Nakahira S

Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer.

Pancreatic cancer is the most lethal of all solid tumors partially because of its chemoresistance. Although gemcitabine is widely used as a first selected agent for the treatment of this disease despite low response rate, molecular mechanisms of gemcitabine resistance in pancreatic cancer still remain obscure. The aim of this study is to elucidate the mechanisms of gemcitabine resistance. The 81‐fold gemcitabine resistant variant MiaPaCa2‐RG was selected from pancreatic cancer cell line MiaPaCa2. By microarray analysis between MiaPaCa2 and MiaPaCa2‐RG, 43 genes (0.04%) were altered expression of more than 2‐fold. The most upregulated gene in MiaPaCa2‐RG was ribonucleotide reductase M1 subunit (RRM1) with 4.5‐fold up‐regulation. Transfection with RRM1‐specific RNAi suppressed more than 90% of RRM1 mRNA and protein expression. After RRM1‐specific RNAi transfection, gemcitabine chemoresistance of MiaPaCa2‐RG was reduced to the same level of MiaPaCa2. The 18 recurrent pancreatic cancer patients treated by gemcitabine were divided into 2 groups by RRM1 levels. There was a significant association between gemcitabine response and RRM1 expression (p = 0.018). Patients with high RRM1 levels had poor survival after gemcitabine treatment than those with low RRM1 levels (p = 0.016). RRM1 should be a key molecule in gemcitabine resistance in human pancreatic cancer through both in vitro and clinical models. RRM1 may have the potential as predictor and modulator of gemcitabine treatment.

Surgical Outcomes of Noninvasive and Minimally Invasive Intraductal Papillary-Mucinous Neoplasms of the Pancreas

BackgroundNoninvasive and minimally invasive intraductal papillary-mucinous neoplasms (IPMNs) have a favorable surgical outcome. However, cases of recurrent noninvasive or minimally invasive IPMN are sometimes encountered, and the patterns of the recurrence of those tumors have not yet been fully clarified. In this study, we evaluated the surgical outcome of noninvasive and minimally invasive IPMNs, concentrating particularly on the pattern of recurrences.MethodsTwenty patients with noninvasive and minimally invasive IPMNs were assessed. Resected specimens were evaluated histopathologically with regard to the malignant nature of the tumors, the status of the surgical margin, and peripancreatic lymph node involvement. Cumulative overall survival rates and recurrence after surgery were assessed.ResultsOf the 20 patients, 13 had benign IPMNs, including adenomas (n = 10) and borderlines (n = 3), and 7 had malignant IPMNs, including carcinomas in situ (n = 4) and minimally invasive IPMNs (n = 3). Histopathologic examination confirmed the absence of tumor involvement in the resected lymph nodes and at the surgical margins. During the follow-up period, one patient with minimally invasive IPMN and one patient with noninvasive IPMN died of tumor recurrence in the peritoneum that was presumably caused by intraoperative manipulation. All of the patients with benign IPMNs survived, whereas the 10-year survival rate of the patients with malignant IPMNs was 67%.ConclusionsSurgical resection can offer a favorable outcome for noninvasive and minimally invasive IPMNs. Tumor recurrence was observed only in the peritoneal cavity. More careful perioperative management concerned with peritoneal recurrence should be emphasized for noninvasive and minimally invasive IPMNs.

Randomized Controlled Trial of Pancreaticojejunostomy versus Stapler Closure of the Pancreatic Stump During Distal Pancreatectomy to Reduce Pancreatic Fistula.

Objectives: The aim of this study was to evaluate in a multicenter randomized controlled trial (RCT) whether pancreaticojejunostomy (PJ) of pancreatic stump decreases the incidence of pancreatic fistula after distal pancreatectomy (DP) compared with stapler closure. Background: Several studies reported that PJ of pancreatic stump reduces the incidence of pancreatic fistula after DP. However, no RCT has confirmed the efficacy of PJ of pancreatic stump. Methods: One hundred thirty-six patients scheduled for DP were enrolled in this study between June 2011 and March 2014 at 6 high-volume surgical centers in Japan. Enrolled patients were randomized to either stapler closure or PJ. The primary endpoint was the incidence of pancreatic fistula based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01384617). Results: Sixty-one patients randomized to stapler and 62 patients randomized to PJ were analyzed by intention-to-treat. Pancreatic fistula occurred in 23 patients (37.7%) in the stapler closure group and 24 (38.7%) in the PJ group (P = 0.332) in intention-to-treat analysis. The incidence of clinically relevant pancreatic fistula (grade B or C) was 16.4% for stapler closure and 9.7% for PJ (P = 0.201). Mortality was zero in both groups. In a subgroup analysis for thickness of pancreas greater than 12 mm, the incidence of clinically relevant pancreatic fistula occurred in 22.2% of the patients in the stapler closure group and in 6.2% of the PJ group (P = 0.080). Conclusions: PJ of the pancreatic stump during DP does not reduce pancreatic fistula compared with stapler closure.

Subcuticular sutures versus staples for skin closure after open gastrointestinal surgery: a phase 3, multicentre, open-label, randomised controlled trial

BACKGROUND Staples have been widely used for skin closure after open gastrointestinal surgery. The potential advantages of subcuticular sutures compared with staples have not been assessed. We assessed the differences in the frequency of wound complications, including superficial incisional surgical site infection and hypertrophic scar formation, depending on whether subcuticular sutures or staples are used. METHODS We did a multicentre, open-label, randomised controlled trial at 24 institutions between June 1, 2009, and Feb 28, 2012. Eligible patients aged 20 years or older, with adequate organ function and undergoing elective open upper or lower gastrointestinal surgery, were randomly assigned preoperatively to either staples or subcuticular sutures for skin closure. Randomisation was done via a computer-generated permuted-block sequence, and was stratified by institution, sex, and type of surgery (ie, upper or lower gastrointestinal surgery). Our primary endpoint was the incidence of wound complications within 30 days of surgery. Analysis was done by intention to treat. This study is registered with UMINCTR, UMIN000002480. FINDINGS 1080 patients were enrolled and randomly assigned in a one to one ratio: 562 to subcuticular sutures and 518 to staples. 1072 were eligible for the primary endpoint and 1058 for the secondary endpoint. Of the 558 patients who received subcuticular sutures, 382 underwent upper gastrointestinal surgery and 176 underwent lower gastrointestinal surgery. Wound complications occurred in 47 of 558 patients (8·4%, 95% CI 6·3-11·0). Of the 514 who received staples, 413 underwent upper gastrointestinal surgery and 101 underwent lower gastrointestinal surgery. Wound complications occurred in 59 of 514 (11·5%, 95% CI 8·9-14·6). Overall, the rate of wound complications did not differ significantly between the subcuticular sutures and staples groups (odds ratio 0·709, 95% CI 0·474-1·062; p=0·12). INTERPRETATION The efficacy of subcuticular sutures was not validated as an improvement over a standard procedure for skin closure to reduce the incidence of wound complications after open gastrointestinal surgery. FUNDING Johnson & Johnson.

Schedule-dependent therapeutic effects of gemcitabine combined with uracil-tegafur in a human pancreatic cancer xenograft model.

Objectives: Gemcitabine is taken up by cells mainly via human equilibrative nucleoside transporter 1 (hENT1). Pretreatment of cancer cell lines with 5-fluorouracil (5-FU) leads to an increase in the expression of hENT1 and augments the effect of single-agent gemcitabine treatment in vitro. The purpose of the present study was to evaluate the relationship between the schedules of gemcitabine/uracil-tegafur (UFT) combination therapy and their effects in pancreatic cancer in vivo. Methods: The expression level of hENT1 mRNA was examined using 6 types of human pancreatic cancer cell lines treated with 5-FU and MiaPaCa-2 xenograft tumors in BALB/c nu/nu mice treated with UFT. A [3H] gemcitabine cellular uptake assay was performed using MiaPaCa-2 cells treated with 5-FU. We compared the effects of 6 different schedules of treatment using UFT and/or gemcitabine on MiaPaCa-2 xenograft tumors. Results: MiaPaCa-2 cell line was one of the lines that showed the highest rate of 5-FU-induced increase in the hENT1 mRNA level. Gemcitabine uptake was significantly increased when cells were treated with 5-FU. Treatment with UFT significantly increased the hENT1 mRNA expression in MiaPaCa-2 tumors. A significant growth inhibition of MiaPaCa-2 tumors was observed in the mice treated with UFT followed by gemcitabine as compared with either untreated mice or UFT alone-treated mice. Conclusions: Our results suggest that the schedule in which the gemcitabine is administered after UFT may be the optimal combination for gemcitabine/UFT treatment in pancreatic cancer.

Pilot study of a combination of S-1 and paclitaxel for patients with peritoneal metastasis from gastric cancer

BackgroundThis pilot study was carried out to evaluate the efficacy of chemotherapy for patients with peritoneal dissemination from gastric cancer or positive lavage cytology diagnosed by staging laparoscopy.MethodsSixteen patients were enrolled. Paclitaxel was administered at 120 mg/m2 on day 1 and S-1 was administered orally at 80 mg/m2 for 14 consecutive days, followed by a 1-week rest, as one course. After five courses of this therapy, the primary gastric tumors were evaluated and second-look laparoscopy was performed for patients showing partial response or stable disease with clinical benefit.ResultsPartial response or stable disease with clinical benefit was confirmed in seven and five patients, respectively, and these patients underwent second-look laparoscopy. No viable cancer cells were detected on cytopathological investigation during second-look laparoscopy in 9 patients who underwent surgical treatment. The intent-to-treat response rate for gastric tumor was 44% and the rate of disappearance of peritoneal metastasis was 38% (6 cases) at surgery. The median survival time was 555 days. Leucopenia of grade 3 and neutropenia of grade 3 were recognized in two and three patients, respectively.ConclusionThis chemotherapy regimen may be an acceptable option for patients with peritoneal dissemination. We plan to study this regimen further in gastric cancer patients with peritoneal dissemination.

Intraperitoneal administration of paclitaxel and oral S-1 for a patient with peritoneal dissemination and hydronephrosis due to advanced gastric cancer

We report a patient with type 3 gastric cancer with peritoneal dissemination and hydronephrosis who was successfully treated with intraperitoneal infusion of paclitaxel and oral administration of S-1. He was diagnosed with unresectable gastric cancer with severe peritoneal dissemination by staging laparoscopy. We selected combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m2 was administered intraperitoneally on days 1 and 8, and S-1 at 100 mg/body was administered orally for 14 days, followed by 7 days’ rest, as one course. After five courses, primary tumor reduction was confirmed and no cancer cells were detected on pathocytological investigation at second-look laparoscopy. The patient underwent total gastrectomy with lymph node dissection. He died from liver metastasis 29 months after the initial treatment, but he had not suffered from peritoneal metastases and had kept a good quality of life (QOL) since that treatment. This chemotherapy can be applied as one of the promising candidates for the treatment of patients with peritoneal metastasis of gastric cancer.

Pilot study of intraperitoneal administration of paclitaxel and oral S-1 for patients with peritoneal metastasis due to advanced gastric cancer

BackgroundThere is no standard treatment for peritoneal dissemination from gastric cancer. A novel combination chemotherapy has been introduced for patients with advanced gastric cancer with peritoneal metastasis.MethodsThis pilot study was performed on four patients to confirm safety and efficacy. They were diagnosed with unresectable gastric cancer with severe peritoneal dissemination by staging laparoscopy, or with metastasis to the transverse colon. We selected combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m2 or 60 mg/body was administered intraperitoneally on days 1 and 8 and S-1, at 80–120 mg/body, was administered orally for 14 days followed by 7 days’ rest, as one course. After five courses of this therapy, the primary gastric tumors were evaluated by conventional examinations, and second-look laparoscopy was performed to assess the efficacy of the treatment against the peritoneal metastases.ResultsAfter five courses, primary tumor reductions were confirmed, and no cancer cells were detected on pathocytological investigation during second-look laparoscopy in any of the patients. Three patients underwent total gastrectomy with lymph node dissection and one underwent left upper abdominal evisceration. Final histological staging showed two stage 3 and two stage 4 patients. The intraperitoneal administration of paclitaxel and the oral administration of S-1 were well tolerated. Three patients died, at 8, 15, and 29 months, respectively, after the initial treatment, and one has been alive for 54 months without recurrence.ConclusionThis chemotherapy can be used in the treatment of patients with peritoneal metastasis of gastric cancer.

Fibrin Sealant with Polyglycolic Acid Felt vs Fibrinogen-Based Collagen Fleece at the Liver Cut Surface for Prevention of Postoperative Bile Leakage and Hemorrhage: A Prospective, Randomized, Controlled Study

BACKGROUND The incidence of postoperative biliary leakage and hemorrhage is low, but these factors remain important in liver surgery, and this studys objective was to explore the efficacy of fibrin sealant (FS) with polyglycolic acid (PGA) vs fibrinogen-based collagen fleece (CF) at the liver cut surface. Fibrinogen-based collagen fleece is generally used for hemostasis; PGA-FS has reduced biliary leakage in several retrospective studies. STUDY DESIGN We designed a multicenter, randomized, controlled trial. The primary outcome was the rate of biliary leakage and hemorrhage. Secondary outcomes included morbidities and effusion at the liver cut surface at 3 months post-surgery. Biliary leakage was diagnosed when the drain/serum bilirubin ratio was >5. Hemorrhage was diagnosed when relaparotomy or transfusion was needed. RESULTS Of 786 patients from 11 institutions enrolled from 2009 to 2014, a total of 391 were randomly assigned to PGA-FS and 395 to CF. Regarding primary outcomes, rates of biliary leakage were 4.1% with PGA-FS and 5.1% with CF, and rates of hemorrhage were 1.0% in each group; groups did not differ significantly. For secondary outcomes, morbidity rates were 18.7% in the PGA-FS group and 24.6% in the CF group (p = 0.0450). Effusion at the cut liver surface was less with PGA-FS (22.2%) than with CF (32.9%) (p = 0.0142). Regarding morbidity, infection around the liver, jaundice, and abdominal paracentesis were less in the PGA-FS group. CONCLUSIONS Compared with CF, PGA-FS did not reduce biliary leakage and hemorrhage. Surgical site infection around the liver, effusion at the liver cut surface, and abdominal paracentesis were less in the PGA-FS group.

Immunohistochemical consistency between primary tumors and lymph node metastases of gastric neuroendocrine carcinoma

BackgroundGastric neuroendocrine carcinoma (G-NEC) is a rare, highly malignant tumor that exhibits aggressive growth leading to vascular invasion, distant metastasis and extremely poor prognosis. We studied the clinicopathological findings of seven patients at our institute to better under this disease.MethodsSeven cases of G-NEC were identified among 1,027 cases of gastric carcinoma that underwent gastrectomy at Kansai Rousai Hospital between 2002 and 2010. We studied the pathological and immunohistochemical features of gastric neuroendocrine carcinomas at both the primary site and metastatic lymph nodes.ResultsThe mean patient age was 73 years (range 63 to 86 years). There were no females in this series. The final staging was Stage I in one case, Stage II in two, Stage III in two and Stage IV in two. A total of 31 metastatic lymph nodes were found in these patients. This study revealed that the ratio of neuroendocrine cells was similar between the primary and metastatic sites, which tended to show the same expression patterns of neuroendocrine markers.ConclusionsMetastatic lymph nodes showed heterogeneous immunohistochemical expression patterns similar to the primary sites. G-NEC is far advanced at diagnosis and rapidly reaches the lymph nodes retaining its heterogeneity, carrying a worse prognosis than common gastric cancer.Mini abstractG-NEC grows rapidly and metastasizes to the lymph nodes, retaining its pathological and immunohistochemical heterogeneity even at the metastatic sites.