tbuckley/cabot-search huggingface dataset:
Pharmacokinetic Evaluation of N-[2-(Dimethylamino)Ethyl]Acridine-4-Carboxamide in Patients by Positron Emission Tomography
Authors: Azeem Saleem, Robert J. Harte, Julian C. Matthews, Safiye Osman, Frank Brady, Sajinder K. Luthra, Gavin D. Brown, Norman Bleehen, Tom Connors, Terry Jones, Pat M. Price, Eric O. Aboagye
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To evaluate tumor, normal tissue, and plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). The study aimed to determine the pharmacokinetics of carbon-11–labeled DACA ([ 11 C]DACA) and evaluate the effect of pharmacologic doses of DACA on radiotracer kinetics. PATIENTS AND METHODS: [ 11 C]DACA (at 1/1,000 phase I starting dose) was administered to 24 patients with advanced cancer (pre–phase I) or during a phase I trial of DACA in five patients. Positron emission tomography (PET) was performed to assess pharmacokinetics and tumor blood flow. Plasma samples were analyzed for metabolite profile of [ 11 C]DACA. RESULTS: There was rapid systemic clearance of [ 11 C]DACA over 60 minutes (1.57 and 1.46 L·min -1 ·m -2 in pre–phase I and phase I studies, respectively) with the production of several radiolabeled plasma metabolites. Tumor, brain, myocardium, vertebra, spleen, liver, lung, and kidneys showed appreciable uptake of 11 C radioactivity. The area under the time-versus-radioactivity curves (AUC) showed the highest variability in tumors. Of interest to potential toxicity, maximum radiotracer concentrations (Cmax) in brain and vertebra were low (0.67 and 0.54 m 2 ·mL -1 , respectively) compared with other tissues. A moderate but significant correlation was observed for tumor blood flow with AUC (r = 0.76; P = .02) and standardized uptake value (SUV) at 55 minutes (r = 0.79; P = .01). A decrease in myocardial AUC ( P = .03) and splenic and myocardial SUV ( P = .01 and .004, respectively) was seen in phase I studies. Significantly higher AUC, SUV, and Cmax were observed in tumors in phase I studies. CONCLUSION: The distribution of [ 11 C]DACA and its radiolabeled metabolites was observed in a variety of tumors and normal tissues. In the presence of unlabeled DACA, pharmacokinetics were altered in myocardium, spleen, and tumors. These data have implications for predicting activity and toxicity of DACA and support the use of PET early in drug development.
Subcutaneous infusion of bleomycin--a practical alternative to intravenous infusion.
Authors: V J Harvey, M L Slevin, G W Aherne, P Littleton, A Johnston, P F Wrigley
Journal: Journal of Clinical Oncology (1987)

The phase specificity and short half-life of bleomycin make it likely that it would be more effective when administered by continuous infusion. This is supported by studies using cell lines, as well as by animal studies and clinical experience in humans. This study was conducted to compare the pharmacokinetics of intravenous (IV) and subcutaneous infusions of bleomycin. The serum concentrations of bleomycin were measured using a sensitive and specific radioimmunoassay. The results demonstrate similar plasma concentrations and area under the curve for both routes. The subcutaneous infusions were well tolerated, without local discomfort or excoriation. Subcutaneous infusion of bleomycin may thus offer a practical alternative to IV infusions and can be administered to patients who are ambulatory and out of hospital.
Prophylactic surgery for the reduction of gynecologic cancer risk in women with Lynch Syndrome/HNPCC
Authors: K. M. Schmeler, P. T. Soliman, M. F. Munsell, M. S. Daniels, K. G. White, S. G. Boyd-Rogers, C. C. Sun, B. M. Slomovitz, D. M. Gershenson, K. H. Lu
Journal: Journal of Clinical Oncology (2005)

9531 Background: Women with Lynch Syndrome/HNPCC have a 40–60% lifetime risk of developing endometrial cancer (EC) and a 10–15% lifetime risk of developing ovarian cancer (OC). Expert panels have been unable to make recommendations regarding prophylactic surgery in this group due to insufficient evidence. The objective of our study was to determine the reduction in gynecologic (gyn) cancer risk of prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) in women with HNPCC. Methods: 72 women with documented HNPCC germline mutations were identified. Patients who had undergone hysterectomy +/- BSO for preventive reasons or benign conditions (cases, n=12) were matched to mutation positive controls of similar age (+/- 5 years) who did not have surgery (n=51). Cases and controls were followed from the date of the subject’s surgery until the occurrence of cancer or until censoring. The incidence density (ID = number of cancers/yrs at risk) was calculated for each group and the prevented fraction (PF) or proportion of potential new cancers was determined. The average length of follow-up was 10.1 yrs for the subjects and 6.8 yrs for the control group. Results: The PF was 1.0 with 100% of potential new gyn cancers prevented by prophylactic surgery. The ID was significantly lower for the cases than the controls (0 cancers/101 yrs vs. 21 cancers/348 yrs, p=0.006). None of the women who had prophylactic surgery developed EC, OC or peritoneal cancer. In the control group, EC was diagnosed in 19 (37%) and OC in 2 (4%) patients. Median age at time of surgery was 38 yrs (range 27–50). Median age at EC/OC diagnosis was 43 yrs (range 29–57). Ten patients had metachronous colon and EC (n=8) or OC (n=2), with 7 of these women diagnosed with the gyn malignancy following their surgery for colon cancer. Conclusions: Our study provides evidence for the protective benefit of prophylactic hysterectomy and BSO in preventing EC and OC in women with HNPCC. In addition, 7/21 (33%) of the gynecologic cancers in our cohort could have been prevented with prophylactic hysterectomy and BSO performed at the time of surgery for colorectal cancer. Prophylactic gyn surgery should be considered in all women with HNPCC following the completion of childbearing. No significant financial relationships to disclose.
Trastuzumab for all? A decision analysis examining tradeoffs between efficacy and cardiac toxicity of adjuvant therapy in HER2 positive breast cancer
Authors: A. K. Gupta, S. F. Mekan, M. H. Eckman
Journal: Journal of Clinical Oncology (2006)

6022 Background: Early results from three randomized trials showed that adjuvant trastuzumab (T) results in significant reduction in recurrence rates in high risk HER2 positive breast cancer patients (pts). However, the long term survival benefits and the balance of risk and benefit of adjuvant T in pts with lower risk of cancer recurrence and a higher risk of cardiac toxicity (elderly and pre-existing heart disease) remain undetermined. Methods: We evaluated these tradeoffs through a Markov state transition decision analytic model to simulate the survival benefits in a variety of subpopulations of HER2 positive cancer pts. Efficacy and cardiac toxicity of T were based on B-31 and N9831 trials. Outcomes were expressed in quality adjusted life years (QALYs) and 10 year survival rates. We explored a number of prototypic scenarios that varied in age, risk of cancer recurrence, and cardiac toxicity rates. Our base case focused on a 50 year-old, 2 cm, node positive, ER/PR negative pt with a 6% cumulative risk of cardiac toxicity. Results: Survival rates and the cardiac death rates for the base case and a hypothetical elderly pt with low risk of cancer recurrence are illustrated in the table . One-way sensitivity analyses on the base case, across a wide range of values for age (50–80); hazard ratio for T efficacy (0.48 to 0.95); annual cancer recurrence risk (0.5–5%) and cardiac toxicity (4–60%) demonstrated that adjuvant T was the more effective strategy. Conclusions: The addition of T in HER2 positive cancer is more effective than standard chemotherapy alone in most cases, including elderly pts with node negative disease and those with increased risk of cardiac toxicity. However, the incremental benefit decreases with advancing age, higher risk of cardiac toxicity and in pts with lower risk of recurrence. This model is a useful clinical tool to quantify risks and benefits of adjuvant T and in predicting long term survival in different subpopulations of HER2 positive breast cancer pts. [Table: see text] No significant financial relationships to disclose.
Oral bisphosphonates for the prevention of androgen deprivation therapy-associated bone loss – Preliminary findings
Authors: R. Y. Lam, M. Scholz, B. Guess, J. Mahoney, H. Johnson, T. Trilling, H. Goodman
Journal: Journal of Clinical Oncology (2004)

4749 Background: Androgen deprivation therapy (ADT) is a widely administered treatment for prostate cancer. However, ADT causes accelerated bone loss. Annual bone loss on ADT ranges between 2.0 to 10.0 percent per year. Intravenous bisphosphonates (pamidronate, zolendronate) have been shown to prevent ADT-related bone loss in randomized phase III trials. The goal of this retrospective analysis was to determine if oral bisphosphonates effectively prevent bone loss in men receiving ADT. Methods: Thirty-two men, ages 55–86, were placed on alendronate or risendronate in conjunction with ADT. Baseline and follow-up bone mineral densitometry (BMD) studies were done with either QCT (n=13) or DEXA scans (n=19). Follow-up BMD studies were performed 12- 39 months after the first BMD (median: 17 months) always using the same type of scan for follow-up as was used at baseline. 31 of 32 men had follow-up BMD before testosterone recovery above 200. Results: The annual mean and median change in BMD measured by QCT was -7.2%/yr and -11.0%/yr, respectively. The annual mean and median change in BMD measured by DEXA was -0.68%/yr and 0.06%yr, respectively. BMD measured by QCT indicated a significant degree of bone loss using t test of dependent samples (p=0.036). There was no significant change in BMD measured by DEXA (p=0.50). There was no unexpected toxicity. Conclusions: In this small, retrospective phase II study, oral bisphosphonates appeared to mitigate bone loss when measurements were performed with DEXA. However, there was a significant degree of bone loss when QCT was the measurement standard. Further QCT data is being accrued. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Proctor and Gamble
Busulfan / Melphalan / Bortezomib (Bu-Mel-Vel) Vs. High Dose Melphalan As Conditioning Regimen For Autologous Hematopoietic Cell Transplantation In Multiple Myeloma (MM)
Authors: Tulio E. Rodriguez, Parameswaran Hari, Patrick J Stiff, Xiaobo Zhong, Danielle Sterrenberg, David H. Vesole
Journal: Blood (2013)
INHALED CORTICOSTEROIDS (ICS) ATTENUATES EPITHELIAL MESENCHYMAL TRANSITION (EMT) IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) - IMPLICATIONS FOR LUNG CANCER PROPHYLAXIS
Authors: S. S. Sohal, D. W. Reid, A. Soltani, C. Ward, S. Weston, H. K. Muller, R. Woodbaker, E. H. Walters
Journal: Journal of Thoracic Oncology (2012)
Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data
Authors: Naveed Sattar, David Preiss, Jennifer G Robinson, C Stephen Djedjos, Mary Elliott, Ransi Somaratne, Scott M Wasserman, Frederick J Raal
Journal: The Lancet Diabetes & Endocrinology (2016)
Why does the “mental shotgun” fire system-justifying bullets?
Authors: Danielle Gaucher, John T. Jost
Journal: Behavioral and Brain Sciences (2014)

Abstract We suggest that people privilege explanations relying on inherent rather than contingent factors not only because of an innate cognitive tendency to monitor reality, but because doing so satisfies the desire to perceive the societal status quo as legitimate. In support, we describe experimental studies linking the activation of system justification motivation to the endorsement of inherence-based (essentialist) explanations.
Abstract 17198: The Prevalence of ECG Anomalies in Young Individuals: Relevance to a Nationwide Cardiac Screening Program
Authors: Navin Chandra, Michael Papadakis, Rachel Bastiaenen, Vasilis Panoulas, Hari Raju, Saqib Ghani, Rebecca Howes, Sanjay Sharma
Journal: Circulation (2012)

Objectives: This study aims to investigate the prevalence of Group 1 and Group 2 ECG abnormalities in young individuals and assess the potential impact of a nationwide screening program for conditi...
Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZEAL)
Authors: R. De Boer, Ó. Arrieta, M. Gottfried, F. H. Blackhall, J. Raats, C. H. Yang, P. Langmuir, T. Milenkova, J. Read, J. Vansteenkiste
Journal: Journal of Clinical Oncology (2009)

8010 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. A phase I trial of vandetanib + pemetrexed (pem) supported further investigation of this combination (de Boer et al, Ann Oncol 2008). Methods: The primary objective was to determine whether vandetanib 100 mg/day + pem 500 mg/m 2 every 21 days (max 6 cycles) prolonged progression-free survival (PFS) vs placebo + pem. Overall survival (OS), objective response rate (ORR), time to deterioration of symptoms (TDS, by Lung Cancer Symptom Scale) and safety were secondary endpoints. Efficacy and safety were assessed in females as a co-primary analysis population. Eligibility criteria included stage IIIB/IV NSCLC, PS 0–2, and previous 1st-line therapy. Results: Between Jan 07-Mar 08, 534 patients (mean age 59 yrs; 38% female; 21% squamous histology; 8% brain metastases; stage IV 84%; PS 0/1/2: 41%/53%/6%) were randomized 1:1 to receive vandetanib + pem (n=256) or placebo + pem (n=278). Baseline characteristics were similar in both arms. Median duration of follow-up was 9.0 months, with 83% patients progressed and 50% deceased. There were positive trends seen for vandetanib + pem for both PFS (hazard ratio [HR] 0.86, 97.58% CI 0.69–1.06; P=0.108) and OS (HR 0.86, 97.54% CI 0.65–1.13; P=0.219); similar advantages were observed for females. There were statistically significant advantages for ORR (19.1% vs 7.9%, P&lt;0.001) and TDS (HR 0.61, P=0.004). The adverse event profile was consistent with previous studies of vandetanib: rash (38% vs 26%), diarrhea (26% vs 18%) and hypertension (12% vs 3%) being more frequent in the vandetanib arm. There was evidence of reduced pem toxicity with the addition of vandetanib: anemia 8% vs 22%, nausea 29% vs 37%, vomiting 15% vs 22%, fatigue 37% vs 45%, and asthenia 11% vs 17%. The incidence of protocol-defined QTc prolongation was &lt;1%. There was no increase in bleeding or thrombotic events in the vandetanib arm. Conclusions: The combination of vandetanib + pem demonstrated evidence of clinical benefit in patients with pretreated advanced NSCLC, although the study did not meet the primary endpoint of statistically significant PFS prolongation vs pem alone. Vandetanib + pem was generally well tolerated. [Table: see text]
Large-Cell Lymphoma Arising in the Mediastinum in Children and Adolescents Is Associated With an Excellent Outcome: A Children’s Cancer Group Report
Authors: Mark A. Lones, Sherrie L. Perkins, Richard Sposto, Marshall E. Kadin, Carl R. Kjeldsberg, John F. Wilson, Mitchell S. Cairo
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Large-cell lymphoma (LCL) arising in the mediastinum (LCL-M) is a heterogeneous group of non-Hodgkin’s lymphoma (NHL) that includes B-cell lymphomas as well as T-cell lymphomas, including anaplastic LCL. LCL-M is well recognized in young adults but is less well characterized and infrequent in children and adolescents. METHODS: A retrospective review of Children’s Cancer Group therapeutic studies for nonlymphoblastic lymphomas (CCG-551, CCG-503, CCG-552, and CCG-5911) identified 20 patients with LCL-M, representing 7.2% of all LCLs classified by central pathology review. RESULTS: The patients ranged in age from 4 to 19 years (median, 12.5 years; mean, 12 years); 55% of the patients were male. Although a variety of chemotherapy regimens were used, response was excellent, with all 20 patients (100%) achieving a complete response. Four patients (20%) experienced relapse locally or in distant sites including brain and kidney. One patient died of sepsis during therapy. For the 20 patients with LCL-M, the product-limit estimated 5-year event-free survival (EFS) and 5-year overall survival (OS) rates are 75% ± 10% and 85% ± 8%, respectively. For disseminated LCLs (192 cases), the EFS and OS rates were 50% ± 4% and 63% ± 4%, respectively, which differ significantly from the those of the LCL-M cases (EFS, P = .025; OS, P = .034). The 5-year EFS and OS rates for patients with localized LCL (67 cases) were 92 ± 3% and 97 ± 2%, respectively. CONCLUSION: LCL-M is a heterogeneous group of NHLs that makes up approximately 7.2% of LCL in children and adolescents. Response to therapy and OS in this young age group seems excellent and superior to that of disseminated LCLs but inferior to that of other localized LCL. Future studies of LCL-M will evaluate short intense chemotherapy administered without radiation therapy.
Aprepitant in multiple-day cisplatin-based chemotherapy.
Authors: Johann-Francois Ouellette Freve, Denis Soulieres, Normand Blais, Nathalie LeTarte
Journal: Journal of Clinical Oncology (2012)

e19591 Background: Aprepitant is a NK-1 inhibitor approved in combination with serotonin antagonists and dexamethasone (Dex) for highly and moderately emetogenic chemotherapy. Antiemetic regimens for multiple-day chemotherapy are not standard and guidelines recommend serotonin antagonists and Dex for each day of chemotherapy and for following days. Studies with aprepitant in that setting are ongoing. In our center, aprepitant use with multiple-day chemotherapy was prescribed at the physician’s discretion. Methods: We did a retrospective study of the use of aprepitant with cisplatin-based multiple-day chemotherapy (CBMDC) regimens from November 2008 to November 2011. Pharmacy files were used to identify patients that received at least one dose of CBMDC. Data was extracted from pharmacy and medical records. Objectives included efficacy (complete response (CR), absence of nausea and vomiting, change in antiemetics) and safety of different regimens. Results: During the study period, 39 patients (34 men) received CBMDC, mostly BEP for testicular cancer. Three patients also received second-line treatment. Patients received BEP (93%), ICE (2%), or TIP (5%) chemotherapy. Eleven patients received 3-day aprepitant, 15 patients 5-day aprepitant and 16 patients did not receive aprepitant at all as primary prophylaxis. Patients were older in the 3-day group. CR was 1% in the 3 day-group, 64% in the 5-day group and 36% in the control group (p=0,08). There was a trend that nausea and vomiting were reported more frequently in the 3-day group. In 4 patients, aprepitant was added for days 4 and 5 in subsequent cycles with better control. Rescue medication was used in 100% of patients receiving the 3-day regimen, 36% in patients receiving the 5-day regimen and 64% of patients not receiving aprepitant. Three patients receiving 5-day aprepitant had to further decrease their Dex dose for adverse events (insomnia, emotional lability, pyrosis, acne). No severe adverse events were reported with the 5-day use of aprepitant. Conclusions: Even within a small population, five-day aprepitant is effective in inducing CR, reducing vomiting and is safe in patients receiving CBMDC. It has been chosen as a standard treatment in our patients.
A randomized phase II trial of early change of a chemotherapeutic doublet compared to four cycles of chemotherapy in advanced non-small cell lung cancer (NSCLC): The 03–01 Groupe Francais de Pneumo-Cancerologie (GFPC) study
Authors: A. Vergnenegre, R. Corre, F. Barlési, H. Bérard, J. Vernejoux, H. Le Caer, P. Fournel, J. Delhoume, D. Arpin, P. Thomas, J. Tillon
Journal: Journal of Clinical Oncology (2007)

7631 Background: The optimal strategy in advanced NSCLC with stable disease is not well known. There is no published study assessing an early change of chemotherapeutic drugs in these patients. This study was designed to evaluate the efficacy and safety of early modification of chemotherapy doublets in patients with advanced non small cell lung cancer with stable disease (SD). Methods: Patients with stage IV NSCLC and measurable disease were included in a randomized phase II trial comparing for patients with stable disease after 2 cycles of a platin (P)-gemcitabine doublet (P d 1 : 75 mg/m 2 , gemcitabine 1 250 mg/m 2 d 1 , d 8 every three weeks) two subsequent cycles of this doublet (arm A) to a switch to another doublet (arm B): paclitaxel 100 mg/m 2 d 1 , d 8 , d 15 , gemcitabine 1 250 mg/m 2 d 1 , d 8 , every four weeks. Results: Between October 2003 and august 2006, 228 patients (pts) were enrolled (187 males, 41 females), median age 57 y (30–70). Evaluation (EVA) 1 showed 11.8% not assessable patients (NA), 19.3% with objective responses (OR), 25.9% with progressive diseases. 98 patients (43%) had stable diseases. 87 patients were randomized in the study. 48.3% with PS0, 51.7% with PS1 and a majority of adenocarcinoma (62.1%). 41.4% had only one metastatic site. There were no differences between the two groups. Efficacy at eva 2 is depicted above. Overall survival (OS) was similar between the two arms: 9.8 months (m) [7.0 - 14.2] for arm A, 9.2 m [7.4 - 10.5] for arm B. TTP was 5.4 m in arm A and 5.7 in arm B. There were 1 grade III/IV haematological toxicities in arm A (1.2%) and 2 in arm B (2.4%). There were 4 grade III/IV non haematological toxicities in arm A (4.8%) and 6 in arm B (7.3%). Conclusions: The switch between the two regimen is feasible without any major toxicities. Despite higher response rate in favour of the switch strategy, OS and TTP are similar between the two arms. No significant financial relationships to disclose. [Table: see text]
Prophylactic treatment of irinotecan-induced diarrhea with neomycin (a randomized, placebo-controlled, double-blind study)
Authors: R. H. Mathijssen, F. A. De Jong, D. F. Kehrer, R. H. Van Schaik, J. Verweij, A. Sparreboom, M. J. De Jonge
Journal: Journal of Clinical Oncology (2006)

3626 Background: Delayed-type diarrhea is a common side-effect of irinotecan, and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestines. We hypothesized that concomitant administration of the aminoglycoside antibiotic neomycin would diminish exposure of the gut to SN-38, ameliorating the incidence of diarrhea. Methods: Patients were treated with irinotecan in a randomized, placebo-controlled, double-blind trial. In arm A, patients received irinotecan (350 mg/m 2 i.v. for 90 minutes once every 3 weeks) combined with neomycin (660 mg orally 3 times daily for 3 consecutive days, starting 2 days before chemotherapy). In arm B, patients received the same irinotecan regimen with placebo. To detect a 50% reduction to less than grade 2 diarrhea (power=.80; P=.05), 60 patients had to be studied. Blood samples for additional pharmacokinetic and pharmacogenetic analyses were obtained after separate informed consent. Results: Sixty-two patients were evaluable for toxicity analysis. Relevant baseline patient characteristics (P&gt;.06), SN-38 plasma concentrations (P=.80; N=43), and UGT1A1*28 genotype status (P=.58; N=52) were similar in both arms. Distribution, severity, and duration of diarrhea did not differ significantly between both arms (P&gt;.32), although grade 3 diarrhea tended to be less frequent in the neomycin arm (45% reduction; P=.19). Grade 2 nausea was more common in this arm (39% vs. 9%; P&lt;.01). The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2–3 diarrhea (69% vs. 34%; P=.01). Conclusions: Our results do not suggest a role for neomycin in the prophylactic treatment of irinotecan-induced diarrhea. In addition, neomycin does not influence systemic SN-38 pharmacokinetics. Also, it is suggested that each patient’s UGT1A1*28 genotype status could be used as a prospective screening tool to prevent severe diarrhea. No significant financial relationships to disclose.