bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of primary tumor sidedness on survival in early-onset colorectal cancer by stage: A National Veterans Affairs retrospective analysis.
Authors: Azar Ibrahim , Almasalmeh Nada , Esfandiarifard Saghi , Virk Gurjiwan , Kiwan Wissam , Shields Anthony Frank , Mehdi Syed Arzoo , Philip Philip Agop 
Published: January 2021

31 Background: The incidence of early-onset colorectal cancer (EOCRC) is rising. Left-sided colorectal cancer (LCC) is associated with better survival and response to therapy compared to right-sided colon cancer (RCC) in the metastatic setting. Current NCCN guidelines recommend the addition of EGFR inhibitors to KRAS/NRAS wild-type metastatic CRC originating from the left-side only. Whether primary tumor sidedness impacts survival in loco-regional disease and in EOCRC is of clinical interest. Methods: Data from the National VA Cancer Cube Registry was studied. 65,940 cases of CRC were diagnosed between 2001 and 2015. EOCRC (2,096 cases) was defined as CRC diagnosis at age <50 years. ICD codes C18 to C20 were used to delineate patients with RCC vs. LCC. RCC was defined as cancer from the cecum to the hepatic flexure (C18.0-C18.3), LCC from the splenic flexure to the rectum (C18.5-18.CRC; C19 & C20). Transverse cancer (C18.4), overlapping and unidentified sites (C18.8; C18.9) were excluded. Results: EOCRC is more likely to originate from the left-side (66.65% LCC in EOCRC vs. 58.77% in the whole CRC dataset). Overall, LCC has better 5-year OS than RCC in Stage I, III and better 1-year OS in stage IV (Table). Stage II RCC has better 5-year OS than LCC (RC 53.39% vs LC 49.28%). In EOCRC, there is no statistically significant difference between LCC and RCC in Stages I-III. Stage IV EOCRC patients with LCC and RCC have a 1-year OS of 73.23% and 59.84%, respectively. Conclusions: EOCRC is more likely than CRC to originate from the left side. In EORCRC patients, LCC is associated with better OS than RCC only in patients with metastatic disease. In the overall population, LCC is associated with better OS in all states except Stage II. The better prognosis of Stage II RCC might be due to the reported high incidence of MSI-high tumors in this subpopulation. [Table: see text]
Modeling sequential systemic therapy for unresectable hepatocellular carcinoma in the era of immunotherapy: What comes next?
Authors: Celsa Ciro , Cabibbo Giuseppe , Enea Marco , Battaglia Salvatore , Rizzo Giacomo Emanuele Maria , Cammà Calogero 
Published: January 2021

324 Background: Atezolizumab plus Bevacizumab represents the new best performing first-line approach for unresectable hepatocellular carcinoma (u-HCC). However, the best sequential strategy after every first-line failure (for progression or intolerance) remains elusive, and options for retreating patients failing Atezolizumab plus Bevacizumab with multi-kinase inhibitors (MKI) or immune checkpoint inhibitor (ICI) are yet undefined. Methods: We developed a Markov model to analyze simulated-Overall Survival (s-OS) of second-line ICIs or MKIs after first-line Atezolizumab plus Bevacizumab over a lifetime horizon. For first-line therapy, PFS of Atezolizumab plus Bevacizumab was extracted from Imbrave 150 trial and it was used as endpoint since it is not influenced by post-progression survival. For second-line retreatment, pooled OS of MKIs (Regorafenib and Cabozantinib), or ICIs (Nivolumab and Pembrolizumab) were adopted. Survival estimates for sequential settings considered the proportion of patients who did not receive second-line therapy due to death during first-line therapy. Individual patient survival data were extracted from PFS and OS Kaplan-Meier curves of RESORCE trial for Regorafenib, CELESTIAL trial for Cabozantinib, CheckMate-040 for Nivolumab and Keynote-240 for Pembrolizumab. Each reconstructed survival curve was inspected for accuracy and was compared with originally published curves. Results: First-line Atezolizumab plus Bevacizumab followed by second-line ICIs turned on from the model as the best sequential strategy (median s-OS 24 months; 95% Confidence Interval (CI) 23-26 months) and extends survival when compared Atezolizumab plus Bevacizumab followed by MKIs (median s-OS 20 months; 95% CI 19-21 months). Conclusions: To our knowledge and given the absence of adequately designed sequential RCTs, this is the first model to date which suggests, with a proper methodological approach, an accurate estimate of outcome of patients with u-HCC treated by sequential systemic therapies. In patients with u-HCC failing first-line treatment, modelling estimates of s-OS for each retreatment strategies may assist in choosing the most promising sequences in order to plan appropriate RCTs.
Telotristat ethyl to enhance cytotoxic chemotherapy response in preclinical cholangiocarcinoma models.
Authors: Awasthi Niranjan , Schwarz Margaret , Schwarz Roderich E. 
Published: January 2021

331 Background: Cholangiocarcinoma (CCA) is the second-most common primary liver cancer after hepatocellular carcinoma. It has a poor prognosis with a 5-year survival rate of 5-15%. The current standard first-line therapy for advanced unresectable CCA is a combination of gemcitabine and cisplatin (GemCis) chemotherapy that leads to a median survival of 6-12 months. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT) is an approved therapy for breast, NSCLC and pancreatic cancer. Elevated levels of serotonin have been reported in CCA that has protumorigenic activity. We tested the hypothesis that telotristat ethyl (TE), an inhibitor of serotonin biosynthesis, has antitumor activity in CCA and it augments GemCis and nab-paclitaxel response in preclinical CCA models. Methods: Tumor growth experiments were performed in mice subcutaneous CCA intrahepatic CCLP-1 xenografts, extrahepatic TFK-1 xenografts and patient-derived xenografts. Animal survival studies were performed using human CCA intrahepatic CCLP-1 cells in the peritoneal dissemination model in NOD/SCID mice. Results: In intrahepatic CCLP-1 subcutaneous xenografts, compared with controls, reduction in tumor growth was observed by TE (53%), GemCis (53%) or NPT (69%). The combination of TE with GemCis or NPT exhibited an additive tumor growth inhibition response, GemCis+TE (85%) and NPT+TE (90%). In extrahepatic TFK-1 subcutaneous xenografts, TE led to a significant reduction in tumor growth (51%), while GemCis and NPT reduced tumor growth by 37% and 56%, respectively. Again, an additive tumor growth inhibition effect was observed by the addition of TE to chemotherapy, GemCis+TE (67%) and NPT+TE (74%). In CCA patient-derived subcutaneous xenografts, GemCis caused the greatest tumor growth reduction (80%) followed by NPT (57%) and TE (40%). Combinations increased tumor inhibition further: GemCis+TE (95%) and NPT+TE (91%). Mouse survival in peritoneal dissemination xenografts was only marginally enhanced by TE (11%) or GemCis (9%) while NPT led to a substantial extension (60%). Interestingly, the combination of TE with GemCis or NPT demonstrated a further extension in mice survival: GemCis+TE (26%) and NPT+TE (68%). Conclusions: TE had antitumor activity and it enhanced chemotherapy effects in several CCA preclinical models indicating that this therapeutic combination has the potential to ameliorate clinical therapy for CCAs of different origin.
Results of biomarker analysis from phase II trial of nivolumab in refractory biliary tract cancer.
Authors: Tan Elaine , Kim Dae Won , Zhou Junmin , Schell Michael J. , Chung Vincent , Alese Olatunji B. , Kim Richard D. 
Published: January 2021

338 Background: Our previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients (pts) with refractory biliary tract cancer (BTC), suggesting the significant clinical benefit of nivolumab in selected pts and identification of potential predictive biomarkers. Here, we report outcomes from the biomarker analysis. Methods: Pre-treatment tumor samples were obtained and assessed for immunohistochemistry (IHC) with PD-1 and PDL-1 antibodies, mRNA sequencing (RNAseq), and whole exome sequencing (WES). Clinical efficacy was correlated with the molecular analysis. Prior cisplatin exposure was reviewed to evaluate the impact of cisplatin on the tumor mutational burden (TMB) and clinical outcome. Results: Among 46 pts who had tumor response evaluation, 31 pts received cisplatin prior to nivolumab, and 15 were cisplatin-naive. Pre-treatment tumor samples were assessed for IHC (n = 42), RNAseq (n = 11), and WES (n = 11) based on tissue availability. There was no statistically significant correlation between prior cisplatin exposure and clinical outcome. Among 42 available tumor samples, 18 (43%) expressed PD-L1 positivity ( > 1%), which was associated with a statistically significant prolonged progression free survival (PFS). Median PFS was 10.4 months for PD-L1 positive vs 2.4 months for PD-L1 negative (HR 0.23, 95% CI 0.10-0.51; P < 0.001), while there was no statistically significant correlation between PD-1 expressing tumor infiltrating lymphocytes and clinical outcome. There was also no statistically significant difference in TMB of cisplatin-exposed (n = 8) vs. cisplatin-naïve tumor samples (n = 3) (9162, SD = 150 vs. 8898, SD = 806, p = 0.62). In comparing the group with prolonged disease control of at least 16 weeks (n = 4) to those with rapid disease progression (n = 7) who had mRNA sequencing performed, levels of AC005609.1, FAT3, TMEM151A, ADARB2, FAM153A were all significantly upregulated (p < 0.01), while levels of CLCA1, MUC2, IGHV3-43, SWORA6, and CRISP3 were all significantly downregulated (p < 0.01). Conclusions: Prior cisplatin exposure did not lead to statistically significant differences in clinical outcome or TMB in advanced BTC pts treated with nivolumab. However, PD-L1 expression > 1% correlated with improved PFS, and variations in level of certain mRNA sequences were noted when comparing pts who had rapid disease progression vs. prolonged disease control with nivolumab. This suggests that BTC pts with positive PD-L1 expression and a particular mRNA profile may have a favorable response to nivolumab. Further studies are needed to confirm these findings. Clinical trial information: NCT02829918.
PALBI and ALBI score as a prognosis factor for liver metastasis undergoing transarterial radioembolization.
Authors: Sanchez-Garcia Jorge , Riegler Randie , Jepperson Maria , Gagnon Andrew , Alonso Diane , Fujita Shiro , Rodriguez-Davalos Manuel , Thota Ramya , Cannon George , Krong Jake , Dow Sean , Gilroy Richard , Kringlen Mark , Zendejas-Ruiz Ivan R 
Published: January 2021

345 Background: Liver metastasis is evident in many oncological patients at the time of initial presentation. Recently, platelet-albumin-bilirubin (PALBI) score was reported to be superior to Child-Pugh classification and albumin-bilirubin (ALBI) score in terms of mortality prediction, while Model for End-Stage Liver Disease (MELD) score is the most frequent used. Trans-arterial radioembolization (TARE) is a minimally invasive therapy used to treat liver tumors. The aim of this study is to assess prognostic performance of pre-TARE liver function scores. Methods: We retrospectively assessed all patients with liver metastasis that underwent TARE between February 2008 and January 2020 at a single institution. Demographic characteristics; and laboratory values were collected to calculate MELD, ALBI, PALBI, within six months before TARE administration. Results are presented as proportions and median (IQR). Multivariate Cox regression analysis was performed to identify risk factors for overall survival. Results: A total of 90 patients were included, 46.7% were females with a median age was 61 (50-69). Colorectal (CR) metastasis was found in 45.6% of cases, neuroendocrine tumors (NET) in 27.8% and the remainder a heterogenous group of metastatic disease. In 90% of cases, TARE was used as destination therapy. The median tumor size was 5.1 (3.3-7.1) cm with 81% having multifocal lesions. The median scores were: MELD 8 (7-10), ALBI -2.77 (-3.01 to -2.56), PALBI -2.58 (-2.77 to -2.32). Other metastatic disease (OR=2.3: 95%CI 1.3-4.3; p=0.02), MELD (OR=1.1: 95%CI 1.002-1.2; p=0.04), ALBI (OR=2: 95%CI 1.2-3.3; p=0.005) and PALBI (OR=2.4: 95%CI 1.2-4.7; p=0.01) were significant in univariate Cox regression. In the multivariate Cox regression, MELD score was not statistically significant when adjusted with diagnosis and PALBI or ALBI score. As expected due to similar variables to calculate score, ALBI and PALBI score were not statistically significance when these are used in the same model (Table). Conclusions: To our knowledge, this is the first report of PALBI as prognostic factor in patients undergoing TARE for metastatic liver disease. Interestingly, the multivariate cox regression showed us that MELD score is not a significant score for these patients. Further non-inferiority assessment of PALBI and ALBI over MELD score should be developed. [Table: see text]
Survival analysis of colorectal cancer patients treated with first-line modified FOLFOX6 with or without bolus fluorouracil.
Authors: Shaib Walid Labib , Draper Amber , Kalu Kalu , Byers Kristina F. , El-Rayes Bassel F. , Wu Christina , Alese Olatunji B. , Akce Mehmet , Goyal Subir , Zakka Katerina Mary 
Published: January 2021

35 Background: The combination of oxaliplatin, bolus 5-FU (b5FU), infusional 5-FU (5-FUCI), and leucovorin (LV) is the preferred first line treatment option for mCRC. This study evaluates the impact of b5FU on survival in first line therapy for mCRC patients treated with mFOLFOX6. Methods: This was a retrospective chart review of patients ≥ 18 years old with mCRC receiving palliative first line mFOLFOX6 chemotherapy with or without b5FU/ LV from January 1, 2010 through June 1, 2019 at Winship Cancer Institute, Emory University. Data collection included the following: demographics (age, race, gender), disease characteristics (tumor sidedness), microsatellite status, KRAS status, BRAF status, addition of monoclonal antibodies (bevacizumab, panitumumab), ECOG PS, grade 3/4 neutropenic events, addition of growth factors, and treatment delays. The primary endpoint was PFS. The multivariable Cox proportional hazards model for PFS and OS was performed with selected covariates of interest. Results: A total of 252 patients with mCRC met the inclusion criteria. Median follow-up time was 2.4 years. 161 patients (64%) received mFOLFOX6 with b5FU/LV and 91 patients (36%) received mFOLFOX6 with no b5FU/LV. More cycles were delivered in the b5FU group as compared to the non-b5FU group (mean, 4.8 v. 3.8 cycles, respectively; p < 0.001). There were no differences in grade 3 and 4 neutropenic events between groups. Growth factor usage was numerically higher in the bolus group though not significantly different (p = 0.06). No difference was observed in treatment delays between groups (p = 0.83). There was no statistical difference in PFS between treatment groups (1.1 years in the b5FU/LV group v. 0.8 years (95% CI, 0.6-1.0) in the no 5-FU/LV bolus group; p = 0.076). The median OS was 2.5 years in the b5FU/LV group compared to 1.8 years in the no b5FU/LV group (p = 0.012). On univariate analysis, tumor sidedness and performance status were significantly different between groups. On multivariate analysis, none of the variables were significantly different between groups. Conclusions: The omission of the b5FU/LV from mFOLFOX6 does not significantly impact PFS, toxicity or treatment delays. However, OS is significantly shorter when the b5FU/LV is omitted suggesting the clinical importance of maintaining bolus administration with 5-FUCI in the first line palliative treatment of mCRC.
Radiographic response of desmoplastic mesenteric lesions to peptide receptor radionuclide therapy (PRRT).
Authors: Pelle Eleonora , Al-Toubah Taymeyah E. , Morse Brian , El-Haddad Ghassan , Strosberg Jonathan R. 
Published: January 2021

362 Background: 177Lu-dotatate PRRT is indicated in well-differentiated, SSTR+ small bowel NETs. These tumors often metastasize to mesenteric lymph nodes and produce a desmoplastic reaction, consisting of tumor cells mixed with fibrotic tissue. We hypothesized that in patients treated with 177Lu-dotatate, mesenteric tumors would remain stable even as liver tumor size changes were observed. Methods: We retrospectively reviewed the records of all patients treated with 177Lu-dotatate between 4/2018 and 12/2019. Among patients with desmoplastic mesenteric tumors and liver metastases, we evaluated changes in tumor size of mesenteric and liver lesions based on pre and post-treatment radiology reports. Due to the infrequency of objective radiographic response (ORR), any reported changes in tumor size were considered significant. Scans were subsequently reviewed by a radiologist to confirm findings. Results: 21 patients met the inclusion criteria: 9 had evidence of shrinkage of liver lesion(s), 1 report described mild progression of liver lesions, 7 described stable hepatic disease and 4 described mixed hepatic progression/response. 2 of the patients with hepatic tumor shrinkage met criteria for PR by RECIST 1.1. Desmoplastic mesenteric lesions remained unchanged in size, regardless of the changes detected on liver lesions. Conclusions: 177Lu-dotatate does not impact desmoplastic mesenteric tumors typically associated with midgut NETs. Patients whose disease is confined to desmoplastic mesenteric lesions are unlikely to respond radiographically to PRRT. Moreover, the inclusion of desmoplastic mesenteric lesions as target lesions in RECIST measurements increases rates of disease stability versus response or progression.
Temozolomide and capecitabine (CAPTEM) is effective in metastatic well-differentiated gastrointestinal neuroendocrine tumors.
Authors: Dogan İzzet , Tastekin Didem , Karabulut Senem , Sakar Burak 
Published: January 2021

366 Background: The study aimed to evaluate patients' outcomes and prognosis with metastatic gastrointestinal neuroendocrine tumors (mgNET) who treated temozolomide and capecitabine (CAPTEM). Methods: The data of forty-three patients were retrospectively evaluated. Clinicopathological features and treatment approaches were recorded. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). Prognostic factors were assessed with Cox-regression analysis. Results: Median age was 59 (27-85) years. The number of male and female patients was 23 (%53.5) and 20 (%46.5), respectively. Pancreas (%51.2) was the most common site of the tumor. The number of patients with well- and poorly-differentiated mgNET was 38 (%88.4) and 5 (%11.6), respectively. The most common metastatic sites were liver (%62.8), lymph node (%58.1), and bone (%18.6). Eleven (%25.6) of the patients previously had undergone surgery, and some patients received radiotherapy (%9.5), chemotherapy (%19), and nuclear therapy (%9.3). Also, patients received octreotide (%86) or lanreotide (%14) with CAPTEM. In patients with well-differentiated mgNET, median PFS was 17.4 months, and disease control ratio %79.4 (%3-complete response, %38.2-partial response, and %38.2-stable response). No response observed in patients with poorly differianted mgNET, and the median PFS was calculated as 4.5 months. Grade 1-2 toxicity was observed in 34 (%79.1) of the patients, and grade 3-4 toxicity in 8 (%18.6). Four (%9.5) patients discontinued therapy for the toxicity. The most common toxicities were anemia (%37.2), thrombocytopenia (%25.6), and fatigue (%16.3). At a median follow-up of 33.8 (2.9-172.73) months, the ratio of five-years OS was %61. In multivariate analysis; gender (p=0.008), age (p=0.007), and Ki-67 levels (p=0.011) were a statistically significant for OS. However, the site of the tumor (p=0.186), number of metastatic sites (p=0.255), and type of somatostatin receptor ligand (p=0.903) were not. Conclusions: In the study, we showed that CAPTEM + somatostatin receptor ligands (octreotide or lanreotide) were effective and well-tolerated in patients with well-differentiated mgNET. But, it was not effective in patients with poorly-differentiated mgNET. Male gender, aged over 60 years, and tumor with a high level of Ki-67 were negative prognostic factors.
Incidence and patterns of secondary malignancies in patients with neuroendocrine neoplasms: A SEER database analysis.
Authors: Sadaps Meena , Mehta Neal , Li Hong , Estfan Bassam N. 
Published: January 2021

374 Background: Neuroendocrine tumors (NETs) are comprised of a group of biologically and clinically heterogenous malignancies arising from a variety of anatomic sites, the majority of which lie within the gastrointestinal tract. Prior literature has reported on the association between NETs and other primary malignancies (OPM), most of which also end up being within the gastrointestinal tract, but these studies are limited by small sample sizes. We aim to further analyze the association of NETs and OPM on a larger scale using a population-based cancer registry. Methods: Malignant primary cancer with NET features were identified from the Surveillance Epidemiology and Ends Results (SEER) registry between 1975 and 2017. The histology/behavior of NET included carcinoid tumor, neuroendocrine carcinoma, pancreatic endocrine tumor, atypical carcinoid tumor, and other including insulinoma, glucagonoma, gastrinoma, VIPoma, somatostatinoma and enterochromaffin cell carcinoid. First NET observation from each patient was examined. Patients with NET were grouped into three categories: only one primary cancer with NET, first primary cancer with NET and first primary cancer without NET based on sequence number of primary cancer recorded in SEER. Distribution of NET between gastrointestinal (GI) and non-GI sites was described. Demographics were compared by NET sequence group and between GI and non-GI sites. Results: 45,896 patients with NET were analyzed (77.9% Caucasian, 47.0% male, median age 62.0 years). More than half (65.7%) of the NETs were observed in GI sites. Within the GI tract, 31.3% were in the small intestine, 25.1% in the rectum, 16.6% in pancreatobiliary, and < 11% in other GI locations. Age at NET diagnosis was younger in those with GI NETs (median 60.0 vs 65.0, p < 0.001 ). 71.2% of NET found in only cancer diagnosis, 10.4% of NET in first followed by a second primary malignancy, and 18.4% in a non-NET primary followed by NET. Mean age was 58.9 for NET primary only, 61.0 for NET primary first and 68.3 for non-NET primary first (p < 0.0001). More Caucasian patients had non-NET primary first (82.3%) compared to NET primary only (76.9%) and NET primary first (75.5%). No gender differences were observed amongst the three groups. Carcinoid tumor histology was more prevalent in NET primary first (78.6%) compared to NET primary only (67.3%) and non-NET primary first (66.6%), while neuroendocrine carcinoma histology was more prevalent in NET only (27.4%) and non-NET first (29.3%) compared to NET first. Conclusions: 28.8% of patients with NETs were found to have OPM, either preceding or following their NET diagnosis. It is imperative that patients with NET undergo age-appropriate cancer screening to help identify any concurrent malignancies. Further research is warranted to identify the location of such additional malignancies and the timeframe in which they occur in relation to the NET.