Small and large intestinal cancer in patients with Crohn's disease studied by surgeons.

PURPOSE: The current study summarized the clinical course and treatment outcomes of intestinal cancer in CD seen in our department and explored the steps to take in the future. METHODS: Subjects were patients who had been diagnosed with CD at our hospital and who underwent surgery in our department from 1985 to 2020. RESULTS: Thirty-one patients had CD and intestinal cancer, including 6 with cancer of the small intestine and 25 with cancer of the large intestine. In all six patients with cancer of the small intestine, the site where cancer or a tumor developed was at or near the site of the anastomosis made at a previous surgery. Of the 25 patients with cancer of the large intestine, 22 developed cancer in the rectum or anal region. CONCLUSION: Many of the patients with cancer of the small intestine had previously undergone surgery, and the cancer developed at or near the site of the anastomosis. In patients who have previously undergone resection of the small intestine, the small intestine needs to be examined regularly. Cancer of the large intestine often developed in the rectum or anal region of our patients, so a detailed examination of the same site needs to be performed.

[A Case of Anastomotic Stenosis with Reconstructed Small Intestine Mucosal Damage during Taking S-1 Orally after Gastrectomy for Gastric Cancer].

An 83-year-old woman underwent laparoscopic distal gastrectomy and Billroth Ⅱ reconstruction for gastric cancer. Since histopathological examination revealed that the lesion was Stage ⅢA, she had started taking S-1 as an adjuvant chemotherapy 7 weeks after gastrectomy. Seventeen days later after taking S-1 administration, she felt nauseous and self-interrupted. Nineteen days later, she was urgently hospitalized. Esophagogastroduodenoscopy(EGD)showed anastomotic lumen was open, but reconstructed small intestine mucosal damage was found, and reconstructed small intestine muscle layer was fused to anastomotic region. On 50th day of hospitalization, mucosa was regenerated and endoscopic balloon dilatation (EBD)was performed from 78th day. She was discharged on 151th day of hospitalization after 7 times of EBD. One year later, she does not need EBD and can be taken orally and has no recurrence.

[A Case of Remnant Gastric Cancer That Completely Responded to Neoadjuvant S-1 and Cisplatin Therapy].

A 69-year-old man, who had undergone distal gastrectomy for duodenal ulcer, was diagnosed with remnant gastric cancer and jejunal mesenteric lymph node metastasis. To improve curability, we planned 2 courses of S-1 and cisplatin therapy. After chemotherapy, primary lesion and lymph node metastases reduced in size drastically. Completion gastrectomy and lymph node dissection were performed with curative intent. The tumor was found to have a pathological complete response(pCR) to chemotherapy on histological examination.

[A Case of Locally Far-Advanced Colon Cancer Resected by Laparoscopic Surgery after Colonic Stent Insertion and Neoadjuvant Chemotherapy].

We report a case of locally far-advanced colon cancer resected by laparoscopic surgery after colonic stent insertion and neoadjuvant chemotherapy. A 71-year-old man with obstructive symptoms was admitted to our hospital in July 2015. CT revealed a sigmoid colon tumor infiltrating the retroperitoneum and small intestine. Lower gastrointestinal endoscopy showed a sigmoid colon cancer. Self-expandable metallic stent insertion for obstructive colon cancer alleviated the patient's symptoms quickly. Four courses of neoadjuvant chemotherapy(XELOX)reduced the primary tumor in size, allowing for laparoscopic surgical resection. Combination therapy with colonic stenting and neoadjuvant chemotherapy can be an effective treatment for obstructive colon cancer. However, further studies and additional cases are needed to assess the safety and efficacy of this combination therapy.

Surgical Management for Patients with Toxic Megacolon due to Ulcerative Colitis.

Objectives: The present study reviewed cases of Toxic megacolon (TM) treated in our department, summarized the timing and technique of surgery, and considered key points for surgical management. Methods: This single-center retrospective study included the medical records of patients clinically diagnosed with TM who underwent surgery between 1985 and 2020. The diagnostic criteria and screening scores for sepsis, such as the systemic inflammatory response syndrome (SIRS) criteria, quick Sequential Organ Failure Assessment (qSOFA) score, and Modified Early Warning Score (MEWS), were validated. The preoperative clinical features and perioperative findings were also investigated. Results: There were eight male and six female patients. Nine patients (64.3%) satisfied the criteria for toxemia proposed by Narabayashi, and 10 patients (71.4%) fulfilled the SIRS criteria. A positive qSOFA score was confirmed in 1 patient (7.1%). The MEWS was high in 2 patients (14.3%). Intestinal perforation occurred in 2 patients (14.3%), and 1 of them died from disseminated intravascular coagulation. The mortality rate of TM with perforation was 50%. Eleven patients (78.6%) underwent total colectomy with end ileostomy. Conclusions: TM does not have well-defined diagnostic criteria, in addition to developing sometimes as borderline or fulminant cases, and must be recognized at an early stage, taking various findings into consideration. The criteria proposed by Narabayashi and the SIRS criteria, which met in a high percentage of our cases, are recommended as indicators for determining the toxicity of TM. It is also important to consider surgery in the early stages of TM, even if clinical findings do not meet all the criteria.

A Bridge to Curative Surgery for Obstructive Colorectal Cancer: Self-expandable Metallic Stent Versus Decompression Tube.

BACKGROUND/AIM: Self-expandable metallic stent (SEMS) placement is becoming the standard bridge-to-surgery (BTS) strategy for potentially curable left-sided obstructive colorectal cancer (OCRC). The study objective was to evaluate the effectiveness of SEMS placement as a BTS strategy for both right- and left-sided OCRC. PATIENTS AND METHODS: We retrospectively compared the short- and long-term outcomes of patients with OCRC who underwent placement of a SEMS versus a trans-nasal/anal decompression tube (DCT). The cohort comprised 57 patients with stage II/III right-sided OCRC (DCT, n=20; SEMS, n=8) or left-sided OCRC (DCT, n=9; SEMS, n=20). The short-term outcomes were the incidence of postoperative complications, rate of laparoscopic surgery, rate of stoma construction, and postoperative hospital stay; long-term outcomes were the 3-year overall survival (OS) and relapse-free survival (RFS). RESULTS: The SEMS group had a higher rate of laparoscopic surgery (85.7% vs. 6.9%, p<0.001), lower rate of stoma construction (10.7% vs. 34.5%, p=0.03), and shorter postoperative hospital stay (14 vs. 17 days, p=0.04) than the DCT group. Both groups had a similar incidence of postoperative complications. The 3-year OS and RFS were also similar in the DCT and SEMS groups for both right-sided OCRC (OS, 75.0% vs. 87.5%, HR=1.51, 95% CI=0.22-10.25, p=0.7; RFS, 65.0% vs. 50.0%, HR=0.97, 95% CI=0.28-3.36, p=0.9) and left-sided OCRC (OS, 88.8% vs. 90.0%, HR=1.19, 95% CI=0.10-14.29, p=0.9; RFS, 77.8% vs. 85.0%, HR=1.03, 95% CI=0.16-6.5, p=0.9). CONCLUSION: SEMS placement is a reasonable BTS strategy for left- and right-sided OCRC that achieves comparable short- and long-term outcomes to DCT insertion.

Contribution of prostaglandin D2 via prostanoid DP receptor to nasal hyperresponsiveness in guinea pigs repeatedly exposed to antigen.

We examined the role of prostanoid DP receptor in nasal blockage in an experimental allergic rhinitis model in guinea pigs. Local inhalation of prostaglandin D(2) (PGD(2)) to the nasal cavity resulted in an increase in intranasal pressure in guinea pigs actively sensitized by repeated antigen exposure but not in non-sensitized guinea pigs. Nasal hyperresponsiveness was observed when the guinea pigs were exposed to histamine and U-46619 (11alpha, 9alpha-epoxymethano-PGH(2); a thromboxane (TX) A(2) mimetic) after repeated antigen exposure. S-5751 ((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid), a prostanoid DP receptor antagonist, inhibited not only PGD(2)-induced nasal blockage but also nasal hyperresponsiveness to histamine and U-46619 in sensitized guinea pigs. Combined exposure of the nasal cavity of guinea pigs to an aerosol of PGD(2) with histamine or U-46619 at sub-threshold concentrations synergistically caused a marked increase in intranasal pressure. These responses were significantly suppressed by S-5751. These results suggest that PGD(2) plays a critical role in the increase in intranasal pressure via prostanoid DP receptor, probably through synergistically enhancing the nasal response with other chemical mediators released from mast cells and other inflammatory cells activated by allergens.

Synergistic effect of PGD2 via prostanoid DP receptor on TNF-alpha-induced production of MCP-1 and IL-8 in human monocytic THP-1 cells.

Prostaglandin (PG) D2, a major cyclooxygenase metabolite generated predominantly from immunologically stimulated mast cells, is thought to contribute to the pathogenesis of allergic diseases via the two PGD2 receptors, prostanoid DP receptor and chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). Monocytes are known to express the prostanoid DP receptor, however, the role of it in inflammatory responses is still unclear. In the present study, to clarify the functional roles of prostanoid DP receptor on monocytes, we examined the effect of PGD2 on the production of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 from a human monocytic cell line, THP-1. Single activation of prostanoid DP receptor hardly produced any cytokines or chemokines. However, activation with PGD2 in the presence of tumor necrosis factor (TNF)-alpha mediated significant production of MCP-1 and IL-8, but not the other cytokines and chemokines, in comparison to single stimulation with TNF-alpha. In addition, the selective prostanoid DP receptor antagonist, pinagladin ((Z)-7-[(1R,2R,3S,5S)-2-(benzothiophen-3-ylcarbonylamide)-10-norpinan-3-yl]hept-5-enoic acid) inhibited the production of MCP-1 and IL-8 upon combined stimulation with PGD2 and TNF-alpha. The synergistic production of MCP-1 and IL-8 by PGD2 was mimicked by dibutyryl cAMP (db-cAMP) and was inhibited by a protein kinase A (PKA) inhibitor. Our findings suggest that activation of the prostanoid DP receptor on THP-1 cells enhances TNF-alpha-induced MCP-1 and IL-8 production via the cAMP/PKA signaling pathway.

Prostanoid DP receptor antagonists suppress symptomatic asthma-like manifestation by distinct actions from a glucocorticoid in rats.

While inhaled glucocorticoids are the best treatment for the majority of chronic asthmatics, there is a small group who do not respond to these drugs or whose disease can only be controlled by high doses of oral glucocorticoids with risks of severe side effects. Therefore, a safe novel anti-asthmatic agent which has a different mechanism from that of glucocorticoids is needed for the management of asthma. We have previously shown that an orally active prostanoid DP receptor antagonist, S-5751, had potent anti-inflammatory effects in guinea pig and sheep asthma models. In this study, using a rat asthma like model, we found that lung neutrophilia and proinflammatory cytokine secretion as well as bronchial hyperresponsiveness and lung eosinophilia were induced by repeated antigen-inhalations after antigen-sensitization. These symptoms are similar to the pathogenesis of symptomatic asthma. Orally-administered prostanoid DP receptor antagonists S-5751 and pinagladin significantly suppressed not only bronchial hyperresponsiveness and lung eosinophilia but also neutrophilia and mucus secretion in the lung, while oral prednisolone inhibited only bronchial hyperresponsiveness and eosinophil infiltration. In addition, prostanoid DP receptor antagonists significantly suppressed interleukin (IL)-1ß, IL-6 and CXCL1 mRNA in contrast to suppression of IL-4 and CCL11 mRNA by prednisolone. The majority of prostanoid DP receptor-expressing cells in both rat and human asthmatic lungs are infiltrative macrophages and/or monocytes. These results suggest that prostanoid DP receptor antagonists utilize different mechanisms from glucocorticoids, and that they would be a novel alternative and/or combination drug for asthma therapy.

Suppression of immunoglobulin production by a novel dihydroorotate dehydrogenase inhibitor, S-2678.

We discovered a novel dihydroorotate dehydrogenase (DHO-DH) inhibitor, S-2678 ([2-fluoro-2',5'-dimethyl-4'-[6-(3-methyl-2-butenyloxy) pyridin-3-yl] biphenyl-4-yl]-(3-methyl-2-butenyl) amine). Its inhibitory activity against DHO-DH was more potent than that of A77 1726, an active metabolite of the anti-rheumatic drug leflunomide. S-2678 suppressed immunoglobulin production in mouse B cells and human peripheral blood mononuclear cells in vitro, with little or no inhibition of cell proliferation, probably through inhibition of class switch recombination in the immunoglobulin heavy chain loci in B cells. In vivo antibody production induced by systemic immunization with ovalbumin was dramatically suppressed by oral administration of S-2678, without any toxicological signs. However, S-2678 did not affect T-cell activation in vitro, and cytokine production induced by intravenous anti-CD3 antibody in mice. S-2678 did not affect host defense in a mouse model of Candida infection, whereas leflunomide severely impaired it. In conclusion, S-2678 selectively acts on B cells, resulting in antibody production, which suggests that it is useful for the treatment of humoral immunity-related diseases.