Comprehending the intricate mechanisms of apoptosis and its interaction with cytotoxic, antioxidant, and HDAC activities is imperative for devising effective cancer therapies. Sulfonamides and Schiff bases are compounds of pharmacological importance with known anticancer activity. Our study aimed to investigate the cytotoxic, antioxidant, HDAC, and apoptotic activities of new sulfonamide-Schiff bases in human colon cancer cells (DLD-1 and HT-29). New sulfonamide-derived Schiff base compounds (3a-d) were synthesized from the condensation of sulfamethoxypyridazine (1) and various aromatic aldehydes, and were characterized by FTIR, NMR (1H and 13C/APT), UV-Vis., and mass spectroscopy. Sulfonamide-derived Schiff bases 3a-d and compound 1 exhibited significant anticancer activity against colorectal cancer cell lines (DLD-1, HT-29). In the MTT assay, 3c was most active in DLD-1 (viability: 37.7%, IC₅₀ = 3.94 µM) and 3b in HT-29 (viability: 46.6%, IC₅₀ = 3.26 µM). In the WST-8 assay, 3c was strongest in DLD-1 (viability: 45.9%, IC₅₀ = 17.95 µM). None of the compounds showed toxicity in normal colon cells (CCD-18Co). qRT-PCR revealed upregulation of apoptotic (BAX, p53, Caspase-3/8/9) and antioxidant (SOD-1/2, CAT, GSS) genes, notably by 3a in DLD-1 and 3d in HT-29, while 3c reduced BCL-2 in HT-29 cells. ELISA confirmed strong antioxidant induction (3a: 70% in DLD-1) and HDAC inhibition (3d: 69% in HT-29). Western blot showed 3a increased p38/MAPK expression sevenfold in DLD-1 and fourfold in HT-29, while decreasing ERK1. Overall, 3c and 3d emerged as the most promising candidates, combining cytotoxic, antioxidant, HDAC inhibitory, and apoptotic effects, and may act as selective therapeutic agents by targeting the p38/MAPK-ERK1 pathway in colorectal cancer.

Invasion plasticity allows malignant cells to toggle between collective, mesenchymal, and amoeboid phenotypes while traversing extracellular matrix (ECM) barriers. Current dogma holds that collective and mesenchymal invasion programs trigger the mobilization of proteinases that digest structural barriers dominated by type I collagen, while amoeboid activity allows cancer cells to marshal mechanical forces to traverse tissues independently of ECM proteolysis. Here, we use cancer spheroid-3-dimensional matrix models, single-cell RNA sequencing, and human tissue explants to identify the mechanisms controlling mesenchymal versus amoeboid invasion. Unexpectedly, collective/mesenchymal- and amoeboid-type invasion programs-though distinct-are each characterized by active tunneling through ECM barriers, with expression of matrix-degradative metalloproteinases. CRISPR/Cas9-mediated targeting of a single membrane-anchored collagenase, MMP14/MT1-MMP, ablates tissue-invasive activity while coregulating cancer cell transcriptional programs. Though changes in matrix architecture, nuclear rigidity, and metabolic stress as well as the presence of cancer-associated fibroblasts are proposed to support amoeboid activity, none of these changes restore invasive activity of MMP14-targeted cancer cells. While a requirement for MMP14 is bypassed in low-density collagen hydrogels, invasion by the proteinase-deleted cells is associated with nuclear envelope and DNA damage, highlighting a proteolytic requirement for maintaining nuclear integrity. Nevertheless, when cancer cells confront explants of live human breast tissue, MMP14 is again required to support invasive activity. Corroborating these results, spatial transcriptomic and immunohistological analyses of human breast cancers identified MMP14 expression in tissue-infiltrating carcinoma cells that were further juxtaposed with proteolyzed type I collagen fragments, underlining the pathophysiologic importance of this proteinase in directing invasive activity in vivo.

Intrinsic and acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) remains a major barrier in treating homologous recombination (HR) repair-deficient tumors, including those with germline or somatic BRCA1/2 mutations. Although PARPi are FDA approved for adjuvant treatment of locally advanced or metastatic breast cancer in patients with germline BRCA1/2 mutations, emerging data support their use as monotherapy in the neoadjuvant setting. Promising safety profiles of newer-generation PARPi further support this potential. However, resistance mechanisms specific to the neoadjuvant setting are poorly understood. To address this gap, we leveraged resources from a phase II neoadjuvant clinical trial (NCT03499353), analyzing tumors from patients with germline BRCA1/2 mutant breast tumors before and after six months of talazoparib monotherapy. Whole-transcriptome analyses were performed on these samples. Additionally, we established orthotopic patient-derived xenograft models from a subset of the patient tumors and conducted whole-exome and whole-transcriptome analysis. This integrative approach revealed both known and previously unknown PARPi resistance mechanisms. In one case, overexpression of BRN2, encoding a transcription factor that plays a critical role in neurogenesis, led to activation of ATR/RAD51 and STAT3 pathways, restoring HR repair. BRN2-driven resistance could be reversed with ATR and STAT3 inhibitors, resensitizing cells to talazoparib. In another, an HR repair proficient tumor subclone lacking Shieldin 2 expression expanded during treatment and accounted for intrinsic resistance. Our findings highlight the need to determine intrinsic and anticipate acquired resistance pathways in treatment-naïve tumors and support combining PARPi with targeted agents to improve outcomes in the neoadjuvant setting.

Multiple biomarkers have been proposed to identify cancer stem cells in tongue squamous cell carcinoma. This study evaluated ALDH1A1, an ALDH1 subtype implicated in head and neck cancer stem cells, and examined its association with histopathological features (depth of invasion, worst pattern of invasion, perineural invasion, grade, inflammation, TNM stage) and prognostic outcomes in tongue tumors.

Leiomyosarcoma (LMS) is a rare and aggressive smooth muscle tumor, and venous leiomyosarcoma (VLMS) is an uncommon subtype, with majority of the cases involving the vena cava. We report a case of a 56-year-old patient initially diagnosed as deep vein thrombosis (DVT) in the common femoral vein who was later diagnosed with primary VLMS originating from the deep femoral vein. Despite anticoagulation therapy, leg edema persisted and imaging studies revealed an intraluminal mass with increased extent and size. Initial duplex ultrasound suggested chronic DVT; however subsequent contrast-enhanced computed tomography and magnetic resonance imaging performed during follow-up demonstrated interval growth of an intraluminal mass, and positron emission tomography-computed tomography later confirmed metabolically active disease, leading to the diagnosis of VLMS. Surgical resection of the mass was performed, followed by reconstruction of the femoral vein using an expanded polytetrafluoroethylene graft. Histopathologic examination confirmed the diagnosis of LMS. The patient had an uneventful postoperative recovery and was referred for adjuvant therapy, including chemotherapy and radiotherapy. This case highlights the importance of a multimodal diagnostic approach in differentiating neoplasms from blood clots and underscores the need for a high level of suspicion when DVT presents with atypical features. Early diagnosis and wide surgical excision with the aim of achieving negative margins are essential for successful management of VLMS.

Gastric cancer is a common malignancy of the digestive system worldwide, and lymph node metastasis is a key determinant for prognosis assessment and therapeutic decision-making. Patterns of lymphatic drainage and nodal spread may differ according to the primary tumor location. This study aimed to investigate the relationship between primary tumor site and lymph node metastatic characteristics. A total of 160 patients who underwent curative gastrectomy between February 2022 and June 2024 were retrospectively reviewed. According to the primary tumor location, patients were categorized into the cardia, body, and antrum groups. Lymph node metastasis rate, involved stations, metastatic extent, and lymph node ratio (LNR) were compared among groups. Multivariate logistic regression was performed to identify independent risk factors. The metastasis rates in the cardia, body, and antrum groups were 74.5%, 63.5%, and 58.5%, respectively, showing a decreasing trend. Cardia tumors predominantly involved stations No. 1 and No. 2, whereas antral tumors mainly involved stations No. 5 and No. 6 (P < .05). Patients with poorly differentiated or special-type histology had significantly higher LNRs. Multivariate analysis indicated that primary tumor located in the cardia, T3-T4 stage, and poor differentiation were independent risk factors (P < .05). Patients with diffuse-type lymphatic spread had markedly lower 3-year disease-free and overall survival compared with those with localized spread. Primary tumor location is closely associated with lymph node metastatic patterns in gastric cancer. Cardia tumors are more prone to longitudinal and cross-regional metastasis, while high T-stage and poor differentiation are linked with extensive nodal involvement and worse prognosis. Combined assessment of primary site and LNR may provide a useful reference for preoperative evaluation and lymphadenectomy planning.

Serum biomarkers that reflect both tumor burden and host response may provide valuable prognostic information in metastatic colorectal cancer (mCRC). Carbohydrate antigen 19-9 (CA19-9) and albumin levels have been associated with disease outcomes; however, the prognostic value of their ratio has not been evaluated in de novo mCRC. This study aimed to investigate the prognostic significance of the pretreatment CA19-9/albumin ratio in patients with de novo mCRC who were treated with standard combination chemotherapy and biologic agents. A total of 178 patients diagnosed with de novo mCRC between 2013 and 2024 were retrospectively analyzed. The CA19-9/albumin ratio was calculated by dividing serum CA19-9 (U/mL) by albumin (g/dL), and the optimal cutoff value was determined using receiver operating characteristic curve analysis. Patients were classified into low- and high-ratio groups. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and independent prognostic factors were identified through multivariate Cox regression analyses. The optimal cutoff value for the CA19-9/albumin ratio was 5.81. Patients with a high-ratio had significantly shorter PFS (median 9.6 vs 16.1 months, P = .002) and OS (median 23.3 vs 32.6 months, P = .005) compared with those with a low-ratio. In multivariate analyses, a high CA19-9/albumin ratio independently predicted shorter PFS (hazard ratio 0.60, 95% confidence interval [CI] 0.41-0.89, P = .011) and OS (hazard ratio 0.66, 95% confidence interval 0.44-0.99, P = .042). The CA19-9/albumin ratio is a simple, inexpensive, and easily obtainable serum biomarker that independently predicts survival in patients with de novo mCRC. This composite biomarker may better reflect the combined effects of tumor burden and host status, providing additional prognostic value beyond conventional markers. Prospective multicenter studies are warranted for further validation.

Oncocytic thyroid carcinoma (OCA) is a rare subtype of thyroid cancer, the patients with distant metastases frequently present a relatively poor survival prognosis. This study aims to establish a nomogram model for predicting the occurrence of distant metastasis in OCA. Data from 770 patients (from 2004-2021) were extracted from the Surveillance, Epidemiology, and End Results database for a retrospective study. The cancer-specific survival of OCA patients with different characteristics was assessed using Kaplan-Meier subgroup analysis curves. Using univariate and multivariate logistic regression analysis methods to identify independent risk factors for establishing a nomogram to predict the risk of distant metastasis. The predictive efficiency of the model was evaluated using the area under the curve, concordance index, and calibration curves. The clinical value of the predictive model was determined through decision curves analysis. Kaplan-Meier analysis found significant differences in cancer-specific survival among groups with different ages, tumor-node-metastasis stages, tumor sizes, and lymph node ratio. Through univariate and multivariate logistic regression, it was identified that age ≥ 55 years, higher T stage (T4), and higher N stage (N1a/N1b) are significant in diagnosing distant metastasis in OCA patients, leading to the establishment of a nomogram model. The model area under the curve and concordance index were 0.903, and calibration curves and the model decision curves analysis curve evaluated its feasibility and clinical utility. Extracting age, T stage, and N stage to establish a predictive model for distant metastasis in OCA patients. The nomogram is of great significance for clinicians to timely identify high-risk patients for distant metastasis and make further clinical decisions.

Primary pulmonary epithelioid trophoblastic tumor (ETT) without a uterine primary is exceptionally rare, with merely 29 cases documented in the English-language literature. Therefore, a standardized management protocol has yet to be established, and the optimal treatment strategy remains poorly defined.

Renal clear cell carcinoma (RCCC) is the most common type of kidney cancer, represents 90% of all renal tumors and approximately 3% of all malignant tumors in adulthood, which has unpredictable behavior. It has a peak incidence between the sixth and eighth decades of the life. Distant metastases are frequently found, these may occur decades after the diagnosis. We present a 81-year-old man with a history of RCCC managed with nephrectomy. After 4 years of follow up, he noticed a mass over the thyroid region. Ultrasonography reported a thyroid nodule. Due to the oncologic history, a total thyroidectomy was performed and the microscopic observation revealed polygonal cells with clear cytoplasm, and a fine capillary network around tumor nets. The tumor immunohistochemistry profile confirmed a metastatic RCCC, as tumor cells disclosed strong immunoreaction to RCC, CD10 and PAX-8, and negative for CK7 and TTF-1. This case emphasizes the importance of considering a metastatic origin when finding a thyroid nodule in a patient with a previous history of RCCC.

Taxane-induced peripheral neuropathy (TIPN) affects quality of life and ability to complete cancer treatment and has limited effective interventions for prevention and treatment.

The bone marrow (BM) niche serves as a critical protective environment for leukemia cells, particularly chemo-resistant leukemia cells, and plays a central role in driving therapeutic resistance and disease relapse in acute myeloid leukemia (AML). This specialized microenvironment not only promotes leukemia cell survival, but also inhibits T cell infiltration, which serves as a major obstacle to the effectiveness of CAR-T therapy in myeloid malignancies. To overcome this limitation, we targeted Rac1 GTPase, a central regulator of cytoskeletal dynamics that controls membrane protrusion and migration, by engineering primary human T cells and CD33 CAR-T cells to express constitutively active Rac1 (Rac1V12). Our results demonstrated that active Rac1 enhanced the migration of T cells and CD33 CAR-T cells and promoted their residence in the BM in vivo. Furthermore, CD33 CAR-T cells expressing Rac1V12 displayed enhanced cytotoxicity against leukemia cells in vitro, as demonstrated by transwell migration-dependent killing assays. Crucially, these engineered CAR-T cells achieved superior robust suppression of leukemia in vivo and significantly prolonged survival in xenograft models. Mechanistically, Rac1V12 CD33 CAR-T cells in the BM demonstrated enhanced immunological memory phenotype and lower tonic signaling, a combination that promotes T cell persistence and enhances anti-tumor efficacy in vivo. Our data suggest that active Rac1-engineered CD33 CAR-T cells represent a novel strategy for targeting BM leukemia cells, with the potential to eradicate AML cells.

Real-world evidence comparing long-term safety between PD-1 and PD-L1 inhibitors is limited, and the impact of competing mortality is unclear.

Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) has been found to be closely associated with the initiation and progression of various tumors; however, its role in oral squamous cell carcinoma (OSCC) remains unclear. AFAP1-AS1 expression in OSCC cells was detected using qRT-PCR. The regulatory effects of AFAP1-AS1 on tumor cell proliferation, migration, and invasive capabilities were systematically evaluated through CCK-8 proliferation, colony formation, wound healing, and Transwell invasion assays. Flow cytometry was employed to quantitatively analyze its impact on cell cycle progression and apoptotic. Based on bioinformatics predictions, a dual-luciferase reporter system was utilized to validate the targeting interactions among AFAP1-AS1, miR-93-3p, and CCND1. Functional rescue experiments were conducted to elucidate the functional regulatory network among them. Furthermore, a xenograft tumor model in nude mice was employed to verify in vivo the promoting effect of AFAP1-AS1 on tumor growth. AFAP1-AS1 was significantly upregulated in OSCC cells. AFAP1-AS1 knockdown inhibited the malignant phenotypes of OSCC cells. Mechanistic studies revealed that AFAP1-AS1 could target miR-93-3p and regulate CCND1 expression, thereby influencing OSCC progression. Subcutaneous tumor model in mice further confirmed the in vivo relevance of the AFAP1-AS1/miR-93-3p/CCND1 axis. AFAP1-AS1 downregulation inhibited OSCC progression through the miR-93-3p/CCND1 axis.

Colon cancer remains one of the most prevalent and aggressive malignancies, underscoring the demand for targeted and biologically safe therapeutic strategies. Arginine deiminase (ADI) has gained increasing interest as a potential anticancer agent due to its ability to modulate cellular arginine availability and inhibit tumor progression.

The intravesical Bacillus Calmette-Guérin (BCG) immunotherapy in Bladder Cancer (BC) is the standard adjuvant therapy with challenges such as limited efficacy and recurrence. We aimed to assess the synergistic antitumor effects of melatonin and BCG in vivo.

Aggressive brain tumors such as glioblastoma (GBM) remain among the most lethal human cancers, with a median survival of only 15 months despite multimodal treatment. Their resistance arises from a triad of barriers-the blood-brain barrier (BBB), marked intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment (TME). Immunotherapeutic strategies based on natural killer (NK) and T cells, leveraging antigen-independent cytotoxicity and antigen-specific precision, respectively, offer potential breakthroughs but are often limited by chronic neuroinflammation. A key driver of TME suppression is prostaglandin E2 (PGE2), produced via the cyclooxygenase-2 (COX-2) pathway. PGE2 exerts a dual role: Intracellularly, it can promote apoptosis, whereas extracellularly, it fosters tumor progression, immune evasion, and therapeutic resistance. Through activation of EP2 and EP4 receptors, PGE2 signals via Gαs proteins to elevate cyclic adenosine monophosphate (cAMP), leading to impaired cytotoxic immunity. This signaling downregulates NK cell activating receptors (e.g., NKG2D, NKp30), induces CD8⁺ T cell exhaustion, and promotes regulatory T cell expansion. The COX-2/PGE₂ axis further mediates resistance to checkpoint inhibitors, CAR-T therapy, and chemotherapy by enhancing neuronal excitation through EP1 receptor activation in GBM. Targeting this pathway has therefore emerged as a compelling therapeutic strategy, which can restore NK and T cell function and sensitize tumors to immunotherapy. Combining PGE₂ modulation with next-generation NK/T cell approaches-including CAR-NK and CAR-T platforms-holds promise to overcome immune resistance and redefine therapeutic paradigms for GBM and other central nervous system malignancies.

Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib remains a significant challenge. Previous studies have shown that sorafenib treatment induces the formation of truncated O-glycans in HCC cells, but the relationship between sorafenib-induced glycosylation changes and acquired therapy resistance remains unclear. Primary natural killer (NK) cells, freshly isolated from peripheral blood or following culture and expansion, expressed the glycoimmune checkpoints Siglec-7 and Siglec-9. HCC cells exhibited varying levels of Siglec-7/9 ligands on their surface. Sorafenib-resistant liver cancer cells displayed hypersialylation, leading to increased expression of surface Siglec-7/9 ligands, which conferred protection against NK cell-mediated cytotoxicity. Silencing ST3GAL1 significantly reduced Siglec-7 ligand expression on liver cancer cells, enhancing their susceptibility to NK-mediated cytotoxicity and cetuximab-induced antibody-dependent cellular cytotoxicity (ADCC) in epidermal growth factor receptor (EGFR)-expressing tumor cells. Furthermore, high ST3GAL1 expression correlated with poor clinical outcomes in patients with stage 1-2 HCC. This study highlights the critical role of ST3GAL1 in regulating Siglec-7 ligands to facilitate immune escape from NK cell cytotoxicity. Moreover, its elevated expression is associated with adverse clinical outcomes in HCC. Targeting ST3GAL1 may represent a promising strategy to enhance NK cell-mediated anti-tumor immunity in HCC.

We explored the fundamental feasibility, technical frame conditions and effectiveness of transcranial Tumor Destructive Mechanical Impulse (TMI) treatment of brain tumors.

Purpose To develop a lung-specific deformable image registration algorithm optimized for lung thermal ablation and evaluate whether three-dimensional (3D) margin assessment predicts time to local recurrence. Materials and Methods This institutional review board-approved, single-institution retrospective study evaluated patients who underwent lung thermal ablation with available pre- and postprocedural CT scans suitable for deformable registration. Images were preprocessed with segmentation of tumor, ablation zone, and lung. A four-stage deformable image registration framework was applied: (a) affine registration, (b) deformable image registration to the cropped lung, (c) lung mask-guided deformable image registration, and (d) local deformable image registration focused on the neighborhood adjacent to the ablation zone. Registrations were performed using free-form B-spline transformations with cost function masking of the ablation zone. Registration accuracy was assessed using target registration error (TRE). The 3D ablation margins were quantified using a distance-transform-based analysis of the spatial relationship between the tumor surface and ablation zone boundary. Associations between margin size and time to local recurrence were evaluated using competing-risks regression, and time-dependent receiver operating characteristic analysis was performed. Results A total of 69 patients (median age, 59 years [IQR, 50-69 years]; 38 female) with 108 ablated lung tumors were included. Mean TRE ± SD was 0.4 mm ± 0.3 and mean ablation margin was 1.6 mm ± 2.1. Larger margins were associated with longer time to local recurrence (subdistribution hazard ratio, 0.5 per millimeter increase [95% CI: 0.4, 0.6]; P < .001) and remained independently associated on multivariate analysis. Using a 2-mm margin threshold, the 2-year local recurrence rate was 3% (95% CI: 1, 8). The area under the receiver operating characteristic curve for predicting 2-year local recurrence was 0.86. Conclusion The four-step lung-optimized deformable image registration framework enabled accurate automated 3D tumor ablation margin quantification, and margin size was associated with time to local recurrence. Keywords: Ablation Techniques, Interventional-Oncology, Percutaneous, Thorax, Lung, Computer Applications-3D, Computational Studies, CT © RSNA, 2026.