Various factors contribute to low reproducibility and replicability of scientific findings. Whilst not all of these are necessarily problematic, there is growing acceptance that there is room for ...improvement. Many sectoral organisations have a role to play in this, by refining incentives and rewards, promoting specific behaviours such as open research practices, and exploring innovations in grant funding and scientific publishing. However, given the systems nature of the challenge, real change will require the coordination of these efforts, and partnerships that ensure alignment of activity and interoperability of training. Efforts to improve research quality will require investment, in infrastructure, training, and research on research to ensure that innovative solutions are evidence-based, and potential unintended consequences are explored (and avoided). National structures (e.g., the planned UK Committee on Research Integrity) should focus on understanding the research system, identifying areas for improvement, and promoting research to understand the impact of novel approaches and innovations, in order to advise on how to maximise benefit and avoid harm.
Peroral endoscopic myotomy is an accepted treatment of achalasia. Some of the treatment failures can be attributable to an insufficient length of the myotomy on the gastric side, because of a more ...technically challenging submucosal dissection. We assessed the feasibility and the impact of an intraoperative esophageal manometry during the peroral endoscopic myotomy procedure. A high-resolution manometry catheter was introduced through the nostril before the endoscope, and left in place during the peroral endoscopic myotomy procedure. The lower esophageal sphincter pressure was recorded throughout the peroral endoscopic myotomy. The myotomy was extended on the gastric side until the lower esophageal sphincter pressure dropped below 10 mmHg. We included 10 patients (mean age = 55 years old, 3 men) treated by peroral endoscopic myotomy for type I (3/10), type II (3/10), type III achalasia (3/10) or esophagogastric junction outflow obstruction (1/10). Manometric recording was possible in all patients. The median (IQR) lower esophageal sphincter resting pressure was 23 (17-37) mmHg before myotomy, 15 (13-19) mmHg at the end of the tunnel, and 7 (6-11) mmHg at the end of the myotomy. In 4 patients out of 10, the myotomy was extended on the base of the intraoperative manometry findings. High-resolution esophageal manometry is feasible during the peroral endoscopic myotomy procedure, and leads to increase the length of the gastric myotomy in 4 out of 10 patients. However, the cumbersome nature of intraoperative high-resolution manometry during peroral endoscopic myotomy and the high frequency of gastro-esophageal reflux disease after extended gastric myotomy suggest to limit this technique to selected patients refractory to a first myotomy.
Background
A novel three-dimensional high-resolution esophageal manometry provides a dynamic 360° representation of the pressure at the esophagogastric junction.
Aims
To describe the ...three-dimensional high-resolution esophageal manometry patterns of achalasia.
Methods
We retrospectively included all consecutive patients who underwent three-dimensional high-resolution esophageal manometry before and after treatment (pneumatic dilatation or per-oral endoscopic myotomy) for achalasia between November 2016 and July 2017. The distribution of the pressures at the esophagogastric junction on three-dimensional high-resolution esophageal manometry was determined.
Results
Eighteen patients were included. Mean integrated relaxation pressure was 20.7 mmHg, and median (range) Eckardt score was 7 (4–10). Nine patients were treated by pneumatic dilatation and seven by myotomy. Nine patients underwent three-dimensional high-resolution esophageal manometry after treatment. Before treatment, the esophagogastric junction pressure distribution was best observed at end expiration and during the 4 s of the integrated relaxation pressure measurement. During the integrated relaxation pressure, the lower esophageal sphincter was asymmetric in 12 patients with a high-pressure zone between the left and the posterior side of the esophagogastric junction. After treatment, five patients had a residual high-pressure point on the left or the posterior side of the esophagogastric junction.
Conclusions
Three-dimensional high-resolution esophageal manometry allows a simple assessment of the pressure topography at the EGJ. In patients with achalasia, we found the esophagogastric junction pressure to be asymmetric with a peak pressure on the greater curvature side. Three-dimensional high-resolution esophageal manometry has the potential to guide initial and redo treatments.
Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic ...variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors.
Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis.
Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008). Multivariate analysis showed that increased cumulated sorafenib (AUC(cum)) was independently associated with any grade ≥ 3 toxicity (p = 0.037); UGT1A9 polymorphism (rs17868320) with grade ≥ 2 diarrhea (p = 0.015) and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018). Using ROC curve, the threshold AUC(cum) value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018).
In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320) identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.
Background and Aim
Zenker's diverticulum (ZD) is the most common type of diverticulum in the esophagus. The endoscopic septotomy of the diverticular wall has become a widely accepted treatment ...modality, but the recurrence rate is unclear. Our aim was to assess short‐term and long‐term success rates after flexible endoscopic septotomy for the treatment of ZD.
Methods
All consecutive patients treated at our department for a ZD between November 2014 and September 2018 were included. Endoscopic septotomy was conducted using a diverticuloscope or a distal attachment cap. Data were retrospectively analyzed from a prospectively collected database. We collected data concerning patients, endoscopic procedures, and short‐term clinical outcomes. All patients were reached by phone between October and December 2018 to assess long‐term results.
Results
Seventy‐seven patients were referred to our department for a ZD. Sixty patients were treated using a diverticuloscope and 17 patients with a distal attachment cap. For all 77 patients, the myotomy was technically successful. Three patients treated with a diverticuloscope reported complications. Initial treatment success was 93%. After a mean (±SEM) follow up of 23 ± 2 months, 66% of patients had persistent clinical remission. The rate of long‐term treatment success was 72% in treatment‐naïve and 50% in previously treated patients (P = 0.13). Treatment success was 68% in patients treated with the diverticuloscope versus 60% in the group treated with a cap (P = 0.75).
Conclusion
The flexible endoscopic septotomy for the treatment of ZD is a safe and effective treatment of ZD, with or without a diverticuloscope.
By using the differential in level of oxidative status between normal and cancer cells, SuperOxide Dismutase (SOD) mimetics can have anti-tumor efficacy and prevent oxaliplatin-induced peripheral ...neuropathy. Our objective was to evaluate the neuroprotective efficacy of MAG, a new SOD mimic. In vitro, the effects of MAG alone or with oxaliplatin were studied on colon cancer cells (HT29 and CT26) and on normal fibroblast cells (NIH3T3). The cell viability (by crystal violet) as well as the production of reactive forms of oxygen and glutathione (by spectrofluorimetric assay) was measured. In vivo, efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. The effects on induced neurotoxicity were measured by specific behavioral Von Frey nociception, cold-plate tests, specific functional neuromuscular assay and electron microscopy. In vitro, MAG induced a production of hydrogen peroxide in all cells. At 24 h-incubation, MAG exhibits a cytotoxic activity in all cell lines. A cytotoxic additive effect of MAG and oxaliplatin was observed through oxidative burst. In vivo, oxaliplatin-treated mice associated with MAG did not counteract oxaliplatin's antitumoral efficacy. After 4 weeks of treatment with oxaliplatin combined with MAG, behavioral and functional tests showed a decrease in peripheral neuropathy induced by oxaliplatin in vivo. Electron microscopy analyses on sciatic nerves revealed an oxaliplatin-induced demyelination which is prevented by the association of MAG to this chemotherapy. In conclusion, MAG prevents the appearance of sensitive axonal neuropathy and neuromuscular disorders induced by oxaliplatin without affecting its antitumor activity.
Summary
Background
The prognosis of patients with metastatic carcinoma of the biliary tract (mBTC) is poor and a systemic therapy with gemcitabine and platinum-based is the gold standard. The ...addition of bevacizumab to the chemotherapy might increase patients’ survival. Our aim was to assess and compare the efficacy of GEMOX (gemcitabine and oxaliplatin regimen) plus bevacizumab to GEMOX alone in mBTC.
Methods
Patients with mBTC who received the GEMOX-bevacizumab (
n
= 32; Group A) or GEMOX (
n
= 25; Group B) regimen as first-line treatment were compared. Treatment was repeated every two weeks until disease progression or unacceptable adverse effects occurred. The primary evaluation criterion was the progression-free survival (PFS).
Results
A quarter of patients (8/32) from Group A and a fifth of patients (13/25) from Group B had an objective response. The median PFS was 6.48 months and 3.72 months in Group A and B, respectively (
p
= 0.049). The median OS was 11.31 months and 10.34 months in Group A and B, respectively. Grade 3/4 sepsis was identified in 9.4% and 12% in Group A and B, respectively, (
p
= 0.64).
Conclusion
In mBTC, the addition of bevacizumab to GEMOX increased the progression-free survival and was associated with manageable toxicity. These data pave the way for further evaluation of antiangiogenic agents in mBTC.
To investigate functional platelet recovery after preoperative withdrawal of aspirin and clopidogrel and platelet function 5 days after treatment resumption.
We conducted an observational study, ...which prospectively included consecutive patients taking aspirin, taking clopidogrel, and untreated controls (15 patients in each group). The antiplatelet drugs were withdrawn five days before surgery (baseline) and were reintroduced two days after surgery. Platelet function was evaluated by optical aggregation in the presence of collagen, arachidonic acid (aspirin) and ADP (clopidogrel) and by VASP assay (clopidogrel). Platelet-leukocyte complex (PLC) level was quantified at each time-point. At baseline, platelet function was efficiently inhibited by aspirin and had recovered fully in most patients 5 days after drug withdrawal. PLC levels five days after aspirin reintroduction were similar to baseline (+4±10%; p = 0.16), in line with an effective platelet inhibition. Chronic clopidogrel treatment was associated with variable platelet inhibition and its withdrawal led to variable functional recovery. PLC levels were significantly increased five days after clopidogrel reintroduction (+10±15%; p = 0.02), compared to baseline.
Aspirin withdrawal 5 days before high-bleeding-risk procedures was associated with functional platelet recovery, and its reintroduction two days after surgery restored antiplaletet efficacy five days later. This was not the case of clopidogrel, and further work is therefore needed to define its optimal perioperative management.
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