tbuckley/cabot-search huggingface dataset:
A prediction model for chemotherapy-associated thrombocytopenia in cancer patients
Authors: N. M. Kuderer, C. W. Francis, J. Crawford, D. C. Dale, D. A. Wolff, E. Culakova, M. S. Poniewierski, G. H. Lyman
Journal: Journal of Clinical Oncology (2006)

8616 Background: Thrombocytopenia (TP) can lead to serious complications, however, little is known about the incidence and risk factors for chemotherapy-associated TP. A prospective, nationwide cohort study was undertaken to better define the impact of TP in cancer treatment. Methods: 2,842 patients with cancer of the breast, lung, colon, ovary or lymphoma initiating a new chemotherapy regimen have been prospectively enrolled at 115 randomly selected US community oncology practices between 2002 and 2005. Risk factors for chemotherapy-associated TP were identified, a multivariate logistic regression model based on pretreatment characteristics was developed, and test performance characteristics were estimated. Results: Over a median of 3 cycles of chemotherapy, minimum recorded platelet counts were: ≥150K in 53% of patients; 100–150K in 26%; 75–100K in 8%; 50–75K in 6% and &lt;50K in 7%. Significant independent predictive factors for platelets &lt;75K include type of cancer (P&lt;.0001), type of chemotherapy including gemcitabine-based (P&lt;.0001), anthracycline-based (P&lt;.0001) and platinum-based (P&lt;.0001) regimens, prior chemotherapy (P&lt;.0001) or surgery (P=.005), age (P=.015), Caucasian ethnicity (P=.022), body surface area (P=.0001), planned relative dose intensity ≥85% (P=.082), diabetes (P=.018), pulmonary disease (P=.011), abnormal baseline platelets (P&lt;.0001), hematocrit (P=0.030), alkaline phosphatase (P=.072) or albumin (P=.017). Model fit was good (Chi-square, P&lt;.0001), R 2 = 0.735 and c-statistic = 0.816 [95% CI: 0.792–0.840, P&lt;.0001]. Model test performance characteristics [95% CI] at a ≥20% risk of TP include: sensitivity 56% [51–61]; specificity 88% [87–89]; likelihood ratio positive 4.63 [4.02–5.33]; likelihood ratio negative 0.50 [0.45–0.57]; and diagnostic odds ratio 9.22 [7.23–11.75]. Validation of the model is underway. Conclusions: This prediction model based on pretreatment factors identifies with high specificity patients at risk for clinically important chemotherapy-associated thrombocytopenia early in the treatment course. It may provide a valuable tool for guiding chemotherapy and new supportive care measures. [Table: see text]
Phase I trial of combination sorafenib and tipifarnib: The experience in advanced differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC).
Authors: M. E. Cabanillas, R. Kurzrock, S. I. Sherman, A. M. Tsimberidou, S. Waguespack, A. Naing, N. Busaidy, R. Gagel, J. J. Wright, D. S. Hong
Journal: Journal of Clinical Oncology (2010)

5586 Background: Metastatic, progressive thyroid cancer, not amenable to standard treatment, is a deadly disease. Ras/Raf/MEK/ERK is the most important pathway in thyroid cancer. Sorafenib has activity against BRAF, RET and VEGFR. Tipifarnib inhibits farnesyl transferase, preventing activation of Ras and selectively killing Ras-transformed cells. Methods: As part of a phase I trial, we treated 35 differentiated and medullary thyroid cancer patients. Secondary endpoints included efficacy. Sorafenib and tipifarnib were given for 21 days and repeated every 28. RECIST was used to determine response. Results: We enrolled 22 patients with metastatic DTC (16 PTC, 5 FTC, 1 poorly differentiated), 13 with MTC, of which 15 DTC and 10 MTC patients were restaged. Ten patients were discontinued from the study prior to first re-staging due to toxicities. Best response in DTC: 1/15 (7%) PR, 13/15 (86%) SD, 1/15 (7%) PD; MTC: 5/10 (50%) PR, 5/10 (50%) SD, 0/10 PD. Durable responses (PR or SD ≥6 months): 13/15 (87%) of DTC; 9/10 (90%) of MTC. The median follow up was 19 months in DTC and 27 months in MTC. Median PFS was 20 months in the DTC group and 15 months in MTC. Median overall survival has not been reached in either group, but at 24 months, overall survival was 79% in DTC and 88% in MTC. Major dose-limiting toxicities in this cohort were grade 3 rash in 4/36 (11%). Other common skin toxicites were grade 1-2 hand-foot skin reaction 13/35 (37%); grade 1-2 rash 15/35 (43%). Maximum tolerated dose was sorafenib 600mg/tipifarnib 200mg (split dosing). Conclusions: Combination sorafenib/tipifarnib is promising for treatment of metastatic DTC and MTC, however, further evaluation in phase II trials is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Johnson & Johnson Bayer, Johnson & Johnson Bayer
Dietary Lipid Effects on the Growth, Membrane Composition, and Prolactin-Binding Capacity of Rat Mammary Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: William T. Cave, Jr.
 5, Joseph J. Jurkowski
Journal: JNCI Journal of the National Cancer Institute (1984)

The effects of qualitative and quantitative differences in dietary lipid on the growth of N-methyl-N-nitrosourea (CAS: 684-93-5)-initiated mammary tumors were evaluated in inbred female (F344) rats. Specific prolactin-binding measurements and qualitative lipid analyses were performed on both tumor and hepatic microsomes from these animals. Our results indicated that 1) when the polyunsaturated lipid component (corn oil) of the diet exceeded 3%, it was the quantitative level of total lipid, rather than the level of polyunsaturated lipid alone, that best correlated with the observed reduction in tumor latent period; 2) when the polyunsaturated lipid content of the diet fell below 3%, there was a decrease in tumor incidence and an increase in the mean latent period; 3) only those changes in tumor development that occurred when the dietary polyunsaturated lipid content was below 3% were associated with alterations in specific prolactin binding capacity.
Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostrate cancer: A phase I/II, open-label study.
Authors: R. Dreicer, D. B. Agus, G. R. MacVicar, J. Wang, D. MacLean, W. M. Stadler
Journal: Journal of Clinical Oncology (2010)

3084 Background: TAK-700 is a selective 17,20 lyase inhibitor that substantially reduced in vivo adrenal androgen levels in preclinical studies. Methods: This phase I/II open-label, dose-escalation study assesses the safety and tolerability of oral twice-daily (BID) TAK-700 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Secondary objectives include assessment of efficacy, as shown by prostate-specific antigen (PSA) response, and TAK-700 pharmacokinetics (PK). Here we report the phase I portion of the study. Results: 26 pts (median age 70 y, 11 had received prior ketoconazole) received TAK-700 at 5 dose levels: 100 (3 pts), 200 (3), 300 (3), 400 (6) or 600 (5) mg BID; a further 6 pts received TAK-700 400 mg BID plus prednisone 5 mg BID. At data cut-off (29 Dec 2009), 11 pts remain on study; 15 patients discontinued, including 6 due to adverse events (AEs), 4 due to radiologic disease progression, 2 due to PSA progression, 2 due to patient request and 1 for other reasons. All pts experienced ≥1 treatment-emergent AE (TEAE); 92% were drug-related and 54% were grade ≥3. The most common TEAE was fatigue (17 pts, 3 grade ≥3 with 600 mg BID), followed by non-dose-related GI events such as nausea (11 pts, 1 grade 3), constipation (10), anorexia (9) and vomiting (7, 2 grade ≥3). Preliminary PK analysis indicates approximate dose- proportional increases in single- and multiple-dose Cmax and AUC0–8hr over the 100–600 mg BID dose range. Multiple-dose PK are consistent with the single-dose PK. At 4 wks, median testosterone and DHEA-S levels had decreased from 5.5 to 0.6 ng/dL and 50.0 μ g/dL to below quantifiable levels, respectively, in all patients treated with TAK-700. All patients treated with ≥300 mg had a PSA decrease; of 15 pts who received TAK-700 ≥300 mg for ≥3 cycles and had a 3-month PSA determination, 12 (80%) had PSA reductions ≥50% and 4 (27%) had reductions ≥90%. Conclusions: TAK-700 ≥300 mg BID appears active and well tolerated in pts with mCRPC. The phase II portion of the study is ongoing (31 pts enrolled by data cut-off) and will further assess the safety and efficacy of TAK-700 and the need for concomitant prednisone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium AstraZeneca, Endo Pharmaceuticals, MethylGene, Millennium, Ortho Biotech, Transgene sanofi-aventis Millennium
Not all schoolchildren prefer team sports
Authors: R. Coffey
Journal: BMJ (1996)

Nomogram for number needed to treat will be of limited use EDITOR,-Gilles Chatellier and colleagues suggest that in calculations of the "number needed to treat" a nomogram based on the formula 1 should be used in Pc x relative risk reduction preference to 1The two formulas are, PC...Pi however, equivalent and will both suffer from the same problems when Pc and Pi differ by an amount greater than Pc.The nomogram is consequently useful in only a limited number of circumstances-for example, when published study results have been adjusted for confounding effects and only relative risks or odds ratios are reported.In these cases such estimates could then be combined with an estimate of the baseline risk to yield the number needed to treat.
Prognostic factors in advanced NSCLC: Experience from the FLEX trial
Authors: R. Pirker, J. Rodrigues-Pereira, A. Szczesna, J. Von Pawel, M. Krzakowski, R. Ramlau, I. Vynnychenko, K. Park, M. Emig, U. Gatzemeier
Journal: Journal of Clinical Oncology (2009)

8083 Background: The FLEX trial demonstrated superior survival for cisplatin/vinorelbine plus cetuximab versus cisplatin/vinorelbine alone in patients with advanced EGFR-positive NSCLC. Here we report on the prognostic factors observed in the trial independent of cetuximab treatmentMethods: 1125 patients were randomized to cisplatin/vinorelbine plus cetuximab or cisplatin/vinorelbine alone. Prognostic factors were determined by both univariate and multivariate analyses. Results: Patient baseline characteristics were: 70% male, median age 59 (18–83) years, 31% older than 65 years, 94% stage IV, 47% adenocarcinoma, 34% squamous cell carcinoma, 83% ECOG 0/1. The trial confirmed the following prognostic factors in the univariate analysis: gender, performance status, histology, smoking status, and ethnicity. Females had longer survival than males (12.7 versus 9.3 months). Patients with ECOG performance status 0, 1, and 2 had median survival times of 13.5, 10.6 and 5.9 months, respectively. Patients with adenocarcinomas had a median survival of 12.4 months and those with squamous cell carcinomas had a median survival of 9.3 months. Smokers, former smokers, and never-smokers had median survival times of 9.0, 11.1 and 14.6 months, respectively. Outcome was better for Asians (n=121) compared to Caucasians (n=946) (median 19.5 versus 9.6 months). Age &lt;65 and age ≥65 did not indicate prognosis. Multivariate analysis confirmed the prognostic significance of performance status, gender, smoking status, region (Europe versus Australasia), and histology. Conclusions: The FLEX trial confirmed several prognostic factors, including gender, performance status, histological subtype, ethnicity, and smoking status for patients with advanced NSCLC. [Table: see text]
High-grade soft tissue sarcomas (STS) of elderly (≥70 years) patients (E-STS): Feasibility and morbidity of anthracycline-based chemotherapy (A-CT) in a selected subset of patients.
Authors: L. D'Ambrosio, D. Galizia, S. Aliberti, R. Ferraris, D. Rota Scalabrini, M. Fizzotti, D. Caravelli, E. Palesandro, G. Grignani, M. Aglietta
Journal: Journal of Clinical Oncology (2010)

e20515 Background: There is an increasing concern on optimal treatment in elderly cancer pts. E-STS represent a further challenge because the required multidisciplinary therapy is feared causing unexpected toxicities. However, E-STS are 30% of all diagnosed STS (USA-SEER 2009). Recently, morbidity was not shown to be increased by either surgery or adjuvant radiotherapy in E-STS (Lev D and Alektiar K 2009). Focusing on chemotherapy related toxicities, we reviewed our prospectively collected database on STS Methods: Between 11/99 and 12/08, 37 out of 68 E-STS received A-CT (±ifosfamide). Principal features were: median age 73yrs (70-88); M/F 17/20; histologies (8 leiomyoS, 6 lipoS, 5 pleomorphic, 4 angioS, 3 fibroS, 11 others), median major comorbidities 1(0-3). Toxicity was assessed considering any grade ≥3 unexpected adverse event (eg: not neutropenia, but febrile neutropenia). A younger group (Y-STS) was derived from our database and matched by histology, site, size, grade, depth for comparisons and p-values calculated. Disease-specific overall (OS) and progression-free survival (PFS) were estimated (Kaplan-Meier) Results: E-STS received a mean of 4.6 cycles of A-CT observing the following toxicities: 3 (8%) hospitalization (febrile neutropenia), 1 (2.7%) chronic renal failure (ifosfamide related), 2 (5.4%) fatigue. Such toxicities were not different from Y-STS ones (CI95% 0.6-1.4). 25 (67%) E-STS died of STS. E-STS and Y-STS median disease- specific OS and PFS were 40.5 (18-63) and 51 (28-73) (p = .124), 8 (7-9) and 17.7 (5.8-29.5) months (p = .004), respectively Conclusions: This retrospective series does not justify different treatment choices based on age, only. Since a prospective randomized trial is unlikely in E-STS, a thorough clinical evaluation and the disease-related mortality should guide the decision-making regarding chemotherapy. No significant financial relationships to disclose.
Concomitant administration of high-dose methotrexate (HDMTX) and ifosfamide in osteosarcoma patients: A clinico-pharmacological study
Authors: F. Goldwasser, O. Mir, J. Alexandre, F. Lemare, A. Babinet, E. Enkaoua, L. Guillevin, P. Anract
Journal: Journal of Clinical Oncology (2005)

9063 Background: HDMTX is active against osteosarcoma but is given sequentially with other anticancer agents because of the high risk of acute nephrotoxicity. We studied the feasibility of a concomitant administration of HDMTX and ifosfamide. Methods: HDMTX was given as a single agent (8–12 g/m2) on day 1 and was given on day 8 with ifosfamide. Ifosfamide was given at 2.5 g/m2/day on days 7 and 8. Thereafter, the two agents were given concomitantly every other week, in the adjuvant setting in good responders to neoadjuvant chemotherapy. Methotrexatemia was measured at H4, H24, H48 and H72 and urinary pH was verified on each miction. Creatininemia was measured on days 1, 3 and 8 after each HDMTX infusion. Results: Between 1999 and 2003, 19 patients were included (7 females, 12 males). Median age: 17 years (range: 15–19). Primary tumors were located on extremities in 15 patients. Nineteen cycles of HDMTX alone (day one) and 285 cycles of the combination of HDMTX + ifosfamide were evaluable for toxicity and for the pharmacokinetics (PK) of MTX. For each patient, the PK of HDMTX given alone was compared to its PK when given with ifosfamide. The Cmax, AUC, and renal clearance of methotrexate were not modified by concomitant administration of ifosfamide. Toxicity included manageable nausea and emesis, and severe hypokaliemia requiring potassium supplementation. In 5 cycles (1.8%) of HDMTX + ifosfamide, reversible creatininemia elevation (< 1.5 ULN) was observed. Grade 3 neutropenia occurred in 65% of patients. No grade 4 toxicity occurred. No re-hospitalisation was required. Conclusions: HDMTX can be administered with ifosfamide the same day in osteosarcoma patients. This result may allow to develop new therapeutic strategies with higher dose-intensity of active anticancer agents in the neoadjuvant setting. No significant financial relationships to disclose.
In vivo activity of AMN107, as selective Bcr-Abl kinase inhibitor, in murine leukemia models
Authors: J. Mestan, J. Brueggen, D. Fabbro, P. W. Manley, G. Gilliland, B. Huntly, E. Weisberg, J. D. Griffin
Journal: Journal of Clinical Oncology (2005)

6522 Background: The Bcr-Abl oncoprotein has unregulated tyrosine kinase activity and causes chronic myelogenous leukemia (CML). Imatinib, a Bcr-Abl kinase inhibitor, is an effective therapy. However in advanced CML and Ph+ acute lymphocytic leukemia, patients may relapse due to emergence of imatinib-resistant forms of mutant Bcr-Abl kinases, prompting the search for new treatments. AMN107 is a novel kinase inhibitor, affecting both the non-mutated p210 Bcr-Abl and many of the mutant forms of Bcr-Abl. Methods: Two murine models of Bcr/Abl leukemia were studied. AMN107, imatinib, or vehicle were administered orally (75 mg/kg q.d.) following injection of p210 Bcr-Abl or imatinib-resistant E255V-Bcr-Abl 32D cells to Balb/c mice, or after injection of p210, E255V- or M351T-Bcr-Abl transduced primary bone-marrow cells to irradiated Balb/c mice. Results: AMN107 (75 mg/kg p.o. in 10%:90% NMP-PEG300) was well absorbed in mice, with mean plasma levels of 25 μM after 24 h (AUC0–24h 641 h.μmol.L). In the p210–32D Balb/c study, vehicle-treated animals (19/20) developed a lethal leukemic disease (survival range 15–36 days) whereas AMN107, administered over 16 days, resulted in the protection of 15/20 animals for 100 days; median spleen weight in AMN107-treated animals were normal (0.085 g; n = 17) compared to that of controls (0.51 g; n = 20). AMN107 also gave a significant reduction in disease burden in the E255V-32D study. In the primary bone-marrow Balb/c model, vehicle-treated animals (12/12) developed splenomegaly and leukocytosis and were sacrificed by day 16, whereas AMN107, administered from day 8, significantly protected animals until the end of the study (day 20). Similar effects were seen with E255V and M351T transduced bone-marrow cells. Conclusions: These studies indicate that AMN107 can protect mice from Bcr-Abl induced disease, including leukemias induced by imatinib-resistant mutants of Bcr-Abl, and that it may have clinical utility in patients with Bcr-Abl+ leukemias. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharma AG Novartis Pharma AG
Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial
Authors: A Hochhaus, G Saglio, T P Hughes, R A Larson, D-W Kim, S Issaragrisil, P D le Coutre, G Etienne, P E Dorlhiac-Llacer, R E Clark, I W Flinn, H Nakamae, B Donohue, W Deng, D Dalal, H D Menssen, H M Kantarjian
Journal: Leukemia (2016)

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.
Abstract P294: Circulating Soluble ICAM-1 is Associated with Aorto-Iliac and Coronary Artery Calcified Plaque 10 years Later in Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Myron D Gross, Jose R Suarez-Lopez, Alex P Reiner, Bharat Thyagarajan, J. J Carr, Daniel A Duprez, David R Jacobs
Journal: Circulation (2012)

Background: Elevated serum soluble intercellular adhesion molecule-1 (sICAM-1) concentration has been associated with cardiovascular disease in older adults. Soluble ICAM-1may have a central role in the development of atherosclerosis, but few studies have investigated the relationship in young adults or evaluated prospective relationships. Objective/Hypothesis: To investigate the relationship between sICAM-1 and subclinical atherosclerosis measured 10 years later in young adults. sICAM-1 will have positive association with the presence of subclinical atherosclerosis. Methods: Soluble ICAM-1 concentrations were assayed in black and white men and women at average age 40 (range 32–47 years). Two markers of subclinical atherosclerosis, namely aorto-iliac calcified plaque (AoIC, n=1621, 55% with AoIC) and coronary artery calcium (CAC, n=1656, 30% with CAC), were measured 10 years later. Associations were evaluated by logistic regression methods. Results: Mean (standard deviation (SD)) of sICAM-1 was 155.1 (45.8) ng/ml. In a minimally adjusted (age, race, sex, clinic) model, sICAM-1 was associated with an increased risk of AoIC (OR=1.56 per SD, CI=1.37–1.78, p&lt;0.0001,). This association remained highly significant (OR=1.22 per SD, CI=1.06–1.40, p&lt;0.006) in a model fully-adjusted (adding education, body mass index, waist, blood lipids, cholesterol-lowering medication, smoking, blood pressure, antihypertensive medication, and exercise). CAC was associated with sICAM-1 (OR=1.41 per SD, CI=1.24–1.59, p&lt;0.0001) in the minimally adjusted model as well as the fully-adjusted model (OR=1.18 per SD, CI=1.04–1.34, p&lt;.01). Conclusion: Elevated concentrations of sICAM-1 were associated with subclinical atherosclerotic calcification, which in turn is known to be highly predictive of future cardiovascular disease. Soluble ICAM-1 assessed at average age 40 predicts the early development of advanced atherosclerosis, only partly mediated by effects of elevations of known risk factors.
Body Weight, Dietary Practices, and Tumor Susceptibility in the Rat&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: M H Ross, E D Lustbader, G Bras
Journal: JNCI Journal of the National Cancer Institute (1983)

The mature body weight of outbred CD-Crl:COBS CD(SD)BR male rats permitted to select their own diets throughout life was shown to correlate linearly with the frequency of spontaneous tumors. In an analysis of the dietary practices of these animals, a multifactorial model was derived--for which prepuberty and early post-puberty data only were used--that accounted for a large proportion of the variance in mature weight. The level of food or calorie intake proved less informative than the following: the interactive effects of food intake relative to body weight, the proportion of protein and carbohydrate constituents in the diet, the intake of each of these components, and, particularly, the efficiency with which the diet consumed was used for growth during early postweaning life. In a prospective study of other rats maintained on a similar feeding regimen, the model was found to be an accurate predictor of mature weight. Several of the explanatory factors necessary for estimation of body weight also contributed to tumor susceptibility. Nonetheless, both dietary and body weight-related factors in a specific time-related sequence were required to explain variation in spontaneous tumor susceptibility.