bluuebunny/crossref_metadata_2025_split huggingface dataset:
Saliva samples for genomic testing for preventive oncology: Improving the yield.
Authors: Manschreck Christopher , Stratton Kelly Lynn , Sullivan John , Schrader Kasmintan A. , Vijai Joseph , Offit Kenneth 
Published: March 2020

e12555 Background: Germline DNA procurement is an integral step in cancer genomic studies. Saliva collection has numerous benefits over blood draws, including lower cost, easier storage, less risk to patients, and ability to mail samples. However a major limitation to saliva is lower yield per extraction, limiting its use in whole genome sequencing studies. We present a modification of the standard protocol for extracting DNA from saliva collected in Oragene Discover 250 kits (DNA Genotek, Kanata, ON) that reduces both labor and reagent costs while providing yields sufficient for whole genome sequencing. Methods: Nineteen saliva samples were collected using the Oragene Discover 250 kit. Randomly, 10 were selected for extraction using the standard protocol. The remaining nine samples were allocated to the modified protocol. In the modified group, the cell mix was enriched by pelleting, removal of supernatant, followed by resuspension. At this point the sample was enriched for cellular material but at a volume suitable for processing according to the standard protocol. Standard quality control (QC) was performed using a spectrophotometer. Statistical analysis used Student’s T-test and Fisher’s Exact test. Results: All extracted samples attained appropriate quality measures with no significant difference between sample purities (mean 260:280 ratio: 1.72 vs 1.73). Samples undergoing modified extraction provided a mean concentration 50% higher than standard protocol (14.9 µg vs 9.9 µg, p=0.0038, 95% CI: 1.8 – 8.0). Comparing yields required to perform whole genome sequencing, the modified protocol provided significantly more samples meeting QC requirements (p=0.011). Conclusions: The advent of next generation sequencing has made DNA procurement vital to performing studies for preventive oncology. Noninvasive methods are preferred by patients and clinicians. Here we present a modification to a common DNA extraction protocol that provides labor and cost savings while producing sufficient yields for whole genome sequencing.
Variations of DICER1 sequence in Chinese women with BRCA1/BRCA2 negative familial breast cancer.
Authors: Cao Wenming , Gao Yun , Yang Hongjian , Xie Shang-Nao , Meng Xuli , Pan Zhi-Wen , Chen zhan-Hong , Jian Huang , Ye Wei-Wu , Xiying Shao , Jia Wang Xiao 
Published: March 2020

e12557 Background: Germline mutations in identified breast cancer susceptibility genes account for less than 20% of Chinese familial breast cancers. Dicer is an essential component of the microRNA producing machinery and germline mutations of DICER1 gene have been confirmed in familial pleuropulmonary blastoma, ovarian sex cord-stromal tumor and so on. Moreover, low expression of DICER1 is frequently detected in breast cancer. However, whether germline mutations of DICER1 occur in familial breast cancers remains unknown. Methods: 65 breast cancer probands from BRCA1/BRCA2 negative Chinese breast cancer families were used for screening of germline mutations in DICER1. In addition, 100 unrelated healthy females were enrolled as the controls. Polymerase chain reaction (PCR)-sequencing assay was employed to screen mutations in the entire coding regions and exon-intron boundaries of DICER1. Genotype and haplotype analyses were studied by widely available programs. Results: No deleterious mutations were identified in the 65 breast cancer probands. However, we found 12 germline variations and 4 of which were novel. In addition, the G allele frequency of rs2297730 (IVS12-91 A>G) was higher in familial breast cancer patients group than that in healthy controls group (OR = 1.873, 95% CI: 1.174-2.988, P = 0.008), and the A/G genotype were significantly associated with familial breast cancer (OR = 3.133; 95% CI: 1.562-6.287, P = 0.004). According to the minimum value of Akaike’s Information Criterion (AIC), the best genetic model was dominant. In addition, the haplotype GCGGAT was significantly associated with familial breast cancer (OR = 2.17, 95% CI: 1.20-3.91, P = 0.011). Conclusions: Although none of deleterious mutations were identified in the DICER1 gene, the current study provided a haplotype analysis of the DICER1 gene polymorphisms. We showed a significantly increased risk of BRCA1/BRCA2 negative familial breast cancer for DICER1 IVS12-91 A>G variant. It might be a potential risk marker for breast cancer in thus population.
Clinical and morphological characteristics of BRCA-associated and sporadic breast cancer in fertile female in the Altai territory.
Authors: Petrova Valentina Dmitrievna , Terekhova Svetlana Aleksandrovna , Sinkina Tatiyana Vladimirovna , Selezneva Inna Anatolievna , Dimitriadi Ylija Nikolaevna , Ermolenko Natalya Aleksandrovna , Boyarskih Ulyana Aleksandrovna , Filipenko Maxim Leonidovich , Lazarev Alexander Fedorovit 
Published: March 2020

e12560 Background: Breast cancer (BC) for more than 10 years is the most frequent cancer in females in the Altai territory of Russian Federation. The share of patients under 40 years old varies from 2.6% to 16.0%. Genetically dependent nature of BC in young female is scientifically confirmed fact. The aim of this study was to analyze characteristics of BRCA-associated and sporadic BC in fertile females. Methods: 161 female patients of fertile age (under 40 years old) with BC were examined. Clinical, morphological and genetic (BRCA1) factors were analyzed. BRCA1 mutation was revealed in 22 patients (139 patients did not have it). Results: 82.0% of patients with BRCA1 mutations had positive family cancer history. In this group BC was diagnosed more frequently at the age of 31-35 y.o. (40.9%), while in the group of sporadic cancer – at the age of 36-40 y.o. (58.2%). Pathomorphological forms of BC were analyzed and in both groups infiltrative forms of BC were the most frequent (95.5% and 91.4% correspondingly). I stage cases of BC were diagnosed more frequently the group of sporadic cancers than in the group of BRCA-associated cancers (23.0% and 4.5% correspondingly, P<0.05). Hormone status of the tumours was analyzed. BRCA-associated cancers were significantly more often ER and PR negative (87.5%, P<0.05). Hyperexpression of Her2neu was not revealed in this group. In the group of patients without BRCA mutation ER and PR negative tumours were also prevalent (60.5%, P<0.05). Hyperexpression of Her2neu (+++) was revealed in 6.9%. Triple negative cancers were prevalent in the both groups, while in the group of BRCA-associated cancers there were 91.7% of such tumours. The percentage of polyneoplasia in the group of patients with BRCA mutations was higher than in the group without them (12.0 and 1.0 correspondingly, P<0.05). Conclusions: In females of fertile age carriage of BRCA mutations in 82.0% connected with family cancer history. In the group of sporadic cancers I stage cases of BC are more frequent. In both groups hormone receptor negative and triple negative cancer are prevalent, but in the group of BRCA-associated cancers the percentage of such tomours and polyneoplasia are significantly higher.
The number of metastatic lymph node in N3M0 breast cancer and influence on survival.
Authors: Solak Mustafa , Turkoz Fatma P. , Keskin Özge , Petekkaya Hilbrahim , Sarici Saim Furkan , Babacan Taner , Esin ECE , Aksoy Sercan , Altundag Kadri 
Published: March 2020

e12563 Background: To evaluate the impact of the number of metastatic lymph node (MLN) in N3M0 breast cancer patients with a sufficient lymph node sampling. Methods: 200 patients with histopathologically confirmed N3M0 breast cancer were analyzed. Patients were divided into three groups according to the MLN; i) MLN:10-15, ii) MLN:16-20, iii) MLN:>20. Pearson Chi-square test and Kaplan-Meier test were used. Results: 25 patients had T1, 91 had T2, 69 had T3 and 15 had T4 tumor. The number of median MLN was 15 (10-48). HER-2, ER and PR status were similar. There were no significant differences in age at diagnosis, menopausal status, stage, grade and treatment among groups (p>0,05). The median follow-up period was 41.5 months. The median OS was 100, 98 and 58 months in group I, II and III, respectively (p=0.06). When we analyzed for two groups; the median OS was significantly shorter in patients with >20 MLN than patients with 10-15 MLN (98 vs. 58 months; p=0.04). We found no significant difference in DFS (p=0.52). The patients with >20 MLN had increased risk of mortality compared to patients with 10-15 MLN (adjusted-HR 1.96 (95%CI 1.1-3.5); p=0.025). Conclusions: To define the subgroups according to MLN in N3 disease may help determining the high-risk patients and making decision in clinical practice. However this finding should be supported by larger studies.
Twenty-five year anniversary of a successful rural, community hospital, comprehensive cancer screening program.
Authors: Waheed Shahid , Linthacum Tonya A 
Published: March 2020

e12569 Background: A 25 year successful comprehensive cancer screening program at a rural community hospital in Mexico, MO, USA, provides a multi-organ cancer detection clinic for asymptomatic women over age of 35. Methods: The Screening Program consists of a Medical Director, day to day oversight by a Family Nurse Practitioner, with nurse practitioner and specialty trained registered nurse examiners. This multi-organ screening program focuses on breast, colon, skin, cervical and prostate cancer early detection. One-hour screening exams for women include detailed cancer risk assessment, prevention education, head-to-toe physical exams including an examination of the skin, clinical breast exam, mammogram, pelvic and Pap test. Additionally, site-specific exams of the abdomen, thyroid, peripheral lymph nodes and rectum are conducted. Male exams include a physical examination of the skin, abdomen, peripheral lymph nodes, thyroid, external genital, digital rectal exam of the prostate and PSA blood education. For all tobacco users, the screening includes an oral examination. Extensive education is provided to participants on prevention modalities, current screening guidelines, and new research findings. Detected abnormalities are referred to the patient’s primary care physician for follow up. A phone call to the patient and the primary care provider four to six weeks after the initial exam obtains the results of the referral visit. Results: 25-year participation rates total 51,223 visits with a ratio of 1 male to 19 females. Return rates over the past year were 94%. 626 cancers have been detected since the inception of the program with 1 breast cancer for every 41 women participating, most identified at early stages. Over 2,500 participants, with a 95% satisfaction rating, from 48 Missouri counties, as well as 21 states of the nation are seen annually for cancer screening. Conclusions: Comprehensive screening programs are effective at decreasing cancer mortality and morbidity through education, prevention, and early detection. Nurse run clinics offer a satisfying, cost effective alternate approach, while continuing to provide competent expertise in the specialized field of cancer prevention.
Training and validation cohort analysis for predicting radiation therapy response in human glioblastoma.
Authors: Corwin David , Rockne Russell , Mrugala Maciej M. , Rockhill Jason K. , Swanson Kristin 
Published: March 2020

e13018 Background: Glioblastomas comprise 50% of primary brain tumors and are the most fatal, with a median survival time of 14 months despite aggressive treatment. Due to disease heterogeneity and the presence of subclinical disease, there is a large variability in treatment response among patients, making it difficult to assess treatment efficacy and confounding clinical decision making. Methods: A patient-specific, mathematical model of glioblastoma has been shown to predict untreated growth as well as the effect of radiation therapy. We expand on the technique presented in Rockne 2010 to determine patient-specific radiosensitivity and post therapy radial growth using only pretreatment data. From a potential cohort of 44 patients we randomly chose a training set of 30 to compute the relationship for the radiosensitivity parameter (alpha) versus the net proliferation rate. We then used that relationship to compute an individualized alpha for the remaining 14 test patients based only on pretreatment information. For each of the test patients we compared the observed T1Gd visible radius at the first post radiotherapy timepoint with the simulated prediction. Results: Half of the patients demonstrated average absolute differences between the observed and simulated post radiotherapy T1Gd radii of less than 5 mm, within the measurement error associated with contouring the tumor on MRI, with a maximum difference of 2.5 cm. The largest errors were observed in patients with significant resection. Conclusions: This patient-specific, mathematical model of glioma growth and response to radiotherapy can potentially predict radioresponse in vivo, prior to the commencement of therapy. As a clinical tool, this can have prognostic applications and separate responders from non-responders before deciding to treat with radiotherapy. The larger error for patients with more extensive resections is not unexpected given the difficulties in contouring and assessing tumor burden post surgery. This can be improved by including other imaging modalities such as pre-gadolinium T1 and improving the quantification of extent of resection.
Application of mechanism-based PKPD model to identify optimal dosing regimens for future development of oraxol.
Authors: Fetterly Gerald J. , Gaudy Allison , Liu Biao , Meholick Patricia D. , Kwan Min-Fun Rudolf , Hangauer David G. , Park Kyung-Mi , Son Jeewoong , Bang Yung-Jue 
Published: March 2020

e13505 Background: Paclitaxel (PTX) is a widely used potent anticancer drug that blocks mitosis by stabilization of microtubules. Previous attempts for oral administration of PTX have been unsuccessful at least partly due to its affinity for the efflux pump, P-gp. Oraxol is an oral formulation of PTX combined with a novel potent P-gp inhibitor, HM30181A, to maximize absorption of paclitaxel without itself being systemically absorbed. A population PK/PD model was developed to characterize the temporal relationship between PTX exposure and neutropenia, and subsequently model-based simulations were utilized to determine the optimal dosing strategy for oraxol. Methods: Oraxol was administered to 68 (51M/17F) patients with various malignancies. Oraxol dose levels ranged from 60 to 420 mg/m2 QW, and 90-150 QWx2 for 3/4 weeks. Population PKPD modeling was performed with the following patient factors: [BSA (1.29-2.15 m2), ECOG PS scores (97% pts ≤ 1), age (36-81.4 yrs), CrCL (39.6-132.8 ml/min), ALB (2.3-4.8 mg/dL), ALT (6-61 IU/L), TBIL (0.2-1.6 mg/dL), and smoking status (NS:57%)]; followed by model validation. Simulations assessed the influence of dose and schedule on the time course and the extent of neutropenia. Results: A precursor-dependent indirect PKPD response model, including three transit compartments was employed to describe the time course of ANC after oraxol administration. Mean predicted (%SEM) baseline ANC and MTT of neutrophils in plasma were 3.6 (3.9) x109 cells/L and 6.3 (4.2) days. The magnitude of the inhibition on marrow cells was 3.3% per 100 ng/mL of PTX. Model validation results showed excellent concordance with the observed and simulated ANC profiles at the 150 mg/m2 dose level. Simulations showed that severity of neutropenia was dose- and schedule-dependent. The optimal dosing scenarios for oraxol 150 mg/m2QDx3 and QDx5 showed the incidence of grade ³3 neutropenia to be 53.8% and 58%, respectively. Simulated grade 4 neutropenia was 25 and 34.6% for the same regimens; similar to IV PTX. Conclusions: A PKPD model quantifying the neutropenic effect of oraxol has been developed. The model predicts that the QDx3 or QDx5 oraxol dosing 3/4 weeks may optimize efficacy with manageable toxicity.
Effect of Sonic hedgehog activation on CXCR7 expression and CXCR4 signaling in medulloblastoma.
Authors: Ward Stacey Anne , Sengupta Rajarshi , Rubin Joshua 
Published: March 2020

e13537 Background: Stratification of pediatric medullolastoma into molecular subtypes elevates hopes that subtype-specific therapy can be more efficacious and less toxic. To realize this goal, the molecular targets that distinguish each subtype must be defined. We found that Sonic hedgehog (Shh)-subtype medulloblastoma can be further divided by CXCR4 expression and that CXCR4 inhibition has potent anti-tumor effects. Here we present data that Shh regulates CXCR4 activity through CXCR7, whose differential expression between normal granule cells and medulloblastoma cells makes its function an ideal therapeutic target. Methods: Single-cell suspensions were plated with or without Shh or cyclopamine followed by treatment with CXCL12. SmoA1 brain tumors were dissociated into single cells and transplanted into nude mice and treated with vehicle, AMD3100, GDC-0449, or both. Tumors were measured and harvested at the conclusion of treatment. Results: Using primary cultures of Shh-driven medulloblastoma we found that Shh activation enhances CXCR4 surface localization and promotes CXCL12-induced signaling, similar to effects of Shh on normal granule cells. We evaluated expression of CXCR4 internalization regulators and found that Shh activation altered the levels of GRKs, arrestins and CXCR7. Among these, CXCR7 expression exhibited the greatest differential response to Shh pathway activation between normal cells and medulloblastoma: CXCR7 expression was highly expressed in normal cells despite Shh effects, but almost completely absent in tumor cells. Conclusions: We conclude that activation of the Shh pathway in medulloblastomas promotes CXCR4 surface localization through inhibition of internalization mediators. This cross-talk is also evident in developing GPCs but with one notable difference: CXCR7 expression (high in normal cells, absent in tumor cells). This distinction suggests that CXCR7 antagonists, which are moving towards clinical trials, may be detrimental to normal cerebellar development and inactive against medulloblastoma. We propose that restoring CXCR7 activity would have negligible effects on granule cells and potently block CXCR4 function in medulloblastoma.
Correlation between development of rash and efficacy of EGFR inhibitors: A meta-regression analysis.
Authors: Ortega-Parra Camilo A. , Donath Elie , Garcia Salvador Ricardo , Jacobson Robert J. 
Published: March 2020

e13539 Background: Treatment with Epidermal Growth Factor (EGFR) inhibitors is frequently characterized by the presence of a rash. Previous research has suggested that developing this rash may be associated with improved outcomes. It has been difficult, however, to establish a direct link between occurrence of a rash and tumor response. Rashes are also likely to occur with greater drug exposure and it is possible that they exist as a confounder in the well established relationship between drug exposure/dosing and tumor response. The purpose of this meta-regression analysis is to define whether a correlation exists between the incidence of rash and clinical outcomes including response rate (RR), progression-free survival (PFS) and overall survival (OS) and then examine whether a similar relationship exists with other adverse events as that would suggest that rash occurrence is simply a function of drug dosing and not necessarily an indicator of tumor response. Methods: A literature search for RCT’s involving EGFR inhibitors in non-small cell lung cancer (NSCLC) identified 31 trials. This included 5 trials of Cetuximab, 13 trials of Gefitinib and 13 trials of Erlotinib. Multivariate meta-regression analysis was performed to evaluate whether all rashes (grades 1-5) and severe rashes (grades 3-5) as well as vomiting and neutropenia (two randomly chosen adverse events) may have influenced effect size (measured by RR, PFS and OS) across this cancer type. Results: The presence of severe rashes in the treatment arm was positively correlated with increased PFS (p<0.01) in NSCLC - a similar correlation was also found for risk of vomiting. Additionally, the presence of any rash in the treatment arm was positively correlated with increased OS (p=0.03) in NSCLC – a similar correlation was found for risk of vomiting and neutropenia. Conclusions: The presence of a rash seems to connote an increased likelihood of tumor response and/or survival in NSCLC. The fact that other adverse events (vomiting and neutropenia) are more evident in these responding patients suggests that rash occurrence may simply be a confounder in the EGFR inhibitors’ dose-response relationship as opposed to being independently associated with any tumor response.
Dose-efficacy relationship for molecularly targeted agents: A literature review of monotherapy phase I cancer clinical trials.
Authors: Arrondeau Jennifer , Paoletti Xavier , Sablin Marie-Paule , Pop Simona , Le Tourneau Christophe 
Published: March 2020

e13553 Background: Data regarding the dose-efficacy relationship for molecularly targeted agents (MTAs) are conflicting and all based on institution data. We report the largest study evaluating this relationship based on an extensive literature review of phase I trials of MTAs administered as single agents over the last decade. Methods: Efficacy defined by the occurrence of partial or complete responses was recorded and related to the dose administered expressed as a percentage of the maximum tolerated dose (MTD) or the maximum administered dose (MAD) when the MTD was not reached. Association was estimated using logit model with random intercept to adjust for the study. Results: Hundred and sixty eight phase I trials evaluating 116 MTAs involving 5,668 patients were reviewed. Efficacy was present in 39% of trials, but in only 134 patients (2.3%). Among these 134 patients, the dose at which signs of efficacy occurred was known for 113 patients. Overall, the crude response rate slightly increased from 4% at doses <40% of the MTD/MAD to 6%, 7% and 7% at doses 40-80%, 80-120% and >120%, respectively. However, statistical significance was not reached (p=0.28), whether or not the MTD had been reached. Conclusions: Antitumor activity infrequently occurs in phase I trials of MTAs administered as single agents. Although efficacy seemed to increase with dose, statistical significance was not reached, possibly due to the low response rate and sample size.