Studies on "Ascites sarcoma".

This review seeks to highlight and celebrate Professor Tomizo Yoshida's famous work on "Establishment and characterization of a rat ascites sarcoma, later named "Yoshida ascites sarcoma". Considering the tremendous contribution of this ascites tumor system to the subsequent promotion of research on cancer biology and cancer chemotherapy, his paper should be regarded as a monumental one in the cancer field. The research was carried out during 1943 and the results were submitted to this Journal in October 1944, when Japan was approaching a debilitating defeat in World War II in August 1945. In 1947, when "Research on Ascites sarcoma" was first comprehensively introduced to researchers in a special lecture at the Annual Meeting of the Japanese Society of Pathology, the whole audience was deeply impressed and was encouraged to resume scientific activity in Japan.

Predictive value of risk score using Kyoto classification of gastritis a few years prior to diagnosis of early gastric cancer.

BACKGROUND AND AIM: Based on past diagnostic classifications of gastritis, the Kyoto classification of gastritis adopts simpler, more objective gastritis findings according to Helicobacter pylori infection status and evaluates the risk of gastric cancer. To clarify whether this score can predict future gastric cancer, we retrospectively examined risk scores obtained using the Kyoto classification of gastritis a few years prior to the diagnosis of early gastric cancer. METHODS: We reviewed data from 50 individuals who had undergone upper gastrointestinal endoscopy 2-3 years prior to the diagnosis of early gastric cancer in our hospital. Two expert endoscopists evaluated and compared risk scores obtained using the Kyoto classification of gastritis between cancer and control groups. RESULTS: With regard to the risk score obtained using the Kyoto classification of gastritis in all cases, atrophy, intestinal metaplasia, diffuse redness, and total score were significantly higher among gastric cancer cases. Among H. pylori-eradicated cases, atrophy score was higher in the gastric cancer group. Among patients for whom H. pylori had been eradicated for >3 years at first endoscopy, atrophy score was still higher in the gastric cancer group. CONCLUSION: This retrospective study suggested that the risk score obtained using the Kyoto classification of gastritis was useful for predicting the onset of gastric cancer. In particular, patients with a high atrophy score even after H. pylori eradication may be at high risk of developing gastric cancer.

Cumulative evidence for reducing recurrence of colonic diverticular bleeding using endoscopic clipping versus band ligation: Systematic review and meta-analysis.

BACKGROUND AND AIM: Either clipping or band ligation will become the most common endoscopic treatment for colonic diverticular bleeding (CDB). Rebleeding is a significant clinical outcome of CDB, but there is no cumulative evidence comparing reduction of short-term and long-term rebleeding between them. Thus, we conducted a systematic review and meta-analysis to determine which endoscopic treatment is more effective to reduce recurrence of CDB. METHODS: A comprehensive search of the databases PubMed/MEDLINE and Embase was performed through December 2019. Main outcomes were early and late rebleeding rates, defined as bleeding within 30 days and 1 year of endoscopic therapy for CDB. Initial hemostasis, need for transcatheter arterial embolization, or surgery were also assessed. Overall pooled estimates were calculated. RESULTS: Sixteen studies fulfilled the eligibility criteria, and a total of 790 participants were included. The pooled prevalence of early rebleeding was significantly lower for band ligation than clipping (0.08 vs 0.19; heterogeneity test, P = 0.012). The pooled prevalence of late rebleeding was significantly lower for band ligation than clipping (0.09 vs 0.29; heterogeneity test, P = 0.024). No significant difference of initial hemostasis rate was noted between the two groups. Pooled prevalence of need for transcatheter arterial embolization or surgery was significantly lower for band ligation than clipping (0.01 vs 0.02; heterogeneity test, P = 0.031). There were two cases with colonic diverticulitis due to band ligation but none in clipping. CONCLUSION: Band ligation therapy was more effective compared with clipping to reduce recurrence of colonic diverticular hemorrhage over short-term and long-term durations.

Pocket Creation Method of Endoscopic Submucosal Dissection to Ensure Curative Resection of Rectal Neuroendocrine Tumors.

PURPOSE: Pancreatic/gastrointestinal tract neuroendocrine neoplasm (NEN) is divided into neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) according to the grade of malignancy, and differences are seen in clinical prognosis. NET, and rectal NET in particular, is often treated endoscopically. Endoscopic mucosal resection (EMR) was previously the main intervention for rectal NET, but EMR with a ligation device (EMR-L) and endoscopic submucosal dissection (ESD) are now also used. However, complete resection with these therapies is not always achieved. The pocket creation method (PCM) is a safe ESD method for colon tumors that offers a high en bloc resection rate compared with conventional colonic ESD. We performed ESD using the PCM for rectal NET and evaluated the complete resection rate. METHODS: We performed ESD using the PCM in 4 patients. This procedure was technically feasible in all patients. RESULTS: Endoscopically, all cases were resected en bloc, and pathological complete resection was achieved in all cases. No complications such as perforation or delayed postoperative bleeding were encountered. CONCLUSIONS: PCM should be considered when treating NET of appropriate size.

OBJECTIVO: As neoplasias neuroendócrinas (NEN) do tracto gastrointestinal e pâncreas são divididas em tumores neuroendócrinos (NET) e carcinomas neuroendócrinos (NEC), dependendo do seu grau de malignidade, com diferenças no seu prognóstico clínico. Os NET, em particular os retais, são frequentemente tratados por endoscopia. A mucosectomia (EMR) foi previamente o método endoscópico principal para a exérese de NET retais mas a mucosectomia com bandas (EMR-L) e a dissecção endoscópica da submucosa (ESD) são agora também utilizadas. Contudo, a ressecção endoscópica completa com estas técnicas não é sempre possível. O método de criação de pocket (PCM) é um método seguro da ESD para ressecção de tumores do cólon que oferece uma taxa alta de ressecção em bloco quando comparado com a ESD convencional do cólon. Realizamos ESD por PCM para NET retais e avaliamos as taxas de ressecção completa. MÉTODOS: Realizamos ESD por PCM em 4 doentes. Este procedimento foi tecnicamente possível em todos. RESULTADOS: Endoscopicamente, todas as lesões foram removidas em bloco e a ressecção patológica completa foi alcançada em todos os casos. Não se verificaram complicações. CONCLUSÕES: O método de PCM deve ser considerado no tratamento de NET retais de tamanho apropriado.

Predictors of 90-day Colonic Diverticular Recurrent Bleeding and Readmission.

Objective Colonic diverticular bleeding often recurs, and readmissions are common. The aim of this study was to identify predictors of colonic diverticular recurrent bleeding and readmission within 90 days. Methods Subjects comprised 144 patients diagnosed with colonic diverticular bleeding who received inpatient hospital care between January 2012 and June 2017. A retrospective comparative study was carried out regarding the clinical characteristics during the hospital stay by dividing the cases into 2 groups: patients with recurrent bleeding requiring readmission within 90 days (n=17) and patients without recurrent bleeding (n=127). Results A univariate analysis showed that recurrent bleeding and readmission were significantly more frequent among cases with hypovolemic shock on admission (p=0.009), blood transfusion during hospitalization (p=0.029), and hyperlipidemia (p=0.020) than among others. Shock on admission (odds ratio, 5.118; 95% confidence interval, 1.168-22.426, p=0.030) remained a significant predictor on a multivariate analysis. Conclusion Shock may predict recurrent colonic diverticular bleeding and readmission within 90 days. Careful and adequate endoscopic hemostasis is recommended for patients showing shock on admission.

Uninodular Fibromyxomatous Gastric Tumor Resected by Endoscopic Submucosal Dissection.

Esophagogastroduodenoscopy of a 45-year-old woman revealed a submucosal tumor in the gastric antrum. Endoscopic submucosal dissection of the tumor was performed. The histological findings revealed a fibromyxomatous tumor composed of myofibroblastic cells with no evidence of malignancy. The growth pattern of the resected specimen was not multinodular or plexiform. We therefore tentatively referred to the present tumor descriptively as a gastric uninodular fibromyxomatous tumor, stressing its singular nodularity. It was initially roughly 10 mm in size but grew over a period of 4 years. A uninodular plexiform fibromyxoma might increase in size but might not become multinodular if it remains small.

Fascin protein stabilization by miR-146a implicated in the process of a chronic inflammation-related colon carcinogenesis model.

OBJECTIVE: In sporadic colon tumors, multistep process of well-known genetic alterations accelerates carcinogenesis; however, this does not appear to be the case in inflammation-related ones. We previously established a model of inflammation-related colon carcinogenesis using human colonic adenoma cells, and identified fascin as a driver gene of this process. We analyzed the microRNAs involved in the stable fascin expression in colon adenocarcinoma cells. MATERIALS AND METHODS: miRNA microarray analysis was performed using FPCK-1-1 adenoma cells and its-derived FPCKpP1-4 adenocarcinoma cells through chronic inflammation. To assess the involvement of miRNA in the inflammation-related carcinogenesis, sphere-forming ability, expression of colon cancer stemness markers, and stability of fascin protein via the proteasome using tough decoy RNA technique. RESULTS: We found that 17 miRNAs including miR-146a were upregulated and 16 miRNAs were downregulated in FPCKpP1-4 adenocarcinoma cells. We revealed that miR-146a in the adenocarcinoma cells brought about acquisition of sphere formation, cancer stemness, and inhibition of proteasomal degradation of the fascin protein. CONCLUSIONS: We found that stable fascin expression is brought about via the inhibition of proteasome degradation by miR-146a in the process of a chronic inflammation-related colon carcinogenesis.

Post-colonoscopy colorectal cancer rate in the era of high-definition colonoscopy.

AIM: To investigate the post-colonoscopy colorectal cancer (PCCRC) rate for high-definition (HD) colonoscopy compared with that for standard-definition colonoscopy reported previously. METHODS: Using medical records at Sano Hospital (SH) and Dokkyo Medical University Koshigaya Hospital (DMUKH), we retrospectively obtained data on consecutive patients diagnosed as having CRC between January 2010 and December 2015. The definition of PCCRC was diagnosis of CRC between 7 and 36 mo after initial high-definition colonoscopy that had detected no cancer, and patients were divided into a PCCRC group and a non-PCCRC group. The primary outcome was the rate of PCCRC for HD colonoscopy. The secondary outcomes were factors associated with PCCRC and possible reason for occurrence of early and advanced PCCRC. RESULTS: Among 892 CRC patients, 11 were diagnosed as having PCCRC and 881 had non-PCCRC. The PCCRC rate was 1.7% (8/471) at SH and 0.7% (3/421) at DMUKH. In comparison with the non-PCCRC group, the PCCRC group had a significantly higher preponderance of smaller tumors (39 mm vs 19 mm, P = 0.002), a shallower invasion depth (T1 rate, 25.4% vs 63.6%, P = 0.01), a non-polypoid macroscopic appearance (39.0% vs 85.7%, P = 0.02) and an earlier stage (59.7% vs 90.9%, P = 0.03). Possible reasons for PCCRC were "missed or new" in 9 patients (82%), "incomplete resection" in 1 (9%), and "inadequate examination'" in 1 (9%). Among 9 "missed or new" PCCRC, the leading cause was non-polypoid shape for early PCCRC and blinded location for advanced PCCRC. CONCLUSION: The PCCRC rate for HD colonoscopy was 0.7%-1.7%, being lower than that for standard-definition colonoscopy (1.8%-9.0%) reported previously employing the same methodology.

A prospective randomized study of the use of an ultrathin colonoscope versus a pediatric colonoscope in sedation-optional colonoscopy.

BACKGROUND: Ultrathin colonoscopes (UTC) reportedly produce less pain during colonoscopy than standard colonoscopes. The aim of this study was to assess the tolerability of an UTC compared with that of a pediatric colonoscope. METHODS: A total of 270 adult patients scheduled to undergo colonoscopy were randomized, with 134 allocated to the UTC group and 136 to the pediatric colonoscope group. Pain was assessed using a visual analog scale. For all procedures, sedation was administered only if requested. Overall pain, rate and time of cecal and terminal ileum intubation, number of patients requesting sedation, adenoma detection rates (ADR), and rate of complications were measured and analyzed. RESULTS: Among all patients, the medians of maximum pain and overall pain were significantly lower in the UTC group than in the pediatric colonoscope group (23 vs. 38, P < 0.001; 12 vs. 22, P = 0.0003, respectively). Significantly fewer patients requested sedation in the UTC group than in the pediatric colonoscope group (1.4 vs. 6.6%; P = 0.0269). No significant differences were seen in either the rate and time of successful cecal and terminal ileum intubation, or in other procedure-related outcomes, including ADR. CONCLUSIONS: Compared with a pediatric colonoscope, the UTC was associated with reduced overall and maximum pain during colonoscopy, with no difference in ADR.

A Case of Gastric Ulcer With Mucosal Bridge.

Endoscopic images of the mucosal bridge with gastric ulcer are unusual. The mucosal bridge is presumed to have changed to a special form based on repeated development of gastric ulcer. The clinical course of mucosal bridge is unclear.

[Thoughts on Cancer Education in Primary Schools].

Cancer prevention is increasingly important in an aging society such as Japan, both in terms of the achievement of national healthy-life elongation and the reduction of the social and economic burden of medical care. Prevention is of principal importance for achieving these purposes. Cancer is considerably preventable by following a healthy lifestyle, including refraining from smoking, having regular health examinations, and receiving vaccines. With respect to lifestyle education, elementary school children are expected to be the most effective target population. However, a governmental committee comprised largely of educational specialists recently recommended that comprehensive cancer education begin in middle high school, because cancer prevention is a topic too difficult for young children to understand and implement. According to the committee 's report, the specialists set lofty aims for cancer education, including empowerment of a living will, promotion of thinking about life and death, and demonstrations of sympathy toward individuals who are weak or have disease. These aims are admirable. However, if these lofty aims prevent the practice of cancer education in elementary schools, then we should rethink the purpose in relation to the setting. This author suggests that the principal purpose of cancer education in elementary schools should be to imprint a healthy lifestyle in children to prevent the development of cancer in the future. In addition, to give a clear understanding that cancer is a"dan-dan"(step by step)disease is important. Although the present author supports efforts in elementary schools to achieve ambitious aims, they should not be so lofty to interfere with the practice of cancer prevention education in these settings.

A case of a child with an APC pathogenic mutation, aberrant expression of splice variants and positive family history of FAP.

Familial adenomatous polyposis is an autosomal dominant hereditary disease characterized by the appearance of hundreds to thousands of colorectal adenomatous polyps; if left untreated, there is nearly a 100% lifetime risk of colorectal cancer. In the present case, adenomatous polyps were observed at 6 years of age. Unlike our previous assumption, adenomatous polyps were detected by colonoscopy at <10 years of age. Considering the clinical importance of early diagnosis, we report this case involving germline adenomatous polyposis coli mutation (c.1958G > C, GenBank: M74088.1) that caused an increase in the isoform without exon 15. Although this isoform has been reported previously, it remains controversial whether the variant is pathogenic or not because it was observed both in patients with familial adenomatous polyposis and in normal controls. Nonetheless, due to quantitative distortion of splice variants in adenomatous polyposis coli transcripts and the early development of adenomatous polyps, we believe that this variant may be pathogenic.

Factors affecting the technical difficulty and clinical outcome of endoscopic submucosal dissection for colorectal tumors.

BACKGROUND: Endoscopic submucosal dissection (ESD) for colorectal tumors is technically difficult due to the anatomy of the large intestine, with its narrow lumen, thin walls, and redundancy. Here, we assessed factors associated with incomplete resection and difficult colorectal ESD. METHODS: Between November 2009 and April 2013, we performed ESD on 151 consecutive colorectal tumors in 147 patients. We evaluated the clinical outcomes of all cases and conducted multiple logistic regression analysis of the following factors related to incomplete resection and difficult procedure: age, gender, location (right colon, left colon or rectum), tumor size (diameter ≥40 or <40 mm), operation time, morphology [granular-type laterally spreading tumor (LST-G), non-granular-type laterally spreading tumor (LST-NG), or protruded type], fibrosis, and paradoxical movement during the procedure. A procedure that required more than 120 min was defined as a difficult colorectal ESD. RESULTS: Average tumor size was 32.1 ± 10.7 mm, and the average procedure length was 71.8 ± 49.5 min. The rate of en bloc resection was 94.7%, while that of en bloc curative resection was 86.8%. Perforation occurred in 1.3% of the ESD procedures. Multivariate logistic regression analysis revealed that only severe fibrosis [odds ratio (OR) 4.51; 95% confidence interval (CI) 1.36-14.91, p = 0.014] contributed to incomplete resection and that a tumor size exceeding 40 mm (OR 5.73 [95% CI 1.66-19.74], p = 0.006), severe fibrosis (OR 23.31 [95% CI 6.59-82.54], p < 0.001), and paradoxical movement (OR 4.26 [95% CI 1.11-16.44], p = 0.035) were independent factors exacerbating the difficulty of colorectal ESD. CONCLUSIONS: Severe fibrosis contributed to both incomplete resection and difficult colorectal ESD. Larger tumor size and paradoxical movement during the procedure were independent factors contributing to the difficulty of colorectal ESD. These factors might enable endoscopists to develop strategies for treating colorectal ESD.

Fascin regulates chronic inflammation-related human colon carcinogenesis by inhibiting cell anoikis.

By a proteomics-based approach, we identified an overexpression of fascin in colon adenocarcinoma cells (FPCKpP-3) that developed from nontumorigenic human colonic adenoma cells (FPCK-1-1) and were converted to tumorigenic by foreign-body-induced chronic inflammation in nude mice. Fascin overexpression was also observed in the tumors arising from rat intestinal epithelial cells (IEC 6) converted to tumorigenic in chronic inflammation which was induced in the same manner. Upregulation of fascin expression in FPCK-1-1 cells by transfection with sense fascin cDNA converted the cells tumorigenic, whereas antisense fascin-cDNA-transfected FPCKpP-3 cells reduced fascin expression and lost their tumor-forming ability in vivo. The tumorigenic potential by fascin expression was consistent with their ability to survive and grow in the three-dimensional multicellular spheroids. We found that resistance to anoikis (apoptotic cell death as a consequence of insufficient cell-to-substrate interactions), which is represented by the three-dimensional growth of solid tumors in vivo, was regulated by fascin expression through caspase-dependent apoptotic signals. From these, we demonstrate that fascin is a potent suppressor to caspase-associated anoikis and accelerator of the conversion of colonic adenoma cells into adenocarcinoma cells by chronic inflammation.

Chronic inflammation-derived nitric oxide causes conversion of human colonic adenoma cells into adenocarcinoma cells.

It has been suggested that nitric oxide (NO) derived from chronically inflamed tissues is a cause of carcinogenesis. We herein demonstrated that administration of an inducible NO synthase inhibitor, aminoguanidine, significantly suppressed the tumorigenic conversion of human colonic adenoma (FPCK-1-1) cells into adenocarcinoma (FPCK/Inflam) cells accelerated by foreign body-induced chronic inflammation in nude mice. To determine whether NO directly promotes carcinogenesis, we exposed FPCK-1-1 cells continuously to chemically generated NO (FPCK/NO), and periodically examined their tumorigenicity. FPCK/NO cells formed tumors, whereas vehicle-treated cells (FPCK/NaOH) did not. We selected a tumorigenic population from FPCK/NO cells kept it in three-dimensional (3D) culture where in vivo-like multicellular spheroidal growth was expected. FPCK/Inflam cells developed large spheroids whereas FPCK/NO cells formed tiny but growing compact aggregates in 3D culture. Meanwhile, FPCK-1-1 and FPCK/NaOH cells underwent anoikis (apoptotic cell death consequential on insufficient cell-to-substrate interactions) through activation of caspase 3. The survived cells in the 3D culture (FPCK/NO/3D), which were derived from FPCK/NO cells, showed a similar tumor incidence to that of FPCK/Inflam cells. These results showed that NO was one of the causative factors for the acceleration of colon carcinogenesis, especially in the conversion from adenoma to adenocarcinoma in the chronic inflammatory environment.

Colonoscopy using a small-caliber colonoscope with passive-bending after incomplete colonoscopy due to sharp angulation or pain.

BACKGROUND: We evaluated the performance of a newly developed small-caliber (SC) colonoscope (PCF-PQ260L). This colonoscope (diameter 9.2 mm) is designed with passive-bending and high-force transmission. The SC colonoscope was used for rescue colonoscopy following incomplete colonoscopy with a standard (SD) colonoscope caused by sharp angulation, loop formation, or pain. METHODS: Records of SC colonoscopy given to patients following an incomplete colonoscopy with the SD colonoscope and in the same session were analyzed. Cecal intubation rate, pain using a visual analog scale (0 = none, 100 = extremely painful) in the first and second colonoscopy, total time, new lesions detected with the SC colonoscopy, dosage of sedation used, and any complications were assessed. Examinations that could not be completed, because the colonoscope was not long enough to reach the cecum due to a redundant colon were excluded. RESULTS: The records of 43 patients who were given SC colonoscopy following incomplete examinations using the SD colonoscope were reviewed. In 97.7 % of cases (42/43), cecal intubation was achieved with the SC colonoscope in the same session. The mean pain score during colonoscopy was significantly lower for the second SC colonoscopy than for the first SD colonoscopy (40.6 ± 14.1 vs. 74.5 ± 10.8, P < 0.001). Lesions were detected with the SC colonoscope in 41.8 % of cases (18/43). CONCLUSIONS: When a colonoscopy with SD colonoscope failed due to sharp angulations, loop formation, or pain, subsequent colonoscopy with a SC colonoscope increased cecal intubation and lesion detection rates and decreased severity of reported pain.

Development of lymphoproliferative diseases by hypoxia inducible factor-1alpha is associated with prolonged lymphocyte survival.

Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.