tbuckley/cabot-search huggingface dataset:
Survival of patients with locally advanced breast cancer treated with modified radical mastectomy followed by adjuvant therapies.
Authors: A. Shaharyar, M. Hafeez, E. Ur Rahman, A. W. Goraya
Journal: Journal of Clinical Oncology (2011)

e11510 Background: Breast cancer is the most common cancer amongst the females of Pakistan. Median age at diagnosis is 47 years. Most patients present in stage III. Majority are treated without neo adjuvant chemotherapy. These patients undergo modified radical mastectomy in surgical institutes where they mostly present and are subsequently treated with PMRT and adjuvant chemo-hormone therapies at cancer treatment facilities. Very few receive therapy direct against Her 2 neu over expression. Here, we report survival of stage III patients treated with surgery followed by adjuvant therapies but without neo adjuvant chemotherapy. Methods: Medical records of patients treated during 2004-2006 were obtained from the department Clinical Oncology Mayo Hospital Lahore. Date of diagnosis and stage was confirmed. Treatment sequence was verified and date of last visit was noted. Patients were contacted on telephone and their follow up was completed up to the end of 2008. The total of 480 patients was studied. Kaplan Meier product limit method was applied for survival analysis. SPSS version 11.5 was used for statistical analysis. Results: A total of 1250 patients of breast cancer were treated during this period. 471 patients were stage IIIA and IIIB and 60 patients were stage IIIC. Most common presentation was stage IIIA with T2N2, T3N1 disease followed by T4b N1 and T4b N2 disease. Majority of the patients were below 50 years of age. FAC, AC or TAC were the commonly used chemotherapies. PMRT was delivered to chest wall and supra-clavicular region. Tamoxifen was prescribed to pre-menopausal and letrazole to post menopausal hormone receptor positive patients.197 deaths were recorded and 274 patients were censored. At a follow up of 5 years median survival was 42 months. Conclusions: Survival of locally advance breast cancer patients treated with primary surgery followed by adjuvant therapies is not very encouraging.
Efficacy of Retreatment with Immunomodulatory Compounds In Patients Receiving Initial Therapy for Newly Diagnosed Multiple Myeloma
Authors: Sumit Madan, Martha Lacy, Angela Dispenzieri, Morie Gertz, Francis Buadi, Suzanne R. Hayman, Kristen Detweiler-Short, David Dingli, Steven Zeldenrust, John Lust, Philip R. Greipp, S. Vincent Rajkumar, Shaji Kumar
Journal: Blood (2010)
Serum adiponectin and overall survival in a prospective cohort of patients with hepatocellular carcinoma.
Authors: Abby B. Siegel, Abhishek Goyal, Rosa Denisse Hidalgo, Shuang Wang, Alfred I. Neugut, Robert S Brown, Jean Emond, Tomoaki Kato, Benjamin Samstein, Lorna Dove, Regina Santella
Journal: Journal of Clinical Oncology (2012)

205 Background: Hepatocellular carcinoma (HCC) is one of the most rapidly increasing causes of cancer death in the United States. Adiponectin, a regulator of glucose metabolism, is reduced in those with diabetes and obesity. Serum adiponectin levels have been shown to correlate with prognosis in several types of cancers, but have not been well studied in patients with HCC. Methods: We have an ongoing prospective study evaluating fasting adipokines and clinicopathological features in patients with newly-diagnosed HCC. We excluded patients who had any previous malignancy, and those with uncompensated Child Pugh (CP) B or C disease. We evaluated common non-pathological prognostic variables in uni- and multivariable models as predictors of all-cause mortality. Results: Of our first 82 patients, median age was 60, 82% were men and 63% had underlying hepatitis C. 65% had a Body Mass Index (BMI)&gt;25, and 33% had diabetes. We found that CP class, AJCC stage, adiponectin and IGF-1 levels were all significantly associated with survival, while age, AFP, etiology of liver disease, leptin and insulin levels were not in univariable analyses. We then created a Cox model which included age, CP class, AJCC stage, AFP&gt;400 ng/mL, serum adiponectin, and IGF-1, and found that stage, adiponectin, and IGF-1 levels were all independently predictive of overall survival. Increased AJCC stage had the highest HR for death (3.9), while increased adiponectin levels (&gt;12,000 ng/mL) led to a 3-fold increased risk of death. IGF-1 was protective, with higher levels (&gt;40 ng/mL) leading to about a 3-fold decreased risk of death. Conclusions: Novel predictive and prognostic biomarkers in patients with HCC are badly needed. We found serum adiponectin to be a robust predictor of all-cause mortality in a diverse prospective cohort of HCC patients in uni-and multivariable analyses. Adiponectin deserves further study as a simple and practical biomarker to assess outcomes in patients with HCC.
The effect of crenolanib (CP-868596) on phosphorylation of the imatinib-resistant D842V PDGFRA activating mutation associated with advanced gastrointestinal stromal tumors.
Authors: M. C. Heinrich, D. Griffith, A. McKinley, A. Presnell, A. Ramachandran
Journal: Journal of Clinical Oncology (2011)

10012 Background: 8-10% of gastrointestinal stromal tumors (GIST) have activating mutations of the platelet-derived growth factor receptor alpha (PDGFRA) gene. The most common PDGFRA mutation is the D842V mutation encoded by exon 18. This gain-of-function mutation results in constitutive tyrosine kinase activity. Currently approved tyrosine kinase inhibitors (TKIs), such as imatinib (IM) or sunitinib, have little to no in vitro activity against this mutation. Clinically, these drugs are ineffective for the treatment of patients whose GIST has a D842V mutation. In addition, the D842V mutation can develop as a secondary IM resistance mutation during treatment of patients with primary IM-sensitive GIST or hypereosinophillic syndrome. Crenolanib (formerly CP-868596) is an orally bioavailable, highly potent and selective PDGFR TKI. Phase I trials of crenolanib (CR) have shown a favorable toxicity profile, and achievable serum concentrations as high as 2,000 nM. Methods: Mutant PDGFRα isoforms were expressed by transient transfection of Chinese hamster ovary cells. The transfected cells were treated with various concentrations of CR or IM. Protein lysates were immunoprecipitated with an anti-PDGFRA antibody, followed by sequential immunoblotting for activated- and total-PDGFRA. IC50 (50% inhibitory concentration) was measured by densitometry of the phosphoPDGFRA bands and normalization using total PDGFRA expression. Results: CR was effective in blocking the activity of single or compound PDGFRA D842V mutant kinases. In contrast, IM had no significant activity against these same mutant kinases. Conclusions: GISTs with PDGFRA D842V mutations are clinically resistant to currently approved TKIs. CR blocks the kinase activity of PDGFRA D842V mutants (single and compound) at clinically achievable concentrations, providing a potential new therapeutic modality for GIST patients. A phase II clinical study of CR for treatment of GIST patients with primary or secondary PDGFRA D842V mutation is currently being initiated. Mutation CR IC50(nM) IM IC50(nM) PDGFRA WT 13 30 PDGFRA D842V 20 >1,000 PDGFRA V561D + D842V 35 >1,000 PDGFRA T674I + D842V 26 >1,000
Percentage of positive biopsy cores to predict distant metastasis of prostate cancer after definitive radiation therapy.
Authors: J. Huang, L. L. Kestin, F. A. Vicini, S. G. Williams, H. Ye, S. D. McGrath, M. Ghilezan, A. Martinez
Journal: Journal of Clinical Oncology (2011)

80 Background: To assess the prognostic value of percentage of positive biopsy cores (PPC) and perineural invasion (PNI) in predicting clinical outcome following radiotherapy (RT) for prostate cancer. Methods: One thousand and fifty-six patients with clinical stage T1-T3 N0 M0 prostate cancer, who had ≥ 4 biopsy cores sampled and complete biopsy core data available, were treated with either adaptive image-guided RT (median 75.6 Gy, n=387), low-dose EBRT (median 66.6 Gy, n=393), or EBRT and high-dose rate brachytherapy boost (n=276) at William Beaumont Hospital (1993-2004). Neoadjuvant and/or adjuvant androgen deprivation (AD) were given to 253 patients (24%). Multivariate cox regression analysis included PPC, gleason score, PSA, T stage, PNI, RT dose, androgen deprivation, and age. Biochemical failure (BF) was scored according to the Phoenix definition. Clinical failure (CF) was defined as any locoregional recurrence (LRR) or distant metastasis (DM). Median follow-up was 7.6 years. Results: Median cores sampled was 7, median PPC was 33%, and 18% had PNI. On univariate Cox regression, both PPC and PNI were predicators of biochemical failure and clinical failure (all P&lt;0.05). On multivariate Cox regression, PPC, either as continuous or categorical variable, remained an independent predicator of BF, CF, DM, cause-specific survival, and overall survival (all P&lt;0.05). PPC of &gt;50% was associated with significantly higher DM (HR 4.01, 95% CI 1.86-8.61), and its independent predicative value remained significant whether AD was given or not (all P&lt;0.05). Combining ≤50% vs ≥50% PPC with NCCN risk group stratification demonstrated added prognostic value of DM for intermediate-risk (HR 5.44, 95% CI 1.78-16.6) and high-risk groups (HR 4.39, 95% CI 1.70-2.84), with or without AD (all P&lt;0.05). On multivariate Cox regression, PNI was an independent predicator of LRR only (HR 2.51, 95% CI 1.18-5.33). Conclusions: PPC is an independent and powerful predicator of DM for intermediate- and high-risk prostate cancer, regardless the use of AD. It should be considered for risk stratification and when designing for future trials testing adjuvant treatment after definitive RT for prostate cancer. No significant financial relationships to disclose.
How to Improve Microbacterial Documentation in Febrile Neutropenia: Impact of Reduced Time Between Collection and Incubation, and New Technics of Identification.
Authors: Cecile Pautas, Yosr Hicheri, Celine Corbel, Sylvie Bastuji-Garin, Stephane Bretagne, Laetitia Gregoire, Emilie Sbidian, Sebastien Maury, Catherine Cordonnier, Emmanuelle Cambeau
Journal: Blood (2009)
Gemcitabine, paclitaxel, and doxorubicin for patients (pts) with urothelial carcinoma (UC) and renal insufficiency: Preliminary results of a multicenter phase II study.
Authors: L. C. Pagliaro, M. Munsell, D. Harris, R. L. Carolla, A. O. Siefker-Radtke
Journal: Journal of Clinical Oncology (2011)

246 Background: The role of cisplatin-based chemotherapy for the treatment of locally advanced or metastatic UC is well established. Pts with impaired renal function cannot receive cisplatin, however, and substitution with carboplatin yielded inferior results. We initiated a phase II study to assess the efficacy of gemcitabine, paclitaxel, and doxorubicin (GTA) treatment for UC in pts with renal insufficiency. Methods: Eligible pts had metastatic or unresectable UC of bladder, urethra, or upper tract, no prior chemotherapy, glomerular filtration rate &lt; 60 ml/min, ECOG performance status ≤ 2, left ventricular ejection fraction &gt; 40%, and adequate hematopoietic and hepatic function. Pts were excluded if they had brain metastasis, peripheral neuropathy ≥ grade 2, significant heart disease within 6 months of enrollment, or required hemodialysis. Outpatient treatment consisted of 900 mg/m 2 gemcitabine, 135 mg/m 2 paclitaxel, and 40 mg/m 2 doxorubicin on day 1 every 2 weeks. Pegfilgrastim 6 mg sc was given immediately after GTA on day 1, or on day 2 if requested by the pt. Tumor evaluation was repeated every 3 cycles (6 weeks); treatment duration was limited to 9 cycles. A Simon 2-stage design was chosen to detect a target overall response rate of 40% and to reject a response rate of 25% or less. Results: Twenty-five pts enrolled and 21 could be assessed for response. Median (range) age was 72.8 years (53.4, 89.3) and 8 pts (32.0%) were female. RECIST responses occurred in 12 pts (4 complete; 8 partial), for an overall response rate of 57.1% (95% CI 34.0-78.2). Notable grade 3 and 4 toxicities were anemia (9 pts), thrombocytopenia (3 pts), neutropenia (2 pts), dyspnea (1 pt), mucositis (1 pt), and sepsis (1 pt). No adverse events were attributed to same-day pegfilgrastim and there were no treatment-related deaths. Eleven pts (44.0%) died of progressive disease; the median (range) follow-up time for 14 surviving pts was 5.5 months (2.3, 17.5). Conclusions: GTA has been well-tolerated in the setting of renal insufficiency, with an observed response rate in advanced UC exceeding the targeted response. The study will continue to a maximum of 72 pts. [Table: see text]
Utilizing BRCA1/2 mutation status to select patients for breast cancer clinical trials: Experience from a prospective phase II trial.
Authors: E. A. Schackmann, S. Vinayak, A. W. Kurian, J. M. Ford, M. L. Telli
Journal: Journal of Clinical Oncology (2011)

161 Background: Information from BRCA1/2 mutation testing is used to guide cancer screening and risk reduction strategies. More recently, BRCA1/2 mutation status is being used to select patients for breast cancer (BC) clinical trials employing new targeted therapies, such as PARP inhibitors. There is concern that current testing practices do not produce results within the timeframe necessary for clinical trial eligibility assessment. Methods: We analyzed BRCA1/2 mutation testing patterns in the context of a prospective phase II neoadjuvant study of gemcitabine, carboplatin and BSI-201 (iniparib) for women with Stage I-IIIA triple-negative or BRCA1/2 mutation-associated BC. Specifically, we analyzed: 1) the proportion of participants who met BRCA1/2 mutation testing criteria per NCCN Guidelines v1.2011 and 2) the proportion who had the Myriad Genetics Single Site, Multisite 3 (Ashkenazi Panel), BRACAnalysis and Comprehensive Rearrangement tests performed and their results. For patients without a known BRCA1/2 mutation prior to BC diagnosis who met testing criteria, we assessed the length of time from BC diagnosis to receipt of test results. Results: Sixty-four patients between the ages of 26 and 73 were enrolled. Results are summarized below. For patients who had BRCA1/2 testing after BC diagnosis, the median number of days from BC diagnosis to receipt of results was 42. Conclusions: The frequency of BRCA1/2 mutations in this cohort is high (20%), though nearly half of these mutations were found after patients provided trial consent. Current standard processes for testing women with newly diagnosed BC for BRCA1/2 mutations do not occur expeditiously enough for many to guide clinical trial selection. [Table: see text]
Correlation between imatinib trough levels and clinical benefit in gastrointestinal stromal tumors (GIST): Results of a prospective population pharmacokinetic study.
Authors: K. Eechoute, M. N. Fransson, U. De Giorgi, A. K. L. Reyners, F. A. de Jong, L. E. Friberg, W. T. Van Der Graaf, A. Sparreboom, J. Verweij, W. J. Loos, R. Mathijssen
Journal: Journal of Clinical Oncology (2011)

10014 Background: Imatinib is mainly metabolized in the liver. We therefore studied the potential effects of metastatic liver involvement on exposure to imatinib in patients with GIST. Additionally, as clearance from a retrospective analysis has been suggested to decrease over time (Judson et al., Cancer Chemother Pharmacol, 2005), while 1 month steady state imatinib trough levels were suggested to be associated with clinical benefit (Demetri et al., J Clin Oncol, 2009), the secondary endpoint of our study was to assess the exposure to imatinib after multiple long-term time-points. Methods: Multicenter prospective population pharmacokinetic study in 50 GIST patients treated with imatinib. Systemic exposure to imatinib was assessed through 24-hour pharmacokinetic sampling on day 1, month 1, 6 and 12. Patients were categorized in 4 groups based on their proportional metastatic liver volumes on CT images which were assessed on day 1, month 6 and 12 of therapy using OsiriX Imaging Software (OsiriX Foundation, Geneva, Switzerland). Possible mean exposure differences between groups and over time were analyzed with one-way ANOVA and unpaired t-tests. Results: Mean imatinib trough levels and exposure showed no significant correlation with hepatic metastatic liver volumes. However, imatinib steady state trough levels and exposure at 6 months were significantly lower as compared to after 1 month, irrespective of metastatic liver involvement (1,204 ± 680 vs. 973 ± 573 ng/mL, P= .001 and 49.1 ± 23.4 vs. 39.3 ± 20.8 µg*h/mL, P=.008, respectively). Hence, trough levels at 6 months in our population dropped below the previously suggested clinically relevant threshold level of 1,100 ng/mL. Conclusions: This is the first prospective pharmacokinetic study in GIST, demonstrating a significant decrease of ~20% in imatinib exposure after long-term treatment. This means that trough level-clinical benefit analyses should be time-point specific. Liver involvement does not affect imatinib exposure.
Palliative radiotherapy for prostate cancer: Outcomes of a weekly schedule of 6 fractions of 5 or 6Gy.
Authors: Shaun P. Tolan, Peter Mbanu, Richard C. Walshaw, Peter Robson, Chinnamani Eswarvee, Azman Ibrahim, Zafar Malik, John Littler, Isabel Syndikus
Journal: Journal of Clinical Oncology (2012)

160 Background: In the current era of PSA screening and advances in image guided intensity modulated radiotherapy, not all patients with carcinoma of the prostate (CaP) are suitable for radical radiotherapy (RT). Some patients have locally advanced disease and are unfit for radical RT or have significant local symptoms with coexisting metastatic disease. The outcomes of a weekly palliative RT schedule of 6 x 5 or 6Gy fractions are reported. Methods: This retrospective analysis identified 80 patients with CaP who received palliative prostate RT between 2003 and 2007. 62 patients received six, weekly fractions of 3D conformal RT and are included in this study. Clinico-pathological data of the cases are presented along with the clinical outcomes and survival data. Median follow up was 16.5 months. Results: 62 patients (median age 70 yrs), received 30Gy (87%) or 36Gy (10%) in 6 fractions over 6 weeks. Two patients received 27Gy. Gleason score at diagnosis was ≤6, 7, or 8–10 in 21%, 16% and 45% of cases respectively and was associated with a median PSA of 53ng/ml, and T3/4 stage in 59%. The median time from diagnosis to RT was 15.9 months and prior to RT, treatment included hormone therapy (100%), TURP (60%) and chemotherapy (13%). Disease was metastatic in 68% and castrate resistant in 77% of cases. ECOG performance status was 0–1 in 44% and 2–3 in 24%. No patients with PS 4 were treated over 6 weeks. Indications for RT were obstructive urinary symptoms (69%), pain (44%), haematuria (35%), obstructive bowel symptoms (23%), and rectal bleeding (2%). At 3–6 months post-RT the frequency of these symptoms was 27%, 13%, 4%, 17% and 2% respectively. RTOG grade 3 or 4 bladder toxicity was 18% and grade 3 or 4 bowel toxicity was 6%. Median overall survival after RT was 16.0 months and on multivariate analysis lower pre-RT PSA and prior use of chemotherapy were predictive of improved survival. Conclusions: A weekly fractionation schedule of 5 or 6Gy over 6 weeks provides effective palliation, particularly for the symptoms of urinary obstruction, pain and haematuria, and is associated with acceptable toxicity. The prognosis of this group of patients remains poor, but can be improved by the use of chemotherapy if clinically appropriate.
Coagulation Factor Concentrates Restore Alterations in Hemostasis Induced by a High Dose of Apixaban: Studies in Vitro with Circulating Human Blood.
Authors: Gines Escolar, Eduardo Arellano-Rodrigo, Joan Carles Reverter, Jaume Villalta, Victoria Veronica Sanz, Patricia Molina, Maribel Diaz-Ricart, Ana M Galan
Journal: Blood (2012)
Neoadjuvant gemcitabine plus carboplatin followed by immediate radical cystectomy in patients with muscle-invasive bladder cancer: A propensity score analysis.
Authors: Takuya Koie, Teppei Okamoto, Yuichiro Suzuki, Yuki Tobisawa, Tohru Yoneyama, Kazuyuki Mori, Hayato Yamamoto, Shingo Hatakeyama, Takahiro Yoneyama, Noritaka Kamimura, Chikara Ohyama
Journal: Journal of Clinical Oncology (2012)

276 Background: Standard neoadjuvant chemotherapy has not yet been established for patients with muscle-invasive bladder cancer. Our pervious phase II trial demonstrated the efficacy and safety of neoadjuvant gemcitabine plus carboplatin (GCarb) chemotherapy followed by immediate radical cystectomy (RC) in patients with muscle-invasive bladder cancer. In the present study, we conducted a propensity score analysis to elucidate clinical significance of the present treatment protocol. Methods: The cohort of neoadjuvant group consists of 120 patients with muscle-invasive bladder cancer. They received 2 courses of GCarb therapy consisting of 800 mg/m 2 gemcitabine on days 1, 8, and 15 and carboplatin with an AUC of 4 on day 2 between March 2005 and June 2011. After the chemotherapy, RC and bilateral pelvic lymph node dissection (PLND) were performed within an interval of 1 month. The cohort of surgery alone group includes 155 patients with muscle-invasive bladder cancer treated with RC and bilateral PLND between May 1994 and December 2004. Propensity score matching was used to adjust for potential selection biases associated with treatment type. The endpoints were overall (OS) and disease-free survival (DFS). Results: Of the 120 patients who received GCarb and RC, 28 (23.3%) RC specimens showed pT0. Grade 3/4 neutropenia occurred in 40 patients (33.9%) and thrombocytopenia in 23 patients (19.8%). Propensity score-matched analysis indicated 112 matched pairs from both groups. The 5-year OS rate was 91.5% for neoadjuvant GCarb versus 51.3% for surgery alone group (P &lt; 0.0001). The DFS rate was 83.8% for neoadjuvant GCarb versus 53.1% for surgery alone (P &lt; 0.0001). Multivariate analysis revealed that the neoadjuvant GCarb regimen was an extremely strong predictor of the improvement in OS and DFS. Conclusions: Although the present study is not randomized, neoadjuvant gemcitabine plus carboplatin therapy followed by immediate RC achieved significantly longer OS and DFS comparing to surgery alone. The clinical usefulness of the present treatment for the patient with muscle-invasive bladder cancer should be verified by further trials.