tbuckley/cabot-search huggingface dataset:
Poly-adeninosinediphosphate-ribose polymerase inhibitors as sensitizers for therapeutic treatments in human tumor and blood mononuclear cells
Authors: J. Ji, C. Redon, Y. Pommier, R. Kinders, R. Parchment, M. Hollingshead, S. Yang, A. Murgo, J. Tomaszewski, J. Doroshow
Journal: Journal of Clinical Oncology (2007)

14024 Background: Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is a molecular sensor of DNA breaks that facilitates DNA repair and controls genomic stability. Treatment with single doses of ABT-888, a novel potent PARP-1 inhibitor, reduced PAR levels in peripheral blood mononuclear cells (PBMCs) and tumor biopsies in an on-going Phase-0 trial at the NIH Clinical Center. As a corollary to this study, we investigated whether ABT-888 can act as a sensitizer for radiation therapy and chemotherapy in human cancer cell culture, xenograft tumors and PBMCs to support future combination clinical trials. Methods: Inhibition of PARP-1 by ABT-888 was determined by a quantitative PAR chemiluminescence immunoassay validated for the Phase 0 trial. Since gamma-H2AX (?-H2AX) is a marker of DNA damage, we also developed and validated ?H2AX assays to monitor the effects of PARP-1 inhibition during treatment with Topo I inhibitors and radiation. Human monocytic leukemia (THP-1) and breast carcinoma (MCF-7) cell lines were treated with Topo I inhibitors including indenoisoquinoline, camptothecin and topotecan or irradiated with 0.5 to 10 Gy in the presence of ABT 888. We further evaluated these effects in human blood ex vivo to confirm the observations made in cell culture. Results: We found that ABT-888 inhibited PAR, but did not significantly increase DNA damage. Combination of ABT-888 with a Topo I inhibitor produced over 275% increase of DNA damage in THP-1 leukemia cells compared to indenoisoquinoline alone. ?H2AX foci per cell were 9.5 ± 0.8 in MCF-7 treated with 0.5 Gy/50 nM ABT-888 in comparison to 4.0 ± 0.6 with radiation alone. When whole blood was treated in the presence of ABT-888, camptothecin- induced DNA damage in PBMCs was also increased 2–3 fold, with maximum ?H2AX expression at 2 hours post treatment. Conclusions: We conclude that ABT-888 is a highly potent PARP-1 inhibitor that can enhance the DNA damaging effects of chemotherapy and radiation therapy of human cancer. Funded by NCI Contract N01-CO-12400. No significant financial relationships to disclose.
Is hypereosinophilic asthma a specific phenotype of asthma
Authors: Pauline Pradère, Yurdagul Uzunhan, Jacques Cadranel, Anne Bergeron-Lafaurie, Dominique Israël-Biet, Gilles Garcia, Stéphane Jouveshomme, Muriel Varrin, Michel Aubier, Bruno Crestani, Camille Taillé
Journal: European Respiratory Journal (2011)

Introduction:  Blood eosinophilia >1000/mm 3  in patients with asthma should evoke particular forms of the disease, especially Churg-Strauss Syndrome (CSS) and allergic bronchopulmonary aspergillosis (ABPA). Little is known about patients who do not fulfill criteria for these diseases, usually referred as Hypereosinophilic Asthma (HA).   Aim of the study:  To describe clinical and functional characteristics of patients with HA and to assess the prevalence of CSS and ABPA in asthma patients with blood hypereosinophilia.   Methods:  Retrospective study of 79 adult asthma patients with blood eosinophils count >1000/mm 3 , compared with a control group of 30 asthma patients without blood hypereosinophilia ( 3 ), defined as Non hyperEosinophilic Asthma (NEA)   Results:  90% of patients and 100% of controls had severe asthma, according to GINA. Main characteristics of the 4 groups are available on table 1.   Conclusion:  When compared with the NEA group, HA seems to represent a subgroup of patients, mostly male, characterized by non atopic disease and high prevalence of nasal polyposis. CSS and HA share many similarities, suggesting an overlap between the diseases in some cases.
The predictive and prognostic value of serum CA 125 kinetics and CA 125 nadir during paclitaxel/platinum based chemotherapy in patients with advanced ovarian carcinoma
Authors: A. Tibau, B. Ojeda, R. Nadal, J. Pérez Altozano, I. Boguña, V. Artigas, A. Gallardo, C. Pérez, J. Lopez, A. Barnadas
Journal: Journal of Clinical Oncology (2009)

e16534 Background: The tumor marker CA 125 is an accurate and reliable marker for monitoring the response to treatment and detecting early relapse in epithelial ovarian cancer (EOC). The aim of this retrospective study is to analyze the predictive and prognostic value of CA 125 kinetics and the implications of the different levels of CA 125 within the normal range after chemotherapy (CT). Methods: Between 1996 and 2008, 127 patients (pts) were treated with standard CT regimen for FIGO stage IIb-IV EOC. Median age was 64 years (24–87). Tumors were classified: 70 (55%) serous, 24 (19%) poorly differentiated, 14 (11%) endometrioid and 19 (15%) clear cell carcinoma. FIGO stage: 12 (9%) II; 95 (75%) III; and 20 (16%) IV. Tumor grade: 1 (1%) G1; 11 (9%) G2; and 115 (90%) G3. Residual disease after initial surgery: 52 (41%) optimal &lt;2cm and 39 (31%) suboptimal. After surgery, 117 (92%) of the pts received a median of 6 cycles/patient with platinum based (cisplatin or carboplatin) CT in combination with paclitaxel. Median follow-up was 31 months. 93 (73%) pts achieved levels &lt;35 U/ml after CT. Survival analyses for disease-free survival (DFS) and overall survival (OS) used univariate (Kaplan-Meier) and multivariate (Cox) model. Results: For 127 stage IIb-IV pts, 88 (69%) relapsed and 60 (47%) died from EOC. The median DFS for 3 groups 1, 2 and 3, was 34, 20, 14 months, respectively (p &lt; 0.0001). The median OS for 3 groups was 7.5, 3 and 3 years, respectively (p &lt; 0.0001). Pre-CT Ca 125 (p &lt; 0.002), and time to negativization (p &lt; 0.043) all had a univariate prognostic value for DFS and OS. In Cox models, FIGO stage (p &lt; 0.0001) and nadir concentration (p &lt; 0.0001) were the most powerful prognostic factors for DFS and OS. We found no differences in DFS and OS related to time to nadir. Conclusions: Serum CA 125 kinetics during early CT has a strong predictive and prognostic relevance for patients with advanced EOC. Within normal range, the differences between CA 125 levels could add prognostic information, stratify pts according to the risk of progression and would be a useful tool when performing consolidation CT in future clinical trials. No significant financial relationships to disclose.
Median time to progression in chemotherapy (chemo)-naive patients with castration-resistant prostate cancer (CRPC) treated with abiraterone acetate and low-dose prednisone (Pred).
Authors: C. J. Ryan, M. R. Smith, C. Logothetis, K. Koepfgen, M. Taplin, A. L. Harzstark, P. Kantoff, T. S. Kheoh, A. Molina, E. J. Small
Journal: Journal of Clinical Oncology (2010)

4671 Background: Abiraterone acetate (AA) is an inhibitor of CYP 17 (17α-hydroxylase and C17,20-lyase), a dual enzyme responsible for androgen synthesis. We have previously reported that a high proportion of patients (pts) with chemo-naïve CRPC experience a clinical response to AA in combination with low-dose Pred, although median response duration had not yet been determined. Methods: Thirty-three (33) pts with progressive, metastatic chemo-naïve CRPC, and normal organ function were prospectively treated with AA plus Pred (1000mg qd and 5mg bid, respectively). Pts previously treated with ketoconazole (keto) were excluded from the study. Results: Between Oct 2007 and May 2008, 33 men with CRPC were enrolled across five study centers. These patients had received a median of 2 prior hormonal therapies (range 2-4). PSA decline ≥ 50% was observed in 26 pts (79%) and sustained at 12 weeks in 22 pts (67%). At the time of analysis the median duration of therapy was 63 weeks. The median time to PSA progression (TTPP) was 71 weeks (95% CI: 40 weeks, not estimable). Twenty pts (61%) continued therapy for at least 36 weeks (8 cycles), with 19 (58%) of these receiving study treatment for at least 48 weeks (12 cycles). Post baseline PSA decline to undetectable (≤ 0.1 ng/mL) level was observed in 2 pts after 14 and 17 months on therapy with stable bone scans and resolution of adenopathy in one case. Conclusions: A significant proportion of pts (58%) with chemo-naïve CRPC experience prolonged responses to abiraterone acetate with a median TTPP Of 71 weeks. Durable complete responses in measurable lesions have been observed. A phase III randomized study is ongoing in this pt population. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cougar Biotechnology Cougar Biotechnology
Lapatinib plus letrozole compared with letrozole alone as first-line therapy in hormone receptor positive HER2+ metastatic breast cancer (MBC): A quality-of-life (QOL) analysis
Authors: B. N. Sherif, B. Sherrill, M. Amonkar, Y. Wu, J. Maltzman, L. O'Rourke, S. Johnston
Journal: Journal of Clinical Oncology (2009)

1039 Background: A phase III randomized double-blind multicenter trial compared lapatinib plus letrozole (L+Let) with letrozole plus placebo (Let), as first-line therapy for hormone receptor positive (HR+) MBC. Median PFS, the primary endpoint of the study, in patients who were HER2+ was significantly prolonged for L+Let compared with Let (8.2 vs 3 months, Hazard Ratio (95% CI)=0.71(0.53,0.96), p=0.019). This analysis focuses on the impact of treatments on QOL in the HER2+ subgroup. Methods: QOL outcomes included the Functional Assessment of Cancer Therapy-Breast (FACT-B) total, FACT-general (FACT-G), and trial outcome index (TOI) scores assessed at screening, every 12 weeks and at withdrawal. Higher scores indicate better QOL. Changes from baseline were analyzed using analysis of covariance. In a responder analysis, patients achieving minimally important differences in QOL scores (QOL responders) were compared with Fisher's exact test. Results: Among 1,286 patients, 219 were identified as HER2+ (L+Let n=111; Let n=108). Baseline QOL scores were comparable in the two arms. In this population, mean changes in subscale and total QOL scores were generally stable over time in both treatment arms for patients who stayed on study. For example, on the FACT-B, the average change from baseline in both groups was positive at all scheduled visits through Week 48 and the maximum difference between arms was 2.6 points (CI: -5.8, 11). There were no significant differences between the two treatment arms in percentage of QOL responders (Table). Conclusions: The addition of lapatinib to letrozole significantly increases PFS while maintaining QOL when compared with letrozole alone thus confirming the clinical benefit of the combination therapy in the HR+, HER2+ MBC patient population. This combination provides an effective option in this patient population by maintaining QOL and delaying the need for chemotherapy and its accompanying side effects. [Table: see text] [Table: see text]
Fixed-dose single administration of pegfilgrastim vs daily filgrastim in patients with breast cancer and lymphoma undergoing autologous peripheral blood stem cell transplantation
Authors: D. Boy, R. Gonella, V. Barbero, A. Nencioni, F. Patrone, A. Ballestrero
Journal: Journal of Clinical Oncology (2006)

16534 Background: Pegylated filgrastim is a new formulation of a granulocyte colony-stimulating factor that has a long circulating half-life, permitting a single dose of filgrastim per cycle of chemotherapy. Methods: To evaluate whether a single subcutaneous injection of pegfilgrastim (6 mg) is as safe and effective as daily filgrastim (5 mcg/kg/day), 40 consecutive autologous stem cell transplantations performed for breast cancer and lymphomas have been analysed. Median age was 47 yrs (20–61) and 48 yrs (30–63) in pegfilgrastim and filgrastim group, respectively. All patients had normal bone marrow biopsy. The first cohort of patients received 5 mcg/kg/day of filgrastim starting from day 5 post transplantation and the second cohort of patients received a single subcutaneous injection of 6 mg pegfilgrastim on day 5 after transplantation. Results: Median duration of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 7 (4–9) and 6 (5–9) days, respectively (P 0.29). Neutropenic fever incidence was significantly higher in filgrastim group, 9/20 vs 16/20 (P 0.048), the median duration was not significantly different, 1 (1–6) vs 3 (1–7) days. The grade 3–4 mucositis was higher in filgrastim patient group, 4/20 vs 13/20 in pegfilgrastim and filgrastim, respectively (P 0.009). The adverse events observed during post-transplant aplasia were attributable to complications arising from myelo-suppressive chemotherapy or the primary disease. The only occurring adverse event considered to be cytokine related was mild to moderate bone pain. The overall incidence of bone pain requiring non-narcotic analgesia was not statistically different, 20% (4/20) in pegfilgrastim patients and 40% (8/20) in filgrastim patients. The patients in filgrastim group received a mean of 9.8 daily injections. Conclusions: A single injection of pegfilgrastim administered at day 5 post transplant shows comparable safety and efficacy profiles to daily injections of filgrastim and may be cost-effective. No significant financial relationships to disclose.
IL-21 enhances chemoimmunotherapy mediated death of chronic lymphocytic leukemia cells
Authors: A. C. Gowda, A. Ramanunni, C. Cheney, J. Roda, W. Kindsvogel, D. Henderson, S. pallavur, W. Carson, N. Muthusamy, J. C. Byrd
Journal: Journal of Clinical Oncology (2007)

7094 Chemoimmunotherapy with fludarabine and rituximab has demonstrated promising clinical activity in CLL. We hypothesized that the IL-21 might enhance the efficacy of this regimen and play a role in immune mediated clearance of CLL cells. Expression of IL21R-a was present (&gt;20% cells +) in 13 of 16 (81%) pts. IL-21 induced direct cytotoxicity of CLL cells (&gt;20% apoptosis) in subset of patients (n=9, 40% ± 15.9, p&lt;0.0001) that directly correlates with expression of surface IL-21 receptor-a (p=0.001). This direct apoptotic effect is time dependent with maximum cytotoxicity observed at 72 hours post treatment at 25ng/ml. IL-21 induced phosphorylation of STAT-1 tyr- 701 and STAT-3 tyr-705 was seen in cells with apoptosis &gt;20% whereas phosphorylation of STAT-1 tyr-701 was not seen in cells failing to undergo apoptosis. In contrast to this, responder and non responder cells exhibited comparable levels of STAT-1, STAT-3 and constitutive Ser 727 phosphorylated STAT-3 levels. Further, IL-21 induced upregulation of Bim was observed in the cells undergoing apoptosis. Interestingly, IL-21 enhanced additively, the direct apoptosis by either antibody (rituximab or alemtuzumab) or fludarabine therapy (Pretreatment of CLL cells with IL-21 for 18–20 hours). In contrast to the enhanced fludarabine mediated direct cytotoxic death of B cells, IL-21 failed to enhance the fludarabine mediated death of T cells (n=5, % alive 56±15 vs 58±16 with IL-21) suggesting that this immunotherapeutic strategy will not augment the immunosuppressive effect of fludarabine. IL-21 also enhanced innate immune activation as demonstrated by killer inhibitory receptor matched autologous natural killer cell mediated antibody dependent cellular cytotoxicity against rituximab coated CLL cells by 33% (E: T ratio 25:1, 42% ± 4.4 versus 28% ± 3.1, p&lt;0.0001). In conclusion, our data demonstrates that IL-21 1) enhances autologous CLL NK cell function against rituximab coated tumor cells 2) mediate direct apoptotic signaling that correlates with STAT1 signaling and BIM up-regulation, and 3) enhance sensitivity to both fludarabine and rituximab mediated direct apoptosis. These results provide strong support for future clinical investigation of IL-21 as a single agent and as part of chemoimmunotherapy regimens for CLL. No significant financial relationships to disclose.
The C282Y mutation in HFE is common in Australian patients and can act independently of HCV to precipitate porphyria cutanea tarda
Authors: K.A. Stuart, F. Busfield, E.C. Jazwinska, P. Gibson, L.A. Butterworth, W.G.E. Cooksley, L.W. Powell, D.H.G. Crawford
Journal: Hepatology (1997)
Phase III open-label comparison of gemcitabine/oxaliplatin versus paclitaxel/carboplatin as first line therapy for advanced non-small cell lung cancer (NSCLC)
Authors: C. H. Weissman, C. H. Reynolds, M. A. Neubauer, I. Steinberg, L. Asmar
Journal: Journal of Clinical Oncology (2008)

8024 Background: Platinum-based doublets are the standard of care for advanced and metastatic NSCLC. Gemcitabine/cisplatin is one of the most active regimens; however many patients cannot tolerate the non-hematological side effects of this combination. This study was designed to compare the efficacy and tolerability of Gemcitabine + Oxaliplatin (GEMOX) to that of Paclitaxel/Carboplatin (PCb) in chemotherapy-naïve Stage IIIB/IV NSCLC patients. Methods: Newly diagnosed patients greater than 18 years of age with histologically proven NSCLC and ECOG PS ≤ 1 were randomly assigned 1:1 and stratified by stage (IIIB vs IV) in a 1:4 proportion to receive either PCb (P 225 mg/m2 day 1 followed by Cb AUC = 6) or GEMOX (GEM 1000mg/m2 days1 and 8 and OX 130 mg/m2 on day 1 after GEM) for a maximum of 6 cycles. The primary endpoint was time-to-progression (TTP), with tumor response rate, overall survival (OS), and quality of life (QoL) as secondary endpoints. Results: A total of 383 patients were randomized; 371 patients received treatment and have full safety data available (184 patients received GEMOX; 187 patients received PCb). Of the 371 patients with safety data, 204 (55.0%) were male, 193 (52.0%) < 65 years old, 340 (91.6 %) were Caucasian and 6 (1.6%) Hispanic, 193 (52.0 %) had an ECOG score = 0, 302 (81.4%) had Stage IV disease at diagnosis and 33 (8.9%) had brain metastases. Mean ± SD number of cycles completed was 4.1 ± 1.8 (range 1–6). There were 26 deaths (7.0%) within 30 days of completing treatment. At the end of the follow-up period (684 days from start of study treatment) 38 pts (10.2%) were still alive. Neutropenia (32.9%) and thrombocytopenia (17.3%) were the most common Grade 4 toxicities. Conclusions: Additional safety and full efficacy data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis
Treatment of gliomatosis cerebri with temozolomide: A retrospective study of the AINO (Italian Association for Neuro- Oncology)
Authors: R. Soffietti, R. Rudà, E. Laguzzi, L. Buttolo, A. Pace, C. Carapella, M. Riva, M. Salvati, A. Silvani, M. Caroli
Journal: Journal of Clinical Oncology (2007)

2033 Background: The optimal management for patients with primary gliomatosis cerebri is unknown, and some recent studies suggest that temozolomide could be useful as an upfront treatment. Methods: Between 1999 and 2005, 46 patients with biopsy proven gliomatosis cerebri were treated with temozolomide either upfront or at progression after prior radiotherapy/chemotherapy. Histological diagnoses were as follows: glioblastoma in 3 patients, malignant glioma in 8, anaplastic astrocytoma in 8, gemistocytic astrocytoma in 2, astrocytoma in 13, anaplastic oligodendroglioma in 1, anaplastic oligoastrocytoma in 1, oligoastrocytoma in 1, oligodendroglioma in 4, glial proliferation consistent with GC in 5. Median age was 49 years (range 14–70), with 20 males and 26 females and a median KPS at diagnosis of 80 (range 50–90). Twenty-three out of 46 (50%) pre-treatment MRI demonstrated some degree of contrast enhancement. Twenty-three of 46 patients were treated upfront, while 23 had received prior radiation therapy or nitrosourea-based chemotherapy. All patients received temozolomide 200 mg/m 2 die for 5 days every 4 weeks until progression or unacceptable toxicity. Response was evaluated, according to Macdonald criteria, on T1-weighted with Gadolinium and FLAIR images. Results: Two patients (4%) showed a CR of the contrast enhancing area, 2 patients (4%) a PR, 5 (11%) a minor response, 18 (39%) a SD and 19 (42%) a PD. Overall response rate (CR + PR + “minor response”) was 19%, while a clinical benefit was observed in 13/46 patients (28%). Median TTP was 9 months (range 1–27), and median survival 14 months (range 3–123). PFS at 6 months was 57%, at 12 months 35%. Oligodendroglial tumours showed a 38% response rate and a TTP of 11 months. Response rate was higher among patients treated at progression compared to those treated upfront (13% versus 26%). Grade III-IV haematological toxicity was mild. Conclusions: Temozolomide has some activity in primary GC (19% response rate), and is well tolerated. A significant neurological improvement can be observed in patients with either response or stable disease on MRI. To improve the efficacy of temozolomide in the upfront setting (in order to delay a large field RT), a phase II study with a dose-dense regimen is ongoing. No significant financial relationships to disclose.
Characteristics of proximal versus distal gastric cancer at the VA: Is there a difference?
Authors: U. Navaneethan, M. S. Beg, R. Komrokji, M. M. Safa
Journal: Journal of Clinical Oncology (2008)

15517 Background: Current literature suggests that proximal gastric cancers differ from distal in terms of biological behavior and prognosis. The aim of this study was to assess the differences in the clinical characteristics, treatment and survival in patients with cancers of the proximal versus distal stomach at the VA. Methods: We searched the Veterans Affairs Central Cancer Registry (VACCR) database for stomach cancer between 1995- 2006 using ICD codes 160–169, classified into proximal (cardia and fundus) and distal. The data then was analyzed using SPSS v.13.0. Results: There were 4,251 (68.5%) and 2,045 (32.5%) patients with cancers of the distal and proximal stomach respectively. Baseline characteristics are summarized in table 1. Both Black and white patients were more likely to have cancer of the distal stomach. (p<0.001) The distribution of cancers of the distal and proximal stomach did not change when the data was compared between 1995–2000 and 2001–2006. Metastatic disease was present in 27.3% of proximal vs. 24.9% in distal stomach cancer. (p=0.09) Patients with distal gastric cancer were more likely to undergo surgery and proximal stomach cancer patients were more likely to undergo chemo or radiotherapy (p<0.001), but there was no difference in the median survival. Cox-regression analysis using variables age, race, stage, treatment, only age, chemotherapy, surgery and the absence of metastatic disease were predictors of survival in distal stomach cancer, while surgery, chemotherapy and the absence of metastatic disease were predictors of survival in proximal stomach. Conclusion: Patients of both races were more likely to have carcinomas of the distal than proximal and this had remained stable over the past decade. The survival outcome was similar and uniformly poor in patients with cancer of the proximal and distal stomach. Further studies are required to study the racial variations and the poor prognosis of gastric cancer. Characteristic Number of patients (N = 6,296) P Value Proximal N = 2,045 Distal N = 4,251 Age (Years) 67.29 69.09 P=0.85 Race Whites 1738 (38.4%) 2789 (61.6%) P<0.001 Blacks 307 (17.4%) 1462 (82.6%) P<0.001 Stage (n = 3,606, 57.3%) Non metastatic 741 (37.2%) 1249 (62.8%) P=0.09 Metastatic 558 (34.5%) 1058 (64.5%) P=0.09 Treatment (n = 4,059, 64.5%) No therapy 623 1614 Surgery 522 (27.4%) 1381 (72.6%) P<0.001 Chemotherapy 219 (30.9%) 489 (69.1%) P<0.001 Radiotherapy 139 (48.4%) 148 (51.6%) P<0.001 Survival (Months) 6.9 5.77 P=0.06 Non metastatic disease 12.13 14.27 P=0.18 Metastatic disease 3.63 2.53 P=0.059 No significant financial relationships to disclose.
Abstract 13968: Beneficial Effects of a Single Prophylactic Hemodialysis on Renal Function Worsening after Percutaneous Coronary Intervention in Patients with Severe CKD
Authors: Tsuburaya Ryuji, Takahashi Jun, Takagi Yusuke, Ohhashi Junko, Itoh Yoshitaka, Matsumoto Yasuharu, Takeda Morihiko, Nakayama Masaharu, Itoh Kenta, Yasuda Satoshi, Shimokawa Hiroaki
Journal: Circulation (2012)