Search

The Prostate Imaging and Reporting and Data System (PI-RADS) version 2.1 (v2.1) has been reported to have an improved reading agreement rate than the prior version. Our study assessed the PI-RADS v2.1 and tumor location in Japanese prostate cancer patients who underwent radical prostatectomy to determine the predictive efficacy of bi-parametric MRI (bp-MRI) for biochemical recurrence (BCR). Retrospective analysis was done on the clinical data from 299 patients who underwent radical prostatectomy at Chiba University Hospital between 2006 to 2018. The median prostate-specific antigen（PSA）before surgery was 7.6 ng/ml. Preoperative PI-RADS v2.1 categories were 1 - 2 /3 /4/ 5 for 35 /56 /138 /70, respectively. Tumor localization at the preoperative MRI was 107 in the transition zone (TZ) and 192 in the peripheral zone (PZ). The duration of BCR-free survival was significantly shortened in the PZ group (p = 0.01). Preoperative PI-RADS category 5, radiological tumor localization, pathological seminal vesicle invasion, and Grade group ≥ 3 of the total prostatectomy specimens were independent prognostic factors of BCR. The four risk factors have the potential to significantly stratify patients and predict prognoses. Radiological tumor localization and PI-RADSv2.1 category using bp-MRI may predict the BCR following radical prostatectomy.

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

(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.

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.

Long-term culture of canine artificial hepatocytes has not been established. We hypothesized that human placental hydrolysate (hPH) may support the long-term culture of differentiated hepatocyte-like cells. Canine bone marrow cells were cultured using modified hepatocyte growth medium supplemented with hPH. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemical analysis for albumin, qualitative RT-PCR for cytochrome P450 1A1 (CYP1A1), hepatocyte growth factor (HGF), Cytokeratin 7 (CK7), CD90, CD44, and CD34, and functional analyses of CYP450 activity and low-density lipoprotein (LDL) uptake were performed. Cultured hepatocyte-like cells were able to maintain hepatocyte characteristics, including morphology, albumin synthesis, CYP450 activity, and LDL uptake for 80 days. Thus, hPH may be a potential facilitator for the long-term culture of hepatocyte-like cells. Clinicopathologically, this culture protocol of artificial hepatocytes will contribute to liver function evaluation.

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.

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.

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.

Understanding of the impact of stem cell donation on donors’ health-related quality of life (HRQOL) remains limited. A prospective observational study of eligible unrelated donors enrolled in the Japan Marrow Donor Program was conducted to compare HRQOL and adverse events (AEs) between peripheral blood stem cell (PBSC) and bone marrow (BM) donors. In total, 107 PBSC donors and 108 BM donors were enrolled. HRQOL scores for physical status were significantly lower in BM donors 1 week post-harvest (P

BACKGROUND The role of testosterone as a prognostic factor for castration-resistant prostate cancer treated with docetaxel in Japan was investigated. METHODS A total of 164 patients with castration-resistant prostate cancer who received docetaxel treatment at Chiba University Hospital and an affiliated hospital were retrospectively analyzed. Testosterone and other clinical factors at the start of docetaxel treatment were evaluated with respect to overall survival and progression-free survival. RESULTS Of the 164 patients, 69 had high-volume tumors. The median prostatic-specific antigen was 27.0 ng/mL. The median testosterone was 13.0 ng/dL. The rates of bone and visceral metastases were 80.1% and 8.8%, respectively. For progression-free survival, testosterone ≥13 ng/dL was an independent prognostic factor only on univariate analysis (hazard ratio, 1.81; P = .0108). For overall survival, testosterone ≥ 1.3 ng/dL (hazard ratio, 3.37; P

The protein binding rates (PBR) of platinum-containing agents cisplatin (CDDP), carboplatin (CBDCA) and oxaliplatin (L-OHP) have been reported as 98%, 25-50% and 98%, respectively. To investigate the protein-binding properties of albumin with cisplatin, carboplatin and oxaliplatin, inductively coupled plasma mass spectrometry (ICP-MS) was used to measure their plasma concentration in rats over time. The study also examined the effects of cisplatin, carboplatin and oxaliplatin-binding on albumin in vitro, using CD spectrometry and native-polyacrylamide gel electrophoresis (native PAGE). The ratios of PBR to irreversible PBR, of cisplatin and oxaliplatin were 98%:98% and 90%:87%, respectively, indicating a higher affinity for irreversible binding with albumin. That of carboplatin was 25%:10%, indicating 60-70% reversible binding with albumin. The plasma protein binding rate concentrations of cisplatin, carboplatin and oxaliplatin after in vivo administration were 96%, 15% and 80%, respectively. The CD spectrometry of albumin was unaffected by cisplatin, carboplatin and oxaliplatin binding. Though similar protein binding rates were observed with oxaliplatin and cisplatin, oxaliplatin had a higher mobility rate during PAGE. It was confirmed that the binding of cisplatin and oxaliplatin with albumin affected its electric charge but not the structure. In conclusion, cisplatin and oxaliplatin bind irreversibly with albumin in plasma and may irreversibly interact with tissue protein and/or DNA. The difficulties involved with predicting the tissue concentrations of cisplatin and oxaliplatin from their plasma concentration inhibits their therapeutic drug monitoring. On the contrary, carboplatin, like some generic drugs, reversibly binds to plasma proteins. It is, therefore, possible to conduct therapeutic drug monitoring for carboplatin.

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.

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.

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.

Metastases to the subcutaneous scrotum are extremely rare. Here, we report a 78-year-old man who presented with pain to the scrotum and inguinal area. Two years ago, he underwent total gastrectomy for gastric cancer. The pain was attributed to increased scrotal wall thickness. Incisional biopsy of the thickened scrotal wall revealed diffused infiltration of the subcutaneous tissue by islands of scirrhous type malignant cells. Moreover, immunohistochemical studies showed that the tumor cells were positive for CK7, CK20, and CDX-2. These features suggested a metastatic adenocarcinoma of upper gastrointestinal origin. Although there were no visceral metastases, the tumor cells were too widely spread to be dissected curatively. Palliative chemotherapy with tegafur, gimeracil, and oteracil (S-1) was restarted, and local pain was subsequently ameliorated. Since scrotal metastasis is unlikely to occur it is difficult to diagnose. Therefore, in patients with groin discomfort or swelling and a history of gastric cancer, metastatic adenocarcinoma should be included in the differential diagnosis for early detection of a tumor.

Aggressive NK-cell leukemia (ANKL) has a fulminant clinical course with a poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment. Using the Japanese transplant registry data, the outcomes of 59 ANKL patients who underwent first allo-HSCT were analyzed. Twenty-nine patients received stem cells from cord blood (CB), 18 from peripheral blood, and 12 from bone marrow. At the time of transplant 21 patients had complete response (CR), and 7 partial response (PR), but 31 without response. The 1-year and 5-year overall survival (OS) were 33.9% and 27.3%, respectively. The 1-year cumulative incidences of relapse or progression was 55.5%, and that of non-relapse mortality was 12.1%. The OS was significantly better for patients with CR or PR at the time of allo-HSCT (P = 0.046), which was equivalent to that for patients who experienced primary induction failure at the time of allo-HSCT but achieved CR afterwards (40.6% versus 32.0% at 5 years; P = 0.95). Patients receiving CB had a significantly better OS than those receiving stem cells from others (37.3% versus 16.2% at 5 years; P = 0.04). Patients achieving event-free survival at 12 months after allo-HSCT had good outcomes with 5-year OS of 85.2%.

Mutations in the connexin 26 (CX26)/gap junction beta-2 (GJB2) gene are the most frequent cause of hereditary deafness worldwide. Using mouse induced pluripotent stem cells (iPSCs) and a BMP4 signal-based floating and adherent culture system, we recently produced in vitro responsible for GJB2-related deafness (CX26-gap junction plaque-forming cells, CX26GJCs). However, to use these cells as a disease model platform for high-throughput drug screening or regenerative therapy, cell yields must be substantially increased. In addition to BMP4, presently uncharacterized factors may also induce CX26 gap junction (GJ) formation. A floating culture with embryonic stem cell (ESC) treatment and BMP4/TGF-β inhibitor (SB431542:SB) has been shown to result in greater production of isolatable CX26-positive small vesicles (CX26+ vesicles) and higher Gjb2 mRNA levels than BMP4 treatment alone, suggesting that SB may promote BMP4-mediated production of CX26+ vesicles in a dose-dependent manner, thereby increasing the yield of highly purified CX26GJCs.In the present study, we first demonstrated that SB accelerates BMP4 induced GJ formation during stem cell differentiation. By controlling the concentration and timing of SB supplementation with CX26+ vesicle purification, large-scale production of highly purified CX26GJCs suitable for high-throughput drug screening or regenerative therapy for GJB2-related deafness may be possible.

Epstein-Barr virus (EBV) is a ubiquitous virus belonging to the human γ-herpes virus subfamily. After primary infection, EBV maintains a life-long latent infection. A major concern is that EBV can cause a diverse range of neoplasms and autoimmune diseases. In addition, patients undergoing hematopoietic stem cell transplantation or solid organ transplantation can experience post-transplant lymphoproliferative disorders (PTLDs) due to dysfunction or suppression of host’s immune system, or uncontrolled proliferation of EBV-infected cells. In recent years, the number of EBV-associated PTLD cases has increased. This review focuses on the current understandings of EBV-associated PTLD pathogenesis, as well as the risk factors and clinical outcomes for patients after allogeneic stem cell transplantation.

The central nervous system (CNS) is rarely involved in plasma cell neoplasms (PCN), especially in patients with advanced disease, harboring poor prognostic chromosomal abnormalities. The prognosis after development of CNS is poor, with a median survival of 2-6 months. Here, we present a 56-year-old woman with isolated CNS relapse of plasma cell leukemia who was admitted to our hospital with back pain, thigh pain, and dysuria. Morphological examination of the cerebrospinal fluid (CSF) confirmed the presence of relapsed plasma cell leukemia, whereas active myeloma lesions were not detectable outside the CNS. Her symptoms did not improve with high doses of methotrexate or intrathecal chemotherapy. However, one cycle of combination therapy with lenalidomide and dexamethasone led to the improvement in clinical symptoms, with complete response seen in the CSF morphology. After 13 cycles, she developed a hematological relapse but maintained complete response in the CSF. The efficacy of lenalidomide in CSF PCN was sporadically reported, and the CNS penetrance of lenalidomide was demonstrated in animal models; however, its efficacy in CNS PCN has not been established. The current case supports the efficacy of combination therapy with lenalidomide as a new therapeutic strategy for CNS PCN.

Mutation of the gene GJB2, encoding connexin 26 (CX26; also known as gap junction beta 2), is the most frequent cause of hereditary deafness worldwide. CX26 is expressed in cochlear nonsensory cells, such as cochlear supporting cells, and forms gap junction plaques (GJPs) at cell-cell borders. Cochlear CX26-GJP-forming cells (Cx26GJCs) are thought to be an important therapeutic target for treatment of hereditary deafness. Nevertheless, the generation of Cx26GJCs-such as cochlear supporting cells-from embryonic stem/induced pluripotent stem (ES/iPS) cells has not been reported to date. Here, we detail a novel strategy for differentiating iPS cells into functional Cx26GJCs such as are found in cochlea. Several assays to characterize the phenotype of iPS-derived Cx26GJCs are described, including qRT-PCR, immunohistological analysis, morphological analysis, a scrape-loading and dye transfer assay, and calcium imaging. This in vitro model has applications in the establishment of inner-ear cell therapies and in drug screening to target GJB2-related hearing loss. © 2019 by John WileySons, Inc. Basic Protocol: Induction of mouse stem cells to create CX26-GJP-forming cells Support Protocol 1: Maintenance and passage of mouse induced pluripotent stem cells Support Protocol 2: Screening for high GJB2 and GJB6 expression in SFEBq culture using quantitative real-time PCR Support Protocol 3: Characterization of cells at different stages of differentiation by immunostaining Support Protocol 4: Ultrastructural analyses of cells at different stages of CX26-GJP-forming cell induction Support Protocol 5: Functional analyses of stem cell-derived CX26-GJP-forming cells.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication after hematopoietic stem cell transplantation (HSCT). Several studies of risk factors for PTLD have been reported; however, the probability of, and risk factors for, PTLD in patients with lymphoma is unknown. Japanese nationwide transplant registry data from 5270 patients with lymphoma after allogeneic HSCT were analyzed. Mature B-cell, T/NK-cell, and T-cell lymphoblastic subtypes accounted for 49%, 26%, and 9.6% of lymphoma cases, respectively. Rituximab was used in 1678 lymphoma patients, most of whom (89%) received HSCT for mature B-cell lymphoma. Thirty-one patients with lymphoma developed PTLD, representing a probability of 0.77% at 2 years post-HSCT, which did not differ significantly from that in patients with other diseases (P = .98). Year of HSCT after 2010 (hazard ratio [HR] = 5.6, 95% confidence interval [CI], 1.48-21.3), antithymocyte globulin (ATG) use in the conditioning regimen (HR = 4.5, 95% CI, 1.61-12.5), and no rituximab use before HSCT (HR = 3.2, 95% CI, 1.26-7.90) were identified as risk factors for PTLD. Probabilities of PTLD at 1 year post-HSCT according to rituximab and ATG use were 0.23% (rituximab+, ATG-), 0.75% (rituximab-, ATG-), 1.25% (rituximab+, ATG+), and 3.53% (rituximab-, ATG+). Regarding lymphoma subtypes, patients with mature B-cell lymphoma had the lowest incidence of PTLD (0.35% at 2 years). Among high-risk patients receiving ATG, the mortality rate due to infection was elevated in those previously treated with rituximab (22%) relative to those without (14%); however, the difference was not significant (P = .10). Rituximab use before HSCT significantly reduces the risk of PTLD. Adding rituximab to the conditioning regimen is potentially a good strategy to prevent the development of PTLD in high-risk patients.

Cisplatin is the most widely used anticancer drug in the world. Mono-chloro and none-chloro complexes of cisplatin may be believed to be the activated compounds. The separation of these compounds using octa decyl silyl column or aminopropylsilyl silica gel column is difficult because of high-reactivity and structural similarity. In this study, cisplatin, hydroxo complexes, and OH-dimer were determined by HPLC using a naphthylethyl group bonded with silica gel (πNAP) column. The analytical conditions of HPLC were as follows: analytical column, πNAP column; wave length, 225 nm; column temperature, 40°C; mobile phase, 0.1 M sodium perchlorate, acetonitrile, and perchloric acid (290 : 10 : 3), flow rate, 1.0 mL/min. Sample (20 µL) was injected onto the HPLC system. Retention time of cisplatin, mono-chloride, OH-dimer, and none-chloride was 3.2, 3.4, 3.6, and, 4.3-6.6 min, respectively. Measurable ranges with this method were 1×10-5 to 4×10-3 M for cisplatin. Correlation coefficient of the calibration curves of cisplatin was 0.999 (p

Summary Mutation of the Gap Junction Beta 2 gene (GJB2) encoding connexin 26 (CX26) is the most frequent cause of hereditary deafness worldwide and accounts for up to 50% of non-syndromic sensorineural hearing loss cases in some populations. Therefore, cochlear CX26-gap junction plaque (GJP)-forming cells such as cochlear supporting cells are thought to be the most important therapeutic target for the treatment of hereditary deafness. The differentiation of pluripotent stem cells into cochlear CX26-GJP-forming cells has not been reported. Here, we detail the development of a novel strategy to differentiate induced pluripotent stem cells into functional CX26-GJP-forming cells that exhibit spontaneous ATP- and hemichannel-mediated Ca2+ transients typical of the developing cochlea. Furthermore, these cells from CX26-deficient mice recapitulated the drastic disruption of GJPs, the primary pathology of GJB2-related hearing loss. These in vitro models should be useful for establishing inner-ear cell therapies and drug screening that target GJB2-related hearing loss., Graphical Abstract, Highlights • Mutation in GJB2 (CX26) is the most frequent cause of hereditary deafness worldwide • Functional CX26-gap junction plaque (GJP)-forming cells were generated from iPSCs • These cells exhibited spontaneous Ca2+ transients typical of the developing cochlea • The drastic disruption of GJP was observed in in vitro disease model of GJB2 mutation, Kamiya and colleagues generated functional CX26-gap junction plaque-forming cells from iPSCs. These cells exhibited spontaneous ATP- and hemichannel-mediated Ca2+ transients typical of the developing cochlea. Furthermore, an in vitro disease model from CX26-deficient deafness mice recapitulated the drastic disruption of gap junction plaques reported to be the primary pathology of GJB2-related hearing loss.

We analyzed data from 64,539 consecutive patients in the Japanese national transplant registry, including 40,195 after allogeneic hematopoietic stem cell transplantation (HSCT), 24,215 after autologous HSCT and 129 after syngeneic HSCT, of whom 299 developed Epstein-Barr virus-positive post-transplant lymphoproliferative disorder (PTLD). The probability of developing PTLD at 2 years post-HSCT was .79% after allogeneic transplantation, .78% after syngeneic transplantation, and .11% after autologous transplantation. The following variables were identified as risk factors after allogeneic HSCT in multivariate analysis: antithymocyte globulin (ATG) use in a conditioning regimen, ATG use for acute graft-versus-host disease (GVHD) treatment, donor other than an HLA-matched related donor, aplastic anemia, second or subsequent allogeneic HSCT, the most recent year of transplantation, and acute GVHD. The probability at 2 years increased particularly after 2009 (1.24%) than before 2009 (.45%). To stratify the risk of PTLD before allogeneic HSCT, we developed a novel 5-point scoring system based on 3 pretransplant risk factors: ATG use in a conditioning regimen (high dose, 2 points; low dose, 1 point), donor type (HLA-mismatched related donor, 1 point; unrelated donor, 1 point; cord blood, 2 points), and aplastic anemia (1 point). Patients were classified into 4 risk groups according to the summed points: low risk (0 or 1 point), intermediate risk (2 points), high risk (3 points), and very high risk (4 or 5 points) groups, with probabilities at 2 years of .3%, 1.3%, 4.6%, and 11.5%, respectively. Our scoring system is useful for predicting patients at high risk for PTLD. Careful observation and close monitoring of Epstein-Barr virus reactivation are warranted for these high-risk patients.

A 69-year-old man presented initially with back pain and incomplete bilateral lower limb paralysis. The level of prostate-specific antigen (PSA) in the patient was elevated to 167.0 ng/ml, and multiple bone metastases were detected. Thoracic laminectomy was performed in an emergency due to spinal decompression. Subsequently, the patient was diagnosed with prostate cancer from an examination of resected bone specimens. Combined androgen blockade with degarelix and bicalutamide was initiated in October 2013. Consequently, the serum PSA level decreased to

Particle saltation on an obliquely oscillating plate is simulated using a mass-point model that considers gravity, fluid resistance, restitution, and friction. The calculated results are in good agreement with results obtained experimentally for particles with different diameters and restitutions. A large particle with high restitution bounces forward and backward repeatedly, whereas a particle with low restitution only bounces forward and consequently has a high transport velocity. The mechanism for the difference in the motion of the particles can be explained by taking into account the phase angle of the oscillating plate and the impulse during particle collision.

Introduction Aggressive natural killer cell leukemia (ANKL) is a rare leukemic form of mature natural killer cell neoplasms that is closely associated with Epstein-Barr virus. ANKL presents a fulminant clinical course, resulting in a poor prognosis with a median overall survival of approximately 2 months. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment, but the long-term outcomes after allo-HSCT remain unclear. Methods Using the national Japanese transplant registry database, the outcomes of 59 ANKL patients who underwent first allo-HSCT between 1997 and 2016 were analyzed. Correlation between groups was examined by the c2 test, Mann-Whitney U test, and Kruskal-Wallis test. Patient survival data were analyzed using the Kaplan-Meier method and compared by the log-lank test. The cumulative incidence of relapse and non-relapse mortality were calculated considering competing risks. Results The median patient age was 37 years (range, 9 to 66), and males accounted for 68%. The median time from diagnosis to allo-HSCT was 3.7 months (range, 1.1 to 13.9). Twenty-nine patients received stem cells from cord blood (CB), 18 received them from peripheral blood (PB), and 12 received them from bone marrow (BM). Two patients had a prior history of autologous HSCT. Twenty-one patients (36%) had a complete response (CR) and 7 (12%) had a partial response (PR), but 31 (52%) were not responding at the time of allo-HSCT. Forty-four patients received myeloablative conditioning and 15 received non-myeloablative conditioning. Thirty-two patients received tacrolimus-based GVHD prophylaxis, including 1 with additional post-transplant cyclophosphamide as part of haploidentical HSCT, whereas 26 received cyclosporin-based GVHD prophylaxis. The median follow-up of survivors was 62 months (range, 0.9 to 193). The median OS and relapse-free survival were 3.9 months and 2.6 months, respectively. The probability of OS and relapse-free survival, and cumulative incidence of relapse and non-relapse mortality 1 year after HSCT were 33.9%, 32.4%, 55.5%, and 12.1%, respectively. The probability of OS was significantly higher for patients with CR or PR at allo-HSCT than for those without a response (40.6% vs 16.1% at 5 years; P = 0.046). Among the 24 patients with primary induction failure (PIF) at allo-HSCT, 15 achieved CR after allo-HSCT. The prognosis of these 15 patients was almost equivalent to that of those who received allo-HSCT in CR or PR, as shown in the Figure (P = 0.95). Regarding the stem cell source, the probability of OS was significantly higher for patients who received stem cells from CB than for those who received them from PB or BM (CB 37.3% vs PB 15.8% and BM 16.7% at 5 years; P = 0.04). Seventeen patients (59%) of those who received stem cells from CB were CR at HSCT, whereas only 4 patients (13%) of those who received stem cells from PB or BM were CR at HSCT. In addition, 5 (83%) of 6 patients who received stem CB transplantation in PIF achieved CR after allo-SCT, whereas 10 (56%) of 18 patients who received PB stem cell transplantation or BM transplantation in PIF achieved CR. The age and year at HSCT were not different between the groups. The time from diagnosis to allo-HSCT did not differ among stem cell sources (median CB 3.3 months, PB 3.7 months and BM 4.1 months; P = 0.31). Regarding the conditioning regimen, the probability of OS was not different between myeloablative and non-myeloablative conditioning regimens (P = 0.58). Patients who developed acute GVHD grade 1/2 had a significantly better prognosis than those with grade 3/4 or without GVHD (P < 0.001). In contrast, chronic GVHD development did not affect the prognosis (P = 0.60). At the last follow-up, 42 patients (71%) had died. The most common cause of death was primary disease (62%), followed by infection (14%) and organ dysfunction (7%). Conclusion Allo-HSCT can lead to long-term survival even for patients with PIF at HSCT. CB is useful as a stem cell source, providing good outcomes and timely allo-HSCT for this rapidly progressive disease. To confirm our findings and evaluate the outcome of allo-SCT in more detail, further studies including patients who did not receive allo-SCT for ANKL are warranted. Figure Disclosures Ishida: Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding; Eli Lily and Company: Research Funding; Celgene: Honoraria; Chugai Pharmaceutical: Consultancy, Research Funding. Izutsu:Celgene: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Symbio: Research Funding; Ono: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Solasia: Research Funding; Zenyaku: Research Funding; Incyte: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; HUYA Bioscience: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Astellas Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; ARIAD: Research Funding; Takeda: Honoraria, Research Funding; Pfizer: Research Funding; Kyowa Kirin: Honoraria; Nihon Medi-physics: Honoraria; Janssen: Honoraria; Dainihon Sumitomo: Honoraria; Bristol-Byers Squibb: Honoraria; Mundi: Honoraria; Otsuka: Honoraria; Asahi Kasei: Honoraria. Suzumiya:Celgene, Kyowa Kirin, Chugai-Roche, Eisai, Takeda, Celltrion, SymBio, Astellas, Ono, AstraZeneca, Ootsuka, Taiho, Mundi, Dainihon-Sumitomo: Research Funding. Mitsui:MSD pharmaceutical: Research Funding; Maruho pharmaceutical: Research Funding; JCR pharmaceutical: Research Funding; Teijin pharmaceutical: Research Funding; Chugai pharmaceutical: Research Funding; Daiichi Sankyo pharmaceutical: Research Funding; Astellas pharmaceutica: Research Funding; Shionogi pharmaceutical: Research Funding. Kanda:Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Daiichi Sankyo Company: Honoraria; MSD: Honoraria; Chugai: Honoraria; Bristol-Meyers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Astellas: Honoraria; JCR Pharmaceuticals: Honoraria; Takeda: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Suzuki:Celgene: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Bristol-Myers Squibb: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria.

The characteristics of surface antigens in canine hepatocellular carcinoma (cHCC) have not been clarified. The objective of this study was to investigate surface antigens, which are considered as stem/progenitor or cancer cell markers, in cHCC cell lines. Expression of various antigens including CD29, CD34, CD44, CD90, CD133 and Dlk-1 was assessed in four cHCC cell lines by flow cytometry. CD44, CD133 and Dlk-1 expression was detectable in all cell lines, and three cell lines expressed CD29. These results indicate that CD29, CD44, CD133 and Dlk-1 have potential as suitable markers in cHCC identification, suggesting that these findings will contribute to the establishment of an early diagnostic tool for the identification of hepatocellular maturation processes.