tbuckley/cabot-search huggingface dataset:
Phase I and DCE-MRI evaluation of NGR-TNF, a novel vascular targeting agent, in patients with solid tumors (EORTC 16041)
Authors: H. van Laarhoven, W. Fiedler, I. M. Desar, S. van Asten, S. Marreaud, R. Belli, C. Bordignon, A. Heerschap, C. J. Punt, C. M. van Herpen
Journal: Journal of Clinical Oncology (2008)

3521 Background: NGR-TNF is a novel agent exploiting a tumor homing peptide (cNGRCG) that selectively targets CD13 that is expressed on tumor neovasculature. Preclinical data show that its antitumor activity is achieved by a change of vascular permeability (at low doses) and damage of tumor-associated blood vessels (at high doses). This phase I study was conducted to assess its safety, PK, PD, MTD, and optimal biological dose in patients (pts) with advanced solid tumors. Methods: NGR-TNF was administered once every 3 weeks by an IV infusion in 20 min in the first 18 pts and in 1 hr IV infusion in the other pts, to cohorts of 3–6 pts. The starting dose was 0.2 μg/m2. Dose escalation was performed with a doubling of the dose until G2 toxicity was observed; thereafter a modified Fibonacci schedule was used. DCE-MRI was performed in Cy 1 at baseline and 2 hours after start of the infusion at each DL. Results: 70 pts were treated with in total 179 Cy (1–12). 17 DLs have been visited (0.2 to 60 μg/m2). 4 DLTs (bronchospasm at 1.3 μg/m2; abdominal pain with hypotension at 8.1 μg/m2; dyspnea and acute infusion reaction at 60 μg/m2 - all G3) were observed. The MTD was 45 μg/m2 with no DLT in 9 pts. Most frequently related adverse events were chills (81%) and fever (58%). No objective responses were observed, 21 pts had SD. DCE-MRI data of 31 pts were available. At dose-levels ≥1.3 μg/m2 the majority of pts showed a decrease in Ktrans compared to baseline. Although the mean kep and Ktrans were not significantly different at baseline and follow-up, at dose-levels ≥1.3 μg/m2 the mean Ktrans significantly decreased (.015 vs .012 a.u. s-1; p <.05). For all DLs, the mean number of pixels with a low fraction of kep and Ktrans significantly increased (p<0.01), as seen with other anti- vascular agents. The change in Ktrans was not related with DL. AUC and Cmax increased dose proportional. TNF-RI and II increased with dose, but a plateau was seen ≥25.4 μg/m2. A dose-dependent increase of MIP-1β and MCP- 1 and decrease of EGF was seen. Generation of anti-NGR-TNF antibodies was not observed. Conclusions: NGR-hTNF is well tolerated; the MTD is 45 μg/m2. The DCE-MRI results suggest an anti-vascular effect of NGR-TNF. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MolMed S.p.A. MolMed S.p.A.
The use of dexrazoxane as a cardioprotectant in patients receiving epirubicin-based chemotherapy for metastatic breast cancer
Authors: A. Monnier, M. Marty, M. Espié, T. Delozier
Journal: Journal of Clinical Oncology (2005)

640 Background: The clinical utility of anthracyclines is limited by dose-related cardiotoxicity. Epirubicin, the 4’-epimer of doxorubicin, is reportedly less cardiotoxic than doxorubicin when administered at equimolar doses. However, the existence of cumulative dose-related cardiotoxicity of epirubucin is now clearly established. Dexrazoxane, a cardioprotective agent, has been shown to reduce the risk of anthracycline-associated cardiotoxicity. Methods: This multicenter, randomized, controlled study enrolled adult female subjects with advanced/metastatic breast cancer who had received prior anthracycline-based chemotherapy. Patients were randomized to receive anthracycline-based chemotherapy with or without dexrazoxane, (dose ratio for dexrazoxane:epirubicin = 10:1). Cardiac assessments were reviewed by an independent Adjudication Committee blinded to treatment arm. A reduction in left ventricular ejection fraction (LVEF) 10% measured by MUGA scan or 15% measured by echocardiography, or a reduction in absolute LVEF to a value below 45% was deemed to constitute a cardiac event. A sub-group analysis of patients treated with epirubicin alone (EPI, n=28) or epirubicin + dexrazoxane (DEX+EPI, n=29) was performed. Results: Median total cumulative doses of epirubicin (including pre-study exposure) were 742mg/M2 (range 375–1200) and 869mg/M2 (419–1188) respectively. Significantly fewer DEX+EPI patients developed a cardiac event (14%, 95% CI:4–32%) compared to the EPI group (43%, 95%CI:24–63%) (p=0.015, Pearson’s Chi Square test). Three patients in the EPI group developed congestive heart failure, (two NYHA grade III and one grade IV, total cumulative EPI doses 991, 952 and 610mg/M2 respectively). There were no cases of CHF in the DEX+EPI group, (p=NS). There was no significant difference in overall tumor response rates between the two groups; DEX+EPI 48% (95% CI 30–67%) vs EPI 25% (95%CI 11–43%), (p=0.054). Conclusions: This study confirms the cardiotoxicity of cumulative epirubicin-based chemotherapy. Dexrazoxane significantly reduces the risk of epirubicin-induced cardiotoxicity, both clinical and sub-clinical, without compromising tumor response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron Biopharmaceuticals Chiron Biopharmaceuticals
Effect of Diosgenin (Fenugreek) on breast cancer cells
Authors: Srinivasan Sowmyalakshmi, Rama Ranga, C. Gary Gairola, Damodaran Chendil
Journal: Cancer Research (2005)

5872   Worldwide, breast cancer is the most common cancer that affects women. It is estimated that one out of eight women in the United States is at risk of developing the disease during her lifetime. Despite the effectiveness of conventional treatments, their side effects call for a treatment modality with equal effect but with lesser side effects. In this context, herbal medicines have gained enormous attention. Fenugreek is one such herb which has been consumed in Asia, Europe and North Africa for a long time and has been reported to possess potent anti-diabetic, anti-inflammatory, anti-oxidant and anti-neoplastic activity. Diosgenin is one of the biologically active constituent of fenugreek seeds. In the present study, the effect of diosgenin on breast cancer cell lines was investigated. Cytotoxic assays showed that diosgenin reduced the viability of both the ER positive MCF-7 cells (20.63% at 25μM concentration) and ER negative MDA 231 cells (20.4% at 25μM concentration). A significant induction of apoptosis by diosgenin was observed in both the breast cancer cell lines-MCF-7 (55% at 20μM and 98% at 40μM) and MDA 231 (52% at 20μM and 98% at 40μM). In MCF-7 cells diosgenin induced p53 protein expression and also down regulated ER activation. However, in MDA 231 cells diosgenin increased caspase activation (6-fold) and also down regulated Bcl-2 protein expression. These results suggest that diosgenin may have a potential as an anti cancer agent in breast cancer therapy irrespective of their ER status. The future studies are planned to further characterize the molecular pathways involved in the mechanism of action of diosgenin as an anti cancer agent effective against breast cancer.
Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclophosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer.
Authors: M Venturini, P Bruzzi, L Del Mastro, O Garrone, G Bertelli, M Guelfi, S Pastorino, R Rosso, M R Sertoli
Journal: Journal of Clinical Oncology (1996)

PURPOSE To evaluate the effect of previous adjuvant chemotherapy with or without anthracyclines on overall survival (OS), progression-free survival (PFS), and objective response (OR) rates of metastatic breast cancer patients treated with cyclophosphamide, epidoxorubicin, and fluorouracil (CEF) as first-line chemotherapy. PATIENTS AND METHODS Three-hundred twenty-six assessable metastatic breast cancer patients entered onto four consecutive randomized trials performed in our Institution and North-West Oncology Group (GONO) cooperative centers from 1983 to 1994. Patients received CEF-based chemotherapy as first-line therapy and were then evaluated. One hundred forty-four patients (44%) did not receive previous adjuvant chemotherapy, and 143 (44%) and 39 (12%) patients received cyclophosphamide, methotrexate, and fluorouracil (CMF)-based and anthracycline-based adjuvant chemotherapy, respectively. RESULTS ORs to CEF chemotherapy were observed in 161 patients (49.4%). On univariate analysis, patients who had received prior adjuvant chemotherapy had a significantly lower probability of response than patients who did not: 43% versus 58% (P=.02). No difference between CMF-based (OR rate, 43%) and anthracycline-based (OR rate, 44%) adjuvant chemotherapy was observed. Stepwise logistic regression analysis indicated that adjuvant chemotherapy (P=.005), bone as dominant metastatic site (P=.02), and previous hormonotherapy for metastatic disease (P=.005) were the most important factors in predicting a poor OR rate. The median PFS and OS times of the whole group were 9.8 and 17.9 months, respectively. Patients who did not receive adjuvant chemotherapy had a longer survival time (21.1 months) compared with patients previously treated with CMF-based (15.3 months) or anthracycline-based (15.8 months) adjuvant chemotherapy. Multivariate analysis confirmed adjuvant chemotherapy to be among the strongest prognostic factors associated with both a poor PFS and OS. CONCLUSION Previous adjuvant chemotherapy adversely affects OR, PFS, and OS in metastatic breast cancer patients treated with the CEF regimen as first-line chemotherapy. No difference was observed between patients previously treated with CMF-based or anthracycline-based adjuvant chemotherapy.
Abstract 17960: Aortic Root Surgery in Patients With Marfan Syndrome in the Current Era: Analysis of Surgical Technique and Outcome in 59 Patients
Authors: Christine H Attenhofer Jost, Heidi M Connolly, Juan M Bowen, Chris Scott, Hartzell Schaff
Journal: Circulation (2012)

Background: There are few data on outcome of aortic root surgery in patients (pts) meeting strict diagnostic criteria for Marfan syndrome (MFS) in the current era. Methods: Pts with MFS referred fo...
Abstract 18591: Anatomically- Versus Clinically-derived Risk Scores Have Markedly Differing Predictive Abilities Following PCI For Multivessel CAD: The “TLR Paradox”
Authors: Jason C Kovacic, Atul M Limaye, Nilusha Gukathasan, Samantha Sartori, Paul Lee, Biana Trost, Birju Narechania, Swathi Roy, Swapna Sayeneni, Michael C Kim, Pedro Moreno Moreno, Usman Baber, Roxana Mehran, George Dangas, Annapoorna S Kini, Samin K Sharma
Journal: Circulation (2012)

Objectives: Risk scores for predicting events after PCI vary widely in their calculation, ranging from purely anatomical (SYNTAX risk score [SRS]) to purely clinical (ACEF, modified ACEF [ACEFmod], NCDR), while other scores combine both elements (Clinical SYNTAX score [CSS], New York State Risk Score [NYSRS]). We sought to clarify the utility of these scores for predicting clinical events in pts with triple vessel CAD undergoing PCI. Methods: Patients with triple vessel and/or LM disease with 12 month follow-up were studied from our single center PCI registry. Exclusion criteria included STEMI presentation, prior revascularization and shock. Clinical events at 12 months were compared to baseline risk scores, based on score tertiles and area under the receiver operating characteristic curves (AUC). Results: We identified 584 eligible patients (69.8±12.3yrs, 405 males). All scores were predictive of mortality, with the SRS being least predictive (AUC=0.66) (Figure). The most accurate scores for mortality were the CSS and ACEF (AUC=0.76 for both: p=0.019 and 0.08 vs. SRS, respectively). In contrast, the SRS and CSS were the only scores predictive of MI (both p&lt;0.05). For TLR, while the SRS trended toward being positively predictive (p=0.075), several scores trended towards a negative association, which reached significance for the NCDR (p=0.045) (Figure). No score was particularly accurate for predicting MACE (death+MI+TLR), with AUCs ranging from 0.53 (NCDR) to 0.63 (SRS). Conclusions: Competing factors influence mortality, MI and TLR after PCI. An increasing burden of comorbidities is associated with mortality, but a paradoxically reduced likelihood of TLR. On the other hand, anatomical complexity predicts MI. By combining these outcomes to predict MACE, all scores show reduced utility.
Significance of anti-HLA immunization in lung transplantation
Authors: Jérémie Reeb, Pierre-Emmanuel Falcoz, Nicola Santelmo, Ziad Mansour, Anne-Catherine Lejay, Stéphane Renaud, Anne Parissiadis, Daniel Hanau, Romain Kessler, Gilbert Massard
Journal: European Respiratory Journal (2011)

Objectives:  HLA immunization is triggered by pregnancy, blood transfusion or organ transplantation. It is recognized factor for graft dysfunction after kidney transplantation. This study explores influence of HLA antibodies on occurrence and severity of Bronchiolitis Obliterans Syndrome (BOS), and survival after lung transplantation (LT).   Methods:  Retrospective study from January 2004 to June 2010 including 99 LT in 96 patients. We determined 3 groups: specifically immunized against their pulmonary graft (group 1, n=16), non-specifically immunized (group 2, n=19), non-immunized (group 3, n=64). We compared FEV1 evolution curves at 1, 3, 6 months and every 6 months, survival with and without BOS (Kaplan Meier and Log rank), incidences of acute cellular rejection (ACR), lower respiratory infections and bronchial stenosis (Chi-2 and ANOVA).   Results:  Specific immunization (group 1) appeared 15 months (±14) after LT. Non-specific immunization (group 2) was detected 9 months (±32) before LT. A decrease of FEV1 was observed in group 1 at 24 and 30 months after LT (compared to group 3: p    Conclusion:  Anti-HLA immunization is related to early onset of BOS. Specific antibodies probably lead to humoral rejection. Non specific antibodies indicated sensitized status with increased incidence of ACR.
Immunological markers of outcome of non-small cell lung cancer
Authors: D. A. Potter, C. Amin, A. Mohiuddin, S. Badve, D. Davidson, K. Kesler, N. Hanna, H. Edenberg, L. Einhorn, R. Mitra
Journal: Journal of Clinical Oncology (2005)

7232 Background Previously, we identified by cDNA microarray analysis that upregulation of immune synapse markers, including CD2, CD3 epsilon, T cell receptor, CD28, HLA class I and II and CD86 correlates with lack of early recurrence of NSCLC in Indiana U. Cancer Center (IUCC) patients treated with surgery alone (all P<0.05). We now ask whether tumor infiltrating (TI) CD2+, CD4+ or CD8+ cells are upregulated in non-recurrent NSCLC and whether this observation can be validated by analysis of paraffin blocks from a Veteran’s Administration Medical Center (VAMC) tumor registry. Methods An observational protocol to study IUCC NSCLC tissue banked from patients with stage Ia-IIIb tumors was implemented. The IUCC patients were stratified into two groups: Group A (58%; n=15) exhibited no recurrence at two years following surgery and Group B (42%; n=11) exhibited recurrence, documented by tissue diagnosis. Group A was 73% stage I, 20% stage II and 7% stage III. Group B was 36% stage I, 9% stage II and 55% stage III. A validation set of 99 NSCLC patients who underwent resection at the Indianapolis VAMC was 66% pathological stage I, 20% stage II, and 13% stage III. Of the VAMC patients, 34% exhibited recurrence at 2 years. CD2+, CD4+ or CD8+ immunohistochemical stains were performed and 500 cells per tumor were counted. Stroma was excluded. Results IUCC Group A tumors exhibited increased TI CD8+ cells compared to Group B, 4.8 vs. 2.2% of total cells (P=0.024). In the VAMC set, TI CD8+ cells were increased in non-recurrent tumors, 1.6 vs. 1.1%, but the P value was not significant (P=0.38). In the VAMC set, TI CD2+ cells were increased in non-recurrent tumors, 2.2 vs. 0.68% (P=0.00034). TI CD4+ cells did not differ significantly in prevalence between recurrent and non-recurrent tumors in the IUCC or VAMC patient populations. CD56 staining exhibited no significant NK cell infiltration. Conclusions Intraepithelial T cell tumor infiltration is confirmed to be negatively associated with relapse and validated in a second patient population. IHC results from rapidly fixed tissue suggest that CD8 T cell mechanisms may influence the outcome of NSCLC following surgical resection with curative intent. Supported by NIH P20-GM66402–02 and the Thoracic Oncology Program at Indiana University. No significant financial relationships to disclose.
A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21)
Authors: M. J. Burnell, M. N. Levine, J. A. Chapman, V. Bramwell, T. Vandenberg, H. I. Chalchal, K. Albain, E. Perez, H. Rugo, K. Pritchard
Journal: Journal of Clinical Oncology (2007)

550 Background: CEF and AC followed by paclitaxel (AC/T) are commonly used adjuvant regimens in women with early breast cancer. In a trial conducted by the EORTC, NCIC CTG, and SAKK three months of dose-dense EC was equivalent to six months of CEF in women with locally advanced breast cancer. We hypothesized that three months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. The results of a planned interim analysis were presented in San Antonio 2006 (Abstract #53). We now present more detailed results on efficacy and toxicity. Methods: Women 60 years of age or younger, with axillary node positive or high risk node negative breast cancer were randomized to CEF, EC/T or AC/T for six months. Results: Between December 2000 and April 2005, 2104 patients were enrolled. The median follow-up is 30.4 months. Hazard ratios for recurrence are: AC/T vs. CEF, 1.49 (95% CI, 1.12–1.99), p=0.005; AC/T vs. EC/T, 1.68 (95% CI, 1.25–2.27), p=0.0006; and EC/T vs. CEF, 0.89 (95% CI, 0.64–1.22), p=0.46. Three year recurrence-free survival rates for CEF, EC/T, and AC/T are 90.1, 89.5 and 85.0%, respectively. There was no significant interaction between ER status and treatment. Multivariate analysis of predictive factors will be presented. The numbers of deaths are 50 (CEF), 47 (EC/T) and 65 (AC/T). There was more toxicity in CEF and EC/T compared to AC/T. Conclusion: AC/T given every three weeks, although less toxic is significantly inferior to CEF or EC/T in terms of relapse-free survival. It is too early to detect any difference between CEF and dose-dense EC/T. Our results indicate that there is still room to explore anthracycline and taxane adjuvant chemotherapy regimens. Supported by: NCI Canada and Canadian Cancer Society, Pfizer, Bristol-Myers Squibb, Amgen, Janssen Ortho, Ortho Biotech, and NCI US. [Table: see text] No significant financial relationships to disclose.
Mitomycin: ten years after approval for marketing.
Authors: D C Doll, R B Weiss, B F Issell
Journal: Journal of Clinical Oncology (1985)

Mitomycin was approved for marketing by the Food and Drug Administration in 1974 for use in gastric and pancreatic carcinomas when combined with other chemotherapeutic agents. Since then, mitomycin has been used extensively in combination chemotherapy for a variety of tumors, particularly in the past seven years. However, the contribution of this agent to the various drug regimens has not been adequately defined. Clear evidence of the drug's activity as a single agent has been seen in the intravesical treatment of superficial bladder carcinoma. Common toxicities include anorexia, vomiting, and myelosuppression. Less common, but potentially lethal, toxicities in the form of fibrosing alveolitis and microangiopathic hemolytic anemia with renal failure are being reported with increasing frequency. These potentially severe adverse effects, coupled with the still undefined role of mitomycin in systemic cancer chemotherapy, suggest that selection of this drug for other than investigational use should be made with care.
Clinical relevance of cyclin D1 protein overexpression in laryngeal squamous cell carcinoma.
Authors: L Pignataro, G Pruneri, N Carboni, P Capaccio, B M Cesana, A Neri, R Buffa
Journal: Journal of Clinical Oncology (1998)

PURPOSE To investigate the prognostic relevance of cyclin D1 gene overexpression in laryngeal squamous cell carcinomas (LSCCs). PATIENTS AND METHODS The overexpression of cyclin D1 was analyzed in 149 LSCC patients with a median follow-up duration of 60 months using the DCS6 monoclonal antibody; only cases that overexpressed cyclin D1 in more than 5% of neoplastic cells were considered positive. RESULTS Forty-eight cases (32.2%) were immunoreactive to the DCS6 antibody. Cyclin D1 overexpression was significantly associated with tobacco smoking and alcohol consumption, tumor extension, advanced clinical stage, and the presence of lymph node metastases. Univariate analysis showed that a shorter disease-free and overall survival were significantly associated with supraglottic site, tumor extension, advanced clinical stage, and cyclin D1 overexpression. At multivariate analysis, tumor extension and cyclin D1 overexpression were significantly associated with tumor recurrence, whereas tumor extension, supraglottic site and, at a borderline level of statistical significance, cyclin D1 overexpression, were associated with reduced overall survival. CONCLUSION The overexpression of cyclin D1 in LSCC is associated with unfavorable clinicopathologic features and represents an independent significant predictor of laryngeal carcinoma prognosis, particularly for disease-free survival. This indicates that cyclin D1 evaluation may be a further useful element for selecting subgroups of patients who should be treated with more aggressive therapies.
Outpatient versus inpatient autologous stem cell transplantation for malignant hematologic disorders
Authors: A. Ghavamzadeh, A. Allahyari, K. Alimoghaddam, A. Karimi, A. Shamshiri, R. Abolhasani, A. Manookian, M. Asadi, F. Khatami
Journal: Journal of Clinical Oncology (2009)

7042 Background: High-dose chemotherapy with autologous stem cell support is utilized for the treatment of a variety of malignancies including Hodgkin/non-Hodgkins lymphoma and acute leukemias. The aim of this study was to compare the time of engraftment and mortality rate and cost of neutropenic treatment in outpatient versus inpatient autologous stem cell transplantation (SCT). Methods: 9 outpatients (5 HL, 2 NHL, and 2 AML) were compared with 32 inpatients (15 HL, 8 NHL, and 9 AML; for whom the outpatient facilities were not ready) from May 2008 to December 2008. All patients were below 45 yrs; median age for outpatients and inpatients were 26 and 30 years respectively. Also all the patients were in complete remission and without significant organ failure. They received conditioning regimen (CEAM for NHL and HL, busulfan and etoposide for AML) and stem cell infusion in hospital. The day after SCT, outpatient group were discharged and followed by outpatient SCT team, and to be re-hospitalized in case of febrile neutropenia, after sepsis workup and performing chest x-ray, they were received the first dose of antibiotic in hospital and treatment continued in home. Results: For outpatients and inpatients, median time to WBC engraftment was 11 and 12 days (p = 0.03), time to PLT engraftment was 15 and 25 days (p = 0.20), number of transfused single donor PLT was 3 and 4.5 units (p = 0.21), duration of neutropenic fever was 6 and 9 days (p = 0.001), duration of hospitalization (after SCT) 0 and 16 (p &lt; 0.001), respectively. All outpatients are alive and 3 patients from other group died between days +35 and +100 after SCT due to transplantation complications. For inpatient group the cost of drugs, just for neutropenic fever antibiotic therapy was six times than outpatient group. Conclusions: Results show that out-patient autologous SCT in malignant hematologic disorders is feasible and comparable with inpatient protocol. We are waiting for more patients and longer follow-up for future conclusions. No significant financial relationships to disclose.