Association of RASSF1A, DCR2, and CASP8 Methylation with Survival in Neuroblastoma: A Pooled Analysis Using Reconstructed Individual Patient Data.

Neuroblastoma (NB) is a heterogeneous tumor affecting children. It shows a wide spectrum of clinical outcomes; therefore, development of risk stratification is critical to provide optimum treatment. Since epigenetic alterations such as DNA methylation have emerged as an important feature of both development and progression in NB, in this study, we aimed to quantify the effect of methylation of three distinct genes (RASSF1A, DCR2, and CASP8) on overall survival in NB patients. We performed a systematic review using PubMed, Embase, and Cochrane libraries. Individual patient data was retrieved from extracted Kaplan-Meier curves. Data from studies was then merged, and analysis was done on the full data set. Seven studies met the inclusion criteria. Methylation of the three genes had worse overall survival than the unmethylated arms. Five-year survival for the methylated arm of RASSF1A, DCR2, and CASP8 was 63.19% (95% CI 56.55-70.60), 57.78% (95% CI 47.63-70.08), and 56.39% (95% CI 49.53-64.19), respectively, while for the unmethylated arm, it was 93.10% (95% CI 87.40-99.1), 84.84% (95% CI 80.04-89.92), and 83.68% (95% CI 80.28-87.22), respectively. In conclusion, our results indicate that in NB patients, RASSF1A, DCR2, and CASP8 methylation is associated with poor prognosis. Large prospective studies will be necessary to confirm definitive correlation between methylation of these genes and survival taking into account all other known risk factors. (PROSPERO registration number CRD42017082264).

Prevalence of prolonged QT interval in patients with HCV-related chronic liver disease.

BACKGROUND: Hepatitis C virus (HCV) is a common disease in Egypt with a high socioeconomic burden and extra-hepatic manifestations as QT prolongation, but previous studies included mainly patients with advanced liver disease, so in this study, we aimed to delineate the prevalence of QT prolongation in early-stage HCV patients. RESULTS: The study included 874 HCV patients with early cirrhosis; in Child's class A, 57 (6.5%) patients had prolonged QT interval corrected (QTc). There was significant higher proportion of cirrhotic patients in the prolonged QTc group (31.6%) vs. in the normal QTc group (11.5%). QTc was 424.39 ± 36.6 vs. 411.51 ± 32.89 ms in cirrhotic and non-cirrhotic patients, respectively (P, 0.001). There was significant higher proportion of Fibrosis 4 (FIB-4) ≥ 1.45 score in the prolonged QTc (77.2%) vs. in the normal QTc group (56.8%) (P, 0.003). QTc interval was 417.76 ± 34.12 ms in patients with FIB-4 score ≥ 1.45 vs. 406.78 ± 31.95 ms in those with FIB-4 < 1.45 (P, < 0.001). FIB-4 score value of 2.108 predicted prolonged QTc with a sensitivity of 63.2% and a specificity of 64.5% (P, < 0.001). Twenty-four patients of long QTc group sent ECGs after HCV eradication, and 19 patients (79%) showed QTc normalization. CONCLUSIONS: HCV is associated with QTc prolongation even in patients with early chronic liver disease stages without significant fibrosis. Also, it is related to the degree of fibrosis and cirrhosis. At a cutoff value of 2.108, FIB-4 score can predict prolonged QTc. HCV eradication is associated with a high incidence of QTc normalization.

Correction to: Prevalence of prolonged QT interval in patients with HCV-related chronic liver disease.

Following publication of the original article [1], the authors reported that the family name of Mohamed El Kassas was incorrectly published as Mohamed ElKassas.

Neonates with cancer and causes of death; lessons from 615 cases in the SEER databases.

Neonatal tumors are rare with no standard treatment approaches to these diseases, and the patients experience poor outcomes. Our aim was to determine the distribution of cancers affecting neonates and compare survival between these cancers and older children. We analyzed SEER data (1973-2007) from patients who were younger than 2 years at diagnosis of malignancy. Special permission was granted to access the detailed (i.e., age in months) data of those patients. The Chi-square Log-rank test was used to compare survival between neonates (aged <1 month) and older children (>1 month to <2 years). We identified 615 neonatal cancers (454 solid tumors, 93 leukemia/lymphoma, and 68 CNS neoplasms). Neuroblastoma was the most common neonatal tumor followed by Germ cell tumors. The 5-year overall survival (OS) for all neonates was 60.3% (95% CI, 56.2-64.4). Neonates with solid tumors had the highest 5-year OS (71.2%; 95% CI, 66.9-75.5), followed by those with leukemia (39.1%; 95% CI, 28.3-49.9) or CNS tumors (15%; 95% CI, 5.4-24.6). Except for neuroblastoma, all neonatal tumors showed inferior outcomes compared to that in the older group. The proportion of neonates who died from causes other than cancer was significantly higher than that of the older children (37.9% vs. 16.4%; P < 0.0005). In general, the outcome of neonatal cancers has not improved over the last 34 years. The distribution of neonatal cancer is different than other pediatric age groups. Although the progress in neonatal and cancer care over the last 30 years, only death from noncancer causes showed improvement. Studying neonatal tumors as part of national studies is essential to understand their etiology, determine the best treatment approaches, and improve survival and quality of life for those patients.

Clinical Research Recession: Training Needs Perception Among Medical Students.

Clinical research is an integrated part of medical education. There is a noticeable decrease in the number of physician-scientists in developing countries, which is reflected by a decrease in research output and publications from these countries. We conducted a survey aiming to identify the gaps in clinical research training from the perspective of medical students. The results can be used to customize future clinical research trainings. The survey tool was divided into six modules which represent the cornerstones of clinical research based on similar surveys done for the same purpose. For each module, questions covered the perceived knowledge of its aspects and how much relevant the responder thought it was to clinical research. Five hundred one candidates have filled the survey. Evidence-based medicine (EBM) had the highest knowledge score of 2.20/4, while "clinical trials execution" knowledge got the lowest score of 1.64/4. Responders perceived EBM as the most relevant aspect of clinical research (3.39/4), while research ethics received the lowest score 3.18/4. "Clinical trials execution" had the largest gap of a difference calculated as 1.60, while EBM had the lowest gap of 1.20. More attention must be paid to clinical research training for medical students in developing countries. These trainings have to be customized to focus on clinical trial execution, research methodology, and biostatistics. In parallel, awareness campaigns targeted toward the medical community emphasizing the importance of the ethics as an aspect of clinical research should be established.

Incidence of orbital, conjunctival and lacrimal gland malignant tumors in USA from Surveillance, Epidemiology and End Results, 1973-2009.

AIM: To determine the types and incidence of tumors affecting the orbit, conjunctiva and lacrimal glands and to study the trend line of these tumors in the United States from 1973 to 2009. METHODS: We used the publicly available Surveillance, Epidemiology and End Results (SEER) database registries to determine the incidence rates. Age was adjusted to the 2000 US Standard Population. Patients were stratified according to age group, gender, race and histological grouping of tumor lesions. Three age groups were defined: 0-19, 20-49 and ≥50y. Annual percentage changes were calculated to examine trends. RESULTS: The overall age adjusted incidence rate was 3.39 (95%CI: 3.27-3.52) per million person-years. The tumors were more prevalent in age group ≥50 counting 9.51 (95%CI: 9.11-9.92) per million person-years. Most of the soft tissue sarcomas occurred in the young age with incidence rate of 0.35 (95%CI: 0.28-0.42) per million person-years. Lymphomas were the dominant subtype in the adult population with incidence rate of 5.74 (95%CI: 5.43-6.06) per million person-years. Incidence rates were higher in males than females with an overall rate ratio of 1.31 (95%CI: 1.21-1.41) mainly caused by the increase in carcinoma subtypes. White race had a higher tumor incidence with a rate ratio of 1.47(95%CI: 1.25-1.73) driven by the higher incidence of most histological subtypes. Orbital tumors showed a higher incidence rate followed by conjunctival and lacrimal gland tumors with incidence rates of 1.59, 1.37 and 0.43 per million person-years respectively. The trend line of overall incidence of tumors showed a significant increase (APC=3.11, 95%CI: 2.61-3.61) mainly due to increase of lymphomas. This increase was higher than the increase of lymphomas at other sites. CONCLUSION: Orbital, conjunctival and lacrimal gland malignant tumors differ among children and adults. Over the years there has been a noticeable increase in incidence rates of orbital and lacrimal gland tumors mainly caused by an increase in lymphomas and an apparent increase due to advances in diagnostic techniques. ICD-O-3 topographical coding should be improved to consider the different orbital bones and ocular structures.

Orbital tumors in USA: difference in survival patterns.

INTRODUCTION: There is a wide range of tumors affecting the orbital adnexa. Key such tumors include lymphomas, carcinomas, melanomas and rhabdomyosarcomas. Several studies have proposed that these histological subtypes differ in their survival outcomes. In this study we aim to describe the difference in survival outcomes between such subtypes. METHODS: The SEER database was used to gather patient information. All 18 SEER registries were used. Patients diagnosed from 1996 to 2005 were included in the analysis. Observed five-year survival rate was calculated using the SEER*Stat software version 8.1.2. Data were extracted into IBM SPSS version 20 to generate Kaplan Meier curve for each group. RESULTS: There were 2180 patients in the SEER databases who met the selection criteria. Lymphomas were the most common histology in adults. The overall five-year observed survival for all lymphoma patients was 75.9% (95% CI: 73.7-78.1). There was statistically significant difference between observed survival rates of lymphoma subtypes. Carcinomas were the second most common tumors. Their five-year observed survival rate in our study was 60.4%. There was no statistically significant difference between carcinoma subtypes' observed survival rates in the 20-49 age group, while, in the older age group, the difference was found to be statistically significant. Rhabdomyosarcomas were the most common tumors in children. The overall five-year observed survival rate for rhabdomyosarcomas patients was 89.8%. There was no statistically significant difference between observed survival rates of rhabdomyosarcomas subtypes. There was no statistically significant difference between relative survival rates according to gender and treatment received except within melanomas. CONCLUSION: In adults, lymphomas have better survival rates than carcinomas. Whereas the lymphoma subtype can be used as a determinant prognostic factor in any age, the carcinoma subtype can be used as such a determinant in older age groups only. In children, rhabdomyosarcomas are the predominant tumors affecting the orbital adnexa. Further studies are needed to determine if the difference between embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma observed survival rates are statistically significant.