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Purpose: This study aimed to evaluate the feasibility and safety of intracorporeal anastomosis with Billroth I, Billroth II, or Roux-en-Y reconstructions in totally laparoscopic distal gastrectomy., Materials and Methods: A single-institution, retrospective, cohort study including 553 patients was conducted. Intracorporeal isosceles right triangle-shaped anastomosis without slack and torsion was created using linear staplers. Billroth I was primarily used. Surgical outcomes and perioperative nutritional status were assessed., Results: Morbidity was 11.5%. Postoperative early complications related to anastomosis occurred in 13 patients (2.4%). Operative time and reconstruction type (Billroth I vs. others) were the only significant independent risk factors determining postoperative early and late complications, respectively. No difference was observed in postoperative changes in nutritional status across the groups, although Billroth II increased reflux esophagitis requiring medication., Conclusions: Intracorporeal isosceles right triangle-shaped anastomosis using linear staplers in totally laparoscopic distal gastrectomy, in combination with our selection algorithm for type of reconstruction, is feasible and safe.

Objective: This study aimed to evaluate the feasibility and effectiveness of a comprehensive theoretical and hands-on training program in performing laparoscopic colonic resections under supervision of an expert surgeon., Materials and Methods: Laparoscopic right colectomy was performed in 78 patients (10 with benign disease, 68 with carcinoma). Demographic, intraoperative, pathologic examination, and short-term outcome data were retrospectively compared between 25 patients operated by surgical residents (R group) and 53 patients operated by senior surgeons (S group). The residents who performed surgeries in the R group had between 1 and 6 years after graduation; no experience with open or laparoscopic colorectal surgery was necessary. The residents completed a training program under supervision of a single expert laparoscopic colorectal surgeon, which included 6 steps, from basic skills to certification., Results: There were no differences in patient age, sex, and body mass index between the R and S groups. Significantly more patients in the R group had early cancer and benign lesions (P<0.05). Thirteen of the 16 residents (81.2 %) had not had prior experience with colonic resection. The time of suturing and knot tying in the dry box did not differ between residents and senior surgeons (68 and 69 s, respectively). All the residents performed laparoscopic right colectomy without intraoperative complications. There were no significant differences in operating time (R group: 173±34 min, S group: 172±52 min), mean estimated blood loss (50±111 vs. 49±100 mL), number of lymph nodes dissected (20.8±12.8 vs. 17.1±9.0), and mean postoperative hospital stay (9.1±3.3 vs. 10.7±4.1 d). On the basis of the year of their residency period, all 3 residents at 6 years after graduation had far greater experience than the other residents and therefore performed the surgery with minor verbal support from the expert. However, residents with 1 or 2 years after graduation had to receive guidance provision by the expert during surgery., Conclusions: When supervised and led by an expert laparoscopic surgeon, surgical residents are capable of performing laparoscopic surgery without negative effects on outcomes.

Laparoscopic partial gastrectomy is the standard surgical treatment for gastric gastrointestinal stromal tumor (GIST). However, to reduce gastric deformation, the tumor margins should be secured so as to minimize the size of the resection as much as possible. This is the report on the 3 laparoscopic resection techniques for gastric GIST depending upon the growth pattern and location of the tumor, and their results. We performed laparoscopic partial gastrectomy for 41 gastric GISTs between 2004 and 2012. Simple resection was used on exophytic or small GISTs. Seromuscular resection was used on exoendophytic (intramural) and relatively small endophytic tumors. Transgastric resection was used in cases of large endophytic tumors. We performed simple resection on 24 lesions (58.5%), seromuscular resection on 14 lesions (34.1%), and transgastric resection on 3 lesions (7.3%). There were no intraoperative complications. Postoperative complications included 1 case (2.5%) of bleeding from the staple line.

Background: Graft arterial disease (GAD) is a major cause of late graft loss after organ transplantation. Alloimmune responses and vascular remodeling eventually cause the transplant organ to develop GAD. In this study, we aimed to limit the development of GAD by inhibiting alloimmune responses and vascular smooth muscle cell (VSMC) proliferation with a new compound, 3-[(dodecylthiocarbonyl)methyl]-glutarimide ([DTCM]-glutarimide), in a murine cardiac model of GAD., Methods: The hearts from B6.CH-2 mice were transplanted into C57BL/6 mouse recipients to examine the extent of GAD. The recipients were treated with either vehicle or DTCM-glutarimide intraperitoneally (40 mg/kg per day) for 4 weeks., Results: The administration of DTCM-glutarimide attenuated GAD formation (luminal occlusion: 37.9 ± 5.9% vs 14.8 ± 5.4%, P < 0.05) by inhibiting the number of graft-infiltrating cells and decreasing alloreactive interferon (IFN)-γ production compared with control mice, as measured by the Enzyme-linked ImmunoSpot assay. In vitro, VSMCs proliferated on stimulation with either basic fibroblast growth factor or IFN-γ and splenocytes after transplantation, but the addition of DTCM-glutarimide resulted in the inhibition of VSMC proliferation. Moreover, DTCM-glutarimide suppressed cyclin D1 expression and inhibited cell cycle progression from G1 to S in VSMCs., Conclusions: The compound DTCM-glutarimide suppressed GAD development by inhibiting not only alloimmune responses but also VSMC proliferation in the graft.

Background: Long-term graft deterioration remains a major obstacle in the success of pancreatic islet transplantation (PITx). Antigen-independent inflammatory and innate immune responses strengthen subsequent antigen-dependent immunity; further, activation of nuclear factor (NF)-κB plays a key role during these responses. In this study, we tested our hypothesis that, by the inhibition of NF-κB activation, the suppression of these early responses after PITx could facilitate graft acceptance., Methods: Full major histocompatibility complex (MHC)-mismatched BALB/c (H-2) mice islets were transplanted into streptozotocin-induced diabetic C57BL/6 (B6: H-2) mice. The NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) was administered for either 3 or 14 days after PITx. To some PITx recipients, tacrolimus was also administered. Islet allograft survival, alloimmune responses, and in vitro effects of DHMEQ on dendritic cells (DCs) were assessed., Results: With a vehicle treatment, 600 islet allografts were promptly rejected after PITx. In contrast, 3-day treatment with DHMEQ, followed by 2-week treatment with tacrolimus, allowed permanent acceptance of islet allografts. The endogenous danger-signaling molecule high mobility group complex 1 (HMGB1) was elevated in sera shortly after PITx, whereas DHMEQ administration abolished this elevation. DHMEQ suppressed HMGB1-driven cellular activation and proinflammatory cytokine secretion in mouse bone marrow-derived DCs and significantly reduced the capacity of DCs to prime allogeneic T-cell proliferation in vitro. Finally, the DHMEQ plus tacrolimus regimen reverted the diabetic state with only 300 islet allografts., Conclusions: Inhibition of NF-κB activation by DHMEQ shortly after PITx suppresses HMGB1, which activates DCs and strengthens the magnitude of alloimmune responses; this permits long-term islet allograft acceptance, even in case of fewer islet allografts.

Background: A newly developed compound, 3-[(dodecylthiocarbonyl)methyl]-glutarimide (DTCM-G), has been shown to inhibit nuclear translocation of c-Fos/c-Jun in a murine macrophage cell line. Herein, we studied the immunosuppressive properties and potency of DTCM-G., Methods: Using purified mouse T cells, the in vitro effects of DTCM-G on activation, cytokine production, proliferation, and cell cycle progression were assessed, and a possible molecular target of DTCM-G was investigated. In a BALB/c (H-2(d)) to C57BL/6 (H-2(d)) mouse heart transplantation model, transplant recipients were administered DTCM-G, a calcineurin inhibitor (tacrolimus), and a nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). Treatment drugs were administered daily for 14 days after transplantation. Alloimmune responses were assessed in addition to graft survival time., Results: After anti-CD3+anti-CD28 monoclonal antibody stimulation, DTCM-G significantly suppressed proliferation, interferon-γ production, and cell cycle progression of activated T cells but not CD25 expression or interleukin-2 production. These effects were accompanied by inhibition of 70-kDa S6 protein kinase phosphorylation, a downstream kinase of the mammalian target of rapamycin. The addition of tacrolimus and DHMEQ to DTCM-G resulted in a robust inhibition of T-cell proliferation. In vivo combination therapy of DTCM-G plus either tacrolimus or DHMEQ significantly suppressed alloreactive interferon-γ-producing precursors and markedly prolonged cardiac allograft survival. Furthermore, combination of all three agents markedly inhibited alloimmune responses and permitted long-term cardiac allograft survival., Conclusions: DTCM-G inhibits T cells by suppressing the downstream signal of mammalian target of rapamycin. DTCM-G in combination with tacrolimus and DHMEQ induces a strong immunosuppressive effect in vivo.

Background: Pharmacologically modulated dendritic cells (DCs) can potentially regulate alloimmune responses. We examined the characteristics of immunoregulatory DCs induced by a novel triazolopyrimidine derivative, NK026680, which has been previously shown to inhibit DC maturation., Methods: DCs were generated from bone marrow progenitor cells from C57BL/6 (B6, H-2 haplotype) mice with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. DCs were cultured with allogeneic BALB/c (H-2) splenocyte lysates with or without NK026680. DC functions were examined in vitro after stimulation of tumor necrosis factor α and in vivo by the intravenous injection of C3He/J (C3H, H-2) DCs cultured with B6 cell lysates and NK026680 into C3H mice. Seven days later, DC-treated mice received B6 heart allografts, and graft survival and alloimmune responses were assessed., Results: In NK026680-treated DCs (NK-DCs), significant inhibition of the up-regulation of surface activation markers (CD40, CD80, CD86, and major histocompatibility complex class II) and IL-12 p40 production was observed after stimulation of tumor necrosis factor α compared with that of control DCs. Furthermore, NK-DCs suppressed alloreactive T-cell proliferation. The modulation of NK-DCs was likely associated with the inhibition of phosphorylation of p38 mitogen-activated protein kinase and the up-regulation of indolamine 2,3-dioxygenase expression. Compared with both noninjected and control DC-injected mice, mice that received a single in vivo infusion of NK-DCs showed significant increases in splenocyte IL-10 production and the splenic CD4 IL-10 T-cell population 7 days after injection, a significantly increased splenic CD4CD25FoxP3 T-cell population 14 days after injection, and markedly prolonged cardiac allograft survival., Conclusions: Ex vivo NK026680 conditioning allows DCs to acquire immunoregulatory properties that suppress alloimmune responses and prolong cardiac allograft survival.

Background: Nuclear factor-κB (NF-κB) is a key molecule in alloimmune responses, however, its role in tolerance induction is not clear. We have previously reported that dehydroxymethylepoxyquinomycin (DHMEQ), a novel NF-κB inhibitor, prolongs cardiac allograft survival. In this study, we evaluated the immunomodulatory effects of DHMEQ when combined with a donor-specific blood transfusion (DST), and assessed whether the treatment induces tolerance in a mouse heart transplantation model., Methods: DST (20×10 splenocytes) was given intravenously at day -7. DHMEQ (30 mg/kg/day) was administered intraperitoneally for 14 days after DST. Graft survival and histology were evaluated. The underlying mechanisms of immunomodulation by DST and DHMEQ treatments were investigated by assessing alloimmune responses after transplantation., Results: In fully mismatched H2-to-H2 heart transplants, DST alone prolonged allograft median survival time to 15 days, whereas when DST was combined with DHMEQ treatment, the graft median survival time was prolonged to 39.5 days. When the donor-recipient strain combination was reversed, that is, H2-to-H2, heart transplants were accepted (>150 days survival) in more than 60% of recipients treated with a DST and DHMEQ, whereas control allografts were all rejected within 8 days. The combined therapy markedly inhibited immune responses by both the direct and indirect allorecognition pathways mainly attributed to promotion of activation-induced cell death and Treg generation., Conclusions: Our results demonstrate the distinctive ability of NF-κB inhibition in combination with donor alloantigen to promote transplantation tolerance through multiple cellular mechanisms.