Body composition changes following chemotherapy for testicular germ cell tumor: obesity is the long-term problem.

Metabolic syndrome is a long-term complication of systemic chemotherapy for testicular germ cell tumor (TGCT). It is believed to be caused by secondary hypogonadism or toxic medicines because of orchidectomy followed by systemic chemotherapy. In this study, changes in the body composition of patients over time were quantitatively analyzed up to 24 months after chemotherapy. This study retrospectively analyzed 44 patients with TGCT who underwent chemotherapy at our institution from January 2008 to December 2016. Subcutaneous and visceral fat areas and psoas and skeletal muscle areas were measured by computed tomography before and immediately after chemotherapy as well as 3 months, 6 months, 12 months, and 24 months after chemotherapy. The subcutaneous and visceral fat indices and psoas and skeletal muscle indices were calculated as each area divided by body height squared. The total fat area had already significantly increased 3 months after the initiation of chemotherapy (P = 0.004). However, it did not return to prechemotherapeutic levels even at 24 months after chemotherapy. The skeletal muscle area was significantly decreased at the end of chemotherapy (P < 0.001); however, the value returned to baseline within 12 months. In multivariable analysis, the prechemotherapeutic skeletal muscle index and number of chemotherapy cycles were independently associated with the reduction of skeletal muscle at the end of chemotherapy (P = 0.001 and P = 0.027, respectively). In patients with TGCT, skeletal muscle mass decreased during chemotherapy and recovered within 12 months, whereas fat mass progressively increased from the initiation of chemotherapy until 24 months after chemotherapy.

Clinical utility of head computed tomography scan during systemic therapy for metastatic renal cell carcinoma.

OBJECTIVES: The utility of brain metastasis screening in asymptomatic metastatic renal cell carcinoma is controversial. Our study evaluated the utility of routine head computed tomography during systemic therapy. METHODS: We retrospectively investigated 152 metastatic renal cell carcinoma patients who did not initially have brain metastasis at Yamagata University Hospital from January 2008 to July 2019. Patients who routinely received head computed tomography scan together with routine contrast-enhanced chest/abdominal/pelvic computed tomography scan every 2-4 months during systemic therapy ("Routine head computed tomography" group, n = 95) and patients without routine head computed tomography ("No routine head computed tomography" group, n = 57) were compared. RESULTS: Brain metastasis occurred in 16 patients in the "Routine head computed tomography" group and six patients in the "No routine head computed tomography" group. There was no statistical difference in overall survival after metastatic renal cell carcinoma diagnosis between groups (53.4 vs 37.3 months, respectively, P = 0.357) and neurological symptom-free survival after metastatic renal cell carcinoma diagnosis (53.4 vs 36.6 months, P = 0.336). Although there was no statistical difference on incidence of unrecovered neurological symptom (25.0% vs 50.0%, P = 0.334), fewer patients in the "Routine head computed tomography" group required craniotomy (0% vs 66.7%, P = 0.002). In the "No routine head computed tomography" group, the neurological symptom resolved for all patients without craniotomy. CONCLUSIONS: Routine head computed tomography during systemic therapy for metastatic renal cell carcinoma is not significantly associated with improved brain metastasis prognosis. However, routine head computed tomography enables brain metastasis diagnosis in the asymptomatic phase, which can avoid craniotomy.

Living kidney transplantation without perioperative anticoagulation therapy for a patient with heparin-induced thrombocytopenia.

INTRODUCTION: Heparin-induced thrombocytopenia is an antibody-mediated acquired prothrombotic state induced by heparin exposure. The risk of thromboembolic diseases in kidney transplantation with heparin-induced thrombocytopenia without perioperative anticoagulation has not been determined. CASE PRESENTATION: A 64-year-old male hemodialysis patient with heparin-induced thrombocytopenia was referred to our hospital for living kidney transplantation. Anti-heparin-induced thrombocytopenia antibody was positive at the time of referral; however, it turned negative 4 months after heparin cessation during hemodialysis sessions. Living kidney transplantation by donation from his wife was performed using the standard technical procedure. Both heparinization and application of medical equipment containing heparin were avoided; however, no anticoagulant was administered intra- and postoperatively. The graft kidney functioned immediately, and no thromboembolic event related to heparin-induced thrombocytopenia occurred. CONCLUSION: Kidney transplantation without perioperative anticoagulation therapy after disappearance of anti-heparin-induced thrombocytopenia antibody is a well-tolerated treatment option for patients with end-stage kidney disease.

New prognostic model for synchronous metastatic renal cell carcinoma.

OBJECTIVES: To create a new model for the prediction of overall survival in synchronous metastatic renal cell carcinoma. METHODS: Medical records of 158 patients with metastatic renal cell carcinoma diagnosed at the Yamagata University Hospital from August 2007 to February 2018 were reviewed. Among them, 77 with synchronous metastatic renal cell carcinoma were retrospectively analyzed using the univariate and multivariate analyses. A new prognostic model was constructed, followed by a bootstrap validation to estimate the model fitting. In addition, these prognostic factors were estimated in 67 metachronous metastatic renal cell carcinoma patients. RESULTS: Five independent prognostic factors were identified in synchronous metastatic renal cell carcinoma: cT3/4, cN1, high corrected calcium, >3.6 neutrophil-to-lymphocyte ratio and central nerve system metastasis. The number (%) and overall survival (95% confidence interval) in the favorable- (0 or 1 risk factor), intermediate- (2 risk factors) and poor-risk (≥3 risk factors) groups were 29 (45.3%) and 67.4 (31.8-NA), 21 (32.8%) and 16.8 (10.0-27.6), and 14 (21.9%) and 9.1 (7.3-13.7) months, respectively. The C-index was 0.72. Patients in the favorable-risk group had better overall survival with nephrectomy than without nephrectomy (hazard ratio 0.29, 95% confidence interval 0.09-0.91 with nephrectomy). In metachronous metastatic renal cell carcinoma, these prognostic factors showed no statistical differences in the overall survival. CONCLUSIONS: Prognostic factors are completely different between synchronous and metachronous metastatic renal cell carcinoma. The new model for synchronous metastatic renal cell carcinoma can predict a good candidate for cytoreductive nephrectomy.

Effect of third- and fourth-line systemic therapies for metastatic renal cell carcinoma.

Data on the outcomes of third- or fourth-line therapy for metastatic renal cell carcinoma (mRCC) are limited. The aim of our study was to evaluate the efficacy of therapy beyond the second line. We retrospectively analysed data of mRCC patients who underwent systemic therapy at Yamagata University Hospital. The best objective response (BOR), response rate (RR), and progression-free survival (PFS) were assessed for each line of treatment. To investigate the correlation between overall survival (OS) and the number of treatment lines during a patient's lifetime, the median OS was assessed using univariate and multivariate analyses. In the first-, second-, and third-line therapies, approximately 20% of patients had long PFS of >15 months. In targeted treatments beyond the third line, only one treatment suppressed disease progression for >10 months. Among patients who died during the follow-up period, those treated with triple and quadruple lines had similar OS (42.5 months vs. 48.4 months, respectively). Multivariate analysis showed that patients with triple or more lines of therapy had better OS; however, quadruple or more lines of therapy was not an independent prognostic factor. We concluded that third-line systemic therapy could improve OS; however, fourth-line therapy could not.

Risk of SOFA Deterioration in Conservative Treatment for Emphysematous Pyelonephritis: Pitfalls of Current Trends in Therapeutics from Multicenter Clinical Experience.

INTRODUCTION: We investigated relationships between therapeutic outcomes of patients with emphysematous pyelonephritis (EPN) and changes in the Sequential Organ Failure Assessment (SOFA) score. MATERIALS AND METHODS: We retrospectively evaluated EPN patients treated in our hospitals using the SOFA score incorporated in the Sepsis-3 updated in 2016. RESULTS: Seventeen typical EPN patients were included in this study, and were treated with medical management with no drainage (n = 3), retrograde stenting (n = 10), or percutaneous drainage (n = 3). One patient without drainage died of sepsis, yielding an overall mortality rate of 5.9%. Twelve patients recovered without increase in the SOFA score during hospitalization. However, the SOFA score deteriorated in the other patients from admission, with the initial scores not significantly different from those of the 12 cases. The changes in the SOFA score were significantly affected by the selected approaches of drainage (100% patients for no drainage, 22% for stenting, and 0% for percutaneous drainage, p = 0.029), but not by other clinical data. CONCLUSION: Most EPN patients can currently be conservatively managed successfully. However, it should be noted that less-invasive management could cause deterioration in SOFA after admission, yielding a risk of septic mortality.

Expression of total and phospho 4EBP1 in metastatic and non-metastatic renal cell carcinoma.

Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) is phosphorylated and activated by mammalian target of rapamycin complex 1, which serves as a regulator of cell growth, cell survival, metastasis and angiogenesis in many types of cancer. The aim of this study was to evaluate the role of phosphorylated 4EBP1 (p4EBP1) in primary renal cell carcinoma (RCC) as a biomarker in metastatic RCC (mRCC) and non-mRCC cohorts. Primary tumor tissue from 254 non-mRCC and 60 mRCC patients were immunohistochemically stained for t4EBP1 and p4EBP1. The disease-free interval (DFI) categorized by the expressions and clinical parameters were assessed by univariate and multivariate analysis in the non-mRCC cohort. Then, the cause-specific survival (CSS) was assessed in the mRCC cohort by the same methods as used in the non-mRCC cohort. In the non-mRCC cohort, patients with t4EBP1 expression had no RCC recurrence. Patients with p4EBP1 expression had the shorter DFI in univariate analysis (P=0.037). p4EBP1 and pT1b-4 expression levels were independent predictors for de novo metastasis. In the mRCC cohort, intermediate/poor MSKCC risk, non-clear cell RCC, and no p4EBP1 expression were correlated with poor CSS on multivariate analysis. Expression of p4EBP1 could be a predictive biomarker for de novo metastasis in non-mRCC patient cohort. By contrast, mRCC patients showing no p4EBP1 expression had shorter CSS than patients with p4EBP1 expression.

Successful Treatment with Paclitaxel, Carboplatin, and Gemcitabine as Second-line Chemotherapy for Recurrent Urothelial Carcinoma of the Bladder with Glandular Differentiation After Radical Cystectomy: A Case Report.

Urothelial carcinoma of the bladder (UCB) with glandular differentiation is a histological variant (HV) that is more likely to have positive extravesical tumors or nodes than those in pure UCB. Cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) is more effective for pure UCB; however, few reports are available on second-line chemotherapy for recurrence of UCB with HV. Here we report a 65-year-old Japanese male diagnosed with local recurrence UCB with HV after NAC + RC who safely achieved complete response with paclitaxel, carboplatin, and gemcitabine combination chemotherapy.

[SAFETY AND EFFICACY OF CONTINUOUS ADMINISTRATION OF ANTITHROMBOTIC DRUGS DURING TRANSURETHRAL RESECTION OF BLADDER TUMORS].

(Objectives) We evaluated the safety and efficacy of continuous administration of antithrombotic drugs during transurethral resection of bladder tumors (TURBT). (Methods) We performed a retrospective review of 351 TURBT procedures performed at our institute from April 2011 to October 2015. Among these, antithrombotic drugs were continued in 31 TURBT cases throughout their perioperative period (continuation group), antithrombotic drugs were discontinued in 26 TURBT cases (discontinuation group), and bridging anticoagulation therapy with heparin after interruption of antithrombotic drugs was performed in 4 TURBT cases (heparin bridging group). The safety and efficacy of continuous administration of antithrombotic drugs during TURBT was evaluated by comparing the rate of perioperative complications, median operative time, duration of hematuria, urethral catheter placement, duration of stay after surgery, and by comparing the duration of stay among the three groups. (Results) The median operative time was 40.0 min in the continuation group, 39.0 min in the discontinuation group, and 31.0 min in the heparin bridging group with no significant differences. There were no significant differences in the median duration of hematuria (1.00 days vs. 1.00 days vs. 1.00 days), urethral catheter placement (3.00 days vs. 2.50 days vs. 2.00 days), or stay after TURBT (4.00 days vs. 3.50 days vs. 3.00 days) among the continuation, discontinuation, and heparin bridging groups. The median duration of stay was 6.00 days in the continuation group, 7.00 days in the discontinuation group, and 16.0 days in the heparin bridging group with significant differences between the continuation group vs. the heparin bridging group and the discontinuation group vs. the heparin bridging group. The rate of complications was 6 (19.4%) in the continuation group and 3 (11.5%) in the discontinuation group with no significant differences. However, a serious complication, cerebral infarction leading to hemiplegia, occurred in the discontinuation group. (Conclusion) Continuous administration of antithrombotic drugs during TURBT is considered to be safe and useful because it may prevent serious thromboembolism without adversely affecting the perioperative course.

Bacillus Calmette-Guerin and BCG cell wall skeleton suppressed viability of bladder cancer cells in vitro.

AIM: Bacillus Calmette-Guerin (BCG) is one of therapeutic options for urothelial carcinoma (UC). The objectives of this study were to determine the direct effect of viable or heat-killed BCG and BCG cell wall skeleton (BCG-CWS) on UC cells in vitro. MATERIALS AND METHODS: UC cell lines were co-cultured with viable or heat-killed BCG Immunobladder® (Tokyo 172 strain) and BCG-CWS. Viability of the cells, apoptosis and BrdU incorporation were estimated. RESULTS: BCG induced cell growth retardation in highly malignant UC bearing integrin α5ß1 (VLA5). VLA5-blocking antibody partially abrogated this effect. BCG treatment induced a modest increase in the sub-G(1) fraction of cells and a decrease of BrdU incorporation. Cell growth retardation effect of viable BCG was reproduced by both heat-killed BCG and BCG-CWS. CONCLUSION: The results indicate that VLA5 may be a biomarker of UC with sensitivity to BCG. Moreover, BCG-CWS is a promising substance which might replace BCG, preventing life-threatening complications of viable BCG treatment.

Aggravation of ischemia-reperfusion-triggered acute renal failure in xCT-deficient mice.

This study examined the question of whether deficiency of xCT, a cystine-transporter gene, exacerbates ischemia-reperfusion-induced acute renal failure (ARF). Two weeks after the right nephrectomy of male mice at 16-18weeks of age, the left renal vessels were clamped for 45min to induce renal ischemia. After (24h) induction of ischemia, xCT(-/-) mice had elevated concentrations of blood urea nitrogen and creatinine indicative of ARF, while in xCT(+/-) and xCT(+/+) mice, these parameters did not differ from the sham-operated mice. Immunohistochemical analyses of kidneys using antibodies against the oxidative stress markers revealed stronger staining in xCT(-/-) mice compared with xCT(+/+) mice. Induction of xCT mRNA in the kidneys of xCT(+/+) mice was demonstrated using reverse transcriptase (RT)-PCR analysis and was further confirmed using quantitative RT-PCR. These data provide the first in vivo evidence that xCT is induced by oxidative stress and helps prevent ischemia-reperfusion injury to kidneys.

The outcome of prostate cancer screening in a normal Japanese population with PSA of 2-4 ng/ml and the free/total PSA under 12%.

OBJECTIVE: No previous study has reported the numbers of prostate cancer (PC) patients existing among a normal Japanese population with prostate-specific antigen (PSA) < 4 ng/ml. The aim of this study was to elucidate the performance of %free PSA as a screening tool for a normal Japanese population with PSA of 2-4 ng/ml and to examine the characteristics of cancer detected using this criterion. METHODS: We conducted a prospective, multi-center study to evaluate the performance of %free PSA among a normal Japanese population. We decided on a %free PSA cutoff value of 12% according to the preliminary results. A total of 5548 consecutive screening volunteers aged 50-79 years were enrolled in the project. Men with total PSA > 4 ng/ml, or men with total PSA of 2-4 ng/ml and %free PSA of < or =12% were indicated to undergo 12 core biopsies. RESULTS: There were 826 (14.9%) men with PSA of 2-4 ng/ml. Among them, those with %free PSA of < or =12% numbered 100 (12.1%). Forty-nine out of 100 men (49%) received biopsy, and 16 PC patients were detected. Among 10 patients undergoing radical prostatectomy, seven were associated with extra-prostatic extension (pT3) or high-grade cancer (Gleason score > or = 8). CONCLUSIONS: We confirmed the ability of %free PSA and demonstrated that there are considerable numbers of PC patients among the normal Japanese population with PSA of 2-4 ng/ml. We ascertained that cancers detected in this study had a variety of tumor characteristics, including those of an aggressive nature.

Deterioration of ischemia/reperfusion-induced acute renal failure in SOD1-deficient mice.

Reactive oxygen species (ROS) are likely candidates for involvement in ischemia/reperfusion-induced acute renal failure (ARF). In this study, the issue of whether superoxide dismutase (SOD1)-deficiency exacerbates the ischemia/reperfusion-induced ARF was examined. At two weeks after a right nephrectomy of mice, the left renal vessels were clipped to induce renal ischemia and were then released after 45 min. The severe renal damage observed at one day was partially recovered at seven days after the induction of ischemia. SOD1-/- mice suffer from severe ARF compared with SOD1+ - and SOD1+/+ mice. The damage was more evident in aged animals (24-28 week old) than younger ones (10-12 week old). The expression of major antioxidative and redox enzymes, except for CuZnSOD, were substantially unchanged. Thus, the increased ARF in SOD1-/- mice appears to be mainly attributable to a deficiency in CuZnSOD. These data support the view that ROS are exacerbating factors in ischemia/reperfusion-induced ARF.