The primary endpoint was the pathological complete response (pCR) rate. Twenty-three patients were included in this study. Of these, 22 (95.7%) completed dual immunotherapy before surgery, while one missed a dose due to immune-related hypophysitis. Sixteen patients (69.6%) underwent surgery, achieving a 100% R0 resection rate. The pCR rate was 81.3% (95% confidence interval (CI): 57.0%-93.4%) and the major pathological response (MPR) rate was 93.8%. Seven patients did not have surgery; five of them, with complete clinical response, opted for a "watch-and-wait" strategy. The event-free survival rate was 95.5% at a median follow-up of 22.1 months, with manageable adverse events. Dual immunotherapy shows promise for T4 locally advanced dMMR/MSI-H gastric/EGJ adenocarcinoma, and the "watch-and-wait" strategy deserves further study in dMMR/MSI-H cases. Larger studies are needed to confirm these results and optimize treatment.

This case report describes a rare presentation of pulmonary melanoma of unknown primary managed through a same-day robotic diagnostic and therapeutic approach. A man in his 70s with an incidentally detected lingular pulmonary nodule suspicious for non-small cell lung cancer underwent robotic navigation bronchoscopy for biopsy and dye marking, immediately followed by robotic-assisted thoracic surgery. Intraoperative frozen section revealed a malignant spindle cell neoplasm, prompting definitive surgical resection during the same anaesthetic event. Final histopathology and molecular analysis confirmed melanoma, with no identifiable cutaneous, mucosal or ocular primary. The patient subsequently received adjuvant immunotherapy and remains disease-free at 24 months. This case highlights the diagnostic challenge of pulmonary melanoma mimicking lung carcinoma and demonstrates how integration of robotic bronchoscopy and robotic surgery can enable rapid diagnosis, definitive management and streamlined care within a single operative session.

The human PROMININ-1 (PROM-1, CD133), detected by its AC133 epitope, is expressed on the surface of leukemia-initiating cells of Philadelphia chromosome-positive (Ph+) leukemia cells. Ninety-five percent of chronic myeloid leukemia (CML) cases are Ph+. Ph+ acute lymphoblastic leukemia (ALL) accounts for twenty-five to thirty percent of adult ALL and is considered a high-risk ALL subgroup. Targeting the t(9;22)-fusion protein BCR::ABL1 with ABL1-directed kinase inhibitors (TKIs) is a proven therapeutic concept for CML and Ph+ ALL. Resistance against TKI comprises mutations in BCR::ABL1, but many patients exhibit a primary resistance with unknown mechanisms. Here, we investigated the impact of PROM-1 on the leukemogenesis and the therapy response of Ph+ leukemias. We applied flow cytometry, co-immunoprecipitation, immunoblotting, stem cell assays, and leukemia induction in vivo to cell lines, syngeneic mouse models, and human Ph+ long-term cultures. We found a direct relationship between BCR::ABL1 and PROM-1, a shift from CML towards ALL upon the loss of Prom-1, as well as a link between the response to TKIs and the PROM-1 expression. In contrast to solid tumors, resistance was accompanied by a progressive loss of PROM-1. Our data suggest that PROM-1 plays an essential role in both cell fate decision and induction of the BCR::ABL1-related leukemic phenotype, highlighting its impact on the drug response of Ph+ leukemias. Teaser abstract The Philadelphia chromosome (Ph) is the product of the t(9;22), which fuses the BCR gene on chromosome 22 to the ABL1 gene on chromosome 9. The result is the BCR::ABL1 oncogene, which is responsible for the induction of chronic myeloid leukemia (CML) and for about a third of acute lymphoblastic leukemia (Ph+ ALL). Only little is known about how t(9;22) induces either CML or ALL, and why there is a difference between the two diseases regarding their response to inhibitors that can inactivate BCR::ABL1. Here, we show that a gene called PROMININ-1 is involved in both processes: determining whether BCR::ABL1 induces CML or ALL, and explaining the weaker response of Ph+ ALL compared to CML to inhibitors of BCR::ABL1. We found that the reduction of PROMININ-1 increased the proportion of ALL induced by BCR::ABL1 in the mouse. We could not reproduce these findings in humans but distinguish CML from Ph+ ALL by the expression of PROMININ-1. Also resistance to BCR::ABL1 inhibitors was associated with low expression of PROMININ-1 in Ph+ ALL. These findings are in contrast to observations in solid tumors where a higher level of PROMININ-1 is accompanied by therapy resistance. Our findings contribute to a better understanding of the different types of Ph+ leukemia and their response to therapy, which will help patients better manage these diseases.

Hypoxia-inducible factor 2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC) and a therapeutic target of the small-molecule inhibitor belzutifan. Genetic studies in murine models have suggested that hypoxia signaling may support T cell effector programs, raising concern that HIF-2α inhibition could impair antitumor immunity. However, whether pharmacologic HIF-2α inhibition alters human T cell biology remains unknown. Here, we investigated the cell-intrinsic effects of EPAS1 (encoding HIF-2α) perturbation in primary human T cells. CRISPR/Cas9-mediated deletion of HIF-2α demonstrated no notable transcriptional effects. Similarly, pharmacologic treatment with belzutifan produced minimal transcriptional changes and did not impair proliferation, cytokine production, polyfunctionality, or cytotoxic activity in T cells derived from healthy donor peripheral blood, peripheral blood from patients with ccRCC, or tumor-infiltrating lymphocytes under hypoxic conditions. High- dimensional immunophenotyping revealed preserved T cell differentiation and activation states following pharmacologic HIF-2α inhibition in vitro and in peripheral blood from patients receiving HIF-2α inhibitor therapy. Together, these findings demonstrate that pharmacologic HIF-2α inhibition preserves key effector programs, providing a mechanistic basis for the immunologic safety of HIF-2α-targeted therapy in ccRCC.

With the increasing prevalence of human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC), there is a need for efficient, minimally invasive methods to evaluate p16 status. This study aimed to assess the concordance of p16 status between ultrasound (US)-guided core needle biopsy (CNB) of cervical lymph nodes and surgical specimens, and to describe the numbers of CNB and surgical sessions required to establish the histopathologic diagnosis. This retrospective study included 39 patients diagnosed with OPSCC or head and neck squamous cell carcinoma of unknown primary (SCCUP) at a single tertiary hospital between March 2019 and March 2024. All included patients underwent US-guided CNB of cervical lymph nodes and a surgical procedure (biopsy or resection), and had evaluable p16 immunohistochemistry (IHC) results on both specimen types. The concordance rate for p16 status between US-guided CNB and surgical specimens was 100.0% (39/39; 95% CI, 91.0-100.0%; 35 p16-positive and 4 p16-negative cases). Sensitivity was 100.0% (35/35; 95% CI, 90.0-100.0%) and specificity was 100.0% (4/4; 95% CI, 39.8-100.0%). In all 39 included patients, a diagnosis of metastatic squamous cell carcinoma and an evaluable p16 result were obtained at the first CNB session. Among the 35 patients with OPSCC, 10 (28.6%) required more than 1 surgical session at the primary tumor site. No immediate complications were observed following US-guided CNB. In this cohort, US-guided CNB of cervical lymph nodes showed complete observed concordance with surgical specimens for p16 status, and a diagnosis with an evaluable p16 result was obtained at the first CNB session in all patients. Prospective, multicenter validation including more p16-negative cases is required before wider adoption.

Cardiovascular-kidney-metabolic (CKM) syndrome represents a pathophysiological continuum from metabolic dysregulation to cardiovascular injury. However, whether dietary interventions confer stage-specific benefits remains unknown. We aimed to examine the association between flavonoid intake and CKM stages and to assess baseline intake and mortality across stages. We analyzed 10,754 US adults from National Health and Nutrition Examination Survey (2007-2010, 2017-2018). CKM stages (0-4) were defined at baseline. Flavonoid intake was assessed via two 24-hour recalls. Mortality was ascertained using the National Death Index linkage in December 2019 (median follow-up, 9.6 years). Cross-sectional associations with CKM stages were examined using multinomial logistic regression. Prospective associations with all-cause, cardiovascular, and cancer mortality were examined using survey-weighted Cox models stratified by CKM stage. Restricted cubic splines and weighted quantile sum regression further characterized dose-response relationships and mixture effects. Higher flavonoid intake was associated with lower odds of advanced CKM stage (stage 2 vs 0: Q4 odds ratio: 0.53; 95% confidence interval [CI]: 0.33-0.83). Stage-specific mortality associations emerged: Q4 reduced cancer mortality in stages 1 to 2 (hazard ratio [HR] = 0.60; 95% CI: 0.37-0.96) and all-cause mortality in stages 3 to 4 (HR = 0.80; 95% CI: 0.65-0.99). An L-shaped dose-response showed an inflection at 218.8 mg/d; below this, each 50 mg/d increment reduced the risk by 9% (HR = 0.91). The inverse associations were stronger in adults aged <65 years and nonusers of lipid-lowering medications (P < .05). Weighted quantile sum regression identified anthocyanidins (50.6%) and flavones (24.8%) as primary contributors to cancer mortality reduction in the early stages, whereas isoflavones contributed 49.7% to all-cause mortality protection. These findings suggest potential stage-specific benefits: anthocyanidin- and flavone-rich diets may warrant further investigation for prevention, whereas isoflavone-focused intake may have relevance for survival in advanced stages. The observed threshold of approximately 219 mg/d provides a potential quantitative target for future research.

Pulmonary tumour thrombotic microangiopathy (PTTM) is a rare but frequently fatal condition characterized by rapidly progressive pulmonary hypertension and right heart failure caused by tumour microemboli in the pulmonary vasculature. We report the case of a 64-year-old man who presented with rapidly progressive respiratory failure. Chest computed tomography demonstrated centrilobular nodules and a tree-in-bud (TIB) pattern. Pulmonary perfusion scintigraphy and transthoracic echocardiography suggested pulmonary hypertension with multiple peripheral perfusion defects, raising strong clinical suspicion for PTTM. Transbronchial lung biopsy (TBLB) revealed TTF-1-positive adenocarcinoma, although the primary tumour site remained undetermined. Based on these findings, clinically suspected PTTM was diagnosed and nivolumab monotherapy was promptly initiated as systemic treatment for the underlying malignancy. Despite transient severe deterioration, the patient's respiratory function improved markedly, and he has remained progression-free for more than 3 years. This case highlights the importance of early clinical recognition of PTTM and prompt initiation of appropriate systemic therapy, even before definitive identification of the primary tumour when clinically warranted.