Norifumi Tsutsumi

Essential Role of PDGFRα-p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo: Role of PDGFRα During Angiogenesis

Discovery of the common and ubiquitous molecular targets for the disruption of angiogenesis, that are independent of the characteristics of malignant tumors, is desired to develop the more effective antitumor drugs. In this study, we propose that the platelet-derived growth factor receptor-&agr;(PDGFR&agr;)-p70S6K signal transduction pathway in mesenchymal cells, which is required for functional angiogenesis induced by fibroblast growth factor-2, is the potent candidate. Using murine limb ischemia as a tumor-free assay system, we demonstrated that p70S6K inhibitor rapamycin (RAPA) targets mesenchymal cells to shut down the sustained expression of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), via silencing of the PDGFR&agr;-p70S6K pathway. Irrespective of the varied expression profiles of angiogenic factors in each tumor tested, RAPA constantly led the tumors to dormancy and severe ischemia in the time course, even associated with upregulated expression of VEGF from tumors. Because RAPA showed only a minimal effect to hypoxia-related expression of VEGF in culture, these results suggest that RAPA targets the host-vasculature rather than tumor itself in vivo. Thus, our current study indicates that the PDGFR&agr;-p70S6K pathway is an essential regulator for FGF-2–mediated therapeutic neovascularization, as well as for the host-derived vasculature but not tumors during tumor angiogenesis, via controlling continuity of expression of multiple angiogenic growth factors.

Impact of Antithrombin III Concentrates on Portal Vein Thrombosis After Splenectomy in Patients With Liver Cirrhosis and Hypersplenism

Objective:The aim of this study was to determine the role of antithrombin III (AT-III) in portal vein thrombosis (PVT) after splenectomy in cirrhotic patients. Summary Background Data:There is no standard treatment for PVT after splenectomy in liver cirrhosis. Methods:A total of 50 consecutive cirrhotic patients who underwent laparoscopic splenectomy for hypersplenism were enrolled into this study. From January 2005 to December 2005, 25 cirrhotic patients received no prophylactic anticoagulation therapy after the operation (AT-III [−] group). From January 2006 to July 2006, 25 cirrhotic patients received prophylactic administration of AT-III concentrates (1500 U/d) on postoperative day (POD) 1, 2, and 3 (AT-III [+] group). Results:In AT-III (−) group, 9 (36.0%) patients developed PVT up to POD 7, and risk factors for PVT were identified as: low platelet counts, low AT-III activity, and increased spleen weight. Although there were no significant differences in the clinical characteristics, including the above risk factors, between the 2 groups, only 1 (4.0%) patient developed PVT on POD 30 in AT-III (+) group, and the incidence of PVT was significantly lower than in AT-III (−) group (P = 0.01). In AT-III (−) group, AT-III activity was significantly decreased from POD 1 to POD 7, as compared with the preoperative level, whereas AT-III concentrates prevented the postoperative decrease in AT-III activity. Conclusions:These results demonstrate that low AT-III activity and further decreases in this activity are associated with PVT after splenectomy in cirrhotic patients, and that treatment with AT-III concentrates is likely to prevent the development of PVT in these patients.

Technical standardization of laparoscopic splenectomy harmonized with hand‐assisted laparoscopic surgery for patients with liver cirrhosis and hypersplenism

BACKGROUND/PURPOSE The aims of this study were to standardize the techniques of laparoscopic splenectomy (LS) to improve safety in liver cirrhosis patients with portal hypertension. METHODS From 1993 to 2008, 265 cirrhotic patients underwent LS. Child-Pugh class was A in 112 patients, B in 124, and C in 29. Since January 2005, we have adopted the standardized LS including the following three points: hand-assisted laparoscopic surgery (HALS) should be performed in patients with splenomegaly (> or =1,000 mL), perisplenic collateral vessels, or Child-Pugh score 9 or more; complete division and sufficient elevation of the upper pole of the spleen should be performed before the splenic hilar division; and when surgeons feel the division of the upper pole of the spleen is too difficult, conversion to HALS should be performed. RESULTS There were no deaths related to LS in this study. After the standardization, conversion to open surgery significantly reduced from 11 (10.3%) of 106 to 3 (1.9%) of 159 patients (P < 0.05). The average operation time and blood loss significantly reduced from 259 to 234 min (P < 0.01) and from 506 to 171 g (P < 0.01), respectively. CONCLUSIONS With the technical standardization, LS becomes a feasible and safe approach in the setting of liver cirrhosis and portal hypertension.

Laparoscopic splenectomy with interferon therapy in 100 hepatitis-C-virus-cirrhotic patients with hypersplenism and thrombocytopenia.

Background and Aim:  We intended to determine whether laparoscopic splenectomy (Lap‐Sp) contributes to treatment with interferon therapy in hepatitis C virus (HCV)‐cirrhotic patients with thrombocytopenia caused by hypersplenism.

Impact of balloon‐occluded retrograde transvenous obliteration on management of isolated fundal gastric variceal bleeding

Aim:  Although endoscopic injection of cyanoacrylate (CA) is the only effective method for treating isolated fundal gastric variceal bleeding, the rebleeding rate is relatively high. This study investigated the efficacy of balloon‐occluded retrograde transvenous obliteration (B‐RTO) for management of isolated fundal gastric variceal bleeding.

Significance of metacognitive skills in laparoscopic surgery assessed by essential task simulation

Abstract Background: Metacognition is the knowledge about ones own methods of perceiving, remembering, thinking, and acting. This study determined the significance of metacognitive skills in laparoscopic surgery with the aim of applying the findings in a laparoscopic surgery training program. Material and methods: Eighteen medical students with no experience in laparoscopic surgery (novice group) and eight expert surgeons who had each performed >100 laparoscopic surgeries (expert group) were enrolled. The examinees in each group performed an evaluation task using a virtual reality simulator and answered questions about the task. Results: The longest performance times, longest path lengths, and most frequent tissue damage occurred at 135° in the novice group and at 180° in the expert group. The greatest recognition of task difficulties, impatience, and irritation occurred at 135° in the novice group and at 180° in the expert group. There were statistically significant correlation coefficients between the instrument path length and task difficulty (metacognition) at 135° (R = 0.74, p = 0.03) and 180° (R = 0.79, p = 0.02) in the expert group, but there were no significant correlations in the novice group. Conclusion: We elucidated the significance of metacognitive skills in laparoscopic surgery. A training program should include recognition feedback systems.

Ultra-minimally invasive local immune cell therapy and regenerative therapy by multi-piercing surgery for abdominal solid tumor: therapeutic simulation by natural orifice translumenal endoscopic surgery-assisted needlescopic surgery using 3-mm diameter robots

Background/purposeWe have invented multi-piercing surgery (MPS) which could potentially solve the triangular formation loss and device clashing which occur in single-port surgery (SPS), as well as restricted visual field, organ damage by needle-type instruments, and impaired removal of a resected organ from the body which occur in needlescopic surgery (NS). MPS is natural orifice translumenal endoscopic surgery (NOTES)-assisted NS. We used 3-mm diameter robots as needle-type instruments for MPS to examine the possibility of local immune cell therapy and regenerative therapy using stem cells for pancreatic cancer.MethodsIn MPS using two robots, the therapeutic cell suspension was injected into a target region of pancreas in two pigs. Both retention of a capsule of liquid cell suspension and invasive level were evaluated.ResultsTriangular formation could be ensured. The use of small-diameter robots allowed (1) the surgical separation of the pancreas and the retroperitoneum, and (2) the formation of the capsule containing the immune cell and stem cell suspension. The endoscope for NOTES provided a clear visual field and also assisted the removal of a resected organ from the body. The visual field of the endoscope could be oriented well by using an electromagnetic navigation system.ConclusionsMPS using small-diameter robots could potentially solve the issues inherent in SPS and NS and could allow minimally invasive local immune cell and stem cell therapy.

Laparoscopic Splenectomy with Technical Standardization and Selection Criteria for Standard or Hand-Assisted Approach in 390 Patients with Liver Cirrhosis and Portal Hypertension

BACKGROUND Laparoscopic splenectomy (LS) is still challenging in patients with liver cirrhosis and portal hypertension. This study was designed to establish safe and less invasive LS in patients with liver cirrhosis and portal hypertension. STUDY DESIGN We analyzed 390 patients with liver cirrhosis and portal hypertension, who underwent LS between 1993 and 2013. Patients were divided into 3 time periods; early (1993 to 2004, n = 106); middle (2005 to 2008, n = 159); and late (2008 to 2013, n = 125). During the middle time period, standardized technique for LS and selection criteria for hand-assisted LS were adopted. Patients with spleen volume ≥ 1,000 mL by CT volumetry, large perisplenic collateral vessels, and/or Child-Pugh score ≥ 9, underwent hand-assisted LS. During the late time period, the selection criteria were refined and patients with spleen volume ≥ 600 mL underwent hand-assisted LS. RESULTS Conversion to open splenectomy decreased (10.4% in the early time period, 1.9% in the middle time period, and 3.2% in the late time period, p = 0.004), median blood loss decreased (300g, 87g, and 98g, respectively, p < 0.001), and the success rate of pure LS tended to improve (87.2%, 89.5%, and 98.0%, respectively, p = 0.110). Mortality was 0% in each time period, Clavien-Dindo grade IIIb or more complications tended to decrease (5.7%, 2.5%, and 0.8%, respectively, p = 0.081), and technique-related complications decreased significantly (10.4%, 3.8%, and 2.4%, respectively, p = 0.014). CONCLUSIONS Laparoscopic splenectomy is now a safe and less invasive approach, even in patients with liver cirrhosis and portal hypertension, because of its technical standardization with the refined selection criteria for pure or hand-assisted LS.

Propranolol alone may not be acceptable to prevent first esophageal variceal bleeding in Japanese cirrhotic patients: Randomized controlled trial

Background and Aim:  In Japan, endoscopic injection sclerotherapy (EIS) is widely used to prevent first esophageal variceal bleeding, in contrast to pharmacological therapy which is the main treatment used in the rest of the world. The present study investigated if propranolol alone is acceptable to prevent first esophageal variceal bleeding in Japanese cirrhotic patients. This was compared with EIS.

Leptomeningeal Carcinomatosis Originating from Advanced Gastric Cancer : A Report of Three Cases and Review of the Literatures

BACKGROUND Leptomeningeal carcinomatosis (LMC) is a rare complication of gastric cancer. Case 1. A 57-year-old female was diagnosed with gastric cancer and underwent distal gastrectomy with D2 lymph node dissection. Two years later, the patient suffered from para-aortic lymph node metastases and provided chemotherapy. During the chemotherapy, the patient emergently visited our hospital with chief complaints of a severe headache and dizziness. The above symptoms promptly abated by meningeal drainage, with a high value of the cerebrospinal fluid (CSF) pressure. Despite the administration of subsequent chemotherapy, the patients clinical state rapidly worsened, including gradual progression of both blindness and hearing loss. Case 2. A 42-year-old male was diagnosed with Stage IV gastric cancer due to both distant lymph node metastases and an ascites. Chemotherapy with S-1 plus docetaxel was initiated. Upon finishing the fifth course of treatment, the patient complained of a severe headache. The magnetic resonance imaging (MRI) findings were suggestive of LMC. Under suspicion of carcinomatous meningitis, the patient underwent both cerebrospinal drainage with a high pressure value of 180 mmH2O and a cytological examination with a diagnosis of Class V. Immediately following the cerebrospinal drainage, the patients symptoms promptly diminished. Case 3. A 66-year-old female was diagnosed with gastric cancer and underwent total gastrectomy with D2 dissection. About a year later, the patient suffered from the peritoneal dissemination, and provided serial chemotherapy regimens for 13 months. Thereafter the patient suffered from mildly stiff shoulders followed by serial severe headaches, and meningeal drainage was performed. The CSF showed pleocytosis and the presence of neoplastic cells, leading a diagnosis of LMC. After the placement of an Ommaya reservoir, the intrathecal chemotherapy was performed. Within two weeks of treatment, the patients condition improved significantly, and the cell counts in the CSF obtained from the Ommaya reservoir remained low for six months after the first diagnosis of LMC. CONCLUSIONS Although gastric LMC-affected patients often exhibit a fatal clinical course, the administration of intrathecal chemotherapy may improve survival. Systemic chemotherapy may be also administered in a limited number of patients with a superior performance status. At present, each case requires the individual making treatment decisions. Further accumulation of clinical cases and improving the overall understanding of the pathogenesis of this disease is needed in order to advance in the treatment of gastric LMC.