bluuebunny/crossref_metadata_2025 huggingface dataset:
Anaerobes in prostate cancer: New approaches to treatment and prevention.
Authors: Oliver Tim RTD , Bhudia Roshni , Chinegwundoh Frank , Wilks Mark
Published: May 2020

e13606

Background: The sun-sensitive microaerophylic bacterium C. acnes, is linked with prostate cancer (PC) in 9 studies 3 of which are cohort studies of 289,043 men followed for 30 years from puberty. That circumcision reduces PC risk further supports a role for anaerobes as they are reduced on the circumcised glans penis. A 1988 study linked anaerobes with PC but considered them opportunists. Reports that H. pylori, linked to stomach cancer, is also a microaerophilic bacterium led us to reinvestigate the association of PC and anaerobes. Methods: The MOLDI-TOF methodology for analysing anaerobes in 18 post rectal exam urine samples has been previously reported ( https://www.nature.com/articles/s41598-017-13782-6 ). This report analyses outcome after a further 21 patients were recruited and follow up was extended from 1 month to a median of 43 months. In total there were 21 diagnosed as PC and 18 BPH. Results: Of the 29 anaerobic isolates, 19 were Chlostridiales family, 2 Prevotella and 7 Actinomycoses (includes C.acnes) family. 12 cases had obligate anaerobes, 7 microaerophylic bacteria and 20 none of these. In 27 patients with PSA > 1.5, 56% had anaerobes, while in 12 with PSA = < 1.5 it was 17% (p < 0.037 Fisher’s exact test) In the 21 with prostate cancer, 7 (64%) of 11 without anaerobes and 2 of 10 (20% ) with anaerobes remain on Active Surveillance (p = 0.08 Fisher’s exact test) vs in 18 without cancer, 10/11 (91%) without and 5/7 (71%) with anaerobes remain without the need of TURP intervention. Conclusions: This is a small study and needs expanding. Given the rising incidence of antibiotic resistance more resources should be focused on the immune deficiency associated with chronic bacterial infection. Expansion of technology used to produce bacterial vaccines to treat women with recurrent cystitis could offer new approaches to prevention of PC and to treat patients with raised PSA and negative biopsy. Modern approaches to immunotherapy against these bacteria with checkpoint inhibitors could be used in combination with androgen suppression and chemotherapy.
Is the incidence of breast cancer increasing? Using the NCDB and autoregressive integrated moving average models (ARIMA) to forecast breast cancer to 2030.
Authors: Elson Leah , Bilani Nadeem , Elimimian Elizabeth Blessing , Arteta-Bulos Rafael , Nahleh Zeina A.
Published: May 2020

e13612

Background: The observed increase in the incidence rate of BC has been described due, in part, to higher, effective public health campaigns for screening, higher sensitivity among diagnostic testing modalities as well as an aging population. While the mortality rate associated with breast cancer has reported to fall by 1.8% every year since 2007, the disease burden itself has continued to grow and increased breast cancer rates will contribute to the strain already experienced within the United States healthcare system infrastructure. Therefore, the authors sought to use a large, national registry to develop a time series model that might help forecast the approximate breast cancer incidence rate, to the year 2030, as captured by the National Cancer Database (NCDB). Methods: In this time series forecast, autoregressive integrated moving average models (ARIMA) were constructed based on 2004-2016 historic breast cancer incidence rates, as reported by the NCDB. Multiple models were generated, using differing autoregressive parameters, and the most predictive model was chosen using the lowest Bayesian Information Criteria (BIC), and mean absolute percentage error (MAPE). Similar methodology has already been published to predict prostate cancer incidence. The best fit model was applied to forecast annual incidence in the NCDB to the year 2030. Statistics were performed using modeling systems in SPSS, version 26. Results: For this model, 12 years of NCDB breast cancer diagnoses were used, which included n = 1,924,425 cases, overall. Using ARIMA modeling, a best fit, stationary average was identified with autoregressive and difference terms of 1 (ARIMA (1,1,0), coefficient = 0.598; P = 0.028). Of the multiple models tested the model with the lowest BIC was chosen, with a MAPE of 4.71%. The best fit model forecasted n = 325,048 new breast cancer diagnoses to be captured annually by the NCDB, by 2030. Conclusions: In this analysis, the annual breast cancer incidence within the NCDB is predicted to increase by 21%, by 2030. This forecast, while slightly lower than previously reported by the National Cancer Institute, utilizes more recent historical data that reflects a period of leveling-off in disease incidence, during 2014-2016, as reported to the NCDB. This innovative model can be utilized to proactively plan public health strategies and allocate appropriate resources focused on reducing the burden of cancer.
Quantification of inequities in breast cancer incidence in New Mexico through Bayesian disease mapping.
Authors: Zahrieh David , Golafshar Michael A , Patel Samir H , DeWees Todd A
Published: May 2020

e13617

Background: Breast cancer (BC) is the most prevalent cancer of women in the United States (US). The incidence rates for BC among American Indian and Alaska Native (AI/AN) women vary across the US. A novel application of Bayesian disease mapping was applied to quantify potential inequities in 10-year BC incidence in New Mexico (NM) in order to better inform health equity initiatives within the AI/AN at-risk population. Methods: Surveillance, Epidemiology, and End Results Program (SEER) data from 2005 to 2014 were used to identify new cases of BC within the 33 counties in NM. Initially, a Poisson-gamma model was applied to quantify the reduction in risk of BC within the at-risk AI/AN population compared with the general at-risk population. To account for spatial variation and to address the small area estimation problem inherent in these data by borrowing strength globally and locally in NM, we applied Bayesian disease mapping to the counts of county-level BC cases. We quantified the disparity effect, as measured by the rate ratio (95% credible interval [CI]), comparing the incidence of BC between at-risk AI/AN and non-AI/AN women, and assessed if the rate ratio differed between counties. Markov chain Monte Carlo sampling was used to estimate posterior quantities and the deviance information criterion was used for model selection. Results: In 2010, 1,041,758 women were at-risk for BC of which 107,656 (10.3%) were AI/AN women. During the 10-year study period, 12,974 new BC cases were recorded in the general at-risk population. In the at-risk AI/AN population, the expected number of new cases during the 10-year study period, therefore, was 1,340.74; however, 597 incidence cases of BC were diagnosed in the at-risk AI/AN population resulting in a posterior mean for the true relative risk of 0.445 (95% CI: 0.410, 0.482). Based on the selected model that accounted for over dispersion and spatial correlation among the 33 counties, the posterior mean of the overall adjusted rate ratio was 0.405 (95% CI: 0.336, 0.478). The adjusted rate of BC in AI/AN women was 0.40 times the corresponding adjusted rate for women who were non-AI/AN. Further, the adjusted rate ratios were similar for each county. Conclusions: The novel application of Bayesian disease mapping to these data provided substantial evidence of a significant overall disparity effect in BC incidence within NM between at-risk AI/AN and non-AI/AN women, which was more marked than previous reports. Targeted state-wide health equity initiatives may lead to reducing disparities in BC incidence in AI/AN at-risk women.
Clinical, sociodemographic, and pathological characteristics of breast cancer in the United States: A cross-sectional analysis from the National Cancer Database (NCDB).
Authors: Nahleh Zeina A. , Bilani Nadeem , Elson Leah , Elimimian Elizabeth Blessing , Zabor Emily Craig
Published: May 2020

e13623

Background: Breast cancer (BC) remains the most commonly-diagnosed malignancy in women. BC encompasses great heterogeneity in patient pathologic and clinical characteristics, as well as treatment approaches and outcome by stage and subtype. This study aims to explore recent differences in characteristics and overall survival (OS) of BC across different facility types. Methods: We conducted a retrospective analysis of patients with BC, diagnosed between 2004-2016, based on the NCDB. Categorical variables were summarized using frequencies/percentages, whereas continuous variables were summarized using the median/interquartile range (IQR). OS was explored using the Kaplan-Meier method. Results: A total of 2,671,549 patients with BC were captured in this dataset. The median age at diagnosis was 61 (range 18-90 years). The majority n = 1,986,450 (75%) were non-Hispanic (NH) white; 286,176 (11%) were NH-black; 124,877 (4.7%) were Hispanic-white; 2,977 (0.1%) were Hispanic-black and 90,484 (6.1%) were Asian. The most common BC subtype was hormone receptor-positive (HR+)/HER2- (58%), followed by HR+/HER2+ (26%), HR-/HER2-negative (10%) and HR-/HER2+ (6.4%). 73% of cases were ductal; 15% lobular; the remaining histological subtypes included 0.9% epithelial-myoepithelial, 0.1% fibroepithelial, 0.4% metaplastic, < 0.1% mesenchymal, 1.6% rare breast carcinomas and 7% other carcinomas. The majority of patients received therapy at comprehensive community cancer programs (CPs) (45%), followed by academic/research CPs (30%), integrated network CPs (15%) and community CPs (9.5%). OS was best at academic (72% 10-year OS), followed by integrated network (69% 10-year OS), comprehensive community (68% 10-year OS) and community (63% 10-year OS) CPs. Significant differences in OS according to facility type remained when stratified by stage of disease (all p < 0.0001). OS was also significantly better for white (69% 10-year OS) versus black (63% 10-year OS) patients. Conclusions: This large database from the NCDB provides a comprehensive, recent overview of BC over the last 12 years. Facility type appears to be significantly associated with OS, such that academically designated centers have superior OS across all stages.
Impact of tuberculosis on mortality and healthcare resource utilization in cancer patients: A nationwide inpatient sample analysis.
Authors: Vohra Ishaan , Lingamaneni Prasanth , Katiyar Vatsala , Moturi Krishna Rekha , Malapati Sindhu Janarthanam , Singh Sunny R K , Gupta Shweta
Published: May 2020

e13625

Background: Tuberculosis (TB) is a major public health concern. Patients with malignancy are at increased risk of developing TB as a result of depressed cellular immunity. The aim of the study is to analyze the prevalence, mortality and healthcare resource utilization of cancer patients with TB. Methods: Adult patients with malignancy and TB (cases) were identified using ICD10 code from Nationwide Inpatient Sample database 2017 and their data was compared to cancer patients without TB (controls). Univariate and multivariable logistic and Poisson regression models were used to analyze mortality and healthcare resource utilization. Results: Among 2,099,294 adult cancer patients admitted in 2017, 1115 were found to have TB. Majority (84%) had pulmonary TB. Mean age of patients was 60.3 years with 65% males and white predominance (33%). Overall prevalence of TB in cancer population was 51.3/100,000 patients, with highest being in Hodgkin lymphoma (182.6/100,000) followed by and MDS/ MPN patients (113.2/100,000) (p < 0.01). Among solid organ malignancies, lung cancer had the highest prevalence of TB (92.1/100,000). After adjusting for the demographic and patient related variables, TB was found to be an independent risk factor for mortality in cancer patients (adjusted HR 1.7, 95% CI 1.13-2.66, p = 0.017). The mortality of cases during inpatient stay was 10.2% compared to 6.2% in controls. The mean length of stay for cases was 12.4 days vs 6.3 days in controls (adjusted coef +6.12, 95% CI 3.64-8.59, P < 0.001) and mean hospital charges in cases was $136,026 vs $67,381 in controls (adjusted coef 68,680, 95% CI 39,053.5-98,306.9, p < 0.001). On multivariate analysis, predictors of mortality in cancer patients with TB were older age, malnutrition, uninsured status, higher Charlson comorbidity score ( = > 3), ICU care, venous thrombo-embolism and Acute renal failure requiring dialysis. Conclusions: TB significantly increases the morbidity and mortality in cancer patients. Widespread TB screening, prompt recognition of infection and treatment can considerably reduce health care costs. [Table: see text]
Reproductive risk factor patterns in the Caribbean affecting breast cancer age of onset.
Authors: Sanchez-Covarrubias Alex , Cerbon Danielle , Barreto Coelho Priscila , Donenberg Talia , Akbari Mohammad R , Ali Jameel , Butler Raleigh , Curling Duvaughn , Dodds Leah , DeGennaro Vincent A. , Dyer Hedda , Halliday Darron Andrew Calvin , Narod Steven , Reis Isildinha N , Schlumbrecht Matthew , Turnquest Theodore A. , Wharfe Gillian , Hurley Judith , George Sophia
Published: May 2020

e13632

Background: Breast cancer is the leading cause of cancer in high-income (HIC) and low to middle-income countries (LMIC); and is the most common diagnosed cancer among women. Factors affecting breast cancer incidence include obesity, parity, age of menarche, age of first pregnancy and mutations in BRCA1/2 and genes involved in the homologous recombination repair pathway. These factors differ between HICs and LMICs including countries in the Caribbean. The majority of women from the Caribbean are of African ancestry and Black women have increased morbidity and mortality rates of breast cancer. Our goal is to study how reproductive patterns affect breast cancer age at presentation in Caribbean-born women. Methods: We conducted a prospective observational study recruiting patients from The Bahamas, Barbados, Cayman Islands, Dominica, Haiti, Jamaica and Trinidad and Tobago. Women were considered eligible if they were diagnosed with primary breast cancer at any age. The cohort was divided into four groups based on the year of birth ( < 1950, 1950 – 1959, 1960 – 1969, > 1970). The following data was collected: age at diagnosis of breast cancer, family history of cancer, age of first pregnancy, number of pregnancies, number of children, number of siblings, BMI at time of enrollment, age of menarche and menopause. Data analysis was conducted using the Chi-square test, ANOVA and logistic regression model. Results: A total of 1015 were enrolled and 995 met inclusion criteria. When comparing women born < 1950 to those > 1970, there was a statistically significant difference between means for the variables: Age at Breast cancer diagnosis (60.7 vs 35, p <.0001); number of siblings (4.5 vs 6.6, p <.0001); age of menarche (13.4 vs 12.3, p <.0001); number of pregnancies (4 vs 2.09); number of children (3.5 vs 1.6, p <.0001) and age of menopause at diagnosis (47.4 vs 37.5, p <.0001). When comparing women who were never pregnant to those who experienced pregnancy, mean age at breast cancer diagnosis was significantly reduced from 47.3 to 41.5 (p < 0.0001). Women who had n = 3 or more children were diagnosed older (mean of 49.9 years), compared to women with 2 or less children, (45.1 years, p < 0.0001). In multivariate analysis a higher likelihood for a positive mutation between year of birth 1960-1969 (aOR 2.19 [1.24 – 3.88], p = 0.007) and > 1970 (aOR 2.02 [1.06 – 3.88], p = 0.034) compared to < 1950. Conclusions: Our data shows that the Caribbean has undergone a rapid change in reproductive patterns in one generation. These changes provide an insight of risk factor patterns for breast cancer incidence which are associated with younger age of onset.
The genes CNV features in the tumor cells in patients with ovarian serous adenocarcinoma.
Authors: Tsandekova Marieta R. , Porkhanova Natalya V. , Kit Oleg Ivanovich , Kutilin Denis S.
Published: May 2020

e13641

Background: Serous adenocarcinoma is the most common subtype of ovarian cancer. Early diagnosis of this disease can significantly improve the prognosis. Development of more effective methods for early diagnosis and identification of more reliable markers require understanding the molecular mechanisms underlying the malignant behavior of ovarian epithelial cells. The aim of the study was to analyze the copy number variation (CNV) of genes that regulate apoptosis, DNA repair, cell proliferation, metabolism and estrogen reception in tumor and normal ovarian cells. Methods: For the study, we used tissue sections from FFPE blocks of 65 patients with serous ovarian adenocarcinoma diagnosis. Tumor and normal ovarian epithelial cells were isolated using laser microdissection with non-contact capture (Palm MicroBeam, Carl Zeiss). DNA was extracted from cells using the phenol-chloroform method. CNV of 33 genes (BRAF, KRAS, EGFR, PIK3CA, PTEN, TP53, BRCA1, BRCA2, PRKCI, NOTCH1, AKT1, BAX, CASP7, CASP3, CASP8, CASP9, MDM2, BCL2, CYP1A1, CYP1A1, CYP1A2, CYP1A2, CYP1A2, CYP1A1, CYP1A2, CYP1, ESR2, GPER, STS, SULT1A, SULT1E1, OCT4, SOX2, C-MYC, SOX18, SCNN1A) were determined by Real-Time qPCR method (reference B2M, GAPDH). Statistical analysis was performed using the Mann-Whitney test. For cluster analysis (Hierarchical Clustering, Euclidean distance) scripts in R were used. Results: A statistically significant (p < 0.005) increase in the CNV of PTEN, MDM2, SOX2, CYP1B1, ESR1, and SULT1E1 by 2.0, 2.0, 1.8, 2.5, 3.0 and 2.0 times, respectively, was found, as well as a 2.0-fold decrease in the CNV of CASP3 and CASP8 in tumor cells relatively to normal ones. Cluster analysis allowed us to distinguish 2 groups of serous adenocarcinoma samples that differed in gene CNV (p < 0.005): in group 1 (n = 40), the copy number of the SOX2, MDM2, ESR1, CYP1B1 and SULT1E1 genes was increased and the copy number of the TP53 and BRCA2 genes was reduced, in group 2 (n = 25), copy number of PTEN, PIK3CA, BCL2 was increased and copy number of BAX, CASP3 and CASP8 was lower. Conclusions: CNV analysis revealed the most characteristic markers of ovarian serous adenocarcinoma cells. Based on the differential CNV, 2 molecular subtypes of serous adenocarcinoma were distinguished.
Analysis of germline mutations in Chinese colorectal cancer patients with next-generation sequencing.
Authors: Gao Jing , Ren Hua , Liao Haiyan , Hai Luo , Cong Yuwei , Zhao Xiaochen , Bai Yuezong
Published: May 2020

e13651

Background: Colorectal cancer (CRC) remains one of the leading causes of morbidity and mortality around the world. Familial cancer syndromes are common in CRC, inherited syndromes including Lynch syndrome (LS), familial adenomatous polyposis (FAP), and MutY human homolog (MUTYH)-associated polyposis (MAP) were well defined. But still, there are not well-established evidence between other several genes and CRC risk. Expanded multi-gene testing may be an alternative to find out the underlying mechanism for genetic susceptibility. Our study aims to assess the germline alternation landscape of Chinese CRC patients. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 381 genes on tissues from patients with CRC between January 01, 2017 and December 02, 2019 in 3D Medicines database. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: 1360 CRC patients were included for analysis, in which 95 (7.0%) patients harbored pathogenic (80/95) and likely pathogenic (15/95) germline mutations in 28 cancer predisposition genes. 33 subjects had pathogenic variants associated with Lynch syndrome (15 mutations in MLH1, 9 mutations in MSH2, 6 mutations in MSH6, 3 mutations in PMS2, respectively). 8 subjects had pathogenic variants associated with FAP (3 APC), MAP (3 MUTYH) and Li-Fraumeni syndrome (2 TP53). In addition, 14 pathogenic mutations in moderate penetrance genes (5 ATM, 3 BLM and 6 CHEK2) were found. The frequency of pathogenic BRCA mutations were 1 alternation in BRCA1 and 3 alternations in BRCA2. Conclusions: 7.0 % of patients with Chinese CRC carried germline cancer susceptibility gene mutations. Multi-gene testing would provide references for assessing genetic susceptibility and managing increased surveillance.
The alteration of TERT in 10,000 Chinese patients with solid tumors.
Authors: Lin Jie , Li Yuehua , Zou Hao , Zhang Li , Xiao Yanbin , Pan Qi , Tang Bo , Wu Huan , Shi Jiaochun , Wang Weifeng
Published: May 2020

e13655

Background: The reactivation of telomerase reverse transcriptase ( TERT) is one of the characters that make cancer cells immortal. TERT expression has been shown in various human cancers.However, the landscape of TERT alterations in Chinese patients with solid tumors still remains unclear. Here, we illustrated the profile of TERT variations of Chinese solid tumor patients by using next generation sequencing (NGS)-based targeted sequencing. Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matching blood samples were collected from 9874 Chinese patients and subjected to a NGS-based panel at a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. All classes of alterations were assessed. Results: FFPE samples from 9874 Chinese solid tumor patients included lung cancers (39.7%), liver cancers (12.5%), colorectal cancers (10.8%), gastric cancers (5.7%), pancreatic cancers (4.9%), biliary tract tumors (4.6%), and other 18 cancer types (21.7%) were assessed. And 1187 (12.0%) out of 9874 cancer samples had TERT variations. TERT variations occurred in all types of cancer with various frequencies: urothelial neoplasms (52.0%), central nervous system tumors (40.0%), melanomas (38.9%), liver cancers (30.7%), thyroid tumors (24.3%), cervical cancers (20.6%), biliary tract tumors (16.3%), head and neck tumors (14.6%), soft tissue tumors (12.2%) and lung cancers (10.3%). Substitution was the most common variation of TERT and accounted for 58.7% of all the alterations, followed by gene amplification (38.8%) and fusions (2.4%). There were 86.8% of substitution variations presented in TERT promoter region comprising of c.-124C > T (70.7%) and c.-146C > T (13.1%). Patients with TERT alterations included 414 females and 773 males with a median age of 59 years old (range: 8-88). Tumors included stage IV (34.0%), stage III (22.2%), stage II (12.7%), stage I (18.7%) and stage 0 (12.3%). TERT variations were correlated with patients’ age (p = 0.00083) and gender (p = 5.59×10−7). There was no significant correlation of TERT alterations with the highly mutated TP53. The frequencies of TERT alterations were similar in patients with mutated and wild type TP53 (12.7% vs 11.1%). Conclusions: Our study revealed that 12.0% Chinese solid tumor patients harbored TERT alterations, especially two hotspots mutations (c.-124C > T and c.-146C > T) in the promoter region. TERT variations had a correlation with patients’ age and gender, but no correlation with hotspot TP53 mutations.
Genomic comparisons between different radiological features in ground glass nodules under 20 mm in diameter.
Authors: Peng Muyun , Zhang Bingyu , Xing Guanlan , Xu Yaping , Yu Fenglei
Published: May 2020

e13664

Background: Radiological features still matters in the management of ground glass nodules (GGNs). The 20 mm in maximum diameter and consolidation tumor ratio (CTR) under 0.5 are pivotal indexes from the lobectomy to segmentectomy decision. However, the feasibility of limited resection remains controversial. Understanding the relationship between genomic characteristics and radiological features of GGNs will provide critical insights to theoretical basis of surgical method decision and expand a novel perspective to risk-stratify patients. Methods: In total, 297 surgically resected GGNs (≤ 20 mm in maximum diameter) were consecutively collected in the study. The summarized radiological features are shown (Table). In order to obtain their comprehensive genomic profiling, these tumor samples were performed using customized panels of 1021 genes. Fisher's exact test, Mann Whitney test and Kruskal-Wallis test were used for statistical analysis. Results: Higher TMB was found in subgroups with the maximum diameter > 10 mm, the volume > 0.40 mL, the CT value > -500 HU, and the mass > 200 mg ( p < 0.05). However, TMB was not associated with the increase of CTR. These data suggested that enlarged nodules occurred with increased mutation events. EGFR, RET, TP53 and RBM10 mutations were significantly enriched in groups with maximum diameter > 10 mm, volume > 0.40 mL, and mass > 0.200 g ( p < 0.05), and significant enrichment in p53-pathway and Myc-pathway were also found ( q < 0.05). ERBB2 and BRAF mutations were significantly enriched in the subgroups with maximum diameter ≤ 10 mm, volume ≤ 0.40 mL, or mass ≤ 0.200 g ( p < 0.05). As compared to the cohort of CTR ≤ 0.5 in all nodules, mutation frequencies of EGFR, RBM10 were similar, those of RET, ALK and TP53 were relatively higher ( p < 0.05), and that of ERBB2 was lower ( p = 1.7×10−5) in the cohort of CTR > 0.5. Conclusions: Our study provides the comprehensive description of the mutational landscape and radio-genomic features of GGNs under 20 mm in diameter. [Table: see text]
Development CRISPR-Cas12-based rapid EGFR mutation detection kit.
Authors: Kunimasa Kei , Bando Yuya , Shiraishi Miyako , Aizawa Emi , Nishino Kazumi , Tamiya Motohiro , Inoue Takako , Kuhara Hanako , Kawachi Hayato , Kuno Kika , Imamura Fumio , Iwai Shigenori , Kumagai Toru , Suzuki Keiichiro
Published: May 2020

e13669

Background: Recently, several cancer gene panel tests have been developed to determine many driver mutations including lung cancer simultaneously. However, the current next-sequencing based platform is not ideal testing method in the clinical practice due to the high examination cost and the time required for the result to reach the field. By refining recently reported CRISPR-Cas-based nucleic acid detection methods, we developed a novel CRISPR-Cas12 family based rapid-detection kit for targetable EGFR mutations in non-small lung cancer (NSCLC) patients. Methods: To develop a powerful CRISPR-based testing method, we focused on unique Cas12 family proteins which contain a single RuvC nuclease domain that cleave target double-stranded DNA adjacent to protospacer adjacent motif (PAM) sequences as well as non-target single-stranded DNA (ssDNA) collaterally. We purified 6 Cas12 family proteins (Cas12a, Cas12c1, Cas12c2, Cas12g, Cas12i1, and Cas12i2) as well as two types of target-defined guide RNA for EGFR Ex.19 del(E746-A750) and L858R mutations. The target sequences including EGFR Ex.19(E746-A750) and L858R mutations were amplified from EGFR mutated cell lines, FFPE lung cancer tissues or cell free DNA (cfDNA) of NSCLC patients using PCR with PrimeSTAR GXL DNA polymerase (Takara, Shiga, Japan) or isothermal recombinase polymerase amplification (RPA) with TwistAmp Basic (TwistDx, Cambridge, UK). CRISPR-Cas12-based cleavage assay was conducted in a reaction buffer consisting of 10 nM Cas12 proteins, 10 nM purified guide RNA, 0.4nM target DNA, and 50 nM collateral ssDNA (quenched fluorescent DNA reporter) in a 20 μl volume at 37 °C for 1 h. The excited fluorescence, which is an indicator of the presence of target cancer mutation, was measured by Synergy H1 hybrid Multi-Mode Reader (BioTek, Vermont, USA). For simpler instrument-free and portable detection lateral flow readouts were also developed and tested using Milenia HybriDetect1 kit (TwistDx). Results: Cas12a, Cas12i1, Cas12i2-based assays successfully detected the EGFR Ex.19 del(E746-A750) and L858R mutations from PCR and RPA products. Lateral flow readout kit could also detect EGFR Ex.19 del (E746-A750) mutation from cfDNA derived from NSCLC patients. It took about 3 hours from plasma collection to DNA extraction, RPA, and measurement with the kit. Conclusions: CRISPR-Cas based lateral flow readout kit can detect EGFR mutation at an unprecedented pace with low cost. Our developed system will be an innovative testing tool for lung cancer patients with low cost, rapid, multiplexable, and noninvasive procedure.
Ki-67 versus MammaPrint/BluePrint for assessing luminal type breast cancer.
Authors: Tian Chen , Fu Lili , Wei Jiyu , Yin Pengfei , Zhang Henghui
Published: May 2020

e13673

Background: Ki-67 is widely used for risk stratification in patients with ER+/HER2- breast cancer. The multigene assay, MammaPrint/BluePrint (MP/BP) test, is validated as a good predictor of recurrence in patients with Luminal type breast cancer and a good tool of molecular subtyping classification. Previous study showed that MP/BP test was able to re-stratify 54% of patients with a Luminal-B pathological subtyping (PS) to a low-risk Luminal A-type group. But there is no study directly show the comparison between Ki67 and MP/BP test result. Here in this study, we compare Ki-67 with MP/BP test result in Chinese patients with luminal type breast cancer. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumour samples or fresh tumour samples from 1008 eligible breast cancer patients were collected from 122 hospitals in China. Tumor RNAs were isolated from samples and analyzed using RNA sequencing technology. Ki-67 protein expression were assessed in FFPE tissue blocks by IHC. The pathology subtyping of patient was categorized based on the 2013 St. Gallen. Comparison of MP/BP result with Ki-67 IHC was performed. Concordance between subtyping by the MP/BP and PS was also evaluated. Results: Of 1008 patients with ER+/HER2- breast cancer, 640 were MP Low-Risk and 368 were MP High-Risk. MammaPrint index was significantly associated with Ki-67 expression (p < 0.001). Among the patients with Ki-67 value lower than 15%, 81.11% were MP Low-Risk, while 65.12% of patients with Ki-67 value between 15%-20% and 46.67% of patients with Ki-67 value between 21%-30% were MP Low Risk. Of the patients with Ki-67 value higher than 30%, 77.24% were MP High-Risk. Among the 453 patients with PS Luminal-A tumours, 77 (17%) were categorized as Luminal-B by MP/BP test. While among the 555 patients with PS Luminal-B tumours, 265 (48%) were categorized as Luminal-A by MP/BP test. Conclusions: Our results show that for the patients with low Ki-67 value ( < 15%) or high Ki-67 value ( > 30%), the risk prediction by MP test are mostly agree with Ki-67 IHC, while for the patients with intermediate Ki-67 value (15-30%), MammaPrint test may provide more information. And compare with the traditional pathological factors, MP/BP test can help to identify a large group of patient with low risk of recurrence.
Clinical use of RNA sequencing and oncobox analytics to predict personalized targeted therapeutic efficacy.
Authors: Poddubskaya Elena , Sorokin Maxim , Garazha Andrew , Glusker Alex , Moisseev Alexey , Sekacheva Marina , Suntsova Maria , Kim Ella L , Gaifullin Nurshat , Tkachev Victor , Giese Alf , Barbara Viktoria , Borisov Nikolay , Buzdin Anton
Published: May 2020

e13676

Background: Analysis of mutation profiles in cancer patients does not provide clinical benefits in 80-90% of cases in the US (Marquart et al., 2018). Gene expression analysis potentially complements standard detection of clinically relevant mutations. Methods: 239 adult late-stage cancer patients. RNA gene expression sequencing completed on solid tumor samples using FFPE blocks. Patient mRNA profiles were analyzed using Oncobox bioinformatics, prioritizing target drugs according to their personalized predicted efficacy. Summary reports were provided to oncologists and resulting treatment selection and outcomes were assessed. Results: As of February 2020, feedback was received from participating doctors for 224 patients; 34 patients died before therapy prescription, 52 patients received treatment other than targeted therapy (chemo, surgery, radiation, or palliative care), 75 patients received at least one targeted therapy (single or combination therapy) predicted to be effective based on Oncobox analysis (“RNAseq cohort”). 63 patients received chemo or other drug therapy predicted to be potentially ineffective from Oncobox analysis (“other cohort”). Therapeutic response was obtained on 46 patients with biopsies collected no longer than 6 months prior to analysis who had no further surgery (30 in the RNAseq cohort and 16 in the other cohort). 63% of the RNAseq cohort obtained either partial response or stable disease using Oncobox guided therapies, compared to 44% of the other cohort (19% increase of disease control). The RNAseq cohort had higher mean prior therapies (1.3) compared to the other cohort (0.8) indicating more advanced disease. The similarly designed WINTHER trial reported ~8% increase of disease control using gene expression-guided vs mutation-guided therapeutics in a cohort of advanced cancer patients averaging three prior therapies (Rodon et al., 2019). Conclusions: Collectively these data suggest that gene expression profiling provides a more clinically relevant therapeutic match, and better response rates, than mutation guided therapeutic treatments. This potentially results in improved clinical outcomes for cancer patients. Clinical trial information: NCT03724097.
Genetic testing experiences and emotional reactions among individuals with variant of uncertain significance results from cancer multiplex genetic testing.
Authors: Hamilton Jada G. , Brower Jamie , Clark Dana , Ebrahimzadeh Jessica E , Kane Sarah R. , Sanchez Pauleen , Wildman Temima , Merrill Margaret , Couch Fergus , Garber Judy Ellen , Offit Kenneth , Robson Mark E. , Domchek Susan M.
Published: May 2020

e13680

Background: Multiplex genetic testing (MGT) simultaneously analyzes multiple cancer susceptibility genes and can reveal genetic variants of uncertain significance (VUS) that have unclear associations with cancer risks. Little is known about how people are prepared for receiving VUS results from MGT, or whether their emotional reactions differ based on the levels of cancer risk to which they may be susceptible. Methods: We recruited participants from the online Prospective Registry of Multiplex Testing (PROMPT). Those with only a VUS in a cancer predisposition gene completed a survey including measures of their MGT experience, distress (range 0-30; α = .87), uncertainty (0-45; α = .83), and positive experiences (0-20; α = .75). We used generalized linear modeling to examine how demographics, awareness of the possibility of VUS before testing, and level of cancer risks associated with their VUS gene were related to emotional outcomes. Results: Data were available from 661 individuals (40% response rate, 95% female, 90% white, 78% college graduate, 69% cancer history, age 23-93) with VUS in a gene of high risk (47%), moderate/low risk (35%) or limited evidence of risk (18%). Among the sample, 80.8% reported ever receiving cancer genetic counseling, and only 50.8% reported being aware of the possibility of VUS when deciding about testing. Participants reported low current distress ( M± SD= 3.25±5.19), uncertainty (9.18±8.35) and positive experiences (7.83±5.98). Distress was associated with younger age, less family cancer history, and being unaware of the possibility of VUS before testing; distress was also higher among those with VUS in a gene of high risk than those with VUS in a gene of moderate/low risk or limited evidence of risk ( ps≤.023). Uncertainty was associated with younger age, non-white race, less education, and being unaware of the possibility of VUS; uncertainty was also higher among those with VUS in a gene of high risk than those with VUS in a gene with limited evidence of risk ( ps≤.05). Fewer positive experiences were associated with more education and more family cancer history; those with VUS in a gene of high risk had fewer positive experiences than those with VUS in a gene with limited evidence of risk ( ps≤.03). Conclusions: Many individuals undergoing MGT may not fully understand the prospect of receiving VUS. Clinicians should consider patients’ background, preparation, and level of cancer risk to which they are potentially susceptible, as these factors may affect their emotional adaptation.
Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-gene blood-based comprehensive genomic profiling assay.
Authors: Woodhouse Ryan , Dennis Lucas , Li Meijuan , Burns Christine , Ma Pei , Meng Wei , Dewal Ninad , Vietz Christine , Hegde Priti
Published: May 2020

e13685

Background: As the availability of precision therapies expand, a well-validated blood-based comprehensive genomic profiling (CGP) assay has the potential to provide considerable value as a complement to tissue-based testing to ensure that potentially life-extending therapies are administered to the patients most likely to benefit. Comprehensive clinical and analytical validity data for blood-based assays are crucial to enabling physicians to understand the true performance of available testing options. Methods: The FoundationOne Liquid CDx assay is a blood-based CGP assay that has been validated for a Premarket Approval (PMA) submission to the Food and Drug Administration (FDA). Validation studies included > 9,000 tests and > 30,000 unique variants across > 300 genes and > 50 cancer types, allowing for a comprehensive assessment of performance. Results: The results of these extensive studies demonstrate a 95% limit of detection (LoD) of 0.40% variant allele fraction (VAF) for select short variants (subs and indels), 0.37% VAF for select rearrangements, 21.7% tumor fraction (TF) for select copy number amplifications, and 30.4% TF for copy number losses. LoD for complex biomarkers such as microsatellite instability (MSI) and blood tumor mutational burden (bTMB) were also determined. The limit of blank (LoB) was shown to be the ideal value of zero. Reproducibility of variant calling was determined to be 99.59% with two-sided exact CI of (99.58%, 99.60%). In comparison with an orthogonal method, an overall PPA (95% CI) of 96.3% (94.8, 97.4%) and NPA (95% CI) of > 99.9% (99.9%, 100.0%) was observed. Critically, clinical validity and concordance with tissue-based CGP results across multiple tumor types were also evaluated. Conclusions: The results of these studies demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations (short variants, rearrangements, and copy number alterations), as well as complex biomarkers, such as MSI, bTMB, and tumor fraction. These data demonstrate that the assay can identify genomic variants that may inform therapeutic decisions for cancer patients with any solid tumor using a single blood sample. Additionally, clinical validation results establish FoundationOne Liquid CDx as an additional tool for physicians in the therapeutic management of cancer patients.
Incidence of non-breast cancer neoplasms (non-BCN) diagnosed prior and subsequent to breast cancer (BC): Single institution experience.
Authors: Tomasevic Zorica , Tomasevic Zoran , Grujicic Danica , Nikitovic Marina , Milovanovic Zorka
Published: May 2020

e13689

Background: The risk for developing subsequent non-BCN in BC patients is recognized as growing problem hence more patients are long term survivors. Limited data are available for non-BCN developed prior to BC. Better defining of types and frequency of non-BCN might be important for recognition of cancer predisposing factors. We aim to evaluate incidence, type, and time of development for all non-BCN in BC patients at the Institute for Oncology and Radiology of Serbia (IORS). Methods: During 2019, 2384 BC patients were seen at the IORS for treatment or follow up, all medical records have been evaluated for potential non-BCN diagnosis. Results: 230 (9.7%) patients also had variety of histologically confirmed non-BCN: in 78 (34%) as prior to BC, median 5 years (1-42); as synchronous with BC in 12 (5%) median 4 months (0 < 12 months) and in 140 (61%) as subsequent to BC, median 8 years (≥1-33). Six most frequent non-BCNs are presented in table. Conclusions: Amongst 230 BC patients 34 different non-BCN were identified. All non-BCNs were more frequently developed subsequently to BC, representing 61% of all non-BCN cases, with expected exception of HL hence 12/13 (92%) occurred prior to BC. EC,TC, OC, CRC and LC, represents 54 % of all non-BCN and were diagnosed more frequently as subsequent to BC while TC had similar incidence as prior and subsequent to BC. Subsequent development might be related solely to genetic factors, but at least in some cases, influence of BC treatment (tamoxifen, cyclophosphamide, radiotherapy) cannot be excluded.[Table: see text]
Effect of access to care on outcomes of rural and elderly patients with primary central nervous system lymphoma.
Authors: Howard Scott C. , Napier Nicholas , Cao Xueyuan , Combs Ryan , Watson Mark Layton , Lam Catherine
Published: May 2020

e14008

Background: Primary central nervous system lymphoma (PCNSL) can often be cured, especially in younger patients, but requires intense chemotherapy with high-dose methotrexate (HDMTX) and rituximab to optimize outcomes. Toxicities can lead to dose reduction or omission that may increase relapse risk, or lead clinicians to select less effective regimens that do not contain HDMTX. Methods: Anonymized, de-identified data of patients from 110 community oncology practices of the Guardian Research Network (GRN, www.GuardianResearch.org ) was analyzed to determine treatments, toxicities, and outcomes of adults with PCNSL. All data from the medical record is available from GRN (diagnoses, demographics, labs, medicines, toxicities, radiology, pathology, procedures, and encounters), so each patient’s journey can be fully characterized. Results: Of 533805 adults with cancer, 49 were treated for PCNSL with HDMTX-containing regimens (n = 35), other chemotherapy regimens (n = 3), or radiation therapy (RT) alone (n = 11). HDMTX patients received HDMTX only in 8 cases, HDMTX plus rituximab in 23 cases, addition of RT in 11 cases, and HDMTX with other chemotherapy but no rituximab in 3 cases. Survival at 5 years was 53% (standard error [SE] 8.6%) for patients treated with HDMTX versus 33% (SE 13%) for those treated with other therapies. Of those treated with HDMTX, survival was 0% for patients who experienced early toxicity that required cessation of HDMTX prior to receiving 3 doses and having response evaluated versus 62% (SE 9.1%) for patients who received 3 or more courses of HDMTX (p < 0.001). In a multivariable Cox proportional hazards model including completion of at least 3 doses of HDMTX, age, race, and sex, only lack of HDMTX toxicity was associated with survival (hazard ratio 0.22, 95% confidence interval 0.07 to 0.70, p = 0.01). Conclusions: Use of HDMTX and prevention of toxicity improves outcomes for PCNSL patients treated in the community.
The pink vans: Bringing cancer screening closer to home.
Authors: Ting Frederic Ivan Leong , Leones Louis Mervyn Banua , Chan Abigail Sy , Ignacio Jorge Garcia
Published: May 2020

e14021

Background: A global survey reported that among 15 Asian countries, the Philippines has the highest breast cancer mortality rate and the lowest mortality-to-incidence ratio. This may be due to the fact that majority of breast cancers are diagnosed in locally advanced or metastatic stages among low- and middle-income countries. Studies show that in the Philippines more than half (53%) of patients with breast cancer were diagnosed at stages III and IV, while only 2-3% of cases were treated at Stage I. This translates to a dismal 58.6 % 5-year survival rate. Furthermore, socioeconomic factors were identified as one of the major causes for the lack of access to early detection and treatment. These include lower educational level, higher poverty rates, inadequate or no health insurance, lack of transportation, and/or the unavailability of health services in far-flung areas. These findings are currently of urgent national concern since the improvements in breast cancer survival rates brought by advances in treatments are mainly dependent on early detection, screening and timely treatment. Methods: In response to this gap in the delivery of services to promote early cancer detection, the University of the Philippines – Philippine General Hospital (UP-PGH) Cancer Institute established the Mobile Breast Cancer Diagnostic Clinic Program, a first in the country where two fully equipped “pink” vans are sent out to far flung areas and provide breast cancer screening and diagnostic services (eg. Mammogram, breast ultrasound, biopsies of suspicious masses, etc). These vans are manned by medical and surgical oncologists, and various paramedical professionals. Results: In the first 6 months of the program, the “pink” vans were able to visit 3 strategically identified areas in the country. These three tours have served a total of 189 women who all underwent screening mammography. 18 had their suspicious lesions biopsied, and two-thirds of which were found to be malignant. These patients were then referred to our institution for further work-up and management. Conclusions: As the Philippine health department continues to emphasize clinical and self-breast exam as part of its breast cancer control program, efforts like the UP-PGH “Pink Vans” may eventually help supplement the gap in the country’s breast cancer screening endeavors with the goal of improving survival by identifying the disease at its earliest stage.
Primary care provider involvement in thyroid cancer survivorship care.
Authors: Radhakrishnan Archana , Reyes-Gastelum David , Hawley Sarah T. , Hamilton Ann S. , Ward Kevin C. , Wallner Lauren P. , Haymart Megan Rist
Published: May 2020

e14028

Background: While prior research has examined how primary care providers (PCPs) can help care for breast and colon cancer survivors, little is known about the role of PCPs in thyroid cancer survivorship. We surveyed PCPs to understand their involvement and confidence in providing several aspects of thyroid cancer survivorship care. Methods: Thyroid cancer patients (N = 2632) diagnosed in 2014-2015 and identified from the Georgia and LA SEER registries, were surveyed, and identified their PCPs, who then were also surveyed (N = 162, 56% response rate). PCPs were asked to report their: 1) involvement in thyroid cancer long-term surveillance (not involved: never/rarely vs. involved: sometimes/often/almost always involved); and 2) confidence in handling four aspects of thyroid cancer survivorship care (low: not at all/a little/somewhat vs. high: quite/very confident). We examined PCP factors (individual, practice, attitudes and beliefs) associated with PCP involvement in long-term surveillance using multivariable logistic regression. We then examined associations between PCP involvement in long-term surveillance and PCP confidence in handling the four aspects of thyroid cancer survivorship care using Chi-squared tests. Results: The majority of PCPs (76%) reported involvement in long-term surveillance. Adjusted odds of PCPs reporting involvement was greater among PCPs who somewhat/strongly believed that PCPs have the skills necessary to provide survivorship care (OR 4.33; 95% CI 1.38-15.37), and PCPs who noted clinical guidelines as being the most influential in guiding treatment (OR 4.48; 95% CI 1.67-13.07). PCP reports of high confidence in handling the four aspects of survivorship care were consistently less than 50%: when to refer patient to specialist (40%), role of neck ultrasound (36%), role of random thyroglobulin levels (27%), and when to end long-term surveillance (14%). PCPs who reported involvement in long-term surveillance were more likely to report high confidence in discussing the role of random thyroglobulin levels (33.3% vs. 7.9% for those not involved, p < 0.01) but not the other aspects of survivorship care. Conclusions: Though many PCPs reported they were involved in thyroid cancer long-term surveillance, gaps remain in their confidence in handling several aspects of thyroid cancer survivorship care. Guidelines were noted as important in influencing management; therefore, developing guidelines that specifically delineate PCP roles in thyroid cancer survivorship may present one opportunity to increase PCPs’ confidence about their participation.