bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]