In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies (MCL,HCL, B-CLL)

A replication defective herpes simplex virus-1 was evaluated as a therapeutic vector. Mantle cell lymphoma (MCL), hairy cell leukemia (HCL), and B-cell chronic lymphocytic leukemia (B-CLL) were chosen because leukemic cells were collectable from peripheral bloods in these diseases. Cells from six MCL, one HCL, and nine B-CLL were infected in vitro with T0Z.1 at 3 multiplicity of infection (MOI). Herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV)-mediated suicide gene therapy showed 14.7% of mean tumor killing against leukemic B-cell malignancies. The mean tumor-killing effects were 8.7 and 17.1% in MCL and B-CLL, respectively. The effect against HCL was 29%. The study indicates that herpes simplex virus (HSV)-based gene therapy might be an effective strategy.     

Werner interacting protein 1 promotes binding of Werner protein to template-primer DNA

Werner interacting protein 1 (WRNIP1) that is highly conserved from Escherichia coli to human was originally identified as a protein that interacts with the Werner syndrome responsible gene product (WRN). Here, human WRNIP1 and WRN are shown to bind to template-primer DNA, and WRNIP1, but not WRN, requires ATP for DNA binding. Under conditions of a limiting amount of WRN, WRNIP1 facilitated binding of WRN to DNA in a dose-dependent manner. However, WRNIP1 did not stimulate the DNA helicase activity of WRN, and WRN displaced pre-bound WRNIP1 from DNA. Functional relationships between WRNIP1 and WRN will be discussed.     

Factors predicting efficacy and adverse effects of enzalutamide in Japanese patients with castration-resistant prostate cancer: results of retrospective multi-institutional study

Background

We aimed to evaluate the factors predicting efficacy and adverse effects of enzalutamide in patients with castration-resistant prostate cancer.

Methods

We retrospectively evaluated data on 345 patients who had received enzalutamide for castration-resistant prostate cancer in 20 hospitals (Kyoto University Hospital and other satellite hospitals). Cox proportional hazards regression analysis was performed to identify factors predicting prostate-specific antigen (PSA) progression after enzalutamide treatment and logistic regression analysis for those associated with development of adverse effects.

Results

PSA titers decreased by >50 % in 197 patients (57 %). The median PSA progression free survival was 163 days. Gleason score >8 (HR 2.078, 95 % CI 1.37–3.153, P = 0.00058), performance status ≥1 (HR 2.292, 95 % CI 1.463–3.592, P = 0.000296), presence of bone metastasis (HR 1.774, 95 % CI 1.019–3.090, P = 0.0429), visceral metastasis (HR 2.127, 95 % CI 1.215–3.722, P = 0.00823), previous steroid treatment (HR 1.780, 95 % CI 1.207–2.626, P = 0.00361) and docetaxel treatment (HR 1.602, 95 % CI 1.051–2.442, P = 0.0284) significantly predicted the efficacy of enzalutamide. Adverse effects, including fatigue or appetite loss, occurred in 169 patients (49 %), 48 (18 %) of whom stopped enzalutamide. Age >75 years (HR 1.980, 95 % CI 1.270–3.09, P = 0.00246) and lower enzalutamide dose (HR 0.437, 95 % CI 0.255–1.270, P = 0.00249) were significantly associated with development of adverse effects.

Conclusions

Enzalutamide treatment is effective in patients with castration-resistant prostate cancer with low Gleason scores, good performance status, without bone or visceral metastasis and no prior steroid or docetaxel treatment. Lower doses of enzalutamide decrease the incidence of adverse effects, especially in older patients.

     

Prognostic significance of high-resolution CT findings in small peripheral adenocarcinoma of the lung: a retrospective study on 64 patients

OBJECTIVE: We studied the prognostic importance of high-resolution CT (HRCT) findings in lung adenocarcinomas. PATIENTS AND METHODS: HRCT findings (lesion size, percentage of ground-glass opacity (GGO) areas of lesion, and presence or absence of lobulation, coarse spiculation, air space, pleural tag, and multiplicity of lesion), clinical data (age and surgical method), and pathologic findings (tumor subtypes and presence or absence of nodal metastasis) in 64 consecutive patients with 64 peripheral adenocarcinomas of 20 mm or less (mean, 13 mm), including 36 women and 28 men with a mean age of 64 years were analyzed and correlated with survival of the patients using Kaplan-Meier method and stepwise Cox proportional hazards modeling. Follow-up periods of the patients ranged from 6 to 45 months (mean, 22 months). Tumors were classified into six subtypes (types A-F) according to tumor growth patterns defined by Noguchi et al. RESULTS: Six (9%) of the 64 patients died of lung cancer. In univariate analyses, a significant difference was noted for lesion size (P=0.043), the percentage of GGO areas (P=0.005), and tumor subtypes (P=0.006). Lesion size of <15 mm (n=35), a lesion with GGO areas of >57% (n=36), and type A (n=16) or type B adenocarcinomas (n=16) indicated a significantly better survival. In multivariate analyses using these three parameters as independent variables, the percentage of GGO areas was the only significant independent factor for survival (P=0.044, relative risk=0.95). CONCLUSION: GGO areas measured on HRCT may have an independent prognostic significance of small adenocarcinomas of the lung.     

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.     

Role of an Atypical Cadherin Gene,Cdh23 in Prepulse Inhibition,and Implication of CDH23 in Schizophrenia

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.     

Large-cell neuroendocrine carcinoma of the skin, with lymphoid stroma

We report two cases of a large-cell neuroendocrine carcinoma of the skin as a distinct histological category. The patients are a 63-year-old woman with a 7-mm reddish round nodule on her nose for 4 months, and a 95-year-old man with several hemorrhagic nodules on the external ear for 28 months. The first patient had two positive sentinel lymph nodes. The tumors from both patients consisted of islands of pleomorphic large cells within a lymphoid stroma.