14 results on '"T. Panella"'
Search Results
2. 1091TiP STARBOARD: Randomized phase III study of encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of metastatic or unresectable locally advanced BRAF V600-mutant melanoma
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A. di Pietro, Antoni Ribas, Reinhard Dummer, Anna Polli, Dirk Schadendorf, T. Panella, Meredith McKean, K. Brill, P.A. Ascierto, C. Robert, Ryan J. Sullivan, and Edgardo S. Santos
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business.industry ,Melanoma ,Mutant ,Locally advanced ,Binimetinib ,Hematology ,Pembrolizumab ,medicine.disease ,First line treatment ,chemistry.chemical_compound ,Oncology ,chemistry ,Encorafenib ,Cancer research ,Medicine ,business - Published
- 2021
3. ONCONASE(ONC), A PROTEIN USED FOR THE THERAPY OF PATIENTS WITH ADVANCED PANCREATIC CANCER (PC)
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Nancy Coombe, T. Panella, D. Meches, J. Costanzi, A. Mittelman, K. Shogen, S. Mikulski, C. Puccio, and Hoo G. Chun
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immunology ,A protein ,medicine.disease ,Phase i ii ,Internal medicine ,Pancreatic cancer ,Immunology and Allergy ,Medicine ,business - Published
- 1994
4. First-line encorafenib plus binimetinib and pembrolizumab for advanced BRAF V600-mutant melanoma: Safety lead-in results from the randomized phase III STARBOARD study.
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Dudnichenko O, Penkov K, McKean M, Mandalà M, Kukushkina M, Panella T, Csőszi T, Gerletti P, Thakur M, Polli A, di Pietro A, and Schadendorf D
- Abstract
Background: BRAF inhibitors plus MEK inhibitors (BRAFi/MEKi) and immune checkpoint inhibitors (CPIs) are approved for BRAF V600-mutant advanced melanoma. Combinations of BRAFi/MEKi with CPIs may further improve outcomes and could offer additional treatment strategies., Methods: STARBOARD (NCT04657991) is a phase III study with an initial safety lead-in (SLI) phase conducted to determine the recommended phase III dose (RP3D) for encorafenib in combination with binimetinib and pembrolizumab. Patients with untreated, unresectable locally advanced or metastatic BRAF V600E/K-mutant cutaneous melanoma received binimetinib 45 mg twice daily and pembrolizumab 200 mg every 3 weeks plus encorafenib 450 mg once daily (COMBO450 plus pembrolizumab) or 300 mg once daily (COMBO300 plus pembrolizumab). The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints included safety, objective response, time to response, and duration of response. Progression-free survival was assessed post hoc., Results: In the SLI, the median follow-up duration was 19.4 months. Twenty patients received COMBO450 plus pembrolizumab and 17 received COMBO300 plus pembrolizumab. DLTs occurred in 1 of 17 DLT-evaluable patients in the COMBO450 plus pembrolizumab arm and in 2 of 17 DLT-evaluable patients in the COMBO300 plus pembrolizumab arm. No treatment-related deaths occurred in either treatment arm. The overall response rate was 65.0 % in the COMBO450 plus pembrolizumab arm and 47.1 % in the COMBO300 plus pembrolizumab arm., Conclusion: The STARBOARD SLI showed that safety across the cohorts was generally comparable to the known safety profile of each agent. The standard dose regimen of COMBO450 plus pembrolizumab was chosen as the RP3D., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Oleksandr Dudnichenko: No disclosures or conflicts of interest to report. Oleksandr Dudnichenko. No disclosures or conflicts of interest to report. Konstantin Penkov. Honoraria: AstraZeneca, Merck Sharp & Dohme, Nektar, Pfizer, Regeneron Pharmaceuticals, Inc., Roche. Meredith McKean. Research Funding: Ascentage Pharma Group, Alpine Immune, Arcus Biosciences, Arvinas, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, Genentech, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, ImmViraPharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kinnate Biopharma, MedImmune, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar Therapeutics, Novartis, Oncorus, PACT Pharma, Pfizer, Plexxikon, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seagen, Synthrox, Tempest Therapeutics, TeneoBio, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences. Consulting or Advisory Role: Array BioPharma, Astellas Pharma, AstraZeneca, BicycleTx Limited, Castle Biosciences, IDEAYA Biosciences, iTeos, Therapeutics, MedPage Today, Pfizer, Regeneron. Mario Mandalà. Honoraria: MSD Oncology, Novartis, Pierre Fabre, Sanofi/Aventis, Bristol Myers Squibb/Sanofi. Consulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre. Research Funding: Novartis (Inst). Mariia Kukushkina. No disclosures or conflicts of interest to report. Timothy Panella. No disclosures or conflicts of interest to report. Tibor Csőszi. No disclosures or conflicts of interest to report. Paola Gerletti. Employment: Formerly Pfizer. Mahgull Thakur. Employment: Formerly Pfizer. Anna Polli. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Alessandra di Pietro. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Dirk Schadendorf. Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, Replimune. Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers’ Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, MSD, Pierre Fabre, Sanofi/Regeneron., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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5. Letter to the Editor: ETV6-NTRK2 Fusion Identified in a Patient with Medullary Thyroid Carcinoma.
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Alsharif O, Panella T, Nodit L, and Hu MI
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- Humans, Oncogene Proteins, Fusion, Carcinoma, Neuroendocrine, Thyroid Neoplasms pathology
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- 2023
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6. STARBOARD: encorafenib + binimetinib + pembrolizumab for first-line metastatic/unresectable BRAF V600-mutant melanoma.
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Schadendorf D, Dummer R, Robert C, Ribas A, Sullivan RJ, Panella T, McKean M, Santos ES, Brill K, Polli A, Pietro AD, and Ascierto PA
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- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Benzimidazoles, Carbamates, Humans, Mutation, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf genetics, Randomized Controlled Trials as Topic, Sulfonamides, Melanoma drug therapy, Melanoma genetics, Neoplasms, Second Primary etiology, Skin Neoplasms drug therapy, Skin Neoplasms genetics
- Abstract
Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600 -mutant melanoma in comparison to pembrolizumab.
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- 2022
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7. Breast Cancer in Elderly Caucasian Women-An Institution-Based Study of Correlation between Breast Cancer Prognostic Markers, TNM Stage, and Overall Survival.
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Orucevic A, Curzon M, Curzon C, Heidel RE, McLoughlin JM, Panella T, and Bell J
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There is still a paucity of data on how breast cancer (BC) biology influences outcomes in elderly patients. We evaluated whether ER/PR/HER2 subtype and TNM stage of invasive BC had a significant impact on overall survival (OS) in a cohort of 232 elderly Caucasian female patients (≥70 year old (y/o)) from our institution over a ten-year interval (January 1998-July 2008). Five ER/PR/HER2 BC subtypes classified per 2011 St. Gallen International Expert Consensus recommendations were further subclassified into three subtypes (traditionally considered "favorable" subtype-ER+/PR+/HER2-, and traditionally considered "unfavorable" BC subtypes: HER2+ and triple negative). OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis, when controlled for TNM stage. The majority of our patients (178/232 = 76.8%) were of the "favorable" BC subtype; 23.2% patients were with "unfavorable" subtype (HER2+ = 12% (28/232) and triple negative = 11.2% (26/232)). Although a trend for better OS was noted in HER2+ patients (68%) vs. 56% in ER+/PR+ HER2- or 58% in triple negative patients, "favorable" BC subtype was not significantly predictive of better OS (p = 0.285). TNM stage was predictive of OS (p < 0.001). These results are similar to our published studies on Caucasian BC patients of all ages in which ER/PR/HER2 status was not predictive of OS, irrespective of classification system used.
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- 2015
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8. Is the TNM staging system for breast cancer still relevant in the era of biomarkers and emerging personalized medicine for breast cancer - an institution's 10-year experience.
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Orucevic A, Chen J, McLoughlin JM, Heidel RE, Panella T, and Bell J
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- Breast Neoplasms blood, Breast Neoplasms classification, Carcinoma, Ductal, Breast blood, Carcinoma, Ductal, Breast classification, Female, Humans, Neoplasm Staging, Precision Medicine methods, Prospective Studies, Receptor, ErbB-2 blood, Receptors, Estrogen blood, Receptors, Progesterone blood, Biomarkers, Tumor blood, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology
- Abstract
We have previously demonstrated that TNM status and age were significant predictors of overall survival (OS) in our study population of Caucasian patients with invasive breast carcinoma (2000-2004 study period). However, estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) biomarker expression was not predictive of OS when using the five-group ER/PR/HER2 subtype classification system recommended by St. Gallen International Consensus Panel in 2011. The current study reassessed the relevance of tumor biomarkers (ER/PR/HER2) in our study population using a recently proposed biologic TNM (bTNM) classification system in which the inclusion of triple negative ER/PR/HER2 phenotype (TNP) could improve the prognostic accuracy of TNM for staging, prognosis and treatment of breast cancer patients. Seven hundred eighty-two Caucasian women diagnosed with invasive ductal carcinoma from 1998 to 2008 were grouped according to their TNM stage and TNP versus non-TNP ER/PR/HER2 phenotype. OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis. TNM stage (Stage II = HR 1.41, 95% CI 1.01-1.97; Stage III = HR 3.96, 95% CI 2.68-5.88; Stage IV = HR 27.25, 95% CI 16.84-44.08), and age (HR 1.05, 95% CI 1.04-1.06) were significant predictors of OS. TNP significantly worsened prognosis/survival only in higher TNM stages (Stage III = HR 3.08, 95% CI 1.88-5.04, Stage IV = HR 24.36, 95% CI 13.81-42.99), but not in lower stages (I and II). Our data support the traditional TNM staging as a continued relevant predictive tool for breast cancer outcomes and show that biomarkers primarily improve the accuracy of TNM staging in advanced stages of breast cancer. We suspect that type of ER/PR/HER2 classification system(s) (St. Gallen, TNP, etc.), characteristics of populations studied (Caucasians, minorities, etc.), and the time period chosen for a study are major factors that determine impact of biomarkers on the prognostic accuracy of TNM. We propose systematic analyses of these factors before biomarkers are fully incorporated into the TNM staging system (bTNM)., (© 2015 Wiley Periodicals, Inc.)
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- 2015
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9. Prognostic value of breast cancer subtypes, Ki-67 proliferation index, age, and pathologic tumor characteristics on breast cancer survival in Caucasian women.
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Ferguson NL, Bell J, Heidel R, Lee S, Vanmeter S, Duncan L, Munsey B, Panella T, and Orucevic A
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- Adult, Age Factors, Aged, Aged, 80 and over, Analysis of Variance, Breast Neoplasms classification, Carcinoma classification, Cell Proliferation, Female, Humans, Kaplan-Meier Estimate, Ki-67 Antigen metabolism, Middle Aged, Multivariate Analysis, Neoplasm Grading, Neoplasm Staging, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Retrospective Studies, Statistics, Nonparametric, Young Adult, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma metabolism, Carcinoma pathology, White People
- Abstract
Estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) status are well-established prognostic markers in breast cancer management. The triple negative breast carcinoma subtype (ER-/PR-/HER2-) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women. We evaluated the prognostic value of breast cancer subtypes, Ki-67 proliferation index (Ki-67PI), and pathologic tumor characteristics on breast cancer survival in Caucasian women in our institution, where greater than 90% of the total patient population is white. From 628 new invasive breast cancer cases in our data base (2000-late 2004), 593 (94%) were identified in Caucasian women. ER/PR/HER2 breast cancer subtypes were classified based on St. Gallen International Expert Consensus recommendations from 2011. ER/PR/HER2 status and its effect on survival were analyzed using a Kaplan-Meier curve. ER/PR/HER2 status, grade, tumor-node-metastasis status (TNM)/anatomic stage, and age were analyzed in terms of survival in a multivariate fashion using a Cox regression. Ki-67PI was analyzed between ER/PR/HER2 groups using the Kruskal-Wallis, Mann-Whitney U-tests, and 2 × 5 ANOVA. Our results showed that patients with stage IIB through stage IV breast carcinomas were 2.1-16 times more likely to die than patients with stages IA-B and IIA disease, respectively (95% CI 1.17-3.81 through 9.68-28.03, respectively), irrespective of ER/PR/HER2 subtype. Similar effect was seen with T2, N2/N3, or M1 tumors in comparison with T1, N0/N1, and M0 tumors. Chances of dying increase approximately 5% for every year increase in age. There was a significant main effect of Ki-67PI between ER/PR/HER2 subtypes, p < .001, but Ki-67PI could not predict survival. In summary, TNM status/anatomic stage of breast carcinomas and age are predictive of survival in our patient population of Caucasian women, but breast carcinoma subtypes and Ki-67 proliferation index are not., (© 2012 Wiley Periodicals, Inc.)
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- 2013
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10. A randomized phase II study of paclitaxel and bevacizumab with and without gemcitabine as first-line treatment for metastatic breast cancer.
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Brufsky A, Hoelzer K, Beck T, Whorf R, Keaton M, Nadella P, Krill-Jackson E, Kroener J, Middleman E, Frontiera M, Paul D, Panella T, Bromund J, Zhao L, Orlando M, Tai F, Marciniak MD, Obasaju C, and Hainsworth J
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Bevacizumab, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, Follow-Up Studies, Humans, Lymphatic Metastasis, Middle Aged, Neoplasm Metastasis, Neoplasm Recurrence, Local pathology, Paclitaxel administration & dosage, Quality of Life, Survival Rate, Treatment Outcome, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Neoplasm Recurrence, Local drug therapy
- Abstract
Background: The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB)., Patients and Methods: In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m(2) (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m(2) (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life., Results: Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia (P = .001) and dyspnea (P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) (P = .021), FACT-B Social/Family Well-being (P = .041), and Breast Cancer-Additional Concerns (P = .008) scores than patients treated with PB+G., Conclusion: The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated., (Copyright © 2011 Elsevier Inc. All rights reserved.)
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- 2011
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11. Sarcoma of mandible.
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Carlson ER, Panella T, and Holmes JD
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- Adult, Chondrosarcoma surgery, Diagnosis, Differential, Female, Humans, Mandibular Neoplasms surgery, Neoplasm Staging, Chondrosarcoma pathology, Mandibular Neoplasms pathology
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- 2004
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12. Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma.
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Mikulski SM, Costanzi JJ, Vogelzang NJ, McCachren S, Taub RN, Chun H, Mittelman A, Panella T, Puccio C, Fine R, and Shogen K
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- Aged, Antineoplastic Agents adverse effects, Female, Humans, Infusions, Intravenous, Male, Mesothelioma mortality, Middle Aged, Multivariate Analysis, Proportional Hazards Models, Ribonucleases adverse effects, Statistics, Nonparametric, Survival Rate, Antineoplastic Agents therapeutic use, Mesothelioma drug therapy, Ribonucleases therapeutic use
- Abstract
Purpose: A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible., Patients and Methods: One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival., Results: Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths., Conclusion: Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.
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- 2002
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13. Relationship between response rate and median survival in patients with advanced nonsmall cell lung-cancer - comparison of onconase(r) with other anticancer agents.
- Author
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Mikulski S, Chun H, Mittelman A, Panella T, Puccio C, Shogen K, and Costanzi J
- Abstract
The role of systemic cytotoxic therapy for the treatment of advanced non-small cell lung cancer (NSCLC) remains controversial. The response rate (RR) and the median survival time (MST) are the two most frequently used parameters for the assessment of efficacy of the anti-cancer therapies. The relationship between the previously reported RRs and MSTs from published chemotherapy trials in patients with advanced NSCLC was examined using linear regression analysis. The MST of the thirty patients with advanced NSCLC treated with ONCONASE (ONC) as a single agent was 7.7 months which compared favorably with the MSTs of patients treated with a variety of chemotherapeutic regimens either as single agents or combinations, as well as placebo and supportive care only. Moreover, the toxicity profile of ONC compared favorably to the profiles of other chemotherapy regimens. ONC had a favorable impact on the overall MST, including patients with stage IV disease, patients with poor performance status, and patients previously treated with radiotherapy and chemotherapy. The MST of 5 patients who had a stabilization of previously progressive disease was 9.3 months. Based on its positive impact on the MST, ONC appears to have a single agent activity in patients with advanced NSCLC, and it should be further investigated, particularly in combination with synergistic drugs, in concurrently controlled and prospectively randomized clinical trials. The duration and the quality of survival should be considered as the most meaningful parameters in assessing clinical efficacy of anti-cancer agents.
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- 1995
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14. Differential molecular mechanism of the estrogen action that regulates lactoferrin gene in human and mouse.
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Teng CT, Liu Y, Yang N, Walmer D, and Panella T
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- Amino Acid Sequence, Animals, Base Sequence, Consensus Sequence, DNA metabolism, Endometrium drug effects, Endometrium metabolism, Endometrium pathology, Estrus, Female, Humans, Hyperplasia, Mice metabolism, Molecular Sequence Data, Receptors, Estrogen metabolism, Sequence Alignment, Sequence Homology, Species Specificity, Enhancer Elements, Genetic, Estrogens pharmacology, Gene Expression Regulation, Lactoferrin genetics, Mice genetics, Promoter Regions, Genetic
- Abstract
The 5'-flanking region of the human lactoferrin gene was isolated from a human placental genomic library. This genomic clone contains a 16-kilobase pair (kbp) insert and produces seven fragments when digested with the SacI restriction enzyme. We sequenced one of the fragments that comprises 1294 bp of the 5'-flanking sequence, 79 bp of the first exon, and 690 bp of the first intron. A major transcription start site was mapped by primer extension. The region immediately upstream from the transcription initiation site following the first exon is abundant in G and C nucleotides. In the promoter and 5'-flanking region within a 300-bp stretch (-465 to -165) of the DNA, we found a noncanonical TATA box (ATAAA), CAAT-like sequence (CAAC) and sequences homologous to the consensus SP1 binding site, Pu.1/Sp.1 binding element (PU box), two half-palindromic estrogen response elements (EREs; GGTCA), an imperfect ERE (GGTCAAGGCGATC), and a sequence resembling the chicken ovalbumin upstream promoter transcription factor (COUP-TF) binding site (GTCTCACAGGTCA). The COUP-TF binding site and the imperfect ERE shared five nucleotides (GGTCA). With the exception of the two half-palindromic EREs, the elements with very well matched sequences were also found in the corresponding positions in the mouse lactoferrin gene. The synthetic oligonucleotide, including the 26 bp of COUP/ERE sequence, was cloned before the SV40 promoter in a chloramphenicol acetyltransferase reporter construct. These chimeric plasmids were transiently transfected into human endometrium carcinoma RL95-2 cells to assess hormone responsiveness. We found that the COUP/ERE element acted as an enhancer in response to estrogen stimulation. In vitro DNase I footprinting analysis showed binding of the estrogen receptor on the imperfect ERE. In contrast to the mouse lactoferrin COUP/ERE element, COUP-TF does not interact with this element, as demonstrated by band shift assay and site-directed mutagenesis. Therefore, the molecular mechanisms of the estrogen action that govern the lactoferrin gene expression differ between mouse and human.
- Published
- 1992
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