bluuebunny/crossref_metadata_2025 huggingface dataset:
The preliminary efficacy of KN026 (Anti-HER2 BsAb) in advanced gastric and gastroesophageal junction cancer patients with HER2 expression.
Authors: Xu Jianming , Zhang Yun , Wu Jun , Xu Nong , Ying Jieer , Xiang Xiaojun , Zhang Yanqiao , Wang Jianhong , Zhao Rusen , Ye Feng , Wu Qiong , Guo Baohong , Liu Yuchen , Liu Juan , Xing Shuning , Xu Ting
Published: June 2021

e16005

Background: HER2 overexpression or amplification has been proven to be a validated therapeutic target for HER2-positive gastric and gastroesophageal junction cancer (GC/GEJ) in ToGA trial. However, there is a huge unmet medical need in the HER2-positive GC/GEJ patients who progressed or were refractory to trastuzumab treatment. In HER2 low expression patients, the benefit of novel HER2-targeted therapeutics, eg. Bispecifics, ADC and CAR-T, remain to be explored. Here we report the preliminary results of KN026, a bispecific antibody binds two distinct epitopes of HER2 receptors, in GC/GEJ patients with prior at least one line treatment. Methods: GC/GEJ patients who failed to ≥first-line treatment were enrolled into two cohorts according to HER2 overexpression (Cohort 1: IHC3+ or IHC 2+ ISH+) and low expression (Cohort 2: IHC 1+/2+ ISH- or IHC 0/1+ISH+), and treated by KN026 QW10mpkor Q2W(20mpk) or Q3W(30mpk) until progression of disease (PD) or intolerable toxicity or 2 years. Results: As of 2020/12/25, a total of 31 pts received KN026 treatment including 20 pts in Cohort 1 and 11 pts in Cohort 2. The median drug exposure period was around 20 wks and 6 wks in two Cohorts, respectively. Among 18 efficacy-evaluable pts in Cohort 1, 11 pts were stilling receiving treatment with 55.6% (10/18) ORR and 72.2% DCR (13/18). The 9-m PFS rate was 60.4% (95%CI: 24.4 to 83.5) in Cohort 1, while the DOR, mPFS and mOS were not reached. Of 9 pts receiving prior-HER2 treatment, the median time from the first dose of KN026 to last prior HER2 treatment was 55 days. The ORR was 44.4% (4/9) with 4.1m DoR, and DCR was 66.7% (6/9). The mPFS and mOS were 5.6m(95%CI:1.3 to NE) and 11.0m(95%CI: 1.4 to NE), respectively. In Cohort 2, two partial response was observed out of 9 efficacy-evaluable pts. The ORR and DCR were both 22.2% (2/9) with 1.4 m mPFS (95%CI: 1.0 to 5.9) and 9.6m mOS (95%CI: 3.0 to NE). The overall incidence of KN026 related adverse events was 87.1%, with 9.7% Gr 3 TRAE. The most common KN026-related treatment emergent adverse events (≥10% TRAE) were aspartate aminotransferase increased (n=8,25.8%), rash (n=6,19.4%), anaemia (n=5,16.1%),alanine aminotransferase increased (n=4, 12.9%) and weight decreased(n=4, 12.9%). The ≥Gr 3 TEAE that KN026 related were infusion related reaction(n=1, 3.2%), blood pressure increased (n=1, 3.2%), ureteral stricture with hydronephrosis (n=1, 3.2%). Conclusions: KN026 demonstrated promising efficacy in HER2 overexpressing GC/GEJ pts and in anti-HER2 treated GC/GEJ pts with a favorable safety profile. Clinical trial number: NCT03925974. Clinical trial information: NCT03925974.
Survival impact among occidental patients with metastatic gastric cancer (mGC) treated with ramucirumab as second line treatment (2L): Local experience of a teaching hospital in Chile.
Authors: Salinas Carlos , Barajas Olga , Villanueva Luis , Vasquez Rodrigo , Ahumada Monica
Published: June 2021

e16007

Background: GC is frequent in Chile, with an incidence of 7.8% and a mortality rate of 11.6% in 2020. Late diagnosis continues to be one of the most important problems, although treatments in advanced stages have experienced important advances in the last 6 years. REGARD and RAINBOW trials showed an increase in median OS when using Ramucirumab alone or in combination with Paclitaxel of 5,2 and 9,4 mths respectively. Although this therapy is not covered by our Public Health Insurance, there are some patients that they can access. Also, there are not too many reports in LATAM pts so we present our local real world data. Methods: We conducted a retrospective study of local data from patients diagnosed with mGC who progressed with standard first-line treatment and were treated with ramucirumab-based regimens from January 2015 to January 2021. Clinical factors were recorded baseline, characteristics of therapy and AE related to toxicity. Toxicity was assessed by CTCAE v5.0 and response to treatment by RECIST 1.1. Results were analyzed by measuring time to progression and survival. Results: The search resulted in 9 pts, 6 men and 3 women between 38 and 72 years (median 59 years). 66% were in ECOG 1 performance status and 33% in ECOG 2, with a median BMI of 23 kg / m2. 33% were smokers and all had some other comorbidity as a medical history. All tumors were adenocarcinomas and 33% had a signet ring cell component on histology. Only one tumor was HER2 +++ and all were MSS (by IHC). The most common first-line treatment received before progression was FOLFOX; 4 to 12 cycles; 8 cycle average. All patients were treated with paclitaxel-ramucirumab as 2L (4 to 19 cycles, mean of 5 cycles). 67% of patients achieved stable disease with the best response. During the follow-up period, 8 patients experienced disease progression in an average of 6.7 months, who switched to 3L with Nivolumab. Relapses during 2L were in the peritoneum and 55% in other sites as well. Only two patients discontinued paclitaxel treatment after 4 cycles due to intolerance and continued to receive Ramucirumab. 44% developed grade 3 toxicities: 50% of them due to taxane-related peripheral neuropathy. Grade 4 or 5 toxicity was not reported. 50% of patients were alive at 6 months of treatment. Conclusions: In our country and LATAM, GC still has a significant medical and socioeconomic burden. Its incidence is still one of the highest in the world, most patients are diagnosed in the metastatic stage and face treatment in deficient PS. In this context, our local real-world data showed consistency with what the literature says, although more data remains to accumulate and describe.
Polymorphism of genes of hemostasis system and methionin exchange in patients with gastrointestinal tumors.
Authors: Kit Oleg I. , Vladimirova Liubov Yu , Zykova Tatiana A. , Katelnitskaya Oksana V. , Maslov Andrey A. , Shevyakova Elena A. , Abramova Natalia A. , Storozhakova Anna E. , Popova Irina L. , Novoselova Kristina A. , Tikhanovskaya Natalia M. , Agieva Aza A. , Ryadinskaya Ludmila A. , Tishina Anna V. , Tishchenko Irina S. , Kabanov Sergey N. , Kalabanova Elena A. , Karnaukhova Valeria S. , Teplyakova Maria A.
Published: June 2021

e16011

Background: The purpose of the study was to analyze the rates of polymorphic allelic variants of genes of the hemostasis system and methionin exchange in patients with gastrointestinal cancers (GICs). Methods: The study included 69 patients with histologically verified GICs (main group): gastric cancer (GC) – 17, colon cancer (CC) – 42, other tumors – 10 (pancreatic cancer – 6, liver cancer – 3, gallbladder cancer – 1) and 50 patients without cancer (control group). 12 polymorphic loci were determined in genomic DNA samples by Real-time PCR: F2 (G20210А, rs1799963), F5 (G1691A, rs6025), F7 (G10976A, rs6046), F13 (G226A, rs5985), FGB G(-455)A (rs1800790), ITGA2-α2 (C807T, rs1126643), ITGB3-b (Т1565С, rs5918), PAI-1 4G(-675)5G, rs1799889), MTHFR (С677Т, rs1801133 and A1298C, rs1801131), MTR (А2756G, rs1805087), MTRR (A66G, rs1801394). Results: The ratio of genotype frequencies maintained in the Hardy-Weinberg equilibrium in all gene loci except FGB G(-455)A in GC patients (p = 0.02). The rate of an alternative allele in the F2 gene among patients with GICs was 1.4%, in the control group – 1.0%; F5 – 1.0% and 4.0%; F7 – 13.0% and 11.0%; F13 – 31.9% and 32.0%; FGB – 29.7% and 22.0%; ITGA2 – 37.7% and 38.0%; ITGB3 – 17.4% and 21.0%; PAI-1 – 55.1% and 56.0%, MTHFR (Т) – 26.6% and 31.3%; MTHFR (С) – 33.0% and 27.5%; MTR – 29.8% and 26.3%; MTRR – 51.1% and 57.5%, respectively (p > 0.05). AA homozygotes at the FGB G(-455)A locus were more frequent in the main group, compared to controls: 4.3% vs 4.0%; p = 0.02. No differences in the frequency of alternative alleles of the studied genes were found between patients with GC and CC. GG genotype at the FGB G(-455)A locus was found in GC patients in 29.4%, in controls – in 60.0% (OR = 0.28, 95% CI 0.08-0.91); GA genotype – in 70.6% and 36.0% (OR = 4.27, 95% CI 1.29-14.06), AA genotype – in 0% and 4.0% (p = 0.04, χ2 = 6.34), respectively. Conclusions: The univariate analysis demonstrated that carriage of the GA genotype at the FGB G(-455)A (rs1800790) locus could be found more often in patients with GC.
Efficacy and safety of intermittent versus continuous dosing schedule of apatinib combined with docetaxel as second-line treatment for advanced gastric cancer.
Authors: He Yifu , Yan Ying , Wang Gang , Sun Yubei , Xu Tengyun , Wu Shusheng , Luo Huiqin , Ke Lihong , Hu Xiaoxiu , Niu Jiayu , Li Huimin , Chen Wenju , Xu Huijun , Cao Lulu , Sun Yancai , Liu Chenxuan , Ji Chushu , Hu Bing
Published: June 2021

e16018

Background: Apatinib, a VEGFR-2 tyrosine kinase inhibitor, is wildly used for the treatment of advanced or metastatic gastric cancer. However, dose modification and interruption are happened frequently due to poor patient conditions and treatment-related toxicity. This study was designed to explore the efficacy and safety of intermittent or continuous apatinib therapy in combination with docetaxel. Methods: This was an open-label, randomized clinical trial. Patients with advanced gastric cancer who progressed from first-line treatment were randomly assigned in a ratio of 1:1 to receive intermittent or continuous dosing schedule. In the intermittent dose group (IG), patients received oral apatinib 500 mg/d for 5 days followed by 2 days off. In the continuous dose group (CG), patients received 500 mg daily without interruption. Docetaxel 60 mg/m2 was administered intravenously to patients on Day 1 in a 21-day cycle in both groups. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and the safety. Results: Between September 15, 2017 and November 30, 2020, 80 patients were screened for eligibility, of which 76 patients were randomly assigned into two groups (38 in the IG and 38 in the CG). In the IG and CG, 38 and 37 patients had ECOG PS 0-1, 16 and 19 patients had history of surgery, both 11 patients with more than 2 metastases, respectively. The baseline characteristics of the two groups were balanced. ORR in the IG was 21.05% vs 18.42% in the CG, and DCR was 60.53% vs 60.53%, respectively. Median PFS were 3.88 months (95% CI, 1.723-6.031) vs 3.98 months (95% CI, 1.055-6.896, p= 0.546), and median OS was 9 months (95% CI, 5.306-12.698) vs 9.40 months (95% CI, 5.204-13.588, p= 0.310) in two groups. The incidence of all grade adverse events (AEs) in the IG and CG were 94.7% and 92.1%, of which the most common AEs were hypertension (55.3% vs 65.8%), anemia (55.3% vs 63.2%), proteinuria (26.3% vs 31.6%), hand-foot syndrome (21.1% vs 26.3%). The incidence of grade ≥3 AEs were 36.8% and 39.5% in the IG and CG, respectively. In addition, the doses of 7 patients were reduced to the 250 mg in the IG, while that of 13 patients in the CG. Conclusions: Apatinib administered intermittently (5 days on/ 2 days off) exhibited similar efficacy to continuous schedule, while with less toxicity. Intermittent dosing schedule of apatinib may be an option for second-line treatment of patients with advanced gastric cancer. Clinical trial information: NCT03334591.
Molecular characteristic of proximal and distal esophagogastric junction adenocarcinomas.
Authors: Xu Lin , Shang Bin , Bi Mingming , Zhong Wei , Zhao Yu , Wang Zhou , Xu Mian , Shi Xiaoliang , Zhang Lin , Chen Gang
Published: June 2021

e16077

Background: Esophagogastric junction adenocarcinomas (EGJA) are devastating diseases with increasing incidence. The 8th Edition TNM staging of American Joint Committeeon Cancer and Union for International Cancer Control defined that the epicenter of EGJA within 2 cm of the cardia (hereinafter referred to proximal EGJA) is staged according to the staging standard of esophageal cancer, while that more than 2 cm distal from the EGJA (hereinafter referred to distal EGJA) is staged according to the staging standard of stomach cancer. However, the rationality of the new definition in clinical practice is still controversial. Methods: A randomized retrospective study was conducted. Targeted next-generation sequencing of 450 cancer-related genes was performed, by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China, for genomic alteration identification. Results: A total of 198 EGJ patients were included in this study with a median age of 63 years (ranged from 39 to 88 years). Among them, 140 were distal EGJA and 58 were proximal EGJA. Genomic alterations with a high mutation frequency in EGJ include There is no significant difference in the frequencies of these genes between proximal EGJA and distal EGJA. Mutation frequencies of FGFR2 and ZEN217 in distal EGJ were significantly higher than those in proximal EGJA (15.8% vs 5.0%, P = 0.02 and 7.0% vs 0.7%, P = 0.03, respectively). Multivariate regression analysis showed that tumor stage and lymph nodes number were the main factors positively associated with the poor prognosis. However, we found that there was no significant difference in OS between proximal and distal (P = 0.139). Furthermore, our results showed that LRP2 and SPTA1 mutations were significantly associated with better OS of the EGJA patients. Conclusions: In conclusion, with the identification of the mutation landscape of EGJA, the FRFR2 and ZNF127 genes mutations were potential biomarkers to distinguish distal EGJA from proximal EGJA, whereas the LRP2 and SPTA1 gene mutations were potential biomarkers for prognosis prediction in EGJA.
A nationwide analysis of inpatient outcomes and healthcare utilization in HIV versus non-HIV patients with esophageal cancer.
Authors: Sherazi Syed Ali Amir , Achebe Ikechukwu , Asotibe Jennifer C , Pannu Bibek Singh , Attar Bashar , Gupta Shweta , Mullane Michael Russell
Published: June 2021

e16106

Background: Esophageal cancer (EC) is an aggressive malignancy with poor 5-year survival rates (19.9%). Due to effective Antiretroviral Therapy, mortality from HIV/AIDS has precipitously decreased leading to longer lifespan and increased risk of developing non-AIDS defining cancers. There is paucity of data regarding outcomes of Esophageal Cancers in patients with HIV (HIV-EC). We undertook this analysis to study the outcomes of HIV-EC with healthcare utilization compared to non-HIV-EC patients. Methods: The Healthcare Cost Utilization Project (HCUP) Nationwide Inpatient Sample was queried to identify patients with HIV and non-HIV-EC using ICD-10 codes. Groups were compared for demographic differences, inpatient mortality, length of stay (LOS) and hospital charges. Secondary outcomes studied included rates of septic shock (SS), Esophageal Obstruction (EO), Anemia, Pneumonia, Tracheoesophageal Fistula (TEF), Upper GI Bleed (UGIB), Acute Kidney Injury (AKI), protein energy malnutrition (PEM). Statistics were performed using the t-test, chi-square test and logistic regression. Results: A total of 330 inpatient admissions with HIV-EC and 117505 with non-HIV-EC were identified. Patients with HIV-EC were significantly younger (mean age 58.5 vs 66.9 years, p < 0.001) with 83% under 65 years of age compared to 41% in non-HIV-EC group (p < 0.001). Higher number of HIV-EC patients were African American (AA) (51.5% vs 10%, p < 0.001) with similar gender ratio (19.7% vs 21.3% women), belonged to lowest income quartile zip codes (42% vs 27%, p = 0.01), more likely to be on Medicaid (36% vs 11%, p < 0.001) and hailed from North East (NE) or Southern regions of the US (79% vs 56%, p = 0.003). The overall mortality rate was significantly higher in the HIV-EC group than non-HIV-EC (13.6% vs 8.8%, p = 0.001). The mean inpatient LOS (7.4 vs 6.98 days) and total hospital charges ($65,358 vs $80,620) were not significantly different between the two groups. Rates of PEM were higher in HIV-EC (61% vs 44%, p < 0.01) but rates of sepsis, SS, UGIB, EO, TEF, Anemia, TLS, AKI were not significantly different than non-HIV-EC. There was no difference in rates of specific medical co-morbidities between groups, although HIV-EC had a significantly higher Charlson Comorbidity Index (p < 0.001). Conclusions: Despite being significantly younger, HIV-EC patients have significantly higher mortality compared to non-HIV-EC. However, the inpatient LOS and total charges were not significantly different. HIV-EC were more likely to be AA on Medicaid and from low-income zip codes from the NE or South of the United States. Further studies are needed to study the role of early diagnosis, perhaps screening in younger patients with HIV to prevent mortality.
A multicenter observational study of lenvatinib for unresectable hepatocellular carcinoma in Japan.
Authors: Izumi Namiki , Kudo Masatoshi , Motomura Kenta , Inaba Yoshitaka , Katamura Yoshio , Kondo Yasuteru , Yabushita Kazuhisa , Motoyoshi Katsuaki , Furuse Junji
Published: June 2021

e16118

Background: Lenvatinib is an oral tyrosine kinase inhibitor that has been available for treatment of unresectable hepatocellular carcinoma (uHCC) in Japan since March 2018. We conducted a multicenter prospective observational study to evaluate the safety and efficacy of lenvatinib in clinical practice. Methods: This study conducted as a prospective study, and enrolled patients with uHCC initially receiving lenvatinib as systemic therapy who gave informed consent from July 2018 through January 2019. The observation period per patient was 12 months and e-CRF was used. Results: 713 patients were registered at 133 clinical sites. The safety analysis set and efficacy analysis set were 703 patients. Patient baseline characteristics included median age:73.0 years (25 to 94), male/ female: 564/139, bodyweight: < 60kg/≥60kg: 323/380, HBV/HCV/alcohol/NAFLD or NASH: 137/287/167/88, Child-Pugh classification A/B or higher: 624/75, BCLC stage A/B/C/D: 57/291/332/11, Vp 0/1/2/3/4: 520/31/52/60/22, with/without extrahepatic metastasis: 236/461. Previous treatment (local and systemic therapy) for hepatocellular carcinoma is with/without TACE: 513/190, median number of TACE treatment: 3.0 times (1 to 26), with/without HAIC: 74/629, with/without TKI pretreatment: 131/572. The initial dose was 8 mg (80.5%) and 12 mg (68.2%) in patients with < 60 kg and ≥60 kg, respectively. Median relative dose intensity was 64.2% and the treatment continuation rate at 3 and 12 months after administration of lenvatinib were 67.3% and 24.8%. Regarding safety, the incidence of treatment-related adverse events (TRAEs) was 84.9% (grade 3 or higher: 42.5%). Common TRAEs (incidence rate ≥10%) were decreased appetite (23.9%), malaise (21.8%), hypertension (21.3%), proteinuria (18.3%), palmar-plantar erythrodysesthesia syndrome (16.5%), hypothyroidism (15.8%), and diarrhea (13.9%). TRAEs of grade 3 or higher （incidence rate ≥2.5%） were proteinuria (6.7%), hypertension (6.4%), malaise (3.8%), decreased appetite (3.6%), platelet count decreased (3.3%), palmar-plantar erythrodysesthesia syndrome (2.7%), diarrhea (2.7%) and hepatic encephalopathy (2.6%). The incidence of TRAEs leading to discontinuation of lenvatinib was 32.9％, and main TRAEs leading to discontinuation of lenvatinib were (incidence rate ≥2%) decreased appetite (6.3%), malaise (4.7%), proteinuria (3.3%) and hepatic encephalopathy (2.4%). Regarding efficacy, the ORR and DCR was 39.5% (95% CI: 35.1, 43.9) and 78.9% (75.1, 82.5) in 494 patients who were evaluated for the best response by mRECIST. The median OS was 498.0 days (95% CI: 439.0, -) in 703 patients. Conclusions: The incidence of TRAEs leading to discontinuation of lenvatinib tended to be higher than in phase 3 REFLECT trials (19.7%), but the safety profile and effectiveness findings for lenvatinib in this study were consistent with previous reports.
A retrospective study on the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma.
Authors: Zeng Zhen , Zhang Linzhi , Wu Tong , Cheng Jiamin , Chen Yan , Lu Yinying
Published: June 2021

e16127

Background: To evaluate the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma. Methods: This retrospective study included patients with advanced/metastatic hepatocellular carcinoma who received sintilimab (iv. 200 mg, Q3W) combined with sorafenib (oral, 400 mg twice-daily) (cohort A) or lenvatinib (oral, 12 mg/day for bodyweight≥60 kg or 8 mg/day for bodyweight < 60 kg) (cohort B) as first line therapy between March 2019 to December 2020 in the 5th medical center of the PLA general hospital of China. The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), Time to Progression (TTP) and safety. Results: 45 patients were enrolled, of which 29 were in the cohort A and 16 were in the cohort B. Except for the extrahepatic metastasis (62.1% vs 25.0%, P= 0.029), there were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous treatment regimens between the two cohorts. The mean (±SD) exposure cycles in the two cohorts were 7.2±6.7 vs 7.1±4.7 ( P= 0.584). The median PFS of cohort A (8.2 months, 95%CI 3.1-19.5) was longer than that of cohort B (5.2 months, 95%CI 2.0-10.8), but there was no significant difference (HR 0.55, 95%CI 0.24-1.29, P = 0.161). However, there was no significant difference between the two cohorts in ORR (24.1% vs 6.3%, P= 0.226), DCR (82.8% vs 75.0%, P= 0.700) and median TTF (8.2 vs 4.6months, HR 0.49, 95%CI 0.21- 1.10, P= 0.074). OS data were not yet mature. There was no significant difference in the incidence of all grades and grade 3-4 adverse events between the two cohorts. The most common grade 3-4 adverse events in the two cohorts were hand-foot syndrome (17.2%, 5/29) and lung infection (12.5%, 2/16). There was 1 patient (immune hepatitis) in cohort A and 2 patients (pulmonary infection) in cohort B leading to treatment interruption due to adverse events, and no deaths due to treatment. Conclusions: Sorafenib or lenvatinib combined with sintilimab showed a good efficacy and safety in patients with advanced hepatocellular carcinoma, the safety and tolerability profiles were consistent with those previously observed. Sorafenib plus sintilimab provided an improved PFS versus lenvatinib, which requires a large sample of randomized controlled trial to confirm.[Table: see text]
Upfront or add-on combination therapeutic strategy exploration in unresectable hepatocellular carcinoma using sorafenib plus sintilimab: A retrospective analysis of real-world evidence.
Authors: Cheng Jiamin , Li Yinyin , Wu Tong , Zhang Zhen , Chen Yan , Su Guodong , Peng Caiyun , Zhang Linzhi , Lu Yinying , Zeng Zhen
Published: June 2021

e16135

Background: Recently, tyrosine kinase inhibitor plus PD-1 inhibitor regimen has shown promising effects on hepatocellular carcinoma (HCC). So far, no study explored the effectiveness of upfront versus add-on combination therapy in patients with systemic treatment-naïve and treatment-experienced HCCThis study aimed to explore the effectiveness and safety of sintilimab combined sorafenib in patients with untreated or sorafenib monotherapy-refractory unresectable HCC. Methods: In this retrospective study, unresectable HCC patients received sintilimab plus sorafenib from January 2018 to December 2020 were enrolled. According to the prior treatment, patients were grouped as first-line and second-line (received sorafenib combined sintilimab after progression on sorafenib alone). Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), safety, and the change of Child-Pugh score from baseline to progression were recorded. The PFS was defined as the time from first dosing of sintilimab until disease progressive or death. Results: A total of 31 patients were reviewed, including 19 patients in first-line group and 12 patients in second-line group. There were two patients with Barcelona Clinic Liver Cancer (BCLC) stage B and 17 patients with BCLC stage C in first-line group, and one patient with BCLC stage A and 11 patients with BCLC stage C in second-line group, respectively. The ORR and DCR were 27.8% and 77.8% in first-line group, and 16.7% and 75.0% in second-line group, respectively. Fourteen cases in first-line group and 10 cases in second-line group showed PD during the follow-up. The 6-month PFS rate of first-line group and second-line group were 47.1% and 64.8%, respectively. Thirteen and 9 patients experienced AE in two groups. Four and 2 grade 3 AEs occurred in two groups, respectively. The most frequency AE were hand-foot-skin reaction in both group (58.0% and 50.0%, respectively). One patient discontinued sintilimab due to AE in second-line group. Among PD patients, the Child-Pugh score improved in 2 cases, maintained in 5 cases, and deteriorated in 7 cases in the first-line group; and improved in 3 cases, miantained in 3 cases, and deteriorated in 4 cases in the second-line group. Conclusions: Sorafenib plus sintilimab showed potential anti-tumor effect and tolerance on unresectable HCC, either as first-line therapy or after progression with sorafenib monotherapy. Outcomes.[Table: see text]
Improving the diagnostic yield of biliary stricture biopsies using a directional atherectomy device.
Authors: Gilcrease Glynn Weldon , Eiswirth Preston , Suchy Hannah Beth , Witt Benjamin L , Hardman Rulon L , Cizman Ziga
Published: June 2021

e16167

Background: Diagnosing the pathologic etiology of biliary strictures presents challenges that have been well-documented. Accuracy of traditional brushing and fine needle aspirate techniques range from 44% to 73%.2 Over the last 2 decades the use of atherectomy catheter biliary biopsy has demonstrated high sensitivity and positive predictive values with a low complication rate. This endoluminal approach allows for larger volume histologic samples, allowing for the potential to obtain adequate tissue for next generation sequencing (NGS). The aim of this retrospective review of a single-center’s experience was to define the accuracy, ease of evaluation, and the ability to obtain NGS for personalized treatment. Methods: A retrospective review was performed under a waiver from the Institutional Review Board. A search of medical records from 1/2016 to 2/2021 yielded 20 biopsies in 19 patients. The 20 biopsies were completed by 4 interventional radiologists with between 2-11 years of experience. All available samples were analysed by a pathologist with greater than 10 years of experience and graded for adequacy and feasibility of NGS. Results: The patient population was 53% female with average age of 65.1 years. 12/19 (63%) patients had prior non-atherectomy biopsy attempts. The average ease of evaluation score for the 19 biopsies was 7.8/9, compared to 6.2/9 for the brushing specimens obtained from a subset of the same patients. Seven biopsies were positive for malignancy, ten were benign and three were non-diagnostic. The 7 biopsies that rendered a definitive diagnosis of malignancy had an average ease of evaluation score 8.7/9. The overall accuracy rate was 78.9%, and 71% of malignant samples were deemed adequate for NGS. There were two biopsy related complications; one pseudoaneurysm treated with embolization and one biliary drain dislodgement. Conclusions: Biliary biopsy using an atherectomy device has similar accuracy to traditional techniques; however, it allows for improved diagnostic yield and increased tissue specimen with 71% of samples adequate for NGS testing.
Impact of hospital type and surgical volume on outcomes of biliary cancer resection.
Authors: Kaur Jasmeet , Qureshi Waqas , Sahai Vaibhav
Published: June 2021

e16168

Background: The mainstay of treatment for patients with early-stage biliary cancer (gallbladder or cholangiocarcinoma) is surgical resection. Herein, we evaluated the predictors for biliary cancer resection outcome and association with hospital volume and teaching status. Methods: A national representative cohort of 18485 biliary cancer patients was included for the years 2016 – 2018 from the national inpatient sample database. The study population included patients ≥ 18 years diagnosed with biliary cancer who underwent elective surgical resection (ICD 10). Hospitals were categorized based on teaching status (yes, if ACGME approved residency program, member of the council of teaching hospitals, or with residents to beds ratio of .25 or higher, versus non-teaching); and hospital volume (high if ≥ 20 biliary cancer surgeries performed per year, otherwise low). The primary outcome was biliary resection and the secondary outcomes included post-operative complications, in-hospital mortality, length of stay (< or ≥ 7 days), and health care cost (< or ≥ median) based on hospital teaching status and biliary cancer surgical volume. Association with outcomes was assessed using multivariable logistic regression models adjusted for age, sex, race, household income, service payer, Elixhauser co-morbidity score, hospital volume, teaching status, bed size, location, and region. Results: Out of 18,485 patients hospitalized with biliary cancer, 7,030 patients underwent elective biliary cancer resection during the study period. Patients undergoing resection were likely to have higher than national household median income with Medicare as primary insurance payor. In multivariate adjusted logistic regression models, high volume centers showed significantly lower length of stay (adjusted odds ratio (aOR) 0.73; 95% CI 0.54 - 0.97; p=0.03), and lower in-hospital mortality (aOR 0.28; 95% CI 0.15 - 0.80; p=0.01), but no significant difference in post-operative complications or healthcare cost compared to low volume centers. Surgeries performed in a teaching hospital were associated with decreased risk of post-operative complications (aOR 0.74; 95% CI 0.55 - 1.0; p=0.05), significant decrease in in-hospital mortality (aOR 0.44; 95% CI 0.27 - 0.69; p=0.001), but higher inflation-adjusted healthcare cost (aOR 1.77; 95% CI 1.37-2.26; p<0.001) with no difference in length of stay. Conclusions: Patients who underwent elective biliary cancer surgery at a teaching or high-volume hospital had a significant decrease in their risk of in-hospital mortality. Additionally, surgeries at teaching hospitals were associated with a significantly lower post-operative complication rate compared to similar procedures at a non-teaching hospital, although teaching hospitals did have a significantly higher healthcare cost when adjusted for length of stay.
Detection of FGFR fusions in intrahepatic cholangiocarcinoma using targeted RNA sequencing.
Authors: Farooq Maria , Markus Havell , McDonald Bradon , Egan Jan B. , Contente-Cuomo Tania , Odenheimer Ahuva , Fernandez-Zapico Martin , Borad Mitesh J. , Murtaza Muhammed
Published: June 2021

e16185

Background: Comprehensive sequencing efforts have identified fibroblast growth factor receptor (FGFR) translocations in numerous cancers. FGFR2 fusions were recently identified as an actionable therapeutic target in ̃17% of cholangiocarcinoma patients, predominantly found in patients with intrahepatic cholangiocarcinoma. Genomic partners for FGFR fusions are variable. In addition, obtaining high yield tissue biopsies for CCA remains challenging and tumor tissue available for molecular analyses is scarce. When combined, these two factors make detection of FGFR fusions in CCA challenging. An accurate molecular assay to detect FGFR fusions in CCA could improve utilization of FGFR-targeted therapies. Methods: The objective of our study was to develop an approach for targeted RNA analysis to improve sensitivity for FGFR fusion detection from limited tumor material. We adapted the sensitive targeted digital sequencing (TARDIS) approach recently developed in our lab for analysis of RNA. This approach utilizes a combination of open-ended targeted amplification followed by ligation, enabling detection of tyrosine kinase fusions without prior knowledge of the precise sequence of the fusion breakpoint or identity of the fusion partner. For evaluation of analytical performance, we analyzed RNA from a CCA organoid model with a known FGFR2 fusion, and Seraseq Fusion RNA Mix v3 Reference Material with two known FGFR3 fusions. Results: Without prior knowledge the partner or coordinates of the fusion breakpoint, we detected an FGFR2-KIF5C fusion in RNA from a CCA organoid model. The fusion breakpoint coordinates predicted by TARDIS-RNA were validated by comparison with RNA-Seq. To assess sensitivity and quantitative performance of the assay, we analyzed a serial dilution of the reference RNA sample from Seraseq with concentration of RNA molecules representing candidate fusions verified by digital PCR. Using TARDIS-RNA to analyze replicates with 5 ng RNA input, we were able to detect candidate fusions represented by as few as 2.7 fusion molecules on average. Concentrations of fusion molecules measured using the two methods were highly correlated (R = 0.96). Conclusions: These results demonstrate sensitivity and quantitative performance of a targeted RNA sequencing assay to detect and quantify FGFR fusions in tumor specimen from intrahepatic cholangiocarcinoma. On-going work is focused on further evaluating assay performance and characterizing FGFR fusions using additional tissue specimen.
Genomic profiling of biliary tract cancers to reveal clinically actionable genes and therapeutic biomarkers.
Authors: Shao Yang , Ou Qiuxiang , Fang Zhenhao , Liu Rui , Bao Hua , Wu Xue
Published: June 2021

e16187

Background: Bile tract cancers are genetically and clinically heterogenous with a poor prognosis. Identifying novel biomarkers for targeted therapy is required to improve the clinical outcome of bile tract cancer patients. Methods: Tumor tissue samples of 482 Chinese biliary tract cancer (BTC) patients were genetically profiled using targeted next generation sequencing. Tumor mutation burden (TMB) was calculated by counting all nonsynonymous mutations per megabase of coding sequences. The R package ReactomePA was used in pathway enrichment analysis. Genomic instability was characterized by an in-house developed NGS-based Homologous Recombination Deficiency (HRD) panel and a HRD score was an unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores. Results: The BTC cohort consisted of 135 gallbladder cancer (GBC), 73 intrahepatic cholangiocarcinoma (iCCA), 18 distal cholangiocarcinoma (dCCA), 14 perihilar cholangiocarcinoma (pCCA), while the remaining 242 BTC patients of no specific subtype information. Most frequently mutated genes included TP53 (56%), KRAS (25%), ARID1A (17%), SMAD4 (11%), and CDKN2A (10%) . A preliminary pathway analysis revealed that mutations of DNA damage repair (DDR) pathway genes were enriched in the cohort ( p< 1e-10), accounting for over 70% of the patients, particularly in homologous recombination repair (HRR), Fanconi anemia (FA), mismatch repair (MMR), and base excision repair (BER) genes. More specifically, approximately 50% of the cohort carried at least one mutation of the HRR genes (43%) or MMR genes (14%). Patients with impaired MMR had increased microsatellite instability status (MSI) comparing to those with wildtype MMR (33% vs. 3.1%, p< 0.0001), and patients harboring HRR mutations demonstrated elevated genomic instability than those without such mutations (median HRD: 18 vs.14, p < 0.05), indicative of potential response to poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damage agents. Furthermore, high TMB was found to be highly correlated with DDR gene alterations ( p =0.004). In addition, we observed higher mutation frequencies of BRCA1/2 genes (including somatic and germline) in GBCs in contrast to other BTC subtypes. Conclusions: We herein reported the genomic features of 482 Chinese BTC samples and highlighted the role of DDR pathways including HRR and MMR. These findings could be useful to establish treatment and diagnostic strategies for BTC patients based on genetic information.
Adjuvant chemotherapy in nonmetastatic goblet cell carcinomas: A population-based analysis.
Authors: Tateo Valentina , Andrini Elisa , Campana Davide , Lamberti Giuseppe
Published: June 2021

e16203

Background: Goblet cell carcinoma (GCC) is a rare mixed endocrine-neuroendocrine tumor arising almost exclusively in the appendix. The optimal management of these patients is still unclear, given GCC rarity and the difficulty in proper pathology diagnosis. We sought to explore the efficacy of adjuvant chemotherapy (ACT) in GCC extracted from the Surveillance, Epidemiology and End Result (SEER) US registry. Methods: Patients with pathology diagnosis of GCC were identified in the SEER registry by the 8243 ICD-09 code. Data about sex, age, tumor stage at diagnosis, number of analyzed and positive lymph-nodes, chemotherapy and survival were collected. Lymph node ratio (LNR) was calculated as the ratio between the number of metastatic lymph-nodes and removed lymph nodes. The best cutoff to predict survival state at 5-year from diagnosis was calculated. The primary endpoint was overall survival (OS). Results: Overall, 1055 GCC patients (51.7% male, median age 57 years) were identified. The median tumor diameter was 20 mm. According to the American Joint Committee on Cancer staging manual 7th edition, 128 patients (12.1%) had nodal involvement (N+): 95 were N1 and 33 were N2, while 66 (6.3%) had distant metastasis (M+). Prognostic LNR cutoff was 0.16. Using this cutoff, LNR was ≤0.16 in 674 patients (63.9%), and > 0.16 in 125 patients (11.8%). The median OS was 232 months (95% confidence interval [95%CI]: 153.4-310.5). Overall, 5-year survival rate (OS-5) was 73.4% (N = 453). At univariate analysis age, tumor diameter, M+, N+, number of lymph nodes removed, number of metastatic lymph nodes and LNR were significantly associated with the risk of death. At multivariate analysis, age, M+, N+, number of removed lymph nodes, and number of metastatic lymph nodes retained their association. After excluding M+ and N+ patients, 897 localized GCC patients (52.8% male) were analyzed. Fifty-five patients (6.1%) received ACT and OS-5 was 83.8% (N = 425). CT was administered more often in tumors with higher histological grade, higher T stage and greater tumor diameter. At the multivariate analysis, only age and number of removed lymph nodes were independently associated with the risk of death. Notably, ACT was not associated with increased survival. Ninety-two patients (57.6% male) had nodal involvement without distant metastases: 73 were N1 and 19 were N2. In 56 patients (60.9%) LNR was ≤0.16, while it was > 0.16 in 35 (38.0%). Thirty-five patients (38%) received ACT, without significant imbalances. OS-5 was 45.2% (N = 28). At univariate analysis, age, N2, number of metastatic lymph nodes and LNR were significantly associated with the risk of death. At multivariate analysis, only the number of metastatic lymph nodes retained its association. Of note, ACT was not associated with increased survival. Conclusions: In GCC, ACT was not associated with increased survival in our population-based analysis, irrespective of nodal involvement.
Toripalimab with nab-paclitaxel/gemcitabine as first-line treatment for advanced pancreatic adenocarcinoma: Updated results of a single-arm, open-label, phase Ib/II clinical study.
Authors: Cheng Ke , Lv Wan-Rui , Li Xiaofen , Tian Bole , Cao Dan
Published: June 2021

e16213

Background: Currently nab-paclitaxel/gemcitabine (AG) is the standard first-line treatment for advanced pancreatic ductal adenocarcinoma (aPDAC), which is still needed to improve. The phase Ib/II study aiming to evaluate safety and efficacy of AG plus toripalimab, an anti-PD-1 monoclonal antibody, showed well tolerability and encouraging efficacy in aPDAC patients (preliminary data presented at 2020 ASCO). Here, we updated new results of this study. Methods: This was a single-arm, open-label, phase Ib/II clinical trial of AG with toripalimab as first-line treatment for aPDAC. Patients received toripalimab (240mg, Q3W), combined with AG (nab-paclitaxel 125 mg/m2, d1, d8 plus gemcitabine 1000 mg/m2, d1, d8) until the disease progresses/unacceptable toxicity or receiving toripalimab maintenance treatment. The primary objectives were safety and OS; the secondary objectives were ORR, DCR and PFS. Predictive biomarkers including MMR protein and PD-L1 expression, the tumor mutation burden (TMB) based on next-generation sequencing, genomic alteration signatures and the number of TILs were evaluated. Results: At data cutoff (Feb 3, 2021), 20 chemotherapy naïve aPDAC patients (female: 65.0%, median age: 55.5 years) with ECOG PS ≤ 2 were enrolled. Of the 17 evaluable patients, the ORR was 35.3%, the DCR was 82.4%, including 5 patients with PR and 1 patient with CR, respectively. 12 patients were alive and the study treatments for 9 patients were still ongoing. Median PFS was 5.0 months (95% CI：4.216-5.784), the 6-month PFS rate was 60%; median OS was 14.0 months (95% CI：9.445-18.555), the 1-year OS rate was 80%. 2 cases of pseudoprogression were observed. The most frequent treatment related adverse events were ALT elevation (35.0%), leukocytopenia (30.0%) metabolic disorder (25.0%) and hypothyroidism (25.0%). 4 patients (20.0%) experienced grade 3/4 TRAE (including myocardial enzyme elevation, neutropenia, vomiting and nausea). In the biomarker analysis, all patients were MMR-proficient status; 14 patients were evaluated for PD-L1 expression compared with PD-L1 negative cases (n = 5), PD-L1 positive cases (n = 9) did not show higher RR or longer PFS, responses were observed in both groups. 10 patients were investigated for NGS, 2 patients with TMB > 10 Muts/Mb, the most frequently mutated genes were KRAS (90%), TP53 (90%) and ARID1A (20%). Conclusions: The updated results of this phase Ib/II study provided preliminary evidence that toripalimab in combination with AG has a manageable safety profile consistent with known safety profile for each agent alone and demonstrates signals of clinical activity. The correlation between biomarkers with clinical efficacy are under investigation. The results supported ongoing combined treatment in aPDAC patients. Clinical trial information: ChiCTR2000032293.
Digital PCR-based cell-free DNA K-Ras mutations analysis and clinical implication in pancreatic cancer.
Authors: Forouzandeh Nahid , Srinivasan Sachin , Jurdi Katia , Wang John Qiang , Tofteland Nathan , Yang Wancai , Salyers William , Lu Jim
Published: June 2021

e16215

Background: Pancreatic cancer is one of the most fatal cancers worldwide. In addition to patients presenting later in the disease, limitations in current testing modalities pose a challenge to early diagnosis and treatment. Somatic mutations of the K-Ras gene have been suggested as a key driver of pancreatic carcinogenesis and thus proposed as a biomarker for diagnosis and therapy. Majority of these studies utilize tissue-based methods for analyzing K-Ras mutations. In recent years, liquid biopsy assay, in particular, analysis of cell-free DNA (cfDNA), has emerged as a promising noninvasive diagnostic approach in oncology, with the respect to the identification of minimal residual diseases, monitoring treatment response, detection recurrence and metastasis, and identification of chemo-resistance mechanisms. The application of digital PCR based plasma cfDNA K-Ras mutation assay in pancreatic cancer has not been reported. Methods: We included patients who underwent evaluation of a pancreatic lesion detected by conventional radiography (CT/MRI) and confirmed by endoscopic ultrasound (EUS) and biopsy. The biopsies from pancreatic tissues were formalin-fixed and paraffin-embedded (FFPE) for pathological diagnosis, and the total DNA was extracted from the FFPE slides. In addition, matched blood from the same patient was collected at the time of biopsy, and plasma cfDNA was extracted. Both DNA quality and concentration were evaluated. 4.0 ng of DNA was used for droplet digital PCR (ddPCR) analysis. K-Ras G12D, G12V, G12R, G12C, G12A, G12S, and G13D mutations were analyzed by multiplexed assay reagents. The sensitivity cut-off of the multiplexed K-Ras G12/G13 assay was 1.0%. Results: cfDNA could be detected in the initiation of pathological diagnosis. Among the twelve patients with pancreatic lesions, eight (67%) were pancreatic ductal adenocarcinoma (PDAC) (head (4), body (2), tail (2) of the pancreas), one was acute pancreatitis, one was a tail cyst and two were unspecified non-malignant lesions. All the eight PDAC (100%) FFPE tissues exhibited K-Ras G12/13 mutations (Scores: 4.2-41.5%), while none of the non-malignant lesions (0%) demonstrated K-Ras mutations. Interestingly, K-Ras mutations were detected from seven of the eight PDAC patient’s plasma cfDNA (87.5%) (Scores: 1.2-20.7%) while the plasma cfDNA from patients with non-malignant lesions did not show any positive K-Ras mutations. Conclusions: Digital PCR-based plasma cfDNA assay for K-Ras mutation is a promising tool for diagnosis of PDAC and is comparable to tissue-based assays. Larger prospective studies can substantiate this and explore their roles in the prediction and early detection of recurrence of PDAC.
Prevalence of germline mutations in pancreatic carcinoma patients (PCP) unselected for family history (FH).
Authors: Rodrigues Livia Munhoz , Maistro Simone , Marques Rocha Vinícius , Lopez Rossana Veronica Mendoza , Koike Folgueira Maria A. A.
Published: June 2021

e16263

Background: Despite being one of the deadliest tumors worldwide, hereditary factors involved in PC are not fully understood. Thus, our objective is to assess the prevalence of germline mutations in PC cohorts not selected for FH. Methods: A systematic review was performed, using the descriptors related to PC and germline mutations, employing Pubmed, Lilacs, Web of Science and Embase, until August/2020. Three investigators were involved in reviewing titles and abstracts by peers. Exclusions comprehended articles of non-English language, studies investigating endocrine PC or case-reports. For the present analysis, the inclusion criteria were: original full paper available for data extraction, studies with patients unselected for FH and evaluating a panel of at least 10 genes, WES or WGS. Results from our group evaluating a cohort of PC Brazilian patients were also considered. We present prevalence results for germline mutations in 8 genes, comprehending ATM, BRCA1, BRCA2, CDKN2A, CHEK2, MSH6, PALB2 (the most frequently mutated genes in PC) and FANCM (previously detected in our Brazilian cohort). Results: After exclusion of duplicate titles, 2, 035 titles were available. Using the criteria described above, 23 articles were selected for analysis and involved cohorts from Australia, Canada, USA, Japan, Czech Republic and our Brazilian cohort, totaling 11, 165 PCP evaluated. The predominant histology was adenocarcinoma (15/24 studies), 22/24 studies evaluated a panel of genes and for studies providing demographic data, the mean age of PCP was 64 (13-93) years (n = 8, 000). Six out of eight genes were evaluated in at least 10, 600 patients, among which BRCA2 mutations had the highest prevalence, followed by ATM. Mutations in CHEK2 occupied the third place in prevalence, despite being evaluated in only 74.5% of the entire cohort. BRCA1, PALB2, CDKN2A, MSH6 and FANCM showed a prevalence of less than 1%, according to the table below. Although being infrequent among PCP, it is interesting to observe that an identical FANCM mutation was detected in two unrelated Brazilian patients. Conclusions: Analysis of cohorts unselected for FH indicates that BRCA2, ATM and CHEK2 are the most frequently mutated genes in these PCP. Further studies are needed to better characterize the spectrum and prevalence of mutations in PCP from populations other than Caucasians, especially in miscegenated people.[Table: see text]