tbuckley/cabot-search huggingface dataset:
Concordance between independently and investigator-assessed progression-free survival in CLEOPATRA.
Authors: David Miles, Sandra M. Swain, Young-Hyuck Im, Adam Knott, Graham Ross, Emma Clark, Mark Benyunes, José Baselga
Journal: Journal of Clinical Oncology (2012)

e11055^ Background: In CLEOPATRA, pertuzumab (P) + trastuzumab (T) + docetaxel (D) was compared to placebo (Pla)+T+D in HER2-positive 1 st -line MBC. In MBC trials, PFS rather than overall survival is often defined as the primary endpoint as PFS data are available earlier and later-line therapy does not impact results. The primary endpoint in CLEOPATRA, PFS, was assessed by an Independent Review Facility (IRF), with investigator (inv)-assessed PFS as a secondary endpoint. As a measure of consistency and robustness, concordance between IRF- and inv-assessed PFS was analyzed. Methods: PFS was defined as time from randomization to first documented radiographic evidence of progressive disease (PD) or death from any cause within 18 wk of the last IRF tumor assessment. Tumor assessments took place every 9 wk and continued until IRF-confirmed PD. Treatment decisions were solely based on the inv’s assessment of PD. Indicators of concordance between IRF- and inv-assessed PFS included: PFS event by IRF only; PFS event by inv only; PFS event by IRF and inv; no PFS event by IRF and inv. These indicators were assessed at any time on study, within 30 d or within 9 wk. Several pre-specified sensitivity analyses for PFS were also performed. Results: 808 pt were enrolled and central tumor assessments performed for 781 pt. Compliance with the schedule of tumor assessments was generally high and comparable between arms, with &gt;78% of pt undergoing assessments within 7 d of the scheduled visit over the 1 st yr. At any time on study, concordance between IRF- and inv-assessed PFS was 85%. Of the 15% discordant cases, an equal proportion was assessed by the IRF as a PFS event but not by the inv and vice versa. Estimates of the median time to PFS event based on IRF and inv assessments were identical, Pla+T+D: 12.4 mo, P+T+D: 18.5 mo (IRF: HR 0.62, P &lt; .0001; inv: HR 0.65, P &lt; .0001). Conclusions: Concordance between IRF- and inv-assessed PFS was high, supporting consistency and robustness of the PFS analyses. The subjective nature of PD and potential for bias were reduced by the double-blind, placebo-controlled study design; RECIST 1.0 criteria; identical schedule of assessments in both arms; IRF review and continuation of tumor assessments until IRF confirmation of PD.
Basic : Establishment of hepatitis C virus in vitro infection system using differentiated mesenchymal stem cell (MSC) to hepatocyte-Like cells (초)
Authors: Jung Eun Choi, Won Hee Hur, Kwang Soo Lyoo, Sung Woo Hong, Sung Woo Kim, Yong Ki Lee, Chang Wook Kim, Sang Wook Choi, Seung Kew Yoon
Journal: Clinical and Molecular Hepatology (2011)
Phase I clinical trial of bavituximab (Bavi) and paclitaxel (P) in patients (pts) with HER2-negative metastatic breast cancer (MBC).
Authors: Pavani Chalasani, Marilyn Marron, Kathryn Clarke, Kathy Schmidt, Alisa Powell, Maria Iannone, Alison Stopeck
Journal: Journal of Clinical Oncology (2013)

567 Background: Bavituximab is a novel tumor vascular targeting agent. It is an unconjugated, chimeric immunoglobulin G1 monoclonal antibody directed against phosphatidylserine (PS). PS is externally expressed on endothelial cells when exposed to hypoxia and/or other physiological stressors frequently observed in tumor-associated vasculature. On attaching to PS, Bavi triggers antitumor effects by inducing antibody-dependent cellular cytotoxicity and promoting antitumor immunity. Methods: We conducted a phase I clinical trial of Bavi in combination with P in pts with HER-2 negative MBC. Pts were treated with weekly P (80mg/m 2 for 3/ 4 weeks) and weekly Bavi (3mg/kg for 4/ 4 wks). Microparticle generation, activation and circulating endothelial cell apoptotic markers were measured by flow cytometry. Results: 14 pts with MBC were enrolled. Median age at MBC diagnosis was 50yrs. Seven pts had triple negative MBC; 4 pts presented with de-novo metastatic disease. Prior treatments included chemotherapy in the adjuvant/neoadjuvant setting (8); metastatic setting (2); adjuvant hormonal therapy (3). Best responses to date include complete response (1), partial response (6), stable disease (1), progressive disease (2) and too early to evaluate (4). Bavi related toxicities include grade2/3 infusion related reactions in 2 pts (1 discontinued Bavi). Bone pain, fatigue, headache and neutropenia were the most common adverse effects. 1 pt had a catheter associated upper extremity thrombosis requiring anticoagulation. Laboratory correlative studies revealed no evidence of platelet activation of PAC-1 or P-Selectin. Median platelet and endothelial microparticles decreased from baseline in response to therapy. Conclusions: Bavi is a novel vascular targeting agent that is well tolerated in combination with P. Early results show promise in terms of clinical responses with 8 of 10 evaluable patients having clinical benefit. Early biomarker results suggest no effect of therapy on platelet activation but decreases in circulating microparticles is observed. Clinical trial information: NCT01288261.
Geographic and site variability in the treatment of patients with metastatic gastric cancer.
Authors: Lisa M. Hess, Yajun Zhu, Astra M. Liepa, Xiaohong Li, William R. Schelman, Charles S. Fuchs, Thomas Adam Abrams
Journal: Journal of Clinical Oncology (2017)

153 Background: Previous work has demonstrated substantial heterogeneity in the treatment of metastatic gastric cancer (mGC) in the U.S. across all lines of therapy. However, the distribution of variability by region and clinical practice site is not well understood. Methods: De-identified patient-level electronic medical record (EMR) and claims data from IMS Oncology EMR and from Truven Marketscan, respectively, were used for this study. Eligible patients were age ≥ 18 years with newly diagnosed GC between 2007 and 2014. Metastases were identified by ICD-9 codes in the EMR and claims data or with evidence of stage IV or M1 disease in EMR. Patients classified with locally advanced/advanced disease were those who received chemotherapy without surgical intervention following diagnosis, regardless of absence or presence of metastases. Variability of treatment by line of therapy was measured by the Herfindahl-Herschman Index (HHI), a commonly used measure of market concentration in the business sector. The HHI was reported overall, by geographic region and practice site over time. Results: Overall, 2,368 IMS and 6,444 Truven patients treated for GC were identified; of these, 728 and 2,457 patients were classified with mGC in the IMS and Truven cohorts, respectively; 5,044 were diagnosed with advanced disease in Truven. Geographically (HHI regional scores ranged from 7-17), by line of therapy (7-17 in first line; 4-15 in second line), and over time, treatment variability was high. Practices treating a high volume of patients did not demonstrate lower variability than sites treating few patients with mGC. In the first-line setting, 83 of 87 and 223 of 228 regimens were used less than 5% of the time in patients with mGC in the IMS and Truven cohorts, respectively. Conclusions: Treatment variability was consistently high for all practice sites, geographic regions and year of diagnosis; in the business world a HHI score &gt; 2000 is reflective of a monopoly whereas in this study, HHI scores were generally &lt; 20, demonstrating high variability and the lack of any consistent treatment strategy. There is a need to identify best treatment practices to ensure care for patients with receive care that is in accordance with treatment guidelines.
Comparison of false positive rates for screening breast MRI in high risk women when studies are done stacked versus alternating.
Authors: Edress Othman, Jue Wang, Brian Sprague, Yongli Ji, Sally D. Herschorn, Marie Wood
Journal: Journal of Clinical Oncology (2013)

1512 Background: Screening breast MRI added to mammography increases screening sensitivity for high risk women. However, false positive rates are high for MRI and the optimal screening schedule is unclear. In this study we compare rates of false positive MRI when studies were performed on a stacked or alternating schedule. Methods: We reviewed charts for women at increased risk for breast cancer who had screening breast MRI between 2004 - 2012 at the University of Vermont. Eligible women had at least 1 MRI and 1 mammogram performed within one year. Charts were abstracted for clinical, radiological, and biopsy data. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined as MRI result of BI-RADS 3-4-5-0 with additional negative imaging within 12 months or benign biopsy. Results: 143 women had screening which met inclusion criteria; 45 per stacked schedule, 52 alternating, 40 mixed and 6 neither. Women in this study had similar characteristics with respect to age, ethnicity, menopausal status and indications for MRI (i.e. family history, BRCA mutation, biopsy history and prior chest irradiation). 371 MRIs were reviewed (165 stacked and 206 alternating). The overall false positive rate was higher in the stacked group vs. alternating [30(18.2%) vs. 21(10.2%), p=0.0264]. Using only BI-RADS 4-5-0 as a positive result that difference was lost. There were significantly more BI-RADS category 3 interpretations in the stacked vs. alternating MRIs [16(9.7%) vs. 6(2.9%), p=0.006]. The rate of BI-RADS category 4-5-0 was not different between the two groups [16(9.7%) vs. 17(8.3%), p= 0.6272]. A similar number of biopsies were performed in both groups Conclusions: MRI added to mammography for women at increased risk for breast cancer was associated with higher rates of false positive interpretations when studies were done on a stacked compared to alternating schedule. In this study the greater number of BI-RADS 3 interpretations with a stacked schedule accounted for this difference. Further studies are needed to identify the optimal screening schedule when adding MRI to mammography.
Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung
Authors: B. P. Wittgen, P. W. Kunst, K. van der Born, G. J. Peters, R. Perez-Soler, B. Metzheiser, S. Nicholson, W. Perkins, F. Pilkiewicz, P. E. Postmus
Journal: Journal of Clinical Oncology (2006)

7131 Background: Investigate the safety and pharmacokinetics of aerosolized SLIT (Sustained release Lipid Inhalation Targeting) cisplatin in patients with carcinoma of the lung. Methods: In this single-center, dose-escalating study patients received SLIT cisplatin for a maximum of 6 cycles. The dose level defines the cycle duration and number of inhalations per day. Safety data, including laboratory parameters, adverse events, pulmonary function tests, bronchial responsiveness, and radiographic imaging were collected and analyzed for all patients in order to determine toxicity. Pharmacokinetic data was collected during the first treatment course. Results: 17 patients and 1 patient on compassionate use received treatment. SLIT cisplatin was well tolerated. No dose limiting toxicity was observed. The maximum delivered dose was 60 mg/m 2 in a 2 week schedule and 40 mg/m 2 on a weekly schedule. Safety data showed no hematological toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Common side effects were nausea (66.7%), vomiting (44.4%), dyspnea (66.7%), hoarseness (27.8%), and fatigue (66.7%). Pharmacokinetic data showed very low systemic concentrations only at the higher doses. CTC grade-2 decrease in FEV1 and DLCO occurred both in 2 patients after 1 course, and grade-1 decrease in FEV1 and DLCO in 6 and 4 patients respectively. Best overall response was stable disease in 13 patients, while 4 had progressive disease (1 patient received only one course). These results indicate that high doses of aerosolized SLIT cisplatin can be inhaled safely. The therapeutic effect of the formulation will be tested in a phase II study. Conclusions: Inhaled SLIT cisplatin was found to be feasible and safe in patients with lung cancer. [Table: see text]
Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: Data from the Italian cohort of ipilimumab expanded access programme (EAP).
Authors: Paolo Antonio Ascierto, Ester Simeone, Vanna Chiarion-Sileni, Paola Queirolo, Michele Del Vecchio, Lorenza Di Guardo, Massimo Guidoboni, Paolo Marchetti, Gian Carlo Antonini Cappellini, Pier Francesco Ferrucci, Francesco Cognetti, Maria Grazia Bernengo, Michele Guida, Riccardo Marconcini, Mario Mandala, Giorgio Parmiani, Gaetana Rinaldi, Massimo Aglietta, Luana Calabro, Michele Maio
Journal: Journal of Clinical Oncology (2013)

9035 Background: Ipilimumab and vemurafenib have recently been approved as single agents for the treatment of unresectable or metastatic melanoma. Currently, limited data exist on the sequential treatment with these agents in patients (pts) with the BRAF mutation; here we evaluate the efficacy outcomes of pts enrolled in the EAP in Italy who sequentially received a BRAF-inhibitor and ipilimumab, or vice versa. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Patients were considered for this analysis if they tested positive for the BRAF mutation and had received a BRAF-inhibitor before or after ipilimumab treatment. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. Out of 173 BRAF positive pts, 93 (53.7%) were treated sequentially with both treatments: 48 pts received a BRAF inhibitor upon disease progression with ipilimumab and 45 pts received ipilimumab upon disease progression with a BRAF inhibitor. As of December 2012, median overall survival was 14.5 months (11.1-17.9) and 9.7 months (4.6-14.9) for the two groups, respectively (p=0.01). Among the 45 BRAF inhibitors pretreated pts, 18 (40%) had rapid disease progression (median overall survival: 5.8 months) and were unable to complete all four induction doses of ipilimumab, while the remaining 27 (60%) pts had slower disease progression (median overall survival: 19.3 months) and were able to complete the therapy with ipilimumab. Conclusions: These preliminary results suggest that, in BRAF-mutated pts, to start the sequential treatment with ipilimumab can provide a better survival than the reverse sequence. These findings deserve confirmation in a prospective study.
Analysis of four sorts of clinical factors associated with radiation-induced lung injury in patients with NSCLC after 3D-CRT
Authors: Y. Zhang, C. Liang, J. Li, S. Tian, J. Yu
Journal: Journal of Clinical Oncology (2009)

7552 Background: There are different clinical factors associated with radiation-induced lung injury in patients with non-small cell lung cancer (NSCLC) after three-dimensional conformal radiation therapy (3D-CRT) that have been studied, whereas their value are not same. According to their source, the factors can be sorted to four types. Methods: 119 NSCLC patients treated with 3D-CRT during 2003–2005 were retrospectively reviewed. They were divided into two arms according to whether grade &gt;2 radiation- induced lung injury named by RTOG 3.0 were observed. The clinical parameters related to radiation-induced lung injury were divided into four sorts: general state of health and systematic sickness (gender, age, KPS, COPD, heart disease, diabetes), tumor-related factors (location, stage, volume), radiotherapy-related factors (dose, fraction per day, target margin, dosimetric parameters), other treatment factors (chemotherapy timing and agents). Univariate and multivariate analyses of the relation between clinical parameters and radiation pneumonitis were performed. Results: Occurrence of grade &gt;2 radiation-induced lung injury was observed in 17/119 patients. In univariate analyses, GTV (p=0.009), ipsilateral mean lung dose (MLD)(p=0.017), ipsilateral lung V20 (p=0.036)and total lung MLD (p=0.034) were associated with radiation-induced lung injury. In multivariate analysis, ipsilateral lung MLD was the only independent factor associated with radiation-induced lung injury (p=0.019). A significant correlation was also observed between the three volumetric parameters (p≤0.001). Conclusions: Ipsilateral lung MLD was the only independent factor associated with grade &gt;2 radiation-induced lung injury in our study, so that it should be included as a dose constraint factor for 3D-CRT of NSCLC. No significant financial relationships to disclose.
Modulation of antitumor T cell responses induced by everolimus in metastatic Renal Cell Carcinoma patients.
Authors: Olivier Adotevi, Laurent Beziaud, Laura Mansi, Caroline Laheurte, Thierry Nguyen, Tristan Maurina, Guillaume Mouillet, Lise Queiroz, Claire Jacquemard, Yann Godet, Bernard Royer, Antoine Thiery-Vuillemin, Christophe Borg
Journal: Journal of Clinical Oncology (2015)

e22113 Background: Everolimus has demonstrated activity in the treatment of metastastic renal cell carcinoma (mRCC) after failure of VEGF-targeted tyrosine kinase inhibitor. However, accumulating evidence highlights a central role for mTOR pathway in T cell activation and differentiation. For example, mTOR inhibition can induce regulatory CD4 T cells (Treg), which promote immunosuppression required to prevent transplant rejection. Furthermore, recent studies have reported that blocking mTOR can also stimulate T cell responses under selective conditions. Thus we performed an immunomonitoring study in order to evaluate simultaneously Treg and antitumor T cell responses in mRCC patients treated with everolimus. Methods: ThirtymRCC patients eligible for everolimus treatment were enrolled in this study and blood lymphocytes were collected prior treatment and every two months thereafter. Blood CD4+CD25+Foxp3+ Tregs were measured by flow cytometry and antitumor T cell reactivity was evaluated by IFN-g ELISpot assay using telomerase as tumor antigen. The inhibitory properties of Treg after everolimus treatment of T cells from healthy donors were analyzed in vitro. Results: We observed that 80 percent of patients had an increase of the Treg cells after everolimus treatment (3.5% at baseline vs 6.2% at the last sample). This increase of Treg following everolimus treatment occurred often at the time of disease progression. In vitro experiments also showed that Tregs cultured in presence of everolimus exhibited higher immune suppressive functions. Paradoxically, we showed strong antitumor T cell responses in some patients upon everolimus treatment and often at the time of disease control, and these responses greatly decreased when tumor progressed. Conclusions: These data suggest that everolimus shape host immune responses, which in turn could contribute to the efficacy of the anti-mTOR therapy. Thus, it could be interesting to take into account the modulation of T antitumor responses induced by anti-mTOR drugs for the management of mRCC patients.
Correlation of chromosome (Chr) 14 loss and 5q gain with outcomes of pazopanib treatment in patients (pts) with metastatic clear cell renal cell carcinoma (mRCC).
Authors: Gary R. Hudes, Jianming Pei, Yuan Liu, Robert C. Gagnon, Christopher Carpenter, Lini Pandite, Joseph Testa
Journal: Journal of Clinical Oncology (2012)

4605 Background: The identification of molecular prognostic and/or predictive determinants of outcome in pts with mRCC is an important challenge. We hypothesized that specific tumor DNA copy number alterations (CNAs) - loss of chr 14 or 14q (14/14q-), and gain of chr 5q (5q+) may predict likelihood of pazopanib treatment benefit in pts with mRCC. Methods: Pts DNA samples from the Phase II (VEG102616) pazopanib trial were analyzed by using Affymetrix OncoScan. Copy no. data were moving smoothed and normalized. The copy no. and allele difference were profiled according to their chromosome locations to interrogate CNA and LOH. Objective response (OR, RECIST) and progression free survival (PFS) were determined by investigators (IN) and an independent review (IR) committee. OR and PFS data were analyzed using exact and Kaplan-Meier tests. Results: Tumor DNA samples from 75 pts were adequate for CNA analysis. 14/14q- was found in 35/75 pts (46.7%), and 5q+ was found in 37/75 (49.3%). 14/14q- was present in the tumors of 12/31 pts (39%) with OR by IR compared with 23/44 (52%) nonresponding pts (p=0.347). 14/14q- did not affect PFS. 5q+ was present in tumors of 17/31 pts (55%) with OR and 20/44 (45%) nonresponding pts (p=0.486). PFS was longer in pts with 5q+ tumors compared with those without 5q+ (log rank p=0.026), with median PFS of 66 vs 35 wks, respectively. The odds of achieving OR decreased as the total number of chromosomal gains/losses increased (p=0.032, odds ratio 0.49), but this had no effect on PFS. In exploratory analysis, we examined the combined effect of both 14/14q- and 5q+ on PFS (Table). Conclusions: Pts with 5q+ tumors have significantly longer PFS, with no effect on OR rate. While 14/14q- alone had no effect on outcomes, the combination of 5q+ and no 14/14q- was associated with significantly greater PFS. Pts with more genetically complex tumors were less likely to obtain OR with pazopanib. [Table: see text]