α-Parvin Expression in Breast Cancer Tissues: Correlation with Clinical Parameters and Prognostic Significance.

Stromal cells play a critical role in the tumor microenvironment of breast cancer (BC), as they are recruited by tumor cells and regulate the metastatic spread. Though high expression of α-parvin, a member of the parvin family of actin-binding proteins, is reported to be associated with a poor prognosis and metastasis in several cancers, its role in carcinogenesis has not been thoroughly explored. Therefore, we aimed to examine the expression of α-parvin in BC patients by compartmentalizing and quantifying tissues to determine whether α-parvin can be a potential therapeutic target. We performed immunohistochemical (IHC) staining of α-parvin in BC tissues, and the IHC scores were calculated in the overall tissue, stroma, and epithelium using image analysis software. The expression of α-parvin was significantly higher in BC tissues (p = 0.0002) and BC stroma (p < 0.0001) than in normal tissues. Furthermore, all α-parvin scores were significantly positively correlated with the proliferation marker Ki67. The overall and stroma scores are associated with the tumor, (lymph) node, and metastasis (TNM) classification, stage, and grade. These results suggest that high expression of α-parvin in stroma is associated with BCs and might be a new predictive marker for diagnosing BC.

Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner.

Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive occlusion of the internal carotid arteries. Genetic studies originally identified RNF213 as an MMD susceptibility gene that encodes a large 591 kDa protein with a functional RING domain and dual AAA+ ATPase domains. As the functions of RNF213 and its relationship to MMD onset are unknown, we set out to characterize the ubiquitin ligase activity of RNF213, and the effects of MMD patient mutations on these activities and on other cellular processes. In vitro ubiquitination assays, using the RNF213 RING domain, identified Ubc13/Uev1A as a key ubiquitin conjugating enzyme that together generate K63-linked polyubiquitin chains. However, nearly all MMD patient mutations in the RING domain greatly reduced this activity. When full-length proteins were overexpressed in HEK293T cells, patient mutations that abolished the ubiquitin ligase activities conversely enhanced nuclear factor κB (NFκB) activation and induced apoptosis accompanied with Caspase-3 activation. These induced activities were dependent on the RNF213 AAA+ domain. Our results suggest that the NFκB- and apoptosis-inducing functions of RNF213 may be negatively regulated by its ubiquitin ligase activity and that disruption of this regulation could contribute towards MMD onset.

DOK7 gene therapy enhances motor activity and life span in ALS model mice.

Amyotrophic lateral sclerosis (ALS) is a progressive, multifactorial motor neurodegenerative disease with severe muscle atrophy. The glutamate release inhibitor riluzole is the only medication approved by the FDA, and prolongs patient life span by a few months, testifying to a strong need for new treatment strategies. In ALS, motor neuron degeneration first becomes evident at the motor nerve terminals in neuromuscular junctions (NMJs), the cholinergic synapse between motor neuron and skeletal muscle; degeneration then progresses proximally, implicating the NMJ as a therapeutic target. We previously demonstrated that activation of muscle-specific kinase MuSK by the cytoplasmic protein Dok-7 is essential for NMJ formation, and forced expression of Dok-7 in muscle activates MuSK and enlarges NMJs. Here, we show that therapeutic administration of an adeno-associated virus vector encoding the human DOK7 gene suppressed motor nerve terminal degeneration at NMJs together with muscle atrophy in the SOD1-G93A ALS mouse model. Ultimately, we show that DOK7 gene therapy enhanced motor activity and life span in ALS model mice.

Postnatal knockdown of dok-7 gene expression in mice causes structural defects in neuromuscular synapses and myasthenic pathology.

The neuromuscular junction (NMJ) is a synapse between a motor neuron and skeletal muscle and is required for muscle contraction. The formation and maintenance of NMJs are governed by the muscle-specific receptor tyrosine kinase MuSK. We previously showed that the muscle cytoplasmic protein Dok-7 is an essential activator of MuSK. Indeed, mice lacking either Dok-7 or MuSK form no NMJs, and defects in the human DOK7 gene underlie a congenital myasthenic syndrome (an NMJ disorder). However, it remains unproven whether Dok-7 is required for the postnatal maintenance of NMJs. In this study, we generated recombinant adeno-associated virus (AAV) vectors encoding short hairpin RNAs targeting the mouse dok-7 gene (AAV-shD7). Systemic administration of AAV-shD7 into 2-week-old mice down-regulated dok-7 expression in muscle and induced myasthenic symptoms including reduction in body weight and motor function. Moreover, AAV-shD7 treatment suppressed MuSK-dependent gene expression of NMJ components and reduced the size of NMJs. These results demonstrate that correct, physiological levels of dok-7 expression are required for the postnatal maintenance of NMJs.

Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction.

The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Defects in NMJ transmission cause muscle weakness, termed myasthenia. The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs. Here, we show in a mouse model of DOK7 myasthenia that therapeutic administration of an adeno-associated virus (AAV) vector encoding the human DOK7 gene resulted in an enlargement of NMJs and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy, DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. These results suggest that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.

Antitumor effect of 1, 8-cineole against colon cancer.

Several essential oils possess pharmacological effects. Among the various constituents of essential oils, 1, 8-cineole has been shown to possess pharmacological effects such as anti-bacterial and anti-inflammatory effects. The effect of 1, 8-cineole on human colorectal cancer cells, however, has not reported previously. In this study, we have investigated the anti-proliferative effect of 1, 8-cineole on human colon cancer cell lines HCT116 and RKO by WST-8 and BrdU assays. The cytotoxicity of 1, 8-cineole was investigated by LDH activity and TUNEL staining. The mechanism of apoptosis by 1, 8-cineole was determined by western blot analyses. In in vivo study, RKO cells were injected into the SCID mice and the effect of 1, 8-cineole was investigated. Specific induction of apoptosis, not necrosis, was observed in human colon cancer cell lines HCT116 and RKO by 1, 8-cineole. The treatment with 1, 8-cineole was associated with inactivation of survivin and Akt and activation of p38. These molecules induced cleaved PARP and caspase-3, finally causing apoptosis. In xenotransplanted SCID mice, the 1, 8-cineole group showed significantly inhibited tumor progression compared to the control group. These results indicated 1, 8-cineole suppressed human colorectal cancer proliferation by inducing apoptosis. Based on these studies 1, 8-cineole would be an effective strategy to treat colorectal cancer.

Phase II clinical study of modified FOLFOX7 (intermittent oxaliplatin administration) plus bevacizumab in patients with unresectable metastatic colorectal cancer-CRAFT study.

PURPOSE: Continuous treatment with FOLFOX therapy is associated with peripheral nerve toxicity, and to improve this inconvenient side effect various methods of administration are being investigated. A regimen of intermittent oxaliplatin administration by continuous infusion therapy, i.e., modified FOLFOX7 (mFOLFOX7) + bevacizumab, was designed with the goal of alleviating severe peripheral nerve disorders and hematological toxicity. A phase II clinical study was conducted to evaluate the efficacy and safety of this regimen. METHODS: Previously untreated patients were assigned to mFOLFOX7 (oxaliplatin 85 mg/m(2), levofolinate [l-LV] 200 mg/m(2), 5-fluorouracil [5-FU] 2400 mg/m(2)) + bevacizumab (5 mg/kg) administered every 2 weeks for 8 cycles, maintenance without oxaliplatin for 8 cycles, and reintroduction of mFOLFOX7 + bevacizumab for 8 cycles or until disease progression. Progression free survival (PFS) following the first dose (PFS 1) and following reintroduction of oxaliplatin (PFS 2) were used as indices for assessing the efficacy of intermittent administration. RESULTS: Fifty-two patients were enrolled, with median age of 64 years (range, 36-74). Median PFS 1 was 11.8 months (95 % confidence interval [CI], 9.5 to 13.7), median time to treatment failure was 10.3 months (95 % CI, 5.6 to 12.1), percentage of patients with neutropenia of grade 3 or higher was 7.8 %, and percentage with peripheral nerve disorders was 3.9 %. Response rate was 50 %, and 84.4 % of patients who started modified simplified LV5FU2 + bevacizumab were reintroduced to oxaliplatin. CONCLUSION: By excluding 5-FU bolus administration and administering bevacizumab continuously the mFOLFOX7 + bevacizumab regimen with preplanned withdrawal of oxaliplatin showed high tolerability and prevented severe peripheral neuropathy and neutropenia without reducing efficacy.

Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells.

Fatty acid synthase is highly expressed in many types of human cancers. Cerulenin, a natural inhibitor of fatty acid synthase, induced apoptosis in the human colon cancer cell lines HCT116 and RKO. Oxaliplatin also induced cell death in these cell lines. Cerulenin treatment was associated with reduced levels of phosphorylated Akt, activation of p38 and induced caspase-3 cleavage and finally caused apoptosis. Oxaliplatin induced activation of the p53-p21 pathway and p38. In combination with cerulenin and oxaliplatin, activation of the p53-p21 pathway and p38 occurred in a smaller concentration and finally induced caspase-3 cleavage in a smaller concentration of cerulenin and oxaliplatin. In xenotransplanted SCID mice, the cerulenin + oxaliplatin group significantly inhibited tumor progression compared to the control, cerulenin and oxaliplatin groups. Based on these studies, inhibiting fatty acid synthase would be an effective strategy to treat unresectable colorectal cancer tumors in combination with oxaliplatin. Fatty acid synthase inhibitor would be one of the best counterparts of oxaliplatin, which reduces the dose and side-effects of oxaliplatin and would make it possible to endure the chemotherapy over a longer period.

Adaptor protein complex of FRS2ß and CIN85/CD2AP provides a novel mechanism for ErbB2/HER2 protein downregulation.

Overexpression of the ErbB2/HER2 receptor tyrosine kinase contributes to tumorigenesis. However, mechanisms regulating ErbB2 protein levels remain largely unclear. Here, we identified novel mechanisms of ErbB2 downregulation. ErbB2 constitutively binds to an adaptor protein FRS2ß. We found that FRS2ß bound to CD2AP and CIN85, which induces endosomal trafficking that targets lysosomes. FRS2ß colocalized with CIN85 in the cytoplasm. Expression of wild type FRS2ß but not its CIN85 non-binding mutant, downregulated the ErbB2 protein and inhibited anchorage-independent cell growth. Moreover, the E3 ubiquitin-protein ligase Cbl was contained within a complex of FRS2ß and CIN85. Knockdown of both CIN85 and CD2AP or of Cbl, or treatment with lysosomal degradation inhibitors diminished FRS2ß downregulation of ErbB2. In addition, knockdown of endogenous FRS2ß caused upregulation of ErbB2 in primary neural cells. Finally, immunohistochemical analysis showed that human breast cancer tissues that overexpress ErbB2 expressed low levels of FRS2ß. Thus, an FRS2ß-CIN85/CD2AP-Cbl axis for downregulation of ErbB2 may regulate ErbB2 protein levels in physiological and pathological settings. Molecular targeting drugs that can increase or stabilize the ErbB2-FRS2ß-CIN85/CD2AP-Cbl axis may have promise for the control of ErbB2-overexpressing tumors.

Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.

Through their ubiquitin ligase activity, Cbl-family proteins suppress signalling mediated by protein-tyrosine kinases (PTKs), but can also function as adaptor proteins to positively regulate signalling. The tyrosine kinase binding (TKB) domain of this family is critical for binding with tyrosine-phosphorylated target proteins. Here, we analysed the crystal structure of the TKB domain of Cbl-c/Cbl-3 (Cbl-c TKB), which is a distinct member of the mammalian Cbl-family. In comparison with Cbl TKB, Cbl-c TKB showed restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB augmenting this flexibility enhanced its binding to target phosphoproteins. These results suggest that proteins, post-translational modifications or mutations that alter structural flexibility of the TKB domain of Cbl-family proteins could regulate their binding to target phosphoproteins and thereby, affect PTK-mediated signalling.

[Evaluation of modified OPTIMOX1 plus bevacizumab as the neoadjuvant therapy for highly advanced rectal cancers].

UNLABELLED: We evaluated the efficacy and safety of neoadjuvant chemotherapy using modified OPTIMOX1 plus bevacizumab for advanced rectal cancer. PATIENTS AND METHODS: Nine cases with highly advanced rectal cancer for which curative surgery was potentially difficult were enrolled(clinical T4 in 7 cases, lateral node metastasis in 3 cases, M1 in 2 cases). RESULTS: The number of courses of modified OPTIMOX1(mFOLFOX6 and sLV5FU2, alternating administration)plus bevacizumab ranged from 1 to 21(median: 10). Surgical procedures consisted of internal sphincter resection(ISR)in 4 patients, ultra-low anterior resection(ULAR)in 2 patients, pelvic exenteration(TPE)in 2 patients, and Hartmann's procedure in 1 patient. Liver resection was conducted in 2 patients. RM1 was confirmed in 2 patients, but curative surgery was performed in the other patients. Histological efficacy of grade x/1a/1b/2were seen in the above 1/4/2/2 cases, respectively. Neurotoxicity associated with oxaliplatin was mild; no grade 3 neurotoxicity was noted. Recurrence has been confirmed in 5 patients at the median follow-up period of 650 days. CONCLUSION: It was suggested that modified OPTIMOX1 plus bevacizumab is effective and safe to administer as a neoadjuvant chemotherapy for curative resection or anus-preserving surgery in patients with highly advanced rectal cancer.

Activation of receptor protein-tyrosine kinases from the cytoplasmic compartment.

It is widely accepted that receptor protein-tyrosine kinases (RTKs) are activated upon dimerization by binding to their extracellular ligands. However, EGF receptor (EGFR) dimerization per se does not require ligand binding. Instead, its cytoplasmic kinase domains have to form characteristic head-to-tail asymmetric dimers to become active, where one 'activator' domain activates the other 'receiver' domain. The non-catalytic, cytoplasmic regions of RTKs, namely the juxtamembrane and carboxy terminal portions, also regulate kinase activity. For instance, the juxtamembrane region of the RTK MuSK inhibits the kinase domain probably together with a cellular factor(s). These findings suggest that RTKs could be activated by cytoplasmic proteins. Indeed, Dok-7 and cytohesin have recently been identified as such activators of MuSK and EGFR, respectively. Given that failure of Dok-7 signaling causes myasthenia, and inhibition of cytohesin signaling reduces the proliferation of EGFR-dependent cancer cells, cytoplasmic activators of RTKs may provide new therapeutic targets.

NYAP: a phosphoprotein family that links PI3K to WAVE1 signalling in neurons.

The phosphoinositide 3-kinase (PI3K) pathway has been extensively studied in neuronal function and morphogenesis. However, the precise molecular mechanisms of PI3K activation and its downstream signalling in neurons remain elusive. Here, we report the identification of the Neuronal tYrosine-phosphorylated Adaptor for the PI 3-kinase (NYAP) family of phosphoproteins, which is composed of NYAP1, NYAP2, and Myosin16/NYAP3. The NYAPs are expressed predominantly in developing neurons. Upon stimulation with Contactin5, the NYAPs are tyrosine phosphorylated by Fyn. Phosphorylated NYAPs interact with PI3K p85 and activate PI3K, Akt, and Rac1. Moreover, the NYAPs interact with the WAVE1 complex which mediates remodelling of the actin cytoskeleton after activation by PI3K-produced PIP(3) and Rac1. By simultaneously interacting with PI3K and the WAVE1 complex, the NYAPs bridge a PI3K-WAVE1 association. Disruption of the NYAP genes in mice affects brain size and neurite elongation. In conclusion, the NYAPs activate PI3K and concomitantly recruit the downstream effector WAVE complex to the close vicinity of PI3K and regulate neuronal morphogenesis.

[An analysis of palliative surgery for the patients with malignant bowel obstruction].

PURPOSE: The objective of this study was to clarify the surgical outcome of patients with palliative surgery for malignant bowel obstruction. OBJECTIVE AND METHODS: This study investigated the clinical features, operative procedures and postoperative course of 35 patients who underwent a palliative surgery for malignant bowel obstruction. And then the patients were divided into two groups; Patients in A group were consisted of 4 patients with hospital death and 7 patients with postoperative complications. Patients in B group were consisted of 24 patients without hospital death or postoperative complications. RESULT: Eighteen patients who had been inserted nasogastric tube or ileus tube in the preoperative state could be removed. Thirty-three of 35 patients(94.3%)could become an oral ingestion. Four of 35 patients(11.4%)could not be discharged; 3 patients died of cancer and 1 patient died of acute myocardial infarction. Postoperative complications were seen in 7 patients except 4 patients with hospital death. The median postoperative stay was 18 days(3-58). Twenty six of 35 patients(74.3%) underwent chemotherapy. The median survival time was 137 days(3-1,614). The patients in A group showed a lower level of albumin(p=0.0071)and hemoglobin,(p=0.0006)and poorer performance status(p=0.0178)than the patients in B group. The median hospital stay of the patients in A group and B group were 28 days and 16 days, respectively(p=0.0823). The median survival time of the patients in A group and B group were 42 days and 119 days, respectively(p=0.0035). CONCLUSION: We concluded that the palliative surgery made an oral ingestion possible and improved a quality of life of the patients with malignant bowel obstruction. However, the surgical indication should be carefully decided for the patients with low albumin, hemoglobin and poor performance status.

Image overlay navigation by markerless surface registration in gastrointestinal, hepatobiliary and pancreatic surgery.

BACKGROUND: We applied a new concept of "image overlay surgery" consisting of the integration of virtual reality (VR) and augmented reality (AR) technology, in which dynamic 3D images were superimposed on the patient's actual body surface and evaluated as a reference for surgical navigation in gastrointestinal, hepatobiliary and pancreatic surgery. METHODS: We carried out seven surgeries, including three cholecystectomies, two gastrectomies and two colectomies. A Macintosh and a DICOM workstation OsiriX were used in the operating room for image analysis. Raw data of the preoperative patient information obtained via MDCT were reconstructed to volume rendering and projected onto the patient's body surface during the surgeries. For accurate registration, OsiriX was first set to reproduce the patient body surface, and the positional coordinates of the umbilicus, left and right nipples, and the inguinal region were fixed as physiological markers on the body surface to reduce the positional error. RESULTS: The registration process was non-invasive and markerlesss, and was completed within 5 min. Image overlay navigation was helpful for 3D anatomical understanding of the surgical target in the gastrointestinal, hepatobiliary and pancreatic anatomies. The surgeon was able to minimize movement of the gaze and could utilize the image assistance without interfering with the forceps operation, reducing the gap from the VR. Unexpected organ injury could be avoided in all procedures. In biliary surgery, the projected virtual cholangiogram on the abdominal wall could advance safely with identification of the bile duct. For early gastric and colorectal cancer, the small tumors and blood vessels, which usually could not be found on the gastric serosa by laparoscopic view, were simultaneously detected on the body surface by carbon dioxide-enhanced MDCT. This provided accurate reconstructions of the tumor and involved lymph node, directly linked with optimization of the surgical procedures. CONCLUSIONS: Our non-invasive markerless registration using physiological markers on the body surface reduced logistical efforts. The image overlay technique is a useful tool when highlighting hidden structures, giving more information.

Carbon dioxide-enhanced virtual MDCT cholangiopancreatography.

BACKGROUND/PURPOSE: We investigated the feasibility of new carbon dioxide-enhanced virtual multidetector computed tomography (MDCT) cholangiopancreatography (CMCP) for intraluminal exploration in 73 patients with hepatobiliary and pancreatic disease. METHODS: CMCP was performed via a percutaneous or transpapillary drainage tube, and, synchronously, intravenous contrast material was employed for virtual angiography; three-dimensional (3D) virtual reality was incorporated using OsiriX and Fovia applications. The capability of carbon dioxide to delineate the biliary and pancreatic system was evaluated. RESULTS: All CMCPs showed complete technical success; complications including pancreatitis or pain never occurred. The incidences of visible third- and fourth-order biliary branches were 100 and 86.0%. The capability of carbon dioxide to pass an obstruction through an occluded hilar bile duct malignancy was 80.0%; it provided feasible information on additional bile duct segments. The full extent of the gallbladder was depicted in 72.7% of the studies. Minimum 2-mm lesions of biliary stones or gallbladder polyps were clearly detected. The main or second-order pancreatic ducts were visible in 100 and 83.3% of the studies, respectively. Carbon dioxide enabled the replacement of mucin and pancreatic juice and facilitated the detection of cystic lesions of intraductal papillary-mucinous neoplasm (IPMN) in 75.0% of the studies. We succeeded in achieving 3D spatial recognition of vascular structures in the cholangiopancreatic region, through the fusion of CMCP and 3DCT arteriography and venography in a single image scanning, and radiation time was decreased. This combined modality proved to be feasible for planning operations and for image-guided navigated surgery in the resection of a malignancy. CONCLUSIONS: To our knowledge, this is the first report to demonstrate the diagnostic accuracy of carbon dioxide MDCT cholangiopancreatography and the use of this modality for depicting biliary, pancreatic, and fusion blood vessels simultaneously. Carbon dioxide possesses many advantages over conventional iodinated contrast agents, and it might replace more invasive diagnostic measures in the near future.

The roles of Dok family adapters in immunoreceptor signaling.

The mammalian Dok protein family has seven members (Dok-1-Dok-7). The Dok proteins share structural similarities characterized by the NH2-terminal pleckstrin homology and phosphotyrosine-binding domains followed by SH2 target motifs in the COOH-terminal moiety, indicating an adapter function. Indeed, Dok-1 was originally identified as a 62 kDa protein that binds with p120 rasGAP, a potent inhibitor of Ras, upon tyrosine phosphorylation by a variety of protein tyrosine kinases. Among the Dok family, only Dok-1, Dok-2, and Dok-3 are preferentially expressed in hematopoietic/immune cells. Dok-1 and its closest relative Dok-2 act as negative regulators of the Ras-Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is believed that recruitment of p120 rasGAP by Dok-1 and Dok-2 is critical to their negative regulation. By contrast, Dok-3 does not bind with p120 rasGAP. However, accumulating evidence has demonstrated that Dok-3 is a negative regulator of the activation of JNK and mobilization of Ca2+ in B-cell receptor-mediated signaling, where the interaction of Dok-3 with SHIP-1 and Grb2 appears to be important. Here, we review the physiological roles and underlying mechanisms of Dok family proteins.

Rendezvous gastrotomy technique using direct percutaneous endoscopic gastrostomy for transgastric cholecystectomy in hybrid natural orifice translumenal endoscopic surgery.

BACKGROUND/PURPOSE: Transgastric access is a major route in natural orifice translumenal endoscopic surgery (NOTES); gastrotomy should be performed unless it would damage surrounding organs in the peritoneal cavity. This article describes a novel rendezvous gastrotomy technique over a direct percutaneous endoscopic gastrostomy (PEG). METHODS: In six live porcines, the gastrotomy involved applying a direct PEG through the abdominal wall into the stomach and exchanging to a needle trocar. An endoscopic balloon catheter was passed through the trocar by rendezvous technique. Then the inflated balloon and endoscope were advanced to the peritoneal cavity through the gastrotomy. Transgastric cholecystectomy was performed with a hybrid needle grasper through the same percutaneous site and the gastrotomy was closed with endoscopic clips. RESULTS: The rendezvous gastrotomy technique could reduce guidewire exchange. The success rate was 100% (6/6). Mean times for transgastric peritoneoscopy and cholecystectomy were 25.5 and 83.5 min. Mortality and morbidity was 0%. The addition of the extra trocar was unnecessary in all procedures. DISCUSSIONS/CONCLUSIONS: The advantage of this introduction system includes the creation of controlled gastric perforation, which is easier to close. It provides reliable transgastric access and increases safety. It simplifies transgastric NOTES and provides less invasive hybrid NOTES procedure.

Evaluation for transvaginal and transgastric NOTES cholecystectomy in human and animal natural orifice translumenal endoscopic surgery.

BACKGROUND/PURPOSE: Natural orifice translumenal endoscopic surgery (NOTES) is a novel concept using an endoscope via a translumenal access for abdominal surgery. This study was designed to evaluate the feasibility and technical aspects of NOTES cholecystectomy from our experience on humans and animals. METHODS: NOTES cholecystectomies were performed in 12 animal experiments, including 8 pigs (6 by transgastric and 2 by transvaginal accesses) and 4 dogs (4 transvaginal accesses), and a human female cadaver. RESULTS: The entire gallbladder could be removed under direct vision in all experiments. The average time was 60 min by transgastric and 40 min by transvaginal in animals. It was 87 min for human transvaginal cholecystectomy. In all animal and human procedures, there was no major complication concerning the operation. DISCUSSION: The transvaginal route may be the easiest route for abdominal NOTES. Percutaneous endoscopic gastrostomy (PEG) allowed the safe performance of a controlled gastric perforation and shortened the time. The hybrid method allowed performance of a safe procedure and shortened the time. CONCLUSIONS: Transvaginal and transgastric NOTES cholecystectomy is technically feasible and safe in both humans and animals. New instrumentation needs to be developed to perform a pure NOTES cholecystectomy without transabdominal assistance.