tbuckley/cabot-search huggingface dataset:
Cisplatin-based combination chemotherapy in elderly patients with metastatic urothelial cancer.
Authors: Aristotelis Bamias, Susanne Krege, Chia-Chi Lin, Noah M. Hahn, Thorsten Ecke, Erin L. Moshier, Guru Sonpavde, James H. Godbold, William K. Oh, Angelos Koutras, Yeong-Shiau Pu, Matt D. Galsky
Journal: Journal of Clinical Oncology (2013)

269 Background: Cisplatin-based combination chemotherapy is considered standard first-line treatment for patients with metastatic urothelial carcinoma. However, cisplatin-based chemotherapy is frequently avoided in elderly patients due to concerns regarding treatment-related toxicities. We analyzed the efficacy, and tolerability, of cisplatin-based chemotherapy in two age groups (&lt; 70 versus ≥ 70 years old). Methods: Individual patient data was pooled from eight phase II and III trials evaluating cisplatin-based first-line chemotherapy in patients with metastatic urothelial carcinoma. Toxicities, treatment delivery, response proportions, and survival outcomes were compared between patients &lt; 70 versus ≥ 70 years old. Results: Of the 543 patients included in the analysis, 162 patients (30%) were ≥ 70 years old. Patients ≥ 70 years old had a significantly lower baseline calculated creatinine clearance (57 vs. 73 ml/min, p&lt;0.0001). All other baseline characteristics, including PS and visceral metastases were well balanced between the two age groups. Patients ≥ 70 years received a median of 1 cycle less of chemotherapy compared with younger patients (median cycles 5 versus 6; p = 0.004). There was no significant difference in the proportions of patients experiencing Grade 3-4 renal failure, febrile neutropenia, or treatment-related death. Response rate among patients ≥ 70 years old was 50% compared to 52% for patients &lt; 70 years old (p=0.65). There was no significant difference in survival between the age groups (p=0.91). The median survival of the patients ≥ 70 years old was 12.1 months compared to 12.8 months for patients &lt; 70 years old. There was no significant difference in survival between age groups when controlling for baseline performance status and/or the presence of visceral metastases. Conclusions: Elderly patients, with adequate renal function and other baseline characteristics suitable for clinical trial enrollment, tolerate cisplatin-based chemotherapy similarly, and achieve comparable clinical outcomes, compared with their younger counterparts. Cisplatin-based therapy need not be withheld from such patients.
Utility of the SEER-Medicare data to identify medical androgen deprivation therapy
Authors: J. U. Oleynick, P. C. Albertsen, M. M. Barry, E. M. Walker-Corkery, S. Yao, G. L. Lu-Yao
Journal: Journal of Clinical Oncology (2006)

6113 Background: Researchers are increasingly using SEER-Medicare data to measure the use of various cancer therapies. However, the validity and completeness of Medicare data as a source of information for identifying medical androgen deprivation has not been established. In this study, we compared the classification of ADT use based on SEER-Medicare linked data and medical record review. Methods: Among patients who were included in the Prostate Cancer Outcomes Study (PCOS) aged 65 or older and have Medicare part A and B coverage as their primary health insurance, their use of medical androgen deprivation therapy (ADT) identified from the SEER-Medicare data was compared with the results of medical record review. The linkage of the datasets was accomplished by using encrypted IDs. Two algorithms were evaluated. Algorithm A defines ADT use liberally, if at least one of the following HCPCS codes is present: J1950, J9202, J9217, J9218, or J9219. Algorithm B, developed by the authors to identify consistent androgen deprivation, defines ADT only if there is evidence of treatment lasting for 3 months or longer, indicated by either the 12-month treatment J9219 or at least 3 months of treatment with J9202 or J9217. Results: For the 673 patients eligible for this validation study, algorithm A has a sensitivity of 92.5% and a specificity of 85.2% in identifying medical ADT compared to medical record review (see table ), while algorithm B has a sensitivity of 81.8% and a specificity of 88.9% ( Table 1 ). When the study was further restricted to patients with Medicare insurance only (N=142), both algorithms improved: 96.2% sensitivity and 85.6% specificity for algorithm A, and 88.5% sensitivity and 91.1% specificity for algorithm B. Conclusions: Both algorithms have reasonable sensitivity and specificity. Medicare claims can be used to track ADT use for the treatment of prostate cancer in the Medicare population. [Table: see text] No significant financial relationships to disclose.
Homocysteine and Risk of Ischemic Heart Disease and Stroke
Authors: None Homocysteine Studies Collaboration
Journal: JAMA (2002)

It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke.To assess the relationship of homocysteine concentrations with vascular disease risk.MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators.Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete.Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression.Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk.This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.
The natural history of severe asthma and influences of early risk factors: a population-based cohort study
Authors: Wenjia Chen, Carlo A Marra, Larry D Lynd, J Mark FitzGerald, Zafar Zafari, Mohsen Sadatsafavi
Journal: Thorax (2016)

<h3>Background</h3> Severe asthma is associated with disproportionately high morbidity, but little is known about its natural history and how risk factors at first year of diagnosis modify its subsequent development. <h3>Methods</h3> Using administrative health data, we retrospectively followed patients 14–55 years of age with newly diagnosed severe asthma in British Columbia, Canada. Based on intensity of resource use (drug therapy) and occurrence of exacerbations, each patient-year was classified into mild, moderate, or severe asthma. We estimated the probability of transition between severity levels or to death over the study period using a four-state Markov model, and used this to assess the 10-year trajectory of severe asthma and the influence of baseline risk factors. <h3>Results</h3> We followed 13 467 patients. Ten years after incident severe asthma, 83% had transitioned to a less severe level (mild: 43%, moderate: 40%). Low socioeconomic status, high comorbidity burden, and high adherence (proportion of days covered (PDC) by asthma controller therapy) in the first year were independently associated with, respectively, 10%, 24% and 35% more time in severe asthma over the next 10 years. Sex was not associated with the clinical course. <h3>Conclusions</h3> Most patients with incident severe asthma used fewer resources over time, indicating a long-term transition to milder asthma. Potentially modifiable risk factors for poor prognosis of severe asthma include low socioeconomic status and high comorbidity burden. The association between PDC and future asthma severity is likely due to residual confounding by disease severity.
Utilization and cancer detection by U.S. prostate biopsies (2005-2011).
Authors: Carl A. Olsson, Deepak A. Kapoor, Ann E. Anderson, Savvas E. Mendrinos, David G. Bostwick
Journal: Journal of Clinical Oncology (2013)

e16076 Background: To assess the positive biopsy rate and core sampling pattern in patients undergoing prostate biopsy in the US at a national reference laboratory and pathology laboratories integrated into urology group practices and analyze the relationship between positive biopsy rates and number of specimen vials per biopsy (v/b). Methods: For the years 2005-11, we collected pathology data from a national reference laboratory (NRL) including number of urologists and urology practices referring samples, total specimen vials submitted per prostate biopsy, and final diagnosis for each case. The diagnoses were categorized as benign, malignant, prostatic intraepithelial neoplasia or atypical small acinar proliferation. Over the same period, similar data was gathered from urology practices with in-house laboratories performing global pathology services (urology practice labs, UPL) identified by a member survey of the Large Urology Group Practice Association. For each year studied, positive biopsy rate and number of specimen vials/biopsy were calculated in aggregate and separately for each site of service. Results: From 2005-11, 437,937 biopsies were submitted in 4,230,129 vials (9.4 v/b); overall positive biopsy rate was 40.3%, identical at both the NRL and UPL (p=0.97). Nationally, the number of specimen vials/biopsy increased sharply from a mean of 8.8 during 2005-8 to 10.3 from 2009-11 (difference 1.5 v/b, p=0.03). For the most recent 3 year period (2009-11), there was no significant difference between the NRL (10.0 v/b) and UPL (10.6 v/b) (p=0.08). Positive biopsy rate correlated strongly (p&lt;0.01) with number of specimen vials/biopsy. Conclusions: The positive prostate biopsy rate of 40.3% is identical across sites of service. Although there was a national trend towards increased specimen vials/biopsy from 2005-11, from 2009-11 there was no significant difference in specimen vials/biopsy across sites of service. Increased cancer detection rate correlated significantly with increased number of specimens examined. Segregation of prostate biopsy cores into 10-12 unique specimen vials has been adopted by urologists across sites of service and can be considered the de facto national standard of care.
The effect of rexinoids (LGD1069 and LG100268) on the breast cell growth
Authors: Hye-Sook Seo, Ja Seok Koo
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4420 

Rexinoids are important in controlling apoptosis and are known to suppress both ER-positive and ER-negative mammary tumor development with reduced toxicity compared to RAR-selective retinoids. Rexinoids are also active in animals in tamoxifen-resistant breast cancer and in ATRA-resistant breast cancer cells. Hence, rexinoids seems to be more efficient and promising chemopreventive and therapeutic drugs compare to RAR-selective ligands. Our goal of the study of the present study is to know whether LGD1069 and LG100268 (rexinoids-from Ligand Pharmaceuticals Inc.) suppress the growth of breast cancer cells, and how these drugs act to inhibit breast cancer development. For that purpose, we tested 5 different breast cell lines; 1 human mammary epithelial cell line (HMEC), 2 different ER-positive cell lines (MCF-7 and T47D) and 2 different ER-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-435). By MTS assay, We found that both LGD1069 and LG100268 inhibited significantly normal HMEC cell growth at 10 uM. We also found that LGD1069 strongly suppressed the growth of T47D (ER-positive) by dose-dependent manner. LGD1069 also induced a mild inhibition of MDA-MB-231 (ER-negative) at 10 uM. MCF-7 and MDA-MB-435 did not have growth suppression by LGD1069 at 10 uM. LG100268 did affect little the cell growth in all 4 breast cancer cell lines suggesting its weak activity compare to LGD1069. We will further enlarge our investigation using three-dimensional (3D) epithelial culture systems, resembling their in vivo architecture to see whether the growth suppressive activity of rexinoids would be differently displayed between monolayer and 3D system. On the other hand, to investigate the mechanism by which LGD1069 suppresses breast tumorigenesis, we have studied the genes modulated by LGD1069 and LG100268. We treated first MDA-MB-231 with LGD1069 and LG100268 at 10 uM for 12 hrs, extracted RNA and then submitted to Affymetrix Microarray. In MDA-MB-231, we identified 333 genes up-regulated and 319 genes down-regulated by LGD1069 with changes in fold induction greater than 2 fold. We also identified 116 genes up-regulated and 431 genes down-regulated by LG100268 with changes in fold induction greater than 2 fold. According to the data, we found several interesting genes induced by LGD1069 and LG100268 in MDA-MB-231 such as several hypothetical proteins, CDC14 cell division cycle 14 homolog A (S. cerevisiae), recombination activating gene 2, tumor protein D52, MDM2, ITGA4, ADh1B, NF2 and cathepsin S (for LGD1069), several hypothetical proteins, zinc finger protein 423, cyclin-dependent kinase inhibitor 1C (p57, Kip2), eukaryotic translation initiation factor 5A, transcription factor 4, MDM2, FGF2, GNRH1, and annexin A9 (for LG100268). We will study their functions. We are also performing gene profiling for HMEC and T47D to identify the genes regulated by LGD 1069 and LG100268. This work is supported by U.S. DOD Grant (W81XWH-04-1-0505).
Inhibition of FGFR4 increases oxaliplatin and 5-fluorouracil sensitivity in <i>Kras</i> wild-type and mutant colorectal cancer cells.
Authors: R. C. Turkington, W. L. Allen, L. Stevenson, V. Coyle, P. V. Jithesh, I. Proutski, C. Fenning, G. Stewart, S. Van Schaeybroeck, D. Longley, P. G. Johnston
Journal: Journal of Clinical Oncology (2011)

e14087 Background: The discovery of underlying mechanisms of drug resistance and the development of novel agents to target these pathways is a priority for patients with advanced colorectal cancer (CRC). The fibroblast growth factor receptor 4 (FGFR4) is frequently overexpressed in solid tumours, such as CRC, and has been shown to be an important regulator of cancer cell growth and motility. The aim of this study was to identify novel targets whose knock-down is important in mediating sensitivity to 5-FU and oxaliplatin in Kras wild-type (WT) and mutant (MT) CRC models. Methods: Transcriptional profiling (Almac Diagnostics CRC Disease Specific Array) of pre-treatment metastatic CRC liver biopsies and oxaliplatin/5-FU resistant HCT116 cell lines followed by Metacoreä and Gene Set Enrichment Analysis (GSEA) were used to identify individual genes from novel drug-sensitivity pathways for incorporation into a RNAi screen. Results: We identified panels of in vitro and clinical genes whose expression is altered (acutely and basally) between sensitive and 5-FU- or oxaliplatin-resistant models. The significant pathways involved in 5-FU/oxaliplatin resistance included cell cycle, focal adhesion, insulin and MAPK signalling. In the MAPK pathway, we found that FGFR4 silencing potently increased apoptosis in KrasWT and MT CRC cells, and this was further enhanced when FGFR4 siRNA was combined with 5-FU or oxaliplatin. Interestingly, FGFR4 inhibition completely inhibited migration of KrasMT HCT116 cells. Mechanistically, we found that FGFR4, silencing resulted in strong inhibition of STAT3 activity in both KrasWT and MT CRC cells. Conclusions: This study demonstrates the utility of microarray expression data, obtained from pre-clinical and clinical samples, and analyzed by pathway and gene set enrichment analysis to identify pathways of oxaliplatin/5-FU sensitivity in CRC. In addition FGFR4 inhibition in combination with 5-FU or oxaliplatin could represent a novel treatment strategy for KrasMT and WT CRC tumours. We are currently investigating FGFR4 small molecule inhibitors in preclinical in vitro and in vivo models.
Relative dose intensity of FEC100: An analysis of outcomes
Authors: S. Hopkins, G. Nicholas, S. Verma, S. Dent, S. Gertler
Journal: Journal of Clinical Oncology (2005)

773 Background: Adjuvant FEC100 is considered to be highly effective at improving disease-free survival (DFS) and overall survival (OS) in patients (pts) with early breast cancer (EBC). Correlation between relative dose intensity (RDI) and outcomes of adjuvant therapy is primarily based on CMF data from Bonadonna (1981). Newer anthracycline-based chemotherapy regimens are more active and may demonstrate a stronger relationship between RDI and clinical outcomes. Methods: A retrospective analysis was undertaken by analyzing a database of chemotherapy administered at The Ottawa Hospital - RCC from 1997 to May 2004. The database was queried to extract all of the epirubicin administered adjuvantly at a dose of 100 mg/m2 to pts with a diagnosis of EBC. Results: 221 pt charts were analyzed. The median RDI (+/− SD) for all pts was 94.5 +/− 6.5%. Overall, 46.6% of pts had reduced RDI. The median time to recurrence for all pts was 19.4 months, with a median follow-up of 24.5 months. Eleven of 118 (9.3%) pts who received high RDI (≥95%) recurred versus 18/103 (17.5%) of those with RDI <95% (p=0.0733). Results of a univariate analysis is shown in table 1. On multivariate analysis, 3 variables were found to be independently predictive of time to progression: Receptor status (ER/PR+vs-) (p=0.0007), stage of disease at presentation (Stage I-II vs III) (p=0.0007) and dose intensity (≥95% RDI vs <95% RDI) (p=0.0807). Conclusions: FEC100 as an adjuvant chemotherapy regimen has a high degree of activity in EBC. This retrospective analysis has shown that a high RDI (≥ 95%) of FEC100 showed an overall trend towards improving DFS. High RDI was significantly more effective in ER positive patients, and a trend towards improved DFS was noted in node positive patients. On multivariate analysis, RDI of ≥ 95% demonstrated a strong trend towards improving DFS. This is the largest series of pts that has been analyzed (retrospectively) to examine the relationship between RDI of FEC100 and clinical outcome. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Pfizer Amgen, Pfizer
KRAS mutations in colorectal cancer is a predictive factor of response and progression free survival in patients treated with Cetuximab.
Authors: Astrid Lievre, Jean-Baptiste Bachet, Marc Ychou, Olivier Bouche, Denis Pezet, Valerie Boige, Bruno Landi, Christophe Louvet, Jean-Francois Emile, Frederic Bibeau, Marie-Danielle Diebold, Gorana Tomasic, Jean-Francois Cote, Jean-Francois Flejou, Philippe Rougier, Frederic Penault-Llorca, Pierre Laurent-Puig
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5671 

Background: The Cetuximab anti-EGFR (epidermal growth factor receptor) antibody has been shown to be efficient in metastatic colorectal cancer (CRC). We previously showed in 30 CRC patients that KRAS mutations were associated with the absence of response to Cetuximab (1). The aim of this retrospective study was to confirm, in a larger series of pts treated with Cetuximab, the predictive value of KRAS mutations in comparison with that of skin toxicity and its impact on progression free survival (PFS).

Patients and Methods: A series of 76 EGFR+ metastatic CRC patients treated with Cetuximab in 7 centers were analyzed for KRAS mutation (exon 2). The mutational analysis was performed by direct sequencing on DNA extracted from fresh frozen or paraffin-embedded tissues. The association between tumor response (RECIST criteria) and KRAS mutations and skin toxicity was analyzed, as PFS of the patients according to the presence or absence of KRAS mutation.

Results : Among the 76 patients analyzed (M/F: 39/37; mean age: 60.1 years), 24 (31.5%) had an objective response to Cetuximab (CR : 2, PR : 22), administered in monotherapy (n=2) or in combination with irinotecan (alone, n=66 ; FOLFIRI regimen, n=8). A KRAS mutation was present in 35.5% of the cases (n=27) and was significantly associated with the absence of response to Cetuximab (0 responder among the 27 mutated patients vs 24 (49%) among the 49 non-mutated patients; p=10-5). A severe skin toxicity was more frequent in responder compared to non responder patients (grade 2-3 toxicity in CR/PR/SD/PD groups: 100%/64%/52%/35%; p=0.02 trend test). Median PFS was 19.2 weeks. In univariate analysis, PFS was longer when tumor was not mutated (median: 32 vs 8.6 weeks, Log-rank p<5.10-6). The prognostic value of KRAS mutations remained significant in multivariate Cox model including age, sex and skin toxicity (progression in the presence of KRAS mutation, HR = 3.50 (IC95% : 1.88-6.51), p<0,0001).

Conclusion : These results confirm the high predictive value of KRAS mutations for the reponse to Cetuximab in CRC and show their association with a shorter PFS, which could be relevant in clinical practice by allowing the identification of patients that could benefit from Cetuximab and those (with KRAS mutation) for whom Cetuximab is likely to be inefficient, and potentially toxic.

(1) Lievre et al. Cancer Res 2006 ; 66 : 3992-95
Pediatric phase I trial and pharmacokinetic (PK) study of dasatinib: A report from the Children’s Oncology Group
Authors: R. Aplenc, L. C. Strauss, S. Shusterman, A. M. Ingle, R. Luo, J. Wright, S. Blaney, P. C. Adamson
Journal: Journal of Clinical Oncology (2007)

14094 Background: Dasatinib is an orally-available tyrosine kinase inhibitor with low-nanomolar activity against SRC-family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGFβ receptor. Methods: A phase I study of dasatinib administered as a single agent in pediatric patients with refractory solid tumors or imatinib refractory Ph+ leukemias is being performed. Dasatinib dose levels of 50, 65, 85 and 110 mg/m 2 /dose, administered orally twice daily for 28 consecutive days, are being studied. Courses repeat without interruption. Results: 8 pts with solid tumor and 3 pts with Ph+ leukemia (median age 11 yrs, range 7–17) have been enrolled, of whom 7 are fully evaluable for toxicity. At the 50 and 65 mg/m 2 dose levels, 0/3 and 0/1 pts experienced DLT. 1 of 3 pts with CML treated at the 50 mg/m 2 dose level had Gr 4 hypokalemia. In 4 pts studied at the 50 mg/m 2 dose level, the median (range) apparent dasatinib clearance was 238.5 L/hr (220.7 - 332.7), terminal half-life was 2.3 hrs (2.2 - 3.1), and the median Cmax was 55.5 ng/ml (36.0 - 161.1). Conclusions: Dasatinib is well tolerated at a dose of 50 mg/m 2 BID on a continuous 28 day dose schedule in pediatric patients. Preliminary PK analysis suggests that drug disposition is similar to that observed in adults. Dose escalation and PK studies are continuing. No significant financial relationships to disclose.