Endoscopic ultrasound as a reliable tool for assessment of pancreatic adenocarcinoma treatment: Example of in situ gene therapy.

Background and study aims In pancreatic cancer, the antitumor effect can only be assessed by means of a computed tomography (CT) scan using RECIST (Response Evaluation Criteria in Solid Tumours) criteria. The aim of this study was to assess the intra-observer and interobserver agreement of endoscopic ultrasound (EUS) imaging in assessing tumor volume in primary pancreatic cancer. Patients and methods During a Phase 1 gene therapy trial, 21 patients had EUS before the first and second EUS-guided in situ gene therapy injections. All anonymized EUS files were then randomly distributed to three gastroenterologists/endosonographers and three radiologists (blind status). The largest tumor diameter was measured and the intraclass correlation coefficient (ICC) was determined. Results Intra-observer and interobserver agreements were good to excellent, regardless of operator experience (junior versus senior member of staff) (ICC: 0.65 to 0.84). A comparison of pretreatment and post-treatment measurements by the investigators highlighted a significant antitumor effect (-11 %; P  = 0.0098), similar to that obtained during the generic protocol (-10 %; P  = 0.0045). Conclusions Interobserver agreement regarding primary pancreatic adenocarcinoma measurements appears good to excellent, thus paving the way for the future inclusion of EUS assessments, particularly in trials assessing local therapies for pancreatic tumors.

Pre-Conditioning Methods and Novel Approaches with Mesenchymal Stem Cells Therapy in Cardiovascular Disease.

Transplantation of mesenchymal stem cells (MSCs) in the setting of cardiovascular disease, such as heart failure, cardiomyopathy and ischemic heart disease, has been associated with good clinical outcomes in several trials. A reduction in left ventricular remodeling, myocardial fibrosis and scar size, an improvement in endothelial dysfunction and prolonged cardiomyocytes survival were reported. The regenerative capacity, in addition to the pro-angiogenic, anti-apoptotic and anti-inflammatory effects represent the main target properties of these cells. Herein, we review the different preconditioning methods of MSCs (hypoxia, chemical and pharmacological agents) and the novel approaches (genetically modified MSCs, MSC-derived exosomes and engineered cardiac patches) suggested to optimize the efficacy of MSC therapy.

Adipose-Derived Stem Cells in the Treatment of Perianal Fistulas in Crohn's Disease: Rationale, Clinical Results and Perspectives.

Between 20 to 25% of Crohn's disease (CD) patients suffer from perianal fistulas, a marker of disease severity. Seton drainage combined with anti-TNFα can result in closure of the fistula in 70 to 75% of patients. For the remaining 25% of patients there is room for in situ injection of autologous or allogenic mesenchymal stem cells such as adipose-derived stem/stromal cells (ADSCs). ADSCs exert their effects on tissues and effector cells through paracrine phenomena, including the secretome and extracellular vesicles. They display anti-inflammatory, anti-apoptotic, pro-angiogenic, proliferative, and immunomodulatory properties, and a homing within the damaged tissue. They also have immuno-evasive properties allowing a clinical allogeneic approach. Numerous clinical trials have been conducted that demonstrate a complete cure rate of anoperineal fistulas in CD ranging from 46 to 90% of cases after in situ injection of autologous or allogenic ADSCs. A pivotal phase III-controlled trial using allogenic ADSCs (Alofisel®) demonstrated that prolonged clinical and radiological remission can be obtained in nearly 60% of cases with a good safety profile. Future studies should be conducted for a better knowledge of the local effect of ADSCs as well as for a standardization in terms of the number of injections and associated procedures.

Direct evidence of sympathetic hyperactivity in patients with vasospastic angina.

BACKGROUND: The autonomic nervous system is reported to be involved in the pathogenesis of vasospastic angina (VSA). Studies based on heart rate variability analysis have shown conflicting results with both a reduction and an enhancement of sympathetic nervous system (SNS) activity in patients with Prinzmetal's variant angina, but direct assessment has never been performed. The aim of our study was to evaluate the SNS activity using microneurography in patients with VSA. METHODS AND RESULTS: The SNS was evaluated by measuring the muscle sympathetic nerve activity (MSNA) with microneurography in 15 patients with VSA confirmed by positive ergonovine provocation test and 15 controls subjects negative for the provocation test. Over the baseline period, SNS activity was higher in patients with VSA compared with control patients (56.8 ± 5 vs. 49.3 ± 6.3 burst/min, p < 0.001, respectively). During mental stress, SNS activity increased significantly only in patients with VSA, which still presented a higher SNS activity than control patients (66.1 ± 7.2 vs. 53.6 ± 8.7 burst/min; p < 0.001, respectively). Furthermore only VSA patients showed significant hemodynamic modifications with an increase in mean arterial blood pressure (96.2 ± 13.4 vs. 86.6 ± 9.6 mmHg in VSA patients and control subjects, respectively; p < 0.05). CONCLUSION: Our results provide the first direct evidence of lasting increased sympathetic activity that is worsened by mental stress in patients with VSA. These results suggest that SNS participate to the pathogenesis of VSA by enhancing coronary vascular tone.

Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes.

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.

Peripheral chemoreflex activation contributes to sympathetic baroreflex impairment in chronic heart failure.

BACKGROUND: Chemoreflex-mediated sympathetic activation contributes to both initiation and progression of chronic heart failure (CHF). METHOD: To study the direct role of increased peripheral chemosensitivity in reducing sympathetic baroreflex function in CHF patients, we compared sympathetic baroreflex function, assessed by the slope of the relationship between muscle sympathetic nerve activity (MSNA) and DBP, in CHF patients with augmented (n = 18) and normal (n = 20) peripheral chemosensitivity. Using a double-blind, randomized, vehicle-controlled study, we examined the effect of chemoreflex deactivation (by breathing 100% oxygen for 15 min) on sympathetic baroreflex function in CHF patients with elevated and with normal chemosensitivity. RESULTS: Baseline MSNA was elevated (60.6 ±â€Š3.2 vs. 48.9 ±â€Š3.7 bursts/min, P < 0.05) and sympathetic baroreflex function impaired (3.06 ±â€Š0.55 vs. 5.51 ±â€Š0.69 % bursts/mmHg, P < 0.05) in CHF patients with augmented peripheral chemosensitivity compared with controls. Administration of 100% oxygen led to a significant decrease in MSNA (from 60.5 ±â€Š3.2 to 52.6 ±â€Š3.2 bursts/min, P < 0.001) and increase in sympathetic baroreflex (from 2.95 ±â€Š0.56 to 6.18 ±â€Š0.77, P < 0.001) in CHF patients with enhanced chemoreflex sensitivity. In contrast, neither room air nor 100% oxygen changed MSNA, hemodynamics or sympathetic baroreflex function in CHF patients with normal chemosensitivity. CONCLUSION: We report for the first time that increased peripheral chemoreflex sensitivity directly decreases sympathetic baroreflex function in CHF patients. This interaction contributes to sympathetic overactivity and blunted sympathetic baroreflex function of CHF patients and may explain how chemoreceptors contribute to the bad prognosis of CHF patients.