tbuckley/cabot-search huggingface dataset:
The ErbB2-antibody 2C4 and cardiac dysfunction in mice.
Authors: N. Maurea, C. G. Tocchetti, C. Coppola, G. Ragone, A. Barbieri, D. Rea, G. Palma, M. Gala, A. Luciano, C. Arra, C. De Lorenzo, R. V. Iaffaioli
Journal: Journal of Clinical Oncology (2011)

e11040 Background: Anti-ErbB2 therapies are associated with increased risk of left ventricular (LV) dysfunction. Trastuzumab increases the frequency of asymptomatic decrease in LV ejection fraction (LVEF) by 3-18%, and the risk of heart failure (HF) by 2-4%. The newer ErbB2 antibody rhuMAb 2C4 (pertuzumab) seems to affect ligand induced ErbB signaling in a more direct fashion, affecting EGFR/ErbB2 dimerization; yet, its cardiac side effects are only beginning to emerge. Here, we test whether the murine 2C4 induces cardiac dysfunction in normal mice. Methods: In vivo cardiac function was measured with LV fractional shortening (FS) by M-mode echocardiography in sedated C57BL/6 mice (2-4 mo. old) at day 0, and after 2 and 6 days of daily i.p. administration of 2C4 (2.25 μg/g/day) or doxorubicin (Doxo, 2.17 μg/g/day) as a positive control, and in sham animals. With Speckle Tracking echocardiography (ST) we also evaluated radial myocardial strain (%), a very sensitive parameter which can predict LV dysfunction. Results: After 2 days, FS was reduced with 2C4: 58±1%, p=.01 vs sham (60±0.4%). The reduction in FS obtained with Doxo was even larger: 52±0.2%, p=.0000001 vs sham, p=.00004 vs 2C4. Myocardial strain was similarly reduced in both 2C4 (40±8%) and Doxo-treated mice (43±3%) compared to sham (66±0.6%; p=.02 vs 2C4, and p=.0005 vs Doxo). After 6 days, LV dysfunction was exacerbated, with FS further reduced to similar values by 2C4 (39±5%) and Doxo (46±2%, p=NS vs 2C4; both p<.05 vs sham and vs 2 days), and strain decreased to 31±7% (2C4) and 40±7% (Doxo, p=NS vs 2C4; both p=.01 vs sham and p=NS vs 2 days). Conclusions: The murine ErbB2 antibody 2C4 is cardiotoxic in mice. The reduction in FS is milder than Doxo early at 2 days, but comparable to Doxo after 6 days. The clear mechanisms of anti ErbB2-induced cardiotoxicity are to be elucidated. Further studies will be crucial to establish the cardiotoxic mechanisms of ErbB2-antagonists, and to influence the design of future anticancer therapies in an attempt to retain anticancer effects, while minimizing cardiac toxicity. We also plan to apply speckle tracking echocardiography to clinical studies, in order to evaluate the impact of early identification of ErbB2-blockers cardiotoxicity in the treatment of women with breast cancer.
Phase I, open-label, dose-escalation study of AZD7762 in combination with irinotecan (irino) in patients (pts) with advanced solid tumors.
Authors: A. L. Ho, J. C. Bendell, J. M. Cleary, G. K. Schwartz, H. A. Burris, P. Oakes, F. Agbo, P. N. Barker, A. M. Senderowicz, G. Shapiro
Journal: Journal of Clinical Oncology (2011)

3033 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has shown synergistic activity with irino in xenograft models. Methods: A 3+3 design evaluated the safety and PK of AZD7762 (6–144 mg iv) ± irino (100 or 125 mg/m2 iv) (NCT00473616). AZD7762 was given alone on days 1 and 8 (Cycle 0); after 7 days’ observation, AZD7762 was given after irino on days 1 and 8 of 21-day cycles until disease progression/discontinuation for any reason. To further confirm safety, an expansion phase was conducted at the MTD. Results: 68 pts received AZD7762 (6 mg [n=11]; 9 mg [3]; 14 mg [9]; 21 mg [4]; 32 mg [5]; 48 mg [7]; 64 mg [5]; 96 mg [19]; 144 mg [5]). Colorectal (n=29) was the most common tumor site. Median exposure to AZD7762 was 43 days (range 1–520). During dose escalation, 1 pt had DLTs of myocardial infarction with Gr 4 ventricular dysfunction during AZD7762 144 mg monotherapy. Three pts had non-cardiac DLTs during Cycle 1: 6 mg (Gr 3 diarrhea/decreased appetite/dehydration); 14 mg (Gr 3 increased alanine aminotransferase); 48 mg (Gr 4 febrile neutropenia). In the expansion phase (AZD7762 96 mg + irino 100 mg/m2), 3/11 evaluable pts had DLTs (Gr 2 left ventricular systolic dysfunction/Gr 4 troponin increase; Gr 3 troponin increase; Gr 3 cardiomyopathy) – all occurred during AZD7762 monotherapy. Overall, the most common AEs were diarrhea, fatigue and nausea. AZD7762 Cmax, C24h, and AUC increased in a linear and dose-proportional manner. Plasma concentrations at doses >21 mg were consistent with those biologically effective in preclinical studies. Irino did not affect AZD7762 PK. By RECIST, 1 CR (48 mg; small cell carcinoma of the ureter; duration ~18 months) and 1 PR (144 mg; colon with prior irino treatment) were observed. Conclusions: During dose escalation, the AZD7762 MTD was 96 mg with irino 100 mg/m2. However, recruitment to the 96 mg safety expansion phase was stopped due to cardiac DLTs during Cycle 0 (AZD7762 monotherapy). DLTs during combination therapy were consistent with those reported with irino alone.
Patient uptake and satisfaction with advanced genomic technologies offered through an employee benefit program.
Authors: Shannon M. Kieran, Kelly Z. Knickelbein, Julie Goldstein, Sara Riordan, Paul Billings
Journal: Journal of Clinical Oncology (2016)

72 Background: Access to advanced genomic technologies for the diagnosis and treatment of cancer is important. As part of an employee benefit program, we offered genomic technologies, such as somatic tumor and inherited germline genetic testing, as well as clinical trial information, medical second opinions, and genetic counseling, as appropriate, to enrollees with cancer. Genetic counselors served as cancer navigators through the process. The study aimed to assess uptake of the services offered and satisfaction with the program. Methods: Established benefit enrollment criteria included a diagnosis of cancer and company status (employee, spouse, dependent child). All data and communications were tracked in an online Patient Resource Management (PRM) system. Data was pulled directly from the PRM system logs. To measure satisfaction, participants were asked to complete an anonymous exit survey following completion of the program. Results: The data set included 131 individuals who inquired about program services. Eighty of the 131 (61%) met criteria and enrolled. Thirty-six of the 80 (45%) had complete data available for analysis. Cancer types varied but mostly included breast, colon, lung, leukemia and lymphoma. The table below shows the specific service uptake rates for the cohort. Seven participants completed the exit survey and all responded that the information gained from the program was useful and that the program increased satisfaction with their employer. Conclusions: Patients with cancer do not always have access to genomic technologies, nor understand the technology applications for their prognosis and treatment. Our experience in developing this program is that enrollees were interested in pursuing services that supported the use of genomic technologies, and satisfaction was high amongst those that provided feedback. Overall, the program directly engaged participants in their care and empowered them through education provided by genetic counselor navigators in ways that are not typically available in most cancer care settings. [Table: see text]
Imatinib Given Concurrently with Induction Chemotherapy Is Superior to Imatinib Subsequent to Induction and Consolidation in Newly Diagnosed Philadelphia-Positive Acute Lymphoblastic Leukemia (PH+ALL).
Authors: Oliver G. Ottmann, Barbara Wassmann, Heike Pfeifer, Nicola Goekbuget, Gesine Bug, Patrick Brueck, Anja Binckebanck, Harald Gschaidmeier, Dieter Hoelzer
Journal: Blood (2004)
The FAMKOL trial: Trans-sectoral screening in high-risk populations, comparing nurse-led counselling versus written information materials in first-degree relatives of patients with colorectal cancer.
Authors: Alexander Bauer, Thomas Seufferlein, Max Reinshagen, Stephan Hollerbach, Madeleine Ritter-Herschbach, Stephanie Boese, Juergen F. Riemann
Journal: Journal of Clinical Oncology (2016)

509 Background: Prevention of colorectal cancer (CRC) is a major health care issue. First-degree relatives (FDR) of patients with colorectal cancer have a 2-4-fold increased risk for colorectal cancer. Thus, in this population an adequate participation in the screening colonoscopy is of particular importance. However, appropriate strategies to increase the participation in screening colonoscopy are still lacking. Methods: Cluster-randomized, single blinded, controlled, multicenter trial. At 64 trial sites, 2,411 patients treated for CRC (index patients) were enrolled and n = 1,158 randomized to either paper-based information material only or additional barriers-focused counselling. Index patients were asked to forward trial materials to their FDR. FDR in the intervention group (IG) also received an additional individualized nurse-led counselling on barriers against colonoscopy and were assisted in making appointments to office-based gastroenterologists. Results: N = 313 FDR (IG n = 148; n = 165 controls) aged 28-85 years participated in the trial. A total of 197 FDR underwent preventive colonoscopy (IG n = 99 [66.9%] vs. n = 98 [59.3%]; p &gt;.05). In these 197 patients, polypectomy was performed in n = 69 patients (IG n = 39 [39.4%] vs. n = 30 [30.6%]; p &lt;.05]). Histological examination revealed n = 2 colorectal carcinoma in 197 patients. Conclusions: The FAMKOL trial confirmed the high effectiveness of an interdisciplinary and trans-sectoral invitation to the screening colonoscopy. FAMKOL also verified the significantly higher risk for adenomas and CRC in the targeted patient population. Hence, the permanent implementation of this invitation program may contribute to decrease CRC mortality. Clinical trial information: NCT01903395.
SUV max of the most intense lesion on fdgpet/CT scan at baseline as a potential prognostic factor in stage IV (NSCLC): A retrospective review.
Authors: Manga Devi Kodali, Amol Takalkar, Runhua Shi, Prakash Peddi, Glenn Morris Mills, Syed Hasan Raza Jafri
Journal: Journal of Clinical Oncology (2013)

e19070 Background: Lung cancer is the leading cause of mortality in United States and worldwide. Stage IV lung cancer has poor prognosis with 5-year survival of 2%. Limited numbers of factors are known to predict survival in stage IV NSCLC (Non Small Cell Lung Cancer) including stage at diagnosis, Performance Status (PS), genomic expression profile. Earlier studies have found SUV max (Maximum Standardized Uptake Value) of primary lung tumor on FDGPET/CT (Fluoro Deoxy Glucose –Positron Emission Tomography/Computed Tomography) correlates with tumor doubling time and survival. However prior studies included stage I-IV NSCLC patients and SUVmax of primary lung tumor. Hence we performed this study with only clinical stage IVNSCLC who underwent FDGPET/CT scan at baseline to determine whether SUVmax value of most intense lesion has any prognostic significance. Methods: Retrospective review identified 46 patients (September 2004- September 2011) that were diagnosed with stage IV NSCLC at our institution. SUVmax of most intense lesion on FDG PET/CT scan was determined utilizing an automated program on a dedicated PET/CT workstation by a single nuclear medicine specialist. Cox regression analysis and Log-rank test were used to analyze data. Results: Descriptive statistics: Median age 61.6 (43.8-77.8), Females 17 (36%), African Americans 26 (56%), Performance status 0-1=36 (80%), number of metastatic sites 1-2=30 (65%), Adenocarcinoma 32 (70%), Chemotherapy 31 (61%), SUV max- primary (65%), other sites (35%). The patient population was subdivided into two groups using the median SUVmax of 17.8. The median survival of patients having SUV max ≤17.8 and SUVmax &gt; 17.8 was 13.4 months and 4.5 months respectively (P =0.0269). Multivariate analysis indicated PS (HR=2.8), any chemotherapy (HR=2.56) and SUV max ≤ 17.8 (HR=1.98, P=0.04) predicted survival. Conclusions: SUV max of the most intense lesion at the time of presentation predicts worse outcome in stage IVNSCLC and needs to be validated in a prospective study. PETCT may be able to predict the areas that harbor resistant clones of cells, described in previous studies as tumor heterogeneity, which may confer prognostic significance.
Large Granular Lymphocyte Infiltration in the Bone Marrow in Children and Young Adults May Suggest Primary Immune Deficiency
Authors: Mervi H Taskinen, Satu Mustjoki, Kirsi Jahnukainen, Luca Trotta, Timo Siitonen, Timo Hautala, Andrey Zavialov, Kaarina Heiskanen, Emma M Haapaniemi, Janna Saarela, Mikko Seppänen
Journal: Blood (2015)
Improving the quality of multidisciplinary care for head and neck cancer.
Authors: Carol M. Lewis, Zhannat Nurgalieva, Stephen Yenzen Lai, Randal S. Weber
Journal: Journal of Clinical Oncology (2014)

232 Background: As specialty- and disease-specific treatment recommendations based on the best available evidence and/or expert consensus, clinical practice guidelines such as those set forth by the National Comprehensive Care Network (NCCN) establish the current standard of quality care; adherence to these guidelines can serve as a measure of the quality and effectiveness of care. We aimed to assess multidisciplinary conference (MC) treatment recommendations’ adherence to NCCN head and neck cancer guidelines, while identifying potential areas for quality improvement. Methods: Patients presented with previously untreated head and neck cancers are being prospectively accrued as they are presented at weekly MC. The charts of patients presented between 10/20/2011 and 10/20/2013 were reviewed for clinical data leading up to MC to allow us to assess whether, based on the available information, the recommendations of conference are compliant with NCCN treatment guidelines. Results: Of 556 enrolled patients, 49.1% had oropharyngeal cancer, 28.2% had oral cavity cancer, 19.3% had laryngeal cancer, and 3.4% had nasopharyngeal cancer. For the entire cohort, the mean age at presentation was 58.9 years (16.4 - 89.3). Four hundred forty three patients (79.7%) were men. The recommendations of conference were non-compliant with NCCN treatment guidelines for 6.2% patients (17/273) with oropharyngeal cancer, 13.4% patients with oral cavity cancer (21/157), 0.9% patients (1/107) with laryngeal cancer, and 15.8% patients (3/19) with nasopharyngeal cancer. The most common reasons for non-compliance were recommended treatment of N2 oropharyngeal disease with definitive radiation alone (13 patients) and recommended over-use of induction chemotherapy (14 patients). Conclusions: NCCN guideline compliance can be used to evaluate the quality of head and neck cancer care. We have identified areas for potential improvement within our institution. Further study is needed to evaluate how care that deviates from NCCN guidelines affects patient outcomes.
Pharmacokinetic food-effect study of abiraterone acetate (AA) in patients with metastatic castration resistant prostate cancer (mCRPC): The ABIFOOD trial (EudraCt number: 2012-003226-25).
Authors: M. Espinosa, A Falcon, A Gutierrez-Valencia, A Cervera, CM Rosso-Fernandez, E Martinez-Lozano, B Perez-Valderrama, J Martinez-Atienza, L Jimenez Gonzalez-Serna, I Sanchez-Simon, M Cruz, A Rodriguez, JA Virizuela, P Maiquez, N Hindi, I Gallego Jimenez, FL Lopez-Cortes, Luis G. Paz-Ares, Ignacio Duran
Journal: Journal of Clinical Oncology (2016)

227 Background: A.A has been approved for the treatment of mCRPC before and after docetaxel. The standard regime consists on daily A.A. 1.000 mg in a fasting state along with prednisone 10mg q.d. However, data from pharmacokinetic (PK) studies in patients (pts) and healthy volunteers has revealed a significant food-effect with up to 7-10 folder increase in area under plasma concentration-time curve (AUC) when A.A is given with food, specially with fat content, [Chi KN, J Clin Pharmacol 2015]. Methods: ABIFOOD is a phase I, randomized trial to evaluate the short and long-term effect of diet on the PKs of A.A. in pts with mCRPC who have progressed to docetaxel. Eligible pts include men ≥ 18 years old with mCRPC, ECOG performance status (PS) &lt; 2 and an adequate organ function. Pts are randomly assigned to receive 4-weekly cycles of 250 mg A.A with standard meal (Arm A), 250 mg A.A with high-fat meal (Arm B) or 1000 mg A.A in fasting conditions (Arm C). PK analyses are conducted at week 1 (W1) and cycle 5. Results: Fifteen pts (5, 3 and 7 in arms A, B and C respectively) have been included and 6 are still on treatment. Median age is 72, 97% have ECOG-PS 1. Gleason Score is &gt; 8 in 6 (40%) pts.Geometric mean abiraterone [AUC (ng.h/ml) (IQR)] at W1 did not significantly differ between treatment arms [arm A: 404.68 (368.4 - 488.2), arm B: 372 (334.6 - 440.5) arm C: 656.51 (387.8 – 1144.5) p 0.15]. PK data did not influence activity or toxicity. Progression free survival was 8.50, 6.33 and 4.86 months in Arms A, B and C respectively (p 0.53). One patient in arm A is still on treatment after 17 cycles. Conclusions: The administration of lower doses of A.A with food [regardless the fat content], might achieve comparable plasma levels to standard dosing with no detriment in efficacy or toxicity parameters. The study is actively recruiting and data on additional pts and long term PK parameters will be presented. Clinical trial information: EudraCt number: 2012-003226-25.
Potential drug interactions in patients with a history of cancer.
Authors: L. Chen, H. Rai, W. Y. Cheung
Journal: Journal of Clinical Oncology (2011)

e19651 Background: Cancer patients (CP) are frequently exposed to polypharmacy, which may increase their risk for drug interactions. Our study aims were to 1) determine and compare the prevalence and clinical significance of potential drug interactions (PDI) in CP vs. non-cancer patients (NCP) and 2) identify clinical risk factors associated with PDI in CP. Methods: Self-reported prescription medication data from 4,975 patients were extracted from the U.S. population-based National Health and Nutrition Examination Survey and screened for PDI using specialized drug interaction software (iFacts, version 13.10). The clinical significance of each PDI was graded on a 5-point scale (1=most significant and 5=least significant). Clinical significance was judged based on the degree of severity of drug interaction, the rate of onset of side effects (immediate vs. delayed), and the level of scientific evidence for the drug interaction. Summary statistics and logistic regression models were used to assess the impact of cancer history on the risk and significance of PDI. Results: After screening, 302 CP and 907 NCP were eligible for analyses: mean ages were 62 (SD=1.14) and 60 (SD=0.92) years; 44% and 41% were men; 88% and 77% were White, respectively. CP indicated using a mean of 4.5 (SD=0.22) different classes of medications while NCP reported using 3.8 (SD=0.09) different drugs. In terms of PDI, 40% and 43% of CP and NCP, respectively, had interactions. Among them, 12% were rated as level 1 in significance in both patient groups. In multivariate analysis, CP were significantly less likely to be at risk for any type of PDI (OR 0.71, 95% CI 0.52-0.97, p=0.034) when compared to NCP. For level 1 PDI, CP remained less at risk than NCP (OR 0.65, 95% CI 0.46-0.92, p=0.017). Additional factors that were associated with any PDI or level 1 PDI in CP were advanced age and low household income. Medications that were most commonly prescribed among CP with level 1 PDI included atorvastatin (5.2%) and digoxin (4.3%). Conclusions: Although CP appear to be less susceptible to PDI than NCP, the prevalence of medication interactions among CP remains suboptimal. Specific subgroups of CP may be particularly prone to PDI, underscoring the importance of increased vigilance.
Incident cancers in people with dysglycemia and other cardiovascular risk factors: Cohort study of the ORIGIN trial.
Authors: L. Bordeleau, G. Dagenais, N. Yakubovich, S. Yusuf, J. Probstfield, M. Riddle, L. Ryden, L. Xu, J. Bosch, H. Gerstein
Journal: Journal of Clinical Oncology (2011)

1504 Background: Type 2 diabetes mellitus (DM) is associated with an increased risk for several cancers (ca), but data relating duration/severity of dysglycemia to incident ca are limited. We measured overall ca incidence in people aged ≥ 50 years who were at high-risk for cardiovascular (CV) events with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), new, or early type 2 DM and who were participating in a large international multicentre randomized trial (the ORIGIN Trial) of the effects of insulin and omega-3 fatty acids on CV outcomes. We also examined the relationship between incident ca hospitalization/death and baseline a) category of dysglycemia; b) fasting plasma glucose (FPG); c) A1C levels; and d) treatment with metformin. Methods: All participants without known ca at randomization were followed until June 30, 2009. Participants were divided into established early DM, newly diagnosed DM, or new IFG and/or IGT. FPG and A1C levels were each divided into tertiles. Overall ca incidence was estimated by the Kaplan-Meier product and compared among groups via the log-rank test. Multivariate analysis was conducted via Cox proportional hazards models. Results: Among the 12,553 participants (4,387 females), 706 developed ca death or hospitalization during 4.5 year mean F/U. The unadjusted cancer risk per 100 person-year was 1) by dysglycemia category: 1.04 (established DM), 1.59 (newly diagnosed DM), and 1.09 (new IFG/IGT); 2) by FPG thirds: 1.00 (lowest), 1.22 (mid), 1.04 (highest); 3) by A1C thirds: 1.09 (lowest), 1.22 (mid), 0.97 (highest). After adjustment, duration of DM, baseline FPG, and A1C levels were not independently associated with incident ca. Incident cases of lung, breast, prostate, and colon ca were not different between groups. Use of metformin (N=3408) did not alter ca risk. Conclusions: In people with abnormal glucose levels at high risk of CV events, incident ca was not associated with the baseline dysglycemia category, FPG, A1C levels or duration of DM. Metformin use at baseline was not associated with reduced risk of incident ca. Future analyses of the effect of insulin-mediated glucose lowering and omega 3 fatty acids on ca incidence in this trial will be of interest.