tbuckley/cabot-search huggingface dataset:
Pilot study of the combination of capecitabine + oxaliplatin as adjuvant therapy for patients with stage III and high risk stage II colon cancer
Authors: C. Olier, C. Reyna, J. M. Aramendia, J. Rodriguez, A. Viudez, A. Chopitea, J. Garcia-Foncillas
Journal: Journal of Clinical Oncology (2008)

15093 Background: FOLFOX has demonstrated to improve survival in patients with CRC stage III and stage II with high risk of recurrence with an acceptable profile of toxicity. On the other hand capecitabine has shown similar efficacy to iv fluorouracil in this setting (Scheithauer et al. 2003). The aim of the present study was to asses the feasibility and activity of the combination of Oxaliplatin and Capecitabine as adjuvant therapy in colon cancer Methods: Patients with stage III or high risk stage II CRC pts were treated with Oxaliplatin 120 mg/m2 iv on day 1 and Capecitabine 850 mg/m2 po b.i.d, (days 1 to 14) every 21 days for six cycles. Toxicity was graded according to the NCI-Toxicity Criteria. Results: A total of 47 patients were treated between july of 2003 and february 2007. The median age was 57.57 years. Thirty-six (76.6%) patients had stage III colon cancer and 23.4% high risk stage II. The median dose intensity of capecitabine and oxaliplatin was 0.87% and 0.83% respectively. After a median follow up of 31 months (10–54) 78.6% and 80% of patients with stage III and stage II respectively remain free of progression. Seven patients relapsed. Sites of relapse included: liver (3/7 pts), peritoneum (1/7), ovary (1/7) and local relapse in one patient. Toxicity was comparable to the study by Schmoll et al. 2006: grade 3 adverse events were hematologic (one patient with leucopenia and another with anemia), stomatitis (one patient), diarrhea (1), neurosensory toxicity (1),and hand-foot syndrome (1). We observed grade 4 neurosensory toxicity in one patient. There were no toxic deaths. Conclusions: The combination of capecitabine with oxaliplatin is an active treatment for patients with stage III and high risk stage II colon cancer with acceptable toxicity. No significant financial relationships to disclose.
Weekly paclitaxel and carboplatin may be an option for salvage chemotherapy in stage IV melanoma patients
Authors: S. G. Holtan, R. D. Rao, E. Creagan, J. Kaur, H. Pitot, S. N. Markovic
Journal: Journal of Clinical Oncology (2005)

7572 Background Patients (pts) with metastatic melanoma (MM) have very few therapy options. Based on anecdotal reports of responses to Paclitaxel and Carboplatin (PC), several MM pts were treated with PC in our institution. Here we review our results with PC in a clinical practice setting. Methods Medical records were used to identify MM pts who had got PC, and data abstracted about pt characteristics and outcomes. Response determinations using clinical criteria were noted, and verified according to RECIST criteria, where possible. Results 17 pts (12 men and 5 women) started received weekly carboplatin (AUC=2) and Paclitaxel (100 mg/m2) between 5/2003 and 9/2004. Response evaluations were performed every 3 weeks. 1 pt was lost to follow up after 9 weeks of therapy. Pts were heavily pre-treated; with a mean of 1.8 (range 1–4) prior systemic therapies per pt. Mean duration of therapy was 8 weeks (range 3–21 w). 7 pts progressed (PROG) at the first evaluation, while a subset of pts appeared to have clear clinical benefit. 2 (12%) pts had a partial responses (PR) (including regression of liver metastases and ascites in 1 pt) and continue on therapy after a mean of 7.5 weeks of therapy. 9 (52%) pts had stabilization of disease (SD). In the SD group, the mean time to progression was 12 weeks, with 2 still on PC. Toxicity was tolerable, with only 1 pt needing to stop PC because of side effects to carboplatin. The median number of prior therapies was 2 in those with SD/PR and 2.5 in the PROG group. 4 pts continue on PC, and 3 are receiving other therapies after progressing on PC. Conclusion The main limitation of our study is its retrospective nature, with the presumed clinical bias in selection of pts. Yet, our clinical experience in MM pts appears to suggest that, when used in the salvage setting, weekly PC results in clear clinical benefit in a subset of pts. The degree of activity noted in our experience in this population is higher than may be predicted by previous prospective clinical trials using these drugs in relatively chemotherapy naïve pts (Hodi, et al, Am J Clin Oncol 25; (3) 283–6, 2002 and Zimpfer-Rechner, et al., Melanoma Res 13 (5),531–6, 2003). Further evaluation of weekly PC, alone or as a ‘backbone’ for other agents, should be considered. No significant financial relationships to disclose.
Safety and efficacy of pentostatin and rituximab in patients with low-grade B-cell non-Hodgkin's lymphoma, including chronic lymphocytic leukemia (Protocol N007)
Authors: R. R. Mena, J. Smith, S. George, G. Geils, G. Geils, F. Yunus
Journal: Journal of Clinical Oncology (2004)

6569 Background: Chemotherapy for patients with low grade B-cell malignancies is seldom curative. Therapies that delay disease progression with limited toxicity may benefit patients considerably. Pentostatin and rituximab have demonstrated activity and safety in single agent and combination therapies against B-cell NHL and CLL. The present study evaluates the safety and efficacy of pentostatin and rituximab in previously treated and untreated patients with low grade NHL and CLL Methods: 143 patients with NHL (N=77) and CLL (N=66) were enrolled in this study. Patients received rituximab (375mg/m2) on study day 1. Patients received rituximab and pentostatin (4mg/m2) on study days 8, 15, 22, 36, 43 and 50. Disease response was evaluated between days 57–64 according to the International Working Group criteria for NHL. Patients with PR or SD, could repeat treatment days 8 through 50, at investigators discretion. Final response evaluation was performed between days 113–119. Safety and time to progression were assessed. Results: Response data have been analyzed for 112 patients to date. OR rate was 70.3% in NHL (N=64) and 43.8% in CLL patients (N=48). Among patients with chemotherapy prior to study, OR rate was 56.6% in NHL (20% CR, 13.3% CRu, 23.3% PR, N=30) and 33.3% in CLL patients (3.7% CR, 3.7% CRu, 25.9 PR, N=27). In patients with no prior chemotherapy, OR rate was 82.3% in NHL (35.3% CR, 8.8% CRu, 38.2 PR, N=34) and 57.1% (14.3% CR, 9.5% CRu, 33.3 PR, N=21) in CLL patients. Grade 3–4 adverse events occurred in 42.7% of intent-to-treat patients. The most frequently observed grade 3–4 adverse events were pneumonia (7.7%), neutropenia (6.3%), fever (3.5%), rash (3.5%), and shortness of breath (3.5%). One patient expired on treatment from causes unrelated to study medications. Conclusions: Preliminary results suggest that in patients with low grade NHL and CLL, combination chemotherapy with pentostatin and rituximab appears well tolerated and effective. Observed grade 3–4 toxicities were similar to pentostatin and rituximab used as single agents. Preliminary results on time to progression will be reported. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration SuperGen, Inc. SuperGen, Inc.
Effects of a highly selective CXCR3 antagonist in two murine models of lung inflammation
Authors: Alexander Vidal, Cecilia Wikell, Ian Dainty
Journal: European Respiratory Journal (2014)

Antagonism of the chemokine receptor CXCR3 is hypothesized to reduce viral exacerbations of asthma and COPD by reducing recruitment of cytotoxic CD8+ T-cells to the lung. Here we describe the pre-clinical in vivo characterization of a highly selective and potent CXCR3 antagonist, Compound X (CX).

Methods: Female BALB/c mice were used. Pseudomonas aeruginosa Lipopolysaccharide (paLPS, 5 mg/mL) was administered via inhalation. H1N1 (40 PFU/mouse) was administered intranasally. CX or vehicle was administered via oral gavage twice daily. CD8+ T-cells in BAL fluid were quantified by flow cytometry. Enhanced pause (Penh) was determined with whole body plethysmography.

Results: Administration of CX (3-30 mg/kg) dose dependently decreased recruitment of CD8+ T-cells into BAL fluid at 72 hours after challenge with paLPS. A maximal effect of 80% inhibition (p<0.001) was achieved with 30 mg/kg CX compared to vehicle control. In a mouse model of H1N1 infection administration of CX at 60 mg/kg caused significant reductions in the % CD8+ T-cells on days 3 (100%, p<0.001), 5 (80%, p<0.001) and 7 (26%, p<0.05). H1N1 viral titres were not affected by CX treatment. Whole body plethysmography measured on days 1, 3, 5 and 7 showed a significant rise in Penh at all times following H1N1 infection. Significant reductions in Penh were observed in the CX treatment group on days 5 and 7.

Conclusions: CX strongly suppressed CD8+ T-cell recruitment in vivo following paLPS or H1N1 challenge. CX was well tolerated and did not affect H1N1 viral titres. Finally, CX significantly reduced Penh at the later time points following H1N1 infection, indicating that CXCR3 antagonism can provide benefit during a viral infection.
A phase II study of AP23573 (an mTOR inhibitor) in patients (pts) with advanced sarcomas
Authors: S. P. Chawla, K. K. Sankhala, V. Chua, L. R. Menendez, F. C. Eilber, J. J. Eckardt, S. T. Daly, G. S. Rana, C. L. Bedrosian, G. D. Demetri
Journal: Journal of Clinical Oncology (2005)

9068 Background: AP23573 (AP) is a non-produg rapamycin analog, which potently inhibits mTOR, a downstream effector of the PI3K/Akt pathway. AP has demonstrated some anti-tumor activity in sarcomas in a phase I study. Methods: Advanced sarcoma patients are being enrolled into a phase II trial, comprising 4 histological cohorts, employing a Simon’s 2-stage design with a minimum of 16 evaluable patients/cohort and up to 176 patients overall. AP is dosed at 12.5 mg IV daily X 5 days every 2 weeks (1 course). Tumor response is being assessed by RECIST criteria after 4 courses of treatment. Pharmacodynamic and biomarker endpoints were chosen based on mTOR/glycolytic pathway relationships, and include [18F] 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) performed before and 5 days after starting AP dosing. Percent difference in sum of maximum standard uptake values on targeted lesions is calculated on the PET scans for this evaluation. Results: 25 pts (14M/11F) were enrolled (age 18–76 yrs, median 57 yrs). Histological subtypes included bone sarcomas (5), leiomyosarcoma (5), liposarcoma (1) and others (14). All but 2 pts received extensive prior therapy. A total of 64 courses of AP were administered (25 pts received 1 course, 19 pts 2 courses, 11 pts 3 courses and 9 pts 4 courses). Among 23 pts with tumor-associated uptake of FDG at baseline, a decrease in overall uptake ≥25% was observed in 9 pts (39%), the remaining 14 pts exhibited an overall uptake change of <25%. Symptomatic improvement in pain, cough and dyspnea was noted in 13 pts. Response assessment by RECIST criteria is pending. The main related adverse events of AP have included mucositis (16 pts), anemia (10 pts), thrombocytopenia (8 pts) and maculopapular rash (5 pts). Most of these events were mild or moderate in severity. One pt with advanced abdominal liposarcoma died of rapidly progressive disease after receiving one course of AP. Conclusions: At this early assessment, 18 of 23 patients demonstrated decrease in overall uptake on PET imaging during the first course of AP. Symptomatic clinical improvement has been observed in 13 pts. These early findings are consistent with promising clinical activity and enrollment is continuing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ariad Ariad Ariad, Cambridge, MA
Phase I study of oral platinum with concurrent radiation therapy in non small cell lung cancer
Authors: H. Choy, R. S. Hughes, M. Dimaio, T. Tran, M. Petrone, S. Juvvadi, S. Yun, J. H. Schiller
Journal: Journal of Clinical Oncology (2008)

7560 We performed a phase I trial of orally-administered platinum (IV) complex, satraplatin to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) with concurrent definitive radiation for patients with non-small cell lung cancer (NSCLC). Satraplatin was given concurrently to optimize its radiosensitizing properties. Eligibility included patients with pathological diagnosis of Non-Small Cell Lung Cancer (NSCLC) who meet one of the following criteria; (a) previously untreated, medically inoperable disease and are to receive radiation therapy to primary disease site; (b) previously resected disease and have relapsed with mediastinal disease; or (c) limited, metastatic disease in no more than one distant site, age>18, ECOG PS 0–2, adequate organ system function, life expectancy of at least 3 months, and informed consent. Satraplatin was administered orally 1–3 hours prior to each radiation treatments: 63Gy/6–7 weeks. Dose escalation of satraplatin was in cohorts of 3 patients. Cohorts were expanded to 6 patients if DLT occurred that was attributable to satraplatin: Fifteen patients were entered onto this study through four dose escalations (from 10 to 40 mg daily). The most common toxicities reported were fatigue (n=11), nausea (n=8), constipation and vomiting (n=6). No DLT at the 1st, 2nd, and 3rd dose level. At the 4th dose level (40 mg/m2/wk), one patient developed grade III elevation of LFT and 2nd patient developed grade III diarrhea with fever at 2week requiring hospitalization. There were 8 PR out of 12 evaluable patients for a response (RR 67%). In conclusion increased LFT and diarrhea appears to be the principal DLT of concurrent daily oral satraplatin, and thoracic radiation in the outpatient setting. The MTD of concurrent satraplatin with thoracic radiation therapy appears to be 30 mg daily. This study is still open to accrual at the 30 mg/m2 with 74Gy RT to confirm the MTD of this combination. Supported by GPC Biotech Dose Level /Daily #Patients #Heme-DLT Non-Hem-DLT Response/Evaluable 10 mg 5 0 0 4/4 20 mg 3 0 0 1/3 30 mg 5 0 0 3/4 40 mg 2 0 2 0/1 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GPC Biotech GPC Biotech
Influence of single agent gemcitabine (GEM) schedule on the pattern of response and toxicity in patients with advanced pancreas, lung and breast carcinoma: A systematic review
Authors: E. Barrajon, A. Lopez, G. Esquerdo
Journal: Journal of Clinical Oncology (2007)

13009 Background: Dose dense chemotherapy has been advocated as a way to improve results in patients with cancer. Increasing dose (and the area under the curve of concentration-time, AUC) may increase response and toxicity, limiting clinical benefit. For phase-specific agents such as GEM, different schedules with the same dose and AUC may produce different patterns of efficacy and toxicity. Partial comparisons between schedules in clinical trials are not able to design optimal schedules. A systematic analysis of all different schedules of GEM, integrating clinical, pharmacodynamic and pharmacokinetic data in a mathematical model may provide an optimum. Methods: Clinical trials of single agent GEM in advanced pancreas, lung and breast carcinoma have been searched in PubMed, references of published clinical trials, and presentations in cancer meetings. Prognostic factors (age, sex, sex, performance status, previous chemotherapy, stage), schedule details (dose, time and frequency of infusions), response rate and toxicity (hematological, mucosal, skin and diarrhea) were analyzed in a multivariate model. In vitro data (concentration and time of exposure) and pharmacokinetic/pharmacodynamic data were included in the model, estimating the AUC above a concentration threshold (AUCt) obtained for every clinical schedule. Results: Ninety five clinical trials including 7917 patients with cancer of the pancreas (39 trials), lung (45 trials) or breast cancer (11 trials) were pooled. GEM was administered at doses of 90–2800 mg/m 2 (median 1000 mg/m 2 ) infused in 0.5–24 hours (median 0.5 h). Except for 1 schedule, treatment was repeated for 1–7 consecutive weeks (median 3) followed by a 2 week rest period. Response rate was 2.7–33.3% (median 8%) for pancreas, 0–38.5% (median 18.5%) for lung and 0–37.1% (median 20%) for breast cancer. Epithelial toxicity was inferior to hematological toxicity (grade 3/4: 0% vs 11% for leucopenia). A mathematical model was applied to 24 different schedules. Conclusions: GEM schedules in literature show great homogeneity, most of them 1000 mg/m 2 for 3 consecutive weeks followed by a 2 week rest period. The model allows simulations to optimize concentration over 12 nM. No significant financial relationships to disclose.
Cost-effectiveness of a biopsy-based 8-protein prognostic assay to optimize treatment decisions in intermediate-risk early-stage prostate cancer.
Authors: Joshua A. Roth, Scott David Ramsey, Josh John Carlson
Journal: Journal of Clinical Oncology (2015)

77 Background: Clinico-pathologic factors alone are insufficient to predict the likelihood of progression of Gleason 3+3 and 3+4 prostate cancer at the time of biopsy. As a result, many patients receive treatment, despite having unaggressive tumors. There is a need for tests that provide a clearer picture of risk to enable more individualized treatment decisions. A novel prognostic assay (ProMark) that uses quantitative measurements of protein biomarkers has been validated to predict prostate cancer aggressiveness at the time of biopsy. Our objective was to evaluate the potential cost-effectiveness of using the 8-protein assay to inform treatment decisions. Methods: We developed a simulation model to estimate quality-adjusted life-year (QALY) and cost outcomes for assay and usual care (NCCN guidelines) strategies. The proportion of patients classified as low, intermediate, and high-risk by the assay and guidelines was derived from the assay’s validation study. Treatment distributions, costs, health state utilities, and mortality rates were derived from peer-reviewed literature. The health outcome impacts of the assay strategy come from increased use of active surveillance (AS) vs treatment, and we evaluated a base case increase in AS of 14.5% (vs usual care), and small and large shift scenarios with 7.8% and 20.2% increases, respectively. We calculated the incremental QALYs, costs, and cost-effectiveness ratio in each scenario. Results: The assay strategy was dominant in all scenarios evaluated. In the base case, the assay strategy resulted in 0.04 more QALYs and $700 less in costs. The small and large shift scenarios resulted 0.02 and 0.05 more QALYs, and $5 and $1,300 less in costs, respectively. Cost-effectiveness outcomes were most sensitive to the assay cost, the AS health state utility, and the proportion of low-risk patients receiving AS in usual care. Conclusions: Our results suggest that the 8-protein prognostic assay has the potential to be a cost-effective alternative to usual care in patients with Gleason 3+3 and 3+4 prostate cancer. Future studies will evaluate the impact of the assay on patient and physician treatment choices in real-world settings.
Reassessment of Protein Tyrosine Phosphorylation in Thrombasthenic Platelets: Evidence That Phosphorylation of Cortactin and a 64-kD Protein Is Dependent on Thrombin Activation and Integrin αIIbβ3
Authors: Jean-Philippe Rosa, Valérie Artçanuthurry, Françoise Grelac, Jacques Maclouf, Jacques P. Caen, Sylviane Lévy-Toledano
Journal: Blood (1997)
University of Chicago Consortium phase II study of ispinesib (SB-715992) in patients (pts) with advanced renal cell carcinoma (RCC)
Authors: K. W. Beekman, R. Dunn, D. Colevas, N. Davis, J. Clark, E. Agamah, S. Thomas, K. Nichols, B. Redman, W. Stadler
Journal: Journal of Clinical Oncology (2007)

15573 Background: Ispinesib is a novel kinesin spindle protein inhibitor that has significant antitumor activity in multiple tumor models and has demonstrated preliminary clinical activity in early phase I and II trials. A phase II study of Ispenisib in patients with metastatic RCC who had received at least one prior therapy was thus conducted. Methods: The primary objective was to assess the RECIST based overall response rate (RR) with optimal Simon two-stage design utilizing 10% and 30% RR as the null and alternative hypotheses, respectively. Eighteen pts were to be accrued during the first stage; if 3 or more responses (PR or CR) were seen, an additional 17 pts would be accrued. Further study would be recommended if 7 or more of the 35 total pts had a response. Secondary objectives included toxicity, time to progression, and overall survival. Pts were treated with 7 mg/m2 over one hour on days 1, 8, and 15 every 28 days with radiologic disease re- evaluation every 8 weeks. Results: 19 pts were accrued in 6 months. Baseline characteristics included clear cell histology in 74%, papillary in 11%, and unclassified in 11%; 1 or =2 prior therapies in 37% and 63%; prior immunotherapy in 53%, and prior sunitinib, sorafenib or bevacizumab in 79%; ECOG performance status 0 in 58% and 1 in 42%. 4 patients are too early for radiologic assessment. None of the 15 patients evaluable responded to treatment (95% CI: 0 - 21.8%). Seven patients (47%) experienced stable disease after 8 weeks. One patient experienced grade 3 neutropenia. No other grade 3 or 4 toxicities were attributable to drug. Grade 1 and 2 toxicities included: fatigue (28%), anemia (28%), leukopenia (33%), elevated alkaline phosphatase (18%), anorexia (11%), hyponatremia (11%), dyspnea (11%), headache (11%), and hypoalbuminemia (11%). Conclusions: Treatment with weekly Ispenesib in metastatic RCC is well tolerated but does not lead to objective responses. Under the hypothesis that Ispenesib is a cytotoxic rather than cytostatic agent, further evaluation in patients with metastatic RCC at this dose and schedule is not indicated. Supported by: NCI #N01-CM-62201 No significant financial relationships to disclose.
Mutant P53 in non-Hodgkin lymphoma
Authors: G. F. El-Wahidy, O. A. Sharaf-eldin, M. A. Awad, H. A. Abdel Ghaffar, M. S. Salama
Journal: Journal of Clinical Oncology (2007)

18537 Background: *Chromosomal aberrations are important events in the pathogenesis of lymphoma &amp; leukaemias P53 belongs to class of genes whose functions involves negative regulation of cell growth through certain protein synthesis which leads to arrest of the cell cycle at growth phase. *Elucidate the nature of P53 in cases with Non Hodjkins lymphoma presented in our province (North east Mediterranean) and the impact of its mutation on known prognostic factors as well as on survival of patients receiving treatment by different chemotherapy protocols. Methods: Study done on 34 patients and 10 normal contorls Conclusions: *P53 +ve mutations in patients with lymphoma outnumbered those with −ve mutations. *Positivity degree is increased in higher grade than lower grade lymphoma. *Dfs is prolonged in those with −ve mutations than in subgroups with +ve mutations. *Subgroups with negative Exon mutations carry better survival than those with +ve mutations. [Table: see text] [Table: see text] [Table: see text] [Table: see text] [Table: see text] [Table: see text] No significant financial relationships to disclose.