Indications and outcomes of colorectal hybrid endoscopic submucosal dissection: a large multicenter 10-year study.

BACKGROUND AND AIMS: Hybrid endoscopic submucosal dissection (ESD) is a colorectal lesion resection procedure that includes both planned and salvage procedures. Previous colorectal hybrid ESD studies have involved single institutions or few operators over a short timeframe, and the size for indication has not been established. In this multicentre study, we investigated the clinical outcomes of hybrid ESD for colorectal tumors that met the 30 mm lesion size criterion. METHODS: From January 2008 to December 2018, colorectal hybrid ESD was performed for 172 lesions (diameter range, ≥ 20- < 30 mm) at Hiroshima GI Endoscopy Research Group. We compared clinicopathological characteristics and outcomes between 56 and 116 lesions in planned and salvage groups, respectively. We also compared data between 2008 and 2013 (the first period) and 2014 and 2018 (the second period) to assess operator experience. RESULTS: No significant difference was found in the complete en bloc resection rate between the planned and salvage groups (92.9% vs. 83.6%, respectively). Procedure time was shorter in the planned group (44.5 min) than in the salvage group (72.0 min, p < 0.01). The perforation rate was higher in the salvage group (21.6%) than in the planned group (0%, p < 0.01); however, the perforation rate during snaring in the salvage group was 1.8%. During the second period relative to the first period, we recorded a significantly higher complete en bloc resection rate (95.7% vs. 75.6%, respectively, p < 0.01) and experienced operator rate (75.5% vs. 53.9%, respectively, p < 0.01). Furthermore, no significant difference was found in the complete en bloc resection rate between the planned and salvage groups during the second period (100% vs. 94.4%, respectively). CONCLUSION: Colorectal hybrid ESD, especially salvage hybrid ESD performed by experienced operators, is adoptable and safe for lesions with diameters ranging from ≥ 20 to < 30 mm.

Clinical outcomes of endoscopic submucosal dissection for colorectal tumors: a large multicenter retrospective study from the Hiroshima GI Endoscopy Research Group.

BACKGROUND AND AIMS: Although advanced high-volume centers have reported good outcomes of colorectal endoscopic submucosal dissection (ESD), a limited number of highly skilled experts in specialized institutions performed these procedures. We undertook a retrospective multicenter survey, which included nonspecialized hospitals, to investigate the clinical outcomes of colorectal ESD. METHODS: We recruited 1233 consecutive patients with 1259 colorectal tumors resected by ESD at 12 institutions. We evaluated the en bloc resection rate, histologic complete resection rate, curative (R0) resection rate, adverse events, and the long-term prognoses, including local recurrence, metachronous tumor development, and survival rate. RESULTS: The en bloc, histologic complete, and R0 resection rates were 92.6%, 87.4%, and 83.7%, respectively. The delayed bleeding, intraoperative perforation, and delayed perforation rates were 3.7%, 3.4%, and .4%, respectively. The long-term outcomes analysis included 1091 patients (88.4%). Local recurrences occurred in 1.7%, and metachronous tumors (>5 mm) developed in 11.0% of the patients. The 3- and 5-year overall survival rates were 95.1% and 92.3%, respectively. The number of colonic tumors, severe submucosal fibrosis, and en bloc resection rates were significantly higher in the high-volume centers (Group H) than those in the low-volume centers (Group L). The average tumor size in Group H was significantly larger than that in Group L. CONCLUSIONS: Colorectal ESDs are feasible, have acceptable adverse event risks, and favorable long-term prognoses. (Clinical trial registration number: UMIN000016197.).

Treatment of children and adolescents with ulcerative colitis by adsorptive depletion of myeloid lineage leucocytes as monotherapy or in combination with low dose prednisolone after failure of first-line medications.

BACKGROUND: Currently available drugs for the treatment of ulcerative colitis (UC) include salicylates, thiopurines, corticosteroids and new anti-tumour necrosis factor (TNF)-α biologics. Among these medications, corticosteroids in children and adolescents may adversely affect the patients' growth and development. Further, UC patients have elevated and activated myeloid lineage leucocytes including the CD14 + CD16+ monocytes, which release TNF-α as a significant exacerbating factor. Accordingly, depletion of these cells by granulocyte/monocyte adsorption (GMA) should alleviate inflammation and promote UC remission. The objective of this study was to evaluate the efficacy of GMA in children and adolescents in whom conventional first-line medications had failed to induce remission. METHODS: In a single centre setting, between 2007 and 2012, a total of 24 consecutive children and adolescents, age 11-19 years were given mesalazine or sulphasalazine as a first-line medication. Seventeen patients relapsed or did not respond to the first-line medications, and received GMA with the Adacolumn, 2 sessions in the first week, and then weekly, up to 11 sessions. Patients who achieved a decrease of ≥5 in the clinical activity index (CAI) were to continue with GMA, while non-responders were to receive 0.5 to 1.0 mg/kg/day prednisolone (PSL) plus additional GMA sessions similar to GMA responder cases. At entry and week 12, patients were clinically and endoscopically evaluated, allowing each patient to serve as her/his own control. RESULTS: Seven patients achieved remission with the first-line medications and did not receive GMA. Five patients did not respond to the first 5 GMA sessions and received PSL plus GMA, while 12 patients responded to the first 5 GMA sessions and received additional sessions. At entry, the average CAI was 12.7 ± 2.5, range 8-17, and the average endoscopic index was 8.5 ± 1.5, range 7-11. The corresponding values at week 12 were 2.1 ± 0.2, range 1-4 (P < 0.001) and 2.4 ± 0.2, range 1-4 (P < 0.001). PSL was tapered to 0 mg within 3 months. CONCLUSIONS: With the strategy we applied in this study, all 24 consecutive patients achieved remission. In growing patients with active UC refractory to first-line medications, GMA was associated with clinical remission and mucosal healing, while in non-responders to GMA monotherapy, addition of a low dose PSL enhanced the efficacy of GMA and tapering of the PSL dose soon after remission was not associated with UC relapse. Therefore, the majority of young corticosteroid naive UC patients in whom first-line salicylates have failed may respond to GMA and be spared from additional drug therapy. Avoiding corticosteroids at an early stage of UC should ensure better long-term clinical course.

Evaluation of individual risk in nonvariceal gastrointestinal bleeding patients with NSAID administration: a multicenter study in Japan.

BACKGROUNDS: Gastrointestinal (GI) toxicity is an undesirable effect of nonsteroidal anti-inflammatory drugs (NSAIDs). We conducted a multicenter study in Japan to clarify the GI risk grade in patients with NSAID-induced GI bleeding. METHODS: Patients with emergent endoscopic hemostasis by nonvariceal bleeding were registered from 36 hospitals in Hiroshima. In cases with NSAID use, the GI risk grade (low, moderate, or high) was evaluated, and concomitant drugs were investigated. We asked 79 gastroenterologists and 234 orthopedists what concomitant drugs they would prescribe to 3 simulated patients. RESULTS: A total of 1,350 patients were registered. NSAIDs were used in 278 cases (21%). Concerning the risk grade in each patient, the largest group was the moderate-risk group (203 patients; 73%), while the high-risk group comprised 10% of all NSAID users with bleeding. A proton pump inhibitor (PPI) or misoprostol was administrated to only 20 patients (7%). A small number of the gastroenterologists and orthopedists who responded to the questionnaire would prescribe PPI or misoprostol to simulated patients with short-term loxoprofen use. CONCLUSIONS: In NSAID users with GI bleeding, the moderate-risk group was the largest group for GI toxicity in Japan. In these cases, PPI or misoprostol was not commonly medicated in clinical practice.

[Usefulness of ultrasonography for diagnosis and treatment in case of superior mesenteric artery (SMA) syndrome].

A 37-year-old man, who had been admitted to another facility because of integration dysfunction syndrome suffered from postprandial epigastric pain, vomiting and weight loss. He was referred to our hospital for further examinations and treatment. Ultrasound examination revealed gastric and duodenal dilatation, reduction of the distance between the superior mesenteric artery (SMA) and aorta and to-and-fro movement in his duodenum, suggesting SMA syndrome. Computed tomography and upper gastrointestinal tract examination also showed findings typical of SMA syndrome. We measured the SMA-aorta distance and the passage of duodenal contents in various body positions using ultrasound. He had to-and-fro movements in his duodenum in a supine, sitting, and left recumbent position. However, when examined in the right recumbent position, the SMA-aorta distance became longest, and intestinal juice flowed from the duodenum to the jejunum. He underwent postural therapy, maintaining a right recumbent position for 30 minutes after every meal, which improved his clinical symptoms.

[Large hepatocellular carcinoma successfully treated with transarterial chemoembolization using cisplatin].

A 83-year-old man was admitted to our hospital with a large hepatic tumor located in lateral segment. Alpha-fetoprotein was 7ng/ml, and protein induced by vitamin K deficiency and antagonist-II (PIVKA-II) was 50792mAU/ml. The tumor was diagnosed as hepatocellular carcinoma (HCC) by angiographically assisted CT. No ascites was detected and major serological findings were T-Bil 0.7mg/dl, Alb 4.2g/dl, and PT 129%. Because of advanced age and a history of heart disease, he was treated with transarterial chemoembolization using cisplatin (Lip-TACE). The total dose was 128mg of cisplatin and 15ml of lipiodol. No adverse effects appeared. After the third session of Lip-TACE, the levels of PIVKA-II became negative and continued within the normal range for 26 months. We confirmed a decrease of HCC with lipiodol accumulation by abdominal CT, and the response rate was PR. He has been well for 3 years since the first Lip-TACE procedure.

Neuropilin-1 is involved in regulation of apoptosis and migration of human colon cancer.

Vascular endothelial growth factor (VEGF) plays critical roles in cancer aggressiveness. We investigated the clinical and biological significance of neuropilin (NP)-1, a member of the VEGF receptor family, in colon carcinoma. We transfected NP-1-specific small interfering RNA (siRNA) into a human colon adenocarcinoma cell line, WiDR, and investigated its effect on proliferation, migration, and apoptosis. We also examined the relationship between clinicopathologic features and NP-1 expression in 146 patients with advanced colorectal carcinoma who had undergone surgery. Inhibition of NP-1 expression in WiDR cells by RNA interference decreased cell migration (no treatment, 143.3/field; mock, 146.8/field; scrambled siRNA, 134.6/field; NP-1 siRNA 79.6/field) and promoted apoptosis (no treatment, 3.52%; scrambled siRNA, 3.80%; NP-1 siRNA, 14.22%), but did not alter cell proliferation. In patients with advanced colorectal carcinoma, those with tumors with high levels of NP-1 staining showed a significantly higher incidence of lymph node (73.0%) or liver (86.2%) metastasis, greater microvessel density (MVD) (60.4/field), greater number of proliferating carcinoma cells (48.6%), and lesser number of apoptotic carcinoma cells (5.70 per thousand) than those with tumors with low levels of NP-1 staining (lymph node, 56.9%; liver, 59.8%; MVD, 47.8/field; proliferating cells, 42.0%; apoptosis, 8.44 per thousand). Survival for patients with tumors with high levels of NP-1 staining was significantly shorter than for those with tumors with low levels of NP-1 staining. Our results suggest that autocrine-NP-1 pathways control the migration and survival of colon carcinoma cells. NP-1 expression may stimulate tumor growth by enhanced angiogenesis and suppression of tumor cell apoptosis, which lead to metastasis and poor prognosis.

Cyclooxygenase-2 is up-regulated by interleukin-1 beta in human colorectal cancer cells via multiple signaling pathways.

Overexpression of cyclooxygenase-2 (COX-2) has been observed in human colorectal cancer. COX-2 expression in human tumors can be induced by growth factors, cytokines, oncogenes, and other factors. The mechanisms regulating COX-2 expression in human colon cancer have not been completely elucidated. We hypothesized that the proinflammatory cytokine interleukin-1 beta (IL-1 beta) mediates COX-2 expression in HT-29 human colon cancer cells. Treatment of HT-29 cells with IL-1 beta induced expression of COX-2 mRNA and protein in a time- and dose-dependent manner. Inhibitors of the extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, P38 mitogen-activated protein kinase, and nuclear factor-kappa B (NF-kappa B) signaling pathways blocked the ability of IL-1 beta to induce COX-2 mRNA. In contrast, Wortmannin, a phosphoinositide 3-kinase inhibitor upstream of protein kinase B/Akt, led to a slight increase in COX-2 mRNA expression after IL-1 beta treatment. Electrophoretic mobility shift assay on nuclear extracts demonstrated that IL-1 beta induced NF-kappa B DNA binding activity in HT-29 cells, and the activated NF-kappa B complex was eliminated after treatment with an inhibitor of NF-kappa B. Supershift assay indicated that the two NF-kappa B subunits, p65 and p50, were involved in activation of NF-kappa B complex by IL-1 beta stimulation. The stability of COX-2 mRNA was not altered by IL-1 beta treatment. These data demonstrate that IL-1 beta induces COX-2 expression in HT-29 cells through multiple signaling pathways and NF-kappa B.

Biology of angiogenesis in tumors of the gastrointestinal tract.

The realization that the growth and spread of tumors are dependent on angiogenesis has created new avenues of research designed to help us to better understand cancer biology and to facilitate the development of new therapeutic strategies. However, the process of angiogenesis consists of multiple, sequential, and interdependent steps with a myriad of positive and negative regulators of angiogenesis being involved. The survival of tumors and thus their metastases are dependent upon the balance of endogenous angiogenic and anti-angiogenic factors such that the outcome favors increased angiogenesis. Several growth factors have been identified that regulate angiogenesis in cancers of the gastrointestinal tract. These include pro-angiogenic factors like vascular endothelial growth factor (VEGF) and anti-angiogenic factors, i.e., thrombospondin. The following review provides a brief overview about the most important factors that are involved in the angiogenic process in tumors derived from colon, stomach, and pancreas. A thorough understanding of the role these factors play in the angiogenic process may lead to the development of novel therapeutic antineoplastic strategies.

Regulation of vascular endothelial growth factor expression in human gastric cancer cells by interleukin-1beta.

BACKGROUND: Vascular endothelial growth factor (VEGF), a dominant angiogenic factor in gastric cancer, is upregulated by cytokines in the tumor microenvironment. Interleukin-1beta (IL-1beta), a proinflammatory cytokine, has been shown to be proangiogenic in vivo, despite its not demonstrating angiogenic activity in vitro. We hypothesized that IL-1beta regulates VEGF expression in human gastric cancer cells and investigated the mechanism by which this occurs. METHODS: We treated the TMK-1 human gastric cancer cell line with IL-1beta for 1 to 24 hours, and then analyzed VEGF mRNA expression by Northern blotting and signaling intermediates by Western blotting. Signaling inhibitors were used to identify the dominant pathways involved in IL-1beta induction of VEGF. VEGF promoter-luciferase constructs and transcription blockers were used to investigate the transcriptional regulation of VEGF by IL-1beta. RESULTS: Treating TMK-1 cells with IL-1beta increased VEGF mRNA levels and activated extracellular signal-regulated kinases 1 and 2 (Erk 1/2) and p38, but not Akt. Inhibitors of the Erk and p38 pathways blocked IL-1beta induction of VEGF mRNA. Treating TMK-1 cells with IL-1beta also increased VEGF promoter activity. VEGF transcriptional activity was found to depend on a 120-bp region just proximal to the transcription start site. CONCLUSIONS: In human gastric cancer cells, IL-1beta induced VEGF through Erk- and p38-dependent pathways; this induction of VEGF was transcriptionally regulated.

Synopsis of angiogenesis inhibitors in oncology.

Angiogenesis is a dynamic process essential for primary tumor growth and metastases. New insights into the basic understanding of the biologic processes responsible for angiogenesis have led to the characterization of potential therapeutic targets. Several strategies for the development of antiangiogenic therapeutic modalities have been employed, including agents that (1) decrease the activity of specific angiogenic factors, (2) decrease th$ activity of endothelial survival factors, (3) increase the activity of naturally occurring antiangiogenic agents, or (4) indirectly downregulate angiogenic and survivalfactor activity. Because antiangiogenic therapy is unlikely to induce tumor regression, the criteria for efficacy must be evaluated by means other than the standard response criteria used to evaluate cytotoxic chemotherapy. Further, the redundancy of molecules responsible for the angiogenic process suggests it is unlikely that a single antiangiogenic agent will provide prolonged inhibition of angiogenesis. Nevertheless, the understanding of the basic principles that drive tumor angiogenesis will lead to the development of therapies that will likely prolong survival without the toxicity associated with standard chemotherapy.

Magnifying colonoscopy used to predict disease relapse in patients with quiescent ulcerative colitis.

BACKGROUND: Many patients with quiescent ulcerative colitis (UC) experience relapse. However, clinical and conventional colonoscopic signs are inadequate for predicting relapse. This study's aim was to investigate the effectiveness of magnifying colonoscopy in predicting relapse in patients with quiescent UC and to evaluate the association of the findings of magnifying colonoscopy with the histological findings. METHODS: Magnifying colonoscopy was performed in 57 patients with clinical and endoscopic inactive UC. Patients were divided into 3 groups according to the findings of magnifying colonoscopy as MR (magnify-regular), MI (magnify-irregular), and MD (magnify-defect). Their subsequent clinical course was compared to assess the clinical usefulness of magnifying observation in predicting relapse. We also compared histological findings according to Riley's criteria to each finding of magnifying colonoscopy. RESULTS: Within 12 months, 1 of 18 patients (6.7%), 10 of 22 patients (45.5%), and 12 of 17 patients (70.6%) with findings of magnifying colonoscopy of MR, MI, and MD, respectively, experienced relapse. The MR group had a significantly low relapse rate compared with the MD and MI groups (P = 0.016, P = 0.002). When histological findings were compared with the findings of magnifying colonoscopy, the mean score of each variable, such as acute inflammatory cell infiltrate, chronic inflammatory cell infiltrate, and crypt architectural irregularities was significantly lower in the MR group than in the MD and MI groups. CONCLUSIONS: The findings of magnifying colonoscopy in patients with quiescent UC is useful for predicting relapse and is associated with histological grade of inflammation.

Role of angiogenesis in the development and growth of liver metastasis.

Cancer metastasis is a highly complex process that involves aberrations in gene expression by cancer cells leading to transformation, growth, angiogenesis, invasion, dissemination, survival in the circulation, and subsequent attachment and growth in the organ of metastasis. Angiogenesis facilitates metastasis formation by providing a mechanism to (1) increase the likelihood of tumor cells entering the blood circulation and (2) provide nutrients and oxygen for growth at the metastatic site. The formation and establishment of metastatic lesions depend on the activation of multiple angiogenic pathways at both primary and metastatic sites. A variety of factors involved in the angiogenesis of liver metastasis have been identified and may serve as prognostic markers and targets for therapy. Vascular endothelial growth factor, interleukin-8, and platelet-derived endothelial cell growth factor are all proangiogenic factors that have been associated with liver metastasis from various primary tumor types. Inhibition of the activity of these factors is a promising therapeutic approach for patients with liver metastases. In addition, inhibition of integrins that mediate endothelial cell survival may also serve as a component of therapeutic regimens for liver metastases. This review focuses on the biology of angiogenesis in liver metastasis formation and growth. Because colorectal carcinoma is the most common tumor to metastasize to the liver, this disease will serve as a paradigm for the study of angiogenesis in liver metastases.