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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.

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.

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.

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.

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.

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.

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).

Glutathione transferase P (GST-P) is specifically induced in rat liver and kidney by lead cation. The increase of GST-P mRNA after lead administration is blocked by actinomycin D, suggesting that GST-P production by lead is regulated at the transcriptional level. To further determine which part of the flanking region of the GST-P gene has the lead-responsive cis-element in vivo, we utilized transgenic rats with five different constructs having GST-P and/or chloramphenicol acetyl-transferase coding sequence. We studied the effect of lead on these transgenic rats and on transfected NRK (normal rat kidney) cells and found that GST-P induction by lead is indeed regulated at the transcriptional level and that the GST-P enhancer I (GPEI) enhancer is an essential cis-element required for the activation of the GST-P gene by lead. GPEI consists of two AP-1 (c-Jun/c-Fos heterodimer) site-like sequences that are palindromically arranged and can bind AP-1, c-jun mRNA in the liver increased after lead administration and GST-P, and c-Jun had patchy expression in the same hepatocytes 24 h after lead exposure. These results suggest that activation of the GST-P gene by lead is mediated in major part by enhancer GPEI and that AP-1 may be involved at least partially. GPEI has been shown to have essential sequence information for the trans-activation of the GST-P gene during chemical hepatocarcinogenesis of the rat (Morimura, S., Suzuki, T., Hochi, S., Yuki, A., Nomura, K., Kitagawa, T., Nagatsu, I., Imagawa, M., and Muramatsu, M. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2065-2068; Suzuki, T., Imagawa, M., Hirabayashi, M., Yuki, A., Hisatake, K., Nomura, K., Kitagawa, T., and Muramatsu, M. (1995) Cancer Res. 55, 2651-2655). The present study establishes that the same enhancer element does operate in the activation of the GST-P gene by lead regardless of the trans-activators involved.

By means of transgenic rats, we have recently shown that the GPEI enhancer of the glutathione transferase P (GST-P) gene, which has two one-base-missmatched AP-1 sites locating palindromically with three-base spacing in between, is sufficient for conferring tumor-specific activation of the gene in vivo. It is noted that there is another consensus AP-1 site near the promoter of this gene. By using seven independent transgenic rats, bearing distinct areas of the GST-P gene that are connected to the chloramphenicol acetyltransferase (CAT) coding sequence, we analyzed CAT expression in various tissues (brain, lung, liver, kidney, spleen) in these transgenic rats. We found that the ECAT gene, which has sufficient of the upstream regulatory region (approx. 2.9 kb) of the gene containing GPEI, is trans-activated in the kidney and lung of transgenic rats in a similar manner to endogenous GST-P. When either the GPEI core sequence or the AP-1 site near the promoter is deleted, CAT expression decreases to almost background level. Substitution of the GPEI core or the AP-1 site near the promoter to this silent construct (5CATGPEIcore) reconstituted CAT expression in the transgenic rats. In these rats, CAT was expressed in the brain and lung rather than in the kidney, showing a somewhat different pattern from the endogenous GST-P. In the brain tissue of the 5CATGPEIcore transgenic rat, CAT was demonstrated in the glia cells, which is consistent with endogenous GST-P expression. These results suggest that a relatively long upstream region (approx. 2.9 kb) is required for tissue-specific expression of the GST-P gene and that GST-P expression in the brain may be regulated differently from its expression in other organs.

The characteristics of lung cancers induced by inhaled chromate were studied in 13 consecutive autopsies on male ex-chromate workers. In addition to histopathology, we examined: (1) the relationship between the occurrence of lung cancer and the amount of chromium (Cr) deposited in the lung as determined by atomic absorptiometry and (2) the chronological changes in five precancerous lung lesions followed by bronchoscopy till death. Twenty-one cancers were identified, including 16 lung tumours observed either during follow-up or at autopsy. Of these 16 tumours, 13 were found in six subjects, implying a high frequency of multiple cancers. Eleven (69%) out of the 16 tumours were of squamous cell type (including carcinoma in situ), this being twice as frequent as in age-matched controls. A further characteristic was predominance in the central part of lung (69%). The lung Cr burden was very much higher [40-15,800 micrograms g-1 (dry)] in patients with lung tumours than in those without (8-28 micrograms g-1). Five of the precancerous lesions followed by bronchoscopy originated at bronchial bifurcations. Four of these cases showed a return to normal histology at autopsy even without therapy, and the other did not progress. Images Figure 2

Frequent development of subcutaneous neurogenic sarcomas was observed in a hepatocellular carcinoma-producing transgenic mouse strain harboring an albumin-promoted simian virus 40 (SV40) large T antigen gene. Found unexpectedly in 19 out of 306 mice (6.2%) by 6 months of age, all the sarcomas were similar and were characterized as neurogenic on the basis of histological features including Homer-Wright type rosette formation, the presence of dense core granules of 100-200 nm diameter under the electron microscope, expression of neuron specific enolase, S-100 protein, and catecholamines, and nerve cell-like differentiation in culture in response to But2cAMP. Immunohistochemical study revealed tiny clusters of SV40 T antigen-expressing cells with neurogenic character in normal-appearing adult mouse subcutis as candidate progenitors of the sarcomas. The tumor cells strongly expressed large T antigen but did not express albumin or albumin mRNA at the detection sensitivity used. Transient transfection assay (CAT assay), however, revealed the presence of transcriptional factor(s) acting on the albumin promoter in tumor cells. Thus, the present investigation suggested the presence of specifically differentiated neurogenic cells in the mouse subcutis with aberrant expression of the transgene.

A new type of mucinous cystic pancreatic neoplasm is described. The lesions, which have been recognized only recently with the progress of diagnostic techniques and have not previously been described in the literature, are characterized by multilocular cysts with papillary proliferation of the lining epithelium. They occur exclusively in the head and body, predominantly in males, and coexistence of well-differentiated adenocarcinoma as well as adenoma components is frequently encountered. These lesions are quite different from hitherto described mucinous cystic neoplasms of pancreas, not only in terms of gross features but also with regard to intrapancreatic location, and sex and age distributions. We propose to classify these lesions as a new pancreatic tumor entity: the ductectatic-type mucinous cystadenoma/cystadenocarcinoma.

Glutathione transferase P (GST-P; glutathione transferase, EC 2.5.1.18) is known to be specifically expressed at high levels in precancerous lesions and in hepatocellular carcinomas from a very early phase of chemically induced hepatocarcinogenesis in the rat. The almost invariable occurrence of this phenotype in these lesions strongly suggests a mechanism by which GST-P gene is activated together with a crucial transforming gene of liver cells. To distinguish the two alternative possibilities--either the GST-P gene is coactivated with a closely located transforming gene by a cis mechanism or it is activated in trans by a common trans-acting factor--we carried out carcinogenesis experiments using transgenic rats harboring the bacterial chloramphenicol acetyltransferase reporter gene ligated to the upstream regulatory sequence of the GST-P gene. In each of three independent lines tested, liver foci and nodules produced by chemical carcinogens (Solt-Farber procedure) were found to express high levels of chloramphenicol acetyltransferase activity, indicating clearly that the GST-P gene is activated by a trans mechanism during hepatocarcinogenesis.

The prevalence of chromosomal translocation t(14;18) was examined in 41 cases of follicular lymphoma covering all histopathological subtypes, using the polymerase chain reaction and hybridization method with non-radioactive oligonucleotide probes. DNAs were extracted from unfixed fresh-frozen and/or formalin-fixed paraffin-embedded biopsy specimens. The t(14;18) chromosomal translocation, resulting in bcl-2-JH (immunoglobulin heavy chain gene joining segment) fusion gene, was detected in 7 (36.8%) of 19 follicular small cleaved cell lymphomas and 6 (54.5%) of 11 follicular mixed, small cleaved cell and large cell lymphomas. Meanwhile, 11 cases of follicular large cell lymphoma revealed no bcl-2-JH fusion gene. There was a statistically significant difference in the frequency of bcl-2-JH rearrangement between follicular, small cleaved cell and large cell lymphoma (two-sided Fisher exact test, P = 0.049). The difference of bcl-2 rearrangement frequency between follicular, mixed and large cell lymphoma was also statistically significant (P = 0.012).

Only a subset of cervical precursor lesions progress to cervical cancer and because of the lack of the predictive markers, it cannot be ascertained which lesions will progress or not. To estimate the risk of disease progression associated with human papillomavirus (HPV) genotypes, we followed 570 Japanese women with cytological LSIL (low-grade squamous intraepithelial lesion) and histological CIN (cervical intraepithelial neoplasia) grade 1-2 lesions (479 CIN 1; 91 CIN 2) at 3 to 4 month intervals for a mean follow-up period of 39.1 months. At entry, we detected HPV DNA in cervical samples by polymerase chain reaction-based methodology. Over the period of follow-up period, 46 lesions progressed to CIN 3 while 362 regressed to normal cytology. Women with multiple HPV infections were more likely to have persistent lesions (hazard ratio [HR] for regression, 0.65; 95% confidence interval [CI], 0.42-1.02; p = 0.07); however, multiple infections did not increase the risk of progression (HR for progression, 1.04; 95% CI, 0.37-2.94; p = 0.94). After adjusting for CIN grade and women's age, HRs for progression to CIN 3 (vs. women with low-risk types or negative for HPV DNA) varied markedly by HPV genotype: type 16 (11.1, 95% CI: 1.39-88.3); 18 (14.1, 0.65-306); 31 (24.7, 2.51-243); 33 (20.3, 1.78-231); 35 (13.7, 0.75-251); 52 (11.6, 1.45-93.3); 58 (8.85, 1.01-77.6); other high-risk types (4.04, 0.47-34.7). HPV 45 was not detected in our study subjects. The cumulative probability of CIN 3 within 5 years was 20.5% for HPV 16, 18, 31, 33, 35, 52 and 58; 6.0% for other high-risk types; 1.7% for low-risk types (p = 0.0001). In conclusion, type-specific HPV testing for women with LSIL/CIN 1-2 lesions is useful for identifying populations at increased or decreased risk of disease progression.

In order to shed light on the causal mechanisms of hepatocarcinogenesis in the transgenic mouse into which the albumin-promotor-regulated SV40-T antigen gene has been introduced (T+ mouse), and especially on the frequent chromosomal aberrations seen in cultured hepatocytes and hepatocellular neoplasms derived from such animals, the frequency of sister chromatid exchange (SCE) and karyotype abnormalities were investigated in a hepatocyte primary culture system. Cells were obtained through collagenase perfusion from T+ mice at 16-18 days of age, when no morphological changes are apparent, and from nontransgenic littermates, and cultured in the presence of bromodeoxyuridine. SCE was seen in transgenic hepatocytes twice as frequently as in their normal counterparts. No karyotype abnormalities in terms of numerical change or gross aberration were detected at this phase. The results thus suggest mutagenic properties for the T antigen, which may play an important role in hepatocarcinogenesis in this transgenic mouse.

The topographical distribution of complete and incomplete types of intestinal metaplasia in human stomach samples was investigated in order to elucidate their mutual histogenetic relationship and significance in carcinogenesis. Subgross stereomicroscopic examination of alcian blue and hematoxylin-stained gastric mucosae allowed clear distinction of complete and incomplete intestinal metaplasia types as white (with or without purple hue) and purple foci, respectively, against the background magenta areas of non-intestinalized mucosa. Intestinal metaplasias which developed in the fundic area were predominantly of the complete type whereas those of the antrum were a mixture of both with a distinct predilection for expression of the incomplete type. Although there was some variation among foci regarding the hue of white or purple, the color feature was principally homogeneous within each individual intestinal metaplasia focus. Thus phenotypic analysis indicated intestinal metaplasia expression to be clearly influenced by intragastric topography. The study did not provide any evidence that a shift from incomplete to complete type intestinal metaplasia may occur with time or that the incomplete type may be more intimately associated with development of well-differentiated carcinomas.

We have developed transgenic mice that inherit albumin promoter-regulated simian virus 40 (SV40) large T antigen gene, expressed specifically in hepatocytes. These mice all develop multifocal hepatocellular carcinomas at around 5 months and die of liver insufficiency by 7 months. Sequential morphological observation of hepatocarcinogenesis revealed 5 distinct stages: (I) newborn to 2 weeks of age, neither recognizable histological changes nor cellular replication in spite of T antigen expression; (II) between 3 and 7 weeks, diffuse cytomegalic change of hepatocytes with numerous abnormal mitoses, usually resulting in cell death; (III) from 7 weeks onwards, quasi-regenerative small hepatocyte foci with a decreased tendency for cytomegaly in spite of T antigen expression, rapidly replacing the hepatic tissue; (IV) 11 weeks of age and thereafter, neoplastic foci and nodules with enzymatic alteration; (V) 20 weeks of age and thereafter, gross hepatocellular carcinomas with occasional pulmonary metastases. Considerable variation existed both in morphological and enzymatic features and T antigen expression among neoplastic lesions, including carcinomas. Thus, these transgenic mice clearly show a multistep process in hepatocarcinogenesis with remarkable synchrony and provide a promising model for analyzing the essential events of carcinogenesis at different stages.

In order to investigate the molecular mechanisms of multistep hepatocarcinogenesis in SV40-T antigen gene-harboring transgenic mice, 9 hepatocellular carcinoma (HCC) lines and 10 “preneoplastic” hepatocyte lines were established from the animals and their biological and molecular changes during culture were investigated. Three of the 9 HCC lines showed progression during culture in terms of growth rate and growth capability in soft agar and in nude mice. This progression was associated with the appearance of activated c-H-ras oncogene. Including these 3 lines, H-ras activation was observed in a total of 7 of the 9 HCC lines (78%), whereas it was found only in 1 of 10 (10%) “preneoplastic” hepatocyte lines. These data thus indicate that H-ras activation may be an event occurring at a relatively late stage of hepatocarcinogenesis in this transgenic mouse system and that it may serve towards completion of the carcinogenic process together with the T-antigen.