Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and KrasG12D mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log2 OR = 1.65, P = 3.08 × 10-3). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67+ cells increased significantly in pancreatic organoids derived from Galc knockout KrasG12D mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC.

The effect of long working hours on cerebrovascular and cardiovascular disease; A case-crossover study.

BACKGROUND: This study investigated the relationship between weekly working hours and the occurrence of cerebro-cardiovascular diseases using a case-crossover study design. METHODS: We investigated average working hours during the 7 days before the onset of illness (hazard period) and average weekly working hours between 8 days and 3 months before the onset of cerebro-cardiovascular diseases (control period) for 1,042 cases from the workers' compensation database for 2009. RESULTS: Among all subjects, the odds ratio by conditional logistic regression for the risk of cerebro-cardiovascular diseases with a 10 hr increase in average weekly working hours was 1.45 (95% confidence interval [CI]: 1.22-1.72), a significant association. CONCLUSIONS: An increase in average weekly working hours may trigger the onset of cerebro-cardiovascular disease. Am. J. Ind. Med. 60:753-761, 2017. © 2017. Wiley Periodicals, Inc.

Assessment of objective responses in thymic epithelial tumors using ITMIG modified criteria.

OBJECTIVES: Pleural metastases of thymic epithelial tumors (TETs) are relatively common, and this unique growth pattern makes the use of RECIST (response evaluation criteria in solid tumors) response criteria difficult. To standardize tumor measurement in TETs, the International Thymic Malignancy Interest Group (ITMIG) has proposed newly developed criteria. We compared evaluation of objective response between ITMIG modified criteria and RECIST 1.1 in patients with TET treated with systemic chemotherapy. PATIENTS AND METHODS: We retrospectively evaluated the tumor response of 40 patients with unresectable TET who were enrolled in a phase II clinical trial using ITMIG modified criteria, and compared the findings with prospectively evaluated tumor response assessed by RECIST 1.1. Agreement analyses for the response at each time point, including overall response and declaring progression, were performed and the time to progression (TTP) was also assessed using the two different measurements. RESULTS: The overall response rate assessed by the two methods did not differ significantly, with kappa value of 0.897. Agreement analysis for declaring progression of disease (PD) at the date of RECIST 1.1-designated PD showed 95% concordance rate with ITMIG modified criteria (p=1.000, kappa index=0.875). The median TTP according to RECIST 1.1 and ITMIG modified criteria was 8.4 and 7.9 months (p=0.983), respectively. Validation with another cohort of 27 TET patients treated with neoadjuvant chemotherapy also showed a 96% concordance rate in overall response between the two different criteria. CONCLUSIONS: ITMIG modified criteria showed a high concordance rate with RECIST 1.1 criteria in response assessment of TETs. Given the rarity of TETs, further evaluation of ITMIG modified criteria in a larger number of patients will be required before their implementation in clinical trials.

The Impact of Molecularly Targeted Treatment on Direct Medical Costs in Patients with Advanced Non-small Cell Lung Cancer.

PURPOSE: To investigate the impact of targeted treatment on direct medical costs of patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Medical records of 108 stage IIIB/IV NSCLC patients treated in Seoul National University Hospital between 2003 and 2009, were reviewed to collect medical resources utilization data from the diagnosis of stage IIIB/IV NSCLC to the end of active anti-cancer treatment. The direct medical costs were calculated by multiplying the number of medical resources used by the unit price. All costs were expressed in US dollars for each patient. RESULTS: The mean total direct medical costs were $34,732 (standard deviation, 21,168) in the study cohort. The mean total direct medical costs were higher in epidermal growth factor receptor ( EGFR ) mutation (EGFR MT)-positive patients than EGFR wild-type (EGFR WT) patients ($41,403 vs. $30,146, p=0.005). However, the mean monthly direct medical costs did not differ significantly between EGFR MT-positive patients and EGFR WT patients ($2,120 vs. $2,702, p=0.119) because of the longer duration of active anti-cancer treatment in EGFR MT-positive patients. This discrepancy was mainly attributable to EGFR MT-positive patients' lower non-chemotherapy costs ($948 vs. $1,522, p=0.007). The total and monthly direct medical costs of ALK fusion-positive patients who did not receive ALK inhibitors did not differ from WT/WT patients. CONCLUSION: This study suggests that the availability of targeted agents for EGFR MT-positive patients lowers the mean monthly medical costs by prolonging survival and diminishing the use of other medical resources, despite the considerable drug costs.