Yusuke Akamaru

Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial

AIM The optimal second-line regimen for treating advanced gastric cancer (AGC) remains unclear. While irinotecan (CPT-11) plus cisplatin (CDDP) combination therapy and CPT-11 monotherapy have been explored in the second-line setting, the superiority of second-line platinum-based therapies for AGC patients initially treated with S-1 monotherapy has not yet been evaluated; therefore, we aimed to examine the survival benefit of CPT-11/CDDP combination over CPT-11 monotherapy. METHODS AGC patients showing progression after S-1 monotherapy for advanced cancer or recurrence within 6 months after completion of S-1 adjuvant therapy were randomly allocated to CPT-11/CDDP (CPT-11, 60 mg/m(2); CDDP, 30 mg/m(2), q2w) or CPT-11 (150 mg/m(2), q2w). RESULTS Sixty-eight advanced and 95 recurrent cases were evaluated. The median overall survivals were 13.9 (95% confidence interval [CI]: 10.8-17.6) and 12.7 (95% CI: 10.3-17.2) months for CPT-11/CDDP and CPT-11, respectively (hazard ratio: 0.834; 95% CI: 0.596-1.167, P = 0.288). No significant differences were observed in the secondary end-points, including progression-free survival (4.6 [95% CI: 3.4-5.9] versus 4.1 [95% CI: 3.3-4.9]months) and response rate (16.9% [95% CI: 8.8-28.3] versus 15.4% [95% CI: 7.6-26.5]). The incidences of grade 3-4 anaemia (16% versus 4%) and elevated serum lactate dehydrogenase levels (5% versus 0%) were higher for CPT-11/CDDP than for CPT-11. Exploratory subgroup analysis revealed that CPT-11/CDDP was significantly more effective for intestinal-type AGC, compared with CPT-11 (overall survival: 15.8 versus 14.0 months; P = 0.019). CONCLUSION No survival benefit was observed upon adding CDDP to CPT-11 after S-1 monotherapy failure.

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.

Stage-dependent effect of pancreatic transplantation on diabetic ocular complications in the spontaneously diabetic torii rat

Background. In terms of the temporal relationship between pancreas transplantation (PTx) and reversal of diabetic ocular complications, it has been difficult but important to determine a “point of no return.” Thus, it is of great clinical interest to evaluate the efficacy of PTx on diabetic ocular complications. Methods. A spontaneous type 2 diabetic model of Spontaneously Diabetic Torii (SDT; RT1a) rats was used in the present study, and syngeneic PTx was performed. Results. In the control SDT rats that received no treatment, hyperglycemia (>250 mg/dL) was developed from 25.2±3.9 weeks of age. Lens opacity was observed in all rats at 15 weeks after the onset of diabetes. Fluorescein angiography and immunohistochemistry detected the nonperfusion area and neovascularization in the retina at 5 weeks of diabetes. Daily insulin treatment could not prevent or reverse the ocular changes in our experiment. Fluorescein filling defect of the retinal vessels was observed at 10 weeks of diabetes. However, in the PTx rats, normoglycemia was achieved at all experimental time points. Diabetic cataract and retinopathy could have been prevented and improved if PTx had been performed at 5 weeks, but not at 10 weeks after the onset of diabetes. With PTx treatment, an inhibition of angiogenesis in the retina at 5 weeks after the onset of diabetes was demonstrated by immunohistochemistry. Conclusions. Our results indicate that the potential use of the SDT rat for diabetes study and the positive effect of PTx performed before the “point of no return” could prevent and cure diabetic ocular complications.

The potent role of graft-derived NKR-P1+TCRalphabeta+ T (NKT) cells in the spontaneous acceptance of rat liver allografts.

Background. The mechanism involved in the spontaneous acceptance of liver allografts in some rat strain combinations remains unclear. Immunoregulatory NKR-P1+TCRαβ+T (NKT) cells primarily produce IL-4 and IFN-γ, and enhance the polarization of immune responses to Th2 and Th1, respectively. The aim of this study was to clarify the role of graft-derived NKT cells in inducing the spontaneous acceptance of rat orthotopic liver transplantation (OLTx) Methods. The experimental groups were divided as follows: Group 1, BN to LEW “low responder (acceptor)” combination; Group 2, DA to LEW “high responder (rejector)” combination; naïve BN (Group 3) or LEW recipients (Group 4) with liver allografts from irradiated BN donors. The recipients had liver allografts from irradiated donors reconstituted from the following cell populations 24 hr before harvesting, spleen cells (SPCs, Group 5), Ig−SPCs (Group 6), Ig−NKR-P1−SPCs (Group 7), and Ig−TCRab−SPCs (Group 8) Results. In Group 1, the percent of graft-derived NKT cells harvested on day 7 posttransplant were significantly higher than in Group 2. In the case of BN liver allografts that had been irradiated and reconstituted with cell populations including NKT cells (Groups 5 and 6), the mean graft survival (MST) was extended to 39.2±5.7 and 38.8±8.0 days, respectively. In contrast, when NKT cells were excluded (Groups 7 and 8), the grafts were acutely rejected within MST of 17.8±4.0 and 18.8±7.7 days, respectively. The concentrations of IL-10 and TGF-β, but not IL-4 in Ig−GICs culture supernatants were predominant in the acceptor, whereas those with IFN-γ predominated in the rejector. Conclusions. Graft-derived NKT cells might be responsible for spontaneous acceptance in the rat OLTx.

Ex vivo and systemic transfer of adenovirus-mediated CTLA4Ig gene combined with a short course of FK506 therapy prolongs islet graft survival.

Adenovirus-mediated CTLA4Ig gene transfer has been reported to enhance graft survival in several rodent transplantation models. In this study, we investigated the efficacy of ex vivo and systemic transfer of the CTLA4Ig gene by adenoviral vectors in pancreatic islet allo-transplantation. Islet grafts from BN rats were transplanted to chemically induced diabetic LEW rats. First, ex vivo CTLA4Ig gene transfer into isolated islets was performed prior to transplantation. Survival of transduced grafts under the kidney capsule was slightly prolonged (8.6+/-1.3 days) compared with survival of untransduced grafts (6.7+/-1.2 days); when combined with a short course of FK506, graft survival was further extended (32.6+/-10.7 days vs. 13.7+/-1.0 days with FK506 alone). Secondly, systemic gene transfer was accomplished by intravenous administration immediately after the transplantation procedure. In these animals, islet grafts under the kidney capsule survived longer (15.2+/-3.3 days) than in controls (6.7+/-1.2 days), and when FK506 was administered perioperatively, all the islet grafts survived for more than 100 days. In systemically transduced recipients, the survival of islet grafts transplanted into the liver was not significantly different from that of the grafts placed under the kidney capsule. In order to examine organ-specific immunogenicity, heterotopic BN cardiac grafts were transplanted to LEW rats intra-abdominally, with the virus transferred systemically as in the islet model. In contrast to the islet grafts, all the cardiac grafts were accepted for longer than 100 days, even without FK506 therapy. Finally, the LEW recipients with long-surviving islet or cardiac grafts were re-transplanted with islet grafts from the same donor strain (BN) on day 100. The second islet grafts survived longer than 100 days in half of the cardiac recipients, but consistently failed in the islet recipients. We conclude that in this transplant model, CTLA4Ig gene transfer and FK506 treatment synergistically improved islet graft survival, systemic transfer of the gene was more effective than ex vivo transfer to the islets, and donor-specific tolerance could not be achieved for islet transplantation but was achieved for cardiac transplantation.

A case of retroperitoneal liposarcoma after delivery with expression of estrogen receptor: Report of a case.

Highlights • Retroperitoneal liposarcoma related pregnancy is rare.• Liposarcoma is sometimes positive for hormone receptor.• Additional therapy for liposarcoma is important to improve prognosis.

Predicting prolonged hospital stay after laparoscopic cholecystectomy.

Widespread application of laparoscopic cholecystectomy (LC) has resulted in a high complication rate and leads to prolonged hospital stays. This study aimed to investigate the preoperative and intraoperative clinical factors that relate to prolongation of hospital stay.

Evaluation of the effects of postoperative oral nutrition support on body weight in gastric cancer patients by using an elemental diet: A randomized study.

110 Background: Postoperative weight loss causes deterioration in the patient’s quality of life and influences long-term prognosis in gastric cancer patients who have undergone gastrectomy. Moreover, recent retrospective studies indicated postoperative weight loss as a risk factor for premature interruption of S-1 adjuvant chemotherapy. We conducted a prospective randomized controlled study to examine whether the early institution of nutritional support comprising an oral elemental diet (ED) prepared for post-gastrectomy patients with depressed digestive/absorptive function would help prevent postoperative weight loss. Methods: After surgery, patients were randomly assigned to the ED or control groups. The groups were divided according to the surgical methods used (total/distal gastrectomy), clinical stage (≤Ia/>Ia), and patients’ body mass index ( 18.5). In patients assigned to the ED group (Elental, 300 kcal) was provided in addition to the regular diet from the day starting soft rice diet or equi...

Dedifferentiated Liposarcoma in the Retroperitoneum in an Atomic Bomb Survivor: Report of a Case

A 76-year-old Japanese man was admitted to Kosei-Nenkin Hospital (Osaka, Japan) in November 2006; his chief complaint was a 10-kg loss in body weight over 3 months prior to admission. Abdominal computed tomography (CT) and dynamic magnetic resonance imaging (MRI) showed three masses in the retroperitoneum. The patient subsequently underwent surgery. The final histopathological diagnosis of tumors 1 and 2 was malignant fibrous histiocytoma of the retroperitoneum, and tumor 3 was a well-differentiated liposarcoma. By the presence of the liposarcoma, tumor 1 and 2 were thought to be the dedifferentiated areas of liposarcomas. At the age of 16, the patient had been exposed to radiation from the atomic bomb at Hiroshima towards the end of the Second World War. We postulate that in this case, radiation from the atomic bomb may have played an important role in the development of the sarcomas.