Novel anti-inflammatory agent 3-[(dodecylthiocarbonyl)-methyl]-glutarimide ameliorates murine models of inflammatory bowel disease.

OBJECTIVE AND DESIGN: To examine the effect of 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel anti-inflammatory agent that inhibits lipopolysaccharide (LPS) activation of RAW264.7 macrophages, on murine models of colitis and RAW264.7 cells. MATERIALS AND METHODS: Colitis was induced by rectally infusing trinitrobenzenesulfonic acid (TNBS) (1.5 mg in 50% ethanol) in BALB/c mice or orally administering 3% dextran sulfate sodium (DSS) for 5 days in C57BL/6 mice. The severity of colitis was assessed after intraperitoneally injecting DTCM-G (40 mg/kg). The anti-inflammatory properties of DTCM-G and its mechanisms were investigated in LPS-stimulated RAW264.7 cells. RESULTS: DTCM-G significantly ameliorated TNBS-induced colitis, according to the body weight loss, disease activity index, colonic obstruction, macroscopic colonic inflammation score, mucosal myeloperoxidase activity, and histopathology. Immunohistochemistry and isolated lamina propria mononuclear cells showed significantly reduced colonic F4/80(+) and CD11b(+) macrophage infiltration. DTCM-G significantly suppressed tumor necrosis factor (TNF)-α and interleukin (IL)-6 messenger RNA expression in the colon and attenuated DSS-induced colitis, according to the disease activity index and histopathology. In RAW264.7 cells, DTCM-G suppressed LPS-induced TNF-α/IL-6 production and enhanced glycogen synthase kinase-3ß phosphorylation. CONCLUSIONS: DTCM-G attenuated murine experimental colitis by inhibiting macrophage infiltration and inflammatory cytokine expression. Thus, DTCM-G may be a promising treatment for inflammatory bowel disease.

[A Case of Laparoscopic Resection of Sigmoid Colon Cancer Complicated by an Iliopsoas Abscess Preceded by Abscess Drainage].

For colon cancer complicated by iliopsoas abscess, it is unclear whether surgery should be performed prior to abscess drainage. We were able to perform laparoscopic sigmoid resection safely after first draining the abscess. We believed it would be beneficial to avoid surgery in the presence of abscess and inflammation, and the minimally invasive operation was performed after improvements of the patient's general status and inflammation.

[Damage Control Surgery for Perforation of Colon Cancer].

Perforation due to colon cancer maycause peritonitis and septic shock. In these cases, we maynot be able to rescue the patients in spite of emergencysurgical intervention; in these conditions, owing to limitations of operation time, it is difficult for us to assess the state or extent of the disease and to perform an ideal oncological surgerywith dissection of lymph nodes. To overcome these limitations, we introduce the concept of "damage control surgery" developed in the trauma region to treat perforations of colon cancer. There are 3 steps: first, the perforated intestine is resected and the peritoneal cavityis lavaged to control contamination. Open abdominal management is used as a temporaryabdominal closure; second, sepsis is treated in the ICU; and third, based on the treatment strategydecided upon after consulting a colorectal surgeon and the patient's family, a colostomy, anastomosis, and extra dissection of lymph node are performed before abdominal closure. We report the fatal case of a 92-year-old woman who had developed severe shock to indicate the significance of this strategy.

Open abdominal management for perforative peritonitis with septic shock: a retrospective analysis on usefulness of a standardized treatment protocol.

BACKGROUND: Damage control surgery (DCS) with open abdominal management (OAM) has been increasingly expanded to include critically ill non-trauma patients. However, there is limited data regarding the usefulness of this protocol for the treatment of severe perforative peritonitis (PP), especially with septic shock (SS). Here, we retrospectively evaluated the usefulness of our OAM protocol for PP with SS. METHODS: We retrospectively reviewed patients with from June 2015 to September 2018. The proposed protocol was composed of the following steps: (1) rapid control of contamination; (2) temporary abdominal closure; (3) repeated washout of the abdominal cavity; and (4) delayed definitive surgery. For temporary abdominal closure, a negative pressure wound therapy device was used. The end points were the morbidity and 30-day mortality rates. Logistic backward regression was performed to identify factors associated with complications. RESULTS: The mortality rate was 4% (1/25) and the overall morbidity rate of surviving patients was 58.3% (14/24). The mean duration of the first DCS was 67.36 ± 22.83 min. The median durations of ventilation and intensive care unit stay were 5 and 7 days, respectively. Although not significant, morbidity might be associated with age, diabetes mellitus, initial operative time, and OAM duration. CONCLUSIONS: A standardized protocol for OAM may improve the outcomes of patients with SS due to PP. This damage control approach can be applied for the treatment of severe abdominal sepsis.

Perioperative Factors Associated With Respiratory Complications Following Open Abdomen Management.

BACKGROUND: Postoperative respiratory complications are often severe and associated with a high risk of mortality in patients who undergo open abdomen (OA) management following emergency damage-control surgery. The causes of postoperative respiratory complications remain unknown. Therefore, we evaluated postoperative factors associated with respiratory complications in nontrauma patients who had undergone OA management using propensity score matching, with a focus on OA-related risk factors. METHODS: This retrospective analysis included subjects who underwent OA management during a 4-y study period. Age, body mass index, and smoking history were selected as covariates. After propensity score matching, we compared postoperative factors (ie, first operative time, duration of OA, initial 3-d fluid balance, length of ICU stay, and in-hospital mortality) in 2 groups of subjects: those who had post-OA respiratory complications (PORCs) and those who did not. RESULTS: 60 subjects (33 men and 27 women) were identified; 38.3% of these subjects had PORCs. After propensity score matching, 18 subjects were matched. The 3-d fluid balance was significantly higher in subjects with PORCs than in those without PORCs (3,513 mL vs 1,087 mL; P = .03). CONCLUSIONS: To our knowledge, this is the first study to examine factors associated with respiratory complications following OA in nontrauma subjects. After adjusting for known co-factors associated with postoperative respiratory complications, the 3-d fluid balance was identified as a significant risk factor for PORCs in subjects who had undergone OA. Clinicians should pay attention to the incidence of PORCs in OA subjects with a positive fluid balance after emergency abdominal surgery.

A retrospective analysis of emergency surgery for cases of acute abdomen during cancer chemotherapy. Case series.

BACKGROUND: Treatment for acute abdomen during chemotherapy is frequently difficult because of the complicated status of the patients, and there have been only a few case series summarizing the outcomes of emergent surgery during chemotherapy. The aim of this study was to clarify the clinical outcomes of emergency surgery for acute abdomen during chemotherapy and identify predictive factors associated with mortality. METHODS: We retrospectively analyzed the records of patients who underwent emergency surgery for acute abdomen within 30-days after anti-cancer drugs administration between 2009 and 2020. RESULTS: Thirty patients were identified. The primary malignancies were hematological (n = 7), colorectal (n = 4), lung (n = 4), stomach (n = 2), breast (n = 2), prostate (n = 2) and others (n = 5). Fifteen patients were treated with the regimen, including molecular-targeted anti-cancer drugs (Bevacizumab: 8 cases, Rituximab: 4, Ramucirumab: 2, and Gefitinib: 1). Indications for emergency surgery were perforation of the gastrointestinal tract (n = 24), appendicitis (n = 3), bowel obstruction (n = 2), and gallbladder perforation (n = 1). Severe morbidity (Clavien-Dindo IIIa or more) occurred in 8 cases (27%), and there were 6 in-hospital deaths (20%). Significant factors related to in-hospital death were age >70 years old (P = 0.029), poor performance status (ECOG score 1 or 2) (P = 0.0088), and serum albumin level <2.6 g/dl (P = 0.026). The incidence of acute abdomen (odds ratio 5.31, P = 0.00017) was significantly higher in the patients receiving anti-VEGF drugs than in those without anti-VEGF drugs. CONCLUSION: This study identified three predictive factors associated with in-hospital death after emergency surgery during chemotherapy: an older age, poor performance status, and low serum albumin level.

Novel laparoscopic methods for inguinal hernia post pelvic fracture: A case report.

INTRODUCTION: Pelvic fractures can occur in minor injuries, such as falls, in the elderly. Extensive adhesion of preperitoneal space is common after pelvic fracture surgery; hence, surgical interventions for inguinal hernia may be challenging. We treated a case of inguinal hernia after pelvic fracture surgery, using novel laparoscopic methods: iliopubic tract repair (IPTR) and modified intraperitoneal onlay mesh (mIPOM) approach. PRESENTATION OF CASE: This is the case of an elderly male with pelvic fracture. Open reduction and internal fixation were performed. Eighteen months after the procedure, a right inguinal bulge appeared, swelling increased, and he opted for surgery. We chose laparoscopic surgery to determine the status of the hernia and anatomy around the pelvis. He was diagnosed with an indirect inguinal hernia, and the inner inguinal ring was widely open. We chose the mIPOM approach and IPTR. He was discharged on day 3 post-operation. He developed a seroma after surgery, which disappeared after a month. Six months post-operation, no recurrence or neurologic pain observed. DISCUSSION: The transabdominal preperitoneal approach (TAPP) was initiated at first; however, the adhesion inside the inferior epigastric vessels was very strong, challenging to break into the preperitoneal space. We switched to the mIPOM method because the peritoneum was fragile and difficult to suture. Additionally, the internal ring was widely opened; hence, we proceeded with IPTR on confirmation that no tension on the abdominal wall was applied. CONCLUSIONS: Laparoscopic surgery is useful in flexibility of surgical options, such as TAPP, IPTR, IPOM, in addition to hybrid conversion.

Intraluminal Apple as a Rare Cause of Small Bowel Obstruction.

Small bowel obstruction due to ingested foreign bodies is rare in adults. A 48-year-old male visited our hospital with abdominal pain and vomiting. Computed tomography revealed intestinal obstruction by a 3 × 4 cm apple-shaped foreign body. Emergency surgery was performed to clear the obstruction which, upon inspection, was caused by a sexual toy made of rubber. Flexible rubber products that are ingested should be carefully followed after they pass thorough the pylorus. For obstructions related to sexual behavior, the patient's sense of shame often delays the process of seeking medical attention, thereby making preoperative diagnosis difficult.

3-[(dodecylthiocarbonyl)methyl]-glutarimide attenuates graft arterial disease by suppressing alloimmune responses and vascular smooth muscle cell proliferation.

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.

Immunosuppressive effects of DTCM-G, a novel inhibitor of the mTOR downstream signaling pathway.

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.

Dendritic cells conditioned with NK026680 prolong cardiac allograft survival in mice.

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.