tbuckley/cabot-search huggingface dataset:
Combined treatment using the anti-p53 drug, APR-246 and eribulin: Synergistic growth inhibition in p53-mutated breast cancer cells.
Authors: Naoise C Synnott, Alyson M. Murray, Norma O'Donovan, Michael J. Duffy, John Crown
Journal: Journal of Clinical Oncology (2017)

e14098 Background: TP53 is the most frequently mutated gene in triple-negative breast cancer, being present in approximately 80% of cases. APR-246 is a novel anticancer drug that acts by reactivating the mutant p53 protein, thereby converting it to a form with wild-type properties. Previously, we showed that APR-246 had antiproliferative, anti-migratory and pro-apoptotic activities in a panel of 23 breast cancer cell lines, including triple-negative (TN) cell lines. The aim of this study was to investigate if combined treatment with APR-246 and different cytotoxic agents resulted in enhanced growth inhibition. Methods: Cell viability was determined using the MTT assay. Combination index (CI) values were calculated using Calcusyn software, based on the Chou-Talalay method. Apoptosis was detected using Annexin V-FITC Apoptosis Detection Kit followed by FACs analysis. Results: Highly synergistic cell growth inhibition was found when APR-246 was combined with eribulin (Eisai Ltd.) in 6 different p53-mutated cell lines (mean CI values range from 0.38 to 0.77). In contrast, enhanced growth inhibition was not found using this combination in the 3 p53-WT cell lines investigated (mean CI values ranged from 1.13 to 2.9). Overall, p53 mutated cell lines had a significantly lower CI values than p53 wild-type cells (p = 0.008). In all the 4 p53-mutated cell lines investigated, a significant increase in apoptosis was also seen when APR-246 was combined with eribulin. This enhanced apoptosis appeared to result from increased mRNA expression of the pro-apoptotic factors PUMA and NOXA by the drug combination compared to either compound alone. In contrast to our findings with eribulin, combined treatment with APR-246 plus docetaxel, doxorubicin, cisplatin or carboplatin was cell line-dependent. Thus, docetaxel plus APR-246 was synergistic in 1/6 cell lines, while doxorubicin, cisplatin or carboplatin plus APR-246 was synergistic in 3/6 cell lines. Conclusions: Clinical trials investigating the combination of APR-246 and eribulin should be considered in patients with a p53 mutation such as triple-negative breast cancer.
OS6.5 Randomized phase III trial comparing GAMMA KNIFE (GK) and LINAC based (EDGE) radiosurgery for brain metastases from solid tumors: results from the GADGET trial
Authors: E Clerici, P Navarria, C Franzese, G A Carta, P Mancosu, G Reggiori, P Picozzi, L Attuati, S Tomatis, M Scorsetti
Journal: Neuro-Oncology (2018)

Brain metastases (BMs) from solid tumors represent a topic of increasing interest for the higher incidence. Stereotactic radiosurgery is the main effective local therapeutic approach used. Different modalities have been employed, but to date no randomized comparative trials are available. We draw a phase III trial comparing Gammaknife (GK) and Linac based (Edge) radiosurgery with the aim to evaluate the incidence of symptomatic radionecrosis, local control and overall survival rates. Patients 18–85 years old, with KPS ≥70, primary solid tumor, expected survival ≥ 3 months, and harboring up to 4 BMs with max tumor diameter ≤30 mm were included. Randomization was stratified according to age, presence of extracranial metastases, and the number of BMs. For Arm A (GK) a single dose of 20–24 Gy at 50% isodose was prescribed. For Arm B a single dose of 24 Gy was prescribed to PTV for all metastases. Outcome evaluation was performed every 3 months with MRI and clinical examination. Radionecrosis was assessed mismatching T1/T2 MRI images, perfusion MRI, and in doubt cases using Methionine-CT/PET. Local response was appraised according to the Response Assessment in Neuro-Oncology (RANO) Working Group criteria. From October 2014 to January 2018, 168 patients for 292 BMs treated were included, 80 in Arm A (GK) and 88 in Arm B (Edge), for 152 BMs in arm A and 140 in Arm B, respectively. Symptomatic radionecrosis occurred in 23 (7.8%) cases, 11 in Arm A and 12 in Arm B; grade II in 8 cases of GK arm at a median time of 6.5 months and in 12 cases of Edge arm at a median time of 9.4 months; grade III RN was recorded in 3 cases, only in GK arm, at a median time of 3 months. The 12, and 18 months LC rates were 97.5% and 94.5% for the whole cohort; 98.8% and 90.9% for arm A; 96.2% and 96.2% for Arm B, comparable for the two groups (p value=0.96). The median, 12, and 18 months OS rates were 17.8 months, 74.1%, and 48.9%, comparable in both arms (p value=0.36). On univariate and multivariate analysis the volume of BMs was the only factor impacting on radionecrosis occurrence (p value=0.005; p value=0.03). Gamma-knife and LINAC based radiosurgery for BMs from solid tumors were comparable in terms of LC rates. The occurrence of G3 radionecrosis was greater and earlier in the GK arm respect to Edge arm.
TCT-802 Effects of Pulmonary Hypertension on Transcatheter Mitral Valve Repair Outcomes: Analysis of The STS/ACC TVT Registry
Authors: Rasha Al-Bawardy, Sreekanth Vemulapalli, Vinod Thourani, Michael Mack, Eyal Ben Assa, Igor Palacios, Ignacio Inglessis, Jacob Dal-Bianco, Jonathan Passeri, Serguei Melnitchouk, Gus Vlahakes, Arminder Jassar, David Dai, Sammy Elmariah
Journal: Journal of the American College of Cardiology (2018)
Multilevel correlates of in-hospital mortality among patients with malignant solid tumors in the United States.
Authors: Kahee A. Mohammed, Nosayaba Osazuwa-Peters, Eric Adjei Boakye, Leslie J. Hinyard, Paula Buchnan, Eric S. Armbrecht, Thomas E. Burroughs
Journal: Journal of Clinical Oncology (2016)

e18115 Background: We aimed to examine the effect of patients’ clinical and sociodemographic, and hospital level factors on in-hospital mortality among patients diagnosed with one of the top 10 deadliest malignant solid tumors (lung, colorectal, pancreas, breast, liver, prostate, bladder, brain, esophagus, and ovary). Methods: We performed a cross-sectional analysis of data from the Nationwide Inpatient Sample 2008 – 2013 to identify patients (n = 1,819,225) with at least one diagnosis of malignant solid tumor using the International Classification of Diseases, ninth edition. Weighted multivariate hierarchical logistic regression model was used to account for hospital level and patient level variation in mortality. Results: The overall in-hospital mortality was 6.28%. The adjusted multilevel analysis indicated that patients with metastatic cancer had 56% higher odds of in-hospital mortality (95% CI = 1.53–1.59). Compared to patients with esophageal cancer, lower odds of mortality were noted in patients with any type of solid tumor except for liver (odds ratio [OR] = 1.19, 95% CI = 1.13 – 1.26) and lung (OR = 1.07, 95% CI = 1.03 – 1.12) tumors. Sociodemographic risk factors for in-hospital mortality included advanced age, male sex (OR = 1.20, 95% CI = 1.18–1.23), Hispanic ethnicity vs Caucasians (OR = 0.91, 95% CI = 0.88 – 0.95), and lack of insurance (OR = 1.98, 95% CI = 1.75–2.23). In addition, advanced comorbidities (OR = 1.06 per 1 unit increase in Elixhauser comorbidity score, 95% CI = 1.05 -1.07), admission to a nonteaching hospital (OR = 1.09, 95% CI = 1.03 - 1.16), admission to a small vs large bed size hospital (OR = 1.11, 95% CI = 1.14 – 1.18), and admission on a weekend (OR = 1.16, 95% CI = 1.04 – 1.18) were associated with in-hospital mortality. Moreover, cancer patients admitted to hospitals in Midwest had 19% lower odds (95% CI = 0.73 – 0.89) of in-hospital mortality compared to their peers admitted to Southern hospitals. Conclusions: Sociodemographic, hospital factors, and advanced comorbidities are associated with increased in-hospital mortality in cancer patients. These findings can lead to the development of prognostic tools to help better identify patients at high risk of death during hospitalization.
Comprehensive analysis of five key immune related adverse events (irAE) from immune checkpoint blockers (ICB) CTLA-4 and PD-1 inhibitors in cancer patients.
Authors: Guillermo de Velasco, Youjin Je, Mark M. Awad, Patrick Alexander Ott, Fabio Augusto Barros Schutz, Joaquim Bellmunt, Guru Sonpavde, F. Stephen Hodi, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2016)

3068 Background: IrAEs have been described with ICB, though the overall risk of irAEs with these drugs remains unclear. Our aim was to determine the incidence and the relative risk (RR) of key irAEs from approved immune checkpoint blockers (ICB) to better characterize their safety profile. Methods: PubMed and Medline databases were searched from Jan1996 to Oct2015. Eligible studies included randomized phase II/III trials with non-ICB control arms. Statistical analyses were conducted to calculate the summary incidence, RRs, and 95% CIs, using random-effects models. The 5 selected key irAEs included: colitis, transaminitis (increased AST), immune-related rash, hypothyroidism, and pneumonitis. Results: A total of 6133 patients (pts) from 12 trials were included: 3499 pts assigned to single-agent ICB arms (nivolumab [n = 1298], pembrolizumab [n = 357], ipilimumab [n = 1844]) and 2634 to non-ICB arms. All-grade incidence of each selected key irAE with ICB was: colitis 3.1%, increased AST 7.8%, rash 16.7%, hypothyroidism 4.2 % and pneumonitis 2.4%. Compared to non-ICB arms, the RR of all-grade irAE with ICB was: colitis 8.88 (95% CI, 5.09 to 15.5; P < 0.001), increased AST 1.89 (95% CI, 1.05 to 3.40; P = 0.034), rash 2.36 (95% CI, 1.39 to 3.99; P < 0.001), hypothyroidism 7.17 (95% CI, 3.57 to 14.4; P < 0.001) and pneumonitis 3.96 (95% CI, 0.68 to 23.2; P = 0.127). Grade 3/4 incidence of each selected key irAE with ICB was: colitis 2.0%, increased AST 2.0%, rash 1.0%, hypothyroidism 0.3% and pneumonitis 0.9%. Compared to non-ICB arms, the RR of grade 3/4 irAE with ICB was: colitis 6.83 (95% CI 2.68 to 17.4; P < 0.001) and increase AST 3.35 (95% CI 1.25 to 8.98; P = 0.016). Ipilimumab had higher RR of grade 3/4 colitis (p = 0.033) and all-grade rash (p = 0.047), than nivolumab/pembrolizumab, but no other significant differences were found. Conclusions: This meta-analysis offers substantial evidence that ICB treatment is associated with a small but significant increase in the risk of several all-grade irAEs analyzed, as well as grade 3/4 colitis and transaminitis compared to non-ICB treated pts.
Novel mutations in sporadic typical carcinoids of the lung (lung-TC): Tumor genomic profile by next generation sequencing (NGS).
Authors: Ivana GABRIELA Sullivan, Ludovic Lacroix, Julien Adam, Aurelie Honore, Nicolas Dorvault, Letizia Gianoncelli, Gwenael Le Teuff, Benjamin Besse, Jean-Charles Soria, Vincent de Montpreville, Jean-Yves Scoazec, Eric Baudin, David Planchard
Journal: Journal of Clinical Oncology (2016)

11596 Background: Diagnosis and treatment of lung-TC (2% of pulmonary neoplasms) represent a clinical challenge. Mutations in chromatin-remodeling genes (i.e. MEN1, histone modifiers, SWI/SNFcomplex) have been reported in pulmonary carcinoids. NGS offers new opportunities for rapid genome-wide discovery of somatic mutations. Methods: Thirty-six consecutive non-pretreated lung-TCsurgical fresh-frozen specimens were collected between Feb 2010 and Nov 2013 from three centers (GR, CCML, ICH). Three independent pathologists reviewed pathology and tumor cell %. We performed targeted NGS covering 50 critical oncogenes or tumor suppressor genes using Ion Torrent technology. The analyses were performed using the Ion AmpliSeq workflow, 1218 primer pairs multiplex PCR based libraries. Reported somatic genetic variants were compared with the relative GRCh37 (h19) reference (Torrent Suite software, variantCaller v4.4.3) and annotated using Galaxy software. Variants with an allele frequency of 10% or, none synonymous and not known as common polymorphisms ( < 0.1% in 1000G and ESV database) were retained as variants of interest. Results: Cohort included15 male and 21 female: mean age 55 (17-78) yrs, 64% non-smokers, 23 (64%) stage I, 10 (28%) stage II, and 3 (8%) stage III. Median follow-up 2.5 yrs (2.1-2.8), no recurrence detected. Median tumor cells was 80% (65-100). Quarter (9 of 36) of samples presented at least one mutation. Two pathogenic mutations were founded in individual samples: the nonsense mutation in NF1 (p.Q2636*) and the missense hot spot activating mutation in HRAS (p.K117N) genes. “Potentially pathogenic” mutations (half of them in genes implicated in the VEGF-pathway) were identified in 7 different samples involving DDR2 (p.D142G), FLT1 (p.Y642H), FGFR4 (p.P568Q), FGFR4 (p.R59W), NOTCH4 (p.P183S), KDR (p.T761M), MET (p.V1236A) and PTEN (p.I28T) genes. FGFR4 (p.R59W) and NOTCH4 (p.P183S)were in the same sample. Conclusions: Using NGS technology we identified molecular alterations in 25% of lung-TC that might provide new treatment opportunities. VEGF but not mTOR pathway was recurrently found altered. Much work remains to define the role of these alterations in lung-TC.
Adjuvant treatment in stage III gastric cancer patients in Brazil and Peru: Results of a retrospective study in two cancer centers in Latin America.
Authors: Jose Eduardo Nunez, Tiago Felismino, Daniel Enriquez, Paola Catherine Montenegro, Felipe Coimbra, Wilson L. Costa Jr., Maria D. Begnami, Luis Taxa, Sandro Casavilca, Ricardo Fogaroli, Ana Caroline Alves, Rossana Mendoza, Celso Lopes Mello
Journal: Journal of Clinical Oncology (2018)

e16101 Background: Gastric cancer (GC) is the fourth most incident cancer in Peru, and the sixth one in Brazil. Mortality is still high in these developing countries. The chance of relapse of patients diagnosed with non-metastatic disease and undergoing surgery is more than 50%. It is suspected that Latin American patients present worse evolution compared to patients treated in Asia or in developed countries, therefore it is fundamental to study factors related to the prognosis and evolution of patients with GC in our continent. We aimed to evaluate the efficacy of adjuvant treatment for Stage III GC in patients from two countries with different racially miscegenation and eating habits, and correlate this with clinicopathological features. Methods: Out of 184 patients with stage I-III GC, we retrospectively analyzed 150 patients with stage III GC who underwent curative surgery and received CRT at AC Camargo Cancer Center (ACCCC) in Brazil and Instituto Nacional de Enfermedades Neoplasicas (INEN) in Peru. CRT was defined as MacDonald protocol. Primary endpoint was overall survival (OS). Cox regression model was performed in order to calculate hazard ratio (HR) and 95% confidence intervals (95%CI). Results: Median follow up time was 33 and 24 months in Brazil and Peru, respectively. Diffuse subtype was predominant (Brazil: 62.1%; Peru: 57.8%). Median OS was 53 and 24 months in Brazil and Peru respectively (p = 0.06). In the Diffuse subtype cohort we found differences in mOS between Brazil and Peru (109 vs. 21 months, respectively, p < 0.02). In the multiple analysis, we found that tumor location (GEJ vs. Non-GEJ; HR = 2.0, 95%CI 1.0-4.3; p = 0.04) was independent prognostic factor adjusted by country of treatment, histological subtype, and gender. Conclusions: Survival differences exist between Brazil and Peru. We observed that patients with diffuse subtype have better survival in Brazil and that tumor location is a prognostic factor in OS. Ethnic/genetic factors, eating habits and other clinicopathological/molecular factors may explain different prognosis. Future studies are warranted to determine these prognostic factors in Latin American gastric cancer patients.
Biomarker analysis of S-1 in SELECT-BC: A randomized phase III study of taxane versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT-BC EURECA).
Authors: Fumikata Hara, Hirofumi Mukai, Shozo Ohsumi, Daisuke Yotsumoto, Tsutomu Takashima, Yasuo Hozumi, Takanori Watanabe, Tsuyoshi Saito, Ken-ichi Watanabe, Junji Tsurutani, Tatsuya Toyama, Hiromitsu Akabane, Reiki Nishimura, Naruto Taira, Yukari Uemura, Yasuo Ohashi
Journal: Journal of Clinical Oncology (2016)

e23274 Background: S-1 is oral fluoropyrimidine which is a biochemically modulated drug to increase 5-FU concentration and to avoid gastrointestinal toxicities. SELECT-BC, a randomized phase III trial demonstrated that S-1 is non-inferior to taxane in overall survival and time to treatment failure (TTF) as a first-line chemotherapy for metastatic breast cancer (MBC) (Takashima T, et al. Lancet Oncol 2016). We aimed to identify predictive markers of S-1 using tumor tissue samples from SELECT-BC. Methods: Patients with HER2 negative MBC received either S-1 or taxane (paclitaxel or docetaxel). Formalin-fixed paraffin-embedded specimens were available for 159 of a total of 618 (25.7%) patients. Fourteen genes involved in pyrimidine metabolic pathway, ER, PgR, HER2, Ki67 and beta-tubulin were measured by RT-PCR in microdissected tumor specimens. Gene expression levels were normalized to the geometric mean expressions of GAPDH, ACTB, and RPLP0, as reference genes. The expression levels of each genes were categorized as low or high at the 33.3rd, 50th or 66.7th percentile. Results: Patient and tumor characteristics in this biomarker study were similar to the main study population. In overall, high MTHFR, PGR, TUBB3 expression were significantly correlated with good prognosis. In respect of predictive marker of S-1, although not significant, there was a moderate qualitative interaction between the treatment arms and the following genes, DPYD, GGH, RRM1, ESR1, and TUBB3 (Table). Conclusions: This biomarker analysis from SELECT BC showed that DPYD, GGH, RRM1, ESR1, and TUBB3 mRNA levels may be predictive markers of 1st line chemotherapy with S-1, especially GGH (p = 0.11). It should be done further evaluation using more samples from another phase III trial SELECT BC CONFIRM (S-1 vs anthracyclines). Clinical trial information: UMIN000014245.TTF in S-1 to Taxane Low expression group High expression group p value for interaction Gene HR 95% CI p value HR 95% CI p value DPYD 0.88 0.58- 1.34 0.54 1.36 0.74- 2.50 0.30 0.25 GGH 0.87 0.57- 1.32 0.46 1.62 0.85- 3.11 0.24 0.11 RRM1 0.85 0.56- 1.31 0.39 1.41 0.79- 2.55 0.30 0.17 ESR1 1.33 0.81- 2.19 0.30 0.85 0.53- 1.38 0.44 0.21 TUBB3 0.69 0.39- 1.24 0.18 1.22 0.80- 1.87 0.41 0.13
Comparison of cancer incidence to available oncology clinical trial slots.
Authors: George Tran, Matthew Harker, Karen Chiswell, Mark Fleury, Bradford Richard Hirsch, Joseph M. Unger, Kimberly Miller, Philip D'Almada, Sheri Tibbs, Yousuf Zafar
Journal: Journal of Clinical Oncology (2018)

e18615 Background: Improvements in cancer outcomes require the successful conduct of clinical trials, but trial enrollment has been a persistent challenge with more than 1 in 5 trials failing to accrue sufficient patients. The aim of this study is to estimate availability of patients for each open enrollment slot in the national oncology clinical research portfolio, to provide a benchmark for better understanding cancer clinical trial feasibility. Methods: The Database for Aggregate Analysis of ClinicalTrials.gov, up to date as of September 3, 2017, was used to identify actively-recruiting, interventional oncology trials at US sites. Observational studies were excluded since not all are registered. Trials were categorized via Medical Subject Headings or free text condition terms and sorted by cancer diagnosis. Trial slot availability was estimated between September 1, 2017, to August 31, 2018. Availability was estimated from total anticipated enrollment. A constant recruitment rate was assumed, and then pro-rated for the proportion of US sites. The 2017 American Cancer Society cancer incidence estimates were used to approximate total US cancer diagnoses. Results: 3914 oncology trials were identified. Overall, the estimated number of patients available for each trial slot was 14.6 (Table). The estimates by cancer diagnosis were: breast (female): 7.5 patients per trial slot; lung & bronchus: 12.4; prostate: 9.2; brain & other nervous system: 1.5; leukemia 4.1; colorectal: 9.0. Conclusions: For all cancers combined, successfully accruing trials would require that approximately one in every 15 patients would need to enroll on a trial. This ratio, however, varies over eightfold for the cancers examined, ranging from 1.5 for brain to 12.4 for lung, indicating that the feasibility of successfully completing accrual for currently open trials varies significantly. Cancer diagnosis Interventional enrollment slots, pro-rated for US sites 2017 Estimated Incidence Estimated number of incident cancers for each enrollment slot Breast (female) 33541 252710 7.5 Lung & bronchus 17900 222500 12.4 Prostate 17487 161360 9.2 Brain & other nervous system 16164 23800 1.5 Leukemia 15182 62130 4.1 Colon and rectum 15077 135430 9.0 All Sites 115528 1688780 14.6
The association of chromium in household dust with urinary chromium in residences adjacent to chromate production waste sites.
Authors: A H Stern, J A Fagliano, J E Savrin, N C Freeman, P J Lioy
Journal: Environmental Health Perspectives (1998)

Several previous studies of exposure to chromium waste in New Jersey have shown that Cr levels are elevated in household dust in homes adjacent to waste sites and that Cr levels in the urine of residents near sites are also elevated compared to control populations. It has not been possible until now, however, to examine these external and internal measures of exposure together in a large population to determine whether the external exposure is predictive of the internal exposure. We investigated the relationship between various adjusted and unadjusted measures of spot urine Cr concentration and household dust Cr from residents and residences adjacent to known Cr waste sites. Statistically significant bivariate relationships were found between log-transformed urine Cr concentration and Cr dust concentration (micrograms of Cr per gram of dust) but not Cr dust loading (nanogram Cr per square centimeter). Log-transformed urine concentration was used as the dependent variable in multiple regression analysis of the total population (n = 329), the population [less than/equal to] 10 years old (n = 67), and the population >10 years old (n = 262), with Cr dust concentration as a mandatory independent variable. Other potential direct influences on urine Cr were investigated as potential confounders of this relationship. In the final models for the entire population and those [less than/equal to] 10 years old, but not for those >10 years old, Cr dust concentration remained significant. This suggests that exposure of young children to Cr in household dust accounts for much of the relationship in the entire population.