tbuckley/cabot-search huggingface dataset:
VEGF-A and VEGF-R1 in benign and malignant ovarian tumors: Correlation with HE4 tumor marker.
Authors: Valeria Bandovkina, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Tatiyana Moiseyenko, Fatima Isakova, Ekaterina V. Verenikina, Tatiyana Georgievna Chalabova, Natalia D. Cheryarina, Irina Stasio Tavaryan, Konstantin Pavlovich Boyko, Viktor Viktorovich Gurnak
Journal: Journal of Clinical Oncology (2016)

e17099 Background: Angiogenesis activity in the adult organism is primarily associated with the processes of blood vessel structure maintenance, wound healing and the menstrual cycle. VEGF-A is a powerful mitogen for endothelial cells, it inhibits apoptosis, stimulating cell survival. In tumor growth, balance of angiogenesis regulators is distorted and it goes out of the organism control meeting the needs of the growing tumor. HE4 is an ovarian cancer tumor marker. Our purpose was to study association between HE4 tumor marker and levels of VEGF-A and VEGF-R1 in ovarian tumor process. Methods: Levels of НЕ4, VEGF-A and VEGF-R1 in 47 patients with benign ovarian cysts (group A) and 76 patients with malignant ovarian tumors (group B) were determined by ELISA using standard test systems. Results: HE4 level increase by 27.5 and 37.6 times was found in 32.1% in group A and in 91.2% in group B, respectively. HE4 in group B did not exceed the norm in patients with metastatic and non-epithelial ovarian cancer. Positive correlation between HE4 and VEGF-A was found in ovarian tumors (group B) (r = 0,911). In patients with high HE4 level, VEGF-A concentration increased by 3.5 times in group A and by 8.5 times in group B. VEGF-A/VEGF-R1 ratio in tissue of tumors with high HE4 level increased by 7.3 times in group A and by 8.7 times in group B. Conclusions: We revealed an association between expression of tumor markers and neoangiogenesis system VEGF-A - VEGF-R1 in ovarian tumors; high HE4 level in ovarian tissue results in VEGF-A concentration increase and decrease of VEGF-A/VEGF-R1 ratio in both benign and malignant tumors.
Genetic variations in endometrial cancer by histology, stage and BMI.
Authors: Dario R. Roque, Tara Castellano, David N. Hayes, A. Mitch Dizon, Leslie Horn Clark, Stuart Pierce, Weiya Zhang Wysham, Rashid Naim, Paola A. Gehrig, Victoria Lin Bae-Jump
Journal: Journal of Clinical Oncology (2016)

5593 Background: We aimed to determine the most common mutations in endometrial cancers (EC) of patients enrolled in UNCSeq and to discern if there was any correlation between the detected mutations and the patients' BMI as well as tumor histology and stage. Methods: Snap-frozen and FFPE tissue samples were collected from EC patients enrolled on UNCSeq (NCT01457196). Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Mutations with a quality score < 100 were filtered from the data set and only mutations rated to have a moderate to high impact were retained. Patient Mutational Counts were associated with clinical correlates via negative binomial regression, and the heterogeneity of mutational counts between groups was assessed via the Fligner-Killeen Test. Results: Data was collected from 126 EC patients. We found 591 mutations that appeared in at least 1 individual. The five most common mutations detected in endometrioid tumors were of PTEN, PIK3CA, ARID1A, PIK3R1 and CTNNB1. The most common mutations in serous tumors were of TP53, PIK3CA, FBXW7, MML2 and MLH1. After limiting the analysis to the 104 patients with endometrioid histology, we did not observe a correlation between BMI and mutation frequency. However, patients with Stage 1 and 2 disease (early) tended to have a much higher mutation frequency than patients with Stage 3 and 4 disease (advanced) (p = 0.004). Similarly, Grade 1 EC also exhibited greater mutational heterogeneity in terms of total number of mutations observed per patient relative to other grades (p = 0.037). Conclusions: We did not find a relationship between BMI and mutated genes in endometrioid EC. Further collection of EC through UNCseq is ongoing. However, mutation heterogeneity appears to be common in low stage and grade tumors. These findings suggest that mutation heterogeneity may be relatively indolent until sub-clonal populations eventually arise as a result of acquired driver mutations, such that one subpopulation predominates, resulting in higher grade and stage EC.
Mediation of black/white race disparity in basal type breast cancer by socioeconomic position and parity.
Authors: Keith A. Dookeran
Journal: Journal of Clinical Oncology (2018)

e13588 Background: It is theorized that the black/white race disparity in aggressive breast cancer (BC) subtype might be transmitted through social and reproductive influences. As few studies have so far investigated, we examined to what extent the black/white race disparity in basal type BC might be transmitted through these influences. Methods: Study sample is a previously reported cohort of 419 consecutively enrolled (331 non-Hispanic (nH) black and 88 nH white) women with primary BC aged 24-94 years, treated between 2000-2005 at an NCI-MBCCOP facility in Chicago, IL (Dookeran 2012). US 2000 census ZIP Code Tabulation Area (ZCTA) data matched to patient address zip codes at diagnosis was used to develop a single binary measure of socioeconomic position (SEP) ( > US poverty mean vs. referent of US poverty mean < / = 9.2%; based on national census data for the number of families living below the poverty level threshold in 1999). Parity (integer values) was used as a single measure of reproductive status. We estimated average controlled direct associations (ACDA) using logistic regression with model-based standardization (predictive margins) to estimate the age/BMI adjusted prevalence difference with bias-corrected bootstrapped 95% confidence intervals (CIs) for basal vs. luminal A type BC by race and performed a series of ACDA (with comparison of rescaled coefficients) controlling for SEP and parity both individually and together. Results: In age/BMI adjusted models, nH black women were 13%-points more likely than nH white to have basal type BC (p = 0.07). This disparity was reduced to 12%-points after adjustment for parity only, 10%-points after adjustment for SEP only, and 8%-points after adjustment for both parity and SEP (95% CI: -0.11, 0.23). Based on the method of rescaled coefficients, parity and SEP individually accounted for approximately 19% and 27% respectively of the black/white disparity in basal type BC when modeled together, accounting in combination for 46% of the disparity (p = 0.07). Conclusions: Our findings support the hypothesis that at least part of the observed black/white disparity in aggressive basal type BC might be transmitted through social influences on tumor biology, in particular via SEP.
The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer.
Authors: Hiromi Watanabe, Toshio Kubo, Takashi Ninomiya, Kadoaki Ohashi, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2017)

e20601 Background: Central nervous system (CNS) metastases (mets) occur in 30% of patients with advanced non-small cell lung cancer (NSCLC) and are associated with poor overall survival (OS). Although nivolumab, a programmed death-1 immune checkpoint inhibitor antibody, has demonstrated a longer survival benefit compared with docetaxel in previously treated NSCLC patients (CheckMate 017 and 057; N Engl J Med, 2015), patients with symptomatic or untreated CNS mets were excluded in these trials. In CheckMate 012 Arm M, 2 of 12 patients (16.7%) with untreated CNS mets showed intracranial responses, but the effect of nivolumab treatment for CNS mets was not fully investigated. Methods: To investigate the effect and safety of nivolumab for CNS mets in NSCLC patients, we retrospectively analyzed 48 patients with NSCLC who were treated with nivolumab from February 2016 to December 2016 at Okayama University Hospital. Results: Twenty-nine patients (60%) had no CNS lesions (group A) and 19 patients (40%) had brain mets (BM) (group B). In group B, 15 patients (79%) received radiotherapy (RT) for BM, including 5 patients who received RT just before nivolumab treatment. The responses of extra-CNS lesions to nivolumab are shown in the table. The PFS was longer in group A than in group B (p=0.14). In group B, the PFS of patients who received prior RT tended to be longer than in those without RT (p=0.42); OS was not reached in either group. In group B, the effects of nivolumab treatment for CNS mets were evaluated in 12 patients: SD occurred in 3 patients (25%), PD in 4 patients (33%), and NE in 5 patients (42%). All 4 patients with PD in the CNS lesion also showed PD in the extra-CNS lesion. In group A, no patients showed progression only in the CNS lesion. Conclusions: In this retrospective study, there were no patients treated only with nivolumab who showed a response to CNS mets. RT prior to nivolumab might be more effective, so future investigations should involve additional cases and prospective studies. [Table: see text]
Enhancement of radiation effect on lung cancer A549 cells by gold nanoparticles.
Authors: Tao Li, GuoJun Zhang
Journal: Journal of Clinical Oncology (2018)

e20505 Background: To study the in vitro radiosensitization effect of Thio-glucose capped gold nanoparticles(Glu-GNPs) combined with kilovolt or megavoltage X-ray on lung adenocarcinoma A549 cells. Methods: The crystal violet method was used to detect the cytotoxicity of Glu-GNPs on A549 cells and the radiosensitive inhibition of proliferation. The distribution of Glu-GNPs in the cells was observed by transmission electron microscopy (TEM). Dose-cell viability scores after irradiation with 160 KeV and 6 MeV X-rays, respectively, were determined by cell clone analysis and radio-biological parameters were calculated using a single-click multi-target model. The DNA double-strand breaks (Foci foci) of A549 cells were detected by γ-H2AX immunofluorescence. Results: TEM showed Glu-GNPs into A549 cells were aggregated state attached to intracellular membrane organelles - lysosomes or endosomes.Glu-GNPs at the concentration of 0-100nmol / L did not significantly inhibit the viability of A549 cells (P > 0.05).Cell cloning experiments showed that the SER of 100nmol / L Glu-GNPs combined with 160KV and 6 MeV irradiation was 1.41 and 1.15, respectively (P < 0.05). Glu-GNPs significantly increased DNA double-strand breaks in A549 cells induced by 160KV and 6 MeV X-rays (P < 0.05). Conclusions: Nano-gold can enter cells by endocytosis and locate in endosomes or lysosomes, and increase the sensitivity of lung adenocarcinoma A549 cells to radiation.
A radiomic signature based on advanced tumor shape parameters (Spiculated-ness) to predict the outcome of locally advanced (LA) HNSCC patients.
Authors: Sylvain Reuz, Elaine Limkin, Dan Ou, Yungan Tao, Antoine Schernberg, Eric Deutsch, Charlotte Robert, Charles Ferte
Journal: Journal of Clinical Oncology (2016)

11571 Background: Tumor invasion patterns are known to be associated with HNSCC pts outcome. Radiomics is a rapidly-emerging field involving the extraction of quantitative imaging features from standard medical images, and their integration with clinical traits. Whether advanced 3D tumor shape parameters reflect the tumor invasiveness and the outcome in HNSCC pts remains unknown. Methods: Two cohorts were analyzed: 120 LA HNSCC pts (Gustave Roussy) and 164 LA HNSCC pts (TCGA HNSCC). Semi-automatic tumor contours of baseline contrast-enhanced CT scans were performed. Advanced 3D tumor shape parameters (n = 31) including convexity, sphericity, distance to centroid, or fractal dimension were generated. Radiomic features were trained for PFS and selected using Lasso (penalized linear regression) bootstrapped models. The predictive performances of the models were evaluated by Concordance Index (CI) and by Kaplan Meier estimates. Unsupervised bi-clustering methods explored radiomics and clinicopathological relationships. We investigated the biological significance of our signature by inferring the mutations and copy number aberrations associated with its predicted values in TCGA HNSCC. Results: We developed a powerful 9 shape feature classifier, which was performant across for OS, PFS and local control predictions (all CI > 0.7, all log rank p values < 0.001, all multivariate analysis P values < .05). The signature combining radiomics + clinical features was superior to the clinical features alone. Notably, an unsupervised biclustering of radiomic features alone correlated with tumor location (P < .01), suggesting specific biological traits being captured by shape features. The comprehensive relationship between our predictor with TCGA HNSCC genomic data will be presented during the ASCO meeting. Conclusions: We developed a highly performant radiomic signature of Spiculated-ness predicting prognosis in LA HNSCC pts, independently from the TNM, the tumor location or the chemoradiation regimen. These promising results have the potential to change the decision making at bedside for LA HNSCC pts and to improve the stratification in future clinical trials.
TCT-407 Sex differences in symptom pattern of chest pain and resolution following coronary revascularization
Authors: Pietro Di Santo, Alisha Labinaz, Rebecca Rochman, Richard Jung, Trevor Simard, Francisco Ramirez, Ian Pitcher, Pouya Motazedian, Robert Moreland, Jeffrey Marbach, Paul Boland, Kiran Sarathy, Saleh Alghofaili, Juan Russo, Etienne Couture, Michel Le May, Marino Labinaz, Chris Glover, Benjamin Hibbert
Journal: Journal of the American College of Cardiology (2018)
Radiotherapy with concurrent Avelumab and Cetuximab as primary treatment in patients with locally advanced squamous cell carcinoma of the head and neck: A phase-IB feasibility trial in patients unfit for cisplatin (NCT02938273).
Authors: Joris B. W. Elbers, Charlotte L. Zuur, Margot Et Tesselaar, Charlotte Lange, Abrahim Al-Mamgani, J. P. De Boer
Journal: Journal of Clinical Oncology (2018)

e18019 Background: Radiotherapy (RT) with concurrent EGFR inhibition (cetuximab) is standard of care in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) unfit for cisplatin treatment. This combination leads to both NK-cell mediated cytotoxicity and an increase in PD-L1 expression on tumor cells. By combining cetuximab-RT with a PD-L1 inhibitor (avelumab), we aim to develop a treatment regimen with at least similar efficacy as chemoradiation but less irreversible toxicity. Methods: Phase-IB trial (10 patients) to assess safety and toxicity of concurrent radiotherapy (5 times a week, total dose 35x2 Gy) with cetuximab (loading dose 400 mg/m2 in week -1, 250 mg/m2 week 1-7) and avelumab (10 mg/kg every 2 weeks concurrent with RT + 4 months maintenance). Results: At the time of analysis, 6 of 10 patients had started their treatment. One patient experienced a grade 3 cetuximab-related infusion reaction and withdrew from study before avelumab was administered. One 81 year old patient discontinued treatment after 2 avelumab cycles and 12x2 Gy RT. This patient experienced no toxicity except grade 2 dysphagia. The other 4 patients completed the prescribed treatment, 2 of them are still treated with maintenance therapy. Median follow-up after starting RT was 5.7 (3.7 – 7.4) months. One patient experienced an avelumab induced grade 3 pneumonitis 3 weeks post RT and discontinued avelumab after 4 cycles. The pneumonitis resolved after 4 days with 1mg/kg prednisone. All patients were in complete remission 2 weeks after completion of RT and 2 weeks after the completion of maintenance therapy (Ojiri 0), one patient had an Ojiri 1 response 2 weeks after maintenance therapy. Conclusions: These preliminary data suggest that avelumab can be safely administered with concurrent cetuximab-RT regimen to patients with locally advanced SCCHN, who are unfit for cisplatin treatment. Preliminary efficacy data in terms of treatment response and immune infiltrate will be further evaluated by ctDNA measurement and immunohistochemistry. Clinical trial information: NCT02938273.
Retinoblastoma mutation to predict poor outcomes in non-small cell lung cancer (NSCLC).
Authors: Priyanka Bhateja, Gary Wildey, Pingfu Fu, Mary Beth Lipka, Fatemeh Ardeshir-Larijani, Neelesh Sharma, Afshin Dowlati
Journal: Journal of Clinical Oncology (2017)

9060 Background: Genomic profiling of tumor DNA has revealed the diversity in NSCLC. The retinoblastoma gene ( RB1) encodes for RB pocket protein that plays an important role in cell cycle progression by interacting with various transcriptional factors. Here we determine the frequency and prognostic significance of RB1mutation in NSCLC and compare it to that in small cell lung cancer (SCLC). Methods: This IRB-approved retrospective review on NSCLC patients included Stage III and IV patients with genomic and clinical data. Primary outcome was median overall survival (OS) and secondary outcome was progression-free survival (PFS). OS and PFS were calculated by the Kaplan-Meier method and compared between mutant and wild-type (wt) RB1using the Log-Rank test. The effect of RB1mutation status on OS and PFS was further evaluated using the multivariable Cox model, controlling the effects of age, sex, stage, smoking history and chemotherapy. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified RB1 mutation in 8.2% of NSCLC patients (16 of 195 patients). With a median follow-up of 15.1 months, the median OS for wt RB1was 28.3 months and for mutant RB1 was 8.3 months (HR = 2.59, p-value = 0.002). The median PFS for wt RB1 was 21.8 months vs 6.4 months for mutant RB1 (HR = 2.85, p-value = 0.0002). RB1 mutation was associated with worse OS ( p= 0.017, HR = 2.17) and PFS ( p= 0.005, HR = 2.37) in multivariate analyses after adjusting for traditional risk factors like, age, sex, stage, smoking history and chemotherapy. Interestingly, a previously described benign deletion (A16-A18) in RB1 protein was identified in 5 of the 16 RB1 mutant patients and was associated with far worse outcomes compared to other RB1 mutations. In contrast to NSCLC, RB1 mutation was identified in 75% of 64 SCLC patients. Furthermore, wt RB1 was associated with significantly shorter OS ( p= 0.002), PFS ( p= 0.004) and chemotherapy refractoriness ( p= 0.033) in SCLC. Conclusions: RB1 mutation is present in a minority of patients with advanced NSCLC and is associated with poor prognosis. In contrast, RB1 mutation is present in the majority of SCLC patients and is associated with a favorable prognosis.
A re-analysis of the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial accounting for ovarian cancer (OVCA) heterogeneity.
Authors: Sarah Madhu Temkin, Eric A Miller, Goli Samimi, Christine D Berg, Paul Pinsky, Lori M. Minasian
Journal: Journal of Clinical Oncology (2017)

5564 Background: A mortality benefit from screening for OVCA has not been demonstrated, but screening efficacy could differ for histologic subtypes. We re-analyzed PLCO evaluating whether OVCA detection and outcomes were affected by the heterogeneous biologic behavior of this disease. Methods: Type 2 tumors (moderately/poorly differentiated serous and adenocarcinoma) were compared to all other tumor (OT) types (low grade serous and endometrioid, clear cell, other, low malignancy potential) (LMP). We examined differences in the distribution of tumor types and stage by study arm and method of diagnosis [screen detected (SD) and interval detected (ID) (i.e. assigned to screening but diagnosed between screening tests)]. Stage distribution and survival were analyzed. Results: Among the entire PLCO population, 531 women were diagnosed with OVCA during the study; 282 (53%) in the screening arm and 249 (47%) in the usual care arm. Of the tumors able to be characterized (n=408; 77%), 74% (n=300) were Type 2 and 26% OT (n=108). In the screening arm, 70% of tumors diagnosed were Type 2 compared to 78% in usual care (p=0.07). Overall, survival was significantly better for OT tumors compared to Type 2 tumors (p&lt;0.01) but there was no difference in survival by study arm for either tumor type separately (Type 2: p=0.50; OT: p=0.23). Within the screening arm, 30% of Type 2 tumors were SD compared to 54% of OT tumors (p=0.02) (see Table). Only 15% of Type 2 SD tumors were Stage I/II, compared to 82% of SD OT tumors (p&lt;0.01). Stage at diagnosis was similar among Type 2 patients whether they were SD or ID (p=0.56) and there was no difference in survival (p=0.56). Conclusions: A significant difference in tumor types by study arm was not observed. However, within the screening arm, Type 2 tumors were less likely to be SD or Stage I/II compared to OT tumors. Survival for Type 2 tumors was similar regardless of method of diagnosis. [Table: see text]
Adoption of immunotherapy into real-world practice: Insights from the use of checkpoint inhibitors.
Authors: Jeremy O'Connor, Kathi Seidl-Rathkopf, Paul You, Nathan C. Nussbaum, Aracelis Z. Torres, Kristen L. Fessele, Katie Darius, Kerin B. Adelson, Emily Yin, Carolyn Jean Presley, Anne C. Chiang, Joseph S. Ross, Amy Pickar Abernethy, Cary Philip Gross
Journal: Journal of Clinical Oncology (2017)

e14583 Background: Cancer research has been criticized regarding the generalizability of trials to older persons, as well as the timeliness of the impact of new trials on real-world practice. Despite growing enthusiasm about programmed death 1 checkpoint inhibitors (anti-PD1s), little is known about the speed with which these drugs are adopted into real-world practice, or whether anti-PD1 treated patients in real-world practice are older than patients treated in trials. Methods: We used retrospective data from Flatiron Health’s electronic health record database, which includes 250 cancer clinics and 1.5 million patients with cancer. We identified patients diagnosed after January 1, 2011 who underwent systemic therapy for: advanced melanoma (n=1,670), advanced non-small cell lung cancer (aNSCLC; n=19,536), or metastatic renal cell carcinoma (mRCC; n=2,018). Then, we determined the proportion treated with anti-PD1s in the 2 nd line or later following US Food and Drug Administration (FDA) approval. Therapy lines containing study drugs were excluded. Chi-square tests were used to compare age distributions of patients treated in real-world practice to patients treated in trials that support FDA approval. Results: At 6 months following FDA approval, 71.9% of patients with melanoma undergoing treatment were receiving anti-PD1s, versus 33.0% of patients with aNSCLC and 46.0% of patients with mRCC. Within 1 year, more than half of all treated patients with these 3 cancers were receiving anti-PD1s (71.0% in melanoma; 51.4% in aNSCLC; and 51.8% in mRCC). The median ages at first receipt of anti-PD1s were ≥65 years (65.1 years in melanoma; 67.9 years in aNSCLC; 66.0 years in mRCC). Anti-PD1 treated patients were significantly older in real-world practice than patients treated in trials (Table: all p&lt;0.001). Conclusions: In a large national sample of patients with cancer, anti-PD1s were adopted rapidly into real-world practice. Compared to patients treated in real-world practice, older patients were underrepresented in clinical trials. [Table: see text]