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Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreatobiliary tract are considered a separate entity from intraductal papillary mucinous neoplasms (IPMNs), especially because of the distinct molecular alterations represented by PRKACA or PRKACB fusion. However, IOPNs display a spectrum of cytoarchitectural features. Typically, an IOPN is composed of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent nucleoli, and intraepithelial lumina, while a significant subset shows atypical morphology: lack of the characteristic cytoarchitectural features such as arborizing papillae and prominent nucleoli, or mixture with nononcocytic IPMN-like components within a single lesion. To elucidate the tumorigenesis and morphologic spectrum of IOPNs, we analyzed 22 IOPNs, including those with atypical morphology for PRKACA/PRKACB fusions in each different component separately using fluorescence in situ hybridization. In total, 18 of 22 (82%) cases harbored PRKACA/PRKACB fusions, including 3 of 3 (100%) purely typical IOPNs and 15 of 19 (79%) IOPNs with atypical morphology. In the latter, PRKACA/PRKACB fusions were noted in atypical components as well as typical IOPN components. Notably, gastric-type IPMN-like components in the fusion-positive cases were usually low grade and had scattered neoplastic cells with eosinophilic cytoplasm, a morphologic feature suggestive of an early lesion of IOPN. In summary, most IOPNs with atypical morphology either lack characteristic cytoarchitectural features or exhibit a mixture with nononcocytic IPMN-like components, harbored PRKACA/PRKACB fusion as did typical IOPN components. Our observations expanded the morphologic spectrum of IOPNs. They are expected to be useful for correct diagnosis of this neoplasm. [ABSTRACT FROM AUTHOR]

This hospital-based, cross-sectional study aimed to explore the association between diet and fluctuating intestinal bacteria in early-stage colorectal cancer (CRC) (Atopobium parvulum, Actinomyces odontolyticus, Solobacterium moorei, and Bifidobacterium longum). Healthy participants (n = 212) who underwent total colonoscopy at National Cancer Center Hospital (Tokyo, Japan) were divided into two groups according to the relative abundance of bacteria in their feces: those in the top 25% of relative bacterial abundance as cases and the bottom 25% as controls. The participants were divided into three groups (low, medium, and high) according to their intake of food groups associated with CRC. Multivariable logistic regression analysis was conducted to estimate the association between dietary intake and higher relative abundance of bacteria. Dairy products were inversely associated with a higher relative abundance of A. parvulum, A. odontolyticus, and S. moorei, with odds ratios (high vs. low) and 95% confidence interval as follows: 0.16 (0.06–0.44), 0.25 (0.08–0.82), and 0.29 (0.11–0.78), respectively. Additionally, dietary fiber was inversely associated with a higher relative abundance of S.moorei (0.29 [0.11–0.78]). No association was observed between diet and B.longum. In conclusion, healthy adults with a higher intake of dairy products and fiber had lower odds of having a higher relative abundance of CRC-associated microbiota. [ABSTRACT FROM AUTHOR]

Objectives: The aim is to evaluate the prevention and development of cervical cancer in systemic lupus erythematosus (SLE) patients in Japan and its background based on a questionnaire survey. Methods: The questionnaire was handed to 460 adult female SLE patients at 12 medical institutions. The participants were grouped by age, and data related to their human papillomavirus vaccination status, age at first coitus, cervical cancer screening, and diagnosis of cervical cancer were analysed. Results: A total of 320 responses were received. Patients aged 35–54 years included a higher proportion of patients whose age at first coitus was <20 years. This group also showed a higher rate of cervical cancer/dysplasia. Only nine patients had a human papillomavirus vaccination history. Adequate frequency of cervical cancer screening was slightly higher (52.1%) among SLE patients than in the Japanese general population. However, 23% of the patients had never undergone examination, primarily because of a feeling of troublesome. The incidence of cervical cancer was significantly higher among SLE patients. One reason for this may be associated with the use of immunosuppressants, although the difference was not significant. Conclusions: SLE patients are at a higher risk of cervical cancer and dysplasia. Rheumatologists should proactively recommend vaccination and screening examinations for SLE female patients. [ABSTRACT FROM AUTHOR]

Background: Colorectal endoscopic resection (C-ER) is spreading due to the increase of colorectal cancer (CRC) in Japan. Gastric cancer (GC) sometimes occurs after C-ER. We aimed to analyze the status of GC after C-ER using large-scale data. Methods: We retrospectively used commercially anonymized health insurance claims data of 5.71 million patients from 2005 to 2018, and extracted 62,392 patients ≥ 50 years old who received C-ER. The incidence and risk factors of GC were analyzed. Additionally, subjects were divided into ≥ 2 cm group and < 2 cm group and risks of GC were analyzed. Results: The median age (range) was 58 (50–75) years and the overall rate of GC was 0.68% (423/62,392). Multivariate analysis showed that significant risk factors for GC [odds rates (OR), 95% confidence interval (CI)] were colorectal lesion size ≥ 2 cm (1.75, 1.24–2.47, p = 0.002), age ≥ 65 y.o. (1.65, 1.31–2.07, p < 0.001), male (2.35, 1. 76–3.13, p < 0.001), diabetes mellitus (1.40, 1.02–1.92, p = 0.035), liver disease (1.54, 1.06–2.24, p = 0.025), Helicobacter pylori infection (2.10, 1.65–2.67, p < 0.001), chronic atrophic gastritis (1.58, 1.14–2.18, p = 0.006), and CRC (1.72, 1.10–2.68, p = 0.017). The rate of GC in the ≥ 2 cm was significantly higher than that in < 2 cm groups (1.17% and 0.65%, p < 0.001). According to the number of significant risk factors, the rates of GC and the hazard ratios of GC (95%CI) were 0.64% and 3.64 (2.20–6.02) and 1.95% and 11.17 (6.57–19.00) for patient with 1–2 and ≥ 3 risk factors, compared with patients without risk factors. Conclusions: Using large-scale data, risk factors for GC, including colorecal lesions ≥ 2 cm after C-ER could be investigated. [ABSTRACT FROM AUTHOR]

Objectives: Molecular‐level research has linked RING finger (RNF) protein family members to carcinogenesis and tumor progression. Among them, RNF128 is related to tumor progression, but reports on its association with lung cancer are few. This study aimed to clarify the unknown association between RNF128 expression and clinical outcomes in patients with lung adenocarcinoma. Methods: Clinical data of 545 patients with therapy‐naïve lung adenocarcinoma who underwent lobectomy with systematic lymph node dissection between 1999 and 2016 were retrospectively reviewed. Histological and immunohistochemical analyses were conducted to evaluate the relationship between RNF128 expression and prognosis. Results: Among adenocarcinoma histologic types, acinar, micropapillary, and solid tumors did not express RNF128 compared with other histologic types (p < 0.001). Patients with high RNF128 expression exhibited fewer clusters of differentiated (CD) 68+ tumor‐associated macrophages (TAMs) and CD163+ TAMs. Multivariate analysis of relapse‐free survival (RFS) and overall survival (OS) revealed that the lack of RNF128 expression was an independent prognostic factor for poor RFS (hazard ratio [HR] 1.60, p = 0.029) and OS (HR 1.83, p = 0.041), suggesting that RNF128 expression is a favorable prognostic factor. Conclusion: RNF128 expression may be an independent predictor of favorable outcomes in Japanese patients with untreated lung adenocarcinoma who undergo surgical resection. Further elucidation of the role of TAM‐related E3 ubiquitin ligase in immune function may facilitate the development of effective immunomodulatory therapies for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair‐defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer‐initiating cells in these patients usually undergo loss of the wild‐type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients. [ABSTRACT FROM AUTHOR]

Cancer is the primary cause of human mortality in Japan since 1981. Although numerous novel therapies have been developed and applied in clinics, the number of deaths from cancer is still increasing worldwide. It is time to consider the strategy of cancer prevention more seriously. Here we propose a hypothesis that cancer can be side effects of long time-use of iron and oxygen and that carcinogenesis is an evolution-like cellular events to obtain "iron addiction with ferroptosis-resistance" where genes and environment interact each other. Among the recognized genetic risk factors for carcinogenesis, we here focus on BRCA1 tumor suppressor gene and how environmental factors, including daily life exposure and diets, may impact toward carcinogenesis under BRCA1 haploinsufficiency. Although mice models of BRCA1 mutants have not been successful for decades in generating phenotype mimicking the human counterparts, a rat model of BRCA1 mutant was recently established that reasonably mimics the human phenotype. Two distinct categories of oxidative stress, one by radiation and one by iron-catalyzed Fenton reaction, promoted carcinogenesis in Brca1 rat mutants. Furthermore, mitochondrial damage followed by alteration of iron metabolism finally resulted in ferroptosis-resistance of target cells in carcinogenesis. These suggest a possibility that cancer prevention by active pharmacological intervention may be possible for BRCA1 mutants to increase the quality of their life rather than preventive mastectomy and/or oophorectomy. [ABSTRACT FROM AUTHOR]

We previously demonstrated that Mac‐2 binding protein (M2BP) is a useful biomarker for nonalcoholic fatty liver disease (NAFLD), particularly NAFLD fibrosis prediction. In the present study, we investigated the prognostic value of M2BP in patients with NAFLD. A total of 506 patients with biopsy‐confirmed NAFLD from 2002 to 2013 were enrolled in this study in Japan. Three hundred fifty‐three of these patients with NAFLD were available for follow‐up for more than 100 days and showed no liver‐related events at the time of entry. Liver‐related events were defined as hepatocellular carcinoma (HCC), decompensation, and gastroesophageal varices with variceal treatment. The mean follow‐up duration of all the subjects was 2716 ± 1621 days (102–7483 days). Eighteen patients developed new liver‐related events (HCC, 8; decompensation, 11; varices, 8). Nine patients developed cardiovascular disease (CVD), and 24 patients developed new cancers in other organs. The median serum M2BP level was 1.603 μg/mL, and we divided our cohort into two groups according to the serum M2BP level: M2BP low group (M2BP Low) and M2BP high group (M2BP Hi). The incidence of HCC was significantly higher in M2BP Hi (n = 8) than in M2BP Low (n = 0). The incidence of liver‐related events was significantly higher in M2BP Hi (n = 16) than in M2BP Low (n = 2). The incidences of death, CVD events, and cancer in other organs were not different between the groups. Interestingly, the incidence of colorectal cancer was significantly higher in M2BP Hi (n = 5) than in M2BP Low (n = 0). Conclusion: M2BP is a useful biomarker to predict liver‐related events, particularly HCC. Additionally, M2BP is a potential predictive biomarker of colorectal cancer development. [ABSTRACT FROM AUTHOR]

Asbestos fibers have been used as an industrial and construction material worldwide due to their high durability and low production cost. Commercial usage of asbestos is currently prohibited in Japan; however, the risk of asbestos‐induced malignant mesothelioma (MM) remains. According to epidemiological data, the onset of MM is estimated to occur after a latent period of 30–40 years from initial exposure to asbestos fibers; thus, the continuous increase in MM is a concern. To explore the molecular mechanisms of MM using animal models, iron saccharate with iron chelator‐induced sarcomatoid mesothelioma (SM) revealed hallmarks of homozygous deletion of Cdkn2a/2b by aCGH and microRNA‐199/214 by expression microarray. Oral treatment of iron chelation by deferasirox decreased the rate of high‐grade SM. Moreover, phlebotomy delayed MM development in crocidolite‐induced MM in rats. In Divalent metal transporter 1 (Dmt1) transgenic mice, MM development was delayed because of low reactive oxygen species (ROS) production. These results indicate the importance of iron and ROS in mesothelial carcinogenesis. The aims of this review focus on the pathogenesis of elongated mineral particles (EMPs), including asbestos fibers and multiwalled carbon nanotubes (MWCNTs) that share similar rod‐like shapes in addition to the molecular mechanisms of MM development. [ABSTRACT FROM AUTHOR]

Background: Mutation, inflammation, and oxidative damage including lipid-peroxidation are factors involved in the development of cancer. We investigated the antimutagenic, in vivo and in vitro anti-inflammatory, and antioxidative effects of the juice of Vitis ficifolia var. ganebu (known as Ryukyu-ganebu in Japan) harvested in Kuchinoshima island (hereafter, the juice is referred to as ganebu-K) in comparison with the juice of Vitis coignetiae (crimson glory vine, known as yamabudo in Japan; hereafter, the juice is referred to as yamabudo) which we found antimutagenic and anti-inflammatory effects. Results: Ganebu-K inhibited the mutagenic activity of several carcinogens, MeIQx, IQ, Trp-P-2(NHOH), and MNNG, model compounds of tumor initiation. Using S. typhimurium YG7108, a strain lacking O6-methylguanine DNA methyltransferases, ganebu-K showed no significant inhibition of the mutagenicity of MNNG. Thus, DNA repair of O6-methylguanine produced by MNNG might be an antimutagenic target of the components in ganebu-K. Topical application of ganebu-K to the dorsal sides of mice resulted in potent suppression of acute edema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Ganebu-K, but not yamabudo, exhibited significant inhibition of the induction of prostaglandin E2 (PGE2) induced by TPA. Components contained in ganebu-K, but not in yamabudo, might be responsible for the inhibition of the induction of PGE2. Ganebu-K inhibited in vivo lipid peroxidation and decreased the level of glutamic oxaloacetic transaminase induced by CCL4 treatment. Conclusions: These results suggest that the active components in ganebu-K juice are not the same as those in yamabudo, and the components in ganebu-K are attractive candidates as chemopreventive agents. [ABSTRACT FROM AUTHOR]

Background: Upper urinary tract urothelial carcinoma (UUT-UC) is a rare and severe urinary malignancy. Several studies have explored the relationship between preoperative urine cytology and intravesical recurrence (IVR) in patients with UUT-UC. However, the results of these studies are controversial or even contradictory, and investigations with UUT-UC patients in northeast China are rare. Methods: We first estimated the prognostic significance of preoperative urine cytology in the outcomes of intravesical recurrence in 231 UUT-UC patients (training cohort = 142, validation cohort = 89) after radical nephroureterectomy (RNU) by the nomogram model. Subsequently, we quantitatively combined our results with the published data after searching several databases to assess whether preoperative positive urine cytology was associated with poor intravesical recurrence-free survival and a high risk of tumor malignant biological behavior. Results: Firstly, the multicenter retrospective cohort study demonstrated that preoperative positive urine cytology correlated with poor intravesical recurrence-free survival and can serve as significant independent predictors of IVR by Kaplan–Meier curves and Cox regression analysis. The construction of the nomogram demonstrated that predictive efficacy and accuracy were significantly improved when preoperative urine cytology was combined. Meanwhile, meta-analysis showed that preoperative positive urine cytology was associated with a 49% increased risk of IVR. In the subgroup analysis by region, study type, and sample size, the pooled hazard ratios (HRs) were statistically significant for the Japan subgroup (HR 1.32), China subgroup (HR 1.88), cohort study subgroup (HR 1.45), and the single-arm study subgroup (HR 1.63). Conclusions: Preoperative urine cytology was validated as a potential predictor of intravesical recurrence in patients with UUT-UC after RNU, although these results need to be generalized with caution. Large, prospective trials are required to further confirm its significance in prognosis and tumor malignant biological behavior. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established., Aim: To investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies., Methods: We studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment., Results: In 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p < 0.0001) and cumulative cancer rates were high. Multidisciplinary therapy other than immune checkpoint inhibitors was administered as treatment for HCC. Two of the three patients who used molecular-targeted drugs discontinued the treatment because of adverse events., Conclusion: HCC is an important cause of death in patients with AIH. Currently available drug therapies are limited and early detection is desirable., Trial Registration: This trial was retrospectively registered in the Ethics Committee of Kagawa University School of Medicine under the identifier 2019 - 238, registered on 4 Feb 2020., (© 2024. The Author(s).)

Introduction and Objectives The animal models for renal carcinogenesis have allowed researchers to better understand the physiopathological, genetic, molecular, and immunological mechanisms underlying the development of human renal cancers from the induction of precancerous lesions to the metastatic process. Our study aimed to review and discuss the characteristics of all the spontaneous animal models of renal carcinogenesis described in scientific literature to date and see how they could address future challenges in the field of personalized medicine. Methods and Materials We reviewed all the papers on PubMed which focus on spontaneous animal models of renal carcinogenesis. To do so, we used the keywords "spontaneous" AND "animal model" AND "renal cancer" in the PubMed search engine. We also conducted a search using the keywords "spontaneous" AND "animal model" AND "kidney cancer." PRISMA recommendations were used for the literature review. Results A total of 213 publications were found on PubMed with the keywords "spontaneous" AND "animal model" AND "kidney cancer." 219 publications were found on PubMed with the keywords "spontaneous" AND "animal model" AND "renal cancer." After pooling these 2 searches and removing the duplicate publications, 233 publications remained. Among these, 220 full-text articles were assessed for eligibility; 160 were removed because they were irrelevant to our topic, and the remaining 60 studies were included in our qualitative synthesis. Conclusions Many spontaneous animal models have been developed to study renal cancer. So far, these models have enabled the understanding of pathophysiological mechanisms underlying renal cancer. Though less appropriate than patient xenografts from the perspective of personalized medicine, we believe animal models can help medical professionals better understand the hows and whys of the genetic events underlying the intratumoral heterogeneity and spatial distribution of metastatic subclones. [ABSTRACT FROM AUTHOR]

The development of novel therapeutic agents has led to an increase in patients with multiple myeloma (MM) who achieve a complete response (CR). Consequently, a good correlation has been established between the CR rate and progression-free survival, and new methods are needed to stratify CR cases based on the measurable residual disease (MRD) and thus predict prognosis. Previously, multiparameter flow cytometry (MFC), which is rapid and widely available, has been used to assess MRD in patients with MM. Although the EuroFlow next-generation flow method was developed as a highly sensitive and standardized method of MRD detection, the procedure is costly within the current Japanese public medical insurance system. Recently, two Japanese clinical laboratory test companies, SRL and BML, respectively developed new and inexpensive 8- and 10-color single-tube MFC methods intended for the assessment of MRD under the current Japanese public medical insurance system. In this article, I have reviewed the most recent updates on MRD monitoring protocols in Japan and the clinical trials of the use of this parameter in patients with MM. [ABSTRACT FROM AUTHOR]

Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen. [ABSTRACT FROM AUTHOR]

Background: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens.Methods: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations.Results: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors.Conclusions: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials. [ABSTRACT FROM AUTHOR]

Aim: The aim of your study is to characterize serrated lesions according to their molecular patterns, specifically BRAF/KRAS mutation, methylation, and microsatellite statuses. We evaluated the molecular patterns of 163 serrated lesions, including 37 microvesicular hyperplastic polyps, 73 sessile serrated adenomas/polyps (SSA/Ps), 31 traditional serrated adenomas, and 22 SSA/Ps with cytological dysplasia/adenocarcinoma.Methods: Mutations in BRAF (V600E)/KRAS (exon 2) and microsatellite status [microsatellite stability (MSS) vs. MSI] were examined using a pyrosequencer and the PCR-based microsatellite method, respectively. DNA methylation status was classified as low (LME), intermediate (IME), or high methylation epigenotype (HME) according to a PCR-based two-step method. In addition, mucin and annexin A10 expression was examined. Finally, we performed a hierarchical clustering analysis of the BRAF/KRAS mutation, DNA methylation, and microsatellite statuses.Results: The molecular patterns observed in the serrated lesions could be divided into five subgroups: lesions characterized by (1) BRAF mutation, HME, and MSI; (2) BRAF mutation, HME, and MSS; (3) BRAF mutation, LME/IME, and MSS; (4) no BRAF/KRAS mutations, LME/IME, and MSS; and (5) KRAS mutation, LME/IME, and MSS. In addition, we demonstrated that these observed molecular patterns help identify the associations of the molecular patterns and markers (i.e., mucin and annexin A10) with the clinicopathological findings, including histological features and histological diagnosis.Conclusions: We suggest that the identified molecular patterns play an important role in the pathway of serrated lesion development. [ABSTRACT FROM AUTHOR]

While data are unavoidably missing or incomplete in most observational studies, consequences of mishandling such incompleteness in analysis are often overlooked. When time-varying information is collected irregularly and infrequently over a long period, even precisely obtained data may implicitly involve substantial incompleteness. Motivated by an analysis to quantitatively evaluate the effects of smoking and radiation on lung cancer risks among Japanese atomic-bomb survivors, we provide a unique application of multiple imputation to incompletely observed smoking histories under the assumption of missing at random. Predicting missing values for the age of smoking initiation and, given initiation, smoking intensity and cessation age, analyses can be based on complete, though partially imputed, smoking histories. A simulation study shows that multiple imputation appropriately conditioned on the outcome and other relevant variables can produce consistent estimates when data are missing at random. Our approach is particularly appealing in large cohort studies where a considerable amount of time-varying information is incomplete under a mechanism depending in a complex manner on other variables. In application to the motivating example, this approach is expected to reduce estimation bias that might be unavoidable in naive analyses, while keeping efficiency by retaining known information. [ABSTRACT FROM AUTHOR]

The third Japanese meeting entitled "Biological Function and Evolution through Interactions between Hosts and Transposable Elements (TEs)" was held on 5-6 September 2016 at National Institute of Genetics (NIG), Mishima, Japan. Supported by NIG, the goal of the meeting was to bring together researchers who study diverse biological phenomena such as schizophrenia, carcinogenesis, cellular reprograming, skin function, placental formation, plant mutagenesis and epigenetics, and small RNA-mediated heterochromatinization, where TEs are involved in various ways. The meeting included 13 invited speakers. Here we present highlights of these invited talks. [ABSTRACT FROM AUTHOR]

Purpose: In Japan, the majority of early gastric cancers (EGCs) are now treated with endoscopic submucosal dissection (ESD). Patients with non-curative lesions treated by ESD are advised to undergo additional surgical resection (ASR) based on guidelines from the Japan Gastroenterological Endoscopy Society (JGES) and Japanese Gastric Cancer Association (JGCA). However, many studies have demonstrated that residual cancer and lymph node metastasis are only rarely found in ASR specimens. Here we retrospectively analyzed the conditions that could enable the avoidance of unnecessary ASR.Methods: The ESD data for 114 absolute indication lesions and 26 lesions of expanded indication lesions were analyzed. The indications and the curability were evaluated according to the JGES/JGCA guidelines.Results: The rates of non-curative resection and ASR were significantly higher in the expanded indication group compared to the absolute indication group (26.9% and 19.2% vs. 7.9% and 0.9%, respectively). ASR was performed for six patients. Three of their ARS specimens contained neither residual cancer nor lymph node metastasis, and the pathological findings of the preceding ESD specimens deviated slightly from the curative criteria defined by the guidelines. The conditions of the lesions that did not meet the curative criteria were as follows: (1) sm1 invasion of undifferentiated-type lesion <10 mm dia., (2) 21-25 mm dia. mucosal undifferentiated-type lesion, or (3) peacemeal resection with a horizontal margin positive for the mucosal differentiated-type.Conclusions: These data suggest that a close follow-up without ASR might be appropriate for patients in the above-mentioned three categories after non-curative ESD for EGC. [ABSTRACT FROM AUTHOR]

The probability that an observed cancer was caused by radiation exposure is usually estimated using cancer rates and risk models from radioepidemiological cohorts and is called assigned share (AS). This definition implicitly assumes that an ongoing carcinogenic process is unaffected by the studied radiation exposure. However, there is strong evidence that radiation can also accelerate an existing clonal development towards cancer. In this work, we define different association measures that an observed cancer was newly induced, accelerated, or retarded. The measures were quantified exemplarily by Monte Carlo simulations that track the development of individual cells. Three biologically based two-stage clonal expansion (TSCE) models were applied. In the first model, radiation initiates cancer development, while in the other two, radiation has a promoting effect, i.e. radiation accelerates the clonal expansion of pre-cancerous cells. The parameters of the TSCE models were derived from breast cancer data from the atomic bomb survivors of Hiroshima and Nagasaki. For exposure at age 30, all three models resulted in similar estimates of AS at age 60. For the initiation model, estimates of association were nearly identical to AS. However, for the promotion models, the cancerous clonal development was frequently accelerated towards younger ages, resulting in associations substantially higher than AS. This work shows that the association between a given cancer and exposure in an affected person depends on the underlying biological mechanism and can be substantially larger than the AS derived from classic radioepidemiology., (© 2022. The Author(s).)

Purpose: To evaluate the clinical features and treatment results of anaplastic histology (AH) Wilms' tumor (WT) patients registered in the Japan Wilms' Tumor Study (JWiTS) group to elucidate the clinical characteristics of AH in the Japanese population.Patients and Methods: Of 344 WT patients who were enrolled in JWiTS between 1995 and 2013, 17 had AH. Treatment using the JWiTS protocols was similar to the fifth National Wilms' Tumor Study 5 (NWTS-5) protocols. Clinical characteristics and mutation status of TP53 gene were evaluated and compared with those in NWST-5 study.Results: AH incidences in JWiTS were 4.9 %, lower than that in NWTS-5. Seven tumors had focal AH and 10 had diffuse AH. Clinical stages of AH patients were stage I in seven, stage II in three, stage III in five, stage IV in one and unknown in one. Four-year event-free survival and overall survival rates were 90.9 and 86.7 %, respectively. Two patients with diffuse AH and none with focal AH had TP53 mutation.Conclusion: Japanese patients presented with higher incidence, earlier stages and may have better outcomes than American patients, indicating a possible biological heterogeneity of AH WT. Further analysis is necessary to elucidate the different characteristic of AH WT between Japanese and American populations. [ABSTRACT FROM AUTHOR]

Background and Study Aim: A slightly elevated flat lesion with wide pits has occasionally been observed at the margin of laterally spreading tumors (LSTs) and is known as a "skirt." The aim of this study was to evaluate the clinicopathological, endoscopic, and genetic characteristics of a skirt.Patients and Methods: Consecutive LSTs were examined to evaluate the pathological, endoscopic, and genetic characteristics. Pathological characteristics, including the dimension of the cryptic opening (DCO), width of the individual gland (WIG), DCO to WIG ratio, and microvessel diameter were elucidated and compared with those of hyperplastic polyps, low grade dysplasia (LGD), and normal mucosa. The endoscopic findings of pit and microvascular patterns were assessed. Gene mutation analyses were performed for the KRAS, BRAF, NRAS, and PIK3CA genes.Results: A skirt was identified in 35 of 1023 LSTs, and 80 % of lesions with a skirt had a component of either intramucosal or submucosal adenocarcinoma. The DCO, WIG, and DCO to WIG ratio of the skirt were significantly larger than those of other lesions. The microvessel diameters in skirts were significantly smaller than those in LGDs. Regarding the endoscopic findings, 30 skirts showed pits with a coral reef-like appearance, and all skirt regions were found to have a type I capillary pattern. KRAS mutation at codon 146 was found in the nodular part in one of five LSTs with a skirt.Conclusion: The skirt is a newly identified lesion distinct from hyperplastic polyps and LGDs, suggesting the presence of a novel pathway for rectal carcinogenesis from LSTs with a skirt. [ABSTRACT FROM AUTHOR]

Background: In human papillomavirus (HPV)-induced carcinogenesis, the arginine (Arg) allele of the TP53 codon 72 polymorphism binds more efficiently to the HPV E6 oncoprotein than the proline (Pro) allele. We investigated the physical status of HPV-16 DNA and the TP53 codon 72 polymorphism in oropharyngeal squamous cell carcinoma (OPSCC).Methods: Tumor samples from 70 p16-positive OPSCC patients were tested for HPV-16 physical status by examining the E2 and E6 open reading frames. The TP53 codon 72 polymorphism was screened by direct sequencing.Results: Of 70 patients, 53 were E6 positive, 29 had integrated forms of HPV-16 DNA, and 24 had mixed or episomal forms. Furthermore, 44 carried the Arg/Arg or Arg/Pro genotype, 3 carried the Pro/Pro genotype, and in 6 patients we were unable to obtain sequencing data.Conclusions: HPV-16 physical status was heterogeneous in our OPSCC patients. Most OPSCC patients had the TP53 Arg/Arg or Arg/Pro genotype. [ABSTRACT FROM AUTHOR]

Background and Aims: A sustained virological response (SVR) decreases the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. We investigated the longterm outcomes of patients who developed HCC after achieving SVR with interferon therapy. Patients: Of 75 patients who developed HCC after SVR, 40 patients underwent radical therapies (SVR group). From 436 patients undergoing surgical resection for hepatitis C virus-positive HCC, 80 patients were randomly chosen as a control cohort, after adjusting for age, gender, and extent of hepatic fibrosis (non- SVR group). Patients were observed for a median of 5.08 years. Results: HCC recurrence was found in 16 SVR patients and in 66 non-SVR patients. The respective HCC recurrence rates of SVR and non-SVR patients were 23 and 56% at 3 years, 42 and 77% at 5 years, and 53 and 90% at 10 years (p = 0.001). The respective overall survival rates in the SVR and non-SVR groups were 93 and 68% at 5 years, 88 and 34% at 10 years, and 53 and 21% at 15 years (p = 0.001). Conclusion: Although SVR patients had a significantly lower HCC recurrence rate than the non-SVR patients, the cumulative recurrence rate of SVR patients increased to 86% at 15 years. [ABSTRACT FROM AUTHOR]

The benchmark dose (BMD) approach is updated to create an international harmonizing process following rapid theoretical sophistication. We calculated the lower limit of BMD confidence interval (BMDL) for carcinogenicity based on 193 tumorigenicity bioassay data published in 50 pesticide risk assessment reports by the Food Safety Commission of Japan (FSCJ) to validate the appropriateness and necessity for the refinement of the FSCJ-established BMD guidance. Three well-known BMD software, PROAST, BMDS, and BBMD were used to compare their BMDLs with no-observed-adverse-effect levels (NOAELs) for carcinogenicity. Recently implemented methodologies such as model averaging or Bayesian inference were also used. Our results indicate that the BMD approach provides a point of departure similar to the NOAEL approach if the data used exhibit a clear dose-response relationship. In some cases, particularly in software with a frequentist approach, the calculation failed to provide BMDL or provided considerably lower BMDLs than NOAELs. However, most of the datasets that resulted in failed calculations or extremely low BMDLs exhibited unclear dose-response relationships, i.e., non-monotonous and sporadic responses. The expert review on the shape of the dose-response plot would help better apply the BMD approach. Furthermore, we observed that Bayesian approaches provided fewer failed or extreme BMD calculations than the frequentist approaches. • Different software to compare BMDL with NOAEL. • Validated the appropriateness and necessity of refinement of the BMD guidance. • 193 datasets were used from carcinogenicity studies of 50 pesticides in rat or mice. [ABSTRACT FROM AUTHOR]

Based on the findings of epidemiological studies in Japan that occupational exposure to 1,2-dichloropropane (1,2-DCP) was associated with increased cholangiocarcinomas, 1,2-DCP has recently been classified as being carcinogenic to humans (Group 1). However, the cholangiocarcinogenicity of 1,2-DCP has not been demonstrated experimentally, and it was negative for cholangiocarcinogenicity in rats and mice. The present study determined the effects of 1,2-DCP on N-nitrosobis(2-oxopropyl)amine (BOP)-induced cholangiocarcinogenesis in male hamsters. We found that 1,2-DCP did not enhance the development of BOP-induced atypical biliary hyperplasia and did not induce any lesions in liver bile duct when administered alone. Notably, 1,2-DCP had no effect on the proliferative activity of bile duct epithelial cells regardless of BOP-initiation. These results demonstrate that 1,2-DCP lacks promoting effects on BOP-induced cholangiocarcinogenesis and suggest the possibility that 1,2-DCP is not cholangiocarcinogenic to the hamster in the present model. In addition, 1,2-DCP also lacks promoting effects on pancreatic, lung, and renal carcinogenesis. As the occurrence of occupational cholangiocarcinomas in Japan might be attributed to exposure to multiple chemicals, the results of the present study indicate that it will be necessary to determine the cholangiocarcinogenic effects of concurrent exposure of 1,2-DCP and the other halogen solvents to which workers with cholangiocarcinomas were exposed. [ABSTRACT FROM AUTHOR]

Despite widening interest in the possible association between infection/ inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue Despite widening interest in the possible association between infection/ inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue [ABSTRACT FROM AUTHOR]

Background: The significance of anti-inflammatory therapy has not been fully evaluated in hepatitis C virus (HCV)-related cirrhosis. Patients and Methods: We analyzed stepwise progression rates from cirrhosis to hepatocellular carcinoma (HCC) and to death using a Markov model in 1,280 patients with HCV-related cirrhosis. During the observation period, 303 patients received interferon and 736 received glycyrrhizin injections as anti-inflammatory therapy. Results: In the entire group, annual progression rates from cirrhosis to HCC and from cirrhosis to death were 6.8 and 1.9%, and the rate from HCC to death was 19.0%. When sustained virological response (SVR) or biochemical response (BR) was attained with interferon, the annual rate to HCC decreased to 2.6%. On the contrary, the progression rates to HCC and to death in the patients without SVR and BR were 7.2 and 2.0%, respectively (p < 0.0001). Continuous interferon administration significantly decreased the carcinogenesis rate to 5.5% (p = 0.0087). In the analysis of the remaining patients with high alanine transaminase of 75 IU/l or more but without interferon response or without interferon administration, glycyrrhizin injection significantly decreased annual non-progression probability (no glycyrrhizin 88.0% vs. glycyrrhizin therapy 92.3%, p = 0.00055). Conclusion: Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Ovarian seromucinous tumors (SMBTs) are relatively rare, and their carcinogenesis is largely unknown. In this study, the molecular features of SMBTs in Japan are assessed. DNA was extracted from microdissected paraffin-embedded sections from 23 SMBT cases. Genetic mutations ( KRAS , BRAF , PIK3CA , and ERBB2 ) were evaluated using Sanger sequencing. Immunohistochemistry for p53, ARID1A, and PTEN was also performed as a surrogate for the loss of functional mutations in these tumor suppressor genes. The prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations was 4.3% (1/23), 8.6% (2/23), 8.6% (2/23), and 17.3% (4/23), respectively. Overexpression or loss of p53 expression occurred in 26% (6/23), loss of ARID1A expression in 4.3% (1/23), and none of the cases showed expression of PTEN loss. These findings suggest that KRAS/BRAF/PIK3CA and PTEN mutations are rare carcinogenic events in SMBTs. The high frequency of positive p53 staining and a low frequency of loss of ARID1A staining suggests that SMBT carcinogenesis may be related to the alteration of p53 rather than that of ARID1A . ERBB2 oncogenic mutations may play an important role in the tumorigenesis of Japanese SMBTs.

Objective Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene ( Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral ( Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects. Patients and Methods For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls. Results Among the 74 eligible patients, two unrelated patients (2·7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116_119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case ( Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation. Conclusion This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies. [ABSTRACT FROM AUTHOR]

Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn's disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described. [ABSTRACT FROM AUTHOR]

Abstract: Nasopharyngeal carcinoma (NPC) is a kind of rare head and neck cancer in Japan. However, NPC has some unique features. It is one of the most popular cancers in southern China, Southeast Asia, the Arctic, and the middle East/north Africa. This distinctive racial, ethnical, and geographic predisposition to NPC implies that both genetic susceptibility and environmental factors contribute to the development of this tumor. NPC is an Epstein-Barr virus – associated tumor. Consistent elevation of EBV antibody titers is a well-established risk factor of development of NPC. Not only pathophysiological relationship, but also molecular mechanism of EBV-mediated carcinogenesis has been enthusiastically investigated. LMP1, an EBV primary oncogene, upregulates each step of metastasis, and contribute to highly metastatic feature of NPC. A tumor suppressor gene p53 is mostly intact and overexpressed in NPC whereas expression of p16, a cyclin-dependent kinase inhibitory protein, is downregulated in 2/3 of NPC. Intention modulated radiotherapy (IMRT) is now getting prevalent for the treatment of NPC because of complicated structure and location of nasopharynx. A good therapeutic result can be achieved by distributing a high dose to the tumor while keeping down normal tissue complications by reducing radiation dose to normal tissues. Chemotherapy is important to control distant metastasis of chemoradiosensitive NPC, and thus, should play an important role. However, most effective combination of anti-tumor drugs, protocol of chemoradiotherapy has not well-established. Finally, molecular targeting therapy, including targeting EBV gene product, has been developing and on the way to the clinical use. [Copyright &y& Elsevier]

The incidence of hepatocellular carcinoma in non-viral-related chronic liver disease has gradually increased in Japan. Obesity and diabetes mellitus type 2 have been established as a significant risk factor for hepatocellular carcinoma (HCC) by epidemiologic observations and experimental studies. The risks of these factors for HCC are likely conferred by two factors: the increased risk for development of non-alcoholic steatohepatitis (NASH) and the carcinogenic potential of themselves. Hepatocellular carcinoma in NASH is difficult to evaluate because histological diagnosis is required for diagnosis of NASH, which can lead selection bias. Furthermore, end-stage NASH is in effect 'burned-out' NASH, for which the diagnosis of NASH cannot be made any more. At all events, previous studies on the etiology of Japanese HCC showed that non-alcoholic fatty liver disease accounts for 1-5% of all HCC (male predominant, median age 72 years). They have high prevalences of obesity and/or diabetes mellitus type 2 and 10-75% of the HCC arose from non-cirrhotic livers. HCC in NASH may be of multicentric origin, similar to HCC based on viral hepatitis. Regular screening for HCC is extremely important especially in cirrhotic NASH patients and recurrence should be warned. In western and Asian countries, the prevalence of non-alcoholic fatty liver disease in the general population is increasing dramatically. Therefore, there is an urgent need to elucidate pathogenesis and clinical features of HCC in NASH. In this review we summarize current concepts for HCC in NASH. [ABSTRACT FROM AUTHOR]

Background and aims Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been reported to be associated with extrapancreatic malignancies, but there have been no prospective studies evaluating the incidence of extrapancreatic cancers in patients with IPMNs. In this study, the frequency of patients with IPMNs developing extrapancreatic cancers during follow-up was examined. Methods 642 patients with IPMNs were prospectively followed up for 4.8 years on average. They underwent clinical examination at least twice a year. The incidence of the observed extrapancreatic malignancies was compared with the expected incidence of the age- and gender-matched general Japanese population based on the Vital Statistics of Japan. Results 40 extrapancreatic cancers developed in 39 patients during follow-up (1.3% per year). The most common malignancies were hepatocellular (n=7), colorectal (n=6), gastric (n=6), lung (n=5) and prostate cancers (n=4). The calculated standardised incidence rate of each of the malignancies was not significant, as follows: hepatocellular 2.17 (95% CI 0.87 to 4.47), colorectal 1.02 (0.37 to 2.21), gastric 0.76 (0.28 to 1.66), lung 0.75 (0.24 to 1.76) and prostate 1.00 (0.71 to 1.29). Pancreatic cancer was observed in 17 patients during the same period, with a standardised incidence rate of 10.7 (6.2 to 17.1). Conclusions The incidence of extrapancreatic malignancies in patients with IPMNs was similar to that in the general population, whereas the incidence of pancreatic cancers was significantly high. Intraductal papillary mucinous neoplasms are not associated with systemic carcinogenesis except for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBCA) is a rare malignancy with a variable incidence worldwide. This study analyzed GBCA patients treated at centers in 3 countries. The aim was to assess for location-specific differences in presentation and outcomes, which might suggest differences in pathogenesis or disease biology. Study Design: Data for consecutive patients submitted to operation at Instituto Oncológico Fundación Arturo López Pérez (FALP, Chile), Yokohama City University (YCU, Japan), and Memorial Sloan-Kettering Cancer Center (MSKCC, USA) between 1999 and 2007 were studied retrospectively. Patient demographics, disease- and treatment-related variables and outcomes were analyzed by chi-square, Kruskal-Wallis, and log-rank test. Results: Two hundred sixty-one patients (MSKCC, 130; FALP, 85; YCU, 46) underwent exploration, and 160 (MSKCC, 91; FALP, 33; YCU, 36) underwent R0 resection. Patients treated at FALP were younger (median 57 years, p < 0.001) and more often female (80%, p < 0.005); at YCU there were fewer patients with incidental tumors (19.5% compared with more than 60% at FALP and MSKCC, p < 0.001). En bloc liver and bile duct resections were performed more commonly at MSKCC and YCU (p < 0.001). Patients treated at FALP had more advanced tumor stage compared with those treated at MSKCC and YCU (p < 0.001). Disease-specific survival (DSS) was not different among the groups when patients submitted to an R0 resection were analyzed (p = 0.12). On multivariate analysis, T-stage, nodal involvement, and bile duct involvement were predictors of DSS; center was not significant. Conclusions: Despite some differences in presentation, disease extent, and surgical treatment, DSS after curative intent resection was similar among all 3 groups. The most important predictors of outcomes were related to tumor extent rather than country of origin. [ABSTRACT FROM AUTHOR]

The article discusses the use of models to predict lifetime excess cancer risks following exposure to radiation. One study proposed a biologically based model for estimating lifetime cancer risks in Japanese atomic bomb survivors based on assumptions regarding the kinetics of radiation-induced tumor initiation and promotion. The importance of better epidemiology and statistically powerful studies of populations exposed to radiation is emphasized.

Methylmercury (Me-Hg) poisoning (Minamata disease: MD) is one of the most severe types of disease caused by humans to humans in Japan. The disease is a special class of food-borne methylmercury intoxication in humans as typified by the outbreak that began in 1953 in Minamata and its vicinity in Kumamoto Prefecture, Japan. There are 450 autopsy cases in Kumamoto and 30 autopsy cases in Niigata Prefecture related to MD in Japan. Two hundred and one cases in Kumamoto and 22 cases in Niigata showed pathological changes of MD. This report provides a brief research history and overview of the pathological changes of MD, and also presents representative cases of adult, infantile and fetal forms of MD among the 450 MD-related autopsy cases in Kumamoto Prefecture. [ABSTRACT FROM AUTHOR]

The article discusses a study on the long incubation time in carcinogenesis resulting from internally deposited alpha-emitters which may be affected by uneven distribution of radionuclides, limited irradiation range, and dynamic movement of tumor precursor cells. The study used data on 64 patients from the Database on Thorotrast Patient in Japan who had Thorotrast-induced intrahepatic cholangiocarcinoma (Th-ICC). A model for determining the relationship between radiation rate and incubation period is also presented.

Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5×10-7) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30×10-7, 3.30×10-7, and 4.41×10-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objectives This article reviews recent data on the biology, pathogenesis and pathophysiology of the different entity of epithelial ovarian cancer (EOC). Study design The present article reviews the English language literature for screening, epidemiology, clinical diagnosis, natural history, preclinical and clinical trials, and promising molecular targets on EOC, particularly for clear cell EOC (cEOC) based on the gene expression profiling studies. Results Prospective ovarian cancer screening trials in Japan showed that (1) serous-type EOC (sEOC) may exhibit a rapid progression possibly through de novo carcinogenesis, (2) the EOC risk was elevated significantly among patients with ovarian endometrioma (SIR = 8.95), (3) advancing age (>40 years) and the diameter of endometriomas (>9 cm) were independent predictors of development of EOC, (4) the benign-appearing ovarian masses are present several years before the EOC diagnosis in patients with endometriosis-associated EOC, and (5) the slightly elevated CA125 level is also typically present many years (>3 years) before the diagnosis in these patients. Upregulation of HNF-1beta and PLK-Emi1 genes were specifically detected in cEOC. In addition, the therapy currently used in renal cell carcinoma (RCC) should be considered as an attractive therapeutic option for cEOC. Conclusions Ovarian endometrioma could be viewed as a neoplastic process, particularly in perimenopausal women. Understanding the mechanisms of endometriosis development and elucidating its pathogenesis and pathophysiology are intrinsic to prevention and the search for effective therapies of endometriosis-associated EOC. [ABSTRACT FROM AUTHOR]

Little is understood about worldwide changes in the epidemiological distribution of the etiology of liver cirrhosis (LC). The present study examines the etiology of liver cirrhosis in Japan using a nationwide survey. We analyzed data from 33,379 patients with LC at 58 hospitals and presented the findings in a poster symposium regarding the etiology and clinical features of LC in Japan that was included in the program of the 44th Annual Meeting of the Japan Society of Hepatology. We identified the distribution of the etiology of LC and compared the present with previous Japanese findings to estimate the future of etiological changes in LC. The etiological agents were as follows: hepatitis B virus (HBV) 13.9%, hepatitis C virus (HCV) 60.9%, alcohol 13.6%, primary biliary cirrhosis (PBC) 2.4% and autoimmune hepatitis (AIH) 1.9%. Cirrhosis was considered to be related to nonalcoholic steatohepatitis (NASH) in 2.1% of the patients. The ratio of HCV-related LC was significantly higher among patients with hepatocellular carcinoma (HCC) ( P < 0.0001) compared to those without, whereas the ratios of alcohol, PBC, AIH were lower. HCC was evident in 31.5% of NASH-related LC. The major etiology of liver cirrhosis in Japan remains HCV. Our survey revealed the prevalence of NASH-related LC in Japan and the frequency of HCC. Future changes in etiology must be considered in establishing preventive or educational strategies, as well as in developing new treatment strategies. [ABSTRACT FROM AUTHOR]

Helicobacter pylori ( H. pylori) infection plays an important role in gastric carcinogenesis. We conducted a systematic review concerning gastric cancer development after H. pylori eradication therapy. In total 15 papers matched our criteria, the results were reviewed. The H. pylori eradication therapy statistically diminished the prevalence of clinical gastric cancer by approximately one-third. The studies from Japan supported this conclusion; however, studies from overseas reported conflicting results. The differences in these conclusions lie in the diagnostic ability of endoscopic examination, since the clinical stage was quite different between these studies. Gastric cancer that developed after eradication revealed a mainly intestinal type histology and depressed-type appearance. The following are possible reasons for reduced gastric cancer: (1) eradication therapy inhibits the new occurrence of gastric cancer, (2) eradication regresses or inhibits the growth of gastric cancer, and (3) eradication interferes with the discovery of gastric cancer. Considering the biological nature of cancer cell proliferation, a sufficiently long-term follow-up may clarify the effect of eradication therapy on inhibition of the development (not discovery) of gastric cancer and reduction of gastric cancer-related mortality. [ABSTRACT FROM AUTHOR]

Human breast cancer cell lines MCF-7 (ER-positive) and Hs578T (ER-negative) were cultured and one lot incubated for 48 h with 5–50 μg/ml of a fermented phytocompound (MK: Manda-Koso, Innoshima, Japan). In vitro, it appeared a dose-dependent decrease of cell viability (5–57%) in MK group in both cell lines ( P < 0.001, plateau: 30 μg/ml), decreased beta-galactosidase activity, enhanced apoptosis, and inversely increased Bax/Bcl2 ratio ( P < 0.01) with an upregulation of p53 ( P < 0.05). In the in vivo model, Balb-c mice were inoculated with tumor cells and the treatment group was fed with 20 mg of MK. Tumor weight in MK-fed group was time-course reduced by 22% to 51% at 2 and 4 weeks, respectively ( P < 0.05) with increased survival ( P < 0.05). Tumour tissue of MK-fed mice showed a downregulated Bcl-2 with increased Bax/Bcl-2 ratio, reduced PCNA, and activated caspase 3. Although more studies are ongoing to foster the clinical applicability of MK integrated within a rational chemopreventive and therapeutic strategy, a p53-mediated mechanism is likely to play a relevant role, besides its reported antioxidant capacity, NK cell activity enhancement, cancer-cytostatic activity properties. [ABSTRACT FROM AUTHOR]

Abstract: This article provides an overview of the on-going molecular epidemiology studies among atomic-bomb survivors conducted at the Radiation Effects Research Foundation in Japan. The focus is on: (a) inter-individual variations in sensitivity to radiation-induced somatic mutations (glycophorin A (GPA) mutations) and their potential relevance to differences in susceptibility to radiation-related cancers and (b) the role of specific mutations/rearrangements in radiation-induced thyroid and colorectal cancers. The glycophorin A mutant fractions showed large differences between the survivors at each of the estimated bone marrow doses. Of note is the finding at doses ≥1Gy; that the slope of the mutant fraction was significantly higher in the ‘cancer group’ than in the ‘non-cancer group’. This study provided the basis for validating the use of γH2AX and reticulocyte micronucleus assays for evaluating radiosensitivity differences and genetic instability, respectively, in our studies in the coming years. Preliminary results from our molecular oncology studies on adult-onset papillary thyroid cancer provide evidence for the induction of RET/PTC rearrangements and BRAF point mutation (both known to be early stage events in adult-onset papillary thyroid cancer) but with a difference: cases associated with the rearrangements were more frequent at high doses, and developed sooner than those with BRAF mutation. In the case of colorectal cancer, the results suggest that radiation exposure might influence microsatellite instability (MSI) status through MSI-related epigenetic and genetic alterations—processes that might occur in the early stage of colorectal carcinogenesis. [Copyright &y& Elsevier]

Several staging systems have been developed to classify patients with hepatocellular carcinoma (HCC), however, there is no consensus on which of these is the most useful and reliable. In this review article, currently available integrated staging systems taking into account both liver function and tumor progression are presented, and their characteristics and applicability for current HCC patients, many of whom are diagnosed in the early stage of the disease and treated by curative therapy, are discussed. Based on the original andsubsequent validation studies of these staging systems, we recommend that further validation studies of staging systems for HCC should focus on the revised Barcelona Clinic Liver Cancer (BCLC) staging classification, Japan Integrated Staging (JIS) score and Tokyo score. [ABSTRACT FROM AUTHOR]