Omineca Herald, May, 23, 1924

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse

Recurrence of Pancreatic Neuroendocrine Tumors and Survival Predicted by Ki67

Background: Despite evidence of different malignant potentials, postoperative follow-up assessment is similar for G1 and G2 pancreatic neuroendocrine tumors (panNETs) and adjuvant treatment currently is not indicated. This study investigated the role of Ki67 with regard to recurrence and survival after curative resection of panNET. Methods: Patients with resected non-functioning panNET diagnosed between 1992 and 2016 from three institutions were retrospectively analyzed. Patients who had G1 or G2 tumor without distant metastases or hereditary syndromes were included in the study. The patients were re-categorized into Ki67 0–5 and Ki67 6–20%. Cox regression analysis with log-rank testing for recurrence and survival was performed. Results: The study enrolled 241 patients (86%) with Ki67 0–5% and 39 patients (14%) with Ki67 6–20%. Recurrence was seen in 34 patients (14%) with Ki67 0–5% after a median period of 34 months and in 16 patients (41%) with Ki67 6–20% after a median period of 16 months (p < 0.001). The 5-year recurrence-free and 10-year disease-specific survival periods were respectively 90 and 91% for Ki67 0–5% and respectively 55 and 26% for Ki67 6–20% (p < 0.001). The overall survival period after recurrence was 44.9 months, which was comparable between the two groups (p = 0.283). In addition to a Ki67 rate higher than 5%, tumor larger than 4 cm and lymph node metastases were independently associated with recurrence. Conclusions: Patients at high risk for recurrence after curative resection of G1 or G2 panNET can be identified by a Ki67 rate higher than 5%. These patients should be more closely monitored postoperatively to detect recurrence early and might benefit from adjuvant treatment. A clear postoperative follow-up regimen is proposed

Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions

Hyperplastic polyposis syndrome: a pilot study for the differentiation of polyps by using high-resolution endoscopy, autofluorescence imaging, and narrow-band imaging

BACKGROUND: Endoscopic differentiation and removal of potentially premalignant sessile serrated adenomas (SSAs) may be important steps in preventing the development of colorectal cancer in hyperplastic polyposis syndrome (HPS). OBJECTIVE: To assess the value of high-resolution endoscopy, autofluorescence imaging (AFI), and narrow-band imaging (NBI) for differentiating polyps in HPS. DESIGN: A prospective polyp series. SETTING: Single tertiary referral center. PATIENTS AND INTERVENTIONS: Seven patients with HPS underwent colonoscopy with endoscopic trimodal imaging, which incorporates high-resolution endoscopy, AFI, and NBI in 1 system. All detected polyps were analyzed with AFI for color and with NBI for Kudo pit pattern and vascular pattern intensity. MAIN OUTCOME MEASUREMENTS: The accuracy, sensitivity, and specificity of AFI and NBI in differentiating detected polyps were determined by using histology as the criterion standard. RESULTS: A total of 19 hyperplastic polyps (HPs), 32 SSAs, and 15 adenomas were detected. For differentiating SSAs from HPs, AFI color, Kudo pit pattern, and vascular pattern intensity resulted in a diagnostic accuracy of 55%, 55%, and 52%, respectively. For differentiating adenomas from HPs, the accuracy was 65%, 94%, and 90%, respectively. Macroscopically, the combination of a size of 3 mm or larger and a proximal location resulted in the highest accuracy (76%) for differentiating SSAs from HPs. LIMITATION: Small sample size. CONCLUSION: Endoscopic differentiation between HPs and SSAs by using endoscopic trimodal imaging proved unsatisfactory. Differentiation of adenomas from HPs was possible with NBI but not with AF

Yield of Screening Colonoscopy in First-degree Relatives of Patients With Serrated Polyposis Syndrome

Goals: We aimed to evaluate the diagnostic yield of screening colonoscopies in first-degree relatives (FDRs) of patients with serrated polyposis syndrome (SPS). Background: Patients with SPS are at an increased risk for colorectal cancer. Although inheritance patterns are unknown, FDRs of these patients have an increased risk for both colorectal cancer and SPS. Prospective studies evaluating the yield of screening colonoscopies in this group are however scarce. This information would be useful to evaluate a possible mode of inheritance and to investigate whether screening colonoscopies are justified in this group. Study: FDR of patients with SPS were invited to undergo colonoscopy. The diagnostic yield was expressed by the number of FDRs with at least 1 significant polyp relative to the total number of included FDRs. Significant polyps were defined adenomas, traditional serrated adenomas, sessile serrated adenoma/ polyp, or proximal hyperplastic polyp. Tissue specimens were reviewed by one expert pathologist. Results: Seventy-seven FDRs underwent colonoscopy (median age 52 y; interquartile range, 41 to 60). Colorectal cancer was not diagnosed. One or more significant polyps were detected in 43% of FDRs. No differences based on age, gender, or familial relationship were observed in the detection of polyps. Seven first-degree (9%) relatives had multiple polyps (>= 5). Eleven (14%) FDRs fulfilled SPS WHO-criterion 2, of whom 1 sibling also met SPS WHO-criterion 3. Conclusions: The yield of a single screening colonoscopy in FDRs of patients with serrated polyposis is substantial, warranting a colonoscopy screening program for these individuals

Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis

BACKGROUND & AIMS: MYH-associated polyposis (MAP) is a disorder caused by a bi-allelic germline MYH mutation, characterized by multiple colorectal adenomas. These adenomas typically harbor G:C-->T:A transversions in the APC and K-ras genes caused by MYH deficiency. Occasional hyperplastic polyps (HPs) have been described in MAP patients but a causal relationship has never been investigated. We examined the presence of HPs and sessile serrated adenomas (SSAs) in 17 MAP patients and studied the occurrence of G:C-->T:A transversions in the APC and K-ras gene in these polyps. METHODS: MAP patients were analyzed for the presence of HPs/SSAs. APC-mutation cluster region and K-ras codon 12 mutation analysis was performed in adenomas (n = 22), HPs (n = 63), and SSAs (n = 10) from these patients and from a control group of sporadic adenomas (n = 17), HPs (n = 24), and SSAs (n = 17). RESULTS: HPs/SSAs were detected in 8 of 17 (47%) MAP patients, of whom 3 (18%) met the criteria for hyperplastic polyposis syndrome. APC mutations were detected only in adenomas and comprised exclusively G:C-->T:A transversions. K-ras mutations were detected in 51 of 73 (70%) HPs/SSAs in MAP patients, compared with 7 of 41 (17%) sporadic HPs/SSAs in the control group (P T:A transversions, compared with 2 of 7 (29%) sporadic HPs/SSAs in the control group (P T:A transversions in the K-ras gene of HPs/SSAs strongly suggests that these polyps are related causally to MYH deficiency. This implies that distinct pathways, that is, APC-gene related in adenomas and nonrelated in HPS/SSAs, appear to be operational in MA