Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era.

PURPOSE: Platelet-derived growth factor receptor-alpha (PDGFRA) mutations are found in approximately 5% to 7% of advanced gastrointestinal stromal tumors (GIST). We sought to extensively assess the activity of imatinib in this subgroup. EXPERIMENTAL DESIGN: We conducted an international survey among GIST referral centers to collect clinical data on patients with advanced PDGFRA-mutant GISTs treated with imatinib for advanced disease. RESULTS: Fifty-eight patients were included, 34 were male (59%), and median age at treatment initiation was 61 (range, 19-83) years. The primary tumor was gastric in 40 cases (69%). Thirty-two patients (55%) had PDGFRA-D842V substitutions whereas 17 (29%) had mutations affecting other codons of exon 18, and nine patients (16%) had mutation in other exons. Fifty-seven patients were evaluable for response, two (4%) had a complete response, eight (14%) had a partial response, and 23 (40%) had stable disease. None of 31 evaluable patients with D842V substitution had a response, whereas 21 of 31 (68%) had progression as their best response. Median progression-free survival was 2.8 [95% confidence interval (CI), 2.6-3.2] months for patients with D842V substitution and 28.5 months (95% CI, 5.4-51.6) for patients with other PDGFRA mutations. With 46 months of follow-up, median overall survival was 14.7 months for patients with D842V substitutions and was not reached for patients with non-D842V mutations. CONCLUSIONS: This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib. Our data confirm that imatinib has little efficacy in the subgroup of patients with D842V substitution in exon 18, whereas other mutations appear to be sensitive to imatinib. Clin Cancer Res; 18(16); 4458-64. ©2012 AACR.

Gastrointestinal immune responses in HIV infected subjects

The gut associated lymphoid tissue is responsible for specific responses to intestinal antigens. During HIV infection, mucosal immune deficiency may account for the gastrointestinal infections. In this review we describe the humoral and cellular mucosal immune responses in normal and HIV-infected subjects.

Patients' preferences on information and involvement in decision-making for gastrointestinal surgery

Objective: The relationship between physicians and patients has undergone¦important changes, and the current emancipation of patients has led to¦a real partnership in medical decision-making. This study aimed to assess¦patients' preferences on different aspects of decision-making during treatment¦and potential complications, as well as the amount and type of preoperative¦information before visceral surgery.¦Methods: Prospective non-randomized study based on a questionnaire given¦to 253 consecutive patients scheduled for elective GI surgery.¦Results: Concerning surgical complications or treatment in the intensive care¦unit, 64% of patients wished to take actively part in any medical decisions.¦The respective figures for cardiac resuscitation and treatment limitations were¦89% and 60%. About information, 73%, 77% and 47% of patients wish¦detailed information, information on a potential ICUhospitalization and cardiac¦resuscitation, respectively. Elderly and low-educated patients were significantly¦less interested in shared medical decision-making (p = 0·003 and 0·015) and in¦information receiving (p = 0·03 and 0·05). Similarly, involvement of the family¦in decision-making was significantly less important in elderly and male patients¦(p = 0·05 and 0·03 respectively). Neither the type of operation (minor or major)¦nor the severity of disease (malignancies vs. non-malignancies) was a significant¦factor for shared decision-making, information or family involvement.¦Conclusion: The vast majority of surgical patients clearly want to get adequate¦preoperative information about their disease and the planned treatment. They¦also consider it as crucial to be involved in any kind of decision-making for¦treatment and complications. The family's role is limited to support the treating¦physicians if the patient is unable to participate in taking decisions.

Female-biased infection and transmission of the gastrointestinal nematode Trichuris arvicolae infecting the common vole, Microtus arvalis.

Previous studies addressing the importance of host gender in parasite transmission have shed light on males as the more important hosts, with the higher transmission potential of males being explained by the fact that they often harbour higher parasite loads than females. However, in some systems females are more heavily infected than males and may be responsible for driving infection under such circumstances. Using a wild population of common voles (Microtus arvalis), we showed that females were more frequently infected by the intestinal nematode Trichuris arvicolae than males (i.e. prevalence based on the presence of eggs in the faeces) and that females were shedding greater numbers of parasite eggs per gram of faeces (EPG) than males. By applying an anthelmintic treatment to either male or female voles, we demonstrated that treating females significantly reduced parasite burdens (i.e. prevalence and EPG) of both male and female hosts, while treating males only reduced parasite burden in males. These findings indicate that in this female-biased infection system females play a more important role than males in driving the dynamics of parasite transmission.

Treatment of gastrointestinal stromal tumor after imatinib and sunitinib.

Purpose of review Tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, have changed the outcome of patients with gastrointestinal stromal tumor (GIST) and prolonged survival by many-fold. Unfortunately, treatment failure and tumor progression seem inevitable over time and constitute an unresolved clinical challenge. This article reviews current efforts to overcome drug resistance and progression. Recent findings The major mechanism of resistance toward imatinib and sunitinib is the development of secondary resistance mutations in the kinase domain of KIT. Recent efforts aim at inhibitors with increased activity against resistance mutations or a broader spectrum of activity. Other strategies include indirect KIT inhibition by modulating KIT chaperone proteins or inhibition of KIT-dependent and independent signaling pathways. Summary dThe rapid improvement of our understanding of GIST biology as well as resistance mechanisms towards imatinib and sunitinib will greatly facilitate the development of novel treatment strategies. This article summarizes the results of recently reported third and fourth-line clinical trials in patients with resistant GIST and reviews data of important proof-of-concept studies.

Complicaciones y secuelas nasales de la cirugía de tumores hipofisarios por abordaje vía transesfenoidal endoscópica

L’abordatje transesfenoidal endoscòpic es, avui dia, una de les tècniques més utilitzades en la cirurgia de tumors d’hipòfisi i, amb un menor nombre de seqüeles encara que, no exempta d’aquestes. El nostre treball preten analitzar les complicacions i seqüeles nasals més freqüents produïdes per la cirurgia transesfenoidal endoscòpica. Hem realitzat un estudi descriptiu amb 57 pacients operats de tumors d’hipòfisi mitjançant cirurgia endocòpica transesfenoidal. Analitzem l’aparició de complicacions nasales postquirúrgiques i, les seqüeles nasals passats més de 6 mesos de la cirurgia. Un 6% de malalts pateixen complicacions nasals potcirurgia i tots tenen alguna seqüela nasal.

Tumores parotídeos: revisión de la distribución demográfica y de la correlación cito-histológica de los pacientes intervenidos por el servicio de Cirugía Maxilofacial del Hospital Universitario Vall d’Hebron

Els tumors parotidis constitueixen un motiu de consulta freqüent en el medi hospitalari. Per conèixer l’origen cel•lular dels mateixos disposem de l’anàlisi citològic pre-quirúrgic. No existeix una correlació exacta entre la citologia pre-quirúrgica i l’anatomia patològica definitiva segons la literatura. S’ha realitzat un estudi retrospectiu de sèries de casos dels pacients atesos per tumors parotidis al servei de Cirurgia Maxil•lofacial de l’Hospital Vall d’Hebron en el qual s’ha avaluat la distribució demogràfica d’aquests tumors i la correlació cito-histològica comparant-la amb altres sèries.

Aspects of gastrointestinal immunology and nutrition in human immunodeficiency virus-1 infection in Brazil

Mucosal surfaces have a fundamental participation in many aspects of the human immunodeficiency virus (HIV) infection pathogenesis. In Brazilian HIV-1 infected subjects, loss of weight and appetite are among the most debilitating symptoms. In this review we describe a defined mucosal immunogen that has profound but transient effects on HIV viral load, and we suggest that gut associated lymphoid tissue under constant immunostimulation is likely to provide a major contribution to the total levels of HIV. We also show that hypermetabolism appears to play a role in the wasting process in Brazilian patients coinfected with HIV and tuberculosis.

Underutilization of upper gastrointestinal endoscopy.

BACKGROUND & AIMS: Efforts to reduce costs in health care may raise concerns about underuse of medical procedures. This study prospectively assessed underuse of upper gastrointestinal endoscopy in a cohort of patients in whom we have recently published data on overuse of endoscopy. METHODS: Underuse was identified by formal necessity criteria for endoscopy, obtained by an explicit panel process. Outpatients were consecutively included in two clinical settings. Setting A consisted of 20 primary care physicians and 7215 patient visits that occurred within 1 month. Setting B consisted of 920 visits that occurred during 3 weeks at an outpatient clinic. RESULTS: During these 8135 visits, 611 patients complained of upper digestive symptoms; 63 of them underwent endoscopy. Underuse was identified in 72 patients (11.8%). The two clinical situations mainly responsible for underuse of endoscopy were uninvestigated peptic symptoms resistant to treatment and dysphagia. At first follow-up, 29 of the patients with initial underuse still fulfilled criteria of necessity (underuse rate, 4.7%). One-year follow-up showed underuse of endoscopy in 5 patients. CONCLUSIONS: This prospective evidence shows that underuse of a medical procedure exists. The estimated overuse and underuse of endoscopy in this cohort were approximately equal (5%). Improving quality of care will require reductions of both overuse and underuse of medical procedures.

Progresión tumoral y búsqueda de nuevas dianas terapéuticas en la familia de tumores del sarcoma de Ewing: función biológica de la caveolina-1

El sarcoma de Ewing es el segundo tumor óseo infantil más frecuente y presenta una alta incidencia de enfermedad metastática. Este tipo de tumores presentan una traslocación génica característica que da origen a una proteína de fusión, normalmente EWS/FLI1. Esta proteína de fusión actúa como factor de transcripción aberrante regulando la expresión de diferentes genes implicados en la iniciación, mantenimiento y progresión del tumor. Nuestro grupo describió como uno de estos genes diana a la caveolina 1 (CAV1) describiendo además su papel determinante en el fenotipo maligno del sarcoma de Ewing, en la tumorigénesis y en la resistencia a apoptosis inducida por quimioterapia. Para investigar el papel concreto de CAV1 en el proceso metastático de este sarcoma, creamos un modelo de baja expresión de CAV1 en líneas celulares de sarcoma de Ewing y determinamos cambios en su capacidad migratoria, invasiva y metastática. En los ensayos in vitro hallamos una menor capacidad migratoria de las células knockdown de CAV1 y una reducción en la expresión de MMP9 y en la actividad de MMP2. La regulación de la actividad de MMP2 parece estar relacionada con la posible regulación que ejerce CAV1 en la función de MT1-MMP, proteína fundamental para la activación de MMP2. Por otro lado, en este estudio proponemos que CAV1 promueve la expresión de MMP9 tanto transcripcionalmente, regulando la vía de señalización ERK1/2, como a nivel post-transcripcional regulando la vía RSK1/rpS6. Además, en los ensayos de metástasis experimental in vivo las células knockdown de CAV1 presentaron una menor incidencia de metástasis pulmonar, hecho que correlacionó con una disminución en la expresión de SPARC, una proteína de adhesión importante en procesos metastáticos. En resumen, nuestros resultados evidencian la importancia de CAV1 en el proceso metastático del sarcoma de Ewing.

Actividad de la vía PI3K-AKT-FOXOp27 como factor pronóstico en tumores astrocitarios

Els tumors astrocitaris són entitats poc freqüents i el seu pronòstic és pobre. Recentment s'ha descrit l'alta freqüència d'alteració de la via de PI3K a aquests tumors. L'objectiu d'aquest estudi és valorar la possible correlació entre la supervivència lliure de progressió d'una sèrie de pacients intervinguts per tumors astrocitarios en el nostre centre i l'activació de la via de PI3K definida mitjançant expressió inmunohistoquímica. Es van analitzar un total de 83 pacients. A més dels factors correlacionats en la literatura amb la supervivència lliure de progressió (grau, cirurgia i edat), l'estudi mostra una correlació directament proporcional amb els nivells de pFOXO i inversament proporcional amb p27. El valor d'aquestes troballes haurà de ser validat posteriorment.

Foodborne infections & gastrointestinal disease on the island Of Ireland in 2002

A safefood consultation paper, ‘Towards the Enhancement of Foodborne Disease Surveillance’ indicated that the guiding principles for the development of surveillance in Northern Ireland and the Republic of Ireland should be the integration of data collection systems and analysis of combined data. The current surveillance systems have developed independently from each other and clinical, food and animal surveillance systems remain un-integrated in both jurisdictions. A more complete and efficient food safety system could be achieved through co-ordination and linkages across the disease surveillance systems and jurisdictions. For that reason, stronger links are being developed between safefood, surveillance agencies, government departments and public health professionals. This report is an examination and review of the clinical surveillance data collected in both jurisdictions. The work was undertaken as part of safefood’s support for the European Programme for Intervention Epidemiology Training (EPIET), which trains EU medical practitioners, public health nurses, microbiologists or veterinarians in all aspects of foodborne disease surveillance.

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

The intestinal epithelium plays a crucial role in providing a barrier between the external environment and the internal milieu of the body. A compromised mucosal barrier is characteristic of mucosal inflammation and is a key determinant of the development of intestinal diseases such as Crohn's disease and ulcerative colitis. The intestinal epithelium is regularly exposed to serine proteinases and this exposure is enhanced in numerous disease states. Thus, it is important to understand how proteinase-activated receptors (PARs), which are activated by serine proteinases, can affect intestinal epithelial function. This review surveys the data which demonstrate the wide distribution of PARs, particularly PAR-1 and PAR-2, in the gastrointestinal tract and accessory organs, focusing on the epithelium and those cells which communicate with the epithelium to affect its function. PARs have a role in regulating secretion by epithelia of the salivary glands, stomach, pancreas and intestine. In addition, PARs located on subepithelial nerves, fibroblasts and mast cells have important implications for epithelial function. Recent data outline the importance of the cellular site of PAR expression, as PARs expressed on epithelia may have effects that are countered by PARs expressed on other cell types. Finally, PARs and their ability to promote epithelial cell proliferation are discussed in terms of colon cancer.

Biomarkers of human gastrointestinal tract regions.

Dysregulation of intestinal epithelial cell performance is associated with an array of pathologies whose onset mechanisms are incompletely understood. While whole-genomics approaches have been valuable for studying the molecular basis of several intestinal diseases, a thorough analysis of gene expression along the healthy gastrointestinal tract is still lacking. The aim of this study was to map gene expression in gastrointestinal regions of healthy human adults and to implement a procedure for microarray data analysis that would allow its use as a reference when screening for pathological deviations. We analyzed the gene expression signature of antrum, duodenum, jejunum, ileum, and transverse colon biopsies using a biostatistical method based on a multivariate and univariate approach to identify region-selective genes. One hundred sixty-six genes were found responsible for distinguishing the five regions considered. Nineteen had never been described in the GI tract, including a semaphorin probably implicated in pathogen invasion and six novel genes. Moreover, by crossing these genes with those retrieved from an existing data set of gene expression in the intestine of ulcerative colitis and Crohn's disease patients, we identified genes that might be biomarkers of Crohn's and/or ulcerative colitis in ileum and/or colon. These include CLCA4 and SLC26A2, both implicated in ion transport. This study furnishes the first map of gene expression along the healthy human gastrointestinal tract. Furthermore, the approach implemented here, and validated by retrieving known gene profiles, allowed the identification of promising new leads in both healthy and disease states.

Epidemiology of Gastrointestinal Infections in Northern ireland 2012

The Public Health Agency (PHA) has a lead role in protecting the population from infection and environmental hazards through a range of core functions including communicable disease surveillance and monitoring, operational support & advice, and education, training & research. The effective management of infectious disease depends on high quality surveillance. Surveillance of communicable gastrointestinal infectious disease provides timely information so that public health action can result. The range of surveillance outputs is broad and includes: � Weekly surveillance - weekly internal report to the Health Protection team. � Monthly/quarterly and annual returns – to various external bodies including the Food Standards Agency, European Centre and Disease Control, Epidemiology of Foodborne Infections Group and Department of Health, Social Services & Public Safety. � Annual reports and data – published yearly on the PHA website. � Analysis of outbreaks – descriptive and/or analytical epidemiological analysis �