Shin-Ichiro Maehara

Early experiences of endoscopic procedures in general surgery assisted by a computer-enhanced surgical system.

We performed a variety of complete total endoscopic general surgical procedures, including colon resection, distal gastrectomy, and splenectomy, successfully with the assistance of the da Vinci computer-enhanced surgical system. The robotic system allowed us to manipulate the endoscopic instruments as effectively as during open surgery. It enhanced visualization of both the operative field and precision of the necessary techniques, as well as being less stressful for the endoscopic operating team. This technological innovation can therefore help surgeons overcome many of the difficulties associated with the endoscopic approach and thus has the potential to enable more precise, safer, and more minimally invasive surgery in the future.

Laparoscopic hepatectomy for hepatocellular carcinoma

S. Maehara Background: No reports exist on the role of laparoscopic hepatectomy in the short- and long-term outcomes of patients with hepatocellular carcinoma (HCC). We present our results from using laparoscopic hepatectomy for HCC and discuss the importance of this procedure. Methods: To investigate the role of laparoscopic hepatectomy in the short- and long-term outcomes, 17 patients with HCC who underwent laparoscopic hepatectomy (laparoscopic hepatectomy group) were compared with 38 patients who underwent conventional open hepatectomy (open hepatectomy group) during the same period. Results: No differences in operation time, blood loss, rate of blood transfusion, or incidence of postoperative complications were found between the two groups. The postoperative hospital stay for the laparoscopic hepatectomy group was significantly shorter than for the open hepatectomy group. With long-term prognosis, no difference was found in survival rate and disease-free survival rate between the two groups. No recurrence was found in the stump of the remaining liver after laparoscopic hepatectomy. Conclusions: Laparoscopic hepatectomy has resulted in a better short-term outcome after surgery than conventional open hepatectomy. The long-term prognosis in the laparoscopic hepatectomy group was similar to that in the open hepatectomy group. Therefore, laparoscopic hepatectomy can be a new alternative for treatment of cirrhotic patients with HCC when patients are strictly selected.

Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells

Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine‐sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1‐R exhibiting a 20‐fold IC50‐value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti‐oxidants, in the KLM1‐R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine‐induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine‐induced ROS levels. Furthermore interferon‐γ suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1‐R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine.

KNK437 Downregulates Heat Shock Protein 27 of Pancreatic Cancer Cells and Enhances the Cytotoxic Effect of Gemcitabine

Background: Our previous proteomic study demonstrated that expression of heat shock protein 27 (HSP27) is upregulated in gemcitabine (GEM)-resistant pancreatic cancer cells and that it suppressed the cytotoxic effect of GEM on the cells. This report describes the benefits of a treatment strategy combining the HSP inhibitor KNK437 with GEM for GEM-resistant pancreatic cancer cells. Methods: We used 2 human pancreatic cancer cell lines, GEM-sensitive KLM1 and GEM-resistant KLM1-R. KLM1-R was treated with KNK437, and we examined the expression of HSP27 by Western blotting. The cytotoxicity of GEM and KNK437 for KLM1-R was investigated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Results: The expression of HSP27 in KLM1-R was dramatically reduced by KNK437. In addition, the in vitro antitumor cytotoxic effect of GEM on KLM1-R was enhanced by combination treatment with KNK437 compared to GEM alone. Conclusion: This study supports the potential therapeutic benefits of a treatment strategy combining KNK437 with GEM.

Cofilin-phosphatase slingshot-1L (SSH1L) is over-expressed in pancreatic cancer (PC) and contributes to tumor cell migration

Slingshot-1L (SSH1L), a cofilin-phosphatase, plays a role in actin dynamics and cell migration by reactivating cofilin-1. However, the expression of SSH1L in malignant diseases is poorly understood. The overexpression of SSH1L in cancerous tissue compared to the matched surrounding non-cancerous tissues from patients with late stages (III-IV) of PC was detected in 90% (9/10) of cases by western blotting. The expression of SSH1L was shown to be upregulated in tumor cells from 10.7% (11/102) of patients with pancreatic cancer (PC) by immunohistochemistry (IHC). The positive rate of SSH1L in patients with PC at stage VI (TNM) categorized as grade 3 was of 50% (2/4) and 15% (6/40), respectively. Moreover, SSH1L expression was shown to be up-regulated in the PC cell lines (KLM1, PANC-1 and MIAPaCa-2) with high metastatic potential. Loss of SSH1L expression was associated with an increase in the phosphorylation of cofilin-1 at serine-3 and further inhibited cell migration (but not proliferation) in KLM1, PANC-1 and MIAPaCa-2. Actin polymerization inhibitor cytochalasin-D was sufficient to abrogate cell migration of PC without changing SSH1L expression. These results reveal that SSH1L is upregulated in a subset of PCs and that the SSH1L/cofilin-1 signal pathway is associated positively in PC with cell migration. Our study may thus provide potential targets to prevent and/or treat PC invasion and metastasis in patients with SSH1L-positive PC.

Decreased expression of osteopontin is related to tumor aggressiveness and clinical outcome of intrahepatic cholangiocarcinoma

Background: Osteopontin (OPN) is known to be a secreted adhesive glycoprotein. Recent studies have reported that the overexpression of OPN is correlated with tumorigenesis, tumor aggressiveness, and poor prognosis in several types of human cancer. The aim of this study was to determine whether the expression of OPN in cases of intrahepatic cholangiocarcinoma (ICC) indicates the clinical outcome.

The role of heat shock protein 27 expression in hepatocellular carcinoma in Japan: Special reference to the difference between hepatitis B and C

Abstract: 
Background: A recent report showed that heat shock protein (HSP)‐27 expression was related to histological grade and survival of patients with hepatocellular carcinoma (HCC).

Gemcitabine induces poly (ADP-ribose) polymerase-1 (PARP-1) degradation through autophagy in pancreatic cancer.

Poly (ADP-ribose) polymerase-1 (PARP-1) and autophagy play increasingly important roles in DNA damage repair and cell death. Gemcitabine (GEM) remains the first-line chemotherapeutic drug for pancreatic cancer (PC). However, little is known about the relationship between PARP-1 expression and autophagy in response to GEM. Here we demonstrate that GEM induces DNA-damage response and degradation of mono-ADP ribosylated PARP-1 through the autophagy pathway in PC cells, which is rescued by inhibiting autophagy. Hypoxia and serum starvation inhibit autophagic activity due to abrogated GEM-induced mono-ADP-ribosylated PARP-1 degradation. Activation of extracellular regulated protein kinases (ERK) induced by serum starvation shows differences in intracellular localization as well as modulation of autophagy and PARP-1 degradation in GEM-sensitive KLM1 and -resistant KLM1-R cells. Our study has revealed a novel role of autophagy in PARP-1 degradation in response to GEM, and the different impacts of MEK/ERK signaling pathway on autophagy between GEM-sensitive and -resistant PC cells.

The short term feasibility of abdominoperineal resection with prostatectomy for locally advanced rectal cancer: open and laparoscopic cases report

Total pelvic exenteration is often selected for advanced rectal cancer with prostatic invasion. The aim of this study was to evaluate the short term feasibility of the abdominoperineal resection with prostatectomy for locally advanced rectal cancer. We performed abdominoperineal resection with prostatectomy for 3 patients with locally advanced rectal cancer, including 2 patients by totally laparoscopic procedure. Patients’ background, intra- and postoperative factors and short-term prognosis were evaluated. All patients underwent complete resection of primary tumor with negative surgical margins. We could perform the surgery by both open and laparoscopic procedure in collaboration with urologist. There was no operation related mortality. One patient who was treated by open procedure had urinary anastomotic leakage. No patient had recurrenced, but one patient died of other disease. Our experience suggests that open or laparoscopic abdominoperineal resection with prostatectomy could be an alternative to total pelvic exenteration for the patients with rectal cancer invading the prostate. The collaboration with the urologist would be important to perform quality-controlled surgery.

Carcinoma of the ampulla of Vater diagnosed after surgical treatment for Lemmel’s syndrome

Lemmel’s syndrome encompasses a range of conditions in which a juxtapapillary duodenal diverticulum exerts mechanical and functional effects on the common bile and pancreatic ducts, leading to jaundice and pancreatitis. In this report, we describe a very rare case of carcinoma of the ampulla of Vater that was detected during postoperative follow-up in a patient who had undergone choledochojejunostomy following a diagnosis of Lemmel’s syndrome. We present our clinical and pathological experiences with the diagnosis and treatment of this case as well as a review of the present literature concerning Lemmel’s syndrome.