bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum vitamin D3 levels and overall survival (OS) in patients (pts) with advanced biliary tract cancer (BTC): Analysis of the NIFTY trial cohort.
Authors: Lee So Heun , Cheon Jaekyung , Kim Ilhwan , Kim Kyu-Pyo , Ryoo Baek-Yeol , Jeong Jae Ho , Kang Myoung Joo , Kang Byung Woog , Ryu Hyewon , Lee Ji Sung , Yoo Changhoon 
Published: January 2023

613 Background: Although growing number of studies have explored the role of vitamin D3 on various cancer types, no study has been conducted in the prospective cohort of advanced BTC. This analysis aimed to evaluate the predictive or prognostic implication of serum vitamin D3 in pts with advanced BTC treated with second-line chemotherapy. Methods: The analysis is the preplanned subgroup analysis of the NIFTY trial, a multicenter, open-label, randomized, phase 2b study which compared the second-line liposomal irinotecan plus 5-FU/leucovorin and 5-FU/leucovorin in pts with advanced BTC. Serum vitamin D3 (25-hydroxyvitamin D [25(OH)D]) levels were measured at baseline (i.e., C1D1) in a total of 176 pts out of 178 pts in the ITT population and were included in the current analysis. Correlation between OS and serum vitamin D3 as a continuous variable was analyzed for linear and non-linear associations. Results: The median age was 64 years (range, 37–84) and 75 patients (42.6%) were women. The baseline serum vitamin D3 levels ranged from 1.39 ng/ml to 140.02 ng/ml in the overall pts. There was no significant difference in the mean vitamin D3 concentration according to the sex (male vs. female: 24.1 vs. 26.7; p=0.43), body mass index (BMI) (<25 vs. 25-29.99 vs. ≥30: 24.0 vs. 30.0 vs 15.9; p=0.18), previous surgery (no vs. yes: 24.1 vs. 27.4; p=0.40), ECOG performance status (0 vs. 1: 24.1 vs. 25.5; p=0.66), and primary tumor site (intrahepatic vs. extrahepatic vs. gallbladder: 25.7 vs. 23.2 vs. 26.2; p=0.74). After adjustment for key prognostic factors including chemotherapy regimens, metastatic sites, or baseline CA 19-9 levels, there was no significant association between baseline serum vitamin D3 and OS (HR=1.06 per 10 increase; 95% CI, 0.97–1.15; p=0.22). In addition, there was no non-linear association between vitamin D3 and OS (p=0.52 for the linear model and p=0.62 for the model with restricted cubic splines). In the subgroup analysis, higher vitamin D3 levels were associated with poorer OS (HR=1.16 per 10 increase; 95% CI, 1.04–1.30; p=0.0072) in female pts. Conclusions: Serum vitamin D3 levels did not show significant relationship with survival in pts with advanced BTC treated with second-line chemotherapy. High vitamin D3 levels might be associated with poorer survival in female pts. Further larger studies are needed.
Survival benefit and optimal timing for re-resection in patients with gallbladder cancer: A National Cancer Database analysis.
Authors: Shah Shivani , Sweeney Ryan , Wegner Rodney E. 
Published: January 2023

614 Background: Often times, gallbladder cancer is diagnosed incidentally after cholecystectomy. Most patients will then undergo re-resection for potential residual disease, however overall survival (OS) benefit data in this scenario is variable. Further, limited literature regarding optimal time to re-resection exists. Prior studies found the optimal time to re-resection to be approximately 4-8 weeks after initial diagnosis; however, additional data is needed to further validate these findings. In this National Cancer Database(NCDB) analysis we compare OS in patients diagnosed with T1b – T3 gallbladder cancer who underwent re-resection and evaluate if time to resection impacts OS. Methods: We reviewed the NCDB for patients who had received initial cholecystectomy for gallbladder cancer and were subsequently eligible for re-resection based on tumor stage (T1b-T3 disease) from 2004-2018. We excluded patients with metastatic M1 disease and T0, T1a, T1, or T4 disease. Patients with re-resection were further subdivided into four cohorts based on time to re-resection: 0-4 weeks, 5-8 weeks, 9-12 weeks and >12 weeks. We used a Cox proportional hazards ratio to identify factors associated with worse survival and logistic regression to evaluate characteristics associated with re-resection. OS was calculated using Kaplan Meier curves. Results: 791 (5.82%) patients received re-resection of 13,601patients meeting inclusion and exclusion criteria. Cox proportional hazards analysis showed a Comorbidity Score of 1 was associated with worse survival. Patients with higher Comorbidity Scores (1,2, or 3) and treatment at comprehensive community, integrated or academic cancer programs were less likely to undergo re-resection (in comparison to community programs). Patients treated at an Urban facility or diagnosed from 2009-2018 were more likely to undergo re-resection. The cohort with no re-resection had the lowest median OS [17.61 months; CI 17.05- 18.20] and re-resection showed significantly improved OS [HR 0.87; 95 CI 0.77-0.98; p=0.02]. Significantly improved survival was noted when re-resection was completed at 5-8 weeks [HR 0.67; CI 0.57- 0.81], 9-12 weeks [HR 0.64; CI 0.52- 0.79], or >12 weeks [HR 0.61; CI 0.47- 0.78]. Conclusions: Despite the retrospective nature and small sample size of our study, the results are consistent with prior studies depicting a survival benefit with re-resection. Additionally, optimal timing to re-resection supports previous data showing a clear benefit at any time >4 weeks. However, there was no significant survival difference as to whether re-resection was completed at 5-8 weeks, 9-12 weeks, or > 12 weeks post initial cholecystectomy. Decreased post-operative inflammation and accurate staging at >4 weeks may account for improved survival with later re-resection; however, future investigations are warranted to delineate underlying causes.
Total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A real-world experience.
Authors: Ruiz-Garcia Erika , Cuervo Cmapos Rogelio , Falcon Juan Carlos , Caderillo-Ruiz German , Diaz Romero Maria del Consuelo , Herrera Marytere , Miyagui-Adame Sayako Mariana , Vela Itzel , Alvarez Nora , Lino-Silva Leonardo 
Published: January 2023

62 Background: The standard treatment of locally advanced rectal cancer (LARC defined as T3-T4, N+) consists of giving chemoradiation therapy (CT/RT) followed by total mesorectal excision (TME) after 6-8 weeks followed by chemotherapy (CT) adjuvant. Recently, total neoadjuvant therapy (TNT) has shown greater efficacy in terms of increasing the rate of complete pathological response (pCR) and reducing local and systemic relapse, in addition to increasing sphincter preservation. The objective of this study was to know the percentage of pCR (ypT0N0) presented by Mexican patients with LARC treated at the National Cancer Institute (INCan) with the TNT (implemented in 2019) vs. standard treatment. Methods: An observational, analytical, and retrospective study was carried out, with a non-probabilistic sampling of patients with LARC treated at INCan from 2016 to 2021. Comparisons of continuous numerical variables for independent samples were analyzed using Student's t test or Mann-Whitney U test (depending on its distribution). To examine the association in the discrete variables, the X2 test or Fisher's exact test (according to the case) was used. The association between continuous variables was analyzed using Pearson's or Spearman's correlation coefficients according to the distribution. Statistical difference was considered significant when p < 0.05. The analysis was performed with the statistical package SPSS v26.0. Results: 286 patients were analyzed (N=76 corresponded to TNT), mean age was 57 years, 43% were female, 84% were stage III and 64% had a lower rectal tumor. Complete TME was present at 78.9%. The pCR rate was 45.16% with TNT vs. 22.39% with CT/RT (RR 0.70, 95% CI (0.56-0.90) p= 0.001). 18% recurrences and/or progressions were identified in the TNT group vs. standard treatment (28.2%) with a tendency to statistical significance (RR 0.6 95% CI (0.36-1.08) p= 0.08). 7% mortality was reported with TNT vs. 19% with standard therapy (RR of 1.15, CI 95% (1.05-1.26) p= 0.013). Conclusions: TNT was shown to increase the percentage of complete pathological responses compared to chemoradiotherapy treatment in real-world population attended at INCan. The follow-up of these patients is still short to know the final impact of TNT in terms of relapse-free survival and overall survival.
NET-02 final results: A randomised, phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line (2L) therapy in patients (pts) with progressive poorly differentiated extrapulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: McNamara Mairead Geraldine , Swain Jayne , Craig Zoe , Sharma Rohini , Faluyi Olusola Olusesan , Wadsley Jonathan , Morgan Carys , Wall Lucy R. , Chau Ian , Reed Nick , Sarker Debashis , Margetts Jane , Krell Daniel , Cave Judith , Sharmila Sothi , Anthoney Alan , Patel Alkesh , Lamarca Angela , Hubner Richard , Valle Juan W. 
Published: January 2023

646 Background: As demonstrated in the primary analysis of NET-02, nal-IRI/5-FU/folinic acid, but not docetaxel, met the primary endpoint of 6 month (mo) progression-free survival (PFS) rate in pts with progressive PD-EP-NEC. Here, the final results are presented. Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy in pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. On disease progression, pts in both arms could receive further systemic treatment as recommended by their physicians. Primary endpoint was 6 mo PFS rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was ≥30% (required level of efficacy); a rate of <15% would give grounds for rejection (additional selection criteria: toxicity and quality of life (QoL)). Intention was to show that regimens were sufficiently active, but not to assess superiority of one regimen over the other. Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), toxicity, QoL (European Organisation for Research and Treatment of Cancer QLQ C30 and GINET21) and translational end-points. Results: Of 58 pts in 15 UK centres (Nov 18-Dec 21), 29 in ARM A (2 pts excluded for efficacy analysis: well-differentiated grade 3 (G3) neuroendocrine tumour and goblet cell adenocarcinoma), 29 in ARM B. Eight pts in both arms (27.6% each) received subsequent chemotherapy. Fifty-four pts (93%) have died; the primary end-point of 6-mo PFS rate was met in ARM A; ORR, median PFS and OS are also presented. Adverse events ≥ G3 occurred in 51.7% and 55.2% in ARM A and B with 1 and 6 discontinuations due to toxicity in ARM A and B, respectively. Health-related QoL was maintained (C30 functional scales & global health status remained stable pre-progression) and potentially improved (sustained improvement in role functioning) with nal-IRI/5-FU/folinic acid, but not docetaxel (all C30 functional scales & global health status worsened between baseline and week 18, and treatment-related symptoms also worsened in GINET21). Translational analysis is on-going. Conclusions: nal-IRI/5-FU warrants further evaluation in pts with PD-EP-NEC, with the results highlighting that conduct of randomised trials in this disease group of unmet need is possible and safe. Clinical trial information: NCT03837977 . [Table: see text]
Real-world outcomes in patients with gastroenteropancreatic neuroendocrine tumors receiving somatostatin analogue: Data from a public hospital in Brazil.
Authors: Almeida Kaique Ferreira Costa de , Peria Fernanda Maris , Guimaraes Matheus , Pereira Anny Alves , Rapatoni Liane 
Published: January 2023

650 Background: Neuroendocrine tumors are rare malignant neoplasms derived from endocrine cells and known for their heterogeneous behavior and histopathological characteristics; however, largely associated with a favorable clinical outcome. Somatostatin analogues (SSA) were initially used to control the symptoms of secretory neuroendocrine tumors, and later, they were considered effective as a first-line systemic treatment in unresectable or metastatic neuroendocrine tumors of the gastroenteropancreatic tract (NET-GEP). Randomized clinical trials are performed in controlled environments, with strict inclusion and exclusion criteria, and therefore, real-world studies can add to efficacy and safety data in the general population. Methods: To evaluate, in the real world scenario of a tertiary hospital of the public health system, the efficacy and toxicities of first-line treatment with somatostatin analogue in patients diagnosed with unresectable or metastatic NET-GEP, to find real-world progression free survival (rwPFS) and real-world overall survival (rwOS), in addition to the toxicity profile in our population and possible subgroups that benefit from first-line treatment, through the analysis of variables. Results: 29 patients met the study inclusion criteria, which were diagnosed in the period from 2009 to 2017. The median wrSLP and wrSG were 4.4 (95% CI 3.2 – 5.6) and 8.2 years (CI 95% 6.2 – 10.2), respectively. In an adjusted analysis of rwSLP, the HR for patients with hindgut tumors compared to midgut tumors was 4.41 with p 0.05, indicating that these patients had a 4x increased risk for disease progression (p 0 .05). In the adjusted analysis of wrSG, a trend towards a more favorable evolution was observed in the group of patients with well-differentiated tumors, with p 0.05. Assessment of toxicities revealed grade 2 and grade 3 adverse events in 34.48% of patients. Abdominal pain was the most incident toxicity, occurring in 17.24%, followed by headache (13.79%) and diarrhea (10.34%). Conclusions: Treatment with SSA was effective in our sample, with rwPFS and rwOS data above those found in randomized clinical trials. The toxicities were easily manageable and caused no documented harm to patients.
Evaluation of chromatin remodelers in pancreatic neuroendocrine neoplasms.
Authors: Ferosh Usman Khan Salma , Yadav Rajni , Dash Nihar Ranjan , Pal Sujoy , Das Prasenjit , Narayan Anand , Jyotsna V P , Shamim Shamim Ahmed , Rastogi Sameer , Agarwal Shipra , Sharma Mehar C 
Published: January 2023

652 Background: Pancreatic neuroendocrine neoplasms (PanNENs) are rare entities comprising 1-2% of gastroenteropancreatic neoplasms with an annual incidence of 0.48/100,000 population in the world. The molecular pathways underpinning the entity are less explored owing to its rarity. We aimed to analyse and correlate the expression of chromatin remodelers in PanNENs from Indian subcontinent. Methods: An ambispective study (prospective 2014-2018 as well as retrospective 2018-2021) was conducted. Haematoxylin and eosin stained slides with immunohistochemistry slides (chromogranin, synaptophysin) of 73 cases of PanNENs were retrieved from archives of Department of Pathology, AlIMS, New Delhi and evaluated for assessment of histopathological parameters. Following slide review, grading and staging were done based on WHO 2017 Classification and AJCC eighth edition respectively. Representative formalin fixed paraffin embedded block was selected after slide review and retrieved for performing immunohistochemical staining with antibodies against ATRX, DAXX, SETD2, H3K36Me3 and ARID1A using Ultra Vision Quanto polymer detection system by Thermo Fisher Scientific. Data was analysed using STATA version SE14. Results: Study cohort of 73 PanNENs had a mean age of presentation 41 years (Range: 8 years -70 years) and male to female ratio of 1.43:1. Majority of the tumors in our study were non functional (63.01%). Loss of nuclear expression of ATRX/DAXX (at least one marker) was seen in 26/73 (35.62%) cases. Loss of expression had significant correlation with pathological stage of the tumor, presence of distant metastasis and adverse prognostic outcome (p value-<0.05). Lower grade tumors with low to intermediate ki67 index had higher preponderance for loss of expression of ARID1A. Loss of expression of any of the chromatin remodelers (ATRX/DAXX/ARID1A/H3K36Me3) was noted in 44/73 cases (60.27%) and was more frequently associated with advanced stage of tumor or recurrence/metastasis/death (p value-0.005). Conclusions: Loss of chromatin remodelers such as ATRX, DAXX, ARID1A, SETD2 and H3K36ME3 is involved in the pathogenesis of pancreatic neuroendocrine neoplasms and are associated with adverse outcomes, so loss or lower immunohistochemical expression for these can serve as a poor prognostic factor and guide for adjuvant therapy.
Age- and sex-based differences in the genomic profiles of patients with gastrointestinal (GI) and pancreatic neuroendocrine neoplasms (NENs).
Authors: Liu Lisa , Li Shuning , Gandhi Nishant , Farrell Alex Patrick , Lou Emil , Soares Heloisa P. , Nazha Bassel , Swensen Jeffrey , Oberley Matthew James , Nabhan Chadi , Abraham Jim , Korn Wolfgang Michael , Kunz Pamela L. , Vijayvergia Namrata 
Published: January 2023

655 Background: Demographic variables such as age and sex have long been associated with risk of cancer incidence, therapeutic response, and mortality. In NENs, specifically, studies have shown differences in overall survival based on age at diagnosis and sex. However, studies investigating the molecular determinants associated with age and gender have been lacking. To delineate the mechanisms of age, gender, and outcomes, we queried a large real-world dataset of NENs originating from the GI-tract and pancreas and characterized their molecular and immune profiles. Methods: 1935 cases (GI: n=1431, Pancreas: n=504) of NENs were analyzed using Next Generation Sequencing or Whole Exome Sequencing of DNA, and 1211/1935 cases (GI: n=917, Pancreas: n=294) underwent Whole Transcriptome Sequencing at Caris Life Sciences (Phoenix, AZ). To study the age-associated effect on the molecular and immune landscapes, we applied two age cutoffs: below 50 and 70 years of age at the time of tissue collection, respectively. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q<0.05). Results: In GI-NEN, TP53, RB1 mutations and high tumor mutation burden (TMB_H; >=10 Mut/Mb) were more prevalent and KRAS mutations were less prevalent with increasing age. Interestingly, in pancreatic NENs (P-NENs), KRAS mutations were more prevalent and TMB_H were less prevalent with increasing age. Mutations specific to the sites of origin such as APC (GI) and MUTYH (pancreas) were negatively associated with age while SMAD4 (pancreas) was positively associated with age. While no differences in immune checkpoint gene (ICG) expression were associated with age, immune cell estimates of M1 macrophages (anti-tumorigenic) in GI-NENs were higher in patients above 70 and M2 macrophages (pro-tumorigenic) were higher in patients below 50 (p<0.05, q>0.05). For the analysis with gender, mutations in p53 were more prevalent among males with GI-NEN while dMMR/MSI-H were more prevalent in females with P-NENs. No significant differences in ICG expression and immune cell estimates were associated with gender. Conclusions: Our study queries one of the largest datasets of GI and P-NENs to date. We observe distinct molecular profiles associated with age and gender in both GI- and P-NENs as well as a distinct immune profile associated with age in GI-NENs. While these results are only hypothesis generating, they are suggestive of how patient demographics may be utilized for rational therapy design. [Table: see text]
The genomic landscape of advanced gastrointestinal (GI) neuroendocrine tumors (NET) and carcinomas (NEC).
Authors: Farha Nicole , Mundi Prabhjot Singh , Wei Wei , Kamath Suneel Deepak , Khorana Alok A. , Fojo Antonio Tito , Laderian Bahar 
Published: January 2023

656 Background: The impact of specific genomic alterations in advanced GI neuroendocrine malignancies on prognosis and treatment decisions has not been fully characterized. In this study, we seek to evaluate next-generation sequencing (NGS) panels and corresponding clinical outcomes in patients with metastatic GI NET/NEC. Methods: Patients with GI-NET/NEC were identified from a database of NGS reports performed at the Cleveland Clinic, and clinical variables were extracted by chart review through an IRB-approved protocol. We provide an analysis of this cohort. Results: Of a total n=45 patients, 53% were male. Median age at diagnosis was 60 (range: 35-90 years) and 82% were non-Hispanic white, while 9% were black. There were n=25 GI-NETs, mostly intermediate or high grade (11 G3, 7 G2), and n=20 GI-NECs. There was a balanced distribution of primary sites, including colorectal (27%), pancreas (24%), small intestine (18%), unknown primary (24%) and a single case of biliary primary. High grade GI-NETs and GI-NECs were over-represented in the colorectal primary group vs other sites. (n=10 of 12; p=0.021). The majority of patients (73%) had at least one somatic variant, including 12 patients (27%) with one or more mutations deemed actionable, but only one patient (with MSH2 mutation) has received a mutation-matched drug (pembrolizumab). Some recurrent alterations appeared to co-segregate with aggressive histology (NEC vs NET), including 12 of 13 TP53 mutations (p<0.05 by Fisher Exact Test), 7 of 8 RB1 (p<0.05), and 5 of 6 APC (p=0.074). The most common mutations per person based on primary site is shown. Microsatellite instability high was rare (n=1) and median tumor mutational burden (TMB) was 3/mb, with TMB lower in NETs vs NECs. A number of patients (35%) underwent germline testing, with 6 of 16 having a pathogenic germline variant. Conclusions: As 42% of the 12 patients with actionable mutations were alive at time of analysis, it is possible that additional patients could be treated with mutation-matched therapies. More input will be needed from providers as to the role played by alternative effective treatments and barriers such as insurance coverage and prior authorization to implementing mutation-matched therapies. Given the overall low TMB of GI-NETs, with several tumors having zero or 1 reported mutation on targeted NGS, whole genome sequencing may prove useful. Finally, certain mutations such as RB1 and TP53 were associated with more aggressive histology (i.e. NEC). Lastly, only 9% of our cohort with NGS were black, a significant under-representation based on epidemiological data, which raises concerns about disparate accessibility and barriers to NGS testing. Further studies are needed to address any possible racial disparity.[Table: see text]