Elucidation and Regulation of Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma Cells from the Perspective of Glutamine Metabolism.

Tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of advanced renal cell carcinoma (RCC). However, there is a lack of useful biomarkers for assessing treatment efficacy. Through urinary metabolite analysis, we identified the metabolites and pathways involved in TKI resistance and elucidated the mechanism of TKI resistance. To verify the involvement of the identified metabolites obtained from urine metabolite analysis, we established sunitinib-resistant RCC cells and elucidated the antitumor effects of controlling the identified metabolic pathways in sunitinib-resistant RCC cells. Through the analysis of VEGFR signaling, we aimed to explore the mechanisms underlying the antitumor effects of metabolic control. Glutamine metabolism has emerged as a significant pathway in urinary metabolite analyses. In vitro and in vivo studies have revealed the antitumor effects of sunitinib-resistant RCC cells via knockdown of glutamine transporters. Furthermore, this antitumor effect is mediated by the control of VEGFR signaling via PTEN. Our findings highlight the involvement of glutamine metabolism in the prognosis and sunitinib resistance in patients with advanced RCC. Additionally, the regulating glutamine metabolism resulted in antitumor effects through sunitinib re-sensitivity in sunitinib-resistant RCC. Our results are expected to contribute to the more effective utilization of TKIs with further improvements in prognosis through current drug therapies.

Contemplation of the Effect of Nivolumab Plus Cabosantinib Therapy on Cerebral Hemorrhage in Patients with Brain Metastasis of Renal Cell Carcinoma: A Case Report.

Although the response to combination therapy has been reported in patients with brain metastases from advanced renal cancer, treatment-related cerebral hemorrhage has not been adequately studied. The CheckMate 9ER clinical trial of nivolumab and cabozantinib excluded patients with brain metastases. Therefore, the associated treatment outcomes in these patients with brain metastases are unclear. Herein, we report a case of bleeding from brain metastases in a patient with advanced renal cancer after gamma knife combination therapy with nivolumab and cabozantinib. Fortunately, the cerebral hemorrhage of the patient was alleviated by conservative treatment. Despite treatment interruption, the metastatic lesions reduced in size, and treatment was gradually resumed. In this case study, we report the risk of cerebral hemorrhage in combination therapy for brain metastasis cases, how to manage hemorrhage cases, and their prognosis.

The Impact of Pathological Grade Group 3 on Relapse-free Survival After Salvage Radiotherapy for Postoperative Prostate Cancer.

BACKGROUND/AIM: This retrospective study aimed to investigate the outcomes of relapse-free survival (RFS) after salvage radiation therapy (SRT) to the prostate bed for postoperative biochemical recurrence of prostate cancer. PATIENTS AND METHODS: A total of 87 patients were analyzed. There were 27, 32, and 24 patients with pathological grade groups of 1-2, 3, and 4-5, respectively. SRT doses of 64, 66 or 70 Gy were administered to 24, 3 and 60 patients, respectively. The Kaplan-Meier method was used to estimate time-to-event outcomes. The multiple imputations method was used to impute missing values, and Cox proportional-hazards models were applied for multivariate analyses. RESULTS: The median follow-up period for patients overall was 58.6 months. The 5-year RFS rates of the whole cohort was 59.4% and those for pathological grade groups 1-2, 3 and 4-5 were 88.9%, 37.7% and 39.5%, respectively. In multivariate analyses, higher pathological grade group [4-5 vs. 3 vs. 1-2: hazard radio (HR)=8.65, p<0.01], negative surgical resection margin (positive vs. negative: HR=0.41, p=0.02) and higher pre-salvage treatment serum prostate-specific antigen (cutoff value 0.31 ng/ml: HR=3.50, p<0.01) were significantly associated with poorer RFS. The cumulative incidences of grade 2 or more late rectal bleeding and late hematuria were 4.9% and 8.7%, respectively, at 5 years and 4.9% and 15.7%, respectively, at 8 years. These toxicities occurred only in the 70 Gy-treated arm. CONCLUSION: Our study revealed that pathological grade group 3 prostate cancer patients experienced moderately unfavorable RFS after SRT. Higher radiation doses might increase late toxicities without improving RFS.

A study of 95 infantile hemangiomas treated with propranolol: A potentially efficacious combination with laser therapy.

We studied 95 patients with infantile hemangioma (IH) treated with propranolol at the Department of Dermatology, Kumamoto University Hospital, from November 2016 to January 2022, based on sex, site, clinical classification, duration of treatment, and residual lesions after treatment. Four of the 95 patients discontinued propranolol due to side effects, and 55 completed follow-ups at our hospital. We observed that 30.1% showed complete resolution of the skin rash, while the remaining 69.8% had erythema or atrophic scarring. Complete resolution occurred in 70% of the cases with the subcutaneous type but only in 15% with the tumor type. Seventeen of the 55 patients who completed follow-ups were treated with propranolol combined with laser therapy. Combined use of propranolol and laser therapy significantly reduced severe erythema compared to the propranolol monotherapy. These results suggest that propranolol therapy in IH often leaves erythema except in the subcutaneous type and that an improvement in erythema can be expected when propranolol is combined with laser therapy.