bluuebunny/crossref_metadata_2025_split huggingface dataset:
The clinical and molecular characteristics of patients with personal or family history of gastrointestinal malignancies/polyposis and checkpoint kinase 2 (CHEK2) mutations.
Authors: Ozair Sana , Gurganus Cassandra , Krishnan Veena , Dosunmu Gideon T , Montoya Motino Delmer Alfredo , Grimm Leander , Phung Thuy , Blount Jessa , Nelson Cindy , Khushman Moh'd M. 
Published: January 2021

44 Background: Checkpoint Kinase 2 (CHEK 2) encodes the protein CHK2, a serine/threonine kinase involved in pathways that conduct DNA repair as well as apoptosis in response to initial DNA damage. Germline mutations in the CHEK2 gene are associated with several malignancies such as colon, breast, stomach, prostate, kidney, thyroid and soft tissue cancers. Here, we describe the clinical and molecular characteristics of patients with personal or family history of gastrointestinal (GI) malignancies/polyposis and CHEK2 gene mutations. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a germline CHEK2 mutation were identified (N = 16). Patients with a CHEK2 mutation and personal and family history of GI malignancies/polyposis were further explored and their clinical and molecualr characteristics are summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services in patients with pathogenic CHEK2 mutations were personal history of colon cancer (N = 3) and family history of colon cancer (N = 4). One patient with the CHEK2 c.1100delC mutation had a personal history of juvenile polyposis syndrome and a family history of colon cancer. In our cohort, 11 out of 16 (69%) patients had a CHEK2 mutation and personal or family history of GI malignancies/polyposis. The median age was 57 years old (25-80). Six (55%) patients were males. All (100%) patients were Caucasians. Seven (64%) patients had a pathogenic germline CHEK2 mutation and 4 (36%) patients had a variant of unknown significance (VUS). Among patients with pathogenic germline CHEK2 mutations (N = 7), 5 (72%) patients had CHEK2 c.1100delC mutation, 1 (14%) patient had CHEK2 c.190G > A mutation and 1 (14%) patient had CHEK2 c.470T > C mutation. The CHEK2 VUS mutations seen in our cohort were CHEK2 c.539G > A, CHEK2 p.V395L, CHEK2 gain of exons 3-15 and CHEK2 c.1421G > A mutations. Conclusions: All patients in our cohort with CHEK2 mutations were Caucasians. The majority of our patients (69%) had an underlying personal or family history of GI malignancies/polyposis. In patients with personal or family history of GI malignancies/polyposis and CHEK2 mutation, 64% were found to have pathogenic CHEK2 mutations. The most common diagnosed CHEK2 mutation in our cohort was CHEK2 c.1100delC mutation.
Cost efficiency and budget-neutral expanded access to antineoplastic therapy from cost-savings derived from conversion to biosimilar pegfilgrastim-cbqv for the prophylaxis of chemotherapy-induced (febrile) neutropenia (CIN/FN):Simulation modeling in metastatic pancreatic cancer.
Authors: McBride Ali , MacDonald Karen , Abraham Ivo 
Published: January 2021

441 Background: Biosimilars have contributed to the reduction in the cost of prophylaxis of CIN/FN in recent years. Savings generated from conversion to biosimilars could be reallocated on a budget-neutral basis to provide expanded access to additional prophylaxis or to anti-neoplastic treatment. To demonstrate this, we simulated: 1) the savings that could be realized from CIN/FN prophylaxis with biosimilar pegfilgrastim-cbqv (BIOSIM-PEG) over reference pegfilgrastim with or without on-body injector (PEG/PEG-OBI), 2) a model of expanded access to BIOSIM-PEG from cost-savings achieved from conversion from PEG/PEG-OBI, 3) a model of expanded access to chemotherapy with oxaliplatin, leucovorin, irinotecan, and fluorouracil (FOLFIRINOX) for metastatic pancreatic cancer (mPC), 4) the number-needed-to-convert (NNC) to BIOSIM-PEG to purchase one additional treatment of BIOSIM-PEG, and 5) the NNC to purchase one cycle of FOLFIRINOX. Methods: This simulation modeling from the US payer perspective utilized: 1) a blended rate of average selling price (ASP; derived from CMS Q4 2020 reimbursement) and wholesale acquisition cost (WAC; Redbook) for PEG/PEG-OBI, BIOSIM-PEG, and all FOLFIRINOX agents proportionate to the estimated 2020 incident pancreatic cancer age distribution per Surveillance, Epidemiology, and End Results Program (67.6% Medicare-insured patients ≥65 years of age; 32.4% commercially insured patients <65 years); 2) between one and twelve cycles of prophylaxis in a panel of 2,500 mPC patients treated with FOLFIRINOX; and 3) conversion rates from PEG/PEG-OBI to BIOSIM-PEG ranging from 10%—100%. Results: Using a current blended ASP/WAC rate, cost-savings of BIOSIM-PEG over PEG/PEG-OBI in a panel of 2,500 mPC patients range from $188,780 (for 1 cycle of prophylaxis at 10% conversion) to $22,653,609 (12 cycles at 100%). In a single cycle of chemotherapy, these savings translate into expanded access to additional BIOSIM-PEG prophylaxis ranging from 53 cycles at 10% conversion from PEG/PEG-OBI to 528 cycles at 100% or to between 321 to 3,214 cycles of FOLFIRINOX, respectively. The savings over twelve cycles could provide up to 6,330 additional cycles of BIOSIM-PEG or 38,571 cycles of FOLFIRINOX (at 100% conversion). The NNC from PEG/PEG-OBI to purchase one additional cycle of BIOSIM-PEG is 4.74; the NNC to purchase once cycle of FOLFIRINOX is 0.78. Conclusions: These simulated models demonstrate the magnitude of the cost savings for CIN/FN prophylaxis that can be generated by conversion to biosimilar pegfilgrastim-cbqv. Further, these savings could be reallocated to provide access to anti-neoplastic treatment on a budget-neutral basis, thus enhancing the value of cancer care to both payers and patients.
The clinical and molecular characteristics of patients with personal history of colorectal cancer evaluated by cancer genetics counseling services.
Authors: Krishnan Veena , Gurganus Cassandra , Montoya Motino Delmer Alfredo , Dosunmu Gideon T , Ozair Sana , Grimm Leander , Phung Thuy , Blount Jessa , Nelson Cindy , Rich Jamie , Khushman Moh'd M. 
Published: January 2021

46 Background: Genetic susceptibility to colorectal cancer (CRC) include well-defined hereditary syndromes such as Lynch Syndrome, Familial Adenomatous Polyposis syndrome (FAP), MUTYH-Associated Polyposis syndrome (MAP) and other less common syndromes. National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals meeting certain criteria have detailed risk assessment and potential genetic testing. Here, we describe the clinical and molecular characteristics of patients with personal history of CRC evaluated by cancer genetics counseling services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of CRC were identified (N = 52) and their clinical and molecular characteristics were summarized. Results: The median age is 50 years-old (29-82). Thirty-five (67%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 75%, 19% and 6% respectively. The primary tumor location was in the right colon, left colon and rectum in 29%, 37% and 27% of our cohort respectively. In 7%, the primary location of the tumor was not available. In our cohort, 11 out of 52 (21%) patients had a pathogenic germline mutation and 9 patients (17%) had a germline variant of unknown significance (VUS). Among patients with pathogenic germline mutations (N = 11), 4 patients had MSH2 mutations (MSH2 c.1759+1G > A, MSH2 c. 1687dupT, MSH2 c.1861C > T and MSH2 c.811_814delTCTG), 1 patient had a MSH6 mutation (MSH6 c.1012A > T), 1 patient had a PMS2 mutation (PMS2 c.2182_2184delACTinsG), 3 patients had CHEK2 mutations (CHEK2 c.1100delC and CHEK2 c.470T > C (p.I157T)), 2 patients had MUTYH mutations (MUTYH c.1187G > A and MUTYH c.536A > G) and 1 patient had a BRCA2 mutation (BRCA2 c.2808_2811delACAA). One patient had a CHEK2 and a MUTYH mutation. The VUS mutations in our cohort were POLE c.1645T > C, POLE c.5480C > T, c.2999G > A, MLH1 c.1628A > G, CTNNA1 c.503G > A, MSH2 c.128A > G, NBN c.16C > T, ATM c.6537T > G and AXIN2, BRCA1, NTHL1 mutations. Conclusions: In our cohort of patients with personal history of CRC, the majority of patients (62%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 21% and 17% of the patients respectively. Lynch Syndrome was the most commonly diagnosed hereditary CRC syndrome with 6 out of 11 patients found to have MMR germline mutations. Other pathogenic mutations were identified in the CHEK2, MUTYH and BRCA2 genes.
Comparison of clinical characteristics and survival outcomes in patients with malignant peritoneal and pleural mesothelioma.
Authors: Katiyar Vatsala , Kumar Rohit , Vohra Ishaan , Rojan Adam 
Published: January 2021

460 Background: Malignant peritoneal mesothelioma (MPeM) is an aggressive tumor strongly associated with asbestos exposure. We analyzed a large nationwide database to better understand the differences in the demographic and clinical patterns of MPeM and pleural mesothelioma (MPlM). Methods: The National Cancer Database (NCDB) 2010-15 was queried to identify all patients diagnosed with MpeM and MPlM. The demographic and clinical characteristics were compared using Pearson’s chi-square test. Kaplan-Meier method and associated log-rank test were used to compare the unadjusted overall survival of the two malignant mesothelioma (MM) sites. A multivariate Cox regression analysis was done to determine survival difference between the 2 groups. Results: Of the 8,668 patients included in the study, 1,081 (12.5%) had MPeM and 7,587 (87.5%) had MPlM. The MPeM cohort was younger (median age at diagnosis 61 vs 73 years), predominantly females (45.7% vs 23.5%), had a lower Charlson Deyo Comorbidity Score ( > = 1: 24.5% vs 32.1%), had higher percentage of uninsured patients (4% vs 2.2%), was less likely to be treated at a community or comprehensive community center (36.1% vs 47.3%) and had lower proportion of sarcomatous or biphasic histology (9.3% vs 22.4%) compared to MPlM cohort. The MPeM cohort was more likely to receive surgery (56.5% vs 28%) and chemotherapy (68.4% vs 54.5%) but less likely to receive radiation (0.8% vs 11%). The p-value was < 0.001 for all comparisons. The median OS was 19.7 and 9.7 months for patients with MPeM and MPlM, respectively (log-rank p value < 0.001). On multivariate Cox proportional hazards analysis, OS was significantly worse for MPlP compared to MPeP [HR adj: 1.19, 95% confidence interval (CI): 1.09-1.30 (p < 0.001)]. Conclusions: There is paucity of data about clinical characteristics and outcomes of MPeM. Much of our current knowledge about MPeM is extrapolated from MPlM. Our study suggests significant differences in prognostic factors and survival outcomes between the two sites.
Stage IV gastrointestinal stromal tumors: Epidemiology, treatment and outcomes in adult US patients.
Authors: Uhlig Johannes , Stein Stacey , Lacy Jill , Cecchini Michael , Kim Kevin 
Published: January 2021

462 Background: To evaluate epidemiology, treatment and outcomes of stage 4 gastrointestinal stromal tumors (GIST). Methods: The 2010-2016 United States National Cancer Database was queried for adult patients diagnosed with invasive GIST (ICD code 8936) at AJCC stage 4, without prior malignant disease. Overall survival (OS) was evaluated using Cox proportional hazards regression, accounting for potential confounders in multivariable models. Results: A total of 1,578 stage 4 GIST were included (13.3% of all GIST) with a male:female ratio of 1.38:1. The most common cancer site was the stomach (55.4%) and small intestine (40% of stage 4 GIST). At diagnosis, median age was 62 years and median tumor diameter 10 cm. Distant organ metastases were reported in 58.7%, the most frequent being hepatic (n = 801, 50.8% of stage 4 GIST). The majority of stage 4 GIST patients received systemic therapy (78.6%), either alone (35.4%) or combined surgery+systemic therapy (43.3%). Systemic therapy was administered neoadjuvant in 6.9%, adjuvant in 32%, and neoadjuvant+adjuvant in 5.1% of surgically resected patients. Another n = 204 patients (12.9% of all stage 4 GIST) were treated with surgical resection alone. GIST overall survival rates were 88%, 77%, 67% and 51% at 1, 2, 3, and 5 years, respectively. On multivariable Cox proportional hazard models, primary GIST treatment independently affected OS: compared to combined surgery+systemic therapy, OS was shorter for patients receiving systemic therapy alone (HR = 2.77 (95% CI: 2.12-3.61, p < 0.001)) and no treatment (HR = 4.2 (95% CI: 2.75-6.43, p < 0.001)). No significant OS difference was evident comparing surgery+systemic therapy and surgery alone (HR = 1.23 (95% CI: 0.88-1.72, p = 0.227)). In subgroup analyses of patients undergoing surgical resection, no statistically significant OS difference was evident comparing neoadjuvant, adjuvant and combined neoadjuvant+adjuvant systemic therapy on multivariable analyses. Treatment at non-academic vs. academic centers was associated with shorter OS (multivariable HR = 1.36 (95% CI: 1.1-1.69, p = 0.005)). Further independent OS predictors were male sex (vs. female HR = 1.28 (95% CI: 1.03-1.59, p = 0.023)), older age, higher comorbidities, higher cancer grade, and larger cancer diameter. Conclusions: Stage 4 GIST is a rare gastrointestinal malignancy that most commonly manifests in the stomach and small intestine in male patients, with frequent hepatic metastases and excellent 5-year OS rates of up to 51%. Combined surgery+systemic therapy demonstrates best outcomes, although surgical resection alone might yield comparable results in selected patients.
Germline testing of patients with personal history of colorectal polyposis by cancer genetics counseling services.
Authors: Dosunmu Gideon T , Gurganus Cassandra , Krishnan Veena , Montoya Motino Delmer Alfredo , Ozair Sana , Grimm Leander , Phung Thuy , Blount Jessa , Nelson Cindy , Rich Jamie , Khushman Mohd 
Published: January 2021

47 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals with >10 adenomatous polyps, ≥2 hamartomatous polyps, or ≥5 serrated polyps proximal to the sigmoid colon have detailed risk assessment and potential genetic testing to rule out polyposis syndrome. Here, we describe germline testing of patients with a personal history of colorectal polyposis by Cancer Genetics Counseling Services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of colorectal polyposis were identified (N=20) and their germline testing results were summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services were personal history of >10 adenomatous polyps (N=13), personal and family history of colorectal polyposis (N=3), personal history of juvenile colorectal polyps (N=3) or personal history of ≥2 hamartomatous polyps (N=1). The median age is 58 years-old (1-84). Ten (50%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 80%, 10% and 10% respectively. In our cohort, 6 out of 20 (30%) patients had a pathogenic germline mutation, 5 (25%) patients had variant of unknown significance (VUS) and 9 (45%) patients had negative testing. Among patients with pathogenic germline mutations, 3 patients had a pathogenic APC mutation (APC c.1659G>A, APC c.2802C>A and APC c.1643dupT) and were diagnosed with Familial Adenomatous Polyposis (FAP). One patient had 2 pathogenic MUTYH mutations (MUTYH c.536A>G and MUTYH c.1187G>A) and was diagnosed with One patient had a pathogenic PTEN c.634+5G>A mutation and was diagnosed with PTEN Hamartoma Tumor Syndrome. Among the 3 patients with a personal history of juvenile colorectal polyps, one patient had a CHEK2 c.190G>A mutation while the other two had negative genetic test results. The VUS mutations in our cohort were MRE11A c.826C>T, BLM c.3478T>C, BRCA2 c.2519T>C, CHEK2 p.V395L and CTNNA1 c.392dupT. Conclusions: In our cohort of patients with personal history of colorectal polyposis, the majority of patients (45%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 30% and 25% of the patients, respectively. FAP Syndrome was the most commonly diagnosed hereditary polyposis syndrome with 3 patients found to have APC germline mutations. Other pathogenic mutations were identified in the MUTYH, PTEN and CHEK2 genes. Patients with MUTYH and PTEN mutations were diagnosed with MAP and PTEN Hamartoma Tumor Syndromes respectively.
Adjuvant therapy in the treatment of resected nonmetastatic gallbladder cancer of stage II-IV: A generalized propensity score analysis.
Authors: Wan Wenze , Zheng Bohao , Sun Wentao , Wang Jiwen , Shen Sheng , Liu Han , Ni Xiaojian , Liu Houbao 
Published: January 2021

471 Background: The benefit of adjuvant therapy for gallbladder cancer (GBC) remains controversial due to the limited evidence. The current study was aimed to explore the efficacy of adjuvant therapy in patients with resected non-metastatic GBC and to establish a prognosis model to predict the survival benefit of GCB patients with different adjuvant therapies. Methods: Patients with resected non-metastatic GBC of stage II-IV were selected from the Surveillance, Epidemiology, and End Results database and divided into non-radiotherapy and chemotherapy (NCRT) group, chemotherapy (CT) group, and chemoradiotherapy (CRT) group. Generalized propensity score (GPS) and inverse probability of treatment weighting (IPTW) was used to reduce the imbalances between groups. Nomogram was constructed based on Cox proportional hazard model, and the model was validated for discrimination and calibration. Results: Among the 2689 enrolled patients, 1193 (44.4%) patients were classified as stage II, 1371 (51.0%) as stage III, and 125 (4.6%) as stage IV according to the 8th American Joint Commotion Cancer staging manual. Patients in NCRT, CT, and CRT groups were 1703, 444, and 542 respectively. After the IPTW, absolute standardized differences of baseline characteristics were less than 0.1 both in patients with stage II tumors and with stage III-IV tumors. In patients with GBC of stage II, no significant difference in OS was observed between the three treatment groups (P > 0.05). In patients with GBC of stage III-IV, CT group has a superior OS compared with the NCRT group (P < 0.001), and CRT group has a superior OS compared with the CT(P < 0.001) and NCRT (P < 0.001) group. Sensitivity analysis showed consistent results. A nomogram was constructed for patients with stage III-IV tumors to predict the survival benefit of adjuvant therapies. The C-index was 0.673 (95% CI: 0.654-0.692) in the validation using the training set (diagnosed at 2004-2012) and was 0.707 (95% CI: 0.677-0·739) in the internal validation using the validation set (diagnosed at 2013-2015). The calibration curves indicated that the predicted probability closely corresponded to the actual observation OS. Conclusions: Patients with GBC of stage II could not benefit from adjuvant therapy. Patients with GBC of stage III-IV could benefit from chemotherapy and chemoradiotherapy while chemoradiotherapy provide a superior OS. A nomogram was built to predict the survival benefit of different adjuvant therapies in patients with GBC of stage III-IV.
Patient characteristics and survival outcomes in gastrointestinal cancers harboring RNF43 mutations or RSPO3 fusions: a retrospective analysis.
Authors: Sackstein Paul , Buechner Garrett , Weinberg Benjamin Adam 
Published: January 2021

473 Background: The growth of intestinal epithelium is dependent on the Wnt/β-catenin signaling pathway. The R-Spondin (RSPO) family of proteins form complexes with Wnt ligand and RNF43 protein, which promote ubiquitination and degradation of Wnt receptors. Patients with gastrointestinal cancers harboring RSPO3 gene fusions or RNF43 gene mutations may benefit from Wnt pathway inhibitors. Methods: We retrospectively studied 51 patients at our institution diagnosed with gastrointestinal cancers with RSPO3 gene fusions or RNF43 gene mutations identified using Caris Life Sciences next-generation sequencing (NGS). Microsatellite-instability (MSI) was evaluated using NGS. Tumor mutational burden (TMB) was estimated from 592 genes by counting all nonsynonymous missense mutations not previously defined as germline mutations, expressed as mutations per megabase. First-line median progression-free survival (PFS) and median overall survival (mOS) were estimated using the Kaplan-Meier method. Results: Of the 51 patients in our study, 44 (86.3%) had RNF43 mutations and 7 (13.7%) had RSPO3 fusions, 6 of whom had colorectal cancer (CRC) and had PTPRK as the fusion partner, 1 case of small bowel cancer had a RSPO3: IFNGR1 fusion. Median age at diagnosis was 64.0 ± 12.0 years. The most common primary tumors were CRC in 23 patients (45.1%) and pancreas in 12 patients (23.5%). Co-occurring mutations in CRC patients with RSPO3 fusions included KRAS (50%, Q61H, G12C, and G12V), BRAF V600E (50%), and TP53 (100%), none were MSI-H, median TMB (mTMB) was 9.5 (range 7-11). Sixty-seven percent of RNF43-mutated CRC patients had the G659fs mutation. Co-occurring findings in RNF43-mutated CRC patients included 67% MSI-H, median TMB 27 (range 6-123), KRAS (28%), BRAF V600E (28%), and TP53 mutations (33%). Twenty-two patients (43.1%) had stage IV disease, 18 (35.3%) had stage III disease and 11 (21.6%) had stage II disease. Thirty RNF43-mutated patients (58.8%) underwent definitive surgical resection, with a mean time to recurrence of 22.2 months and mOS of 43.0 months (95% CI, 15.6-70.4). Among RNF43-mutated stage IV CRC (mCRC) patients, median PFS was 8.0 months (95% CI, 5.9-10.1). Stratified by stage, mOS was 111.0 months for stage II disease, 72.0 months for stage III disease, and 37.0 months for stage IV disease (95% CI, 14.7-59.3). Conclusions: RNF43 correlates with overall favorable mOS in patients with mCRC. mOS in RNF43-mutated mCRC is similar to those of RAS and BRAF wild-type subgroups as reported in the TRIBE study (Cremolini et al. 2015). Therefore, RNF43 mutational status appears to be useful in predicting clinical outcomes for patients with stage IV CRC and overlaps significantly with MSI-H. RSPO3 fusions are rare events and the clinical outcomes of this subset of patients with tumors with RSPO3 fusions remains largely unknown.