Paired comparisons of mutational profiles before and after brachytherapy in asian uveal melanoma patients.

Uveal melanoma(UM) is the most common primary intraocular malignancy in adults. However, the incidence of UM in Asia is 10 to 20 times less than in Western populations. Therefore, for the first time, we report our whole exome sequencing (WES) data analysis to discover differences in the molecular features of Asian and Western UM, and to determine the disparities between the primary tumor before brachytherapy and enucleated samples after brachytherapy. WES of 19 samples (13 primary tumors, 5 enucleation samples after brachytherapy, and 1 liver metastasis) from 13 patients diagnosed with UM and treated between 2007 and 2019 at the Yonsei University Health System (YUHS) were analyzed using bioinformatics pipelines. We identified significantly altered genes in Asian UM and changes in mutational profiles before and after brachytherapy using various algorithms. GNAQ, BAP1, GNA11, SF3B1 and CYSLTR2 were significantly mutated in Asian UM, which is similar that reported frequently in previous Western-based UM studies. There were also similar copy number alterations (M3, 1p loss, 6p gain, 8q gain) in both groups. In paired comparisons of the same patients, DICER1 and LRP1B were distinctly mutated only in tumor samples obtained after brachytherapy using rare-variant association tests (P = 0.01, 0.01, respectively). The mutational profiles of Asian UM were generally similar to the data from previous Western-based studies. DICER1 and LRP1B were newly mutated genes with statistical significance in the regrowth samples after brachytherapy compared to the primary tumors, which may be related to resistance to brachytherapy.

Utilization patterns of insulin for patients with type 2 diabetes from national health insurance claims data in South Korea.

Type 2 diabetes mellitus (T2DM) is a chronic disease that requires long-term therapy and regular check-ups to prevent complications. In this study, insurance claim data from the National Health Insurance Service (NHIS) of Korea were used to investigate insulin use in T2DM patients according to the economic status of patients and their access to primary physicians, operationally defined as the frequently used medical care providers at the time of T2DM diagnosis. A total of 91,810 participants were included from the NHIS claims database for the period between 2002 and 2013. The utilization pattern of insulin was set as the dependent variable and classified as one of the following: non-use of antidiabetic drugs, use of oral antidiabetic drugs only, or use of insulin with or without oral antidiabetic drugs. The main independent variables of interest were level of income and access to a frequently-visited physician. Multivariate Cox proportional hazards analysis was performed. Insulin was used by 9,281 patients during the study period, while use was 2.874 times more frequent in the Medical-aid group than in the highest premium group [hazard ratio (HR): 2.874, 95% confidence interval (CI): 2.588-3.192]. Insulin was also used ~50% more often in the patients managed by a frequently-visited physician than in those managed by other healthcare professionals (HR: 1.549, 95% CI: 1.434-1.624). The lag time to starting insulin was shorter when the patients had a low income and no frequently-visited physicians. Patients with a low level of income were more likely to use insulin and to have a shorter lag time from diagnosis to starting insulin. The likelihood of insulin being used was higher when the patients had a frequently-visited physician, particularly if they also had a low level of income. Therefore, the economic statuses of patients should be considered to ensure effective management of T2DM. Utilizing frequently-visited physicians might improve the management of T2DM, particularly for patients with a low income.

Clinical necessity of the immunohistochemical reassessment of para-aortic lymph nodes in resected pancreatic ductal adenocarcinoma.

Para-aortic lymph node (PALN) metastasis is widely regarded as a systemic disease in cancer. Undetected PALN micrometastases during routine hematoxylin and eosin (HE) staining may be a cause of poor prognosis following a potentially curative pancreatectomy for pancreatic cancer. In the present study, paraffin-embedded PALN tissue blocks from 99 patients who underwent a pancreatectomy were re-evaluated by immunohistochemical staining using cytokeratin (CK)-19. Patients with PALN metastasis were summarized according to the clinicopathological data. A total of 484 PALNs (median, 4.9 nodes per patient; range, 1-19) were evaluated. PALN metastases were revealed in eight patients (8.1%) by routine HE staining of frozen section biopsies and in one patient (1.0%) by HE staining of a permanent section. Only one patient (1.0%) demonstrated micrometastasis by IHC; this patient did not display any adverse pathological characteristics and had a relatively favorable survival period of 41 months. The present study concluded that an additional reassessment for micrometastasis in PALNs using CK-19 immunohistochemistry (IHC) is not a viable method for determining the survival outcome. A careful examination of a frozen section biopsy is sufficient for attempting curative surgery.

Molecular markers predict distant metastases after adjuvant chemoradiation for rectal cancer.

PURPOSE: The outcomes of adjuvant chemoradiation for locally advanced rectal cancer are nonuniform among patients with matching prognostic factors. We explored the role of molecular markers for predicting the outcome of adjuvant chemoradiation for rectal cancer patients. METHODS AND MATERIALS: The study included 68 patients with stages II to III rectal adenocarcinoma who were treated with total mesorectal excision and adjuvant chemoradiation. Chemotherapy based on 5-fluorouracil and leucovorin was intravenously administered each month for 6-12 cycles. Radiation therapy consisted of 54 Gy delivered in 30 fractions. Immunostaining of surgical specimens for COX-2, EGFR, VEGF, thymidine synthase (TS), and Raf kinase inhibitor protein (RKIP) was performed. RESULTS: The median follow-up was 65 months. Eight locoregional (11.8%) and 13 distant (19.1%) recurrences occurred. Five-year locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates for all patients were 83.9%, 78.7%, 66.7%, and 73.8%, respectively. LRFFS was not correlated with TNM stage, surgical margin, or any of the molecular markers. VEGF overexpression was significantly correlated with decreased DMFS (P=.045), while RKIP-positive results were correlated with increased DMFS (P=.025). In multivariate analyses, positive findings for COX-2 (COX-2+) and VEGF (VEGF+) and negative findings for RKIP (RKIP-) were independent prognostic factors for DMFS, DFS, and OS (P=.035, .014, and .007 for DMFS; .021, .010, and <.0001 for DFS; and .004, .012, and .001 for OS). The combination of both COX-2+ and VEGF+ (COX-2+/VEGF+) showed a strong correlation with decreased DFS (P=.007), and the combinations of RKIP+/COX-2- and RKIP+/VEGF- showed strong correlations with improved DFS compared with the rest of the patients (P=.001 and <.0001, respectively). CONCLUSIONS: Molecular markers can be valuable in predicting treatment outcome of adjuvant chemoradiation for rectal cancer patients.

Cytogenetics and prognosis for uveal melanoma in Korean patients.

PURPOSE: To determine the rate of mortality for uveal melanoma in the Korean population and assess whether it correlates with cytogenetic data, and clinical and histopathological factors. METHODS: A retrospective review of medical files from 33 uveal melanoma patients who underwent enucleation at Yonsei University, Seoul, Korea, between January, 1994 and December, 2009 was performed. Dual-colour fluorescence in situ hybridization was performed using centromeric probes for chromosome 3 and 8 in archived patient tissues. RESULTS: The mean age of patients was 53.2 years (range; 29-78), and the mean largest basal diameter was 11.8 mm (range; 6.0-18.1). Of the 20 tissue blocks with available cytogenetic data, there was monosomy 3 in seven (35%) and polysomy 8 in four (20%). The presence of monosomy 3 (p < 0.001), polysomy 8 (p < 0.001), ciliary body involvement (p < 0.001), a mitotic rate ≥5/40 high-power fields (p = 0.006), closed extravascular matrix loop (p = 0.025), large basal tumour diameter (p = 0.029) and epithelioid cellularity (p = 0.038) predicted melanoma-related mortality. The median time from enucleation to liver metastasis was 16 months (range; 10-70), and the median survival after metastasis was 5 months (range; 1-9). The Kaplan--Meier survival curve estimated the metastatic death rate to be 22% for 5 years and 30% for 10 years. CONCLUSIONS: Korean patients with uveal melanoma are younger and appear to exhibit no worse prognosis than Caucasian. Cytogenetic abnormality of chromosome 3 and 8 highly predicted metastatic death.

Malakoplakia of the kidney extending to the descending colon in a patient with secondary adrenal insufficiency: a case report.

Malakoplakia is an uncommon but distinctive type of chronic granulomatous inflammation that occurs most commonly in the genitourinary tract, especially the urinary bladder. Most patients have associated conditions characterized by some degree of immunosuppression, as seen in solid-organ transplants, autoimmune diseases requiring steroid use, chemotherapy, chronic systemic diseases, alcohol abuse and poorly controlled diabetes. We report an unusual case of the renal malakoplakia that involved the perirenal space, extending to the descending colon in a 65-year-old Korean woman with secondary adrenal insufficiency and diabetes mellitus.

Retroperitoneal giant liposarcoma.

Retroperitoneal liposarcoma is an infrequent, locally aggressive malignancy. We report two cases of huge retroperitoneal liposarcomas. The presence of a palpable abdominal mass was a common symptom of the two patients. Preoperative imaging study showed huge retroperitoneal tumors. Both patients underwent complete surgical resections, and a negative microscopic margin was achieved in both cases. The histopathologic diagnosis was a well-differentiated retroperitoneal liposarcoma. Neither of the two patients developed a recurring tumor during the 1.5 years of follow-up.

Robot-assisted laparoscopic removal of extraluminal leiomyoma confused with urachal cyst.

Pedunculated extra-luminal leiomyoma is a rare solid tumor. We present a case of a 20-year-old Caucasian woman with a painful pedunculated extraluminal mass located on the bladder dome and associated with dysuria. She underwent robot-assisted laparoscopic resection, and the histological findings confirmed a leiomyoma.

Pyrrolidine dithiocarbamate and zinc inhibit proteasome-dependent proteolysis.

Proteasomes play important roles in a variety of cellular processes such as cell cycle progression, signal transduction and immune responses. Proteasome activity is important in maintaining rapid turnover of short-lived proteins, as well as preventing accumulation of misfolded or damaged proteins. Alteration in ubiquitin-proteasome function may be detrimental to its crucial role in maintaining cellular homeostasis. Here, we have found that treatment of pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, resulted in the accumulation of several proteasome substrates including p53 and p21 in HeLa cells. The PDTC effect was due to an extended half-life of these proteins through the mobilization of zinc. PDTC and/or zinc also increased fluorescence intensity of Ub(G76V)-GFP fusion protein that is degraded rapidly by the ubiquitin-proteasome system. Treatment of cells with zinc induced formation of ubiquitinated inclusions in the centrosome, a histological marker of proteasome inhibition. Western blotting showed zinc-induced increase in laddering bands of polyubiquitin-conjugated proteins. In vitro study, zinc inhibited the ubiquitin-independent proteasomal degradations of p21 and alpha-synuclein. These results suggest that zinc may modulate cell functions through its action on the turnover of proteins that are susceptible to proteasome-dependent proteolysis.