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

Chromoendoscopy versus autofluorescence imaging for neoplasia detection in patients with longstanding ulcerative colitis (FIND-UC): an international, multicentre, randomised controlled trial

Background: Patients with longstanding ulcerative colitis (UC) undergo regular dysplasia surveillance because of increased colorectal cancer risk. Previous studies demonstrated that autofluorescence imaging (AFI) and chromoendoscopy (CE) increased dysplasia detection. The aim of this study was to determine whether AFI should be further studied as an alternative method for dysplasia surveillance in patients with longstanding UC. Methods: In this prospective international, randomised trial, 210 patients undergoing colonoscopy surveillance for longstanding UC were randomised between 1 August 2013 and 10 March 2017 for inspection with either AFI or CE (105:105). Randomisation was minimised for a previous history of dysplasia and a previous history of primary sclerosing cholangitis. The main outcome was the relative dysplasia detection rate calculated by the ratio of AFI versus CE. This relative dysplasia detection rate was determined for the proportion of UC patients in which at least one dysplastic lesion was detected and for the mean number of dysplastic lesions per patient. The relative dysplasia detection rate needed to be above 0·67 for both outcomes to support performing a subsequent large non-inferiority trial, using an 80% confidence interval. Analysis was performed per protocol. The trial is registered at Netherlands Trial Register (NTR4062). Findings: AFI detected dysplasia in 13 (12·4%) patients, compared to 20 patients (19·1%) with CE. The relative dysplasia detection rate of CE versus AFI for the proportion of UC patients with at least one dysplastic lesion was 0·65 (80% CI; 0·43-0·99). The mean number of detected dysplastic lesions per patient was 0·13 for AFI compared to 0·37 for CE (relative dysplasia detection rate 0·36, 80% CI; 0·21-0·61). Two patients experienced an adverse event (intraprocedural mild bleeding = 1, abdominal pain = 1) in the AFI-arm and three patients (intraprocedural mild bleeding = 2, perforation = 1) in the CE-arm. Interpretation: In this randomised study comparing AFI with CE for dysplasia surveillance in patients with longstanding UC, AFI did not meet criteria for proceeding to a large non-inferiority trial. Therefore, current AFI technology should not be further investigated as an alternative dysplasia surveillance method. Funding: Olympus Europe and Olympus Keymed, Oxford and Nottingham NIHR biomedical research centres

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

Historical, current and future perspectives on gastrointestinal and pancreatic endocrine tumors

Gastrointestinal and pancreatic endocrine tumors are neoplasms of which the pathogenesis is not completely understood and of which the clinical behavior is difficult to predict. Originally, Masson suggested that the cell of origin was an endocrine cell derived from the gastrointestinal epithelium. However, Pearse showed that the endocrine cells throughout the body shared various features, among others the amine precursor uptake and decarboxylation (APUD) capacity, and postulated the neural crest as the common origin for all APUD cells, a hypothesis that received support from the scientific community for many years. Now, biologists start to elucidate the various transcription factors that drive gastrointestinal development, and it has become evident that Masson was presumably right. Transcription factors relevant for development may also operate during tumorigenesis, and their expression may determine tumor biology. With other genetic factors, they may play a role in the pathogenesis of gastrointestinal and pancreatic endocrine tumors, and perhaps, their expression will turn out to be of prognostic or therapeutic value. In this review, current knowledge on the development of endocrine cells, hypotheses on the origin of endocrine tumors, genetic alterations, and prognostic factors are discussed. It is suggested that the increasing understanding of the normal development of gastrointestinal and pancreatic endocrine cells, the accumulating data on genetic alterations in endocrine tumors and the reappraisal of the hypotheses on their pathogenesis formulated in the past may help in elucidating their pathogenesis and in more accurately predicting prognosi

Unexpected Detection of Nodular Melanoma of the Skin on the Scalp by I-123 IBZM Brain SPECT

Melanocytes and dopaminergic neurons share the same ectodermal origin and can both produce melanin. Indeed, in vivo studies have shown that the radiopharmaceutical iodine-123-iodobenzamide (I-123 IBZM), which binds in vivo to dopamine D-2/3 receptors, is also able to detect melanoma, and particularly melanotic melanoma. We report a case of intense IBZM uptake in nodular melanoma of the skin on the scalp. The presence of unexpected focal IBZM uptake of the skin justified histologic examination, which revealed nodular melanoma. Melanoma should be considered when one is confronted with atypical focal uptake of benzamide derivatives like IBZM, in or outside the brai

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

Performance of Common Disease Activity Markers as a Reflection of Inflammatory Burden in Ulcerative Colitis

The inflammatory burden influences therapeutic decisions in patients with ulcerative colitis (UC). We aimed to study which commonly used markers of disease activity correlate best with inflammatory burden in patients with UC using leukocyte scintigraphy (single-photon emission computed tomography [SPECT-CT]) as the gold standard. Patients with different severity of UC underwent colonoscopy with biopsies and leukocyte SPECT-CT scintigraphy. Serum C-reactive protein (CRP), fecal calprotectin, and clinical questionnaires were collected. The maximum uptake of technetium-labeled leukocytes was calculated as a SPECT score for each colon segment and a summed activity score for 5 colonic segments combined. Thirty patients with UC were included; 14 of 30 (47%) had left-sided colitis, and 16 of 30 (53%) had pancolitis. One patient (3%) had inactive UC, 5 of 30 (17%) had mild, 11 of 30 (37%) had moderate, and 13 of 30 (43%) had severe disease activity based on the endoscopic Mayo score. The endoscopic Mayo score correlated better with the SPECT score than with the ulcerative colitis endoscopic index of severity (UCEIS) (r = 0.50; P < 0.01 and r = 0.32; P = 0.08, respectively). The Geboes UC histologic score correlated equally well as the Mayo score (r = 0.50; P < 0.01). We found a significant correlation between scintigraphy and fecal calprotectin (r = 0.44; P = 0.02) but not with serum CRP (r = 0.25; P = 0.18). Fecal calprotectin reflected inflammatory burden significantly better in left-sided colitis (r = 0.80; P = 0.001) than in pancolitis (r = 0.22; P = 0.41). The inflammatory burden in patients with UC, measured by SPECT-CT, is better reflected by the endoscopic Mayo score and the Geboes histologic score than by the UCEIS. Fecal calprotectin is a more accurate inflammatory marker than CRP, predominantly in patients with left-sided colitis. This study was approved by the Ethics Committee Review at October 22, 2012 and, in accordance with Dutch legislation, prospectively registered at the CCMO (Dutch central commission for human research) https://www.toetsingonline.nl with NL39801.018.1