Promoter hypermethylation of CCNA1, RARRES1, and HRASLS3 in nasopharyngeal carcinoma

In search for putative tumor suppressor genes critical of nasopharyngeal carcinoma (NPC), we analyzed the available information from the expression profiling in conjunction with the comprehensive alleotyping published data relevant to this malignancy. Integration of this information suggested eight potential candidate tumor suppressor genes, CCNA1, HRASLS3, RARRES1, CLMN, EML1, TSC22, LOH11CR2A and MCC. However, to confirm the above observations, we chose to investigate if promoter hypermethylation of these candidate genes would be one of the mechanisms responsible for the de-regulation of gene expression in NPC in addition to the loss of genetic materials. In this study, we detected consistent hypermethylation of the 5' element of CCNA1, RARRES1, and HRASLS in NPC tissues with prevalence of 48%, 51%, and 17%, respectively. Moreover, we found a similar profile of promoter hypermethylation in primary cultured NPC cells but none in normal nasopharyngeal epithelium or leukocytes, which further substantiate our hypothesis. Our data indicate that CCNA1, RARRES1, and HRASLS3 may be the putative tumor suppressor genes in NPC.     

The role of SHP-1 promoter 2 hypermethylation detection of lymph node micrometastasis in resectable stage I non-small cell lung cancer as a prognostic marker of disease recurrence

Background

Despite adequate surgical management of stage I non-small cell lung cancer (NSCLC), many patients still relapse. Nodal micrometastases which cannot be detected by the standard hematoxylin and eosin (H&E) method are the postulated mechanism. We conducted a study of an epithelial-specific methylation marker, SHP-1 promoter 2 (SHP1P2) methylation, as a potential molecular marker to determine its association with a high risk of disease relapse.

Material and method

Lymph nodes from stage II–IIIA NSCLC patients were examined to explore the potential role of SHP1P2 methylation in detecting metastatic carcinoma according to H&E staining. Further study was done in lymph nodes from stage I NSCLC patients who underwent curative resection and follow-up at The King Chulalongkorn Memorial Hospital, Bangkok, Thailand. No adjuvant treatment was given, according to the standard treatment in that stage. Patients who relapsed within 40 months after resection were defined as high risk.

Results

The nodal SHP1P2 methylation level from stage II–IIIA NSCLC patients was significantly higher in the metastasis group, median 674 [0–3536] ng, compared with the no metastasis group, median 230 [0–3832] ng (p = 0.004). One-hundred and ninety-eight lymph nodes from stage I NSCLC patients were analyzed, including hilar and mediastinal nodes. With a median follow-up period of 65 [46–109] months, high SHP1P2 methylation levels of more than 140 ng in hilar lymph nodes were associated with early relapse, with sensitivity and specificity of 85 and 54 %, respectively (hazard ratio 5.3; 95 % confidence interval 5.0–5.6; p < 0.0001).

Conclusion

A high level of SHP1P2 methylation of hilar lymph nodes from stage I NSCLC patients is associated with early relapse of disease.     

Central nervous system lymphoma and Epstein-Barr virus in immunocompetent patients in Thailand

A series of 11 apparently immunocompetent patients with primary non-Hodgkin's lymphoma of the central nervous system (NHL-CNS) together with six patients with systemic lymphoma involving the spinal cord and/or brain were studied for immunophenotyping and the presence of Epstein-Barr virus (EBV). Immunohistochemistry and polymerase chain reaction (PCR) were performed on paraffin-embedded tissues. Nine of 11 primary NHL-CNS and all six secondary CNS lesions were of B cell origin. The EBV sequences were detected in six primary tumors and four systemic lesions by PCR while the immuno-histochemical marker for the EBV-latent membrane protein was positive in five primary lesions and three secondary neoplasms. Our results suggest that the association of EBV and NHL-CNS is not only restricted to patients with immunosuppression but that it includes a broad spectrum of conditions in which this relationship occurs in patients without immunodeficiency. The mortality rate is high particularly in patients with EBV-associated NHL-CNS.     

Depot-medroxyprogesterone acetate (dmpa) and risk of edometrial cancer

This is a report of results from a case-control study of the relationship of the long-acting progestational contraceptive, depot-medroxyprogesterone acetate (DMPA) to risk of endometrial carcinoma. Prior use of DMPA and information on known and suspected risk factors for endometrial cancer were ascertained in personal interviews with 122 women with histologically confirmed disease and 939 controls selected from 2 hospitals in Bangkok and 1 in Chiang Mai, Thailand. Based on 3 exposed cases and 84 exposed controls, the relative risk of endometrial cancer was estimated to be 0.21 (95% confidence interval = 0.06,0.79) in women who had ever used DMPA (but who had not first used DMPA in the year prior to diagnosis). All 3 exposed cases had also received estrogens pre-menopausally. Exposure to such estrogens enhanced risk of endometrial cancer and reduced the apparent protective effect of DMPA. Although based on small numbers of exposed women, the protective effect of DMPA appeared to last for at least 8 years after cessation of use. The reduction in risk of endometrial cancer is at least as great for DMPA as for combined oral contraceptives.     

Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation

Overexpression of the type II transmembrane serine protease matriptase is a highly consistent feature of human epithelial tumors. Here we show that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1. Modest orthotopic overexpression of matriptase in the skin of transgenic mice caused spontaneous squamous cell carcinoma and dramatically potentiated carcinogen-induced tumor formation. Matriptase-induced malignant conversion was preceded by progressive interfollicular hyperplasia, dysplasia, follicular transdifferentiation, fibrosis, and dermal inflammation. Furthermore, matriptase induced activation of the pro-tumorigenic PI3K-Akt signaling pathway. This activation was frequently accompanied by H-ras or K-ras mutations in carcinogen-induced tumors, whereas matriptase-induced spontaneous carcinoma formation occurred independently of ras activation. Increasing epidermal HAI-1 expression completely negated the oncogenic effects of matriptase. The data implicate dysregulated matriptase expression in malignant epithelial transformation.     

Significance of preoperative hematologic scoring in predicting death among patients with non-metastatic renal cell carcinoma undergoing nephrectomy

PurposeNeutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are hematologic scoring and indicators of the systemic inflammatory response. The increasing use of NLR and PLR have been associated with poor outcome in various types of malignancy. We evaluated the effect of NLR and PLR on survival outcomes of nonmetastatic renal cell carcinoma (RCC).Materials and methodsWe retrospectively review 150 patients who had undergone nephrectomy for nonmetastatic RCC between 2006 and 2016. Cancer specific survival (CSS) was assessed using Kaplan–Meier method and compared using log-rank test. We applied univariate and multivariate Cox regression model to analyze the association of NLP and PLR with clinical outcome.ResultsAt median follow up of 33 months, 45 patients had died. High PLR (>100) was an independent prognostic hematologic marker for CSS (hazard ratio [HR] 2.61, 95% confidence interval [CI],1.08–6.31; P = 0.034). Univariate analysis identified elevated NLR (p = 0.005), and anemia (p = 0.023) were significantly associated with CSS.ConclusionElevated PLR is a strong hematologic prognosis factor in term of survival for patients with nonmetastatic RCC undergoing nephrectomy with curative intent. The PLR is an easily obtained biomarker which is useful for preoperative risk stratification.     

Randomized trial of two different doses of pyridoxine in the prevention of capecitabine-associated palmar-plantar erythrodysesthesia

Aim: The aim of the present study was to compare the efficacy of 200 mg versus 400 mg daily of pyridoxine in preventing or delaying the onset of palmar‐plantar erythrodysesthesia (PPE) in capecitabine‐treated patients. Methods: Patients with histologically confirmed breast cancer or colorectal cancer receiving single agent capecitabine started at 2000 to 2500 mg/m² daily from day 1 to 14 every 3 weeks were randomly assigned to receive 200 mg or 400 mg daily of pyridoxine for PPE prophylaxis. The primary endpoint was the reduction of incidence of grade 2 or greater PPE. Secondary endpoints were reduction of severe PPE and prolongation of time to development of grade 2 or greater PPE. Results: There were 56 patients in this study. The baseline characteristics were generally similar in both groups. The high dose arm had less PPE than the low dose arm (11 of 28 or 39% vs 20 of 28 or 71%, relative risk = 0.26 [0.08, 0.79], P = 0.031). Grade III PPE developed in 3 of 28 (10.7%) versus none in patients receiving 200 mg versus 400 mg pyridoxine, respectively (relative risk 2.12 [1.594, 2.819], P = 0.24). High dose pyridoxine had a longer time to development of grade 2 or greater PPE compared to the low dose arm, 87 days versus 62 days. The 400 mg pyridoxine group had, however, a worsened tumor response and tended to have greater tumor treatment failure and shorter time to treatment failure. Conclusion: With the limitation of sample size in this study, there was a trend to improve PPE incidence and time to event with a higher dose of pyridoxine. Further validation of these results in a larger population is warranted.