A patient with oligometastatic hormone-sensitive prostate cancer who achieved long-term progression-free survival following cytoreductive radical prostatectomy and metastasectomy.

Introduction: Oligometastatic prostate cancer can be well-controlled through combined local and metastasis-directed therapies. However, the effects of cytoreductive radical prostatectomy and metastasectomy remain unclear. Case presentation: A 52-year-old man presented with prostate cancer and isolated bone metastasis to the thoracic spine. Six months after neoadjuvant hormonal therapy, the patient underwent cytoreductive radical prostatectomy and total en bloc spondylectomy. The postoperative course was uneventful. Hormonal therapy was terminated 5 years after surgery, and no biochemical or radiological progression was observed at 7 years postoperatively. Conclusion: Although careful patient selection is necessary, cytoreductive radical prostatectomy and metastasectomy are effective treatments for well-selected patients with oligometastatic prostate cancer.

Increased expression of ATP-binding cassette transporters in enfortumab vedotin-resistant urothelial cancer.

Introduction: In addition to reduced nectin-4 expression, the upregulation of ATP-binding cassette transporters has been suggested as a potential mechanism of resistance to enfortumab vedotin. Case presentation: A 76-year-old man previously treated with platinum-containing chemotherapy and pembrolizumab for metastatic bladder cancer was administered enfortumab vedotin because of disease progression. Subsequently, metastasectomy was performed for oligometastatic lesions (in the lung and adrenal gland) that exhibited growth during enfortumab vedotin therapy. Immunostaining analysis revealed decreased nectin-4 expression and elevated MDR1, MRP1, and BCRP expression in the metastatic lesions. Conclusion: Decreased nectin-4 expression and increased ATP-binding cassette transporter expression are potential factors in the development of enfortumab vedotin resistance in urothelial carcinoma. Immunohistochemical evaluation of these proteins may aid in predicting treatment efficacy.

Association between Immune Checkpoint Inhibitor Treatment Outcomes and Body Composition Factors in Metastatic Renal Cell Carcinoma Patients.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC); however, validating body composition-related biomarkers for their efficacy remains incomplete. We evaluated the association between body composition-related markers and the prognosis of patients with mRCC who received ICI-based first-line therapies. PATIENTS AND METHODS: We retrospectively investigated 60 patients with mRCC who underwent ICI-based therapy as their first-line treatment between 2019 and 2023. Body composition variables, including skeletal muscle, subcutaneous fat, and visceral fat indices, were calculated using baseline computed tomography scans. Sarcopenia was defined according to sex-specific cut-off values of the skeletal mass index. The associations between body composition indices and objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: Patients with sarcopenia had lower ORR and DCR than those without sarcopenia (33.3% vs. 61.1%, p = 0.0436 and 52.4% vs. 94.4%, p = 0.0024, respectively). Patients with sarcopenia had a significantly shorter median PFS (14 months vs. not reached, p = 0.0020) and OS (21 months vs. not reached, p = 0.0023) than patients without sarcopenia did. Sarcopenia was a significant predictor of PFS (hazard ratio [HR], 4.31; 95% confidence interval [CI], 1.65-14.8; p = 0.0018) and OS (HR, 5.44; 95% CI, 1.83-23.4; p = 0.0013) along with poor IMDC risk. No association was found between the subcutaneous, visceral, and total fat indices and the therapeutic effect of ICI-based therapy. CONCLUSIONS: Sarcopenia was associated with a lower response and shorter survival rates in patients with mRCC who received first-line ICI-based therapy.

A case of adrenal undifferentiated pleomorphic sarcoma with tertiary lymphoid structures responded to pembrolizumab.

Introduction: Although undifferentiated pleomorphic sarcomas are aggressive, a subset of these tumors are immunogenic and may respond to immunotherapy. Case presentation: A 69-year-old man developed bilateral adrenal tumors and underwent bilateral adrenalectomy. Pathological examination revealed undifferentiated pleomorphic sarcoma harboring tertiary lymphoid structures and infiltration of CD8+ T cells. Genome profiling revealed PD-L1 amplification, microsatellite instability, and a high tumor mutation burden. He developed local recurrence and multiple peritoneal dissemination 2 months after surgery; adriamycin chemotherapy was ineffective for these lesions. Sustained complete remission of all lesions was achieved by administering pembrolizumab. Conclusion: Immunohistochemical analysis focusing on tertiary lymphoid structures and genome profiling to evaluate microsatellite instability and tumor mutation burden are essential for precision medicine and informed clinical decision-making when treating advanced undifferentiated pleomorphic sarcoma.

Presurgical avelumab plus axitinib in an immunosenescent octogenarian with renal cell carcinoma invading the vena cava.

Application of immune checkpoint inhibitors (ICIs) in elderly patients remains challenging due to the scarcity of safety and efficacy data. An 84 year-old female with a right renal cell carcinoma invading the vena cava received two cycles of avelumab plus axitinib. As the thrombus showed a marked reduction, right nephrectomy and vena cava thrombectomy were performed. Pathological examination revealed intra-tumor infiltration of CD8+ T cells suggesting the efficacy of immunotherapy. Although immune function deteriorates with age (immunosenescence), our findings suggest that older patients may not necessarily be excluded from ICI therapy.

Efficacy of cabozantinib therapy for brain metastases from renal cell carcinoma.

Introduction: We report two cases of renal cell carcinoma with brain metastases that showed remarkable responses to cabozantinib. Case presentation: (Case 1) A 70-year-old man with cT3aN0M0 clear cell renal cell carcinoma underwent radical nephrectomy and developed multiple brain metastases 2 months postoperatively. The brain lesions regressed after stereotactic radiotherapy followed by ipilimumab plus nivolumab therapy, but a new brain metastasis that caused hemiplegia developed after 6 months and showed no response to stereotactic radiotherapy. However, complete remission was achieved, and hemiplegia ceased within 2 weeks of cabozantinib therapy. (Case 2) A 63-year-old man with cT3aN0M1 clear cell renal cell carcinoma and brain metastases underwent upfront cytoreductive nephrectomy. The brain lesions progressed rapidly 1 month postoperatively. The lesions disappeared 2 weeks after cabozantinib plus nivolumab therapy. Conclusion: Cabozantinib, alone or in combination with immune checkpoint inhibitors, may be a viable option for clear cell renal cell carcinoma with brain metastases.

Increased expression of Nrf2 and elevated glucose uptake in pheochromocytoma and paraganglioma with SDHB gene mutation.

BACKGROUND: Pheochromocytomas (PCC) and paragangliomas (PGL) are catecholamine-producing neuroendocrine tumors. According to the World Health Organization Classification 2017, all PCC/PGL are considered to have malignant potential. There is growing evidence that PCC/PGL represent a metabolic disease that leads to aerobic glycolysis. Cellular energy metabolism involves both transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and succinate dehydrogenase (SDH) subtypes, but the association of these substances with PCC/PGL is largely unknown. METHODS: We investigated SDHB gene mutation and protein expressions for SDHB and Nrf2 in surgical specimens from 29 PCC/PGL. We also assessed preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy-glucose positron emission tomography and mRNA levels for Nrf2. RESULTS: Among 5 PCC/PGL with a PASS Score ≥ 4 or with a moderately to poorly differentiated type in the GAPP Score, 4 were metastatic and found to be SDHB mutants with homogeneous deletion of SDHB protein. SDHB mutants showed a higher expression of Nrf2 protein and a higher preoperative SUVmax than non-SDHB mutants with a PASS < 4 or a well-differentiated GAPP type. Furthermore, protein expression of Nrf2 was positively associated with preoperative SUVmax. The Nrf2 mRNA level positively correlated with malignant phenotype, higher expression for Nrf2 protein and SDHB gene mutant, but negatively correlated with expression for SDHB protein. There was also a positive correlation between Nrf2 mRNA level and SUVmax. CONCLUSION: These results suggest that activation of Nrf2 and elevated metabolism play roles in PCC/PGL with malignant potential that have SDHB gene mutation and SDHB deficiency.

Factors affecting urinary frequency after low-dose-rate brachytherapy for prostate cancer.

OBJECTIVES: Lower urinary tract symptoms are transiently exacerbated by low-dose-rate brachytherapy (LDR-BT) for prostate cancer and recover to pretreatment levels 1 year thereafter. Generally, these symptoms are influenced by temperature. We aimed to search for factors affecting the lower urinary tract symptoms after seed implant including seasons. METHODS: We retrospectively enrolled 812 patients who underwent LDR-BT at Nara Medical University Hospital from January 2010 to December 2018 and for whom the International Prostate Symptom Score, Overactive Bladder Symptom Score, and frequency volume charts were available. We investigated the relationships between lower urinary tract symptoms, 24-hours urinary frequency, 24-hours urinary volume before and after seed implant, radiation dose, and season of seed implant. RESULTS: The mean age was 69.5 years. The mean prostate volume was 24.2 mL. The International Prostate Symptom Score, Overactive Bladder Symptom Score, and 24-hours urinary frequency increased until 3 months and gradually decreased over 6 months after seed implant. Multiple linear regression analysis revealed that 24-hours urinary frequency at 3 months after seed implant was significantly influenced by external beam radiotherapy, larger prostate volume before implant, higher 24-hours urinary frequency at baseline, larger 24-hours urinary volume at 3 months after implant, and performance of implant in summer. CONCLUSIONS: Lower urinary tract symptoms worsened 3 months after seed implant of LDR-BT regardless of the season of implant. The urinary frequency 3 months after seed implant was slightly lower when seed implant was performed in the summer.

A case of clear cell renal cell carcinoma with vena cava thrombus responding to presurgical avelumab, and axitinib.

INTRODUCTION: We report a case of renal cell carcinoma with vena cava thrombus showing a marked reduction with presurgical avelumab plus axitinib, facilitating nephrectomy with thrombectomy. CASE PRESENTATION: A 50-year-old man was taken to emergent care unit due to spontaneous renal rupture and was diagnosed to have left-sided renal cell carcinoma with level IV tumor thrombus. After hemostasis was obtained via transcatheter arterial embolization, avelumab plus axitinib was introduced because upfront surgery was deemed unfeasible due to poor performance status and possible retroperitoneal tumor dissemination. After four treatment cycles, thrombus was reduced to level II, and nephrectomy with thrombectomy was performed. Histological analyses revealed massive CD8+ T cell infiltration in the thrombus, suggesting immunotherapy efficacy. He has remained recurrence-free without any additional treatment for eight months. CONCLUSION: For locally advanced renal cell carcinoma with vena cava thrombus, presurgical combination therapy with avelumab plus axitinib could be an option to facilitate curative surgery.

[Retrospective Analysis of Severe Renal Infections Requiring Nephrectomy to Control Infection].

Patients who contract severe renal infections often suffer from urosepsis. Therefore, early diagnosis and treatment are required. Sometimes, the treatment with antibiotics is not enough for control of the infections. Most of the patients also require surgical interventions including transurethral drainage and nephrectomy. Twenty-two patients with severe renal infections treated between April 2010 and October 2019 at our institute were evaluated retrospectively. Eleven patients had undergone nephrectomy. Open nephrectomy was performed on 10 patients. Laparoscopic nephrectomy was attempted in the other patient but was converted to open nephrectomy because severe adhesion was found around the tissues. Nephrectomy was performed by the retroperitoneal approach on 9 patients and by the transperitoneal approach on 2 patients. The reteroperitoneal approach was used on two patients who suffered postoperative colon perforation. Inflammatory involvement of renal pelvis, hilum and adjacent structures leads to dense fibrotic reaction and obliteration of tissue planes, which makes the nephrectomy procedure challenging. Therefore, it is important to choose the most appropriate nephrectomy procedure for each patient when they have contracted severe renal infections.

[A Case Report of Severe Ischemic Priapism Treated Aggressively by Proximal Shunt].

Priapism is defined as a full or partial erection for >4 hours without sexual stimulation or orgasm. Ischemic priapism is an emergency disease that urgently requires surgery to reduce pressure in the corpora cavernosa. We encountered a case of severe ischemic priapism that required a proximal shunt. The patient was a 71-year-old man who had been diagnosed with benign prostatic hyperplasia ; hence, oral administration of tamsulosin had been initiated at a local hospital. His penis became gradually rigid and presented with prolonged erection. Then he consulted our hospital. Penile aspiration was impossible, and phenylephrine injection was not effective. He was subsequently transferred to our hospital. He did not have severe pain but had complete erection. We could not correctly evaluate blood gas from the corpora cavernosa and color Doppler ultrasonography showed little blood flow in the corpora cavernosa. We judged that the patient had ischemic priapism. The erection could not be controlled by distal shunt plastic surgery performed using the T shunt and Al-Ghorab methods. Therefore, a proximal shunt plastic surgery as described by Sacher was performed. The surgery was effective, but it caused erectile dysfunction.

5-Fluorouracil-based adjuvant chemotherapy improves the clinical outcomes of patients with lymphovascular invasion of upper urinary tract cancer and low expression of dihydropyrimidine dehydrogenase.

Lymphovascular invasion (LVI) by urothelial carcinoma of the upper urinary tract (UC-UUT) is associated with an unfavorable prognosis. However, a high proportion of patients with UC-UUT are unable to receive the recommended doses of cisplatin-based adjuvant chemotherapy due to advanced age or renal dysfunction resulting from nephroureterectomy. Tegafur-uracil is an oral form of 5-fluorouracil whose efficacy is influenced by the activities of enzymes associated with its metabolism, such as dihydropyrimidine dehydrogenase (DPD), orotatephosphoribosyltransferase (OPRT) and thymidylate synthase (TS). The aim of the present study was to investigate the efficacy of adjuvant 5-fluorouracil chemotherapy for UC-UUT with LVI, and to assess the expression of enzymes associated with 5-fluorouracil metabolism as promising biomarkers of therapy efficacy. The present study retrospectively investigated 52 cases of UC-UUT. Following nephroureterectomy, tegafur-uracil was administered to 15 out of 30 patients with LVI who were not eligible for cisplatin-based adjuvant chemotherapy. Levels of DPD, OPRT and TS expression in tumor specimens were determined by reverse transcription-quantitative polymerase chain reaction, and their associations with the efficacy of adjuvant 5-fluorouracil chemotherapy were analyzed. The levels of DPD, OPRT and TS expression were not associated with pathological factors or outcome, although a higher expression of TS was associated with a poorer outcome. Adjuvant 5-fluorouracil chemotherapy significantly improved the outcome of patients with lower DPD expression. However, the levels of OPRT and TS expression did not influence therapeutic efficacy. Adjuvant 5-fluorouracil chemotherapy appears to be effective for lymphovascular-invasive UC-UUT in patients with lower DPD expression.

Immunohistochemical expressionof sodium-dependent glucose transporter - 2 (SGLT-2) in clear cell renal carcinoma: possible prognostic implications

ABSTRACT Purpose: Glucose is a major energy resource for tumor cell survival and growth, and its influx into cells is mainly carried out by facilitative glucose transporters (GLUTs). Sodium - dependent glucose transporters (SGLTs) have been highlighted as playing important roles in diabetic treatment. However, their potential roles in cancer remain unclear. We examined expression patterns of SGLTs in tumor tissues together with conventional pathological variables to determine prognostic significance in patients with renal cell carcinoma (RCC). Materials and Methods: Nephrectomy specimens were obtained from 68 patients. GLUT - 1, - 2 and SGLT - 1, - 2 expression in tumor and adjacent normal tissues were analyzed by immunohistochemical staining, and intensity was quantified using an image analyzer. Results: The four glucose transporters evaluated were broadly distributed in tumor tissues as well as throughout the normal parenchyma. There was no significant correlation between transporter expression and conventional pathological variables. However, increased SGLT - 2 expression was significantly associated with shorter overall survival (p < 0.01), regardless of metastatic status. Conclusions: We propose possible prognostic significance of SGLT - 2 expression in human RCC. Given that glucose is a major energy resource for tumor cells and that glucose transport is largely mediated by SGLT, SGLT - 2 may serve as a possible therapeutic target in RCC.

Immunohistochemical expressionof sodium-dependent glucose transporter - 2 (SGLT-2) in clear cell renal carcinoma: possible prognostic implications.

PURPOSE: Glucose is a major energy resource for tumor cell survival and growth, and its influx into cells is mainly carried out by facilitative glucose transporters (GLUTs). Sodium - dependent glucose transporters (SGLTs) have been highlighted as playing important roles in diabetic treatment. However, their potential roles in cancer remain unclear. We examined expression patterns of SGLTs in tumor tissues together with conventional pathological variables to determine prognostic significance in patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: Nephrectomy specimens were obtained from 68 patients. GLUT - 1, - 2 and SGLT - 1, - 2 expression in tumor and adjacent normal tissues were analyzed by immunohistochemical staining, and intensity was quantified using an image analyzer. RESULTS: The four glucose transporters evaluated were broadly distributed in tumor tissues as well as throughout the normal parenchyma. There was no significant correlation between transporter expression and conventional pathological variables. However, increased SGLT - 2 expression was significantly associated with shorter overall survival (p < 0.01), regardless of metastatic status. CONCLUSIONS: We propose possible prognostic significance of SGLT - 2 expression in human RCC. Given that glucose is a major energy resource for tumor cells and that glucose transport is largely mediated by SGLT, SGLT - 2 may serve as a possible therapeutic target in RCC.

The Predictive Value of Glycated Hemoglobin and Albumin for the Clinical Course Following Hospitalization of Patients with Febrile Urinary Tract Infection.

BACKGROUND: Diabetes is considered a risk factor for acquisition of febrile urinary tract infection (f-UTI), but information on the association of diabetes with subsequent course of the disease is lacking. Thus, we investigated the clinical variables including diabetic status which determined the clinical course in patients with community-acquired f-UTI. MATERIALS AND METHODS: Patients hospitalized consecutively for f-UTI between February 2016 and January 2018 were used for this single center study. The routine laboratory tests including blood glucose and glycated hemoglobin (HbA1c) were done and empiric treatment with parenteral antibiotics was commenced on admission. The clinical course such as duration of fever (DOF) and length of hospital stay (LOS) were compared among groups classified by the clinical variables. RESULTS: Among the101 patients admitted for f-UTI, 15 patients with diabetes (14.9%) experienced significantly longer febrile period and hospitalization compared to those with hyperglycemia (n = 18, 17.8%) or those without diabetes and hyperglycemia (n = 68, 67.3%). Of the laboratory parameters tested on admission and several clinical factors, the presence of diabetes and risk factors for severe complicated infection (hydronephrosis, urosepsis, and disseminated intravascular coagulopathy) as well as HbA1c and albumin were identified as predictors for LOS by univariate analysis, whereas none of the variables failed to predict DOF. In the subsequent multivariate analysis, HbA1c levels and albumin levels were isolated as independent predictors of LOS. CONCLUSION: Patients with higher HbA1c and lower albumin levels required the longest period of hospitalization. Thus, an evaluation of diabetic and nutritional status on admission will be feasible to foretell the clinical course and better manage the subset of patients at risk of prolonged hospitalization.

Elevated serum levels of cardiovascular biomarkers are associated with progression of renal cancer.

Objective: Renal cell carcinoma (RCC) is a hypervascular tumour due to high constitutive production of vascular endothelial growth factor (VEGF), which is activated by hypoxia-inducible factor (HIF). Elevated levels of cardiovascular peptides, including brain natriuretic peptide (BNP), have been reported in patients with cancer, regardless of whether they have overt cardiovascular disease. Furthermore, it has been demonstrated that hypoxia stimulates BNP production by an HIF-dependent manner. However, the clinical implications of such cardiovascular peptides in patients with RCC have not been assessed. Methods: In patients with clear cell RCC who underwent nephrectomy, we investigated the relationship between the serum level of BNP or N-terminal pro-BNP (NT-proBNP) and various clinicopathological characteristics, including serum VEGF and expression of BNP and HIF-2 alpha in the primary tumour. Results: Elevated preoperative serum levels of BNP, NT-proBNP and VEGF, as well as increased tumour expression of HIF-2 alpha, were associated with a worse performance status, local invasion, distant metastasis and shorter overall survival. HIF-2 alpha expression showed a positive correlation with the preoperative serum VEGF level, while there was no relation between the serum levels of BNP/NT-proBNP and VEGF or tumour expression of HIF-2 alpha. BNP expression was very low in both tumour tissues and normal kidney tissues. Serum levels of BNP, NT-proBNP and VEGF all decreased significantly after nephrectomy. Conclusions: Our findings suggested that the preoperative serum levels of BNP and NT-proBNP are markers of tumour progression, as well as indicators of subclinical functional and structural myocardial damage in patients with advanced RCC.

Significance of sarcopenia as a prognostic factor for metastatic urothelial carcinoma patients treated with systemic chemotherapy.

BACKGROUND: Recently, numerous studies have reported an association between sarcopenia and poor outcomes in various kinds of malignancies. We investigated whether sarcopenia predicts the survival of patients with metastatic urothelial carcinoma who underwent systemic chemotherapy. METHODS: We reviewed 87 metastatic urothelial carcinoma patients who underwent chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin for cisplatin-unfit patients) between 2007 and 2015. A computed tomography scan prior to chemotherapy was used for evaluating sarcopenia, and we measured three cross-sectional areas of skeletal muscle at the third lumbar vertebra and calculated the skeletal muscle index (SMI), the paraspinal muscle index (PSMI), and the total psoas area (TPA) of each patient. Predictive values of survival were assessed using Cox regression analysis. RESULTS: The median overall survival (OS) was 16 months (95% CI 13.5-18). Although SMI alone was not a significant predictor of shorter OS (P = 0.117) in univariate analysis, SMI stratified by the value of the body mass index (BMI) was a significant predictor of shorter OS in univariate analysis (P = 0.037) and was also an independent predictor of shorter OS in multivariate analysis (P = 0.026). PSMI and TPA were not significant prognostic factors even when stratified by BMI (P = 0.294 and 0.448), respectively. CONCLUSION: Neither PSMI nor TPA could substitute SMI as a predictor for poor outcomes in metastatic urothelial carcinoma patients treated with systemic chemotherapy in our study. SMI stratified by BMI is a useful predictor of prognosis in these patients.