bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transition of the tumor microenvironment with clonal evolution of hepatocellular carcinoma.
Authors: Kanzaki Hiroaki , Ogasawara Sadahisa , Sakuma Takafumi , Fujita Naoto , Kojima Ryuta , Koroki Keisuke , Kobayashi Kazufumi , Nakamura Masato , Kanogawa Naoya , Kiyono Soichiro , Kondo Takayuki , Saito Tomoko , Nakagawa Ryo , Nakamoto Shingo , Muroyama Ryosuke , Chiba Tetsuhiro , Ikeda Junichiro , Ohtsuka Masayuki , Kato Naoya 
Published: January 2022

467 Background: The combination of atezolizumab and bevacizumab has become a standard treatment for advanced hepatocellular carcinoma (HCC). The indications for combination immunotherapy, including adjuvant therapy and combination with local therapy, are expected to expand in the future. Although exploring the tumor microenvironment has essential clinical implications in the era of combination immunotherapy, most studies on the tumor microenvironment in HCC are based on the analysis of archival samples at the time of HCC diagnosis. Considering the lengthy clinical course and characteristics of multicentric carcinogenesis, the tumor microenvironment may not be constant, but may differ from that at the time of advanced HCC. The present study aimed to assess the changes in the tumor microenvironment during the evolution to advanced HCC using archival samples and samples obtained prior to systemic therapy from the same patients. Methods: The tumor microenvironment was compared in 20 cases by immunohistochemical analyses of CD8, PD-L1, and VEGF expression. Levels of CD8-positive lymphocytes were defined as the mean number of CD8-positive lymphocytes in the tumor per 1 mm2 and classified as low or high infiltration using the median value. PD-L1 expression was classified as negative (< 1%) or positive (≥1%). VEGF expression was classified as low (< 50%) or high (≥50%). Of the 20 cases, gene expression analysis was performed by the PanCancer IO360 Panel in 14 cases. Results: Approximately 40% of the archived samples were obtained at the early stage. Comparison of the tumor microenvironment between the two time points showed that 35% of the patients changed to CD8-positive lymphocyte high infiltration, 20% to positive PD-L1 expression, and 29% to high VEGF expression. The result of comparing gene profile was different between the archival samples and those prior to systemic therapy in 64% of the patients on the expression heat map. Gene set enrichment analysis showed significant changes in T cell cytotoxicity between the two time points. Conclusions: The tumor microenvironment might not be constant, but may change during the evolution to advanced HCC. In the present study, based on the results of the gene mutation analysis using whole-exome sequencing, we also reported the analyses by carcinogenic patterns such as multicentric occurrence and intrahepatic metastasis.
IMbrave150: Exploratory efficacy and safety in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab beyond radiological progression until loss of clinical benefit in a global phase III study.
Authors: Toh Han Chong , Galle Peter R. , Zhu Andrew X. , Nicholas Alan , Gaillard Vincent , Ducreux Michel , Cheng Ann-Lii , Finn Richard S. 
Published: January 2022

470 Background: First-line atezolizumab (atezo) + bevacizumab (bev) has been approved in > 80 countries based on significantly longer survival vs sorafenib (sor) in systemic treatment (tx)–naive patients (pts) with unresectable HCC in IMbrave150 (NCT03434379; Finn NEJM 2020). This clinically meaningful tx benefit was maintained with an additional 12 months of follow-up (Finn ASCO GI 2021). We report the efficacy and safety in pts who received atezo beyond radiological progression until loss of clinical benefit. Methods: Pts were randomized 2:1 to receive atezo 1,200 mg IV + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator (INV). In the presence of clinical benefit, pts with progressive disease (PD) per INV RECIST 1.1 (not at a critical anatomical site) could continue study tx. Pts from the atezo + bev arm who had PD and continued atezo were included. Results: Of the 336 pts who received atezo + bev, 236 had PD, of whom 130 continued atezo (± bev), 60 had other tx, and 46 received no tx on or after first PD. Of the pts who continued atezo, 78% were Barcelona Clinic Liver Cancer (BCLC) stage C and 80% Child-Pugh A5 vs pts receiving other tx (85% BCLC stage C, 72% Child-Pugh A5). Sor (13% and 53%) and lenvatinib (14% and 35%) were the most common other txs received post PD among pts who continued atezo or received other tx, respectively. At clinical cutoff (August 31, 2020), the median number of cycles of atezo received post PD was 5 (range, 1-33) and 41 (32%) pts received ≥ 10 cycles. 60 of 130 (46%) pts who continued atezo died vs 180 of 336 (54%) receiving atezo + bev in the ITT population. See Table for efficacy data from baseline (BL) and PD. Grade (Gr) 3/4 and tx-related Gr 3/4 AEs occurred in 30 (23%) and 21 (16%) pts who continued atezo, respectively. There were 6 (5%) Gr 5 AEs, none tx-related. Conclusions: Atezo + bev is the standard of care for pts with unresectable HCC. In IMbrave150, pts with maintained clinical benefit continuing atezo after PD may have further benefited from staying on tx, although interpretation is limited by selection bias (prespecified criteria excluding pts with loss of clinical benefit). These data suggest that tx with atezo until loss of clinical benefit may contribute to post-PD outcomes. Beyond this exploratory analysis in select pts, the value of tx with atezo beyond formal progression will be assessed prospectively in IMbrave251 (NCT04770896). Clinical trial information: NCT03434379. [Table: see text]
Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy.
Authors: D'abrigeon Constance , McNamara Mairead Geraldine , Le Sourd Samuel , Lamarca Angela , Lièvre Astrid , Hubner Richard A , Valle Juan W. , Edeline Julien 
Published: January 2022

475 Background: Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its impact on the management of advanced disease is not established. Methods: Retrospective analysis of patients (pts) treated with systemic chemotherapy for advanced iCC in the first-line setting at 2 tertiary cancer referral centers, the second center used to validate findings from the first. Cirrhosis was diagnosed based on at least one element among pathological diagnosis, baseline platelet < 150 G/L, portal hypertension and/or dysmorphic liver at imaging. Results: In the first center (n=185), 55 pts (29.7%) had cirrhosis (74.5 % based on pathological diagnosis). Main aetiology of cirrhosis was alcohol for 17 pts (31%), non-alcoolic steato-hepatitis (NASH) for 10 pts (18.2%), and mixed alcohol and NASH for 9 pts (16.4%). 102 (57.0%) pts received gemcitabine-cisplatin, 55 (30.7%) pts received gemcitabine-oxaliplatin, and 11 (6%) pts received gemcitabine, with no difference between cirrhotic and non-cirrhotic pts (p=0.38). Second-line treatment was less frequent in cirrhotic pts (21.8% vs. 50.0%, p=0.001). Cirrhotic pts experienced more grade 3/4 hematologic toxicity than non-cirrhotic pts (38% vs. 20%, respectively, p=0,014), and more grade 3/4 non-hematologic toxicity (28% vs. 15%, respectively, p=0.048). The overall survival (OS) was significantly shorter in cirrhotic pts; median: 9.0 vs. 13.8 months for non-cirrhotic pts (HR = 1.54 [95%CI: 1.09-2.16]; p = 0.014); confirmed on multivariable analysis, adjusted on ALBI-score, ECOG PS, extension of the disease (liver only disease and bilobar) (HR = 1.53 [95% CI: 1.01-2.33]; p=0.046). However, PFS was not significantly shorter in cirrhotic pts: median 9,9 months vs. 11.7 for non-cirrhotics (p = 0.35). In the second center (n=102), similar results were seen: 27 (26.5%) pts had cirrhosis. The cirrhotic pts experienced more grade 3/4 hematologic toxicities than non-cirrhotic pts (55.6% vs. 25.4%, respectively, p=0.005), and more grade 3/4 non-hematologic toxicity (44.4% vs. 12.7%, respectively, p = 0.001). OS was shorter in cirrhotic pts; median 9.1 months vs. 11.7 months for non-cirrhotic pts (HR = 1.81 [95%CI: 1.14-2.87]; p = 0.011). PFS was not significantly shorter in cirrhotic pts: 7.5 months for patients without cirrhosis, and 4.2 months for pts with cirrhosis (p=0.221). Conclusions: Cirrhosis was frequent in pts with advanced iCC, and had a negative impact on patients’ outcomes, with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in the therapeutic management should be recommended and could lead to a dose adjustment.
Prevalence of germline mutations and homologous recombination deficiency (HRD) in a real-world biliary tract cancer (BTC) cohort.
Authors: Kelley Robin Kate , Ashok Arya , Mauer Elizabeth , Abdel-Wahab Reham , Azad Nilofer Saba 
Published: January 2022

476 Background: Biliary tract cancers (BTC) are a heterogeneous family of cancers including intrahepatic and extrahepatic cholangiocarcinomas (ICC, ECC) and gallbladder carcinomas (GBC). Treatment options remain limited and prognosis is poor for advanced BTC, underscoring the need for early detection and new therapeutic targets. Next-generation sequencing (NGS) studies have identified mutations associated with homologous recombination deficiency (HRD) in up to 25% of BTC patients, but the proportion with germline (GMut) versus somatic (SMut) mutations has not been established. This retrospective study was designed to determine the prevalence of GMut and HRD-associated SMut in a large BTC convenience sample and their association with key clinical parameters. Methods: We retrospectively analyzed de-identified records from 804 BTC patients who received tumor/normal (T/N) matched NGS between 2017-2021 via the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage; full transcriptome RNA-seq). This targeted panel detects single nucleotide variants (SNVs), indels, copy number variants (CNVs), and a selection of rearrangements. Analyses focused on pathogenic/likely pathogenic SMut and CNVs, as well as incidental GMut limited to SNVs and small indels in 50 hereditary cancer genes. HRD-associated GMut and SMut were analyzed across 9 and 18 HRR pathway genes, respectively. Results: We identified a cohort of 804 patients with BTC, composed of ICC (n=499), ECC (n=83), and GBC (n=222). The median age was 66 years; 55% were female; and race was White/Black/Asian in 78%/12%/6%. The prevalence of GMut was 4.6% overall. Subgroup analyses showed GMut in 5% of ICC, 4.8% of ECC, and 3.6% of GBC. For patients <50 years of age at diagnosis, pooled prevalence was 6.1% (n=82) vs. 4.5% (n=641) for age ≥50 years (p=0.6). HRD-associated GMut were present in 3.2%. HRD-associated SMut or CNVs were present in 13%, and showed significant variation across subsite (p=0.002) with highest prevalence in GBC (19%, Table). HRD-associated GMut were identified in ATM (n=8), BRCA2 (n=6), and BRCA1 (n=5). Microsatellite instability was present in 1.4% of samples. Conclusions: A significant proportion of BTC patients harbors potentially clinically-relevant GMut and SMut associated with HRD. Future studies are warranted to define the role of germline testing and to examine the activity of HRD-targeted therapies in BTC patients.[Table: see text]
Perioperative optimization with nutritional supplements in patients undergoing gastrointestinal surgery for cancer: A randomized, placebo controlled feasibility clinical trial.
Authors: Serrano Aybar Pablo Emilio , Parpia Sameer , Simunovic Marko , Duceppe Emmanuelle , Pinto-Sanchez Maria Ines , Bhandari Mohit , Levine Mark Norman 
Published: January 2022

482 Background: Nutritional status is a major determinant of outcomes following surgery. Perioperative nutritional supplementation may improve postoperative outcomes, however, studies on the topic have led to controversial results. Methods: Single-centre, feasibility randomized trial among gastrointestinal cancer patients undergoing surgery, comparing perioperative nutritional supplements versus placebo. The supplements included: protein supplementation (preoperative day 30-6), “immunonutrition” (preoperative day 5-1 and postoperative day 1-5), and carbohydrate loading (surgery day). Primary outcome was enrollment fraction (i.e., enrolled/eligible patients). Secondary outcomes were patient compliance with study packages (target > 70% of total packages provided) and 90-day postoperative complication rate, including postoperative infectious complications. A priori, we considered protocol modifications to improve enrollment fraction and compliance. Results: From October 2018 to March 2020, 495 patients were screened, of which, 144 were eligible and 71 were enrolled (enrollment fraction: 49%, 95%CI, 41-57%). Patients did not enroll for various reasons including refusal without reason (n = 33) and too much burden (n = 25). Protocol modifications did not impact enrollment fraction or compliance. Modifications included decreasing the interval from enrollment to surgery from 4 weeks to 2 weeks, and decreasing the complexity and length of the baseline assessment. Median overall compliance was 80%, lower for intervention versus control arm (67% and 87%, respectively). Postoperative complication rates were similar between control (18/31 (58%, 95% CI: 41-74)) and intervention (22/34 (65%, 95%CI 48-79)) arms. There was a trend for lower postoperative infectious rates in the intervention arm (12/34 (35%, 95%CI 22-52)) compared to control (16/31 (52%, 95%CI 35-68)). Conclusions: A trial like this is feasible, with an enrollment fraction of 49% and an overall patient compliance with study packages of 80%. Pilot trial protocol modifications did not increase these proportions. Clinical trial information: NCT03445260.
Early-onset well differentiated pancreatic neuroendocrine tumors: Clinical presentation, pathologic features, and oncological outcomes.
Authors: Pulvirenti Alessandra , Hauser Haley , Le Tiffany , McIntyre Caitlin A. , Reidy Diane Lauren , Wei Alice Chia-chi , Raj Nitya Prabhakar 
Published: January 2022

507 Background: Young onset of several gastrointestinal cancers is associated with more advanced disease and poor oncological outcomes, however, this association has not been fully investigated for well differentiated pancreatic neuroendocrine tumors (PanNET). Our study aimed to evaluate clinical and pathological differences as well as disease outcomes between young-onset PanNET (YO-PanNET) and late-onset PanNET (LO-PanNET). Methods: Patients with localized PanNET who underwent surgery at Memorial Sloan Kettering Cancer Center between 2000 to 2017 were identified. Those with hereditary syndromes, metastatic disease, and postoperative mortality were excluded. YO-PanNET was defined as <50 and LO-PanNET >50 years of age at time of diagnosis. Family history, clinical and pathology characteristics, were recorded. Fisher’s exact test was used to detect difference between the age groups. Kaplan-Meier method was used to investigate age prognostic significance. Results: A total of 366 patients were identified, 84 (23%) with YO-PanNET. Compared with LO-PanNET, YO-PanNET were less likely to have a personal history of another cancer (p<0.001) and a first-line relative with cancer (p<0.015). We did not observe any significant differences between YO-PanNET and LO-PanNET with regards to pathology features such as tumor grade (p=0.7), size (p=0.5), nodal metastases (p=0.8), and stage of disease (p=0.7). With a median follow-up of 68 months (range 0-238), 5-year recurrence-free survival was 76% and 83%, and 10-year RFS was 69% and 78%, respectively, in YO-PanNET and LO-PanNET (p=0.12; see Table) with similar 5- and 10-year overall survival (p=0.31). Conclusions: In this large retrospective surgical series, we found that YO-PanNET is not associated with an increased rate of personal or familial history of cancer. Pathological characteristics and long-term oncological outcomes do not significantly differ between YO-PanNET and LO-PanNET. Current efforts include next-generation sequencing analysis in the resected surgical specimens to evaluate for genomic biomarkers of recurrence.[Table: see text]
Temozolomide treatment duration and secondary hematological neoplasms: A review of the literature and implications for patients with neuroendocrine tumors.
Authors: Park Robin , Amin Manik A. , Trikalinos Nikolaos A. 
Published: January 2022

510 Background: Evidence-based recommendations for the optimal duration of temozolomide-based treatment in advanced neuroendocrine neoplasms are lacking. Because of the relatively long median survival of NEN and the potential long-term myelotoxicities of temozolomide, suggestions have been made to optimize the duration of temozolomide-based therapy. Here, we have conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. Methods: A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematologic disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically and descriptively analyzed. Results: A total of 14 studies with 25 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 15 months and 18000 mg/m 2 respectively. Most patients (20/25) were diagnosed on or after 12 months while only one patient was diagnosed before 6 months of treatment. Majority of the patients were diagnosed while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m 2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 – 37.5 months. Conclusions: Taken together, treatment-related hematologic neoplasms appear to develop beyond the 12-month mark while still on treatment with temozolomide. We suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to 12 months or establishing closer vigilance beyond 12 months.
Association between Environmental Quality Index and metastatic pancreatic cancer.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Khatib Jude , Al Mutar Salwan , Aguilera Todd Anthony , Zeh Herbert , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali 
Published: January 2022

521 Background: Pancreatic cancer ranks as the 3rd leading cause of cancer mortality. Overall more than 50% of patients have metastatic disease at diagnosis. In this study, we evaluated the association between the national level Environmental Quality Index (EQI) and metastatic pancreatic cancer in the US. Methods: Adult patients with pancreatic cancer in the SEER database from 2010-2016 were included in this study. The unknown stage was excluded. Patients were categorized into two groups: metastatic vs. non-metastatic disease. EQI provides county-level environmental quality data from 2005-2010 and presents five domains (built, sociodemographic, air, water, land). EQI was categorized into quintiles, with the 5th quantile representing a poorer environmental quality. We used the multivariable logistic regression analysis to assess the association between EQI quintiles and metastatic pancreatic cancer adjusting by age, gender, and race (White, Black, and Others). In addition, the SEER*Stat was used to evaluate the age-adjusted incidence rate, and the correlation coefficient between EQI domains and incidence rate was calculated. Results: A total of 75,461 pancreatic cancer patients were included; 55% had metastatic disease. In the adjusted multivariable analysis, metastatic pancreatic cancer was associated with poor built EQI (OR 1.06 [1.01-1.11]). Among metastatic pancreatic cancer patients, poor overall EQI was strongly associated with age > 50 years (OR 1.06 [1.01-1.11]) and Black race (OR 1.29 [1.10-1.51]). Lower built EQI domain was associated with > 50 (OR 1.07 [1.02-1.12]) and White race (OR 1.07 [1.02-1.12]). The incidence rate of metastatic pancreatic cancer was positively correlated with total EQI (rho=0.02, p<0.001), sociodemographic EQI (rho=0.23, p<0.001), land EQI (rho=0.14, p<0.001), and air EQI (rho=0.34, p<0.001). Conclusions: Using population-based environmental data, we found built EQI to be associated with metastatic pancreatic cancer. Among metastatic pancreatic cancer patients, total environmental quality was associated with older age at diagnosis and the Black race, while built EQI domain was associated with older age at diagnosis and the White race. Environmental quality was positively correlated with the incidence rate of metastatic pancreatic cancer.[Table: see text]
Large scale proteomics of circulating extracellular vesicles to reveal novel biomarkers for pancreatic cancer.
Authors: Bockorny Bruno , Muthuswamy Lakshmi , Huang Ling , Hadisurya Marco , Tsai Leo , Gill Ritu R. , Wei Jesse , Bullock Andrea J. , Grossman Joseph Elan , Besaw Robert J. , Lim Christine Maria , Narasimhan Supraja , Perea Sofia , Sawhney Mandeep , Tao W. Andy , Freedman Steven , Hidalgo Manuel , Iliuk Anton , Muthuswamy Senthil 
Published: January 2022

523 Background: Robust biomarkers are urgently needed to assist in diagnosing pancreatic cancer. Earlier cancer diagnosis could increase survival rates by an estimated 5-fold and more reliable and real-time assessment of treatment effects in patients with cancer could improve quality of life and reduce healthcare costs. Isolation of circulating extracellular vesicles (cEVs) as ‘liquid biopsies’ offers an advantageous approach to diagnose and monitor disease status. Methods: We conducted a comprehensive proteomics study of cEVs from plasma samples to identify EV proteins that may be used as biomarkers for the diagnosis and prognosis of pancreatic cancer. Patients with pancreatic ductal adenocarcinoma (PDAC) of various tumor stages, chronic pancreatitis, intraductal papillary mucinous neoplasm (IPMN), and age-matched controls were enrolled. EVs were isolated directly from plasma samples using the affinity-based EVTrap method then subject to quantitation by liquid chromatography-tandem mass spectrometry. Results: A total of 124 patients (93 with PDAC, 12 with chronic pancreatitis, 8 with IPMN and 11 controls) were included in the discovery cohort. The isolation of EVs with EVtrap allowed the identification on average of 912 EV proteins per 100µL of sample. Principal component analysis of the cEV proteome showed clear separation between PDAC and benign pancreatic diseases. Individuals with IPMN were more closely related to controls, whereas chronic pancreatitis cases were more related to PDAC. At the functional level, we noted that cytokeratin, protein folding chaperons, and actin dynamics regulators were among protein clusters more highly altered in the cEV of patients with PDAC. We further identified new cEV markers associated with metastatic disease, such as PSMB4, RUVBL2, and ANKAR, as well as other EV proteins with strong correlation to prognosis, such as CRP, RALB, and CD55. Finally, we validated a 7-protein PDACEV signature in a validation cohort of 36 separate patients (24 with PDAC, 6 with chronic pancreatitis and 6 with IPMN) which yielded an 89% prediction accuracy for the diagnosis of PDAC. Conclusions: This study provides a valuable resource to the scientific community with a comprehensive catalog of novel proteins on circulating EVs that may assist in the development of novel biomarkers and improve the outcomes of patients with pancreatic cancer.