tbuckley/cabot-search huggingface dataset:
Overall survival of participants compared to non-participants in a randomized-controlled trial (SELECT BC): A prospective cohort study.
Authors: Kazutaka Narui, Shinji Ohno, Hirofumi Mukai, Yasuo Hozumi, Yasuo Miyoshi, Hiroshi Yoshino, Hiroyoshi Doihara, Akihiko Suto, Motoshi Tamura, Takashi Morimoto, Hisamitsu Zaha, Takashi Chishima, Reiki Nishimura, Takashi Ishikawa, Yukari Uemura, Yasuo Ohashi
Journal: Journal of Clinical Oncology (2016)

2527 Background: Whether participation in a randomized-controlled trial provides benefits to patients is controversial. Some studies have showed that participants have longer prognosis than non-participants. However, in such studies, underlying bias always exists, such as patient condition, patient selection by physicians, and differences in the care provided. Therefore, to minimize such bias, we enrolled non-participants at the time of patient recruitment for a randomized-controlled trial, and prospectively compared the prognoses of participants and non-participants. Methods: This was a prospective cohort study accompanying the “SELection of Effective ChemoTherapy for Breast Cancer” (SELECT BC) study, which compared S-1 and taxane as first-line treatment for metastatic breast cancer and reported the non-inferiority of S-1 with respect to overall survival. Prognoses of trial participants and non-participants were compared. The endpoint was overall survival [Lancet Oncol 17:90-98, 2016]. All patients met the eligibility criteria set for SELECT BC. Results: From August 2009, when this study started, to July 2010, 228 patients were enrolled in SELECT BC, while 65 patients were registered as non-participants in this study. The median follow-up period was 32.5 months. The median overall survival of participants (36.8 months) was longer than that of non-participants (25.2 months) (hazard ratio [HR]: 1.48; 95% confidential interval [CI]: 1.06-2.07; p = 0.023). Standard chemotherapy was administered to 48 non-participants (74%); 34 (52%) of them received standard taxane regimen or S-1, which was to be administered if they participated in the trial. However, the median overall survival of these 34 patients (22.0 months) was shorter than that of the trial participants (36.8 months) (HR: 2.03; 95% CI: 1.35-3.06; p = 0.0007). Conclusions: Randomized-controlled trial participants had longer overall survival than non-participants. Several factors, such as mental status, relationship between physicians and patients, or difficulties in receiving the recommended treatment could have influenced the prognosis. Clinical trial information: 000020645.
Effect of metformin chemoprevention on metabolomics profiles in Li-Fraumeni Syndrome (LFS).
Authors: Farzana L. Walcott, Christina M. Annunziata, Eduardo M. Sotomayor, Antonio Tito Fojo
Journal: Journal of Clinical Oncology (2017)

1556 Background: LFS is a highly-penetrant, autosomal dominant, cancer predisposition disorder characterized by early onset cancer; germline mutations in TP53are present in 70% of LFS. We previously observed metformin inhibition on mitochondrial function in LFS patients. Metformin may reduce TCA cycle and glycolytic intermediates during cellular transformation, indicating inhibition of complex I of the mitochondria. To further explore this, we performed untargeted metabolomics profiling on stored serum of study participants. To our knowledge, there are no previous studies of metabolomics profiling in LFS patients treated with metformin. Methods: Adult LFS patients (≥18 years old) were enrolled for 20 weeks. Metformin was initiated at 500 mg per day and increased in 500 mg dose increments every two weeks to a maintenance dose of 2000 mg of metformin. Patients were taken off metformin for the last six weeks of the study (week 20). Global biochemical profiles were determined in human serum samples collected in 21 patients, each providing one sample at baseline, week 14 (on 2000 mg metformin) and week 20 (off metformin). Metabolomics analyses were performed by Metabolon, Inc. Results: Treatment with metformin induced a strong metabolic signature of increased fatty acid beta-oxidation in LFS patients. Acylcarnitines, long chain fatty acids, and 3-hydroxy fatty acids were significantly elevated following metformin treatment. TCA cycle intermediates, aconitate, malate, and fumarate were also increased as were levels of ketone body 3-hydroxybutyrate (BHBA)indicating robust β-oxidation, presumably to support increased energy production via the TCA cycle. Clearance of metformin results in normalization of levels to comparable baseline values, indicating a causal role of metformin in these changes. Conclusions: Global metabolomics profiling suggests an increase in TCA cycle intermediates and a strong signature of fatty acid oxidation with metformin treatment in LFS, suggesting metformin effect on the mitochondria and TCA cycle is more dynamic than previously shown. LFS patients may have distinct metabolic profiles which may be altered by treatment with metformin. Funding: ASCO Young Investigator’s Award 2016. Clinical trial information: NCT01981525.
The heritability of retinoblastoma: An institutional review.
Authors: Michael Francis Walsh, Jacob Musinsky, Megan Harlan Fleischut, Jennifer Kennedy, Anne Lincoln, Zsofia Kinga Stadler, Mark E. Robson, Ira J. Dunkel, David H. Abramson, Kenneth Offit
Journal: Journal of Clinical Oncology (2016)

1591 Background: Retinoblastoma (RB) accounts for ~3% of pediatric cancer and is the most common primary intraocular malignancy. Patients with bilateral disease and about 15% of patients with unilateral disease harbor a germline RB1 mutation. As a means too confirm these historical estimates of genomic alterations predisposing to RB, we have reviewed our institutional experience. Methods: Three hundred thirteen children with retinoblastoma were consented for germline analysis at MSKCC from 2006-2015. Full-gene sequencing was carried out for patients without a family history of retinoblastoma and single-site sequencing was carried out for patients with known familial mutations. Karyotyping for 13q deletion was performed in some cases. Gender, age at diagnosis, ethnicity, family history, testing laboratory, type of testing performed, somatic mutations detected, treatment and vital status information was collected for each patient. Results: Of the 313 children tested, 172(55%) were female and 141 (45%) male. Germline RB1 mutations were detected in 162 (51.7%). Of 184 patients with unilateral disease, 35 (19%) had mutations. Of 129 patients with bilateral (n = 126) or trilateral (n = 3) disease, 129 (100%) had germline RB1 mutations. Eight variants of uncertain significance (VUS) were detected, of which 2/126 (1.6%) were bilateral cases and 6/184 (3.2%) unilateral. 20/162 (12.3%) of patients with pathogenic mutations demonstrated allele frequencies consistent with mosaicism, of which 7/126 (5.5%) were bilateral cases and 13/35 (37%) unilateral cases. 69.5% (n = 87/126) of bilateral cases presented before 12 months of age. Conclusions: In comparison to historic data, our institutional experience revealed a higher proportion of children with both unilateral and bilateral retinoblastoma harboring germline mutations. Further analysis of family history and other factors is underway to explore possible ascertainment bias among cases referred to a treatment center of excellence However, these results underscore the importance of germline analysis in all RB cases, and suggest a potential role for additional genomic profiling, including RNA sequencing to detect germline lesions in cases wild-type for RB1.
Is axillary node dissection needed after mastectomy with positive sentinel nodes?
Authors: Salman Hasan, Divya Arora, Eneida Male, Jessica Pruszynski, Celine Ord, Ashwini Bhat, Arundhati Rao, Deb Niloyjyoti
Journal: Journal of Clinical Oncology (2016)

531 Background: A positive sentinel lymph node has traditionally required subsequent axillary dissection. Over time, the paradigm has shifted to omit axillary dissection, if possible. The ACOSOG Z11 trial of sentinel lymph node positive patients undergoing breast- conserving surgery found no difference in Overall Survival (OS) and Disease Free Survival (DFS) in those patients who underwent subsequent Axillary Lymph Node Dissection (ALND) vs. observation. Notably, the Z11 trial excluded patients who underwent mastectomies. The purpose of this study is to determine the benefit of subsequent ALND in patients with a positive SLN after mastectomy. Methods: This was a retrospective review from an integrated health institution (n = 75) that delivered standardized, multi-disciplinary care for breast cancer. Inclusion criteria: patients with clinically negative nodes, treated with mastectomy, with 1 to 3 positive SLN. Exclusion criteria: stage IV disease and neoadjuvant chemotherapy. The primary end points of recurrence, OS, and DFS were estimated by the Kaplan-Meier method. Results: Of 75 patients, 25 had SLN sampling alone and 50 had SLN + ALND. There was no difference in race, comorbidities, histology, T stage, N stage, overall stage, estrogen receptor status, Her-2-neu receptor status, ECE, use of adjuvant chemotherapy, and radiation therapy. Those with ALND had more positive lymph nodes, lymph node ratio, and LVSI (p = 0.017, p ≤ 0.0001, p = 0.0118 respectively). There was no difference in the presence of post-operative lymphedema or paresthesia, although there was a trend towards more complications with ALND. Recurrence, OS, and DFS were not significantly different for patients with SLN alone versus SLN + ALND (p = 1.00, p = 0.223, p = 0.053). There was a trend towards a difference favoring SLN + ALND after about 5 years (p = 0.223). Conclusions: In clinically node negative patients who underwent mastectomy with positive sentinel lymph nodes (N1), there was no difference in OS or DFS between SLN alone versus SLN followed by ALND. ALND may be avoided in these patients although a prospective randomized trial needs to confirm these results.
Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin
Authors: Pasquale Piccolo, Patrizia Annunziata, Leandro R. Soria, Sergio Attanasio, Anna Barbato, Raffaele Castello, Annamaria Carissimo, Luca Quagliata, Luigi M. Terracciano, Nicola Brunetti‐Pierri
Journal: Hepatology (2017)

α 1 ‐Antitrypsin (AAT) deficiency is one of the most common genetic disorders and the liver disease due to the Z mutant of AAT (ATZ) is a prototype of conformational disorder due to protein misfolding with consequent aberrant intermolecular protein aggregation. In the present study, we found that livers of PiZ transgenic mice expressing human ATZ have altered expression of a network of hepatocyte transcriptional factors, including hepatocyte nuclear factor‐4α, that is early down‐regulated and induces a transcriptional repression of ATZ expression. Reduced hepatocyte nuclear factor‐4α was associated with activation of β‐catenin, which regulates liver zonation. Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturbation of liver zonation. Functionally, PiZ mice showed a severe defect of ureagenesis, as shown by increased baseline ammonia, and reduced urea production and survival after an ammonia challenge. Down‐regulation of hepatocyte nuclear factor‐4α expression and defective zonation in livers have not been recognized so far as features of the liver disease caused by ATZ and are likely involved in metabolic disturbances and in the increased risk of hepatocellular carcinoma in patients with AAT deficiency. Conclusion : The findings of this study are consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation have broad effects on metabolic liver functions. (H epatology 2017;66:124–135).
Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy
Authors: Waleed M. Abuzeid, Xiaoling Jiang, Guoli Shi, Hui Wang, David Paulson, Koji Araki, David Jungreis, James Carney, Bert W. O’Malley, Daqing Li
Journal: Journal of Clinical Investigation (2012)

In Figure 6A, the representative PNA FISH stain images for the "Cisplatin" and "Cisplatin + DL312" groups were identical.The correct figure is below.
Safety of multiplex gene testing for inherited cancer risk in a fully accrued prospective trial.
Authors: Allison W. Kurian, Gregory Idos, Charite Nicolette Ricker, Julie Culver, Duveen Sturgeon, Kerry Kingham, Rachel Koff, Katrina Lowstuter, Nicolette M. Chun, Courtney Rowe-Teeter, Katlyn Partynski, Anne-Renee Hartman, Brian Allen, John Kidd, Meredith Mills, Christine Hong, Kevin McDonnell, Uri Ladabaum, James M. Ford, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2017)

1576 Background: Sequencing more genes increases the chance of finding a pathogenic mutation and/or a variant of uncertain significance (VUS). Little is known about potential harms of multiplex testing for cancer risk, such as unwarranted surgery or adverse psychological effects. Methods: We conducted a prospective trial of sequencing 25 genes : APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were eligible if they met standard testing guidelines or predictive models estimated ≥2.5% mutation probability. Participants were surveyed 3 months post-test: the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale measured distress, uncertainty and positive experiences. We report on the fully accrued trial (N = 2000). Results: 1998/2000 (99.9%) participants currently have reported results: 12.1% tested positive for a pathogenic mutation (Pos), 34.5% had VUS only and 53.5% tested negative (Neg). Median age was 51, 81% were female, 40% Hispanic, and 72% had a cancer history. Self-reported preventive surgery rates were low (mastectomy 9.3%, hysterectomy 1.5%, oophorectomy 1.6%), with no difference between VUS and Neg patients (p = 0.346). Most patients never or rarely had thoughts of cancer affecting daily activities (Pos 59.5%, VUS 66.9%, Neg 71.0%), never regretted testing (Pos 84.1%, VUS 90.0%, Neg 93.6%), and wanted to know all results, even those that doctors do not fully understand (Pos 81.7%, VUS 78.8%, Neg 77.1%). Pos patients had higher MICRA distress and uncertainty scores than VUS and Neg patients, whose distress and uncertainty scores did not differ significantly (p = 0.165, p = 0.129). Relatives of Pos patients completed genetic testing (30.4%) more often than VUS (5.8%) or Neg patients (5.1%, p &lt; 0.001). Conclusions: After multiplex testing of 2000 diverse patients, few reported preventive surgery at 3 months; VUS patients had no more distress, regret or uncertainty than Neg patients. Pos patients most often advised relatives to test, suggesting that participants understood the implications of test results. Longer-term follow-up of test-related outcomes is underway. Clinical trial information: NCT02324062.
American Thoracic Society/National Heart, Lung, and Blood Institute Asthma–Chronic Obstructive Pulmonary Disease Overlap Workshop Report
Authors: Prescott G. Woodruff, Maarten van den Berge, Richard C. Boucher, Christopher Brightling, Esteban G. Burchard, Stephanie A. Christenson, MeiLan K. Han, Michael J. Holtzman, Monica Kraft, David A. Lynch, Fernando D. Martinez, Helen K. Reddel, Don D. Sin, George R. Washko, Sally E. Wenzel, Antonello Punturieri, Michelle M. Freemer, Robert A. Wise
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Section:ChooseTop of pageAbstract <<ACO: Clinical FeaturesRole of Imaging in ACOIs ACO Traceable to Early...Mucociliary Clearance, Ch...ACO: Cell and Molecular B...ConclusionsReferencesCITING ARTICLES
Phase 1b open-label randomized study of the oncolytic adenovirus DNX-2401 administered with or without interferon gamma for recurrent glioblastoma.
Authors: Frederick F. Lang, Nam D. Tran, Vinay K. Puduvalli, J. Bradley Elder, Karen L. Fink, Charles A. Conrad, W. K. Alfred Yung, Marta Penas-Prado, Candelaria Gomez-Manzano, Joanna Peterkin, Juan Fueyo
Journal: Journal of Clinical Oncology (2017)

2002 Background: DNX-2401 is a replication-competent, tumor-selective, oncolytic adenovirus with enhanced infectivity that causes durable tumor control by killing tumor cells and eliciting antitumor immunity. To increase immune activation, a phase 1b randomized study of intratumoral DNX-2401 alone versus DNX-2401 with interferon gamma (IFN) was conducted. Methods: A total of 27 patients with biopsy-confirmed glioblastoma at first or second recurrence received a single intratumoral injection of 3e10 vp DNX-2401. Patients were randomized in a 2:1 ratio to receive 50 mcg/m 2 of subcutaneous IFN (Actimmune) Q3W initiated 14 days after DNX-2401 or to be followed without further treatment for safety and survival. Results: Twenty-seven (27) patients were enrolled following first (59%) or second (41%) recurrence having previously failed surgery, radiation, and temozolomide (100%). The median longest tumor diameter was 40 mm (range 20-77 mm). Patients were randomized to DNX-2401 followed by IFN (n = 18) or to DNX-2401 alone (n = 9). Due to the poor tolerability of IFN, the median duration of treatment was only 6 weeks (range 0-30 weeks), and two patients did not initiate treatment as scheduled due to early clinical deterioration. The most frequent grade 3-4 AEs across treatment groups were fatigue, headache, and seizures consistent with pre-existing symptoms, underlying disease and/or surgery. Based upon a preliminary intent-to-treat analysis, IFN did not appear to provide additional benefit. However, OS-12 and OS-18 for all patients enrolled was 33% and 22%, respectively regardless of treatment assignment. Three patients remain alive at 19, 21, and 22 months (DNX-2401, n = 1; DNX-2401 + IFN, n = 2). Interestingly, 50% of patients with a baseline tumor diameter of ≤ 42 mm survived beyond 12 months, potentially identifying a sub-population of patients that may live longer following intratumoral DNX-2401. Conclusions: DNX-2401 was well tolerated as monotherapy. Although the addition of IFN did not improve survival, clinical activity following a single injection of DNX-2401 is encouraging and supports an ongoing Phase II study of DNX-2401 for recurrent glioblastoma. Clinical trial information: NCT02197169.
The scientific impact and value of large, NCI-sponsored randomized phase III cancer prevention trials.
Authors: Joseph M. Unger, William E. Barlow, Catherine M. Tangen, Scott David Ramsey, Ian Murchie Thompson, Eric A. Klein, Michael Leo LeBlanc, Charles David Blanke, Phyllis J. Goodman, Lori M. Minasian, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2017)

1541 Background: The cooperative cancer research groups of the National Cancer Institute’s National Clinical Trials Network have a history of successful conduct of large randomized phase III trials of prevention for cancer. An important question for funding agencies is whether the conduct of large prevention trials provides strong scientific return on investment. Methods: We used study data from a single NCI-sponsored cooperative group (SWOG) over a 20-year period (1990-2009, inclusive). During this time, SWOG conducted two large prevention trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin E Cancer Prevention Trial) and numerous treatment trials. Scientific impact for prevention and treatment trials was examined using citation analysis. Average annual citation counts were compared using t-tests. Scientific impact was also assessed as a function of trial costs. Results: Twenty-six treatment trials with 16,391 patients and two prevention trials with 54,415 patients were examined. The mean annual citation rate for primary articles was higher for prevention trials compared to treatment trials (173.6 vs. 41.7, p = .003). For both primary and secondary article publications, mean annual citations for articles associated with prevention trials were also higher (557.2 vs. 67.6, p &lt; .0001). Large prevention trials were estimated to provide 70% greater scientific impact on a cost-adjusted basis. Conclusions: Based on these criteria, the scientific impact of large phase III cancer prevention trials was very high in absolute terms and after accounting for trial costs. For appropriate scientific questions, large prevention trials provide a strong scientific return on investment for federal funding agencies.
Regulated Expansion and Survival of Chimeric Antigen Receptor-Modified T Cells Using Small Molecule-Dependent Inducible MyD88/CD40
Authors: Aaron E. Foster, Aruna Mahendravada, Nicholas P. Shinners, Wei-Chun Chang, Jeannette Crisostomo, An Lu, Mariam Khalil, Eva Morschl, Joanne L. Shaw, Sunandan Saha, MyLinh T. Duong, Matthew R. Collinson-Pautz, David L. Torres, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, J. Henri Bayle, Kevin M. Slawin, David M. Spencer
Journal: Molecular Therapy (2017)

Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4+ and CD8+ T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function. Here, we present a novel strategy to activate TLR and CD40 signaling in human T cells using inducible MyD88/CD40 (iMC), which can be triggered in vivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified T cells. Importantly, the concurrent activation of iMC (with rimiducid) and CAR (by antigen recognition) is required for interleukin (IL)-2 production and robust CAR-T cell expansion and may provide a user-controlled mechanism to amplify CAR-T cell levels in vivo and augment anti-tumor efficacy.
Dynamic Changes in MDS Clonal Architecture Following Allogeneic Stem Cell Transplant
Authors: Meagan A. Jacoby, Eric J. Duncavage, Gue Su Chang, Christopher A. Miller, Jin Shao, Kevin Elliott, Robert S. Fulton, Catrina Fronick, Michelle O'Laughlin, Daniel C. Link, John F DiPersio, Peter Westervelt, Timothy J. Ley, Timothy A. Graubert, Matthew J. Walter, Richard K Wilson
Journal: Blood (2016)