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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., 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.

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.

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.

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.

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. 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. 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. 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.

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.

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. 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. 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

目的：C型慢性肝炎患者に対するインターフェロン(IFN)療法後の肝発癌について検討した．方法：C型慢性肝炎に対してIFN療法が施行された180例を対象とした．非発癌群と発癌群の間で，治療前の背景因子と半年後のウイルス学的著効(SVR24)の有無，治療後のALT，AFPについて比較した．また，それぞれの因子別に発癌曲線を作成して発癌率を比較した．結果：IFN治療によるSVR24の達成率は68.9％(124/180)であり，36.3ヶ月の観察期間で全体の発癌率は2.3％(5/180)であった．発癌群では非発癌群に比べ，高齢者，男性，SVR24非達成例，ALT高値例が多い傾向にあった．治療後のALT高値，AFP高値例は発癌が多かったが，特にAFPでは統計学的な有意差を認めた．結論：IFN治療前の線維化進展例と高齢者，男性，治療後ALT高値，AFP高値は肝発癌率が高い傾向にある．特に治療後AFP高値は肝発癌予測因子になる．

症例は31歳女性．クローン病再燃に対して抗TNF-α抗体製剤であるInfliximab治療中に，Streptococcus intermediusによる肝膿瘍と膿胸を発症し，治療に難渋するも抗菌薬治療，経皮経肝膿瘍ドレナージにて軽快した．Infliximab投与は，易感染性により様々な感染症を合併する可能性があるが，肝膿瘍の合併は非常にまれながら診断・治療の遅れが重篤になりやすく注意が必要である．

症例は70歳代の女性．7年前に膵尾部単純性嚢胞と診断され，経過観察中であった．4ヶ月持続する発熱と心窩部痛の精査を目的として入院した．入院時のCTでは多発肝腫瘍を認め，嚢胞内には結節病変を，嚢胞周囲には出血・感染を示唆する所見を認めた．以上より，嚢胞性病変が癌化して転移・浸潤をきたし，嚢胞周囲に膿瘍を形成したものと考えて対症的に治療したが，第15病日に死亡した．剖検所見から嚢胞の癌化は否定され，嚢胞に近接して発生した膵未分化癌と，肝転移，肺転移等の多臓器転移，腹膜播種と診断された．

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.

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.

To investigate the natural course of low-grade squamous intraepithelial lesions (LSILs) that cannot be histologically confirmed by colposcopy-directed biopsy.In a multicenter, prospective, cohort study of Japanese women with LSILs, we analyzed the follow-up data from 64 women who had a negative biopsy result at the initial colposcopy (biopsy-negative LSIL) in comparison with those from 479 women who had a histologic diagnosis of cervical intraepithelial neoplasia grade 1 (LSIL/CIN1). Patients were monitored by cytology and colposcopy every 4 months for a mean follow-up period of 39.0 months, with cytologic regression defined as two consecutive negative smears and normal colposcopy.In women with biopsy-negative LSILs, there were no cases of CIN3 or worse (CIN3+) diagnosed within 2 years; the difference in the 2-year risk of CIN3+ between the two groups was marginally significant (0 vs. 5.5%; P = 0.07). The cumulative probability of cytologic regression within 12 months was much higher in the biopsy-negative LSIL group (71.2 vs. 48.6%; P = 0.0001). The percentage of women positive for high-risk human papillomaviruses (hrHPVs) was significantly lower in the biopsy-negative LSIL group than in the LSIL/CIN1 group (62.1 vs. 78.4%; P = 0.01); however, the 12-month regression rate of biopsy-negative LSIL was similar between hrHPV-positive and -negative women (67.3 vs. 74.4%, P = 0.73).In women with biopsy-negative LSILs, the risk of CIN3+ diagnosed within 2 years was low; furthermore, approximately 70% underwent cytologic regression within 12 months, regardless of HPV testing results. Biopsy-negative LSILs may represent regressing lesions rather than lesions missed by colposcopy.

The role of tobacco smoking in the multistage carcinogenesis at the cervix is not fully understood because of a paucity of prospective data. To assess the relationship between smoking and spontaneous regression of cervical precursor lesions, a total of 516 women with low-grade squamous intraepithelial lesion (LSIL) were monitored by cytology and colposcopy every 4 months. Probability of LSIL regression within 2 years was analyzed in relation to smoking behaviors, with regression defined as at least two consecutive negative Pap smears and normal colposcopy. Women's age, initial biopsy results, and human papillomavirus (HPV) genotypes were included in the multivariate models for adjustments. Our study subjects included 258 never-smokers and 258 smokers (179 current and 79 former smokers). During a mean follow-up time of 39.8 months, 320 lesions regressed to normal cytology. Probability of regression within 2 years was significantly lower in smokers than in never-smokers (55.0%vs 68.8%, P = 0.004). The risk of LSIL persistence increased with smoking intensity and duration and with younger age at starting smoking (P = 0.003, P < 0.001, and P = 0.03, respectively). Smokers had twice as high a risk of persistent HPV infection compared to never-smokers (odds ratio, 2.50; 95% confidence interval, 1.30-4.81; P = 0.006). In young women, passive smoking since childhood reduced probability of regression within 2 years (56.7%vs 85.9%, P < 0.001). Further adjustments for a wide range of cervical cancer risk factors did not change the findings. In conclusion, tobacco smoking may interfere with regression of cervical precursor lesions. Childhood exposure to second-hand smoke may increase a risk of persistent cervical abnormalities among young women.

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.

Background Various studies have revealed that cervical cancer (CC) screening significantly reduces both CC incidence and mortality in developed countries. Although Japan introduced a nationwide government funded annual CC screening for the women aged 30+ in 1982, the effectiveness of CC screening on CC mortality has not yet been evaluated by any prospective cohort study. Therefore, the present study evaluated the association of CC mortality with self-reported CC screening and some other factors by a nationwide cohort study. Methods Baseline survey of the Japan Collaborative Cohort Study for the enrollment of subjects was completed during 1988-90 and followed until 2003. This study only analyzed 63,541 women, aged 30-79 years, who were free from any cancer history at enrollment. Results During the follow-up period, 38 CC deaths were identified. The mean age at mortality was 67.0 years, with a mortality rate of 4.2 per 100,000 person-years. Participation rate in CC screening was 46.9%. Age-adjusted Cox model indicated significantly lower CC mortality [hazard ratio (HR) = 0.30, 95% confidence interval (CI) = 0.12-0.74] due to CC screening. Protectiveness remained almost the same (HR = 0.30, 95% CI = 0.12-0.76) when adjusted for age, body mass index and number of deliveries. The results also revealed that CC screening could reduce at least 50% of CC deaths even after excluding the effect of possible self-selection bias. Conclusions CC screening in Japan may reduce CC mortality significantly for women aged 30-79 years. However, further studies with more CC deaths and increased statistical power are needed to validate the findings.

Well-differentiated liposarcoma (WD) acquires fully malignant potential when the histological progression named dedifferentiation occurs. This progression is supposed to occur in a time-dependent manner but this is still a debated issue. Clinically, the prediction of dedifferentiation for WD is very important from the therapeutic point of view. To identify genes that are predictive of dedifferentiation and to understand the mechanism of dedifferentiation, we investigated clinical information of 50 cases and studied the gene expression profiles of 36 lipomatous tumors using cDNA microarray. The clinical study showed that the dedifferentiation did not always seem to occur in a time-dependent manner. Interestingly, from the gene expression study, unsupervised hierarchical clustering analysis of well-differentiated lesions obtained from dedifferentiated liposarcoma (DD) cases that were indistinguishable from WD pathologically showed a clearly distinct gene expression pattern from WD. Using the pattern-matching program, 1687 genes including 487 known genes were identified, which discriminated WD cases from well-differentiated lipomatous lesions obtained from DD cases. These results suggest that the dedifferentiation may arise from different types of WD that could be distinguished from gene expression profiling but could hardly be classified by the pathological studies.

The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops seven times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analysed lung tumorigenesis in BALB/cByJ--BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2- and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mbp segment containing three known genes, Poli, Mbd2 and Dcc. Among those, the Poli seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation because of an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Poli cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/HeJ lungs revealed 21 BALB/cByJ-specific single-nucleotide polymorphisms in the coding region accompanied by seven amino-acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of Kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation.

Skin tumors were induced by gamma-irradiation in F(1) mice between C3H/He or BALB/c and MSM carrying a p53-deficient allele. The incidence was 39.1% (34/87) in p53(KO/+) mice of the C3H/MSM genetic background and 14.3% (19/133) in those of the BALB/MSM background. Interestingly, most of the tumors (82%) lost the wild-type p53 allele and no skin tumor was found in p53(+ / +) F(1) mice. This suggests a requirement of p53 loss for the skin cancer development. Genome scan localized a chromosomal locus showing frequent allelic losses near D12Mit2, which may harbor a tumor suppressor gene. In addition, 23 loci distributed on 13 chromosomes exhibited allelic losses at frequencies of more than 20%. The genome-wide occurrence of allelic losses suggests that genomic instability of the skin tumors may be implicated in radiation-induced carcinogenesis. The present study is the first to report a mouse model system useful for the analysis of radiation induction of skin cancer in man.

BALB/cByJ mice are 14 times more resistant to urethane-induction of pulmonary adenomas than the susceptible A/J strain. Our previous linkage analysis of (A/J x BALB/cByJ)F1 x A/J backcross mice provided statistical evidence that a major resistance locus of BALB/cByJ with a dominant effect, designated Par2 (Pulmonary adenoma resistance 2), exists within an approximately 25 cM section of distal chromosome 18. To facilitate molecular identification of the Par2 locus, the present study was conducted to finely localize its chromosomal position utilizing Par2-congenic mice. Male BALB/cByJ mice were mated with female C57BL/6J mice carrying recessive Par2 alleles and their male F1 progeny were backcrossed to female BALB/cByJ mice. A male backcross mouse heterozygous within the Par2 interval of 25 cM was randomly selected and again backcrossed to female BALB/cByJ mice. This backcross-selection cycle was simply repeated to produce semi-congenic mice with a general BALB/cByJ genetic background except for the Par2 interval, where the mice were heterozygous with paternal C57BL/6J alleles and maternal BALB/cByJ alleles. After the 6th or 7th backcross, nine male mice possessing a recombination within the paternal Par2 interval were retained and crossed to female A/J mice. Resultant progeny were treated with urethane and examined for lung tumor development in order to deduce the Par2 genotypes of the recombinants through linkage analysis. By comparing the deduced Par2 genotype of each recombinant with its recombinational breakpoint, the Par2 locus was confined to an approximately 0.5 cM region flanked by D18Mit103 and D18Mit188 loci. Our results indicate that fully congenic mice conventionally established by at least nine simple backcrosses or by the speed congenic method are not necessarily required for fine mapping of quantitative trait loci. In the case of the Par2 locus, we found that semi-congenic mice after as few as four simple backcrosses were useful for this purpose. The map information obtained in this study should enable subsequent positional cloning of the Par2 gene.

We have previously observed that all human hepatocellular carcinomas (HCCs) from HBV carriers examined had the integrated X region. In this study, HBV DNA was isolated from an integration site in one HCC that had a single, very small integrated viral DNA including the X region, but it had no expression of X gene as poly(A)RNA. It was found that HBV DNA was present between alphoid repetitive sequences, and it included Enhancer and X regions, encompassing the adr sequence from 910 to 1811. Nucleotides for 8 amino acids at the 3' end, a stop codon of X gene and a poly(A) signal downstream of X gene were lost by integration, and nucleotides for 7 amino acids and a stop codon were substituted by a connected alphoid sequence. When this cloned HBV DNA was transfected with an expression vector to an immortalized mouse liver epithelial cell line, MLE-10, malignant transformation occurred. Transformants having expressed poly(A)RNA of the X gene showed anchorage-independent growth in soft agar and tumor formation in the subcutis of nude mice. The mRNA level of EGFR was found to be remarkably enhanced in X-transformed cells, in contrast with the absence of this mRNA in parental and ras-transformed MLE-10. Our data provide evidence that the Enhancer-X region alone is the key contributor to the malignant change of pre-malignant liver cells in HBV carriers through activation of some specific genes, such as EGFR.

Purpose: Although preoperative chemotherapy for advanced gastric cancer is now commonly applied with favorable results, convincing evidence for life prolongation and predictive markers for a good prognosis are both lacking. We report here 5 cases that have shown a distinct positive effect of preoperative chemotherapy together with the results of a precise histological examination of materials indicating features predicting a favorable outcome. Patients and methods: A total of 18 patients with a far-advanced gastric carcinoma subjected to gastrectomy after FLEP (5-fluorouracil, leucovorin, etoposide, cisplatin) in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, could be divided into two distinct groups: 5 surviving over 5 years (group A) and 13 who died within 13 months (group B). Histological features (subtypes) of the carcinomas and chemotherapeutic effects were studied with reference to biopsy materials and resected stomachs and lymph nodes. Results: In group A, 3 of 5 patients had solid-type poorly differentiated adenocarcinomas. In contrast, in group B, 9 had tubular adenocarcinomas (well or moderately differentiated) and 3 non-solid or diffuse-type poorly differentiated adenocarcinomas and there was only one solid-type tumor. In group A, remarkable therapeutic effects were apparent histologically in 4 of the 5 patients with almost complete disappearance of cancer cells from metastases in lymph nodes, whereas no such changes were evident in group B. Conclusion: FLEP is distinctly beneficial for certain types of advanced gastric carcinoma, especially solid-type poorly differentiated adenocarcinomas, and favorable results can be predicted, to a certain extent, on the basis of findings for the material resected after chemotherapy.

Purpose: This present study aimed to investigate the genetic changes in gallbladder carcinogenesis. Methods: Eleven intramucosal gallbladder carcinomas were compared with 31 invasive lesions for loss of heterozygosity (LOH) on chromosomes 5q, 9p, 17p and 18q, frame-shift mutations in a ten-adenine repeat site within the gene encoding the transforming growth factor β type II receptor (TGFβRII) and an eight-guanine repeat site within BAX, and point mutations in codon 12 of Ki-ras. Results: The incidences of LOH in intramucosal and invasive carcinomas were 14% and 17% on 5q, 9% and 52% on 9p, 64% and 65% on 17p, and 13% and 32% on 18q. No frame-shift mutations were found at TGFβRII or BAX, and point mutations in codon 12 of Ki-ras were present in only 8% of the samples. Thus, LOH on 17p was by far the most frequent lesion with similar results in both intramucosal and invasive carcinomas. In contrast, the frequency of LOH on 9p and 18q was distinctly higher in invasive lesions. Conclusion: The present data suggest that LOH on 17p may play an important role in the evolution of gallbladder carcinoma from a relatively early phase, while LOH on 9p and 18q may play roles in progression.

The mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) suppresses cell growth through binding to the insulin-like growth factor 2 (IGF2) and latent complex of the transforming growth factor-beta (TGF-beta). Recently, it was reported in the United States that loss of heterozygosity (LOH) and mutations in exons 27, 28, and 31 of the M6P/IGF2R gene are frequent in hepatocellular carcinomas (HCCs) and adenomas. In view of the possible importance of this finding, especially for differential diagnosis of small hepatic lesions, we analyzed 43 primary HCCs, 2 adenomatous hyperplasias (AHs), and 3 regenerative nodules (RNs) developing in 42 Japanese patients in Japan for LOH using the polymorphic locus and for mutations by both single strand conformation polymorphism (SSCP) and direct sequencing methods. In the LOH study, 21 out of 22 informative HCCs and all of the informative AHs and RNs showed no allelic loss. In mutational studies of exons 27, 28, and 31, no mutations were detected either by SSCP or direct sequencing analysis in any of the 48 lesions. Thus inactivation of the M6P/IGF2R gene because of genetic alteration does not appear to be essential for hepatocarcinogenesis in Japan.

This special report discusses problems relevant to histological diagnosis of cancer after chemo- and/or radiotherapy. One of the issues relates to pitfalls, i.e. over-, under- or misdiagnosis or oversight, stemming from a lack of concern or awareness of therapeutic effects on tumors or normal tissues. Another set of questions concerns inadequacy or insufficiency in the evaluation of therapeutic effects stemming from practical difficulties. In view of the importance of this area, we should set out a comprehensive research programme with close cooperation among clinicians, pathologists and molecular biologists to overcome these problems.

We investigated expression of insulin-like growth factor II (Igf2) in primary cultured hepatocytes, liver epithelial (LE) cell lines derived from normal hepatocytes, and hepatocellular carcinoma (HCC) cell lines from crosses between C3H/HeJ (C3H) and Mus musculus molossinus mice (MSM). Igf2 mRNA was detected by reverse transcriptase–polymerase chain reaction in primary cultured hepatocytes from 5 d after the start of cultivation and in all 12 LE and 16 HCC cell lines. Analysis of the untranslated region of Igf2 exon 6, which contains polymorphic CA repeats, revealed that 13 of the 16 HCC cell lines had biallelic expression, whereas monoallelic expression was retained in the primary cultured hepatocytes and all 12 LE cell lines. The Igf2 transcripts contained exons 1–3 in all the HCC cell lines but only exons 2 and 3 in cultures of hepatocytes and LE cell lines, indicating difference in promoter use. However, the biallelic HCC cell lines did not have larger amounts of Igf2 mRNA and protein than did the monoallelic lines, suggesting that loss of imprinting may not be directly related to the level of Igf2 expression. Mol. Carcinog. 23:248–253, 1998. © 1998 Wiley-Liss, Inc.

Although the osteosarcoma is considered to be among the most chemosensitive malignancies and preoperative chemotherapy is commonly applied, an appreciable proportion of cases are in fact quite insensitive. Predictive markers for chemosensitivity are therefore desirable in order to develop effective treatment strategies. Thirty-two cases of conventional osteosa rcomas treated at the Cancer Institute Hospital, Tokyo, were analyzed. The sensitivity to preoperative chemotherapy was investigated with reference to loss of heterozygosity (LOH) at the 17p13 (p53) and 13q14 (Rb) loci and expression of the cell-cycle associated p roteins, p53, Rb, p21/Waf-1, mdm-2 and Ki-67, as detected immunohistochemically. LOH was detected by analyzing polymerase chain reaction products at marker microsatellite loci. The efficacy of chemotherapy was evaluated both radiologically and histologically. LOH at p53 or Rb loci was seen in 54% (13/24) and 58% (14/24) of cases, respectively. Only 15% of osteosarcomas with LOH at the p53 locus were sensitive to preoperative chemotherapy, as compared to 64% of tumors without such loss (P < < <

A total of 69 gastric carcinomas of very old people (aged > or = 85) were collected and pathologically analyzed in comparison with those of young to middle-aged (30-39) and elderly (65-69) people, with special attention to their phase. In the very old, almost all (34/35) carcinomas in the early phase belonged to well-differentiated categories. In the advanced phase, half of them (17/34) were classified into poorly differentiated categories when determined from the predominant pattern, but a well-differentiated pattern almost always coexisted in the superficial site. Thus, the gastric carcinomas in the very old may principally develop as well-differentiated carcinomas which then progress to poorly differentiated carcinomas with time, in contrast to those of the young to middle-aged, most of which emerged from the very early phase as poorly differentiated lesions. The gross features of the carcinomas were also in line with these histological observations. The carcinomas of the elderly showed distinct similarity to those of the very old. The results suggest that poorly differentiated carcinomas of the young to middle-aged and the old may be better classified and analyzed separately in view of the generally recognized etiological (e.g., specifically close causal relationship with environmental factors of the intestinal-type carcinoma of the old) and biological (e.g., practically no tendency for hematogenous metastasis of the diffuse-type carcinoma of the young to middle-aged) differences, although in the General Rules for Gastric Cancer Study of Japan, both are placed in the same category, por (por2).

A 1-year-old boy with Wiskott-Aldrich Syndrome (WAS) who developed malignant lymphoma is described. He showed various complications such as atypical lymphocytosis, disseminated intravascular coagulation (DIC), intracranial hemorrhage, macroamylasemia, and monoclonal gammopathy (immunoglobulin A kappa chain). Epstein-Barr virus (EBV) DNA was detected in the tumor tissue, and the monoclonality of B cells from the tumor tissue was established. EBV-associated lymphoma is frequently observed in immunocompromised patients including those with WAS. The development of macroamylasemia, which is rare in childhood, is discussed in relation to lymphoma and monoclonal gammopathy. This case is unique in that the EBV-associated malignant lymphoma developed at an early age and was accompanied by macroamylasemia.

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. 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

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.

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.

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. 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. 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

Transgenic mouse which produces human α-fetoprotein (AFP) ubiquitously was used to study carbohydrate structures of AFP produced by various tissues as well as that in the serum. A series of tissues from the transgenic mouse were cultured in vitro and the AFP produced was analyzed by affinity electrophoreses with 4 kinds of lectins. Variable electrophoretic profiles of them suggested that the fine structures of the carbohydrate of human AFPs expressed in the mouse tissues were different. The characterization of human AFP produced by mouse hepatoma which developed in offspring between the AFP transgenic mouse and hepatoma-developing transgenic mouse indicated that the hepatoma AFP was distinct from the liver AFP and that the malignancy-specific phenotypic alteration was common to human and mouse.