Age-related remodelling of oesophageal epithelia by mutated cancer drivers.

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

Proteinuria frequency and subsequent renal dysfunction in bevacizumab-treated patients: a single center, retrospective, observational study.

BACKGROUND: Proteinuria is a common adverse event observed during treatment with antivascular endothelial growth factor (VEGF) antibodies. Proteinuria is a risk factor for renal dysfunction and cardiovascular complications in patients with chronic kidney disease. However, the association between anti-VEGF antibody-induced proteinuria and renal dysfunction or cardiovascular complications remains unclear. METHODS: This retrospective, observational study included patients with cancer that were treated with bevacizumab (BV) at Kyoto University Hospital (Kyoto, Japan) between January 2006 and March 2018. Adverse event rates were compared between patients who developed qualitative ≥ 2 + proteinuria and those who developed < 1 + proteinuria. Adverse events were defined as renal dysfunction (i.e., ≥ 57% decrease in the eGFR, compared to the rate at the initial treatment) and hospitalization due to BV-associated cardiovascular complications and other adverse events. RESULTS: In total, 734 patients were included in this analysis. Renal dysfunction was more common in patients with ≥ 2 + proteinuria than in those with < 1 + proteinuria (13/199, 6.5% vs. 12/535, 2.3%). Seven of these 13 patients with ≥ 2 + proteinuria had transient reversible renal dysfunction. Only four (2.0%) patients had BV-associated renal dysfunction. Of the 734 patients, six patients, 16 patients, and 13 patients were hospitalized because of the adverse events of cardiovascular complications, thromboembolisms, and cerebrovascular complications, respectively. No relationship was observed between these adverse events and proteinuria. CONCLUSION: BV treatment-induced proteinuria was not associated with renal dysfunction or other adverse events. Continuing BV with caution is a possible treatment option, even after proteinuria develops, in patients with cancer and a limited prognosis.

Time course of adverse reactions following BNT162b2 vaccination in healthy and allergic disease individuals aged 5-11 years and comparison with individuals aged 12-15 years: an observational and historical cohort study.

We aimed to investigate the type and frequency of adverse events over 7 days following the first and second BNT162b2 vaccination. This observational and historical cohort study included patients aged 5-11 years who received two doses of BNT162b2 and provided consent along with their guardians. We collected data on sex, age, height, weight, blood type, history of Bacille Calmette-Guerin vaccination, allergic disease, medication, history of coronavirus disease 2019 (COVID-19), and adverse reactions 7 days following the first and second BNT162b2 vaccination using a questionnaire. Our results were compared with previously reported results for individuals aged 12-15 years. A total of 421 participants were eligible for this study. Among the 216 patients with allergic disease, 48 (22.2%) had experienced worsening of their chronic diseases, and the frequency of fatigue and dizziness after the second dose was higher than that of healthy individuals. The experience of systemic adverse reactions was associated with asthma. The frequency of headache, diarrhea, fatigue, muscle/joint pain, and fever after the second BNT162b2 vaccination was lower in individuals aged 5-11 years than in those aged 12-15 years. Fever was the only systemic adverse reaction that lasted longer than 5 days (1.0% of participants). CONCLUSIONS: Individuals with allergic diseases, who are potentially susceptible to COVID-19, may experience worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. To ensure that children with allergic diseases receive the vaccine safely, further information needs to be collected. WHAT IS KNOWN: • Adverse reactions after BNT162b2 vaccination among individuals aged 5-11 years are generally nonserious, more common after second vaccination, and substantially less common compared to those observed among individuals aged 12-15 years. WHAT IS NEW: • Individuals with allergic diseases experienced worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. • Systemic adverse reactions were associated with asthma. Fever was the only systemic adverse reaction that lasted longer than 5 days.

Challenges when going on excursions with children with medical complexity in Japan.

BACKGROUND: With advances in medical technology, the number of children with medical complexity (CMC) has increased. Excursions with such children encourage their social participation and have been shown to have a positive impact on their caregivers. However, the first-hand experience of the excursions has not yet been evaluated regarding the difficulties faced by CMC and their caregivers during preparation, transportation, and in the local area. METHODS: Semi-structured interviews were conducted with eight informal and eight formal caregivers of CMC who attended an excursion to Tokyo Disney Land (TDL) via video conference. We investigated challenges that they had experienced through the excursion, performing inductive thematic analysis. RESULTS: Three themes were identified: the preparation stage (Theme 1), problems encountered while traveling to the theme park (Theme 2), and problems at the theme park (Theme 3). In the preparation stage, three subthemes, i.e. preparation for the trip, cooperation with related parties, and researching about the theme park and asking for help, are reported. Theme 2 includes four subthemes: activities of daily living, respiratory care, luggage, and weather changes. Theme 3 has three subthemes: activities of daily living, physical condition management, and issues for the theme parks. CONCLUSIONS: We found that securing the power supply, location, and time for daily procedures are challenges in realizing excursions for CMC, but with sufficient preparation, it is possible in Japan without major difficulty.

Emotional impacts of excursions on parents of children with medical complexity.

BACKGROUND: Parents of children with medical complexity (CMC) have extra child-raising responsibilities because of the time commitments necessary for care, and their social participation is often compromised. Experiencing leisure excursions with such children may be a solution to some of these problems but the first-hand experience of excursions in regard to their psychological impact on the caregivers of CMC remains to be appraised. METHODS: Semi-structured interviews were conducted, via video conference, with eight informal and eight formal caregivers of CMC who attended an excursion to Tokyo Disney Land (TDL). We investigated the psychological changes that they had experienced through the excursion, performing inductive thematic analysis. RESULTS: Three themes were identified among parents and five were identified among medical professionals. Themes reported by the parents were: Increased trust in the public and society (Theme 1); confidence for other challenges (Theme 2), and connection with other parents in the non-medical settings (Theme 3). Themes reported by medical professionals were: Expanding the initiative to other CMC (Theme 1); feeling bonded with other caregivers within the working group (Theme 2); information exchange across different working groups (Theme 3), positive responses from CMC (Theme 4); families' confidence to go out (Theme 5). CONCLUSIONS: This study showed that the excursion to TDL led to positive psychological changes in both medical professionals and parents of CMC, enhancing trust, connection, and confidence. The promising results of this study suggest a need for further research about the impact of an excursion on caregivers of CMC.

Insights and viewpoints from a small-scale survey on current nuclear disaster preparedness measures in Japan after the Fukushima Daiichi Nuclear Power Plant accident.

In nuclear disaster prevention, it is essential not only to make daily efforts to prevent accidents from occurring but also to properly apply lessons learnt from actual disasters. Although significant changes have been made to nuclear disaster preparedness in Japan since the Fukushima Daiichi Nuclear Power Plant accident, there is insufficient information on whether these changes have been evaluated as practical and appropriate for the needs of the Japanese public. In this survey, 20 officials of the Cabinet Office and Japan Atomic Energy Agency, in charge of planning nuclear disaster prevention policy, were asked to evaluate the current nuclear disaster prevention plan through a questionnaire, and compare it with that before the accident, and indicate what elements are lacking in the current plan. The survey results revealed that 30% of the participants (six respondents) had a positive view of the enhancement of resources, including physical and human assets. However, as many as 60% (12 respondents) expressed negative sentiments, primarily due to perceived deficiencies in organisational measures, particularly the coordination of these resources. Moreover, the participants expressed keen interest in obtaining health data during evacuation, along with information on the physical and mental effects on evacuees living in evacuation centres. These crucial insights can inform the formulation of effective future preparedness plans for evacuation and radiation protection.

Decision making for anti-VEGF inhibitor continuation: dip stick? or urine protein/creatinine ratio? (VERSiON UP study).

BACKGROUND: Monitoring proteinuria is important for the management of patients with cancer treated with anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR) inhibitors (VEGF/Ri). Here we investigated the difference between the urine protein/creatinine ratio (UPCR) and a qualitative value test (QV) on the decision making of treatment continuation and the usefulness of UPCR testing in patients with gastrointestinal cancer treated with anti-VEGF/Ri. METHODS: From January 2017 to December 2018, a survey was conducted based on the medical records of patients with gastrointestinal cancer with a QV of ≥2+ during the use of anti-VEGF/Ri at seven Japanese institutions participating in the Onco-nephrology Consortium. The primary endpoint was the ratio of the worst UPCR < 2.0 (low UPCR) in cases with a QV2+ at the point of the first proteinuria onset. The secondary endpoints were a comparison of low UPCR and worst UPCR ≥2.0 (high UPCR), the concordance rate between UPCR and QV in the Common Terminology Criteria for Adverse Events (CTCAE) grading, and the differences in the decision making for anti-VEGF/Ri continuation. RESULTS: Among the 71 patients enrolled, the proportion of low UPCR in onset QV2+ (n = 53) was 66% (n = 35). In a comparison between low (n = 36) and high UPCR cases (n = 24), body weight (P = 0.036), onset QV status (P = 0.0134), and worst QV status (P < 0.0001) were significantly associated with UPCR levels. The concordance rate for CTCAE Grade 2 of both the QV and UPCR was 83%. Regarding the judgment of anti-VEGF/Ri continuation, treatment was continued in 42.4% of cases when the QV became 3+, whereas only 25% continued treatment when the UPCR value became high. CONCLUSION: Urine dipstick test results may overestimate proteinuria, and the UPCR result tended to be more critical than the QV when deciding the treatment policy. TRIAL REGISTRATION: This study is a multiple institutional retrospectively registered observational trial. CLINICAL TRIAL NUMBER: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (protocol ID UMIN000042545 ).

Clinical impact of physician staffing transition in intensive care units: a retrospective observational study.

BACKGROUND: Intensivists play an essential role in improving the outcomes of critically ill patients in intensive care units (ICUs). The transition of ICU physician staffing from low-intensity ICUs (elective intensivist or no intensivist consultation) to high-intensity ICUs (mandatory intensivist consultation or a closed ICU) improves clinical outcomes. However, whether a transition from high-intensity to low-intensity ICU staffing affects ICU outcomes and quality of care remains unknown. METHODS: A retrospective observational study was conducted to examine the impact of high- versus low-intensity staffing models on all-cause mortality in a suburban secondary community hospital with 400 general beds and 8 ICU beds. The ICU was switched from a high-intensity staffing model (high-former period) to low-intensity staffing in July 2019 (low-mid period) and then back to high-intensity staffing in March 2020 (high-latter period). Patients admitted from the emergency department, general ward, or operating room after emergency surgery were enrolled in these three periods and compared, balancing the predicted mortality and covariates of the patients. The primary outcome was all-cause mortality analyzed using hazard ratios (HRs) from Cox proportional hazards regression. An interrupted time-series analysis (ITSA) was also conducted to evaluate the effects of events (level change) and time. RESULTS: There were 962 eligible admissions, of which 251, 213, and 498 occurred in the high-former, low-mid, and high-latter periods, respectively. In the matched group (n = 600), the all-cause mortality rate comparing the high-former period with the low-mid period showed an HR of 0.88 [95% confidence interval (CI), 0.56, 1.39; p = 0.58] and that comparing the high-latter period with the low-mid period showed an HR of 0.84 [95% CI, 0.54, 1.30; p = 0.43]. The result for comparison between the three periods was p = 0.80. ITSA showed level changes of 4.05% [95% CI, -13.1, 21.2; p = 0.63] when ICU staffing changed from the high-former to the low-mid period and 1.35% [95% CI, -13.8, 16.5; p = 0.86] when ICU staffing changed from the low-mid to the high-latter period. CONCLUSION: There was no statistically significant difference in all-cause mortality among the three ICU staffing periods. This study suggests that low-intensity ICU staffing might not worsen clinical outcomes in the ICU in a medium-sized community hospital. Multiple factors, including the presence of an intensivist, other medical staff, and practical guidelines, influence the prognosis of critically ill patients.

Factors associated with inaccurate size estimation of colorectal polyps: A multicenter cross-sectional study.

BACKGROUND AND AIM: Accurate polyp size estimation is essential in deciding the therapeutic strategy of colorectal polyps and endoscopic surveillance intervals. However, many endoscopists frequently make incorrect size estimations without being aware of their errors. This cross-sectional study aimed to clarify the characteristics of endoscopists associated with inaccurate estimation. METHODS: We previously conducted a web trial involving 261 endoscopists in 51 institutions in Japan to assess their ability to estimate polyp size. Participants answered questions about polyp size using visual estimates in a test involving images of 30 polyps. Here, we investigated the relationships between inaccurate size estimation and the backgrounds of participants. The rates of overestimation and underestimation of polyp size were also compared to clarify any trends in the answers of participants with low accuracy (< 50%). RESULTS: Multivariable logistic regression analysis revealed that the number of colonoscopic procedures in the past year was the only factor associated with a low accuracy of polyp size estimation (odds ratio 0.750, 95% confidence interval 0.609-0.925; P = 0.007). Endoscopists with low accuracy had a greater tendency to overestimate polyp size (42.3% overestimation and 21.2% underestimation, P < 0.001) compared with other endoscopists (16.6% overestimation and 17.9% underestimation, P = 0.951). CONCLUSIONS: Endoscopists with limited experience of colonoscopy in the past year were more likely to make frequent errors in size estimation. Furthermore, endoscopists making inaccurate size estimations had a propensity to overestimate polyp size.

Videoconferencing for Home Care Delivery in Japan: Observational Study.

BACKGROUND: Telemedicine has been increasingly used in many health care fields, including home care, where patients receive medical care at home. Owing to the current COVID-19 crisis, the value of telemedicine via videoconferencing is more recognized, particularly in allowing immobile patients to continue receiving care. However, the efficacy of telemedicine in home care settings in Japan remains to be fully appraised. OBJECTIVE: This study aims to identify the use and impact of telemedicine in a singular home care delivery setting in Japan. METHODS: A retrospective observational study was conducted using patient and other administrative records from a home care clinic. We considered patients who were involved in videoconferencing with home care physicians and telepresenters serving patients during 2018 and 2019. We extracted sociodemographic data of the patients and details of the videoconferencing and descriptively illustrated some specific cases. RESULTS: In a home care clinic in Japan, videoconferencing was conducted in 17 cases (involving 14 patients) over a 2-year period. Of all the cases, 12% (2/17) required emergency transfers and were hospitalized. A total of 88% (15/17) of cases remained; 71% (12/17) of cases were found to need extra medication or to go to a medical facility for consultation, whereas 18% (3/17) of cases were found not to be in need of urgent attention and were asked to rest. Problematic symptoms subsequently improved in 82% (14/17) of cases, and only 6% (1/17) of cases were later hospitalized. CONCLUSIONS: Telemedicine was deemed effective for assessing patients' conditions in the home care setting in situations where home visits by a physician cannot be carried out. Our findings indicate that consultations via videoconferencing are safe and effective, suggesting more active use of videoconferencing in other clinical contexts.

Mental health of medical workers in Japan during COVID-19: Relationships with loneliness, hope and self-compassion.

The current pandemic of the coronavirus disease 2019 (COVID-19) has negatively impacted medical workers' mental health in many countries including Japan. Although research identified poor mental health of medical workers in COVID-19, protective factors for their mental health remain to be appraised. Accordingly, this study aimed to investigate relationships between mental health problems, loneliness, hope and self-compassion among Japanese medical workers, and compare with the general population. Online self-report measures regarding those four constructs were completed by 142 medical workers and 138 individuals in the general population. T-tests and multiple regression analysis were performed. Medical workers had higher levels of mental health problems and loneliness, and lower levels of hope and self-compassion than the general population. Loneliness was the strongest predictor of mental health problems in the medical workers. Findings suggest that Japanese medical workplaces may benefit from targeting workplace loneliness to prevent mental health problems among the medical staff.

The risks and characteristics of the delayed bleeding after endoscopic submucosal dissection for early gastric carcinoma in cases with anticoagulants.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early gastric carcinoma. Vitamin K antagonists and direct oral anticoagulants (DOAC) were reported to increase the risk of delayed bleeding after ESD. However, the evaluation of ESD cases taking anticoagulants is scarce. We analyzed the risk and characteristics of delayed bleeding after gastric ESD in patients on anticoagulants. METHODS: We performed a retrospective observational study at a single center. Consecutive patients who underwent ESD for early gastric carcinoma and took anticoagulants, including warfarin, rivaroxaban, dabigatran, apixaban, and edoxaban, between January 2012 and December 2018, were analyzed. We also calculated delayed bleeding rates for those without anticoagulants. RESULTS: Of 1855 eligible patients who underwent gastric ESDs, 143 took anticoagulants. Delayed bleeding occurred in 30 (21.0%) cases taking anticoagulants, with 15 (19.5%) cases in the DOAC group [rivaroxaban, seven cases (21.2%); dabigatran, four cases (20.0%); apixaban, four cases (23.5%); and edoxaban, zero cases (0%)] and 15 cases (22.7%) in the warfarin group. Furthermore, 43/344 (12.5%) patients taking antiplatelets and 76/1368 (5.6%) patients without antithrombic drugs experienced delayed bleeding. Multivariable logistic analysis revealed post-heart valve replacement (OR, 6.56; 95% CI, 1.75-24.7; p < .05) as a risk for delayed bleeding in warfarin-taking patients, while no statistically significant factor was found in DOAC-taking patients. CONCLUSIONS: Anticoagulants were associated with a high incidence of severe delayed bleeding. Careful attention should be paid to patients on anticoagulants after gastric ESD, especially those on warfarin after heart valve replacement.

Chemotherapy for patients with unresectable or metastatic small bowel adenocarcinoma: a systematic review.

BACKGROUND: There is no standard chemotherapy available for unresectable or metastatic small bowel adenocarcinoma (SBA) because of its rarity. This systematic review aims to assess the efficacy and safety of chemotherapy for patients with unresectable or metastatic SBA. METHODS: In accordance with the PRISMA statements, literature search was conducted using PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The included studies were prospective randomized, nonrandomized, or observational studies. Risk of bias was assessed the ROBINS-I tool. RESULTS: Seven prospective single-arm Phase II studies were included in this review. Six of them were assessed as having a moderate risk of bias and one as having a serious risk of bias. A meta-analysis was not performed, because the studies were single-arm. Systemic chemotherapy based on fluoropyrimidine regimens achieved favorable outcomes with acceptable adverse effects as a first therapy; however, the regimens differed in each study. The object response rate was 18-50%, and the disease control rate was 29-87%. With 5-fluorouracil, adriamycin, and mitomycin-C regimen, one treatment-related death occurred. A second line of therapy including chemotherapy with nab-paclitaxel also showed favorable efficacy. The object response rate was 20%, and the disease control rate was 50%. CONCLUSIONS: Systemic chemotherapy based on fluoropyrimidine regimens was mainly used for unresectable or metastatic SBA. While it may achieve favorable outcomes with acceptable adverse effects, further evidence is needed.

Short educational video to improve the accuracy of colorectal polyp size estimation: Multicenter prospective study.

BACKGROUND AND AIM: Accurate polyp size estimation is necessary for appropriate management of colorectal polyps. Polyp size is often determined by subjective visual estimation in clinical situations; however, it is inaccurate, especially for beginner endoscopists. We aimed to clarify the usefulness of our short training video, available on the Internet, for accurate polyp size estimation. METHODS: We conducted a multicenter prospective controlled study in Japan. After completing a pretest composed of near and far images of 30 polyps, participants received the educational video lecture (<10 min long). The educational content included the knowledge of strategies based on polyp size and criteria for size estimation including the endoscopic equipment size and videos of polyps in vivo. After one month, the participants undertook a posttest. The primary outcome was a change in the accuracy of polyp size visual estimation between the pretest and posttest in beginners. RESULTS: Participants including 111 beginners, 52 intermediates, and 97 experts from 51 institutions completed both tests. Accuracy of polyp size estimation in the beginners showed a significant increase after the video lecture [54.1% (51.3-57.0%) to 59.0% (56.5-61.5%), P = 0.003]. Multivariable logistic regression analysis showed that the category of beginners and a low score on pretest (P = 0.020 and <0.001, respectively) were the factors that contributed to an increase of ≥10% in the accuracy. CONCLUSION: Our educational video led to an improvement in polyp size estimation in beginners. Furthermore, this video may be useful for non-beginners with insufficient polyp size estimation accuracy.

Severe esophagitis associated with cytomegalovirus during concurrent chemoradiotherapy for esophageal cancer.

Although radiation esophagitis is one of the most common adverse events that occurs during chemoradiotherapy (CRT) in patients with esophageal cancer, CRT-associated cytomegalovirus (CMV) esophagitis is rare. CMV esophagitis typically occurs in patients with an immunosuppressed status. Here we report a case of CMV esophagitis during CRT initially treated as radiation esophagitis. A 64-year-old man with mid-thoracic esophageal cancer was admitted to our hospital with clinical stage cT4bN1M1 (supraclavicular lymph node metastasis) Stage IV according to the UICC ver. 7 guidelines, and he was administered definitive concurrent CRT. From the 39th day of CRT onwards, he presented with a sustained fever and severe odynophagia that was resistant to antibiotic therapy. An esophagoscopy revealed severe esophagitis with a circumferential ulcer throughout the entire esophagus, and CMV esophagitis was clinically suspected because of positive result of CMV antigenemia. Subsequently, antiviral therapy for CMV provided dramatic relief of his symptoms. Later, CMV DNA was confirmed with a polymerase chain reaction in the biopsy specimen.The symptoms of CMV esophagitis resemble those of radiation esophagitis and can make the diagnosis difficult. Thus, CMV esophagitis associated CRT may be overlooked or masked by radiation esophagitis and can cause a delay in healing. Therefore, CMV esophagitis may be considered when severe intractable esophagitis is observed during CRT.

Association between UGT1A1*28*28 genotype and lung cancer in the Japanese population.

BACKGROUND: Lung cancer is the leading cause of cancer death and is closely linked to tobacco smoking. Genetic polymorphisms in genes that encode enzymes involved in metabolizing tobacco carcinogens could affect an individual's risk for lung cancer. While polymorphism of UDP-glucuronosyltransferase1A1 (UGT1A1) is involved in detoxification of benzo(a)pyrene-7,8-dihydrodiol(-), a major tobacco carcinogen, the association between UGT1A1 genotype and lung cancer has not been examined. METHODS: We retrieved the clinical data of 5,285 patients who underwent systemic chemotherapy at Kyoto University Hospital. A total of 765 patients (194 lung cancer patients and 671 patients with other malignancies) with UGT1A1 genotyping data were included in this analysis. We used logistic regression with recessive, dominant, and additive models to identify differences in genotype frequencies between lung cancer and other malignancies. RESULTS: In the recessive model, UGT1A1*28*28 genotype was significantly associated with lung cancer compared to other malignancies (odds ratio 5.3, P = 0.0083). Among lung cancer patients with a smoking history, squamous cell carcinoma was significantly predominant in patients with UGT1A1*28*28 compared to those with other UGT1A1 genotypes (P = 0.024). CONCLUSION: This is the first study to demonstrate a significant association between the homozygous UGT1A1*28 genotype and lung cancer.