tbuckley/cabot-search huggingface dataset:
Differential microRNA expression in pleural mesothelioma: Implications for early detection and prognostication
Authors: H. I. Pass, A. Beck, M. Hoshen, H. Benjamin, H. Cholakh, E. Kostenko, M. Zepeniuk, D. Cohen
Journal: Journal of Clinical Oncology (2008)

11027 Background: MicroRNAs (mirs) are non-coding RNAs of ≈22 nucleotides that suppress translation of target genes by binding their mRNA and have a central role in gene regulation in health and disease. Malignant mesothelioma (MM) is an asbestos induced pleural neoplasm with a median survival (MS) of 12 months, and relatively little is known about the molecular events that lead to the development of this highly aggressive disease. Using a unique platform, we examined whether there were distinct mir profiles between MM and normal mesothelium, and whether mirs were associated with demographic/prognostic features in MM patients. Methods: 36 MM (8F,28M) with 20 matching peritoneum from the time of their resections were used for mir analysis. There were 10 Stage I/II (MS= 24 months) and 26 Stage III/IV patients (MS= 8 months). Samples were hybridized to Rosetta Genomics microRNA microarray. Stepwise Cox regression allowed the evaluation of the significance of individual and combined mirs on patient survival, alone or in tandem with clinical risk factors, such as stage, age, smoking and gender. Kaplan Meier plots and logrank analysis were used to compare survival and time to progress profiles of discrete groups. Results: For the 20 matched tumor/normal pairs, there were 136 miRs mirs expressed in at least one set of samples. Of these, 66 mirs were significantly differentially expressed (p<0.005) between MM and normal abdominal mesothelium. 34 mirs were upregulated in tumor vs. normal, while 32 were downregulated respectively. No differences in mir expression were seen with regards to gender, age, or the histology of the MM. In a univariate analysis, lower stage, epithelial histology, absence of lymph node involvement, minimal asbestos exposure and female gender were predictive of longer survival. The presence of 4 mirs significantly improved (p=9·10-6) survival in MM patients (MS >38 months) compared to those who did not express the mirs (MS =5 months). Conclusions: These data represent the first use of mirs for the discovery of potentially novel biomarkers as well as the prognostication of MM. Validation in larger subsets is ongoing and results will be discussed at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Rosetta Genomics Ltd. Rosetta Genomics Ltd. Rosetta Genomics Ltd. Rosetta Genomics Ltd. Rosetta Genomics Ltd.
Temozolomide (TMZ) and cisplatin (CDDP) combination in naïve patients with stage IV melanoma. Definitive results of a phase II multicenter trial
Authors: J. Tourani, E. Wiersbicka, L. Mourey, B. Guillot, B. Sassolas, C. Bedane
Journal: Journal of Clinical Oncology (2007)

8572 Background: TMZ, an imidazol derivative, is a second-generation alkylating agent. TMZ has shown some efficacy in metastatic melanoma and recently received extended approval to treat brain tumours. The purpose of this study was to test the efficacy and safety of combination therapy with TMZ plus CDDP in patients with metastatic melanoma. Methods: Patients with stage IV melanoma were required to have histologically proven measurable metastasis. Patients received as a first-line therapy a combined treatment with TMZ (200 mg/m 2 /day), days 1–5 and CDDP (75 mg/m 2 /day) on day 1.The treatment was given every 28 days, maximum 6 cycles. The primary end point was an overall response rate. Secondary end points were: tolerance, progression free survival (PFS) and OS. Results: Thirty patients (pts) were enrolled from 09–2003 to 11–2005: 17 males and 13 females. Median age was 59 years (min: 26; max: 83). Initial performances status was 0 (22 pts) and 1 (8 pts). A total of 126 cycles of chemotherapy were administered. Clinical toxicity was mild and no toxic death occurred. Dose modifications for TMZ were required in 40% of pts and for CDDP in 13.3% of pts. 21 cycles of chemotherapy (21/126) had to be delayed due to toxicity. Grade 3 and 4 toxicity was observed in 12 pts (40 %). 16 pts withdrew because of tumor progression, 4 were removed because of adverse events including neutropenia (3 pts) and medullar aplasia and sepsis (1 pt). No complete response was observed among the 28 evaluable pts. Five pts (17.8%) achieved a partial response. An additional 6 pts (21.4%) showed disease stabilization &amp; 17 pts (60.7%) revealed progressive disease. So the overall response rate was 17.8%. Median PFS of 29 evaluable pts was 111 days (min: 28; max: 808). Median response duration was 216 days. Conclusions: This combination therapy with TMZ and CDDP according to this schedule had an acceptable tolerance but gave a poor response rate comparatively to those reported previously by Tas and al (30%). Definitive data will be produced in June 2007. No significant financial relationships to disclose.
Phase II and pharmacokinetic (pk) study of induction docetaxel/cisplatin followed by pulsed docetaxel chemoradiation for stage III non-small cell lung cancer (NSCLC)
Authors: Y. Chen, K. J. Pandya, T. Smudzin, S. Strychor, B. Sidone, W. C. Zamboni
Journal: Journal of Clinical Oncology (2007)

18142 Background: We have previously reported that docetaxel (Doc) demonstrates longer G2/M arrest and better synergistic effects with irradiation when compared with paclitaxel in human lung cancer cell lines. We designed a phase II clinical study targeting micrometastasis using upfront induction chemotherapy (CT) with Doc/cisplatin (CP) followed by sensitizing Doc chemoradiation (CRT) for patients (pts) with stage III NSCLC. Methods: Pts with inoperable stage III NSCLC were eligible. Induction CT consisted of Doc 75 mg/m 2 and CP 75 mg/m 2 on d 1 followed by rhG-CSF (150 ug/m 2 sq on d 2 to 10). The CRT consisted of sensitizing Doc 12 mg/m 2 twice per wk with daily RT (64.8 Gy to gross tumors and 45–57.6 Gy to subclinical disease). PK studies of Doc were performed during CT and CRT in each pt. The clearance (CL) and area under the plasma concentration versus time curve (AUC) were estimated. Results: 26 pts were enrolled and 16 completed study. Overall response rate was 69% [50% (8/16) PR and19% (3/16) CR]. 2-year survival was 57 %. During induction CT, primary grade (G) 3 toxicities were allergic reaction (10%), non-neutropenic infection (20%), nausea/vomiting (N/V) (10%), fatigue (10%), hypertension (5%) hyperglycemia (5%), dyspnea (5%) &amp; fatigue (5%). There was no G3/4 hematologic toxicity. During CRT, 50% (4/8) of pts developed G3 esophagitis after Doc at 12 mg/m 2 . The next 8 pts received Doc at 10 mg/m 2 with only 1 pt developing G3 esophagitis. Other G3 toxicities from CRT were N/V (28%), fatigue (14%), loss of appetite (14%), flushing (7%), chest pain (7%), &amp; diarrhea (7%). No G3 or 4 pneumonitis or any G4 toxicity. Mean ± SD Doc CL at 75 and 10 mg/m 2 were 20 ± 5 and 22 ± 10 L/h/m 2 , respectively. Ratio of Doc CL at 75 to 10 mg/m2 within a pt was 1.0 ± 0.4. Doc AUC at 75 and 10 mg/m 2 were 3,933 ± 1,028 and 566 ± 257ng/ml·h, respectively. Conclusions: One-cycle full- dose Doc/CP with rhG-CSF followed by pulsed low-dose Doc CRT is associated with promising antitumor activity and low hematologic toxicity. Grade 3 esophagitis was associated with dose intensity of radiosensitizing Doc, and was minimized by dose reduction. Results suggest that this regimen should be further evaluated in pts with NSCLC. The PK disposition of Doc was similar at 75 and 10 mg/m 2 . No significant financial relationships to disclose.
Coagulation factors in citrated plasma predict for benefit from bevacizumab (B) in patients with advanced pancreatic cancer (APC): Results from CALGB 80303 (Alliance).
Authors: Jeffrey Melson Clarke, Herbert Pang, Mark D. Starr, Ace Joseph Hatch, Hedy Lee Kindler, Eileen Mary O'Reilly, Federico Innocenti, Alan P. Venook, Herbert Hurwitz, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2015)

306 Background: CALGB 80303 evaluated gemcitabine (G) in combination with either B or placebo (P) in 602 patients (pts) with APC. No significant difference in overall survival (OS) between treatment arms was observed. Previously, plasma EDTA samples from CALGB 80303 were analyzed and potential predictive biomarkers for B were identified. This follow-up analysis evaluated citrated plasma samples for circulating proteins related to matrix remodeling and coagulation. Methods: Multiplex ELISA analysis was employed to assess the following circulating factors: E-selectin, matrix metalloprotease (MMP) 2, MMP9, von Willebrand factor (vWF), D-dimer, thrombospondin 1, and tissue factor (TF). Thrombin-antithrombin complex (TAT) was analyzed using a standard enzyme immunoassay. Prognostic characteristics were determined by associating baseline values with OS using a Cox model. Predictive markers were identified with inclusion of a treatment by marker interaction term. Results: Baseline citrated plasma samples from 109 pts were included in this analysis (59 pts G+P; 50 pts G+B). Negative prognostic factors for OS were identified, including E-selectin (p &lt;0.01) for patients receiving G-based therapy, and E-selectin, TF, and vWF (p &lt;0.05) in pts receiving G+P. Potential biomarkers predicting for OS benefit from B were also identified. Pts with low (&lt; median) levels of TAT (interaction p=0.034) exhibited a median OS of 6.0 months (mo) vs. 8.3 mo (HR=0.49; 95%CI 0.28-0.88) when receiving G+P vs. G+B, respectively. Furthermore, pts with elevated levels of TF (&gt;Q3) were found to benefit from B (interaction p=0.021), with median OS of 4.3 mo vs 4.8 mo (HR=0.44;95%CI 0.18-1.08), respectively. Longitudinal analysis of samples collected at baseline and at cycle 3 indicated that only vWF changed in pts receiving G+P, with an increase in vWF (p&lt;0.05). Conclusions: In patients with APC, baseline levels of TAT and TF were identified as potential predictors of benefit from B. These data emphasize the importance of coagulation factors in modulating tumor angiogenesis. The potential predictive value of these factors warrants further validation.
Phase I study of vandetanib (V) and bevacizumab (B) combination therapy evaluating the VEGF and EGF signal transduction pathways in adults with solid tumors and NHL
Authors: M. Gutierrez, A. J. Murgo, D. Allen, I. Turkbey, E. R. Gardner, J. Trepel, H. Chen, G. Giaccone, J. H. Doroshow, S. Kummar
Journal: Journal of Clinical Oncology (2009)

3522 Background: (V), a small molecule tyrosine kinase inhibitor, has strong inhibitory activity against VEGFR-2 and the EGF RTK. (B), a humanized anti-VEGF monoclonal antibody, blocks the binding of human VEGF to its receptors. We proposed that dual blockade of the VEGF pathway provides an added therapeutic effect compared with either agent alone. Methods: A standard 3–6 pt/cohort design, dose-escalation Phase I study was performed. (V) was self-administered PO, days 1–21 of each 21-day cycle. (B) was administered by IV infusion Q 3 wks. Objectives: Determine the toxicity profile and the MTD of the combination of (V+B); evaluate (V) pharmacokinetics, changes in tumor vascularity by dynamic contrast enhanced MRI (DCE-MRI) and effects of (V+B) treatment on circulating endothelial progenitors and mature circulating endothelial cells. Eligibility: ECOG ≤ 2, adequate organ function. The MTD is the dose level at which no more than 1 of 6 patients experience DLT during the first 2 cycles of treatment, and the dose below at which at least 2 (of ≤6) patients have DLT due to drug treatment. Results: 9 pts have been accrued to date. Diagnosis: pancreatic-1, NSCLC-1, colorectal-3, peritoneal mesothelioma-1, melanoma-1, NHL-1, jejunal adenocarcinoma (JAC)-1. 1 DLT (gr 3 Allergic reaction) was observed at DL 2. HTN was the most common toxicity at DL 2. Other gr 2–3 toxicities seen beyond 2 cycles included: diarrhea, elevated creatinine, leucopenia, anemia, thrombocytopenia, hemorrhage, prolonged QTc interval, proteinuria, rash (hand-foot syndrome / acneiform). Partial Response (PR) was achieved in 2 pts (pancreatic 14 mos + and JAC 6 mos); disease stabilization in 5 pts (4 mos +). DCE-MRI results showed a reduction in the parameters of permeability, (ktrans and kep), associated with one PR. Conclusions: We decided not to escalate beyond DL 2 due to the gr 2–3 toxicities observed with chronic therapy. We recommend (V): 200mg daily and (B): 5mg/kg IV q3 weeks as the Phase II dose. [Table: see text] No significant financial relationships to disclose.
Evaluation of carfilzomib to disrupt the apoptotic threshold of B-cell lymphomas by targeting Bcl-2 family members and overcome rituximab (R) chemotherapy resistance.
Authors: G. P. Kaufman, F. J. Hernandez-Ilizaliturri, C. Mavis, R. Patil, M. S. Czuczman
Journal: Journal of Clinical Oncology (2010)

e18514 Background: The addition of R to chemotherapy has improved the clinical outcome of B-cell lymphoma, but also appears to be changing the biology of relapsed disease. We found that repeated exposure of lymphoma cells to R induced deregulation of Bcl-2 family members and the ubiquitin-proteasome system resulting in R and chemotherapy resistance. In an attempt to develop strategies targeting key regulators of the apoptotic pathway, we evaluated the biological effects of carfilzomib, a novel proteasome inhibitor, in lymphoma pre-clinical models. Methods: Experiments were conducted in various rituximab-chemotherapy sensitive (RSCL) and rituximab-chemotherapy resistant (RRCL) or in primary tumor cells isolated from biopsy specimens of patients with B-cell lymphoma [including: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Burkitt's lymphoma (BL)]. RSCL and RRCL were exposed to carfilzomib [LC50 for 48 hours], and changes in Bcl-2 family member levels were evaluated by Western blotting. RSCL, RRCL or tumor cells were exposed to escalating doses of carfilzomib alone or in combination with vorinostat. Changes in mitochondrial potential at 48hrs were quantified via alamar blue reduction and cell viability was determined using the CellTiter-Glo assay. Results: Carfilzomib was active in both RSCL/RRCL and in tumor cells derived from DLBCL, FL and BL. In vitro exposure to carfilzomib resulted in an upregulation of Bak and Noxa levels in RRCL but not in RSCL. Current data demonstrates that in vitro exposure of RSCL or RRCL to carfilzomib enhanced the anti-tumor effects of vorinostat. We are evaluating the effects of carfilzomib in combination with chemotherapy agents. Conclusions: Carfilzomib alters the balance of Bcl-2 members and induces cell death in B-cell lymphoma. In addition, it significantly enhances the anti-tumor activity of vorisnostat. Carfilzomib has the potential of becoming a novel and potent therapeutic strategy in the treatment of rituximab-chemotherapy resistant B-cell lymphomas. No significant financial relationships to disclose.
Abstract 16639: A Longer Qt Interval is Associated with Increased Risk of Atrial Fibrillation
Authors: Mala C Mandyam, Elsayed Z Soliman, Alvaro Alonso, Susan R Heckbert, Eric Vittinghoff, Gregory M Marcus
Journal: Circulation (2012)

Introduction: Abnormal activity of cardiac late sodium channels leads to increased intracellular calcium, a phenomenon believed to be important in atrial fibrillation (AF). Increased late sodium en...
Influence of loco-regional radiation therapy on subsequent cancer risk among BC pts with p53 germline mutations
Authors: A. Rahal, O. Caron, C. Bourgier, T. Frebourg, B. Bressac de Paillerets, L. Barreau, C. Pachet, M. Mathieu, H. Marsiglia, S. Delaloge
Journal: Journal of Clinical Oncology (2009)

11043 Background: The management of breast cancer (BC) patients (pts) with germline p53 mutations, a rare genetic condition, is not the object of specific recommendations. Preclinical data and preliminary clinical observations suggest a theoretically major radio-sensitivity and high risk of secondary radio-induced malignancies. It remains discussed whether the knowledge of a germline p53 mutation may influence treatment (trt) choices and have prognostic importance. We reviewed our cohort of BC diagnosed as first tumor in pts with germline p53 mutations within the past 11 years, with an attempt to describe secondary malignancies occurring after trt of primary tumor. Patients and Methods: 9 pts have been diagnosed and treated in our institution within the past 11 years for BC as first tumor in the context of a documented germline p53 mutation. Their tumor characteristics, treatment and follow-up data were extracted from prospectively-registered medical records. Results: Median age at diagnosis of primary BC was 32 (22–48). 7/9 pts had a family history compatible with Li Fraumeni syndrome, while 2 had no family history. No pt had previous knowledge of her p53 mutation. Primary tumors were ductal carcinoma in situ (4), infiltrating ductal carcinoma (4), phyllode tumor (1). 3 pts had conservative surgery and 6/9 underwent mastectomy (M). 6 received loco-regional radiation therapy (RT). None had prophylactic contra lateral mastectomy. Loco-regional (LRR) and contra-lateral relapses are listed in the Table , as well as incidence of second primaries within or outside radiation field. Second primaries were sarcoma in 3/4 cases and 1 was papillary thyroid carcinoma. Conclusions: Because of high risk of second breast primary and probably very high risk of radio-induced breast cancer, BC pts with germline p53 mutations should be advised bilateral prophylactic mastectomy and avoidance of radiation therapy. In this context, the knowledge of the mutation might be of great importance. [Table: see text] No significant financial relationships to disclose.
A phase II study of epothilone B analog (EpoB)-BMS 247550 (NSC#710428) in stage IV malignant melanoma (MM)
Authors: A. C. Pavlick, M. Millward, K. Farrell, A. Hamilton, A. Broseus, N. Haas, T. Shore, A. Jacquotte, D. Colevas, F. Muggia
Journal: Journal of Clinical Oncology (2004)

7542 Background: EpoB is a new non-taxane microtubule binding agent that leads to mitotic arrest. EpoB demonstrated activity in MM in phase I trials justifying this phase II study. Methods: Eligibility: Stage IV MM patients, treated and stable brain mets allowed, ECOG performance status 0–2, adequate hematologic and organ function, no pre-existing grade 2–4 peripheral neuropathy. Pts were stratified into previously untreated and prior therapy groups. Pts in the pre-treated group must have received DTIC or temoxolomide and may have received a maximum of 2 prior chemotherapies. Premeds of diphenhydramine, dexamethasone, ranitidine and ondansetron were given prior to EpoB 20 mg/m2, 1 h infusion, weekly ×3 every 4 weeks. Responses were evaluated every 2 cycles. Primary endpoint: Response rate (RR). Secondary endpoint: Time to progression (TTP). Results: 12 untreated and 12 pre-treated patients were accrued. 6 had prior immunotherapy. 5 had prior radiation. LDH was elevated in 9/23. 23 patients were evaluable. The inevaluable patient (no prior therapy) developed neurtopenic, septic shock after the first cycle of therapy and died. No responses were seen in either arm (RR=0,CI=95%). 18 patients progressed after 2 cycles. 5 patients received 3–6 cycles and had stable disease, but were removed due to toxicity. (Median TTP= 8 weeks). Grade III/IV toxicity included peripheral neuropathy (n= 6), neutropenia (n=3), dyspnea (n=4), fatigue (n=7), diarrhea (n=5), arthralgias (n=1) and myalgias (n=1). Conclusion: EpoB is inactive in untreated and previously treated MM. Moreover, this schedule may be more toxic than the every 3 week EpoB schedule. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CTEP
The frequency of febrile neutropenia in oncology patients receiving chemotherapy
Authors: K. Chohan, D. Lai, M. McNamara, L. Grogan, O. S. Breathnach
Journal: Journal of Clinical Oncology (2009)

e20691 Background:Febrile neutropenia (F/N) is a relatively common and serious side effect for oncology patients undergoing chemotherapy. Due to varying dosages and frequency of cytotoxic agents administered to oncology patients, the incidence and grade of neutropenia varies. The purpose of this study was to establish the frequency of febrile neutropenia in different chemotherapy regimens. Methods: Data was collected on 343 patients who underwent chemotherapy over a 9 month period. Regimens that caused at least one episode of febrile neutropenia in patients within that period were assessed in the study. A list of the patients on identified chemotherapy regimens during the time period was generated by the pharmacy department. Data on patients who had febrile neutropenia was obtained from their clinical notes. Clinical data was then obtained on all those patients. This information was then used to compare the frequency of febrile neutropenia in the included chemotherapy regimens. Results: 343 patients were included in this study. Of those, 41 patients developed febrile neutropenia within the 9 month period (11%); there were 49 cases of febrile neutropenia (14%) in total as some patients had more than one episode. Conclusions: Febrile neutropenia (FN) is a known potential side-effect from treatment with chemotherapy. This study highlights the rates of FN in patients treated within one centre. In patients being treated with specific chemotherapy regimens this study may guide the increased use of G-CSF and better outline the risk profile of such therapy to patients. [Table: see text] No significant financial relationships to disclose.
Infusion of a Non HLA-Matched Off-the-Shelf Ex Vivo Expanded Cord Blood Progenitor Cell Product Following Myeloablative Cord Blood Transplantation Is Safe, Decreases the Time to Hematopoietic Recovery, and Results in Excellent Overall Survival
Authors: Filippo Milano, Shelly Heimfeld, Ivy B. Riffkin, Ian Nicoud, Frederick R. Appelbaum, Irwin D. Bernstein, Colleen Delaney
Journal: Blood (2014)