Height, body mass index, physical activity, and risk of colorectal cancer in relation to expression of insulin receptor: The Japan Public Health Center-based Prospective Study.

To ascertain the involvement of insulin receptors (IRs) in colorectal carcinogenesis, we investigated the association of height, body mass index (BMI), and physical activity with colorectal cancer (CRC) and two subtypes of CRC according to the expression level of IR. We utilized data from a large-scale, population-based prospective cohort study of 18,158 middle-aged and elderly subjects in Akita and Okinawa, Japan. In the statistical analysis, we used the Cox proportional hazards model and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subtypes as defined by immunohistochemistry of IRß, a transmembrane subunit of IR. In the IRß-defined subtypes, height showed no apparent association with the risk of IRß-positive CRC. In contrast, a multivariable HR of IRß-positive CRC was 1.77 (95% CI = 1.04-3.03) with a BMI of ≥30.0 kg/m2 (i.e., obesity), compared to a BMI of <25.0 kg/m2. Further, an increase in physical activity was significantly associated with decreased risk of IRß-positive CRC (multivariable HR per 5 METs-hour/day = 0.93, 95% CI = 0.88-0.99). Meanwhile, we found no significant association between any exposure and IRß-negative CRC. Likewise, heterogeneity between the two subtypes of CRC was not statistically significant. These findings imply that obesity and physical activity exert promoting and suppressing effects on the development of CRC expressing IRs, respectively.

A Novel Dry Simulator Model for Learning Comprehensive Endoscopic Retrograde Cholangiopancreatography/Endoscopic Sphincterotomy Procedures while Minimizing Adverse Bleeding Events (with Video).

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) are essential skills for performing endoscopic cholangiopancreatic procedures. However, these procedures have a high incidence of adverse events, and current training predominantly relies on patient-based approaches. Herein, we aimed to develop an ERCP/EST simulator model to address the need for safer training alternatives, especially for learners with limited ERCP experience. METHODS: The model was designed to facilitate the use of actual endoscopic devices, supporting learning objectives that align with the components of the validated Bethesda ERCP Skill Assessment Tool (BESAT). BESAT focuses on skills, such as papillary alignment, maintenance of duodenoscope position, gentle and efficient cannulation, controlled sphincterotomy in the correct trajectory, and guidewire manipulation. Thirty gastroenterology trainees used the simulator between May 2022 and March 2023, and their satisfaction was assessed using a visual analog scale (VAS) and pre- and post-training questionnaires. RESULTS: The novel simulator model comprised a disposable duodenal papillary section, suitable for incision with an electrosurgical knife, alongside washable upper gastrointestinal tract and bile duct sections for repeated use. The duodenal papillary section enabled reproduction of a realistic endoscope position and the adverse bleeding events due to improper incisions. The bile duct section allowed for the reproduction of fluoroscopic-like images, enabling learners to practice guidewire guidance and insertion of other devices. Following training, the median VAS score reflecting the expectation for model learning significantly increased from 69.5 (interquartile range [IQR]: 55.5-76.5) to 85.5 (IQR: 78.0-92.0) (p < 0.01). All participants expressed a desire for repeated simulator training sessions. CONCLUSIONS: This innovative simulator could serve as a practical educational tool, particularly beneficial for novices in ERCP. It could facilitate hands-on practice with actual devices, enhancing procedural fluency and understanding of precise incisions to minimize the risk of bleeding complications during EST.

Assessment of anthracycline-induced cardiotoxicity in childhood cancer survivors during long-term follow-up using strain analysis and intraventricular pressure gradient measurements.

BACKGROUND: Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in childhood cancer survivors (CCS), and the cumulative incidence of cardiac events has continued to increase. This study identifies an adequate indicator of cardiac dysfunction during long-term follow-up. PROCEDURE: In total, 116 patients (median age: 15.5 [range: 4.7-40.2] years) with childhood cancer who were treated with anthracycline were divided into three age groups for analysis (C1: 4-12 years of age, C2: 13-18 years of age, C3: 19-40 years of age), and 116 control patients of similar ages were divided into three corresponding groups (N1, N2, and N3). Layer-specific strains were assessed for longitudinal strain (LS) and circumferential strain (CS). The total and segmental intraventricular pressure gradients (IVPG) were also calculated based on Doppler imaging of the mitral inflow using Euler's equation. RESULTS: Conventional echocardiographic parameters were not significantly different between the patients and controls. All layers of the LS and inner and middle layers of the basal and papillary CS in all ages and all IVPGs in C2 and C3 decreased compared to those of corresponding age groups. Interestingly, basal CS and basal IVPG in CCS showed moderate correlation and both tended to rapidly decrease with aging. Furthermore, basal IVPG and anthracycline dose showed significant correlations. CONCLUSIONS: Basal CS and total and basal IVPGs may be particularly useful indicators of cardiotoxicity in long-term follow-up.

Is blue light imaging without magnification satisfactory as screening for esophageal squamous cell carcinoma? Post-hoc analysis of multicenter randomized controlled trial.

OBJECTIVES: Narrow light observation is currently recommended as an alternative to Lugol chromoendoscopy (LCE) to detect esophageal squamous cell carcinoma (ESCC). Studies revealed little difference in sensitivity between the two modalities in expert settings; however, these included small numbers of cases. We aimed to determine whether blue light imaging (BLI) without magnification is satisfactory for preventing misses of ESCC. METHODS: This was a post-hoc analysis of a multicenter randomized controlled trial targeting patients at high risk of ESCC in expert settings. In this study, BLI without magnification followed by LCE was performed. The evaluation parameters included: (i) the diagnostic abilities of ESCC; (ii) the endoscopic characteristics of lesions with diagnostic differences between the two modalities; and (iii) the color difference between cancerous and noncancerous areas in BLI and LCE. RESULTS: This study identified ESCC in 49 of 699 cases. Of these cases, nine (18.4%) were missed by BLI but detected by LCE. In per-patient analysis, the sensitivity of BLI was lower than that of LCE following BLI (83.7% vs. 100.0%; P = 0.013), whereas the specificity and accuracy of BLI were higher (88.2% vs. 81.2%; P < 0.001 and 87.8% vs. 82.5%; P < 0.001, respectively). No significant endoscopic characteristics were identified, but the color difference was lower in BLI than in LCE (21.4 vs. 25.1; P = 0.003). CONCLUSION: LCE following BLI outperformed BLI in terms of sensitivity in patients with high-risk ESCC. Therefore, LCE, in addition to BLI, would still be required in screening esophagogastroduodenoscopy even by expert endoscopists.

Smoking and risk of colorectal cancer according to KRAS and BRAF mutation status in a Japanese prospective Study.

Although smoking is a major modifiable risk factor for many types of cancer, evidence for colorectal cancer is equivocal in Asian populations. Recent Western studies have proposed that the association between smoking and colorectal cancer is restricted to specific tumor molecular subtypes. However, no studies have evaluated the association according to tumor molecular subtypes in Asian populations. In a Japanese prospective population-based cohort study of 18 773 participants, we collected tumor tissues from incident colorectal cancer cases and evaluated KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B) mutation status using target sequencing. Multivariable-adjusted Cox proportional hazard model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of smoking with the risk of overall colorectal cancer and its subtypes defined by KRAS and BRAF mutation status. Among 339 cases, KRAS and BRAF mutations were identified in 164 (48.4%) and 16 (4.7%) cases, respectively. The multivariable-adjusted HR for ever smoking compared with never smoking was 1.24 [95% CI: 0.93-1.66], 1.75 [1.14-2.68], 0.87 [0.59-1.29], 1.24 [0.93-1.67] and 1.22 [0.38-3.93] for overall, KRAS wild-type, KRAS-mutated, BRAF wild-type and BRAF-mutated colorectal cancer, respectively. The statistically significant heterogeneity was indicated between KRAS mutation status (Pheterogeneity = 0.01) but not between BRAF mutation status. This study is the first to demonstrate that smokers have an approximately 2-fold higher risk of KRAS wild-type colorectal cancer than never smokers in an Asian population. Our findings support that smoking is a risk factor for colorectal cancer, especially for its subtype without KRAS mutations, in Asian populations.

Blue light imaging and linked color imaging as a screening mode for esophageal squamous cell carcinoma in high-risk patients: Multicenter randomized trial.

OBJECTIVES: Blue light imaging (BLI) and linked color imaging (LCI) are superior to conventional white light imaging for detecting esophageal squamous cell carcinoma (ESCC). Hence, we compared their diagnostic performances in ESCC screening. METHODS: This open-labeled, randomized controlled trial was performed at seven hospitals. Patients with a high risk of ESCC were randomly assigned to the BLI group (BLI followed by LCI) and LCI group (LCI followed by BLI). The primary end-point was the detection rate of ESCC in the primary mode. The main secondary end-point was its miss rate in the primary mode. RESULTS: In total, 699 patients were enrolled. The detection rate of ESCC did not significantly differ between the BLI and LCI groups (4.0% [14/351] vs. 4.9% [17/348]; P = 0.565); however, the number of patients with ESCC tended to be smaller in the BLI group (19 vs. 30). Notably, the miss rate of ESCC was lower in the BLI group (26.3% [5/19] vs. 63.3% [19/30]; P = 0.012) and LCI detected no ESCCs missed by BLI. The sensitivity was higher in BLI (75.0% vs. 47.6%; P = 0.042); on the other hand, the positive predictive value in BLI tended to be lower (28.8% vs. 45.5%; P = 0.092). CONCLUSIONS: The detection rates of ESCC did not significantly differ between BLI and LCI. Although BLI may have the potential to be advantageous over LCI for the diagnosis of ESCC, it is still unclear whether BLI is superior to LCI, and a further large-scale study is needed. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT1022190018-1).

Pharmacological Activation of YAP/TAZ by Targeting LATS1/2 Enhances Periodontal Tissue Regeneration in a Murine Model.

Due to their multi-differentiation potential, periodontal ligament fibroblasts (PDLF) play pivotal roles in periodontal tissue regeneration in vivo. Several in vitro studies have suggested that PDLFs can transmit mechanical stress into favorable basic cellular functions. However, the application of mechanical force for periodontal regeneration therapy is not expected to exhibit an effective prognosis since mechanical forces, such as traumatic occlusion, also exacerbate periodontal tissue degeneration and loss. Herein, we established a standardized murine periodontal regeneration model and evaluated the regeneration process associated with cementum remodeling. By administering a kinase inhibitor of YAP/TAZ suppressor molecules, such as large tumor suppressor homolog 1/2 (LATS1/2), we found that the activation of YAP/TAZ, a key downstream effector of mechanical signals, accelerated periodontal tissue regeneration due to the activation of PDLF cell proliferation. Mechanistically, among six kinds of MAP4Ks previously reported as upstream kinases that suppressed YAP/TAZ transcriptional activity through LATS1/2 in various types of cells, MAP4K4 was identified as the predominant MAP4K in PDLF and contributed to cell proliferation and differentiation depending on its kinase activity. Ultimately, pharmacological activation of YAP/TAZ by inhibiting upstream inhibitory kinase in PDLFs is a valuable strategy for improving the clinical outcomes of periodontal regeneration therapies.

Salivary leukocyte esterase activity by SillHa is a risk indicator of periodontal disease.

BACKGROUND: There is increasing evidence that diagnostic salivary tests measuring inflammatory biomarkers are being developed to assess inflammatory status for early detection, prevention, and progression of periodontal disease. Therefore, the aim of the present study was to investigate and identify the salivary biomarker that can predict the inflammatory status of periodontal disease. METHODS: A total of 36 patients (28 women and 8 men) with an average age of 57 years were investigated. Unstimulated saliva was collected from the recruited subjects and analyzed using SillHa, a saliva-testing device that measures bacteria count, saliva buffer capacity, acidity, leukocyte esterase, protein, and ammonia. Periodontal parameters were then obtained by clinical examination and initial periodontal therapy was performed. Data obtained with SillHa were compared with clinical periodontal parameters at baseline, re-examination (three months from baseline), and final examination (six months from re-examination). RESULTS: Leukocyte esterase activity in saliva measured by SillHa; BOP and PCR measured by clinical examination showed a significant difference between baseline and final examination and between re-examination and final examination. Patients in the lower median group (group 1) had a significant difference in leukocyte esterase activity between baseline and final examination and re-examination and final examination. In addition, patients in Group 1 had significantly lower BOP between baseline and final examination. While patients in the higher median group (group 2) showed a modest decrease in leukocyte esterase activity, which was significant only between baseline and final examination, no significant changes were observed concerning BOP. Furthermore, the associated systemic disease was observed in 30% and 81.2% of group 1 and 2 patients, respectively. CONCLUSION: The results suggest that leukocyte esterase activity in saliva measured by SillHa could serve as a reliable diagnostic marker for monitoring inflammatory status in periodontal disease.

Japanese Laws and the Current Status of Regenerative Medicine in the Tohoku Region.

AIM: The aim of this study was to review Japanese laws regarding regenerative medicine and the current status of clinical application of regenerative medicine, to learn about the advantages and problems, and to thereby serve as a reference for measures necessary for the development of regenerative medicine. BACKGROUND: Regenerative medicine started in 1957 with the transplantation of hematopoietic stem cells, followed by the establishment of embryonic stem cells in 1981 and induced pluripotent stem cells in 2006, and continues to evolve progressively. At the same time, however, problems have emerged due to lax legal regulations, such as the use of treatments that lack scientific evidence. REVIEW RESULTS: The Japanese government enacted two laws to regulate regenerative medicine: the Law to Ensure the Safety of Regenerative Medicine and the Amend the Pharmaceutical Affairs Law in 2013. These laws were enacted with the aim of providing safe regenerative medicine promptly and smoothly and developing many regenerative medicine products. In these laws, regenerative medicine is defined as medical treatment that restores lost functions of damaged organs and tissues with the help of cellular and tissue-based products. Nowadays, there are two major methods of regenerative medicine. One representative method involves the transplantation of devices that activates self-regenerative ability by introducing living cells into patients' body. The other method is the activation and differentiation of endogenous stem cells with cell growth and differentiation factors. CONCLUSION: The current status of regenerative medicine in the Tohoku region after the enactment of these laws is described in detail. This clarified the advantages and disadvantages associated with regenerative medicine as it is currently practiced in Japan. CLINICAL SIGNIFICANCE: Development of regenerative medicine in dentistry will be advanced by learning about its clinical application in medicine.

Nitric oxide could promote development of Barrett's esophagus by S-nitrosylation-induced inhibition of Rho-ROCK signaling in esophageal fibroblasts.

Barrett's esophagus arises in the process of wound healing in distal esophageal epithelium damaged by gastroesophageal reflux disease. Differentiation of fibroblast into myofibroblasts, a smooth muscle cell-like phenotype and tissue contraction are crucial processes in wound healing. No study has evaluated mechanism by which luminal esophageal nitric oxide (NO) affect Rho-associated coiled coil-forming protein kinase (Rho-ROCK) signaling pathway, a key factor of tissue contraction, in stromal fibroblasts to develop Barrett's esophagus. Using esophageal fibroblasts, we performed collagen-based cell contraction assays and evaluated influence of Rho-ROCK signaling in the exposure to acidic bile salts and NOC-9, which is an NO donor. We found that enhanced cell contraction induced by acidic bile salts was inhibited by NO, accompanied by decrease in phosphorylated myosin light chain expression and stress fiber formation. NO directly S-nitrosylated GTP-RhoA and consequently blocked Rho-ROCK signaling. Moreover, exposure to NO and Y27632, a Rho-ROCK signaling inhibitor, decreased α-SMA expression and increased bone morphogenetic protein-4 (BMP4) expression and secretion. These findings could account for the increased expression of BMP4 in the columnar epithelial cells and stromal fibroblasts in human Barrett's esophagus. NO could impair wound contraction by blocking the Rho-ROCK signaling pathway and promote the development of Barrett's esophagus.NEW & NOTEWORTHY Barrett's esophagus is the condition where esophageal epithelium damaged by gastroesophageal reflux disease (GERD) is abnormally healed via replacing of metaplastic columnar epithelium, but very few studies have conducted focusing wound healing in the development of Barrett's esophagus. Esophageal luminal nitric oxide inhibits Rho-ROCK signaling pathway in esophageal fibroblasts, which leads to delay tissue contraction, a pivotal step in proper wound healing. Moreover, this inhibition increases tissue BMP4 expression. Impaired wound healing could be related to Barrett's esophagus.

Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma.

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

Predictors of early and late mortality after the treatment for early gastric cancers.

OBJECTIVES: Although many patients with early gastric cancers (EGCs) die of non-gastric cancer-related causes, the association of the risk categories of lymph node metastasis (LNM) with all-cause mortality remains unclear. We aimed to clarify the predictors of early and late mortality, separately. METHODS: Patients with endoscopic resection or gastrectomy for EGCs between 2003 and 2017 were retrospectively enrolled. We analyzed predictors for early and late mortality, including risk categories of LNM, treatment method, and nine non-cancer-related indices, separately, with a cut-off value of 3 years. RESULTS: We enrolled 1439 patients with a median follow-up period of 79 months. The 5-year overall survival rate was 86.8%. In the multivariate Cox analysis, the most important predictors for early and late mortality were age ≥85 years (hazard ratio [HR] 2.88 and 4.54, respectively) and Eastern Cooperative Oncology Group Performance Status ≥2 (HR 3.00 and 4.19, respectively). Charlson comorbidity index ≥2 (HR 2.76 and 1.99, respectively), American Society of Anesthesiologists Physical Status ≥3 (HR 2.35 and 1.79, respectively), and C-reactive protein/albumin ratio ≥0.028 (HR 2.30 and 1.58, respectively) were also predictors for both early and late mortality. Male (HR 2.26), intermediate- (HR 2.12)/high-risk (HR 1.85) of LNM in eCura system, and sarcopenia evaluated by the psoas muscle mass index (HR 1.70) were predictors for early mortality. CONCLUSION: The combined assessment of multiple predictors might help to predict early and/or late mortality in patients with EGCs. The eCura system was associated with early mortality.

A case series describing the risk of periodontal disease in Marfan syndrome patients harboring a possible aortic aneurysm or dissection.

BACKGROUND: Marfan syndrome (MFS) is a systemic disorder of connective tissues caused by insufficient elastic fiber formation that leads to structural weakness and results in various tissue disorders, including cardiovascular and periodontal disease. Notably however, the risk of periodontal disease in MFS patients affected by an aortic aneurysm or dissection has not yet been clarified. METHODS: We investigated the periodontal condition in the following three groups: MFS patients diagnosed with an aortic aneurysm or dissection with a planned aortic surgery (MFS surgery), MFS patients who had already undergone aortic surgery (MFS post-surgery) and healthy control patients (Healthy). The periodontal condition of all of these patients was evaluated at their first visit, reassessed again at two-month after the first visit, and evaluated again at a six-month follow-up after the reassessment. RESULTS: A total of 14 participants, 3 MFS surgery patients, 4 MFS post-surgery patients and 7 healthy control volunteers were examined. Saliva examinations revealed no significant differences between any of the groups at the first visit, reassessment, or follow-up. Interestingly, the MFS surgery cases showed a higher BOP and PISA at the first visit and follow-up compared with the other groups. In contrast, the MFS surgery patients showed an improvement in their LVDd and EF values, both markers of cardiac function, at the reassessment and follow-up compared with the first visit. CONCLUSIONS: MFS associated with an aortic aneurysm or dissection leads to a higher risk of periodontal disease, indicating the need for more frequent oral hygiene maintenance in these patients. In addition, MFS patients who undergo frequent professional cleaning of their teeth show a lower onset of cardiovascular disease, suggesting that professional oral hygiene in these cases contributes to a healthier condition.

Visceral obesity is associated with an increased risk of developing esophago-gastric junctional adenocarcinoma in Japan: a population-based case-control study in Akita Prefecture.

BACKGROUND: While an association between esophago-gastric junctional adenocarcinomas (EGJACs) and obesity, especially visceral obesity, has been suggested in Western countries, the association remains unclear in Asia, including Japan. In this population-based case-control study, we investigated the association between EGJACs and obesity. METHODS: To perform near-population-based data collection for all early-stage EGJACs occurring in Akita Prefecture from 2014 to 2019, clinical data, including endoscopic and computed tomography (CT) findings, were collected from 11 cancer treatment base hospitals in the area. Age- and gender-matched controls were extracted at a case-to-control ratio of 1:2 from healthy subjects who received health checkups in the same area. The visceral fat area (VFA) was calculated using CT images. Logistic regression analyses were performed to investigate the associations between EGJACs and obesity-related parameters. RESULTS: In total, 74 EGJAC cases (62 males, median age of 70 years old) and 148 controls were extracted. Multivariable analyses showed a significantly negative association between the BMI and EGJACs and a significantly positive association between the VFA and EGJACs with odds ratios (ORs) (95% confidence intervals [CIs]) of 0.65 (0.53-0.80) and 1.01 (1.01-1.02), respectively. These findings were confirmed in another dataset (40 EGJACs and 80 controls). In addition, as a categorical variable, VFA ≥ 100 cm2 showed a significantly positive association with EGJACs (OR [95% CI] 1.96 [1.02-3.76]). CONCLUSIONS: We found paradoxical associations between EGJACs and obesity-related parameters (BMI vs. VFA) in a Japanese population, suggesting a potentially pivotal role of the VFA rather than the BMI as a risk factor for EGJACs.

The Ameliorating Effect of Switching to Vonoprazan: A Novel Potassium-Competitive Acid Blocker in Patients with Proton Pump Inhibitor Refractory Non-Erosive Reflux Disease.

INTRODUCTION: Weakly acidic reflux has been reported to be the major cause of symptoms in patients with proton pump inhibitor (PPI)-refractory nonerosive reflux disease (NERD) undergoing PPI treatment. We previously reported that reflux at pH 4-5 was the main factor that induced symptoms in such patients. The present study aimed to elucidate the symptom-ameliorating effect of vonoprazan (VPZ) by evaluating the change in the pH value of the refluxate using multichannel intraluminal impedance and pH (MII-pH) monitoring. METHODS: We retrospectively evaluated the records of MII-pH monitoring in 29 symptom index (SI) and/or symptom association probability (SAP)-positive patients with PPI-refractory NERD. After switching to VPZ 20 mg/day, we performed MII-pH monitoring again. We assessed the change in the score of the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), the pH value of the refluxate, and the percent times of intragastric pH <4 or <5 before and after switching. We divided the patients into the following 2 groups according to the FSSG score after switching: effective and noneffective groups. RESULTS: Among of the 29 SI/SAP-positive patients, 16 underwent switching to VPZ. Furthermore, of these 16 patients, 10 underwent MII-pH monitoring again after switching. The FSSG score decreased, the pH value of the refluxate increased, and the percent times of intragastric pH <4 or <5 reduced after switching when compared with the findings before switching. In the effective group, both the proportion of reflux at pH <4 and that of reflux at pH 4-5 decreased while taking VPZ when compared with the findings while taking double-dose PPI. In the noneffective group, the proportion of reflux at pH <4 decreased but that of reflux at pH 4-5 increased and that of reflux at pH <5 did not change overall while taking VPZ. In addition, the percent times of intragastric pH <5 values were low in the effective group. CONCLUSION: Symptom suppression appears to be inadequate in patients with persistent reflux at pH 4-5 even with VPZ 20 mg/day. Strong acid suppressive therapy with VPZ to increase the pH value of the refluxate to ≥5 is useful for symptom improvement.

Morphological and Morphometrical Analyses of Fracture-Healing Sites of an Atypical Femoral Fracture in Patients with and without Long-Term Bisphosphonate Treatment for Osteoporosis: A Report of Two Cases.

Bisphosphonates have been the first drug of choice for osteoporosis in the recent years because of their known ability to suppress osteoclast activity. The adverse effect of long-term bisphosphonate administration in the fracture-healing process is controversial. The aim of our study was to observe not only morphology but also morphometry of the fracture site of atypical femoral fracture with and without long-term bisphosphonate administration, in a case study of two difficult-to-obtain human samples. The patients with insufficient healing of atypical femoral fracture were treated with valgus wedge osteotomy. Histomorphometrical analysis was performed in bone samples of fracture sites harvested during osteotomy. The thickness of the femoral cortex was measured in the fracture site and the adjacent, non-fracture site. A comparative analysis of the content of hypertrophic osteoclasts in fracture sites, shape and size of osteons, mass, and ratio of the woven bone to the total bone mass was performed, comparing bisphosphonate-treated and untreated samples. In bisphosphonate-treated samples, we observed femoral cortex thickening at the fracture site; the appearance of hypertrophic osteoclasts; decreased bone resorption surface, decreased osteoclast numbers on the bone resorption surface, and increased ratio of multinuclear osteoclasts; osteons were misshapen and thin; and the mass and ratio of the woven bone to the total bone mass were higher. This study demonstrated that long-term bisphosphonate administration can alter the morphological features of the fracture site compared to its physiological state.

Predictors of Early and Late Mortality after Endoscopic Resection for Esophageal Squamous Cell Carcinoma.

In esophageal squamous cell carcinoma (ESCC) comprising 90% of cases with esophageal cancer, endoscopic resection (ER) is recommended for patients with negligible risk of ESCC-related mortality. In fact, a main cause of death in patients underwent ER is not ESCC. We thus aimed to clarify the predictors for early and late mortality among patients underwent ER of ESCC between 2005 and 2018 at our institution. In this retrospective cohort study, we investigated the prognosis and predictors of early and late mortality with the cut-off value of 3 years. We enrolled 407 patients with a median 69 months follow-up. The 5-year overall survival and disease-specific survival, an indicator of ESCC-related mortality, were 83.4% and 98.4%, respectively. In multivariate Cox analyses, Eastern Cooperative Oncology Group performance status (ECOG-PS), consisting of six grades by a patient's level of activity, ≥ 2 was a predictor for early and late morality [hazard ratio (HR), 7.21 (P = 0.007) and 15.62 (P = 0.021), respectively]. Charlson comorbidity index (CCI), which is an index for predicting mortality by comorbid conditions, ≥ 2 was also a predictor for both mortality [HR, 2.97 (P = 0.017) and 1.90 (P = 0.019), respectively]. However, age was a predictor only for late mortality [HR, 3.08 (P = 0.010) in 80-84 years and 8.38 (P < 0.001) in ≥ 85 years]. Considering the predictive ability for early mortality, we propose that ECOG-PS and/or CCI are better indices compared with age in deciding treatment strategy after ER for ESCC.

Long-term endoscopic surveillance for Barrett's esophagus in Japan: Multicenter prospective cohort study.

OBJECTS: Although a recent study showed the cancer incidence of Barrett's esophagus (BE) to be 1.2%/year in 251 patient-years in Japan, the long-term outcomes remain unclear. The present study estimated the cancer risk of BE in Japan using our original prospective multicenter cohort. METHODS: A total of 98 patients with BE of maximum length of ≥2 cm were enrolled during the period of 2010-2012 and received at least one follow-up endoscopy over 5 years thereafter. Cancer incidence rates with 95% confidence interval for occurrence of esophageal adenocarcinoma (EAC) were calculated as the number of events divided by patient-years of follow-up and were expressed as %/year. RESULTS: Overall, the median endoscopic follow-up period was 59.9 (first and third quartiles, 48.5-60.8) months, constituting a total of 427 patient-years of observation. Since two EAC cases developed, the cancer incidence was 0.47% (0.01%-1.81%)/year. The cancer incidence was 0.39% (-0.16% to 2.44%) in 232 patient-years and 0.31% (-0.13% to 1.95%)/year in 318 patient-years for 55 cases with specialized intestinal metaplasia and 70 with BE ≥3 cm (maximum), respectively. At the end of follow-up, 12 of 92 patients (13.0%) died, but none died from EAC. CONCLUSION: This is the largest prospective follow-up study with endoscopy to investigate the incidence of EAC in unequivocal BE with the maximum length of ≥2 cm in Japan. Although a further large-scale study will be required to validate our results, the cancer risk of BE in Japan would be lower than previously reported (0.47% vs 1.2%/year).

PPARγ-Induced Global H3K27 Acetylation Maintains Osteo/Cementogenic Abilities of Periodontal Ligament Fibroblasts.

The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ.

An experimental intraradicular biofilm model in the pig for evaluating irrigation techniques.

BACKGROUND: We established an in vivo intraradicular biofilm model of apical periodontitis in pigs in which we compared the efficacy of different irrigant activation techniques for biofilm removal. METHODS: Twenty roots from the deciduous mandibular second premolar of 5 male pigs were used. After pulpectomy, canals were left open for 2 weeks and then sealed for 4 weeks to enable the development of an intracanal biofilm. The intraradicular biofilms was evaluated using SEM and bacterial 16S rRNA gene-sequencing. To investigate the efficacy of biofilm removal, root canal irrigations were performed using conventional needle, passive ultrasonic, subsonic, or laser-activated irrigation. Real-time PCR was conducted to quantitate the remaining biofilm components. Statistical analysis was performed using ANOVA followed by a Tukey kramer post-hoc test with α = 0.05. RESULTS: The pulp exposure model was effective in inducing apical periodontitis and SEM analysis revealed a multi-layer biofilm formation inside the root canal. 16S rRNA sequence analysis identified Firmicutes, Bacteroidetes, and Fusobacteria as the predominant bacterial phyla components, which is similar to the microbiome profile seen in humans. None of the tested irrigation techniques completely eradicated the biofilm components from the root canal, but the subsonic and laser-activated irrigation methods produced the lowest bacterial counts (p < 0.05). CONCLUSIONS: An experimental intraradicular biofilm model has been successfully established in pigs. Within the limitations of the study, subsonic or laser-activated irrigation demonstrated the best biofilm removal results in the pig system.