Natural orifice surgery: initial clinical experience

Natural orifice translumenal endoscopic surgery (NOTES) has moved quickly from preclinical investigation to clinical implementation. However, several major technical problems limit clinical NOTES including safe access, retraction and dissection of the gallbladder, and clipping of key structures. This study aimed to identify challenges and develop solutions for NOTES during the initial clinical experience. Under an Institutional Review Board (IRB)-approved protocol, patients consented to a natural orifice operation for removal of either the gallbladder or the appendix via either the vagina or the stomach using a single umbilical trocar for safety and assistance. Nine transvaginal cholecystectomies, one transgastric appendectomy, and one transvaginal appendectomy have been completed to date. All but one patient were discharged on postoperative day 1 as per protocol. No complications occurred. The limited initial evidence from this study demonstrates that NOTES is feasible and safe. The addition of an umbilical trocar is a bridge allowing safe performance of NOTES procedures until better instruments become available. The addition of a flexible long grasper through the vagina and a flexible operating platform through the stomach has enabled the performance of NOTES in a safe and easily reproducible manner. The use of a uterine manipulator has facilitated visualization of the cul de sac in women with a uterus to allow for safe transvaginal access

Magnetic retraction for NOTES transvaginal cholecystectomy

Natural orifice translumenal endoscopic surgery (NOTES) has the potential to decrease the burden of an operation on a patient. Limitations of the endoscopic platform require innovative solutions to provide retraction and create an operation comparable with the gold standard, laparoscopic cholecystectomy. Four patients underwent transvaginal cholecystectomy. All procedures were performed under laparoscopic vision to ensure safety. The endoscope and a long articulating RealHand instrument were placed via a 15-mm vaginal trocar. A magnetic retraction system was used to retract the gallbladder safely. Laparoscopic clips were used to ligate the cystic duct and artery. All four gallbladders were successfully removed. No complications occurred. The mean operating time was 102 min. All four procedures were completed without complications. The four patients all were discharged shortly after surgery and reported normal sexual activity without pain. Transvaginal cholecystectomy can be completed safely using current technology. Further studies are needed to determine the safety of the procedure and to determine whether it confers any benefits other than cosmesis

NOTES: transvaginal cholecystectomy with assisting articulating instruments

Transvaginal cholecystectomy has been performed at several institutions using hybrid natural orifice translumenal endoscopic surgery (NOTES) techniques. A 42-year-old woman with symptomatic cholelithiasis was taken to the operating room for transvaginal cholecystectomy after giving informed consent. A single 5-mm laparoscope was placed at the umbilicus, followed by a 15-mm trocar through the vaginal conduit. The endoscope and a long flexible RealHand surgical instrument (Novare, Cupertino, CA) were placed via the vaginal trocar. The cystic duct and artery were identified and clipped using laparoscopic clips from the umbilical port. The long articulating laparoscopic instrument provided stable retraction. Hook cautery was used to dissect the gallbladder, which was removed via the vaginal trocar. The vaginal incision was closed using a single figure-of-eight absorbable suture under direct vision. The procedure lasted 96 min. The cholecystectomy was successfully performed without spillage of bile. The patient was kept overnight for observation only as a precaution. She reported no pain and did not require a discharge prescription for narcotics. The described technique for NOTES cholecystectomy results in a virtually scarless operation. The single 5-mm umbilical trocar allows for safe clipping of the cystic duct. Further work is needed to determine the efficacy of this approach

The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

Anaplastic large cell lymphoma represents a subset of neoplasms caused by translocations that juxtapose the anaplastic lymphoma kinase (ALK) to dimerization partners. The constitutive activation of ALK fusion proteins leads to cellular transformation through a complex signaling network. To elucidate the ALK pathways sustaining lymphomagenesis and tumor maintenance, we analyzed the tyrosine-kinase protein profiles of ALK-positive cell lines using 2 complementary proteomic-based approaches, taking advantage of a specific ALK RNA interference (RNAi) or cell-permeable inhibitors. A well-defined set of ALK-associated tyrosine phosphopeptides, including metabolic enzymes, kinases, ribosomal and cytoskeletal proteins, was identified. Validation studies confirmed that vasodilator-stimulated phosphoprotein and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) associated with nucleophosmin (NPM)–ALK, and their phosphorylation required ALK activity. ATIC phosphorylation was documented in cell lines and primary tumors carrying ALK proteins and other tyrosine kinases, including TPR-Met and wild type c-Met. Functional analyses revealed that ALK-mediated ATIC phosphorylation enhanced its enzymatic activity, dampening the methotrexate-mediated transformylase activity inhibition. These findings demonstrate that proteomic approaches in well-controlled experimental settings allow the definition of informative proteomic profiles and the discovery of novel ALK downstream players that contribute to the maintenance of the neoplastic phenotype. Prediction of tumor responses to methotrexate may justify specific molecular-based chemotherapy