bluuebunny/crossref_metadata_2025_split huggingface dataset:
Number of subsequent treatments and time to recurrence in hepatocellular carcinoma.
Authors: Juarez Juan Jose , Birda Vaibhav , Sucre Santiago , Garita Esteban , Pacheco-Barrios Kevin , Paredes Rodrigo , Bullock Andrea J. , Sarwar Ammar , Peters Mary Linton Bounetheau 
Published: January 2024

526 Background: Hepatocellular carcinoma (HCC) is often managed with locoregional therapies including surgical resection, ablation, transcatheter arterial chemoembolization (TACE), and selective internal radiation therapy (Y90). Most patients require multiple treatments over several years due to ongoing development of new lesions, distinct from other cancer types. Our project aims to analyze this treatment trajectory and the impact of treatment selection. Here we present an interim analysis focusing on the number of subsequent therapies and time to first recurrence (TTR). Methods: We identified 202 patients newly diagnosed with HCC between 2019-2021 who were seen in the BIDMC Liver Tumor Multidisciplinary Clinic. Complete abstraction of medical records was performed in 51 patients to date. Our primary outcome was of the number of subsequent therapies depending on the selected first-line locoregional therapy. Incidence risk ratios (IRR) were obtained via a crude and adjusted (age, gender, race, Child Pugh) linear regression model. Ablation was used as the reference treatment. Secondary outcomes included survival analysis of TTR, overall survival (OS) and time to initiation of systemic therapy. TTR was defined as the appearance of new lesions, excluding residual disease. Results: Mean age at diagnosis was 65 years old, 73% were male, and 92% ECOG 0. 37 patients out of 50 had recurrence, almost all local (97%). The total number of subsequent therapies received was 110; the most common treatment received on first recurrence was ablation (59%) followed by Y90 (24%). Patients who received TACE were more likely to undergo a higher number of subsequent therapies in both the unadjusted (IRR 2.51, p<0.001, 95%CI 1.6-3.9) and adjusted analysis (IRR 4.43 p<0.001, 95%CI 2.5-8.1) with 4.4 (2-9) mean subsequent treatments when compared to ablation with a mean number of subsequent treatments of 1.47 (0-7). Y90 had 1.85 (0-7) mean subsequent treatments and surgery 1.87 (0-7), with inconclusive results regarding IRR when compared to ablation. Median TTR was 19.1 months (10.2-29.3) with ablation having the longest time with 22.2 months (13.2-31.1), followed by surgery with 20.3 months (13.3-29.3), Y90 with 19.1 months (6-NR) and TACE with 12.1 (6.1-21.2). Median OS was not reached, and only 5 patients started systemic therapy. Conclusions: This interim analysis shows that patients treated with TACE as the first locoregional therapy are likely to undergo a higher number of subsequent treatments when compared to ablation.
Molecular predictors of response to first-line systemic therapies in advanced hepatocellular carcinoma.
Authors: Chang Jeremy , Conner Elizabeth , Fowler Kathryn J , Tamayo Pablo , Burgoyne Adam 
Published: January 2024

534 Background: With numerous advances in systemic therapy for advanced hepatocellular carcinoma (HCC) over the past several years, there are now multiple first-line treatment options which can be considered. These options include combination atezolizumab with bevacizumab (atezo/bev), programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) targeted agents, and oral multikinase inhibitor monotherapy. However, further guidance is needed to predict which patients will respond to best to each regimen. Methods: We performed a single center, retrospective study to determine the association between responses to first-line therapies in advanced HCC and various molecular alterations. Patients received first-line therapy with either atezo/bev, PD-1/PD-L1 monotherapy, or oral multikinase inhibitor monotherapy with treatment responses determined by imaging. All patients underwent next-generation sequencing (NGS) with testing performed on peripheral blood or tumor tissue. Results: A total of 116 patients with advanced HCC were included in this study. For first-line therapies, 45 (38.8%) patients received atezo/bev, 41 (35.3%) received oral multikinase inhibitor monotherapy, and 30 (25.9%) received PD-1/PD-L1 monotherapy. There was no association between treatment responses and patient ethnicity, age, or underlying cirrhosis etiology for any regimen. However, when analyzing NGS results, atezo/bev recipients with telomerase reverse transcriptase (TERT) promoter alterations had significantly higher rates of disease progression (PD) compared those without TERT promoter alterations (91.7% vs 54.6%, p = 0.03). In addition, in the oral multikinase inhibitor monotherapy group, those with CTNNB1 alterations had significantly greater PD rates compared to patients without these alterations (66.7% vs 31%, p = 0.04). There were no significant correlations between molecular alterations and responses in the PD-1/PD-L1 monotherapy group (Table). Conclusions: In our study, advanced HCC patients who received first-line systemic therapies were found to have significant correlations between TERT promoter and CTNNB1 alterations and responses to atezo/bev and oral multikinase inhibitor monotherapy, respectively. Given the widespread use of these regimens in the HCC treatment paradigm, additional studies are needed to confirm these findings and determine their impact on survival outcomes.[Table: see text]
Genomic and immune landscape of biliary tract cancers with ARID1A, PBRM1, and BAP1 alterations.
Authors: King Gentry Teng , Berg Rachel , Yilma Binyam , Stoppler Melissa Conrad , Hsieh Ronan Wenhan , Safyan Rachael A , Zhen David Bing , Coveler Andrew L. , Cohen Stacey A. , Shankaran Veena , Chiorean E. Gabriela , Harris William Proctor 
Published: January 2024

557 Background: Alterations in ARID1A, PBRM1 and BAP1 subunits of the SWI/SNF complex are common in biliary tract cancers (BTCs) and have been implicated in tumor microenvironment (TME) immunomodulation. However, there is heterogeneity in outcomes, with PBRM1 and BAP1 conferring improved survival vs worse survival with ARID1A. We explored relationships between ARID1A, PBRM1 and BAP1 alterations with putative immunotherapy biomarkers and genomic co-alterations. Methods: We examined BTC patients in the Tempus database with ARID1A, PBRM1 and BAP1 alterations. Co-alterations were identified through next-generation sequencing (NGS) using the Tempus xT assay, a targeted, tumor-normal-matched DNA panel that detects SNVs, indels, and CNVs in 648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Samples additionally underwent whole transcriptome RNA-seq via the Tempus xR assay (Tempus Labs, Chicago, IL). Immune biomarkers explored include MSI-H, PD-L1, Tumor Mutation Burden (TMB), and immune cell infiltration by RNA sequencing. Parameters were analyzed between two groups: BTC with ARID1A, vs BTC with PBRM1 and/or BAP1 alterations. Results: 696 BTC patients with ARID1A, PBRM1 and BAP1 alterations were included. Overall, there was low frequency of MSI-H (3.2%), PD-L1-positivity (5.7%) and TMB >10 mt/Mb (4.7%). Among the two groups, there was a higher proportion of MSI-H patients in ARID1A BTC vs PBRM1 and/or BAP1 BTC (4.9% vs 1.4%, p=0.01). Macrophages were the predominant immune cell (46%), followed by CD4+ T-cells (23%) and NK cells (12%). CD8+ T cells were the least encountered (5%). B-Cells were seen more in ARID1A vs PBRM1 and/or BAP1 (9% vs 6%, p <0.001) while macrophages were more frequent in PBRM1 and/or BAP1 vs ARID1A (49% vs 44%, P <0.001). Co-alterations in SMAD4, TP53, ARID2 and KRAS were more frequent in ARID1A BTC while IDH2 and NRAS were more common in PBRM1 and/or BAP1. Within the PBRM1 subgroup, TP53 was most frequently encountered (33%), while CDKN2A alterations were most frequently encountered in BAP1 BTC (35%) (Table 1). Conclusions: This is the largest known data set exploring the genomic and immune landscape of BTC with ARID1A, PBRM1 and BAP1 alterations. Macrophages were the dominant immune cell TME and may be a target of interest. Co-alteration profile is distinct between ARID1A- vs PBRM1- and/or BAP1-altered BTC.[Table: see text]
Survival and progression-free survival in patients undergoing curative resection for intrahepatic cholangiocarcinoma.
Authors: Ozturk Nazli Begum , Jamil Laith H. 
Published: January 2024

562 Background: Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare but increasingly prevalent form of primary liver cancer. Surgical resection with negative margins is the mainstay of the treatment for patients with resectable-iCCA. However, given the rarity of iCCA and its low resectability rate, well-defined prognostic markers and outcomes for patients undergoing curative hepatectomy are lacking. We aimed to analyze the characteristics and outcomes of patients undergoing liver resection for iCCA. Methods: All consecutive patients with confirmed iCCA who underwent hepatectomy between 7/2006-3/2023 at our institution were included. Patients who received neoadjuvant therapy were excluded. Demographic, clinical, radiological, histopathological, recurrence, and survival data were collected. Overall survival was calculated from the date of liver resection to the date of death or last clinical encounter. Continuous variables are reported as median and interquartile range (IQR) 1 and IQR3, and categorical variables as counts and percentages. Results: A total of 83 patients (43 male, 40 female) were included in the final analysis. The median age at resection was 67 years (58.0-74.0). Histologically proven liver disease was present in 30.12% and liver cirrhosis was present in 9.63% of patients. Among all patients, hypertension was present in 61.44%, diabetes mellitus in 25.30%, inflammatory bowel disease in 7.22%. The median tumor size was 4.4 cm (3.0-6.2). Tumor histologic grade was 55.42% moderately differentiated tumor, 37.3% poorly differentiated tumor, and 7.22% well differentiated tumor. Of all patients, 37.66% had lymph node invasion, 35.61% had perineural invasion, and 30.76% had vascular invasion on liver histology. Positive surgical margins were present in 20.73% of patients. The duration from liver resection to the last follow-up or death was 1.6 years (0.80-3.20). The 1-, 3-, and 5-year recurrence-free survival rates were 72.78, 34.95, and 15.88% respectively. The 1-, 3-, and 5-year overall survival rates were 90.9%, 65.9, 44.2%, respectively. Advanced iCCA stage at diagnosis ( p<0.001), presence of lymph node metastasis ( p=0.03), vascular invasion ( p=0.02), and age<50 ( p=0.01) were associated with significantly worse overall survival. There was no statistically significant survival difference between patients with concurrent liver disease and those without (6.88 vs 4.35 years, p=0.46.). Conclusions: Our results demonstrate that iCCA carries a substantial risk of recurrence despite curative resection. The presence of advanced stage at diagnosis, lymph node involvement, vascular invasion, and age<50 were associated with significantly worse overall survival. Liver disease had no significant effect on the survival outcomes. Predictive markers of recurrence and survival in patients vary in the literature and remain to be validated.
Real-world 177Lu-DOTATATE peptide receptor radionuclide therapy: Treatment outcomes with dosing variations and in non-midgut neuroendocrine tumors.
Authors: Lee Hwan , Kipnis Sarit , O'Brien Sophia , Eads Jennifer Rachel , Katona Bryson W. , Pryma Daniel A. 
Published: January 2024

593 Background: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE has been used for neuroendocrine tumors (NETs) since its approval in the United States based on demonstrated progression-free survival benefit in grade 1-2 midgut NETs. The recommended dosing is 7.4 GBq (200 mCi) every 8 weeks for 4 doses in total. We examined the post-PRRT outcomes with dosing variations and in patients with non-midgut NETs. Methods: The medical records of 108 PRRT-naïve NET patients who received at least one cycle of PRRT at a single academic institution were reviewed. Among the patients with Ki-67 index ≤ 20%, progression-free survival (PFS) and overall survival (OS) were compared between midgut and non-midgut NETs. Among the patients who did not develop disease progression or mortality during the treatment course, PFS and OS were compared based on dosing variations. Dosing variations were defined as "reduced” (50% of 7.4 GBq/cycle), “delayed” (>12 weeks between cycles), or “fewer” (<4 cycles) doses. Kaplan-Meier survival analysis with log-rank test was used for statistical analysis. Results: Median clinical follow-up was 18.7 months, during which disease progression and death occurred in 54 (50%) and 20 (18%) patients, respectively. Among the 98 patients with Ki-67 index ≤ 20%, those with non-midgut tumors (n=55) showed significantly shorter PFS compared to those with midgut tumors (n=43) with the hazard ratio of 2.0 ( P=0.014, median of 15.6 vs. 26.9 mo.). No difference in OS was found between the two groups ( P=0.83). Among the 93 patients who did not develop disease progression or mortality during the course of PRRT, dosing variations were used in 23 patients. The types of dosing variations were “reduced” in 4 (17%) patients, “delayed” in 16 (70%) patients, and “fewer” in 7 (30%) patients. The reasons for dosing variations were hematologic in 9 (39%) patients, hepatic in 2 (9%) patients, renal in 1 (4%) patient, other medical in 3 (13%) patients, functional in 3 (13%) patients, and logistical in 6 (26%) patients. No difference in PFS ( P=0.20) or OS ( P=0.24) was found based on the presence or absence of dosing variations. Conclusions: Patients with non-midgut NETs show approximately twice the rate of disease progression over time following PRRT than those with midgut NETs. Administering reduced, delayed, or fewer doses of PRRT may still offer comparable benefit compared to the recommended dosing.
Liquid biopsies for faster diagnosis of suspected advanced pancreatic and biliary tract cancers: ACCESS, a UK innovation programme.
Authors: Jones Lauren , Mencel Justin , Mullen Reed , Sardo Infirri Sofia , MacDonald Alan , Fribbens Charlotte Victoria , Rao Sheela , Mahmood Asif , Galloway Daniel , Gupta Sanjay , Chadwick Georgina , Chau Ian , Ni Melody , McVeigh Terri Patricia , Popat Sanjay , Hubank Michael , Cunningham David , George Angela Joy , Starling Naureen 
Published: January 2024

614 Background: Tissue diagnosis in biliary tract (BTC) and pancreatic (PC) cancer is challenging due to anatomical location and patient (pt) factors (frailty, sepsis); approximately 25% of invasive biopsies are nondiagnostic, requiring repeat procedure. Most BTC and PC pts present with advanced disease. In stage III and IV solid tumours, Guardant 360 (G360) 74 gene panel liquid biopsy (LB) detects ctDNA in 80%/85% of BTC/PC. ACCESS is a real-world innovation programme evaluating the impact of adding G360 to the current invasive diagnostic pathway for suspected BTC/PC in 6 hospitals in West London; (n=240). Methods: This is a pre-planned interim analysis of the first sequential 65 pts with G360 in ACCESS. Patients were age>18 years, ECOG ≤ 2 with high radiographic suspicion of stage III/IV BTC or PC without histological diagnosis at registration or other malignancies within 3 years. Positive LBs were reviewed at molecular tumour board with 4 pre-specified levels of diagnostic certainty: diagnostic/consistent/possibly/not consistent. Tumour board review followed. Endpoints include repeat biopsy rate, change in time to diagnosis, quality of life, health economic assessment and patient satisfaction. Results: 64 patients were analysed (1 excluded). 50% female, median age 73 years (43-94), suspected cancer sites 14%/77%/9% BTC/PC/either BTC or PC. Suspected stage III/IV disease 38%/62%. ctDNA detection rate was 80%/100%/82% in overall cohort/BTC/PC. Most commonly detected LB alterations in suspected BTC/PC were TP53, APC, ATM, CDK/TP53, KRAS, CDKN2A, ARID1A. In BTC and PC, diagnostic method was liquid biopsy alone/liquid and tissue biopsy/tissue alone in 16%/49%/33%. 17% had repeat biopsy. Sensitivity/specificity of cancer diagnosis (all-comers) using liquid biopsy was 86% (95% CI 73.3-94.2)/38.5% (95% CI 13.9-68.4). Conclusions: There is a high ctDNA detection rate with high level diagnostic certainty, promising for future genomic transformation of BTC/PC diagnostic pathways, potentially reducing repeat invasive biopsies, speeding up diagnosis, facilitating precision therapy, with ACCESS defining a blueprint for molecular integration of liquid biopsies. Full recruitment is planned to complete in March 2024.
Amplified Sciences PanCyst Pro Panel to accurately identify non-mucinous pancreatic cyst fluid.
Authors: Thomas Mini , Sheik Daniel , Byers Kaleb , Rajesh U. Chinna , Ramsey Curtis , Davisson V. Jo 
Published: January 2024

617 Background: Pancreatic cysts are rarely symptomatic, and, consequently, are detected incidentally during routine imaging analyses for unrelated disorders. Guidelines for diagnosis of pancreatic cysts rely on imaging and supportive analyses of fluid extracted during endoscopic ultrasound with fine-needle aspiration (EUS-FNA). Unfortunately, currently available protein markers and assays are not sufficiently accurate to rule-out patients in whom a non-mucinous pancreatic cyst has formed. Since non-mucinous pancreatic cysts seldom progress to cancer, this patient population is at risk of being subjected to the severe physical, emotional, and financial burdens associated with unwarranted surveillance, testing, and possible surgical intervention. Furthermore, identification of mucinous pancreatic cysts does not establish the risk of progression to cancer (rule-in) or the need for surgical intervention. Methods: To address the unmet needs in pancreatic cyst diagnosis, Amplified Sciences has combined a panel of markers with a clinically translated surface enhanced Raman spectroscopy (SERS)-based protease activity assay as a rule-out diagnostic tool. The tri-analyte panel was tested on a cohort of 185 retrospective samples gathered from three separate institutions (UPMC, IU Health, and UCSF) and consumed only 12 µL of cyst fluid per sample. The goals of this study were to establish the negative predictive value (NPV) of this panel prior to translation to a CLIA-regulated laboratory and create a preliminary algorithm for analysis. Results: The results of this statistically powered study show that protease activity outperforms carcinoembryonic antigen (CEA), a current standard diagnostic marker for pancreatic cyst fluid, in sensitivity, specificity, and NPV. Furthermore, in combination, the tri-analyte panel identifies non-mucinous pancreatic cysts with 99% sensitivity and a negative predictive value >95%. Conclusions: These results support the use of this panel in clinical settings as a diagnostic tool to rule-out patients from surgical intervention, as well as the use of SERS as an optical detection mode for clinical diagnostics. Future work will continue to address the unmet need for improved diagnostic information through multiplexed analyses of markers that consume comparatively minimal volume of pancreatic cyst fluid samples. Studies will also seek to build on the SERS platform by introducing more dyes, substrates, assays, and analytical methods. Amplified Sciences would like to acknowledge significant efforts to build the clinical samples cohort from Gina Zhu, Kelli Ifuku, and Dr. Kimberly Kirkwood from USCF, Christine Decapite and Dr. Randall Brand from UPMC, and Michele Yip-Schneider and Dr. C. Max Schmidt from IU Health.
Neoadjuvant chemotherapy vs upfront resection: A challenging choice in resectable pancreatic ductal adenocarcinoma.
Authors: Fekrmandi Fatemeh , Hagerty Brendan , Liu Qian , Schneider Tyce , Malik Nadia , Fountzilas Christos , Kukar Moshim , Cherkassky Leonid , Calvo Benjamin 
Published: January 2024

620 Background: Pancreatic ductal adenocarcinoma (PDAC) remains an immense challenge within oncology, with only 15-20% of cases initially qualifying as resectable. Based on National Cancer Database analyses there is an increase in neoadjuvant chemotherapy (NACT) use, with potential downstaging effects. Yet, a subset of neoadjuvant-treated patients fail to proceed with curative-intent surgery, leading to worse outcomes. This retrospective analysis aims to uncover factors that predict NACT use and the impact on survival outcomes. Methods: A cohort of 543 consecutive non-metastatic PDAC patients treated at an NCCN-designated comprehensive cancer center between 2015 and 2022 were prospectively enrolled into a REDCap database. Based on NCCN resectability criteria, initial CT staging placed 96 patients as upfront resectable. Survival outcomes were compared using univariate and multivariate cox regression analyses. Results: Within 96 resectable patients, 45 (47%) underwent upfront surgery, 36 (37%) received NACT followed by surgery and 15 (16%) only received chemotherapy. The majority were CA19-9 secretors (94%) with 54% lower values during chemotherapy. While 60% of patients experienced up to 35% tumor size reductions on NACT, 20% had stable disease, and 20% showed progressive disease. The patients who received NACT were significantly younger (p = 0.01), with higher baseline CA19-9 (p < 0.01) and more frequently underwent stent placement (p = 0.01), table 1. Median overall survival for the upfront surgery, NACT+surgery and chemotherapy groups were 32.8, 23.7 and 20.2 months (log-rank test p<0.01) subsequently. On univariate analysis initial presentation with weight loss (p = 0.02, HR = 2.08) and high baseline CA19-9 (log2-scaled, p = 0.01, HR = 1.13) were predictive of worse overall survival. After adjusting for potential confounding variables, patients in chemotherapy group had significantly worse survival compared to the upfront surgery group (P < 0.01, HR = 3.14). These 15 patients failed to undergo surgery due to diverse reasons, including distant progression (7), local progression (3), performance status decline or death during chemotherapy (2), refusal due to chemotherapy side effects (2), and indecision and loss to follow-up (1). Conclusions: These findings underscore the need for more robust selection criteria in resectable PDAC patients to undergo NACT. Leveraging real-world data helps identify predictive factors of treatment decision making and their impact on patient survival outcomes. [Table: see text]