Gastric carcinoma poses a significant global health challenge, often diagnosed late due to its similarity to chronic gastric conditions. Helicobacter pylori (Hp) infection plays a crucial role in gastric carcinogenesis through inflammation and the release of virulent products.

Ovarian cancer remains the most lethal gynecologic cancer and has the worst prognosis among all female reproductive malignancies worldwide. In Ethiopia, ovarian cancer is the third most prevalent malignancy among women, following breast and cervical cancers. Despite extensive research on the topic, evidence regarding the determinants of mortality among ovarian cancer patients remains limited. Therefore, the primary aim of this study was to identify predictors of ovarian cancer mortality among patients receiving care at oncology centers in Addis Ababa, Ethiopia.

Pulmonary metastasectomy is an established part of the multimodal treatment of various malignant diseases. While the procedure typically focuses on complete removal of metastatic lesions, the role of mediastinal lymph node involvement remains unclear. We aimed to analyze the prevalence of lymph node involvement and its impact on prognosis in patients undergoing pulmonary metastasectomy.

T cell dysfunction (TCD) plays a critical role in cancer progression and significantly impacts patient outcomes. Despite its importance, the exact molecular mechanisms underlying TCD remain poorly understood. To address this, we constructed a comprehensive pan-cancer landscape of TCD, with a particular focus on identifying miRNA biomarkers that define and predict TCD severity. Our analysis revealed six key miRNAs (miR-203b, miR-214, miR-4772, miR-141, miR-200a, and miR-200b) that were closely associated with varying degrees of TCD. These prognostic miRNAs not only exhibited distinct expression patterns across four identified TCD subtypes (from low to high TCD severity) but also demonstrated strong predictive performance in classifying patients with different levels of TCD. The identified miRNA signatures serve as reliable biomarkers for stratifying patients into high-risk and low-risk groups, with higher TCD levels correlating to poorer overall survival. In addition to miRNA biomarkers, we observed that patients with severe TCD exhibited increased infiltration of immune cells and macrophages and dysregulation of DNA methylation patterns. Patients with higher degrees of TCD displayed low methylation levels, which further contributed to the progression of T cell dysfunction. In summary, our study highlights the pivotal role of miRNA biomarkers in shaping the landscape of T cell dysfunction across cancers. These miRNAs serve as both prognostic indicators and predictive tools, enabling accurate classification of TCD severity and offering new avenues for therapeutic exploration and patient stratification in cancer immunotherapy.

Breast cancer treatment depends on tumour subtypes. In particular, patients with oestrogen receptor-positive (ER+) tumours are treated with hormonal therapy. In Sweden, the recommended treatment duration is five years, with current guidelines advising an additional five years for women at high risk of disease recurrence. However, the impact of extended therapy on metastatic progression has not been thoroughly quantified at the population level. In this article, we use a modelling approach to estimate the time-varying effect of hormonal treatment on time to metastasis. The model is then used to compare 5- and 10-year treatment durations at different tumour sizes. Rather than using a common statistical modelling approach, we incorporate the effect of endocrine therapy within a biologically inspired natural history model of breast cancer to accommodate key features of the expected treatment-outcome relationship. We fitted the model using maximum likelihood and data from a cohort of 9,716 incident cases diagnosed with invasive ER+ breast cancer between 2005 and 2020. Based on our main model estimates, the 10-year metastasis-free survival would improve from 92.8% to 96.1% for a symptomatic patient with a 20 mm tumour with ten years (instead of five) of hormonal treatment. Our natural history model quantifies the impact of prolonged hormonal treatment on metastatic events in ER+ breast cancer patients, including features that are not captured by traditional statistical approaches. Results suggest a significant reduction in metastatic tumour growth rates during treatment, supporting the extension of endocrine therapy to 10 years for people with large tumours.

Although some patients with cervical cancer respond well to therapy, others show minimal response and develop recurrence after treatment. A better understanding of the molecular features that distinguish and drive the variable responses to therapy is needed to improve patient stratification and treatment. In this issue of Cancer Research, Sandoval and colleagues conduct integrated multiomic analyses of longitudinal patient cohorts to characterize the molecular and cellular reprogramming induced by chemoradiation therapy (CRT). The analyses show that treatment fundamentally reshapes the tumor microenvironment, inducing a shift from lymphoid-dominant to myeloid-dominant immune infiltration. The authors also identify the induction of MDM2-dependent DNA damage response specifically in tumor cells. Leveraging both treatment-naïve and CRT-exposed patient-derived xenografts, they demonstrate that MDM2 inhibition enhances radiation response, with the greatest efficacy in therapy-resistant tumors. These findings identify MDM2 as a rational, therapy-induced target emerging from unbiased analysis. As the field moves toward integrating targeted therapies and immunotherapy with standard chemoradiation, this study underscores the importance of understanding when, where, and in whom to intervene. See related article by Sandoval et al., p. 1639.

Serous tubal intraepithelial carcinomas (STIC) are precursors of high-grade serous carcinoma (HGSC), the deadliest subtype of ovarian carcinoma. To establish clinically actionable strategies against these lesions, a better understanding of the mutational, transcriptional, and genetic/epigenetic alterations, as well as interactions among epithelial, immune, and stromal cells, is essential. In this issue of Cancer Research, Shih and colleagues conducted the first integrated spatial multiomics analysis of ovarian precancerous lesions, revealing substantial heterogeneity within the fallopian tube epithelium that may influence cancer susceptibility. They described four molecular subclasses of STICs according to their epithelial transcriptomic profiles: proliferative, immunoreactive, mixed, and dormant (PIMD) subtypes. Molecular links of this "PIMD" STIC subclassification to tumor progression were proposed, uncovering early events in ovarian tumorigenesis and potential genetic drivers of STIC heterogeneity. Furthermore, the STIC subtypes showed distinct histologic and molecular characteristics that warrant further investigation to develop a deeper understanding of the molecular and cellular processes driving the evolution of STIC heterogeneity, which may facilitate the development of early diagnostic approaches for HGSC. Collectively, the findings that not all STICs are equal open new avenues for further clinicopathologic, translational, and basic research to improve risk classification and early intervention in HGSC. See related article by Chang et al., p. 1739.

Tensins are a family of adhesion proteins that play a role in constructing the cytoskeleton, as well as in intracellular and extracellular communication. Their expression was evaluated in 22 pancreatic cancer patients using the immunohistochemistry method. TNS1 expression occurred more frequently among patients with tumor diameter ≥ 2 cm, which may suggest an association with the development of pancreatic cancer. Intraductal TNS1 was observed less often with presence of necrosis and hemorrhages in tumor. The fact that cancer cells secrete TNS1 suggests that it could be investigated as a potential target for liquid biopsies. TNS4 expression occurred more frequently among females and was observed when necrosis in tumor was strong. TNS2 and TNS3 are not involved in the development of ductal pancreatic adenocarcinoma.

Early-stage diffuse large B-cell lymphoma (ESDLBCL) in older adults is understudied, and existing prognostic tools such as the stage-adjusted International Prognostic Index (Sa-IPI) may not adequately account for comorbidity and age-related vulnerability. This study evaluated long-term outcomes and developed a simplified prognostic index for patients aged ≥ 60 years with ESDLBCL.

ObjectiveTo assess the overall survival (OS) and cancer-specific survival (CSS) in patients with different primary locations of hypopharyngeal squamous cell carcinoma (HSCC) and to develop a predictive model incorporating key clinical and treatment variables (including systemic therapy) to serve as a prognostic reference for patients with locally advanced HSCC.MethodsThis retrospective cohort study extracted data for 1,591 patients with locally advanced HSCC from the Surveillance, Epidemiology, and End Results (SEER) database. X-tile software was used to determine optimal cutoff values for continuous variables. Kaplan-Meier analysis compared survival by primary site. Independent risk factors were identified using stepwise Cox regression, and a nomogram was constructed. Model performance was assessed using the concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA).ResultsOS and CSS differed significantly by primary site. Stepwise Cox analysis identified 13 independent prognostic factors. The nomogram showed a C-index of 0.727 in both training and validation sets. The AUCs for 1-, 3-, and 5-year OS were 0.792, 0.791, 0.788 (training) and 0.780, 0.796, 0.789 (validation). Calibration curves indicated good agreement between predicted and observed outcomes. DCA demonstrated superior net benefit over TNM staging alone.ConclusionPrognosis in locally advanced HSCC varies by primary site. The developed nomogram provides moderate prognostic accuracy and may serve as a supplementary tool for risk stratification and clinical discussion, though external validation is warranted.

Tenosynovial giant cell tumors (TGCTs), a rare benign mesenchymal neoplasm of synovial tissue, often incurs chronic pain, joint destruction and repeated surgery, markedly impairing quality of life. Historically, surgery was the only effective option. The colony-stimulating factor 1 receptor (CSF1R) inhibitor pexidartinib broke this therapeutic deadlock, pioneering systemic therapy and shaping subsequent drug development. Further exploration of pexidartinib and associated clinical studies in the field of TGCT have continued following its approval, with updated data and outcomes continuing to play a crucial role in guiding the clinical application of pexidartinib for treatment of TGCT. This review provides a comprehensive summary of the preclinical and clinical development of pexidartinib for treatment of TGCT, and highlights the recent updates in clinical studies and findings since its approval. These include long-term efficacy, optimization of therapeutic strategies, management of risks associated with long-term use, and real-world patient-reported outcomes, all of importance and value for patients and physicians in clinical practice. Here we aim to provide guidance for the improved clinical application of this drug class to enhance patient benefits in TGCT treatment.

Bladder cancer is a common urogenital malignancy that remains difficult to treat, particularly due to therapeutic resistance, such as resistance to cisplatin, in which cancer stem cells (CSCs) play a central role. This study investigates the combination of 5-aminolevulinic acid-mediated photodynamic therapy (5-ALA-PDT) and berbamine as a potential multimodal treatment strategy using the bladder cancer cell lines RT112 and J82, their cisplatin-resistant variants, and generated CSC-like cells. Berbamine is a natural plant compound and was confirmed in this study to have anticancer properties by inhibiting cell migration and invasion, and by inducing apoptosis. This study also showed that berbamine enhances the accumulation of protoporphyrin IX (PpIX), the photosensitizer induced by 5-ALA. 5-ALA-PDT destroys cancer cells by stimulating PpIX via 635 nm red laser light to produce reactive oxygen species (ROS). This was found to happen in all tested cell lines, whereas berbamine could modulate the cell destruction in a concentration-dependent manner and was influenced by the specific biological characteristics of the tested cell variants. CSCs showed the strongest response to the combination therapy approach, suggesting that they may represent more vulnerable cell variants to the tested treatment. Cisplatin-resistant cell lines could also be treated successfully with 5-ALA-PDT, whereas berbamine could enhance its efficacy in the cisplatin-resistant J82 LTT. These findings suggest that the combination treatment of 5-ALA-PDT and berbamine may serve as a promising approach to overcome therapeutic resistance in bladder cancer, particularly in cisplatin-resistant and CSC-enriched tumour types.

Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

Lung resection is a standard treatment for localized lung cancer, but prolonged air leakage is a common complication with health and economic burdens. Interventions such as staplers, sealants, and adjunctive materials are used, yet real-world data describing their utilization remain limited.

We report a case of Hodgkinoid histiocytosis (HH) with protracted skin manifestations. A 72-year-old Japanese woman presented with fever of unknown origin, lymphadenopathy, eosinophilia, and a generalized pruritic and erythematous maculopapular rash. Biopsy of an inguinal lymph node indicated a proliferation of large cells with clear cytoplasm, mimicking Hodgkin lymphoma (HL). Immunohistochemical analysis showed that the Hodgkin-like cells were positive for S-100 protein and CD30 but negative for langerin, CD20, PAX5, and CD3. The cells were also positive for PD-L1. The histological findings were similar to those of HL; conversely, immunohistochemical results suggested a histiocytic/dendritic cell origin. Therefore, the patient was diagnosed with HH. Systemic corticosteroid therapy markedly improved her systemic manifestations; nonetheless, cutaneous symptoms persisted. Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) was suspected because of the prolonged cutaneous manifestations, and the diagnostic criteria for these conditions were fulfilled. Discontinuation of the culprit drug resulted in the remission of cutaneous symptoms. Because lymph node lesions in DIHS/DRESS also demonstrate HL-like histology, this case suggests that HH, while a novel and distinct histiocytic/dendritic cell disorder, may be associated with lymph nodal lesions occurring in the context of DIHS/DRESS.

Primary gastrointestinal lymphoma accounts for only 1-4% of all gastrointestinal malignancies, yet the gastrointestinal tract is the most common extranodal site of non-Hodgkin lymphoma, comprising 10-15% of all non-Hodgkin lymphomas. Among these, diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue lymphoma frequently affect the stomach and small intestine. Protein-losing enteropathy associated with malignant lymphoma is exceedingly rare, particularly when caused by CD5-positive DLBCL. We report the case of a 60-year-old woman with a four-year history of refractory diarrhea and progressive lower extremity edema, ultimately diagnosed with CD5-positive DLBCL of the small intestine. Diagnostic workup revealed hypoproteinemia with significant protein leakage in the ascending colon and distal small intestine. Double-balloon endoscopy demonstrated shallow, wide ulcers with patchy whitish exudates, and histopathology confirmed a diagnosis of de novo CD5-positive DLBCL. Chemotherapy with rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R) led to prompt improvement in serum albumin levels and resolution of the protein-losing enteropathy. Subsequent high-dose chemotherapy with autologous stem cell transplantation has maintained remission. Given the rarity of this presentation and its strong similarity to a previously reported case of CD5-positive DLBCL with protein-losing enteropathy, we propose that this might represent a distinct clinical entity.

To clarify the karyotype evolution of multiple myeloma (MM), multiple karyotypes of 22 patients with MM were analyzed using G-banding, and their karyotype evolutions were depicted as phylogenetic trees. Eleven patients exhibited highly complex karyotype evolutions, combining branched evolution, linear evolution, parallel evolution and macroevolution. While chromosomal structural abnormalities involving 14q32 were detected at the roots of the phylogenetic trees of karyotype evolution, aneuploidies and the other structural abnormalities were identified in both the initial clones and karyotypically evolved subclones. The findings indicated that aneuploidies might be caused by unequal chromosomal segregation, loss of the chromosome with unbalanced whole-arm translocation, and whole-chromosome doubling in patients with near-tetraploidy. Four patients had karyotype abnormalities (three del(20)(q) and one del(5)(q)) associated with myelodysplastic syndrome independent of the karyotype evolution of MM. In conclusion, the phylogenetic trees depicted by G-banding present the karyotype evolution of MM.

Peritoneal metastasis (PM) from gastric cancer (GC) is associated with poor prognosis and limited treatment options. We investigated a novel peritoneal-targeted therapy using CF33-human sodium iodide symporter (hNIS), a chimeric orthopoxvirus, combined with anti-PD-L1 immune checkpoint blockade in an immunocompetent mouse model of GCPM.

Insufficient T-cell infiltration limits the effectiveness of immunotherapy in sarcoma, yet the tumor-intrinsic mechanisms that govern immune exclusion remain poorly defined.

Immune checkpoint inhibitors (ICIs) therapy targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) shows promising clinical benefits in non-small cell lung cancer (NSCLC). However, the relatively low response rate highlights the need to elucidate the regulatory mechanism of PD-L1 expression, and develop an alternative strategy to target PD-1/PD-L1 immune checkpoint pathway. Our study focuses on the role and mechanism of ubiquitin-specific protease 15 (USP15) and its derived peptide U10 on NSCLC immune evasion.