tbuckley/cabot-search huggingface dataset:
Inhibition of functional osteoblasts with the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (PCa)
Authors: P. Mathew, J. Yang, S.-J. Kim, I. Fidler, C. Bucana, P. Troncoso, X. Wang, P. Thall, C. Logothetis, N. Navone
Journal: Journal of Clinical Oncology (2004)

4625 Background: In a clinical trial in men with PCa and bone metastases (Proc Am Soc Clin Oncol 2003; 22:410), monotherapy with the PDGFR inhibitor, imatinib mesylate, for 30 days, led to decreases in alkaline phosphatase (AlkP), but not a significant decline in PSA. Nevertheless, patients with any decrease in AlkP had a higher likelihood of subsequent 50% decline in PSA with subsequent combination imatinib and docetaxel therapy, as compared to patients with any increase in AlkP. Goals: To investigate whether 1) Osteoblast (OB) proliferation in PCa is regulated by PDGF and 2) effective inhibition of OBs results in enhanced therapeutic efficacy with cytotoxic therapy in PCa. Methods: 1) PDGFR immunohistochemistry in bone marrow biopsies from PCa bone metastases 2) In a co-culture model of MDA-PCa2b cells and OBs, which results in induction of OB proliferation, the effects of imatinib, alone and in combination with docetaxel therapy were studied. Results: OBs from PCa bone metastases stain positively for PDGFR. Imatinib treatment resulted in marked inhibition of OB proliferation induced by MDA-PCa2b cells. A PDGF neutralizing antibody resulted in similar inhibition. Inhibition of OB proliferation with imatinib did not result in enhanced cytotoxic efficacy in the co-culture model. Conclusions: PDGF regulates OB proliferation induced by PCa cells and likely contributes to the osteoblastic phenotype. Inhibition of OBs is insufficient to induce responses in PCa or result in enhanced in vitro cytotoxicity. A decrease in AlkP alone is not a surrogate of clinical benefit in PCa but may serve as a pharmacodynamic measure of inhibition of PDGFR activation in vivo by imatinib. The improved response to combination therapy in patients with decreased AlkP may therefore be due to alternate mechanisms, such as targeting PDGFR on tumor vascular endothelial cells (JNCI 2003; 95:558–570). The present findings offer a critical insight into the role of OBs in PCa bone metastases. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Novartis; Orphan Medical Aventis; Novartis Aventis
Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse.
Authors: Xabier Garcia-Albeniz, June M. Chan, Alan T Paciorek, Roger W Logan, Stacey A. Kenfield, Matthew R. Cooperberg, Peter Caroll, Miguel Hernan
Journal: Journal of Clinical Oncology (2014)

5003 Background: The optimal timing to start androgen deprivation therapy (ADT) in patients with rising PSA as the only sign of relapse is unknown. ASCO guidelines state “the critical issue is to determine whether there is benefit and how large it is for starting ADT while patients are asymptomatic.” Methods: We studied 2,022 men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a national prospective registry, staged < cT3aN0M0, treated with radical prostatectomy (RP) or radiotherapy (RT) and had a PSA relapse (> 0.2 ng/mL [RP] or three rising determinations one month apart [RT]). Exclusion criteria included ADT in the 12 months before inclusion, metastatic disease by CT scan or bone scan, and symptoms. We assigned patients to the “immediate” strategy if they initiated ADT within 3 months (grace period) of PSA relapse and to the “deferred” strategy if they initiated ADT 2 or more years after PSA relapse or when they presented with metastasis, symptoms or a short PSA doubling time. We did not allow a treatment other than ADT for PSA relapse (e.g., rescue RT). We censored patients when they deviated from the assigned strategy and adjusted for this censoring via inverse probability weighting where the weights are a function of time-varying confounders: PSA, Karnofsky, weight loss, and bone pain. Results: Of the 2,022 patients analyzed, median age was 69 (range 63 to 74) years, 33.8% had a Gleason score >7, 31.8% received radiotherapy as primary treatment, and median time from primary treatment to PSA relapse was 27 (range 14 to 51) months. After relapse, patients were followed a median of 53.2 months. All cause mortality HR for “immediate ADT” vs. “deferred ADT” was 1.06 (95% CI: 0.59 to 1.89), corresponding to a survival difference at 5 years of -5.5% (95% CI: -15.1 % to 4.2%). The prostate-cancer specific mortality HR was 1.48 (95% CI 0.69-3.16), corresponding to a 5-year survival difference of -5.6% (95% CI: -12.5% to 1.3%). Conclusions: Our study suggests little or no survival benefit of immediate ADT initiation for immediate ADT initiation compared with deferred ADT initiation (at clinical progression or at least two years after PSA relapse) among prostate cancer patients with PSA-only relapse.
Long-term survival of patients with advanced melanoma who received ipilimumab administered at 10 mg/kg every 3 weeks for 4 doses (induction dosing)
Authors: W. J. Urba, J. S. Weber, S. J. O'Day, J. D. Powderly, M. J. Yellin, G. Nichol, E. M. Hersh
Journal: Journal of Clinical Oncology (2008)

3018 Background: Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4), a critical suppressor of antitumor immune activity. Previously presented data from the phase I/II study MDX010–15 showed that ipilimumab induction dosing (10 mg/kg every 3 weeks [Q3W] X 4) resulted in an improved disease control rate (complete+ partial response [CR + PR] + stable disease [SD]) compared with other dosing regimens in patients with previously treated advanced melanoma. Disease control was durable, lasting > 6 months in most patients. This analysis describes overall survival data to date from the 10 mg/kg Q3W X 4 induction dosing cohort. Methods: Patients enrolled and treated in study MDX010–15 had unresectable stage III or IV melanoma and at least 1 measurable lesion. SD or progressive disease (PD) was allowed for study inclusion. Patients (n= 24) were treated with 10 mg/kg ipilimumab Q3W X 4 induction dosing. This group of patients was highly treatment-refractory: all patients had prior surgery; 13 (54%) had ≥2 prior therapies; 18 (75%) had prior immunotherapy; and 11 (46%) had prior systemic chemotherapy. Overall survival (OS) data were collected. Results: Data from all patients were collected and analyzed, except for 1 patient with lung cancer who was inadvertently enrolled and treated. Seven of 23 patients (30%) are still alive at 2 years of follow-up; this included patients who, at MDX-010–15 study end, had the following best overall response: 1 CR, 1 PR, 3 SD, and 2 PD. At 18 months of follow-up, 9 patients (39%) were still alive. The median OS at 2 years was 402 (95% CI, 285 - 591) days (∼14.4 months). Updated data will be presented. Conclusions: After ipilimumab induction dosing at 10 mg/kg Q3W X 4, 30% of pretreated patients with advanced melanoma were still alive after 2 years, including 1 CR, 1 PR, 3 SD, and 2 PD. Therefore, even patients with PD following ipilimumab administration may derive benefit in the long term. Long-term follow-up of patients who participated in other ipilimumab trials (eg, CA184–008) will provide additional data. Further investigation to assess factors that may contribute to the durability of response from CTLA-4 inhibition is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medarex, Inc. Bristol-Myers Squibb, Medarex, Inc. Medarex, Inc Bristol-Myers Squibb, Medarex Bristol-Myers Squibb, Medarex, Inc.
Expansion of memory type CD8+t-cells correlates with the failure of early immunosuppression withdrawal after cadaver liver transplantation using high doses atg induction and rapamycin
Authors: Vincent Donckier de Donceel, Ligia Craciun, Roberto Troisi, Valerio Lucidi, Xavier Rogiers, Nathalie Boon, Delphine Degre, Alexis Buggenhout, Christophe Moreno, Thierry Gustot, Nadine Bourgeois, Isabelle Colle, Hans Van Vlierberghe, Patrick Miqueu, Myriam Remmelink, Alain Le Moine, Bernard de Hemptinne, Michel Goldman
Journal: Hepatology (2012)
Prospective evaluation of patient perceptions and willingness to undergo pharmacodynamic and pharmacokinetic tests in early phase oncology trials
Authors: J. Smith, M. Benjamin, J. H. Yim, R. L. James, R. K. Ramanathan, S. P. Anthony, M. Borad, R. C. Bay, B. F. Piper, R. Tibes
Journal: Journal of Clinical Oncology (2009)

6587 Background: Increasing numbers of clinical trials include optional or mandatory pharmaco-dynamic and -kinetic assays. Since little is known about patients’ (pts) perceived willingness to undergo specific tests and the number of tests pts would tolerate on a single trial, this study was conducted. Secondary purposes included correlating test number and type with demographics, prior test experience, coverage, and inconvenience. Methods: Exploratory correlative study using a multi-item self-report questionnaire to measure pts willingness (0–10 scale, 0 = not willing, 10 = very willing) to undergo imaging (e.g., MRI, ECHO), invasive (e.g., tumor, skin biopsies [bx]) and less invasive tests (e.g., blood, urine). 61 pts (22 female, 39 male) with advanced malignancies participating in phase I or II trials at one institution were enrolled from June 2008-December 2008. Descriptive and non-parametric statistics were used. Results: Statistically significant (p &lt; 0.01) inverse relationships were found between the number of imaging studies (e.g., CT, ECHO), tests required (e.g., tumor, skin bx, blood draws) and pts reported willingness to undergo these tests. Pts were least willing to undergo tumor bx (median 5.5, interquartile range [IQR] 3.5–10), skin bx (6.8, 3.1–10), and unexpectedly MRIs (8, 4–10) (all p &lt; 0.01). Surprisingly, inconvenience and prior negative experiences for the more invasive tests (e.g., skin bx) did not negatively affect willingness to undergo these tests in the future as opposed to most imaging studies. College-educated were more willing to undergo tests than non-college educated. Few pts were unwilling to undergo tests/procedures at all, if mandatory for enrollment. Conclusions: Results provide improved understanding of pts willingness to undergo trial requirements and suggest that adequate explanation (e.g., MRI) and test rationale may affect willingness to undergo tests. Findings can be used to improve study design and consent procedures to minimize patient discomfort and inconvenience. The overall willingness of advanced stage cancer pts to undergo study specific tests/procedures is high. No significant financial relationships to disclose.
The progress of small cell lung cancer management using irinotecan plus cisplatin chemotherapy
Authors: J. S. Lee, J. Han, S. Yu, S. Yoon, E. Lim, H. Pyo, H. Kim, D. Lee, H. Kim, K. Cho, G. Lee
Journal: Journal of Clinical Oncology (2007)

7721 Background: Etoposide/cisplatin (EP) is the most widely used regimen resulting in a median survival of 8–10 mos and 17–20 mos respectively for patients (pts) with extensive-disease (ED) and limited-disease (LD). Encouraged by a phase III trial result that showed better survival outcome after Irinotecan/cisplatin (IP) combination as compared with EP, we previously reported promising activity of IP regimen for LD-SCLC and also for ED-SCLC. To further evaluate the role of IP in SCLC pts, we conducted two additional phase II studies. Methods: Between May 2003 and June 2006, a total of 196 SCLC pts (ED: 120, LD: 76) were enrolled in two separate trials. All pts were chemo-naive and ECOG PS of 0–2. Pts with ED-SCLC received irinotecan 60 mg/m 2 intravenously (IV) and cisplatin 30 mg/m 2 IV on days 1 and 8 every 21 days for 8 cycles followed by 6 cycles of irinotecan maintenance or observation. Treatment for LD-SCLC consisted of two 28-day cycles of cisplatin 30 mg/m 2 IV on days 1 and 8 plus irinotecan 60 mg/m 2 IV on days 1, 8, and 15, followed by two 21-day cycles of cisplatin 60 mg/m 2 IV on day 1, plus etoposide 100 mg/m 2 IV on days 1 to 3 with concurrent twice-daily thoracic radiation of total 45 Gy. Hoping to modify the treatment-related toxicity, 36 pts were given epoietin and 20 were given amifostine while 15 received neither during the concurrent chemo-radiation therapy. Results: For ED- SCLC, overall response rate was 92.6% with CR rate of 11.1%. The median survival was 13.8 mos (95% CI, 12.2 to15.3) with 1-and 2-year survival rates of 58.6% and 18.9%. The median progression-free survival (PFS) was 7.3 mos with 1-and 2-year PFS rates of 18.1% and 5.4%. Irinotecan maintenance did not affect the outcome, however. For LD-SCLC, the response rate was 97.1% with CR rate of 44.9%. The median survival was 24.9 mos (95% CI, 18.5 to 31.3) with 1-and 2-year survival rates of 75.2% and 51.4%. The median PFS was 11.0 mos (95% CI, 7.8–14.2) with 1-year PFS rates of 46.8%. The most common toxicity associated with IP treatment was grade 3 or 4 neutropenia (64.6% for ED, 45.3% for LD). Grade 3 diarrhea was developed in 12.4% for ED and 4% for LD pts. Conclusion: Significant antitumor activity of IP chemotherapy as shown suggests further progress in SCLC therapy. No significant financial relationships to disclose.
Diagnostic Tumor Mirna Profiling Predicts Molecular Relapse in Mantle Cell Lymphoma Patients Prospectively Followed for Minimal Residual Disease. Results from the Nordic MCL2-3 Trials
Authors: Simon Husby, Lone Bredo Pedersen, Ulrik Ralfkiær, Christian Garde, Sara Ek, Arne Kolstad, Mats Jerkeman, Anna Laurell, Riikka Räty, Anja Pedersen, Christer Sundström, Marja-Liisa Karjalainen-Lindsberg, Jan Delabie, Erik Clasen-Linde, Christopher Workman, Christian H Geisler, Kirsten Grønbæk
Journal: Blood (2014)
Heterogeneity in disease-free survival in breast cancer patients
Authors: S. Yahyazadeh Jabbari, R. Khodabakhshi, M. R. Gohari, S. Mortzavi, A. Alidoosti, J. Shahidi, A. Moradi, F. Bahoor
Journal: Journal of Clinical Oncology (2007)

11106 Background: Breast cancer is the most common cancer and women’s health problems in Iran. There are some known prognostic factors for occurrence of metastasis after surgery. However, there are some other unknown factors affect the risk of metastasis. The purpose of this study was to determine the value of known prognostic factors by accounting for patient-specific effect, the rate metastasis in breast cancer patients who received surgical treatment followed by adjuvant treatment in Iran. Methods: Among 174 women whom have been undergone surgery followed by adjuvant therapy at three hospitals in Tehran, Iran during 3 years 117 have met the including criteria. Women with defined breast cancer with no distant metastases in time of diagnosis whom have been undergone MRM or BCS were enrolled. Tumors were classified according to the TNM system of the American Joint Committee on cancer (AJCC). Grading was performed according to Scarff-Bloom-Richardson method. ER and C-erb2 was measured by immunohistochemistry (IHC) method. The patients have been followed regularly by routine clinical, lab profile, serologic markers (CEA,CA15–3) and Para clinical examinations. Results: The median relapse- free survival for patients in study was 49.6 month. The median time to experience second metastasis was 22.5 month. 44 (38% ) patients developed metastasis. 20 (45%) of those experienced second metastasis. the Frailty model showed that age, size of tumor, number of positive lymph nodes and histologic grade had a significant effect on the risk of metastasis (p&lt;.05) and there was a heterogeneity between patients after adjusting for covariates. Conclusion: Many patients who referred to cancer centers were not detected at early stage and they will meet more risk for relapse. The known risk factors describe the risk of metastasis partly and other unknown or unmeasured factors, such as environmental or genetics, are important to describe the risk of metastasis in breast cancer. Family history has no significant effect on event- free survival. No significant financial relationships to disclose.
Bevacizumab does not increase bleeding in patients with metastatic colorectal cancer receiving concurrent anticoagulation
Authors: J. Hambleton, W. F. Novotny, H. Hurwitz, L. Fehrenbacher, T. Cartwright, J. Hainsworth, W. Heim, J. Berlin, F. Kabbinavar, E. Holmgren
Journal: Journal of Clinical Oncology (2004)

3528 Background. Bevacizumab (BV, Avastin), a recombinant, humanized monoclonal antibody directed against VEGF, improves survival in combination with chemotherapy for first line treatment of metastatic colorectal cancer (CRC). The addition of BV to irinotecan/5-FU/leucovorin (IFL) resulted in a significant improvement in survival compared with IFL alone (p=0.00004; median survival increased from 15.6 to 20.3 months). Experience with BV in phase II studies, particularly in NSCLC, suggested that bleeding might be a safety signal. Therefore, patients receiving full-dose anticoagulation (FDAC) were excluded from the phase III CRC study. This analysis assesses the outcomes of patients with metastatic CRC who had a thrombotic event while receiving study treatment (BV or placebo), and remained on study while receiving FDAC. Methods. Patients with previously untreated metastatic CRC were randomized to IFL plus placebo (Arm 1) versus IFL plus BV (5 mg/kg; Arm 2). Thrombotic complications, including deep venous thrombosis, pulmonary embolus, and arterial events, and treatment were analyzed. FDAC was achieved with warfarin. Results.The overall rate of arterial and venous thromboembolic events was 16.2% in Arm 1 and 19.4% in Arm 2. Arterial events, such as myocardial infarction and stroke, were rare: 1% Arm 1 and 3.3% in Arm 2. Venous event rates were similar; 15.2% in Arm 1, 16.6% in Arm 2. Of those patients with a thrombotic event treated with FDAC, 30 patients (54.5%) in Arm 1 and 53 patients (82.8%) in Arm 2 continued on study drug. Grade 3/4 bleeding rates for those on FDAC and study drug are shown in Table 1. Conclusion. Use of concomitant full-dose anticoagulation therapy with Bevacizumab in combination with chemotherapy does not appear to increase the risk of hemorrhagic complications in patients with metastatic colorectal cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech Genentech Genentech
Is minimally invasive œsophagectomy for cancer decreasing pulmonary complications? Results from a case-control study.
Authors: N. Briez, G. Piessen, A. Claret, J. Triboulet, C. Mariette
Journal: Journal of Clinical Oncology (2010)

4071 Background: Morbidity after œsophagectomy for cancer remains high, especially due to pulmonary complications. Rapid development of minimally invasive surgery is related to less morbidity because of its less aggressive approach. The aim of our study was to compare 30-day pulmonary morbidity of oesophageal cancer patients who underwent surgical resection by open standard technique (including laparotomy and right thoracotomy = S group) versus minimally invasive procedure (including abdominal laparoscopy and open right thoracotomy = MI group). Methods: Between January 2002 and June 2008, 331 œsophageal resections were performed for cancer. The laparoscopic approach for gastroplasty achievement has been progressively introduced since 2005 for unselected patients. We carried out a prospective case control study among patients who benefited from the mini-invasive laparoscopic procedure (MI) and control patients with the standard technique (S). Sixty seven patients from the MI group were matched according to age, gender, location and tumoral status, physical status score, histological type, weight loss and neoadjuvant chemoradiotherapy to patients from the S group (n = 183). Results: The two groups were similar in terms of the previous matching criteria. Global post-operative mortality and morbidity rates were 2.4 % and 41.2% respectively. Conversion rate was 1.6% (n = 4). Pulmonary complications occurred significantly less frequently in the MI group (16.4% vs. 34.4%, p = 0.006) and were of lesser gravity (14.9% of major pulmonary complications in the MI group vs. 30.0% p = 0.016). There was no difference concerning mortality (1.5% vs. 2.7%), overall morbidity (388% vs. 42.0%), anastomotic leak (5.9% vs. 3.8%), reoperation (6.0% vs 8.7%), gastroplasty distention (5.9% vs. 2.2%) and septic complications (13.4% vs. 18.6%). Conclusions: This is to our knowledge, the most important prospective study showing a decrease of both incidence and gravity of pulmonary complications by using the mini-invasive surgical approach in the oesophageal cancer treatment. Further long term oncological results should still be evaluated. A French multicentric randomized trial is beginning from this perspective. No significant financial relationships to disclose.
The complex relationship of lung tumor volume to survival in patients with non-small cell lung cancer (NSCLC) treated by definitive radiotherapy (RT): (Trans Tasman Radiation Oncology Group Study 9905)
Authors: David Ball, Richard Fisher, Bryan Burmeister, Michael Poulsen, Peter Graham, Michael Penniment, Shalini Vinod, Hedley Krawitz, David Joseph, Greg Wheeler, Bev McClure
Journal: Journal of Thoracic Oncology (2009)
Risk of adverse cardiovascular events (CVE) and incident diabetes mellitus (DM) in patients (pts) with prostate cancer (PC) treated with androgen deprivation therapy (ADT): A meta-analysis of adjusted observational results.
Authors: Lorenzo D'Ambrosio, Federica Brusa, Fabrizio D'Ascenzo, Erica Cavallero, Giuseppe Biondi-Zoccai, Paola Boccone, Paolo Bironzo, Glenn N Levin, Robert H Eckel, Richard V Milani, Arthur I. Sagalowsky, Mauro Gasparini, Giovanni Grignani, Fiorenzo Gaita, Libero Ciuffreda, Massimo Aglietta
Journal: Journal of Clinical Oncology (2012)

e15192 Background: ADT is a mainstay treatment in pts with PC and is supposedly associated to an unfavorable metabolic and cardiovascular profile. Recently, a meta-analysis of randomized controlled trials (RCT) found no association between ADT and increased risk of CVE (JAMA 2011). However, no conclusive data were available about ADT association with metabolic changes and adverse CVE or DM because of pts selection in RCT. Therefore, we performed a meta-analysis of adjusted observational results in order to look for DM and CVE onset in an ADT unselected population. Methods: Medline, Cochrane Library and Biomed Central were searched for articles addressing adverse events related to ADT in patients with PC. Selection criteria were: not RCT, pts assigned to ADT or not, adjusted risk of CVE and DM according to ADT. Exclusion criteria were: duplicate publication, comparison of two different strategies of ADT (different drugs or duration). Cardiovascular death was the primary endpoint; non-fatal myocardial infarction (MI), stroke/transient ischemic attack (TIA) and new DM onset were secondary endpoints. Random effects model with generic inverse variance weighting was used to estimate adjusted risks as odds ratios (OR) with 99% confidence interval (CI). Results: We selected 12/2100 screened studies. We included 208643 pts of which 102177 received ADT. At a follow up of 5 years (4-7.5), ADT did not result as an independent risk factor for cardiovascular death (OR= 1.04; 99% CI= 0.94-1.14). No increased risk of MI (OR= 1.13; CI= 0.86-1.48) or of stroke/TIA (OR= 1.11; CI= 0.78-1.57) were detected. Incident DM was more frequent among ADT pts (OR= 1.32; CI= 1.14-1-53). Even in 7205 pts with previous CVE (2450 received ADT), ADT was not associated with an increased risk of overall death (OR= 1.23; CI= 0.87-1.75). Meta-regression analysis showed no significant interactions between duration of ADT and cardiovascular death or incident DM. Conclusions: In non-selected pts,ADT appears to increase the risk of incident DM, but not of CVE or stroke/TIA. Moreover, overall mortality is not increased in pts with a history of CVE.