Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas, but their incidence appears to be dependent to ultraviolet light exposure. Thus, BRAF mutations have the highest incidence in non-chronic sun damaged (CSD), and are uncommon in acral, mucosal and CSD melanomas. More recently, activating KIT mutations have been described in rare cases of metastatic melanoma, without further reference to their clinical phenotypes. This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions. In this study, we investigated a group of anal melanomas for the presence of BRAF, NRAS, KIT and PDGFRA mutations. A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested. The 3 KIT mutation-carrying tumors were strongly immunopositive for KIT protein. No KIT mutations were identified in tumors with less than 41 KIT immunostaining. NRAS mutation was identified in one tumor. No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas. In vitro drug testing of stable transformant Ba/F3 KIT L576P mutant cells showed sensitivity for dasatinib (previously known as BMS-354825), a dual SRC/ABL kinase inhibitor, and imatinib. However, compared to an imatinib-sensitive KIT mutant, dasatinib was potent at lower doses than imatinib in the KIT L576P mutant. These results suggest that a subset of anal melanomas show activating KIT mutations, which are susceptible for therapy with specific kinase inhibitors. ' 2007 Wiley-Liss, Inc.Key words: melanoma; anal; mucosal; KIT; NRAS; BRAF mutations The KIT receptor tyrosine kinase plays a critical role in the normal development and function of the melanocytes during embryonic stage and in the postnatal organism.1,2 Loss-of-function mutations in KIT and its ligand result in white spotting phenotype in mice and humans. [3][4][5] In contrast, activating KIT mutations have been implicated in the pathogenesis of certain human malignancies, such as gastrointestinal stromal tumors, seminomas, mastocytomas, but were not reported until recently in patients with malignant melanoma. Furthermore, KIT expression, typically found in normal melanocytes, benign nevi and in situ melanoma, appears to be downregulated in invasive and metastatic melanomas.6 This progressive decrease in KIT immunopositivity is associated with increasing dermal invasiveness of the tumor. One hypothesis is that KIT signaling may be important in regulating cell differentiation and tissue morphogenesis, and therefore loss of its expression may be a required step in the course of tumor progression. 7 In this context, isolated reports of activating KIT mutations in melanoma patients, 8,9 are intriguing and suggest an alternative mechanism, in which constitutive activation of KIT through oncogenic mutations positively regulate mitogenesis and induces neoplastic transformation.The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indi...

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Background MET, the receptor for hepatocyte growth factor has been proposed as a therapeutic target in gastric cancer. This study assessed the incidence of MET expression and gene amplification in tumors of Western patients with gastric cancer. Methods Tumor specimens from patients enrolled on a preoperative chemotherapy study (NCI 5700) were examined for presence of MET gene amplification by fluorescence in situ hybridization (FISH), MET mRNA expression by quantitative polymerase chain reaction, MET overexpression by immunohistochemistry (IHC), and for evidence of MET pathway activation by p-MET IHC. Results Although high-level of MET protein and mRNA were commonly encountered (in 63% and 50% of resected tumor specimens, respectively), none of these tumors had MET gene amplification by FISH, and only 6.6% had evidence of MET tyrosine kinase activity by p-MET IHC. Conclusions In this cohort of patients with localized gastric cancer, the presence of high MET protein and RNA expression does not correlate with MET gene amplification or pathway activation as evidenced by the absence of amplification by FISH and negative p-MET IHC analysis. Impact This paper demonstrates a lack of MET amplification and pathway activation in a cohort of 38 patients with localized gastric cancer, suggesting that MET-driven gastric cancers are relatively rare in Western patients.

Background Acute diverticulitis (AD) presents a unique diagnostic and therapeutic challenge for general surgeons. This collaborative project between EAES and SAGES aimed to summarize recent evidence and draw statements of recommendation to guide our members on comprehensive AD management. Methods Systematic reviews of the literature were conducted across six AD topics by an international steering group including experts from both societies. Topics encompassed the epidemiology, diagnosis, management of non-complicated and complicated AD as well as emergency and elective operative AD management. Consensus statements and recommendations were generated, and the quality of the evidence and recommendation strength rated with the GRADE system. Modified Delphi methodology was used to reach consensus among experts prior to surveying the EAES and SAGES membership on the recommendations and likelihood to impact their practice. Results were presented at both EAES and SAGES annual meetings with live re-voting carried out for recommendations with < 70% agreement. Results A total of 51 consensus statements and 41 recommendations across all six topics were agreed upon by the experts and submitted for members’ online voting. Based on 1004 complete surveys and over 300 live votes at the SAGES and EAES Diverticulitis Consensus Conference (DCC), consensus was achieved for 97.6% (40/41) of recommendations with 92% (38/41) agreement on the likelihood that these recommendations would change practice if not already applied. Areas of persistent disagreement included the selective use of imaging to guide AD diagnosis, recommendations against antibiotics in non-complicated AD, and routine colonic evaluation after resolution of non-complicated diverticulitis. Conclusion This joint EAES and SAGES consensus conference updates clinicians on the current evidence and provides a set of recommendations that can guide clinical AD management practice. Electronic supplementary material The online version of this article (10.1007/s00464-019-06882-z) contains supplementary material, which is available to authorized users.

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Aim Low anterior resection syndrome (LARS) is pragmatically defined as disordered bowel function after rectal resection leading to a detriment in quality of life. This broad characterization does not allow for precise estimates of prevalence. The LARS score was designed as a simple tool for clinical evaluation of LARS. Although the LARS score has good clinical utility, it may not capture all important aspects that patients may experience. The aim of this collaboration was to develop an international consensus definition of LARS that encompasses all aspects of the condition and is informed by all stakeholders. Method This international patient–provider initiative used an online Delphi survey, regional patient consultation meetings, and an international consensus meeting. Three expert groups participated: patients, surgeons and other health professionals from five regions (Australasia, Denmark, Spain, Great Britain and Ireland, and North America) and in three languages (English, Spanish, and Danish). The primary outcome measured was the priorities for the definition of LARS. Results Three hundred twenty‐five participants (156 patients) registered. The response rates for successive rounds of the Delphi survey were 86%, 96% and 99%. Eighteen priorities emerged from the Delphi survey. Patient consultation and consensus meetings refined these priorities to eight symptoms and eight consequences that capture essential aspects of the syndrome. Sampling bias may have been present, in particular, in the patient panel because social media was used extensively in recruitment. There was also dominance of the surgical panel at the final consensus meeting despite attempts to mitigate this. Conclusion This is the first definition of LARS developed with direct input from a large international patient panel. The involvement of patients in all phases has ensured that the definition presented encompasses the vital aspects of the patient experience of LARS. The novel separation of symptoms and consequences may enable greater sensitivity to detect changes in LARS over time and with intervention.

A laparoscopic approach to ileal pouch formation was associated with a significant reduction in both major and minor complications compared with the traditional open approach. Given the high financial costs associated with complications arising from this procedure, this study provides support for the adoption of the laparoscopic approach in the formation of an IPAA.