Innate-like T cells in patients with cancer

Innate-like T cells, including invariant natural killer T (NKT), mucosal associated invariant T (MAIT) cells or g T cells are associated with regulation of anti-tumour responses in humans and mice, although their exact role remains controversial. We have studied innate-like T cells from tumour infiltrating lymphocytes (TILS), peripheral blood mononuclear cells (PBMCs) and bone marrow (BM) derived cells from patients undergoing treatment for cancer and compared their characteristics to cells from healthy donors. We identifed that the overall frequency of innate-like T cells was variably deficient in patients with blood or solid cancers. Interestingly, the deficiency of innate-like T cells appeared to be more severe than that of other T cells suggesting a specific impact. An increased proportion of activated g T cells and MAIT cells suggested they could have a functional role in responses to cancer cells. Despite the deficiency of these subsets in patient tissue samples, we showed that anti-tumour capacity of innate-like T cells was intact as innate-like T cells in most patient groups had a similar cytokine response to stimulation as cells from healthy donors. Finally, we also showed that innate-like T cells appeared not to broadly recognize cancer cells, as no direct impact was identified in their overall frequency or cytokine expression when exposed to autologous tumour cells, cancer lysates or lipids extracted from patient tumours, or colorectal cancer cell lines. This project was aimed at providing an overview of potential defects in innate-like T cells based on my analysis of a wide range of samples in the Fiona Elsey Cancer Research Institute (FECRI) Tissue Bank. As a result of my studies, we have established a clear understanding of innate cells in cancer, which provides a basis for future studies. Our novel findings include analysis of frequency distribution and functional capacity of MAIT cells in solid tumours other than colorectal cancer and in patients with blood cancers such as chronic lymphocytic leukaemia (CLL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) or other haematological malignancies, something not previously reported. Taken together, we showed that a deficiency of innate-like T cells is common in patient groups with cancer and could be a risk factor for disease and possibly a target for immunotherapies, but the functional capacity was intact for cytokine responses.Doctor of Philosoph

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure

Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.Peer reviewe

An emerging role for immune regulatory subsets in chronic lymphocytic leukaemia

The last few years has seen the burgeoning of a new category of therapeutics for cancer targeting immune regulatory pathways. Antibodies that block the PD-1/PD-L1 interaction are perhaps the most prominent of these new anti-cancer therapies, but several other inhibitory receptor ligand interactions have also shown promise as targets in clinical trials, including CTLA-4/CD80 and Lag-3/MHC class II. Related to this is a rapidly improving knowledge of 'regulatory' lymphocyte lineages, including NKT cells, MATT cells, B regulatory cells and others. These cells have potent cytokine responses that can influence the functioning of other immune cells and many researchers believe that they could be effective targets for therapies designed to enhance immune responses to cancer. This review will outline our current understanding of FOXP3 + 'Tregs', NKT cells, MAIT cells and B regulatory cells immune regulatory cell populations in cancer, with a particular focus on chronic lymphocytic leukaemia (CLL). We will discuss evidence linking CLL with immune regulatory dysfunction and the potential for new therapies targeting regulatory cells. (C) 2015 Elsevier B.V. All rights reserved

Propensity score-matching analysis to compare clinical outcomes of endoscopic submucosal dissection for early gastric cancer in the postoperative and non-operative stomachs

Abstract Background Endoscopic submucosal dissection (ESD) of the postoperative stomach (ESD-P) for early gastric cancer (EGC) is considered a technically difficult procedure. However, it is difficult to compare the outcomes of ESD-P and ESD of the non-operative stomach (ESD-N) because their baseline characteristics are different. Therefore, we aimed to compare the technical outcomes of ESD-P with those of ESD-N using a propensity score-matching analysis to compensate for the differences. Methods The chart records of 1046 patients with EGC who were treated with ESD between January 2004 and July 2016 at Kitakyushu Municipal Medical Center in Japan were reviewed in this retrospective study. Multivariate analyses and propensity score-matching were performed for age, sex, lesion location, lesion size, tumor invasion, tumor size, ulcer (scar), and operator skill. The primary outcome was procedure time. Secondary outcomes were percentages of en bloc, complete, and curative resections, and percentages of adverse events, which were evaluated between the two groups. Results Forty-one patients were in the ESD-P group and 1005 patients were in the ESD-N group. Propensity score-matching created 41 matched pairs. According to the adjusted comparisons, ESD-P required a significantly longer procedure time (85 min vs 51 min, p < 0.001). Other treatment outcomes showed an en bloc resection rate of 100% for both groups (p = 1) and complete resection rates of 95.1 and 97.6% (p = 1), curative resection rates of 90.2 and 90.2% (p = 1), perforation during ESD rates of 2.4 and 0% (p = 1), and postprocedure bleeding rates of 2.4 and 2.4% (p = 1) for the ESD-P and ESD-N groups, respectively. For the ESD-P group, lesions on the suture line or anastomotic site were significantly associated with longer procedure times (p = 0.038). Conclusions ESD-P was a more time-consuming procedure than ESD-N. However, ESD-P and ESD-N achieved high rates of curative resection with a low rate of adverse events for the treatment of EGC. ESD could be selected as the treatment for EGC even in the postoperative stomach provided that careful attention is given to lesions on the suture line or anastomotic site

Intrapancreatic recurrence of intraductal tubulopapillary neoplasm (ITPN) 16 years after the initial surgery for noninvasive ITPN: a case report

Abstract Background Intraductal tubulopapillary neoplasm (ITPN) is a rare pancreatic intraductal neoplasm. It is characterized by a tubulopapillary growth pattern, entirely high-grade atypical cells, minimal cytoplasmic mucin, and no obvious luminal mucin secretion. Most of its biological nature remains unclear. Case presentation We herein report a case of intrapancreatic recurrence of ITPN in the remnant pancreas of a patient who underwent pancreatoduodenectomy 16 years previously for a noninvasive intraductal pancreatic head tumor. We reexamined the primary tumor and compared it with the most recently resected specimen. Histologically, the primary tumor showed a tubulopapillary growth of high-grade atypical cells with scanty cytoplasmic mucin, which was similar to the recently resected specimen except for the invasive area. Immunohistochemically, the neoplastic cells in both specimens showed focal staining of MUC1 and positivity for MUC6 but negativity for MUC2, MUC5AC, CDX2, and trypsin. Molecular analysis revealed no KRAS/GNAS/BRAF/PIK3CA mutations in either of the specimens. Conclusions These findings of the original tumor and recently resected tumor were compatible with the features of ITPN. Thus, recurrence is possible even for a primary noninvasive ITPN, and long-term surveillance is recommended

Efficacy of Early Endoscopic Ultrasound-Guided Transluminal Drainage for Postoperative Pancreatic Fistula

Background. Endoscopic ultrasound-guided transluminal drainage (EUS-TD) is generally performed 4 weeks after disease onset for evacuating pancreatic fluid collections. However, the optimal timing for conducting the procedure in those diagnosed with postoperative pancreatic fistula (POPF) has not been established. We aimed to elucidate the efficacy and safety of early EUS-TD procedures for treating POPF. Methods. We retrospectively reviewed patients diagnosed with POPF who underwent EUS-TD in the Kyushu University Hospital between 2008 and 2019. Clinical features were comparatively analyzed between the two patient groups who underwent either early (≤15 days postoperatively) or late (>15 days postoperatively) EUS-TD. Factors prolonging hospital stay were also analyzed using Cox proportional hazard models. Results. Thirty patients (median age, 64.5 years) were enrolled. The most common initial operation was distal pancreatectomy with splenectomy (60.0%). Median size of POPF was 69.5 (range, 38–145) mm, and median time interval between surgery and EUS-TD was 17.5 (range, 3–232) days. Totally, 47% patients underwent early EUS-TD. Rates of technical success, clinical success, and complications were 100%, 97%, and 6.9%, respectively. No recurrence of POPF occurred during a median follow-up period of 14 months. Clinical characteristics and outcomes were comparable between the early and late drainage patient groups, except for the rates of infection and nonencapsulation of POPF, which were significantly higher in the early drainage group. Performing simultaneous internal and external drainage (hazard ratio (HR): 0.31; 95% confidence interval (CI): 0.11–0.93, p=0.04) and conducting ≥2 treatment sessions (HR: 0.26; 95% CI: 0.08–0.84, p=0.02) were significantly associated with prolonged hospitalization after EUS-TD. Conclusions. EUS-TD is a safe and effective method for managing POPF, regardless of when it is performed in the postoperative period. Once infected POPF occurs, clinicians should not hesitate to perform EUS-TD even within 15 days of the initial operation

Gastric Glomus Tumor Diagnosed by Endoscopic Ultrasound-Guided Fine-Needle Aspiration Biopsy : Report of a Case

A glomus tumor of the stomach is rare. It is difficult to diagnose the tumor before surgery by only endoscopic biopsy and radiography, and there is no established method of diagnosis before surgical treatment. Esophagogastroduodenoscopy (EGD) on a 50-year-old Japanese woman revealed a 10mm submucosal tumor in the anterior wall of the gastric angle. Follow-up EGD revealed an increase in the size of the tumor to 15mm. Endoscopic ultrasonography (EUS) demonstrated a 15mm subepithelial hypoechoic solid tumor with continuity to the proper muscle layer. Histologic diagnosis by endoscopic ultrasonography guided fine needle aspiration (EUS-FNA) was glomus tumor. The tumor was treated by laparoscopic local resection. The histologic diagnosis of the resected tumor was similar to the preoperative EUS-FNA results. EUS-FNA would appear to be an effective histologic test for early diagnosis of gastric glomus tumor.胃グロムス腫瘍はまれな疾患であり，上部消化管内視鏡検査(EGD)による生検や画像診断のみでは手術前に診断に至ることは難しい．現在のところ胃グロムス腫瘍を術前に診断することは困難である．症例は50歳の日本人女性．近医にて施行されたEGDにて胃角部前壁に10mm大の粘膜下腫瘍を指摘された．1年後のフォローアップのEGDでサイズは15mm大に増大しており精査加療のため当院を紹介された．当院で施行した超音波内視鏡検査(EUS)で粘膜下に筋層と連続する15mm大の低エコー充実性腫瘤を指摘．超音波内視鏡下穿刺吸引法(EUS-FNA)を施行しグロムス腫瘍と病理組織学的に診断した．当院外科へ紹介し腹腔鏡下胃局所切除術が施行され，術後の病理組織は術前のEUS-FNAで採取された組織とほぼ同様でグロムス腫瘍と診断された．EUS-FNAは胃グロムス腫瘍の早期診断に有用な方法であると考えられた