bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of anlotinib with PD-1 inhibitors in the treatment of advanced hepatocellular carcinoma: A real-world study.
Authors: Chen Kehe , Huang Xianshi , Yu Lei , Lu Jianxun , Huang Fei , Wang Zhiguang , Wei Yan , Hou Encun , Luo Min , Huang Shiqing , Hu Hongbo , Ou Mei 
Published: January 2023

583 Background: The IMbrave 150 study opened the door of immuno-oncology (IO) combined with targeted therapy in patients (pts) with hepatocellular carcinoma (HCC). At present, some other combination of IO and tyrosine kinase inhibitors (TKIs) had been proved as efficient regimens in China and there are many ongoing studies on this approach with preliminarily considerable efficacy. Furthermore, the efficacy of this combination still needs to be explored in real-world patients. The aim of this study is to explore the efficacy and safety of anlotinib plus PD-1 inhibitors in the treatment of HCC in real-world. Methods: This is a multi-center, prospective real-world study in pts (N=200) diagnosed as advanced HCC, who evaluated by physician would get benefits from anlotinib alone or in combination with PD-1 inhibitors. The enrolled patients received treatment according to physicians. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigators according to RECIST version 1.1. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: As of data cutoff date of Aug, 2022, a total of 119 patients were enrolled with a median age of 55 years (range 29-83). Among them 78% ECOG PS 0-1, 21% ECOG PS 2 and 1% ECOG PS 4. 75 pts received anlotinib plus PD-1 inhibitors as first-line treatment, 17 pts as second-line treatment and 7 pts as third-line and above. 76 patients were eligible for response evaluation. The ORR as best response was 11.8% (95%CI: 5.6%, 21.3%). The DCR was 73.7% (95%CI: 62.3%, 83.1%). The preliminarily results indicated that the median OS was 12.5 months (95%CI: 9.7, 15.4), the median PFS was 8.1 months (95%CI: 5.9, 10.3). Any grade treatment-related adverse events (TRAEs) observed in 50% of pts. The most common TRAEs were hypoalbuminemia (18.6%), hypertension (11.4%), decreased white blood cell count (11.4%) and decreased platelet count (10%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 inhibitors exhibited potential efficacy and manageable adverse events in the treatment of advanced HCC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521 .
The oncologic implications of tumor multiplicity in intrahepatic cholangiocarcinoma: Its prognostic value might be underestimated.
Authors: Yoon So Jeong , Oh Subin , Jeon Hyun Jeong , Jeong Hye Jeong , Lim Soo Yeun , Shin Sang Hyun , Heo Jin Seok , Han In Woong 
Published: January 2023

611 Background: In the latest staging system of the American Joint Committee on Cancer (AJCC) for intrahepatic cholangiocarcinoma (IHCCC), solitary tumor with vascular invasion and multiple tumors are grouped together as T2. However, recent studies have reported that multifocal IHCCC have worse prognosis than a single lesion. This study aimed to investigate risk factors of IHCCC and to explore the prognostic significance of multiplicity identified by surgical resection. Methods: A total of 277 patients underwent surgery for IHCCC from 2010 to 2019 and the clinicopathological data were retrospectively reviewed. Risk factor analysis was performed to identify variables associated with survival of resected IHCCC. Survival outcomes were compared between patients with solitary tumors and those with multiple tumors. Results: In multivariable analysis, presence of preoperative symptoms, tumor size, lymph node ratio, multiplicity, and tumor differentiation were risk factors for survival. Among 82 patients with T2, overall survival was significantly better in patients with solitary tumors (sT2) than in those with multiple tumors (mT2) (p = 0.017). Survival was compared among patients with stage II-sT2, stage II-mT2, and stage III. Stage II-sT2 group showed prolonged survival than those with stage II-mT2 or stage III. Survival of stage II-mT2 patients was not statistically different from that of stage III patients. Conclusions: Tumor multiplicity was an independent risk factor for overall survival of IHCCC after surgical resection. Patients with multiple tumors showed poorer survival than patients with a single tumor. The oncologic significance of multiplicity in IHCCC should be reappraised and be reflected in the next update of staging system.[Table: see text]
Three-dimensional radiotherapy dose prediction in patients with liver and pancreas cancer treated with the Viewray system.
Authors: Kim Dong-Yun , Jang Bum-Sup , Kim Eunji , Kim Jae Sik , Chie Eui Kyu 
Published: January 2023

612 Background: The radiotherapy (RT) planning process for patients with gastrointestinal tract cancers is regarded as a time-consuming and complicated task due to proximity of multiple organs at risk (OARs). Dose prediction model based on deep learning might be a solution to increase efficiency by reducing the time required to find the optimal plan. Dose distribution model was developed using a three-dimensional (3D) U-Net deep learning. Methods: Altogether RT plan of patients with liver cancer (N=40) and pancreatic cancer (N=26) were acquired from the MRIdian (Viewray Technologies, Oakwood Village, OH) treatment planning system from 2016 to 2018. Magnetic resonance (MR) images for RT, planning dose, and contoured RT structures were retrospectively collected. The 3D U-Net was employed, and transfer-learning was performed on the training set (N=60, 91.3%). The initial learning rate was 0.1, decreasing by 10% every 5 epochs, for a total of 200 epochs. A developed model was evaluated by the testing set (N=5, 7.7%). The difference between ground truth and predicted dose was compared by calculating normalized minimum, maximum, and mean doses of the planning target volume (PTV) and OARs. Results: Root-mean-square error (RMSE) of voxels between ground truth and predictive dose was 3.04 (range 2.29-3.79). Percentage of mean dose difference and standard deviation between clinical and prediction models were 1.75 ± 2.84%, 0.08 ± 0.11%, 0.13 ± 0.08%, 0.05 ± 0.03%, 0.07 ± 0.05% for PTV, duodenum, liver, kidney, and stomach, respectively. And the percentage of max dose difference between the two were 0.91 ± 0.01%, 0.34 ± 0.43%, 0.63 ± 0.39%, 0.25 ± 0.18%, 0.33 ± 0.30%, respectively. Overall, the predicted normalized target DVH metrics were within 2% of the ground truth plans. Conclusions: We developed a deep learning model for dose prediction in liver and pancreatic cancer using MR images acquired from MRIdian system. Larger-scale training and validation are required to prove the efficacy of the dose prediction model by the 3D U-Net.
Liver-directed therapy of neuroendocrine liver metastases.
Authors: Meloche-Dumas Léamarie , Mercier Frédéric , Barabash Tori , Law Calvin , Singh Simron , Myrehaug Sten , Chan Wing , Hallet Julie 
Published: January 2023

647 Background: While there have been major advances in the care of neuroendocrine tumors (NETs), there is still no widely adopted therapeutic sequencing in metastatic NETs. The roles and benefits of locoregional treatments need reassessment, in order to define a modern therapeutic algorithm. We examined contemporary short-term outcomes of liver-directed therapy for metastatic NETs. Methods: We conducted a population-based retrospective cohort study of patients with metastatic NETs (2000-2019) undergoing liver embolization (LE) or liver resection (LR). Outcomes were 30-day major morbidity (Clavien-Dindo grade 3-5) and/or re-admission (composite) and length of hospital stay. Modified Poisson regression accounting for clustering at the hospital level examined factors associated with outcomes in both treatment groups. Results: Overall, 1,224 LEs and 502 LRs were performed for 5,159 patients with metastatic NETs. Median length of hospital stay was 1 day (IQR 1-4) for liver embolization and 7 days (IQR 5-9) for liver resection. 30-day major morbidity and re-admission occurred after 213 LEs (17.4%) including 40 (3.3%) deaths, and 138 LRs (27.5%) including 11 (2.2%) deaths. There were 25 (2%) LEs followed by infectious complications. Factors independently associated with increased risk after LE were prior LE treatment (adjusted relative risk- aRR 0.62; 95%CI 0.44-0.88), rural residence (aRR 0.43; 95%CI 0.20-0.91) and high comorbidity burden (aRR 1.85; 95%CI 1.34-2.54). The only factor independently associated with increased risk after LR was metachronous metastases (RR 0.60; 95%CI 0.37-0.98). Conclusions: In this contemporary cohort, LE was associated with mortality similar to that of LR. Prior LE, rural residence, comorbidities, and metachronous metastatic diagnosis were associated with higher risk of major morbidity and re-admission. This information is important when discussing the use of and choice of liver-directed therapies in the multi-disciplinary management of metastatic NETs. Further characterization of long-term outcomes and patient-reported outcomes will further support decision-making, counselling, and patient preparation.
Molecular characterization and clinical outcomes of pancreatic neuroendocrine tumors (pNENs) harboring PAK4-NAMPT alterations.
Authors: Azar Ibrahim , Gandhi Nishant , Nagasaka Misako , Gong Jun , Nazha Bassel , Choucair Khalil , Khushman Moh'd M. , Soares Heloisa P. , El-Deiry Wafik S. , Philip Philip Agop , Lou Emil , Farrell Alex Patrick , Swensen Jeffrey , Oberley Matthew James , Abraham Jim , Nabhan Chadi , Goel Sanjay , Korn Wolfgang Michael , Shields Anthony Frank , Azmi Asfar S. 
Published: January 2023

649 Background: The mTOR inhibitor, Everolimus (EVE), is FDA-approved for the treatment of advanced PNENs on the basis of delay of progression. The RADIANT-3 trial showed an increase in PFS from 4.6 to 11 months compared to placebo with an ORR of only 5%. Prior studies suggest that targeting the aberrant expression of mTOR regulators p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) in PNENs sensitizes these tumors to EVE. To further qualify these observations, we queried a large real-world dataset of PNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression. Methods: 294 cases of PNENs were analyzed using Next Generation Sequencing (NextSeq) and Whole Exome and Whole Transcriptome Sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ). For our analyses, we stratified our study cohort into four groups based on the median expression of PAK4 and NAMPT: PAK4-low/NAMPT-low, PAK4-low/NAMPT-high, PAK4-high/NAMPT-low and PAK4-high/NAMPT-high. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q < 0.05). Results: High prevalence of mutations in PTEN (10.71% vs 1.18%; p < 0.05, q > 0.05), a tumor suppressor of the mTOR pathway and high expression of genes activated in response to mTOR activation such as SLC2A1 (3.07-fold), PFKP (3.32-fold), SCD (2.70-fold), MVK (2.92-fold) and G6PD (2.58-fold) were observed in PAK4-high/NAMPT-high compared to the PAK4-low/NAMPT-low tumors (all q < 0.05). A congruent enrichment of PI3K/AKT/mTOR and glycolysis pathways by single-sample gene set enrichment analysis was observed in these tumors (all q < 0.05). When querying the immune landscape, we observed enrichment in inflammatory response, IL6/JAK/STAT3, IL2/STAT5 signaling pathways and immune checkpoint genes such as PDCD1 (5.14-fold), CD274 (2.84-fold), PDCD1LG2 (2.44-fold), CD80 (3.00-fold), CD86 (2.82-fold), IDO1 (1.92-fold), LAG3 (3.09-fold), HAVCR2 (2.66-fold) and CTLA4 (4.49-fold) in the PAK4-high/NAMPT-high tumors (all q < 0.05). Immune cell infiltration estimates revealed an increase in Neutrophils, NK cells and Tregs in the PAK4-high/NAMPT-high tumors (p < 0.05, q > 0.05). Conclusions: Our study demonstrates that PAK4-high/NAMPT-high PNENs are associated with distinct molecular and immune profiles. While the dual blockade of PAK4 and NAMPT has been reported to enhance the efficacy of EVE in PNENs, whether such a blockade would enhance the efficacy of immunotherapeutics warrants further investigation.
Disparities in late-stage pancreatic cancer: Retrospective analysis of genomic testing and outcomes between Hispanics and non-Hispanics.
Authors: Estrada-Mendizabal Ricardo J. , Halder Ritika , Rao Amith , Cheng Ce , Dominguez Isabellyana , Veeravelli Sumana , Recio-Boiles Alejandro 
Published: January 2023

663 Background: Late-Stage Pancreatic Cancer (LS-PC) represents the 7th leading cause of cancer-related deaths worldwide. Hispanic (H) ethnicity is underrepresented in genomic studies and disparities have been demonstrated in overall treatment and outcomes. Germline, somatic tissue, and somatic liquid testing are effective tools that aid in identifying targeted genetic alterations. We comprehensively evaluated the differences in genomic testing among H and Non-Hispanic (NH) patients with LS-PC. Methods: This is a retrospective analysis of LS-PC with ductal adenocarcinoma from the University of Arizona Cancer Center from 2013 to 2021. Data collected included: patient demographics, clinical characteristics, treatment regimens, germline, somatic tissue, and somatic liquid genetic testing, and outcomes. LS was defined as unresectable and/or metastatic de novo or recurrence. Univariate comparisons used parametric and nonparametric tests as appropriate to evaluate for differences between H and NH groups. Fisher's exact tests were performed to evaluate the difference in frequency. Kaplan Meier and Cox regression analysis assessed progression-free and overall survival. Results: The analysis included 198 patients who had LS-PC with 20.7% H. 64.1%, 48.9%, and 48.9% of the patients had germline, somatic tissue, and somatic liquid testing, respectively. No significant differences were noted in baseline characteristics, treatments, and outcomes [PFS (HR 1.1, 95% CI 0.7-1.6, p=0.70) / OS (HR 1.2, 95% CI 0.7-1.9, p= 0.54)]. There was no statistically significant difference in common mutations or variants among groups. Conclusions: To our knowledge, this is the first and largest study to report LS-PC genomic and therapeutic implications in H patients. H were significantly less likely to receive germline screening and more likely to have potentially actionable pathogenic variants via somatic tissue and liquid biopsy testing. This highlights the importance of genetic testing to reveal mutations that can be targeted by clinical trials for LS-PC on minorities. Although our review revealed increased germline, somatic tissue, and somatic liquid biopsy genetic testing over time, there remains a critical need towards advancing genomic sequencing efforts to improve outcomes for LS-PC in the underrepresented H population.[Table: see text]
Evolution of pancreatic ductal adenocarcinoma diagnosis during the last decade.
Authors: Jiménez Rodríguez Roberto , Gonzalez Caraballo Irene , Martín Lozano Rocío , Alva Bianchi Manuel , de Lucas Mónica Benavente , Gómez María Palma , Muñoz Marc Ariant Cañete , Lobato Delgado Bárbara , Tirado Anula Victoria , Morón García Blanca , Ruiz Zamorano Magdalena , Marquez-Rodas Ivan , Echavarria Diaz Guardamino Isabel , Torres Pérez-Solero Gabriela , Calvo Ferrándiz Aitana , Ortega Laura , Soria Jose Manuel , Garcia-Alfonso Pilar , Martin Miguel , Muñoz Martín Andrés J. 
Published: January 2023

670 Background: Pancreatic Ductal Adenocarcinoma (PDAC) has historically been an important diagnostic and therapeutic challenge. The multidisciplinary approach and new diagnostic techniques’ implementation have modified this process. Methods: We conducted a retrospective analysis based on clinical data of patients with PDAC between the years 2010 to 2021, analyzing the diagnosis and initial treatment evolution. Results: 673 patients between 2010-2021 with a suspected diagnosis of pancreatic adenocarcinoma were reviewed. Most of them were metastatic (n=362; 53.8%), followed by locally advanced unresectable (n=166; 24.7%) and resectable or borderline resectable (n=145; 21.5%). Regarding the pathological diagnosis, it was not possible in 62 patients (9.2%), varying over time from 21.2% in 2010-2012 to 1% in 2019-2021 (p<0,0001). Moreover, the number of biopsies has decreased with a mean number of biopsies to obtain a pathological diagnosis of 1.55 (2010-2012) vs 1.31 (2019-2021). During this last period, most of the diagnoses were made by cytological analysis (61.4%; n=121). Specifically in the 2019-2021 patients subgroup, we found that 18 NGS (9,1%) were performed in this period (solid tumor), with 4 patients having actionable mutations (22.2%; 3 KRAS G12C). Germline (g) mutational panels were carried out in 89 patients, finding only 9 positive cases (10.1%), being 3 of them gBRCA1/2 mutated (3,4%). In our study, a decrease in palliative management was evidenced over time. In 2010-2012, 28,8% of patients received exclusively palliative care against 9,6% in 2019-21 (p< 0.0001). An increase in PDAC diagnosis was observed since 2010, 44 patients/year in 2010-12 vs. 66 patients/year in 2019-21 (including COVID-19 pandemic period). All previous results are summarized. Conclusions: The diagnosis of PDAC has changed throughout the last decade, increasing the percentage of patients with a pathological diagnosis without increasing the number of invasive procedures. The number of patients suitable for anti-cancer therapy has also increased among time. In our cohort, the implementation of molecular testing would change the therapeutic approach in more than 20% of patients.[Table: see text]
Early detection of pancreatic cancer using 5-hydroxymethylation profiles in plasma-derived cell-free DNA.
Authors: Bergamaschi Anna , Haan David , Collins Micah , Guler Gulfem , Peters Melissa , Gigliotti Lauren , Chowdhury Shimul , Volkmuth Wayne , Levy Samuel 
Published: January 2023

672 Background: Pancreatic cancer is one of the deadliest cancers, with approximately 15-20% of patients who present at diagnosis with a resectable disease. The major barrier to better outcomes is the lack of early-detection molecular tools to enable timely intervention. We have developed a test that enables the detection of pancreatic cancer from a simple blood draw. The test incorporates a novel, genome-wide sequencing-based epigenomics detection method that enriches for DNA loci that undergo active de-methylation. The measurement of 5-hydroxymethylcytosine (5hmC) provides a unique and stable biomarker for the early detection of cancer including pancreatic cancer. Methods: Whole-blood was obtained from a training cohort of 660 individuals (consisting of 132 pancreatic cancers (PaCa) and 528 non-cancers) and a validation cohort of 2,150 individuals (consisting of 102 PaCa and 2,048 non-cancers). Cell-free DNA (cfDNA) was isolated from plasma from which 5hmC and whole-genome libraries were generated and sequenced. Logistic regression algorithms were employed using 5hmC feature sets combined with physical characteristics of DNA fragments to optimally partition cancer from non-cancer samples. Results: Cross validation of the training model yielded an overall sensitivity of 65.9%,(95% CI, 57.2%–73.9%), early-stage (stage I-II) sensitivity of 57.1% (95% CI, 44%–69.5%) and a specificity of 98%. The model was further validated in a separate, non-overlapping set of blinded and independently processed samples and yielded an early-stage sensitivity of 68.3% (95% CI, 51.9%–81.9%) and a specificity of 96.9% (95% CI, 96.0%–97.6%). Conclusions: Our results demonstrate that plasma-derived cfDNA 5hmC profiles enable the accurate detection of early-stage PaCa, providing a valuable non-invasive tool especially for those individuals at high risk for the disease, including individuals with genetic predisposition and newly diagnosed type 2 diabetes. A larger clinical study (NODMED - NCT05188586) is ongoing and will provide clinical validation for the detection in individuals at high risk for this deadly disease.
The prognostic value of C-reactive protein/albumin ratio and platelet-lymphocyte ratio in patients with pancreatic cancer.
Authors: Shen Yang-Chen , Chu Chi-Hsiang , Chen Po-See , Lin Cheng-Feng , Liu Ping-Yen , Lin Peng-Chan , Yen Chia-Jui , Shan Yan-Shen 
Published: January 2023

678 Background: Pancreatic cancer is a highly malignant tumor with poor prognosis. Therefore, identification of prognostic markers is very crucial for improved risk stratification in pancreatic cancer patients. Although various systemic inflammatory markers have been investigated for their prognostic roles in pancreatic cancer, inconsistent results have been found across studies. Accordingly, the present study aimed to identify the prognostic value of inflammatory markers for patients with pancreatic cancer. Methods: The study enrolled 185 patients with pancreatic cancer. The inflammatory markers, namely, the modified Glasgow Prognostic Score (mGPS), the prognostic nutritional index (PNI), the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), the C-reactive protein (CRP)/albumin ratio (CAR), the platelet/albumin ratio (PAR), and the CRP/lymphocyte ratio (CLR), were evaluated. Receiver operating characteristics curve analysis was performed to determine the cut-off values. The Cox proportional hazards model was used to analyze the factors affecting the prognosis. Results: The mean age of the patients was 64.1 years (with a standard deviation of 11.1), and their average overall survival (OS) was 10.5 months (95% confidence interval [CI] = 9.7–11.4). In the univariate analysis, metastatic disease, carbohydrate antigen (CA)19-9, mGPS, PNI, NLR, PLR, CAR, and CLR were significantly associated with OS ( P< 0.05). In the multivariate analysis, metastatic diseases (hazard ratio [HR] = 2.52, 95% CI = 1.03–6.15, P = 0.04), CA19-9 (HR = 3.96, 95% CI = 2.01–7.79, P< 0.001), PLR (HR = 2.37, 95% CI = 1.11–5.04, P = 0.03), and CAR (HR = 4.45, 95% CI = 2.19–9.03, P < 0.001) were identified as independent prognostic factors for OS. Conclusions: Pretreatment PLR, CAR, CA 19-9 , and metastatic diseases were found to be independent indicators of poor prognosis in patients with pancreatic cancer. We believe that our findings will shed light on the identification of prognostic factors, which might enable a better risk stratification in pancreatic cancer patients.