Laparoscopic myotomy can durably relieve dysphagia symptoms. High preoperative LES pressures represent the strongest predictor of a positive outcome, probably reflecting a less severely damaged esophageal muscle.
This is the first study by a surgical group to assess the outcome of surgery in 3 manometric achalasia subtypes: patients with panesophageal pressurization have the best outcome after laparoscopic Heller-Dor myotomy.
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The vast majority of GISTs are driven by oncogenic activation of KIT, PDGFRA or, less commonly, BRAF. Loss of succinate dehydrogenase complex activity has been identified in subsets of KIT/PDGFRA/BRAF-mutation negative tumours, yet a significant fraction of GISTs are devoid of any of such alterations. To address the pathobiology of these 'quadruple-negative' GISTs, we sought to explore the possible involvement of fusion genes. To this end we performed transcriptome sequencing on five KIT/PDGFRA/BRAF-mutation negative, SDH-proficient tumours. Intriguingly, the analysis unveiled the presence of an ETV6-NTRK3 gene fusion. The screening by FISH of 26 additional cases, including KIT/PDGFRA-mutated GISTs, failed to detect other ETV6 rearrangements beside the index case. This was a 'quadruple-negative' GIST located in the rectum, an uncommon primary site for GIST development (∼4% of all GISTs). The fusion transcript identified encompasses exon 4 of ETV6 and exon 14 of NTRK3 and therefore differs from the canonical ETV6-NTRK3 chimera of infantile fibrosarcomas. However, it retains the ability to induce IRS1 phosphorylation, activate the IGF1R downstream signalling pathway and to be targeted by IGF1R and ALK inhibitors. Thus, the ETV6-NTRK3 fusion might identify a subset of GISTs with peculiar clinicopathological characteristics which could be eligible for such therapies. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Twist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we found that Twist1 acts as a mechanism alternative to TP53 mutation and MDM2 overexpression to inactivate p53 in mesenchymal tumors. We provide evidence that Twist1 binds p53 C terminus through the Twist box. This interaction hinders key posttranslational modifications of p53 and facilitates its MDM2-mediated degradation. Our study suggests the existence of a Twist box code of p53 inactivation and provides the proof of principle that targeting the Twist box:p53 interaction might offer additional avenues for cancer treatment.
Purpose: Angiomatoid fibrous histiocytoma (AFH) is a low-grade mesenchymal neoplasm which usually occurs in children and adolescents. Either FUS-ATF1 or EWSR1-ATF1 have been detected in the few cases published, pointing to the interchangeable role of FUS and EWSR1 in this entity. EWSR1-ATF1 also represents the most frequent genetic alteration in clear cell sarcoma, suggesting the existence of a molecular homology between these two histotypes.We investigated the presence of EWSR1-CREB1, recently found in gastrointestinal clear cell sarcoma, and FUS-CREB1, as well as the already reported FUS-ATF1 and EWSR1-ATF1 in a series of AFH. Experimental Design: Fourteen cases were analyzed by fluorescence in situ hybridization (FISH) on paraffin-embedded tissue sections, using a commercial EWSR1 probe and customdesigned probes for FUS, ATF1, and CREB1. In two cases, four-color FISH was also done. Reverse transcription-PCR for the four hypothetical fusion genes was done in one case, for which frozen material was available. Results:Thirteen cases showed rearrangements of both EWSR1 and CREB1, whereas one case showed the rearrangement of both EWSR1 and ATF1. Four-color FISH confirmed the results in two selected cases. Reverse transcription-PCR showed EWSR1-CREB1 transcript in the case analyzed. Conclusion: We identified the presence of either EWSR1-CREB1 or EWSR1-ATF1 in all the cases, strengthening the concept of chromosomal promiscuity between AFH and clear cell sarcoma. Either the occurrence of a second unknown tumor-specific molecular event or, perhaps more likely, divergent differentiation programs of the putatively distinct precursor cells of AFH and clear cell sarcoma might be invoked in order to explain the two different phenotypes.Angiomatoid fibrous histiocytoma (AFH) represents a lowgrade mesenchymal neoplasm of uncertain differentiation (1), which usually occurs in the extremities of children and young adults. Morphologically, it is a multinodular proliferation of bland spindle to ovoid eosinophilic cells, sometimes lining pseudoangiomatoid spaces and surrounded by a thick fibrous pseudocapsule, often featuring a prominent lymphoplasmacytic infiltrate. Immunohistochemically, the most relevant finding is represented by the expression of desmin in f40% of cases, suggesting myogenic differentiation (2, 3). The recurrence rate is between 2% and 11%, and the metastatic rate is <1%. In the context of an uncommon tumor type with a very low rate of metastasis, it is unsurprising that no histologic or immunophenotypic features have thus far been identified to predict patients' outcome.Until recently, only five cases of AFH studied by cytogenetics (4, 5) and/or molecular genetics (4 -7) have been published in detail. Two of them were characterized by the expression of an FUS-ATF1 fusion gene (4, 6), resulting from a t(12;16) (q13;p11) (ref. 4), whereas in the remaining three cases, a EWSR1-ATF1 fusion gene was detected (5, 7), resulting from a t(12;22)(q13;q12) (ref. 5). EWSR1 and FUS are members of the TET family, ...
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