Copyright: © 2026 Crane et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PURPOSE:The discovery of KRAS G12C as a therapeutic target has transformed oncology with the development of specific inhibitors. This study aimed to characterize the prevalence and clinicogenomic features of KRAS G12C mutations in genitourinary malignancies, an area with limited prior data despite recent FDA approvals of KRAS G12C-targeted therapies. MATERIALS AND METHODS:Comprehensive genomic profiling was performed on 13,654 formalin-fixed paraffin-embedded specimens, including 1,453 renal clear cell carcinomas (RCCC), 3,879 urothelial bladder carcinomas (UBC), and 8,322 prostate acinar adenocarcinomas (PAAC). Tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression (Dako 22C3) were also assessed. RESULTS:KRAS alterations were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%) cases. KRAS G12C variants were detected in 0 RCCC (0%), 24 UBC (12%), and 1 PAAC (<1%) cases. No KRAS G12C-mutated tumors showed MSI-high status. In UBC, KRAS G12C-positive cases demonstrated significantly lower TERT co-mutations and higher KDM6A alterations compared to KRAS G12C-negative cases (both p < 0.05). Age and sex distributions were similar across subtypes. Predominant co-alterations included VHL, SETD2, and PBRM1 in RCCC, and TP53, CDKN2A, and TERT in UBC. CONCLUSIONS:KRAS G12C mutations occur infrequently in major genitourinary malignancies. However, given the expanding therapeutic landscape of KRAS G12C inhibitors and potential for basket trials, further investigation in bladder and prostate cancers is warranted. These agents may offer meaningful benefit to the small subset of patients harboring this actionable alteration.
Copyright: © 2026 McKernan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Recent work by Achs et al. (2025) claimed to demonstrate no excessive residual DNA in COVID-19 mRNA vaccines using four orthogonal approaches. Since this work is being cited by regulatory authorities to claim DNA levels in mRNA vaccines are within limits, it is imperative that a robust public discussion occur regarding the methods strengths and weaknesses. We present a comprehensive critique identifying critical methodological flaws that systematically bias results toward underestimation of residual DNA contamination. These include: (1) inappropriate plasmid molecular weight calculations producing 1.5–10× underestimation (plasmid equivalents), (2) fragment size bias in primer design favoring detection of non-functional sequences over spike-encoding DNA, (3) thermal degradation of samples during library preparation, (4) analytical detection limits exceeding regulatory thresholds, (5) platform limitations excluding detection of kilobase-length DNA fragments, and (6) failure to account for RNA:DNA hybrid formation protecting spike DNA from degradation. Collectively, these flaws render the study's conclusions invalid for regulatory assessment of residual DNA contamination.
Copyright: © 2026 dos Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Ewing sarcoma (ES) is an aggressive childhood tumor. We have previously shown that tropomyosin receptor kinase (Trk) neurotrophin receptors regulate viability, and the Trk and multi-kinase inhibitor K252a restores sensitivity to chemotherapy, in ES cells. Here, we show that administration of K252a in mice transiently delays ES tumor growth and reduces expression and phosphorylation of multiple targets. BALB/c nu/nu nude mice inoculated with SK-ES-1 ES cells were given daily intraperitoneal (i.p.) injections of K252a for 18 days. Immunohistochemical analysis of tumors was performed to quantify the expression and phosphorylation of Trk receptors, phosphoinositide 3-kinase (PI3K), and insulin-like growth factor 1 receptor (IGF1R). Treatment with K252a led to a partial and transient delay in ES tumor growth and reduced the expression and phosphorylation of TrkA, TrkB, PI3K, and IGF1R. Combined treatment with K252a and the IGF1R inhibitor NVP-ADW742 was more effective in reducing ES cell viability than each compound alone. Associations between genes encoding Trks, PI3K, and IGF1R and overall survival (OS) in patients with ES was examined. Significant associations between expression of NTRK genes and patient OS were found, indicating that NTRK genes should be further evaluated as biomarkers for prognosis in patients with ES.
Copyright: © 2026 El-Deiry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Multiple primary cancers (MPC), the occurrence of two or more distinct malignancies in the same patient, pose significant clinical challenges due to their complexity and the need for individualized treatment strategies. This case, discussed at the WIN Consortium International Molecular Tumor Board, illustrates the clinical journey of a 48-year-old female with a BRCA1 germline mutation who developed multiple primary cancers: breast, skin, high-grade serous carcinoma of the ovary, colon and small bowel cancers. Her treatment history included doxorubicin and cyclophosphamide for breast cancer, Mohs surgery for basal cell carcinoma, and carboplatin and paclitaxel for ovarian cancer. After participating in the PRIMA trial with niraparib, she was diagnosed with PIK3CA-mutated colon cancer, leading to resection and CAPOX chemotherapy. A subsequent diagnosis of small bowel adenocarcinoma, molecularly resembling her colon cancer, along with a unique BRCA1-STARD3 fusion in inguinal lymph nodes prompted a comprehensive MTB review. The panel discussed several precision strategies, including combinations of cetuximab, niraparib, and temsirolimus; FOLFIRI with anti-EGFR inhibitors; anti-CTLA-4 and anti-PD-1 (botensilimab and balstilimab); regorafenib with anti-CTLA-4 and anti-PD-1 (ipilimumab and nivolumab); trifluridine/tipiracil with bevacizumab; regorafenib alone; aspirin for potential benefits in patients with PIK3CA mutations; therapies targeting PIK3CA and EGFR alterations; regular imaging and liquid biopsies assessments for monitoring disease progression and guide future treatment decisions; and vaccines targeting PIK3CA, STARD3 and TP53. This case underscores the complexity of managing MPC and highlights the essential role of international molecular tumor boards in generating innovative, tailored treatment recommendations for patients with rare and multifaceted disease courses.
Copyright: © 2026 Kalfoutzou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Renal oncocytoma is a rare benign kidney tumor arising from the intercalated cells of the distal renal tubules. These tumors are often asymptomatic and incidentally discovered on imaging. This report presents an 82-year-old female patient with gross hematuria, who was subsequently diagnosed with a small renal oncocytoma. A computed tomography (CT) scan of the abdomen revealed a lesion in the upper left kidney, diagnosed as a renal oncocytoma by histopathological examination of a tissue specimen obtained via a CT-guided biopsy. After multidisciplinary review, the tumor board recommended local treatment with percutaneous cryoablation due to the lesion’s small size and indolent nature. The patient has been on annual follow-up with imaging showing no disease progression over two years. This case highlights the management considerations for renal oncocytoma, particularly in elderly patients, and underscores the role of biopsy and multidisciplinary evaluation in deciding optimal, minimally invasive treatment strategies for benign renal tumors.
Copyright: © 2026 Khursheed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Breast cancer is considered to be one of the most widespread malignancies, however, its molecular processes are not fully comprehended. Another important epigenetic process that regulates the expression of genes in cancer is promoter methylation. TRAIL-R2 is also a key mediator of apoptosis but its clinical implications and epigenetic regulation in breast cancer are not clearly understood. In this research, the level of the promoter of the gene TRAIL-R2 in the matched tumor and normal breast tissues was analyzed using methylation-specific PCR and the level of the mRNA and protein products in the matched tumor and normal breast tissues were measured using quantitative real-time PCR and western blotting. Methylation of TRAIL-R2 promoter was significantly enhanced in tumor tissues and was negatively correlated with the levels of mRNA and protein. We found that hypermethylation was much more common in invasive ductal carcinoma patients and in patients with a history of use of oral contraceptives. A decreased expression of mRNA of TRAIL-R2 was significantly related to advanced TNM stage (III–IV) and the absence of progesterone receptor, and low protein expression was significantly related to postmenopausal status. These results suggest that aggressive clinicopathological phenotypes are associated with TRAIL-R2 silencing via promoter hypermethylation that may be relevant as a prognostic biomarker and therapeutic target in breast cancer.
Copyright: © 2026 Shalabaev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. BACKGROUND:Laryngeal leiomyosarcoma (LLMS) is an exceptionally rare malignant tumor, accounting for less than 1 % of all laryngeal cancers, which are predominantly epithelial in origin. Since the first description in 1939, fewer than 70 cases have been reported worldwide. In the largest pooled analysis reported a 5-year overall survival rate of 64%, with distant metastasis identified as the main adverse prognostic factor. CASE PRESENTATION:We report a 64-year-old male who presented with progressive dyspnea and hoarseness caused by a supraglottic mass. Preoperative biopsy revealed spindle-cell proliferation consistent with leiomyosarcoma (SMA +, Vimentin +, Ki-67 60 %). Comprehensive staging with CT, MRI, and ultrasound excluded regional and distant metastases. The patient underwent extended laryngectomy with R0 margins and left neck dissection (levels II–IV). Based on multidisciplinary tumor-board discussion, four cycles of adjuvant doxorubicin and ifosfamide were administered according to national sarcoma guidelines. At 12-month follow-up, the patient remains alive and free of disease. CONCLUSIONS:This report, representing the first documented case of LLMS from Central Asia, contributes to the limited global experience with this rare tumor. Our review identified four additional LLMS cases published between 2021 and 2024, totaling five recent reports including the present case. Collectively, these demonstrate persistent male predominance, glottic and supraglottic predilection, and survival outcomes consistent with previous observations. Complete surgical excision remains the cornerstone of therapy, while multidisciplinary-guided adjuvant treatment may benefit selected high-grade or high-risk patients. Continued accumulation and molecular characterization of cases are needed to refine prognostic assessment and optimize management strategies.
Copyright: © 2026 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The protein-acyltransferase DHHC3 supports a few different tumor malignancies, but mechanisms have been unclear. Here we report that DHHC3-null B16F10 melanoma cells showed markedly elevated oxidative stress and senescence, accompanied by diminished tumor growth within immunocompetent C57/BL6 mice, but not in immunodeficient NOD-SCID mice. These results suggest that absence of DHHC3 enhances innate and/or adaptive anti-melanoma immunity. Consistent with this, DHHC3-null melanomas contained elevated numbers of anti-tumor cells (M1 macrophages, NK, CD4+T, CD8+T), whereas pro-tumor cells (M2 macrophages, MDSCs) were diminished. Unexpectedly, DHHC3 ablation minimally affected experimental metastasis of cells injected into either immunocompetent C57/BL6 or immunodeficient NOD-SCID mice. We conclude that DHHC3 ablation does not fundamentally alter melanoma cell growth and invasion/metastasis (independent of the immune system) despite its effects on oxidative stress and senescence. However, DHHC3 does control primary melanoma growth by supporting anti-melanoma immunity.
Copyright: © 2026 Bivens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. OBJECTIVES:The main goals were to assess safety and efficacy (i.e., recurrence reduction). RESULTS:Seventeen patients were enrolled. The most common adverse events were grades 1 and 2 injection site reactions, and they occurred more frequently in the PepCan group (p < 0.0001). Two patients had allergic reactions (grade 2 and grade 3), at the 6th vaccination, which were considered to be a dose-limiting toxicity. No serious adverse events were reported. In the intention-to-treat analyses, 45% (5/11) had non-recurrence in the PepCan group while 80% (4/5) had non-recurrence in the placebo group (p = not significant). Those who received PepCan and experienced non-recurrence showed a trend of having higher new peripheral T cell immune responses to human papillomavirus type 16 E6 (p = 0.05). Pre-vaccination T helper type 1 cells were higher in the PepCan non-recurrence group compared to the PepCan recurrence group (p = 0.01). METHODS:PepCan consists of four human papillomavirus type16 E6 peptides and a Candida skin testing reagent. Patients with head and neck squamous cell carcinoma who had no evidence of disease after standard of care treatments were randomized at 3:1 to PepCan versus placebo (saline). Seven intradermal injections were given followed with two observational visits. Safety was assessed using CTCAE version 5, and efficacy was assessed based on not having recurrence within 2 years. In addition, immune responses and oral and gut microbiome were assessed. CONCLUSIONS:PepCan was well tolerated. PepCan does not seem to be effective in reducing recurrence; however, the results are inconclusive given the small patient numbers.
Copyright: © 2026 Ofosu-Asante et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. There remains an unmet need for effective drugs targeting KRAS-driven cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to disrupt hyperactive mutant KRAS in cancer. Here, we determined the effects of PCAIs on the viability and downstream mediators of KRAS on pancreatic cancer-derived PANC-1 and MIAPaCa-2 cells. NSL-YHJ-2-45 and NSL-YHJ-2-27 were the most potent of the analogs with EC50 values of 3.6 and 3.8 μM, respectively. NSL-YHJ-2-27 treatment of PANC-1 cells stimulated BRAF, MEK 1/2, ERK 1/2 and p90RSK phosphorylation levels by 64 to 150% while CRAF phosphorylation significantly decreased by 27%. Furthermore, 5 μM NSL-YHJ-2-27 depleted 20 to 61% of the monomeric G-proteins, CDC42, RHOA and RAC 1/2/3 while increasing pAKT (Ser 473) and pAKT (Thr 308) phosphorylation by 72 and 190%, respectively. Reactive oxygen species production significantly increased at 3 μM NSL-YHJ-27 in PANC-1 and MIA PaCa-2 by 2- and 9-fold, respectively. Bulk RNA sequencing analysis revealed that treatment of MIA PaCa-2 cells with 3 μM NSL-YHJ-27 resulted in significant differential expression of 88 genes. NSLYHJ-2-27 at 1 μM inhibited over 90% of pancreatic cancer cell migration. The PCAIs induced apoptosis in both PANC-1 and MIA PaCa-2 3D spheroids while doubling caspase 3/7 activity in PANC-1 cells. Taken together, these data obtained using pancreatic cancer cells with KRAS mutations suggest the ability of the PCAIs to prevent metastasis and tumor growth, strongly indicating their potential to serve as effective targeted therapies for treating cancer types driven by the multiple mutant forms of KRAS.
Copyright: © 2026 Duval et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Collagen triple helix repeat containing 1 (CTHRC1) is a secreted protein that has previously been explored for its role in tissue remodeling and cancer. However, its function in the tumor microenvironment (TME) remains poorly understood, despite its known expression in tumor-associated stroma. Colorectal cancer (CRC), a malignancy characterized by extensive stromal involvement, poses an excellent opportunity to investigate this gap. Here, we provide the first evidence that host-derived CTHRC1 drives colon cancer progression, with this effect consistently observed across three independent cohorts. Specifically, when injected with CRC cells, Cthrc1 null (global knockout, KO) mice develop significantly smaller and less dense tumors compared to wild-type (WT) mice. Additionally, median survival increased approximately 2.5-fold in Cthrc1 KO mice, from 28 days post-inoculation in WT (n = 10) to 69 days in CTHRC1-deficient mice (n = 10), suggesting CTHRC1 promotes tumor growth within the TME. Immune cell profiling revealed differences in the composition of tumors and spleens of these mice; specifically, Cthrc1 KO mice exhibited an increased percentage of CD3+ T cells in both tumors and spleens and decreased Gr-1+ myeloid cells in the spleen, compared to WT, indicating an immunoregulatory role for CTHRC1 in CRC. These results identify CTHRC1 as a key driver of CRC that may suppress the immune system, allowing for easier immune evasion by tumor cells, highlighting CTHRC1 as a potential new target for therapy.
