tbuckley/cabot-search huggingface dataset:
Impact of health care professional interventions on completion of therapy in patients receiving high-dose interferon-alfa 2b adjuvant therapy for high-risk melanoma.
Authors: Teresa M. Petrella, Richard Tozer, Gregory John Knight, Jose Chang, Bryn Lloyd Pressnail, Sudhashree Rajagopal, Nancy Gregorio, Caroline M. Hamm, Tina Cheng, Michael Smylie, Andre Galarneau, Jean-François Pouliot
Journal: Journal of Clinical Oncology (2014)

e20038^ Background: Melanoma incidence increased dramatically in the last decades. Intron A is the only adjuvant therapy shown to significantly increase progression-free and overall survival in high-risk melanoma, but is associated with numerous side-effects (SE) leading to early discontinuations, decreased drug exposure and potentially sub-optimal therapeutic benefit. The Heath Management Program II (HMP II) was designed to understand the factors influencing completion of therapy. Methods: Patients scheduled to receive high dose Interferon alpha-2b (IFN) adjuvant therapy [20 MIU/m2 5 days/week intravenously for 4 weeks (induction), followed by 10 MIU/m23 times/week subcutaneously for 48 weeks (maintenance)] were educated by oncology nurses on procedures known to minimize and prevent SEs. Emphasis was also given to other health care professional interventions and exercise. During the study period, patients were seen or contacted regularly to closely monitor, manage and prevent SEs. Results: From Apr 2006 to Sep 2012, 294 patients were enrolled in 12 centers across Canada. The one year completion rate was 41%. Only 28 patients (9.5%) discontinued during the induction phase vs. 146 (49%) during the maintenance phase. Reasons for early discontinuation included adverse events (AEs) (51%), progression (27%), and patient/physician decision (22%). AEs leading to discontinuation included: fatigue (26%), flu-like symptoms (17%), depression (13%), gastro-intestinal (13%), liver or hematological abnormalities (11%), autoimmunity (10%), and others (10%). Activity levels were mostly impaired during the induction phase. Patients with higher activity levels were 10% more likely to complete therapy. Regular visits to general practitioners (GP) or dermatologists (DERM) were associated with a 30% increase in completion of therapy. Conclusions: Despite aggressive intervention, a large proportion of patients do not complete interferon adjuvant therapy. Although it is unclear whether AE management or patient counseling has the most impact; visits to GPs and DERMs significantly increased the likelihood of completing IFN therapy. Clinical trial information: NCT00723710.
Phase 1 study of PF-03446962 (anti-ALK-1 mAb) in hepatocellular carcinoma (HCC): Correlation of tumor and serum biomarker data with disease control.
Authors: Matteo Simonelli, Crystal Shereen Denlinger, Laura Williams Goff, Cristina Noberasco, Tae-You Kim, Melanie B. Thomas, Filippo G. De Braud, Paolo A. Zucali, Armando Santoro, Patricia A English, Corrado Gallo-Stampino, Erjian Wang, Marina Carpentieri, James Andrew Williams
Journal: Journal of Clinical Oncology (2014)

4095 Background: PF-03446962 ,a fully human IgG2 mAb against ALK-1 (Activin-Receptor Like Kinase-1, a specific TGF-β receptor selectively expressed on vasculature), demonstrated a favorable safety profile in a Phase 1 expansion cohort of HCC patients (pts) whose disease progressed after sorafenib ± other systemic anti-angiogenic therapies. Tumor immunohistochemistry (IHC), multiplex serum soluble protein, and pharmacokinetic (PK) results are reported here along with disease control data. Methods: Child-Pugh A HCC pts progressive on/intolerant to VEGFR TKI were included. Pts were treated with PF-03446962 at 7 mg/kg IV on Day 1, Day 29 and then q 2 weeks. PF-03446962 PK was also monitored. Archival (pre-sorafenib) and de novo (pre-PF-03446962) tumor specimens were assessed by IHC for TGF-β (low affinity ALK-1 ligand), ALK-1, c-MET and CD31. A multiplex approach was used for assessment of 15 serum soluble proteins involved in angiogenesis and TGF-β pathways, including BMP-9 (a high affinity ALK-1 ligand) at baseline, Cycle2 Day1, Cycle3 Day1 and end of treatment. Biomarker data were correlated with Disease Control at 12 weeks (DC) and Objective Tumor Response (OR) by RECIST. Results: Higher mean tumor tissue archival (ratio = 15) and de novo (1.7) c-MET expression, higher (1.5) mean baseline serum levels of BMP-9, and lower mean baseline serum levels of TGF-β (0.44) and VEGFR3 (0.66) were found in the patients with disease control at 12 weeks vs. those patients with progressive disease. No ORs were reported, DCR was 29.2% and mTTP was 3.0 months. In 7 pts, PF-03446962 achieved stable disease ≥ 12 weeks, suggesting a role of ALK-1 in sustaining tumor growth. PF-03446962 serum trough concentrations in these pts well exceeded the therapeutic level suggested by non-clinical data. Conclusions: Higher tumor c-MET and serum BMP-9, and low serum TGF-β and VEGFR3 were found in patients with disease control at 12 weeks vs. those patients with progressive disease. Expanded molecular approaches to identify biomarkers for PF-03446962 are being assessed in an ongoing phase 2 study. The selection of 7 mg/kg every 2 weeks as the RP2D dose is supported by PK results in this population. Clinical trial information: NCT00557856.
Survival benefit of Asian females in the era of targeted therapy for advanced lung cancer.
Authors: Daniel Jacob Becker, Lena Masri, Michael L. Grossbard, Benjamin Philip Levy
Journal: Journal of Clinical Oncology (2014)

e17659 Background: Development of the EGFR tyrosine kinase inhibitors (TKI’s) and FDA approval of erlotinib in 2004 began a decade of advances in targeted therapy for advanced lung cancer. Lung adenocarcinomas in Asian females are highly enriched for EGFR mutations. Despite randomized studies with improvements in progression free survival, TKI’s have not yet proven to extend survival for patients harboring EGFR mutations. We sought to examine the survival advantage attributable to the use of TKI’s, by comparing outcomes before and after the implementation of TKI therapy. Methods: We examined the SEER database for cases of stage IV adenocarcinoma of the lung diagnosed 1998- 2010. We divided our cohort into those diagnosed 1998-2004 (no TKI), and diagnosed 2005-2010 (TKI); and further by race/gender into Asian females (AF) and non-Asian males (NAM). We constructed Kaplan-Meier curves and compared curves by log-rank test. We used Cox Proportional Hazards models to evaluate lung cancer specific survival differences between recently and remotely diagnosed cases, controlling for known predictive variables. Results: We included 2381 AF with stage IV adenocarcinoma diagnosed 1998-2010: 964 (40.5%) diagnosed 1998-2004, and 1417 (59.5%) diagnosed 2005-2010; and 28862 NAM: 13322 (46.2%) diagnosed 1998-2004, and 15540 (53.8%) diagnosed 2005-2010. Median age (67 for AF and 66 for NAM) and grade were comparable between groups. There were 1734 (72.8%) lung cancer related deaths in AF, and 24872 (85.9%) in NAM. Asian females diagnosed 2005-2010 had a survival advantage (mortality HR 0.76 [95% CI 0.69-0.83]) relative to AF diagnosed 1998-2004, controlling for age and tumor grade. Non-Asian males diagnosed 2005-2010 had a survival advantage ( mortality HR 0.85 [95%CI 0.83-0.87]) relative to NAM diagnosed 1998-2004, controlling for age, grade, race (black/white), and Hispanic ethnicity. Conclusions: Patients diagnosed with stage IV adenocarcinoma of the lung 2005-2010, regardless of ethnicity, had a survival benefit relative to those diagnosed 1998-2004. The benefit for Asian females was significantly larger than the benefit for non-Asian males. The additional survival benefit is likely attributable in part to the effects of TKI’s.
Randomized trial of Tibetan yoga in breast cancer patients undergoing chemotherapy.
Authors: Lorenzo Cohen, Amy Spelman, Rosalinda Engle, Banu Arun, Qi Wei, Carol Harrison, George H. Perkins, Vicente Valero, Gildy Babiera, Tenzin Wangyal, Alejandro Chaoul
Journal: Journal of Clinical Oncology (2014)

9539 Background: Mind-body practices improve quality of life (QOL), yet prior trials have not included active control groups. Our prior work found a Tibetan Yoga Program (TYP) resulted in fewer sleep disturbances. This study assessed the effects of TYP versus Stretching Program (STP) and Usual Care (UC) on sleep, fatigue and QOL of breast cancer patients undergoing chemotherapy. Methods: Patients with stage I-III breast cancer undergoing chemotherapy were eligible. Participants were randomized to TYP, STP or UC. TYP and STP consisted of four 90-minute sessions. TYP consisted of controlled breathing, visualization, meditation and postures. STP included common stretches for recovery and mirrored TYP postures. Sleep disturbances (PSQI), fatigue (BFI) and breast cancer-specific QOL (FACT-B) were assessed at baseline, 1 week and 1 and 6 months after the last session. Results: Participants were 283 women (mean age=48.8 years). We analyzed participants who completed baseline and at least one follow-up with GLM, controlling for corresponding baseline measures and age, menopausal status, stage, time since diagnosis, surgical procedure and chemotherapy regimen. Analyses revealed a significant group main effect at 6-months post-intervention for sleep duration (means: TYP=0.85; STP=1.33; UC=1.21; p=0.02), with TYP reporting greater sleep duration than STP (p=0.008) and UC (p=0.02). Similar results were found for sleep efficiency (means: TYP=1.57; STP=2.17; UC=2.29; p=0.06), with TYP being significantly different from UC (p=002). There were no significant group differences for BFI. For FACT-B, there was a significant group effect at 1-week post-intervention (means: TYP=12.5; STP=14.3; UC=13.9; p=0.05), with TYP reporting fewer symptoms than STP (p=0.02) and UC (marginal at p=0.06). At 3-months post-intervention, there was a significant group effect for FACT-B (means: TYP=7.9; SG=10.5; UC=8.7; p=0.04), with group differences between TYP and STP (p=0.01). Conclusions: Participating in a Tibetan yoga program resulted in better long-term sleep quality and QOL than an active control intervention or usual care. Tibetan yoga should be considered to help improve these symptoms for breast cancer patients undergoing chemotherapy. Clinical trial information: NCT00507923.
Chronic Obstructive Pulmonary Disease Biomarkers and Their Interpretation
Authors: Robert A. Stockley, David M. G. Halpin, Bartolome R. Celli, Dave Singh
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

The pathology and impact of chronic obstructive pulmonary disease (COPD) results from an abnormal inflammatory process resulting in tissue damage with ineffective repair in response to toxic inhalants (especially cigarette smoke). Identification of mechanisms provides the opportunity to develop new therapies and a personalized approach to management. The collection of multiple genetic and detailed biochemical data from small and large patient cohorts has led to an explosion of studies investigating biomarkers to achieve these aims. Despite widespread enthusiasm and many statistically significant associations, the interpretation of COPD biomarker results requires thought and leaves many questions unanswered. The present review assesses the importance of these associations, whether they represent cause or effect, reflect disease severity or activity, the complexity of the pathway to the final pathogenic and hence interventional step, and problems with interpreting cross-sectional studies without knowing individual disease trajectories. The complexity of biomarker specificity without sufficient clinical phenotype and endotype information contributes to problems of interpretation. A strategic change is needed to develop useful COPD biomarkers; this includes focusing on endotype biomarkers within specific clinical phenotypes, biomarkers in early COPD, exacerbation subtype biomarkers, and biomarkers to predict or measure drug effects.
Hyper-Editing of Cell-Cycle Regulatory and Tumor Suppressor RNA Promotes Malignant Progenitor Propagation
Authors: Qingfei Jiang, Jane Isquith, Maria Anna Zipeto, Raymond H. Diep, Jessica Pham, Nathan Delos Santos, Eduardo Reynoso, Julisia Chau, Heather Leu, Elisa Lazzari, Etienne Melese, Wenxue Ma, Rongxin Fang, Mark Minden, Sheldon Morris, Bing Ren, Gabriel Pineda, Frida Holm, Catriona Jamieson
Journal: Cancer Cell (2019)

Highlights•A-to-I RNA editing alters cell-cycle transit by impairing pri-miR-26a maturation•Enforced miR-26a expression reduces BC CML progenitor propagation in vivo•pri-miR-155 downregulation by ADAR1 stabilizes MDM2 in CML progenitors•Hyper-editing of 3′ UTR of MDM2 prevents miR-155 binding in CML progenitorsSummaryAdenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3′ UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation. These data reveal a dual mechanism governing malignant transformation of progenitors that is predicated on hyper-editing of cell-cycle-regulatory miRNAs and the 3′ UTR binding site of tumor suppressor miRNAs.Graphical abstract
Early Clinical Experience of CD19 x CD22 Dual Specific CAR T Cells for Enhanced Anti-Leukemic Targeting of Acute Lymphoblastic Leukemia
Authors: Rebecca Gardner, Colleen Annesley, Olivia Finney, Corinne Summers, Adam J. Lamble, Julie Rivers, Kaelin Crews, Lauren Huang, Christopher Brown, Stephanie Mgebroff, Catherine Lindgren, Karen Spratt, Josh Gustafson, Adam Johnson, Julie R. Park, Michael C. Jensen
Journal: Blood (2018)
Ewing sarcoma: A third-level hospital experience in a low-income country.
Authors: Farina Esther Arreguin-Gonzalez, Sandra Paez, Yadira Janet Gonzalez-Paredes, Karla Noemi Arredondo-Martinez, Marta Zapata-Tarres, Guadalupe Frias-Vazquez, Jose de Jesus Figueroa Carbajal
Journal: Journal of Clinical Oncology (2014)

e21017 Background: Ewing sarcoma (ES) is the second most common type of primary bone malignancy in children and adolescents. The literature reports that survival rates for localized ES have improved up of 70% with aggressive chemotherapy and local control . On the other hand, there has been little improvement in survival rates for patients with metastatic or recurrent ES. Objective: To report the experience of a third level hospital in a low income country. Methods: We performed a retrospective, retrolective and descriptive study of 28 patients diagnosed with ES at Centro Medico Nacional 20 de Noviembre ISSSTE between 1998 and 2013. Results: Clinical features at diagnosis are similar as described in literature. 32% was referred to our hospital from second level hospitals from Mexico city, the rest was referred from other Mexican states. 47% were metastatic at diagnosis. Only in 36% radical surgery was performed. Chemotherapy treatments had no changes along time. Around 23% relapsed. Conclusions: Outcomes for patients with metastatic and recurrent Ewing sarcoma remain poor specially in a low income hospital like ours and a better understanding of the biology of this malignancy is critical to the development of prognostic biomarkers and novel therapies.
Survival benefit with low-molecular-weight heparin in patients with advanced solid tumors: A post hoc analysis of PROTECHT trial.
Authors: Sandro Barni, Fausto Petrelli, Erminio Bonizzoni, Melina Verso, Gualberto Gussoni, Tania Perrone, Giancarlo Agnelli
Journal: Journal of Clinical Oncology (2014)

9640 Background: Use of low molecular weight heparin (LMWH) are approved to reduce the thromboembolic events in patients with solid tumors. The effect of LMWH on overall survival (OS) has been debated but not demonstrated, and current guidelines recommend against its use to increase OS. We have conducted a post hoc analysis of PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) randomized study that compared nadroparin to placebo in patients with metastatic or locally advanced solid tumors. Methods: In our post-hoc analysis, individual patient data (n=1,150) was reviewed and analyzed to assess response to chemotherapy and overall survival. Tumor response to chemotherapy was assessed using Response Evaluation Criteria in Solid Tumors. Survival analysis was performed through a Cox regression model with treatment, response to chemotherapy and their interaction term (treatment-by- response to chemotherapy) as covariates. A statistically significant interaction indicates that an overall comparison between the two treatments is inappropriate, and therefore hazard ratios (HRs) with associated 95% CI and p-values must be evaluated separately in each group (disease control / no disease control). Results: A statistically significant interaction between treatment and response to chemotherapy (P=0.0435) was found, suggesting the hypothesis that OS treatment difference depends on the response to chemotherapy. A statistically significant difference in OS in favour of nadroparin treatment was found in the subgroup of patients with disease control (HR=0.665 [95%CI 0.442 - 1.00], P=0.05), but not in the subgroup of patients without disease control (HR=1.077 [95%CI 0.857 - 1.35], P=0.525). In patients with disease control, 1-year survival rate was 83% [95%CI 79% - 87%] in nadroparin and 76% [95%CI 70% - 83%] in placebo respectively; conversely in patients without disease control 1-year OS was 49% [95%CI 44% - 53%] in nadroparin and 51% [95%CI 45% - 58%] in placebo. Conclusions: this post hoc analysis support the hypothesis that LMWH could increase survival albeit limited to patients responding to chemotherapy. Clinical trial information: NCT 00951574.
Ibrutinib Reduces Obinutuzumab-Gazyva Infusion Related Reactions (IRR) in Patients with Chronic Lymphocytic Leukemia (CLL) and It Is Associated with Changes on Plasma Cytokine Levels
Authors: Juliana Velez Lujan, Chaja Jacobs, Paula A Lengerke Diaz, Eider F Moreno-Cortes, Cesar A Ramirez-Segura, Michael Y. Choi, Colin McCarthy, Alaina Heinen, Carlos Amaya-Chanaga, Thomas J. Kipps, Januario E Castro
Journal: Blood (2018)
Long-term Absolute Risk for Cardiovascular Disease Stratified by Fasting Glucose Level
Authors: Michael P. Bancks, Hongyan Ning, Norrina B. Allen, Alain G. Bertoni, Mercedes R. Carnethon, Adolfo Correa, Justin B. Echouffo-Tcheugui, Leslie A. Lange, Donald M. Lloyd-Jones, John T. Wilkins
Journal: Diabetes Care (2019)

OBJECTIVE To estimate the long-term absolute risk for cardiovascular disease (CVD) according to fasting glucose (FG) levels below the threshold of diabetes. RESEARCH DESIGN AND METHODS We pooled data from seven observational cohorts of U.S. black and white men and women followed from 1960 to 2015. We categorized FG as follows: &amp;lt;5.0, 5.0–5.5, 5.6–6.2, 6.3–6.9 mmol/L, and diabetes (FG ≥7.0 mmol/L or use of diabetes medications). CVD was defined as fatal/nonfatal coronary heart disease and fatal/nonfatal stroke. We estimated the risk of CVD by FG category at index age 55 years using a modified Kaplan-Meier survival analysis, adjusted for the competing risk of non-CVD death. We also assessed risk for incident CVD according to change in FG before 50 years of age, specifically among the categories &amp;lt;5.6 mmol/L, 5.6–6.9 mmol/L, and diabetes. RESULTS Our sample included 19,630 individuals (6,197 blacks and 11,015 women) without a prior CVD event. Risk for CVD through 85 years of age ranged from 15.3% (&amp;lt;5.0 mmol/L) to 38.6% (diabetes levels) among women and from 21.5% (5.0–5.5 mmol/L) to 47.7% (diabetes levels) among men. An FG of 6.3–6.9 mmol/L was associated with higher long-term CVD risk compared with the lowest FG among men but not women. Increases in glucose during midlife with conversion to diabetes were associated with higher cardiovascular risk (1.3- to 3.6-fold) than increases in glucose below the diabetes threshold. CONCLUSIONS Middle-age individuals with diabetes have high long-term absolute risk for CVD. These data strongly support the importance of blood glucose monitoring in midlife for CVD prevention.
Efficacy and Safety of Daratumumab Based Regimens for Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Muhammad Abu Zar, Ahmad Kamal, Ali Younas Khan, Saad Ullah Malik, Mustafa Nadeem Malik, Abdul Rafae, Ceren Durer, Seren Durer, Insija Ilyas Selene, Anum Qureshi, Jemin Aby Jose, Hafiz Muhammad Fazeel, Zunairah Shah, Muhammad Adil Rehman, Faiz Anwer
Journal: Blood (2018)
Dose-seeking phase I trials (DSP1T) for currently approved molecular-targeted therapies (MTT): We are still far from using appropriate designs.
Authors: Nuria Kotecki, Ahmad Awada, Jacques Bonneterre, Mohamed Hebbar, Antoine Adenis, Alexis B. Cortot, Sophie Cousin, Stephanie Clisant, Alain Duhamel, Andrew Kramar, Nicolas Penel
Journal: Journal of Clinical Oncology (2014)

3034 Background: To explore the use of innovative and more appropriate designs (Continual Reassessment method [CRM], dose-escalation driven by PK or target inhibition …). Methods: We have reviewed fully published (2001-2013) single-agent DSPT1 (n=38) investigating MTT (n=20), currently approved for solid tumors treatment. Results: Eligible criteria included target expression/molecular profiling in only 6 trials (15%). In all cases but one, the trials were based on dose-escalation, mainly toxicity-driven (36 trials, 94%). In 33 trials, the period for assessing DLTs was ≤28 days (87%). DLTs were defined in 31 DSPT1; these definitions took into account the drugs mechanism of action in only 8 cases (25%). In 23 trials, the definitions were strictly similar to those used for cytotoxic agents (75%). “3+3 design”, CRM and randomization were used in 17 (44%), 2 (5%) and 3 (8%) DSPTA, respectively. The dose increment was based on “Fibonacci-like” schema, PK or CRM in 25 (65%), 3 (8%) and 2 (5%) DSPT1, respectively. Median numbers of pts and dose-levels were 53 (12-206) and 6 (1-21). There was an expanded cohort at P2RD in 24 trials (63%) with a median number of pts of 12 (3-82). The P2RD was defined in 22 trials (58%). P2RD was identical to the latter approved dose in only 20 trials. The selection of the P2RD also integrated clinical activity (10 trials, 26%), PK (31, 81%), target inhibition or PD (4, 11%) and the results of parallel DSP1T (3, 8%). The probability to experience DLT at the P2RD was ranged from 0% to 33% (median 14%). Conclusions: Most of the designs of DSP1T investigating MTT are old-fashioned. The period for assessing DLTs was too short and might be not appropriate in the perspective of long-term drug administration scheduling. This may underestimate the MTT toxicity profile. It is of utmost importance to move ahead to more adapted and innovative designs.
Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study
Authors: Mohamed L. Sorror, Barry E. Storer, Aaron T. Gerds, Bruno C. Medeiros, Paul J Shami, John P. Galvin, Kehinde U. Adekola, Selina Luger, Maria R. Baer, David A. Rizzieri, Tanya M. Wildes, Eunice S. Wang, Stefan Faderl, Jamie L. Koprivnikar, Mikkael A. Sekeres, Sudipto Mukherjee, Julie Smith, Mitchell Garrison, Kiarash Kojouri, Jennifer E. Nyland, Rachelle R. Moore, Sophie L. Fleuret, Ylinne Lynch, Pamela S. Becker, Mary-Elizabeth M. Percival, Brenda M. Sandmaier, Frederick R. Appelbaum, Elihu H. Estey
Journal: Blood (2018)