L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity.

L-type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed in various carcinomas, and it is postulated to play an important role in the proliferation of cancer cells through the uptake of essential amino acids. Cabazitaxel is a widely used anticancer drug for treating castration-resistant prostate cancer (CRPC); however, its effectiveness is lost when cancer cells acquire drug resistance. In this study, we investigated the expression of LAT1 and the effects of a LAT1-specific inhibitor, JPH203, in cabazitaxel-resistant prostate cancer cells. LAT1 was more highly expressed in the cabazitaxel-resistant strains than in the normal strains. Administration of JPH203 inhibited the growth, migration, and invasive ability of cabazitaxel-resistant strains in vitro. Phosphoproteomics using liquid chromatography-mass spectrometry to comprehensively investigate changes in phosphorylation due to JPH203 administration revealed that cell cycle-related pathways were affected by JPH203, and that JPH203 significantly reduced the kinase activity of cyclin-dependent kinases 1 and 2. Moreover, JPH203 inhibited the proliferation of cabazitaxel-resistant cells in vivo. Taken together, the present study results suggest that LAT1 might be a valuable therapeutic target in cabazitaxel-resistant prostate cancer.

A case of ipsilateral three simultaneous renal cell carcinomas with different histologic types.

Introduction: Few reports have presented sporadic multifocal renal cell carcinomas of different histologic types occurring simultaneously in a single kidney. Here, we present a case of three ipsilateral renal cell carcinomas with three histologic types. Case presentation: A 44-year-old man with end-stage renal disease due to nephrosclerosis was referred to our hospital for an incidental renal tumor. Following the introduction of hemodialysis, enhanced computed tomography revealed a renal tumor suggestive of clear-cell renal cell carcinoma with a cystic component. With a preoperative diagnosis of one renal tumor, he underwent laparoscopic radical nephrectomy. However, pathological examination revealed three renal cell carcinomas with three histological diagnoses: clear-cell, papillary, and clear-cell papillary renal cell carcinomas. Conclusion: Preoperative imaging may not detect all synchronous ipsilateral multifocal renal cell carcinomas. Patients with severe renal function impairment may have synchronous multifocal renal cell carcinomas.

A case of bladder cancer after bilateral lung transplantation following bone marrow transplantation.

Introduction: The incidence of bladder cancer following transplantation is high; however, no previous studies have reported the development of bladder cancer following bone marrow and bilateral lung transplantations. Case presentation: A 42-year-old man who was followed for bilateral lung transplantation due to chronic graft-versus-host disease following bone marrow transplantation complained of gross hematuria. Transurethral resection of the bladder tumor was performed for cT1N0M0 bladder cancer. On the following night, he experienced severe respiratory failure and was intubated. He was discharged on postoperative day 32 with the introduction of home oxygen therapy. The pathological diagnosis was invasive urothelial carcinoma, high-grade, pT1, with urothelial carcinoma in situ. Further treatment could not be performed because of his poor performance status and immunosuppressive state. Conclusion: Vigorous screening for bladder cancer coexisting with other malignancies should be performed for transplant recipients for the early diagnosis and prompt treatment of a relatively aggressive bladder cancer.

Preoperative PI-RADS v2.1 Scoring System Improves Risk Classification in Patients Undergoing Radical Prostatectomy.

BACKGROUND/AIM: The purpose of this study was to examine the prognostic value of Prostate imaging-reporting and data system (PI-RADS) v2.1 scoring system in patients who underwent radical prostatectomy (RP). PATIENTS AND METHODS: Clinical data of 294 patients who received RP between 2006 and 2018 were reviewed and multiple parameters including PI-RADS v2.1 score were employed to identify predictive factors for biochemical recurrence (BCR). Tumor volume was calculated from prostatectomy specimens. RESULTS: Median age at operation and initial PSA level were 67 years old and 7.68 ng/ml, respectively. 44.9 and 24.8% of patients were diagnosed with PI-RADS score 4 and 5 prior to biopsies, respectively. BCR was observed in 17% of patients and median observation period was 63.43 months. After multivariate analysis, PI-RADS v2.1 score 5 [hazard ratio (HR)=2.24, p=0.0124] was an independent predictive factor of BCR in addition to clinical T stage (≥2c) (HR=2.32, p=0.0093) and biopsy Gleason score (≥8) (HR=2.81, p=0.0007). Furthermore, PI-RADS score 5 significantly stratified the prognosis in D'Amico intermediate- and high-risk groups (p=0.0174 and p=0.0013, respectively). We established novel risk classifications including PI-RADS v2.1 score and found that prognostic capabilities were improved as compared to the D'Amico classification. CONCLUSION: The PI-RADS v2.1 score exhibited significant prognostic value in patients with localized prostate cancer following RP. Risk classifications based on PI-RADS v2.1 score might provide better ability for predicting oncological outcomes as compared to the D'Amico classification system.

Tumor localization by Prostate Imaging and Reporting and Data System (PI-RADS) version 2.1 predicts prognosis of prostate cancer after radical prostatectomy.

An improved reading agreement rate has been reported in version 2.1 (v2.1) of the Prostate Imaging and Reporting and Data System (PI-RADS) compared with earlier versions. To determine the predictive efficacy of bi-parametric MRI (bp-MRI) for biochemical recurrence (BCR), our study assessed PI-RADS v2.1 score and tumor location in Japanese prostate cancer patients who underwent radical prostatectomy. Retrospective analysis was performed on the clinical data of 299 patients who underwent radical prostatectomy at Chiba University Hospital between 2006 and 2018. The median prostate-specific antigen (PSA) level before surgery was 7.6 ng/mL. Preoperative PI-RADS v2.1 categories were 1-2, 3, 4, and 5 in 35, 56, 138, and 70 patients, respectively. Tumor location on preoperative MRI was 107 in the transition zone (TZ) and 192 in the peripheral zone (PZ). BCR-free survival was significantly shorter in the PZ group (p = 0.001). In the total prostatectomy specimens, preoperative PI-RADS category 5, radiological tumor location, pathological seminal vesicle invasion, and Grade Group ≥ 3 were independent prognostic factors of BCR. These four risk factors have significant potential to stratify patients and predict prognosis. Radiological tumor location and PI-RADS v2.1 category using bp-MRI may enable prediction of BCR following radical prostatectomy.

A case of metastatic renal cell carcinoma successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy.

Introduction: Combination therapy using immuno-oncology drugs with tyrosine kinase inhibitors is increasingly important in the therapeutic strategy for metastatic renal cell carcinomas. Here, we report a case of metastatic renal cell carcinoma that was successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy. Case presentation: A 49-year-old man was referred to our hospital with a diagnosis of advanced right kidney cancer with multiple lung metastases (cT3aN0M1). The size of the primary tumor was so huge that it exceeded 20 cm in diameter, pushing the liver and intestines to the left. After administration of lenvatinib and pembrolizumab combination as first-line treatment, all the metastatic lung lesions disappeared, and the primary lesion shrank significantly. Robot-assisted radical nephrectomy was successfully performed, resulting in complete surgical remission. Conclusion: Deferred cytoreductive nephrectomy following a lenvatinib plus pembrolizumab combination is a useful therapeutic strategy for achieving complete remission of metastatic renal cell carcinomas.

Tumor Location and a Tumor Volume over 2.8 cc Predict the Prognosis for Japanese Localized Prostate Cancer.

(1) Objective: Our study investigated the prognostic value of tumor volume and location in prostate cancer patients who received radical prostatectomy (RP). (2) Methods: The prognostic significance of tumor volume and location, together with other clinical factors, was studied using 557 patients who received RP. (3) Results: The receiver operating characteristic (ROC) curve identified the optimal cutoff value of tumor volume as 2.8 cc for predicting biochemical recurrence (BCR). Cox regression analysis revealed that a tumor in the posterior area (p = 0.031), peripheral zone (p = 0.0472), and tumor volume ≥ 2.8 cc (p < 0.0001) were predictive factors in univariate analysis. After multivariate analysis, tumor volume ≥ 2.8 cc (p = 0.0225) was an independent predictive factor for BCR. Among them, a novel risk model was established using tumor volume and location in the posterior area and peripheral zone. The progression-free survival (PFS) of patients who met the three criteria (unfavorable group) was significantly worse than other groups (p ≤ 0.001). Furthermore, multivariate analysis showed that the unfavorable risk was an independent prognostic factor for BCR. The prognostic significance of our risk model was observed in low- to intermediate-risk patients, although it was not observed in high-risk patients. (4) Conclusion: Tumor volume (≥2.8 cc) and localization (posterior/peripheral zone) may be a novel prognostic factor in patients undergoing RP.

Occupational safety and health aspects of corporate social responsibility reporting in Japan: comparison between 2012 and 2020.

OBJECTIVE: To survey the content of occupational safety and health (OSH) disclosed in corporate social responsibility (CSR)-related reports and integrated reports in 2020 and to compare the changes between 2012 and 2020 according to industry and company size. RESULTS: Among all companies, 441 (20.3%) issued CSR-related reports and 590 (28.1%) issued integrated reports. The number (percentage) of companies that issued either CSR-related reports or integrated reports was 880 (40.5%). The percentages of both CSR-related reports and integrated reports increased with increased company size. The number (percentage) of companies reporting OSH in CSR-related reports was 391 (88.7%) and that in integrated reports was 493 (83.6%). The percentage of OSH reporting in CSR-related reports and integrated reports was high in secondary industries and low in tertiary industries.

Case of Pulmonary Extramedullary Hematopoiesis Responding to Ruxolitinib.

We report a case of 43-year-old woman diagnosed with essential thrombocythemia in 1992. She was diagnosed with secondary myelofibrosis in 2011. Later, she suffered mild dyspnea, which gradually worsened. She was admitted to our hospital to evaluate the cause in 2014. Chest computed tomography showed ground-glass opacity (GGO) in the lungs. A lung biopsy revealed various hematopoietic cells, including abnormal megakaryocytes, infiltrating the alveolar septum, suggesting pulmonary extramedullary hematopoiesis. She was successfully treated by ruxolitinib and her disease is well controlled for more than 7 years. To keep this phenomenon in mind when see the patients with dyspnea is important.

Expression of tertiary lymphoid structure in deferred cytoreductive nephrectomy of metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

INTRODUCTION: Tertiary lymphoid structure expression and immune checkpoint inhibitors have been attracting attention, and their relationship with renal cell carcinoma is controversial. CASE PRESENTATION: Two patients with nivolumab plus ipilimumab treatment response for metastatic renal cell carcinoma underwent cytoreductive nephrectomy and regional lymph node dissection. In both cases, the renal tumor site expressed tertiary lymphoid structures. Despite the absence of treatment after a deferred cytoreductive nephrectomy and the short postoperative observation period, the patients still survived. CONCLUSION: Tertiary lymphoid structures were expressed in deferred cytoreductive nephrectomy specimen in cases treated with nivolumab plus ipilimumab.

Renal Function Improves After the Discontinuation of Androgen Deprivation Therapy in Japanese Patients With Prostate Cancer.

BACKGROUND: Androgen deprivation therapy (ADT) is one of the most effective treatments for advanced prostate cancer (PCa). However, it has been reported that the use of ADT is significantly associated with an increased risk of acute kidney injury (AKI) among patients with newly diagnosed non-metastatic PCa. We investigated changes in renal function that occurred in Japanese patients with PCa after ADT was discontinued. PATIENTS AND METHODS: Among 121 patients who underwent prostate biopsies, were pathologically diagnosed with PCa, and received ADT for ≥6 months at our Institution between 2009 and 2014, 60 patients who underwent radiotherapy for stage B or C PCa were eligible for inclusion in this retrospective study. Renal function was assessed using the estimated glomerular filtration rate (eGFR) before treatment and at 1, 3, 6, 9, and 12 months after the initiation of ADT and the rate of change in the eGFR (ΔeGFR) during ADT and after the discontinuation of ADT was investigated. We divided patients into two groups: Group 1 received ADT for 6 months, and group 2 received ADT for 12 months. Age; ΔeGFR; prostate-specific antigen, testosterone and hemoglobin levels; clinical stage; Gleason score; comorbidities; body mass index; heart rate; and the cardiothoracic ratio were analyzed. RESULTS: A total of 60 patients (group 1: n=23, group 2: n=37) were analyzed. The Gleason score of group 2 was higher than that of group 1 (p=0.0011). Regarding clinical stage, group 1 had more patients with stage B disease, and group 2 had more with stage C (p<0.0001). The eGFR decreased with the duration of ADT treatment. At 12 months, renal function had started to recover in group 1, while it had continued to decrease in group 2. CONCLUSION: Discontinuation of ADT tended to result in improvements in renal function. Furthermore, this study indicated that renal dysfunction caused by 6 months of ADT is transient. Normalization of the serum testosterone level seen after the discontinuation of ADT may be associated with improvements in renal function. Thus, intermittent ADT may be a useful treatment for PCa, as it would help to preserve renal function.

Predictors of failure of intersegmental line creation using bronchoscopic jet ventilation for thoracoscopic pulmonary segmentectomy.

BACKGROUND: During pulmonary segmentectomy, identification of the target segment is essential. We used bronchoscopic jet ventilation (BJV) to delineate the intersegmental plane by selectively sending air into the target segment. The purpose of this study was to investigate the factors associated with BJV failure. METHODS: Data were retrospectively collected from 48 patients who underwent pulmonary segmentectomy with BJV between March 2014 and May 2019 at a single center. Data were compared between BJV succeeded cases and failed cases. RESULTS: In 13 cases (27%), BJV were unsuccessful. The Brinkman index was significantly higher in failed cases (962 ± 965 failed vs. 395 ± 415 successful, P = 0.0067). The success rate was significantly lower when BJV was applied to the posterior basal segmental bronchus (B10) (B10: 1/5 (20%) vs others: 34/43 (79%), P = 0.015). CONCLUSION: Long-term smoking and the bronchus corresponding to the posterior basal segment might make successful performance of BJV difficult.

The heavy chain of 4F2 antigen promote prostate cancer progression via SKP-2.

The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc's impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.

[Allogeneic stem cell transplantation for aggressive NK cell leukemia].

Aggressive NK cell leukemia (ANKL) is a rare leukemic form of mature NK cell neoplasms. ANKL presents a fulminant clinical course with a median overall survival (OS) of 2-3 months after diagnosis. Currently, allogeneic stem cell transplantation (allo-HSCT) is the only curative treatment for ANKL patients. Although a few recent reports have evaluated the efficacy of allo-HSCT for ANKL patients, detailed outcomes of allo-HSCT are obscure. We conducted a nationwide retrospective analysis of 59 ANKL patients who underwent first allo-HSCT between 1997 and 2016 in Japan. The median age was 37 years, and 68% were male. The 1- and 5-year OS were 33.9% and 27.3%, respectively; the 1-year cumulative incidence of relapse or progression was 55.5%. The OS was significantly better for patients with complete or partial responses as the time of allo-HSCT, which was equivalent to that for patients who experienced primary induction failure but achieved complete response after allo-HSCT. Patients who underwent cord blood transplantation had significantly better outcomes than those who underwent allo-HSCT from other sources. Therefore, our study demonstrates that allo-HSCT is a promising treatment that can provide a durable response in a subset of ANKL patients. A larger-scale study including unselected ANKL patients is warranted in the future.

Impact of event-free survival status after stem cell transplantation on subsequent survival of patients with lymphoma.

We evaluated the impact of event-free survival (EFS) status at 24 months (EFS24) and 60 months (EFS60) after hematopoietic stem cell transplantation (HSCT) using registry data. Patients who underwent their first autologous HSCT (auto-HSCT) or allogeneic HSCT (allo-HSCT) for lymphoma between 1981 and 2018 were included. Overall survival was compared with that of the age-, sex, and calendar period-matched general population. A total of 14 977 patients, including 10 964 and 4013 who underwent auto-HSCT and allo-HSCT, respectively, were analyzed. Although patients who achieved EFS24 and EFS60 had favorable outcomes, most had significantly poorer survival rates than the general population. The standardized mortality ratios (SMRs) of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were significantly higher than that of the general population even after achieving EFS24 or EFS60. The SMRs of those after auto-HSCT were 2.5 to 3.5 and 2.7 to 3.7, respectively. The SMR was consistently highest in Hodgkin lymphoma (HL) patients after HSCT. By contrast, subsequent survival of patients with primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified, who achieved EFS60 after auto-HSCT, and those with extranodal natural killer/T-cell lymphoma who achieved EFS60 after allo-HSCT did not significantly differ from that of the general population, with SMRs of 1.6, 1.2, 1.8, and 1.3, respectively. Our results suggest that EFS24 and EFS60 were clinically useful end points after HSCT for lymphoma patients. Furthermore, patients with certain lymphoma subtypes who achieved EFS had a comparable prognosis with that of the general population and were potentially cured after HSCT.

Anticipated health effects and proposed countermeasures following the immediate introduction of telework in response to the spread of COVID-19: The findings of a rapid health impact assessment in Japan.

OBJECTIVES: The health effects of telework, which was introduced extensively in the immediate context of the COVID-19 pandemic crisis in Japan, on teleworkers, their families, and non-teleworkers, are unknown. Accordingly, we developed a rapid health impact assessment (HIA) to evaluate positive and negative health effects of telework on these groups and recommended easily implementable countermeasures. METHODS: Immediately after an emergency was declared in Japan, we implemented a rapid, five-step HIA. We screened and categorized health effects of telework for the three above-mentioned groups, extracting their content, directionality, and likelihood. Following a scoping exercise to determine the HIA's overall implementation, five experienced occupational health physicians appraised and prioritized the screened items and added new items. We outlined specific countermeasures and disseminated the results on our website. A short-term evaluation was conducted by three external occupational health physicians and three nurses. RESULTS: Following screening and appraisal, 59, 29, and 27 items were listed for teleworkers, non-teleworkers, and family members of teleworkers, respectively, covering work, lifestyle, disease and medical care, and home and community. Targeted countermeasures focused on the work environment, business management, communications, and lifestyles for teleworkers; safety and medical guidelines, work prioritization, and regular communication for non-teleworkers; and shared responsibilities within families and communication outside families for family members of teleworkers. CONCLUSION: The HIA's validity and the countermeasures' practical applicability were confirmed by the external evaluators. They can be easily applied and adapted across diverse industries to mitigate the wider negative effects of telework and enhance its positive effects.

False-positive 123I-metaiodobenzylguanidine scan in a patient with renal cell carcinoma: A case of chromophobe renal cell carcinoma oncocytic variant with a complicated clinical course.

INTRODUCTION: 123I-metaiodobenzylguanidine scanning has high sensitivity and specificity for the diagnosis of tumors derived from sympathetic nerves or the adrenal medulla. We report the rare case of a 123I-metaiodobenzylguanidine false-positive renal cell carcinoma. CASE PRESENTATION: The patient was referred to our hospital with an incidental left renal mass during evaluation for hypertension. An ovarian tumor and prominent ascites were also observed. Serum and urine catecholamine levels were high to suspect a catecholamine-producing tumor of the kidney. 123I-metaiodobenzylguanidine scintigraphy showed increased 123I-metaiodobenzylguanidine intake in the tumor. Laparoscopic radical left nephrectomy was performed. The pathologic diagnosis was an oncocytic variant of chromophobe renal cell carcinoma. No pheochromocytoma features were found. CONCLUSION: We report the first case of a 123I-metaiodobenzylguanidine false-positive renal cell carcinoma. This case was diagnosed with primary aldosteronism and Meigs' syndrome, which made the clinical course more complicated.

Population pharmacokinetics of tacrolimus in umbilical cord blood transplant patients focusing on the variation in red blood cell counts.

WHAT IS KNOWN AND OBJECTIVE: The distribution of tacrolimus (TAC), an immunosuppressant used during cord blood transplantation (CBT)-one of the haematopoietic stem cell transplantations, to red blood cell (RBC) is approximately 90% in whole blood. In CBT patients, the total RBC count shows dramatic fluctuation due to conditioning before transplantation, including anticancer agents and total body irradiation, as well as RBC transfusions during the treatment period. Therefore, the amount of TAC in whole blood may show wide variation. However, therapeutic drug monitoring (TDM) of TAC has been performed based on the whole blood concentration. In this study, to contribute to TDM of TAC in CBT, we performed the population pharmacokinetic (PPK) analysis of TAC in 56 CBT patients and investigated the factors that affected the concentration of TAC, focusing the variation of RBC count. METHOD: A one-compartment model was applied to the observed whole blood TAC concentrations, and a PPK analysis was conducted with a non-linear mixed effect model. RESULTS AND DISCUSSION: Our final PPK model indicated good robustness and accuracy. In addition, haemoglobin (Hb) level was an influential covariate on Vd, which was expressed as Vd(L) = 91.4 × (Hb/8.2)(-1.07) . WHAT IS NEW AND CONCLUSION: In this study, our results showed the necessity for the Hb level monitoring during TDM of TAC in CBT patients and provided useful information for improving TDM strategy of TAC.

Simultaneous Discordant B-Lymphoblastic Lymphoma and Follicular Lymphoma.

OBJECTIVES: We report a rare case of B-lymphoblastic lymphoma (B-LBL) and low-grade follicular lymphoma (FL) identified concurrently in biopsies from different sites at the initial diagnosis in a 39-year-old man. The clonal relationship between the 2 histologic subtypes was investigated. METHODS: A diagnosis of FL grade 1/2 (low grade) was made by bone marrow (BM) biopsy. B-LBL was identified in biopsies from the testis and pancreas. Cytogenetic and molecular analyses were performed to investigate their clonal relationship. RESULTS: Interphase fluorescence in situ hybridization analyses and G-banding karyotype analyses identified the BCL2-IGH and MYC-IGH translocation in tumor cells from both the BM and testis. The tumor cells from the BM and testis shared the same IGH VDJ usage and a high degree of somatic mutations. These findings suggest that acquisition of MYC gene rearrangement is a critical event for lymphoblastic transformation of FL. Of note, the presence of intraclonal diversity in the B-LBL sample further suggests an earlier or concurrent event of MYC translocation than the somatic IGH mutation in the germinal center and the dedifferentiation of lymphoma cells to a precursor stage of B-cell development. CONCLUSIONS: B-lymphoblastic transformation of FL can occur with MYC gene rearrangement.