Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial.

PURPOSE: Treatment options for patients with unresectable or recurrent biliary tract cancer (BTC) who progress on a gemcitabine-containing regimen are limited. In addition, the significance of anti-human epidermal growth factor receptor 2 (HER2) therapy in HER2-expressing BTC has not been sufficiently investigated. METHODS: In this phase II trial, participants from five institutions in Japan were enrolled. Eligible patients had pathologically confirmed unresectable or recurrent BTC with centrally confirmed HER2-positive (immunohistochemistry [IHC]3+ or IHC2+ and in situ hybridization [ISH]+) or HER2-low (IHC2+ and ISH-, IHC1+, and IHC0 and ISH+) and were refractory or intolerant to a gemcitabine-containing regimen. The patients received 5.4 mg/kg trastuzumab deruxtecan (T-DXd) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was the confirmed objective response rate (ORR) in HER2-positive BTC by an independent central review (threshold ORR, 15%; expected ORR, 40%). RESULTS: A total of 32 patients were enrolled and treated. Among these patients, 22 with HER2-positive disease comprised the primary efficacy population and had a confirmed ORR of 36.4% (90% CI, 19.6 to 56.1; P = .01), meeting the primary end point. Eight with HER2-low disease comprised the exploratory population and had a confirmed ORR of 12.5%. The most common ≥grade 3 treatment-related adverse events were anemia (53.1%) and neutropenia (31.3%). Eight patients (25.0%) had interstitial lung disease (ILD), including two grade 5 events. CONCLUSION: T-DXd showed promising activity in patients with HER2-positive BTC and a signal of efficacy in patients with HER2-low BTC. Although the safety profile was generally manageable, ILD requires careful monitoring and early intervention.

A Phase 1b Study of Lenvatinib plus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma: Extended Analysis of Study 116.

Introduction: Lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh <60 kg, the dose was 8 mg/day) plus pembrolizumab 200 mg once every 3 weeks demonstrated antitumor activity and a manageable safety profile in patients with first-line unresectable hepatocellular carcinoma (uHCC) in the open-label phase 1b Study 116/KEYNOTE-524 (primary analysis data cutoff date: October 31, 2019; median follow-up: 10.6 months). This analysis (updated data cutoff date: March 31, 2021) reports efficacy results from 17 months of additional follow-up time. Methods: 100 patients with uHCC were included in the primary analysis (median follow-up: 27.6 months). Endpoints included overall survival (OS), investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per modified RECIST. Landmark analyses of OS by the best response at 3 and 9 months were performed. Pembrolizumab antidrug antibodies (ADAs) and concentrations were also measured (cutoff date: August 7, 2020). Results: ORR was 43.0% (95% CI 33.1-53.3%) and median DOR was 17.1 months (95% CI 6.9-19.3 months). Median PFS and OS were 9.3 months (95% CI 7.4-9.8 months) and 20.4 months (95% CI 14.4-25.9 months), respectively. No treatment-emergent ADAs were detected. Conclusion: Results show a sustained treatment effect with lenvatinib plus pembrolizumab in patients with uHCC in the first-line setting.

Comparison of stent patency between EUS-guided hepaticogastrostomy with bridging and endoscopic transpapillary biliary drainage for hilar obstruction.

Background and study aims Endoscopic ultrasound-guided hepaticogastrostomy with bridging between the left and right bile ducts is an alternative to endoscopic transpapillary drainage for malignant hilar biliary obstruction. We aimed to analyze the long-term stent patency of endoscopic ultrasound-guided hepaticogastrostomy with bridging. Patients and methods Patients who underwent endoscopic ultrasound-guided hepaticogastrostomy with bridging between April 2018 and July 2023 were retrospectively analyzed. We retrospectively compared the stent patency of these patients with that of the individuals who underwent endoscopic transpapillary drainage-multi-stenting using unmatched (entire) and propensity score-matched cohorts. Results Endoscopic ultrasound-guided hepaticogastrostomy with bridging had a technical success rate of 90% (18/20). Adverse events were minimal. The number of clinical success cases was 17 and 82 for endoscopic ultrasound-guided hepaticogastrostomy with bridging using metallic stent and endoscopic transpapillary drainage-multi-stenting, respectively. The recurrent biliary obstruction rate was 17.6% and 58.5% for endoscopic ultrasound-guided hepaticogastrostomy with bridging and endoscopic transpapillary drainage-multi-stenting, respectively; the median time to recurrent biliary obstruction (days) was significantly longer for endoscopic ultrasound-guided hepaticogastrostomy with bridging in the entire (not reached vs. 104, P =0.03) and propensity score-matched (183 vs. 79, P =0.05) cohorts. The non-recurrent biliary obstruction rate for endoscopic ultrasound-guided hepaticogastrostomy with bridging was 91.6% at 3 and 6 months and 57% at 12 months. Multivariate analyses revealed that endoscopic ultrasound-guided hepaticogastrostomy with bridging contributed to a lower recurrent biliary obstruction incidence (hazard ratio, 0.31, P =0.05) without significant difference. Conclusions Stent patency was significantly better for endoscopic ultrasound-guided hepaticogastrostomy with bridging. However, future prospective studies are needed.

Diagnostic performance of EUS-guided tissue acquisition for solid pancreatic lesions ≤10 mm.

Background and Objectives: EUS tissue acquisition (EUS-TA) is the standard diagnostic method for solid pancreatic lesions (SPLs); however, there are few reports on EUS-TA results for SPLs ≤10 mm. Furthermore, given the recent advent of fine-needle biopsy, the current diagnostic accuracy of EUS-TA for SPLs ≤10 mm is unknown. This study aimed to evaluate the diagnostic accuracy and efficacy of EUS-TA for SPLs ≤10 mm. Methods: We retrospectively analyzed the data of 109 patients with SPLs ≤10 mm who underwent EUS-TA. All patients underwent rapid on-site specimen evaluation. Results: The median tumor diameter was 8 mm (range, 2.5-10 mm), and the technical success rate was 99.1% (108/109). Adverse events were observed in 3 patients (2.8%). The diagnostic performance was as follows: sensitivity, 90.1% (64/71); specificity, 97.3% (36/37); accuracy, 92.6% (100/108); positive predictive value, 98.5% (64/65); and negative predictive value, 83.7% (36/43). Multivariate analysis revealed that the number of punctures (odds ratio, 7.03; 95% confidence interval, 1.32-37.5; P = 0.023) and tumor type (odds ratio, 11.90; 95% confidence interval, 1.38-102.0; P = 0.024) were independent risk factors for inaccurate EUS-TA results. The diagnostic accuracy of EUS-TA for pancreatic ductal adenocarcinoma was 87.5% (14/16). No EUS-TA-related needle-tract seeding was observed in patients with pancreatic ductal adenocarcinoma during the observation period. Conclusions: EUS-TA for SPLs ≤10 mm showed adequate diagnostic accuracy and was safe for use with rapid on-site specimen evaluation in all cases.

Japanese classification of pancreatic carcinoma by the Japan Pancreas Society: Eighth edition.

In 2023, the Japan Pancreas Society (JPS) published the new eighth edition of the Japanese classification of pancreatic carcinoma. We present here an excerpted version in English, based on the latest edition. The major changes in this revision are as follows: In the eighth edition of the Union for International Cancer Control (UICC), the T category was changed to be based on tumor size; however, the eighth edition of the Japanese classification retains the previous T category based on local invasion factors. Lymph nodes have been renamed, and regional lymph nodes have been defined by location. Peritoneal cytology, which was not previously included in distant metastasis (M), has now been included in the M category. Moreover, significant additions have been made regarding the pathological diagnosis of endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) and criteria for histological assessment of the effects after chemotherapy and radiation therapy. Although this classification is aimed at carcinoma originating in the pancreas, not in the bile duct or duodenum, if the differentiation of the primary organ is difficult, this classification should be applied. It is also desirable to describe tumors other than carcinoma and metastatic tumors to the pancreas in accordance with this classification.

A novel method of bilateral biliary decompression by EUS-guided hepaticogastrostomy with bridging stenting using the partial stent-in-stent method for reintervention of multiple metal stent failure.

Video 1A novel method of bilateral biliary decompression by EUS-guided hepaticogastrostomy with bridging stenting using the partial stent-in-stent method for reintervention of multiple metal stent failure.We report a case in which anterior and posterior drainage was performed using the partial stent-in-stent method via the transpapillary approach. The patient had a bismuth type IV biliary obstruction, but only the right hepatic lobe was drained due to obstruction of the left portal vein. For the recurrent stent dysfunction, the patient underwent placement of a plastic stent within an uncovered self-expanding metal stent to correct stent dysfunction. A 7F plastic stent inside a metal stent is shown.The patient later experienced stent failure and jaundice due to tumor progression and was admitted for plastic stent replacement. Neither imaging results nor symptoms suggested duodenal stenosis. The transpapillary approach was attempted first but was unsuccessful. Duodenoscopy was challenging to perform because of duodenal stenosis. Fluoroscopy confirmed the duodenal stenosis. The plastic stent was extracted using an upper endoscope. Multiple uncovered metal stents are shown (1 stent in the anterior bile duct and 2 stents in the posterior bile duct). Jaundice did not resolve despite plastic stent removal.The patient refused to undergo percutaneous biliary drainage, so a decision was made to perform an EUS-guided hepaticogastrostomy (HGS) instead. The left bile duct was observed in the stomach. The left bile duct was punctured with a 19-gauge FNA needle. A 0.025-inch hydrophilic guidewire was directed into the left bile duct. Enhancement of the bile duct showing malignant hilar biliary obstruction (bismuth IV) is seen. Insertion of the guide wire into the posterior bile duct is shown.The stent mesh was then dilated using a balloon dilator. However, there was difficulty inserting the catheter. Additional dilation was performed using a spiral dilator. This instrument is a tapered tip dilator that fits into 0.025-inch guidewires and is expandable to 7F. Insertion of a second guidewire with a larger caliber was done to straighten the bile duct and help stabilize stent insertion. A 0.035-inch hydrophilic guidewire into the posterior bile duct using a double-lumen cannula and insertion of a 0.025-inch hydrophilic guidewire into the anterior bile duct are shown.The stent mesh was then dilated using a spiral dilator. A metal stent was placed through the anterior bile duct at a steep angle. Insertion and deployment of the first uncovered self-expanding metal stent (8 × 60 mm) from the anterior bile duct into the left bile duct is shown. Multiple metal stents were implanted into the hilar area, and the new stent was placed using the partial stent-in-stent method to prevent overexpansion. Guidewire seeking the posterior bile duct from inside the deployed stent through the stent mesh is shown.The stent mesh was then dilated using a balloon dilator. Insertion and deployment of an uncovered self-expanding metal stent (8 × 60 mm) from the posterior bile duct to the left bile duct using the partial stent-in-stent method is shown. Enhancement of the bile duct shows drainage from the right bile duct. The fistula of the HGS was only dilated with the spiral dilator. The risk of bile leakage was low, so we decided to implant a plastic stent. A 7F × 15-cm plastic stent was placed from the posterior bile duct into the stomach. Anterior and posterior segment drainage by EUS-HGS with bridging stenting using the partial stent-in-stent method is shown, with left segment drainage by EUS-HGS with the plastic stent.We performed EUS-HGS on a patient with multiple metal stents in place. There were no adverse events, and total bilirubin levels were reduced by more than half within 2 weeks. Six months have passed without stent dysfunction.

Current status of the cost burden of first-line systemic treatment for patients with advanced hepatocellular carcinoma in Japan, 2021-22.

BACKGROUND: Although recent advances in systemic therapies for hepatocellular carcinoma (HCC) have led to prolonged patient survival, the high costs of the drugs place a heavy burden on both patients and society. The objectives of this study were to examine the treatment regimens used as first-line systemic treatment for patients with advanced HCC in Japan and to estimate the treatment costs per regimen. METHODS: For this study, we aggregated the data of patients who had received first-line systemic treatment for advanced HCC between July 2021 and June 2022. The treatment cost per month of each regimen was estimated based on standard usage, assuming an average weight of 60 kg for male patients. The data were categorized by the treatment regimen, and the treatments were categorized based on the cost into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month) and other (<500 000 JPY/month) treatments. RESULTS: Of the total of 552 patients from 24 institutions whose data were analyzed in this study, 439 (79.5%) received atezolizumab plus bevacizumab, 98 (17.8%) received lenvatinib and 15 (2.7%) received sorafenib as the first-line treatment. The treatment cost per month for each of the above regimens was as follows: atezolizumab plus bevacizumab, 1 176 284 JPY; lenvatinib, 362 295 JPY and sorafenib, 571 644 JPY. In total, 82.2% of patients received high-cost regimens, and the majority of these patients received a very high-cost regimen of atezolizumab plus bevacizumab. CONCLUSIONS: Advances in systemic therapies for HCC have led to prolonged patient survival. However, the treatment costs are also increasing, imposing a burden on both the patients and society.

Efficacy of hemostasis by gastroduodenal covered metal stent placement for hemorrhagic duodenal stenosis due to pancreatobiliary cancer invasion: a retrospective study.

Background/Aims: Advanced pancreatic and biliary tract cancers can invade the duodenum and cause duodenal hemorrhagic stenosis. This study aimed to evaluate the efficacy of covered self-expandable metal stents in the treatment of cancer-related duodenal hemorrhage with stenosis. Methods: Between January 2014 and December 2016, metal stents were placed in 51 patients with duodenal stenosis. Among these patients, a self-expandable covered metal stent was endoscopically placed in 10 patients with hemorrhagic duodenal stenosis caused by pancreatobiliary cancer progression. We retrospectively analyzed the therapeutic efficacy of the stents by evaluating the technical and clinical success rates based on successful stent placement, degree of oral intake, hemostasis, stent patency, and overall survival. Results: The technical and clinical success rates were 100%. All 10 patients achieved a Gastric Outlet Obstruction Scoring System score of three within two weeks after the procedure and had no recurrence of melena. The median stent patency duration and overall survival after stent placement were 52 days (range, 20-220 days) and 66.5 days (range, 31-220 days), respectively. Conclusions: Endoscopic placement of a covered metal stent for hemorrhagic duodenal stenosis associated with pancreatic or biliary tract cancer resulted in duodenal hemostasis, recanalization, and improved quality of life.

Feasibility and safety of a novel plastic stent designed specifically for endoscopic ultrasound-guided pancreatic duct drainage.

Background and study aims Endoscopic ultrasound-guided pancreatic duct drainage (EUS-PD) is emerging as an effective alternative treatment for obstructive pancreatitis after unsuccessful endoscopic retrograde pancreatography (ERP). However, the high incidence of adverse events associated with EUS-PD (approximately 20%) remains an issue. Recently, we developed a novel plastic stent for EUS-PD, with a radiopaque marker positioned at approximately one-third of the length from the distal end of the stent and side holes positioned exclusively distal to the marker. This study aimed to evaluate the feasibility and safety of using this stent in EUS-PD. Patients and methods We retrospectively reviewed data from 10 patients who underwent EUS-PD with the novel plastic stent at the National Cancer Center Hospital between March 2021 and October 2023. Technical and clinical success, procedure times, adverse events (AEs), recurrent pancreatic duct obstruction (RPO), and time to RPO were assessed. Results Of the 10 patients, five had postoperative benign pancreaticojejunal anastomotic strictures and five had malignant pancreatic duct obstruction. The technical and clinical success rates were both 100% (10/10). An AE (self-limited abdominal pain) occurred in one patient (10.0%). Two patients (20.0%) died of their primary disease during the follow-up period (median, 44 days; range, 25-272 days). The incidence of RPO was 10.0% (1/10), and the 3-month non-RPO rate was 83.3%. Conclusions The novel plastic stent shows potential as a useful and safe tool in EUS-PD.

Efficacy of endoscopic ultrasound-guided gastroenterostomy using self-expandable metallic stent for afferent loop syndrome: A single-center retrospective study.

BACKGROUND AND AIM: Endoscopic ultrasound-guided gastroenterostomy is a procedure used to connect the stomach and dilated afferent loop using a stent under endoscopic ultrasound for afferent loop syndrome. However, the actual efficacy and safety of this procedure remain unclear. Therefore, this retrospective study aimed to evaluate the efficacy and safety of endoscopic ultrasound-guided gastroenterostomy using a laser-cut-type fully covered self-expandable metallic stent and an anchoring plastic stent for afferent loop syndrome. METHODS: Technical and clinical success rates, adverse events, recurrent intestinal obstruction rates, time to recurrent intestinal obstruction, and technical and clinical success rates of re-intervention were evaluated in intended patients who underwent endoscopic ultrasound-guided gastroenterostomy for afferent loop syndrome from October 2018 to August 2022. RESULTS: In 25 intended patients with afferent loop syndrome who intended endoscopic ultrasound-guided gastroenterostomy, the technical success rate was 100% (25/25), whereas the clinical success rate was 96% (24/25). Two patients experienced grade ≥ 3 early adverse events, including one with intra-abdominal abscess and one with hypotension. Both events were attributed to intestinal fluid leakage. No late adverse events were observed. The recurrent intestinal obstruction rate was 32% (8/25), and the median time to recurrent intestinal obstruction was 6.5 months (95% confidence interval: 2.8-not available). The technical and clinical success rates of re-intervention were both 100% (8/8). CONCLUSIONS: Endoscopic ultrasound-guided gastroenterostomy using a fully covered self-expandable metallic stent and an anchoring plastic stent is effective and safe as a treatment procedure for afferent loop syndrome.

Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

Multicenter Phase II Trial of Lenvatinib plus Hepatic Intra-Arterial Infusion Chemotherapy with Cisplatin for Advanced Hepatocellular Carcinoma: LEOPARD.

Introduction: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin and lenvatinib exhibits strong antitumor effects against advanced hepatocellular carcinoma (HCC). Higher antitumor activity is expected for the combination treatment. The aim of this trial was to evaluate the efficacy and safety of lenvatinib in combination with HAIC using cisplatin in patients with advanced HCC. Methods: In this multicenter, open-labeled, single-arm, phase II trial, patients with advanced HCC categorized as Child-Pugh class A with no prior history of systemic therapy were enrolled. Patients received lenvatinib plus HAIC with cisplatin (lenvatinib: 12 mg once daily for patients ≥60 kg, 8 mg once daily for patients <60 kg; HAIC with cisplatin: 65 mg/m2, day 1, every 4-6 weeks, maximum of six cycles). The primary endpoint was the objective response rate (ORR) assessed using modified RECIST by the Independent Review Committee. The secondary endpoints were the ORR assessed using RECIST v1.1, progression-free survival, overall survival, and frequency of adverse events associated with the treatment. Results: A total of 36 patients were enrolled between September 2018 and March 2020. In the 34 evaluable patients, the ORR assessed by the Independent Review Committee using modified RECIST and RECIST v1.1 were 64.7% (95% confidence interval [CI]: 46.5-80.3%) and 45.7% (95% CI: 28.8-63.4%), respectively. The median progression-free survival and overall survival were 6.3 months (95% CI: 5.1-7.9 months) and 17.2 months (95% CI: 10.9 - not available, months), respectively. The main grade 3-4 adverse events were increased aspartate aminotransferase (34%), leukopenia (22%), increased alanine aminotransferase (19%), and hypertension (11%). Conclusion: Lenvatinib plus HAIC with cisplatin yielded a favorable ORR and overall survival and was well tolerated in patients with advanced HCC. Further evaluation of this regimen in a phase III trial is warranted.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. METHODS: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. FINDINGS: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. INTERPRETATION: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. FUNDING: AstraZeneca.

Immune-related adverse event-associated sclerosing cholangitis due to immune checkpoint inhibitors: imaging findings and treatments.

OBJECTIVES: Immune-related adverse event-sclerosing cholangitis caused by treatment with immune checkpoint inhibitors is rare, and the diagnostic criteria and treatment strategy remain unclear. In this study, we confirmed the clinicopathological features of immune-related adverse event-sclerosing cholangitis and clarified its diagnosis and appropriate management. METHODS: We retrospectively evaluated 10 patients diagnosed with immune-related adverse event-sclerosing cholangitis and identified by electronic database searches. RESULTS: Blood tests revealed liver dysfunction with a predominance of biliary tract enzymes in all patients; however, jaundice was present in only one patient. Contrast-enhanced computed tomography revealed diffuse hypertrophy of the extrahepatic bile duct wall as the most frequent finding; however, endoscopic retrograde cholangiopancreatography showed various imaging features, such as the pruned-tree appearance of intrahepatic bile ducts, in all patients. Transpapillary bile duct biopsy showed inflammatory cell infiltration using immunostaining, with a predominance of cluster of differentiation 8-positive T cells in 63% of the cases. Initial steroid therapy was effective in two cases. Mycophenolate mofetil and tacrolimus were used in steroid-refractory cases. Although six patients showed improvements, all of the remaining patients died owing to immune-related adverse event-sclerosing cholangitis. CONCLUSIONS: Various bile duct imaging findings of immune-related adverse event-sclerosing cholangitis were revealed; transpapillary bile duct biopsy may be useful in the diagnosis of immune-related adverse event-sclerosing cholangitis. Despite the combination of multiple immunosuppressive agents, prognosis of immune-related adverse event-sclerosing cholangitis remains poor. Longer follow-up and larger clinical studies are necessary to establish its treatment strategy.

Identification of barriers to implementation of precision oncology in patients with rare cancers.

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice.

Association of D-dimer level with thrombotic events, bleeding, and mortality in Japanese patients with solid tumors: a Cancer-VTE Registry subanalysis.

BACKGROUND: The D-dimer test is a simple test frequently used in routine clinical screening for venous thromboembolism (VTE). The Cancer-VTE Registry was a large-scale, multicenter, prospective, observational study in Japanese patients with cancer. This study aimed to clarify the relationship between D-dimer level at cancer diagnosis (baseline) and the incidence of events during cancer treatment (1-year follow-up period). METHODS: This was a post hoc sub-analysis of patients from the Cancer-VTE Registry whose D-dimer levels were measured at baseline. The incidence of events during the 1-year follow-up period was evaluated stratified by baseline D-dimer level. Adjusted hazard ratios for D-dimer level and events during the follow-up period were evaluated. RESULTS: Among the total enrolled patients, baseline D-dimer level was measured in 9020 patients. The mean ± standard deviation baseline D-dimer level was 1.57 ± 3.94 µg/mL. During the follow-up period, the incidence of VTE, cerebral infarction/transient ischemic attack (TIA)/systemic embolic events (SEE), bleeding, and all-cause death increased with increasing baseline D-dimer level. The incidence of all-cause death increased with increasing D-dimer level regardless of cancer stage. The adjusted hazard ratio of all-cause death was 1.03 (95% confidence interval: 1.02-1.03) per 1.0-µg/mL increase in baseline D-dimer level. CONCLUSIONS: Increases in D-dimer levels were associated with a higher risk of thrombotic events, such as VTE and cerebral infarction/TIA/SEE, during cancer treatment. Furthermore, higher D-dimer levels at cancer diagnosis were associated with a higher mortality rate, regardless of cancer stage.

Incidence and factors associated with stent dysfunction and pancreatitis after gastroduodenal stenting for malignant gastric outlet obstruction.

Background and study aims Endoscopic gastroduodenal stent (GDS) deployment is currently a standard treatment for malignant gastric outlet obstruction (mGOO) in patients with limited life expectancy; however, stent dysfunction (SD) and complicated pancreatitis often occur after GDS deployment. We investigated incidence and contributing factors of SD and complicated pancreatitis. Patients and methods We retrospectively reviewed 203 patients who underwent initial GDS deployment for palliation of mGOO symptoms between October 2017 and July 2022, including 109 who underwent GDS deployment across the duodenal papilla (sub-cohort). Results SDs, including tumor ingrowth (n = 26), kinking (n = 14), and migration (n = 13), occurred in 68 patients (33.5%). Cumulative SD incidence was 41.1% (95% confidence interval, 32.6-49.4%). SD incidence increased to 0.4%, 0.16%, and 0.06% per day at < 8, 8-16, and>16 weeks, respectively. On multivariate analysis, Niti-S pyloric/duodenal stent deployment (sub-distribution hazard ratio [sHR] 0.26, P = 0.01) and survival length ≥ 90 days (sHR 2.5, P = 0.01) were respectively identified as favorable and risk factors significantly associated with SD. Pancreatitis developed in 14 patients (12.8%) in the sub-cohort, which had significantly higher parenchymal diameter ( P < 0.01) and lower main pancreatic duct (MPD) caliber ( P < 0.01) than the non-pancreatitis cohort. On multivariate analysis, MPD caliber < 3 mm independently predicted pancreatitis (odds ratio 6.8, P = 0.03). Conclusions Deployment of the Niti-S pyloric/duodenal stent, with conformability even for angulated strictures, significantly reduced the incidence of SD. Stent selection, life expectancy, and MPD caliber should be taken into consideration during decision-making for GDS deployment for mGOO.