tbuckley/cabot-search huggingface dataset:
On-line breath analysis of volatile organic compounds as a method for colorectal cancer detection.
Authors: Francisco Zambrana Tevar, Ana Herrero, Guillermo Vidal-de-Miguel, Gonzalo Bailador, Ernesto Criado, Isabel Marquina, Carmen Sanchez-Avila, Maria Sereno, Cesar Gomez Raposo, Miriam Lopez-Gomez, Maria Merino, Cristina Aguayo, Mario Alvarez-Gallego, Jose Carlos Erdozain, Carmen Comas, Noemi Mancenido, Jaime Feliu, Damian Garcia, Enrique Casado
Journal: Journal of Clinical Oncology (2012)

1570 Background: Analysis of exhaled volatile organic compounds (VOCs) in breath is an emerging approach for cancer diagnosis, but little is known about its potential use as a biomarker for colorectal cancer (CRC). We investigated whether a combination of VOCs could distinct CRC patients from healthy volunteers. Methods: In a pilot study, we prospectively analyzed breath exhalations of 38 CRC patient and 43 healthy controls all scheduled for colonoscopy, older than 50 in the average-risk category. The samples were ionized and analyzed using a Secondary ElectroSpray Ionization (SESI) coupled with a Time-of-Flight Mass Spectrometer (SESI-MS). After a minimum of 2 hours fasting, volunteers deeply exhaled into the system. Each test requires three soft exhalations and takes less than ten minutes. No breath condensate or collection are required and VOCs masses are detected in real time, also allowing for a spirometric profile to be analyzed along with the VOCs. A new sampling system precludes ambient air from entering the system, so background contamination is reduced by an overall factor of ten. Potential confounding variables from the patient or the environment that could interfere with results were analyzed. Results: 255 VOCs, with masses ranging from 30 to 431 Dalton have been identified in the exhaled breath. Using a classification technique based on the ROC curve for each VOC, a set of 9 biomarkers discriminating the presence of CRC from healthy volunteers was obtained, showing an average recognition rate of 81.94%, a sensitivity of 87.04% and specificity of 76.85%. Conclusions: A combination of cualitative and cuantitative analysis of VOCs in the exhaled breath could be a powerful diagnostic tool for average-risk CRC population. These results should be taken with precaution, as many endogenous or exogenous contaminants could interfere as confounding variables. On-line analysis with SESI-MS is less time-consuming and doesn’t need sample preparation. We are recruiting in a new pilot study including breath cleaning procedures and spirometric analysis incorporated into the postprocessing algorithms, to better control for confounding variables.
Diagnosis of pseudoprogression using ferumoxytol perfusion MRI in patients with glioblastoma to predict better outcome.
Authors: Edward A. Neuwelt, Rochelle Fu, Seymur Gahramanov, Sakir H Gultekin, Cynthia Lacy, Morad Nasseri, Joao Prola Netto, Rose Marie Tyson, Tricia White, Randy L Woltjer, Leslie L. Muldoon
Journal: Journal of Clinical Oncology (2014)

2010 Background: This retrospective IRB approved study determined the survival of GBM patients with or without pseudoprogression. Methods: Patients with histologically-proven newly diagnosed GBM at Oregon Health and Science University from January 2006 to June 2012 after standard CRT received adjuvant temozolomide (TMZ) until tumor progression. Diagnosis of pseudoprogression was made by perfusion MRI with ferumoxytol (an iron oxide nanoparticle) and updated Response Assessment in Neuro-Oncology Working Group (RANO) criteria. Survival was determined using Kaplan-Meier product limit analysis and Cox regression model. Results: A total of 68 patients were included. The overall median survival was 19.9 months (95% CI 15.1-22.5). Median survival in 24 (35.3%) patients with pseudoprogression was 34.7 months (95% CI 20.3-54.1), significantly longer than the 13.4 months (95% CI 11.1-19.5) in 44 (64.7%) patients without pseudoprogression (P<0.0001). The longest survival was seen in patients with combination of pseudoprogression and MGMT promoter methylation, 54.1 months (Table). Conclusions: Pseudoprogression is associated with better survival, especially if concurs with MGMT promoter methylation. The patients that experienced true tumor progression had poor survival. This study emphasizes the importance of differentiating tumor progression and pseudoprogression using ferumoxytol to assess perfusion. Death/patients Hazard ratio (95% CI) Median survival (months; 95% CI) Overall survival 56/68 -- 19.9 (15.1, 22.5) Pseudoprogression status No 43/44 Reference 13.4 (11.1, 19.5) Yes 13/24 0.24 (0.13, 0.47) 34.7 (20.3, 54.1) MGMT status Nonhypermethylated 6/10 Reference 28.2 (19.0, 49.1) Hypermethylated 6/12 0.49 (0.15, 1.60) 54.1 (19.9, 79.9)
ADAM17 as a novel therapeutic target for HER2-positive breast cancer.
Authors: Sumainizah Sukor, Patricia M. McGowan, Maeve Mullooly, Aisling Pierce, John Crown, Norma O'Donovan, Michael J. Duffy
Journal: Journal of Clinical Oncology (2012)

622 Background: Although the HER2 gene is amplifiend/overexpressed in 15-20% of breast cancers, only a proportion of these patients benefit from anti-HER2 therapy. Clearly additional biomarkers and/or therapeutic targets are necessary to enhance efficacy and improve outcome in these patients. Here, we tested the hypothesis that inhibition of ADAM17-mediated release of HER ligands may enhance response to trastuzumab and lapatinib. Methods: The ADAM17-selective inhibitor, PF-5480090 (Pfizer) both alone and in combination with lapatinib, trastuzumab or 5FU was tested for potential growth inhibitory effects on a panel of 4 HER2-positive breast cancer cell lines (BT474, MDA-MB-453, SKBR3 and JIMT-1). Results: Using the MTT viability assay, treatment with 1 µM TMI-2 resulted in a significant reduction in cell proliferation compared to vehicle control in BT474 (p=0.01), MDA-MB-453 (p &lt; 0.005), JIMT-1 (p=0.002) and SKBR3 cells (p &lt; 0.005). Addition of PF-5480090 to lapatinib resulted in a significant reduction in cell growth compared to lapatinib alone (JIMT-1: p &lt; 0.005; SKBR3: p &lt; 0.005; MDA-MB-453: p &lt; 0.005), while addition of PF-5480090 to trastuzumab resulted in significant reduction in cell growth compared to trastuzumab alone (JIMT-1: p &lt; 0.005; SKBR3: p &lt; 0.005; MDA-MB-453: p=0.001). Addition of PF-5480090 to 5FU resulted in significant reduction in growth compared to 5FU alone (JIMT-1: p &lt; 0.005; SKBR3: p &lt; 0.005; MDA-MB-453: p=0.001). Consistent with its ability to block proliferation, addition of PF-5480090 significantly reduced release of TGFalpha (BT474: p=0.003; JIMT1: p=0.023; SKBR3: p=0.036 and MDA-MB-453: p=0.014). Conclusions: Inhibitionof ADAM17 resulted in growth inhibitory responses in HER2-positive breast cancer cell lines. Furthermore, addition of PF-5480090 to lapatinib, trastuzumab or 5FU resulted in significant growth inhibition compared to these agents alone. We propose that inhibition of ADAM17 may be used in combination with existing treatments for HER2-positive breast cancer. Acknowledgement. The authors thank SFI (SRC award, 08/SRC/B1410 to MTCI) for funding this work.
When is a pathologic diagnosis preferred before stereotactic ablative radiotherapy for stage I lung cancer? A decision analysis.
Authors: Alexander V. Louie, Suresh Senan, Pretesh Patel, Bart S Ferket, Frank J Lagerwaard, George Rodrigues, Joseph Kamel Salama, Christopher Ryan Kelsey, David Palma, Myriam Hunink
Journal: Journal of Clinical Oncology (2014)

7534 Background: The practice of treating a solitary pulmonary nodule (SPN) suspicious for stage I NSCLC with stereotactic ablative radiotherapy (SABR) in the absence of pathologic confirmation of malignancy is growing. In the absence of randomized evidence, the appropriate lung cancer prevalence threshold of when such a strategy is warranted can be informed using decision analysis. Methods: A decision tree and Markov model were constructed to evaluate the relative merits of observation, performing SABR without pathology, or performing a biopsy prior to SABR, when faced with a SPN at different lung cancer prevalences. Diagnostic characteristics, as well as disease, treatment, and toxicity parameters were extracted from the literature. Toxicity, recurrence rates, and health utilities (derived via mapping procedures) were abstracted from a prospectively collected database of 382 patients receiving SABR for confirmed or suspected stage I NSCLC. Deterministic analysis and probabilistic sensitivity analyses on all model inputs were performed to inform the appropriate lung cancer prevalence threshold between treatment strategies. The model was validated internally and externally. A 5-year time horizon using a cycle length of one month was employed and quality adjusted life years (QALYs) were discounted at a rate of 3%. Results: At a lung cancer prevalence of 65%, performing a biopsy was the preferred treatment strategy, yielding 2.640 QALYs, compared to 2.563 and 2.086 for the no biopsy and observation strategies, respectively. The prevalence threshold between observation and performing a biopsy was 17.0%; and between performing SABR without pathology and performing a biopsy prior to SABR was 85.0%. The latter finding was confirmed on probabilistic sensitivity analysis (85.2%; 95% CI: 80.0%–87.2%). This predicted lung cancer prevalence threshold was most sensitive to the diagnostic sensitivity of transthoracic biopsy (range: 77.2–94.0%). Conclusions: This model suggests that if there are concerns about increased morbidity related to biopsy for a SPN, SABR is warranted as a treatment strategy when the prevalence of lung cancer exceeds a point estimate of 85%.
Low Recombination Proficiency Score (RPS) Predicts Heightened Sensitivity to DNA-Damaging Chemotherapy in Breast Cancer
Authors: Sean P. Pitroda, Riyue Bao, Jorge Andrade, Ralph R. Weichselbaum, Philip P. Connell
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Molecular-based cancer tests have been developed to augment the standard clinical and pathologic features used to tailor treatments to individual breast cancer patients. Homologous recombination (HR) repairs double-stranded DNA breaks and promotes tolerance to lesions that disrupt DNA replication. Recombination Proficiency Score (RPS) quantifies HR efficiency based on the expression of four genes involved in DNA damage repair. We hypothesized low RPS values can identify HR-deficient breast cancers most sensitive to DNA-damaging chemotherapy. Experimental Design: We collected pathologic tumor responses and tumor gene expression values for breast cancer patients that were prospectively enrolled on clinical trials involving preoperative chemotherapy followed by surgery (N = 513). We developed an algorithm to calculate breast cancer–specific RPS (RPSb) values on an individual sample basis. Results: Low RPSb tumors are approximately twice as likely to exhibit a complete pathologic response or minimal residual disease to preoperative anthracycline-based chemotherapy as compared with high RPSb tumors. Basal, HER2-enriched, and luminal B breast cancer subtypes exhibit low RPSb values. In addition, RPSb predicts treatment responsiveness after controlling for clinical and pathologic features, as well as intrinsic breast subtype. Conclusions: Overall, our findings indicate that low RPS breast cancers exhibit aggressive features at baseline, but they have heightened sensitivity to DNA-damaging chemotherapy. Low RPSb values in basal, HER2-enriched, and luminal B subtypes provide a mechanistic explanation for their clinical behaviors and genomic instability. RPSb augments standard clinical and pathologic features used to tailor treatments, thereby enabling more personalized treatment strategies for individual breast cancer patients. Clin Cancer Res; 23(15); 4493–500. ©2017 AACR.
Hypertension in patients treated with VEGF TKIs: A comprehensive, up-to-date systematic review and meta-analysis of randomized trials.
Authors: Jeffrey J. Leow, William Martin-Doyle, Vanessa W Lim, Andre Poisl Fay, Laurence Albiges, Quoc-Dien Trinh, Maxine Sun, Marina Dusevic Kaymakcalan, Joaquim Bellmunt, Steven L. Chang, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2014)

e15558 Background: Tyrosine kinase inhibitors of vascular endothelial growth factor (VEGF TKIs) are commonly used in renal-cell (RCCs) and other cancers. One major side effect is hypertension and hypertension-related adverse events, with varying incidences reported by randomized clinical trials (RCTs). We performed a systematic review and meta-analysis of published RCTs to establish the incidence and relative risk (RR) of hypertension associated with all FDA-approved VEGF TKIs. Methods: To identify eligible studies, we searched PubMed/Medline, CENTRAL, clinicaltrials.gov, and abstracts presented at meetings of the American Society of Clinical Oncology (ASCO, January 2007 to May 2013). Eligible studies were limited to trials of US Food and Drug Administration–approved VEGF TKIs, using the keywords "sorafenib" or "sunitinib" or "pazopanib" or "axitinib" or "cabozantinib" or "vandetanib" or "regorafenib", we performed our literature search, limiting to only human studies and RCTs published in English. Non-randomized single-arm trials were excluded. Results: From a total of 410 articles screened, we identified 34 studies published from 2007-2013, including a total of 14,976 patients with RCC or other solid tumors, were selected. The use of VEGF TKIs was associated with an increased risk of hypertension (RR 3.33, 95% CI: 2.45-4.52), with the risk among RCCs lower at 2.20 (1.47-3.29) compared to non-RCCs (4.01, 95% CI: 2.48-6.48) (all p<0.001). VEGF TKI was associated with an increased risk of high-grade hypertension (RR 3.16, 95% CI: 2.02-4.94), with the risk among RCCs also lower at 2.26 (1.29-3.96) compared to non-RCCs (RR 3.77, 95% CI: 1.76-8.07) (all p<0.01). For both outcomes, significant heterogeneity was observed (both Cochrane p<0.0001; I2=92% and 83% respectively), necessitating use of random-effects models. There was no significant evidence of publication bias. Conclusions: Cancer patients treated with VEGF TKIs have significant risk of developing hypertension, albeit the risk seems lower in RCC patients.
Safety and activity of the chemotherapy-free triplet of ublituximab, TGR-1202, and ibrutinib in relapsed B-cell malignancies.
Authors: Nathan Hale Fowler, Loretta J. Nastoupil, Matthew Alexander Lunning, Julie Vose, Tanya Siddiqi, Christopher Flowers, Jonathon Brett Cohen, Marshall T. Schreeder, Myra Miguel, Susan Blumel, Brianna Phye, Warner H Tse, Emily K. Pauli, Kathy Cutter, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, Swaroop V.S. Vakkalanka, Srikant Viswanadha, Susan Mary O'Brien
Journal: Journal of Clinical Oncology (2015)

8501 Background: Multiple novel targeted agents are emerging for B-cell malignancies, but few studies have successfully and safely combined these agents. Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. TGR-1202 is a next generation, once daily, PI3Kδ inhibitor, active in patients (pts) with rel/ref hematologic malignancies (Burris, 2014). This Ph 1 trial evaluates the safety of the first triplet combination of a novel anti-CD20 + PI3Kδ + BTK inhibitor in pts with B-cell malignancies. Methods: Eligible pts had rel/ref CLL (including Richter’s) or B-cell NHL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. Pts refractory to prior PI3Kδ or BTK were eligible. CLL & NHL cohorts were evaluated independently in a 3+3 dose escalation design to evaluate safety and dose limiting toxicities (DLT). UTX was dosed at 900mg on D 1, 8, 15 of Cyc 1 & 2 and D 1 on Cyc 4, 6, 9 & 12. TGR-1202 was dose escalated (400mg, 600mg, 800mg, 1200mg). Ibrutinib was dosed at 420mg (CLL) and 560mg (NHL). Preliminary efficacy was examined (CLL per Hallek 2008 / NHL per Cheson 2007). Results: As of Feb 2015, 10 pts were evaluable for safety: 4 follicular (FL), 3 CLL/SLL, 1 marginal zone (MZL), 1 mantle cell (MCL) and 1 Richter’s DLBCL. Med age 61 yo (range 51-76); 8 M/2 F; median prior Tx = 3 (range 1-4). No DLTs have occurred up to the current dose (600 mg TGR-1202). AEs (all causality) included: diarrhea, constipation and fatigue (30% each, no G 3/4), Day 1 infusion related reactions at 20% (no G 3/4) and neutropenia at 20% with 1 event G 3/4. 7 pts were evaluable for efficacy. ORR was 86% with all pts except the Richter’s responding (FL (2), CLL/SLL (2), MZL (1) and MCL (1)). All responses were observed by week 8 (1 CR / 5 PR’s). Patients remain on study from 1 – 5+ months. Conclusions: To date, this is the first combination of an anti-CD20, a PI3Kδ and a BTK inhibitor. UTX + TGR-1202 + ibrutinb was well tolerated with significant early activity across heavily pre-treated and high-risk B-cell malignancies. Dose escalation continues with TGR-1202 at 800mg. Based upon the early activity of the triplet, Ph II studies are planned. Clinical trial information: NCT02006485.
Patient-reported outcomes and behavioral risk factors as predictors of chemoprevention adherence among women in the National Surgical Adjuvant Breast and Bowel Program (NSABP) Breast Cancer Prevention P-1 trial.
Authors: Stephanie R. Land, Farzana L Walcott, Qing Liu, Donald Lawrence Wickerham, Joseph P. Costantino, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2014)

1512 Background: Despite a 50% reduction in the risk of breast cancer (BC) for tamoxifen (T) vs. placebo (P), many women at risk of BC do not adhere to the 5 year course. Using prospectively-collected data from the double-blind NSABP P-1, we evaluated whether patient-reported outcomes were associated with drug adherence, and whether baseline behavioral risk factors modified those associations. Methods: 13,338 women at high risk of BC were randomly assigned to T vs. P (20 mg/day); we analyzed the 11,064 enrolled more than 3 years before trial unblinding 5/98. Mixed effects logistic regression was used to evaluate whether baseline and 3-month (mo) SF-36 mental (MCS) and physical (PCS) quality of life scales, depressive symptoms (CES-D), and possible treatment-related symptoms (BCPT symptom scales) predicted 12-mo drug adherence (using over 75% of assigned medication), accounting for Gail model estimated breast cancer risk and education; and whether associations were modified by baseline smoking status, alcohol consumption, body mass index (BMI, continuous variable), T vs. P, and age (continuous variable). Results: At 12 mo, 10,572 women were expected to be on therapy (excluding patients who never initiated therapy or experienced protocol required discontinuation); 84.2% were adherent. Sexual symptoms at 3 mo were associated with reduced adherence, but only among younger women (for example at age 45, odds ratio (OR) 0.8, p=.048); other symptoms predicted greater adherence among normal weight (OR=1.5 per 1 point, p=.016) but not among overweight women; 3-mo PCS predicted higher adherence among smokers (OR=1.4 per 10 points, p=.02), 3-mo MCS predicted adherence among women assigned to P (OR=1.4 per 10 points, p<.001). No significant associations were found with CES-D. Conclusions: Quality of life and symptoms at 3 months were associated with chemoprevention adherence at 12 months, and the associations differed according to age, treatment, BMI, and smoking status. Behavioral risk factors and patient-reported outcomes will help identify particular patients who may need greater adherence support. Clinical trial information: NCT00003906.
Changing chemotherapy (C) with concurrent radiation (RT) followed by surgery after sub-optimal FDG-PET response to induction chemotherapy improves outcomes in locally advanced (LA) esophageal adenocarcinoma (EA).
Authors: Anuja Kriplani, Yelena Yuriy Janjigian, David Paul Kelsen, Valerie W. Rusch, Manjit S. Bains, Nabil P. Rizk, Joanne F. Chou, Marinela Capanu, Abraham Jing-Ching Wu, Karyn A. Goodman, David H. Ilson, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2015)

4054 Background: Pre-operative CRT is a standard-of-care for LA EA. We showed that PET scan after induction C prior to CRT and surgery predicts outcomes (Cancer 118:2820; 2012). PET responders (PET+, defined as > 35% decrease in mSUV of tumor) had superior pathologic complete response (pCR) rates and progression-free survival (PFS) vs. PET non-responders (PET-, < 35% decrease). Some Pts with progression (PD) on PET after induction C had long-term overall survival (OS) when changed to alternative C during RT. Methods: We retrospectively reviewed all Pts with LA EA who received induction C and chemoRT prior to planned surgery. All Pts had PET scan before and after induction C. Results: 201 Pts were treated between 2002 to 2013, median age 62, 76% with uN+ disease. Induction C regimens included cisplatin/irinotecan (± bevacizumab on study) in 63% and carboplatin/paclitaxel in 29%. 113 Pts (56%) were PET+ and 88 (44%) were PET-. All PET+ received same C during RT. Of PET-, 49 (56%) continued with same C during RT (PET-/no change) and 39 (44%) received different C with RT (PET-/change). 49 Pts (24%) did not undergo surgery because of PD (16%), medical inoperability (6%), or refusal given clinical CR (2%). Of 152 operated Pts, 13/86 PET+ (15%) achieved a pCR vs. 1/35 (3%) of PET-/no change (p = 0.046) vs. 3/31 (10%) of PET-/change (p = 0.26 for PET-/no change vs. PET-/change). Median PFS (23.4 vs. 10.1 mos, p = 0.003) and OS (38.7 vs. 25.3 mos, p = 0.017) for all Pts were significantly better for PET+ vs. PET-/no change. Median PFS for PET-/change was not reached and was superior to PET-/no change (p = 0.02) and not different from PET+ (p = 0.73). The 3-yr OS rates were 48% for PET-/change vs. 31% for PET-/no change (p = 0.18). Median OS for PET-/change was not different than for PET-/no change (25.8 vs. 25.3 mos, p = 0.22). Conclusions: PET scan after induction C predicts for outcomes in LA EA Pts who undergo CRT and surgery. Median PFS is improved, and trends toward improved pCR rate and OS appear possible in PET- who change C during RT. The ongoing CALGB 80803 study (NCT01333033) is evaluating this strategy.