tbuckley/cabot-search huggingface dataset:
Phase I study of pemetrexed in recurrent/metastatic head and neck squamous cell cancer (HNSCC) and to assess the need for steroid premedication
Authors: A. Coscio, W. N. William, L. Feng, B. Glisson, R. Ayuste, L. Ginsberg, J. J. Lee, C. Obasaju, S. M. Lippman, E. S. Kim
Journal: Journal of Clinical Oncology (2009)

e17009 Background: Pemetrexed is a novel antimetabolite that inhibits both purine and pyrimidine biosynthesis. Because its mechanism of action is similar to that of both methotrexate and 5-FU, it may also have activity in recurrent/metastatic HNSCC, a disease with limited treatment options and very poor median survival. Pemetrexed is traditionally prescribed with steroids due to skin toxicities observed in early studies; however vitamin supplementation (B12 and folic acid) was not standard at the time of those studies. No study to date has evaluated the optimal use of steroids with pemetrexed in the era of vitamin supplementation. Methods: All patients had metastatic or recurrent HNSCC, were treated with at least one prior chemotherapy regimen, and had ECOG PS of 0–2. The first cohort of patients received pemetrexed 500 mg/m 2 every 3 weeks and the next receiving 600 mg/m 2 based on a predefined standard dose escalation design. Within each dose level, patients were randomized to one of 3 premedication regimens: no dexamethasone, 20 mg IV on day 1, or standard 4 mg orally bid for 3 days. All patients received vitamin supplementation. The primary endpoint of the study was to determine the maximum tolerated dose of pemetrexed based on steroid premedication. Results: From October 2005 to March 2008, 36 patients were enrolled and 31 were available for evaluation. Median age was 57 years (range 42–82). 51.5% of patients had more than one prior chemotherapy regimens, 81.8% of patients had prior radiation therapy, and 48.5% of patients had prior surgery. Incidence of rash and combined skin toxicities were: 1/11 (9%) and 3/11 (27%) of patients without steroids, 1/11 (9%) and 3/11 (27%) with single IV dose, and 4/9 (44%) and 5/9 (55%) with oral steroids. No treatment-related grade 3 toxicities were observed. One patient initially received no steroid and required dose reduction and addition of steroid due to grade 2 rash. A partial response was observed in one patient (3.2%), and stable disease in 8 patients (25.8%) for a disease control rate of 29%. Conclusions: This is the first study to report the role of steroids as a premedication for pemetrexed. Our data suggests that no steroid premedication is needed with pemetrexed and vitamin supplementation. [Table: see text]
A comparative serum proteomic analysis of responders versus non-responders in a phase II study of recombinant human Angiostatin (rhAngiostatin) protein + carboplatin + paclitaxel in advanced non-small cell lung cancer (NSCLC)
Authors: A. Kurup, R. J. Hickey, L. E. Dobrolecki, L. J. Rosenberg, C. Pan, D. D. Estes, N. H. Hanna
Journal: Journal of Clinical Oncology (2004)

7151
Abstract 93: A Percutaneous Left Ventricular Assist Device Improves Survival in a Porcine Model of Cardiac Arrest and Resuscitation
Authors: Matthias Derwall, Andreas Ebeling, Philipp Föhr, Anne Brücken, Christoph Nix, Michael Fries
Journal: Circulation (2012)

Introduction: Manual chest compressions usually result in 20-30% of normal vital organ blood flow. Hence, improving circulation during cardiopulmonary resuscitation (CPR) may increase the number of successfully resuscitated patients. Hypothesis: Optimizing intra- and post-CPR hemodynamics by using a percutaneous intravascular left-ventricular-assist device (LVAD) instead of chest compressions increases the rate of return of spontaneous circulation (ROSC). Methods: Seven pigs were instrumented with an LVAD (Impella 2.5, Abiomed, Danvers, MA) and a pulmonary artery catheter to measure mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), mean pulmonary artery pressure (MPAP) and pulmonary capillary wedge pressure (PCWCP). Data from previous experiments (Derwall et al. Shock 2010) using conventional CPR with a piston driven chest compressor served as control (n=8). In both groups CA was electrically induced and left untreated for 10 minutes before CPR was attempted, either by activating the LVAD at the highest possible flow, or performing chest compressions at a rate of 100/min. After two injections of 1mg adrenaline and a total of 6 minutes CPR, defibrillation was attempted. Hemodynamic values were recorded for 120 minutes before animals were weaned from the respirator. Results: On average, the LVAD delivered 1.3 ± 0.1 L/min during CPR (34 % of baseline CO) resulting in an increase in MAP from 18 ± 10 mmHg after 10 minutes of CA to 35 ± 2 mmHg before defibrillation (see Figure ; * indicates p&lt;0.05 for MAP at 10 vs. 16 min). MAP, HR, MPAP and PCWP did not differ before CA or after 120 minutes following CPR. While all animals (n=7) in the LVAD group presented with ROSC following CPR, only 50% (n=4) of the animals in the chest compressions group could be successfully resuscitated (p=0.035). Conclusion: Using a percutaneous LVAD instead of conventional chest compressions did not significantly alter post-CPR hemodynamics, but improved the rate of ROSC in this model.
Molecular predictors of response to antiangiogenic therapy in HCC: Data from bevacizumab and erlotinib phase II study.
Authors: A. O. Kaseb, J. Morris, M. Hassan, M. Iwasaki, L. Deaton, M. M. Javle, E. Garrett-Mayer, G. Onicescu, J. L. Abbruzzese, M. B. Thomas
Journal: Journal of Clinical Oncology (2010)

4046 Background: It is well established that angiogenesis is the hallmark of hepatocellular carcinoma (HCC). Although targeting the vascular endothelial growth factor (VEGF) pathway has been shown to be of benefit to patients with HCC in phase III clinical trials, the benefit is marginal on the order of a few months. Therefore, it is essential to identify those patients who are likely to benefit from therapy. Our recent phase II trial of 40 patients with the combination of bevacizumab (anti-VEGF) plus erlotinib (anti-EGFR) was the first to report the clinical activity of the combination of these agents in HCC. We investigated the relationship between baseline plasma biomarkers and clinical outcomes. Methods: ELISAs were used to measure the plasma levels of VEGF-A, C, D; VEGFR-1, 2; angiopoietin-2 (Ang-2), PDGFR, and EGFR. Blip plots were made to explore the distribution of each marker. The Kruskal-Wallis test was used to compare expression level by response: complete response (CR)/partial response (PR), stable disease and progressive disease. The Log-rank test, univariate and multivariate Cox proportional hazards regression analyses were used to assess the association between markers and association of markers with the overall survival (OS) and the progression-free survival (PFS) using RECIST criteria. Spearman correlation coefficient and Fisher's exact test were computed to determine the association of VEGF with other markers. Results: We found statistically significant association between: (1) higher Ang-2 and decreased OS (HR = 3.75, 95% CI 1.22-11.5, p = 0.02), and (2) higher VEGFR-2 and decreased PFS (HR =2.59, 95% CI 1.21-5.54, p < 0.01). VEGF was significantly associated with Ang2 (coefficient rho = 0.34 and p-value = 0.04; Fisher's exact test p value = 0.02). Furthermore, patients with progressive disease had the lowest expression of plasma EGFR compared with patients with stable disease or CR/PR (p = 0.004). Conclusions: These results suggest that circulating baseline levels of cytokines mediators may select for patients who could benefit from targeted antiangiogenic therapy. Prospective validation is warranted. No significant financial relationships to disclose.
Abstract 18138: Liver Stiffness Shown by Transient Elastography - Potential Marker for Liver Dysfunction in Heart Failure
Authors: Tatsunori Taniguchi, Tomohito Ohtani, Toshinari Onishi, Hidetaka Kioka, Yasumasa Tsukamoto, Osamu Yamaguchi, Koichi Toda, Satoshi Nakatani, Yoshiki Sawa, Yasushi Sakata
Journal: Circulation (2014)

Background: Several studies have reported the prognostic importance of liver function test (LFT) abnormalities in patients with heart failure (HF). Recently, we illustrated a strong association between liver stiffness (LS) assessed by transient elastography and right-sided filling pressure in HF patients. The aim of this study was to investigate whether LS is better for predicting outcome than LFTs. Methods: We determined LS values using a Fibroscan® device prior to discharge in 157 HF patients (age 64±15 years, male 69%, LVEF 44±18%). Routine laboratory tests including LFTs (AST, ALT, GGT, ALP, LDH, total and direct bilirubin) and brain natriuretic peptide (BNP) measurements were also performed. Patients were followed for cardiac death or re-hospitalization for HF. Cox proportional-hazards regression was used to adjust for the effect of differences in covariates on clinical event rate. The incremental value for each measurement was assessed by comparing model χ2 statistics. Results: Forty-three patients ...
Outcome of rare types of breast cancer in Hispanic woman.
Authors: Saul Campos Gomez, Marlid Cruz, Sandra Ileana Perez Alvarez, Armando Gamboa Dominguez, Alejandra Soriano Rodriguez, Eucario Leon Rodriguez
Journal: Journal of Clinical Oncology (2012)

96 Background: Rarer histological types of breast cancer represent less than 5% of all cases. The identification might be of value in assessing prognosis and predicting response to therapy in a Hispanic population. Methods: A total of 1,400 consecutive woman diagnosed with any type of breast cancer between 1991 and 2010 were identified. Histological types were classified according to World Health Organization criteria and the Armed Forces. Ductal, lobular and mixed ductal/lobular carcinomas and women with missing data were excluded, leaving a total of 60 patients. Tumor grade, vascular invasion, hormonal receptor status, ki-67 labeling index, HER2 overexpression, tumor size and nodal status were recorded and analyzed by histologic type. Survival curves were calculated by histology. Results: A total of 60 patients were classified according histology in order of frequency as mucinous (36.7%), medullary (10%), papillary (8.3%), metaplastic (8.3%), tubulo-lobular (6.7%), tubular (5.0%), metaplastic with epidermoid differentiation (3.3%), signet cell adenocarcinoma (3.3%), apocrine (3.3%), neuroendocrine (3.3%), acinary (1.7%), histiocytoid (1.7%), leiomyosarcome (1.7%), phyllodes (1.7%), high grade sarcoma (1.7%), and mucinous papillary (1.7%). Women with leiomysarcome type had the youngest mean age at diagnosis (27y) followed by mucinous (32y), and high grade sarcoma was the oldest mean age (76yrs). Most of histologists (82%) presented as stage I and II at diagnosis. Only mucinous, medullary and metaplastic presented with advanced disease (4%). With respect to ER/PR status, 36% of mucinous cases and 60% of papillary cases were ER+/PR+, while 50% of medullary cases and 60% of metaplastic cases were ER−/PR−. Only 13% had overexpression of HER2. Compared with OS reported for ductal and lobular carcinoma, median survival was significantly longer 54 months (40.4–67.5) and DFS median 66.1 months (48-82 months). Conclusions: Rare breast carcinomas are a heterogeneous group with more favorable prognosis compared to ductal carcinoma. Though many of these histologic subtypes are quite rare, an accurate and reliable histopathology assessment is crucial in order to determinate treatment, principally to the need for systemic treatment.
Cellular immunotherapy redirected by bispecific antibodies in primary ovarian cancer cells: A preclinical study
Authors: J. K. Chan, C. A. Hamilton, M. K. Cheung, S. Schulz, S. H. Thorne, E. M. Anderson, J. Baker, A. Husain, N. N. Teng, C. H. Contag, R. S. Negrin
Journal: Journal of Clinical Oncology (2006)

2518 Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. This preclinical study demonstrates the enhanced effect of CIK killing in primary ovarian carcinoma using bispecific antibodies (BSAbs) and the potential of translating our findings to a clinical trial. Methods: Primary ovarian cancer cells and autologous CIKs were collected and cultured under IRB approval. Cytotoxicity enhancing BSAbs against CA125 (BSAbxCA125) and Her2/neu (BSAbxHer2) were designed using chemical conjugation methods. Tumor cell lysis of ovarian primary ovarian cancer cells was quantified using 51 Cr release assays. Anti-NKG2D monoclonal antibodies were used in antibody blocking assays. Using a SCID mouse model of minimal residual disease, tumor progression was monitored using the bioluminescence imaging (BLI) system. Three-color immunofluorescence analysis was performed on pathologic specimens to localize CIK migration to tumor cells. Results: The mean percent lysis with an Effector:Target (E:T) ratio at 100:1 was 22.2% (±2.0) in primary cells in 4-hour killing assays. Redirection with BSAbxCA125 significantly enhanced cytolysis to 65.7% (±0.6). Adding BSAbxHer2 significantly enhanced cytolysis of cell lines to 89.4% (±1.3). Anti-NKG2D antibodies significantly attenuated the CIK activity by 54%. In vivo BLI studies in SCID mice showed that CIK treatment at a 10:1 E:T ratio was well-tolerated and effective in reducing tumor burden by 80% after 21 days post-treatment compared to untreated mice (p&lt;0.0001). Immunofluorescence staining clearly depicted the in vivo infiltration of CIK (CD8 + NKG2D + ) cells into Her2-expressing tumor targets. Conclusions: Bispecific antibodies effectively enhanced the cytotoxicity of autologous CIK cells against fresh ovarian tumors. Our in vivo studies suggest that CIK cells may ultimately prove to be efficacious immunotheraputic modality in the treatment of resistant ovarian cancer. No significant financial relationships to disclose.
Can an annual infusion of zoledronic acid protect against cancer-treatment induced bone loss (CTIBL)?
Authors: J. E. Brown, J. Lester, S. Ellis, S. Gutcher, L. Turner, O.-P. Purohit, B. Hancock, R. Coleman
Journal: Journal of Clinical Oncology (2005)

8023 Background: With improved cure rates for certain malignancies, there are increasing numbers of long-term survivors, but cancer treatments may accelerate the normal processes of bone loss, leading to an increased risk of osteoporosis. Bisphosphonates are the treatment of choice in CTIBL with the new, potent bisphosphonates, such as zoledronic acid, offering a convenient, potentially effective option. Methods: The effect on bone mineral density (BMD) of an annual infusion of zoledronic acid (4 mg) is being assessed in 80 cancer survivors (at least one year since completion of curative therapy) who are osteopenic or osteoporotic using WHO T-score criteria on DEXA scan. In this single arm, open, phase II study, osteopenic patients are given a single IV infusion of 4 mg zoledronic acid at baseline and osteoporotic patients are given an infusion of 4 mg zoledronic acid at baseline, but receive a further infusion of 4 mg zoledronic acid after 12 months. BMD is measured by DEXA scan at the lumbar spine and hip at baseline and 6-monthly for 2 years. The bone resorption marker N-telopeptide (Ntx) is measured at baseline, 6 weeks, 3 months and then 3 monthly for 2 years. We report interim data in 75 patients (58 osteopaenic, 17 osteoporotic; 50 breast cancer, 12 testicular cancer, 13 lymphoma). Results: BMD showed significant increases from baseline with time at both the spine and hip (see table). In all patients, there was a significant, rapid fall in Ntx of approximately 60%, which was maintained in osteoporotic patients given a second zoledronic acid infusion. In osteopaenic patients, Ntx slowly increased with time but, remarkably, it remained approximately 30% below baseline, 24 months after a single infusion. Conclusion: The data have demonstrated in cancer survivors that a single infusion of zoledronic acid can lead to a significant steady increase in BMD and a reduction in bone resorption markers for up to 2 years. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
<i>NPM1</i> mutations as an independent prognosticator for older cytogenetically normal acute myeloid leukemia (CN AML)
Authors: H. Becker, G. Marcucci, K. Maharry, D. Margeson, M. D. Radmacher, S. P. Whitman, K. Mrózek, M. R. Baer, R. A. Larson, C. D. Bloomfield
Journal: Journal of Clinical Oncology (2009)

7000 Background: In younger CN AML without FLT3-ITD, NPM1 mutations predict favorable outcome. Their prognostic impact in older [≥60 years (y)] patients (pts) requires further evaluation. Methods: Pretreatment marrow was studied in 189 older CN AML pts [median age 69 y (60 - 83 y); 162 de novo &amp; 27 secondary (s; prior hematologic disorders) cases] enrolled on CALGB 9720 (n=106) &amp; 10201 (n=83). Both protocols had standard-dose (100 mg/m 2 /d) cytarabine (AraC)/daunorubicin (DN)-based induction; consolidation was based on standard-dose AraC/DN/etoposide (1 cycle) in 9720 &amp; intermediate-dose (2 g/m 2 /d) AraC (2 cycles) in 10201. Pts transplanted in 1 st complete remission (CR) were excluded. Median follow-up was 3.3 y for pts alive. Analyses of NPM1 exon 12 by direct sequencing, gene &amp; microRNA (miR) expression profiling by Affymetrix U133 plus 2.0 &amp; OSU CCC v4.0 arrays, &amp; other markers (FLT3-ITD, FLT3-TKD, WT1mut) were performed centrally. Results: In de novo CN AML, NPM1 mutated (NPM1mut) pts (54%) had more CRs (85% v 45%, P&lt;.0001) &amp; longer relapse-free (RFS) (P=.02; 3 y rates 23% v 10%) &amp; overall survival (OS) (P&lt;.0001; 3 y 34% v 7%) than NPM1 wild-type (NPM1wt) pts. In multivariable models, NPM1 mutations independently predicted favorable outcome (Table) - NPM1mut pts had 10-fold higher odds of CR &amp; 64% reduction in relapse risk. In genome-wide analyses, miR-10 &amp; miR-16 were upregulated in NPM1mut pts, accompanied by highly expressed HOX genes &amp; downregulated BCL2, respectively. NPM1mut were rare in sAML pts (15%), precluding study of their impact. Conclusions: NPM1 mutations independently predict better outcome in older CN AML. Upregulation of proapoptotic microRNAs &amp; downregulation of antiapoptotic microRNA targets may explain the impact of NPM1 mutations. [Table: see text] No significant financial relationships to disclose.
Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis
Authors: Bo Ri Seo, Priya Bhardwaj, Siyoung Choi, Jacqueline Gonzalez, Roberto C. Andresen Eguiluz, Karin Wang, Sunish Mohanan, Patrick G. Morris, Baoheng Du, Xi K. Zhou, Linda T. Vahdat, Akanksha Verma, Olivier Elemento, Clifford A. Hudis, Rebecca M. Williams, Delphine Gourdon, Andrew J. Dannenberg, Claudia Fischbach
Journal: Science Translational Medicine (2015)

Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
In Reply
Authors: Pier Luigi Zinzani, Pietro Quaglino, Nicola Pimpinelli, Emilio Berti, Gianandrea Baliva, Serena Rupoli, Maurizio Martelli, Mauro Alaibac, Giovanni Borroni, Sergio Chimenti, Renato Alterini, Lapo Alinari, Maria Teresa Fierro, Nazario Cappello, Alessandro Pileri, Davide Soligo, Marco Paulli, Stefano Pileri, Marco Santucci, Maria Grazia Bernengo
Journal: Journal of Clinical Oncology (2006)
Prolonged response to oral gefitinib, topotecan and cyclophosphamide in relapsed/resistant pediatric tumors
Authors: A. Donfrancesco
Journal: Journal of Clinical Oncology (2006)

13165 Background: Continuous schedule oral chemotherapy might be a suitable approach for resistant/relapsed pediatric tumors. Gefitinib (G) is an Epidermal Growth Factor Receptor (EGFR, HER1) inhibitor with documented activity in phase I/II adult tumor studies harboring activating mutations in the EGFR gene. Oral topotecan (TPT) and cyclophosphamide (CPM) in association have shown activity in a recent phase I study in pediatric patients (pts). Our study was aimed at evaluating the feasibility of a regimen based on oral G combined with oral TPT and CPM in pretreated pediatric pts. Methods: Pts received oral CPM (50 mg/m 2 /day) followed by TPT (0.8 mg/m 2 /day) plus G at the fixed dose of 250 mg/day for 14 consecutive days in an outpatient setting. Courses were repeated every 28 days and response was evaluated every two courses. EGFR mRNA expression in primary tumors was assessed by RT-PCR. Results: 7 pts (5M/2F), median age 8.7 years (range 4.4–22.5) were enrolled: 4 neuroblastoma (NB) pts relapsed after PBSCT and 3 sarcoma pts (1 rhabdomyosarcoma and 2 synovial sarcomas). 5 pts had PD at the time of inclusion, while 2 pts had SD after salvage therapy. Variable levels of EGFR mRNA were detected in 6/7 tumors, the only negative case being the rhabdomyosarcoma. A median of 6 courses (range 1–14) were administered. After a median follow-up of 7 months (range 3–15), 3 pts are DOD (1, 3, 8 months) and 4 pts are alive: 1 with PD, 2 with SD and 1 with CR at 13+, 7+, 7+ and 15+ months since inclusion, respectively. Median PFS was 7 months (range 1–15). Toxicity was mainly hematological (neutropenia), grade 4 according to CTC in 3/7 pts; cutaneous (rash) grade 2 and hepatic (LFT increase) grade 3 toxicity was reported in 1 pt each. 2 episodes of neutropenic fever (1 sepsis) were recorded. Conclusions: This regimen was feasible and well tolerated; a median PFS of 7+ months is encouraging and deserves further evaluation. Of the 4 NB pts, 2 are progression free at 7+ and 15+ months since inclusion (9 and 22 months after relapse). If the preliminary results reported in NB pts will be confirmed, this oral chemotherapy could be evaluated in the setting of minimal residual disease after megatherapy. No significant financial relationships to disclose.