BRAF V600E-mutant metastatic colorectal cancer (mCRC) is characterized by aggressive disease behavior and limited responsiveness to conventional systemic therapy. Although BRAF/EGFR-targeted therapies have improved clinical outcomes, durable complete remission remains uncommon, particularly in microsatellite-stable (MSS) disease. We report the case of a 26-year-old woman with MSS, BRAF V600E-mutant sigmoid colon adenocarcinoma and synchronous liver and omental metastases (cT4aN2M1c, stage IVC). Pretreatment biopsy demonstrated high programmed death-ligand 1 (PD-L1) expression (combined positive score = 20) and a high density of intratumoral CD8+ T cells (350 cells/mm2). Because the patient declined cytotoxic chemotherapy, first-line treatment consisted of tislelizumab combined with cetuximab and dabrafenib. After approximately 4 months of systemic therapy, radiological assessment showed a partial response, accompanied by normalization of serum marker levels, enabling conversion surgery. Histopathological examination confirmed a pathological complete response in the primary tumor and all resected metastatic lesions. A personalized tumor-informed circulating tumor DNA assay performed 3 months after surgery was negative. At the latest follow-up (35 months after treatment initiation), the patient remained free of clinical and radiological evidence of disease recurrence. This case highlights the possibility that selected patients with MSS, BRAF V600E-mutant mCRC may achieve durable remission with combined programmed cell death protein 1 blockade and dual-targeted therapy. The observed association between high intratumoral CD8+ T-cell infiltration, elevated PD-L1 expression, and favorable treatment response should be considered hypothesis-generating and requires validation in prospective biomarker-driven studies.

To determine whether innate immune-sensing activity is associated with epithelial-mesenchymal transition (EMT) and related tumor-aggressiveness programs in human breast cancer. We analyzed RNA sequencing and clinical data from The Cancer Genome Atlas breast cancer cohort (n = 1087). Gene expression-based signatures were constructed for innate immune sensing, interferon signaling, CD8 T cells, macrophages, EMT, invasion, and metastasis. Associations were evaluated using Pearson correlation, Cox proportional hazards models, and multivariable linear regression, including adjustment for PAM50 molecular subtype and immune cell signatures. Innate immune-sensing signatures were strongly correlated with interferon signaling (r = 0.73) and macrophage-associated signatures (r = 0.77), indicating a coordinated inflammatory program. Innate immune sensing was moderately associated with EMT (r = 0.48), invasion (r = 0.45), and metastasis-related transcriptional programs (r = 0.48). In multivariable models, innate immune sensing remained associated with EMT after adjustment for molecular subtype and immune cell signatures (β = 0.17, P < 0.001), while macrophage signatures were the dominant predictors (β = 0.51, P < 2 × 10-16) and CD8 signatures were inversely associated (β = -0.14, P < 0.001). No association with overall survival was observed. Innate immune-sensing signatures are associated with macrophage-driven EMT programs in breast cancer, consistent with activation of inflammatory pathways within the tumor microenvironment.

The study aimed to characterize clinical heterogeneity among patients with primary resistant disease (PRD) after first-line nivolumab plus ipilimumab (NIVO+IPI) for metastatic renal cell carcinoma (mRCC) and to explore clinical factors associated with death within 1 year among patients with PRD. We retrospectively analyzed 151 patients with mRCC who received first-line NIVO+IPI at four institutions in Japan between May 2018 and January 2025. PRD was defined as disease progression occurring within 3 months after treatment initiation, based on radiographic and clinical assessment, or death from any cause within the same period. For exploratory analyses, primary resistant disease with early mortality (PRD-EM) was defined as death within 1 year among patients with PRD. Survival was estimated by the Kaplan-Meier method. Because the PRD subgroup was small and several variables had sparse cell counts, associations with PRD-EM were assessed using Firth penalized logistic regression. PRD occurred in 31 of 151 patients (20.5%). Median overall survival was 3.9 months [95% confidence interval (CI) = 1.8-13.6] in patients with PRD and 46.7 months (95% CI = 38.8-62.8) in those without PRD (log-rank P < 0.001). Among patients with PRD, 20 of 31 (64.5%) met the exploratory PRD-EM definition. In the parsimonious two-variable Firth model, baseline C-reactive protein (CRP) ≥2 mg/dL [adjusted odds ratio (OR) = 7.95; 95% CI = 1.32-68.18; P = 0.023] and lymph node involvement (adjusted OR = 11.65; 95% CI = 1.78-142.82; P = 0.009) were associated with PRD-EM. PRD after first-line NIVO+IPI was associated with heterogeneous clinical outcomes. Elevated baseline CRP and lymph node involvement were associated with PRD-EM in an exploratory analysis. The PRD-EM classification and these associations require validation in larger independent cohorts before they can be used for clinical decision-making.

Glioma remains difficult to treat because malignant cells show rapid proliferation, diffuse invasion, and frequent recurrence. This study investigated the direct antitumor effects of anlotinib in human glioma cells and examined whether these effects were associated with hepatocyte growth factor receptor/protein kinase B/mechanistic target of rapamycin (c-MET/AKT/mTOR) signaling, apoptosis-associated responses, mesenchymal-transition-related proteins, and autophagy-associated proteins. U87 and U251 cells were treated with anlotinib in vitro. Cell viability was assessed using Cell Counting Kit-8 assays, migration and invasion were evaluated using wound-healing and Transwell assays, Hoechst 33342 staining was used for qualitative assessment of apoptosis-associated nuclear morphology; and protein expression was analyzed by western blotting. Anlotinib reduced cell viability in a concentration-dependent manner, with estimated 24 h IC50 values of 68.00 μM for U87 cells and 45.53 μM for U251 cells. At lower concentrations, anlotinib reduced wound closure and Transwell invasion, decreased Vimentin, N-cadherin, and β-catenin expression, increased B-cell lymphoma 2 (BCL-2)-associated X protein, decreased BCL-2, altered poly(ADP-ribose) polymerase/caspase-9 expression, reduced total c-MET expression, and decreased AKT/mTOR phosphorylation. Analysis of autophagy-associated proteins showed an increased LC3-II/LC3-I and time-dependent p62 changes. Anlotinib may suppress malignant glioma-cell phenotypes in vitro. These phenotypic changes were associated with alterations in c-MET/AKT/mTOR pathway proteins, apoptosis-associated responses, mesenchymal-transition-related proteins, and autophagy-associated protein expression.

Oxaliplatin-induced peripheral vascular pain (OIVP) often requires central venous port placement. Conventional preventive strategies have limited efficacy, and the use of some effective analgesics is restricted. This single-center retrospective study evaluated the efficacy and safety of prophylactic tramadol. Electronic medical records of patients who received oxaliplatin-based chemotherapy via a peripheral intravenous line and experienced vascular pain [numerical rating scale (NRS) score ≥ 4] were reviewed. Patients who received prophylactic tramadol in a subsequent cycle were included (n = 23). The primary endpoint was the response rate (≥30% reduction in the NRS score from baseline). The secondary endpoint was the change in NRS score compared with the baseline score in the previous cycle. The response rate was 73.9% [95% confidence interval (CI): 51.6-89.8%]. The median NRS score for OIVP decreased significantly from 7.0 at baseline to 3.0 following tramadol administration (P < 0.0001). Administration greater than or equal to 60 min before infusion was associated with a higher response rate (88.9%; 95% CI: 51.8-99.7%) than administration at 30 min (64.3%; 95% CI: 35.1-87.2%), although this difference was not statistically significant (P = 0.208). Adverse events were mild, with grade 2 nausea reported in two (8.7%; 95% CI: 1.1-28.0%) patients. This exploratory study suggested that prophylactic tramadol was associated with a reduction in pain severity in OIVP, with a favorable safety profile. Thus, tramadol may be a promising and accessible prophylactic option, particularly when access to controlled analgesics is limited.

Breast cancer is a major cause of cancer-related mortality among women, and many patients eventually experience recurrence and progression to metastasis, despite advances in treatment. Estrogen-related receptor α (ERRα), an orphan nuclear receptor, is frequently overexpressed in aggressive breast cancer subtypes and is associated with poor prognosis and an increased risk of recurrence. This study aimed to investigate the role of transforming growth factor β (TGFβ) signaling in ERRα-mediated epithelial-mesenchymal transition (EMT), migration, and invasion in breast cancer cells. ERRα expression was modulated in breast cancer cells using XCT790-mediated inhibition, shRNA-mediated knockdown, and overexpression. Cell viability, clonogenicity, migration, invasion, EMT marker expression, and matrix metalloproteinase (MMP) activity were evaluated. TGFβ1 secretion and Smad signaling were also evaluated. XCT790-mediated inhibition or shRNA-mediated silencing of ERRα significantly reduced cell viability, migration, invasion, and MMP secretion in breast cancer cell lines, whereas ERRα overexpression upregulated migration, invasion, and MMP levels. ERRα suppression also upregulated the epithelial marker ZO-1 and downregulated mesenchymal markers, such as vimentin and β-catenin. This effect was associated with a significant decrease in TGFβ secretion, downregulation of TGFβ-mediated Smad signaling, and reduced expression of its downstream target ANGPTL4. These findings indicate that ERRα promotes EMT, migration, and invasion in breast cancer by upregulating TGFβ secretion and its signaling, underscoring its potential as a therapeutic target.

Capecitabine is an oral fluoropyrimidine prodrug widely used in the treatment of various malignancies, including colorectal cancer. While it is generally well-tolerated, rare and life-threatening toxicities can occur. Pneumonitis is an exceedingly rare complication associated with capecitabine monotherapy. A 36-year-old male with pT3N0 (stage IIA) colon adenocarcinoma underwent curative resection and was started on adjuvant capecitabine monotherapy. During the second cycle, the patient developed a cough and exertional dyspnea. Symptoms progressed during the third cycle, leading to hospitalization. Imaging revealed diffuse ground-glass opacities, and pulmonary function tests showed a severely reduced diffusion capacity of the lung for carbon monoxide (38% of predicted). Dihydropyrimidine dehydrogenase deficiency was ruled out. Based on clinical and radiological findings, a diagnosis of capecitabine-induced pneumonitis was made. Capecitabine was discontinued, and intravenous methylprednisolone (1 mg/kg) was initiated. The patient showed rapid symptomatic improvement and was discharged with a tapered steroid regimen. Follow-up imaging at 1 month showed complete resolution of pulmonary opacities. The patient remains in remission at a 3-year follow-up. Although capecitabine-induced pneumonitis is remarkably rare, it carries a risk of significant morbidity. Clinicians should maintain a high index of suspicion for drug-induced pulmonary toxicity in patients presenting with new respiratory symptoms during capecitabine therapy, as early recognition and treatment are crucial for recovery.

Pancreatic cancer is a highly lethal digestive malignancy characterized by insidious onset and rapid progression. Approximately 80% of patients are diagnosed at an advanced stage with metastasis, missing the opportunity for radical surgery, and chemotherapy remains the main palliative treatment. Its incidence is rising annually, highlighting the urgent need for novel therapeutic strategies. MLN4924 (Pevonedistat), a first-in-class NEDD8-activating enzyme inhibitor, exhibits promising antitumor activity in various cancers, yet its role and mechanism in pancreatic cancer remain largely undefined. Potential hub targets of MLN4924 in pancreatic cancer were screened using Swiss Target-Prediction and Gene-Cards databases. Western blot was used to detect the expression of hub genes and the activity of the prostaglandin G/H synthase 2 (PTGS2)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)/RAC-gamma serine/threonine-protein kinase (Akt)/serine/threonine-protein kinase (mTOR) axis following MLN4924 intervention. CCK-8, EdU, and wound-healing assays were performed to evaluate cell proliferation and migration after MLN4924 treatment. Furthermore, PTGS2 knockdown via siRNA transfection was applied to verify its effects on EGFR-PI3K/Akt/mTOR pathway activity, malignant phenotypes, and gemcitabine sensitivity in pancreatic cancer cells. We identified four hub genes (CASP3, PTGS2, MMP9, and MAPK8) of MLN4924 in pancreatic cancer. We validated that MLN4924 suppressed proliferation and migration of pancreatic cancer cells, downregulated hub gene expression, and inhibited the PTGS2-mediated PI3K/AKT/mTOR signaling pathway. Furthermore, siRNA-mediated silencing of PTGS2 phenocopied the inhibitory effects of MLN4924 on cell proliferation. Notably, both MLN4924 and PTGS2 knockdown significantly enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine. Collectively, our results demonstrate that MLN4924 exerts antitumor effects in pancreatic cancer by targeting the PTGS2-EGFR-PI3K/AKT/mTOR axis, providing a mechanistic rationale for its clinical application in pancreatic cancer therapy.

Tertiary lymphoid structures (TLS) are associated with prognosis in solid tumours. Their value for predicting axillary nodal involvement in oestrogen receptor-positive luminal breast cancer remains uncertain. Three published TLS signatures were scored by single-sample gene set enrichment analysis in oestrogen receptor-positive luminal tumours. The Cancer Genome Atlas Breast Invasive Carcinoma cohort (TCGA-BRCA) included 632 cases, of which 379 met strict consensus. METABRIC included 1086 cases, of which 663 met strict consensus. Logistic models adjusted for age and pathological tumour stage. Strict consensus, majority vote, and continuous scores were compared. Performance assessment included bootstrapped changes in area under the receiver-operating-characteristic curve, Brier scores, calibration, and decision-curve analysis. Survival was evaluated in METABRIC and explored in TCGA-BRCA. Strict-consensus TLS status was not associated with nodal positivity in TCGA-BRCA (adjusted odds ratio: 0.95, 95% confidence interval: 0.62-1.45, P = 0.822). METABRIC was similar (odds ratio: 0.76, 95% confidence interval: 0.55-1.06, P = 0.105). Full-cohort METABRIC analyses detected small majority-vote and continuous-score associations, absent in TCGA-BRCA. Across specifications, bootstrapped changes in area under the receiver-operating-characteristic curve ranged from 0.0002 to 0.0089, with minimal Brier-score improvement and no stable decision-curve benefit. In METABRIC, the univariable overall survival association attenuated after age adjustment (hazard ratio: 1.33-1.10). TCGA-BRCA survival analyses were nonsignificant. TLS transcriptomic signals showed small, cohort-dependent associations with nodal status but no reproducible or clinically meaningful incremental predictive value. These data do not support replacing sentinel lymph node biopsy with a TLS signature in oestrogen receptor-positive luminal breast cancer.

Dysregulation of the phosphoinositide 3-kinase/protein kinase B (AKT)/mechanistic target of rapamycin pathway is a hallmark of breast cancer, making AKT a focus of therapeutic interest. AKT inhibitor-IV is a benzimidazolium compound that inhibits AKT phosphorylation, but its activity and binding mechanism in breast cancer cells have not been characterized in detail. We compared AKT inhibitor-IV with tamoxifen in MCF-7 cells. Cell viability after 24-h treatment was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay (AKT inhibitor-IV: 0.1-5 μM; tamoxifen: 5-50 μM); apoptotic death was quantified by nucleosome ELISA; and AKT1 , BCL-2 , BAX , and CASP3 mRNA levels were measured by quantitative real-time PCR. Both compounds were docked into the ATP-binding pockets of 3-phosphoinositide-dependent protein kinase-1 (PDK1) (PDB 1H1W) and AKT1 (PDB 3MVH) using AutoDock Vina v1.2.6. AKT inhibitor-IV reduced viability with an IC50 of 1.1 μM, compared with 5.2 μM for tamoxifen, and induced 5.9-fold apoptosis enrichment versus 3.65-fold for tamoxifen. AKT inhibitor-IV downregulated AKT1 (0.32-fold) and BCL-2 (0.55-fold) and upregulated BAX (5.97-fold) and CASP3 (6.43-fold) mRNA; tamoxifen showed qualitatively similar but quantitatively weaker transcriptional changes. Docking returned affinities of -9.91 kcal/mol for PDK1 and -9.66 kcal/mol for AKT1 , with AKT inhibitor-IV contacting catalytic-core residues of both kinases. AKT inhibitor-IV was more potent than tamoxifen in this in-vitro setting and warrants further preclinical evaluation. Because MCF-7 cells carry the CASP3 exon 3 deletion and lack functional caspase-3 protein, the observed CASP3 mRNA upregulation reflects transcriptional reprogramming rather than restored executioner activity. The modest docking difference requires biochemical confirmation before any PDK1-versus- AKT1 selectivity claim can be established.

Refractory metastatic colorectal cancer (mCRC) management is further complicated when fluoropyrimidine-based therapy is contraindicated, leaving few systemic options. We present a 57-year-old man with KRAS G13D-mutant, liver-dominant metastatic rectal adenocarcinoma and recurrent fluoropyrimidine-associated coronary vasospasm precluding 5-fluorouracil and capecitabine. After multimodal first-line therapy and regorafenib, trifluridine/tipiracil (TAS-102) plus bevacizumab was initiated and integrated with liver-directed treatments for oligoprogressive disease. This combined strategy achieved approximately 16.6 months of disease control, substantially exceeding the median progression-free survival reported in the SUNLIGHT trial, with manageable hematological toxicity and preserved performance status. This case highlights the value of TAS-102 plus bevacizumab combined with focal liver-directed therapy as a feasible long-term strategy for selected patients with oligoprogressive mCRC when fluoropyrimidines cannot be used.