tbuckley/cabot-search huggingface dataset:
Treatment of advanced non-small cell lung cancer (NSCLC) in patients older than 70.
Authors: M. E. Richardet
Journal: Journal of Clinical Oncology (2010)

e18098 Background: More than 50% of advanced NSCLC patients (p) are older than 65 years old (y), with a median age at diagnosis of 68 y. This group of patients have been usually underrepresented in clinical trials. The aim of our study is to compare whether clinical characteristics, toxicity, response rate, overall survival (OS), and progression-free survival (PFS) are different in p age > 70 vs. < 70, treated with platinum-based chemotherapy. Methods: We reviewed the database of the Instituto Oncologico Córdoba, Argentina (IONC), from 2004 to 2009. Survival curves were made up by Kaplan-Maier method and compared using the log-rank test. Results: Out of 198p, 103 p (52 %) were age < 70, and 95 p (48 %) > 70. We found significant differences in OS (9.4 vs. 7.5 months, p=0.003) and PFS (6.4 vs. 5.1 months, p=0.002). Significant differences in OS were also found between the two groups regarding anemia, Performance status (PS) and response rate with no difference on sex and histology. Conclusions: Significant differences in OS and PFS were evident between both groups. We observed increased toxicity in p age > 70, but without greater treatment-related mortality. OS and PFS were superior in patients treated with platinum-based doublets when compared to monotherapy (according to historical records); therefore we should choose the former in elderly patients. Age cohort Age <70 (%) Age >70 (%) p Toxicity (95% CI) Neutropenia 3 9 NS Anemia 26 70 0.00001 Thrombocytopenia 38 39 NS Neurotoxicity 31 57 0.0003 Nauseas 30 51 0.0004 Outcome PFS (m) 6.4 5.1 0.002 OS (m) 9.4 7.5 0.003 No significant financial relationships to disclose.
Prognostic impact of clinical and pathologic criteria in neuroendocrine and aggressive variant prostate cancer.
Authors: Beerinder S. Karir, Panagiotis J. Vlachostergios, Paul J. Christos, Victor RA Febles, Kavya Pinto-Chengot, Ana M. Molina, David M. Nanus, Himisha Beltran, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2016)

268 Background: Various clinical and pathologic criteria have been proposed to identify neuroendocrine (NE) or aggressive variant (AV) prostate cancer (PC). We assessed the prognostic value of clinical parameters in a single-institution cohort. Methods: An IRB-approved database was screened for clinical and/or pathologic criteria (Table 1) for NE/AV PC. Patients with advanced CRPC not meeting any of the criteria served as contemporary controls. Overall survival (OS) for each group was assessed using Kaplan-Meier method and comparisons with log-rank test. Results: 249 men were identified, median age 71.5 (45.1-90.8 years). 145 patients met at least 1 criterion suggestive of NE/AV PC, whereas 104 were CRPC only. Median OS for each subgroup, the combined NE/AV PC group, and the CRPC cohort are provided in Table 1. OS for NE/AV PC vs. CRPC cohort was 25.4 vs 33 months (p = 0.26). Patients with parenchymal brain metastasis had the worst survival of 5.2 mo [95%CI 2.1, 8.3]. On multivariate analysis, bulky high-grade disease in prostate/pelvis carried the highest risk of death (HR 1.71 [1.07, 2.74; p = 0.02]). Conclusions: A number of clinical and pathologic criteria have been used to define NE/AV PC for clinical practice or trial enrollment. Some criteria are associated with a shorter survival than others. Additional studies are warranted to further define both prognostic and molecularly defined subgroups. [Table: see text]
The Role of Mcl-1 Expression and Phosphorlyation in Resistance to Chemotherapy and Kinase Inhibitors in FLT3-ITD-Positive Acute Myeloid Leukemia (AML)
Authors: Florian H Heidel, Henning Schulze-Bergkamen, Binje Vick, Daniel B Lipka, Fian K Mirea, Toni Urbanik, Joseph T Opferman, Thomas Fischer
Journal: Blood (2008)
Correlation of CA 27.29 and circulating tumor cells before, at the end, and 2 years after adjuvant chemotherapy in patients with primary breast cancer: The SUCCESS trial.
Authors: P. G. M. Hepp, B. K. Rack, H. Tesch, M. Rezai, T. Beck, J. Salmen, U. Andergassen, U. Ortmann, T. Zwingers, M. W. Beckmann, W. Lichtenegger, J. W. Janni
Journal: Journal of Clinical Oncology (2011)

10626 Background: While evidence for the prognostic value of circulating tumor cells (CTC) in the adjuvant setting is swiftly increasing the role of tumor markers like CA27.29 in this setting is still controversial. In the SUCCESS Trial CTC and CA27.29 have been measured before, after and 2 years after adjuvant chemotherapy. Our goal was to examine the correlation of these 2 factors at the 3 points in time. Methods: The SUCCESS Trial compared FEC-docetaxel (Doc) vs. FEC-Doc-gemcitabine (Doc-G) regime and 2 vs. 5 year treatment with zoledronat in 3754 patients with primary breast cancer (N+ or high risk). CA27.29 has been measured with ST AIA-PACK Ca27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Belgium). The cutoff for positivity of CA27.29 was >31 U/ml. CTC were assessed with the CellSearchSystem (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labeled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish between epithelial cells and leukocytes. The cutoff for positivity was >1 CTC/15ml. Results: CA27.29 and CTC data are available of 2011 patients before, 1525 after and 1000 pts 2 years after chemotherapy. Before CHT 7.86% of pts were CA27.29 positive and 9.40% were CTC positive. 1.29% were CA27.29 and CTC positive (p=0.0015). After CHT 20.92% of pts were CA27.29 positive and 8.59% were CTC positive. 1.18% were CA27.29 and CTC positive (p=0.0346). 2 years after CHT 2.60% of pts were CA27.29 positive and 7.40% were CTC positive. 0.40% were CA27.29 and CTC positive (p=0.1115). Concerning correlation of positive CA27.29 with other prognostic factors we found a significant (p<0.05) correlation to histology and menopausal status before CHT. After CHT there was a significant correlation to menopausal status only and 2 years after CHT no correlation to any other prognostic factor could be found. Conclusions: In conclusion there seems to be a relationship between CA27.29 and CTC before treatment which resolves in the course of the treatment and beyond. Therefore clarification of the prognostic value of CA27.29 and CTC after adjuvant treatment as independent tools is needed.
Evaluating the implementation of computerized prescriber order entry (CPOE) for systemic treatment (ST) in Ontario.
Authors: Sharon Gradin, Nancy Wolf, Marta Yurcan, Tim Yardley, Leonard Kaizer, Vishal Kukreti
Journal: Journal of Clinical Oncology (2014)

54 Background: A successful effort was led in Ontario to increase ST CPOE adoption from 73% to 92% to support safety of patients receiving complex systemic treatment. This work included implementation at 19 hospitals from 2011-2013. The implementation process included identification of multidisciplinary team champions, baseline workflow analysis and development of a future desired state. Findings from this project’s benefits evaluation are presented. Methods: Each hospital was required to collect pre and post implementation measurements for medication errors, transcription errors and order clarity/completeness. Six months post implementation, a semi-structured telephone interview was conducted with representative hospitals (9/19) to obtain qualitative feedback on how implementation impacted workflow, inter-professional practice and workload. Results: Hospitals that implemented showed: 1) decrease in overall medication error rates. 2) decrease in transcription error rates and 3) decrease in number of unclear or incomplete orders. Qualitative feedback from hospital leads indicated that the “future desired” workflow was achieved by all. Most hospital respondents indicated that clarity of inter-professional communication regarding orders improved and in most cases overall workload did not increase. Conclusions: The findings reinforce the benefit associated with implementation of ST CPOE in outpatient settings. Lessons learned in Ontario can be leveraged to support successful implementation of ST CPOE in other jurisdictions. Critical implementation success factors included: 1) leadership and multi-disciplinary involvement; 2) provision of funding and cost sharing; 3) facilitation of process improvement through established methodologies, 4) knowledge transfer and peer group led education and training sessions. [Table: see text]
Relationship between biomarkers and everolimus efficacy in the phase III RECORD-1 trial of patients with metastatic renal cell carcinoma (mRCC).
Authors: Stephane Oudard, Bernard J. Escudier, John A. Thompson, Viktor Grünwald, Cristina Masini, Sergio Bracarda, Ashok Panneerselvam, Sven Gogov, David Chen, Robert John Motzer
Journal: Journal of Clinical Oncology (2013)

352 Background: Compared with placebo, everolimus provided significant improvement in median PFS in the RECORD-1 study of VEGFr-TKI-refractory mRCC. To investigate the role of angiogenesis pathway molecules as potential biomarkers of everolimus efficacy in RECORD-1, plasma levels of sVEGFR-2, VEGF-A, and bFGF were estimated. Methods: In addition to best supportive care, patients received everolimus 10 mg/day (n = 277) or placebo (n = 139). Placebo patients who progressed were offered everolimus. Predose blood samples were collected on day 1 of the first four 28-day treatment cycles. Plasma levels of sVEGFR-2, VEGF-A, and bFGF were assessed by ELISA. Effect of treatment over time on each biomarker was assessed by a mixed effects model. Hazard ratios (HR) for prognostic effects were obtained using log baseline biomarker values as continuous variables in a stratified Cox proportional hazards model. Results: Plasma levels of sVEGFR-2, VEGF-A, and bFGF were available for 45%, 45%, and 39% of everolimus patients and 50%, 50%, and 45% of placebo patients. Patients with biomarker data had baseline characteristics similar to those of the overall population. Mean baseline levels (pg/mL) of sVEGFR-2, VEGF-A, and bFGF were similar for everolimus (8945, 245, and 8, respectively) and placebo (8985, 253, and 13, respectively). Everolimus significantly improved median PFS over placebo irrespective of baseline levels of the analyzed biomarkers (p &lt; 0.001), indicating they are not predictive of everolimus efficacy. Prolonged PFS in the biomarker population was associated with lower VEGF-A baseline level (HR, 1.27; 95% CI, 1.03-1.57; p = 0.028), suggesting VEGF-A may be prognostic for mRCC. Compared with placebo, everolimus significantly reduced bFGF (p = 0.0095) and sVEGFR-2 (p&lt; 0.001) levels over the time course of the study; no effect on VEGF-A levels was observed. Conclusions: Everolimus significantly improved PFS compared with placebo, regardless of baseline biomarker levels. Lower VEGF-A levels may be a potential prognostic factor for longer PFS. Everolimus treatment significantly downregulated plasma levels of bFGF and sVEGFR-2 from baseline. Clinical trial information: NCT00410124.
Obesity, ethnicity, and surgical outcomes for clinically localized prostate cancer
Authors: M. Gross, S. Jo, D. Huang, J. Mirocha, R. Shazer, S. Holden, D. Agus
Journal: Journal of Clinical Oncology (2005)

9615 Background: Some reports have shown obesity is associated with poor outcomes for prostate cancer (PC). Studies differ by the definition of obesity and the presence of confounding variables (such as ethnicity). We investigated the interaction between obesity, ethnicity, and surgical outcomes for pts with PC treated by radical prostatectomy (RP). Methods: Records of RP at Cedars-Sinai Medical Center between 1994 and 2002 were reviewed (1069 pts). Pts were excluded for pre-operative treatment (131 pts) or if full preoperative staging data was unavailable (501 pts). The analysis included 437 pts. Clinical variables examined included: age, PSA, pre-operative hemoglobin (Hgb), ethnicity, and body mass index (BMI). Obesity was defined as BMI >= 30 kg/m2. Surgical outcomes included: estimated blood loss (EBL), Gleason score >= 7 (GS>7), extra-capsular extension (ECE), positive margins (MR+), positive lymph node (LN+), seminal vesicle invasion (SVI+), and pathologic stage (pT2 vs. pT3/T4). Variables were compared by t-tests and Fisher exact tests. A step-wise logistic regression analysis was used to determine odds ratio (OR) in relation to multiple predictors. Results: Mean +/- standard deviation for pre-operative data included: age 62.5 +/- 7.6 yrs; PSA 8.6 +/- 7.1 ng/dl; Hgb 13.5 +/- 1.4 g/dl; and BMI 26.5 +/- 4.0 kg/m2. Pt reported ethnicities included: white (358 pts), Black/African-American (55 pts), Asian/Pacific Islander (16 pts), Hispanic (8 pts). A weak, but significant association was observed between BMI and EBL (Spearman correlation=0.16, p=0.0007). No association was observed between BMI and ethnicity. 67 pts were obese. Obesity was significantly associated with ECE and pT3/T4, but not GS>=7, MR+, LN+, or SVI. Regression models showed that obesity was independently associated with ECE (OR 3.7, 95% CI 1.7–7.9) and pT3/T4 (OR 2.5, 95% CI 1.3–4.7), but not other surgical outcomes. Conclusion: In distinction to other studies, no association was found between obesity and ethnicity. There is a suggestion of increased technical difficulty of RP in obese pts. Obesity is associated with advanced pathologic stage including ECE and pT3/T4. These results support an association between obesity and risk of early disease recurrence. No significant financial relationships to disclose.
Immunohistochemical expression and gene amplification of HER family members in human biliary tract carcinoma
Authors: T. Kawamoto, K. Ishige, H. Suzuki, S. Krishnamurthy, M. Thomas, M. Yamamoto, I. Hyodo, J. Shoda
Journal: Journal of Clinical Oncology (2008)

15563 Background: Biliary tract carcinomas (BTCs) develop in BK5.erbB2 transgenic mice, which in turn proves involvement of erbB2 in biliary carcinogenesis. Supporting this, the gene amplification of HER2 was found in ca. 20% of human BTCs (Kawamoto, et al. ASCO 2006). Following these results, a Phase II study of Trastuzumab for treatment of BTCs (NSC 688097) is being conducted. Although the mechanism of HER2 activation has not been elucidated, the role of HER3 in HER2-driven tumorigenesis has recently been discussed. In this study, we determined HER family members in human BTCs by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Methods: A total of 91 tissue specimens from 67 gallbladder carcinoma (GBC), 8 bile duct carcinoma (BDC), and 16 cholangiocarcinoma (CC) were examined. pStage (AJCC) of the patients was: I: 20, II: 45, III: 12, IV: 14. Histologic grade was G1 and G2: 45, G3: 46. All cases were screened for HER2, HER3 and EGFR by IHC (more than 2+ intensity indicated overexpression). HER2, HER3 and EGFR gene amplification (FISH + was defined as an each HER/each CEP ratio of 2.0 or greater) was performed. Results: HER2, HER3 and EGFR overexpression by IHC was found in 38%, 50% and 0% of BDCs, 31%, 50% and 0% of CCs, and 33%, 34% and 13% of GBCs, respectively. Phosphorylated (p-) HER2 was found in 13% of BDCs, 10% of CCs, and 27% of GBCs. However, p-EGFR was found in 10% of GBCs but not in BDCs and CCs. FISH analysis on tissue sections was considered successful in the same serial sections for 5 of 8 BDCs, 5 of 16 CCs, and 46 of 67 GBCs. HER2, HER3 and EGFR FISH (+) was found in 20%, 0% and 0% of BDCs, 20%, 0% and 0% of CCs, and 24%, 26% and 4% of GBCs, respectively. Overexpression of both HER2 and HER3, which was recognized in 2 BDCs (25%), 3 CCs (19%) and 10 GBCs (15%), was associated with that of p-Akt and m-TOR. However, overexpression of both HER2 and EGFR or both HER3 and EGFR were scarcely found. There was no significant correlation between expression of HER family members and pStage or histologic grade. Conclusions: More than 20% of BTCs overexpress both HER2 and HER3. These HER family members may form heterodimer, which in turn results in tumor promotion through the transphosphorylation of HER3 coupled with the activation of PI3K pathway. No significant financial relationships to disclose.
A novel therapeutic strategy for effective elimination of glioblastoma stem cells using biochemical mechanism-based drug combinations.
Authors: S. Yuan, F. Wang, L. Wang, H. Zhang, G. Chen, L. Feng, R. Xu, J. Wang, P. Huang
Journal: Journal of Clinical Oncology (2011)

e12504 Background: Glioblastoma stem cells (GSCs) in hypoxic and low-nutrient environments contribute significantly to the therapy resistance of glioblastoma multiforme, the most prevalent and aggressive type of brain tumor. Our recent study indicated that GSCs rely highly on glycolysis to generate ATP for maintenance of cell metabolism, survival, and self-renewal. We postulated that ATP depletion by inhibition of glycolysis might cause a severe energy crisis that makes GSCs incapable of repairing DNA damage induced by conventional chemotherapeutic agents. Methods: Two GSC lines (GSC11 and GSC23) with high expression of CD133 were tested; cell viability was assessed by MTS assay and flow cytometry analysis; self-renewal and tumorigenicity of GSCs were measured by neurosphere-forming assay and orthotopic inoculation in NOD/SCID mice, respectively. Results: This study demonstrated that treatment of CSCs with the novel glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP) sensitized the killing effect of the conventional chemotherapeutic agent carmustine (BCNU) with striking synergistic elimination of GSCs, especially under hypoxic conditions. The self-renewal capability and tumorigenicity in NOD/SCID mice by orthotopic inoculation of GSCs was dramatically attenuated after 6 h of treatment with this combination. Importantly, this combination preferentially targeted GSCs and non-stem tumor cells with low toxicity to normal human astrocytes. Dramatic ATP depletion in GSCs treated with the combination of 15 μM 3-BrOP and 200 μM BCNU for 6 h significantly enhanced irreversible DNA damage induced by BCNU, which alone caused reversible damage. We further showed that a synergistic inhibition of BCNU and 3-BrOP on glyceraldehyde-3-phosphate dehydrogenase is a key mechanism of energy crisis that enhances DNA damage caused by BCNU in GSCs. Conclusions: Inhibition of glycolysis can effectively sensitize GSCs to the anticancer effect of BCNU, resulting in striking synergistic elimination of these stem-like cancer cells. This therapeutic approach merits further study in vivo and in clinical evaluation for treatment of glioblastoma.
Modeling acute urinary toxicity after radiotherapy for prostate cancer.
Authors: Viviana Carillo, Tiziana Rancati, Cesare Cozzarini, Sergio Villa, Andrea Botti, Valeria Casanova Borca, Gabriella Cattari, Francesco Civardi, Claudio Degli Esposti, Pierfrancesco Franco, Giuseppe Girelli, Angelo Maggio, Alessandro Muraglia, Marcella Palombarini, Alessio Pierelli, Emanuele Pignoli, Vittorio Vavassori, Michele Zeverino, Riccardo Valdagni, Claudio Fiorino
Journal: Journal of Clinical Oncology (2014)

156 Background: DUE-01 is a multi-centric observational study aimed at developing predictive models of genito-urinary toxicity and erectile dysfunction for prostate cancer patients treated with conventional (1.8-2Gy/fr, CONV) or moderate hypofractionation (2.5-2.7Gy/fr, HYPO). Current analysis focused on modelling the relationship between the risk of IPSS≥15 (IPSS15end) at the end of radiotherapy and clinincal/dosimetric risk factors. Methods: Planning data and relevant clinical factors were prospectively collected, including DVH/DSH referred to the whole treatment and to the weekly delivered dose (DVHw/DSHw). Best discriminating DVH/DSH parameters were selected by the differences between patients with/without IPSS15end=1 (t-test). Bootstrap variable selection techniques (300 resamples) in the framework of logistic backward feature selection was used to improve model building (El Naqa, IJROBP 2006). Graphical and quantitative analyses of the variable selection process applied to bootstrap data replicates was used to avoid underfitting/overfitting and to assess the final multivariable model. Results: 247 patients were available (CONV:116, HYPO:131). Seventy one out of 247 (28.7%) reported IPSS15end=1. The most predictive dosimetric tools were the absolute weekly delivered dose (DSHw and DVHw). DSHw and DVHw were alternatively inserted in the bootstrap variable selection flow, together with clinical risk factors. Due to the number of events, a logistic model containing six variables was accepted On the basis of observed frequency of variables in the top six positions, a model including basal IPSS (median OR=1.22, p=0.00001), use of anti-hypertensives (median OR=2.7, p=0.01), absolute bladder surface receiving more than 10.5 Gy/week (s10.5w, median OR=1.16, p=0.0001), and s12.5w (median OR=1.07, p=0.005), was choosen. AUC of this model was 0.80. Silmilar results were obtained when using DVHw. Conclusions: Basal IPSS, use of anti-hypertensive drugs, s10.5w/v10.5w and s12.5w/v12.5w are the main predictors of IPSS&gt;=15 at the end of radiotherapy Bootstrap variable selection technique gives the modeler more insight into the importance and stability of the different variables selected and allows development of more robust models
Patients with metastatic renal cell carcinoma treated with everolimus in REACT: Hyperglycemia and hypercholesterolemia and associated outcomes.
Authors: Petri Bono, Svetozar Gogov, Ashok Panneerselvam, Carlos A. Garay, Viktor Grünwald
Journal: Journal of Clinical Oncology (2012)

407 Background: Correlation between specific adverse events (AEs) and clinical efficacy of targeted therapies in the treatment of patients with metastatic renal cell carcinoma (mRCC) has been noted. Subanalyses of REACT (RAD001 Expanded Access Clinical Trial in RCC) evaluated potential association of hyperglycemia and hypercholesterolemia with outcomes in patients with mRCC treated with everolimus (EVE). Methods: The open-label, international, expanded-access clinical trial REACT (Clinicaltrials.gov: NCT00655252 ) evaluated long-term safety and efficacy of EVE 10 mg/day in patients with mRCC who were intolerant of, or progressed while on, VEGFR-TKI therapy. Based on Common Toxicity Criteria AE v3.0 criteria, all grade 3/4 AEs and any grade 1/2 AEs resulting in study drug modification, temporary interruption, or treatment discontinuation were collected. Subgroup analyses of patients who developed hyperglycemia or hypercholesterolemia of any grade were performed. Results: There were 1364 patients enrolled in REACT, of whom 78 developed hyperglycemia and 14 developed hypercholesterolemia. Median EVE treatment duration was longer for patients who developed hyperglycemia or hypercholesterolemia than for the overall population (19.14, 19.71, and 14.0 weeks, respectively). Overall, 30.3% of REACT patients remained on EVE for ≥6 months compared with 42.3% and 35.7% of patients with hyperglycemia and hypercholesterolemia, respectively. Best overall response was stable disease in 51.6% (overall) compared with 65.4% of patients with hyperglycemia and 71.4% of patients with hypercholesterolemia. Conclusions: Most patients with hyperglycemia and hypercholesterolemia remained on EVE longer than the overall REACT population, suggesting these AEs do not lead to permanent EVE treatment discontinuations. Hyperglycemia and especially hypercholesterolemia were observed in low numbers of patients, but may be associated with improved response to EVE treatment and should be further explored as putative biomarkers for mTOR inhibition.