Autologous Myoblasts for the Treatment of Fecal Incontinence: Results of a Phase 2 Randomized Placebo-controlled Study (MIAS).

OBJECTIVE: The aim of this study was to evaluate the efficacy of intrasphincteric injections of autologous myoblasts (AMs) in fecal incontinence (FI) in a controlled study. SUMMARY OF BACKGROUND DATA: Adult stem cell therapy is expected to definitively cure FI by regenerating damaged sphincter. Preclinical data and results of open-label trials suggest that myoblast therapy may represent a noninvasive treatment option. METHODS: We conducted a phase 2 randomized, double-blind, placebo-controlled study of intrasphincteric injections of AM in 24 patients. The study compared outcome after AM (n = 12) or placebo (n = 12) injection using Cleveland Clinic Incontinence (CCI), score at 6 and 12 months. Patients in the placebo group were eligible to receive frozen AM after 1 year. RESULTS: At 6 months, the median CCI score significantly decreased from baseline in both the AM (9 vs 15, P = 0.02) and placebo (10 vs 15, P = 0.01) groups. Hence, no significant difference was found between the 2 groups (primary endpoint) at 6 months. At 12 months, the median CCI score continued to ameliorate in the AM group (6.5 vs 15, P = 0.006), while effect was lost in the placebo group (14 vs 15, P = 0.35). Consequently, there was a higher response rate at 12 months in the treated than the placebo arm (58% vs 8%, P = 0.03). After delayed frozen AM injection in the placebo group, the response rate was 60% (6/10) at 12 months. CONCLUSIONS: Intrasphincteric AM injections in FI patients have shown tolerance, safety, and clinical benefit at 12 months despite a transient placebo effect at 6 months.

A step toward NOTES total mesorectal excision for rectal cancer: endoscopic transanal proctectomy.

BACKGROUND: Previous publications have suggested that endoscopic transanal proctectomy (ETAP) is a promising technique and may be an alternative to conventional low anterior resection for rectal cancer. The aim of this study was to evaluate the technical feasibility of ETAP, with a particular focus on postoperative and oncological results and on functional outcomes. METHODS: This study was a multicenter prospective study of unselected consecutive patients with low rectal cancer requiring proctectomy and coloanal anastomosis. All patients underwent a standardized procedure. The study endpoints were the safety and adequacy of the oncological resection criteria. All patients were evaluated with the Wexner Fecal Incontinence Questionnaire after stoma closure. RESULTS: Fifty-six consecutive patients (41 men) underwent ETAP between February 2010 and June 2012. The median age was 65 years (39-83), and the median body mass index was 27 (20-42). No intraoperative complications were encountered. There was no postoperative mortality, and the morbidity rate was 26%. The mesorectum was complete in 47 cases (84%) and nearly complete in 9 cases (16%). The median number of lymph nodes retrieved was 12 (range, 7-29) per patient. The median radial and distal margins were 8 mm (0-20) and 10 mm (3-40), respectively. R0 resection was achieved in 53 patients (94.6%). The median Wexner score was 4 (3-12). Thirteen (28%) patients reported stool fragmentation and difficult evacuation. CONCLUSIONS: ETAP is a feasible alternative surgical option to conventional laparoscopy for rectal resection and may represent a promising step toward rectal natural orifice transluminal endoscopic surgery (NOTES).

Disclosure of funding sources and conflicts of interest in phase III surgical trials: survey of ten general surgery journals.

BACKGROUND: Discussions regarding disclosure of funding sources and conflicts of interest (COI) in published peer-reviewed journal articles are becoming increasingly more common and intense. The aim of the present study was to examine whether randomized controlled trials (RCTs) published in leading surgery journals report funding sources and COI. METHODS: All articles reporting randomized controlled phase III trials published January 2005 through December 2010 were chosen for review from ten international journals. We evaluated the number of disclosed funding sources and COI, and the factors associated with such disclosures. RESULTS: From a review of 657 RCT from the ten journals, we discovered that presence or absence of a funding source and COI was disclosed by 47 % (309) and 25.1 % (165), respectively. Most articles in "International Committee of Medical Journal Editors (ICMJE)-affiliated journals" did not disclose COI. Disclosure of funding was associated with a journal impact factor >3 (51.7 vs 41.6 %; p < 0.01), statistician/epidemiologist involvement (64.2 vs 43.7 %; p < 0.001), publication after 2008 (52.9 vs 41.1 %; p < 0.01), and the journal being ICMJE-affiliated (49.3 vs 40 %; p < 0.05). Conflict of interest disclosure was associated with publication after 2008 (38.7 vs 11.3 %; p < 0.001), and with the journal not being affiliated with ICMJE (36.9 vs 21.3 %; p < 0.001). CONCLUSIONS: Of the published studies we investigated, over half did not disclose funding sources (i.e., whether or not there was a funding source), and almost three quarters did not disclose whether COI existed. Our findings suggest the need to adopt best current practices regarding disclosure of competing interests to fulfill responsibilities to readers and, ultimately, to patients.

Reporting of ethical requirements in phase III surgical trials.

BACKGROUND: Disclosure of obtaining informed consent from patients (ICP) and research ethics committee (REC) approval in published reports is sometimes omitted. To date, no disclosure data are available on surgical research. OBJECTIVE: Our aim was to assess whether REC approval and ICP were documented in surgical trials. STUDY DESIGN: Overall, 657 randomised trials, published between 2005 and 2010 in 10 international journals, were included. We collected the report rate of REC approval and ICP and contacted the corresponding author when ethical information was lacking. RESULTS: Among the 657 randomised controlled trials (RCT), 576 (87.7%) stated that an REC had approved the research, and 606 (92.2%) stated that ICP had been requested. Furthermore, 28 RCTs (4.3%) reported neither REC nor ICP. CONCLUSIONS: The phase III randomised surgical trials that were analysed were shown to have respected fundamental ethical principles in approximately 90% of the cases examines.

Transanal minimal invasive surgery with the Endorec(TM) trocar: a low cost but effective technique.

PURPOSE: Transanal endoscopic microsurgery (TEM) is a well-established surgical approach for local excision of benign adenomas and early-stage rectal cancer. This technique is expensive and associated with a long learning curve. To avoid these obstacles, we have developed an alternative approach using the Endorec(TM) trocar (Aspide, France), which combines the advantages of local transanal excision and single-port access. The aim of this study was to evaluate the feasibility of this technique. PATIENTS AND METHODS: Fourteen consecutive patients underwent transanal resection using Endorec trocar and standard laparoscopic instruments. A retrospective evaluation of the outcome of this technique was performed. RESULTS: Fourteen patients were successfully operated. Rectal lesions included adenoma in ten patients, T1 adenocarcinoma in three and one T2 adenocarcinoma not amenable for abdominal surgery. The average distal margin from the anal verge was 10 cm (range 5-17 cm), and the mean diameter was 3.5 cm (range 1-5 cm). Negative margins were obtained in 13 patients (92,8 %). Median operating time was 60 min (range 20-100). The excisional area was sutured in nine patients. Median postoperative stay was 4 days (range 1-13). Postoperative complications (21 %) included postoperative fever in one patient and two patients were readmitted with rectal blood loss 6 and 15 days postoperatively and were treated with conservative measures. CONCLUSIONS: Our current data show that transanal surgery using Endorec trocar is feasible and safe. Although long-term outcomes and definite indications should be yet evaluated, we believe that this new technique offers a promising alternative to TEM.

Chromosomal instability but lack of transformation in human myoblast preparations.

Genetic alterations have recently been described as emerging during the culture of embryonic stem cells or induced pluripotent stem cells, raising concerns about their safety in future clinical use. Myoblasts are adult stem cells with important therapeutic potential that have been used in clinical trials for almost 20 years, but their genome integrity has not yet been established. Here we produced 10 human myoblast preparations and investigated their genomic stability. At the third passage, half of the preparations had a normal karyotype and half showed one to four alterations/30 metaphases. Chromosome 2 trisomy was found in 1-2/30 metaphases and/or 2/100 nuclei by FISH in 3/10 samples, and there was no other recurrent anomaly. When prolonging cultures, these erratic abnormalities were never associated with a growth advantage. Cellular senescence was manifested in all samples by growth arrest before passage 15. Expression of TERT was always negative. Molecular analysis of individual p53 transcripts did not reveal tumorigenic mutations. CGH array (10 samples) and exome sequencing (one sample) failed to detect copy number variations or accumulation of mutations, respectively. Myoblasts did not grow either in soft agar or in vivo after injection in immunodeficient mice. Hence, occasional genomic abnormalities may occur during myoblast culture but are not associated with risk of transformation.

Hemophagocytic syndrome: an unusual and underestimated complication of cytoreduction surgery with heated intraperitoneal oxaliplatin.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) improves the survival of select patients with peritoneal carcinomatosis. Hemophagocytic syndrome (HS) is a rare and potentially fatal disease. We describe our experience with five patients who developed HS following oxaliplatin HIPEC and propose a management procedure. METHODS: Hyperthermic intraperitoneal chemotherapy was performed using the open-abdomen technique (43 °C) with oxaliplatin (460 mg/m (2) ) for 30 min. If thrombocytopenia occurred from days 5 to 14, heparin-induced thrombocytopenia was evaluated. For thrombocytopenia with unknown etiology, we performed a bone marrow analysis (BMA). A BMA indicating HS stimulated an extensive infectious disease workup. Herein, we describe "reactive septic HS" and HS of unknown origin. RESULTS: We documented five patients with HS as a result of severe thrombocytopenia. Underlying infections were present in two patients who were treated with antibiotics and survived. For the remaining three patients, we found no underlying etiology of HS; multidisciplinary staff adapted the clinical management daily. Two patients died on postoperative days 40 and 29. The third patient survived after several operations and treatment with the VAC abdominal dressing system. CONCLUSIONS: We present these cases to ensure that physicians are aware of the symptoms of HS after HIPEC, which are important for initiating immediate life-saving therapy. This condition is a diagnostic and therapeutic emergency. When HS complicates HIPEC, aggressive, early medical, and surgical management is required. However, the optimal management has not been defined.

[Surgical treatment of anal incontinence]. / Prise en charge chirurgicale de l'incontinence anale.

An epidemiologic assessment of the frequency of anal incontinence and the assessment of the social and economic impact of this handicap allowed progress of the surgery: muscular repair by myorraphy, mainly posterior myorraphy (postanal repair) or sphincteroplasty by direct suture of external anal sphincter, development of an invasive surgery by implantation of a neosphincter (artificial anal sphincter), development of mini-invasive surgery by sacral nerve stimulation, failure of mini-invasive procedures by injection of a bulking agent or radiofrequency, development of cellular therapy by injection of autologous myoblasts. In the same time, progress of digestive functional explorations (anorectal manometry, electrophysiological tests, endoanal ultra sonography, MRI, colonic transit time) and a better knowledge of colonic and ano-rectal physiology improved the surgical thought.

[Surgery for anal incontinence: developments in the past two decades and future directions]. / Chirurgie de l'incontinence anale: évolution depuis vingt ans et perspectives.

Studies showing the frequency of anal incontinence and its social and economic impact have driven progress in surgical treatment, from muscle repair by myorraphy (mainly posterior myorraphy) or sphincteroplasty by direct suture of the external anal sphincter some 20 years ago, to invasive surgery with implantation of an artificial anal sphincter in 1993, mini-invasive surgery based on sacral nerve stimulation in 1998, failure of mini-invasive procedures with injection of a bulking agent or radiofrequency in 2000-2010, and development in 2012 of cellular therapy based on injection of autologous myoblasts. Progress in functional gut exploration (anorectal manometry, electrophysiological tests, endoanal ultrasonography, MRI, colonic transit time) and better knowledge of colonic and ano-rectal physiology will lead to further surgical advances.

Methodological and ethical quality of randomized controlled clinical trials in gastrointestinal surgery.

BACKGROUND: The randomized controlled trial (RCT) is the gold standard tool used to evaluate therapeutic interventions. Methodological and ethical aspects should be adequately reported to enable readers to make informed and justified judgments regarding the validity of a trial and the treatment effectiveness. OBJECTIVE: The aim of this study was to evaluate the methodological and ethical qualities of randomized clinical trials in gastrointestinal surgery and to assess the relationship between these two qualities. STUDY DESIGN: All of the articles chosen for review reported on phase III randomized controlled gastrointestinal surgical trials were published in 12 international journals during 2006 and 2007. The eligible studies were identified, selected, and then evaluated based on a broad set of predetermined criteria. The methodological quality was evaluated using the Jadad scale, and the ethical quality was evaluated using the Berdeu score. RESULTS: The mean Jadad score was 9.7 ± 1.78. The methodological quality was insufficient in 64 RCTs (37.4 %; Jadad score <9). The mean Berdeu score was 0.36 ± 0.08. The journal impact factor, number of randomized patients, and number of centers correlated with the outcome of the Jadad score, and the journal impact factor, industry funding, and year in which the trial began correlated with the outcome of the Berdeu score. Informed consent from patients was not obtained in 7 % (n = 12) of the RCTs, and research ethics committee approval was not mentioned in 14.6 % (n = 25) of the RCTs. CONCLUSIONS: The reporting of gastrointestinal surgery RCTs is less than optimal. In our study, the trials of higher methodological quality were more likely to provide information about their ethical aspects. These results suggest the need for more attention to be paid to the conduct of clinical research and the reporting of ethical aspects. The appropriation of the ethical rules by surgeons involved in human clinical trials could improve the methodology and reporting of RCTs in gastrointestinal surgery.

Long term efficacy of gastric electrical stimulation in intractable nausea and vomiting.

BACKGROUND: Although the efficacy of gastric electrical stimulation has been reported in short-term studies, there is a lack of data on the long-term improvement of nausea and vomiting by gastric electrical stimulation in patients with delayed or normal gastric emptying. METHODS: Thirty-one patients were implanted at our centre for medically refractory severe and chronic nausea and/or vomiting. Patients were evaluated at baseline, 6 months then 5 years after implantation (mean follow-up 80±4 months) using a symptomatic and quality of life scores. KEY RESULTS: Amongst the 31 patients, 4 were lost to follow-up, 6 explanted due to lack of improvement, and 1 patient died. Out of the 20 patients evaluated over 5 years, the quality of life score showed 27% improvement (p<0.01), including nausea (62%; p<0.01), vomiting (111%; p=0.03), satiety (158%; p<0.01), bloating (67%; p<0.01) and epigastric pain (43%; p=0.03). Over 5 years, 15/20 patients reported a 50% improvement with a global satisfaction rated at 64±6%. Therefore, 15/27 patients (56%) were improved by gastric electrical stimulation over 5 years in intention to treat. Improvement of nausea 6 months after implantation was predictive of 5-year success of gastric electrical stimulation (p=0.04). Finally, patients with delayed gastric emptying or with normal gastric emptying rate before surgery were similarly improved over 5 years (60% versus 50% respectively). CONCLUSION: Gastric electrical stimulation is safe and effective in the long term in patients with medically refractory nausea and vomiting, with an efficacy over 50% beyond 5 years in intention to treat. Gastric emptying measured before implantation did not influence the response rate over 5 years.

Combined transanal and laparoscopic approach for the treatment of deep endometriosis infiltrating the rectum.

BACKGROUND: Two surgical approaches are employed in the treatment of deep infiltrating endometriosis of the rectum (DIER): colorectal resection and nodule excision. In 2009, we introduced a new technique for transanal full thickness disc excision of endometriotic nodules infiltrating the low and middle rectum, using the Contour® Transtar™ stapler (Ethicon Endo-Surgery inc., Cincinnati, OH, USA). The aim of this retrospective study was to describe the technique and to present data on the feasibility of this technique. METHODS: From April 2009 to October 2010, all patients presenting with DIER and undergoing full thickness excision using the Contour® Transtar™ stapler were enrolled in the study. Pre-, intra- and post-operative data were collected and reported. RESULTS: Six nulliparous women were managed using this technique during the study period. The rectal wall discs removed measured from 40 × 45 to 60 × 50 mm. In two cases, microscopic foci were noted on one of the margins but in four cases the limits were clear. Operating time varied from 180 to 450 min. Four women were completely free of post-operative digestive complaints. CONCLUSIONS: Despite the small numbers in this series, our data suggest that the new technique of transanal rectal disc excision using the contour stapler may be applied in patients with infiltrating endometrial nodules of the rectum up to 10 cm from the anal margin and up to 5 cm in diameter. This new procedure promises to be a useful addition to the surgeon's armamentarium in a multidisciplinary approach to deep pelvic endometriosis.

[Rectal cancer: situation where a referral center is needed]. / Le cancer du rectum en situation de recours.

One of the objectives of the French strategic plan for cancer 2009-2013 is to structure the need for referral surgery, particularly for low rectal carcinoma. However, low rectal cancer is not the only situation in the field of rectal surgery where expert unit are needed for the referral of appropriate patients. We developed the multidisciplinary strategies for low rectal cancer, advanced rectal cancer, recurrent rectal cancer and peritoneal carcinomatosis. Optimal management of these difficult situations can give a chance of long term survival while a non-optimal management could jeopardise the future of patients by changing a potentially curable disease into an incurable one.

Outcome and cost analysis of sacral nerve modulation for treating urinary and/or fecal incontinence.

BACKGROUND: Sacral nerve modulation (SNM) is an established treatment for urinary and fecal incontinence in patients for whom conservative management has failed. OBJECTIVE: This study assessed the outcome and cost analysis of SNM compared to alternative medical and surgical treatments. METHODS: Clinical outcome and cost-effectiveness analyses were performed in parallel with a prospective, multicenter cohort study that included 369 consecutive patients with urge urinary and/or fecal incontinence. The duration of follow-up was 24 months, and costs were estimated from the national health perspective. Cost-effectiveness outcomes were expressed as incremental costs per 50% of improved severity scores (incremental cost-effectiveness ratio). RESULTS: The SNM significantly improved the continence status (P < 0.005) and quality of life (P < 0.05) of patients with urge urinary and/or fecal incontinence compared to alternative treatments. The average cost of SNM for urge urinary incontinence was ∈8525 (95% confidence interval, ∈6686-∈10,364; P = 0.001) more for the first 2 years compared to alternative treatments. The corresponding increase in cost for subjects with fecal incontinence was ∈6581 (95% confidence interval, ∈2077-∈11,084; P = 0.006). When an improvement of more than 50% in the continence severity score was used as the unit of effectiveness, the incremental cost-effectiveness ratio for SNM was ∈94,204 and ∈185,160 at 24 months of follow-up for urinary and fecal incontinence, respectively. CONCLUSIONS: The SNM is a cost-effective treatment for urge urinary and/or fecal incontinence.

Emergency preoperative stenting versus surgery for acute left-sided malignant colonic obstruction: a multicenter randomized controlled trial.

BACKGROUND: Surgical management of left colonic cancer presenting as an acute obstruction remains controversial and still is associated with high mortality and morbidity rates. Recently, self-expandable metallic stents (SEMS) have been used as a bridge to surgery in an attempt to decompress the colon and then allow elective one-stage surgical resection without stoma placement. This study aimed to compare the outcomes of emergency surgery alone with emergency placement of colonic SEMS as a bridge to surgery in terms of efficiency and reduction of the stoma placement rate. METHODS: A multicenter prospective, randomized, controlled trial was conducted according to the consolidated standards of reporting trials (CONSORT) Statement criteria. Patients eligible for the study were randomized to either emergency surgery or emergency SEMS as a bridge to surgery. The primary outcome was the need for a stoma (temporary or permanent) for any reason. The secondary end points were mortality, morbidity, and length of hospital stay. RESULTS: Nine centers participated in the trial. Among the 70 patients eligible for the study, 60 were randomized and included for the final analysis, 30 patients in each group. Seven patients were randomized but did not fulfill the entry requirements, whereas three further eligible patients were not randomized for various reasons. Concerning the primary outcome, 17 patients in the surgery group sustained a stoma placement versus 13 patients in the SEMS group (p=0.30). No statistically significant difference was noted concerning the secondary outcomes. A total of 16 attempts at SEMS placement (53.3%) were technical failures. Two colonic perforations directly related to the stent placement procedure occurred among the 30 randomized patients and 1 perforation occurred among the nonrandomized patients, leading to premature closure of inclusions in the study before the expected number of 80 patients was reached. CONCLUSION: This randomized trial failed to demonstrate that emergency preoperative SEMS for patients presenting with acute left-sided malignant colonic obstruction could significantly decrease the need for stoma placement.

Surgical management of deep infiltrating endometriosis of the rectum: pleading for a symptom-guided approach.

Two surgical approaches are usually employed in the treatment of deep infiltrating endometriosis of the rectum (DIER): colorectal resection removing the rectal segment affected by the disease, and nodule excision either without opening the rectum (shaving) or by removing the nodule along with the surrounding rectal wall (full thickness or disc excision). Although the present available data are from retrospective series reported by surgeons who generally perform only one technique, there is no evidence to support the risk of recurrences as a valid argument in favour of colorectal resection over rectal nodule excision. The advantage of a lower morbidity associated with nodule excision is not necessarily at the cost of an increased rate of pain recurrences, especially in women benefiting from post-operative medical treatment. The symptom-guided surgical approach in DIER primarily focuses on the relief of digestive symptoms and pelvic pains, rather than on mandatory 'carcinologic' resection of lesions. In addition, the risk of new post-operative unpleasant symptoms as a result of a compulsory and systematic excision of all endometriotic foci may be avoided. In a majority of cases, pelvic anatomy and digestive function can be restored by shaving or disc excision, as well as by colorectal resection; thus digestive complaints can be resolved even when the rectum is conserved. The most accurate evaluation of the results of DIER surgery should be provided by post-operative evolution in digestive function. Even though quality of life is improved for the majority of patients managed by colorectal resection, the question is whether or not a greater health improvement can be achieved by performing nodule excision, which avoids various post-operative and functional digestive complications. In addition, continuous medical treatment leads to a decrease in endometriotic nodules and prevents post-operative pain recurrences. Instead of choosing between medical and surgical management in the treatment of DIER, it is most likely that the two therapies should be associated.

Reporting on quality of life in randomised controlled trials in gastrointestinal surgery.

BACKGROUND: Although health-related quality of life (HRQOL) has become an important outcome measure in surgical trials, questions still remain about the quality of its reporting. The aim of this study was to evaluate HRQOL assessment methodology of randomised clinical trials concerning gastrointestinal surgery. METHODS: All articles published in the calendar years 2006 and 2007 that purported to assess quality of life as end points or make some conclusion about quality of life were chosen for review from eight general surgical journals and four medical journals. Identified eligible studies were selected and then evaluated on a broad set of predetermined criteria. RESULTS: Twenty-four published randomised controlled clinical trials (RCTs)s with an HRQOL component were identified. Although most trials exhibited good-quality research, some methodological limitations were identified: Only 21% of the studies gave a rationale for selecting a specific HRQOL measure, 46% of the studies failed to report information about the administration of the HRQOL measure, and 37% did not give details on missing data. CONCLUSIONS: Although it is clear that HRQOL is an important end point in surgical RCTs because the information helps to influence treatment recommendations, a number of methodological shortcomings have to be further addressed in future studies.

Prognostic value of circulating mutant DNA in unresectable metastatic colorectal cancer.

OBJECTIVE: No validated biologic prognostic marker is presently available in metastatic colorectal cancer (MCRC). We prospectively evaluated the prognostic value of circulating mutant DNA in 31 patients presenting an unresectable MCRC treated by chemotherapy, and we used, as tumor markers, KRAS mutations and methylation of the RASSF2A promoter. METHODS: Detection in the serum of KRAS mutation and RASSF2A methylation were performed using sensitive methods, respectively, real-time polymerase chain reaction (PCR) performed in the presence of a peptide nucleic acid specific of the wild-type sequence and methyl-specific PCR after bisulfite treatment. RESULTS: Among 29 MCRC patients for whom DNA from the primary tumor was available, 23 (79%) presented at least one of the markers in their primary tumor, and 12 of them presented the same alteration in serum. For the 2 remaining patients, RASSF2A methylation was detected in serum indicating that this alteration was present in the primary tumor. These 14 patients with a detectable tumor marker in their serum were designed sDNA+ patients. After 6 months of follow-up, 11/14 (79%) sDNA+ and 1/11 (9%) sDNA- patients presented a progressive disease (P = 0.001). The median progression free survival was 5 months in sDNA+ patients versus 14 months in sDNA- patients (P = 0.004). After 1 year of follow-up, 2 of 14 (14%) sDNA+ and 8 of 11 (73%) sDNA- patients presented no signs of disease progression (P = 0.005). CONCLUSIONS: This study suggests that the presence of circulating mutant DNA in unresectable MCRC patients, which can be detected using simple methods such as methylation-specific PCR or real-time PCR, is highly predictive of clinical outcome.