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.

Abbreviations & Acronyms CI = confidence interval CNS = central nervous system CRP = C-reactive protein ECOG PS = Eastern Cooperative Oncology Group Performance Status HR = hazard ratio IMDC = International Metastatic Renal Cell Carcinoma Database Consortium LDH = lactate dehydrogenase LNL = lower normal limit mRCC = metastatic renal cell carcinoma MSKCC = Memorial Sloan Kettering Cancer Center NA = not available NLR = neutrophil-tolymphocyte ratio OS = overall survival RCC = renal cell carcinoma TKI = tyrosine kinase inhibitor UNL = upper normal limit 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.

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.

Background: This study analyzed the safety and performance of the Perceval valve for aortic valve replacement (AVR) in patients at 1 year after undergoing aortic stenosis (AS) treatment, and its effect on significant declines in the platelet count during the immediate postoperative period.Methods and Results: Data were collected retrospectively for the initial 121 patients (median age 77 years; 47.1% females) who underwent Perceval sutureless AVR between May 2019 and July 2022. Implantation was successful in all (100%), with median cross-clamp and CPB times of 59 and 100 min, respectively. Postoperative thrombocytopenia (platelet count <50×10 3 /μL) was noted in 80 (66.1%) patients. Multivariate analysis showed advanced age (>80 years), preoperative low platelet count (<200×10 3 /μL), and a sternotomy approach as significant risk factors for postoperative thrombocytopenia. One (0.8%) patient died within 30 days after the procedure. The 2-year site-reported event rate was 14% (n=17) for all-cause mortality, 0.8% (n=1) for cardiac mortality, 4.1% (n=5) for stroke, and 1.7% (n=2) for endocarditis and valve-related reoperation; there were no instances of paravalvular leakage or structural valve deterioration. Conclusions:Thrombocytopenia was common after Perceval sutureless AVR, although its impact was not significant. Although Perceval sutureless AVR was found to be a safe and effective option, preoperative assessment of potential bleeding should be performed and the Perceval valve should not be used for patients with a high bleeding risk.

Background: We investigated the roles of eIF4E phosphorylation (Ser209) in tumour recurrence after curative nephrectomy for localized clear cell renal cell carcinoma (ccRCC). Methods: Expression of eIF4E, p eIF4E and MNKs (MAPK interacting kinases), was evaluated in surgical specimens obtained from consecutive non metastatic ccRCC patients ( n = 290) by immunohistochemistry (IHC), immunoblotting, and qRT PCR at the protein and mRNA levels. In human RCC cell lines, the effects of eIF4E phosphorylation were examined using immunoblotting, proliferation, migration and invasion assays with pharmacological inhibitors (CGP57380 or ETP45835) and specific small interfering (si) RNAs against MNK1/2(a/b). Results: In postoperative follow-up (median, 7.9 y), 40 patients experienced metastatic recurrence. In multivariate Cox analyses, higher IHC expression of p eIF4E in ccRCC significantly predicted a longer recurrence-free interval. eIF4E is phosphorylated mainly by MNK2a in tumour specimens and cell lines. In 786-O and A-498 cell lines, pharmacological inhibition of MNKs decreased p-eIF4E and increased vimentin and N cadherin but did not influence proliferation. Similarly, MNK2 or MNK2a inhibition with siRNA reduced p-eIF4E and enhanced vimentin translation, cell migration and invasion in the cell lines. Conclusions: MNK2a-induced eIF4E phosphorylation may suppress metastatic recurrence of ccRCC, partially due to vimentin downregulation at the translational level, consequently leading to inhibition of epithelial–mesenchymal transition.