Residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer: locations undetected by endoscopic biopsies in the preSANO trial.

BACKGROUND: Active surveillance has been proposed for patients with oesophageal cancer in whom there is a complete clinical response after neoadjuvant chemoradiotherapy (nCRT). However, endoscopic biopsies have limited negative predictive value in detecting residual disease. This study determined the location of residual tumour following surgery to improve surveillance and endoscopic strategies. METHODS: The present study was based on patients who participated in the prospective preSANO trial with adenocarcinoma or squamous cell carcinoma of the oesophagus or oesophagogastric junction treated in four Dutch hospitals between 2013 and 2016. Resection specimens and endoscopic biopsies taken during clinical response evaluations after nCRT were reviewed by two expert gastrointestinal pathologists. The exact location of residual disease in the oesophageal wall was determined in resection specimens. Endoscopic biopsies were assessed for the presence of structures representing the submucosal layer of the oesophageal wall. RESULTS: In total, 119 eligible patients underwent clinical response evaluations after nCRT followed by standard surgery. Residual tumour was present in endoscopic biopsies from 70 patients, confirmed on histological analysis of the resected organ. Residual tumour was present in the resection specimen from 27 of the other 49 patients, despite endoscopic biopsies being negative. Of these 27 patients, residual tumour was located in the mucosa in 18, and in the submucosa beneath tumour-free mucosa in eight. One patient had tumour in muscle beneath tumour-free mucosa and submucosa. CONCLUSION: Most residual disease after nCRT missed by endoscopic biopsies was located in the mucosa. Active surveillance could be improved by more sampling and considering submucosal biopsies.

ANTECEDENTES: Se ha propuesto un seguimiento activo para los pacientes con cáncer de esófago en los que se logra una respuesta clínica completa tras quimiorradioterapia neoadyuvante (neoadjuvant chemoradiotherapy, nCRT). Sin embargo, las biopsias endoscópicas tienen un valor predictivo limitado para detectar la enfermedad residual. En este estudio se evaluó la localización del tumor residual tras la cirugía para poder determinar estrategias de seguimiento y endoscópicas. MÉTODOS: Este estudio se basa en pacientes que participaron en el ensayo prospectivo preSANO (adenocarcinoma o carcinoma escamoso del esófago o unión esofagogástrica en cuatro hospitales de los Países Bajos entre 2013 y 2016). Los especímenes quirúrgicos, así como las biopsias endoscópicas efectuadas durante las evaluaciones de la respuesta clínica después de nCRT fueron revisadas por dos patólogos gastrointestinales expertos. En los especímenes de resección, se determinó la localización exacta de la enfermedad residual en la pared del esófago. Se evaluaron las biopsias endoscópicas para identificar estructuras que constituyeran la capa submucosa de la pared del esófago. RESULTADOS: En total, 119 pacientes elegibles fueron sometidos a evaluaciones de la respuesta clínica tras nCRT seguida de cirugía estándar. Se detectó tumor residual en las biopsias endoscópicas de 70 pacientes, luego confirmadas en la histología de la pieza extirpada. Se identificó tumor residual en la pieza de resección de 27 de los otros 49 pacientes, a pesar de que las biopsias endoscópicas fueron negativas. En estos 27 pacientes, 18 presentaban tumor residual en la mucosa y ocho pacientes en la submucosa mas allá de una mucosa libre de tumor. Un paciente tenía tumor en el músculo más allá de una mucosa y submucosa libres de tumor. CONCLUSIÓN: La mayoría de los casos de enfermedad residual tras nCRT que no se detectaron en las biopsias endoscópicas, se localizaban en la mucosa. El seguimiento activo podría mejorar con la toma de más muestras y considerando las biopsias submucosas.

Interventions that Facilitate Shared Decision-Making in Cancers with Active Surveillance as Treatment Option: a Systematic Review of Literature.

PURPOSE OF REVIEW: Medical decisions concerning active surveillance are complex, especially when evidence on superiority of one of the treatments is lacking. Decision aids have been developed to facilitate shared decision-making on whether to pursue an active surveillance strategy. However, it is unclear how these decision aids are designed and which outcomes are considered relevant. The purpose of this study is to systematically review all decision aids in the field of oncological active surveillance strategies and outcomes used by authors to assess their efficacy. RECENT FINDINGS: A search was performed in Embase, Medline, Web of Science, Cochrane, PsycINFO Ovid and Google Scholar until June 2019. Eligible studies concerned interventions aiming to facilitate shared decision-making for patients confronted with several treatment alternatives, with active surveillance being one of the treatment alternatives. Twenty-three eligible articles were included. Twenty-one articles included patients with prostate cancer, one with thyroid cancer and one with ovarian cancer. Interventions mostly consisted of an interactive web-based decision aid format. After categorization of outcomes, seven main groups were identified: knowledge, involvement in decision-making, decisional conflict, treatment preference, decision regret, anxiety and health-related outcomes. Although active surveillance has been implemented for several malignancies, interventions that facilitate shared decision-making between active surveillance and other equally effective treatment alternatives are scarce. Future research should focus on developing interventions for malignancies like rectal cancer and oesophageal cancer as well. The efficacy of interventions is mostly assessed using short-term outcomes.

Neoadjuvant chemoradiotherapy for resectable oesophageal cancer.

At present, treatment of potentially curable oesophageal cancer includes neoadjuvant chemoradiotherapy followed by oesophagectomy. Alternatively, neoadjuvant chemotherapy is used. To date, strong evidence on the superiority of one modality over the other has not been provided. Currently, up to one-third of patients show a pathologically complete response after neoadjuvant chemoradiotherapy. To optimise the efficacy of neoadjuvant treatment for individual patients, prediction of response to neoadjuvant treatment is highly desired. Therefore, several clinical diagnostic modalities have been investigated for early response evaluation, of which positron emission tomography (PET) has been studied most extensively. To identify patients who might benefit from postponing or even omitting surgery, recent advances have been made in evaluating response after completion of neoadjuvant chemoradiotherapy. This review provides an overview of current evidence and recent advances in neoadjuvant chemoradiotherapy for oesophageal cancer and discusses the use of neoadjuvant chemotherapy compared to chemoradiotherapy. Moreover, clinical response evaluation to neoadjuvant chemoradiotherapy is reviewed.

Inhibition of alpha-lytic protease by pro region C-terminal steric occlusion of the active site.

alpha-Lytic protease, a chymotrypsin-like serine protease, is synthesized with an N-terminal 166 amino acid pro region which is absolutely required for folding of the protease. The pro region is also the most potent inhibitor of the protease known with a Ki of approximately 10(-10) M. Compared to its role in the folding reaction, relatively little is known about the mechanism by which the pro region inhibits the mature protease. While proteinaceous protease inhibitors generally function by occluding the active sites of their respective targets [Bode, W., & Huber, R. (1992) Eur. J. Biochem. 204, 433-451], the pro region of alpha-lytic protease with its dual roles in folding and inhibition might be expected to show a novel mechanism of inhibition. However, experiments that probe both the structural and enzymatic consequences of pro region binding indicate that the pro region does not measurably distort the protease active site. Instead, the catalytic site is fully functional in the complex. Pro region inhibition of the protease is due to simple steric obstruction; the pro region C-terminus lies in the substrate binding sites of the protease. The implications of these results are discussed with regard to alpha-lytic protease maturation and folding. In addition, the proposed mechanism of alpha-lytic protease pro region inhibition is discussed with respect to data from other pro region families.

Functional linkage between the active site of alpha-lytic protease and distant regions of structure: scanning alanine mutagenesis of a surface loop affects activity and substrate specificity.

Previous structural and kinetic characterization of mutations within the active site of alpha-lytic protease have demonstrated that amino acid residues in direct contact with the substrate are major substrate specificity determinants. The experiments described here identify residues 216-226 of alpha-lytic protease as a region of structure peripheral to the active site that also plays an important role in establishing the substrate specificity of the enzyme. Alanine substitution mutations within this surface loop of 19 amino acid residues significantly perturb the enzyme's specificity profile, despite being as far as 21 A from the hydroxyl group of Ser195. The kinetic consequences of the mutations are remarkably independent of position within the loop and suggest that active site plasticity is affected more than static structure. Kinetic characterization of double mutants with the Met190-->Ala broad-specificity active site mutation reveals varying degrees of non-additivity and indicates that active site plasticity can be influenced through multiple sets of interactions. Although these results clearly demonstrate that tuning of serine protease activity is possible through remodelling of structure surrounding the active site, practical issues such as retaining compatibility with the folding mechanism and stability of the mature enzyme present significant obstacles to general application of the technique.

Importance of amino acids on vasopressin-stimulated water flow.

The presence of several naturally occurring amino acids in the serosal bath of toad urinary bladder significantly alters the hydrosmotic response of this tissue to vasopressin. We found that histidine, glutamate, and lysine increase vasopressin-stimulated water flow by 75%, 60%, and 43%, respectively. In contrast, alanine did not alter vasopressin-stimulated water flow, whereas glutamine decreased it by 25%. The effect of each amino acid represents intracellular events because their effects on theophylline-stimulated water flow were similar to those found with vasopressin. However, the site of action of amino acids varied, with some operating at steps before and others at steps after cyclic AMP generation. The fact that the metabolically inactive D-histidine and D-glutamate are as effective as their metabolically active L-counterparts suggests that the action of amino acids depends upon some physicochemical properties of their molecules. The ability of amino acids to influence the hydrosmotic effects of vasopressin was shown to be independent of prostaglandin generation, ionic composition, and molecular charge. In the case of histidine, we were able to obtain some understanding of the mechanism responsible for its action. We first showed that the effect of histidine does not depend upon its metabolism. In addition to D-histidine being as effective as the metabolically active L-histidine, we also showed that histidine is effective when its metabolism is abolished by low ambient temperature and also when its incorporation into proteins was prevented by cycloheximide. These findings suggest that histidine operates through some physicochemical property localized on its molecule. We were able to show that this property resides on the imidazole part of histidine. Imidazole, similar to histidine, increases vasopressin-stimulated water flow. Methylation of histidine on the imidazole ring completely abolished its effectiveness in increasing vasopressin-stimulated water flow. In contrast, methylation of histidine at the side chain increased vasopressin action similar to that found for histidine. We provide evidence that the physicochemical property of the imidazole ring of histidine is that of chelating Zn++ intracellularly, and that the intracellular site of action of histidine is closely linked to microtubules formation and/or action.