Didier Roulin

Guidelines for Perioperative Care in Elective Colonic Surgery: Enhanced Recovery After Surgery (ERAS ® ) Society Recommendations

BackgroundThis review aims to present a consensus for optimal perioperative care in colonic surgery and to provide graded recommendations for items for an evidenced-based enhanced perioperative protocol.MethodsStudies were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English-language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group.ResultsFor most of the protocol items, recommendations are based on good-quality trials or meta-analyses of good-quality trials (quality of evidence and recommendations according to the GRADE system).ConclusionsBased on the evidence available for each item of the multimodal perioperative care pathway, the Enhanced Recovery After Surgery (ERAS) Society, International Association for Surgical Metabolism and Nutrition (IASMEN) and European Society for Clinical Nutrition and Metabolism (ESPEN) present a comprehensive evidence-based consensus review of perioperative care for colonic surgery.

Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations☆

BACKGROUND This review aims to present a consensus for optimal perioperative care in colonic surgery and to provide graded recommendations for items for an evidenced-based enhanced perioperative protocol. METHODS Studies were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English-language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group. RESULTS For most of the protocol items, recommendations are based on good-quality trials or meta-analyses of good-quality trials (quality of evidence and recommendations according to the GRADE system). CONCLUSIONS Based on the evidence available for each item of the multimodal perioperative-care pathway, the Enhanced Recovery After Surgery (ERAS) Society, International Association for Surgical Metabolism and Nutrition (IASMEN) and European Society for Clinical Nutrition and Metabolism (ESPEN) present a comprehensive evidence-based consensus review of perioperative care for colonic surgery.

Cost-effectiveness of the implementation of an enhanced recovery protocol for colorectal surgery.

Enhanced recovery protocols may reduce postoperative complications and length of hospital stay. However, the implementation of these protocols requires time and financial investment. This study evaluated the cost‐effectiveness of enhanced recovery implementation.

Randomized clinical trial on epidural versus patient-controlled analgesia for laparoscopic colorectal surgery within an enhanced recovery pathway.

OBJECTIVE To compare epidural analgesia (EDA) to patient-controlled opioid-based analgesia (PCA) in patients undergoing laparoscopic colorectal surgery. BACKGROUND EDA is mainstay of multimodal pain management within enhanced recovery pathways [enhanced recovery after surgery (ERAS)]. For laparoscopic colorectal resections, the benefit of epidurals remains debated. Some consider EDA as useful, whereas others perceive epidurals as unnecessary or even deleterious. METHODS A total of 128 patients undergoing elective laparoscopic colorectal resections were enrolled in a randomized clinical trial comparing EDA versus PCA. Primary end point was medical recovery. Overall complications, hospital stay, perioperative vasopressor requirements, and postoperative pain scores were secondary outcome measures. Analysis was performed according to the intention-to-treat principle. RESULTS Final analysis included 65 EDA patients and 57 PCA patients. Both groups were similar regarding baseline characteristics. Medical recovery required a median of 5 days (interquartile range [IQR], 3-7.5 days) in EDA patients and 4 days (IQR, 3-6 days) in the PCA group (P = 0.082). PCA patients had significantly less overall complications [19 (33%) vs 35 (54%); P = 0.029] but a similar hospital stay [5 days (IQR, 4-8 days) vs 7 days (IQR, 4.5-12 days); P = 0.434]. Significantly more EDA patients needed vasopressor treatment perioperatively (90% vs 74%, P = 0.018), the day of surgery (27% vs 4%, P < 0.001), and on postoperative day 1 (29% vs 4%, P < 0.001), whereas no difference in postoperative pain scores was noted. CONCLUSIONS Epidurals seem to slow down recovery after laparoscopic colorectal resections without adding obvious benefits. EDA can therefore not be recommended as part of ERAS pathways in laparoscopic colorectal surgery.

Systematic Review of Delayed Postoperative Hemorrhage after Pancreatic Resection

IntroductionThis review assesses the presentation, management, and outcome of delayed postpancreatectomy hemorrhage (PPH) and suggests a novel algorithm as possible standard of care.MethodsAn electronic search of Medline and Embase databases from January 1990 to February 2010 was undertaken. A random-effect meta-analysis for success rate and mortality of laparotomy vs. interventional radiology after delayed PPH was performed.ResultsFifteen studies comprising of 248 patients with delayed PPH were included. Its incidence was of 3.3%. A sentinel bleed heralding a delayed PPH was observed in 45% of cases. Pancreatic leaks or intraabdominal abscesses were found in 62%. Interventional radiology was attempted in 41%, and laparotomy was undertaken in 49%. On meta-analysis comparing laparotomy vs. interventional radiology, no significant difference could be found in terms of complete hemostasis (76% vs. 80%; P = 0.35). A statistically significant difference favored interventional radiology vs. laparotomy in term of mortality (22% vs. 47%; P = 0.02).ConclusionsProper management of postoperative complications, such as pancreatic leak and intraabdominal abscess, minimizes the risk of delayed PPH. Sentinel bleeding needs to be thoroughly investigated. If a pseudoaneurysm is detected, it has to be treated by interventional angiography, in order to prevent a further delayed PPH. Early angiography and embolization or stenting is safe and should be the procedure of choice. Surgery remains a therapeutic option if no interventional radiology is available, or patients cannot be resuscitated for an interventional treatment.

Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo

The mammalian target of rapamycin (mTOR), which exists in two functionally distinct complexes, mTORC1 and mTORC2 plays an important role in tumor growth. Whereas the role of mTORC1 has been well characterized in this process, little is known about the functions of mTORC2 in cancer progression. In this study, we explored the specific role of mTORC2 in colon cancer using a short hairpin RNA expression system to silence the mTORC2-associated protein rictor. We found that downregulation of rictor in HT29 and LS174T colon cancer cells significantly reduced cell proliferation. Knockdown of rictor also resulted in a G1 arrest as observed by cell cycle analysis. We further observed that LS174T cells deficient for rictor failed to form tumors in a nude mice xenograft model. Taken together, these results show that the inhibition of mTORC2 reduces colon cancer cell proliferation in vitro and tumor xenograft formation in vivo. They also suggest that specifically targeting mTORC2 may provide a novel treatment strategy for colorectal cancer.

Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib

BackgroundTargeted therapies for metastatic renal cell carcinoma (RCC), including mammalian target of rapamycin (mTOR) inhibitors and small-molecule multikinase inhibitors, have produced clinical effects. However, most patients acquire resistance over time. Thus, new therapeutic strategies need to be developed. Here, we evaluated the effect of the dual PI3K/mTOR inhibitor NVP-BEZ235, in combination with the multikinase inhibitor sorafenib on renal cancer cell proliferation and survival in vitro as well as on tumor growth in vivo.MethodsThe renal carcinoma cell lines 786-0 and Caki-1 were treated with NVP-BEZ235 or sorafenib, either alone or in combination. Tumor cell proliferation and apoptosis were investigated in vitro. The anticancer efficacy of NVP-BEZ235 alone, or in combination with sorafenib, was also evaluated on RCC xenografts in nude mice.ResultsTreatment of 786-0 and Caki-1 cells with NVP-BEZ235 or sorafenib resulted in reduced tumor cell proliferation and increased tumor cell apoptosis in vitro. The combination of NVP-BEZ235 and sorafenib was more effective than each compound alone. Similarly, in vivo, NVP-BEZ235 or sorafenib reduced the growth of xenografts generated from 786-0 or Caki-1 cells. The antitumor efficacy of NVP-BEZ235 in combination with sorafenib was superior to NVP-BEZ235 or sorafenib alone.ConclusionsOur findings indicate that the simultaneous use of NVP-BEZ235 and sorafenib has greater antitumor benefit compared to either drug alone and thus provides a treatment strategy in RCC.

The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors.

The mammalian target of rapamycin (mTOR) which is part of two functionally distinct complexes, mTORC1 and mTORC2, plays an important role in vascular endothelial cells. Indeed, the inhibition of mTOR with an allosteric inhibitor such as rapamycin reduces the growth of endothelial cell in vitro and inhibits angiogenesis in vivo. Recent studies have shown that blocking mTOR results in the activation of other prosurvival signals such as Akt or MAPK which counteract the growth inhibitory properties of mTOR inhibitors. However, little is known about the interactions between mTOR and MAPK in endothelial cells and their relevance to angiogenesis. Here we found that blocking mTOR with ATP-competitive inhibitors of mTOR or with rapamycin induced the activation of the mitogen-activated protein kinase (MAPK) in endothelial cells. Downregulation of mTORC1 but not mTORC2 had similar effects showing that the inhibition of mTORC1 is responsible for the activation of MAPK. Treatment of endothelial cells with mTOR inhibitors in combination with MAPK inhibitors reduced endothelial cell survival, proliferation, migration and tube formation more significantly than either inhibition alone. Similarly, in a tumor xenograft model, the anti-angiogenic efficacy of mTOR inhibitors was enhanced by the pharmacological blockade of MAPK. Taken together these results show that blocking mTORC1 in endothelial cells activates MAPK and that a combined inhibition of MAPK and mTOR has additive anti-angiogenic effects. They also provide a rationale to target both mTOR and MAPK simultaneously in anti-angiogenic treatment.

Early Versus Delayed Cholecystectomy for Acute Cholecystitis, Are the 72 hours Still the Rule?: A Randomized Trial.

Objective: The aim of this study was to compare clinical outcomes of early versus delayed laparoscopic cholecystectomy (LC) in acute cholecystitis with more than 72 hours of symptoms. Background: LC is the treatment of acute cholecystitis, with consensus recommendation that patients should be operated within 72 hours of evolution. Data however remain weak with no prospective study focusing on patients beyond 72 hours of symptoms. Methods: Patients with acute cholecystitis and more than 72 hours of symptoms were randomly assigned to early LC (ELC) or delayed LC (DLC). ELC was performed following hospital admission. DLC was planned at least 6 weeks after initial antibiotic treatment. Primary outcome was overall morbidity following initial diagnosis. Secondary outcomes were total length of stay, duration of antibiotic therapy, hospital costs, and surgical outcome. Results: Eighty-six patients were randomized (42 in ELC and 44 in DLC group). Overall morbidity was lower in ELC [6 (14%) vs 17 (39%) patients, P = 0.015]. Median total length of stay (4 vs 7 days, P < 0.001) and duration of antibiotic therapy (2 vs 10 days, P < 0.001) were shorter in the ELC group. Total hospital costs were lower in ELC (9349&OV0556; vs 12,361 &OV0556;, P = 0.018). Operative time and postoperative complications were similar (91 vs 88 min; P = 0.910) and (15% vs 17%; P = 1.000), respectively. Conclusions: ELC for acute cholecystitis even beyond 72 hours of symptoms is safe and associated with less overall morbidity, shorter total hospital stay, and duration of antibiotic therapy, as well as reduced cost compared with delayed cholecystectomy (NCT01548339).

ATP-competitive inhibitors of mTOR: new perspectives in the treatment of renal cell carcinoma

Targeting mTOR (mammalian target of rapamycin) is an effective approach in the treatment of advanced RCC (renal cell carcinoma). Rapamycin-like drugs (rapalogues) have shown clinical activities and have been approved for the treatment of RCC. Recently, with the development of ATP-competitive inhibitors of mTOR, therapies targeting mTOR have entered a new era. Here, we discuss the biological relevance of blocking mTOR in RCC and review the mechanisms of action of rapalogues in RCC. We also advance some perspectives on the use of ATP-competitive inhibitors of mTOR in RCC.