tbuckley/cabot-search huggingface dataset:
Serum proteomic prediction of progression-free survival in HER2-negative metastatic breast cancer patients receiving docetaxel as first-line treatment
Authors: A. Goncalves, M. Deblock, B. Esterni, Y. Toiron, C. Tarpin, E. Charaffe-Jauffret, C. Chabannon, J. M. Extra, P. Viens, J. P. Borg
Journal: Journal of Clinical Oncology (2007)

1010 Background: Docetaxel has become a standard in management of metastatic breast cancer (MBC) patients (pts). However, there is no validated clinical or biological marker allowing to predict which pts are most likely to benefit from it. We evaluated the ability of Surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) to identify serum proteins that could predict for docetaxel activity. Methods: We prospectively collected pretreatment serum of 81 HER2- MBC pts receiving docetaxel as first-line treatment. Serum samples were denatured, and then incubated in triplicates with three different ProteinChip arrays (Ciphergen): H50, IMAC30-Cu and CM10. Arrays were analysed using a PBSIIc ProteinChip reader (Ciphergen). Results: Pt characteristics were the following: median age, 53 ys (34 -71); Hormonal Receptivity (HR) (yes/no/na, %) 76/15/9; Disease-free interval (DFI) (≤24 months/&gt;24 months, %) 42/58; visceral disease (yes/no, %) 35/65; metastatic sites (&lt;3/≥3,%) 85/15; Median follow-up, 19.8 months (95%CI, 16.1–21.9); Median Progression-free survival (PFS), 12.9 months (95%CI, 8.8–18). Overall, 521 protein peaks were resolved. Univariate Cox proportional hazards regression identified 20 proteins significantly associated to PFS (P &lt; 0.01). A stepwise procedure using the Akaike information criterion was applied to build a Cox model with 7 protein peaks allowing to calculate a risk index for each pt. Using the risk index median value as cut-off, high-risk and low-risk populations with dramatic differences in PFS were identified (2-year PFS of 0% and 54.6%, p = 1.45 10–8). Validation methods included leave-one-out cross validation and iterative resampling. In a multivariate Cox regression including conventional prognostic factors (HR, DFI, visceral metastasis) and serum protein risk index, the latter retained the strongest independent prognostic significance for PFS. Identification of proteins with differential expression according to clinical outcome is ongoing. Conclusions: Serum proteomic profiling may help select MBC Pts who will benefit from treatment with docetaxel. Validation on an independent dataset is planned. No significant financial relationships to disclose.
The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function
Authors: Igor Kovacevic, Miriam Müller, Baktybek Kojonazarov, Alexander Ehrke, Voahanginirina Randriamboavonjy, Karin Kohlstedt, Tanja Hindemith, Ralph Theo Schermuly, Ingrid Fleming, Meike Hoffmeister, Stefanie Oess
Journal: Circulation Research (2015)

Endothelial dysfunction is an early event in cardiovascular disease and characterized by reduced production of nitric oxide (NO). The F-BAR protein NO synthase traffic inducer (NOSTRIN) is an interaction partner of endothelial NO synthase and modulates its subcellular localization, but the role of NOSTRIN in pathophysiology in vivo is unclear.We analyzed the consequences of deleting the NOSTRIN gene in endothelial cells on NO production and cardiovascular function in vivo using NOSTRIN knockout mice.The levels of NO and cGMP were significantly reduced in mice with endothelial cell-specific deletion of the NOSTRIN gene resulting in diastolic heart dysfunction. In addition, systemic blood pressure was increased, and myograph measurements indicated an impaired acetylcholine-induced relaxation of isolated aortic rings and resistance arteries. We found that the muscarinic acetylcholine receptor subtype M3 (M3R) interacted directly with NOSTRIN, and the latter was necessary for correct localization of the M3R at the plasma membrane in murine aorta. In the absence of NOSTRIN, the acetylcholine-induced increase in intracellular Ca(2+) in primary endothelial cells was abolished. Moreover, the activating phosphorylation and Golgi translocation of endothelial NO synthase in response to the M3R agonist carbachol were diminished.NOSTRIN is crucial for the localization and function of the M3R and NO production. The loss of NOSTRIN in mice leads to endothelial dysfunction, increased blood pressure, and diastolic heart failure.
Searching for CHRNA3, CHRNA4, CHRNA5, and CHRNB4 genes polymorphisms influencing nicotine dependence in the ethnic population of Kashubians, North Poland
Authors: Alicja Sieminska, Karolina Kita, Beata Wajda, Lucyna Gorska, Ewa Jassem
Journal: European Respiratory Journal (2012)

Genome wide association studies showed that genes encoding nicotinic receptor CHRN subunits might be potentially involved in the pathogenesis of nicotine dependence.  We aimed to investigate whether polymorphisms in the sites rs12914008, rs16969968, rs2236196, rs578776, rs7743870 of CHRNA5, CHRNA3, CHRNA4 and CHRNB4 subunits genes influenced nicotine dependence.  The survey was conducted in closed, ethnically homogenic population of Kashubians. The study sample consisted of 455 unrelated subjects, daily or occasional smokers. Several variables of smoking habit were recorded, and the nicotine dependence was scored with the use The Fagerstrom Test for Nicotine Dependence (FTND). Genotyping was performed in blood samples, and genotypes were correlated with the severity of nicotine dependence with the use of multivariate logistic regression analysis.  Results: Distributions of genotypes for all polymorphisms did not deviate from expectations predicted by the Hardy-Weinberg equilibrium. We found that A allele carriers of rs16969968 polymorphism had higher risk of heavier smoking, i.e. 10 or more cigarettes per day, than G allele carriers (OR = 1.54; 95% CI: 1.00-2.35). In the separate analysis, performed in the group of subjects with the history of smoking shorter than 5 years, higher risk of a stronger nicotine dependence (i.e. FTND score 4 or more) in A allele carriers of rs12914008 polymorphism than in G allele carriers was found (OR = 14.96; 95% CI: 1.42-158.0).  Conclusion: Polymorphisms in the sites rs16969968 and rs578776 of CHRNA5 and CHRNA3 subunits genes may influence the severity of nicotine dependence.
Detection of P-glycoprotein in ovarian cancer: a molecular marker associated with multidrug resistance.
Authors: D R Bell, J H Gerlach, N Kartner, R N Buick, V Ling
Journal: Journal of Clinical Oncology (1985)

A multidrug resistance phenotype is frequently observed in animal and human cell lines selected for in vitro resistance to a single chemotherapeutic agent. Overexpression of a highly conserved cell-surface glycoprotein (P-glycoprotein) is consistently associated with this phenotype in these mutant lines. A monoclonal antibody against P-glycoprotein was used to examine tumor samples from five patients with advanced ovarian cancer for evidence of P-glycoprotein overexpression. High levels of P-glycoprotein were detected in samples from two patients suggesting that a multidrug resistance mutation may also occur in ovarian cancer. This finding has broad implications for the understanding of nonresponse to chemotherapy in a variety of human neoplasms, and may provide a rational explanation for failure of chemotherapy in treatment of advanced ovarian cancer.
The combination of a Retinoid X Receptor (RXR) agonist LGD1069 (bexarotene) and vinorelbine produce synergistic growth inhibitory activity in non-small-cell lung cancer (NSCLC) cell lines
Authors: R. P. Bissonnette, P. Tooker, T. Hermann, B. Fan, K. Roegner, W.-C. Yen, A. Negro-Vilar, W. W. Lamph
Journal: Journal of Clinical Oncology (2004)

7358 Background: NSCLC is one of the leading causes of cancer-related deaths world wide. Targretin® (bexarotene) is a selective RXR agonist approved for the treatment of CTCL. Bexarotene has also shown phase I/IIa activity by enhancing survival and delaying progression in NSCLC patients (Clin Cancer Res 5:1658, 1999; J Clin Oncol 19:2626, 2001). Methods: We evaluated the anti-proliferative effects in vitro of LGD1069 as a single agent or in combination with the cytotoxic agents vinorelbine or paclitaxel in 10 NSCLC cell lines of different histologies. Cells were treated with LGD1069 alone or in combination with cytotoxic agents, growth and viability were examined. The combinations were carried out either concomitantly or sequentially. Results: LGD1069 as a single agent had modest growth inhibitory effects (at > 1 μM) in a subset of the NSCLC cell lines. LGD1069 combined with vinorelbine produced enhanced growth inhibitory activity (a left-ward shift of 3 –10 fold in the IC50) when compared to vinorelbine alone. Analysis of synergy between LGD1069 and vinorelbine showed synergistic (CI<1) growth inhibition in several NSCLC cell lines. The extent of synergy of the LGD1069/vinorelbine combo was greater at a modest drug effect (≤IC50). Moreover, when several NSCLC cell lines were pretreated with vinorelbine and then allowed to recover LGD1069 strongly inhibited re-growth as much as 75% when compared to the absence of LGD1069. We observed similar results when LGD1069/paclitaxel combos were evaluated. We also found enhanced anti-tumor efficacy (compared to single agents) in vivo with a LGD1069/paclitaxel combination in two different NSCLC xenograft tumor models. Conclusions: These results suggest that LGD1069 can cooperate with cytotoxic agents to decrease proliferation of NSCLC cells both in vitro and in vivo. These data support the use of Targretin/chemotherapy combinations in NSCLC. Targretin is currently in pivotal phase III trials in advanced NSCLC in combination regimens with cytotoxic chemotherapeutic agents (cisplatin/vinorelbine or carboplatin/paclitaxel). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Pharmaceuticals Ligand Pharmaceuticals
A pharmacokinetic study of Genetaxyl (G) together with cyclosporin A (CsA) administered orally in cancer patients
Authors: C. Liau, E. Lepper, H. Wang, M. Yang, T. Chiou, P. Chen, Z. Chu, W. Figg, A. Sparreboom, J. Chen
Journal: Journal of Clinical Oncology (2006)

12002 Background: Oral administration of paclitaxel given with CsA has shown promising activity in Phase II trials, but the apparent bioavailability is low and dose-dependent due to the presence of high concentrations of Cremophor EL (CrEL). We hypothesized that the use of a novel oral paclitaxel formulation containing only 20% CrEL (Genetaxyl [G]; Genovate Biotechnology Ltd., Taiwan), given with CsA is associated with an improved pharmacokinetic (PK) profile. Methods: Cohorts of 6 patients with cancer were treated with oral G at a dose of 60, 120, or 180 mg/m 2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received IV G (175 mg/m 2 , 3-h infusion). Three additional patients received generic IV paclitaxel (GIP). Serial blood samples were analyzed by LC/MS/MS and equilibrium dialysis, to determine total and unbound paclitaxel PK. Results: The mean (± SD) total paclitaxel AUCs were 1299±189, 1682±636, and 2204±1407 ng.h/mL at the 3 consecutive dose levels, suggesting nonlinear PK. However, based on unbound AUC, the oral bioavailability was dose-independent (P=.62), with a mean value of 37.2±18.6% (n=15). As expected, the total paclitaxel AUC following IV G (9024±4648 ng·h/mL) was lower than that for IV GIP (13,732±3983 ng·h/mL), as a result of increased clearance (39.6 vs 18.3 L/h) and a larger volume of distribution (768 vs 268 L). Interestingly, the unbound paclitaxel AUC was similar between the two IV formulations (P=.25), as the ratio of unbound/total paclitaxel for G was 2.5 times higher than that for GIP (12.5 vs 4.9%). Toxicity profiles were mild, with only 2 patients experiencing ≥ Gr 3 myelosuppression following oral G at 180 mg/m 2 . Conclusions: The mean bioavailability of paclitaxel following oral Genetaxyl with CsA was about 37%, which is higher than that observed previously with paclitaxel (range, 21–31%). Further clinical exploration of oral Genetaxyl in taxane-sensitive diseases is warranted. [Table: see text]
Association of tumor burden characteristics with outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib
Authors: A. R. Golshayan, P. Elson, L. S. Wood, J. A. Garcia, R. Dreicer, B. I. Rini
Journal: Journal of Clinical Oncology (2009)

5043 Background: An important goal of non-curative therapy for mRCC is tumor burden (TB) control. However, the impact of tumor burden characteristics on clinical outcome has not been studied in mRCC pts treated with VEGF-targeted therapy. Methods: Pts with clear-cell mRCC treated with sunitinib from June 1, 2004, to October 5, 2007, were retrospectively identified. CT scan images were re-reviewed from baseline, at the time of maximal tumor burden shrinkage (TS), at time of disease progression and at time of last assessment prior to death. TB and percent TS were measured per RECIST criteria. Results: Sixty-nine pts were identified. The majority (54%) were favorable risk based on CCF TKI risk group classification. All pts underwent prior nephrectomy and 77% had received prior systemic therapy. Sites of metastases included: lung (87%), mediastinal lymph nodes (52%), retroperitoneal lymph nodes (36%), adrenal (29%), bone (38%), liver (22%), pancreas (14%), kidney (7%), and brain (6%). There were a median of 8 metastatic deposits across all organs (range, 1–20). Median TB at start of therapy was 14.0 cm (range, 3.0–42.2 cm). Overall response rate was 52% and 87% had some degree of TS. Median progression-free survival (PFS) and overall survival (OS) were 13.5 months and 30.9 months, respectively. In multivariable analysis, disease confined to above the diaphragm (p = 0.03) and total TB &lt;13cm (p = 0.09) prior to sunitinib were independent positive predictors of PFS. Total number of metastases &lt;10 (p &lt; 0.001) and tumor volume above the diaphragm &lt;6.5 cm (p = 0.05) were independent positive predictors of OS. Increased TS while on sunitinib was also prognostic for OS (p &lt; 0.001). Fifty-nine pts (86%) have progressed. At time of disease progression (PD), tumor location and pattern of progression were not associated with OS. However, total TB (p = 0.003) and total number of metastatic deposits (≤12 vs. &gt;12, p &lt; 0.001) were significant predictors of OS from PD. At the time of last assessment prior to death, median TB was 23.9 cm, significantly higher (p &lt; 0.001) than in pts still alive (median TB 14.4 cm). Conclusions: Tumor burden shrinkage and tumor burden at time of disease progression are associated with overall survival in pts with mRCC treated with sunitinib. [Table: see text]
Chemotherapeutic and surgical induction of pathological complete remission and whole abdominal irradiation for consolidation does not enhance the cure of stage III ovarian carcinoma.
Authors: Z Fuks, S Rizel, S Biran
Journal: Journal of Clinical Oncology (1988)

Thirty-eight patients with stage III ovarian carcinoma were treated with a protocol consisting of an initial phase of induction of remission with cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD) combination chemotherapy and a second laparotomy for resection of residual tumors, followed by a consolidation phase with curative doses of whole abdominal radiation. Six patients (16%) had stage IIIA disease, ten (26%) IIIB, and 22 (58%) had stage IIIC disease. All patients received three to 14 courses of CHAD chemotherapy with a clinical response rate (complete [CR] and partial [PR]) of 91%. Thirty-three patients underwent the second operation. In 14 patients no residual tumor was found, and in another 11 residual tumors found were totally resected. Thus, 25 of 33 (76%) were classified as in pathological complete remission (PCR) after this operation. Whole abdominal irradiation was well tolerated, although 12 of 29 (42%) of the irradiated patients required more than a 2-week interruption of the treatment course because of leukopenia and/or thrombocytopenia. The actuarial 5-year survival and disease-free survival rates for the whole group were 27% and 17%, respectively, and for the 29 patients who received the complete sequence of the prescribed protocol treatments, 35% and 20%, respectively. A univariate analysis of clinical parameters showed that inherent biological features, such as histology and grade, were the most dominant factors affecting prognosis, and that neither the aggressive surgical approach employed, nor the high-dose whole abdominal irradiation, significantly affected the outcome. The long-term results suggest that although our combined modality protocol was well tolerated, it failed to enhance the cure of stage III ovarian carcinoma. The possible biological and therapeutic vectors affecting this outcome are discussed.
Epoetin beta treatment to prevent anemia in solid tumor patients receiving platinum-based chemotherapy
Authors: A. Ordóñez, M. González-Barón, D. Isla, A. Sánchez, A. Arrivi, J. L. Manzano
Journal: Journal of Clinical Oncology (2005)

8230 Background: The aim of this study was to determine whether epoetin treatment in solid tumor patients receiving platinum (Pt)-based chemotherapy (CT) might prevent anemia and improve patients' quality of life (QoL). Methods: Patients with solid tumors, receiving Pt-based CT were enrolled in this open-label, single-arm, multicenter study if baseline hemoglobin (Hb) levels were ≤13 g/dl (men) or ≤12 g/dl (women), or fell to these levels after 1 or more CT cycles. Patients received epoetin beta 450 IU/kg/week (∼30 000 IU/week), divided into 3 doses until 4 weeks after the last CT cycle. After 4 weeks, epoetin dose was doubled if Hb decreased by >1 g/dl. Treatment efficacy was measured by response rate (Hb increase of >1 g/dl) and QoL (visual analogue scale). Adverse events were recorded. Results: Of the 270 patients enrolled (255 evaluable), 40% had lung, 13.3% had head and neck, 10.2% had colorectal, 7.8% had ovarian cancer and 28.7% had other tumor types. The majority (98.8%) had a baseline ECOG status of 0–2 (69.8% ECOG status 1). Mean duration of treatment was 74.9 days. 62.4% of patients showed a Hb response, with a further 29.4% maintaining baseline Hb ±1 g/dl. Although patients received Pt-based CT, overall QoL significantly improved in patients with a Hb response (p<0.01) and was maintained in non-responders (p=0.765). Final Hb in responders was significantly increased from baseline (final 12.9 g/dl; p<0.01). Performance status (baseline vs final) was maintained in patients responding to epoetin beta (p=0.162), but significantly deteriorated in non-responders (p<0.01). Epoetin beta was well tolerated. Conclusions: Epoetin beta prevents anemia in the majority of patients with solid tumors receiving Pt-based CT. In addition, improvement in Hb with epoetin beta translated into an improvement in QoL for patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Ltd.
Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study
Authors: H. S. Hochster, L. L. Hart, R. K. Ramanathan, J. D. Hainsworth, E. E. Hedrick, B. H. Childs
Journal: Journal of Clinical Oncology (2006)

3510 Background: The addition of bevacizumab (bev) to fluorouracil-based combination chemotherapy results in statistically significant improvement in survival among patients (pts) with mCRC. This randomized, multicenter trial was designed to assess the safety, tolerability and efficacy of each of three oxaliplatin (OX) plus bolus (b), infusional, or oral fluoropyrimidine (FP) regimens without (TREE1 cohort) or with (TREE2 cohort) bev for 1 st line tx of mCRC. Methods: Eligibility included age ≥ 18 years, measurable, untreated mCRC, ECOG performance status ≤1. Primary endpoint: incidence of grade (gr) 3–4 toxicities (tox) on each arm during the 1 st 12 weeks of therapy; secondary endpoints: ORR, TTP, OS. Regimens TREE-1: FOLFOX: OX 85mg/m 2 , leucovorin (LV) 350mg, 5-FU bolus 400mg/m 2 and 2400mg/m 2 CIV over 46 hours ; bFOL : OX 85mg/m 2 days (d) 1&amp;15, LV 20 mg/m 2 and bolus 5-FU 500mg/m 2 d 1,8,15 q 4 wks; CapeOx: OX 130 mg/m 2 d 1, Capecitabine 1000–850 mg/m 2 bid for 14 d. In TREE-2 bev 5 mg/kg q14 or 7.5 q 21 d was added. Results: 147 pts were treated in TREE1 and 213 treated in TREE2. Overall, incidence of any gr 3–4 toxicity (TREE1 vs. TREE2 respectively) = FOLFOX 75% vs. 66%, bFOL 42% vs. 59%, CapeOx 73% vs. 54%. Addition of bev in TREE2 caused more gr 3–4 hypertension, impaired wound healing, and bowel perforation in each arm. Confirmed ITT ORR (TREE1 vs TREE2 respectively) = FOLFOX 41% vs.52%, bFOL 20% vs.39%, CapeOx 27% vs. 46%. Median TTP (months) + 95% CI (TREE1 vs TREE2 respectively) = FOLFOX 8.7 (6.5, 9.8) vs. 9.9 (7.9, 11.7), bFOL 6.9 (4.2, 8.0) vs. 8.3 (6.6, 9.9), CapeOx 5.9 (5.1, 7.4) vs.10.3 (8.6, 12.5). Probability of survival at 18 months (TREE1 vs. TREE2 respectively) = FOLFOX 53% vs. 63%, bFOL 50% vs. 63%, CapeOx 49% vs. 68%. As of January 9, 2006, 56 TREE1 pts (38%) and 122 TREE2 pts (57%) are alive. Conclusions: These data demonstrate these three Ox/FP regimens to be tolerable and effective. Addition of bev to Ox/FP regimens improves response rate and TTP with acceptable tolerability, and no unexpected toxicity. [Table: see text]