Linker and Conjugation Site Synergy in Antibody-Drug Conjugates: Impacts on Biological Activity.

Antibody-drug conjugates (ADCs) produced using general conjugation methods yield heterogeneous products containing mixtures of species with different numbers of payloads per antibody (drug-antibody ratios) conjugated at multiple sites. This heterogeneity affects the stability, efficacy, and safety of ADCs. Thus, various site-specific conjugation methods have been developed to achieve homogeneity in ADCs. It was reported that linker structures and conjugation sites generally affected the characteristics of site-specific ADCs such as stability, efficacy, and safety. However, the combined effects of conjugation sites and linker structures on the physicochemical and biological characteristics of site-specific ADCs have remained unclear. In this study, we generated 30 homogeneous site-specific ADCs with a combination of six conjugation sites and five linker structures using THIOMAB technology and evaluated the characteristics of these homogeneous ADCs. We found that both conjugation sites and linker structures affected characteristics unique to ADCs (linker stability as well as target-dependent and target-independent cytotoxicity) in site-specific ADCs. Especially, conjugation to the constant regions of the light chain and the presence of polyethylene glycol structures in the linker are important for those ADC-specific characteristics. Interestingly, we also found that the effects of linker structures on the target-independent cytotoxicity of homogeneous ADCs at certain conjugation sites differed from those seen in conventional heterogeneous ADCs. Our results suggest that optimizing linker structures based on the conjugation site may be necessary for site-specific ADCs.

Prospective multicenter surveillance study of branch-duct intraductal papillary mucinous neoplasm of the pancreas; risk of dual carcinogenesis.

BACKGROUND: The natural history of branch-duct intraductal papillary mucinous cystic neoplasms (BD-IPMNs) in the pancreas remains unclear. This study aimed to answer this clinical question by focusing on the development of concomitant pancreatic ductal adenocarcinomas (cPDAC). METHODS: The Japan Pancreas Society conducted a prospective multicenter surveillance study of BD-IPMN every six months for five years. The primary endpoints were progression of BD-IPMN, progression to high-grade dysplasia/invasive carcinoma (HGD/IC), and cPDAC. Factors predicting the progression of BD-IPMN to HGD/IC and development of cPDAC were also assessed as secondary endpoints. RESULTS: Among the 2104 non-operated patients, 348 (16.5 %) showed progression of primary BD-IPMN. Cumulative incidences of BD-IPMN with HGD/IC and cPDAC during the 5.17-year surveillance period were 1.90 % and 2.11 %, respectively, and standard incidence ratios of BD-IPMN with HGD/IC and cPDAC were 5.28 and 5.73, respectively. Of 38 cPDACs diagnosed during surveillance, 25 (65.8 %) were resectable. The significant predictive characteristics of BD-IPMN for progression to HGD/IC were larger cyst size (p = 0.03), larger main pancreatic duct size (p < 0.01), and mural nodules (p = 0.02). Significant predictive characteristics for the development of cPDAC were male sex (p = 0.03) and older age (p = 0.02), while the size of IPMN was not significant. CONCLUSION: Careful attention should be given to "dual carcinogenesis" during BD-IPMN surveillance, indicating the progression of BD-IPMN to HGD/IC and development of cPDAC distinct from BD-IPMN, although the establishment of risk factors that predict cPDAC development remains a challenge (UMIN000007349).

FcγRIIIa-158V/F polymorphism affects the performance of FcγRIIIa-related bioassay.

Bioassays are important for estimating biosimilarity between biological products. Comparability studies including bioassays are needed to demonstrate that a biosimilar product has no meaningful differences that affect safety and efficacy compared with the reference product. Among the most important biological characteristics of therapeutic mAbs are Fc-mediated functions, which induce immune-cell activation which can affect both efficacy and safety. Thus, when developing biosimilar products of therapeutic mAbs, it is necessary to compare the Fc-mediated functions by using various bioassays. Though it is reported that polymorphism of Fcγ receptors (FcγRs) affects Fc-mediated cellular activations of therapeutic mAbs, the impacts of the polymorphism of FcγRs on bioassay performance are still unclear. In this study, we evaluated the impact of FcγRIIIa-158V/F polymorphism on assay performance in distinguishing differences in the biological activities of therapeutic mAbs. The results showed that different bioassay methods produced different assessments of biological activities of mAbs, and that the FcγRIIIa-158V/F polymorphism clearly affected the performance of the FcγRIIIa-binding assay using recombinant proteins and FcγRIIIa-expressing reporter assays. That is, the assays using the FcγRIIIa-158F variant were superior to those using the FcγRIIIa-158V variant in distinguishing the difference in FcγRIIIa-binding and -activation properties. These results indicate that we should evaluate the comparability of biosimilars by considering the impacts of FcγRIIIa-158V/F polymorphism on bioassay performance.

Fcγ Receptor-Dependent Internalization and Off-Target Cytotoxicity of Antibody-Drug Conjugate Aggregates.

PURPOSE: Antibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific delivery of payloads in accordance with mAbs' function. On the other hand, the conjugation of payloads often increases the hydrophobicity of mAbs, resulting in reduced stability and increased aggregation. It is considered that mAb aggregates have potential risk for activating Fcγ receptors (FcγRs) on immune cells, and are internalized into cells via FcγRs. Based on the mechanism of action of ADCs, the internalization of ADCs into target-negative cells may cause the off-target toxicity. However, the impacts of aggregation on the safety of ADCs including off-target cytotoxicity have been unclear. In this study, we investigated the cytotoxicity of ADC aggregates in target-negative cells. METHODS: The ADC aggregates were generated by stirring stress or thermal stress. The off-target cytotoxicity of ADC aggregates was evaluated in several target-negative cell lines, and FcγR-activation properties of ADC aggregates were characterized using a reporter cell assay. RESULTS: Aggregation of ADCs enhanced the off-target cytotoxicity in several target-negative cell lines compared with non-stressed ADCs. Notably, ADC aggregates with FcγR-activation properties showed dramatically enhanced cytotoxicity in FcγR-expressing cells. The FcγR-mediated off-target cytotoxicity of ADC aggregates was reduced by using a FcγR-blocking antibody or Fc-engineering for silencing Fc-mediated effector functions. CONCLUSIONS: These results indicated that FcγRs play an important role for internalization of ADC aggregates into non-target cells, and the aggregation of ADCs increases the potential risk for off-target toxicity.

Long-term Risk of Malignancy in Branch-Duct Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: Long-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years of surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]) over 20 years in a large population of patients. METHODS: We identified 1404 consecutive patients (52% women; mean age, 67.5 years) with a diagnosis of branch-duct IPMN, from 1994 through 2017, at the University of Tokyo in Japan. Using a competing risk analysis, we estimated cumulative incidence of pancreatic carcinoma, overall and by carcinoma type. We used competing risks proportional hazards models to estimate subdistribution hazard ratios (SHRs) for incidences of carcinomas. To differentiate IPMN-derived and concomitant carcinomas, we collected genomic DNA from available paired samples of IPMNs and carcinomas and detected mutations in GNAS and KRAS by polymerase chain reaction and pyrosequencing. RESULTS: During 9231 person-years of follow-up, we identified 68 patients with pancreatic carcinomas (38 patients with IPMN-derived carcinomas and 30 patients with concomitant PDACs); the overall incidence rates were 3.3%, 6.6%, and 15.0% at 5, 10, and 15 years, respectively. Among 804 patients followed more than 5 years, overall cumulative incidence rates of pancreatic carcinoma were 3.5% at 10 years and 12.0% at 15 years from the initial diagnosis. The size of the IPMN and the diameter of the main pancreatic duct associated with incidence of IPMN-derived carcinoma (SHR 1.85; 95% confidence interval 1.38-2.48 for a 10-mm increase in the IPMN size and SHR 1.56; 95% confidence interval 1.33-1.83 for a 1-mm increase in the main pancreatic duct diameter) but not with incidence of concomitant PDAC. CONCLUSIONS: In a large long-term study of patients with branch-duct IPMNs, we found the 5-year incidence rate of pancreatic malignancy to be 3.3%, reaching 15.0% at 15 years after IPMN diagnosis. We observed heterogeneous risk factor profiles between IPMN-derived and concomitant carcinomas.

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

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.

Recovery of bowel function after transperitoneal or retroperitoneal laparoscopic pyeloplasty. A multi-center study.

AIM: To document the recovery of bowel function (BF) in children after transperitoneal (TP) or retroperitoneal (RP) laparoscopic pyeloplasty. METHODS: Data were obtained retrospectively from four centers between 2008 and 2019 for TP (n = 51) and RP (n = 58). Each surgeon chose which technique to perform. RESULTS: Subject demographics were not significantly different. Differences in operative times were not significant (RP: 241 min versus TP: 225 min). Mean duration/requirement for postoperative epidural/intravenous analgesia were not significantly different (TP: 1.4 days versus RP: 1.3 days) and (TP: 66.7% versus RP: 67.2%), respectively. Postoperative nasogastric (NG) intubation was more common in RP (TP: 19.6% versus RP: 44.8%; p < .05). NG aspiration (TP: 0.15 mL/kg/hr versus RP: 0.16 mL/kg/hr), nausea (TP: 31.4% versus RP: 17.2%), and vomiting (TP: 19.6% versus RP: 15.5%) were not significantly different. There were no perioperative complications (including ileus). Abdominal distention was problematic in one case per group (TP: 2.0% versus RP: 1.7%). Times for oral liquid (TP: 0.69 day versus RP: 0.83 day), solid food (TP: 0.88 day versus RP 1.07 days), and the first bowel movement (TP: 2.86 days versus RP: 2.79 days), were not significantly different. CONCLUSIONS: BF recovery would appear to be consistent, independent of technique.

A prospective study of fully covered metal stents for different types of refractory benign biliary strictures.

BACKGROUND: While endoscopic management of benign biliary strictures (BBSs) is the standard of care, long-term treatment remains the issue in refractory cases, especially for anastomotic strictures after living-donor liver transplantation (LDLT) and hepaticojejunostomy anastomotic strictures (HJAS). The aim of this prospective study was to evaluate the safety and effectiveness of a fully covered self-expandable metal stent (FCSEMS) for patients with refractory BBSs. METHODS: Patients with BBSs that were unamenable to endoscopic plastic stent placement with a treatment period of more than 6 months were eligible. An FCSEMS was placed endoscopically and removed after 90 days. In patients with surgically altered anatomy, an FCSEMS was placed using a double-balloon endoscope. The primary outcome was stricture resolution at FCSEMS removal. The secondary outcomes included stricture recurrence and adverse events. RESULTS: A total of 30 patients were enrolled: the causes of their BBSs were anastomotic stricture after LDLT in 13, HJAS in 12, post-cholecystectomy in two, chronic pancreatitis in two, and post-hepatectomy in one. The technical success rate of FCSEMS placement was 100 % and all FCSEMSs were successfully removed. The rate of stricture resolution at FCSEMS removal was 96.6 % (91.7 % in the post-LDLT group and 100 % in the HJAS group). Stricture recurrence occurred in three HJAS patients (10.7 %) during a median follow-up period of 15.6 months. Adverse events were observed in 12.1 %: five cholangitis, one pancreatitis, and one perforation. CONCLUSION: Temporary placement of an FCSEMS was a feasible and effective treatment option for refractory BBSs, especially for post-LDLT strictures and HJAS.

Regular Statin Use and Incidence of Postendoscopic Retrograde Cholangiopancreatography Pancreatitis.

GOALS AND BACKGROUND: Endoscopic retrograde cholangiopancreatography is widely utilized to diagnose and treat various pancreaticobiliary diseases, but postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) can be a fatal adverse event. Evidence suggests that statins may exhibit suppressive effects on inflammation in the pancreas. We carried out an observational cohort study to examine the protective effect of statins on PEP. STUDY: We retrospectively identified consecutive patients who underwent endoscopic retrograde cholangiopancreatography at a tertiary care center in Japan between January 2010 and January 2019. The incidences of PEP were compared between regular and nonregular statin users. Using the multivariable logistic regression model, we examined the association of regular statin use with the incidence of PEP controlling for potential risk factors for PEP. RESULTS: We included 2664 patients (328 regular statin users and 2336 nonregular users). The incidence of PEP did not differ by statin use status (P=0.52): 8.8% in regular statin users and 7.9% in nonregular users. The multivariable-adjusted odds ratio for PEP comparing regular statin use with nonregular use was 1.08 (95% confidence interval, 0.67-1.72; P=0.76). When we examined specific statin types (hydrophilic and lipophilic statins), we consistently observed the null association: 6.8% of 132 hydrophilic statin users and 10% of 196 lipophilic statin users (P=0.74 and 0.27, respectively, compared with nonregular users). CONCLUSIONS: Regular statin use was not shown to be protective against PEP. A further investigation is warranted before this medication is tested in prospective randomized trials.

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

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.

Double-balloon endoscopy-assisted treatment of hepaticojejunostomy anastomotic strictures and predictive factors for treatment success.

BACKGROUND: Endoscopic management of hepaticojejunostomy anastomotic strictures is technically demanding due to surgically altered anatomy. The promise of double-balloon endoscope-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) has been reported in this setting. No large study has examined long-term outcomes of this new treatment modality and predictive factors for the stricture resolution. METHODS: We included 102 patients who received DB-ERCP for a hepaticojejunostomy anastomotic stricture between 2008 and 2018. Balloon dilation was performed as a first-line treatment, and plastic stent(s) were placed for refractory cases. Potential predictive factors for the stricture resolution were examined using multivariable logistic regression analyses. RESULTS: DB-ERCP was technically successful in 91 patients (89.2%). Overall, stricture resolution was achieved in 70 patients (76.9%) with a median follow-up period of 30.9 months (range 1-118.5 months). Among 64 patients (71.9%) who underwent successful re-canalization via balloon dilation, anastomotic stricture recurred in 22 patients (34.4%). In cases with refractory or recurrent stricture after balloon dilation, 20 patients (52.6%) underwent stricture resolution via plastic stent placement, and the recurrence was observed in two patients (10%). Post-operative time to DB-ERCP of > 12 months and the scar-like appearance around the anastomosis were associated with a higher rate of stricture resolution (odds ratios, 5.59 [95% CI 1.69-18.5] and 5.22 [95% CI 1.29-21.1], respectively). CONCLUSIONS: Treatment of hepaticojejunostomy anastomotic strictures via DB-ERCP was technically feasible, providing a reasonably high rate of stricture resolution. Alternative treatment should be explored for refractory cases.

Retrospective Comparative Study of Side-by-Side and Stent-in-Stent Metal Stent Placement for Hilar Malignant Biliary Obstruction.

BACKGROUND: In patients with unresectable hilar malignant biliary obstruction (MBO), bilateral metal stent placement is recommended. However, treatment selection between partially stent-in-stent (SIS) and side-by-side (SBS) methods is still controversial. STUDY: Clinical outcomes of bilateral metal stent placement by SBS and SIS methods for hilar MBO were retrospectively studied in four Japanese centers. While large-cell-type uncovered metal stents were placed above the papilla in SIS, braided-type uncovered metal stents were placed across the papilla in SBS. RESULTS: A total of 64 patients with hilar MBO (40 SIS and 24 SBS) were included in the analysis. Technical success rate was 100% in SIS and 96% in SBS. Functional success rate was 93% in SIS and 96% in SBS. Early adverse event rates were higher in SBS (46%) than in SIS (23%), though not statistically significant (P = 0.09). Post-procedure pancreatitis was exclusively observed in SBS group (29%). Recurrent biliary obstruction rates were 48% and 43%, and the median time to recurrent biliary obstruction was 169 and 205 days in SIS and SBS, respectively. CONCLUSIONS: Other than a trend to higher adverse event rates including post-procedure pancreatitis in SBS, clinical outcomes of SIS and SBS methods were comparable in patients with unresectable hilar MBO.

Development of anti-drug monoclonal antibody panels against adalimumab and infliximab.

The generation of anti-drug antibodies (ADAs) is one of the most serious problems in therapy using monoclonal antibodies (mAbs), because ADAs can impact the pharmacokinetics, efficacy, and safety of mAbs. It is therefore important to detect the generated ADAs in patients. For the appropriate detection of ADAs, methods that detect various types of ADAs (e.g., low- and high-affinity ADAs) are needed, but since there are no adequate reference preparations of ADAs relevant to human ADAs in most cases, it is difficult to determine whether or not the developed methods have enough analytical performance. Here, we developed human-rat chimeric ADA panels against the anti-TNF-α therapeutic antibodies infliximab and adalimumab. The developed ADA panels consist of 7 (for infliximab) and 11 (for adalimumab) ADAs with various binding characters, and most of the ADAs are neutralizing antibodies. Using these ADA panels, we compared the detectability of model methods, i.e., binding assays using SPR, BLI, and ECL, and a cell-based assay to detect neutralization activity. Since we obtained ADAs showing low and high responses with the various methods, the ADA panels we developed were shown to be useful for the development of ADA assays.

Human-rat chimeric anti-occludin monoclonal antibodies inhibit hepatitis C virus infection.

Occludin (OCLN), an integral tetra-spanning plasma membrane protein, is a host entry factor essential for hepatitis C virus (HCV) infection, making it a promising host-targeting molecule for HCV therapeutic intervention. We previously generated rat anti-OCLN monoclonal antibodies (mAbs) that strongly prevented HCV infection in vitro and in vivo. In the present study, we attempted to improve the druggability of the extracellular loop domain-recognizing anti-OCLN mAbs, namely clones 1-3 and 37-5, using genetic engineering. To avoid adverse reactions induced by antibody-dependent cellular cytotoxicity and enhance the antibody stability, we developed human-rat chimeric immunoglobulin G4 S228P mutant (IgG4m) forms of clones 1-3 and 37-5 (named Xi 1-3 and Xi 37-5, respectively) by grafting the variable regions of the light and heavy chains of each rat anti-OCLN mAb into those of human IgG4m. The constructed Xi 1-3 and Xi 37-5 chimeras demonstrated levels of affinity and specificity similar to each parental rat anti-OCLN mAb, and the Fcγ receptor Ⅲa was not activated by the antigen-bound chimeric mAbs, as expected. Both chimeric mAbs inhibited in vitro infection with various HCV genotypes. These results indicate that the IgG4m forms of human-rat chimeric anti-OCLN mAbs may be potential candidate molecules of host-targeting antivirals with pan-genotypic anti-HCV activity.

Visceral adiposity and high adiponectin levels are associated with the prevalence of pancreatic cystic lesions.

OBJECTIVES: Obesity is increasing in developed countries and is a risk factor for pancreatic cancer (PaC). We previously reported that obesity was associated with pancreatic cystic lesions (PCLs), which are both precursors of, and risk factors for, PaC. In the present study, we further investigated the relationship between visceral adiposity and adiponectin levels and the extent of PCLs. METHODS: Individuals who underwent comprehensive health screening at our institution between January 2008 and March 2013 were analyzed. PCLs were diagnosed via magnetic resonance imaging using a 3.0 Tesla system. The volumes of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured from computed tomographic volume data. Serum levels of adiponectin were measured using a sandwich enzyme-linked immunosorbent assay. RESULTS: The prevalences of PCLs were 14.2% in males (N = 2683; mean age, 56.4 years) and 16.2% in females (N = 1741; mean age, 57.1 years). The prevalence of PCLs increased gradually as VAT volume increased (P < 0.001). PCLs were more prevalent in individuals with high adiponectin levels (18.7% vs. 13.8%, P = 0.005). VAT volume (odds ratio [OR] for the highest quartiles, 1.52 [1.07-2.16]; P = 0.025) and adiponectin level (OR for the highest quartiles, 1.31 [1.08-1.59]; P = 0.007) but not SAT volume (P = 0.828) was significantly associated with PCLs in multivariate analyses. CONCLUSIONS: Visceral adiposity and high adiponectin levels were associated with PCL prevalence. Further work is needed to explore the relationships between visceral adiposity and adiponectin levels, and PCLs and PaC.

A phase II trial of gemcitabine, S-1 and LV combination (GSL) therapy in patients with advanced pancreatic cancer.

Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naïve patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks. Primary end point was progression free survival (PFS). Results A total of 49 patients with advanced pancreatic cancer (19 locally advanced and 30 metastatic) were enrolled. Overall response rate and disease control rate were 32.7% and 87.8%. The median PFS and overall survival (OS) were 10.8 (95% confidence interval [CI], 7.4-13.5) and 20.7 (95% CI 13.0-NA) months with 1-year survival rate of 73.4%. Major Grade 3-4 toxicities were neutropenia (22.4%) and stomatitis (14.3%). No toxicity related death was observed. Conclusions In this single center, phase II trial, gemcitabine, S-1 and LV combination therapy was tolerable and can potentially be a treatment option for advanced pancreatic cancer.

Diagnostic yield of the plasma free amino acid index for pancreatic cancer in patients with diabetes mellitus.

OBJECTIVES: A multivariate index calculated using plasma free amino acids (PFAA index) was reported as a diagnostic biomarker for pancreatic cancer (PaC). Although diabetes mellitus (DM) is expected to be an early diagnostic indicator of PaC, identifying the high-risk individuals among patients with DM is warranted. We evaluated the diagnostic yield of the PFAA index for PaC in patients with DM. METHODS: We compared the diagnostic yield of the PFAA index between individuals with and those without DM. Cases and controls were recruited prospectively, and controls were matched to cases at a 1:1 ratio for age, sex, and DM status. RESULTS: A total of 180 case-control pairs were included in the analysis. The prevalence of DM was 53.3%. The sensitivity of the PFAA index was 66.7% in cases with DM and 56.0% in those without DM (P = 0.14), and the specificity was 92.7% in controls with DM and 94.0% in those without DM (P = 0.95). CONCLUSIONS: This matched case-control study revealed a comparable diagnostic yield of the PFAA index for PaC in individuals with and those without DM. The PFAA index can be used as a biomarker for further diagnostic imaging in selected patients with DM.

Long-term outcomes of endoscopic treatment for duct-to-duct anastomotic strictures after living donor liver transplantation.

BACKGROUND AND AIMS: The anastomotic biliary stricture is a clinically important complication after living donor liver transplantation (LDLT) with a duct-to-duct anastomosis. Although endoscopic management of post-LDLT biliary strictures using balloon dilation (BD) and plastic stents (PSs) has provided acceptable short-term outcomes, long-term outcomes and prognostic factors for treatment success remain unclear. METHODS: We included 96 patients with post-LDLT biliary strictures who were endoscopically managed between 2003 and 2016. BD was utilized as a first-line treatment strategy, and PS placement was carried out for refractory cases. Potential prognostic factors for biliary stricture resolution were analysed using logistic regression analyses. RESULTS: Endoscopic treatment was technically successful in 84 patients (87.5%). The overall rate of biliary stricture resolution was 44.8% (43 of 96 patients) with a median follow-up duration of 90.9 months (interquartile range, 30.9-122.3 months). Bile duct kinking was associated with a lower rate of biliary stricture resolution (odds ratio, 0.33; 95% confidence interval, 0.13-0.87). After successful endoscopic treatment, biliary strictures recurred in 22 patients (57.9%) after BD, and in one patient (4%) after PS treatment. CONCLUSIONS: Despite a high technical success rate, endoscopic treatment only provided a low rate of resolution of anastomotic biliary strictures among LDLT patients and required prolonged treatment duration. Alternative strategies including the use of a covered metal stent should be evaluated to further improve the treatment outcomes of post-LDLT biliary strictures, particularly in those accompanied by the bile duct kinking.

Multiple recurrences after endoscopic removal of common bile duct stones: A retrospective analysis of 976 cases.

BACKGROUND AND AIM: Recurrences after endoscopic treatment of common bile duct stones (CBDS) are common. The aims of this study were to identify risk factors for recurrences of CBDS and to evaluate the effect of interventions for prevention of further recurrences. METHODS: A total of 976 patients who underwent endoscopic treatment of CBDS were retrospectively studied. Risk factors for single and multiple recurrent CBDS were evaluated using a Cox hazard regression model. The incidences of further recurrences were evaluated according to the additional interventions. RESULTS: The mean age was 69.3 years, and 39.3% were female. Endoscopic papillary balloon dilation, endoscopic sphincterotomy, and endoscopic papillary large balloon dilation were performed in 858, 77, and 41 patients, respectively. The rates of one or more recurrence and multiple recurrences of CBDS were 12.4% and 2.7%, respectively. In the multivariate analyses, the significant risk factors were the bile duct size (hazard ratio [HR] 1.07, P = 0.012), gallbladder left in situ with stones (HR 1.91, P = 0.046), and pneumobilia after treatment (HR 2.10, P = 0.047) for single recurrence and the number of stones at the first recurrence (HR 1.16, P = 0.021) for multiple recurrences. In five out of nine cases with multiple recurrences, further recurrence was not observed after additional sphincteroplasty in addition to cholecystectomy. CONCLUSIONS: The incidence of multiple recurrences was not uncommon after the first recurrence of CBDS.

Early pancreatic stent placement in wire-guided biliary cannulation: A multicenter retrospective study.

BACKGROUND AND AIM: Guidewire insertion to a pancreatic duct under wire-guided cannulation (WGC) during endoscopic retrograde cholangiopancreatography (ERCP) is associated with a high incidence of post-ERCP pancreatitis (PEP). Pancreatic stent placement followed by WGC (PS-WGC) is considered for these cases to reduce PEP. This study was aimed to examine the effectiveness of PS-WGC compared with repeated WGC. METHODS: The consecutive data of patients without history of ERCP who underwent ERCP for biliary intervention were retrospectively collected from five centers. Patients without guidewire insertion to the pancreatic duct were excluded. Pancreatic stent was immediately placed after guidewire insertion to the pancreatic duct in the PS-WGC group. The association between the method of biliary cannulation (PS-WGC or repeated WGC) and PEP was analyzed using multivariable logistic regression model. RESULTS: A total of 590 patients (183 in the PS-WGC and 407 in the repeated WGC group) were included. PS-WGC decreased PEP (8.7% vs 19%, P = 0.001) and improved its severity (moderate and severe PEP; 2.2% vs 6.4%, P = 0.04) compared with repeated WGC. PS-WGC was associated with reduction of PEP in the multivariable model (Odds ratio 0.31, P < 0.001). The rates of difficult cannulation and overall successful biliary cannulation were not different between the two groups (66% vs 70%, P = 0.39 and 98% vs 96%, P = 0.21 in the PS-WGC and repeated WGC group, respectively). CONCLUSIONS: Pancreatic stent placement followed by WGC reduced PEP in patients with guidewire insertion to the pancreatic duct during WGC for native papilla compared with repeated WGC.