Publications by authors named "Tsuyoshi Hamada"

221 Publications

Disconnected pancreatic duct syndrome and outcomes of endoscopic ultrasound-guided treatment of pancreatic fluid collections: Systematic review and meta-analysis.

Dig Endosc 2021 Sep 20. Epub 2021 Sep 20.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Disconnected pancreatic duct syndrome (DPDS) frequently occurs in patients with acute necrotizing pancreatitis and resultant pancreatic fluid collection (PFC). We performed a systematic review and meta-analysis to evaluate outcomes of endoscopic ultrasound-guided treatment of PFCs according to the presence of DPDS.

Methods: Using PubMed, Embase, and the Cochrane database, we identified clinical studies published until January 2021 with data comparing outcomes of endoscopic ultrasound-guided drainage of PFCs between DPDS and non-DPDS patients. We pooled data on technical and clinical success rates, PFC recurrence, and adverse events using the random-effects model.

Results: We identified five eligible articles including 941 PFC patients treated with endoscopic ultrasound-guided interventions. Clinical success, defined as resolution of the PFC and symptoms, was achieved in a majority of the cases irrespective of DPDS (pooled odds ratio [OR] comparing DPDS to non-DPDS patients, 0.77; 95% confidence interval [CI] 0.33-1.81). Compared to patients without DPDS, patients with DPDS were more likely to undergo PFC recurrence (pooled OR 6.72; 95% CI 2.72-16.6) after clinical resolution of PFC. Prolonged plastic stent placement following the clinical resolution was more frequently performed in DPDS patients than in non-DPDS patients (pooled OR 15.9; 95% CI 2.76-91.9). No statistically significant difference was observed between the groups in terms of the rate of technical success, adverse events, or mortality.

Conclusion: Disconnected pancreatic duct syndrome was associated with higher rate of PFC recurrence after successful endoscopic treatment of PFCs. Future studies should evaluate effectiveness and optimal duration of long-term placement of transmural plastic stents for PFCs with DPDS.
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http://dx.doi.org/10.1111/den.14142DOI Listing
September 2021

Use of proton pump inhibitors and cholangitis complicated with multi-drug resistant bacteria.

J Hepatobiliary Pancreat Sci 2021 Aug 12. Epub 2021 Aug 12.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Multidrug-resistant bacteria (MDRB) has rapidly spread worldwide and become a serious problem. Proton pump inhibitors (PPIs) are a class of commonly prescribed medications, but recent studies have suggested the increased risk of infection with MDRB in PPI users. We evaluated the association between PPI use and incidence of cholangitis with MDRB.

Methods: Consecutive patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 2010 and August 2019 were included in this retrospective study. The incidence of cholangitis with MDRB was compared between regular and non-regular PPI users.

Results: A total of 1224 regular PPI users and 1528 non-regular PPI users were identified. There was no clinically significant difference in age and sex between the groups. Indication of ERCP was different between the groups. The number of ERCP sessions during the study periods was higher in regular PPI users. The incidence of cholangitis with MDRB was significantly higher in regular PPI users (3.0% vs 1.1%; P < .001). Multivariable-adjusted odds ratio for cholangitis with MDRB comparing regular PPI users to non-regular users was 2.19 (95% confidence interval 1.20-4.00; P = .01).

Conclusions: Regular PPI use was associated with a higher risk of cholangitis with MDRB.
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http://dx.doi.org/10.1002/jhbp.1035DOI Listing
August 2021

The "zipline" technique for double-balloon enteroscopy-assisted removal of a migrated stent in a peripheral bile duct.

Endoscopy 2021 Jul 19. Epub 2021 Jul 19.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1055/a-1530-4969DOI Listing
July 2021

Prognosis of primary sclerosing cholangitis according to age of onset.

J Hepatobiliary Pancreat Sci 2021 Apr 2. Epub 2021 Apr 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Liver failure and biliary tract cancer (BTC) are major life-threatening events in the clinical course of primary sclerosing cholangitis (PSC). Although these are competing events, they are typically evaluated as a composite prognostic endpoint. In Japan, the clinical characteristics and prognosis of PSC reportedly differ according to age of onset. We compared the prognosis of younger- versus older-onset PSC by competing risk analysis.

Methods: This was a retrospective analysis of 144 patients with PSC who were followed up for a median of 6.7 years. The patients were divided into two groups according to a cutoff age of onset of 44 years. We compared the prognosis of younger-onset PSC (n = 91) and older-onset PSC (n = 53) by competing risk analysis, incorporating mortality related and that unrelated to BTC as competing events.

Results: There was no difference in BTC-related mortality between patients with younger-onset and those with older-onset PSC (subdistribution hazard ratio [SHR], 0.89; 95% confidence interval [CI], 0.17-4.56, P = .888). The cumulative incidence of mortality due to other causes, including liver transplantation and liver failure, was non-significantly higher in patients with older-onset PSC (SHR, 1.58; 95% CI, 0.88-2.84; P = .129).

Conclusions: Although we did not find a significant difference in prognosis by onset age, patients with older-onset PSC had worse liver-transplantation-free survival than those with younger-onset PSC. A large cohort study is needed to evaluate the clinical outcomes of older- and younger-onset PSC.
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http://dx.doi.org/10.1002/jhbp.952DOI Listing
April 2021

Long-term outcome of endotherapy for pancreatic stones by using a dedicated pancreatic basket catheter.

J Gastroenterol Hepatol 2021 Sep 22;36(9):2424-2431. Epub 2021 Mar 22.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background And Aim: Although endotherapy for pancreatic stones is less invasive compared with surgical interventions, its recurrence rate is high and residual pancreatic stones can be a cause of recurrence. We previously reported usefulness of a novel basket catheter with nitinol fine reticular structure for pancreatic stone retraction. In this retrospective study, we aimed to evaluate the long-term outcomes of endotherapy for pancreatic stones with and without the use of this dedicated basket catheter.

Methods: We retrospectively compared patients with symptomatic pancreatic stones who underwent the initial endotherapy between 2008 and 2019. The primary outcome was the symptomatic recurrence after complete stone clearance. Secondary outcomes were the rate of complete stone clearance, complications, risk factors for recurrences, and the treatment cost.

Results: A total of 101 patients who underwent endotherapy for pancreatic stones were analyzed: 41 patients by using the dedicated basket catheter and 60 patients by only the conventional devices. The complete stone clearance was achieved in 87.8% in the dedicated basket group and 88.3% in the conventional device group. Symptomatic recurrence was observed in 16.7% of the dedicated basket group and 47.2% of the conventional device group (P < 0.01). In the multivariate analysis, the use of the dedicated basket catheter was significantly associated with the reduced risk of symptomatic recurrence (hazard ratio, 0.40; 95% confidence interval, 0.15-0.92, P = 0.031). The complication rate and the cost were comparable between the two groups.

Conclusion: The use of this dedicated pancreatic basket catheter significantly reduced symptomatic recurrence after complete pancreatic stone removal.
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http://dx.doi.org/10.1111/jgh.15481DOI Listing
September 2021

ABO Blood Group and Risk of Pancreatic Carcinogenesis in Intraductal Papillary Mucinous Neoplasms.

Cancer Epidemiol Biomarkers Prev 2021 05 2;30(5):1020-1028. Epub 2021 Mar 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: ABO blood group has been associated with risks of various malignancies, including pancreatic cancer. No study has evaluated the association of ABO blood group with incidence of pancreatic carcinogenesis during follow-up of patients with intraductal papillary mucinous neoplasms (IPMN).

Methods: Among 3,164 patients diagnosed with pancreatic cysts at the University of Tokyo (Tokyo, Japan) from 1994 through 2019, we identified 1,815 patients with IPMN with available data on ABO blood group. We studied the association of ABO blood group with incidence of pancreatic carcinoma, overall and by carcinoma types [IPMN-derived carcinoma or concomitant pancreatic ductal adenocarcinoma (PDAC)]. Utilizing competing-risks proportional hazards models, we estimated subdistribution hazard ratios (SHR) for incidence of pancreatic carcinoma with adjustment for potential confounders, including cyst characteristics.

Results: During 11,518 person-years of follow-up, we identified 97 patients diagnosed with pancreatic carcinoma (53 with IPMN-derived carcinoma and 44 with concomitant PDAC). Compared with patients with blood group O, patients with blood groups A, B, and AB had multivariable SHRs (95% confidence intervals) for pancreatic carcinoma of 2.25 (1.25-4.07; = 0.007), 2.09 (1.08-4.05; = 0.028), and 1.17 (0.43-3.19; = 0.76), respectively. We observed no differential association of ABO blood group with pancreatic carcinoma incidence by carcinoma types.

Conclusions: In this large long-term study, patients with IPMN with blood group A or B appeared to be at higher risk of pancreatic carcinoma compared with those with blood group O.

Impact: ABO blood group can be a biomarker for pancreatic cancer risk among patients with IPMNs.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1581DOI Listing
May 2021

Association of with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.

Clin Cancer Res 2021 May 25;27(10):2816-2826. Epub 2021 Feb 25.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Purpose: While evidence indicates that () may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.

Experimental Design: We measured DNA within tumor tissue by quantitative PCR on 933 cases (including 128 -positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on , microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between and T-cell subsets.

Results: The amount of was inversely associated with tumor stromal CD3 lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28-0.79, for -high vs. -negative category; = 0.0004] and specifically stromal CD3CD4CD45RO cells (corresponding multivariable OR, 0.52; 95% CI, 0.32-0.85; = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs.

Conclusions: The amount of tissue is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127352PMC
May 2021

A Meta-analysis of Slow Pull versus Suction for Endoscopic Ultrasound-Guided Tissue Acquisition.

Gut Liver 2021 07;15(4):625-633

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background/aims: Endoscopic ultrasound (EUS)-guided tissue acquisition is widely utilized as a diagnostic modality for intra-abdominal masses, but there remains debate regarding which suction technique, slow pull (SP) or conventional suction (CS), is better. A meta-analysis of reported studies was conducted to compare the diagnostic yields of SP and CS during EUS-guided tissue acquisition.

Methods: We conducted a systematic electronic search using MEDLINE/PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials to identify clinical studies comparing SP and CS. We meta-analyzed accuracy, sensitivity, blood contamination and cellularity using the random-effects model.

Results: A total of 17 studies (seven randomized controlled trials, four prospective studies, and six retrospective studies) with 1,616 cases were included in the analysis. Compared to CS, there was a trend toward better accuracy (odds ratio [OR], 1.48; 95% confidence interval [CI], 0.97 to 2.27; p=0.07) and sensitivity (OR, 1.67; 95% CI, 0.95 to 2.93; p=0.08) with SP and a significantly lower rate of blood contamination (OR, 0.48; 95% CI, 0.33 to 0.69; p<0.01). However, there was no significant difference in cellularity between SP and CS, with an OR of 1.28 (95% CI, 0.68 to 2.40; p=0.45). When the use of a 25-gauge needle was analyzed, the accuracy and sensitivity of SP were significantly better than those of CS, with ORs of 4.81 (95% CI, 1.99 to 11.62; p<0.01) and 4.69 (95% CI, 1.93 to 11.40; p<0.01), respectively.

Conclusions: Compared to CS, SP appears to provide better accuracy and sensitivity in EUSguided tissue acquisition, especially when a 25-gauge needle is used.
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http://dx.doi.org/10.5009/gnl20270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283288PMC
July 2021

Depressed Colorectal Cancer: A New Paradigm in Early Colorectal Cancer.

Clin Transl Gastroenterol 2020 12;11(12):e00269

Kyushu University Beppu Hospital, Beppu, Japan.

Introduction: In contrast to most colorectal carcinomas arising from pedunculated or sessile protruded adenomas, submucosal-invasive (pT1) colorectal carcinoma exhibiting a depressed surface (hereinafter, "depressed colorectal carcinoma," identified by means of high-definition endoscopy) is considered to be derived from depressed precursors. We hypothesized that depressed colorectal neoplasms have unique clinicopathological features different that are different from those of protruded and flat colorectal neoplasms.

Methods: We classified 27,129 colorectal neoplasms (909 pT1 carcinomas and 26,220 adenomas) resected between 2001 and 2017 into depressed (211 carcinomas and 109 adenomas), flat (304 carcinomas and 11,246 adenomas), and protruded subtypes (394 carcinomas and 14,865 adenomas) and compared their clinicopathological features. As exploratory analyses of pT1 carcinomas, we conducted whole-exome sequencing for 19 depressed and 8 protruded subtypes and RNA sequencing for 8 depressed and 8 protruded subtypes.

Results: pT1 carcinomas were more common in depressed lesions (66%) than in protruded (2.6%) and flat lesions (2.6%) (P < 0.001). Compared with nondepressed pT1 carcinomas, depressed pT1 carcinomas were positively correlated with lymphovascular invasion, tumor budding, and massive submucosal invasion and inversely correlated with the presence of an adenoma component (all P < 0.001). Depressed adenomas were more likely to contain high-grade dysplasia than nondepressed adenomas (49% vs 11%, P < 0.001). A KRAS mutation was observed only in one of the 19 depressed pT1 carcinomas. Relative to protruded carcinomas, depressed carcinomas generally exhibited higher expression of genes related to angiogenesis and epithelial-mesenchymal transition.

Discussion: Depressed colorectal neoplasms may harbor a unique combination of malignant histopathological phenotypes and molecular features.
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http://dx.doi.org/10.14309/ctg.0000000000000269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732270PMC
December 2020

Small-caliber plastic stent for endoscopic ultrasound-guided drainage of a non-dilated pancreatic duct.

Endoscopy 2021 Nov 14;53(11):E407-E408. Epub 2021 Jan 14.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1055/a-1333-0538DOI Listing
November 2021

Rising incidence of early-onset colorectal cancer - a call to action.

Nat Rev Clin Oncol 2021 04 20;18(4):230-243. Epub 2020 Nov 20.

Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

The incidence of early-onset colorectal cancer (CRC), which occurs in individuals <50 years of age, has been increasing worldwide and particularly in high-income countries. The reasons for this increase remain unknown but plausible hypotheses include greater exposure to potential risk factors, such as a Western-style diet, obesity, physical inactivity and antibiotic use, especially during the early prenatal to adolescent periods of life. These exposures can not only cause genetic and epigenetic alterations in colorectal epithelial cells but also affect the gut microbiota and host immunity. Early-onset CRCs have differential clinical, pathological and molecular features compared with later-onset CRCs. Certain existing resources can be utilized to elucidate the aetiology of early-onset CRC and inform the development of effective prevention, early detection and therapeutic strategies; however, additional life-course cohort studies spanning childhood and young adulthood, integrated with prospective biospecimen collections, omics biomarker analyses and a molecular pathological epidemiology approach, are needed to better understand and manage this disease entity. In this Perspective, we summarize our current understanding of early-onset CRC and discuss how we should strategize future research to improve its prevention and clinical management.
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http://dx.doi.org/10.1038/s41571-020-00445-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994182PMC
April 2021

Role of Endoscopic Ultrasonography-Guided Fine Needle Aspiration/Biopsy in the Diagnosis of Autoimmune Pancreatitis.

Diagnostics (Basel) 2020 Nov 15;10(11). Epub 2020 Nov 15.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Type 1 autoimmune pancreatitis (AIP) is histologically characterized by lymphoplasmacytic sclerosing pancreatitis (LPSP). Recently, the diagnostic yield of endoscopic ultrasonography-guided fine needle aspiration/biopsy (EUS-FNA/B) for AIP has been reported. However, its role in the diagnostic flow of AIP is not fully elucidated. We retrospectively reviewed 53 consecutive patients who were suspected with AIP and underwent EUS-FNA/B. We evaluated the contribution of EUS-FNA/B to the diagnosis of AIP before considering response to steroid therapy among patients with diffuse enlargement of the pancreas and those with focal enlargement, respectively. Twenty-two patients showed diffuse pancreatic enlargement and 31 showed focal enlargement. The final diagnosis was definitive AIP in 32 patients, probable AIP in 2, possible AIP in 1, and mass-forming focal pancreatitis in 18. There was no change in diagnosis after EUS-FNA/B among patients with diffuse pancreatic enlargement, while diagnosis changed in 38.7% (12/31) among those with focal enlargement-there was a probable to definitive diagnosis in 4 patients, unspecified to definitive in 3, and unspecified to probable in 5. EUS-FNB provided a significantly higher sensitivity for typical pathological findings of LPSP than EUS-FNA, and 10 patients were diagnosed as pathologically definitive AIP by EUS-FNB, though none were by EUS-FNA ( = 0.002). EUS-FNA/B was useful in the diagnosis of focal type AIP, and steroid therapy could be introduced after the diagnosis was confirmed. Meanwhile, EUS-FNA/B provided no contribution to diagnosis of diffuse type AIP. EUS-FNB showed a higher diagnostic yield than FNA.
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http://dx.doi.org/10.3390/diagnostics10110954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698022PMC
November 2020

The microbiome, genetics, and gastrointestinal neoplasms: the evolving field of molecular pathological epidemiology to analyze the tumor-immune-microbiome interaction.

Hum Genet 2021 May 12;140(5):725-746. Epub 2020 Nov 12.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, MA, 02115, USA.

Metagenomic studies using next-generation sequencing technologies have revealed rich human intestinal microbiome, which likely influence host immunity and health conditions including cancer. Evidence indicates a biological link between altered microbiome and cancers in the digestive system. Escherichia coli and Bacteroides fragilis have been found to be enriched in colorectal mucosal tissues from patients with familial adenomatous polyposis that is caused by germline APC mutations. In addition, recent studies have found enrichment of certain oral bacteria, viruses, and fungi in tumor tissue and fecal specimens from patients with gastrointestinal cancer. An integrative approach is required to elucidate the role of microorganisms in the pathogenic process of gastrointestinal cancers, which develop through the accumulation of somatic genetic and epigenetic alterations in neoplastic cells, influenced by host genetic variations, immunity, microbiome, and environmental exposures. The transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to link germline genetics and environmental factors (including diet, lifestyle, and pharmacological factors) to pathologic phenotypes. The integration of microbiology into the MPE model (microbiology-MPE) can contribute to better understanding of the interactive role of environment, tumor cells, immune cells, and microbiome in various diseases. We review major clinical and experimental studies on the microbiome, and describe emerging evidence from the microbiology-MPE research in gastrointestinal cancers. Together with basic experimental research, this new research paradigm can help us to develop new prevention and treatment strategies for gastrointestinal cancers through targeting of the microbiome.
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http://dx.doi.org/10.1007/s00439-020-02235-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052267PMC
May 2021

A retrospective comparative study of S-IROX and modified FOLFIRINOX for patients with advanced pancreatic cancer refractory to gemcitabine plus nab-paclitaxel.

Invest New Drugs 2021 04 23;39(2):605-613. Epub 2020 Oct 23.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: The aim of this study was to evaluate the efficacy and tolerability of S-IROX and modified FOLFIRINOX (mFFX) after gemcitabine plus nab-paclitaxel for advanced pancreatic cancer (PC) in the real world setting.

Methods: Consecutive patients receiving S-IROX or mFFX as a second-line chemotherapy for advanced PC refractory to gemcitabine plus nab-paclitaxel were retrospectively studied. Patients were treated every 2 weeks: S-1 40 mg/m was administered orally twice daily on days 1 to 7 in S-IROX and 5-fluorouracil 2400 mg/m was intravenously administered for 46 h without bolus infusion in mFFX, in addition to intravenous oxaliplatin 85 mg/m and irinotecan 150 mg/m on day 1 in both regimens.

Results: Fifty-four patients with advanced PC who received S-IROX (n = 19) or mFFX (n = 35) were retrospectively studied. The disease control rate and response rate were 73.7% and 10.5% in the S-IROX group and 62.2% and 2.7% in the mFFX group, respectively. The median progression free survival (PFS) was 7.8 and 5.7 months in the S-IROX and mFFX groups (p = 0.24). The median overall survival (OS) was 14.2 and 11.5 months in the S-IROX and mFFX groups (p = 0.34). There were no significant differences in the incidences of grade 3-4 adverse effects. The subgroup analyses suggested S-IROX demonstrated favorable OS in patients with PFS ≥6 months of first-line gemcitabine plus nab-paclitaxel (p for interaction = 0.02).

Conclusions: S-IROX and mFFX were similarly tolerable and effective as a second-line chemotherapy in patients with PC refractory to gemcitabine plus nab-paclitaxel.
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http://dx.doi.org/10.1007/s10637-020-01022-0DOI Listing
April 2021

Smoking Status at Diagnosis and Colorectal Cancer Prognosis According to Tumor Lymphocytic Reaction.

JNCI Cancer Spectr 2020 Aug 14;4(5):pkaa040. Epub 2020 May 14.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Smoking has been associated with worse colorectal cancer patient survival and may potentially suppress the immune response in the tumor microenvironment. We hypothesized that the prognostic association of smoking behavior at colorectal cancer diagnosis might differ by lymphocytic reaction patterns in cancer tissue.

Methods: Using 1474 colon and rectal cancer patients within 2 large prospective cohort studies (Nurses' Health Study and Health Professionals Follow-up Study), we characterized 4 patterns of histopathologic lymphocytic reaction, including tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral lymphocytic reaction, and Crohn's-like lymphoid reaction. Using covariate data of 4420 incident colorectal cancer patients in total, an inverse probability weighted multivariable Cox proportional hazards regression model was conducted to adjust for selection bias due to tissue availability and potential confounders, including tumor differentiation, disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, and , , and mutations.

Results: The prognostic association of smoking status at diagnosis differed by TIL status. Compared with never smokers, the multivariable-adjusted colorectal cancer-specific mortality hazard ratio for current smokers was 1.50 (95% confidence interval = 1.10 to 2.06) in tumors with negative or low TIL and 0.43 (95% confidence interval = 0.16 to 1.12) in tumors with intermediate or high TIL (2-sided = .009). No statistically significant interactions were observed in the other patterns of lymphocytic reaction.

Conclusions: The association of smoking status at diagnosis with colorectal cancer mortality may be stronger for carcinomas with negative or low TIL, suggesting a potential interplay of smoking and lymphocytic reaction in the colorectal cancer microenvironment.
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http://dx.doi.org/10.1093/jncics/pkaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477375PMC
August 2020

Feasibility of balloon endoscope-assisted endoscopic retrograde cholangiopancreatography for the elderly.

Endosc Int Open 2020 Sep 31;8(9):E1202-E1211. Epub 2020 Aug 31.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Endoscopic retrograde cholangiopancreatography (ERCP) for patients with surgically altered anatomy is challenging. Recently, balloon endoscopy has been shown to facilitate ERCP for this population with a high technical success rate, but adverse events (AEs) are not uncommon. Compared to non-elderly patients, elderly patients may be at higher risk of AEs due to underlying comorbidities. The current study aimed to evaluate the feasibility of balloon endoscope-assisted ERCP (BE-ERCP) for the elderly. We retrospectively identified patients who underwent BE-ERCP between January 2010 and September 2019. For patients who underwent multiple procedures during the study period, the first session was analyzed. Early AEs associated with BE-ERCP were compared between elderly (≥ 75 years) and non-elderly patients. A total of 1,363 BE-ERCP procedures were performed, and 568 patients (211 elderly and 357 non-elderly) were included for the analyses. Technical success rates were high in both the elderly and non-elderly groups (80 % vs. 80 %, respectively). The rates of early AEs were similar between the groups (12 % vs. 9.0 % in the elderly and non-elderly group, respectively;  = 0.31). The mltivariable-adjusted odds ratio for early AEs comparing elderly to non-elderly patients was 1.36 (95 % confidence interval, 0.74-2.51;  = 0.32). Specifically, we did not observe between-group differences in rates of gastrointestinal perforation (2.4 % vs. 2.8 % in elderly and non-elderly groups, respectively;  = 0.99) and aspiration pneumonia (1.9 % vs. 0.6 %,  = 0.20). BE-ERCP is a feasible procedure for elderly individuals with surgically altered anatomy.
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http://dx.doi.org/10.1055/a-1216-1363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458759PMC
September 2020

A Novel Technique of Endoscopic Papillectomy with Hybrid Endoscopic Submucosal Dissection for Ampullary Tumors: A Proof-of-Concept Study (with Video).

J Clin Med 2020 Aug 18;9(8). Epub 2020 Aug 18.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Background: Endoscopic papillectomy (EP) carries a potential risk of procedure-related adverse events and incomplete resection. Since hybrid endoscopic submucosal dissection (ESD) had been established as an alternative option for relatively large and difficult gastrointestinal tumors, we evaluated a novel EP with hybrid ESD (hybrid ESD-EP) for curative safe margin in this proof-of-concept study.

Methods: A total of eight cases who underwent hybrid ESD-EP between 2018 and 2020 were identified from our prospectively maintained database. Hybrid ESD-EP involved a (sub)circumferential incision with partial submucosal dissection, and subsequent snare resection of ampullary tumors, which was performed by two endoscopists with expertise in ESD or endoscopic retrograde cholangiopancreatography. Demographic data and clinicopathological outcomes were retrospectively evaluated.

Results: En bloc resection was achieved by hybrid ESD-EP in all eight cases, with the median procedure time of 112 (range: 65-170) minutes. The median diameters of the resected specimens and tumors were 18 and 12 mm, respectively. All lateral margins were clear, whereas vertical margin was uncertain in three (38%), resulting in the complete resection rate of 63%. Postoperative bleeding and pancreatitis developed in each one (13%). No tumor recurrence was observed even in those cases with uncertain vertical margin, after a median follow-up of 244 (range, 97-678) days.

Conclusions: Hybrid ESD-EP seems to be feasible and promising in ensuring the lateral resection margin. However, further investigations, especially to secure the vertical margin and to shorten the procedure time, should be required.
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http://dx.doi.org/10.3390/jcm9082671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466163PMC
August 2020

Screening Strategy of Pancreatic Cancer in Patients with Diabetes Mellitus.

Diagnostics (Basel) 2020 Aug 8;10(8). Epub 2020 Aug 8.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

The incidence of pancreatic cancer (PCa) is increasing worldwide and has become one of the leading causes of cancer-related death. Screening for high risk populations is fundamental to overcome this intractable malignancy. Diabetes mellitus (DM) is classically known as a risk factor for PCa. Recently the reverse causality is in the spotlight, that is to say, DM is considered to be a manifestation of PCa. Numbers of epidemiological studies clarified that new-onset DM (≤2-year duration) was predominant in PCa patients and the relative risk for PCa inversely correlated with duration of DM. Among patients with new-onset DM, elder onset, weight loss, and rapid exacerbation of glycemic control were reported to be promising risk factors and signs, and the model was developed by combining these factors. Several pilot studies disclosed the possible utility of biomarkers to discriminate PCa-associated DM from type 2 DM. However, there is no reliable biomarkers to be used in the practice. We previously reported the application of a multivariate index for PCa based on the profile of plasma free amino acids (PFAAs) among diabetic patients. We are further investigating on the PFAA profile of PCa-associated DM, and it can be useful for developing the novel biomarker in the near future.
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http://dx.doi.org/10.3390/diagnostics10080572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460163PMC
August 2020

A phase I study of intraperitoneal paclitaxel combined with gemcitabine plus nab-paclitaxel for pancreatic cancer with peritoneal metastasis.

Invest New Drugs 2021 02 8;39(1):175-181. Epub 2020 Aug 8.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Purpose: A phase I study of intraperitoneal paclitaxel (ip PTX) combined with gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) (GnP) was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in pancreatic cancer patients with peritoneal metastasis in first-line setting.

Methods: Based on the 3 + 3 dose-escalation model, ip PTX, GEM and nab-PTX were administered at doses of 20 or 30 mg/m, 800 or 1000 mg/m and 100 or 125 mg/m (level 1, 2 and 3, respectively) on days 1, 8 and 15 in 4-week cycles. Dose-limiting toxicity (DLT) defined as severe adverse events was evaluated during the first cycle of the treatment. Safety and preliminary efficacy were also investigated.

Results: In total, 12 patients were enrolled. While 2 of the first 6 patients enrolled at level 1 experienced DLTs (grade 3 ip port dysfunction and grade 3 pneumonia), no DLT was observed in the next 6 patients enrolled at level 2 and 3. Therefore, we did not reach the MTD and the RD was determined to be level 3 (ip PTX of 30 mg/m, GEM of 1000 mg/m, and nab-PTX of 125 mg/m). The major grade 3/4 adverse events included neutropenia (58%), anemia (33%), and ip port dysfunction (25%). The response rate was 25% and the median PFS was 5.4 (95% confidence interval; 2.4-16.0). The cytological status in peritoneal lavage turned negative in 8 patients (67%).

Conclusions: Ip PTX combined with GnP was feasible and potentially effective in pancreatic cancer with peritoneal metastasis as a first-line treatment deserved further evaluations.
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http://dx.doi.org/10.1007/s10637-020-00982-7DOI Listing
February 2021

Novel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice.

Neurotherapeutics 2020 10;17(4):1836-1849

Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.

The accumulation of abnormal prion protein (PrP) produced by the structure conversion of PrP (PrP) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the "hot spot," stabilizes the structure of PrP and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrP levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrP accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use. Our results indicate that in silico drug discovery using NUDE/DEGIMA may be widely useful to identify candidate compounds that effectively stabilize the protein.
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http://dx.doi.org/10.1007/s13311-020-00903-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851219PMC
October 2020

Endoscopic treatment of hepaticojejunostomy anastomotic strictures using fully-covered metal stents.

Dig Endosc 2021 Mar 28;33(3):451-457. Epub 2020 Aug 28.

Departments of, Department of, Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: With the emergence of the double-balloon endoscope (DBE), hepaticojejunostomy anastomotic strictures (HJASs) are increasingly managed endoscopically. However, balloon dilation and/or plastic stent placement may be associated with low stricture resolution rates and long treatment duration. We utilized a fully-covered metal stent (FCSEMS), which was designed for temporary placement for benign biliary strictures, and assessed its feasibility for patients with HJASs.

Methods: We retrospectively studied 20 patients who underwent DBE-assisted FCSEMS placement for HJASs between June 2017 and March 2019. The FCSEMS was removed endoscopically at three months of stent placement. The outcomes investigated were the stricture resolution at the time of FCSEMS removal, the stricture recurrence, and adverse events.

Results: Among 20 patients treated, stricture resolution was achieved in 17 patients (85.0%) at three months of stent placement. The FCSEMS was removed endoscopically without any technical difficulties in all cases except for two with asymptomatic stent migration due to stricture resolution. During a median follow-up period of 11.9 months (interquartile range, 7.5-18.0 months), an HJAS recurred in one patient (5.9%). For two patients without stricture resolution and one patient with recurrent stricture, another FCSEMS placement for 77, 84, and 186 days resolved the stricture. The overall stricture resolution rate was 95.0%. In one patient with FCSEMS-induced de novo stricture, long-term plastic stent placement was required. Procedure-related adverse events included mild cholangitis in two patients and mild pancreatitis in one patient.

Conclusions: Endoscopic treatment using a FCSEMS via DB-ERCP was a feasible and effective treatment option for a HJAS.
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http://dx.doi.org/10.1111/den.13773DOI Listing
March 2021

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1586-1595. Epub 2020 May 28.

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes.

Methods: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors.

Results: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; = 0.032). -mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, < 0.001).

Conclusions: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC.

Impact: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415636PMC
August 2020

Endoscopic Ultrasound-Guided Tissue Acquisition by 22-Gauge Franseen and Standard Needles for Solid Pancreatic Lesions.

Gut Liver 2020 11;14(6):817-825

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.

Background/aims: Recently, a three-plane symmetric needle with Franseen geometry was developed for endoscopic ultrasound-guided fine needle biopsy (EUS-FNB). In this retrospective study, tissue acquisition per pass was compared between 22-gauge Franseen FNB and standard fine needle aspiration (FNA) needles in patients with solid pancreatic lesions.

Methods: Consecutive patients who underwent EUSFNA or EUS-FNB for solid pancreatic lesions between October 2014 and March 2018 were retrospectively studied. The tissue acquisition rate and the diagnostic performance per session, per pass, and at first pass were compared.

Results: A total of 663 passes (300 by the FNB needle and 363 by the standard FNA needle) were performed in 154 patients (71 FNB and 83 FNA). The tissue acquisition rate per session and at first pass in the FNB and FNA groups was 100% and 95% (p=0.13) and 87% and 69% (p=0.007), respectively. The multivariate analysis revealed that among the patients, EUS-FNB (odds ratio, 3.07; p=0.01) was associated with a higher first-pass tissue acquisition rate. While the tissue acquisition rate reached a plateau after the 4th pass with FNA, it reached a plateau after the 2nd pass with FNB. Among the 129 malignant cases, the histological tissue acquisition rate per session was similar (100% and 94%), but the sensitivity by histology alone per session was higher for FNB than for FNA (93% and 73%, p<0.01).

Conclusions: The results of our retrospective analysis indicated that compared with a standard FNA needle, a 22-gauge Franseen FNB needle was associated with a higher first-pass tissue acquisition rate.
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http://dx.doi.org/10.5009/gnl19171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667934PMC
November 2020

Double Guidewire Technique Using an Uneven Double Lumen Catheter for Endoscopic Ultrasound-Guided Interventions.

Dig Dis Sci 2021 05 20;66(5):1540-1547. Epub 2020 May 20.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Endoscopic ultrasonography (EUS)-guided interventions are often performed using a single guidewire (SGW), but there are a few reports on the use of double guidewire (DGW) technique to facilitate multiple drainage placement during EUS-guided drainage of pancreatic fluid collections. This DGW technique may have advantages other than multiple drainage placement during EUS-guided interventions such as scope stabilization, support for stone extraction and device insertion.

Methods: Consecutive patients who underwent EUS-guided interventions between Feb 2012 and Apr 2019 were retrospectively reviewed. The rate and reasons of DGW technique, and clinical outcomes were evaluated. DGW technique was performed, using an uneven double lumen cannula (UDLC), which facilitates insertion of 0.025-in. and 0.035-in. guidewires.

Results: A total of 249 EUS-guided interventions were analyzed, and DGW technique was utilized primarily in 65 cases (25.7%) and as a salvage after failed SGW technique in 18 cases (7.1%). The reasons for DGW technique were 60 multiple drainage placement, 10 scope stabilization, 7 device insertion, 5 safety guidewire, and 4 antegrade stone removal. Insertion of UDLC and DGW was successful in 100%. Technical success rate of preplanned interventions was 92.7% (96.9% in primary DGW and 77.8% in salvage DGW technique). Adverse events were observed in 19.5% after DGW but were not related to DGW technique.

Conclusions: DGW technique using UDLC during EUS-guided interventions was technically feasible and safe. In addition to multiple drainage insertion, it can potentially support complex EUS-guided interventions.
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http://dx.doi.org/10.1007/s10620-020-06345-9DOI Listing
May 2021

Endoscopic management of pancreatic diseases in patients with surgically altered anatomy: clinical outcomes of combination of double-balloon endoscopy- and endoscopic ultrasound-guided interventions.

Dig Endosc 2021 Mar 22;33(3):441-450. Epub 2020 Jul 22.

Departments of, Department of, Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: In patients with surgically altered anatomy, endoscopic treatment of pancreatic diseases is technically challenging. We aimed to evaluate the feasibility, effectiveness, and safety of an interchangeable combination of double-balloon endoscope-assisted ERP (DB-ERP) and endoscopic ultrasonography-guided pancreatic duct drainage (EUS-PD) in this clinical setting.

Methods: Consecutive patients with surgically altered anatomy undergoing endoscopic treatment (DB-ERP, EUS-PD, or both) for pancreatic diseases were studied. The primary outcome was technical success; secondary outcomes were clinical success and adverse events.

Results: Forty patients who underwent DB-ERP (38) and EUS-PD (2) as an initial intervention were retrospectively studied. Indications for intervention included 18 pancreaticojejunostomy anastomotic stricture (PJAS), four pancreatic duct stone (PDS), four pancreatic fistula (PF), 11 PJAS with PDS, and three PJAS with PF. Prior surgical reconstruction was 26 Billroth-II, 13 Roux-en-Y, and one Imanaga reconstruction. Along with salvage procedures including three DB-ERP and seven EUS-PD, the overall technical success rates of DB-ERP and EUS-PD were 70.7% (29/41) and 100% (9/9), respectively. Clinical success was achieved in 85.0% (34/40) by combination of DB-ERP and EUS-PD; successful drainage for PJAS, complete removal of PDS, and resolution of PF were achieved in 90.6%, 80.0%, and 71.4%, respectively. Adverse event rates were 12.2% (5/41; one perforation, and four pancreatitis) in DB-ERP and 55.6% (5/9; three pancreatic leakage, and two abdominal pain) in EUS-PD.

Conclusions: A combination of DB-ERP and EUS-PD can achieve high technical and clinical success for pancreatic diseases in surgically altered anatomy patients. A prospective multicenter study to investigate an appropriate treatment algorithm is warranted.
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http://dx.doi.org/10.1111/den.13746DOI Listing
March 2021

Long-term outcomes of a long, partially covered metal stent for EUS-guided hepaticogastrostomy in patients with malignant biliary obstruction (with video).

Gastrointest Endosc 2020 09 9;92(3):623-631.e1. Epub 2020 Apr 9.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background And Aims: We previously reported safety and effectiveness of EUS-guided hepaticogastrostomy (EUS-HGS) using a long, partially covered metal stent (LP-CMS) for malignant biliary obstruction (MBO). In this study, we aimed to evaluate long-term outcomes of EUS-HGS in an expanded cohort.

Methods: One hundred ten patients undergoing EUS-HGS using an LP-CMS in 2 centers were retrospectively studied. Technical and functional success, adverse events, recurrent biliary obstruction (RBO), and reinterventions were evaluated.

Results: The cause of MBO was pancreatic cancer in 50%, and the location of MBO was distal in 68%. The stent length was 8 cm in 2%, 10 cm in 84%, and 12 cm in 15%, with a median intragastric stent length of 54 mm. Technical and functional success rates were 100% and 94%, respectively. The adverse event rate was 25% (mild 15%, moderate 7%, severe 3%), but about one-half of adverse events were mild transient fever and abdominal pain. RBO developed in 33%, with a median cumulative time to RBO of 6.3 months. The major cause of RBO was hyperplasia at an uncovered portion. The presence of prior biliary drainage and short intragastric stent length were significantly associated with RBO. Reintervention for RBO was successfully achieved through the EUS-HGS route in 92%. The remaining reintervention procedures were 1 EUS-HGS and 2 percutaneous transhepatic biliary drainage all in cases with hilar MBO.

Conclusions: EUS-HGS using an LP-CMS for unresectable MBO was safe and effective. RBO was not uncommon, but reintervention through the EUS-HGS route was technically possible in most cases.
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http://dx.doi.org/10.1016/j.gie.2020.03.3856DOI Listing
September 2020

The impact of age and comorbidity in advanced or recurrent biliary tract cancer receiving palliative chemotherapy.

J Gastroenterol Hepatol 2020 Oct 23;35(10):1828-1835. Epub 2020 Apr 23.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background And Aim: Limited data are available on age and comorbidity assessment in patients with biliary tract cancer (BTC). This study aimed to evaluate the association of age and comorbidity burden with clinical outcomes of chemotherapy for BTC.

Methods: Consecutive 197 BTC patients undergoing first-line chemotherapy between 2007 and 2017 were retrospectively studied. Patients were classified to three groups according to the age-adjusted Charlson comorbidity index (ACCI) excluding the score about BTC and progression-free survival, overall survival (OS), and safety were compared.

Results: Fifty-one patients (26%) were elderly (≥ 75 years), and ACCI was 0-2 in 73 patients (37%), 3-4 in 98 (50%), and ≥ 5 in 26 (13%). ACCI was associated with the administration of first-line combination chemotherapy (89% in 0-2, 80% in 3-4, and 64% in ≥ 5, P < 0.01) and second-line chemotherapy (67% in 0-2, 51% in 3-4, and 35% in ≥ 5, P = 0.01). ACCI was prognostic for OS in addition to performance status, disease status, and CA19-9: The hazard ratios in ACCI of 3-4 and ≥ 5 were 1.39 and 1.79, compared with ACCI of 0-2 (P = 0.04). While overall safety profile did not differ by ACCI, higher ACCI score group developed Grade 3-4 neutropenia more frequently (26% in 0-2, 42% in 3-4, and 46% in ≥ 5, P = 0.04).

Conclusion: Age and comorbidity burden did affect OS and safety profile in BTC patients undergoing first-line palliative chemotherapy. ACCI can be a simple and useful tool to evaluate the age and comorbidity burden in these patients.
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http://dx.doi.org/10.1111/jgh.15066DOI Listing
October 2020

Antireflux metal stent for biliary obstruction: Any benefits?

Dig Endosc 2021 Mar 16;33(3):310-320. Epub 2020 Jun 16.

Departments of, Department of, Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Endoscopic retrograde cholangiopancreatography with stent placement has been utilized as standard palliative management of distal malignant biliary obstruction (MBO). Compared to plastic stents, metal stents can provide longer-term relief of symptoms. When a large-bore metal stent is placed across the ampulla, patients are predisposed to the risk of cholangitis or stent dysfunction due to reflux of duodenal contents. To mitigate the risk of adverse events associated with the duodenobiliary reflux, efforts have been directed to development of antireflux metal stents (ARMSs). The antireflux property has been introduced through adding of an antireflux valve to the duodenal stent end. Evidence from clinical studies indicates that ARMSs may not only reduce the risk of ascending cholangitis during follow-up but also prolong stent patency time. However, the results of clinical studies testing ARMSs are inconsistent owing to heterogeneous designs of antireflux valves and stent bodies. Metal stents are increasingly indicated for benign biliary strictures and MBO in the setting of neoadjuvant chemotherapy, and therefore, research is warranted to evaluate ARMSs for those indications. Given that endoscopic ultrasound (EUS)-guided transmural biliary drainage has gained popularity, the optimal timing of placing an ARMS in relation to EUS-guided and percutaneous drainage should be investigated. Development and evaluation of ARMSs require an integrative approach utilizing phantom and animal models, measurements of stent mechanical properties, and in vivo functional study after stent placement. In this review article, we summarize updated evidence on ARMSs for MBO and discuss issues that should be addressed in future studies.
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http://dx.doi.org/10.1111/den.13679DOI Listing
March 2021

Lenvatinib-induced acute acalculous cholecystitis in a patient with hepatocellular carcinoma.

Clin J Gastroenterol 2020 Aug 2;13(4):568-571. Epub 2020 Apr 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The patient was a 67-year-old man with advanced hepatocellular carcinoma (HCC) due to chronic hepatitis B. Due to refractoriness to radiofrequency ablation and transcatheter arterial chemoembolization, lenvatinib, a new oral mutikinase inhibitor, was started with a daily dose of 12 mg. However, on day 6 the patient developed acute-onset, right upper quadrant pain associated with fever; laboratory tests revealed leukocytosis and liver dysfunction. CT scan showed the swollen gallbladder with wall thickening with no evidence of gallstones, and the diagnosis of acute acalculous cholecystitis was made. After the resolution of cholecystitis by antibiotics and endoscopic nasogallbladder drainage placement, lenvatinib was resumed at a reduced daily dose of 4 mg. However, acute acalculous cholecystitis recurred, supporting lenvatinib as a cause of acute acalculous cholecystitis. Using the Naranjo adverse drug reaction probability scale, a score of 6 was derived, which indicates that this adverse event was probably caused by lenvatinib. In summary, we present a patient with advanced HCC who underwent repeated episodes of acute acalculous cholecystitis as a rare adverse event associated with lenvatinib.
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http://dx.doi.org/10.1007/s12328-020-01116-5DOI Listing
August 2020

An integrated analysis of lymphocytic reaction, tumour molecular characteristics and patient survival in colorectal cancer.

Br J Cancer 2020 04 11;122(9):1367-1377. Epub 2020 Mar 11.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Histological lymphocytic reaction is regarded as an independent prognostic marker in colorectal cancer. Considering the lack of adequate statistical power, adjustment for selection bias and comprehensive tumour molecular data in most previous studies, we investigated the strengths of the prognostic associations of lymphocytic reaction in colorectal carcinoma by utilising an integrative database of two prospective cohort studies.

Methods: We examined Crohn's-like reaction, intratumoural periglandular reaction, peritumoural reaction and tumour-infiltrating lymphocytes in 1465 colorectal carcinoma cases. Using covariate data of 4420 colorectal cancer cases in total, inverse probability-weighted Cox proportional hazard regression model was used to control for selection bias (due to tissue availability) and potential confounders, including stage, MSI status, LINE-1 methylation, PTGS2 and CTNNB1 expression, KRAS, BRAF and PIK3CA mutations, and tumour neoantigen load.

Results: Higher levels of each lymphocytic reaction component were associated with better colorectal cancer-specific survival (P < 0.002). Compared with cases with negative/low intratumoural periglandular reaction, multivariable-adjusted HRs were 0.55 (95% CI, 0.42-0.71) in cases with intermediate reaction and 0.20 (95% CI, 0.12-0.35) in cases with high reaction. These relationships were consistent in strata of MSI status or neoantigen loads (P > 0.2).

Conclusions: The four lymphocytic reaction components are prognostic biomarkers in colorectal carcinoma.
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http://dx.doi.org/10.1038/s41416-020-0780-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188805PMC
April 2020
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