[A Case of Primary Adenocarcinoma Mucinous Subtype of the Bladder].

A 48-year-old man who presented with asymptomatic gross hematuria in July 202X had been followed up without treatment. In January 202X, he was referred to our department due to the exacerbation of his hematuria. Contrast-enhanced magnetic resonance imaging revealed bladder cancer suggested bilateral seminal vesicle and prostate invasion, and enlarged right internal and external iliac lymph nodes. The pathological diagnosis was mucinous bladder adenocarcinoma. Prostate biopsy results were negative. Upper and lower gastrointestinal examinations were unremarkable. We suspected bladder cancer cT4aN2M0. In March 202X＋1, the patient underwent robotic-assisted laparoscopic total bladder resection, pelvic lymph node dissection, and intracorporeal urinary tract modification (ileal conduit creation). The final diagnosis was primary mucinous adenocarcinoma pT4aN2M0 of the bladder. Given the heightened risk of recurrence, the patient was administered a three-month course of oxaliplatin and capecitabine (XELOX) as adjuvant postoperative chemotherapy. The patient remains free of progression at 8 months postoperatively. Adenocarcinoma of the bladder is an exceedingly rare entity, with no established chemotherapeutic protocols. Primary mucinous adenocarcinoma of the bladder is even more exceptional. Presently, only regimens similar to those for colorectal cancer or adenocarcinoma of unknown primary, including 5-fluorouracil, are considered. In our particular case, we elected to pursue XELOX therapy, aligning with the principles governing the management of colorectal cancer.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Muscular stress is equal when resistance exercise with blood flow restriction is matched in total work volume: A cross-sectional, cross-over study.

AIM: We compared muscular metabolic stress during exercise performed at multiple intensities, from very low to moderate, with blood flow restriction (BFR) adjusted by the same work volume. METHODS: Twenty-five healthy young adults performed unilateral plantar flexion at 1 repetition/2 s in a magnetic resonance system. The BFR exercise protocols were as follows: (A) exercise with 10% of one repetition maximum (1-RM) for 360 s, (B) 15% 1-RM for 240 s, (C) 20% 1-RM for 180 s, (D) 30% 1-RM for 120 s, and (E) 40% 1-RM for 90 s. All protocols had the same total work volume (load × repetitions = 1800). A high-intensity protocol at 65% 1-RM without BFR (60 s) was also performed for comparison. We used 31 P-magnetic resonance spectroscopy to evaluate the muscular metabolic stress in the subjects' calf muscle, defined as decreases in phosphocreatine and intramuscular pH. RESULTS: The phosphocreatine depletion (A: 15.6 ± 0.7, B: 14.8 ± 0.8, C: 15.2 ± 0.6, D: 14.3 ± 0.6, E: 10.9 ± 0.5 mM; no significant difference [ns]) and the intramuscular pH decrease (A: 6.82 ± 0.02, B: 6.84 ± 0.01, C: 6.83 ± 0.02, D: 6.83 ± 0.02, E: 6.77 ± 0.02; ns) at the end of each exercise were similar and greater than those produced by the 65% 1-RM without BFR. CONCLUSION: If the total work volumes are equal, the metabolic stress in exercising muscle may reach similar levels at the end of exercise with BFR and could provide similar successful training effects.

The AppCare-HF randomized clinical trial: a feasibility study of a novel self-care support mobile app for individuals with chronic heart failure.

Aims: We evaluated a self-care intervention with a novel mobile application (app) in chronic heart failure (HF) patients. To facilitate patient-centred care in HF management, we developed a self-care support mobile app to boost HF patients' optimal self-care. Methods and results: We conducted a multicentre, randomized, controlled study evaluating the feasibility of the self-care support mobile app designed for use by HF patients. The app consists of a self-monitoring assistant, education, and automated alerts of possible worsening HF. The intervention group received a tablet personal computer (PC) with the self-care support app installed, and the control group received a HF diary. All patients performed self-monitoring at home for 2 months. Their self-care behaviours were evaluated by the European Heart Failure Self-Care Behaviour Scale. We enrolled 24 outpatients with chronic HF (ages 31-78 years; 6 women, 18 men) who had a history of HF hospitalization. During the 2 month study period, the intervention group (n = 13) showed excellent adherence to the self-monitoring of each vital sign, with a median [interquartile range (IQR)] ratio of self-monitoring adherence for blood pressure, body weight, and body temperature at 100% (92-100%) and for oxygen saturation at 100% (91-100%). At 2 months, the intervention group's self-care behaviour score was significantly improved compared with the control group (n = 11) [median (IQR): 16 (16-22) vs. 28 (20-36), P = 0.02], but the HF Knowledge Scale, the General Self-Efficacy Scale, and the Short Form-8 Health Survey scores did not differ between the groups. Conclusion: The novel mobile app for HF is feasible.

Pre-treatment metastatic growth rate is associated with clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been approved for the treatment of metastatic renal cell carcinoma (mRCC). However, the response rate is still limited, and it is urgent to pursue novel and concise markers of responses to ICIs that allow the determination of clinical benefits. Recently, it was reported that the metastatic growth rate (MGR) is an independent factor associated with clinical outcome for anticancer therapy in some types of cancer. METHODS: We investigated pre-treatment MGR before starting nivolumab for mRCC patients between September 2016 to October 2019. In addition, we examined clinicopathological factors including MGR and analyzed the correlation between pre-treatment MGR and clinical efficacy of nivolumab. RESULTS: Of all patients, the median age was 63 years (range, 42-81), and the median observation period was 13.6 months (range, 1.7-40.3). Twenty-three patients and sixteen patients were classified as the low and the high MGR group, respectively, with the cutoff value of 2.2 mm/month. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients in the low MGR group (p = 0.005 and p = 0.01). Importantly, in multivariate analysis, only the high MGR was significantly associated with a decrease of PFS (Hazard ratio (HR): 2.69, p = 0.03) and OS (HR: 5.27, p = 0.02). CONCLUSIONS: Pre-treatment MGR may serve as the simple and valid indicator obtained from imaging studies, and the prominent surrogate marker associated with OS and PFS in mRCC patients treated with nivolumab.

Giant Spin-Valve Effect in Planar Spin Devices Using an Artificially Implemented Nanolength Mott-Insulator Region.

Developing technology to realize oxide-based nanoscale planar integrated circuits is in high demand for next-generation multifunctional electronics. Oxide circuits can have a variety of unique functions, including ferromagnetism, ferroelectricity, multiferroicity, superconductivity, and mechanical flexibility. In particular, for spin-transistor applications, the wide tunability of the physical properties due to the presence of multiple oxide phases is valuable for precise conductivity matching between the channel and ferromagnetic electrodes. This feature is essential for realistic spin-transistor operations. Here, a substantially large magnetoresistance (MR) ratio of up to ≈140% is demonstrated for planar-type (La,Sr)MnO3 (LSMO)-based spin-valve devices. This MR ratio is 10-100 times larger than the best values obtained for semiconductor-based planar devices, which have been studied over the past three decades. This structure is prepared by implementing an artificial nanolength Mott-insulator barrier region using the phase transition of metallic LSMO. The barrier height of the Mott-insulator region is only 55 meV, which enables the large MR ratio. Furthermore, a successful current modulation, which is a fundamental functionality for spin transistors, is shown. These results open up a new avenue for realizing oxide planar circuits with unique functionalities that conventional semiconductors cannot achieve.

Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults.

Systemic inflammation underlies the association between obesity and nonalcoholic fatty liver disease (NAFLD). Here, we investigated functional changes in leukocytes' mitochondria in obese individuals and their associations with NAFLD. We analyzed 14 obese male Japanese university students whose body mass index was > 30 kg/m2 and 15 healthy age- and sex-matched lean university students as controls. We observed that the mitochondrial oxidative phosphorylation (OXPHOS) capacity with complex I + II-linked substrates in peripheral blood mononuclear cells (PBMCs), which was measured using a high-resolution respirometry, was significantly higher in the obese group versus the controls. The PBMCs' mitochondrial complex IV capacity was also higher in the obese subjects. All of the obese subjects had hepatic steatosis defined by a fatty liver index (FLI) score ≥ 60, and there was a positive correlation between their FLI scores and their PBMCs' mitochondrial OXPHOS capacity. The increased PBMCs' mitochondrial OXPHOS capacity was associated with insulin resistance, systemic inflammation, and higher serum levels of interleukin-6 in the entire series of subjects. Our results suggest that the mitochondrial respiratory capacity is increased in the PBMCs at the early stage of obesity, and the enhanced PBMCs' mitochondrial oxidative metabolism is associated with hepatic steatosis in obese young adults.

A case of mediastinal teratoma with malignant transformation into angiosarcoma and relapse with multiple bone metastases that was cured by a multidisciplinary treatment.

Introduction: Complete resection is essential for the treatment of teratoma with malignant transformation, and if metastasis occurs, it will be difficult to cure. We report a case of primary mediastinal teratoma with differentiation into angiosarcoma that caused bone metastases but was cured by multidisciplinary treatment. Case presentation: A 31-year-old man with a primary mediastinal germ cell tumor underwent primary chemotherapy followed by post-chemotherapy resection, with angiosarcoma due to malignant transformation found in the surgical specimen. Femoral diaphyseal metastasis was manifested, and he underwent femur curettage followed by radiation therapy of 60 Gy in parallel with 4 cycles of chemotherapy combining gemcitabine and docetaxel. Although thoracic vertebral bone metastasis emerged 5 months after treatment, intensity-modulated radiation therapy was successful, and metastatic lesions have remained shrunken for 39 months after treatment. Conclusion: Even if complete resection is difficult, teratoma with malignant transformation may be cured by multidisciplinary treatment based on histopathology.

A comparative study on nivolumab and axitinib as secondary treatment in patients with metastatic renal cell carcinoma: A multi-institutional retrospective study in Japan.

OBJECTIVES: When primary treatment has been inadequate, nivolumab and axitinib are often used as a secondary treatments for patients with metastatic renal cell carcinoma (mRCC). However, there have been few reports comparing the efficacy and safety of these drugs. METHODS: We retrospectively investigated 58 patients treated with nivolumab and 57 patients treated with axitinib as secondary treatment between April 2013 and December 2019. We then assessed the clinical efficacy and safety of the treatments in both groups. RESULTS: The most common primary therapy was sunitinib (61.7%). Both nivolumab and axitinib groups showed no significant differences in terms of the objective response rate and disease control rate (p = 0.280 and p = 0.518, respectively). Importantly, progression-free survival (PFS) and overall survival (OS) seemed to be similar in patients treated with nivolumab and axitinib (p = 0.527 and p = 0.266, respectively), irrespective of the objective response to primary therapy. Furthermore, a Cox proportional hazards model showed that pretreatment Karnofsky Performance Status was significantly associated with PFS and OS. Although the incidence of adverse events was significantly higher in the patients treated with axitinib, there was no significant difference in time to treatment failure between the two groups. CONCLUSIONS: Nivolumab and axitinib showed similar clinical benefits as secondary treatment in patients with mRCC; thus, they should be an option in sequential therapy following treatment with tyrosine kinase inhibitors (TKIs). Future studies and feasible therapeutic biomarkers would help predict the clinical response to TKIs or immune checkpoint inhibitors in patients with mRCC.

Diagnostic and prognostic significance of tartrate-resistant acid phosphatase type 5b in newly diagnosed prostate cancer with bone metastasis: A real-world multi-institutional study.

OBJECTIVES: Approximately, 90% of men with advanced prostate cancer will develop bone metastasis. However, there have been few reports about noninvasive biomarker to detect and predict clinical outcome of bone metastasis (BM) in prostate cancer patients. METHODS: We examined 1127 patients who underwent prostate biopsy from August 2012 to June 2017. We also investigated bone turnover markers such as bone-specific alkaline phosphatase, type I collagen cross-linked N-terminal telopeptide, C-terminal pyridinoline cross-linked telopeptide of type I collagen, and tartrate-resistant acid phosphatase type 5b (TRACP 5b). RESULTS: A total of 282 patients were diagnosed as prostate cancer with complete clinical data, and 34 patients with bone metastasis. Multivariate analysis revealed C-terminal pyridinoline cross-linked telopeptide of type I collagen, tartrate-resistant acid phosphatase type 5b, and prostate-specific antigen (PSA) were independent biomarkers in detection of BM (p < 0.05, respectively). Furthermore, we developed predictive model formula based on tartrate-resistant acid phosphatase type 5b and PSA, for which the area under the curve was 0.95. In patients with bone metastasis, multivariate cox proportional hazards analysis revealed that this model was significantly associated with poor clinical outcome of cancer-specific survival (p < 0.05). In validation cohort with 137 patients, we also confirmed the utility of this model for diagnosis of BM (the area under the curve = 0.95). CONCLUSIONS: Our developed formula of tartrate-resistant acid phosphatase type 5b in accordance with PSA may serve as the useful tool in diagnosis and prediction of clinical outcome for prostate cancer with bone metastasis.

Ergogenic effects of caffeine are mediated by myokines.

Exercise has long been known to effectively improve and enhance skeletal muscle function and performance. The favorable effects of exercise on remote organs other than skeletal muscle are well known, but the underlying mechanism has remained elusive. Recent studies have indicated that skeletal muscle not only enables body movement, but also contributes to body homeostasis and the systemic stress response via the expression and/or secretion of cytokines (so-called myokines). Not only the induction of muscle contraction itself, but also changes in intracellular calcium concentration ([Ca2+]i) have been suggested to be involved in myokine production and secretion. Caffeine is widely known as a Ca2+ ionophore, which improves skeletal muscle function and exercise performance (i.e., an "ergogenic aid"). Interestingly, some studies reported that caffeine or an increase in [Ca2+]i enhances the expression and/or secretion of myokines. In this review, we discuss the association between caffeine as an ergogenic aid and myokine regulation.

Cross-disease communication between cancer and heart failure provides a rational approach to prevention and treatment of both diseases.

Accumulating clinical data have demonstrated a clear positive association between cancer and cardiac disorders, particularly chronic heart failure (CHF). These two diseases can be mutual drivers of each other, and hence frequently co-occur in patients. The immune system is the core mechanism that eliminates transformed cells from our bodies. However, immune cells often play distinct or even conflicting roles in cancer and CHF. Moreover, CHF alters the properties of immune cells, particularly those of regulatory T cells. Our previous study showed that the oxidative phosphorylation capacity of peripheral blood mononuclear cells is impaired in CHF, leading to the increased production of reactive oxygen species. Therefore, the co-occurrence of cancer and CHF becomes a serious problem, affecting the treatment of both diseases, and consequently negatively affecting patient survival rates. To date, few methods have been identified that effectively treat both diseases at the same time. Mitochondria activity may change in immune cells during their activation and exhaustion, and in CHF. Mitochondria activity is also largely affected in myocardia in CHF. We here focus on the mitochondrial abnormalities of immune cells in cancer and CHF, and discuss possible ways to treat cancer and CHF at the same time by targeting mitochondrial abnormalities. Many cancer cells are inevitably produced daily in our bodies, mostly owing to enzymatic nucleotide errors of DNA replication and repair. Therefore, the possibility of ways to prevent cancer by preventing the onset of heart failure will also be discussed.

Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure.

Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

Giant spin-to-charge conversion at an all-epitaxial single-crystal-oxide Rashba interface with a strongly correlated metal interlayer.

The two-dimensional electron gas (2DEG) formed at interfaces between SrTiO3 (STO) and other oxide insulating layers is promising for use in efficient spin-charge conversion due to the large Rashba spin-orbit interaction (RSOI). However, these insulating layers on STO prevent the propagation of a spin current injected from an adjacent ferromagnetic layer. Moreover, the mechanism of the spin-current flow in these insulating layers is still unexplored. Here, using a strongly correlated polar-metal LaTiO3+δ (LTO) interlayer and the 2DEG formed at the LTO/STO interface in an all-epitaxial heterostructure, we demonstrate giant spin-to-charge current conversion efficiencies, up to ~190 nm, using spin-pumping ferromagnetic-resonance voltage measurements. This value is the highest among those reported for all materials, including spin Hall systems. Our results suggest that the strong on-site Coulomb repulsion in LTO and the giant RSOI of LTO/STO may be the key to efficient spin-charge conversion with suppressed spin-flip scattering. Our findings highlight the hidden inherent possibilities of oxide interfaces for spin-orbitronics applications.

Multimodal therapy including robot-assisted radical cystoprostatectomy for locally advanced prostate cancer with bladder and ureteral invasion: A case report.

Introduction: It remains unclear whether robot-assisted radical cystoprostatectomy for locally advanced prostate cancer represents excessive treatment. Case presentation: A 58-year-old man presented with urinary retention and renal failure. Prostate-specific antigen level was 38.07 ng/mL and computed tomography scans revealed bilateral hydronephrosis due to prostate enlargement. Prostate biopsy revealed a Gleason score of 5 + 5 adenocarcinoma, and bilateral hydronephrosis persisted even after urethral catheter placement. We diagnosed locally advanced prostate cancer with bladder and ureteral invasion. Percutaneous bilateral nephrostomy was performed, and neoadjuvant hormone therapy was initiated. Four months after the start of hormone therapy, robot-assisted radical cystoprostatectomy and an intracorporeal ileal conduit were performed, followed by adjuvant radiation therapy for lymph node metastasis. Seven months after the surgery, the patient was free of disease with prostate-specific antigen level <0.03 ng/mL. Conclusion: Robot-assisted radical cystoprostatectomy can be an effective multimodal therapy for locally advanced prostate cancer with bladder and ureteral invasion by locally advanced prostate cancer.

EphA2 on urinary extracellular vesicles as a novel biomarker for bladder cancer diagnosis and its effect on the invasiveness of bladder cancer.

BACKGROUND: Urinary extracellular vesicles (uEVs) secreted from bladder cancer contain cancer-specific proteins that are potential diagnostic biomarkers. We identified and evaluated a uEV-based protein biomarker for bladder cancer diagnosis and analysed its functions. METHODS: Biomarker candidates, selected by shotgun proteomics, were validated using targeted proteomics of uEVs obtained from 49 patients with and 48 individuals without bladder cancer, including patients with non-malignant haematuria. We developed an enzyme-linked immunosorbent assay (ELISA) for quantifying the uEV protein biomarker without ultracentrifugation and evaluated urine samples from 36 patients with and 36 patients without bladder cancer. RESULTS: Thirteen membrane proteins were significantly upregulated in the uEVs from patients with bladder cancer in shotgun proteomics. Among them, eight proteins were validated by target proteomics, and Ephrin type-A receptor 2 (EphA2) was the only protein significantly upregulated in the uEVs of patients with bladder cancer, compared with that of patients with non-malignant haematuria. The EV-EphA2-CD9 ELISA demonstrated good diagnostic performance (sensitivity: 61.1%, specificity: 97.2%). We showed that EphA2 promotes proliferation, invasion and migration and EV-EphA2 promotes the invasion and migration of bladder cancer cells. CONCLUSIONS: We established EV-EphA2-CD9 ELISA for uEV-EphA2 detection for the non-invasive early clinical diagnosis of bladder cancer.

Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation.

Abnormal mitochondrial fragmentation by dynamin-related protein1 (Drp1) is associated with the progression of aging-associated heart diseases, including heart failure and myocardial infarction (MI). Here, we report a protective role of outer mitochondrial membrane (OMM)-localized E3 ubiquitin ligase MITOL/MARCH5 against cardiac senescence and MI, partly through Drp1 clearance by OMM-associated degradation (OMMAD). Persistent Drp1 accumulation in cardiomyocyte-specific MITOL conditional-knockout mice induced mitochondrial fragmentation and dysfunction, including reduced ATP production and increased ROS generation, ultimately leading to myocardial senescence and chronic heart failure. Furthermore, ischemic stress-induced acute downregulation of MITOL, which permitted mitochondrial accumulation of Drp1, resulted in mitochondrial fragmentation. Adeno-associated virus-mediated delivery of the MITOL gene to cardiomyocytes ameliorated cardiac dysfunction induced by MI. Our findings suggest that OMMAD activation by MITOL can be a therapeutic target for aging-associated heart diseases, including heart failure and MI.

Real-world efficacy and safety of nivolumab plus ipilimumab in untreated metastatic renal cell carcinoma, and the impact of previous nephrectomy on clinical outcome: Japanese multi-institutional retrospective study.

BACKGROUND: In metastatic renal-cell carcinoma (mRCC), recent clinical trials have shown efficacy of first-line combination therapy, as evidenced by better clinical outcome over target therapy. However, there are insufficient real-world evidences in mRCC patients in Japan. METHODS: We performed a multicenter retrospective study of 72 mRCC patients who received nivolumab plus ipilimumab as first-line treatment between September 2018 and July 2021. Patient's characteristics, clinical outcomes and safety were retrospectively reviewed. We analyzed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients treated with combination therapy. RESULTS: Of all patients, the median age was 70 years (range, 36-86) and the major type of histology was clear cell RCC (n = 55; 76.4%). Progressive disease (n = 25; 34.8%) and irAEs (n = 22; 30.6%) were the most common causes for discontinuing treatment. Median PFS and OS seemed similar between patients who discontinued treatment because of irAEs and for patients who did not (p = 0.360 and p = 0.069, respectively). Importantly, for patients with synchronous metastatic disease at diagnosis (n = 56), nephrectomy before initiating nivolumab plus ipilimumab had a significantly positive impact on better OS when compared to that in patients without nephrectomy (p = 0.028). CONCLUSION: This study confirms efficacy and safety of nivolumab plus ipilimumab for mRCC patients in real-world settings. Furthermore, nivolumab plus ipilimumab was associated with a better outcome in patients who had undergone nephrectomy at diagnosis for synchronous mRCC.

Treatments for skeletal muscle abnormalities in heart failure: sodium-glucose transporter 2 and ketone bodies.

Various skeletal muscle abnormalities are known to occur in heart failure (HF) and are closely associated with exercise intolerance. Particularly, abnormal energy metabolism caused by mitochondrial dysfunction in skeletal muscle is a cause of decreased endurance exercise capacity. However, to date, no specific drug treatment has been established for the skeletal muscle abnormalities and exercise intolerance occurring in patients with HF. Sodium-glucose transporter 2 (SGLT2) inhibitors promote glucose excretion by suppressing glucose reabsorption in the renal tubules, which has a hypoglycemic effect independent of insulin secretion. Recently, large clinical trials have demonstrated that treatment with SGLT2 inhibitors suppresses cardiovascular events in patients who have HF with systolic dysfunction. Mechanisms of the therapeutic effects of SGLT2 inhibitors for HF have been suggested to be diuretic, suppression of neurohumoral factor activation, renal protection, and improvement of myocardial metabolism, but this has not been clarified to date. SGLT2 inhibitors are known to increase blood ketone bodies. This suggests that they may improve the abnormal skeletal muscle metabolism in HF, that is, improve fatty acid metabolism, suppress glycolysis, and use ketone bodies in mitochondrial energy production. Ultimately, they may improve aerobic metabolism in skeletal muscle, suppress anaerobic metabolism, and improve aerobic exercise capacity at the level of the anaerobic threshold. The potential actions of such SGLT2 inhibitors explain their effectiveness in HF and may be candidates for new drug treatments aimed at improving exercise intolerance. In this review, we outlined the effects of SGLT2 inhibitors on skeletal muscle metabolism, with a particular focus on ketone metabolism.