tbuckley/cabot-search huggingface dataset:
Molecular subtypes, body mass index (BMI), and their time-varying prognostic impact in node-positive breast cancer (BC): Pooled analysis from the WSG AM-01 and -02 trials.
Authors: O. Gluz, C. Liedtke, R. E. Kates, J. B. Huober, S. Mohrmann, A. Hartmann, C. Thomssen, V. Moebus, U. Nitz, N. Harbeck
Journal: Journal of Clinical Oncology (2011)

1021 Background: Obesity has been reported to be associated with aggressive tumor characteristics and poor prognosis in early BC in mostly unselected collectives. This study was performed to investigate the prognostic impact of obesity taking into account molecular subtypes in randomized node-positive BC cohort treated by chemotherapy (Cht). Methods: Pooled analysis in 2353 patients was done using data from the WSG-AM-01 (high risk BC with >9 positive lymph nodes (LN), treated by either tandem high dose or dose-dense Cht) and AM-02 trials (intermediate risk BC with 1−3 positive LN treated by CEF/CMF or EC-Doc). Data on hormone receptors (HR) and HER2 were available in 2045 pts, molecular subtypes (luminal A vs. B (by Ki-67 or HER2), basal/non-basal triple negative (TN) BC and HER2) by central pathology review in 865 pts. Time-varying Cox proportional hazards regression models were used to assess the prognostic impact of BMI after adjusting for other factors. Results: Median follow up was 59 months. BMI was available in 2302 pts (median BMI 24.9 kg/m2). 133 pts were found to be severely obese (BMI>35 kg/m2). Higher BMI was moderately associated with increasing age and larger tumor size. Interestingly, there was a significant association between higher BMI and TNBC as well higher Ki-67 levels, yet only in younger (<50 years) pts. No further association between molecular subtypes and BMI in both age subgroups could be observed. Only severe (>35 kg/m2) obesity was predictive for relapse risk by univariate analysis (HR=1.5; p=0.02). However if multivariate analysis was performed (including LN, age, grade, HR, HER2, TNBC, obesity and time-varying interaction between obesity and late relapse (>5 years), severe obesity was highly predictive only for late (HR=3,638, p<0.000) relapse. Conclusions: In this pooled analysis of two randomized chemotherapy trials, higher BMI was associated with TNBC only in younger patients. By time-varying multivariate analysis, only severe obesity was predictive for late relapse and next to counselling on life style changes, this factor may be suitable as a possible marker for patient selection regarding extended adjuvant therapy.
Health plan budget impact of introducing everolimus for treatment of advanced progressive pancreatic neuroendocrine tumors in the United States.
Authors: Roman Casciano, Maruit Chulikavit, Michelle Sriprasert, Zhimei Liu, Xufang Wang, Louis P Garrison
Journal: Journal of Clinical Oncology (2012)

229 Background: Everolimus was recently approved for treatment of patients with advanced progressive pancreatic neuroendocrine tumors (pNET) based on a clinically meaningful and statistically significant increase in progression-free survival. To understand the financial impact of introducing everolimus into the market, a model was developed to simulate a typical health plan in the United States (US). Methods: A cross-sectional budget impact model with a one-year time horizon was developed. Disease prevalence and drug usage data were derived from a real-world data source. Costs for anti-tumor therapy and underlying care included concomitant medications, physician visits, treatment infusion, surgical procedures, tests, hospitalizations, and adverse event (AE) management. Resource utilization rates were derived from a physician survey-based resource utilization study; treatment-related AE rates were taken from secondary literature. Drug costs were Wholesale Acquisition Costs (2011). Medical procedure and hospitalization costs were based on Medicare fee schedules for current procedure terminology and diagnosis-related group codes. AE costs were obtained from the literature. The model assessed the initial annual budget impact, under the assumption that everolimus and sunitinib, another recently approved targeted therapy, replace most currently available chemotherapy treatments. Results: Based on published prevalence rates, for a health plan with 1,000,000 members, an annual count of 12 advanced pNET patients was projected. The model estimated a $22,657 budget increase ($0.0019 per member per month or $0.0227 per member per year [PMPY]). The largest percent increase in budget was associated with anti-tumor treatments; infusions and surgical procedures represented the largest percent decrease in costs. Scenario analyses indicated that increasing the percentage of everolimus use (by reducing that of sunitinib) resulted in a decrease in the overall budget compared to baseline. Conclusions: Our model predicts that treating pNET patients with everolimus will have a minimal budget impact on US health plans, amounting to about $0.027 PMPY.
Idarubicin, Cytarabine and Pravastatin As Induction Therapy for Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome
Authors: Mazyar Shadman, Raya Mawad, Carol Dean, Kathleen Shannon-Dorcy, Vicky Sandhu, Paul C. Hendrie, Bart L. Scott, Roland B. Walter, Pamela S. Becker, John Pagel, Elihu H. Estey
Journal: Blood (2014)
Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and six months of combined androgen blockade.
Authors: N. E. Martin, M. Chen, P. L. Nguyen, C. Beard, P. W. Kantoff, A. V. D'Amico
Journal: Journal of Clinical Oncology (2011)

191 Background: An increased duration of testosterone (T) suppression (TS) after 6 months (mo) of combined hormonal blockade (CHB) with an LHRH agonist and an anti-androgen plus external beam radiation therapy (RT) is associated with decreased mortality. We investigated whether the biopsy Gleason score (BGS) was associated with duration of TS. Methods: The study cohort consisted of 120 men with node negative prostate cancer (PCa) treated with RT and 6 mo of CHB between 1996 and 2005 at a single academic and associated suburban center. We defined the duration of TS as the time between the last day of CHB and the date the T returned to ≥252 ng/dL (10% below the lower limit of normal on the assay used). We used Cox regression multivariable analysis to determine whether BGS was significantly associated with the duration of TS following cessation of CHB adjusting for age, PSA, baseline T, clinical tumor category, body mass index and a history of diabetes mellitus. Results: The median age of the cohort was 70.1 years (IQR: 64.7, 73.9). The median time to T rebound (MTR) was 19.5 mo for all men (table). BGS 8-10 had an adjusted hazard ratio (AHR) of 1.85 (95% confidence interval [CI] 1.06-3.22; p=0.03) indicating a faster time to T rebound. Specifically men with BGS 8-10 had a MTR of 14.0 mo compared to 19.5 and 22.4 mo for the Gleason ≤6 and 7 respectively. Increasing age was significantly associated with a longer duration of TS [AHR of 0.95 (95% CI 0.92-0.98; p&lt;0.001)]. Conclusions: A BGS of 8-10 is associated with a shorter period of TS following 6 mo of CHB + RT. These data are consistent with the hypothesis that a factor released from high grade PCa cells may impact T production. [Table: see text] No significant financial relationships to disclose.
Neoadjuvant trial of sunitinib malate and androgen ablation (ADT) in patients with localized prostate cancer (PCa) at high risk for recurrence.
Authors: A. J. Zurita, J. F. Ward, J. C. Araujo, C. A. Pettaway, P. Dieringer, X. Wang, P. Troncoso, C. Logothetis
Journal: Journal of Clinical Oncology (2011)

143 Background: Presurgical ADT does not improve long-term outcomes in patients (pts) with high-risk localized PCa. Since the VEGF and PDGF signaling pathways have been implicated in PCa progression, and ADT results in endothelial cell apoptosis in the prostate by a VEGF-mediated mechanism, we hypothesized that combined treatment with sunitinib malate (SU), an oral inhibitor of the tyrosine kinases of VEGFR and PDGFR, might improve the efficacy of ADT in this pt population. Methods: Pts with no radiological evidence of metastases and either PCa ≥ clinical (c)T3 disease or Gleason grade 8-10 or serum prostate-specific antigen (PSA) ≥ 20 ng/mL or cT2b-c and Gleason 7 and PSA ≥10 ng/mL (AJCC, 1992), received i.m. leuprolide and oral SU for three 30-day cycles followed by surgery. SU was administered continuously at 37.5 mg daily (25 mg daily in the initial 6 pts). The primary endpoint of this phase II trial was rate of pathologic complete response (pCR). Secondary endpoints included safety and time to progression (TTP). Unresectable pelvic nodal disease, confirmed post-operative PSA ≥ 0.2 ng/mL, or administration of post-operative radiation or ADT, defined treatment failure. Results: Forty-four pts completed accrual, with a median age of 58 years (range 47-72); 34 Caucasian, 5 African-American, 4 Hispanic, and 1 Indian. High-risk criteria included cT3 (24/44), Gleason 8-10 (30/44), PSA ≥ 20 ng/mL (16/44). Two men were ineligible/declined therapy and one postponed surgery. No grade 4 toxicities or related discontinuations were observed. Thirty-five pts completed 3 months on 37.5 mg daily SU plus ADT and surgery with no unexpected complications. Of these, 2 pts experienced a pCR. Twenty (57%) pts have failed treatment or died, with a median TTP 27 months (95% CI: 12 – not estimable). The median follow-up of the remaining event-free pts is 35 months (range 23-41). Conclusions: The 3-months preoperative combination of SU and ADT is safe and well tolerated in pts with high-risk primary PCa. We observed 2 complete remissions in 35 patients. Ongoing characterization of molecular changes in the epithelial and stromal compartments will help understand the mechanisms of SU activity in PCa. [Table: see text]
Correlation between circulating tumor biomarkers and positron-emission tomography in advanced non-small cell lung cancer
Authors: F. Biello, E. Rijavec, C. Genova, G. Barletta, C. Maggioni, M.G. Dal Bello, A. Alama, S. Coco, A. Truini, I. Vanni, S. Morbelli, G. Ferrarazzo, F. Bongioanni, M. Massollo, G. Sambuceti, F. Grossi
Journal: Annals of Oncology (2015)
Pretreatment serum biomarkers and clinical outcome in the phase II trial of zibotentan (endothelin A receptor antagonist) in metastatic CRPC.
Authors: Julia Shelkey, Ajit Bisen, Kim Leitzel, Suhail M. Ali, Walter P. Carney, Allan Lipton
Journal: Journal of Clinical Oncology (2012)

154 Background: Three angiogenesis-related serum biomarkers [TIMP-1 (tissue inhibitor of metalloproteinase-1), CA IX (carbonic anhydrase 9), and VEGF] and PSA were correlated with outcome in the phase II zibotentan [endothelin A (ET A ) receptor inhibitor] trial in metastatic CRPC. Methods: Pretreatment serum samples were available from 206 of 312 patients enrolled in the multicenter phase II trial evaluating zibotentan in patients with metastatic CRPC and bone metastases who were pain free or mildly symptomatic for pain, with a 1:1:1 randomization to zibotentan 10mg, 15mg, or placebo. The CA IX, TIMP-1, and VEGF ELISAs were from WILEX Inc./Oncogene Science, Cambridge, MA. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling. Results: In the final efficacy report, there were no statistical differences in PFS, but a trend for OS improvement was observed in the zibotentan arms compared with placebo: 15 mg (HR 0.76; 80% CI 0.61–0.94; p= 0.103) and 10 mg (HR 0.83; 80% CI 0.67–1.02; p= 0.254) (James et al, BJUI 106L966-973, 2010). In the retrospective serum biomarker analysis (206 patients), there were no apparent differences for PFS with any of the 3 novel biomarkers in the whole population, or within treatment arms. For OS in the whole population, patients with higher serum TIMP (&gt; median) had reduced OS (17.5 mos), compared with patients who had lower serum TIMP-1 (&lt; median) (28.4 mos). Within treatment arms, patients with higher serum CA IX (&gt; median) treated with zibotentan had increased OS in both the 10 mg arm (median 28.4 mos), and the 15 mg arm (median 25.7 mos) compared with those in the placebo arm (median 15.4 mos). In a Cox model, including serum biomarkers and bisphosphonate use, for PFS only PSA was significant (p&lt; 0.0001); for OS only PSA (p&lt; 0.0001) and TIMP-1 (p&lt; 0.002) were significant. Conclusions: Higher pretreatment serum CA IX (a marker of hypoxia) may identify a cohort of metastatic CRPC patients more sensitive to zibotentan treatment, and higher serum TIMP-1 may identify patients at risk for reduced overall survival. These serum biomarkers deserve further study in larger ET A receptor inhibitor trials.
Prospective phase II trial with intra-operative radiotherapy in initial breast cancer using nondedicated linear accelerator.
Authors: S. A. Hanna, E. Martella, H. d. A. Carvalho, J. L. F. da Silva, A. C. S. D. de Barros
Journal: Journal of Clinical Oncology (2011)

e11560 Background: To report single-institution series of breast intra-operative radiotherapy (IORT) using nondedicated linear accelerator. Methods: Prospective phaseII trial opened in May 2004. Eligibility criteria: single-focal breast infiltrating ductal carcinoma, age >40 years, size <3cm (after February 2009 >50 years and <2cm) and cN0. Exclusion criteria: carcinoma in situ or lobular types, impossibility of breast-conserving surgery, metastasis or another cancer. Patients underwent classic quadrantectomy with intraoperative margins and SLN evaluation. If both negative, IORT was prescribed (21Gy). Adjuvant treatment considered after definitive pathology report. Endpoints: oncologic, toxicity, aesthetics, and technical issues. Results: From May/2004 to May/2010, 161 patients were enrolled (intention-to-treat analysis) and 34 were excluded. Thus, 127 patients were analyzed. Oncologic analysis involved patients with follow-up ≥24 months (n=83) or breast events. Median age was 56 (40-86) years and median follow-up was 43 (24-72) months. The table summarizes all findings. Conclusions: Single-dose breast IORT presents early oncologic, toxicity, and aesthetic results similar to previously reported trials. Nondedicated facilities have advantages: lower costs; allow higher electron energies; and portal film imaging before treatments. Long-term results will be necessary to strength this data. Summarized results. Parameter Value (%) cT (x, 1, 2) 62.9, 29.9, 7 pT (1,2) 85.8, 14.1 pN (0,1) 86.7, 13.3 Menopausal status (post, pre) 74.5, 25.5 Hormonal receptors (E, P) 84.3, 76 Grade (I, II, III) 33, 24.5, 62.5 Chemotherapy, hormones 15.7, 66.6 3-year survival Overall 97.6 Cause-specific 98.4 Disease-free 96 Recurrences (cumulative) Local 2.4 Loco-regional 1.2 Distant 2.4 Toxicities < 1 month (n) Redness (5), seroma (3),dehiscence (2) ≥ 1 month (n) Fat necrosis (10), fibrosis (20),lymphedema (2), and papillaretraction (3) One-year aesthetic evaluation (RTOG/NSABP score)(excellent, good, regular, bad) 91.7, 4.5, 1.8, 0.9 Electron energies (6, 9, 12, 15, 18 MeV) 7.8, 51.5, 35.1, 3.9, 0.7 Shield repositioning (no, yes) 70.3, 29.7 In-hospital infections None
Reduced-Intensity Conditioning Including Fludarabine, Cyclophosphamide, Low Dose Total Body Irradiation and Anti-Thymocyte Globulin Providing Tolerable Toxicity and Patient-Adapted Treatment.
Authors: L. Mueller, M. Christopeit, S. Theurich, S. Guenther, T. Weber, A. Muetherig, W. Grothe, G. Behre
Journal: Blood (2006)
Abstract 15574: A Subcutaneous Platform for RNAi Therapeutics Targeting ANGPTL3
Authors: William Querbes, Scott Barros, Renta Hutabarat, Stuart Milstein, Rajeev Kallanthottathil, Satya Kuchimanchi, Klaus Charisse, Rachel Myers, Muthiah Manoharan, Martin Maier, Kevin Fitzgerald
Journal: Circulation (2013)

RNAi therapeutics have gone from an idea in 2002 to positive clinical trial results in phase 1 and 2 by 2013, remarkable progress for a novel technology. Our initial clinical delivery systems consisted of siRNA formulated in lipid nanoparticles (LNPs) dosed via an intravenous route. Utilizing this system we were able to demonstrate proof of concept in humans with ALN-PCS, an RNAi therapeutic targeting PCSK9, which reduced both plasma PCSK9 as well as the clinically validated endpoint of LDL-C. For many metabolic diseases, however, a subcutaneous route of administration is much preferred. We have recently demonstrated that subcutaneous delivery of siRNA conjugated to a triantennary  N -acetylgalactosamine ligand enables robust and sustained target silencing with siRNA uptake mediated by the hepatocyte-specific asiologlycoprotein receptor (ASGPR). Angiopoietin-like 3 (ANGPTL3) was recently implicated via human genetic studies in the regulation of lipoprotein levels. We have identified active siRNA molecules targeting ANGPTL3 and have demonstrated their ability to lower circulating ANGPTL3 protein, resulting in the reduction of Total-cholesterol, Low Density Lipoprotein Cholesterol and Triglycerides in various animal models of metabolic disease. In addition, we have identified several potent siRNA-GalNAc conjugates capable of lowering ANGPLT3 via subcutaneous dosing. Results from pre-clinical studies on ANGPTL3 and the application of a subcutaneous platform for RNAi therapeutics targeting genes implicated in metabolic disease will be presented
Commitment to talking not just treating
Authors: Pamela Levack, Gordon Paterson
Journal: BMJ (2016)

Wise’s article on the survival benefits of chemotherapy is timely1 and echoes other recent publications on how to treat metastatic cancer.2 As he says, patients rarely question their specialist about a proposed course of chemotherapy if it is presented as the best hope or only treatment option. Patients can only make informed decisions …
The role of chemotherapy in advanced hemangiopericyoma/solitary fibrous tumor.
Authors: M. S. Park, S. Patel, V. Ravi, A. P. Conley, J. C. Trent, A. J. F. Lazar, D. Lev, X. Wang, R. S. Benjamin, D. M. Araujo
Journal: Journal of Clinical Oncology (2011)

10097 Background: Tumors comprising the histologic spectrum of hemangiopericytoma/solitary fibrous tumor (HPC/SFT) are rare soft tissue sarcomas with poor prognosis in the advanced setting. Little data exist regarding the response rate and progression-free survival in HPC/SFT patients treated with conventional chemotherapy. Methods: We retrospectively analyzed the clinical outcome of all patients with histopathologically confirmed HPC/SFT who were evaluated at our institution for treatment between 1994 and 2007. Descriptive statistics were performed from the data obtained. Best response to therapy was assessed using RECIST 1.1. Results: We identified 23 patients with measurable disease who received chemotherapy (M:F = 13:10; median age 50 (19-74). Nineteen patients had metastatic disease deemed surgically unresectable, while 4 patients had localized potentially resectable disease who received neoadjuvant chemotherapy. Fifteen patients received doxorubicin-based therapy, 4 patients received gemcitabine-based therapy, and 4 patients received paclitaxel therapy. Eighteen patients underwent treatment as first-line therapy and 5 patients as second-line therapy. The median number of cycles received was 4 (2-10). Reasons for stopping therapy included disease progression (n=11), toxicities (n=5), physician decision to give treatment break (n=3), surgical consolidation (n=3), and radiotherapy consolidation (n=1). Best response assessment using RECIST showed that 0/23 (0%) achieved complete response/partial response (CR/PR), 19/23 (83%) maintained stable disease (SD) ≥ 2 months , while 4/23 (17%) developed disease progression (PD). The median progression-free survival (PFS) was 4.6 months (1.3-15.7). Conclusions: Conventional chemotherapy has only modest activity in advanced HPC/SFT, as shown by the RECIST response rate of 0% and median PFS of 4.6 months in this retrospective series. Our findings can serve a reference for response and outcome in the assessment of novel agents in these histological subtypes.
Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis with Myeloid Metaplasia (MMM) - Transplantation Should Be Performed before Transfusion Dependence Occurs.
Authors: Herrad Baurmann, Irina Burlakowa, Joerg Kaltenhaeuser, Dirk Judith, Mansoor Heshmat, Frauke Collenbusch, Roland Conradi, Michael Schleuning, Rainer Schwerdtfeger
Journal: Blood (2004)
A prospective trial assessing the effects of clamp ischemia during partial nephrectomy on renal function, biomarkers, and structure.
Authors: Barbara Ercole, Kathleen Torkko, William Hilton, Prasad Devarajan, Manjery A. Venkatachalam, Joel M. Weinberg, Dipen J. Parekh
Journal: Journal of Clinical Oncology (2012)

367 Background: Tolerance of the human kidney to clamp ischemia (CI) during partial nephrectomy (PN) has been considered to be limited to 20–30 min. We determined the utility of new biomarkers for following renal injury in this setting. Methods: 40 patients undergoing open PN without ( N=27, avg clamp time 32.3 min, range 15–53 min., 74% &gt; 30 min.) or with cooling ( N=13 avg clamp 48 min. range 30–61 min.) had biopsies of uninvolved areas of the kidney preclamp, during clamping and 5 min. after clamp release, along with serial measurements of standard renal functional parameters plus measurement of serum cystatin C and NGAL, and of urine NGAL, cystatin C, NAG, LFABP, NGAL, KIM-1 and IL-18. Results: Serum creatinine transiently increased at 24 hours by 21.9±6.4% after warm CI and 27.2±7.9% after cold CI (Ps &lt; .001), but serum cystatin C did not change and plasma NGAL was minimally affected. Urine biomarkers increased irrespective of whether they were factored for creatinine, with particularly large changes in KIM-1 and LFABP, but did not correlate with duration of CI, the change in creatinine at 24 hours, or the use of cold or warm CI. Ultrastructure and staining for actin, phosphotyrosine, B1 integrin, and ICAM-1 showed changes consistent with CI, but much milder than predicted from animal models. Creatinine has remained stable in the patient cohort at up to 18 months of follow-up. Conclusions: The data indicate that the insult to the clamped kidney from 30–60 minutes of CI under conditions of open partial nephrectomy is well tolerated despite increases of urinary biomarkers, which may in part reflect local effects of the surgery itself, expand indications for PN in the management of renal cancers, and support the use of CI as opposed to more complex procedures for PN.
Enhancing Effects of Heparin/Low Molecular Weight Heparin/Heparan Sulfate on Antigen Presentation and Antigen-Specific Cytotoxic T Lymphocyte (CTL) Induction by Monocyte-Derived Dendritic Cells.
Authors: Asuka Sekiguchi, Miwako Narita, Toshio Yano, Naoko Sato, Anri Saito, Norihiro Watanabe, Ayumi Yokoyama, Flavio Ayres, Louie Alldawi, Tatsuo Furukawa, Ken Toba, Yoko Watanabe, Yoshiaki Takahashi, Masuhiro Takahashi
Journal: Blood (2004)