tbuckley/cabot-search huggingface dataset:
Efficacy of darbepoetin alfa in chemotherapy-induced anemia in gastrointestinal cancers
Authors: D. Blayney, S. Vadhan-Raj, D. Tomita, G. Rossi, B. Mirtsching
Journal: Journal of Clinical Oncology (2005)

8210 Background: Chemotherapy-induced anemia (CIA) is common in colorectal (CRC) and other gastrointestinal (GI) cancer patients (pts). Darbepoetin alfa (DA) has been shown to increase hemoglobin (Hb), decrease transfusions, and reduce fatigue. NCCN evidence-based guidelines recommend a target Hb of 11–12 g/dL for efficacy and safety. We report here an efficacy analysis of DA in achieving and maintaining Hb within this target range in these pts. Methods: Two sequentially conducted, multicenter, single-arm studies using either DA 3 mcg/kg Q2W (Study 1; SOAR) or DA 200 mcg Q2W (Study 2; SURPASS) were analyzed for a subset of pts with CRC/GI cancers. Eligibility criteria were generally similar: ≥ 18 years, anemic (Hb < 11 g/dL) and receiving chemotherapy. Dose withholding rules for Study 1: Hb > 14 g/dL for women and > 15 g/dL for men; Study 2: any pt with a Hb > 13 g/dL. Hb at week 17, the % of pts achieving target Hb and mean Hb after reaching target were analyzed. These endpoints were analyzed with and without imputation of missing Hb values. Pt reported outcomes were evaluated using the change in FACT-F scale, at end of study (EOS) compared to baseline. Results: 671 pts with CRC/GI cancers were analyzed (Study 1: n = 228; Study 2: n = 443). Baseline demographics were similar. In both studies, DA Q2W was effective in increasing Hb levels to NCCN recommended target range (Hb > 11 g/dL) and improving pt reported fatigue. Dose titration rules between the studies appeared to impact the ability to maintain Hb within NCCN guidelines. In Study 2, with a lower Hb dose-withholding threshold, mean maintenance Hb was 11.8 g/dL. For Study 1, with a higher dose-withholding threshold, mean Hb was 12.2 g/dL. In Study 1, 22% of pts who achieved target Hb range maintained a mean Hb above 13 g/dL compared with only 6% of pts in Study 2. Transfusions (week 5 to week 17) were the same at 11%. Conclusions: Patients with CRC/GI cancers who develop CIA can be effectively treated with fewer injections with DA 200 mcg Q2W. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen, Genentech, Johnson & Johnson Amgen Amgen
Phase II trial of motexafin gadolinium (MGd) for treatment of metastatic renal cell carcinoma (MRCC)
Authors: A. Misellati, S. Phan, R. J. Amato
Journal: Journal of Clinical Oncology (2006)

14518 Background: MGd inhibits thioredoxin reductase. Thioredoxin is implicated in activation of hypoxia-inducible factor-1 alpha, which is overexpressed in &gt;85% of renal cell carcinomas (RCC). We evaluated anti-tumor and safety activity of MGd in patients (pts) with progressive MRCC. Methods: Eligibility included: measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤2, life expectancy ≥12 weeks, ≤2 prior therapies and no active CNS involvement. MGd was infused intravenously over 30 minutes at 5mg/kg on days 1–5 and 15–19 of each 28-day cycle. Evaluation was performed after every 3 cycles. RECIST criteria were utilized to determine response rate. Time to progression (TTP) is determined from time of study entry. Results: 25 evaluable pts were enrolled 19 male/6 female, median age 63 years (range 38–76). All pts had histologic confirmed RCC; 9 pts had clear cell carcinoma, 9 pts with predominant clear cell carcinoma component, 2 pts with papillary and 1 pt with collecting duct. 23 pts received prior systemic therapy, median 2 treatments. 16 pts had ZPS of 0, 8 pts had ZPS of 1, and 1 pt had ZPS of 2. All pts had progressive MRCC. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 6 pts had 2 and 12 pts had 3 or more. 20 pts have completed at least 12 weeks of therapy. 5 pts progressed within 3 months. 1 pt had a complete response of lung metastasis but progressed in the CNS. Median TTP is 12 weeks (3–69). Median overall survival is 10.1+ months (1–19+). Grade 1/2 toxicity consisted of: skin discoloration, fatigue, nausea, and headache. Grade 3/4 toxicity consisted of: blisters of the digits and hypophosphatemia. Conclusions: MGd was well tolerated and stabilization of disease was observed in pts with progressive disease. These results show promise for MGd in the previously treated MRCC population and potentially can be used in combination with other MRCC agents. [Table: see text]
A randomized phase II trial with gemcitabine with or without pertuzumab (rhuMAb 2C4) in platinum-resistant ovarian cancer (OC): Preliminary safety data
Authors: D. Glenn, F. Ueland, A. Bicher, D. Dizon, M. Gold, S. Makhija, G. F. Fleming, U. Matulonis, W. P. McGuire, G. Lieberman
Journal: Journal of Clinical Oncology (2006)

13001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Single agent P has demonstrated clinical benefit in advanced OC (ASCO 2005 abstract #5051). Methods: 40 pts with platinum-resistant OC (progressed within 6 months of receiving a platinum-based chemotherapy) were enrolled in this 1:1 randomized, double blind, placebo controlled trial of gemcitabine with or without P. Gemcitabine was administered IV on day 1 and 8 at 800 mg/m 2 of a 21 day cycle. Blinded placebo or 420 mg P was administered IV on day 1. Gemcitabine was dose reduced for neutropenia or thrombocytopenia. P was not dose reduced. Results: 40 pts have been enrolled and treated with at least 1 cycle of gemcitabine in combination with blinded study drug. The median age was 58.5 (range 18–82); 26 had PS ECOG 0, 13 ECOG 1, 1 ECOG 2. The most common grade 3/4 events were neutropenia in 7 pts (17.5%), thrombocytopenia in 6 pts (15%), small bowel obstruction in 4 pts (10%), constipation in 3 pts (7.5%) and elevated ALT in 3 pts (7.4%). There was one grade 3 diarrhea, but no grade 3 or 4 rash. There were 4 serious adverse events (SAEs) attributed to study drug. These were a pleural effusion, thrombocytopenia, febrile neutropenia, and a deep vein thrombosis. Nine pts required one or two dose reductions of gemcitabine for hematological toxicity. Of 29 pts with post-baseline echo or MUGA values obtained, no pt had LVEF drop to &lt;50%. The adverse events evaluated after 40 pts did not meet the prespecified criteria to call for an independent safety monitoring board evaluation of unblinded data. Conclusions: Preliminary safety data indicate that pertuzumab or placebo combined with gemcitabine is well tolerated with no unexpected additive toxicity. The nature and frequency of the adverse events are similar to what has been observed with either single agent gemcitabine or P. Updated data will be presented at ASCO. [Table: see text]
The Long-term Impact of Newly Discovered Glucose Abnormalities in Patients With Acute Myocardial Infarction
Authors: Viveca Ritsinger, Eleni Tanoglidi, Per Näsman, Klas Malmberg, Lars Rydén, Åke Tenerz, Anna Norhammar
Journal: Circulation (2013)

The Long-term Impact of Newly Discovered Glucose Abnormalities in Patients With Acute Myocardial Infarction
Barriers to treatment in patients with locally advanced breast cancer.
Authors: L. Bourdeanu, T. H. Luu, J. E. Mortimer, A. Hurria, C. T. Chung, D. D. Smith, N. Baker, S. Swain-Cabriales, S. Helton, G. Somlo
Journal: Journal of Clinical Oncology (2010)

6040 Background: Despite a decrease in breast cancer (BC) mortality, partly due to increased awareness and more effective screening, many patients (pts) still present for treatment after extended delays. We set out to identify reasons why pts encounter delays in initiating oncologic treatment, once symptoms appear. Methods: A 39-item Likert-scale questionnaire was administered to pts with stage III BC who had experienced a 3-month or greater delay in diagnosis or initiation of oncologic treatment from time of onset of symptoms. Results: Forty pts (median age 52; range: 30-78) completed the questionnaire. Of these, there were 32.5% Caucasian, 47.5% Hispanic, 12.5% Black and 7.5% Asians. Pts experienced 13 to 74 week-delay (mean = 25.78) to oncologic treatment. Barriers to treatment were divided into the following categories: patient barriers: The most commonly reported barrier among participants was “waiting for the scheduled visit to get results” (47.5%). Additional barriers included the fear of losing their breast (37.5%), the perception that breast symptoms would resolve with time (28.5%), or that the breast symptoms were due to infection, muscle strain, or related to menstrual cycle (25%). Physician barriers: 20% of the pts reported that the physician of initial contact did not believe that their breast lump/symptom was related to cancer or did not think that a biopsy was necessary (15%). System barriers: The most prevalent system barrier was the “delay in scheduling diagnostic test” (40%) and “obtaining insurance authorization for tests, treatment, or physician visits”(30%). Conclusions: We observed substantial delays between symptom presentation and diagnosis in pts who came to seek therapy at a tertiary comprehensive cancer center in Southern California. Pts and health care providers including physicians need to be educated on the importance of timely diagnostic tests and follow-up visits. We need to identify predictive factors for women at risk for encountering barriers to healthcare so that for these subpopulations, appropriate interventions can be implemented to reduce breast cancer morbidity and mortality. No significant financial relationships to disclose.
Inter-observer reliability for the diagnosis of lung cancer in a clinical cohort using the WHO classification system, version
Authors: J. E. Grilley-Olson, D. N. Hayes, R. D. Miller, M. A. Socinski, T. E. Stinchcombe, M. Hayward, B. F. Qaqish, D. T. Moore, W. K. Funkhouser
Journal: Journal of Clinical Oncology (2008)

22020 Background: Personalized medicine implies correlation of patients/tumors/diagnoses with therapies. In parallel, precise pathologic classification permits more meaningful phenotype-outcome associations. A current morphologic standard for diagnosis of lung cancer is the World Health Organization classification, version 3 (WHOC). This system is based on expert consensus; validation of the current version has not been well described. Using a lung cancer cohort, we estimate the reliability of the WHOC to be only moderately precise. Methods: We generated an incident cohort of 96 lung cancer patients treated at our institution over a 10 year period. Sample selection was based on surgical resection, frozen samples available from the same patient (to correlate with future molecular analyses), satisfactory H&E stains, primary lung tumor. Viewing was standardized by creating a single representative virtual slide for each tumor, using Aperio Scanscope. Pathologists classified tumors using the WHOC. We determined that 24 pathologists reviewing 24 slides each would allow for kappa(K)=0.7 and standard error(SE)=0.09. Results: Response to the survey was generally positive. One pathologist objected to the technology. Based on participant self-identification, 25% of participants were “expert” lung pathologists, 50% generalist, and 25% expert in another area. 1% of the digital slides were self reported as “uninterpertable.” A specific diagnosis was not made in 4% but was reached in the remaining 95%. The overall K=0.36 with SE=0.07, K= 0.33 for squamous cell carcinoma, 0.58 for adenocarcinoma, and 0.21 for large cell. Conclusions: We demonstrated fair agreement overall and in many subclassifications of the WHOC, with the best reliability in adenocarcinoma. Infrequently used categories likely contributed to the relatively poor inter-observer agreement, suggesting this schema may be difficult to implement for clinical diagnostic purposes. Use of immunohistochemicals and multiple slides may increase the K. Although this model assesses the reliability of the WHOC, not the diagnosis of lung cancer, it provides a baseline for improvements such as the addition of molecular markers. No significant financial relationships to disclose.
Comparison of doxorubicin and its non-pegylated liposomal form as radiosensitizer in high grade glioma xenografts
Authors: P. B. Chastagner, M. Labussière, S. Pinel, V. Bernier, F. Fouyssac, F. Plénat
Journal: Journal of Clinical Oncology (2005)

1542 Background: Doxorubicin (dox) has been shown to be one of the most effective agents against glioma cells in vitro but is not used in clinical practice because of its poor blood-brain barrier penetration. The latter can be improved by liposomal encapsulation. We studied the potential radiopotentiation of Myocet (myo: not pegylated liposomal doxorubicin encapsulation) versus doxorubicin on a human glioblastoma xenografted in nude mice. Methods: The U87 high grade glioma was used. 6 treatment groups were designed: control (10 mice), doxorubicin (9), Myocet (9), radiotherapy (RT 9), dox + RT (8), myo + RT (8). Dox and myo were injected IP at the dose of 2 mg/kg, 3 times a week for 2 consecutive weeks. RT consisted on 2 Gy/d, 5 days a week for 2 consecutive weeks, initiated at the same time as dox or myo. Results: Only mice treated with dox died of toxicity (dox alone: 4, dox + RT: 7). Tumor growth delay was not statistically different for dox and myo (p = .14). Radiopotentiation could not be assessed in the dox + RT group due to high mortality, while no mortality occurred in the myo + RT group. An enhancement ratio of 1.22 was observed in the myo + RT group. Conclusions: Given at the same dose as doxorubicin, Myocet is markedly less toxic than doxorubicin and appears as a radiosensitizer. An orthotopic xenograft model using Myocet + RT is under study. No significant financial relationships to disclose.
Biological and Molecular Characterization by Integrative Genomics Approach of CMA-03/06, a Newly Established Interleukin-6 Independent Variant of the CMA-03 Human Myeloma Cell Line.
Authors: Donata Verdelli, Lucia Nobili, Katia Todoerti, Laura Mosca, Sonia Fabris, Giorgio Lambertenghi Deliliers, Antonino Neri
Journal: Blood (2009)
Metabolic profiles as predictive biomarkers of erlotinib-induced adverse effects in patients with non-small cell lung cancer.
Authors: A. Hamada, J. Sasaki, S. Saeki, N. Iwamoto, M. Inaba, S. Ushijima, H. Kishi, S. Fujii, H. Semba, K. Kashiwabara, Y. Tsubata, Y. Kai, T. Isobe, H. Kohrogi, H. Saito
Journal: Journal of Clinical Oncology (2011)

2593 Background: Erlotinib is an orally available, selective inhibitor of EGFR tyrosine kinase activity used in the treatment of patients with non-small cell lung cancer (NSCLC), and skin rash is a common adverse effect. We previously reported that the adverse effects of erlotinib were correlated with its systemic exposure, but that inter-individual variability in its pharmacokinetics remained. Erlotinib is eliminated predominantly by metabolism in the liver and intestine. Unchanged erlotinib represents <2% of dose; however, it remains unknown whether these metabolites influence the development of severe toxicity, particularly >grade 3 skin rash or interstitial lung disease (ILD). Therefore, we investigated the relationship between metabolites and metabolic profiles of erlotinib, and erlotinib-induced toxicity in Japanese patients. Methods: Fifty patients received erlotinib orally at 150 mg. Metabolite profiles of plasma samples at day 1 and stable phase were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The association between toxicity grade and metabolic ratio calculated as intact erlotinib/metabolites was then evaluated. Results: Skin rash and diarrhea occurred in 46 patients (Grade 0/1/2/3 = 4/17/25/4) and 10 patients (Grade 0/1/2 = 40/5/5), respectively. Two patients developed grade 3 ILD. Fourteen metabolites in trough plasma were identified using the LC-MS/MS system; nine oxidative metabolites, four glucuronides, and one sulfate conjugate. The metabolic ratios (means±SD) of oxidative metabolites and glucuronides were 43±12 and 1753±1337, respectively. None of the oxidative metabolites or the sulfate conjugate were associated with the development of erlotinib-induced toxicity; however, the metabolic ratio of glucuronides in patients with grade 3 skin rash or ILD was 2-fold higher than that in patients tolerant of erlotinib treatment (p = 0.03). A significant difference in metabolic ratio of glucuronides at m/z of 512 and 556 was observed (p = 0.007 and 0.03). Conclusions: These results suggest that the glucuronide conjugation activity of erlotinib may be involved in the development of its severe adverse effects.
<i>KSR1</i> gene polymorphism in mCRC patients treated with first-line FOLFIRI and bevacizumab.
Authors: Marta Schirripa, Fotios Loupakis, Chiara Cremolini, Dongyun Yang, Melissa Janae Labonte, Wu Zhang, Lisa Salvatore, Takeru Wakatsuki, Rita El-Khoueiry, Carlotta Antoniotti, Giuseppe Aprile, Martin Karl Herbert Maus, Sara Lucchesi, Giacomo Allegrini, Fernando De Vita, Hua Zhang, Georgios Giamas, Justin Stebbing, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2012)

3546 Background: Kinase suppressor of Ras (KSR) 1 is a scaffolding protein regulating the Raf/Mek/ERK cascade. Preclinical data showed that KSR1 could increase estrogen receptor transcriptional activity after exposure to estrogens. Recent retrospective analyses suggested a possible role for KSR1 rs2241906 C/T polymorphism in predicting the outcome of patients with mCRC. Methods: MCRC patients receiving first-line FOLFIRI+bevacizumab prospectively enrolled in a translational research program were selected on the basis of KRAS and BRAF mutational status availability. KSR1 rs2241906 polymorphism was analyzed on DNA extracted from peripheral blood by means of PCR and direct sequencing. Taking into account the connection between estrogen pathway and KSR1, subgroup analyses according to gender were pre-planned. Results: 287 patients were included. Main patients’ characteristics were the following: M/F=175/112; median age=62 (range 26-79); ECOG-PS 0/1-2=240/47; synchronous/metachronous disease=213/74; Köhne score (low/intermediate/high/data missing)=122/129/22/14; KRAS-BRAF mutational status (wt-wt/mut-wt/wt-mut)= 123/146/18. In the overall KRAS-BRAF wt population, KSR1 polymorphism did not affect the outcome. The analysis performed according to gender showed that in the KRAS-BRAF wt population females with KSR1 rs2241906 T/- achieved a significantly better PFS (median 15.9 mos) in comparison to C/C variant carriers (median 8.8 mos) (HR=0.44 [95%CI 0.21-0.91], p=0.010); meanwhile males with T/- showed a worse PFS in comparison to those carrying the C/C variant (HR=1.92 [95%CI 1.05-3.53], p=0.021). These results were significant also in a multivariate model and a significant interaction of gender with PFS according to KSR1 allelic variants was demonstrated (p=0.004). Conclusions: This prospectively conceived pharmacogenetic study confims the role of KSR1 polymorphisms in affecting the outcome of mCRC KRAS-BRAF wt patients. In particular, these results indirectly indicate that estrogenic stimulation could affect the proliferation of KRAS-BRAF wt CRC cells through an interaction with KSR1. Preclinical investigations to further explore this preliminary hypothesis are ongoing.
Treatment with antidepressant and anti-anxiety medications after breast cancer diagnosis in a large HMO.
Authors: V. P. Quinn, C. C. Avila, J. E. Schottinger, A. H. Fisher, R. Haque
Journal: Journal of Clinical Oncology (2010)

9045 Background: 30% of the 200,000 U.S. women diagnosed each year with breast cancer (BCa) suffer significant distress at some point in their illness trajectory. Beyond medical and functional consequences of the diagnosis and treatment, women experience worry, persistent anxiety, fear and depressive disorders. The Institute of Medicine and National Cancer Institute call for treatment of common symptoms such as depression and anxiety among BCa survivors, yet there are only limited reports on the prevalence of treatment, and even fewer studies have examined potential differences by race/ethnicity, age, or tumor characteristics. Methods: We identified all women diagnosed with primary BCa between 2000-2006 who were members of Kaiser Permanente Southern California (KPSC) for 1+ years and who had not been treated for depression/anxiety in the year prior to diagnosis (n = 10,408). KPSC is a nonprofit prepaid health plan serving 3.3 million socioeconomically diverse members. Data were obtained from the KPSC SEER-affiliated cancer registry and automated clinical, pharmacy, and membership databases. We examined patient and tumor characteristics associated with new use of pharmacotherapy for depression/anxiety. Overall odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. Results: 35% of women were newly prescribed either anti-depressant or anti-anxiety medications within a year of BCa diagnosis. Younger women (e.g., OR = 1.44, CI = 1.28-1.63 for 40-49 year olds vs. 60- 69 year olds) and women with higher stage (e.g., OR = 3.40, CI = 2.87-4.04 for Stage 3 vs. Stage 0) were more likely to receive these treatments. African-American (OR = 0.81, CI = 0.72-0.92) and Asian-Pacific Islander (0.73, CI = 0.64-0.84) women were less likely to be prescribed medications compared to non- Hispanic white women. Conclusions: Pharmacotherapy utilization in this insured population is consistent with national reports of the prevalence of psychosocial distress experienced after BCa diagnosis. Future research needs to examine the number of BCa survivors screened and diagnosed with depression/anxiety. Potential age and race/ethnicity disparities are of concern and need further study. No significant financial relationships to disclose.