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Background and Aims: Evidence for endoscopic resection (ER) in elderly patients with early gastric cancer (EGC) is limited. We assessed its clinical outcomes and explored new indications and curability criteria., Methods: We analyzed data from a Japanese multicenter, prospective cohort study. Patients aged ≥75 years with EGC treated with ER were included. We classified eCuraC-2 (corresponding to noncurative ER, defined in the Japanese gastric cancer treatment guidelines) into elderly-high (>10% estimated metastatic risk) and elderly-low (EL-L) (≤10% estimated metastatic risk)., Results: In total, 3371 patients with 3821 EGCs were included; endoscopic submucosal dissection was the prominent treatment choice. Among them, 3586 lesions met the guidelines' ER indications, and 235 did not. The proportions of en bloc and R0 resections and perforations were 98.9%, 94.4%, and 0.8%, respectively, in EGCs within the indications. In EGCs beyond the indications, they were 99.5%, 85.4%, and 5.9%, respectively, for lesions diagnosed as ≤3 cm and 96.0%, 64.0%, and 18.0%, respectively, for those >3 cm. Curative ER and EL-L were observed in 83.6% and 6.2% of lesions within the indications, respectively, and in 44.2% and 16.8% of lesions <3 cm beyond the indications, respectively. The 5-year cumulative gastric cancer death rates after curative ER and elderly-high were 0.3% (95% confidence interval [CI], 0.2-0.6) and 3.5% (95% CI, 2.0-5.7), respectively. After EL-L, the rate was 0.9% (95% CI, 0.2-3.5) even without subsequent treatment., Conclusions: The usefulness of endoscopic submucosal dissection for elderly EGC patients was confirmed by their clinical outcomes. Lesions of ≤3 cm and EL-L emerged as new ER indication and curability criteria, respectively. (Clinical trial registration number: UMIN000005871.)., Competing Interests: Disclosure All authors disclosed no financial relationships. This study was supported by a grant for Clinical Cancer Research from the Japanese Ministry of Health, Labor, and Welfare (H21-022); a grant from Daiwa Securities Health Foundation (H24-16); and grants for the National Cancer Center Research and Development from the Japanese Ministry of Health, Labor, and Welfare (25-A-12, 28-K-1, 29-A-13, and 2021-A-18)., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Perforation is one of the most important complications of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Several studies have examined risk factors for intraoperative and delayed perforations, but most were retrospective analyses with small numbers of patients., Methods: This study represents a secondary analysis of a Japanese multicenter prospective cohort study. We investigated the factors associated with each type of perforation using 9015 patients with 9975 EGCs undergoing ESD between July 2010 and June 2012., Results: Intraoperative perforation occurred in 198 patients (2.2%) with 203 lesions (2.0%), necessitating emergency surgery for four lesions (0.04% [2.0%, 4/203]). Delayed perforation occurred in another 37 patients (0.4%) with 42 lesions (0.4%), requiring emergency surgery for 12 lesions (0.12% [28.6%, 12/42]). Factors showing significant independent correlations with intraoperative perforation were upper or middle third of the stomach; remnant stomach or gastric tube; procedure time ≥100 min; tumor size >35 mm; body mass index (BMI) < 18.5 kg/m 2 ; and ≥72 years. Factors showing significant independent correlations with delayed perforation were procedure time ≥60 min; BMI < 18.5 kg/m 2 ; ≥75 years; ulceration; and tumor size >20 mm. Intraoperative perforation occurred most frequently at the greater curvature in the upper third of the stomach (7.9%), whereas delayed perforation occurred most frequently at the greater curvature in the middle third (1.2%)., Conclusion: This multicenter prospective cohort study clarified the risk and risk factors of intraoperative and delayed perforation related to ESD for EGCs, providing information to help endoscopists reduce perforation., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

MYH9-related disorders are a group of autosomal dominant disorders caused by mutations in MYH9, and are characterized by thrombocytopenia, sensorineural hearing loss, cataracts, and renal failure. Here, we report a case of chronic renal failure due to MYH9-related disorder with renal symptoms in a patient who underwent living-donor renal transplantation. The patient was diagnosed with proteinuria during a health checkup at the age of 12 years. Her renal function gradually deteriorated, and hemodialysis was initiated at 34 years of age. No definitive diagnosis of renal disease was made through renal biopsy. At the age of 35, she underwent living-donor renal transplantation from her mother as the donor. Six years after transplantation, her renal function remained stable, and no evidence of recurrent nephritis was found during renal biopsies. The family history revealed that her father, uncle, and younger brother had end-stage kidney disease. Genetic testing revealed a mutation (p.E1653D) related to the MYH9 gene. As her father had a history of renal biopsy and was diagnosed with focal segmental glomerulosclerosis (FSGS), we diagnosed chronic renal failure due to FSGS associated with MYH9 disorder. There were no findings suggestive of hearing loss, cataracts, or thrombocytopenia in the recipient or their family members with renal failure, and no symptoms other than renal failure were noted., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: Advances in upper gastrointestinal endoscopic technology have enabled early detection and treatment of hypopharyngeal cancer. However, in-depth pharyngeal observations require sedation and are invasive. It is important to establish a minimally invasive and simple evaluation method to identify high-risk patients., Methods: Eighty-seven patients with superficial hypopharyngeal cancer and 51 healthy controls were recruited. We assessed the methylation status of DCC, PTGDR1, EDNRB, and ECAD, in tissue and saliva samples and verified the diagnostic accuracy by methylation analyses of their promoter regions using quantitative methylation-specific PCR., Results: Significant differences between cancer and their surrounding non-cancerous tissues were observed in the methylation values of DCC (p = 0.003), EDNRB (p = 0.001), and ECAD (p = 0.043). Using receiver operating characteristic analyses of the methylation values in saliva samples, DCC showed the highest area under the curve values for the detection of superficial hypopharyngeal cancer (0.917, 95% confidence interval = 0.864-0.970), compared with those for EDNRB (0.680) and ECAD (0.639). When the cutoff for the methylation values of DCC was set at ≥0.163, the sensitivity to detect hypopharyngeal cancer was 82.8% and the specificity was 90.2%., Conclusions: DCC methylation in saliva samples could be a non-invasive and efficient tool for early detection of hypopharyngeal cancer in high-risk patients., (© 2024. The Author(s).)

Background/aim: Malignant tumors are diagnosed using various methods, including diagnostic imaging methods. The measurement of tumor markers is commonly used because of its noninvasiveness and convenience. Furthermore, it is known that the excretion and metabolism of some tumor markers are affected by impaired renal function. In the present study, we investigated the effect of improved renal function on pre-and post-transplantation changes in tumor marker levels [carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and prostate-specific antigen (PSA)] in renal transplant recipients., Patients and Methods: A total of 116 renal transplant recipients, who had not been diagnosed with malignancies between January 2012 and December 2019, were included, and tumor markers were investigated., Results: CEA showed a significant decrease after kidney transplantation, regardless of the dialysis type (3.6→2.6 ng/ml, p<0.001), while other tumor markers showed a significant increase (AFP: 3.6→3.7 ng/ml; CA19-9: 16.2→19.5 U/ml; PSA: 0.95→1.05 ng/ml; all p<0.05). Pre- and postoperative eGFR ratios and postoperative liver function were identified as factors influencing the postoperative CEA and CA19-9 values, while PSA was influenced by the duration of dialysis. No statistically significant factors were found for AFP levels., Conclusion: Caution should be exercised when investigating tumor markers in patients with renal dysfunction, as tumor marker levels may vary depending on the pathophysiology of each patient., Competing Interests: The Authors declare no conflicts of interest associated with this manuscript., (Copyright 2024, International Institute of Anticancer Research.)

The aim of the "Japanese Clinical Practice Guidelines for Head and Neck Cancer - 2022 Update" is to review the latest evidence regarding head and neck cancer and to present the current standard approaches for diagnosis and treatment. These evidence-based recommendations were created with the consensus of the Guideline Committee, which is composed of otorhinolaryngologists and head and neck surgeons, together with radiologists, radiation oncologists, medical oncologists, plastic surgeons, dentists, palliative care physicians, and rehabilitation physicians. These guidelines were created by the Clinical Practice Guideline Committee of the Japan Society for Head and Neck Cancer based on the "Head and Neck Cancer Treatment Guidelines 2018 Edition," and the revised draft was compiled after evaluation by the Assessment Committee and public comments. The 'Clinical questions and recommendations' section consists of 13 categories, and 59 clinical questions are described in total. Here we describe 6 clinical questions specific to other sets of guidelines with recommendations and comments., (Copyright © 2023. Published by Elsevier B.V.)

The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.

Background: There is no consensus on the postoperative outcomes of tongue reconstruction. Therefore, the authors developed a novel risk model for predicting dysphagia after tongue reconstruction., Methods: This retrospective study was conducted by the Oral Pharyngeal Esophageal Operation and Reconstruction Analytical, or OPERA, group across 31 cancer centers and university hospitals in Japan. A total of 532 patients [390 (73.3%) men and 142 (26.7%) women; median age at surgery, 60 years (range, 15 to 88 years)] who were diagnosed with oral tongue squamous cell carcinoma and underwent tongue reconstruction following glossectomy between 2009 and 2013 were included. Independent risk factors were identified using univariate regression analysis and converted to a binary format for multivariate analysis. An integer value was assigned to each risk factor to calculate a total score capable of quantifying the risk of feeding tube dependence., Results: Overall, 54 patients (10.2%) required a feeding tube at the time of evaluation. Predictive factors for feeding tube dependence were advanced age, lower American Society of Anesthesiologists physical status, low body mass index, lower serum albumin, comorbid hypertension and diabetes, extended tongue defect, resection beyond the tongue, laryngeal suspension, postoperative radiation therapy, and no functional teeth. In multivariate logistic regression analysis, age greater than or equal to 58.5 years, postoperative radiation therapy, wider tongue defect, and body mass index less than 21.27 kg/m 2 earned 6, 4, 3, and 2 points, respectively, for a maximum total score of 15., Conclusion: The authors' risk model provides a mathematical tool for estimating the individual risk of postoperative feeding tube dependence before tongue reconstruction., Clinical Question/level of Evidence: Risk, III., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons.)

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis., (© 2023. Springer Nature Limited.)

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development 1-3 . However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves., (© 2023. The Author(s).)

Azacitidine is a mainstay of therapy for myelodysplastic syndrome (MDS)-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their posttreatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pretreatment (n = 449) and posttreatment (n = 289) bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their posttreatment clone size on treatment outcomes. In Cox proportional hazard modeling, multihit TP53 mutation (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.42-2.91; P < .001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P = .009), and DDX41 mutation (HR, 0.33; 95% CI, 0.17-0.62; P < .001), together with age, high-risk karyotypes, low platelets, and high blast counts, independently predicted OS. Posttreatment clone size accounting for all drivers significantly correlated with International Working Group (IWG) response (P < .001, using trend test), except for that of DDX41-mutated clones, which did not predict IWG response. Combined, IWG response and posttreatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, the molecular International Prognostic Scoring System (IPSS-M; c-index, 0.653 vs 0.688; P < .001, using likelihood ratio test). In conclusion, evaluation of posttreatment clone size, together with the pretreatment mutational profile as well as the IWG response play a role in better prognostication of azacitidine-treated patients with myelodysplasia., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Pharyngocutaneous fistula formation represents a major postoperative complication following total laryngectomy. We aimed to investigate the risk factors for pharyngocutaneous fistula development after total laryngectomy and to identify factors that lead to severe cases of pharyngocutaneous fistula., Methods: Patients who underwent total laryngectomy between January 2013 and February 2021 were included in the study and were divided into 2 groups: Those with and without pharyngocutaneous fistula. The severity of pharyngocutaneous fistula was graded using the Clavien-Dindo classification., Results: Patients with pharyngocutaneous fistula experienced longer operative time, greater intraoperative blood loss, greater decrease in perioperative hemoglobin level, and longer postoperative hospitalization. Unlike in lower-severity cases, patients with grade IIIb pharyngocutaneous fistula underwent preoperative radiotherapy or chemoradiotherapy; preoperative treatment was thus a risk factor for higher severity of pharyngocutaneous fistula (odds ratio, 35; P = 0.004)., Conclusion: Salvage laryngectomy was found to be a predictor of severe pharyngocutaneous fistula development. Prolonged operative time, increased intraoperative blood loss, and decreased postoperative hemoglobin level were found to be predictors of postlaryngectomy pharyngocutaneous fistula formation., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sessile serrated lesions (SSLs) are precursors of colon cancer, especially in cases of large, right colon. However, they are difficult to not only detect, but only clarify the margin of the lesion, which can lead to the poor endoscopic treatment outcomes., Aims: This study evaluated the usefulness of acetic acid spray with narrow-band imaging (A-NBI) for the better visualization of the margin of SSLs., Methods: From January 2013 to March 2022, patients with superficial elevated polyps suspected of being SSLs ≥ 10 mm with an endoscopic diagnosis that had been endoscopically resected at Hiroshima City Hiroshima Citizens Hospital were enrolled. Endoscopic images with white-light imaging (WLI), narrow-band imaging (NBI), indigo-carmine (IC), and A-NBI were recorded in each lesion and were randomly arranged and assessed by 10 endoscopists. We compared the visibility score (1 to 4) and color differences (ΔE) between inside and outside of the lesions among WLI, NBI, IC, and A-NBI., Results: Forty-one lesions in 33 cases were included, and a total of 164 images were evaluated. As for the visibility score, most of the lesions were scored as 1 or 2 on WLI, whereas most were scored 4 on A-NBI. The median ΔE of A-NBI was also significantly higher than that of WLI, NBI, or IC (20.5 vs. 8.3 vs. 8.2 vs. 12.3, P < 0.01). A significant correlation was observed between the color difference and visibility score (r = 0.53, P < 0.01)., Conclusions: A-NBI may be a useful modality for identifying the margin of SSLs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: An oxyntic gland neoplasm confined to the mucosal layer (T1a) is classified as an oxyntic gland adenoma, whereas that with submucosal invasion (T1b) is defined as gastric adenocarcinoma of the fundic gland type (GA-FG)., Methods: To reveal the differences in clinical features between them, we retrospectively investigated 136 patients with 150 oxyntic gland adenoma and GA-FG lesions., Results: The univariate analysis revealed that the mean size (GA-FG vs. oxyntic gland adenoma, 7.7±5.4 vs. 5.5±3.1 mm), the prevalence of elevated morphology (79.1% vs. 51.8%), black pigmentation within the lesion (23.9% vs. 9.6%), and non or closed-type atrophy (81.2% vs. 65.1%) were different between the two groups. A multivariate logistic regression analysis revealed that ≥5 mm lesion size (odds ratio, 2.96; 95% confidence interval: 1.21-7.23), elevated morphology (odds ratio, 2.40; 95% confidence interval: 1.06-5.45), and no or closed-type atrophy (odds ratio, 2.49; 95% confidence interval: 1.07-5.80) were factors in distinguishing GA-FG from oxyntic gland adenoma. When oxyntic gland neoplasms with no or one feature were judged as oxyntic gland adenomas and those with two or three features were judged as GA-FG, the sensitivity and specificity were 85.1% and 43.4% for GA-FG, respectively., Conclusions: We identified three possible distinctive features of GA-FG compared to oxyntic gland adenoma: lesion size ≥5 mm, elevated morphology, and no or closed-type atrophy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-870/coif). The authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

Bile duct cancer (BDC) frequently invades the nerve fibers, making complete surgical resection difficult. A single tumor mass contains cells of variable malignancy and cell-differentiation states, with cancer stem cells (CSCs) considered responsible for poor clinical outcomes. This study aimed to investigate the contribution of autosynthesized dopamine to CSC-related properties in BDC. Sphere formation assays using 13 commercially available BDC cell lines demonstrated that blocking dopamine receptor D1 (DRD1) signaling promoted CSC-related anchorage-independent growth. Additionally, we newly established four new BDC patient-derived organoids (PDOs) and found that blocking DRD1 increased resistance to chemotherapy and enabled xenotransplantation in vivo. Single-cell analysis revealed that the BDC PDO cells varied in their cell-differentiation states and responses to dopamine signaling. Further, DRD1 inhibition increased WNT7B expression in cells with bile duct-like phenotype, and it induced proliferation of other cell types expressing Wnt receptors and stem cell-like signatures. Reagents that inhibited Wnt function canceled the effect of DRD1 inhibition and reduced cell proliferation in BDC PDOs. In summary, in BDCs, DRD1 is a crucial protein involved in autonomous CSC proliferation through the regulation of endogenous WNT7B. As such, inhibition of the DRD1 feedback signaling may be a potential treatment strategy for BDC., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs., (© 2023 by The American Society of Hematology.)

Background & Aims: We aimed to clarify the long-term outcomes of endoscopic resection (ER) for early gastric cancers (EGCs) based on pathological curability in a multicenter prospective cohort study., Methods: We analyzed the long-term outcomes of 9054 patients with 10,021 EGCs undergoing ER between July 2010 and June 2012. Primary endpoint was the 5-year overall survival (OS). The hazard ratio for all-cause mortality was calculated using the Cox proportional hazards model. We also compared the 5-year OS with the expected one calculated for the surgically resected patients with EGC. If the lower limit of the 95% confidence interval (CI) of the 5-year OS exceeded the expected 5-year OS minus a margin of 5% (threshold 5-year OS), ER was considered to be effective. Pathological curability was categorized into en bloc resection, negative margins, and negative lymphovascular invasion: differentiated-type, pT1a, ulcer negative, ≤2 cm (Category A1); differentiated-type, pT1a, ulcer negative, >2 cm or ulcer positive, ≤3 cm (Category A2); undifferentiated-type, pT1a, ulcer negative, ≤2 cm (Category A3); differentiated-type, pT1b (SM1), ≤3 cm (Category B); or noncurative resections (Category C)., Results: Overall, the 5-year OS was 89.0% (95% CI, 88.3%-89.6%). In a multivariate analysis, no significant differences were observed when the hazard ratio of Categories A2, A3, and B were compared with that of A1. In all the pathological curability categories, the lower limit of the 95% CI for the 5-year OS exceeded the threshold 5-year OS., Conclusion: ER can be recommended as a standard treatment for patients with EGCs fulfilling Category A2, A3, and B, as well as A1 (UMIN Clinical Trial Registry, UMIN000005871)., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Wearable sensors have seen remarkable recent technological developments, and their role in healthcare is expected to expand. Specifically, monitoring tissue circulation in patients who have undergone reconstructive surgery is critical because blood flow deficiencies must be rescued within hours or the transplant will fail due to thrombosis/haematoma within the artery or vein. We design a wearable, wireless, continuous, multipoint sensor to monitor tissue circulation. The system measures pulse waves, skin colour, and tissue temperature to reproduce physician assessment. Data are analysed in real time for patient risk using an algorithm. This multicentre clinical trial involved 73 patients who underwent transplant surgery and had their tissue circulation monitored until postoperative day 7. Herein, we show that the overall agreement rate between physician and sensor findings is 99.2%. In addition, the patient questionnaire results indicate that the device is easy to wear. The sensor demonstrates non-invasive, real-time, continuous, multi-point, wireless, and reliable monitoring for postoperative care. This wearable system can improve the success rate of reconstructive surgeries., (© 2022. The Author(s).)

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL., Significance: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: To establish whether gastrectomy for early gastric cancer (EGC) in elderly patients is related to poor survival., Methods: The subjects of this retrospective study were patients aged ≥ 75 years with primary stage IA EGC, who underwent curative resection with endoscopic submucosal dissection (ESD) or surgery., Results: We analyzed data on 365 patients who underwent ESD and 170 patients who underwent surgery. Overall survival (OS) was not significantly different for the ESD group vs. the surgery group (5-year cumulative rates, 81.5% vs. 79.7%; log-rank test, P = 0.506). Multivariate analysis revealed that treatments; namely, ESD or surgery, were not associated with OS (hazard ratio 1.09, 95% confidence interval 0.77-1.51). Similar results were observed even in the subgroups with worse conditions, such as age > 80 years, Eastern Cooperative Oncology Group performance status 2-3, Charlson comorbidity index ≥ 2, and prognostic nutritional index ≤ 46.7. Using propensity score matching, we selected 88 pairs of patients who underwent ESD or surgery with baseline characteristics matched and found that OS was not different between the two groups (log-rank test, P = 0.829)., Conclusion: OS was comparable for elderly patients who underwent ESD and those who underwent surgery for EGC. Surgical invasiveness did not worsen the prognosis, even for elderly patients., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: The NCCN guidelines define pancreatic cancer that has contact with an aberrant right hepatic artery (A-RHA) as a borderline-resectable tumor. However, the impact of tumor contact with an A-RHA on surgical and survival outcomes has not been well discussed., Methods: A total of 541 patients who underwent pancreatoduodenectomy for resectable and borderline-resectable pancreatic cancer between 2002 and 2019 were retrospectively analyzed. The presence of an A-RHA and tumor contact with an A-RHA were evaluated based on the preoperative computed tomography findings. Patients with resectable tumors and tumors with A-RHA-contact (having contact with an A-RHA without involvement of the major arteries) were generally treated by upfront surgery, whereas those with borderline-resectable tumors generally underwent neoadjuvant therapy and subsequent resection., Results: Among the 541 patients, 116 (21.4%) had an A-RHA and 15 (2.8%) had tumor with A-RHA-contact. The A-RHA was resected in 12, and arterial reconstruction was performed in 8. The rates of morbidity and R1 resection in patients with an A-RHA (32.8 and 10.3%, respectively) were comparable to those without an A-RHA (27.3 and 11.3%, respectively). The overall survival in patients with A-RHA-contact was significantly worse than that in patients with borderline-resectable tumors (median survival time, 14.6 vs. 35.3 months, p = 0.048)., Conclusions: Although upfront resection was safely performed and led to a high R0 resection rate in patients with A-RHA-contact, the survival outcome was dismal. A tumor with A-RHA-contact should be regarded as technically resectable but oncologically borderline-resectable. Upfront surgery may not be appropriate for patients with A-RHA-contact., (© 2022. Society of Surgical Oncology.)

Background: The endoscopic features of oxyntic gland adenoma and gastric adenocarcinoma of the fundic gland type have not been fully investigated in relation to Helicobacter pylori infection status. We compared the morphology, color, and location of these lesions between patients with and without H. pylori infection., Methods: We retrospectively enrolled 165 patients (180 lesions) from 10 institutions. We divided the patients into the (i) Hp group (patients with current H. pylori infection [active gastritis, n = 13] and those with past infection [inactive gastritis, n = 76]) and (ii) uninfected group (H. pylori-uninfected patients, n = 52). We compared the clinical and endoscopic features of the two groups. We also performed an analysis between (i) lesions with atrophy of the surrounding gastric mucosa (atrophy group) and (ii) lesions without atrophy of the surrounding gastric mucosa (non-atrophy group)., Results: The average age was older in the Hp group than in the uninfected group (68.1 ± 8.1 vs. 63.4 ± 8.7 years, p < 0.01). Although the difference was not statistically significant (p = 0.09), multiple lesions were observed in 9 of 89 patients (10.1%) in the Hp group and in only 1 of 52 patients (1.9%) in the uninfected group. Meanwhile, significant differences were observed in the prevalence of lesions located in the gastric fornix or cardia (uninfected group: 67.3% vs. Hp group: 38.0%, p < 0.01), with an elevated morphology (80.0% vs. 56.0%, p < 0.01), with a subepithelial-like appearance (78.2% vs. 42.0%, p < 0.01), and with a color similar to that of the peripheral mucosa (43.6% vs. 25.0%, p = 0.02). The male-to-female ratio, lesion size, and presence or absence of vascular dilatation or black pigmentation on the surface were not different between the two groups. In the analysis comparing lesions with and without mucosal atrophy, the prevalence of multiple lesions was significantly higher (p = 0.02) in the atrophy group (5/25 patients, 20.0%) than in the non-atrophy group (7/141 patients, 5.0%)., Conclusions: The endoscopic features of oxyntic gland adenoma and gastric adenocarcinoma of the fundic gland type differ between patients with and without H. pylori infection., (© 2022. The Author(s).)

Background: Treatment strategies for superficial esophageal squamous cell carcinoma (SESCC) are determined mainly on the basis of the invasion depth. The Japan Esophageal Society (JES) developed a simplified magnifying endoscopic classification for estimating the invasion depth of SESCC. We aimed to evaluate its accuracy., Methods: We prospectively applied the JES classification for estimating the invasion depth of SESCC to 204 consecutive lesions from 6 hospitals in Japan between April 2016 and October 2018. We analyzed the accuracy of the endoscopic diagnosis by adding the following two categories to the JES classification: ≥ 7 mm lesion in B2 vessels (defined as B2 ≥ 7 mm) and B2 vessels with inflammation (defined as B2i)., Results: After applying the exclusion criteria, 201 lesions remained in the analysis. The diagnostic value of type B1, B2, B3 vessels were as follows: sensitivity, 93.9%, 68.0%, 25.0%; specificity, 81.1%, 89.2%, 99.4%; positive predictive value (PPV), 95.6%, 47.2%, 75.0%; negative predictive value (NPV), 75.0%, 95.1%, 95.4%; and accuracy, 91.5%, 86.5%, 95.0%, respectively. A retrospective analysis showed that the diagnostic accuracy was higher in type B2 vessels (86.5% to 92.0%). An avascular area (AVA) was found in 55 (27%) of the 201 lesions, which tended to be associated with a deeper pathological diagnosis of each Type B vessel. In an additional analysis, B2 ≥ 7 mm and B2i improved the diagnostic accuracy of type B2 vessels from 86.5% to 92.0%., Conclusions: The JES classification is useful for estimating the invasion depth of SESCC. The diagnostic accuracy for type B2 vessels was low, which may be improved by using B2 ≥ 7 mm and B2i., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Anorectal transplantation is a challenging procedure but a promising option for patients with weakened or completely absent anorectal function., Summary Background Data: We constructed a canine model of anorectal transplantation, evaluated the long-term outcomes, and controlled rejection and infection in allotransplantation., Methods: In the pudendal nerve function study, 6 dogs were randomly divided into 2 groups, transection and anastomosis, and were compared with a control using anorectal manometry, electromyography, and histological examination. In the anorectal transplantation model, 4 dogs were assigned to 4 groups: autotransplant, allotransplant with immunosuppression, allotransplant without immunosuppression, and normal control. Long-term function was evaluated by defecography, videography, and histological examination., Results: In the pudendal nerve function study, anorectal manometry indicated that the anastomosis group recovered partial function 6 months postoperatively. Microscopically, the pudendal nerve and the sphincter muscle regenerated in the anastomosis group. Anorectal transplantation was technically successful with a 3-stage operation: colostomy preparation, anorectal transplantation, and stoma closure. The dog who underwent allotransplantation and immunosuppression had 2 episodes of mild rejection, which were reversed with methylprednisolone and tacrolimus. The dog who underwent allotransplantation without immunosuppression had a severe acute rejection that resulted in graft necrosis. Successful dogs had full defecation control at the end of the study., Conclusions: We describe the critical role of the pudendal nerve in anorectal function and the first long-term success with anorectal transplantation in a canine model. This report is a proof-of-concept study for anorectal transplantation as a treatment for patients with an ostomy because of anorectal dysfunction., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Chronic active antibody-mediated rejection (CAAMR) is a frequent cause of late graft loss. However, effective treatment for CAAMR after kidney transplantation has not yet been established. Here, we present the case of a kidney transplant recipient who recovered from CAAMR after administration of rabbit anti-thymocyte globulin. A 61-year-old man underwent ABO-compatible living-donor kidney transplantation for end-stage kidney disease; the kidney was donated by his wife. Five years after the transplant, the patient's serum creatinine level and urine protein-to-creatinine ratio increased. He was subsequently diagnosed with CAAMR based on the kidney allograft biopsy and the presence of donor-specific human leukocyte antigen antibodies. Rabbit anti-thymocyte globulin treatment was administered following steroid pulse therapy. Subsequently, his serum creatinine levels and urine protein to creatinine ratio improved. There was also an improvement in the pathological findings seen on biopsy and the mean fluorescence intensity of donor-specific antibodies. In conclusion, this report describes the case of a kidney transplant recipient who developed CAAMR, treated using rabbit anti-thymocyte globulin. This strategy might be a viable treatment option for CAAMR after a kidney transplant., (© 2021. Japanese Society of Nephrology.)

Purpose: Nonampullary duodenal adenocarcinoma (NADA) is a rare disease. Although several prognostic factors have been reported for this disease, they remain controversial due to their rarity. In this study, we retrospectively analyzed 54 cases of invasive NADA, focusing on the microsatellite instability (MSI) phenotype, programmed cell death-ligand 1 (PD-L1) expression, and prognostic factors., Methods: Expression of the PD-L1 protein and cell differentiation markers in tumors was detected by immunohistochemistry. Microsatellite markers (NR-21, NR-22, NR-24, BAT-25, and BAT-26) were amplified for MSI assessment by PCR., Results: The incidence of MSI in invasive NADA was 35.2%. No significant correlation between the MSI phenotype and clinicopathological factors was observed. Positive expression of PD-L1 by immune cells was common in advanced-stage disease (p = 0.054), and positive expression of PD-L1 in cancer cells correlated significantly with the histologically undifferentiated type (p = 0.016). Kaplan-Meier survival analysis demonstrated a significantly better overall survival (OS) in patients with MSI (p = 0.013) and at early-stage disease (p = 0.000) than in those with microsatellite-stable or at late tumor stages. Univariate and multivariate analyses showed that MSI (hazard ratio [HR]: 0.282, 95% confidence interval [CI]: 0.106-0.751, p = 0.011) and early tumor stage (stage I-II) (HR: 8.81, 95% CI: 2.545-30.500, p = 0.001) were independent better prognostic factors of OS., Conclusions: MSI and early tumor stage (stage I-II) were independent better prognostic factors of OS. A high proportion of MSI phenotypes and positive PD-L1 expression may be helpful for identifying immune checkpoint inhibitors as a novel therapeutic strategy., (© 2022 S. Karger AG, Basel.)

Objective Although Barrett's adenocarcinoma (BA) remains a minor disease in Japan, its incidence has been gradually increasing. We analyzed the characteristics of BA in Japanese populations. Methods We retrospectively reviewed medical records and analyzed the clinicopathological differences between short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE), as well as metastasis. Local recurrence and metachronous lesions were analyzed only in patients who underwent endoscopic resection (ER). Patients Consecutive patients who had pathological T1 BAs resected by ER or surgery from January 2003 to December 2017. Results A total of 168 patients were analyzed, including 139 with SSBE and 29 with LSBE. In total, 67% of the SSBE lesions and 32% of the LSBE lesions were located between 0 and 3 o'clock (p=0.0014). No patients who achieved pathological margin-free resection (pR0) and 17% of patients who did not achieve pR0 experienced local recurrence (p=0.0131). None of the patients without lymphovascular involvement, a poorly differentiated component, lesion size of >30 mm, and submucosal invasion of >500 μm experienced metastasis. The 5-year cumulative incidence rate of metachronous BA after ER was 0% in patients with SSBE and 40% in patients with LSBE (p=0.0005). Conclusion Superficial BA was likely to be detected at the right anterior wall of SSBE in the Japanese population. The risk for metachronous BA after ER was high in Japanese patients with LSBE, as in Western patients.

Introduction: The genomic characterization of primary nonampullary duodenal adenocarcinoma indicates a genetic resemblance to gastric and colorectal cancers. However, a correlation between the clinical and molecular characteristics of these cancers has not been established. This study aimed to elucidate the clinicopathological features of sporadic nonampullary duodenal epithelial tumors, including their molecular characteristics and prognostic factors., Methods: One hundred forty-eight patients with sporadic nonampullary duodenal epithelial tumors were examined in this study. Patient sex, age, TNM stage, tumor location, treatment methods, histology, KRAS mutation, BRAF mutation, Fusobacterium nucleatum, mucin phenotype, and programmed death-ligand 1 (PD-L1) status were evaluated. KRAS and BRAF mutations, Fusobacterium nucleatum, mucin phenotype, and PD-L1 status were analyzed by direct sequencing, quantitative polymerase chain reaction, and immunochemical staining., Results: The median follow-up duration was 119.4 months. There were no deaths from duodenal adenoma (the primary disease). Kaplan-Meier analysis for duodenal adenocarcinoma showed a significant effect of TNM stage (P < 0.01). In univariate analysis of primary deaths from duodenal adenocarcinoma, TNM stage II or higher, undifferentiated, KRAS mutations, gastric phenotype, intestinal phenotype, and PD-L1 status were significant factors. In multivariate analysis, TNM stage II or higher (hazard ratio: 1.63 × 1010, 95% confidence interval: 18.66-6.69 × 1036) and KRAS mutation (hazard ratio: 3.49, confidence interval: 1.52-7.91) were significant factors., Discussion: Only KRAS mutation was a significant prognostic factor in primary sporadic nonampullary duodenal adenocarcinoma in cases in which TNM stage was considered., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Project High-tech Omics-based Patient Evaluation (HOPE), which used whole-exome sequencing and gene expression profiling, was launched in 2014. A total of ~2,000 patients were enrolled until March 2016, and the survival time was observed up to July 2019. In our previous study, a tumor microenvironment immune type classification based on the expression levels of the programmed death-ligand 1 (PD-L1) and CD8B genes was performed based on four types: A, adaptive immune resistance; B, intrinsic induction; C, immunological ignorance; and D, tolerance. Type A (PD-L1 + and CD8B + ) exhibited upregulated features of T helper 1 antitumor responses. In the present study, survival time analysis at 5 years revealed that patients in type A had a better prognosis than those in other categories [5 year survival rate (%); A (80.5) vs. B (73.9), C (73.4) and D (72.6), P=0.0005]. Based on the expression data of 293 immune response-associated genes, 62 specific genes were upregulated in the type A group. Among these genes, 18 specific genes, such as activated effector T-cell markers (CD8/CD40LG/GZMB), effector memory T-cell markers (PD-1/CD27/ICOS), chemokine markers (CXCL9/CXCL10) and activated dendritic cell markers (CD80/CD274/SLAMF1), were significantly associated with a good prognosis using overall survival time analysis. Finally, multivariate Cox proportional hazard regression analyses of overall survival demonstrated that four genes (GZMB, HAVCR2, CXCL9 and CD40LG) were independent prognostic markers, and GZMB, CXCL9 and CD40LG may contribute to the survival benefit of patients in the immune type A group., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kondou et al.)

A 71-year-old man was referred to our hospital for treatment of a 2 cm-sized right renal mass incidentally found by computed tomography (CT) and was diagnosed with right renal cell carcinoma cT1aN0M0. Contrast-enhanced CT revealed that the aorta was completely occluded below the inferior mesenteric artery origin, and Leriche syndrome was diagnosed. CT angiography showed several collateral arteries along the abdominal wall. A robot-assisted laparoscopic partial nephrectomy was performed to treat renal cell carcinoma. Preoperatively, we marked the collateral arteries using ultrasonography to avoid injury during trocar insertion. We did not observe any decrease in blood flow in the right leg during the operation. The pathological diagnosis was clear cell renal cell carcinoma. Leriche syndrome is a chronic occlusive disease involving the infrarenal aorta and the iliac arteries. Since lower limb blood flow is dependent on collateral circulation, it is important to avoid injuring the collateral arteries during surgery.

Abstract: Sporadic non-ampullary duodenal adenoma (SNADA) is a rare disease, and therefore, its clinical characteristics have not been comprehensively investigated. Furthermore, owing to the high complication rates and severity of endoscopic resection, treatment strategies vary among facilities. In the present study, we aimed to clarify the clinical characteristics and course of SNADA.We extracted clinical and histological records of SNADA cases diagnosed in 11 hospitals between September 1999 and August 2014. The patients were divided into "no-resection" and "resection" groups based on the initial treatment approach. We investigated the long-term outcome of the "no-resection" group and treatment results of the "resection" group, with particular interest in endoscopic resection.Overall, 299 patients were diagnosed with SNADA. The median age at diagnosis was 67 years (range, 31-88 years), with approximately twice as many men as women. The median tumor size was 8.0 mm (2-60 mm). In total, 161 patients were initially selected for no-resection and 138 underwent resection. Age >70 years and the presence of either severe illness or poor performance status were significantly related to opting for no-resection. In the no-resection group, 101 patients underwent endoscopic follow-up for at least 1 year. During the observational period (2.5 ± 2.2 years), 27 lesions (27%) disappeared following cold forceps biopsy, and 13 lesions (14%) presented lateral growth. Four lesions (4%) changed to mucosal carcinoma, 3 were treated endoscopically, and 1 was surgically resected. Nineteen patients died; however, no one died of duodenal carcinoma. In the endoscopic resection group, en bloc resection was achieved in 78% of patients. However, the complication rate for perforation was 7%, and endoscopic submucosal dissection was associated with a 36% perforation rate.With the low incidence of cancer development and no disease specific death, the strategy of initially not performing resection could be considered especially for the older adults, poor-prognosis patients, or small lesions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The rare incidence of submucosal invasive non-ampullary duodenal carcinoma has led to scant information in literature; therefore, we compared the clinicopathological features between submucosal invasive carcinoma (SM-Ca), mucosal carcinoma (M-Ca), and advanced carcinoma (Ad-Ca)., Materials: We retrospectively analyzed 165 patients with sporadic non-ampullary duodenal carcinomas (SNADCs) from four institutions between January 2003 and December 2018. The SNADCs were divided to three groups according to histological diagnosis: SM-Ca, M-Ca, and Ad-Ca. The clinicopathological characteristics and mucin phenotypes were compared between groups., Results: Among the 165 SNADCs, 11 (7%) were classified as SM-Ca, 70 (42%) as M-Ca, and 84 (51%) as Ad-Ca. We found that all SM-Ca (P = 0.013) and most Ad-Ca (P = 0.020) lesions were located on the oral-Vater; however, an almost equal distribution of M-Ca lesions was found between the oral- and anal-Vater. No significant difference was observed between the tumor diameter of M-Ca and SM-Ca; however, 45% (5/11) of SM-Ca were ≤10 mm. A total of 73% (8/11) of SM-Ca were classified as gastric phenotype and no lesions were classified as intestinal phenotype; whereas most M-Ca were classified as intestinal phenotype (67%, 8/12)., Conclusions: SM-Ca lesions were all located on the oral-Vater and were highly associated with the gastric mucin phenotype, which were different from the features of most M-Ca., Competing Interests: NO authors have competing interests.

Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen's disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews., (© 2021 Japanese Dermatological Association.)

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC., Competing Interests: Declaration of interests D.B.S. has consulted with and received honoraria from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics and BridgeBio., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Significance: A multipurpose disinfecting solution (MPDS), which contains povidone-iodine (PI) as a disinfectant, has high disinfecting efficacy not only on planktonic bacterium but also on the case biofilms. The addition of case hygiene practice removed more bacteria from cases than MPDS alone., Purpose: This study compared the ability of two MPDSs, one containing PI and another containing polyaminopropyl biguanide and polyquaternium, to reduce bacterial numbers in solution or adhered to the cases following case hygiene procedures., Methods: Bacterial strains (Delftia acidovorans, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Serratia marcescens, Staphylococcus aureus, and Staphylococcus epidermidis) were exposed to the MPDSs for the recommended disinfection times, and the viable number evaluated according to ISO 14729. Cases were inoculated with bacterial strains and incubated for 24 hours to allow for biofilm formation. Cases were disinfected with both disinfecting solutions for 4 hours and rinsed, followed by recapping or air-drying, or tissue-wiping and air-drying for 18 hours. The number of survivors was counted using standard culture techniques., Results: Both products exceeded the recommended 3-log reduction against planktonic bacteria. Regarding biofilm, after rinsing and recapping wet, the numbers of D. acidovorans (mean difference [95% confidence interval] log10 colony-forming units per case, -2.9 [0.8 to -4.6], P < .01), P. aeruginosa (-2.0 [0.5 to -3.1], P < .01), S. marcescens (-1.7 [0.8 to -3.5], P < .05), and S. epidermidis (-2.1 [0.6 to -3.5], P < .05) in PI cases were significantly lower than in the dual-disinfectant MPDS storage cases. After air-drying, the PI storage cases had significantly lower numbers of S. maltophilia (-2.6 [0.6 to -4.0], P < .01), D. acidovorans (-1.6 [0.7 to -3.3], P < .05), and S. aureus (-1.6 [0.7 to -3.1], P < .05). The addition of tissue-wiping reduced the bacterial numbers in the MPDS storage cases to levels in the PI storage cases., Conclusions: Contact lens users should be recommended to tissue-wipe and air-dry their lens storage cases after disinfection with regular MPDS., Competing Interests: Conflict of Interest Disclosure: The authors listed report a financial conflict of interest (MN, RN). MN and RN are employees of Ophtecs Corporation. Ophtecs Corporation provided the disinfecting solutions and contact lens cases for the study., (Copyright © 2021 American Academy of Optometry.)

The aim of this study was to reveal the histological features of oxyntic gland adenomas and gastric adenocarcinoma of the fundic-gland type (GA-FG). We retrospectively examined the histological features of 126 lesions of oxyntic gland adenoma and/or GA-FG in 116 patients. The prevalence of oxyntic gland adenomas and GA-FG was approximately equal. The majority of the lesions were resected by endoscopic mucosal resection using a diathermic snare (EMR, n = 42) or endoscopic submucosal dissection (ESD, n = 72). Histologically, there were no lesions with invasion at the level of the muscularis propria or deeper, and lymphovascular invasion was present in 1.6%. Of the ESD and EMR specimens, there were no lesions that were positive for vertical margins. Among the eight GA-FG patients with deep (≥ 500 μm) submucosal invasion, six were treated with endoscopic resection alone, and no recurrence was documented. No patients died of the disease during the median follow-up period of 14.5 months. In conclusion, all lesions were confined to the mucosa or submucosa and were negative for vertical margins. Lymphovascular invasion was present in only 1.6% of the patients. Thus, we believe that endoscopic resection is a suitable initial treatment method for oxyntic gland adenoma and GA-FG.

Background: Recent improvements in the prognosis of patients with esophageal cancer have led to the increased occurrence of gastric tube cancer (GTC) in the reconstructed gastric tube. However, there are few reports on the treatment results of endoscopic submucosal dissection (ESD) for GTC., Aim: To evaluate the efficacy and safety of ESD for GTC after esophagectomy in a multicenter trial., Methods: We retrospectively investigated 48 GTC lesions in 38 consecutive patients with GTC in the reconstructed gastric tube after esophagectomy who had undergone ESD between January 2005 and December 2019 at 8 institutions participating in the Okayama Gut Study group. The clinical indications of ESD for early gastric cancer were similarly applied for GTC after esophagectomy. ESD specimens were evaluated in 2-mm slices according to the Japanese Classification of Gastric Carcinoma with curability assessments divided into curative and non-curative resection based on the Gastric Cancer Treatment Guidelines. Patient characteristics, treatment results, clinical course, and treatment outcomes were analyzed., Results: The median age of patients was 71.5 years (range, 57-84years), and there were 34 men and 4 women. The median observation period after ESD was 884 d (range, 8-4040 d). The median procedure time was 81 min (range, 29-334 min), the en bloc resection rate was 91.7% (44/48), and the curative resection rate was 79% (38/48). Complications during ESD were seen in 4% (2/48) of case, and those after ESD were seen in 10% (5/48) of case. The survival rate at 5 years was 59.5%. During the observation period after ESD, 10 patients died of other diseases. Although there were differences in the procedure time between institutions, a multivariate analysis showed that tumor size was the only factor associated with prolonged procedure time., Conclusion: ESD for GTC after esophagectomy was shown to be safe and effective., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: While endoscopic submucosal dissection (ESD) is recognized as a minimally invasive standard treatment for differentiated early gastric cancers (EGCs), it has not been indicated for undifferentiated EGC (UD-EGC) because of a relatively high risk of lymph node metastasis (LNM). However, patients with surgically resected mucosal (cT1a) UD-EGC ≤ 2 cm in size with no lymphovascular invasion or ulceration are reported to be at a very low risk of LNM. This multicenter, single-arm, confirmatory trial was conducted to evaluate the efficacy and safety of ESD for UD-EGC., Methods: The key eligibility criteria were endoscopically diagnosed cT1a/N0/M0, single primary lesion, size ≤ 2 cm, no ulceration and histologically proven components of undifferentiated adenocarcinoma on biopsy. Based on the histological findings after ESD, additional gastrectomy was indicated if the criteria for curative resection were not satisfied. The subjects of the primary analysis were patients with UD-EGC as the dominant component. The primary endpoint was 5-year overall survival (OS) of patients with UD-EGC., Results: Three hundred 46 patients were enrolled from 49 institutions. The proportion of en bloc resection was 99%. No ESD-related Grade 4 adverse events were noted. Delayed bleeding and intraoperative and delayed perforation occurred in 25 (7.3%), 13 (3.8%), and 6 (1.7%) patients, respectively. Among the 275 patients who were the subjects of the primary analysis, curative resection was achieved in 195 patients (71%), and 5-year OS was 99.3% (95% CI: 97.1-99.8)., Conclusions: ESD can be a curative and less invasive treatment for UD-EGC for patients meeting the eligibility criteria of this study.

Background: Little is known about the association between immune-related adverse events (irAEs) and the efficacy and survival outcomes of nivolumab in patients with advanced gastric cancer (AGC)., Objective: The present study examined the association between irAEs and the prognosis of patients with AGC treated with nivolumab., Patients and Methods: From July 2017 to November 2020, patients who had been diagnosed with advanced unresected gastric cancer and treated with nivolumab at our institution were included in this analysis. We compared the clinical and survival outcomes between the irAE and non-irAE groups. We also evaluated the factors associated with better survival in patients treated with nivolumab., Results: A total of 52 patients were included in the present study, and irAEs were observed in 13 (25%). Among the patients with measurable lesions (n = 29), the disease control rates were significantly higher in the irAE group than in the non-irAE group (88 vs. 24%; P = 0.0033). At the 8- and 12-week landmark analyses, the median overall survival (OS) in the irAE group was significantly longer than that in the non-irAE group, whereas the median progression-free survival was comparable between the groups. A multivariate analysis by Cox proportional hazard regression at the 8-week landmark revealed that the development of irAEs (hazard ratio 0.18; 95% confidence interval 0.0099-0.86) alone was positively associated with a longer OS., Conclusions: The development of irAEs might be associated with survival outcomes with nivolumab treatment in patients with AGC.

Appropriate positioning of the inframammary fold (IMF) is essential for breast reconstruction. The purpose of this study was to quantitatively measure and evaluate the anthropometric position of the IMF in the thorax. A total of 145 Japanese women with unilateral breast cancer were analyzed. To indicate the superior-inferior position of the IMF on the non-diseased side, the distances from the sternal notch (SN) to the IMF along the midline (SN-IMFM) and from the SN to the umbilicus (UB) (SN-UB) were measured. A new index, the thorax anthropometric position (TAP) index for the IMF, was then defined as the ratio of SN-IMFM to SN-UB. The TAP index was calculated for each patient, and its correlations with demographic parameters, including age, body height, and body mass index, were statistically assessed. The TAP index was normally distributed and ranged from 0.500 to 0.704, with a mean of 0.590. Multivariate analysis revealed that age was an independent factor associated with a higher TAP index ( p  < .01). In addition, the paired t -test showed that the TAP index was significantly greater in the standing position than in the supine position ( p  < .001). The position of the IMF in the thorax could be objectively described by the TAP index, and it was suggested to become inferior with age and the standing position. The index, along with these findings, will provide useful information for the evaluation of the breast contour in an objective and simple manner.

A 41-year-old female who suffered local recurrence of cervical cancer after receiving chemoradiotherapy underwent radical hysterectomy, radical vaginal resection, and pelvic and paraaortic lymph node dissection. After surgery, bilateral hydronephrosis due to right ureteral stenosis and left uretero-vaginal fistula occurred. We therefore placed a bilateral ureteral stent. Thereafter, we continued to replace the bilateral ureteral stent once every 3 months, but the replacement of the right ureteral stent became impossible three years after the initial placement. We thus performed bilateral upper urinary tract reconstruction using an ileal ureter with the aim of both eliminating the left ureteral vaginal fistula and resolving the right ureteral stricture.

Background: Esophageal squamous cell carcinoma (ESCC) confined to the muscularis mucosae (MM) or up to 200 µm of the submucosa (SM1) confers the risk for lymph node metastasis, and is defined as relative indication for endoscopic submucosal dissection (ESD) by the Japan Esophageal Society guidelines. Although additional surgical treatment after ESD is recommended, long-term outcomes of ESD compared with those of surgery have not been clarified. This study aimed to evaluate the long-term outcomes of ESD and surgery for cN0M0 relative indication lesions of ESCC., Methods: Between 2006 and 2016, patients with relative indication lesions of ESCC who underwent ESD or surgery at nine participating hospitals were examined retrospectively. Using propensity score matching, we evaluated survival curves for and hazard ratios associated with endoscopic submucosal dissection and surgery., Results: In total, 155 lesions in the ESD group and 106 lesions in the surgery group met the pathological criteria of relative indication for endoscopic resection. After matching, 50 matched pairs of patients who underwent ESD or surgery were selected. The 5-year overall survival rates were 84.5% [95% confidence interval (CI) 68-93] in the ESD group and 79% [95% CI 60-90] in the surgery group. The hazard ratio of mortality for ESD compared with that for surgery estimated by Cox regression analysis was 0.79 (95% CI 0.3-2.06, p = 0.63)., Conclusions: Compared with surgery, ESD does not compromise long-term outcomes. ESD alone or ESD with chemotherapy and/or radiotherapy may be an option for the treatment of MM and SM1 ESCC.

Background: Pedicled jejunal flap can be utilized with various tips for esophageal reconstruction in patients with a history of gastrectomy or those who have undergone synchronous esophagogastrectomy. However, the rate of anastomosis leakage is high; therefore, we considered the evaluation of blood flow of the remnant esophagus with indocyanine green in setting the anastomosis site., Methods: Fifty patients who underwent radical esophagectomy with pedicled jejunal flap between January 2011 and June 2020 were identified. From June 2019, blood flow in the pedicled jejunum and remnant esophagus were evaluated to set the anastomosis site of the latter. Usually, the second and third jejunal vessels are transected, and if the jejunal flap cannot reach to the anastomosis point, we actively transect the marginal vessels to stretch the jejunal flap. Microvascular anastomosis between the jejunal branches and the internal thoracic vessels is usually made, and the anastomosis site is set at the well-stained part of the esophagus., Results: Overall, 39 patients underwent the procedure before June 2019 (Group A), and 11 patients underwent the procedure since June 2019 (Group B). No significant difference was found in the patients' background, type of preoperative therapy, presence or absence of ligation of marginal vessels and two-stage operation between the groups. Group A had 16 cases of anastomosis leakage; B had only 1 case ( p  < 0.05). There were no cases of pedicled jejunum graft necrosis., Conclusion: Assessing remnant esophageal perfusion by indocyanine green imaging in pedicled jejunum reconstruction resulted in a lower anastomotic leak rate., Competing Interests: The authors declare that they have no conflicts of interest., (© 2021 The Authors.)

Aims: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies., Methods: Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours., Results: All patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH ; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence., Conclusions: HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)