bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of NGS panel of hereditary breast and ovarian cancer in Lebanese women.
Authors: Al Ajami Joseph , Jalkh Nadine , Moubarak Ghadi , Eid Roland , Haddad Fady , Kattan Joseph Gergi , Ghosn Marwan , Atallah David M. , Chouery Khoury Eliane , Kourie Hampig Raphael
Published: May 2019

e13045

Background: Hereditary breast (BC) and ovarian cancer (OC) genetic alterations are considered the most prevalent among familial cancer. To date, four studies have exposed the mutations related to hereditary BC predisposition in the Lebanese population , with percentage of BRCA-related pathogenic mutations ranging between 5 % and 15 %. Methods: Between 2017 and 2019, 117 patients with high risk hereditary breast and ovarian cancer were referred to undergo the testing at the Unité de Génétique médicale (UGM) of Saint-Joseph University of Beirut, Lebanon. The sequencing was accomplished by using the 21-panel Next-Generation Sequencing (NGS) method for all of our patients, to which we also added the MLPA technique followed by the Sanger sequencing for validation whenever a genetic alteration was found. Results: From 117 Lebanese women with high-risk hereditary breast and ovarian cancer predisposition, 19 pathogenic mutations were identified in this study: 11 BRCA1, 1 BRCA2, 2 PALB2, 1 ATM, 1 CDH1, 1 MSH6, 1 RAD51C, and 1 BRIP1. Among those, 13 patients had BC, one had OC and five were healthy individuals. Five similar mutations were found within the BRCA1 gene, the p.C44F mutation, accounting for 45.4 %, thus suggesting a founder effect. Average age at diagnosis in the BC patients carrying a mutation was 41 years and 38.5% had a triple negative BC. Conclusions: The overall pathogenic mutation rate was equal to 16.2% while the BRCA deleterious mutation rate was 10.3% lower to those reported in the literature. The p.C44F mutation appeared five times suggesting a founder effect. [Table: see text]
Colorectal cancer: Improving screening in a rural clinic.
Authors: Le Thuy Thanh Thi , Johnson-wall Helen
Published: May 2019

e13054

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Between 2012-2016, the age adjusted mortality rate was 18-25 per 100,000 persons in Robeson County, North Carolina. During this timeframe, it is estimated that if all people aged 50 and older in NC were routinely screened, 40 out of 100 deaths from late stage CRC can be prevented. A chart review in a rural primary care clinic identified patients not being appropriately screened for targeted intervention. Methods: Our retrospective chart review at Lumberton Medical Clinic, a rural outpatient Internal Medicine Clinic, reviewed 1622 records from adults 50-75 years old during the timeframe September 2017 through August 2018. Patients with history of CRC or status-post colectomy for other reasons were excluded from this study. Patient records were assessed for compliance with USPTF CRC screening guidelines. USPTF recommends adults aged 50 to 75 years receive screening as follows: 1) Fecal occult blood testing (FOBT) annually 2) Flexible sigmoidoscopy every 5 years 3) Colonoscopy every 10 years OR 4) Combined FOBT (every 3 years) plus flexible sigmoidoscopy (every 5 years). Results: The review showed that during the timeframe studied, 56% of patients received appropriate screening, 44% were found with no documentation of screening, and 17% were never offered screening or informed about current guidelines. Following data analysis, intervention to increase screening rates has been initiated. This involves provider education, posters in clinic, and individualized letters mailed to patients found deficient during the study. The success of this direct patient outreach effort will be measured over six months. Conclusions: The mortality rate from CRC cancer is higher in Robeson County compared to the NC state rate. Additionally, 40% of deaths from late-stage CRC may be prevented by doing a routine screening. It is the responsibility of providers to emphasize the importance of proper screening. This retrospective review found that a large percentage (44%) of adults are not being adequately screened in our rural clinic. Direct outreach is underway to increase compliance rates in this high-risk population served by our rural clinic.
The results of colorectal cancer screening in the Republic of Kazakhstan during the period from 2013 to 2018.
Authors: Kaidarova Dilyara , Zhylkaydarova Alma , Ukolova Yelena , Jumanov Abay
Published: May 2019

e13074

Background: Colorectal cancer (CRC) remains one of the actual problems in oncology. In 2017, in the structure of oncopathology of the Republic of Kazakhstan (RK), CRC took the 3rd place in terms of incidence - 17.5, and in mortality - 8.2 per 100 thousand people. The population screening of CRC has been introduced in the Republic of Kazakhstan since 2011, among the population aged 50 to 70 years, with a survey interval every 2 years. Fecal immunochemical test (FIT) and total colonoscopy (TC) were introduced in 2013. Methods: For the period 2013 - 2018, 5133602 subjects were examined. The analysis of screening indicators was carried out: the number of positive results of FIT, completion rate of follow-up colonoscopy and CRC detection rate. The analyzed groups were divided into regions with: A - high (26 - 30.7 per 100 thousand people), B - medium (13.2-21.8), C - low (5.9 - 10.8) incidence. Results: The positive FIT for the study period was found on average, in 1.23% (62971) positive results in the Republic of Kazakhstan, in group A it was 1.50% (27675), in group B - 1.26% (17178), and in group C - 0.94% (18118). The number of TC: in group A - 76.1% (21067), in group B - 75.8% (13016), in group C was 66.7% (12080), in total - 46163 cases in the Republic of Kazakhstan, which is 73.3% of indications. During the period of study 2480 patients with colorectal cancer were identified: in group A - 0.07% (1236), in group B - 0.05% (638), in group C - 0.03% (606) people. Conclusions: For regions with different incidence rates is necessary to define performance indicators to improve the quality assurance in CRC screening.
Features of adolescent and young adult cancer patients in Japan.
Authors: Suzuki Hideo , Aida Yuka , Fukushima Hiroko , Bando Hiroko , Hashimoto Sachie , Ishikawa Eiichi , Muroi Ai , Satoh Toyomi , Shikama Ayumi , Sekine Ikuo
Published: May 2019

e13081

Background: The number of deaths because of cancer among adolescent and young adults (AYAs) in Japan is about 2,300 per year, which accounts for 17.3% of all deaths in these populations. This study aimed to investigate the clinicopathological features of AYA cancer patients. Methods: Patients registered to the Ibaraki Cancer Registry from our hospital between 2007 and 2017 were included in this study. The proportion of patients by cancer types were calculated by age groups and gender. Results: There were 27281 cancer patients in the registry, among whom, 1972 patients (7.2%) were aged between 15 and 39 years (AYA group) and 2445 were aged between 64 and 66 years (reference group). Female patients were the majority (68.2%) in the AYA group, whereas male patients were the majority (59.7%) in the reference group. Among male patients, central nervous system (22.3%) and germ cell (22.3%) tumors were the most common types in the AYA group, whereas prostate (14.7%) and lung (11.3%) cancers were the dominant ones in the reference group. Among female patients, cervical (35.8%) and breast (14.5%) cancers were the top two cancer types in the AYA group, whereas breast (19.3%) and lung (8.2%) cancers were the dominant ones in the reference group. The proportion of cancer types by 5-year age bands showed three distinctive patterns that could be associated with their etiology. Pattern 1 included central nervous system neoplasm, ovarian cancer, hematopoietic malignancy, bone sarcoma, soft tissue sarcoma, and germ cell tumor, in which the proportion peaked in teenage year group and gradually decreased in the older age groups. Pattern 2 included thyroid, breast, cervix, and uterine cancers, as well as malignant melanoma and lymphoma, which peaked in the twenties and thirties. The other cancer types belonged to pattern 3, in which the proportion increased with age and peaked in the sixties. Conclusions: Cancers in AYAs had a distinctive pattern compared to that in older age patients. The proportion of each cancer by age groups showed three different patterns.
Geographic variation in the incidence of marginal zone lymphoma (MZL) subtypes and infectious risk factors.
Authors: Di Mengyang , Olszewski Adam J.
Published: May 2019

e13094

Background: Helicobacter pylori is a known etiologic factor for gastric MZL, but data for infectious etiology in other MZL subtypes are controversial. Proposed hypothetical factors include Borrelia burgdorferi for cutaneous MZL (cMZL), Campylobacter (Cmp) for intestinal MZL (iMZL), and hepatitis C (HCV) for splenic (SMZL) or nodal MZL (NMZL). We explored geographic variation in the incidence rate (IR) of MZL and reportable infections in the United States (US) to examine these hypotheses. Methods: Using the National Program of Cancer Registries, we calculated age-adjusted IR (per 100 000 person-years) of MZL subtypes for each US state in 2001-2015. We linked them to the 2010 US census data, data on IR (per 10 000) of Lyme disease (2001-2015) and Cmp infections (2016) from the Center for Disease Control, and to published estimates of HCV prevalence (2013-2016). We examined the hypotheses in multivariable Poisson models adjusting for median age, proportion of men, Black or Asian individuals in each state, reporting adjusted IR ratios (IRR) with 95% confidence intervals (CI). Results: The study included 5,085 cases of cMZL, 3,948 of iMZL, 26,648 of NMZL, and 12,184 of SMZL. Across the US, IR varied between 0.02 and 0.22 for cMZL, 0.04-0.12 for iMZL, 0.33-0.91 for NMZL, and 0.12-0.47 for SMZL. For all subtypes, IR was highest in the Northeast, and lowest in the South ( P<.0001), consistent with general lymphoma epidemiology. However, the IRR for South relative to Northeast was significantly lower for cMZL (0.42; CI, 0.38-0.45) than iMZL (0.65), NMZL (0.65), SMZL (0.67), or aggregate MZL (0.65; CI, 0.64-0.66). In adjusted models, IR of Lyme disease was significantly associated with increased IR of cMZL (IRR=1.11; CI, 1.07-1.16), and Cmp infection was associated with iMZL (IRR=1.19; CI, 1.02-1.38). In contrast, HCV, prevalent in the South, was inversely associated with all MZL subtypes. Conclusions: These results support the putative association between cMZL and Lyme disease, and between iMZL and Cmp infection. Conversely, lack of positive association between any MZL subtype and HCV suggests that it is not a major pathogenic factor in the US. These ecological results do not rule out associations at the individual level, which will require further research.
Metformin, aspirin and statin and risk of cancer: A population-based study in Thailand.
Authors: Oranratnachai Songporn , Phetchoo Piyaporn , Rattanasiri Sasivimol , Thakkinstian Ammarin , Lukerak Somthawin , Vathesatogkit Prin , Sritara Piyamitr , Sirachainan Ekaphop , Reungwetwatttana Thanyanan
Published: May 2019

e13095

Background: : There were the conflicted results of the association of ASA, metformin or statin and risk of cancer in the previous studies. This is a population-based study in Thai population which aims to investigate the association between these drugs and the risk of cancer. Methods: A population-based retrospective study was done in Electricity Generating Authority of Thailand (EGAT) 1 and 2 databases which have been contained the 27-year and 15-year follow-up time, respectively. This database composed of the clinical characteristics, onset of cancer, and history of interested drugs from the questionnaire, together with the laboratory result from January 2002 to December 2015. We adjusted for age, sex, BMI, smoking and alcohol consumption. The incidence rate ratio (IRR) was estimated for the association between incidence of cancer and interested drugs. Results: Among 2508 and 2731 participants in EGAT1 and 2 respectively, the incidence of cancer was 8.3% in EGAT 1 and 3.5% in EGAT 2. From univariate analysis, use of interested drugs was significant associated with increased risk of cancer with IRR 1.74 ( P< 0.001) for ASA, IRR 1.54 ( P= 0.043) for metformin and IRR 1.64 ( P= 0.001) for statin. In multivariate analysis, only ASA showed significant increasing risk of cancer with IRR 1.47 ( P= 0.021). There was a trend increasing risk of cancer for metformin and statin users but not significant. Older age, low BMI, and female significantly associated with higher risk of cancer. In sub-group analysis, age and alcohol were significantly increased risk of GI cancer, while ASA use showed a non-significant trend of increasing risk of GI cancer. HBV infection was a strongly risk factor for hepatobiliary cancer and statin use had a trend lowering risk of this cancer but it was not statistically significant. Metformin also showed a non-significant trend of increasing risk of thoracic cancer. Conclusions: ASA use significantly associated with increasing risk of cancer but metformin and statin showed a trend of higher risk of cancer. These drugs may associate with cancer metabolome pathway which maybe an important role of carcinogenesis. However, ASA, metformin or statin use and risk of cancer is needed to confirm in the longer follow-up and larger cohort.
Interim analysis of the data of non-interventional study to determine the prevalence of EGFR mutations in advanced NSCLC Russian patients (ORTUS).
Authors: Laktionov Konstantin K. , Demidova Irina , Ageev Aleksandr , Breder Valeriy Vladimirovich , Grigoriev Pavel , Gordiev Marat , Gurina Liudmila , Ivanova Evgenia , Imianitov Evgenii , Kekeeva Tatiana , Kozlov Vadim , Prikhod'ko Viktor , Ragulin Yury , Sakaeva Dina , Statsenko Galina , Filippov Aleksandr , Filipenko Maxim , Khaylenko Viktor , Andreev Sergei , Karaseva Vera
Published: May 2019

e13109

Background: There is a little information of correlation between EGFRm rate in cytology and plasma samples in Russian NSCLC population. The interim analysis of the study aimed to evaluate the prevalence and types of EGFR mutations in paired cytology and plasma samples in treatment-naive patients with advanced NSCLC. Methods: ORTUS is a multicenter, non-interventional, prospective study to determine EGFR mutations rate in treatmentnaive Russian patients with advanced NSCLC. ClinicalTrials.gov identifier: NCT02321046. The study enrolled 426 patients in stage IIIB / IV of NSCLC. Interim analysis covered the data of 214 cytology verified patients (mean age - 62.6 (range 32-86) years, 58,4% of men) with EGFRm test results in paired cytology and ctDNA samples. 99.5% cases were adenocarcinoma. The proportion of non-smokers/smokers/exsmokers was 46.3%/36%/17.8% respectively. Stage IV disease was in 81% of cases; 84.1% of patients had symptoms. DNA isolation performed using QIAamp DNA FFPE Tissue Kit for cytology and Qiagen Circulating Nucleic Acid Kit for ctDNA according to the manufacturer’s instructions. EGFR gene mutations were analyzed using THerascreen RGQ EGFR PCR Kit in cytology samples and RGQ Plasma EGFR PCR kit in plasma (Qiagen). Results: EGFRm was identified in 17,8% cytology samples (38/214) that is close to 20,2% (1759/8716) in Russian tissue EGFRm study (Imyanitov et al., 2016). 10,3% of paired ctDNA samples were EGFRm positive. Sensitivity and specificity for ctDNA were 42.1%, and 97.1% respectively. The EGFRm rate was 3,9% and 2,6% in smokers, 5,3% and 0% in ex-smokers and 33,3% and 21,2% in nonsmokers in cytology and plasma samples respectively. EGFRm rate and concordance between cytology and ctDNA are presented in a table. EGFRm in ctDNA were detected more frequently in M1a/b groups (p = 0,028). Conclusions: Cytology samples are appropriate for EGFRm testing in NSCLC patients in comparison with tumor tissue ones. High tumor burden (positive metastatic status) is an important factor for successful mutation analysis in ctDNA. [Table: see text]
A retrospective study of mortality among teenage and young adult (TYA) cancer patients in India.
Authors: Chitalkar Prakash , Punia Ankur , Punia Anushree , Yadlapalli C Deepak
Published: May 2019

e13110

Background: TYAs are a unique group struggling with cancer but also with personal transitions of life. Outcomes of cancer in this group are poorly reported as most reports either address pediatric or adult patients. We evaluated mortality among TYA cancer retrospectively to better understand their journey with cancer. Methods: Teenage and Young adults (15 – 29 years) , from four institutes were included in the retrospective study for the year 2017. Eight hundred and seven of 1310 patients with cancer diagnoses or caregivers were telephonically contacted, in a predefined questionnaire including questions on mortality. Results: Three hundred seventy-two (46.1%) of 807 TYA cancer patients died . Distance and time travel to hospital, demography and alternative medicine were a significant factor for increased mortality. Gender and the age epochs within the TYA group did not determine mortality. One hundred and sixty-two patients died while on treatment whereas 136 patients died while not on any treatment. Seventy-four patients died at disease relapse. Those who died of cancer survived for a median of 180 days (5 - 2340 days). One hundred and four patients (12.9%) died within 90 days of diagnosis.There were significantly more deaths ( 30.4%) in patients who abandoned treatment, than among patients who went on therapy ( 18.6%). ( p 0.0001). Conclusions: Mortality among TYAs with cancer in India is high and is determined largely by factors like demography and logistics.
Prevalence and clinicopathological factors of the EGFR mutation status of Vietnamese non-small cell lung cancer patients.
Authors: Mai Khoa Trong , Pham Cam Phuong , Nguyen LUNG TIEN , Vo Quynh Thi Thuy , Anh Nguyen TUAN , Binh Nguyen HUY , Hien NGO Thi Thu , Loi Nguyen Thuan , Dinh Ha Tran
Published: May 2019

e13120

Background: To determine the epidermal growth factor receptor ( EGFR) mutation status in non-small cell lung cancer (NSCLC) patients in Vietnamese population at Bach Mai Hospital, and relation of different variables to the frequency of EGFR mutations. Methods: The EGFR mutation status of 1451 tissue samples in NSCLC patients and correlation among different variables of age, gender, smoking habit and histology groups were evaluated. Results: A total of EGFR mutation analysis was performed, with an overall mutation rate of 40.7%. The most prevalent categories were in-frame deletions in exon 19 (57.2% of the overall mutations); followed by L858R and L861Q in exon 21 (35.7%); exon 18 (4,6%); double mutation: 2.9%; The T790M mutation in exon 20 represented approximately 2.5%; The pooled prevalence of EGFR mutation was higher in female (60.6%), non-smokers (61.1%), and patients with adenocarcinoma (42.2%). Conclusions: The prevalence of EGFR mutations of NSCLC in Vietnam is higher than that in the West, but comparably equal to that in some Asian countries. It is associated with female sex, non-smoker status, and adenocarcinoma, sample tissue type and age, but not depends on disease stage and tumor sampling.
Co-occurring genetic alterations and primary EGFR T790M mutations detected by next-generation sequencing in pre-TKI treated patients with non-small cell lung cancer.
Authors: Tang Yuan , Wei Bing , Yu Yang , Gao Yun , Che Nanying , Shi Huaiyin , Fu Shijun , Gao Min , Lin Dongmei , Ma Jie
Published: May 2019

e13128

Background: With the development of targeted drugs, there are more therapeutic options for patients with non-small cell lung cancer (NSCLC) harboring corresponding genetic alterations. However, cancers are frequently caused by alterations on multiple genes, which collaborate to promote tumor development. Methods: A total of 1353 NSCLC patients from five different clinical institutions were enrolled in this study. Concurrent DNA and RNA NGS analysis was performed using the Ion Ampliseq Colon and Lung Cancer gene panel v2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel using FFPE samples from surgically resected NSCLC tumors. Results: Of the 1293 mutations that were detected, 2338 variants were identified in 24 genes, while 27 of the tumor samples were identified to have co-occurring DNA mutations (including insertions, deletions and point mutations) and RNA fusion mutations. Analysis of the 975 patients with EGFR-gene mutations revealed that the incidence of dual EGFR L858R/T790M mutations were higher compared to EGFR 19del/T790M, and the MAF of T790M was lower compared to 19del in dual EGFR 19del/T790M patients. Conclusions: Even with the non-random cohort of patients in this study, the genetic alterations detected in this study had a certain degree of representation of NSCLC (especially lung adenocarcinoma) in the Chinese population. The differences in the MAF of EGFR T790M may determine different responses to TKI therapy in patients harboring dual mutations.
Use of computer algorithms in the electronic health record to identify and triage primary care patients for hereditary evaluation.
Authors: Kohlmann Wendy , Tobik Katie , Flynn Michael , Hess Rachel , Weir Charlene R , Bradshaw Richard L , Del Fiol Guilherme , Kawamoto Kensaku , Schiffman Joshua David
Published: May 2019

e13137

Background: Identifying individuals with inherited cancer susceptibility is critical for optimal cancer prevention and screening. Family history is a significant predictor of inherited risk. Algorithms to extract and analyze family histories in electronic health records (EHRs) provide an opportunity for enhanced identification. Methods: Algorithms were developed to screen existing family history information in the EHR and identify patients meeting genetic evaluation guidelines for hereditary breast, ovarian, and/or colorectal cancer. In a pilot implementation, the patients of 5 primary care physicians at 2 community clinics were screened with the algorithms. Patients for genetic counseling were notified through the patient portal or mail. Follow-up phone calls were made to non-responders. Results: The algorithms identified 40 patients meeting criteria. Fifteen (38%) scheduled an appointment, 9 (22%) declined/will think about it, and 16 (40%) did not respond and were unable to be reached by phone. To date, 9 patients completed appointments. The family history used by the algorithm was accurate in 8 of 9 cases. For one case, the EHR family history was for adoptive relatives. Six of the 9 patients had additional family history not in the EHR, including 2 patients at-risk for familial mutations in ATM and ACVRL1. Patients who responded had their last visit within the healthcare system an average of 0.25 years ago versus 1.13 years for non-responders (p = 0.0002). Conclusions: Algorithms for screening existing family history in the EHR can identify primary care patients for hereditary cancer evaluation. While this approach has a low rate of false positives, it will likely miss appropriate individuals as 78% of patients had incomplete EHR-based family history as compared to a gold-standard genetic counselor obtained pedigree. However, use of automated algorithms will allow healthcare system to begin offering genetic services to those who can be identified. Ongoing efforts include use of natural language processing to extract family history from narrative data and use of a standards-based approach for replicability across EHRs.
An optimized workflow for a fast molecular diagnosis of non-small cell lung cancer.
Authors: Wei Bing , Li Jun , Ren Pengfei , Chang Yuxi , Zhao Chengzhi , Xia Qingxin , Groen Harry J.M. , Ma Jie , Guo Yongjun
Published: May 2019

e13139

Background: Lung cancer is the most common and lethal malignancy throughout the world, in which non-small cell lung cancer (NSCLC) is the dominant subtype. To distinguish between different cell types of NSCLC, i.e. adenocarcinoma or squamous cell carcinoma, the morphologic features of cancer cells are important, as well as specific molecular markers, i.e. TTF1, p63 and p40. Genomic studies have revealed different genetic aberrations between specific subtypes of NSCLC, and distinct response to targeted therapy. Therefore, molecular testing is essential for precision diagnosis and personalized treatment. The canonical workflow from diagnosis to next generation sequencing (NGS) tests needs about two weeks. Importantly, sometimes the residue material left after diagnostic staining may not be enough for NGS tests. This means a secondary biopsy is needed, which is not patient friendly. Methods: We optimized the canonical workflow by using BIOCO, a magnetic collector attached to microtome knife holder that can collect the abandoned tissue during slicing FFPE blocks. Therefore, the material used for NGS test was collected simultaneous during slicing for pathological diagnosis. In total 123 FFPE tumor blocks from suspicious NSCLC patients were included to evaluate: 1. how long it will take from diagnosis to make treatment decision? 2. If the material collected by BIOCO is sufficient for NGS test and whether the result can be trusted. Results: 1. The BIOCO workflow only needs 7 days for the diagnosis and making therapeutic plan. 2. The BIOCO could collect enough FFPE tissue for NGS test even with HE, IHC stanning and FISH test for all the samples; however, 14 samples failed NGS test because of insufficient material left following the canonical workflow. 3. the detection sensitivity and specificity of the BIOCO method are comparable with the canonical workflow, with a consistence of 94.9%. Conclusions: Here we propose an optimized workflow by using the BIOCO collector we invented, which shortens the canonical workflow from two weeks to one week, and it fully utilizes the limited biopsy tissue for NGS testing so that the secondary biopsies are avoided.
Germline genetic testing in ovarian cancer patients: Identifying barriers to care and opportunities for improvement.
Authors: Stock Elizabeth , Cowan Matthew , Romero Iris L , Yamada Seiko Diane
Published: May 2019

e13142

Background: Despite recommendations that all patients with non-mucinous high grade epithelial ovarian cancer (EOC) undergo germline genetic testing, only 10-15% of patients nationwide are tested. The aim of this study was to determine the rate of genetic testing at a single academic institution, identify patient characteristics associated with undergoing testing and improve delivery of care by identifying barriers to testing. Methods: An IRB-approved single institution ovarian cancer database was used to identify patients with non-mucinous high grade EOC treated between 1996 and 2017. The rate of genetic testing was calculated and the referral and testing process was mapped. Patient demographics, clinical characteristics and family history was obtained from the medical record. Univariate and multivariate logistic regression was performed. Results: From 1996 to 2017, 588 patients were treated for non-mucinous EOC. Of those, 200 patients (34%) were referred for genetic counseling and 175 (30%) were tested. Younger patients were more likely to undergo testing. Fewer African Americans had genetic testing than Caucasians (18% vs 33%, p = 0.003) and patients with public insurance were less likely to undergo testing compared to those with private insurance (23% vs 34%, p = 0.005). Patients with recurrent disease were less likely to undergo testing but rates did not vary by cancer stage or histology. A family history of cancer was the most significant predictor (43% vs 11%, OR = 5.85, p < 0.001). For patients diagnosed in the past 5 years, the testing rate improved to 57.9%. When the referral and testing process was mapped, a complex internal referral system was revealed. Barriers to testing included provider awareness, additional patient visits, patient preference and insurance coverage. Conclusions: Rates of germline genetic testing for patients with ovarian cancer have increased over time as guidelines for genetic testing have evolved, however, over two thirds of patients were not tested and African Americans were less likely to be tested. These findings support increasing provider education and patient counseling, testing directly in the gyn/oncology office and consideration for instituting a Traceback program.
Combinational analysis of IDH1/IDH2 mutations, 1p/19q deletions and MGMT promoter methylation for molecular testing of glioma.
Authors: Zhang Xiaoni , Qu Hongyue , Yang Qing , Zhu Ziyang , Huang Tanxiao , Chen Shifu , Edwards Jeremy , Xu Mingyan
Published: May 2019

e13152

Background: Mutations in IDH1 and IDH2, co-deletion of 1p and 19q, and the hyper methylation of the MGMT promoter are the most reported genetic alterations in glioma tumors. Therefore, we designed a study to analyze the prevalence of these biomarkers in glioma, and the correlation of these biomarkers with diagnosis and prognosis. Methods: From September 2018 to January 2019, eighteen patients with primary glioma were prospectively enrolled. For each patient, freshly frozen tissue or FFPE samples were collected. DNA was extracted from these samples and sequenced to at least 5,000× coverage. IDH1/IDH2 mutations and 1p/19q deletions were detected from the sequencing data, whereas MGMT promoter methylation was evaluated by real-time fluorescence qPCR. Results: Of the eighteen patients, 44.4%(8/18) and 33.3%(6/18) harbored IDH1 /IDH2 mutations and 1p/19q deletions, respectively, and 72.2%(13/18) contained MGMT promoter hyper methylation. Within these patients, we found a correlation between IDH1/IDH2 mutation and 1p/19q deletion. Namely, among the 8 patients with a IDH1/IDH2 mutation, 75%(6/8) also contained a 1p/19q deletion, whereas none of the 10 patients with wide-type IDH1/IDH2 displayed the 1p/19q deletion. There was also a correlation between mutations at the loci and MGMT promoter hyper-methylation, specifically, 87.5%(7/8) of the patients with IDH1/IDH2 mutations also exhibited hyper-methylation in MGMT, whereas only hyper-methylation was observed in only 40% (4/10) of IDH1/IDH2 negative patients. Conclusions: From our preliminary result, IDH1/IDH2 mutations may be associated with 1p/19q deletion. To further verify this result, a larger, longitudinal study is ongoing at our institution.
Early non-invasive detection of stage Ia lung cancer using circulating tumor DNA methylation haplotypes (ctmDNA) in plasma.
Authors: Zhang Kun , Wang Zhoufeng , Li Zhe , Lu Jingyi , Min Jun , Gore Athurva Jayavant , Gole Jeffrey , Liu Rui , Gao Yuan , Li Weimin
Published: May 2019

e13159

Background: Lung cancer is one of the most common forms of cancer and is responsible for approximately 1.8 million deaths per year worldwide. The current 5-year survival rate for lung cancer is only 18%; however, this improves to 56% if the cancer is detected early. While low-dose CT scans have shown promise as an early detection method, only 16% of lung cancer is currently detected at an early stage. We therefore set out to develop a non-invasive blood-based screening assay to identify lung cancer at an early stage using ctmDNA (circulating tumor methylated DNA haplotypes). Methods: Blood samples were prospectively collected from two partner hospitals from 325 healthy individuals and 116 individuals diagnosed with lung nodules by low-dose CT scan in EDTA or Streck BCT tubes and immediately separated into plasma. Patients with lung nodules that appeared cancerous then underwent surgical resection, and cancer diagnosis was confirmed via pathology. Patients were matched between healthy and cancer groups by age, sex, and smoking status. Plasma samples were processed using the Singlera Genomics LUNA assay, a targeted bisulfite sequencing method which identifies methylation haplotype patterns related to early-stage lung cancer. 241 samples were used to train a classification model based on pathology results, and 200 samples were used as a test set to validate the model. Results: In the independent test set, the LUNA assay was able to show a sensitivity of 91.9% to detect early-stage lung cancer with a specificity of 93.3% in healthy patients. Even patients with stage Ia lung cancer were readily detected by the LUNA assay (sensitivity of 91.7%). Conclusions: We have shown that ctmDNA can be utilized to non-invasively screen for early-stage lung cancer with high sensitivity and specificity, paving the way for a blood-based lung cancer early screening assay.
DNA Input, sequencing depth, and maximum somatic allele frequency may affect the concordance between blood TMB and tumor TMB.
Authors: Huang Yuqing , Liu Qiang , Min Xianjun , Yang Yingshun , Pei Guotian , Wang Shuai , Wang Xiaoyu , Li Hui , Zhang Xiaoni , Qu Hongyue , Wen Mingxin , Chen Yaru , Edwards Jeremy , Chen Shifu , Wang Jun
Published: May 2019

e13163

Background: Tumor mutation burden (TMB) is recognized as a promising biomarker for PD-1/PD-L1 blockade therapy. However, a tissue biopsy is often not available, and hence a liquid biopsy using blood can be used to evaluate TMB (which is known as blood TMB). Unfortunately, the concordance of blood TMB (bTMB) and tissue TMB (tTMB) is not stable, and may be affected by the sample preparation methodology and sequencing depth. Therefore, e designed a study to explore the factors, which may significantly impact the concordance between bTMB and tTMB. Methods: From September 2018 to January 2019, 98 patients with pan-cancer were prospectively enrolled. For each patient, a tissue sample and paired plasma sample were collected. These samples were sequenced using a custom 605 cancer specificgene panel. Results: The data indicated that bTMB and tTMB were correlated, but the DNA input, sequencing depth and maximum somatic allele frequency (MSAF) might affect their concordance. The Spearman’s rank correlation (SRC) between bTMB and tTMB of 38 patients with > = 25ng cfDNA vs. 60 patients with < 25ng cfDNA was 0.77 vs. 0.15, respectively. Additionally, we explored the impact of sequencing depth and determined that the SRC (between bTMB and tTMB) of 25 patients with a sequencing depth > = 2,500x vs. 73 patients with a sequencing depth < 2,500x was 0.74 vs. 0.28, respectively. Finally, we showed that the allele frequency was critically important as well. We determined that the SRC (between bTMB and tTMB) of 50 patients with cfDNA MSAF > = 1% vs. 48 patients with cfDNA < 1% was 0.71 vs. -0.03. Conclusions: To improve concordance between bTMB and tTMB for better predicting efficacy of immunotherapy, we recommend that cfDNA input should be more than 25ng, and average effective sequencing depth should be higher than 2,500x, and the correlation hold for an allele frequency treating than 1%.
De novo malignancy in recipients of solid organ transplant from donors with intracranial cancer.
Authors: Carsky Katie , Carr Christopher , Werner Cassidy , Khadra Helmi , Hamner John Blair , Paramesh Anil S , Dumont Aaron S
Published: May 2019

e13507

Background: In 2016, 33,610 organ transplants were performed in the US. Nevertheless, there is a critical deficiency of available organs. Currently, malignant neoplasms in the donor preclude organ donation, with some exceptions, such as certain CNS tumors without metastatic disease. The literature illustrates the risk of CNS tumor transmission with organ transplantation as 0-3% in the absence of additional risk factors, but organs from fewer than 0.5% of the 13,000 patients that die of glioma annually are procured. Given the critical need, we sought to reaffirm the safety of organs from donors with intracranial cancer by examining de novo malignancy outcomes in a large dataset. Methods: We examined the UNOS database to determine whether recipients of solid organ transplant from donors with intracranial cancer were at increased risk of de novo malignancy. Included were 119,430 subjects ages 18 to 65 who underwent heart, heart and lung, intestine, kidney, kidney and pancreas, liver, lung, or pancreas transplant from 1987 to 2012 and for whom there was complete data on donor history of intracranial cancer. 2-by-2 contingency tables were used to calculate odds ratios of exposure to donors with intracranial cancer. Outcomes included five-year survival, composite development of any malignancy, and development of specific malignancies including melanoma, esophageal, stomach, small intestine, pancreas, larynx, mouth, colorectal, primary liver tumor, and metastasis to liver. A p value of ≤ 0.05 was statistically significant. Results: 718 (0.60%) organs came from donors with intracranial cancer. 437 (79.02%) recipients of organs from donors with intracranial cancer survived 5 years, versus 71,055 (77.64%) recipients of organs from donors without intracranial cancer (p = 0.47). 113 (15.74%) recipients of organs from donors with intracranial cancer developed de novo malignancy, versus 17,963 (15.13%) recipients of organs from donors without intracranial cancer (p = 0.60). Of 17 contingency analyses of development of specific malignancies, we detected only 1 statistically significant positive association, de novo colorectal cancer in recipients of solid organ transplant from donors with intracranial cancer (p = 0.048, OR = 2.56). Given the large number of analyses and marginal significance of this in a very large dataset, it is likely type I error. Conclusions: Metastasis of primary CNS tumors beyond the CNS is a rare occurrence without additional risk factors. With the current organ shortage, donors with primary CNS malignancy are ideal candidates for organ donation.
A prospective study on the circulation and central nervous system after primary central nervous system B cell lymphoma treatment with rituximab.
Authors: Lin Tongyu , Peng Chen , Liu Shu , Guo Cheng-cheng , Wang Zhao , Huang He , Fang Xiaojie , Hong Huang Ming , Ren Quanguang , Li Fangfang , Li Xue Ying , Tian Ying
Published: May 2019

e13518

Background: The use of rituximab(RTX)for the treatment of primary central nervous system lymphoma(PCNSL) is controversial, and whether the RTX permeability of the blood-brain barrier can be improved by craniotomy is unknown. Methods: ImmunocompetentPCNSL patients newly diagnosed via craniotomy or stereotactic biopsy were enrolled and received RTX (375 mg/m2, Q3w) treatment. Systemicnon-Hodgkin's B cell lymphoma (systemic-B-NHL)patients without CNS involvement served as the control group. The trough concentrations of RTX (CRTX) and CD19 levels in cerebrospinal fluid (CSF) and plasma were analyzed by ELISA and flow cytometry methods during each treatment cycle.The efficacy and adverse effects were recorded. Results: From December 2016 to February 2018, 21 PCNSL and 32 systemic-B-NHL patientswere enrolled. The CSF CRTXin the craniotomy-PCNSL group (0.2198±0.1866μg/ml) was significantly higher than those in the stereotactic-PCNSLgroup (0.0613±0.0408 μg/ml, P = 0.031) and the systemic-B-NHLgroup (0.0799±0.0614μg/ml, P = 0.046). The BBB penetrabilityof RTX in the craniotomy-PCNSL group (1.52±1.05%) was nearly four times that in the stereotactic-PCNSL group (0.41±0.19%, P = 0.048) and nearly three timesthat in the systemic-B-NHL group (0.54±0.61%, P = 0.012). No significant differences in the CRTXor BBB penetrability of RTX were observedbetween the stereotactic-PCNSL and systemic-B-NHL groups. CD19 levels in plasma fell below 0.1% in all patients before the second cycle of chemotherapy, and the time required for CSF CD19cell clearance in craniotomy-PCNSL patients tended to be reduced compared with that required by stereotactic-PCNSL patients. The CR and ORR rates of craniotomy-PCNSL patientswere 30% higher than those of stereotactic-PCNSL patients. Conclusions: The BBB penetrability of RTXand the CSF CRTXare significantly improved in PCNSL patients diagnosed via craniotomy.Rituximab could be recommended for routine use in craniotomy PCNSL patients. Clinical trial information: ChiCTR-TRC-11001687.
Proteogenomic characterization in glioblastoma multiforme.
Authors: Asif Samia , Fatima Rawish , Krc Rebecca , Bennett Joesph G. , Raza Shahzad
Published: May 2019

e13521

Background: Glioblastoma (GBM) is an aggressive primary brain tumor carrying a dismal prognosis. Understanding molecular architecture of GBM is crucial for development of successful therapies against it. In this study, we performed an integrated proteogenomic analysis to determine a more comprehensive understanding of GBM phenotype. Methods: We performed quantitative proteomics and integrative genomic analysis based on The Cancer Genome Atlas (TCGA) datasets of GBM on 17 consecutive GBM patients. We collected information on driver mutations, oncogenes, major pathway alterations, mutation burden and molecular changes at both gene and protein level as well as clinical, treatment and survival data for the entire group. Results: Significantly mutated genes include TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR alterations by DNA amplification with multiple mutation allele frequencies were seen in 5(29.4%) patients including EGFRvIII expression, L816Q EGFR missense mutation on exon 21 and EGFR fusion (FGFR3-TACC3); all three are potential therapeutic targets of novel agents including EGFRvIII-specific dendritic cell vaccine, EGFR inhibitors and FGFR inhibitors. TP53 mutation was noticed in 30% of patients. TP53 Mutations were noticed in COSMIC hot spot driver gene and accompany IDH1 and ATRX mutations suggesting transformation from low to high-grade glioma. Only 1 patient had a high mutation burden and expired 17 months after initial diagnosis. In contrast, proteomics showed significantly high(n = 9,53%) EGFR expression. 75% of GBMs were MGMT methylated, a predictive marker of response to temozolomide. Twelve of the 17 patients are still alive; median overall survival was 16.5 months. Lowest survival observed was 5 months. Conclusions: This study identifies a distinct biological process that may characterize each glioblastoma differently. Proteogenomic data effectively recognizes potential therapeutic targets of GBM such as Exon 21 missense mutation, previously reported in lung adenocarcinoma with promising response to anti-EGFR antibodies. Incorporation of Whole Genome Sequencing into clinical practice will allow identification of new treatment options for GBM.
Access to diagnostics and treatment of neuroendocrine tumors (NETs): The difference between patient perception and reality.
Authors: Leyden Simone , Kolarova Teodora , Bouvier Catherine , Caplin Martyn E. , Conroy Siobhan , Davies Philippa , Dureja Sugandha , Falconi Massimo , Ferolla Piero , Fisher George A. , Goldstein Grace , Hicks Rodney J. , Lawrence Benjamin James , Majima Yoshiyuki , Metz David C. , O'Toole Dermot , Ruszniewski Philippe B. , Wiedenmann Bertram , Hollander Ron ,   International Neuroendocrine Cancer Alliance
Published: May 2019

e13524

Background: The aim of this global patient survey was to better understand the needs and expectations of patients with NETs regarding access to diagnostic tools and treatment. Methods: In 2017, an online, questionnaire survey of NET patients/family members, patient advocates and healthcare professionals (HCPs) was conducted. Results: In total, 443 participants from 26 countries responded: 338 patients/families; 35 advocates; 70 HCPs. Following NET diagnosis, many patients use patient association (69%) and HCP (48%) websites to fulfill their informational needs. Patients overestimated the availability of key diagnostic tools and treatments compared to HCPs: Gallium-68-Dotatate PET/CT scan was believed available by 28% of patients vs. 14% of HCPs; fluorodeoxyglucose PET by 77% of patients vs. 64% of HCPs; peptide receptor radionuclide therapy by 58% of patients vs. 23% of HCPs; genetic test/precision medicine by 75% of patients vs. 71% of HCPs; and transplantation by 86% of patients vs. 55% of HCPs. Reasons reported by patients and advocates for unavailability of treatment were: not provided by healthcare system (28% & 67%, respectively); non-referral (19% & 33%, respectively), unable to afford treatment (18% & 57%, respectively); treatment not covered by insurance (17% & 24%, respectively); distance to treatment centre (15% & 48%, respectively). Almost a third (30%) of patients had to travel more than 300 km/186 miles for treatment or consultation with a NET specialist, while 34% of patients did not have access to an MDT and those that did may be in contact with them less than once per year (14%). In contrast, advocates and HCPs believe there is wider availability of MDTs (94% and 70%, respectively). Conclusions: Patients are increasingly well-educated about NETs and often travel considerable distances to obtain specialist treatment. However, there remains considerable disparity in what patients feel is available to them in terms of the latest tools and treatments, compared to what is there in reality. This significant difference in perception needs to be managed delicately by both advocates and healthcare professionals.
Treatment monitoring of immunotherapy and targeted therapy using FET PET in patients with melanoma and lung cancer brain metastases: Initial experiences.
Authors: Galldiks Norbert , Abdulla Diana S.Y. , Scheffler Matthias , Schweinsberg Viola , Schlaak Max , Kreuzberg Nicole , Landsberg Jennifer , Lohmann Philipp , Ceccon Garry , Werner Jan-Michael , Celik Eren , Ruge Maximilian I. , Kocher Martin , Marnitz Simone , Fink Gereon R. , Langen Karl-Josef , Wolf Juergen , Mauch Cornelia
Published: May 2019

e13525

Background: Due to the lack of specificity of contrast-enhanced (CE) MRI, the differentiation of progression from pseudoprogression (PsP) following immunotherapy using checkpoint inhibitors (IT) or targeted therapy (TT) may be challenging, especially when IT or TT is applied in combination with radiotherapy (RT). Similarly, for response assessment of RT plus IT or targeted therapy (TT), the use of CE MRI alone may also be difficult. For problem solving, the integration of advanced imaging methods may add valuable information. Here, we evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in comparison to CE MRI for these important clinical situations in patients with brain metastases (BM) secondary to malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Methods: From 2015-2018, we retrospectively identified 31 patients with 74 BM secondary to MM (n = 20 with 42 BM) and NSCLC (n = 11 with 32 BM) who underwent 52 FET PET scans during the course of disease. All patients had RT prior to IT or TT initiation (61%) or RT concurrent to IT or TT (39%). In 13 patients, FET PET was performed for treatment response assessment of IT or TT using baseline and follow-up scans (median time between scans, 4.2 months). In the remaining 18 patients, FET PET was used for the differentiation of progression from PsP related to RT plus IT or TT. In all BM, metabolic activity on FET PET was evaluated by calculation of tumor/brain ratios. FET PET imaging findings were compared to CE MRI and correlated to the clinical follow-up or neuropathological findings after neuroimaging. Results: In 4 of 13 patients (31%), FET PET provided additional information for treatment response evaluation beyond the information provided by CE MRI alone. Furthermore, responding patients on FET PET had a median stable clinical follow-up of 10 months. In 10 of 18 patients (56%) with CE MRI findings suggesting progression, FET PET detected PsP. In 9 of these 10 patients, PsP was confirmed by a median stable clinical follow-up of 11 months. Conclusions: FET PET may add valuable information for treatment monitoring in individual BM patients undergoing RT in combination with IT or TT.