BACKGROUND:Glioblastoma (GBM) is a common brain cancer with a poor prognosis and a high recurrence rate. DNA damage repair plays a crucial role in GBM carcinogenesis and treatment resistance. Human endogenous bornavirus-like nucleoprotein 1 (EBLN1) regulates cellular processes and genetic stability. However, the biological role of EBLN1 in GBM remains unclear. AIMS:This study aims to determine the role of EBLN1 in the regulation of cellular processes and DNA double-strand breaks (DSBs) in GBM and to investigate the underlying molecular mechanisms. METHODS AND RESULTS:U-87 MG GBM cells were infected with an shRNA-expressing lentivirus to knock down EBLN1. Then, cell proliferation and apoptosis were evaluated. The levels of DSBs, as well as the activities of two key DSB repair regulators-ataxia telangiectasia mutated (ATM) kinase and breast cancer Type 1 susceptibility protein (BRCA1)-were detected. Furthermore, after reactivating ATM, cellular processes and the levels of DSBs were re-detected to verify the mechanisms underlying EBLN1-mediated DNA repair regulation in GBM. EBLN1-silenced U-87 MG cells displayed a significant reduction in cell growth as early as the second day postinfection (p < 0.05) and a higher apoptosis ratio (p < 0.001). After EBLN1-silencing, U-87 MG cells exhibited a remarkable increase in the expression of γH2AX (p < 0.001) and significantly lower expression levels of ATM and BRCA1 (p < 0.001). After reactivation of ATM in EBLN1-silenced U-87 MG cells, DSB levels in the treated cells were significantly decreased (p < 0.001). Meanwhile, cell proliferation was significantly increased (p < 0.001), while apoptosis was markedly suppressed (p < 0.001). CONCLUSION:This study uncovers a novel molecular mechanism that EBLN1 regulates cellular processes via modulating DNA double-strand break repair in glioblastoma cells, providing a new perspective for understanding the pathogenesis of GBM.
BACKGROUND:Ovarian cancer is one of the leading causes of death from gynecological cancer worldwide. Genetic mutations in genes involved in key cellular functions such as BRCA1/2 play a central role in tumorigenesis and have major implications for targeted therapeutic strategies, especially the use of poly (ADP-ribose) polymerase (PARP) inhibitors. CASE:Herein, we described a case of a 50-year-old woman diagnosed with severe anemia secondary to heavy menometrorrhagia. Initial gynecological evaluation, including transvaginal ultrasound, was unremarkable, and endometrial biopsy was not indicated. Imaging revealed no ovarian abnormalities; however, exploratory laparotomy identified a peritoneal nodule, leading to further investigation. Targeted NGS was performed on somatic and germline DNA samples and showed a frame shift deletion of 10 bp (c.1256_1265del: p.R419Ter) in the BRCA1 gene. This variant, identified only in tumor tissues, is novel and classified as pathogenic in ClinVar and ACMG databases. Additional somatic alterations were detected in TP53 and MSH6, while germline testing revealed only a variant of uncertain significance in BARD1. After first-line chemotherapy, the patient benefited from olaparib and achieved a progression-free survival of 23 months with good tolerance and no evidence of disease recurrence. CONCLUSION:This finding highlights the importance of integrating tumor-based genomic profiling with germline testing to identify actionable mutations and guide precision oncology. The identification of a novel somatic BRCA1 mutation expands the mutational spectrum of HGSOC and underscores the need to include underrepresented populations, such as those from North Africa, in genomic studies.
BACKGROUND:Finding reliable prognostic markers for patients with brain metastases would be beneficial since they could be used in clinical practice when making treatment decisions. Recent literature has analyzed the role of temporalis muscle thickness (TMT) as a prognostic marker in patients with brain metastases with mixed results. Previous studies have generally focused on patients younger than 65 years. AIMS:The purpose of this study was to evaluate the effect of TMT measured from head CT scans on the prognosis of patients with brain metastases receiving radiotherapy aged 70 years or older. METHODS AND RESULTS:We identified all patients with brain metastases treated with radiotherapy and measured their TMT from head CT scans at the date of treatment planning CT scans. The patients' demographic data, primary tumor, and treatment allocation were recorded. Sex-specific cut-offs for low TMT (males: 4.3 mm, females: 3.975 mm) were determined by maximizing Youden's index for 3-month survival. We evaluated the association between TMT and 1-, 3-, 6-, and 12-month overall survival (OS) using Cox proportional hazards modelling. This retrospective study included 249 patients. The mean age of the patients in the cohort was 76.0 ± 4.9 years. Male patients had higher TMT than females (4.7 ± 1.6 vs. 3.7 ± 1.5 mm, p < 0.001). Altogether, 35 (14.1%), 125 (50.2%), 178 (71.5%), and 216 (86.7%) patients had deceased at 1-month, 3-month, 6-month, and 12-month points, respectively. Although having low TMT was associated with a higher risk of death at 3- and 6-month timepoints (hazard ratio range: 1.41-1.54) in univariate analyses, TMT was not associated with 3- or 6-month survival after adjustment for other clinical factors. CONCLUSION:Low TMT is not an independent marker of lower prognosis in patients aged 70 years or older with brain metastases treated with radiotherapy.
ABSTRACT Background Resistance to 5‐fluorouracil (5‐FU) remains a major obstacle in colorectal cancer (CRC) treatment. Trifluridine (FTD), the active component of TAS‐102, exerts cytotoxicity through DNA incorporation and reportedly remains active in 5‐FU‐resistant tumors, though with limited clinical efficacy. Aims We investigated whether AZD6738, an inhibitor of ataxia telangiectasia and Rad3‐related kinase (ATR) that regulates the G2/M checkpoint, could enhance FTD efficacy in 5‐FU‐resistant CRC. Methods and Results Parental and 5‐FU‐resistant HCT116 (p53 wild‐type) and DLD‐1 (p53 mutant‐type) sublines were evaluated using WST‐1 viability assays, flow cytometry, and immunoblotting for γH2AX, cleaved caspase‐3, and p‐Chk1 (Ser345). Antitumor efficacy and safety of TAS‐102 + AZD6738 were examined in a DLD‐1/5FUR xenograft model by measuring tumor volumes and weights, body and organ weights, blood counts, and γH2AX immunohistochemistry. A noncytotoxic AZD6738 concentration significantly enhanced FTD cytotoxicity across a wide concentration range in both parental and resistant cells. The combination increased γH2AX and cleaved caspase‐3 while suppressing FTD‐induced Chk1 phosphorylation, findings consistent with increased DNA damage and apoptosis following pharmacological treatment with AZD6738. Flow cytometry analysis revealed that AZD6738 abrogated FTD‐induced G2/M arrest. In vivo, TAS‐102 + AZD6738 significantly suppressed tumor growth compared with monotherapy without increasing hematologic or systemic toxicity. Conclusion AZD6738 enhances the antitumor activity of FTD in preclinical models of 5‐FU‐resistant CRC and is associated with increased DNA damage and apoptosis. These findings provide proof‐of‐concept supporting further mechanistic and translational investigation of this combination.
BACKGROUND:Young-onset breast cancer is associated with inferior disease-free survival (DFS), but the contribution of additional molecular heterogeneity remains unclear. AIMS:To identify an exploratory age-associated gene expression signature linked to recurrence-related outcomes and evaluate its prognostic association. METHODS AND RESULTS:We analyzed clinicopathological and RNA-sequencing data from 821 patients with Stages I-III invasive ductal or lobular carcinoma in The Cancer Genome Atlas, including 142 patients aged ≤ 45 years. Genes associated with both age and DFS were screened, followed by LASSO-Cox and stepwise multivariable Cox regression. A four-gene signature (Sig4: C4orf14 [NOA1], LINC01124, ZNF704, and AGFG2) was identified. Young patients had significantly worse DFS than older patients, whereas overall and disease-specific survival did not differ significantly. After adjustment for clinicopathological factors, young age remained associated with worse DFS. Following inclusion of the continuous Sig4 score, the age association was attenuated and no longer statistically significant, while Sig4 remained independently associated with worse DFS. Sig4-high tumors were enriched for proliferation, cell-cycle, DNA-repair, metabolic, and stress-response pathways. In METABRIC, the fixed TCGA-derived Sig4 score was associated with worse relapse-free survival in the overall cohort but not in patients aged ≤ 45 years. CONCLUSION:Sig4 is an exploratory age-associated four-gene signature with potential general prognostic relevance in breast cancer. Its utility for risk stratification specifically in young-onset breast cancer was not externally validated and requires confirmation in independent prospective cohorts enriched for young patients.
BACKGROUND:Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma with rapid proliferation and early systemic dissemination. Neuromuscular manifestations are rare and are typically secondary to direct infiltration or metabolic complications. Paraneoplastic myopathy as the initial presentation of BL is exceedingly uncommon, particularly in immunocompetent adults. CASE PRESENTATION:We report the case of an immunocompetent adult male who presented with acute progressive proximal muscle weakness and markedly elevated creatine phosphokinase (CPK) levels. Extensive autoimmune, metabolic, and endocrine evaluations were unremarkable. Electrophysiological studies supported a primary myopathic process. Contrast-enhanced computed tomography revealed left axillary lymphadenopathy and splenomegaly without generalized lymphadenopathy. Excisional lymph node biopsy confirmed sporadic Burkitt's lymphoma with MYC rearrangement. Muscle biopsy was deferred due to rapid disease progression and the urgent need for oncologic treatment. The patient was treated with the Hyper-CVAD regimen combined with rituximab and central nervous system prophylaxis. Following chemotherapy, muscle strength improved rapidly, accompanied by a marked decline in serum CPK levels. CONCLUSION:This case highlights a rare paraneoplastic manifestation of Burkitt's lymphoma presenting as acute myopathy. Rapid clinical and biochemical response to chemotherapy supports a tumor-mediated mechanism. Clinicians should consider underlying hematologic malignancy in patients with unexplained myopathy and elevated muscle enzymes, as early diagnosis and prompt treatment may significantly improve outcomes.
BACKGROUND:Breast cancer remains a topic of interest due to its high mortality rate among Cameroonian women. The barks of Erythrina excelsa are traditionally used for medicinal purposes in the management of various conditions including cancer. AIMS:This study evaluated the phytochemical composition, antioxidant properties, and anticancer effects of Erythrina excelsa bark extract in vitro and in vivo. METHODS AND RESULTS:Phytochemical profiling and antioxidant assays (DPPH, FRAP) were conducted to determine secondary metabolite content and free radical scavenging capacity. Cytotoxicity, apoptosis, and cell cycle arrest were assessed in MCF-7 and MDA-MB-231 breast cancer cell lines. In vivo chemopreventive efficacy was evaluated using a DMBA-induced mammary carcinogenesis in 42 female rats aged 55 to 65 days (~100 g), except the normal group (n = 7). The normal (NOR) and negative (DMBA) groups were treated daily with the vehicle (2% ethanol in distilled water) while the positive (Tamox) and test groups received tamoxifen (3.3 mg/kg) and Erythrina excelsa extract (75, 150, 300 mg/kg BW), respectively for 20 weeks. Tumor parameters, serum biomarkers (CA 15-3, cytokines), oxidative stress markers, hematological and biochemical indices, and organ toxicity were assessed. As results, both aqueous (AE) and ethanolic (EE) extracts of E. excelsa inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells in a dose-dependent manner after 24 h, induced apoptosis, and promoted G2/M cell cycle arrest. In vivo, E. excelsa aqueous extract (AE) significantly reduced tumor incidence, volume, and weight in a DMBA-induced mammary carcinogenesis rat model, while lowering serum CA15-3 and pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-12). Treatment also enhanced antioxidant defenses (SOD, catalase, GSH), reduced lipid peroxidation (MDA), improved hematological and biochemical parameters, and mitigated DMBA-induced hepatic and renal toxicity, without evidence of systemic side effects. CONCLUSION:Erythrina excelsa barks exhibited an anticancer potential mediated by its antioxidant, anti-inflammatory, pro-apoptotic, and cell cycle-modulating effects, and support its further investigation as a promising natural source for cancer therapy.
BACKGROUND:Rural patients experience healthcare disparities due to multiple factors including travel distance. However, the impact on colorectal cancer (CRC) care for Veterans remains undefined. AIMS:We aimed to describe the association between distance and timeliness of care for Veterans with CRC. METHODS AND RESULTS:We assembled a retrospective cohort of Veterans with Stage I-III CRC who underwent resection at a Veterans Affairs Medical Center (VAMC) between 2001 and 2018. Time from diagnosis to initiation of treatment, length of stay, 30-day readmissions and mortality were compared based on distance (≤ 40 mi; 41-100 mi, and > 100 mi). Among 375 patients, the median travel distance was 67.9 mi and median time to treatment initiation was 33 days. In a multivariable linear regression adjusted for age, stage, year of surgery, race and co-morbidities, the time to initial treatment was 11.8 days longer for patients > 100 mi away compared to those who live within 40 mi (CI 1.4-22.1, p = 0.026). No significant difference was observed for patients within 40 mi vs. 41-100 mi away (0.13 days, CI -9.4 to 9.8, 0.98). Common contributors to delays > 60 days included transitions from non-VAMC care, cardiac optimization and additional testing or treatment. There were no associations between distance and surgical length of stay, 30-day readmissions, or mortality. CONCLUSION:Travel distance > 100 mi was associated with timeliness of care for Veterans, though no differences in clinical outcomes were observed. Distance-related outcome disparities may be mitigated through integrated, high-volume VA care system.
BACKGROUND:Prostate cancer (PCa) remains one of the most frequently diagnosed malignancies worldwide and represents a major contributor to premature mortality among men. This study aimed to estimate survival and investigate factors associated with PCa-specific mortality among men treated within the oncology care network of a Brazilian state. MATERIAL AND METHODS:Retrospective cohort study was conducted using data obtained from hospital-based cancer registries linked to the state Mortality Information System. The cohort included 10 556 men diagnosed with PCa between 2000 and 2016, with follow-up through 2021. Outcomes were categorized as death from PCa, death from other causes, or alive at the end of follow-up. Associations with PCa-specific mortality were examined using cause-specific Cox proportional hazards regression models. RESULTS:At the end of 2021, 6388 patients were alive, 1936 had died from PCa and 2232 deaths from other causes. The 5-year PCa-specific survival was 87.7%. In the multivariable analysis, increasing age at diagnosis (per 10-year increment) was associated with a higher cause-specific hazard of PCa mortality (HR = 1.14; 95% CI: 1.06-1.22). Lower educational level was also associated with increased mortality, while patients with basic education (HR = 0.82; 95% CI: 0.71-0.95) and middle or high education (HR = 0.64; 95% CI: 0.52-0.80) showed a lower risk of death compared to those with no formal education. Referral from non-SUS services was associated with a slightly higher risk of PCa mortality (HR = 1.14; 95% CI: 1.00-1.30). Regarding treatment variables, surgery was associated with a lower cause-specific hazard of mortality (HR = 0.41; 95% CI: 0.33-0.52), whereas hormone therapy was associated with an increased cause-specific hazard of death (HR = 1.98; 95% CI: 1.75-2.24). CONCLUSIONS:Age, educational level, presence of distant metastasis, referral source, and treatment modalities were associated with PCa-specific mortality. However, treatment-related associations should be interpreted with caution, as they likely reflect underlying disease severity and treatment selection patterns rather than causal effects. These findings highlight the importance of early diagnosis, reducing social inequalities in access to care, and strengthening oncology care networks to improve outcomes in patients with PCa.
ABSTRACT Introduction Denileukin diftitox (DD)‐cxdl, a fusion protein comprising diphtheria toxin fragments and human interleukin‐2, is a treatment for peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL). Previous trials have enrolled a limited number of patients, and there is a need to evaluate DD‐cxdl in a more diverse population, including those with different ages and treatment histories. Methods This observational post‐marketing study (19 May 2021 to 1 February 2024) was conducted in over 200 institutions in Japan to evaluate the safety and effectiveness of DD‐cxdl in patients with relapsed or refractory PTCL and CTCL (NCT05137847; jRCT2031220196). Patient characteristics, status of drug administration, adverse events (AEs), adverse drug reactions (ADRs), and effectiveness were assessed. Capillary leak syndrome was specified as an AE of special interest. Results Data from 104 patients were analyzed (PTCL: 85; CTCL: 19), including 57 male patients (54.8%). The median age was 74 (range: 20–88) years. The median number of prior chemotherapy lines was 3.5 (1.0–10.0), and approximately half (55.8%) of the patients discontinued treatment during cycle 1. Most patients experienced AEs (94.2%) and ADRs (84.6%), and the most common serious ADR was capillary leak syndrome (22.1%). Effectiveness could be assessed in 80/104 patients. The overall objective response rate was 16.3% (95% confidence interval: 8.9, 26.2), and in patients with PTCL and CTCL it was 15.4% (7.6, 26.5) and 20.0% (4.3, 48.1), respectively. Four patients (6.2%) with PTCL achieved a complete response. Conclusions This is the first observational study to evaluate the safety and effectiveness of DD‐cxdl in Japanese patients with relapsed or refractory PTCL and CTCL in daily clinical practice. No new safety concerns were identified. Clinicians should remain aware of the risk of capillary leak syndrome. Trail Registration: ClinicalTrials.gov identifier: NCT05137847 and Japan Registry of Clinical Trials identifier: jRCT2031220196.
ABSTRACT Background and Aims Acute myeloid leukemia (AML) remains the most common cause of death in adults with acute leukemia. Tyrosine kinase inhibitors (TKIs) have shown significant clinical efficacy in defined patient subgroups. Real‐world outcomes of AML patients undergoing TKI therapy have not been widely reported. Methods In this real‐world retrospective study, we included 482 adult patients with AML treated with a TKI targeting FLT3, IDH1, or IDH2 from January 1, 2015, to December 31, 2023, in the countrywide Flatiron Health electronic health record‐derived deidentified database. We utilized unadjusted Kaplan–Meier methods to calculate median real‐world event‐free survival (rwEFS) and overall survival (rwOS). We utilized a multivariable Cox regression model to evaluate characteristics associated with rwOS, modeling post‐TKI stem cell transplant (SCT) as a time‐varying covariate. Results Those who received treatment at 1L (first‐line) and 2L+ (second‐line and beyond) had similar length of TKI therapy (3.7 vs. 3.4 months), rwEFS (2.2 vs. 2.5 months), and rwOS (12.3 vs. 13.1 months), respectively. Among all patients, greater rwOS was associated with receiving pre‐TKI SCT (p < 0.001), commercial insurance (vs. Medicaid; p = 0.035), younger age (p = 0.043), and favorable 2017 ELN risk classification (vs. adverse; p = 0.032). When restricted to patients treated with TKI at 2L+ without prior SCT, rwEFS were 1.4, 1.6, and 2.1 months by targetable mutation (IDH2, IDH1, and FLT3), and rwOS were 8.7, 15.4, and 9.5 months, respectively. Conclusion Patients treated with HMA plus TKI did not have significant differences compared to TKI alone. In this substantial, real‐world cohort of AML patients receiving TKIs, clinical outcomes remained deficient irrespective of timing of TKI start, mutational target, and concurrent HMA.
ABSTRACT Background Mesothelioma of the tunica vaginalis testis is a rare neoplasm, accounting for less than 1% of all mesothelioma cases. Due to the rarity of this disease, a standard treatment has not been established. Clinical management is generally adapted from the strategies used for pleural mesothelioma. Although immune checkpoint inhibitors (ICIs) have demonstrated efficacy in treating pleural mesothelioma, their role in mesothelioma of the tunica vaginalis testis remains uncharacterized due to a lack of evidence. This is the first report documenting a clinical response to nivolumab in chemoresistant mesothelioma of the tunica vaginalis testis. Case A 71‐year‐old man presented with painless left scrotal swelling and was initially diagnosed with a hydrocele at the referring hospital. One year later, hydrocelectomy revealed partial thickening of the tunica without malignancy. A subsequent magnetic resonance imaging analysis revealed a new intratesticular nodule. Orchiectomy was performed, and the pathological findings revealed an epithelioid mesothelioma. He was referred to Tsukuba University Hospital for further treatment. He also had a history of Self‐Defense Force service, which suggested possible asbestos exposure. Imaging revealed pelvic lymphadenopathy with fluorodeoxyglucose uptake in the right external iliac lymph nodes. He received four cycles of cisplatin and pemetrexed every 3 weeks, resulting in stable disease. Bilateral pelvic lymph node dissection was performed and confirmed the presence of metastatic mesothelioma. Nine months after the surgery, bilateral inguinal lymph node recurrence occurred, and he received cisplatin monotherapy because of renal impairment. Despite four additional cycles of cisplatin monotherapy, the disease progressed. Therefore, chemotherapy was discontinued, and nivolumab was administered. Nivolumab resulted in sustained tumor shrinkage. However, after 3 months of treatment, he developed immune‐related encephalitis requiring corticosteroid therapy and nivolumab discontinuation. After 16 months of nivolumab initiation, he was dead from the disease. Conclusion This is the first report documenting the clinical response of a chemoresistant mesothelioma of the tunica vaginalis testis to nivolumab. ICIs are a promising treatment option for this rare and challenging disease.
ABSTRACT Background Programmed death‐ligand 1 (PD‐L1) expression is widely used to guide immune checkpoint inhibitor (ICI) therapy in advanced nonsmall cell lung cancer (NSCLC); however, substantial heterogeneity in clinical outcomes persists among patients with high PD‐L1 expression. Reliable biomarkers for further stratifying this population are still lacking. This study investigated whether genomic alterations and features of the tumor immune microenvironment could explain this variability. Methods We conducted a retrospective single‐center study including 91 patients with advanced NSCLC and PD‐L1 tumor proportion score (TPS) ≥ 50% who received ICI‐based therapy. Clinical outcomes were assessed according to PD‐L1 expression levels, genomic profiles, and tumor immune microenvironment characteristics. Tumor‐infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) were evaluated in available tumor specimens from 75 patients. Multiplex immunohistochemistry (mIHC) was performed in a subset of 30 patients to characterize the immune cellular composition underlying TIL‐based stratification. Kaplan–Meier survival analysis and multivariable Cox regression were used to identify factors associated with progression‐free survival (PFS) and overall survival (OS). Results At a median follow‐up of 19.1 months, the objective response rate was 31.9%, the median PFS was 10.7 months, and the median OS was 43.5 months. No significant survival differences were observed between the TPS 50%–89% and TPS ≥ 90% subgroups. TP53 mutation was associated with shorter PFS and remained an independent adverse prognostic factor. In contrast, high TIL infiltration was independently associated with improved PFS and OS, and this OS benefit was most pronounced in the TPS ≥ 90% subgroup. mIHC analysis revealed that high‐TIL tumors exhibited increased stromal CD8+ T‐cell infiltration, enriched NK‐cell populations, and a more proinflammatory macrophage profile, providing biological support for TIL‐based stratification. TLS presence was not significantly associated with survival outcomes. Conclusions PD‐L1 expression alone does not fully account for the outcome heterogeneity observed in PD‐L1‐high NSCLC treated with ICIs. Integrating genomic alterations—particularly TP53 mutation status—with tumor immune microenvironment features, such as TIL density, may help refine prognostic stratification in this population.
ABSTRACT Background Ovarian carcinosarcoma (OCS) is a rare, aggressive tumor composed of both carcinomatous and sarcomatous components, typically associated with poor prognosis. Due to its rarity, the molecular characteristics, immune microenvironment, and optimal treatment of OCS remain unclear. This study aimed to characterize the genomic profiles, Trop‐2 expression, and immune microenvironment of the carcinomatous and sarcomatous components of OCS separately, and to explore candidate therapeutic targets for this rare and aggressive tumor. Case This retrospective, single‐institution study analyzed nine cases of ovarian or fallopian tube carcinosarcoma treated between 2013 and 2023. Targeted next‐generation sequencing of 160 cancer‐related genes was performed in eight cases, and immunohistochemistry for p53, Trop‐2, CD8, and PD‐L1 was performed in nine cases, with the carcinomatous and sarcomatous components evaluated separately whenever they were separable. All tumors contained high‐grade serous carcinoma components. Targeted sequencing revealed TP53 mutations in all samples. Most genetic alterations were shared by both components, supporting the role of epithelial‐mesenchymal transition in OCS pathogenesis. Amplifications in CCND1, CCNE1, PRKCI, and GNAS (37.5%), and ERBB2 (12.5%) were detected, and whole genome duplication was observed in two cases (25%). One case (12.5%) showed high microsatellite instability and was associated with Lynch syndrome. Immunohistochemistry showed Trop‐2 positivity in all carcinomatous components, with a trend toward higher expression compared with sarcomatous areas (p = 0.0625). CD8 and PD‐L1 levels were low, consistent with a relatively non‐inflamed, immune‐cold‐like microenvironment. Conclusion These findings suggest molecular similarities between OCS and high‐grade serous carcinoma and highlight the role of epithelial‐mesenchymal transition. The low immune marker expression suggests limited benefit from immune checkpoint inhibitors, except in select Lynch syndrome cases. In contrast, the consistently high Trop‐2 expression in the carcinomatous component may warrant further investigation of Trop‐2‐targeted antibody–drug conjugates as a hypothesis‐generating therapeutic candidate for OCS.
ABSTRACT Background The treatment landscape for relapse/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has evolved with recent novel agents. With the availability of novel agents that slow disease progression, managing treatment side effects and monitoring response in patients with these hematologic malignancies may present a challenge for healthcare providers. The imperative to engage patients in the management of their condition demands that specialists are knowledgeable about new treatment options and are skilled and confident in educating patients to manage and monitor for potential side effects. Aims This study aimed to establish the current knowledge, skills and confidence levels of oncologists, hematologists and hematologist‐oncologists (ONC/HEM) and identify the challenges they experience when managing and monitoring treatment and engaging patients with CLL or MCL in shared decision‐making. The long‐term aim is to inform evidence‐based continuing medical education to optimize ONC/HEM competencies. Methods and Results This cross‐sectional study employed a quantitative survey, completed by 285 ONC/HEM practicing in academic or community settings in Brazil, France, Germany, the United Kingdom, and the United States. Using 5‐point Likert‐type scales, participants reported their knowledge/skills/confidence levels, and their agreement with selected statements. Sub‐optimal levels of knowledge/skills to identify and manage side effects associated with treatments for CLL or MCL were reported. Challenges with patient risk stratification and engaging patients in shared decision‐making were reported, with a greater proportion reported by those in community settings. Of note, 31% of participants reported sub‐optimal skills identifying patients at higher risk for progression and using stratification to plan and manage treatment, and 58% never/rarely/sometimes considered patients' concerns about treatment safety. Conclusion Continuing medical education activities to improve knowledge of new treatments and associated pathways for patients with CLL or MCL, and to develop skills/confidence to engage in shared decision‐making are recommended. Setting‐specific issues should be integrated into interventions to ensure relevant educational support for the ONC/HEM.
ABSTRACT Background Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy with a poor prognosis. However, the molecular mechanisms underlying CCA and its treatment options remain unclear and limited. Aims This study aims to identify novel prognostic biomarkers and potential therapeutic targets for CCA through transcriptomics and whole‐exome sequencing analysis. Methods and Results We analyzed the relationship between overall survival and various risk factors in 255 CCA samples from a published dataset and 36 samples from The Cancer Genome Atlas (TCGA) database. Transcriptomics analysis was used to identify genes whose expression plays a crucial role in CCA development and progression. Targeted drug databases were used to examine which gene expression signatures represent potential therapeutic targets for CCA. Mutated genes were analyzed to explore potential mechanisms. Standard statistical methods were applied to analyze associations between clinical data and candidate targets. A nomogram was constructed to predict the prognostic impact of the optimal candidate. Cell experiments were used to demonstrate the role of PKLR in CCA growth and metastasis. We identified FOLH1, PKLR, PTH1R, GPR114, KCNH2, LCN2, MMP10, PORCN, RIPK3, and SRPK3 as potential therapeutic targets for CCA, with PKLR being the most promising candidate based on the computational analyses. PKLR was lowly expressed in CCA tissues. PKLR expression was closely associated with ARID1A and KRAS mutations. PKLR mRNA levels were significantly correlated with tumor size (p = 0.024) and metastasis (p = 0.014). Low PKLR expression in CCA was positively associated with poor survival. A nomogram accurately predicted the prognosis of CCA patients based on PKLR expression levels. Silencing PKLR expression promotes growth and metastasis of CCA in vitro. Conclusion Our findings indicate that PKLR, an independent protective factor in CCA, is a potential prognostic biomarker and a candidate for further investigation as a therapeutic target. PKLR expression is significantly associated with ARID1A and KRAS mutations.
ABSTRACT Background Small mothers against decapentaplegic homologue 4 (SMAD4) plays an important role in transforming growth factor (TGF)‐β signaling and is associated with various cancers. However, little is known about SMAD4 expression in oral squamous cell carcinoma (OSCC). Aim To investigate the clinical and biological significance of SMAD4 expression in OSCC. Methods and Results Immunohistochemical analysis was performed to detect SMAD4 expression in 90 OSCC specimens obtained from patients who underwent preoperative chemoradiotherapy and surgery (phase II study). We also investigated the correlation between SMAD4 expression and various clinicopathological features. In vitro experiments were performed to assess the effects of SMAD4 expression on chemosensitivity and changes in apoptosis‐related molecules. Notably, low SMAD4 expression was significantly correlated with an increased risk of lymph node metastasis, poor response to chemoradiotherapy, and adverse prognosis in patients with OSCC who underwent preoperative 5‐FU‐based chemoradiotherapy. Additionally, SMAD4 downregulation in OSCC cells decreased sensitivity to cisplatin and 5‐fluorouracil and was associated with an increase in cIAP2 expression. Conclusion The reduced expression of SMAD4 has been linked to both chemotherapy resistance and prognosis in OSCC. However, it may not function as an independent prognostic biomarker. Further research is necessary to determine whether these findings can be generalized to the broader OSCC population.
ABSTRACT Background and Aim Lung cancer remains one of the leading causes of cancer‐related mortality worldwide. Type 2 diabetes mellitus (T2DM), the most prevalent endocrine disorder, is commonly managed with Metformin, an antidiabetic medication that has demonstrated potential anticancer properties. This meta‐analysis aimed to discover the association between Metformin use and the risk of lung cancer in patients with T2DM. Methods A comprehensive search of online databases was conducted up to January 1, 2026, to identify relevant observational studies. After screening, appropriate data were extracted. Meta‐analyses utilized the most fully adjusted hazard ratio (HR) with corresponding 95% confidence intervals (CI) as the effect measures. All statistical analyses were performed using R Statistical Software. Results The pooled analysis of 29 observational studies showed a significant reduction in lung cancer risk among Metformin users compared with nonusers (HR: 0.85, 95% CI: [0.77–0.94], p = 0.002). Subgroup analyses revealed significant associations in cohort studies (HR: 0.79, 95% CI: [0.70–0.89], p < 0.01) and in studies conducted in Asia (HR: 0.82, 95% CI: [0.68–0.99], p = 0.04). Extended Metformin use (> 3 years) was associated with a significant reduction in lung cancer risk (HR: 0.87, 95% CI: [0.79–0.95]; p < 0.01), whereas no significant effect was observed for shorter durations. Conclusion This meta‐analysis indicated a potential protective effect of Metformin use in individuals with T2DM against lung cancer, with a significant risk reduction observed, particularly among long‐term users and in Asian populations. The significant associations identified in cohort studies and in extended‐duration use underscore metformin's promise in lung cancer prevention.
ABSTRACT Background An increasing number of octogenarian patients are being diagnosed with lung cancer, but they are less likely to receive surgery because of fragility. As a result, the optimal management of lung cancer in octogenarians remains unclear. Here we report a case of an octogenarian patient with locally advanced non‐small‐cell lung cancer (NSCLC) who achieved long‐term survival via surgery followed by adjuvant targeted therapy. Case An 82‐year‐old male patient was admitted to our center for lung cancer surgery in April 2020 at West China Hospital, Sichuan University. He was clinically diagnosed with cT2N1M0(cIIB, AJCC 8th edition) lung cancer in the right lower lobe. Because of his good cardiopulmonary function without comorbidities, the patient was scheduled for thoracoscopic surgery. However, due to tumor invasion into the middle lobe and dense adhesions to the bronchus and vessels, the patient underwent conversion to open thoracotomy and finally received bilobectomy with systematic lymph node dissection. The patient recovered uneventfully and was discharged on postoperative day 5. After surgery, the patient was pathologically diagnosed with pT3N2M0(pIIIB) lung adenocarcinoma harboring an EGFR L858R gene mutation and began adjuvant icotinib. The patient progressed with multiple pulmonary metastasis at 13 months after starting icotinib and his liquid biopsy revealed a T790M mutation; he began treatment with the third‐generation EGFR‐TKI aumolertinib. In the last follow‐up in December 2025, the patient remained on aumolertinib therapy and remained alive without progression. Conclusion Age alone is not a contraindication for lung cancer surgery and octogenarian patients may tolerate surgical resection following careful preoperative evaluation. Adjuvant targeted therapy may prolong survival in octogenarian lung cancer patients harboring oncogenic driving gene mutation after surgery.
ABSTRACT Background miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment. Recent Findings Advances in spatial transcriptomics, single‐cell profiling, and longitudinal liquid biopsy technologies have provided new insights into the dynamic regulation of oncomiRNAs. These approaches reveal significant spatiotemporal variability in miRNA expression and are increasingly implicated in shaping tumor heterogeneity, therapeutic resistance, immune evasion, and divergent clinical outcomes. Emerging evidence underscores the importance of integrating these dynamic molecular patterns into biomarker discovery frameworks and precision oncology strategies. Furthermore, the incorporation of artificial intelligence and multi‐omics data integration is enhancing patient stratification and predictive modeling. Conclusion A comprehensive understanding of the spatiotemporal regulation of oncomiRNAs is essential for advancing next‐generation cancer diagnostics and therapeutics. Future efforts should focus on systematic multi‐region and longitudinal study designs, as well as their integration into adaptive clinical trials. Leveraging these insights may enable miRNA‐guided, stage‐adapted precision cancer theranostics in heterogeneous malignancies.
