Studies of the gastro-oesophageal junction in normal and overweight healthy volunteers

Introduction: Oesophageal adenocarcinoma has increased dramatically in incidence over the past three decades with a particularly high burden of disease at the gastro-oesophageal junction. Many cases occur in individuals without known gastro-oesophageal reflux disease and in the absence of Barrett’s oesophagus suggesting that mechanisms other than traditional reflux may be important. Distal squamous mucosa may be prone to acid damage even in the absence of traditional reflux by the mechanism of distal opening of the lower oesophageal sphincter. This is splaying of the distal segment of lower oesophageal sphincter allowing acid ingress without traditional reflux. It has been suggested that the cardiac mucosa at the gastro-oesophageal junction, separating oesophageal squamous mucosa and acid secreting columnar mucosa of the stomach may be an abnormal mucosa arising as a consequence of acid damage. By this theory the cardiac mucosa is metaplastic and akin to ultra-short Barrett’s oesophagus. Obesity is a known risk factor for adenocarcinoma at the gastro-oesophageal junction and its rise has paralleled that of oesophageal cancer. Some of this excess risk undoubtedly operates through stress on the gastro-oesophageal junction and a predisposition to reflux. However we sought to explore the impact of obesity on the gastro-oesophageal junction in healthy volunteers without reflux and in particular to determine the characteristics of the cardiac mucosa and mechanisms of reflux in this group. Methods: 61 healthy volunteers with normal and increased waist circumference were recruited. 15 were found to have a hiatus hernia during the study protocol and were analysed separately. Volunteers had comprehensive pathological, physiological and anatomical assessments of the gastro-oesophageal junction including endoscopy with biopsies, MRI scanning before and after a standardised meal, prolonged recording of pH and manometry before and after a meal and screening by fluoroscopy to identify the squamo-columnar junction. In the course of the early manometric assessments a potential error associated with the manometry system recordings was identified. We therefore also sought to document and address this on the benchtop and in vivo. Key Findings: 1. In documenting the behaviour of the manoscan we described an immediate effect of temperature change on the pressure recorded by the sensors; ‘thermal effect’ and an ongoing drift of the recorded pressure with time; ‘baseline drift’. Thermal effect was well compensated within the standard operation of the system but baseline drift not addressed. Applying a linear correction to recorded data substantially reduced the error associated with baseline drift. 2. In asymptomatic healthy volunteers there was lengthening of the cardiac mucosa in association with central obesity and age. Furthermore, the cardiac mucosa in healthy volunteers demonstrated an almost identical immunophenotype to non-IM Barrett’s mucosa, which is considered to arise by metaplasia of oesophageal squamous mucosa. These findings support the hypothesis that the cardia is metaplastic in origin. 3. We have demonstrated a plausible mechanism of damage to distal squamous mucosa in association with obesity. In those with a large waist circumference we observed increased ingress of acid within but not across the lower oesophageal sphincter; ‘intrasphincteric reflux’ 4. The 15 healthy volunteers with a hiatus hernia were compared to 15 controls matched for age, gender and waist circumference. Those with a hiatus hernia had a longer cardiac mucosa and although they did not have excess traditional reflux they had excess distal acid exposure by short segment acid reflux and intrasphincteric acid reflux. Conclusions: These findings are likely to be relevant to adenocarcinoma of the gastro-oesophageal junction

Prevalence of Barrett Esophagus in Adolescents and Young Adults With Esophageal Atresia

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Botulinum toxin in masticatory muscles of the adult rat induces bone loss at the condyle and alveolar regions of the mandible associated with a bone proliferation at a muscle enthesis

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Valor diagnóstico del pepsinógeno i/ii como biomarcador de lesiones pre-malignas y malignas gástricas: revisión sistemática

Antecedentes: El cáncer gástrico se diagnostica tardíamente. Sólo en países como Corea y Japón existen políticas de tamizaje, que se justificarían en cualquier país con alta prevalencia de cáncer gástrico como Colombia o Chile. El análisis del pepsinógeno sérico se ha propuesto para el diagnóstico de lesiones premalignas y malignas gástricas, por lo cual se pretende revisar sistemáticamente en la literatura el valor diagnóstico del cociente pepsinógeno I/II como marcador de lesiones premalignas y malignas gástricas. Metodología: Se revisó la literatura hasta septiembre del 2016 con palabras claves lesiones malignas, premalignas gástricas y pepsinógeno en las bases de datos PubMed, OVID, EMBASE, EBSCO, LILACS, OPENGRAY y Dialnet, artículos de prueba diagnóstica que evaluaran el cociente pepsinógeno I/II en relación con los hallazgos histológicos. Resultados: Se incluyeron 21 artículos conun total de 20601 pacientes, que demuestranuna sensibilidad entre13.7% - 91.2%, una especificidad entre 38.5% - 100%, un Valor Predictivo Positivo entre 6.3% - 100% y un Valor Predictivo Negativo entre 33.3% - 98.8%del cociente pepsinógeno I/II en relación con el diagnósticode lesiones premalignas y malignas gástricas. Conclusiones: Los valores del cociente pepsinógeno I/II disminuidos se relacionan con la presencia delesiones premalignas y malignas gástricas.Dado que tiene mejor especificidad que sensibilidad, en cuanto prueba para tamizaje, sería útil para la selección de pacientes que se beneficiaríande la EVDA. Se requieren más estudios de prueba diagnóstica para validar un punto de corte específico que pueda ser utilizado como valor estándar.

Targeting epigenetic mechanisms in gastric cancer

Gastric cancer (GC) is a hard challenge for medical oncology, with globally over one million of new diagnoses each year and low survival rates. Gastric carcinogenesis is guided by the interaction of several risk factors, exerting through sequential histopathologic steps, including chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and cancer. GC is classified on the basis of anatomical, histological or molecular classification, reflecting the wide cancer heterogeneity, also highlighted by the inefficacy of the actual treatment schedules. Epigenetic mechanisms alterations affecting DNA methylation, histone methylation and acetylation, are a recognized hallmark of cancer and stand at the basis of gastric carcinogenesis and tumor development. The pharmacological targeting of these altered mechanisms is an attractive option for new cancer treatments. Aim of this study was to test the therapeutic potential of the compound CM-272 for GC, a selective and strong dual inhibitor of DNMT1 and EHMT2, which reached important results in pre-clinical models of other gastrointestinal malignancies. Moreover, in a GC patients case series, the expression of the target of the compound was tested, to prove the rationale for inhibition of DNMT1, EHMT2 and their functional adaptor were over-expressed in the majority of GC patients tissues. Through in-vitro testing of CM-272 alone and in combination with the most used chemotherapeutic treatments for GC in a panel of GC cell lines, this study demonstrated that the compound has a strong ability in inhibiting GC cells growth. Even though not directly inducing apoptosis, CM-272 was able to induce a senescent phenotype in GC cells, and to epigenetically reprogram the transcription of genes involved in phosphorylation cascades and mitochondria metabolism, thus affecting the growth and energetic machinery of cancer cells. In conclusion, the pharmacological targeting of epigenetic mechanisms demonstrated good potential pre-clinical models of GC, and further investigations to test in-vivo efficacy are needed.

Riscontri istologici in individui transgender AFAB in terapia con testosterone

CONTESTO: Il rischio oncologico dell’esposizione al testosterone (T) di organi genitali in transgender AFAB non è noto. SCOPO: valutazione istologica di utero, cervice, salpingi e ovaia asportati in corso di intervento chirurgico di affermazione di genere (GAS) in AFAB che assumevano testosterone. MATERIALI E METODI: valutazione dei dati istologici condotta retrospettivamente tramite la consultazione di 187 cartelle cliniche di soggetti transgender AFAB sottoposti a GAS presso la Ginecologia dell’IRCCS Sant’Orsola, Bologna. RISULTATI: 187 transgender AFAB sono stati sottoposti a isteroannessiectomia bilaterale. Nessun paziente sottoposto a ovariectomia, chemioterapia o radioterapia prima della chirurgia. La mediana della durata di assunzione di T era di 36 mesi (12 mesi-14 anni). 96/187 (51.4%) uteri presentavano endometrio ipoattivo/atrofico, mentre 1 caso di iperplasia senza atipie cellulari è stato identificato (0.5%), 8/187 (4.3%) endometrio polipoide e 4/187 (2.2%) secretivo. Il più comune riscontro istologico cervicale è stata la cervicite cronica (n=174, 93%) associata a metaplasia (n=131,76%). Le salpingi sono risultate indenni in 90/187 (48.1%) casi e con infiammazione cronica in 91/187 (48,7%) casi. La maggior parte delle ovaie analizzate mostravano follicoli in diversi stati di maturazione (n=117, 62.5%). In 20 analisi istologiche sono stati identificati corpi lutei/corpi lutei emorragici (10.7%). CONCLUSIONI: Nessuna lesione premaligna o maligna è stata riscontrata in questi 187 soggetti che assumevano testosterone fino a un massimo di 168 mesi prima della chirurgia. La presenza di follicoli in vari stadi di sviluppo e di corpi lutei suggerisce la possibilità di cicli ovulatori in corso di terapia con testosterone. I risultati di questo studio confermano la sicurezza dell'uso prolungato di T sugli organi genitali di transgender AFAB. Seppur ancora limitate, le evidenze suggeriscono sempre più la mancanza di necessità assoluta di rimuovere utero e ovaia nei soggetti trasgender in terapia con T con il solo fine di prevenire patologie oncologiche.