Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma.

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations.

BMPR1B gene in brachydactyly type 2-A family with de novo R486W mutation and a disease phenotype.

BACKGROUND: Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients' phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene. METHODS: We employed next-generation sequencing to identify mutations in culpable genes. RESULTS AND CONCLUSION: In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients' family revealed that the mutation occurred de novo in the proband and was transmitted to his 26-month-old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult.

Author Correction: Risk factors for serious morbidity, prolonged length of stay and hospital readmission after laparoscopic appendectomy - results from Pol-LA (Polish Laparoscopic Appendectomy) multicenter large cohort study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Risk factors for serious morbidity, prolonged length of stay and hospital readmission after laparoscopic appendectomy - results from Pol-LA (Polish Laparoscopic Appendectomy) multicenter large cohort study.

Laparoscopic appendectomy (LA) for treatment of acute appendicitis has gained acceptance with its considerable benefits over open appendectomy. LA, however, can involve some adverse outcomes: morbidity, prolonged length of hospital stay (LOS) and hospital readmission. Identification of predictive factors may help to identify and tailor treatment for patients with higher risk of these adverse events. Our aim was to identify risk factors for serious morbidity, prolonged LOS and hospital readmission after LA. A database compiled information of patients admitted for acute appendicitis from eighteen Polish and German surgical centers. It included factors related to the patient characteristics, peri- and postoperative period. Univariate and multivariate logistic regression models were used to identify risk factors for serious perioperative complications, prolonged LOS, and hospital readmissions in acute appendicitis cases. 4618 laparoscopic appendectomy patients were included. First, although several risk factors for serious perioperative complications (C-D III-V) were found in the univariate analysis, in the multivariate model only the presence of intraoperative adverse events (OR 4.09, 95% CI 1.32-12.65, p = 0.014) and complicated appendicitis (OR 3.63, 95% CI 1.74-7.61, p = 0.001) was statistically significant. Second, prolonged LOS was associated with the presence of complicated appendicitis (OR 2.8, 95% CI: 1.53-5.12, p = 0.001), postoperative morbidity (OR 5.01, 95% CI: 2.33-10.75, p < 0.001), conversions (OR 6.48, 95% CI: 3.48-12.08, p < 0.001) and reinterventions after primary procedure (OR 8.79, 95% CI: 3.2-24.14, p < 0.001) in the multivariate model. Third, although several risk factors for hospital readmissions were found in univariate analysis, in the multivariate model only the presence of postoperative complications (OR 10.33, 95% CI: 4.27-25.00), reintervention after primary procedure (OR 5.62, 95% CI: 2.17-14.54), and LA performed by resident (OR 1.96, 95% CI: 1.03-3.70) remained significant. Laparoscopic appendectomy is a safe procedure associated with low rates of complications, prolonged LOS, and readmissions. Risk factors for these adverse events include complicated appendicitis, postoperative morbidity, conversion, and re-intervention after the primary procedure. Any occurrence of these factors during treatment should alert the healthcare team to identify the patients that require more customized treatment to minimize the risk for adverse outcomes.

The significant impact of age on the clinical outcomes of laparoscopic appendectomy: Results from the Polish Laparoscopic Appendectomy multicenter large cohort study.

Acute appendicitis (AA) is the most common surgical emergency and can occur at any age. Nearly all of the studies comparing outcomes of appendectomy between younger and older patients set cut-off point at 65 years. In this multicenter observational study, we aimed to compare laparoscopic appendectomy for AA in various groups of patients with particular interest in the elderly and very elderly in comparison to younger adults.Our multicenter observational study of 18 surgical units assessed the outcomes of 4618 laparoscopic appendectomies for AA. Patients were divided in 4 groups according to their age: Group 1-<40 years old; Group 2-between 40 and 64 years old; Group 3-between 65 and 74 years old; and Group 4-75 years old or older. Groups were compared in terms of peri- and postoperative outcomes.The ratio of complicated appendicitis grew with age (20.97% vs 37.50% vs 43.97% vs 56.84%, P < .001). Similarly, elderly patients more frequently suffered from perioperative complications (5.06% vs 9.3% vs 10.88% vs 13.68%, P < .001) and had the longest median length of stay (3 [Interquartile Range (IQR) 2-4] vs 3 [IQR 3-5], vs 4 [IQR 3-5], vs 5 [IQR 3-6], P < .001) as well as the rate of patients with prolonged length of hospital stay (LOS) >8 days. Logistic regression models comparing perioperative results of each of the 3 oldest groups compared with the youngest one showed significant differences in odds ratios of symptoms lasting >48 hours, presence of complicated appendicitis, perioperative morbidity, conversion rate, prolonged LOS (>8 days).The findings of this study confirm that the outcomes of laparoscopic approach to AA in different age groups are not the same regarding outcomes and the clinical picture. Older patients are at high risk both in the preoperative, intraoperative, and postoperative period. The differences are visible already at the age of 40 years old. Since delayed diagnosis and postponed surgery result in the development of complicated appendicitis, more effort should be placed in improving treatment patterns for the elderly and their clinical outcome.

Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer.

PURPOSE: Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC. EXPERIMENTAL DESIGN: Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013. RESULTS: Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P = 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02-2.49; P = 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14-3.13; P = 0.014). Higher rs966423-associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67-7.22; P < 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16-10.4; P = 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15-3.73; P = 0.013). CONCLUSIONS: The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy.