Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report

Background RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. Case presentation A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3 '-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. Conclusions We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production

A Case of Gingival Metastasis from Rectal Cancer in Which Immunohistochemistry and PET-CT Were Useful for the Diagnostic Procedure

A 50-year-old man was referred to our hospital because of a 2-month history of painful gingival swelling. Histopathological examination of the biopsy specimen showed a metastatic adenocarcinoma, and a chest-abdominopelvic CT showed multiple metastases in the lung, liver, and spleen, but failed to demonstrate the primary tumor. He had never complained of abdominal symptoms, and physical examination did not show any abnormality in the abdomen. However, immunohistochemical staining including caudal-related homeobox transcription factor (CDX-2) of the gingival tumor and PET-CT findings strongly suggested colorectal cancer as the origin. Colonoscopy then revealed a tumor in the rectum, and systemic chemotherapy was started immediately

Prophylactic Alpha Interferon Treatment Increases the Therapeutic Index of Oncolytic Vesicular Stomatitis Virus Virotherapy for Advanced Hepatocellular Carcinoma in Immune-Competent Rats

Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with intrinsic oncolytic specificity due to substantially attenuated antiviral responses in many tumors. We have recently reported that recombinant VSV vector can be used as an effective oncolytic agent to safely treat multifocal hepatocellular carcinoma (HCC) in the livers of immune-competent rats via hepatic artery infusion. When administered at doses above the maximum tolerated dose (MTD), however, the animals suffered from neurotoxicity and/or acute lethal hepatotoxicity. Since VSV is extremely sensitive to the antiviral actions of alpha/beta interferon (IFN-α/β) in normal cells, we tested if prophylactic treatment with rat IFN-α would enhance VSV safety without compromising treatment efficacy in tumor-bearing rats. We found that VSV retained its replication potential in human and rat HCC cells after preincubation with relatively high doses of rat and human IFN-α in vitro, and its MTD in tumor-bearing rats treated systemically with rat IFN-α at 66 IU/g body weight (BW), equivalent to a human IFN-α dose that is currently prescribed for patients with viral hepatitis, was elevated by more than 1/2 log unit. Furthermore, we demonstrate that intratumoral replication of VSV was not attenuated by administration of 66 IU/g BW rat IFN-α, as tumor response and survival advantage in VSV-treated rats in the presence or absence of rat IFN-α were equivalent. The results suggest that prophylactic rat IFN-α treatment elevates the therapeutic index of hepatic arterial VSV therapy for multifocal HCC in rats. Since human IFN-α is currently in clinical use, its prophylactic application should be considered in future clinical translational protocols for VSV-mediated oncolytic virotherapy as a novel therapeutic modality in patients with advanced HCC, as well as other types of cancer

Childhood socioeconomic disadvantage is associated with lower mortality in older Japanese men: the JAGES cohort study

Background: Childhood socioeconomic disadvantage has been previously linked to increased mortality risk in adulthood. However, most previous studies have focused on middle-aged adults in Western contexts. Here, we sought to examine the association between childhood socioeconomic status (SES) and mortality among healthy older Japanese adults. Methods: We conducted a 3-year follow-up of participants in the Japan Gerontological Evaluation Study (JAGES), a population-based cohort of 65- to 103-year-old Japanese adults. Childhood SES was assessed by survey at baseline. Mortality from 2010 to 2013 was analysed for 15 449 respondents (7143 men and 8306 women). Cox regression models were used to estimate hazard ratios (HR) for risk of death. Results: A total of 754 deaths occurred during the 3-year follow-up. Lower childhood SES was significantly associated with lower mortality in men, but not in women. Compared with men growing up in more advantaged childhood socioeconomic circumstances, the age-adjusted HR for men from low childhood SES backgrounds was 0.75 [95% confidence interval (CI): 0.56–1.00]. The association remained significant after adjustment for height, education, adult SES, municipalities of residence, health behaviours, disease status and current social relationships (HR = 0.64; 95% CI 0.47–0.87). This association was stronger among men aged 75 years or older, HR = 0.67 (95% CI: 0.47–0.95), compared with men aged 65–74 years, HR = 0.90 (95% CI: 0.54–1.51). Conclusions: Childhood socioeconomic disadvantage is associated with lower mortality among men aged 75 years or older, which may be due to selective survival, or alternatively to childhood physical training or postwar calorie restriction in this generation of Japanese males

A single institution experience of the treatment of pancreatic ductal carcinoma: The demand and the role of radiation therapy.

We aimed to demonstrate a single institution experience of treatment of pancreatic ductal carcinoma and to identify the role of radiation therapy. We assessed all patients who were diagnosed with pancreatic ductal carcinoma from January 2011 to December 2017. A total of 342 patients were enrolled. Thirteen, 131, 36, and 162 patients had stage I, II, III, and IV disease, respectively (UICC TNM, 7th edition). Among the patients with stages I-III disease, 94 underwent surgery, and the median overall survival (OS) was 33 months. Of patients with stages I-III disease who were not suitable for surgery, 58 patients received chemotherapy, and the median OS was 12 months. Among them, 17 patients received chemoradiotherapy added on chemotherapy and their OS was significantly better than that of patients who received chemotherapy alone. Of patients with stage IV disease, 111 received chemotherapy, and the median OS was 6 months. This study evaluated the demand, role, and outcome of each treatment modality and demonstrated a single institution experience of treatment of pancreatic ductal carcinoma. The demand and role of radiation therapy remained small; however, radiation therapy might have some importance as a local treatment