Phosphorylated ACC (pACC), a downstream effector of the LKB1/AMPK pathway, may support tumor bioenergetics and exert a tumor-promoting role in glioblastoma (GBM). In the randomized REGOMA trial, pACC expression was associated with improved overall survival (OS) in GBM patients treated with regorafenib, but its validity in large cohorts is unclear. This study aimed to characterize pACC and phosphorylated AMPK (pAMPK) expression in a real-world GBM cohort and to assess their prognostic and predictive value in patients receiving second-line regorafenib or fotemustine/lomustine. In this retrospective, multicenter translational study, pACC and pAMPK were assessed by immunohistochemistry on FFPE tumor sections from 174 IDH-wild-type GBM patients treated with regorafenib (n = 84) or fotemustine/lomustine (n = 90). Staining was performed with a validated anti-pACC monoclonal antibody and quantified by digital pathology. Survival analyses included univariable and multivariable Cox proportional hazards models, with interaction testing. pACC and pAMPK were expressed in 85.6% and 95.4% of samples, respectively, with heterogeneous spatial patterns. Neither marker was significantly associated with OS in the univariable analyses, and neither retained independent prognostic value in multivariable analysis. Regorafenib was associated with significantly longer OS than alkylating agents (10.4 vs. 6.3 months; p = 0.0021). However, the treatment-by-pACC interaction test was not statistically significant (adjusted p = 0.610), providing no formal evidence of a differential treatment effect by pACC status. Although pACC-positive expression was enriched among patients experiencing longer overall survival under regorafenib, formal treatment-by-biomarker interaction was non-significant. These exploratory findings indicate that pACC is not an established predictive biomarker and warrant prospectively powered evaluation.

Nitrosoureas are cytotoxic chemotherapeutic drugs that cause cell death by DNA damage. They are used to treat malignancies, including malignant glioblastomas, Hodgkin's and non-Hodgkin lymphomas, and pancreatic islet cell tumors. Three of the most commonly used nitrosourea compounds are carmustine (BCNU), lomustine (CCNU), and fotemustine. Nitrosoureas are lipophilic chemicals with antitumor and cytotoxic effects via alkylating and carbamoylating compounds; they are active in multiple cell cycle phases. Lomustine readily crosses the blood-brain barrier and is commonly used for recurrent glioblastoma multiforme; in some European countries, fotemustine is used instead of lomustine. Carmustine was the first nitrosourea developed for public use (United States Food and Drug Administration approval in 1977). The drug has been widely discontinued due to toxicity, intravenous (IV) administration, and low availability.. Nitrosoureas are used alongside other chemotherapeutic agents (such as procarbazine, lomustine, and vincristine, a first-line regimen for oligodendroglioma) or as stand-alone chemotherapy agents. Streptozocin has methylnitrosourea activity against pancreatic islet cell tumors. Nitrosoureas are associated with significant and severe adverse effects, including leukoencephalopathy, pulmonary toxicity, nephrotoxicity, hepatotoxicity, neurotoxicity, myelosuppression, secondary leukemias, nausea, vomiting, stomatitis, alopecia, anemia, anorexia, and phlebitis and burning at the injection site. Due to their severe side effect profiles, nitrosoureas are mostly used for tumor recurrence or refractory cases. Nitrosourea metabolites are primarily excreted through the kidneys. 

This report describes 2 cases of extremely rare primary vaginal T-cell lymphoma involving the cervix in dogs, diagnosed through comprehensive imaging, histopathological, and immunophenotypic evaluations. Case 1 involved a 12-year-old spayed female Shiba Inu dog that was presented with dyschezia and vulvar bleeding. Cytologic evaluation of fine-needle aspirates was nondiagnostic, necessitating tissue biopsy for definitive diagnosis. Computed tomography revealed a large vaginal mass with poor contrast enhancement and a uniformly hypodense internal structure. Chemotherapy with prednisolone, L-asparaginase, and lomustine resulted in temporary tumor regression; however, disease progression was noted by Day 50, and the dog died on Day 56. Case 2 involved a 10-year-old spayed female mixed-breed dog that was presented with dyschezia, dysuria, and hematuria. A CT scan revealed a large mass extending from the vaginal canal into the pelvic cavity. Cytologic evaluation was inconclusive. Surgical excision of the mass and urinary diversion was done, followed by chemotherapy with L-asparaginase, prednisolone, and lomustine. Despite these interventions, the clinical condition rapidly deteriorated, and the dog died on Day 44. Necropsy revealed widespread systemic dissemination of lymphoma and findings consistent with disseminated intravascular coagulation. These cases highlight the aggressive clinical behavior of this disease and underscore the importance of early histopathological diagnosis for appropriate therapeutic intervention. Key clinical message: Lymphoma should be considered as a differential diagnosis in dogs with primary vaginal masses.

Reticulocalbin-1 (RCN1), an endoplasmic reticulum (ER)-related gene, demonstrates critical regulatory functions in cellular growth. RCN1 has been previously revealed to be closely associated with initiation, metastasis and chemosensitivity in some tumors. However, the prognostic significance of RCN1 and its influence on the cancer immune microenvironment remains unclear. By leveraging multi-omics data from TCGA and GEO, this study delineated the expression profile of RCN1 across various human malignancies and normal tissues. Analysis of RCN1 expression in correlation with tumor immune microenvironment characteristics was performed using CIBERSORT and ssGSEA. Pan-cancer prognostic value was assessed via multiple survival models. In glioma, immunohistochemistry, co-culture, and qPCR were utilized to further investigate the role of RCN1 in tumor immunity and prognosis. Drug-specific responses to RCN1 expression were probed for cisplatin, irinotecan, carmustine and lomustine, which are the common chemotherapeutic agents used in glioma clinical treatment. The results indicate that RCN1 is a key gene with the potential to promote the progression of multiple tumors and is closely associated with tumor immune response, particularly macrophage activation. In glioma, overexpression of RCN1 promotes tumor proliferation and indicates poor prognosis, and is closely related to endoplasmic reticulum stress. Knockdown of RCN1 enhances the chemotherapeutic efficacy of carmustine and lomustine. In conclusion, our research positioned RCN1 as an important oncogene from a pan-cancer perspective and validated its role in glioma. In particular, RCN1 is closely associated with the immune microenvironment and endoplasmic reticulum stress during tumorigenesis. In addition, RCN1 has broad prospects in guiding tumor chemotherapy pending physiological in vivo validation.

Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is the most common subtype of autoimmune encephalitis, typically associated with ovarian teratomas, but also reported in men and children. We describe an exceptionally rare case of anti-NMDA receptor encephalitis following glioma resection. A 34-year-old man with no prior medical history presented with severe headache and generalized tonic-clonic seizure. Brain MRI suggested a tumor in the right insular region, and surgical resection confirmed a diffuse astrocytoma, WHO grade II. Postoperatively, the patient developed fever, seizures, confusion, and visual symptoms. Initial cerebrospinal fluid analysis suggested viral encephalitis, but repeated testing revealed marked pleocytosis and elevated protein. Autoimmune antibody panel confirmed anti-NMDA receptor antibody, while other antibodies and viral studies were negative. High-dose methylprednisolone and intravenous immunoglobulin therapy resulted in clinical improvement. The patient subsequently received adjuvant chemotherapy with procarbazine and lomustine for glioma, and no recurrence of encephalitis was observed during a 4-year follow-up. This case highlights the diagnostic challenge of distinguishing glioma-related neuropsychiatric symptoms from anti-NMDA receptor encephalitis, and raises the possibility that surgical manipulation may act as a trigger. Early recognition and appropriate immunotherapy remain essential for favorable outcomes. Further studies are needed to clarify the role of chemotherapy in long-term prognosis of tumor-associated anti-NMDA receptor encephalitis.

Cases of natural killer (NK)-cell large granular lymphocyte lymphoma are extremely rare, accounting for approximately 0.8% to 2.56% of lymphomas in dogs. A 5-year-old male Rottweiler presented with multiple cutaneous nodules and progressive weight loss, with a clinical course of less than 2 months. Following inconclusive cytology, an incisional biopsy was performed for histopathological and immunohistochemical analyses. Histopathological examination revealed a neoplastic proliferation of round cells infiltrating the deep dermis and subcutaneous tissue. The microscopic features, combined with the immunostaining profile-negative for CD3 and CD79a and positive for CD18 and granzyme-indicated a diagnosis of large granular lymphocyte lymphoma with a non-B/non-T immunophenotype of NK-cell origin. The patient underwent chemotherapy with lomustine and completed three treatment sessions before being euthanized, with a survival time of 93 days. Necropsy revealed involvement of the lymph nodes, heart, stomach, liver, and skin. Histopathological and immunohistochemical findings confirmed the antemortem diagnosis at all sites. To the best of our knowledge, this is the first report of cutaneous, cardiac, gastric, and hepatic involvement associated with non-B, non-T large granular lymphocyte lymphoma in dogs.

Immune checkpoint inhibitors have not demonstrated a survival benefit in unselected high-grade glioma populations; however, a subset of patients may achieve durable disease control. We report the case of a 30-year-old male patient diagnosed with a right temporoparietal high-grade glioma, initially classified as anaplastic astrocytoma and later evolving to astrocytoma, isocitrate dehydrogenase (IDH)-mutant, grade 4 according to the 2021 World Health Organization classification. The patient underwent multiple surgical resections followed by radiotherapy with concomitant temozolomide and subsequent adjuvant temozolomide (Stupp protocol). Upon disease recurrence, he received second-line treatment with lomustine plus bevacizumab, with documented progression across successive lines of therapy. In the absence of standard therapeutic options, off-label nivolumab was initiated in November 2018 following further progression. The tumor harbored an IDH1 R132H mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Corticosteroids were discontinued prior to immunotherapy initiation. Serial magnetic resonance imaging demonstrated sustained radiological stability, without evidence of nodular enhancement or increased perfusion suggestive of recurrence. The most recent imaging assessment (March 2026) confirmed ongoing disease stability of more than seven years after treatment initiation. Treatment was well tolerated, with only mild immune-related arthralgias reported. The patient remains functionally independent, with stable mild residual hemiparesis. This case highlights the potential for prolonged disease stability under anti-Programmed cell death protein 1 (PD-1) therapy in selected patients with high-grade glioma. Although immunotherapy has not shown benefit in unselected populations, molecular features such as IDH mutation and MGMT promoter methylation, as well as the absence of corticosteroid use, may contribute to enhanced treatment responsiveness and warrant further investigation.

Effective chemotherapy for glioma remains limited by the restrictive nature of the blood-brain barrier (BBB). In this work, a pH-responsive polysorbate 80-coated liposomal nanocarrier loaded with lomustine (CCNU@T80-LIP) was developed to enhance the delivery and therapeutic efficacy of lomustine (CCNU) against glioma. The liposomes exhibited spherical morphology, uniform size distribution, and high encapsulation efficiency. The formulation demonstrated pH-triggered drug release under acidic conditions, supporting its potential for endosomal escape and controlled intracellular delivery. In vitro studies revealed that CCNU@T80-LIP exhibited strong, dose-dependent cytotoxicity against U87-MG glioma cells while maintaining minimal toxicity toward hCMEC/D3 endothelial cells. In 3D tumor spheroids, the formulation achieved enhanced penetration and reduced cell viability to 76.81 ± 14.29%, compared with 92.32 ± 9.79% for free CCNU. Furthermore, in a coculture BBB model in a transwell system, coumarin-6 loaded T80-LIP displayed approximately 1.5-fold higher permeability than the uncoated formulation (Cou6@LIP) and significantly decreased glioma viability (64.37 ± 3.54%) without compromising endothelial integrity. Overall, CCNU@T80-LIP demonstrates efficient BBB translocation, pH-responsive release, and potent tumor-selective cytotoxicity, highlighting its potential as an effective nanocarrier for glioma chemotherapy.