Efficacy and safety of axitinib for metastatic renal cell carcinoma: Real-world data on patients with renal impairment.

OBJECTIVES: Limited information is currently available on the efficacy and safety of axitinib for metastatic renal cell carcinoma (mRCC) patients with renal impairment. Therefore, the present study investigated the efficacy and toxicity of axitinib in patients with chronic kidney disease. METHODS: Post-hoc analyses were performed on a Japanese multicenter cohort study of 477 mRCC patients who received axitinib followed by 1 or 2 regimens of systemic antiangiogenic therapy between January 2012 and December 2016. Differences in clinical characteristics and the efficacy and safety of axitinib were assessed based on pretreatment renal function. RESULTS: Patients were categorized into the following 5 renal function groups according to baseline renal function: estimated glomerular filtration rate (eGFR) ≥60 ml/min (n = 133), 45 ml/min ≤eGFR <60 ml/min (n = 153), 30 ml/min ≤eGFR< 45 ml/min (n = 130), eGFR <30 ml/min (n = 45), and dialysis (n = 16). Median progression-free survival (PFS) (95% confidence interval [CI]) in the 5 groups was 11 (8-16), 14 (11-19), 14 (10-19), 12 (8-24), and 6 (3-NR) months, respectively (p = 0.781). After adjustments for treatment-related confounders, the renal function group was not a significant prognostic factor for PFS. Objective response rates in the 5 groups were 22%, 23%, 23%, 18%, 20%, and 38%, respectively (p = 0.468). Regarding adverse events of all grades, hypertension (p = 0.0006) and renal and urinary disorders (p < 0.0001) were more frequently observed in the eGFR <30 ml/min group than in the other groups. CONCLUSIONS: Since renal function at the initiation of treatment with axitinib does not adversely affect the efficacy of VEGF-TKI therapy, clinicians do not need to avoid its administration to mRCC patients with impaired renal function in consideration of the risk of progression to end-stage renal disease.

External validation of the albumin, C-reactive protein and lactate dehydrogenase model in patients with metastatic renal cell carcinoma receiving second-line axitinib therapy in a Japanese multi-center cohort.

PURPOSE: To externally validate the utility of the albumin, C-reactive protein and lactate dehydrogenase model to predict the overall survival of previously treated metastatic renal cell carcinoma patients. PATIENTS AND METHODS: The ability of the albumin, C-reactive protein and lactate dehydrogenase model to predict overall survival was validated and compared with those of other prognostication models using data from 421 metastatic renal cell carcinoma patients receiving second-line axitinib therapy at 36 hospitals belonging to the Japan Urologic Oncology Group. RESULTS: The following factors in this cohort were independently associated with poor overall survival in a multivariate analysis: a low Karnofsky performance status, <1 year from diagnosis to targeted therapy, a high neutrophil count, and low albumin, elevated C-reactive protein, and elevated lactate dehydrogenase, and the Japan Urologic Oncology Group model was newly developed based on the presence/absence of these independent factors. In this cohort, 151 (35.9%), 125 (27.7%) and 145 (34.4%) patients were classified into the favorable, intermediate and poor risk groups, respectively, according to the albumin, C-reactive protein and lactate dehydrogenase model; however, the proportions of patients in the intermediate risk group stratified by the Japan Urologic Oncology Group, Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium models were >50%. The superiority of the albumin, C-reactive protein and lactate dehydrogenase model to the Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium models, but not the Japan Urologic Oncology Group model, was demonstrated by multiple statistical analyses. CONCLUSIONS: The utility of the albumin, C-reactive protein and lactate dehydrogenase model as a simple and objective prognostication tool was successfully validated using data from 421 metastatic renal cell carcinoma patients receiving second-line axitinib.

Oncological outcomes of a multicenter cohort treated with axitinib for metastatic renal cell carcinoma.

The present study aimed to evaluate the efficacy of the real-world use of axitinib and to develop a prognostic model for stratifying patients who could derive long-term benefit from axitinib. This was a retrospective, descriptive study evaluating the efficacy of axitinib in patients with metastatic renal cell carcinoma that had been treated with 1 or 2 systemic antiangiogenic therapy regimens at 1 of 36 hospitals belonging to the Japan Urologic Oncology Group between January 2012 and February 2019. The primary outcome was overall survival (OS). Using a split-sample method, candidate variables that exhibited significant relationships with OS were chosen to create a model. The new model was validated using the rest of the cohort. In total, 485 patients were enrolled. The median OS was 34 months in the entire study population, whereas it was not reached, 27 months, and 14 months in the favorable, intermediate, and poor risk groups, respectively, according to the new risk classification model. The following 4 variables were included in the final risk model: the disease stage at diagnosis, number of metastatic sites at the start of axitinib therapy, serum albumin level, and neutrophil : lymphocyte ratio. The adjusted area under the curve values of the new model at 12, 36, and 60 months were 0.77, 0.82, and 0.82, respectively. The efficacy of axitinib in routine practice is comparable or even superior to that reported previously. The patients in the new model's favorable risk group might derive a long-term survival benefit from axitinib treatment.

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.

Impact of eIF4E phosphorylation at Ser209 via MNK2a on tumour recurrence after curative surgery in localized clear cell renal cell carcinoma.

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.

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.

[High Orchidectomy and Histopathology to Differentiate Granulomatous Orchitis from Testicular Malignancy : Case Report and Literature Review].

A 59-year-old man presented with pain and swelling of the right scrotum. Magnetic resonance imaging revealed a mass withsignal intensity similar to background on an apparent diffusion coefficient (ADC)-map of the upper region of the right testis. Inflammation was considered, but a testicular tumor could not be ruled out. Right high orchidectomy and histopathological assessment revealed granulomatous orchitis. The cause, clinical course and treatment of rare granulomatous orchitis remain unknown. Granulomatous orchitis and testicular tumor are difficult to discriminate, and high orchidectomy is usually applied along with histopathological assessment to achieve a definitive diagnosis. On the other hand, some patients who were only medically treated for granulomatous orchitis have recovered. We recently found that diffusionweighted imaging and ADC values derived from magnetic resonance images can differentiate testicular tumor from orchitis. We suggest an algorithm for the diagnosis and treatment of granulomatous orchitis considering the present patient and previous reports.

[PRIMARY MALIGNANT LYMPHOMA OF THE BLADDER DIAGNOSED BY TRANSURETHRAL BLADDER TUMOR RESECTION: A CASE REPORT].

A 72-year-old woman underwent computed tomography (CT) to identify the underlying cause of thrombocytosis. The CT showed a bladder tumor. Urine cytology was negative. Cystoscopic examination showed a dome-shaped bulge at the right lateral wall of the bladder, suggesting a submucosal tumor. The bladder tumor was immediately resected transurethrally. The histological diagnosis was malignant lymphoma of mucosa-associated lymphoid tissue. Positron emission tomography-CT showed no lesions other than the bladder tumor. The patient was diagnosed with primary malignant lymphoma of the bladder.The tumor was low-grade, and strict follow-up was subsequently carried out. There was no evidence of recurrence or metastasis at 13 months after treatment.

[Two Cases of Urachal Carcinoma Treated by TS-1/CDDP as Adjuvant Chemotherapy].

Case 1 : A 48-year-old man presenting with gross hematuria was suspected to have a tumor located in the bladder dome. He was referred to our department for further examination and treatment. Cystoscopy showed a dome-shaped mass in the supravesical region. Computed tomography and magnetic resonance imaging indicated the possibility of urachal carcinoma and peritoneal dissemination. Therefore, partial cystectomy with urachal resection was performed. The intraoperative findings were disseminated peritoneal nodules and mucus entering the peritoneal cavity from the tumor. On pathological examination, the tumor was classified as a mucinous-type adenocarcinoma, and 6 courses of TS-1/cisplatin (CDDP) therapy were administered to the patient as adjuvant chemotherapy. To date (10 months since the surgery), there has been no disease progression. Case 2 : A 76-year-old woman was referred to our department with a finding of a tumor in the bladder dome during her detailed examination for lung tumors. Cystoscopy showed nodular tumors, indicating lung metastases of the urachal carcinoma. Therefore, partial cystectomy with urachal resection was performed. On pathological examination, the tumor was classified as an enteric-type adenocarcinoma, and 2 courses of TS-1/CDDP therapy were administered to the patient as adjuvant chemotherapy. However, due to the development of marked bone marrow depression, the drugs had to be discontinued. Nonetheless, the lung metastases markedly diminished in size. To date (9 months since the discontinuation of chemotherapy), there has been no disease progression.

[A CASE OF BLEEDING AFTER PROSTATE BIOPSY WITH CONSERVATIVELY-TREATED GIANT RETROPERITONEAL HEMATOMA WHICH HAD EXTENDED INTRAPERITONEALLY].

The patient was a 61-year old male on maintenance dialysis who underwent transrectal prostate biopsy due to a high PSA level. The patient started suffering from intense pain in the anal region 1 hour after the biopsy, and in 7 hours, intense lower abdominal pain and bilious vomiting developed. Progressive anemia was observed with a giant retroperitoneal hematoma which had partially extended intraperitoneally on a non-contrast CT image. These findings might have been caused by arterial bleeding which occurred during the prostate biopsy. The general condition was stable, and the symptoms were improved by blood transfusion and conservative treatments.

[Availability of Local Therapy to Castration-Resistant Prostate Cancer for M0 Patients with Initial Prostate Specific Antigen 100 ng/ml or Higher].

Prostate cancer patients with initial PSA 100 ng/ml or greater who received transrectal ultrasoundguided prostate biopsy and were staged as M0 by imaging studies from 2011 to 2014 in seven hospitals, were enrolled in the study. Castration-resistant prostate cancer (CRPC)-free survival was compared between the two treatment groups : androgen deprivation therapy (ADT) alone and ADT plus local therapy. Of 142 prostate cancer patients with initial PSA 100 ng/ml or greater, 49 (34.5%) had no metastases and final analysis was performed on 46 patients. Thirty one M0 patients received ADT alone, and 15 received ADT plus local therapy. During follow-up (median 31 months, range 1-56 months) 13 patients (42%) in the ADT alone group progressed to CRPC. One- and two-year CRPC-free survival rates were 72.5 and 53%, respectively. No patients with ADT plus local therapy developed CRPC, and time to CRPC was prolonged significantly (p=0.002). On multivariate analysis for the group with ADT alone, PSA nadir of more than 0. 2 ng/ml and cN1 were independent predictors for progression to CRPC (p=0.009, 0.031). About one third of prostate cancer patients with initial PSA 100 ng/ml or greater had clinically no metastases. Local therapy to prostate combined with ADT may prolong time to CRPC compared with ADT alone. A subset of men with a PSA nadir of more than 0.2 ng/ml after ADT and cN1 could benefit from local therapy.

[SPONTANEOUS RENAL RUPTURE TREATED BY TRANSCATHETER ARTERIAL EMBOLIZATION: A CASE REPORT].

We describe our experience with a case of spontaneous renal rupture. A 43-year-old man visited our hospital with a chief complaint of left back pain with no identifiable triggering factors. A CT scan showed a rupture involving the left renal parenchyma and hematoma around the kidney. However, there were no apparent causes of the renal rupture, such as tumors and vascular lesions. Based on these findings, he was diagnosed with spontaneous renal rupture. Due to progression of anemia during the course, he underwent transcatheter arterial embolization of the kidney. He continues to undergo imaging examinations on a regular basis and has shown no development of apparent neoplastic lesions for 13 months.