Search

The southern Chinese Osmunda Xmildei has been suggested to be an intersubgeneric hybrid, i.e., O. japonica (subgenus Osmunda) X O. angustifolia (subgenus Plenasium) or O. japonica X O. vacheUii (subgenus Plenasium). These interpretations were based on morphological, cytological, and/or chloroplast DNA data, yet the parents of the hybrid remained unclear. Molecular phylogenetic relationships inferred here from chloroplast rbcL sequences and three nuclear DNA markers show that O. Xmildei is most likely a hybrid between the paternal O. japonica and the maternal O. vacheUii [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) may be an important factor affecting breast cancer outcome. Studies conducted mainly in Western countries have reported a relationship between higher BMI and a higher risk of all-cause death or breast cancer-specific death among women with breast cancer, but only a few studies have been reported in Japan so far. In the present prospective study, we investigated the associations between BMI and the risk of all-cause and breast cancer-specific death among breast cancer patients overall and by menopausal status and hormone receptor status. Methods: The study included 653 breast cancer patients admitted to a single hospital in Japan, between 1997 and 2005. BMI was assessed using a self-administered questionnaire. The patients were completely followed up until December, 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated according to quartile points of BMI categories, respectively: <21.2, ≥21.2 to <23.3 (reference), ≥23.3 to <25.8 and ≥25.8 kg/m². Results: During the follow-up period, 136 all-cause and 108 breast cancer-specific deaths were observed. After adjustment for clinical and confounding factors, higher BMI was associated with an increased risk of all-cause death (HR = 2.61; 95% CI: 1.01-6.78 for BMI 25.8 vs. 21.2 to <23.3 kg/m²) among premenopausal patients. According to hormonal receptor status, BMI 25.8 kg/m² was associated with breast cancer-specific death (HR = 4.95; 95% CI: 1.05-23.35) and BMI <21.2 kg/m²2 was associated with all-cause (HR = 2.91; 95% CI: 1.09-7.77) and breast cancer-specific death (HR = 7.23; 95% CI: 1.57-33.34) among patients with ER+ or PgR+ tumors. Analysis by hormonal receptor status also showed a positive association between BMI and mortality risk among patients with ER+ or PgR+ tumors and with BMI ≥21.2 kg/m² (p for trend: 0.02 and 0.031 for all-cause and breast cancer-specific death, respectively). Conclusions: Our results suggest that both higher BMI and lower BMI are associated with an increased risk of mortality, especially among premenopausal patients or among patients with hormonal receptor positive tumors. Breast cancer patients should be informed of the potential importance of maintaining an appropriate body weight after they have been diagnosed. [ABSTRACT FROM AUTHOR]

A 36-year-old woman presented to our hospital with a complaint of melena. Examinations revealed type 3 gastric cancer with left supraclavicular lymph node(Virchow's node)and para-aortic lymph node(PAN)metastases. The patient was treated with S-1 and CDDP combination chemotherapy. After 2 courses of chemotherapy, the lymph node metastases were significantly reduced. Subsequently, a total gastrectomy with D2 plus PAN dissection was performed. Histopathological examination revealed the complete absence of cancer cells in both the primary lesion of the stomach and all dissected lymph nodes. No additional surgery or radiation therapy was performed for Virchow's node metastasis. Postoperatively, she received S-1 chemotherapy for 2.5 years. She remains well 9.5 years after the surgery, without any evidence of recurrent disease.

It has been postulated that being breastfed in infancy affects not only health status in childhood but also disease risk in adulthood. To investigate the association of being breastfed with the risks of adult colorectal cancer and benign tumor, we conducted a case-control study including 1190 colorectal cancer and 1585 benign tumor cases and 5301 controls, admitted to a single hospital in Miyagi Prefecture, Japan, between 1997 and 2013. History of having been breastfed was assessed using a self-administered questionnaire, and odds ratios (ORs) were estimated using unconditional logistic regression. There was no association between being breastfed and colorectal cancer risk (breastfed versus formula-only fed, OR = 1.21; 95% CI 0.87-1.67). There was also no association with the risk of benign tumor (OR = 1.04). On the other hand, analyses stratified by sex and birth year found heterogeneous associations. Women born after 1950 who had been breastfed tended to have increased risks of colorectal cancer (OR = 1.58) and benign tumor (OR = 1.51) relative to those who had been formula-only fed, although not statistically significant. In men born after 1950, being breastfed was associated with a significantly decreased risk of benign tumor (OR = 0.57; 95% CI 0.33-0.98)., (© 2024. The Author(s).)

Background and Aims: In familial adenomatous polyposis (FAP), neoplastic lesions outside the colon have become increasingly important. The genotype-phenotype correlation has been established for duodenal polyps, and regular screening is recommended. However, this correlation remains unclear for small-intestinal lesions, except for reports on the relationship between their occurrence and Spigelman stage. Here, we used small-bowel capsule endoscopy (SBCE) to investigate the genotype-phenotype correlation of small-intestinal polyps in FAP., Methods: The genotype-phenotype correlation of small-intestinal polyps was investigated in patients with FAP who underwent SBCE, Esophagogastroduodenoscopy (EGD), and adenomatous polyposis coli (APC) gene analysis. Of 64 patients with FAP who underwent SBCE, 41 were included in the final analysis, 4 did not undergo a complete small intestine examination, and 19 did not undergo genetic analysis., Results: The prevalence (median number) of small-intestinal polyps by Spigelman stage was 26% (1.5), 0% (0), 44% (5), 60% (4), and 73% (25.5) for stages 0 to IV, respectively. Significantly more small-intestinal polyps were found in Spigelman stage III and IV groups than in the stage 0 group (P < .05). The APC variant was negative for 6 patients (15%), and the sites associated with more than 5 small-intestinal polyps were codons 278, 1062, 1114, 1281, 1307, 1314, and 1504., Conclusions: In FAP patients, SBCE surveillance is potentially recommended for patients with pathogenic variants in the APC gene at codons 278 and 1062 to 1504 or with Spigelman stage III or higher., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aim: This study aimed to investigate the relationship between the histological type of colorectal lymphoma and its endoscopic features., Methods: We retrospectively analyzed patients with primary colorectal lymphoma who were diagnosed using colonoscopy and biopsy specimens at the National Cancer Center Hospital, Tokyo, Japan. The lesions were macroscopically classified into the following types via colonoscopy: polypoid, ulcerative, multiple lymphomatous polyposis, diffuse, and mixed., Results: A total of 117 lesions were identified in 90 patients enrolled in this study. Of these, 59 (50%) were located in the ileocecal region, 23 (20%) in the rectum, 9 (8%) in the transverse colon, 8 (7%) in the sigmoid colon, 7 (6%) in the descending colon, and 4 (3%) in the ascending colon. Moreover, the most common histological subtypes were diffuse large B-cell lymphoma (DLBCL) in 39 patients (43%) and mantle cell lymphoma (MCL) in 23 patients (26%), followed by follicular lymphoma (FL; 17%), mucosa-associated lymphoid tissue (MALT) lymphoma (9%), peripheral T-cell lymphoma-NOS (2%), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL; 2%), and Burkitt lymphoma (1%). More than half of the DLBCL (52%), MCL (52%), and MALT (56%) lymphomas were macroscopically classified as polypoid types. In contrast, FL lesions showed various macroscopic types. The majority of DLBCL (62%) and FL (78%) lesions were distributed in the ileocecal region. MCL lesions tended to be widely spread in various sites of the large intestine., Conclusions: Colorectal lymphomas showed macroscopically distinctive features depending on the histological type. Understanding the macroscopic classification of the lesions by colonoscopy and its distribution may be helpful in diagnosing the type of lymphoma and determining the malignant grade based on the histological types., (© 2022 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Escherichia coli containing polyketide synthase in the gut microbiota (pks + E coli) produce a polyketide-peptide genotoxin, colibactin, and are suspected to play a role in the development of colorectal neoplasia. To clarify the role of pks + E coli in the early stage of tumorigenesis, we investigated whether the pks status of E coli was associated with the prevalence of colorectal neoplasia. This cross-sectional analysis of data from a prospective cohort in Izu Oshima, Japan included asymptomatic residents aged 40-79 years who underwent screening colonoscopy and provided a stool sample. We identified 543 participants with colorectal neoplasia (22 colorectal cancer and 521 adenoma) as cases and 425 participants with normal colon as controls. The pks status of E coli was assayed using stool DNA and specific primers that detected pks + E coli. The proportion of pks + E coli was 32.6% among cases and 30.8% among controls. Compared with those with pks - E coli, the odds ratio (OR) (95% confidence interval) for participants with pks + E coli was 1.04 (0.77-1.41) after adjusting for potential confounders. No statistically significant associations were observed regardless of tumor site or number of colorectal adenoma lesions. However, stratified analyses revealed increased ORs among participants who consumed cereals over the median intake or vegetables under the median intake. Overall, we found no statistically significant association between pks + E coli and the prevalence of colorectal adenoma lesions among this Japanese cohort. However, positive associations were suggested under certain intake levels of cereals or vegetables., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: TP53 status based on TP53 signature, a gene expression profile to determine the presence or absence of TP53 mutation, is an independent prognostic factor of breast cancer. The purpose of this study was to develop a simple diagnostic system for TP53 signature status., Methods: We developed a multiplex reverse transcription-polymerase chain reaction system to determine TP53 status. Based on this system, prospectively collected 189 patients with stage I and II breast cancer were determined to have TP53 mutant signature or TP53 wild-type signature. The prognostic significance of the TP53 signature by the diagnostic system was analyzed., Results: The diagnostic accuracy of TP53 status and reproducibility of this diagnosis system was confirmed. Using the diagnostic system, 89 patients were classified as TP53 mutant signature and the remaining 100 cases were classified as TP53 wild-type signature. Recurrence-free survival (RFS) among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature. On univariate and multivariate analyses, the TP53 signature status was an independent predictor of RFS. RFS among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature in a cohort of estrogen receptor-positive breast cancer. Although a difference was not significant, no recurrent cases was observed in TP53 wild-type signature group in triple negative breast cancer., Conclusion: This simple and precise diagnostic system to determine TP53 signature status may help in prognostic assessment, therapeutic decision-making, and treatment optimization in patients with breast cancer., (© 2021. The Author(s).)

Background and Aim: The evidence of associations between some types of advanced colorectal neoplasia (ACN) at baseline and the risk of metachronous neoplasia is inconsistent. This study aimed to elucidate the incidence of metachronous neoplasia during post-polypectomy surveillance in individuals with ACN at baseline and examine the risk factors for its high incidence., Methods: Data from individuals who underwent endoscopic resection for ACN and received surveillance colonoscopy were analyzed. Data from individuals with no neoplastic lesions at baseline were used as reference. The incidence of metachronous ACN and clinically significant neoplasia (ACN and nonadvanced adenomas sized ≥ 5 mm) were evaluated. Risk factors for the higher incidence of these lesions were examined in individuals with ACN at baseline., Results: During the median follow-up period of 61.8 months, metachronous ACN and nonadvanced adenomas sized ≥ 5 mm were detected in 9.6% and 32.4% of individuals with ACN at baseline (n = 136), respectively. The cumulative incidence of metachronous ACN and clinically significant neoplasia in individuals with ACN at baseline (3-year incidence: 5.5% and 16.9%, respectively) was higher than that in individuals with no neoplastic lesions at baseline (P < 0.01 for both). The presence of advanced histology at baseline, ≥ 5 neoplastic lesions at baseline, and family history of colorectal cancer were identified as risk factors for the higher incidence of clinically significant neoplasia., Conclusions: The relatively high incidence of metachronous neoplasia in individuals with ACN at baseline was confirmed; careful surveillance is required for these individuals, particularly in those with the risk factors., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: Noninvasive colorectal cancer (CRC) screening methods with higher sensitivity for advanced colorectal neoplasia (ACN) than the fecal immunochemical test (FIT) alone are warranted. This study aimed to elucidate the diagnostic performance of a risk stratification score calculated using baseline individual characteristics and its combination with FIT for detecting ACN., Methods: This cross-sectional analysis of data from a prospective cohort in Izu Oshima, Japan, included asymptomatic individuals age 40-79 years who underwent both 2-day quantitative FIT and screening colonoscopy. The 8-point risk score, calculated based on age, sex, CRC family history, body mass index, and smoking history, was assessed. Colonoscopy results were used as reference., Results: Overall, 1,191 individuals were included, and 112 had ACN. The sensitivity and specificity of the 1-/2-day FIT (cutoff: 50-200 ng Hb/mL) for ACN were 17.9%-33.9% (4.9%-22.0% for right-sided ACN) and 91.8%-97.6%, respectively. The risk score's c-statistic for ACN was 0.66, and combining the score (cutoff: 5 points) with 1-/2-day FIT (cutoff: 50-200 ng Hb/mL) yielded a sensitivity and specificity for ACN of 46.4%-56.3% (43.9%-48.8% for right-sided ACN) and 76.6%-80.8%, respectively. The specificity of the risk score and FIT combination for all adenomatous lesions was 82.4%-86.4%., Discussion: The 8-point risk score remarkably increased the sensitivity for ACN, particularly for right-sided ACN. Although the specificity decreased, it was still maintained at a relatively high level. The risk score and FIT combination has the potential to become a viable noninvasive CRC screening option.

Background and Aim: Serrated lesions (SLs) have attracted attention as precursors of colorectal cancer (CRC). However, their prevalence, risk factors, and clinical significance have not been satisfactorily elucidated. This study used high-quality colonoscopy data to determine the prevalence of SLs and to identify their risk factors and relationship with synchronous advanced colorectal neoplasia (ACN) in asymptomatic screened individuals., Methods: This study included data for 5218 individuals who underwent first-time screening colonoscopy by highly experienced endoscopists. The relationships between baseline characteristics and the presence of SLs and those between the presence of SLs and synchronous ACN were assessed using the chi-squared test and multivariate logistic regression., Results: The proportions of individuals with SLs and right-sided SLs were 23.3% and 7.6%, respectively. Age, sex, family history of CRC, smoking, and body mass index were significantly related with the presence of SLs, and current smoking was most strongly associated with SLs (adjusted odds ratio [aOR] 2.6, 95% confidence interval [CI] 2.1-3.2). The aOR (95% CI) of the presence of SLs, SLs sized ≥ 10 mm, and right-sided SLs ≥ 5 mm for synchronous ACN was 1.4 (1.1-1.9), 3.5 (1.3-9.6), and 1.9 (1.0-3.8), respectively. The presence of left-sided SLs ≥ 10 mm (without right-sided SLs) was also significantly associated with ACN (aOR 8.1, 95% CI 2.0-33.7)., Conclusions: The relatively high prevalence of SLs and risk factors in screened individuals were elucidated and the significant relationship between SLs, particularly SLs ≥ 10 mm and right-sided SLs ≥ 5 mm, and synchronous ACN was confirmed., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Although intake of highly sugary foods is considered to be a potential risk factor for colorectal cancer through hyperinsulinemia, the association of sugar intake and colorectal adenoma, a precursor lesion to most colorectal cancer, is poorly understood, particularly in Asian populations. We undertook a cross-sectional study in a Japanese population to investigate the association between dietary sugar intake and the prevalence of colorectal adenoma. Study subjects were selected from participants who underwent magnifying colonoscopy with dye spraying as part of a cancer screening program and who responded to a self-administered questionnaire before the colonoscopy. A total of 738 cases with colorectal adenoma and 697 controls were enrolled. Dietary intakes of glucose, fructose, galactose, sucrose, maltose, lactose, and total sugars (sum of these six mono- or disaccharides) were calculated from a food frequency questionnaire, and divided into quartiles based on the distribution among controls. Odds ratios and 95% confidence intervals of colorectal adenoma were estimated using unconditional logistic regression models, with adjustment for potential confounding factors. Total sugar intake was not significantly associated with the prevalence of colorectal adenoma (odds ratio for the highest intake group compared to reference group = 1.18; 95% confidence interval, 0.81-1.73; P for trend = .34). Furthermore, no statistically significant positive associations were observed for any of the six mono- or disaccharides. Findings were similar on additional analyses by site, size, and number of adenomas. Our findings do not support an association between high sugar intake and increased odds ratios of colorectal adenoma., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background and Aims: The clinical significance of a family history (FH) of colorectal cancer (CRC) in first-degree relatives (FDRs) in CRC screening stratified by different age groups of screened individuals is not fully understood. We investigated the relationship between FH and the presence of advanced colorectal neoplasia (ACN) in screened individuals in different age groups., Methods: Data from screened individuals aged 40 to 54 years (n = 2263) and 55 to 69 years (n = 2621) who underwent their first-ever screening colonoscopy were analyzed. The relationship between FH and ACN was examined, and a multivariate logistic regression analysis incorporating other baseline characteristics was performed., Results: Among individuals aged 40 to 54 years, the prevalence of ACN was significantly higher in 249 individuals with affected FDRs than in those without (5.6% vs 1.6%; P < .01), with an adjusted odds ratio of 3.7 (95% confidence interval, 1.9-7.0; P < .01); the prevalence was particularly high in those having FDRs with CRC mortality (7.3%). Among individuals aged 55 to 69 years, the prevalence of ACN was not significantly different between 291 individuals with affected FDRs and those without (5.8% vs 5.8%; P = .95); however, individuals with 2 FDRs with CRC and mortality showed a high prevalence of ACN (17.4% and 42.9%, respectively)., Conclusions: An FH of CRC in FDRs was associated with a higher prevalence of ACN in younger individuals, with a particularly high impact of FH of CRC mortality. In contrast, the impact of FH was weaker in older individuals except those having 2 FDRs with CRC or mortality., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aim: With the increasing necessity of colorectal cancer screening, observational screening colonoscopy during which only endoscopic observation and diagnosis is performed is worth consideration. However, whether detected lesions can be correctly identified at secondary colonoscopy performed for polypectomy is unclear. Further, whether new neoplastic lesions can be detected at secondary colonoscopy has not been fully examined. This study was performed to investigate the detectability of adenomatous polyps and advanced colorectal neoplasia (ACN) at secondary colonoscopy., Methods: Data were analyzed from individuals who underwent initial observational screening colonoscopy followed by secondary colonoscopy for polypectomy. The proportion of correct detection at secondary colonoscopy of the lesions detected at initial colonoscopy was assessed. The number and characteristics of lesions that were newly detected at secondary colonoscopy were also evaluated., Results: Data of 587 individuals were assessed. Among the 1 331 lesions detected at the initial colonoscopy, 1 151 (86.5%) were properly detected at the secondary colonoscopy. The proportions of correct detection at the secondary colonoscopy for ACN, non-advanced adenomas sized 5 to 9 mm, and non-advanced adenomas sized 1 to 4 mm were 100%, 95.4%, and 70.3%, respectively. In total, 175 adenomatous polyps and ACNs were newly detected at secondary colonoscopy in 112 individuals (19.1% of all individuals). Most of the lesions (165 lesions, 94.3%) were non-advanced adenomas, while advanced adenomas (5.7%) were also found., Conclusion: Screening by observational colonoscopy followed by deferred polypectomy is a feasible option in terms of lesion detectability, particularly when lesions sized ≥ 5 mm are the treatment target., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Objectives: Allogenic hematopoietic stem cell transplantation (allo-SCT) is a curative therapy for hematological malignancies, but transplant-related mortality (TRM) remains a concern. This study aimed to determine the efficacy of capsule endoscopy (CE) by evaluating the correlation between inflammatory findings on CE and TRM., Methods: The data of patients after allo-SCT were retrospectively collected. The association between findings on CE and TRM at 100 days from the CE was evaluated., Results: Of the 94 patients included in the study, 47 showed inflammatory findings on CE. The findings were diagnosed as graft-versus-host disease (GVHD; n = 17), cytomegalovirus (CMV) infection (n = 14), and GVHD with CMV infection (n = 16). Of the 47 patients, 13 (28%) had TRM. Endoscopic diagnoses of these TRM cases were GVHD (n = 4), CMV infection (n = 0), and GVHD with CMV infection (n = 9). In contrast, in the remaining 47 patients who showed no inflammatory findings on CE, 2 patients (4%) had TRM. The proportion of TRM was higher in patients with inflammatory findings than in those without it (28 vs. 4%, p < 0.01)., Conclusions: CE may predict TRM in patients who developed gastrointestinal symptoms after allo-SCT., (© 2019 S. Karger AG, Basel.)

Background: It is unclear whether alcohol consumption may impact survival after breast cancer diagnosis. To clarify the association between pretreatment alcohol consumption and survival in breast cancer patients, a prospective patient cohort study was conducted., Methods: The cohort comprised 1,420 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. Alcohol drinking and other lifestyle factors were assessed by questionnaire survey at the initial admission. The patients were followed until December 31, 2016. The crude associations of pretreatment alcohol intake with survival were evaluated by Kaplan-Meier analysis. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) controlled by confounders., Results: During a median follow-up period of 8.6 years, 261 all-cause and 193 breast cancer-specific deaths were documented. Survival curves showed that ever-drinkers tended to have better survival than never-drinkers (breast cancer-specific survival, log-rank p = 0.0381). Better survival was also observed for light drinkers with an intake of <5.0 g per day. In the Cox model, ever-drinking was associated with a decreased risk of all-cause (HR: 0.75; 95% CI: 0.54-1.05) and breast cancer-specific death (HR: 0.68; 95% CI: 0.46-0.99). Light drinkers had a lower risk of breast cancer-specific death (frequency of drinking, HR = 0.57 for occasional or 1-2 times per week and 0.72 for 3-7 times per week; amount of alcohol consumed per day, HR = 0.57 for <5.0 g and 0.68 for ≥5.0 g compared with never-drinking). In terms of hormone receptor status, a significantly decreased risk of death associated with ever-drinking was observed among women with receptor-negative cancer (ER-/PR-, HR = 0.41; 95% CI: 0.20-0.84 for breast cancer-specific death)., Conclusions: Pretreatment, i.e., pre-diagnosis alcohol consumption is unlikely to have an adverse effect on survival after breast cancer diagnosis. Light alcohol consumption may have a beneficial effect on patient survival., Competing Interests: The authors have declared that no competing interests exist.

Background: Reproductive factors may influence breast cancer progression and patient survival; however, evidence has been limited., Methods: The associations of reproductive factors with tumor characteristics and patient survival were analyzed among 1468 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. The patients were followed until 2016. During a median follow-up period of 8.6 years, 272 all-cause and 199 breast cancer deaths were documented., Results: In case-case comparisons, later age at menarche was inversely associated with advanced tumors. Nulliparous patients tended to have receptor-positive [estrogen receptor (ER)+ or progesterone receptor (PR)+] tumors. Conversely, the Cox proportional-hazards model including adjustment for tumor characteristics revealed U-shaped relationship between parity number and the risk of all-cause death among the patients overall [hazard ratio (HR) = 2.10 for nulliparous, 1.28 for 2, and 1.50 for ≥ 3 vs. one child]. According to hormone receptor, later age at menarche and later age at last birth were positively associated with the risk of all-cause death among patients with ER- and PR- cancer (menarche, HR = 2.18 for ≥ 15 vs. ≤ 12 years, p trend  = 0.03; last birth, HR = 3.10 for ≥ 35 vs. ≤ 29 years, p trend  = 0.01). A shorter time since last birth was associated with the risk of death among receptor-positive patients (HR = 5.72 for ≤ 4 vs. ≥ 10 years, p trend  = 0.004)., Conclusion: The results indicate that the timing of menarche and parity have significant effects on patient survival, providing clues for understanding the association between women's life course and breast cancer outcome.

Objectives: Because of the increasing number of detected diminutive colorectal adenomas, the "diagnose-and-do-not-resect" approach has recently attracted attention as an alternative to resection. We evaluated the cumulative incidence of advanced colorectal neoplasia (ACN) in individuals with untreated diminutive adenomas and compared this incidence in individuals without adenomas., Methods: Data from 1,378 individuals who underwent first screening colonoscopy (CS) and at least one follow-up CS without polypectomy were analyzed. Patients with no adenomas or with only nonadvanced diminutive adenomas (<5 mm) diagnosed by magnifying image-enhanced endoscopy were scheduled to undergo a follow-up CS within 5 years after the initial CS without treatment. The participants were divided into 2 groups: those with untreated diminutive adenomas (group A) and those with no adenomas (group B). The cumulative incidence of ACN and the hazard ratio were assessed using Gray's test and the Fine and Gray model., Results: During the median follow-up period of 60.9 months, 21 ACNs were detected. The 5-year cumulative incidences of ACN in group A (n = 361) and group B (n = 1,017) were 1.4% (95% confidence interval [CI]: 0.5-3.4) and 0.8% (95% CI: 0.3-1.7), respectively, without a statistically significant difference (P = 0.23). No ACNs developed from unresected adenomas. The smoking status was significantly associated with the incidence of ACN, and the hazard ratio for ACN in group A vs group B adjusted for smoking status was 1.43 (95% CI: 0.52-3.90; P = 0.48)., Discussion: The low 5-year cumulative incidence of ACN suggests the potential to adopt the "diagnose-and-do-not-resect" strategy as an alternative option for diminutive adenomas not requiring excessive surveillance.

Background: Risk stratification of screened populations could help improve colorectal cancer (CRC) screening. Use of the modified Asia-Pacific Colorectal Screening (APCS) score has been proposed in the Asia-Pacific region. This study was performed to build a new useful scoring model for CRC screening., Methods: Data were reviewed from 5218 asymptomatic Japanese individuals who underwent their first screening colonoscopy. Multivariate logistic regression was used to investigate risk factors for advanced colorectal neoplasia (ACN), and a new scoring model for the prediction of ACN was developed based on the results. The discriminatory capability of the new model and the modified APCS score were assessed and compared. Internal validation was also performed., Results: ACN was detected in 225 participants. An 8-point scoring model for the prediction of ACN was developed using five independent risk factors for ACN (male sex, higher age, presence of two or more first-degree relatives with CRC, body mass index of > 22.5 kg/m 2 , and smoking history of > 18.5 pack-years). The prevalence of ACN was 1.6% (34/2172), 5.3% (127/2419), and 10.2% (64/627) in participants with scores of < 3, ≥ 3 to < 5, and ≥ 5, respectively. The c-statistic of the scoring model was 0.70 (95% confidence interval, 0.67-0.73) in both the development and internal validation sets, and this value was higher than that of the modified APCS score [0.68 (95% confidence interval, 0.65-0.71), P = 0.03]., Conclusions: We built a new simple scoring model for prediction of ACN in a Japanese population that could stratify the screened population into low-, moderate-, and high-risk groups.

Cigarette smoking and alcohol drinking may affect the prognosis of stomach cancer, but evidence has been inconsistent. We investigated the associations between pretreatment smoking and alcohol drinking and the risk of all-cause and stomach cancer death among 1,576 patients with histologically confirmed stomach cancer diagnosed during 1997-2010 at a single hospital in Japan. Histories of smoking and alcohol drinking were assessed using a self-administered questionnaire. The patients were followed until December 31, 2013. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 9,625.1 person-years, 670 all-cause and 419 stomach cancer deaths were documented. Among the patients overall, ever-drinking was significantly associated with an increased risk of all-cause death (HR: 1.25; 95% CI: 1.03-1.51), but not stomach cancer death. Positive linear associations with the frequency of drinking (p trend  = 0.02) and the amount of alcohol consumed per day (p trend  = 0.03) were observed for the risk of all-cause death. Ever-smoking was not related to either the risk of all-cause or stomach cancer death. Conversely, among the patients who underwent curative resection, a significant positive association was found between ever-smoking and the risk of stomach cancer death (HR: 2.44; 95% CI: 1.17-5.08). A positive association was also found for earlier age at start of smoking (p trend  = 0.0046). Pretreatment smoking and alcohol drinking have significant effects on stomach cancer survival. Lifestyle adjustments throughout life may improve survival., (© 2018 UICC.)

Here, we address the function of protein phosphatase 6 (PP6) loss on K-ras-initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen-inducible double mutant (K-ras G12D -expressing and Ppp6c-deficient) mice in which K-ras G12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly-mutant mice showed early onset tumor formation in lips, nipples, external genitalia, anus and palms, and had to be killed by 3 weeks after induction by tamoxifen, while comparably-treated K-ras G12D -expressing mice did not. H&E-staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinomas. Immunohistochemical analysis of lips of doubly-mutant vs K-ras G12D mice revealed that cell proliferation and cell size increased approximately 2-fold relative to K-ras G12D -expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K-ras G12D -only mice. Moreover, AKT phosphorylation increased in K-ras G12D -expressing/Ppp6c-deficient cells, as did phosphorylation of the downstream effectors 4EBP1, S6 and GSK3, suggesting that protein synthesis and survival signals are enhanced in lip tissues of doubly-mutant mice. Finally, increased numbers of K14-positive cells were present in the suprabasal layer of doubly-mutant mice, indicating abnormal keratinocyte differentiation, and γH2AX-positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K-ras G12D -dependent tumor promotion., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: TP53 signature has a robust predictive performance for prognosis in early-stage breast cancer, but the experiment that reported this relied on public microarray data and fresh-frozen samples. Before TP53 signature can be used in a clinical setting, a simple and low-cost diagnostic system using formalin-fixed paraffin-embedded (FFPE) samples is needed. New treatments based on the biological characteristics of TP53 signature are expected to follow., Experimental Design: TP53 signature was evaluated in 174 FFPE early breast cancer specimens using digital quantification via the nCounter technique (NanoString). Patients were classified as TP53 signature mutant type ( n = 64) or wild type ( n = 110). Predictive power of TP53 signature was compared with those of other gene expression signatures in 153 fresh-frozen samples of the same cohort by RNA-seq. The molecular features of TP53 signature were elucidated using TCGA omics data and RNA-seq data to explore new therapeutic strategies for patients with TP53 signature mutant type., Results: TP53 signature was a strong predictor of prognosis and was also more accurate than other gene expression signatures and independent of other clinicopathological factors. TCGA data analysis showed that risk score of TP53 signature was an index of chromosomal and genomic instability and that TP53 signature mutant type was associated with higher PD-L1 expression, variation in copy numbers, and numbers of somatic mutations., Conclusions: TP53 signature as diagnosed using the nCounter system is not only a robust predictor of prognosis but also a potential predictor of responsiveness to immune checkpoint inhibitors., Competing Interests: CONFLICTS OF INTEREST S.T. received grant support from Merck Serono. C.I. received grant support from Mochida, Kyowa-Kirin, Eizai, Chugai, Tsumura, Novartis, Merck- Serono, Daiichi-Sankyo, Takeda, Nihon-Kayaku, Yakult, Taiho, Ono, Astellas, Asahikasei-Parma, Kissei, Bristol. S.K. received grant support from Novartis, Chugai, Taiho, and Merck- Serono. All remaining authors have no conflicts of interest.

Genetic and epigenetic alterations are both involved in carcinogenesis, and their low-level accumulation in normal tissues constitutes cancer risk. However, their relative importance has never been examined, as measurement of low-level mutations has been difficult. Here, we measured low-level accumulations of genetic and epigenetic alterations in normal tissues with low, intermediate, and high cancer risk and analyzed their relative effects on cancer risk in the esophagus and stomach. Accumulation of genetic alterations, estimated as a frequency of rare base substitution mutations, significantly increased according to cancer risk in esophageal mucosae, but not in gastric mucosae. The mutation patterns reflected the exposure to lifestyle risk factors. In contrast, the accumulation of epigenetic alterations, measured as DNA methylation levels of marker genes, significantly increased according to cancer risk in both tissues. Patients with cancer (high-risk individuals) were precisely discriminated from healthy individuals with exposure to risk factors (intermediate-risk individuals) by a combination of alterations in the esophagus (odds ratio, 18.2; 95% confidence interval, 3.69-89.9) and by only epigenetic alterations in the stomach (odds ratio, 7.67; 95% confidence interval, 2.52-23.3). The relative importance of epigenetic alterations upon genetic alterations was 1.04 in the esophagus and 2.31 in the stomach. The differential impacts among tissues will be critically important for effective cancer prevention and precision cancer risk diagnosis., Competing Interests: Conflict of interest statement: S.Y. and T.U. made a patent application with Sysmex Corporation.

Alcohol consumption is a risk factor for breast cancer in Western countries, but few studies have evaluated the risk for Japanese women, who have a relatively low alcohol intake. This case-control study investigated the association of alcohol consumption with breast cancer risk according to estrogen-receptor and progesterone-receptor (ER/PgR) status in Japanese women. From female patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2011, 1,256 breast cancer cases (669 ER+/PgR+, 162 ER+/PgR-, 21 ER-/PgR+, 305 ER-/PgR-, and 99 missing) and 2,933 controls were selected. Alcohol-related measures were assessed using a self-administered questionnaire. Unconditional logistic regression analysis was performed. Alcohol-related measures were not associated with breast cancer risk among the women overall. Moreover, no association was observed between ever drinking and the risk of a concordant receptor subtype (ER+/PgR+ or ER-/PgR-). Conversely, ever drinking was inversely associated with the risk of discordant subtype (ER+/PgR-, odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.41-0.95; ER-/PgR+, OR = 0.44, 95% CI: 0.14-1.42). For ER+/PgR-, an inverse association with the amount of alcohol consumed per day was observed (P for trend = 0.04), and this inverse association was limited to premenopausal women. Alcohol consumption may have differential effects on concordant and discordant receptor subtypes of breast cancer. In view of the low frequency of discordant subtype in Japanese women and their relatively low alcohol intake, our findings may provide a clue for elucidating the etiology of breast cancer rather than for preventing discordant subtype.

Introduction: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.

The quantitative sensitivity and dynamic range of conventional immunohistochemistry (IHC) with 3,3'-diaminobenzidine (IHC-DAB) used in pathological diagnosis in hospitals are poor, because enzyme activity can affect the IHC-DAB chromogenic reaction. Although fluorescent IHC can effectively increase the quantitative sensitivity of conventional IHC, tissue autofluorescence interferes with the sensitivity. Here, we created new fluorescent nanoparticles called phosphor-integrated dots (PIDs). PIDs have 100-fold greater brightness and a more than 300-fold greater dynamic range than those of commercially available fluorescent nanoparticles, quantum dots, whose fluorescence intensity is comparable to tissue autofluorescence. Additionally, a newly developed image-processing method enabled the calculation of the PID particle number in the obtained image. To quantify the sensitivity of IHC using PIDs (IHC-PIDs), the IHC-PIDs method was compared with fluorescence-activated cell sorting (FACS), a method well suited for evaluating total protein amount, and the two values exhibited strong correlation (R = 0.94). We next applied IHC-PIDs to categorize the response to molecular target-based drug therapy in breast cancer patients. The results suggested that the PID particle number estimated by IHC-PIDs of breast cancer tissues obtained from biopsy before chemotherapy can provide a score for predicting the therapeutic effect of the human epidermal growth factor receptor 2-targeted drug trastuzumab.

Introduction: Given modern treatment strategies, controversy remains regarding whether postmastectomy radiation therapy (PMRT) is necessary for breast cancer patients with 1-3 positive axillary lymph nodes (ALN). Our aim was to assess the significance of PMRT in the modern treatment era for these patients., Material and Methods: We have conducted the retrospective multicenter study and identified 658 patients with 1-3 positive ALN who were treated with mastectomy and ALN dissection between 1999 and 2012. Propensity score weighting was used to minimize the influence of confounding factors between the PMRT and no-PMRT groups. The variables including tumor size, lymph nodes status, skin and/or muscle invasion, histological grade, lymphovascular invasion and ER positivity which were statistically unbalanced between the groups were used to define the propensity scores., Results: The median follow-up time was 7.3 years. In the modern era (2006-2012), no significant difference in locoregional recurrence (LRR)-free survival was noted between the PMRT and no-PMRT groups (P = 0.3625). The 8-year LRR-free survival rates of the PMRT and no-PMRT groups were 98.2% and 95.3%, respectively. After matching patients by propensity scores, the PMRT group, compared to the no-PMRT group, exhibited significantly better locoregional control (P = 0.0366) in the entire cohort. The 10-year LRR-free survival rates were 97.8% and 88.4% in the PMRT and no-PMRT groups, respectively. In contrast, no significant difference in LRR-free survival was noted between the PMRT and no-PMRT groups in the modern era (P = 0.5298). The 8-year LRR-free survival rates of patients treated in the modern era were approximately the same between the groups (98.0% and 95.7% in the PMRT and no-PMRT groups, respectively). Particularly, LRR-free survival of HER2 positive breast cancer significantly improved in the modern treatment era, compared with that of the old treatment era (P = 0.0349)., Conclusion: PMRT had minimal impact on LRR for breast cancer patients with 1-3 positive ALN in the modern treatment era., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the performance of 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) for esophageal cancer (EC) screening., Methods: We retrospectively analyzed the data of consecutive asymptomatic individuals who underwent FDG-PET and esophagogastroduodenoscopy (EGD) simultaneously for cancer screening at our institution from February 2004 to March 2013. In total, 14790 FDG-PET and EGD procedures performed for 8468 individuals were included in this study, and the performance of FDG-PET for EC screening was assessed by comparing the results of FDG-PET and EGD, considering the latter as the reference., Results: Thirty-two EC lesions were detected in 28 individuals (31 squamous cell carcinomas and 1 adenocarcinoma). The median tumor size was 12.5 mm, and the depths of the lesions were as follows: Tis ( n = 12), T1a ( n = 15), and T1b ( n = 5). Among the 14790 FDG-PET procedures, 51 examinations (0.3%) showed positive findings in the esophagus; only 1 was a true-positive finding. The screen sensitivity, specificity, positive predictive value, and negative predictive value of FDG-PET for ECs were 3.6% (95%CI: 0.1-18.3), 99.7% (95%CI: 99.6-99.7), 2.0% (95%CI: 0.0-10.4), and 99.8% (95%CI: 99.7-99.9), respectively. Of the 50 FDG-PET false-positive cases, 31 were observed in the lower esophagus, and gastroesophageal reflux disease was observed in 17 of these 31 cases., Conclusion: This study is the first to clarify the FDG-PET performance for EC screening. Based on the low screen sensitivity, FDG-PET is considered to be difficult to use as a screening modality for ECs., Competing Interests: Conflict-of-interest statement: None of the authors report a conflict of interest.