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.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

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.

[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.

Higher serum testosterone levels predict poor prognosis in castration-resistant prostate cancer patients treated with docetaxel.

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 < .0001), high volume (hazard ratio, 3.06; P = .0009), and prostate-specific antigen ≥ 27.0 ng/mL (hazard ratio, 2.75; P = .0013) were independent prognostic factors on multivariate analysis. When assessing related clinical factors, higher serum testosterone was associated with visceral metastasis, high volume, and prostate-specific antigen. Based on three prognostic factors (testosterone, high volume, prostate-specific antigen), a risk classification was developed. The high-risk group (3 risk factors) showed a significantly shorter overall survival compared to the moderate-risk (2 risk factors) and low-risk (0-1 risk factor) groups (P < .0001). CONCLUSIONS: The present study identified higher serum testosterone (≥13 ng/dL) as a significant prognostic factor in castration-resistant prostate cancer patients treated with docetaxel therapy.

Low incidence of posttransplant lymphoproliferative disorder after allogeneic stem cell transplantation in patients with lymphoma treated with rituximab.

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.

[A Case of Subcutaneous Scrotal Metastasis from Primary Gastric Cancer].

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.

Risk Factors and Predictive Scoring System For Post-Transplant Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation.

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.

Interaction of platinum agents, cisplatin, carboplatin and oxaliplatin against albumin in vivo rats and in vitro study using inductively coupled plasma-mass spectrometory.

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.

[Successful treatment with lenalidomide-containing regimen of plasma cell leukemia accompanied by meningeal involvement].

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.