Identification of a unique subset of tissue-resident memory CD4+ T cells in Crohn's disease.

T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4+ tissue-resident memory T cell (Trm) subset that is increased in Crohn's disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4+ Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4+ Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4+ Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4+ T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.

Postoperative XELOX therapy for patients with curatively resected high-risk stage II and stage III rectal cancer without preoperative chemoradiation: a prospective, multicenter, open-label, single-arm phase II study.

BACKGROUND: Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer. METHODS: We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stage II and stage III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS). RESULTS: Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29-77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of '0' and 14 had scores of '1'. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8-78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7). CONCLUSIONS: Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides adequate 3-year DFS prospects. TRIAL REGISTRATION: This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.

A Novel Predictive Nomogram for Early Endoscopic Recurrence after Intestinal Resection for Crohn's Disease.

BACKGROUND/AIMS: Endoscopic recurrence (ER) after intestinal resection for Crohn's disease (CD) precedes the clinical recurrence, and the severity of ER correlates with the severity of the subsequent clinical recurrence. This study aimed to identify risk factors related to early ER after intestinal resection for CD and to create a prediction model. METHODS: The patients who underwent intestinal resection for CD between April 2008 and April 2017 and took endoscopic evaluation between 6 and 12 months after surgery were retrospectively analyzed. RESULTS: A total of 15 out of 52 (29%) patients developed early ER. A univariate analysis demonstrated that early ER was significantly correlated with history of prior intestinal resections for CD (p = 0.005), low preoperative albumin levels (p = 0.035), and excessive perioperative inflammation (i.e., high C-reactive protein levels in both preoperative and postoperative periods; p = 0.034). Based on these clinical factors, a nomogram for predicting early ER was created with the area under the curve 0.808. CONCLUSION: We developed a novel predictive nomogram for early ER after intestinal resection for CD. This prediction model might assist clinicians in managing patients with CD after an intestinal resection. Additional validation studies are currently being developed.

[A Case of Intractable Bile Leakage after Surgery for Gallbladder Cancer Successfully Treated by Transcatheter Arterial Embolization].

An 83-year-old man underwent extended cholecystectomy for gallbladder cancer. On postoperative day 13, he developed fever and computed tomography (CT) revealed fluid collection at the cut surface of the liver. Ultrasound-guided fluid drainage was conducted, and he was diagnosed with biliary leakage. Radiological examination using a contrast agent revealed that the anterior branch of the bile duct (B5) was completely interrupted. Simple drainage and ethanol injections into the bile duct proved ineffective. Thus, we performed transcatheter arterial embolization (TAE) in the anterior segmental artery (A5) to stop the production of bile in the injured part of anterior segment. The treatment was effective, and he was discharged 15 days after TAE. TAE might be a useful method for treating intractable interrupted-type bile leakage.

[Effect of Post-Gastrectomy Adjuvant S-1 Chemotherapy on Muscle Volume in Gastric Cancer Patients].

OBJECTIVE: To examine the effect of S-1 adjuvant chemotherapy on muscle volume after curative gastrectomy in gastric cancer patients. PATIENTS: Forty-eight gastric cancer patients (31 men and 17 women) who underwent curative gastrectomy (distal gastrectomy: n=37, and total gastrectomy: n=11) between April 2010 and July 2011 were enrolled in this study. Sixteen patients underwent S-1 adjuvant chemotherapy (S-1 group) for 1 year after the operation, and 32 patients did not (NT group). METHODS: The psoas muscle areas were measured at the fourth lumbar vertebrae on CT images obtained before the operation, and at 6, 12, and 24 months after the operation. Muscle areas was statistically examined by comparing the preoperative and postoperative ratios. RESULTS: The muscle areas 12 months after the operation decreased to 0.86 ± 0.11 in the S-1 group and to 0.96 ± 0.08 in the NT group (p<0.05), and the significant difference disappeared at 24 months (0.93 ± 0.10 vs. 0.93 ± 0.11, NS). In the patients who underwent distal gastrectomy, the muscle areas decreased to 0.90 ± 0.05 in the S-1 group and to 0.96 ± 0.09 in the NT group at 12 months (p<0.05). Meanwhile, in those who underwent total gastrectomy, the muscle areas decreased to 0.80 ± 0.15 and 0.93 ± 0.03, respectively (NS). CONCLUSIONS: S-1 adjuvant chemotherapy affected muscle volume loss after gastrectomy in the gastric cancer patients, but the patients recovered from the adverse effect by 12 months after chemotherapy.

Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain.

Cancer-specific cell surface antigens are ideal therapeutic targets for monoclonal antibody (mAb)-based therapy. Here, we report that multiple myeloma (MM), an incurable hematological malignancy, can be specifically targeted by an mAb that recognizes a ubiquitously present protein, CD98 heavy chain (hc) (also known as SLC3A2). We screened more than 10,000 mAb clones raised against MM cells and identified R8H283, an mAb that bound MM cells but not normal hematopoietic or nonhematopoietic cells. R8H283 specifically recognized CD98hc. R8H283 did not react with monomers of CD98hc; instead, it bound CD98hc in heterodimers with a CD98 light chain (CD98lc), a complex that functions as an amino acid transporter. CD98 heterodimers were abundant on MM cells and took up amino acids for constitutive production of immunoglobulin. Although CD98 heterodimers were also present on normal leukocytes, R8H283 did not react with them. The glycoforms of CD98hc present on normal leukocytes were distinct from those present on MM cells, which may explain the lack of R8H283 reactivity to normal leukocytes. R8H283 exerted anti-MM effects without damaging normal hematopoietic cells. These findings suggested that R8H283 is a candidate for mAb-based therapies for MM. In addition, our findings showed that a cancer-specific conformational epitope in a ubiquitous protein, which cannot be identified by transcriptome or proteome analyses, can be found by extensive screening of primary human tumor samples.

Human NKp44+ Group 3 Innate Lymphoid Cells Associate with Tumor-Associated Tertiary Lymphoid Structures in Colorectal Cancer.

Innate lymphoid cells (ILC) are responsible for mucosal tissue homeostasis and are involved in the progression and suppression of several types of cancer. However, the effects of ILCs on colorectal cancer are poorly understood. We characterized human ILCs in normal colon and colorectal cancer tissue, investigating their role in the tumor immune microenvironment. Normal mucosa and tumor tissues were obtained from patients with colorectal cancer, and the cells were isolated by enzymatic digestion. NKp44+ ILC3s with high expression of tertiary lymphoid structure (TLS) formation-related genes, including LTA, LTB, and TNF, accumulated in the normal colonic mucosa and T1/T2 tumors. However, the number of NKp44+ ILC3s was significantly reduced in T3/T4 tumors compared with normal colonic mucosa and T1/T2 tumors. NKp44+ ILC3s present in T3/T4 tumors had decreased expression of TLS formation-related genes, whereas stromal cells had decreased expression of CXCL13, CCL19, and CCL21 The decreasing number of NKp44+ ILC3s during tumor progression correlated with the TLS density in tumors. Thus, our results indicate that NKp44+ ILC3s infiltrate colorectal cancer tissue, but the number of cells decreases in T3/T4 tumors with associated decreases in TLS induction.

Colonic ischemia developed after laparoscopic colectomy for rectosigmoid cancer with focal infrarenal aortic stenosis.

A 69-year-old woman with focal infrarenal aortic stenosis was diagnosed with rectosigmoid cancer. Because radical resection for colon cancer required dissection of vessels that supplied blood flow to the legs, revascularization by aortic stent placement was performed before the colectomy. We subsequently performed laparoscopic low anterior resection without any complications. Two and a half years after colectomy, however, the patient developed colonic ischemia due to thrombosis of the dilated marginal artery that served as a collateral artery before stenting. We performed laparoscopic partial colectomy, including the resection of the dilated marginal artery filled with thrombus. An abnormally dilated ex-collateral artery was thought to have caused vessel occlusion, presumably due to an imbalance in blood flow and vascular diameter.

Diverticular colitis with progression to ulcerative colitis after sigmoidectomy.

Diverticular colitis is chronic inflammation of the colon where diverticula are present. The endoscopic and histopathological findings of this disease are sometimes similar to those of ulcerative colitis, and several reports describe cases of diverticular colitis that progressed to typical ulcerative colitis. A 77-year-old woman with intramesenteric penetration of the sigmoid diverticulum underwent low anterior resection. One month later, the patient experienced anastomotic leakage, and transverse colostomy was performed. Six months after the colostomy, the patient returned to the hospital with complaints of bloody discharge from the rectum and stoma. Colonoscopy revealed newly developed loss of vascular pattern and a granular appearance of the mucosa in the rectum that had not been present at prior examinations. She was diagnosed with ulcerative colitis, which developed after colectomy, and treated with mesalazine and high-dose prednisolone, but the clinical and endoscopic response was poor. Finally, the patient underwent total proctocolectomy and ileal pouch anal anastomosis with diverting ileostomy. As a few reports have described, diverticular colitis can progress to typical ulcerative colitis after surgery in some cases, suggesting a possible pathogenic similarity between the two diseases and association between colorectal surgery and disease progression.