Structure of pathological TDP-43 filaments from ALS with FTLD.

The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD)1,2. It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282-360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro3,4. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts ß-strand length, which results in an absence of ß-sheet stacking that is associated with cross-ß amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.

The origin of esterase activity of Parkinson's disease causative factor DJ-1 implied by evolutionary trace analysis of its prokaryotic homolog HchA.

DJ-1, a causative gene for hereditary recessive Parkinsonism, is evolutionarily conserved across eukaryotes and prokaryotes. Structural analyses of DJ-1 and its homologs suggested the 106th Cys is a nucleophilic cysteine functioning as the catalytic center of hydratase or hydrolase activity. Indeed, DJ-1 and its homologs can convert highly electrophilic α-oxoaldehydes such as methylglyoxal into α-hydroxy acids as hydratase in vitro, and oxidation-dependent ester hydrolase (esterase) activity has also been reported for DJ-1. The mechanism underlying such plural activities, however, has not been fully characterized. To address this knowledge gap, we conducted a series of biochemical assays assessing the enzymatic activity of DJ-1 and its homologs. We found no evidence for esterase activity in any of the Escherichia coli DJ-1 homologs. Furthermore, contrary to previous reports, we found that oxidation inactivated rather than facilitated DJ-1 esterase activity. The E. coli DJ-1 homolog HchA possesses phenylglyoxalase and methylglyoxalase activities but lacks esterase activity. Since evolutionary trace analysis identified the 186th H as a candidate residue involved in functional differentiation between HchA and DJ-1, we focused on H186 of HchA and found that an esterase activity was acquired by H186A mutation. Introduction of reverse mutations into the equivalent position in DJ-1 (A107H) selectively eliminated its esterase activity without compromising α-oxoaldehyde hydratase activity. The obtained results suggest that differences in the amino acid sequences near the active site contributed to acquisition of esterase activity in vitro, and provide an important clue to the origin and significance of DJ-1 esterase activity.

Thirty-two years' experience of treating fulminant hepatitis in a Japanese single center.

AIM: The prognosis of patients with acute liver failure has improved dramatically in the past three decades due to advances in medical critical care and use of liver transplantation (LT) in Western countries, where the etiology of acute liver failure is different from that in Japan. We analyzed patients with fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) admitted to our unit over a 32-year period to clarify the nature of Japanese patients with FH and LOHF. METHODS: A total of 137 Japanese patients with FH and LOHF between 1986 and 2017 were analyzed for etiologies, disease types, treatment protocols, and outcome. RESULTS: Of 137 patients, 124 were FH (53 acute type and 71 subacute type) and 13 LOHF. The major etiology was due to viral infections in 48% of patients. A total of 23.4% of patients recovered without LT, 7.3% received LT, and 69.3% died without LT. The number of patients showed rise and fall without an evident decrease during the period. Patients with autoimmune hepatitis increased after the establishment of autoimmune hepatitis criteria in 1999 (p < 0.001), and that with indeterminate cause decreased (p < 0.01). The mean age was older in the last decade than in the first decade (p = 0.036). Spontaneous and overall survival rates were not different during the period. CONCLUSIONS: The prognosis of our patients with FH and LOHF has not improved, probably because of aging and the increasing proportion of etiologies with poor prognosis and difficult-to-treat patients without response to medications regardless of advancement of clinical management, including artificial liver support devices and LT.

Carcinogenic potential in regenerated mucosa after endoscopic resection of esophageal squamous cell carcinoma.

BACKGROUND AND AIM: Little is known about genetic mutations in the regenerated mucosa (RM) after endoscopic resection (ER) of esophageal carcinoma. Thus, this study investigates the status of genetic variation in RM after ER of esophageal squamous cell carcinoma (ESCC). METHODS: The study cohort included 19 patients with ESCC. We used an esophageal carcinoma panel to identify target sequences for squamous cell carcinoma (SCC), background mucosa (BM), and RM after ER of ESCC. We used OncoKB to check whether each mutation was a putative driver. RESULTS: We identified 77 mutations of 32 genes in SCC, 133 mutations of 34 genes in BM, and 100 mutations of 29 genes in RM. Putative driver mutations were identified in 20 mutations in 14 cases in SCC, 16 mutations in 10 cases in BM, and 7 mutations in 11 cases in RM. The rate of putative driver mutations to total mutations was significantly lower in RM (26% in SCC vs 12% in BM vs 7% in RM, P = 0.009). Additionally, the rate of cases with TP53 putative driver mutations was significantly lower in RM (63% in SCC vs 37% in BM vs 16% in RM, P = 0.011). The percentage of putative driver mutations and the percentage of cases with a putative driver of TP53 were significantly lower in RM. CONCLUSION: Esophageal RM after ER of ESCC could have a lower risk of carcinogenesis.

A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/ß-Catenin Signaling Pathway.

The vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their regulatory mechanisms are incompletely understood. Considering the wide range of potential contributions of lncRNAs to physiological processes and pathological conditions, we hypothesized that lncRNAs in osteocytes, which have not been reported, could be involved in bone metabolism. Here, we first isolated osteocytes from femurs of mice with osteocyte-specific GFP expression. Then, through RNA-sequencing, we identified osteocyte-specific lncRNAs and focused on a novel lncRNA, 9530026P05Rik (lncRNA953Rik), which strongly suppressed osteogenic differentiation. In the IDG-SW3 osteocyte line with lncRNA953Rik overexpression, the expression of Osterix and its downstream genes was reduced. RNA pull-down and subsequent LC-MS/MS analysis revealed that lncRNA953Rik bound the nuclear protein CCAR2. We demonstrated that CCAR2 promoted Wnt/ß-catenin signaling and that lncRNA953Rik inhibited this pathway. lncRNA953Rik sequestered CCAR2 from HDAC1, leading to deacetylation of H3K27 in the Osterix promoter and consequent transcriptional downregulation of Osterix. This research is the first to clarify the role of a lncRNA in osteocytes. Our findings can pave the way for novel therapeutic options targeting lncRNAs in osteocytes to treat bone metabolic diseases such as osteoporosis.

Traditional Chinese medicine Jia Wei Gui Pi Tang improves behavioural and psychological symptoms of dementia and favourable positive emotions in patients.

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are challenging to manage, leading to caregiver burden and often to subsequent transfer of patients to a nursing home or psychiatric hospital for treatment. Eliciting favourable positive emotions should be an important goal in the treatment of negative emotions associated with BPSD. To date, no data have indicated that antipsychotic medications can improve positive emotions. BPSD are known to be associated with anxiety in patients with dementia. The traditional Chinese medicine Jia Wei Gui Pi Tang is officially indicated and approved for anxiety treatment in Japan. METHODS: Here, we performed a multicentre, randomised, observer-blind control study of the effect of Jia Wei Gui Pi Tang on BPSD in Alzheimer's disease (AD) patients. Patients with AD or AD with cerebral vascular disease were randomly divided into the Jia Wei Gui Pi Tang treatment group and the control group that received no traditional Chinese medicine. BPSD were scored using the Neuropsychiatric Inventory Nursing Home Version (NPI-NH) and by favourable positive emotions using the Delightful Emotional Index (DEI). RESULTS: A total of 63 participants (18 male and 45 female; mean age: 83.3 ± 6.0 years) were included in the study. Changes in NPI-NH scores differed significantly between the two groups (one-way analysis of variance, P < 0.001). Within the treatment group, there was a significant improvement in the NPI-NH score from 29.8 ± 17.3 at baseline to 13.2 ± 9.4 at the endpoint (paired t-test, P < 0.001), whereas there was no statistically significant change in the control group. Changes in DEI scores differed significantly between the two groups. Within the treatment group, there was a significant improvement in the DEI score from 24.3 ± 23.0 at baseline to 32.5 ± 21.2 at the endpoint (paired t-test, P = 0.001), whereas there was no statistically significant change in the control group. CONCLUSION: The traditional Chinese medicine Jia Wei Gui Pi Tang significantly improved both BPSD and positive emotions.

Plasma unconjugated bile acids as novel biomarker for schizophrenia.

In this study, we measured conjugated and unconjugated free bile acids (BAs) in plasma from patients with schizophrenia and healthy subjects to examine the possibility of BA as a biomarker for schizophrenia. Although the levels of each BA conjugate showed no significant differences, significant differences for three unconjugated bile acids were observed in the plasma between patients with schizophrenia and healthy subjects. Additionally, a more than three times difference between patients and healthy subjects was observed in the mean value of the total concentrations of primary BAs. These results indicate that cholic acid and chenodeoxycholic acid levels in plasma may be novel diagnostic markers for a sub-population of patients with schizophrenia. Thus, future studies should elucidate the relationship between this increase in BA levels and the pathology of schizophrenia and verify the potential of unconjugated BA in plasma as biomarkers for schizophrenia.

Utility of underwater EMR for nonpolypoid superficial nonampullary duodenal epithelial tumors ≤20 mm.

BACKGROUND AND AIMS: The application of underwater EMR (UEMR) for nonpolypoid superficial nonampullary duodenal epithelial tumors (SNADETs) has not been comprehensively assessed. Therefore, the current study aimed to validate the efficacy of UEMR versus conventional EMR and cap-assisted EMR (EMRC) for SNADETs measuring ≤20 mm. METHODS: We retrospectively analyzed patients with sporadic nonpolypoid SNADETs measuring ≤20 mm undergoing EMR, EMRC, or UEMR at Chiba University Hospital between May 2004 and October 2020 (EMR, 21 patients and 23 SNADETs; UEMR, 60 patients and 61 SNADETs; EMRC, 45 patients and 48 SNADETs). A weighted logistic regression analysis was performed to analyze outcomes. Univariate and multivariate logistic regression models were used to identify the predictors of RX/1 and piecemeal resection. The recurrence rate of lesions observed ≥12 months after resection was assessed. RESULTS: Both UEMR and EMRC had a significantly higher R0 resection rate than EMR. UEMR had significantly lower multiple resection and postbleeding rates than EMR. Only 1 patient (2.1%) who underwent EMRC experienced intraoperative and postoperative perforation. EMR was involved in RX/1 and piecemeal resection. The recurrence rates of EMR, UEMR, and EMRC were 4.3%, 2.0%, and 6.3%, respectively. CONCLUSIONS: UEMR had significantly higher R0 resection and lower postbleeding rates than EMR. Moreover, it was safer than EMRC and was associated with a lower incidence of recurrences. The significant results of the retrospective analysis suggest a randomized controlled study with adequate numbers needs to be conducted to confirm the superior efficacy of UEMR before it is recommended for primary treatment option for SNADETs measuring ≤20 mm.

Development and evaluation of a double-check support system using artificial intelligence in endoscopic screening for gastric cancer.

BACKGROUND: This study aimed to prevent missing gastric cancer and point out low-quality images by developing a double-check support system (DCSS) for esophagogastroduodenoscopy (EGD) still images using artificial intelligence. METHODS: We extracted 12,977 still EGD images from 855 cases with cancer [821 with early gastric carcinoma (EGC) and 34 malignant lymphoma (ML)] and developed a lesion detection system using 10,994 images. The remaining images were used as a test dataset. Additional validation was performed using a new dataset containing 50 EGC and 1,200 non-GC images by comparing the interpretation of ten endoscopists (five trainees and five experts). Furthermore, we developed another system to detect low-quality images, which are not suitable for diagnosis, using 2198 images. RESULTS: In the validation of 1983 images from the 124 cancer cases, the DCSS diagnosed cancer with a sensitivity of 89.2%, positive predictive value (PPV) of 93.3%, and an accuracy of 83.3%. EGC was detected in 93.2% and ML in 92.5% of cases. Comparing with the endoscopists, sensitivity was significantly higher in the DCSS, and the average diagnostic time was significantly shorter using the DCSS than that by the trainees. The sensitivity, specificity, PPV, and accuracy in detecting low-quality images were 65.8%, 93.1%, 79.6%, and 85.2% for "Blur" and 57.8%, 91.7%, 82.2%, and 78.1% for "Mucus adhesion," respectively. CONCLUSIONS: The DCSS showed excellent capability in detecting lesions and pointing out low-quality images.

Long-term outcomes of cold snare polypectomy for superficial non-ampullary duodenal epithelial tumors.

BACKGROUND AND AIM: The effectiveness of cold snare polypectomy (CSP) for superficial non-ampullary duodenal epithelial tumors (SNADETs) regarding long-term outcomes is not fully clarified. This study aimed to investigate long-term outcomes of CSP for SNADETs. METHODS: Patients diagnosed with sporadic SNADETs and treated with CSP at Chiba University Hospital between March 2015 and May 2018 were retrospectively analyzed. Long-term outcomes, short-term outcomes, and adverse events were investigated. RESULTS: In total, 35 patients with 46 lesions were included. The en-bloc resection rate was 97.8%. Thirty-seven lesions (80.4%) were diagnosed as adenomatous. The R0 resection rate for adenomatous lesions was 70.3%. Follow-up investigations more than 12 months after CSP were completed for 35 adenomatous lesions (94.6%). The median observation period after CSP was 48 months. One patient whose observation period was only 3 months died from chronic heart failure with cardiac sarcoidosis 6 months after CSP. No patient died from SNADETs. The relapse-free survival rate at 12 months after CSP was 97.1%. One recurrence (2.7%) was observed 12 months after CSP. We removed the recurrence lesion with CSP and cold forceps polypectomy. No new recurrence occurred within the observation period. No perforation or post-operative bleeding occurred for CSP. CONCLUSIONS: Cold snare polypectomy for diminutive and small SNADETs is a safe and useful procedure with a high en-bloc resection rate and long-term local control capability.

Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study.

BACKGROUND: We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy. METHODS: In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs). RESULTS: Overall, 256 patients received a median of 6.0 doses (range: 1-52) of nivolumab over a median duration of 72.5 days (range: 1-736). Median OS was 9.5 months [95% confidence interval (CI) 8.2-12.0] and median PFS was 2.1 months (95% CI 1.8-2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9-11.9) and 3.5 months (95% CI 2.3-5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis. CONCLUSIONS: Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis.

BACKGROUND: With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles. METHODS: Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel®) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation® CDx was investigated. RESULTS: In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne® CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion. CONCLUSIONS: Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.

X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization.

AIM: The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case-control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies. METHODS: To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies. RESULTS: Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (P = 0.028) and 47, XXX (P = 0.011). Phenotypic data were available from 12 patients. Treatment-resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment-resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations. CONCLUSION: These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms.

Near-Infrared Time-Resolved Spectroscopy Shows Anterior Prefrontal Blood Volume Reduction in Schizophrenia but Not in Major Depressive Disorder.

Previous studies using various brain imaging methods have reported prefrontal blood flow disturbances in psychiatric disorders, including schizophrenia and major depressive disorder. In both disorders, alterations of the resting blood flow, in addition to that of the activation in response to task load, have been shown, but the results are not consistent. The present study aimed to examine the anterior prefrontal hemoglobin concentration at the resting state in schizophrenia and depression using near-infrared time-resolved spectroscopy (NIR-TRS), which estimates the optical absorption coefficients and calculates the absolute concentrations of oxygenated (oxy-Hb), deoxygenated (deoxy-Hb), and total (total-Hb; sum of oxy-Hb and deoxy-Hb) hemoglobin. Their ratios to systemic blood hemoglobin concentration (blood-Hb) were also assessed. In agreement with our previous data, total-Hb and total-Hb/blood-Hb in schizophrenia were significantly lower. The present study further revealed that both oxy-Hb/blood-Hb and deoxy-Hb/blood-Hb in schizophrenia were reduced. In depression, total-Hb, total-Hb/blood-Hb, oxy-Hb, and oxy-Hb/blood-Hb were higher than in schizophrenia and were not different from the control. The oxygen saturation (oxy-Hb/total-Hb), in addition to the optical pathlengths, did not show group differences. Lowered oxy-Hb/blood-Hb and deoxy-Hb/blood-Hb together with unchanged oxygen saturation may indicate that the prefrontal blood volume is reduced in schizophrenia. The present findings suggest that NIR-TRS is useful in analyzing the hemodynamic aspects of prefrontal dysfunction in schizophrenia and differentiating schizophrenia from depression.

Disclosure of secondary findings in exome sequencing of 2480 Japanese cancer patients.

High-throughput sequencing has greatly contributed to precision medicine. However, challenges remain in reporting secondary findings (SFs) of germline pathogenic variants and managing the affected patients. The aim of this study was to examine the incidence of SFs in Japanese cancer patients using whole exome sequencing (WES) and to understand patient preferences regarding SF disclosure. WES was conducted for 2480 cancer patients. Genomic data were screened and classified for variants of 59 genes listed by the American College of Medical Genetics and Genomics SF v2.0 and for an additional 13 hereditary cancer-related genes. Majority of the participants (68.9%; 1709/2480) opted for disclosure of their SFs. Thirty-two pathogenic or likely pathogenic variants, including BRCA1 (7 patients), BRCA2 (4), CHEK2 (4), PTEN (3), MLH1 (3), SDHB (2), MSH6 (1), NF1 (1), EXT2 (1), NF1 (1), NTRK1 (1), MYH7 (3), MYL2 (1), TNNT2 (1), LDLR (2), FBN1 (1), and KCNH2 (1) were recognized in 36 patients (1.5%). Twenty-eight (77.8%) patients underwent genetic counseling and received their SF results. Eighteen (64.3%) patients underwent clinical management for SFs. Genetic validation tests were administered significantly more frequently to patients with than without a SF-related personal history (P = 0.025). This was a first attempt at a large-scale systematic exome analysis in Japan; nevertheless, many cancer patients opted for disclosure of SFs and accepted or considered clinical management.

Computer-aided diagnosis system using only white-light endoscopy for the prediction of invasion depth in colorectal cancer.

BACKGROUND AND AIMS: Endoscopic treatment is recommended for low-grade dysplasia (LGD), high-grade dysplasia (HGD), and colorectal cancer (CRC) with submucosal (SM) invasion <1000 µm. However, diagnosis of invasion depth requires experience and is often difficult. This study developed and evaluated a novel computer-aided diagnosis (CAD) system to determine whether endoscopic treatment is appropriate for colorectal lesions using only white-light endoscopy (WLE). METHODS: We extracted 3442 images from 1035 consecutive colorectal lesions (105 LGDs, 377 HGDs, 107 CRCs with SM <1000 µm, 146 CRCs with SM ≥1000 µm, and 300 advanced CRCs). All images were WLE, nonmagnified, and nonstained. We developed a novel CAD system using 2751 images; the remaining 691 images were evaluated by the CAD system as a test set. The capability of the CAD system to distinguish endoscopically treatable lesions and untreatable lesions was assessed and compared with the results from 2 trainees and 2 experts. RESULTS: The CAD system distinguished endoscopically treatable from untreatable lesions with 96.7% sensitivity, 75.0% specificity, and 90.3% accuracy. These values were significantly higher than those from trainees (92.1%, 67.6%, and 84.9%; P < .01, <.01, and <.01, respectively) and were comparable with those from experts (96.5%, 72.5%, and 89.4%, respectively). Trainees assisted by the CAD system demonstrated a diagnostic capability comparable with that of experts. CONCLUSIONS: The CAD system had good diagnostic capability for making treatment decisions for colorectal lesions. This system may enable a more convenient and accurate diagnosis using only WLE.

Water-assisted colonoscopy: an international modified Delphi review on definitions and practice recommendations.

BACKGROUND AND AIMS: Since 2008, a plethora of research studies has compared the efficacy of water-assisted (aided) colonoscopy (WAC) and underwater resection (UWR) of colorectal lesions with standard colonoscopy. We reviewed and graded the research evidence with potential clinical application. We conducted a modified Delphi consensus among experienced colonoscopists on definitions and practice of water immersion (WI), water exchange (WE), and UWR. METHODS: Major databases were searched to obtain research reports that could potentially shape clinical practice related to WAC and UWR. Pertinent references were graded (Grading of Recommendations, Assessment, Development and Evaluation). Extracted data supporting evidence-based statements were tabulated and provided to respondents. We received responses from 55 (85% surveyed) experienced colonoscopists (37 experts and 18 nonexperts in WAC) from 16 countries in 3 rounds. Voting was conducted anonymously in the second and third round, with ≥80% agreement defined as consensus. We aimed to obtain consensus in all statements. RESULTS: In the first and the second modified Delphi rounds, 20 proposed statements were decreased to 14 and then 11 statements. After the third round, the combined responses from all respondents depicted the consensus in 11 statements (S): definitions of WI (S1) and WE (S2), procedural features (S3-S5), impact on bowel cleanliness (S6), adenoma detection (S7), pain score (S8), and UWR (S9-S11). CONCLUSIONS: The most important consensus statements are that WI and WE are not the same in implementation and outcomes. Because studies that could potentially shape clinical practice of WAC and UWR were chosen for review, this modified Delphi consensus supports recommendations for the use of WAC in clinical practice.

Second-generation narrow-band imaging to detect colorectal adenomas: A prospective study including community hospitals.

BACKGROUND AND AIM: It is unclear whether second-generation narrow-band imaging (NBI) improves colorectal adenoma detection in clinical practice. We aimed to evaluate the ability of NBI to detect adenomas in academic and community hospitals. METHODS: This observational, multicenter study was conducted in four academic and four community hospitals between July 2018 and April 2019. We enrolled patients aged ≥ 20 years who underwent colonoscopy for screening, polyp surveillance, or diagnostic workup. The primary endpoint was the adenoma detection rate (ADR) between NBI (NBI group) and white-light imaging colonoscopies (WLI group) after propensity score (PS) matching. RESULTS: Of 1831 patients analyzed before PS matching, the NBI and WLI groups included 742 and 1089 patients, respectively. After PS matching, 711 pairs from both groups were analyzed. ADR and the mean number of adenomas per patient did not differ significantly between the NBI and WLI groups (43.5% vs 44.4%, P = 0.71; 0.90 ± 1.38 vs 0.91 ± 1.40, P = 0.95, respectively). Academic hospitals showed higher ADR in the NBI group (60.5% vs 53.8%), whereas community hospitals showed higher ADR in the WLI group (35.8% vs 40.5%). In the NBI group, ADR was significantly higher among NBI-screening-experienced endoscopists than among NBI-screening-inexperienced endoscopists (63.2% vs 39.2%, P < 0.001). The mean number of flat and depressed lesions detected per patient was significantly higher with NBI than with WLI (0.62 ± 1.34 vs 0.44 ± 1.01, P = 0.035). CONCLUSIONS: Second-generation NBI could not surpass WLI in terms of ADR based on patient recruitment from both academic and community hospitals but improved the detection of easily overlooked flat and depressed lesions.

Current status of medical oncology in Japan and changes over the most recent 7-year period: results of a questionnaire sent to designated cancer care hospitals.

BACKGROUND: According to a questionnaire sent to Designated Cancer Care Hospitals in Japan in 2013, only 39.4% of the institutes had medical oncology departments. Furthermore, most of these medical oncology departments were primarily responsible for the treatment of limited disease categories and the administration of newly developed therapeutic modalities, including molecular-targeted therapy. The aim of the present study was to update these previous findings and to clarify the changes over the intervening 7-year period. METHODS: The questionnaire was sent to all 393 Designated Cancer Care Hospitals on 13 March 2020. Similar to the previous questionnaires, questions were asked regarding the presence of a medical oncology department, the number of physicians in the department and the degrees of responsibility for drug therapies provided by medical oncologists to adult patients with solid cancers. RESULTS: In total, 270 institutions (68.7%) responded. Overall, 145 of these 270 institutions (53.7%) had medical oncology departments, representing a significant increase compared with the results of the previous study (P < 0.01). Among the institutions with a medical oncology department, these departments were responsible for the administration of over 30% of all cytotoxic and molecular-targeted drug therapies for extragonadal germ cell tumors, cancers of unknown primary site, soft tissues, head and neck, esophagus, stomach, colon and rectum, and pancreas as well as the administration of immune checkpoint inhibitors (ICI) for microsatellite instability-high tumors, cancers of the stomach, esophagus and head and neck, and melanoma. CONCLUSION: The proportion of institutes with medical oncology departments in Japan has increased. In addition, the responsibility of medical oncology departments has expanded to include newly emerging drugs, such as ICIs.

Colonoscopic evaluation of diarrhea/colitis occurring as an immune-related adverse event.

OBJECTIVE: Diarrhea is often observed as an immune-related adverse event. In this study, we conducted a retrospective review of the severity of diarrhea, its treatment and the endoscopic findings in patients developing diarrhea as an immune-related adverse event. METHODS: From August 2015 to June 2019, a total of 369 patients received treatment with immune checkpoint inhibitors at our hospital. For this study, development of grade 2 or more diarrhea in these patients was defined as an immune-related adverse event. We analyzed the histopathological severity of the bowel lesions according to the Nancy histological index for ulcerative colitis. RESULTS: Of the 369 patients, 27 (7.3%) developed diarrhea as an immune-related adverse event. Of these 27 patients, 18 received steroid treatment. Colonoscopy was performed in 17 patients and culture of the feces in 18. The tests revealed evidence of bacterial colitis (Aeromonas hydrophila) in two patients. The Nancy histological index was 4, 3, 2, 1 and 0 in two, three, two, two and seven patients, respectively. No findings on colonoscopy were observed in 7 of the 17 patients (41%) who underwent colonoscopy, and most of these patients recovered without steroid treatment. Patients with lower values of the Nancy histological index tended to show better responses to steroid treatment. CONCLUSIONS: To avoid unnecessary steroid administration, colonoscopic evaluation is essential in patients receiving treatment with immune checkpoint inhibitors who present with diarrhea as an immune-related adverse event. In addition, the endoscopic findings could be useful to predict the response to steroid treatment.