bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical insights for hematological malignancies from an artificial intelligence decision-support tool.
Authors: Kim Miyoung , Snowdon Jane , Weeraratne S Dilhan , Felix Winnie , Lim Lionel , Dankwa-Mullan Irene , Lee Young Kyung , Lee Eunyup , Jeon Kibum , Lee Jee-Soo , Zang Dae Young , Kim Hyo Jung , Kim Ho Young , Han Boram
Published: May 2019

e13023

Background: Next generation sequencing (NGS) in hematological tumors is increasingly shaping clinical treatment decisions at the point of care. While the impact of NGS panels in solid tumors is largely therapeutic, targeted sequencing in hematological tumors can additionally provide diagnostic and prognostic insights. Additional data generated in hematological tumor sequencing makes manual interpretation and annotation of variants tedious and non-scalable. In this study we compared hematological tumor variant interpretation using an artificial intelligence decision-support system, Watsonä for Genomics (WfG), with expert guided manual curation. Methods: Patients with hematological tumors at Hallym University, College of Medicine between December 2017 and December 2018, were sequenced using the 54 gene Illumina TruSight Myeloid Panel. WfG interpreted and annotated all patients’ sequencing results, a subset of which were assessed manually to ascertain concordance. Results: 54 South Korean patients with hematological malignancies were analyzed (23 Acute Myeloid Leukemia, 12 myeloproliferative neoplasm, 5 myelodysplastic syndrome, 5 multiple myeloma and 9 others). Comparison of manual and WfG interpretation of 10 randomly selected cases yielded 90% (9/10) concordance and identification of 9 clinically actionable variants (33%) not found in manual interpretation. In total, WfG identified that 71% (38/54) of all cases had at least one clinically actionable therapeutic alteration (a variant targeted by a US FDA approved drug, off-label drug, or clinical trial). 33% (18/54) of cases had genes that were targeted by a US FDA approved therapy including JAK2, IDH1, IDH2, and FLT3. In cases without therapeutic alterations, WfG identified diagnostic or prognostic insights in an additional 20% (11/54) of patients. 9% (5/54) had no clinically actionable information. Conclusions: WfG variant interpretation correlated well with manually curated expert opinion and identified clinically actionable insights missed by manual interpretation. WfG has obviated the need for labor-intensive manual curation of clinical trials and therapy, enabling our center to exponentially scale our NGS operations.
Comparative analysis of prognostic molecular signatures in Asian and Caucasian AML populations.
Authors: Kim Miyoung , Weeraratne S Dilhan , Snowdon Jane , Felix Winnie , Lim Lionel , Lee Young Kyung , Lee Eunyup , Jeon Kibum , Lee Jiwon , Zang Dae Young , Han Boram
Published: May 2019

e13025

Background: Next generation sequencing (NGS) studies on various cancer types have revealed clinical insights on the molecular etiology of tumors and defined new treatment paradigms. However, the genomic landscape of a tumor type may be predicated on race. Application of broad-brush findings from one population to another may lead to erroneous treatment decisions. While the majority of published NGS cancer studies focus on Caucasian populations, few studies evaluate the molecular profiles of a tumor type between different demographies. In this study, acute myeloid leukemia (AML) patients of East Asian descent were sequenced at a South Korean hospital, interpreted, and compared with the Caucasian population from The Cancer Genome Atlas (TCGA). Methods: 23 South Korean AML patients were sequenced in 2018 using the 54 gene Illumina TruSight Myeloid Panel at Hallym University, College of Medicine. Orthogonal testing for FLT3-internal tandem duplication (ITD) was done by Sanger sequencing. Watsonä for Genomics (WfG), an artificial intelligence decision-support system, was used for variant interpretation and annotation. Additionally, 181 AML patients of Caucasian descent from the TCGA dataset were analyzed for comparison. Results: WfG identified at least 1 clinically actionable therapeutic alteration in 70% (16/23) of all Asian cohort cases. FLT3-ITD or tyrosine kinase domain (TKD) mutations were reported in 27% (49/181) of cases in the TCGA cohort but only 9% (2/23) of the Asian cohort. DNMT3A mutations were detected in 25% (45/181) and 74% (17/23) of the TCGA and Asian cohorts, respectively. Other oncogenic mutations in AML including NRAS, IDH1, IDH2, CEBPA, TET2, and NPM1 were represented at comparable frequencies between the two populations. Conclusions: Tumor biomarkers that affect prognosis can be informative in the clinical setting. In our study, FLT3 and DNMT3A, predictors of poor prognosis in AML, demonstrated decreased and increased respective frequencies in South Koreans compared to Caucasians, suggesting that some mutational signatures that predict cancer outcome may vary by race.
RAS activation and CDKN2A deletion to predict prognosis in cancer of unknown primary.
Authors: Bochtler Tilmann , Reiling Anna , Endris Volker , Hielscher Thomas , Volckmar Anna-Lena , Neumann Olaf , Kirchner Martina , Budczies Jan , Heukamp Lukas , Leichsenring Jonas , Allgäuer Michael , Schirmacher Peter , Stenzinger Albrecht , Kraemer Alwin
Published: May 2019

e13026

Background: Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Given the typically dismal response to empiric chemotherapy, the deciphering of molecular profiles holds a particular promise for targeted therapy. Here, we address the prognostic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Methods: We performed targeted panel sequencing in a series of 252 CUP patients. Median age was 60.3 years and 59.1% were female. 71.2% of patients had unfavorable CUP. Lymph nodes, bone marrow, lung, peritoneum and pleura were the most frequent metastatic sites. Among histologic subtypes, adeno- (74.7%) and squamous cell carcinomas (13.7%) prevailed. DNA was extracted from micro-dissected formalin-fixed, paraffin-embedded tissue samples. For library preparation mostly multiplex PCR-based Ion Torrent AmpliSeq technology (Life Technologies) with Oncomine comprehensive assays v1 and v3 was used. Results: The prevailing genetic alterations were deletions in tumor suppressor genes TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01) and PIK3CA activation in squamous cell carcinomas (p = 0.03). Regarding prognosis, male sex, high ECOG score, unfavorable CUP subtype, a higher number of involved organs as well as RAS activation predicted decreased event-free and overall survival in multivariate analysis. Deletions in CDKN2A were a poor prognostic factor regarding overall survival. Markedly, TP53 mutations did not significantly influence prognosis. Since July 2015, 17/198 (8.6%) patients received a recommendation for molecularly guided therapy. However, due to lack of coverage by insurers or rapid clinical deterioration only 7 of these patients (3.5%) actually received targeted treatment. Conclusions: Besides offering targets for therapy, targeted panel sequencing in CUP is prognostically relevant, with RAS activation and CDKNA2 deletion emerging as independent risk factors in a comprehensive assessment with clinical risk factors.
Analysis of mutation detection in cell-free DNA in ascites using comprehensive NGS panel.
Authors: Shi Chunmei , Zhang Yan , Zhu Lingjun , Dai Pingping , Tang Yong , Zhang Junping , Gao Jie , Zhang Chi , Guan Yan-Fang , Xia Xuefeng , Yang Ling , Yi Xin
Published: May 2019

e13029

Background: Ascites is one of complications for patients with malignancies in advanced stage. Detection and characterization of cell-free DNA (cfDNA) from ascites effusions have not yet been studied. Herein, we analysis genomic alterations present in advanced cancer with ascites. Methods: We implemented targeted capture NGS with a panel of 1021 cancer-relevant genes on 85 ascites ctDNA, also on 46 matched plasma and 9 tissue from 85 patients. Results: Among 85 patients with advanced cancer, 42 digest system cancer (DC), 16 gynecologic cancer (GC), 14 non-small cell lung cancer(NSCLC) and 13 other solid tumors included. Overall, 90%(77/85) patients detected somatic mutations, which were identified predominantly in TP53 and KRAS for DC and TP53 for GC. Among NSCLC patients with ascites, nine were treated with EGFR TKI-targeted therapy previously. Mutations lead to the resistance of EGFR-TKI were identified in 55.6% (5/9) cases, including acquired EGFR T790M/C797S and primary BRAF V600E. These indicate ctDNA in ascites can used to guide tumor treatment and monitor of resistance. For the 46 pairs of ascites and plasma samples, actionable variations with on label, off-label, or experimental drugs available, were identified in 61% (n = 28) of ascites effusion samples, whereas plasma was 46% (n = 21). Median number of ascites somatic mutations was 4, while the median number was 3 in plasma samples. Of that, 85% and 61% of plasma ctDNA and ascites cfDNA samples were observed with the highest MAF above 1%. In addition, 63% and 35% of plasma ctDNA and pleural cfDNA samples were observed with the highest MAF above 10%. For the 9 groups of plasma, ascites and tumor tissue samples, at least 1 mutations within tissue was detected in 8 ascites samples and 6 in plasma samples. Conclusions: Our results suggest that cfDNA from ascites is more sensitive than plasma and had higher similarity with the tumor tissues for advanced cancer patients. With higher MAF and detection rate of actionable variations, cfDNA from ascites might provide additional information not detected with plasma cell-free DNA guide more precise cancer treatment.
RNA sequencing analysis for profiling activation of cancer-associated molecular pathways.
Authors: Buzdin Anton , Garazha Andrew , Sorokin Maxim , Glusker Alex , Aleshin Alexey , Allina Daria , Suntsova Maria , Tkachev Victor , Borger Pieter , Borisov Nikolay , Gaifullin Nurshat
Published: May 2019

e13032

Background: Intracellular molecular pathways (IMPs) control all major events in the living cell. They are considered hotspots in contemporary oncology because knowledge of IMPs activation is essential for understanding mechanisms of molecular pathogenesis in oncology. Profiling IMPs requires RNA-seq data for tumors and for a collection of reference normal tissues. However, there is a shortage now in such profiles for normal tissues from healthy human donors, uniformly profiled in a single series of experiments. Access to the largest dataset of normal profiles GTEx is only partly available through the dbGaP. In TCGA database, norms are adjacent to surgically removed tumors and may be affected by tumor-linked growth factors, inflammation and altered vascularization. ENCODE datasets were for the autopsies of normal tissues, but they can’t form statistically significant reference groups. Methods: Tissue samples representing 20 organs were taken from post-mortal human healthy donors killed in road accidents no later than 36 hours after death, blood samples were taken from healthy volunteers. Gene expression was profiled in RNA-seq experiments using the same reagents, equipment and protocols. Bioinformatic algorithms for IMP analysis were developed and validated using experimental and public gene expression datasets. Results: From original sequencing data we constructed the biggest fully open reference expression database of normal human tissues including 465 profiles termed Oncobox Atlas of Normal Tissue Expression (ANTE, original data: GSE120795). We next developed a method termed Oncobox for interrogating activation of IMPs in human cancers. It includes modules of expression data harmonization and comparison and an algorithm for automatic annotation of molecular pathways. The Oncobox system enables accurate scoring of thousands molecular pathways using RNA-seq data. Oncobox pathway analysis is also applicable for quantitative proteomics and microRNA data in oncology. Conclusions: The Oncobox system can be used for a plethora of applications in cancer research including finding differentially regulated genes and IMPs, and for discovery of new pathway-related diagnostic and prognostic biomarkers.
Clinical impact of comprehensive versus targeted genomic analysis for precision oncology.
Authors: Lamping Mario , Rieke Damian Tobias , Klauschen Frederick , Jöhrens Korinna , Anagnostopoulos Ioannis , Lenze Dido , Tinhofer Inge , Benary Manuela , Ochsenreither Sebastian , Klinghammer Konrad Friedrich , Burock Susen , Jann Henning , Stüven Anna Kathrin , Ditzen Doreen , Beule Dieter , Messerschmidt Clemens , Blanc Eric , Schäfer Reinhold , Keilholz Ulrich
Published: May 2019

e13033

Background: Panel sequencing (PS) has become a standard-of-care in cancer diagnostics. More comprehensive analyses such as whole-exome (WES) or RNA sequencing (RNAseq) allow for the detection of rare and unknown genetic aberrations that are not covered by predefined assays. The clinical impact of targeted versus comprehensive genomic assays were analyzed in patients presented at the Charité Molecular Tumor Board (MTB). Methods: Patients (pts) with advanced and/or metastatic cancer for whom no standard therapy was available were discussed in the MTB to allocate diagnostic profiling and guide biomarker-based treatment (BBT). Pts had to be < 50 years of age or diagnosed with a rare tumor entity to undergo WES/RNAseq, performed on fresh tissue. If ineligible, standard PS was performed on archival tissue. BBT recommendations, ranked by pre-specified evidence levels, were made by the MTB and pts were followed up. Results: 228 patients (median age 49 years, 108 female and 120 male) were discussed in the MTB between January 2016 and February 2019. We assigned 73 and 155 pts to PS and WES/RNAseq and results were obtained for 78.1% (n = 57/73) and 54.8% (n = 85/155) pts, respectively. Sequencing failed for 11 (PS; 15.1%) and 62 (WES/RNAseq; 40%) pts, most commonly due to insufficient tissue (n = 29). Sequencing was ongoing in 5 (PS) and 8 (WES/RNAseq) pts at the time of analysis. A median of 2 BBTs were recommended for 75.4% (43/57) of PS (range r: 1-3) and 90.6% (77/85) of WES/RNAseq pts (r: 1-6) each. 22% (n = 17/77) of WES/RNAseq pts had ≥4 BBTs made by the MTB. Treatment was initiated in 30.2% (n = 13/43) of PS and 40.2% (n = 31/77) of WES/RNAseq pts. Clinical benefit rates (CBRs) were 23.1% (2 PR, 1 SD) for PS and 45.2% (2 CR, 3 PR, 9 SD) for WES/RNAseq pts. Overall survival data was immature at the time of analysis. Conclusions: Utilizing WES/RNAseq is a feasible approach to perform tumor profiling in a heterogeneous cohort. We here show a higher rate of pts receiving confident evidence-based treatment recommendations in the WES/RNAseq group and a higher rate of treatment initiation. The CBR nearly doubled in the WES/RNAseq cohort when compared to standard PS pts, thus emphasizing the need for larger comparative analyses to guide diagnostic decision-making.
Diagnostic accuracy of the Videssa protein-based liquid biopsy for breast cancer in suspicious mammography.
Authors: Chen Cynthia , Poole Lisa , Sizer Lina , Carter W. Bradford , Frazier Thomas G.
Published: May 2019

e13034

Background: The Videssa protein-based blood test (Provista Diagnostics) is a combined proteomic biomarker assay that aims to detect established breast cancer – rendering it useful in patients with abnormal or difficult-to-interpret mammograms. Since the incidence of malignancy for BI-RADS 4 biopsies is approximately 20%, a significant percentage of patients undergo needle biopsy unnecessarily. The Videssa assay provides an alternative diagnostic method by way of a non-invasive liquid biopsy. Methods: Our goal was to assess whether this liquid biopsy combined with 3D tomographraphic mammography could accurately predict disease status to reduce the amount of unnecessary tissue biopsies. An IRB-approved, prospective, single-arm study had patients with BI-RADS4 lesions with calcifications requiring tissue biopsy undergo the blood test prior to stereotactic core biopsy. Subsequent results and biopsy pathology were correlated. Results: 46 patients were initially entered with BI-RADS4 calcifications. 9 patients had DCIS (19.6%) and 37 patients had benign calcifications (80.4%). No patient had invasive cancer. Liquid biopsy results were elevated in 2 patients with DCIS (22% sensitivity) and in 5 patients with benign biopsies (10.8%). At interim analysis, the liquid biopsy demonstrated a 28.5% positive predictive value (PPV) and 82% negative predictive value (NPV). Tumor grade did not affect results. We subsequently discontinued using the blood test for BI-RADS4 calcifications and enrolled 13 patients with non-palpable solid lesions to determine the correlation. The liquid biopsy was elevated in 1 of 4 patients with invasive cancer (25% sensitivity) and was not elevated in all 9 patients with benign biopsies (100% NPV). At one-year follow-up, 3 of the 5 patients with an elevated blood assay and negative biopsy have had no incidence of cancer on subsequent imaging. The remaining 2 patients are scheduled for follow-up. Conclusions: In our study, the NPV of the Videssa liquid biopsy is not robust enough to defer tissue biopsy in any patient with indeterminate calcifications on imaging, nor is it specific enough to help predict results in high risk solid lesions. We do not see this liquid biopsy changing our current practice.
Low likelihood that potential germline findings identified during somatic tumor testing are evaluated: Room for improvement.
Authors: Wright Heather , Melissa Cuke , Folefac Edmund , Verschraegen Claire F. , Wood Marie
Published: May 2019

e13037

Background: Genomic testing, useful for treatment planning, may indicate the presence of a germline mutation. We evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of follow-up referrals for genetic counseling and germline testing among patients with potential germline mutations. Methods: This was a retrospective chart review of patients who underwent genomic testing at The University of Vermont Cancer Center (UVMCC). Test reports were reviewed for mutations in 24 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Medical record review was performed to identify patients referred for genetic counseling and results of germline testing. Results: Between 8/2009 and 9/2016 157 patients underwent genomic testing at UVMCC. Eighty-one percent (127/157) had a mutation in ≥ 1 gene associated with hereditary cancer (range 0-4 mutations per patient), and 46% (73/157) had mutations in more than one gene. Potential germline mutations were most commonly identified in TP53, CDKN2A, RB1, PTEN, STK11 and APC (each with mutations in > 10% of patients). To date only 12% (15/127) of patients with potential germline mutations have been referred for genetic counseling. Two were referred for evaluation of findings seen on genomic testing others being referred for personal or family history of cancer. The majority (11/15) of referred patients have undergone genetic testing with 27% (3/11) having germline mutations identified; 2/3 of which were also identified on genomic testing. Conclusions: Genomic testing can be an important tool for identifying hereditary cancer syndromes. While the majority (81%) of patient’s undergoing genomic testing had mutations genes associated with hereditary cancer, the low rate of referral (12%) for genetic counseling to determine if these are truly germline represents a significant missed opportunity. Identification of germline mutations has implications for both the patient (for treatment and risk of second cancers) and their family. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.
Implementation of HPV vaccination pilot project in Kazakhstan: Successes and challenges.
Authors: Kaidarova Dilyara , Chingissova Zhanna , Dushimova Zaure , Kukubassov Yerlan , Zhylkaidarova Alma , Sadykova Tolkyn , Bolatbekova Raikhan
Published: May 2019

e13056

Background: Cervical cancer (CC) is the second most frequent cancer of women after breast cancer. Prophylactic vaccines for human papillomavirus (HPV) are being introduced in many countries more than 10 years ago. The standardized incidence of СС in Kazakhstan (KZ) in 2017 was 17.1 per 100,000 women. From 2013 to 2016, there was a pilot project of school-based HPV vaccination of adolescent girls in four districts of KZ. Vaccination was carried out with two vaccines (Gardasil and Cervarix) on the choice of parents in a three-dose regimen. Due to the high rejection of vaccination, this program was completed in 2016. Aim of study was to analyze the results of HPV vaccination in KZ. Methods: The results of vaccination of adolescent girls from 9 to 15 years old were evaluated. We analyzed database registry of Kazakhstani vaccinated girls to evaluate vaccine coverage in four district of KZ. Results: A total 11,648 adolescent girls were fully vaccinated during the pilot program for 2013-2016. The average age of the vaccinated is 12.67 ± 1.04. In 2013, immunization was performed for 1,816 girls aged 11–13 years. In 2014, the age range of the target group was expanded to 15 years. The number of vaccinated girls increased to 5,699 adolescent girls. 7,136 girls were fully vaccinated in 2015. 10,004 girls have not received full doses of vaccine. Overall coverage rates of fully vaccinated were 14.8%. The majority of coverage results was stastically similar except for Almaty, where coverage was higher than the average coverage (17.9% vs. 14.8%, p < 0.05). Conclusions: Pilot project of vaccination in Kazakhstan was declared unsuccessful. This situation is associated with a lack of information campaigns on vaccination. This findings highlights the need for phased implementation of vaccination through an educational campaign of parents.
Primary prevention and smoking habit among BRCA1/2 mutation carriers.
Authors: Cordeiro Patricia , Lesta Rocio , Gómez-Randulfe Igor , Reboredo Rendo Cristina , Molina Díaz Aurea , Quindós Varela Maria , Antolín Novoa Silvia , Pérez López María Eva , Calvo Martínez Lourdes , Lopez Cortabitarte Belen , Prato Javier , Suárez Vanessa , Mosquera Martínez Joaquín , Rodríguez Sánchez Berta , Rodríguez Pedreira Montserrat , Czestokowa Carlota , Bouzón Alberto , Albaina Latorre Luis , Cereijo Garea Carmen , Graña-Suárez Begoña
Published: May 2019

e13061

Background: Smoking is the leading cause of avoidable death in the world. Although controversial for years, current prospective studies suggest that smoking increases the risk of cancer in women with a deleterious BRCA1/2 mutation. Actually, we have very limited information about tobacco habit among BRCA1/2 carriers. Methods: We report an observational retrospective study of a consecutive sample of 198 BRCA1/2 carriers studied between April 2014 and March 2018 at the Family Cancer Clinic of the University Hospital of Coruña (NW-Spain). The main objective of the study is to know the prevalence of smoking in BRCA1/2 women, and to determine if carriers undergoing risk-reducing surgeries (RRS) abandon their tobacco habit as part of the primary prevention strategy. Results: The sample includes 136 patients affected by cancer (84% breast, 19% ovary) and 62 healthy women. During their follow-up [Median = 22, (1-43) months], 85 carriers underwent RRS (29% mammary, 54% prophylactic salpingo-oophorectomy, 16% both). At first visit, 46 were active smokers, 47 ex-smokers, 77 non-smokers and 28 did not specify their habit. The percentage of smokers and never smokers is similar between sick and healthy BRCA1/2 carriers, presenting a greater proportion of former smokers among those affected of cancer (30% vs. 23%), and of active smokers among healthy women (35% vs. 23%) [p > 0.5)]. Moreover, 23% of BRCA1/2 carriers are active smokers despite a previous diagnosis of cancer. RRS are not associated to a greater tobacco cessation, persisting in the habit 18% of the women that underwent any preventive surgery (p > 0.5). Conclusions: Smoking habit is high (55%) among BRCA1/2 carriers followed at our family cancer clinic. At least 23% of our BRCA1/2 positive women are active smokers despite a previous diagnosis of cancer.The performance of aggressive RRS is not associated with greater abandonment of tobacco in carriers, persisting in the smoking habit 18% of operated women.It is essential to improve anti-tobacco strategies in family cancer consultations if we want to be efficient in the management of high-risk cancer individuals.
Assessment of breast cancer risk in BRCA carriers with ovarian cancer: Evaluation of data from longitudinal observation.
Authors: Safra Tamar , Waissengrin Barliz , Gerber Deanna , Bernstein Molho Rinat , Amit Amnon , Salman Lina , Josephy Dana , Chen-Shtoyerman Rakefet , Bruchim Ilan , Frey Melissa Kristen , Pothuri Bhavana , Muggia Franco
Published: May 2019

e13062

Background: To confirm data from older studies reporting reduced risks of breast cancer (BC) in BRCA mutated (BRCA+) ovarian cancer (OC) patients and to re-evaluate BC surveillance and/or prophylactic mastectomy in OC patients. Methods: Data on 430 BRCA+ mutation carriers diagnosed with OC between 2000 and 2017 in 6 medical centers (one in the USA and five in Israel) were analyzed. Data included demographics, breast surveillance type, family history, BRCA mutation types, timing of BC diagnosis (before or after OC diagnosis) and family history of cancer. Results: Median age at diagnosis of OC was 55.4 years (range, 31.3-90) and median follow-up was 4.6 years. Most patients were BRCA1 (66.6%), and 35.7% had 185delAG. Most patients (68.4%) were Ashkenazi Jews, 27.4% had a family history of BC and 16.5% were diagnosed with BC before OC. Five percent developed BC following OC diagnosis with a median time to BC diagnosis of 68 months (range, 11-210). Of those diagnosed with BC, 50% had triple-negative BC, 40% had luminal B ER+, PR-, Her2-neg and 10% had luminal A -ER+, PR+, her2-neg. There was a non-significant increase in BC after OC, and in BC prior to OC diagnosis; there was no correlation of BC with family history. No definite deaths from BC were recorded. Conclusions: The incidence of BC after OC diagnosis in the BRCA+ population at a median follow-up of 4.6 years is consistent with prior series. Prophylactic bilateral Surveillance measures should be re-evaluated in this population and may only be needed in long-term disease-free survivors and/or subpopulations to be identified. Clinical trial information: 07-146.
HPV test self collection versus CO-testing (2015-2018): New experience in a screening program in a northern province of Argentina, Tucumán.
Authors: Zarba Juan Jose , Holgado Silvia Victoria , Cinto Conrado Oscar , Ali Veronica , Arrieta Maria Fernanda , Gonzalez Adriana Beatriz , Abete Claudia Veronica
Published: May 2019

e13063

Background: The benefits of population screening under the program in women at risk of uterine cervical cancer both methodsof detection, the search of lesions by gynecological cytology or the search for infection by oncogenic virus of the VPH family is widely demonstrated. Each of them has considerations to favor and others against. In Tucuman the two are applied since December 2014. Objective:to analyze partial results of the first stage of application of two methods under population screening program in women at risk of cervical cancer in Tucumán, Argentina. Methods: We analized the period December 2014 December 2018 of the files of the national register (SITAM: Sistema de Información de tamizaje- It is an on-line information system that allows the nominalized registration of women who access studies, diagnoses and treatments for the prevention of cervical cancer).49337samples from non-pregnant, aged 30 and older women without health insurance were included. 2 collection methods were applied: "Co-testing" (CT), cytological for PAP test and biological sampling for HPV Test ((T-HPV) and "Self-collected sampling" (SC) biological material for T-HPV. In cytology, Pap smear were stained with Papanicolaou and for the biological material, T-HPV Hybrid Capture was applied to detect 13 oncogenic HPV types. Bethesda System was used for cytological diagnosis. Results: until 2019 January, 49337 samples were processed, 7352 (14,8%) womenhave HPV oncogenic. Conclusions: the application of T-HPV to SC samples showed a interesting positivity,demonstrating once again T-HPV is an important strategy in the cervical cáncer prevention program.[Table: see text]
Demographic characteristics of smoldering multiple myeloma patients: A hospital-based study including 11,643 patients.
Authors: Chamoun Kamal , Kyasaram Ravi Kumar , Metheny Leland L. , Gallogly Molly , Caimi Paolo Fabrizio , Gerson Stanton L. , De Lima Marcos J.G. , Malek Ehsan
Published: May 2019

e13064

Background: SMM is the requisite asymptomatic phase that precedes Multiple Myeloma (MM). Observation until progression to MM has been the standard of care. However, the improvement in risk assessment and utility of chemoprevention strategies stemmed from large trials (e.g. QUIREDEX and E3A06) is beginning to shift the paradigm toward early detection of SMM by implementing screening strategies (e.g., PROMIS study). Lack of specific ICD code for SMM has been a major problem in epidemiologic studies aiming at characterizing the demographics and temporal dynamics of SMM. Here, we used the National Cancer Data Base (NCDB), which covers more than 70% of cancer pts in the USA, for this purpose. Methods: NCDB data from year 2010 to 2014 was analyzed. We defined SMM as pts with ICD-O 9732 that were placed on active surveillance or did not receive any therapy in the first 3 months (m) after diagnosis (Ravindran et al. Blood Cancer J. 2016). Institution size was categorized as small, medium and large if they reported < 10, 10-50, and > 50 cases per year, respectively. Results: Out of a total of 68234 MM pts, we identified 11643 (17%) with SMM. Median follow up was 32 m (0 - 85). Median age was 65 years (26 - 90), 52% were males, 71% were white and 24% were black. Median survival was 77.7 and 49.8 m for pts with SMM and MM, respectively ( p= 0.001). Median age at diagnosis of SMM was 62 and 66 years in blacks and whites, respectively ( p= 0.01). Over 87% of pts were diagnosed in small and medium size institutions (38% and 49%, respectively). Medicare was the main insurance payer (57%), followed by private insurance (32%) and Medicaid (5%), and 3% were not insured. The majority of pts (59.5%) lived in areas where the median income is less than $46K/year. Median distance traveled to treatment facility was 8.5 miles. During the first two years from diagnosis 18% needed treatment which is compatible with known estimated 10% per year risk of progression from SMM to MM. Conclusions: This large study of over 11,000 SMM pts highlights the national demographics of SMM diagnosed between years 2010 and 2014. Our results indicate that targeting small and medium size facilities should be an essential part of SMM screening strategies.
Protamine sulfate may prevent infections by pathogens that require heparan sulfate proteoglycan interactions, including high- and low-risk Human Papillomaviruses and Chlamydia trachomatis..
Authors: Gomez Ricardo , Young Jesse , Ozbun Michelle
Published: May 2019

e13065

Background: Human papillomaviruses (HPVs) are the most common pathogens of the reproductive tract with 80% of the population acquiring an infection at least once in their lifetime. Globally, high-risk (oncogenic) HPVs cause 630,000 new cancer cases per year and are responsible for 99% of cervical cancers. Regardless of available screening and preventive measures, cervical cancer is the fourth most common malignancy in women worldwide causing more than 445,000 new cases and 270,000 deaths annually. Like many pathogens of the reproductive tract, initiation of HPV infections require attachment to negatively-charged heparan sulfate proteoglycans (HSPG) present in the extracellular matrix and plasma membrane of host cells. To better define the role of HSPGs in HPV infections, we used protamine sulfate (PrS), a polycationic peptide that is FDA approved to neutralize heparin. Structural similarities between HSPGs and heparin allow PrS to bind HSPGs preventing HPV-HSPG interactions and infection. In order to further evaluate proof of concept for PrS we expanded our investigation to Chlamydia trachomatis, another genital tract pathogen whose mechanism of infection has been reported to rely on HSPGs. Methods: High and low risk HPV viruses were used in prophylactic and post exposure cell-based assays and a preclinical prophylactic mouse vaginal challenge model to evaluate the effects of PrS on infection. Chlamydia trachomatis serovar L2 was also used in prophylactic cell-based assays to evaluate the effects of PrS on infection. Results: A single dose prophylactic application of PrS reduced infection by high- and low-risk HPV genotypes by up to 95% in vitro (p-value < 0.001) in a dose response manner and 60% in vivo (p-value 0.05). In addition, post-HPV exposure PrS treatment significantly decreased infection. PrS showed the greatest effectiveness in the first two hours after HPV exposure. In line with our data on HPV, Chlamydia trachomatis infection showed a statistically significant decrease in cells pretreated with PrS (p-value 0.05). Conclusions: Inhibition of attachment by PrS presents a unique opportunity to provide a new cheap prophylactic modality for HPV infection, which would reduce cervical cancer global burden.
Data from an integrated cancer prevention center screening for multiple cancer types.
Authors: Bernstein Ezra , Isakov Ofer , Galazan Lior , Leshno Ari , Shaked Meital , Liberman Eliezer , Gur Eyal , Elran Hanoch , Sror Miri , Harlap-Gat Amira , Kleinman Shlomi , Steiner Moran , Aviram Galit , Blachar Arye , Kessler Ada , Golan Orit , Shapira Shiran , Geva Ravit , Wolf Ido , Arber Nadir
Published: May 2019

e13069

Background: Cancer is the second leading cause of death globally, and was responsible for ~9.6 million deaths in 2018. Importantly, between 30–50% of cancers can be prevented by avoiding risk factors and implementing existing evidence-based prevention strategies. Methods: We present the results of 15758 adults who came to our clinic between 2006 and 2018. Patients were counseled on reducing risk factors and screened for early detection of 11 of the most common cancer types. Patients were examined by specialists in internal medicine, surgery, plastic surgery, OBGYN, urology, oncology, oral surgery, gastroenterology, and others. Women underwent vaginal US, pap smear, mammography (40yr) and US/MRI of the breast with a clinical indication. Men underwent PSA/free PSA ( > 40yr). LDCT for moderate smokers. Colonoscopy was recommended to all subjects ( > 40yr). Results: A total of 7900 (50.1%) men and 7857 women (49.9%) mean age 46.9±11.3 years were screened. A total of 418 (2.7%) malignant lesions were detected in patients who had been screened, 245 (1.6%) of which were detected through our screening: skin 66 (0.4%), prostate 30 (0.2%), thyroid 28 (0.2%), breast 28 (0.2%), colorectal 19 (0.1%), urinary 13 (0.08%), lung 11 (0.07%), cervical 11 (0.07%), other/unknown 9 (0.06%), hematologic 8 (0.05%), ovarian 5 (0.03%), uterine 5 (0.03%), pancreas 3 (0.02%), testicular 3 (0.02%), oropharyngeal 2 (0.01%), hepatobiliary 2 (0.01%), stomach 1 (0.01%), larynx 1 (0.01%). A total of 17 (0.1%) malignant lesions were missed: breast 3 (0.02%), colorectal 3 (0.02%), skin 2 (0.01%), thyroid 2 (0.01%), hematologic 2 (0.01%), pancreas 2 (0.01%), kidney 1 (0.01%), lung 1 (0.01%), brain 1 (0.01%). A total of 147 (0.9%) malignant lesions developed > 1year after a visit. Only forty-nine of the cancer patients (12.5%) died after 18.9±17.8 months at a mean age of 66.5±12.2 years. Significantly, better than the expected cancer mortality in general. First-degree family member with cancer (HR = 1.46) and advanced age (HR = 21.8) was associated with increased cancer risk (P < 0.05). Conclusions: One stop shop cancer screening, in the setting of a multidisciplinary outpatient clinic is feasible, can detect cancer at an early stage, and can significantly improve survival.
Risk of colonic adenoma in patients with non–colorectal cancers.
Authors: Abu-Sbeih Hamzah , Ali Faisal , Qiao Wei , Lum Phillip , Shafi Mehnaz , Bresalier Robert , Hawk Ernest , Gottumukkala Raju S. , Wang Yinghong
Published: May 2019

e13070

Background: In the last two decades, the incidence of colorectal cancer (CRC) has decreased dramatically after the implementation of CRC screening in the United States. Several risk factors for colonic adenoma (CA), the main precursor for CRC, have been found. Whether personal history of non-colorectal cancer (NCRC) is a risk factor for CA has not been studied. Here, we assess the risk of CA in patients with NCRCs. Methods: We conducted a retrospective study of cancer patients who underwent colonoscopy after cancer diagnosis between 2009 and 2018. We included patients without history of NCRC as a control group. Multivariate logistic regression was used to assess independent risk factors for CA (Table 1). Results: Total of 9408 patients with NCRC were included; CA was detected in 4503 (48%). Histology revealed tubulovillous features in 611 (14%) patients and villous in 51 (1%). High grade dysplasia was detected in 1,317 (29%) patients and adenocarcinoma in 388 (9%). The rate of adenocarcinoma was the highest in patients with multiple myeloma (14%). Adenoma detection rate (ADR) was 30% in patients younger than 40 years ( n= 1621), 32% in patients between 40 and 50 years ( n= 812), 47% in patients between 50 and 60 years ( n= 2892), and 55% in patients older than 60 years ( n= 4493). Multivariate analysis revealed an increased risk of CA with old age, male sex, family history of CRC, and high body mass index ( P< 0.05). The median time from NCRC diagnosis to CA detection was 3 years (IQR 1-8). Conclusions: ADR in patients with a personal history of NCRC is higher than the ADR of patients without NCRC. CRC screening should be performed after the diagnosis of NCRC is made, even if it was before the standard threshold of CRC screening age of 50 years.[Table: see text]
Development of a plasma cell-free DNA chromosome instabilities assay for early cancer detection and treatment response monitoring of multiple tumor types.
Authors: Yang Yang , Yin Wei , Li Nan , Xu Wensheng , Ma Fei , Chen Xiaosong , Cao Wen-Ming , Yan Wangjun , Wang Jiandong , Nai Dongxing , Qin Chenjie , Ziliang Qian
Published: May 2019

e13072

Background: Tumor cells keep shedding DNA into blood stream. Here we present a retrospective study to investigate the potential of CIN in plasma cell-free DNA (cfDNA) as a minimal-invasive biomarker for early cancer detection and cancer treatment responses monitoring. Methods: To characterization cfDNA CIN, 160 plasma samples from non-cancer individuals and 569 from cancer patients, including tumors from the brain, respiratory tract, gastrointestinal tract, urinary tract, liver, gallbladder, female reproductive system, prostate, breast and sarcoma. cfDNA was extracted and sent to low-coverage whole genome sequencing by the Illumina X10, followed by CIN analyses by a customized workflow Ultrasensitive Chromosomal Instability Detector (UCAD). Results: In non-cancer individuals, increased CIN in cfDNA was found associated with active EBV infections(P<0.01) and HBV infection (P=0.042). No statistical significances were found for the other parameters, including age, hypertension, diabetes, chronic kidney diseases, family history of cancer and etc. cfDNA CIN increased along with the development of lung cancer lesions, from adenocarcinoma in-situ, minimal invasive adenocarcinoma, invasive adenocarcinoma (P=0.034) to relapsed cancer (P<0.01). The sensitivity of early lung cancer detection was 30.7%, 37.5%, 45.5%, 50.0% and 98.1% for AIS, MIA, IAC, SCC and relapsed lung cancer, at a specificity of 75%. cfDNA CIN levels did not show statistical differences regarding metastases sites. cfDNA CIN were further increased in relapsed breast cancer (P<0.01). The sensitivity of relapsed breast cancer detection was 73.3%, 94.4%, 89.6% and 80.0% for HER2+, Luminal A, Luminal B and triple negative breast cancer, at a specificity of 90%. In primary liver cancer, cfDNA CIN decreased after curative therapies, including R0 resections and liver transplant. R0 resections showed similar performance as compared to liver transplant (P=0.35) in terms of cfDNA CIN decreasing. Furthermore, cfDNA CIN was higher in patients after R0 resections (P=0.003) and liver transplant (P=0.03) than that of HBV-positive cancer-free patients, indicating the potential risk of disease relapses. For advanced stage patients, continuously increasing cfDNA CIN level was found associated with worse survival, and a decreasing trend predicting better prognosis vice versa. Conclusions: Plasma cfDNA CIN analysis might be a useful tool for cancer management.
Community-based lung cancer screening program: A five-year comprehensive review.
Authors: Hakimian Ari , Joob Axel , Aversano Jennifer , Vercillo Michael , Oconnor Michael , Liu Yangyang
Published: May 2019

e13080

Background: Low-dose chest CT for lung cancer screening has been shown to have a significant impact on the early diagnosis of lung cancer. Initial trials have shown an approximate 20% decrease in overall lung cancer mortality (NLST, 2011). This study incorporates all patients who were evaluated by the Center for Thoracic Disease in a community-based lung cancer screening program from 2013 to 2018. Over the course of the study, thoracic surgeons have evaluated these patients with subsequent interval-based scans to monitor the progression of suspicious nodules. Methods: Eligibility criteria for the program included patients within the age range of 55-80, with a > 30 pack year smoking history, and that were current smokers or quit tobacco less than 15 years ago. Individuals between 50-55 years old were also included if they had > 20 pack year smoking history and at least one additional lung cancer risk factor. All patients included in this analysis completed an initial lung cancer screening consultation and recommended follow-up evaluations with thoracic surgeons from March 2013 to December 2018. All patients with suggestive abnormalities were discussed at a multidisciplinary conference prior to embarking on any invasive procedures. Patient data was collected on REDCap. Descriptive statistics for all continuous (mean ± SD) and categorical [N (%)] variables were calculated on patients. Results: 470 patients were included in the final analysis. The majority of the patients were males (56.4%), mean age was 64 years old (range: 50-81), and 55.3% were current smokers. The average smoking history was 42.3 pack years. 223 (47.6%) patients had a family history of cancer and 70 (14.5%) patients had a personal history of cancer. 25 patients (5.3%) had a diagnosis of primary lung cancer, among whom, 16 patients (64%) had early stage lung cancer (stage 1 and stage 2), 5 patients (20%) had stage 3, and 4 patients (16%) had stage 4 lung cancer. The cancer distribution included 17 adenocarcinomas (68%), 3 squamous cell carcinomas (12%), 3 small cell cancers (12%), 1 large cell cancer (4%) and 1 carcinoid tumor (4%). Conclusions: This study has demonstrated the value of enrolling patients in a community-based lung cancer screening program. Our results have reiterated the prevalence of discovering early staged lung cancer in high risk patients. This comprehensive five-year review indicates the importance of physician coordinated follow-up and evaluation in lung cancer screening patients.
Characteristics, treatment patterns, and survival from three cohorts of advanced or metastatic cancer patients using healthcare claims data in the United States.
Authors: Lamy Francois-Xavier , Beachler Daniel C , Russo Leo J , Lanes Stephan , Dinh Jade , Taylor Devon H , Yin Ruihua , Jamal-Allial Aziza , Verpillat Patrice
Published: May 2019

e13082

Background: Our main objective was to identify, in healthcare claims data, patients with advanced or metastatic: urothelial carcinoma (amUC), gastric cancer (amGC) and non-small cell lung cancer (amNSCLC) and to report on their characteristics, treatments, and survival rates using contemporaneous real-world data. Methods: This cohort study was conducted in the HealthCore Integrated Research Database (HIRD), from January 2010 to January 2018, which contains healthcare claims data from commercial health plans across the US (60 million lives). We applied algorithms, previously validated on registry data, to the HIRD to define 3 cohorts of advanced stage cancer. Cohort characteristics and treatment patterns were described. Patient vital status was captured through probabilistic linkage with the National Death Index (NDI) and survival was assessed using the Kaplan-Meier method. Results: Algorithms to predict advanced stage cancer resulted in the following cohorts: 1,501 amUC, 6,253 amGC and 38,451 amNSCLC cases. Most patients in each cohort were de novo advanced or metastatic, but subsets were diagnosed at early stage and progressed to advanced stage (ranging from 15.1% for amNSCLC to 23.1% for amUC). Patient characteristics, treatments and survival outcomes are described in Table. Not all received systemic treatment; Immune Checkpoint inhibitors (ICI) were used in 5.3%, 2.2% and 10.8% of treated amUC, amGC and amNSCLC patients, respectively. Conclusions: In these cohorts of advanced or metastatic cancer patients, median survival time was limited despite most receiving treatment: radiation, systemic therapy or surgery. Treatment with ICI was low despite recent data in amUC and amNSCLC. Characteristics, treatments, and survival from estimated advanced stage date. [Table: see text]
Association of leisure time physical activity with breast cancer risk and breast cancer sub-types in Nigerian women.
Authors: Bigman Galya , Adebamowo Sally Nneoma , Jedy-Agba Elima Enaji , Achusi Izuchukwu Benerdin , Adebamowo Clement Adebayo
Published: May 2019

e13085

Background: The association between physical activity and breast cancer has not been studied among Nigerian women and in particular by breast cancer sub-types. Therefore are studies aims are to examine the association between leisure time physical activity (LTPA) and breast cancer in Nigerian women and to examine the association between LTPA and estrogen receptor positive (ER+), triple negative breast cancer (TNBC+), Luminal A breast cancer in Nigerian women. Methods: We enrolled 739 newly diagnosed primary invasive breast cancer and 739 age-matched controls in Nigeria from 01/2014 to 07/2016. This analysis is restricted to the 40% of cases for whom we have complete ER, TNBC and Luminal-A data and their matched controls. We derived the average amount of time per week spent on LTPA over the past one year using a modified Nurses’ Health Study II PA questionnaire. LTPA was calculated from the total metabolic equivalent (METs) assigned for each reported physical activity hour/week (i.e. walking, cycling, and dancing). We examined LTPA by comparing participants who attained the WHO physical activity recommendations of at least 150 minutes of moderate-intensity or/and 75 minutes of vigorous-intensity aerobic activity weekly with those who did not. We used conditional logistic regression to estimate the adjusted Odds Ratio (OR) of LTPA and overall as well as subtypes of breast cancer. Results: The mean (SD) age of cases was 41.6 (9.1) and controls was 43.9 (11.8) years. Women who attained the WHO physical activity recommendations had 43% decreased risk of breast cancer (OR = 0.57 95% CI:0.42-0.77) compared with those who did not, after controlling for demographic, anthropometric and fertility related factors. LTPA was also associated with reduced risk of breast cancer subtypes by 41% for ER+, 59% for TNBC+ and 59% for Luminal A. Conclusions: Physical activity is associated with reduced risk of breast cancer overall and by subtypes in Nigerian women.