tbuckley/cabot-search huggingface dataset:
Combination of bevacizumab plus irinotecan in recurrent malignant gliomas (MG): A retrospective study of efficacy and safety
Authors: M. J. Gil Gil Sr., M. Martinez-Garcia, G. Reynes, E. Costas, C. Fernández-Chacón, S. Pernas, M. Benavides, A. Herrero, J. Perez-Martin, C. Balañá
Journal: Journal of Clinical Oncology (2008)

13011 Background: Recurrent MG have poor prognosis and low response rates to available treatments. Following data from Vredenburg´s phase II trial (pro ASCO 2005) some centres began to treat recurrent MG with bevacizumab and irinotecan. The aim of this study is to confirm efficacy and safety of this combination in non-selected consecutive patients (pts). Methods: Data from 6 Spanish hospitals was collected retrospectively. All pts were > 18 years, had to sign an informed consent and to present: histological documented MG; progression after radiation and temozolomide; measurable disease on MRI; have received at least 3 infusions of treatment schedule: Irinotecan 125mg/m2 and bevacizumab 10 mg/kg every 2 weeks for a maximum of a year. Response rate (RR) was determinate by MRI (performed every 6 cycles) using McDonald criteria. Progression free survival (PFS) and overall survival (OS) were calculated by Kaplan Meier method. Results: From August 2006 to October 2007, 44 consecutive pts (28 Glioblastoma, 11 Anaplastic Astrocitoma & 5 Anaplastic Oligoastrocitoma) were treated with this combination. Median age: 53 years (25–73). Median number of prior chemotherapy: 2 (1–4). Six cases had received irinotecan previously. Median KPS: 70% (60–100). Median Barthel Index: 100% (55–100). 26 pts received dexamethasone with median dosage: 4 mg (1–18). 29 were taking a non enzyme-inducing antiepileptic drug. Median cycles received: 9 (4–23) Toxicity grade 3–4: Asthenia in 6 pts; thrombocytopenia 1; neutropenia 1; mucositis 2 pts; thomboembolic complications (TEC) 3 pts, skin 1, haemorrhage out of CNS 2 pts and severe cognitive impairment 4 cases. Efficacy: 25 pts had response (4 complete response); 12 pts stable disease ≥ 3 months and 7 progression as best response. RR was 56.8% (95% CI [41–71.6]) Mean follow-up: 5.8 months (1.6–16.2). Mean PFS was 7.4 months (4,6–10,1). OS was 9.8 months (6.8–12.8). Conclusion: Our experience suggests that the combination of bevacizumab plus irinotecan in recurrent MG improves the RR, PFS and OS when compared with historical figures. However, this regimen is not free of severe toxicity (TEC and severe cognitive impairment) and requires a careful selection of patients. A phase 3 trials to validate this combination is needed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche
The prognostic value of STAT3 protein in patients with head and neck squamous cell carcinoma (HNSCC) harboring PTEN loss.
Authors: G. Fountzilas, E. Pectasides, P. Kountourakis, P. Gouveris, C. Sasaki, D. Duffey, D. G. Pectasides, D. Rimm, B. Burtness, D. Psyrri
Journal: Journal of Clinical Oncology (2010)

5550 Background: STAT3 plays a pro-oncogenic or tumor-suppressive role in gliomas depending on the mutational profile of the tumor. In PTEN deficient cells, STAT3 functions as a tumor suppressor whereas in cells bearing mutant epidermal growth factor receptor (EGFRVIII) STAT3 functions as an oncogene. The elucidation of opposing STAT3 functions in PTEN loss- and EGFRvIII-induced transformation in genetic studies in mouse astrocytes prompted us to consider the role of STAT3 in HNSCC. We addressed this question by measuring the levels of PTEN, EGFR, mutant EGFR (EGFRVIII) and STAT3 in a cohort of HNSCC. Methods: A tissue microarray composed of 102 specimens from primary HNSCC cases was constructed. Protein expression levels for PTEN, EGFR, EGFRVIII and STAT3 were analyzed using an immunofluorescence-based assay that provides an automated, quantitative analysis of expression within subcellular compartments (AQUA). The EGFRVIII antibody was kindly provided by Dr Darell Bigner (Duke University). Correlations between biomarkers were performed using Spearman correlation. Primary study endpoints were progression-free and overall survival. Survival analysis was performed by Kaplan-Meier method with log-rank test for determining statistical significance. Results: Mean follow-up time for the cohort was 42 months. A positive correlation was found between PTEN expression and EGFRvIII and STAT3 expression with a Spearman rank correlation coefficient (r) of 0.246 (p=0.022) and 0.406 (p=0.001) respectively. Low nuclear STAT3 correlates with poor survival in patients with PTEN loss and retains its prognostic significance in multivariable analysis. STAT3 had no prognostic impact in patients bearing EGFRVIII mutation or in those with high EGFR levels. Conclusions: Our results indicate that nuclear STAT3 is a positive prognostic indicator in HNSCC bearing loss of PTEN. The molecular changes associated with STAT3 oncogenic function in HNSCC remain to be elucidated. These findings provide a rationale for tailored therapeutic intervention in HNSCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration HistoRx HistoRx
Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukemia
Authors: D. M. Te Loo, R. M. van Schie, P. M. Hoogerbrugge
Journal: Journal of Clinical Oncology (2009)

10049 Background: Vincristine is one of the corner stitches in the treatment of children with acute lymphoblastic leukemia (ALL). Constipation and other peripheral and central neurotoxicities are the most common side effects. Drugs interfering with the metabolism of vincristine might potentiate these side effects. A group of drugs that interact with the metabolism of vincristine are azoles. Several case reports suggest that co-administration of azoles and vincristine lead to increased toxicity. A comparative study exploring toxicity in patients receiving vincristine with and without azoles, is lacking. For this reason, we retrospectively analyzed neurotoxicity induced by vincristine with (n = 20) and without (n = 20) co-administration of azoles in the same patient group. Methods: In total, twenty pediatric patients with de novo ALL were included in this study. Vincristine toxicity was graded retrospectively according to the National Cancer Institute toxicity scale without information considering comedication. Statistical analysis was performed using the Wilcoxon Signed Rank test and McNemar test. Results: Patients receiving vincristine in combination with prophylactic azole treatment experienced significantly more complaints of constipation and peripheral neurotoxicity (P = 0.001 and P&lt; 0.001, respectively). Three patients (15%) treated with azole therapy developed severe toxicity and needed treatment at the pediatric intensive care unit. Vincristine induced CNS toxicity (convulsions, toxic encephalopathy and SIADH) was seen in 6 patients (30%). All these patients were treated with vincristine in combination with an azole. CNS toxicity was not observed in patients receiving vincristine alone (P = 0 .014). Because of severe toxicities, vincristine treatment was significantly reduced (50% of normal dose) in several patients. Conclusions: This study shows that vincristine toxicity is significantly increased when combined with azole treatment and even can be life threatening. Therefore we advise to avoid the combination of azole and vincristine treatment in patients with ALL. No significant financial relationships to disclose.
Long-term complications of cancer chemotherapy.
Authors: J Pedersen-Bjergaard
Journal: Journal of Clinical Oncology (1995)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1995.13.7.1534 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 7602341 Long-term complications of cancer chemotherapy. J Pedersen-BjergaardxJ Pedersen-BjergaardSearch for articles by this author https://doi.org/10.1200/JCO.1995.13.7.1534 First Page PDF © 1995 by American Society of Clinical Oncology
Fully human antibody MOR202 against CD38 for the treatment of multiple myeloma and other blood-borne malignancies
Authors: M. Tesar
Journal: Journal of Clinical Oncology (2007)

8106 MOR202 is one of MorphoSys’ internal development programs targeting the cell surface antigen CD38 that is found to be expressed on various cell lines derived from B cell, T cell, and myeloid/monocytic tumors. Especially in the indication of multiple myeloma (MM), which remains an incurable malignancy with a median survival of 3–4 years, a strong expression has been reported in the majority of patients’ tumor samples. CD38-specific human antibodies were selected from MorphoSys’ proprietary HuCAL GOLD phage display library by cell panning strategies. A lead candidate (MOR202) was selected from several antibodies recognizing different epitopes on CD38 and subjected to further in vitro and in vivo characterization as follows: MOR202 exhibits an affinity in the low nanomolar range, recognizes CD38 on many cell lines of different cancer origin and most importantly on all primary MM-patient samples in FACS and IHC. The fully human IgG1 MOR202 is able to kill CD38-expressing cell lines and primary MM cells from patients efficiently by ADCC in a concentration-dependent manner, whereas early progenitor cells are not affected as demonstrated by a clonogenic assay. Finally, excellent efficacy could be shown in a SCID-mouse xenograft model, resulting in significantly reduced tumour growth (RPMI8226) and overall survival, which was even superior to bortezomib tested in the same model. No significant financial relationships to disclose.
Contemporary trends in receipt of local therapy for men with clinically localized high-risk prostate cancer.
Authors: Lora S Wang, Elizabeth Handorf, Colin T. Murphy, Mohammed Haseebuddin, Nikhil Waingankar, Robert G. Uzzo, Alexander Kutikov, Justin E. Bekelman, Eric M. Horwitz, Marc C. Smaldone
Journal: Journal of Clinical Oncology (2015)

111 Background: Level I evidence suggests local treatment results in improved survival as compared to androgen deprivation therapy (ADT) alone or watchful waiting for high risk prostate cancer (CaP), but contemporary trends in primary treatment for high risk CaP are poorly understood. Our aim is to examine local therapy utilization for patients with high risk CaP using a large national cancer registry. Methods: Using the National Cancer Database (NCDB), patients with clinically localized CaP meeting National Comprehensive Cancer Network high risk criteria were identified from 2004-2009. Men with node positive or metastatic disease were excluded. Adjusting for diagnosis year and demographic we examined the association between patient characteristics and local therapy, defined as radical prostatectomy (RP) or radiation (RT), in men with high risk CaP using logistic regression models. Results: A total of 132,369 men met inclusion criteria with 80% receiving local therapy and 12% receiving no treatment. There was a small but significant increase in local therapy utilization from 2004-2009 (79 to 81%, p&lt;0.001) with the largest changes seen in increased use of RP alone (24 to 31%, p&lt;0.001) and decreased use of RT+ADT (33 to 29%, p&lt;0.001). In comparison, minor changes were noted in the rates of RT alone (14 to 13%, p=0.02), RP+RT (2.2 to 2.9%, p&lt;0.001), RP+RT+ADT (1.6 to 1.9%, p=0.01), and ADT alone (8.9 to 7.0%, p&lt;0.001). Following adjustment, patients with age &gt;70 years (OR 0.27, CI 0.23-0.30) or Charlson morbidity count &gt; 2 (OR 0.43, CI 0.39-0.46) were less likely to receive local therapy. Further, men of African American race (OR 0.7, CI 0.67-0.74) and Medicare (OR 0.82, CI 0.77-0.87) or Medicaid (OR 0.6, 0.53-0.68) insurance were less likely to receive primary treatment than Caucasian patients or those with private insurance. Conclusions: In the NCDB, 80% of men presenting with clinically localized high risk CaP undergo local therapy as part of multimodality treatment or as monotherapy, with RP overtaking RT+ADT as the primary local treatment of choice. Furthermore, racial and insurance disparities in the receipt of primary treatment are still evident, providing targets for emerging CaP quality of care initiatives.
A phase II, double-blind, randomized multicenter study of cediranib with FOLFOX versus bevacizumab with FOLFOX in patients with previously treated metastatic colorectal cancer (mCRC): Final PFS results
Authors: D. Cunningham, R. P. Wong, G. D'haens, J. Douillard, J. Robertson, O. Saunders, A. M. Stone, E. Van Cutsem
Journal: Journal of Clinical Oncology (2008)

4028 Background: Cediranib (AZD2171) is an oral, highly potent and selective inhibitor of VEGF signaling, with activity against VEGFR-1, -2, and -3. Recent trials have shown that the combination of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A (VEGF-A) with 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (OX; FOLFOX) provides clinical benefit in patients with mCRC, in previously untreated (Saltz et al. Proc Am Soc Clin Oncol 2007; abst 4028) and previously treated (Giantonio et al. J Clin Oncol 2007;25:1,539) patients. This head-to-head study compares cediranib plus FOLFOX to bevacizumab plus FOLFOX in patients with mCRC who have failed initial therapy. Methods: Male and female patients (≥18 years) with adenocarcinoma of the colon or rectum, who had received one prior therapy for metastatic disease were randomized to one of the following treatment groups: cediranib 20 mg/day; cediranib 30 mg/day or bevacizumab 10 mg/kg every 2 weeks. All patients received mFOLFOX6 every 2 weeks (OX 85 mg/m2 and LV 400 mg/m2; followed by 5-FU 400 mg/m2 bolus and then 2,400 mg/m2). Patients were excluded if they had received prior OX in the previous 12 months, any prior VEGF-inhibitor therapy or had a history of uncontrolled hypertension or unstable brain metastases. The primary objective is to compare progression-free survival (PFS) of the three treatment groups. Secondary endpoints include overall response rate, overall survival, safety and quality of life. PFS will be analyzed when 120 progression events have been observed using a log-rank test, stratified by performance status (0 or 1/2), baseline albumin (<4 and ≥4 g/dL) and baseline alkaline phosphatase (≤160 and >160 u/L). Results: Between January 2006 and July 2007, 215 patients were randomized from 42 centers in 10 countries in Europe and Canada. Results will be available for presentation at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca, Merck, Roche
Use of prolyl 3-hydroxylases (P3H) to predict endocrine sensitivity in primary breast cancer.
Authors: P. Schmid, C. Fleischmann, M. Wischnewsky, N. Syed, R. Shah, P. Quinlan, L. Tooth, S. Kuemmel, A. M. Thompson, T. Crook
Journal: Journal of Clinical Oncology (2010)

592 Background: The prolyl hydroxylases are essential for the posttranslational modification and assembly of collagen, but are also been implicated in the regulation of HIF. We recently identified the P3Hs P3H2 and P3H3 as targets for epigenetic inactivation in breast cancer (BC). This study was performed to study the effect of P3H2 and P3H3 methylation on recurrence-free survival (RFS) and to explore interactions with adjuvant therapy in a well-annotated set of primary BCs with linked mature outcome data. Methods: A total of 236 stage I-III BCs (stages I/II/III, 22.9%/58.9%/18.2%; ER+ 76.3%; ER&PR+ 54.7%) were randomly selected from the Tayside Tissue Bank. Adjuvant chemotherapy (CT) and endocrine therapy (ET) followed defined protocols. Tissue samples were subject to histopath. review to ensure adequate representation of cancer cells. Genomic DNA was extracted using the M48 Qiagen DNA extraction robot. P3H2 and P3H3 methylation was assessed by methylation-specific PCR using primers previously validated by bisulphite sequencing. Results: P3H2 and P3H3 methylation was found in 44.9% and 25.0% of cases. P3H2 methylation was associated with ER positivity (p < 0.01), and P3H3 methylation was linked with higher Nottingham Prognostic Index (p < 0.01) and grade (p < 0.01). Although no effect of P3H2 and P3H3 methylation on RFS was observed for the whole group, there was significant interaction with the type of adjuvant therapy. Patients treated with ET had a significantly shorter RFS if either P3H2 or P3H3 was methylated compared to patients without methylation (HR = 3.28; 95%CI 1.06-10.2; p = 0.04). Methylation of both P3H2 and P3H3 described a group with a very high risk of recurrence with ET (HR = 4.65; 95%CI 1.36-15.9; p = 0.01). Multivariate analysis confirmed P3H2 and P3H3 as independent predictors of RFS. No significant interaction was observed in patients receiving CT (P3H2: HR = 0.67, p = 0.53; P3H3: HR = 0.63, p = 0.54). Conclusions: Methylation of P3Hs is an important event in early BC associated with an increased risk of recurrence in patients treated with ET. PH3s may have utility as predictive biomarkers to better define which patients should receive combined adjuvant CT and ET. An independent validation study is under way. No significant financial relationships to disclose.
Characterization of blood vessels in brain autopsies of GBM patients who received antiangiogenic treatment
Authors: E. di Tomaso, M. P. Frosch, P. K. Auluck, D. Cahill, D. G. Duda, S. R. Plotkin, J. S. Loeffler, A. G. Sorensen, T. T. Batchelor, R. K. Jain
Journal: Journal of Clinical Oncology (2008)

2009 Background: GBs have two types of vessels: co-opted and angiogenic. We hypothesize that antiangiogenic therapy normalizes angiogenic blood vessels and increases co-option of host vessels. However, to date the morphological changes in blood vessels of human tumors treated with antiangiogenic agents have not been studied. Methods: Interim results of a phase II clinical trial with a potent oral, pan-VEGF receptor tyrosine kinase inhibitor with activity against VEGF and PDGF receptors (Cediranib; AZD2171) showed a decrease in tumor contrast enhancement of more than 50% in 16/30 patients, decreased vessel permeability and vessel diameter - all hallmarks of vascular normalization. Autopsy specimens were obtained from 3 patients who were enrolled in this trial and received AZD2171 for 56, 120, and 140 days. All these patients had stable disease and none of these patients had radiographic progression at the time of AZD2171 termination. The interval between the last dose of AZD2171 and time of death ranged from 16 days to 3 months. Sections were stained for a series of markers relevant to microvessel integrity [CD31, CD71, MDR-1, nestin, CXCR4, SDF1a, PDGFRα,β] and analyses performed on two tumor areas and two corresponding contralateral areas free of bulk tumor for each patient. Results: Morphologically, the treated tumor vessels appeared more normal: endothelial hyperproliferation and glomeruloid-like vessels dramatically decreased and vessel density was restored close to that in the contralateral brain. PDGFRβ, which was expressed on all tumor vessels prior to treatment was nearly undetectable, and CD71 (a marker of the blood-brain-barrier) expression was partially restored. These changes were not seen in patients treated with temozolomide and radiation. Conclusions: Inhibition of VEGF and PDGF receptors led to significant changes in the tumor blood vessels. The vessel density increased while the endothelium morphology reverted to a more normal phenotype (monolayer), supporting the hypothesis that anti-VEGF therapy leads to vascular normalization and to vessel co-option. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Dyax, Pfizer Pharmaceutical, Takeda Pharmaceutical AstraZeneca
Low vemurafenib plasma exposure as a short-term predictive parameter of progression disease in metastatic <i>BRAFV600<sup>mut</sup></i> melanoma.
Authors: Lauriane Goldwirt, Ichrak Chami, Jean Paul Feugeas, Florence Brunet-Possenti, Cécile Pagès, Clara Allayous, Barouyr Baroudjian, Isabelle Madelaine, Helene Sauvageon, Samia Mourah, Celeste Lebbe
Journal: Journal of Clinical Oncology (2015)

9072 Background: The BRAF inhibitor Vemurafenib (V) improves survival in BRAFV600 mutated metastatic melanoma patients, with a 59% response rate (BRIM-3). The aim of this retrospective study is to explore the potential relationship between V plasma concentration (plVC) and progression disease (PD). Methods: Patients with AJCC stage IIIb/c (n = 9) or IV (n = 39) BRAFV600E melanoma treated with V in monotherapy were retrospectively included according a signed informed consent. Blood samples were collected monthly. Response evaluation (RECIST 1.1) and toxicity evaluation were performed monthly after V initiation. plVC were quantified using a routine HPLC-UV method. All samples were included in the response-concentration analysis. Regression analysis was performed with R- software. plVC cut-off to predict progression was determined with ROC curve analysis (pROC R Package). Progression-free survival (PFS) was assessed with multivariate Cox analysis (survival R package). Results: plVC obtained in 48 patients (148 blood collections) displayed a wide inter- and intra-individual variability (5.3 to 135.2μg/mL, median 66.8). All patients declared high compliance to treatment. Eleven patients (23%) experienced PD during V treatment. With a median follow-up of 12 months (1 to 50), progression on V occurred after a median 5 months treatment duration (14±9). Median plVC tended to be lower in patients experiencing PD (51±22μg/mL) compared to complete, partial or stable responders (67±24 μg/mL, p = 0.06). Maximal concentrations were higher in responding patients (67 vs 51 μg/mL, p = 0.01). Patients with at least one value reaching 65 μg/mL tended to have a lower risk of disease progression than other patients (p = 0.11). This threshold value of 65 μg/mL predicted progression with 78% specificity and 82% sensibility. Interestingly, this effect appeared to be more significant before 6 month (PFS6). Conclusions: plVC was confirmed highly variable at steady state. As low exposure was associated to higher progression risk and lower PFS6, therapeutic drug monitoring should be performed at least for 6 months from treatment initiation of V that is now used in combination to the MEK inhibitor cobimetinib.
Effects of letrozole on mammographic density (MD) in post-menopausal (PM) women at high risk for breast cancer (BC)
Authors: E. Andreopoulou, G. Ursin, K. Carapetyan, M. Utate, M. Alvear, M. Rosell, F. Muggia, J. Smith
Journal: Journal of Clinical Oncology (2007)

1548 Background: Letrozole BC chemoprevention is supported by reductions in contralateral cancer in aromatase inhibitor adjuvant BC trials. Decreased MD may be a surrogate for efficacy in prevention trials. Objective: to evaluate the effects of 12-mo letrozole on MD in PM women at high risk for BC. Methods: 20 healthy PM women had Gail model risk profile and baseline MD prior to letrozole 2.5/d for 1 y. MD was determined by a computer assisted method (Cancer Epidemiol Biomarkers and Prevention 2003;12:332–338) and read blindly (baseline, 6mo films and eventually also 12mo by GU). Health status, lipid profile, bone density, and cognitive function were monitored. Results: by December (&lt;1y): 14 Caucasian, 1 Hispanic, 3 Asians, and 2 Blacks were accrued. The table shows changes in MD at baseline &amp; 6mo in the first 6 women: * reader considered this MD technically unsatisfactory (insufficient contrast). Conclusions: One woman discontinued treatment at 3 mo due to muscle aches. Six and 12mo comparisons will be ready in June 2007. Concordant results and decrease in density are suggested by the available data. Acknowledgements: This work is supported in part by The Lynne Cohen Foundation. [Table: see text] [Table: see text]