tbuckley/cabot-search huggingface dataset:
Project data sphere (PDS) in prostate cancer: A first look including concomitant medication use.
Authors: Bethany Gill, Leila Khoja, Zhu Juan Li, Robert James Hamilton, Marianne Koritzinsky, Linda Penn, Kald Abdallah, Melania Pintilie, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2015)

204 Background: PDS enables patient-level analyses of control arms of cancer trials. The interface (www.projectdatasphere.org) allows for both web-based and download-based analyses. We aimed to validate established prostate cancer prognostic models and explore the effect of concomitant medications on survival in mCRPC. Methods: Data was obtained for 2,747 control subjects with mCRPC from 7 Phase III clinical trials with 1962 subjects available for OS analyses from 5 studies. Overall survival was estimated using the Kaplan-Meier Method. Cox-proportional hazards models, stratified by trial, were used to estimate hazard ratios. Results: Metastatic site was significant for overall survival (Median: Node only 23.69m, Bone 18.17m, Lung 14.72m, Liver 9.43m; p &lt; 0.001). Of the 23 types of medication examined, after adjusting for metastatic site, patients taking proton pump inhibitors (HR: 1.155, p=0.017) and Erythropoietin (HR: 1.49, p-value&lt;.001) had worse overall survival whilst patients taking fish oil (HR:0.68, p-value=0.033) and non-lipophilic statins (HR:0.69, p=.00277) had improved overall survival. Within the limits of available data, we validated the prognostic models for overall survival proposed by Templeton et al. and Sonpavde et al individually and after inclusion of concomitant medication where patients taking metformin (HR=0.729, p=.0082) and Cox 2 inhibitors (HR=0.708, p=.015) had improved OS whilst those taking low molecular weight heparin (HR=1.352, p=.004) had worse OS. Conclusions: As a first project utilizing open-source PDS data in prostate cancer, we validated two prostate cancer prognostic models and illuminated the ability to undertake novel analyses such as the association of concomitant medications with outcome. Limitations of the data relate to incomplete and inconsistent data entry. Future expansion of patient trials and numbers will help to facilitate future analyses.
Phase II trial comparing folinic acid, fluorouracil, and gemcitabine (FFG) and FOLFOX4 regimens with added bevacizumab (B) in metastatic colorectal cancer (mCRC)
Authors: S. Madajewicz, D. M. Waterhouse, P. Ritch, M. Khan, D. Higby, C. G. Leichman, S. K. Malik, P. Hentschel, L. Zhao, S. J. Nicol
Journal: Journal of Clinical Oncology (2009)

e15098 Background: FOLFOX4 is a standard chemotherapy for mCRC. FFG has shown substantial activity in mCRC. This trial compared the safety and efficacy of FFG and FOLFOX4 regimens in patients (pts) with mCRC. B was added to each arm after FDA approval in 2004 as first-line treatment of mCRC. Methods: Pts with mCRC, chemonaïve except for adjuvant treatment, were randomized to two treatment arms: FFG given weekly for 6 weeks of an 8-week cycle; FOLFOX4 had a 2-week cycle. Pts in both groups received B at 5 mg/kg every 2 weeks. Treatment continued until disease progression. Planned enrollment was 150 pts. Primary endpoint was overall response rate (ORR); secondary endpoints included toxicity, overall survival (OS), and time to progression (TTP). Response was assessed by RECIST. Post-hoc analysis of disease control rate (DCR) was added. Results: Forty-two pts (18 pts given B) were randomized to each arm. Thirty-one cycles of FFG and 248 cycles of FOLFOX4 were delivered. FFG produced greater myelosuppression than FOLFOX4. Two cases each of MI and DVT were observed in the FOLFOX4(B) subgroup; one pt had DVT with FFG alone. The incidence of gastrointestinal hemorrhage was low and similar for FFG and FOLFOX4. Peripheral neuropathy was highest in the FOLFOX4(B) subgroup. ORR and DCR were significantly greater for FOLFOX4(B) than for FFG(B). Median TTP and OS were not statistically different for FFG and FOLFOX4 groups. The trial was stopped due to low enrollment; planned statistical power was not achieved. Conclusions: FFG and FOLFOX4 regimens were generally well tolerated, with greater neuropathy in FOLFOX4 and greater myelosuppression in FFG. ORR was greatest in the FOLFOX4(B) subgroup. TTP and OS results comparing FFG and FOLFOX4 groups were inconclusive due to low enrollment. Rapid changes in mCRC “standard of care” during this trial may have constrained pt accrual. [Table: see text] [Table: see text]
Elevated blood pressure profile and left ventricular mass in children and young adults with autosomal dominant polycystic kidney disease.
Authors: M Zeier, S Geberth, K G Schmidt, A Mandelbaum, E Ritz
Journal: Journal of the American Society of Nephrology (1993)

Twelve children (< 15 yr) and 12 young adults with autosomal dominant polycystic kidney disease (ADPKD) confirmed by ultrasonography and 24 nonaffected individuals matched for age, sex, and body surface area were examined with ambulatory blood pressure monitoring and echocardiography. All patients and controls had normal renal function (median serum creatinine, 0.85 mg/dL; range, 0.5 to 1.1). In children, daytime and nighttime blood pressures were not significantly different from those of controls; the median left ventricular mass index (in grams per square meter) was higher in patients (66.6 g/m2) than in controls (61.3 g/m2; P < 0.002), although all values remained within the normal range. In young adults with ADPKD, mean arterial blood pressure was significantly higher than that in controls both during daytime (98.3 mm Hg; range, 74 to 126 versus 90.6 mm Hg; range, 73 to 116; P < 0.006) and during nighttime (83.2 mm Hg; range, 66.5 to 125 versus 79.0 mm Hg; range, 63 to 91; P < 0.05). In parallel, the median left ventricular mass index was significantly higher in young adults (81.8 g/m2; range, 62 to 174 versus 64.3 g/m2; range, 52 to 102; P < 0.02). The results document that ambulatory daytime and nighttime blood pressures and left ventricular mass indices are higher in asymptomatic carriers of the ADPKD trait compared with controls, although most values are still within the normal range.
Analysis of ixabepilone exposure-response for neutropenia in patients with metastatic breast cancer
Authors: A. Roy, H. Zhu, M. Cohen, L. Zhang, M. Pfister
Journal: Journal of Clinical Oncology (2008)

2511 Background: Ixabepilone, the first in a new class of antimicrotubule agents: the epothilones, is indicated in the US for the treatment of resistant/refractory metastatic breast cancer (MBC). In MBC phase II trials, grade 3/4 neutropenia occurred in 53–58% of patients treated with single agent ixabepilone, but febrile neutropenia was uncommon (≤5%). An exposure-response model was used to characterize the relationship between ixabepilone exposure and neutropenia, and to examine the effect of covariates. Methods: The analysis was performed on data from 114 MBC patients from 2 phase II monotherapy studies, administered 30 to 50 mg/m2 ixabepilone as IV infusion (1 to 3 hr), every 3 weeks. These data were analyzed using a semi-mechanistic nonlinear mixed effects model of neutrophil dynamics, parameterized in terms of mean transit time (MTT), baseline ANC, the feedback effect of peripheral ANC value on the formation of neutrophil progenitors (γ), and the ixabepilone plasma concentration at which inhibition of neutrophil progenitor formation is half-maximal (EC50). The model was developed with data from Course 1, and evaluated with data from subsequent courses. Results: ANC versus time after ixabepilone administration was effectively described by this model, and all of the model parameters not specific to ixabepilone were consistent with previously reported values (MTT=105 hr, CN,0= 4080/μL, and γ= 0.132). Ixabepilone plasma concentration was found to affect neutrophil progenitor formation by an inhibitory hyperbolic function. The EC50 was 14.1 ng/mL. Model-based trial simulation predicted that the percent of pts with grade 3/4 neutropenia during course 1 (within 21 days) of receiving 30, 40, and 50 mg/m2 doses of ixabepilone would be 31%, 38%, and 42%, respectively, very similar to the actual rate of 39%-41% seen in phase II/III trials at 40 mg/m2 during Course 1. Age, baseline ANC, ECOG performance score, and prior therapy did not have a statistically significant effect on neutrophil dynamics. Conclusions: The semi-mechanistic model is able to describe the entire ANC time-profile based on the ixabepilone time-profile, and is suitable for predicting the incidence and severity of neutropenia for alternative schedules. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
Abstract 4296: Dextran sodium sulfate-induced colitis in dendritic cell deletion mice
Authors: Junko Masuda, Atsuhi Kitani, Ivan Fuss, Masaharu Seno, Warren Strober
Journal: Cancer Research (2015)

Abstract Dendritic cells (DC) located in lamina propria are critical for converting to CD4+Foxp3+ regulatory T (Treg) cells from CD4+Foxp3- in the presence of retinoic acid and TGF-beta. However, role of DC and Treg in immunological tolerance with commensal bacteria is still controversial. To address this question, we bred constitutively CD11c+ DC-depleted mice on C57BL/6 background. Although CD4+ T cells isolated from splenocytes showed normal in vitro differentiation into Th1 and Th17 cells, these DC-depleted mice were more protective than that of control against dextran sodium sulfate (DSS) -induced colitis. Treg expression level of DC-depleted mice was lower than that of control and not changed even after colitis. These results suggest that other cell populations regulate gastrointestinal system in both static and chronic inflammatory state in DC-depleted mice. Citation Format: Junko Masuda, Atsuhi Kitani, Ivan Fuss, Masaharu Seno, Warren Strober. Dextran sodium sulfate-induced colitis in dendritic cell deletion mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4296. doi:10.1158/1538-7445.AM2015-4296
A randomized phase III trial on maintenance treatment with bevacizumab (bev) alone or in combination with erlotinib (erlo) after chemotherapy and bev in metastatic colorectal cancer (mCRC).
Authors: A. Johnsson, J. Frodin, A. Berglund, H. Hagman, J. Sundberg, D. Bergstrom, R. d. Christensen, N. Keldsen, K. G. Spindler, A. K. M. Jakobsen
Journal: Journal of Clinical Oncology (2011)

3526 Background: To improve the management of patients (pts) with mCRC, it is important to identify maintenance strategies that may contribute to prolonged survival with sustained QoL. The aim of the present study was to compare bev with bev + erlo following induction treatment with chemotherapy and bev. Progression free survival (PFS) was the primary end point. Methods: Pts with previously untreated mCRC, performance status (PS) 0-1, and adequate hepatic/renal/hematological function were included between May 2007 and Oct 2009 at 16 sites in Sweden and Denmark. Induction treatment consisted of XELOX, XELIRI, FOLFOX or FOLFIRI (investigator’s choice) + bev for 18 weeks. Pts without tumor progression were eligible for randomization to maintenance treatment with bev 7.5 mg/kg q3w +/- erlo 150 mg daily, until progression or unacceptable toxicity. Results: 249 pts were enrolled, median age 66 years (range 27-84), 58% male, 67% PS 0, primary site; colon/rectum/both: 60/34/6%, 35% had primary tumor in situ, 48% had liver metastases only. 73% received oxaliplatin-containing induction treatment. Response rate on induction treatment among 231 evaluable pts were PR/SD/PD: 48/43/9%. 161 pts were randomized. Reasons for non-randomization were PD in 23 pts and intended surgery in 19 pts. Median time on maintenance treatment was 15 weeks (range 0-102). Adverse events grade III-IV occurred in 44% of pts during induction phase. In the maintenance phase 31% experienced grade III-IV toxicity, with rash in 8%, hypertension in 4% and bleeding in 2% of pts. There were 3 toxic deaths; intestinal perforation (n=2) and abdominal bleeding (n=1). Conclusions: Maintenance treatment with bev +/- erlo after first-line chemotherapy in pts with mCRC seems to be a feasible strategy with limited side-effects. The primary study endpoint, PFS in the randomized population, will be reported at the meeting.
A large, multicenter, retrospective epidemiological survey: The incidence and treatment of bone metastatic disease in Chinese cancer patients.
Authors: L. Zhang, S. Yu, G. Xie, B. Xu, Z. Jiang, S. Lu, H. Wang, Y. Sun
Journal: Journal of Clinical Oncology (2010)

e19612 Background: Bisphosphonates (BPs) had been used for bone metastases patients to prevent or delay the development of skeletal related events (SRE). The objective of this survey was to identify clinical features and treatment strategies in Chinese cancer patients with BM as well as SRE. Methods: This survey included consecutive patients with solid tumor and diagnosed with BM and treated with BPs, enrolled in 5 months on average, from January 2008. Data included demographics, tumor type, sites of BM, incidence and proportion of SRE in different tumor type, type and duration of BPs treatments, the association between BPs use and change in the subsequent rates of SRE Results: Totally, 3,223 cancer patients were included from 53 hospitals located 30 provinces throughout china. The common tumor types were lung (37%), breast (31%), prostate (9%) and GI tumor (5%). The sites of BM included thoracic spine (56%), lumber spine (47%), ribs (33%), Ilium+sacrum (23%), femur (18%). The incidence of SRE was 23.1% and SRE occur in 26%, 20% and 18% of patients with lung, breast, and prostate cancer respectively. The Proportion of SRE defined as radiation to the bone and spinal cord compression were higher than other type of SRE in the patients with lung (58%, 35%) and prostate cancer (48%, 26%). But in breast cancer, radiation to the bone and pathologic fracture were higher (45%, 36%). 80% of patients were treated by the third generation of BPs (e.g. zoledronic acids). The mean treatment duration of BPs was 2.71 month. 45.5% of patients initiated the BPs treatment right after the BM diagnosis established. But 47.4% of patients delay to initiate BPs treatment for more than 3 months or begin the BPs treatment after patients already experienced SRE. The mean time to subsequent SRE was 21 months in those who persisted for > 10 months versus 4 months in those who persisted for <10 months (P <0.0001). Conclusions: This survey confirmed SREs were common in Chinese cancer patients with BM. The results indicated that use BPs can delay the time to subsequent SRE. This survey indicated more education are needed for physicians to use BPs treatment as soon as the BM diagnosis established. No significant financial relationships to disclose.
A phase II, window study of SP1049C as first-line therapy in inoperable metastatic adenocarcinoma of the oesophagus
Authors: J. W. Valle, J. Lawrance, J. Brewer, A. Clayton, P. Corrie, V. Alakhov, M. Ranson
Journal: Journal of Clinical Oncology (2004)

4195 Background: SP1049C is a block co-polymer incorporating doxorubicin resulting in broad in vitro activity and superior anti-tumour activity in 9 out of 9 in vivo animal tumour models compared to doxorubicin. Methods: Chemotherapy- or radiotherapy-naïve patients with measurable, inoperable or metastatic, biopsy-proven, adenocarcinoma of the oesophagus; KP ≥60; normal cardiac LVEF; adequate swallowing and adequate renal, hepatic and bone marrow function were eligible. Treatment: SP1049C 75mg/m2 IV 30-minute infusion was given q3w, for up to 6 cycles. Radiological response was assessed after cycles 2, 4 and 6. Upon disease progression (PD) patients were offered standard chemotherapy. Other assessments included: QoL (by QLQ-C30 and QLQ-OES24 questionnaires), toxicity, disease-related symptoms and cardiac function. Results: From February 2002 to date, 17 male patients; median age 62 years (range 49 – 78); 16 with stage IV disease and 1 unknown stage (TxN1M0); were enrolled. 10 patients are eligible for efficacy analysis. Radiological response after 2 cycles: one (10%) PR, 8 (80%) SD (including 4 (40%) with minor responses) and one (10%) PD. Further partial responses have been seen after cycles 4 and 6 (by investigator assessment) and will be reported in due course. One responding patient underwent salvage resection (pT2N0 (Stage 2A) tumour). Toxicity data is available for 2 cycles for the first 11 patients. Gd 3–4 haematological toxicity (by patient): neutropaenia 8 (73%), leucopaenia 7 (64%), anaemia (0%) and platelets (0%) resulting in six (55%) patients being dose-reduced to 55 mg/m2 at cycle 2. Non-haematological toxicity (Gd1–2,Gd3–4): nausea (73%,0%), anorexia (45%,9%), lethargy (55%,18%), febrile neutropaenia (0%,36%), weight loss (35%,0%), vomiting (45%,18%), mucositis (55%,9%), and Gd 1–2 alopecia in 55%. A significant fall in LVEF (pre-defined as an absolute ≥15% drop from baseline value) was seen in 2 patients. Conclusions: SP1049C appears to be active in advanced oesophageal adenocarcinoma based on the preliminary results of the first 10 patients and the study will continue accrual to a total of 24 evaluable patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc.
Evaluation of minimal residual disease (MRD) in peripheral blood (PB) assessed prospectively by RT-PCR for melanoma-associated genes as a prognostic factor for survival in stage III melanoma (Mel) patients (pts) enrolled onto an intergroup adjuvant trial S0008.
Authors: J. A. Sosman, J. Moon, P. Liu, L. E. Flaherty, M. B. Atkins, K. A. Margolin, J. M. Kirkwood, V. K. Sondak
Journal: Journal of Clinical Oncology (2010)

8513 Background: In addition to known prognostic factors, the analysis of PB for expression of mel genes by RT-PCR (MRD) may provide insight into the likelihood of relapse and/or death in pts with high-risk mel and inform decisions regarding adjuvant therapy. Prior studies have provided conflicting results on the utility of PB RT-PCR testing. Methods: In Intergroup phase III trial S0008 of adjuvant therapy in pts with stage III mel (Txb+N1a or ≥N2a or N1b) MRD was assessed by RT-PCR of mel associated genes (tyrosinase, MART-1, gp-100 or MAGE-3) at baseline, day 90, and day 365. Pts were randomized to biochemotherapy (BCT) (9 wks) or standard adjuvant interferon (HD IFN) (52 wks). MRD monitoring was instituted after trial enrollment was initiated and represented data for 219 of 420 pts. Although survival data are not yet mature, the SWOG DSMC gave permission for a preliminary analysis of the impact of MRD on clinical outcomes blinded to treatment arm. Results: Two hundred nineteen of 420 enrolled pts had pre-treatment MRD testing. The baseline characteristics of these 219 pts were similar to the entire 420 pts; 64% with macrometastases, 44% ulcerated primary, and 33% with N3 disease. In a Cox model adjusted for known baseline characteristics, baseline RT-PCR+ for ≥ 1 gene (present in 24 pts) was a significant negative prognostic factor for overall survival (OS) (p = 0.005, HR 2.26). Using landmark analysis of OS, RT-PCR+ at day 90 (216 pts, 25 RT-PCR+) was associated with poor outcome (p = 0.01) but not at day 365 (193 pts,19 RT-PCR+) (p = 0.11). The strongest association with outcome was for tyrosinase and/or MART-1 (p = 0.001) and with no impact detected for gp-100 (p = 0.43) or MAGE-3 (p = 0.59). Conclusions: This prospective analysis of pts with high-risk mel treated either with adjuvant HD IFN or BCT demonstrates that the presence of PB RT-PCR markers of 1 or more melanoma-associated genes increases the risk of death after adjusting for all other known prognostic factors. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Roche, Schering-Plough Novartis, Roche, Schering-Plough
Locoregional recurrence (LRR) after neoadjuvant chemotherapy (NAC): Pooled-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC).
Authors: Eleftherios P. Mamounas, Patricia Cortazar, Lijun Zhang, Gunter Von Minckwitz, Keyur Mehta, David A. Cameron, Herve R. Bonnefoi, Luca Gianni, Pinuccia Valagussa, Norman Wolmark, Sibylle Loibl, Jan Bogaerts, Sandra M. Swain, Rajeshwari Sridhara, Joseph P. Costantino, Priya Rastogi, Charles E. Geyer, Holger Eidtmann, Bernd Gerber, Michael Untch
Journal: Journal of Clinical Oncology (2014)

61 Background: There is limited information on LRR rates in pts treated with NAC. Methods: 12 large NAC BC trials (11,955 pts) with pCR information and long-term F/U for LRR, EFS and OS were included. Primary aims were to assess LRR rates by pCR, tumor subtype, surgery type and other clinico-pathologic factors. Main definition of pCR was ypT0/is ypN0. Results: Median F/U: 5.4 years. Median age: 49, T2 tumors: 61%, Inflammatory BC: 4%; Clinically(+) nodes: 47%. Overall LRR: 6.8% (95% CI: 6.3, 7.2). LRR was 5.5% with pCR (ypT0/isypN0) vs. 7.1% without. After lumpectomy, LRR rates were similar with pCR (6.0%) vs. without (6.3%). After mastectomy, LRR rates were lower with pCR (3.8%) vs. without (8.1%), irrespective of XRT use. In HR(+)/HER2(-) BC, LRR rates were low with pCR (1.9%) or without (3.3%) with similarly low LRR rates in grade 1/2 tumors (pCR: 2%, no-pCR: 2.6%). In HR(+)/HER2(-)/grade 3 BC LRR rates were lower with pCR (1%) vs. without (5.3%). In HER2(+) BC LRR rates were similar with pCR (5.1%) or without (7.3%), mainly seen in HER2(+)/HR(+) BC (5.7% vs. 5.5%). In contrast, in HER2(+)/HR(-) BC LRR rates were lower with pCR (4.9%) vs. without (9.8%). Also, in HR(-) /HER2(-) BC LRR rates were lower with pCR (4.9%) vs. without (8.6%). LRR varied with path nodal status and TNM stage at surgery: node(-): 5.6% vs. node(+) 8.9%; stage 0: 5.3%; stage 1: 5.2%; stage 2: 7.3%; stage 3: 10.1%. Conclusions: LRR rates after NAC are low and vary by pCR status, tumor subtype, type of surgery, stage and path nodal status. This information may have clinical implications on selecting appropriate candidates for XRT. [Table: see text]