tbuckley/cabot-search huggingface dataset:
Economic burden of brain metastases in breast cancer patients in a US managed-care population
Authors: M. M. Amonkar, E. M. Pelletier, B. Shim
Journal: Journal of Clinical Oncology (2007)

17069 Background: Limited data are available evaluating health resource use and costs of breast cancer (BC) patients who develop secondary brain metastases (BM). This study estimated the economic burden among BC patients diagnosed with incident BM. Methods: Female BC patients aged 18+ years, newly diagnosed with BM between 1/2002 and 12/2004 were identified from a private payer database (PharMetrics, Inc). The index date was the date of the incident BM diagnosis. BC was identified during a 1-year look-back period. BM patients were matched to a control group of BC patients with no evidence of BM during the study period. Patients not continuously enrolled in a health plan for 1 year before and at least 1 month after the index date and those aged 65+ years and not in Medicare Risk were excluded. Paid claims were used to estimate resource utilization and costs. Results: 775 incident and control patients resulted from a 1:1 match (mean age=54 years). At 6 months follow-up (N=398), BM patients had significantly more hospital stays (mean 1.1 vs. 0.5, p&lt;0.001) and remained hospitalized for a longer period (mean 8.0 days vs. 2.5 days, p&lt;0.001) compared to controls. BM patients also averaged more outpatient services, including physician office visits (32.8 vs. 24.3, p&lt;0.001), as well as pharmacy claims (56.0 vs. 39.1, p&lt;0.001). Similar differences were found at 1 year (N=230), with greater mean inpatient, outpatient, and pharmacy services (p&lt;0.001) in BM patients. Average total costs for BM patients at 6 months were $60,045 compared to $28,193 (p&lt;0.001) for controls; this difference was driven by higher mean inpatient ($17,462 vs. $5,362, p&lt;0.001) and outpatient ($26,209 vs. $11,652, p&lt;0.001) costs among BM patients. At 1 year, higher mean total costs persisted in BM patients ($99,899 vs. $47,719, p&lt;0.001). After adjusting for key variables, mean costs for BM patients were 123% higher than those for control group patients. Conclusions: Patients with BC and secondary BM incurred significantly more healthcare resources following diagnosis compared to those with BC but no BM. Mean total costs for BM patients were more than double those of patients without BM at 6 months and 1 year. These findings underscore important economic implications of BM and the call for new therapies that improve outcomes in patients with BM. No significant financial relationships to disclose.
Abstract 11932: Distinct Patterns of Ca2+ Cycling Protein Abundance and Phosphorylation Level Facilitate Robust and Rhythmic Local Ca2+ Releases to Regulate Spontaneous Beating of Cardiac Pacemaker Cells
Authors: Tatiana M Vinogradova, Daniel R Riordon, Dongmei Yang, Syevda Sirenko, Alexey E Lyashkov, Yue Li, Edward G Lakatta
Journal: Circulation (2014)

Spontaneous firing of sinoatrial node cells (SANC) is regulated by spontaneous submembrane local Ca2+ releases (LCR) from ryanodine receptors (RyRs). LCR activate inward Na+-Ca2+ exchange current during diastolic depolarization and thus regulate spontaneous SANC firing. In contrast to spontaneous diastolic Ca2+ sparks in ventricular myocytes (VM), which are small and stochastic, spontaneous diastolic LCR in SANC are large and rhythmic. To understand why SANC, but not VM, generate robust and rhythmic LCR under basal physiological conditions we compared expression and phosphorylation status of proteins involved in SR Ca2+ cycling in rabbit SANC and VM, using western blot or immunostaining techniques. Our data showed that phosphorylation of RyR at CaMKII-dependent Ser2815 site and PKA- and CaMKII-dependent Ser2809 site was ~10-fold and ~2-fold higher, respectively, in SANC than in VM. An increase in RyR phosphorylation facilitates RyR activation leading to generation of robust LCR in SANC. To support elevate...
Clinical benefit in phase I trials of novel molecularly targeted agents: Does dose matter?
Authors: S. C. Postel-Vinay, H. Arkenau, S. Ashley, J. Barriuso, D. Olmos, H. Shaw, M. Wright, I. Judson, J. De-Bono, S. B. Kaye
Journal: Journal of Clinical Oncology (2008)

2509 Background: Phase I trials of novel molecularly targeted, non-cytotoxic agents, traditionally involve escalation to determine MTD, even though the need for this is uncertain. While the potential for response in phase I trials of classical cytotoxic agents has generally been considered to increase at higher dose levels, the same may not be true for molecularly targeted agents. For this drug class, in which cytostasis may be the main outcome, the clinical benefit rate (CBR)—defined as CR/PR/SD for at least 3 months by RECIST criteria—is a relevant measure of response. Methods: We analysed 252 consecutive patients (pts) who were treated in one of 29 phase I trials from Jan 05 to Jun 06. We excluded trials involving conventional chemotherapy, or trials involving molecularly targeted agents where the MTD was not reached. Three cohorts of pts were identified according to the percentage of the final trial MTD (0–33%, 34–65% and 66–100% of the MTD). Results: 145 pts included in 16 eligible trials were analysed. All pts had PD prior to entry. The median age was 57 yrs (range 20 - 86) and the male:female ratio was 2:1. Thirty-two (22%) pts received between 0–33% of the MTD, 24 pts (17%) between 34–65% and 89 pts (61%) between 66 and 100% of the MTD. CBR was 43% (63 pts) after the first tumour evaluation at 6–8 weeks, and has been maintained at 29% and 15% at three and six months, respectively. There were no significant differences in CBR at 3 and 6 months between the 3 cohorts (table 1). The median duration of clinical benefit was 17 weeks (95%-CI= 13–22), and was not correlated with the MTD (p=0.9). Conclusions: This analysis showed that a substantial proportion of pts experienced clinical benefit from participating in a phase I trial of molecularly targeted agents, with no detriment to treatment at lower dose levels. These data may be helpful in the development of new phase I trial designs. % of MTD 0 - 33 34 - 65 66–100 Total Patients (n) 32 24 89 145 Pts with CB at first assessment (n / %) 11 / 34 13 / 54 39 / 44 63 / 43 3 month CBR (n / %) 6 / 19 * 10 / 42 * 26 / 29 * 42 / 29 6 month CBR (n / %) 4 / 12 5 / 21 12 / 14 21 / 15 * p=0.9 No significant financial relationships to disclose.
Surgical and immunohistochemical (IC) risk factors for metastatic disease in stage IB1 cervical cancer (CC)
Authors: J. De La Mota, B. Thomas, W. Fengwei, B. Micaily, H. Yajue, E. Hernandez
Journal: Journal of Clinical Oncology (2009)

e16578 Background: Stage IB1 CC is treated with radical abdominal hysterectomy (RH) and pelvic lymph node dissection (LND) because of presumed risk of parametrial and nodal involvement. We sought to identify surgical and IC risk factors for metastatic disease. Methods: Retrospective chart review of all stage IB1 CC patients who underwent RH and LND from 1996–2008. Results: Of the 35 patients identified, 25 (71%) had squamous cell, 9 (26%) adenocarcinoma, and 1 (3%) adenosquamous histology. Median tumor diameter of patients without lymphovascular space involvement (LVI), with LVI, and with positive LN was 1.2, 2.0, and 2.5 cm respectively. Median of 24 LNs was removed. LVI was noted in 13 (37%) patients of whom 5 (38%) had positive LN. None of the 22 patients without LVI had LN involvement. Only 2 of 35 (6%) had parametrial involvement, both of which had positive LN. All patients with positive LN received chemo-radiation. In addition six patients with LVI and deep cervical stromal invasion received adjuvant radiation therapy. Median follow-up was 14 months. Postoperatively 8 (23%) and 4 (11%) patients had early and late complications respectively. There was one (3%) vaginal recurrence in a patient with positive LN. The 5-year progression-free survival and overall survival was 95% and 100%, respectively. Immunohistochemical (IC) staining was performed on 29 cases (10 LVI, 4 positive LN) for bcl-2, p53, Ki-67. There was increased staining for Ki-67 in patients with LVI (61% vs. 44%, p = 0.01), and in those with positive LN (66% vs. 48%, p = 0.04). No correlation was found with p53 or Bcl-2. Conclusions: The rate of LN metastasis in patients with stage IB1 CC is significant (14 %), as is the rate of parametrial involvement (6%). However, it occurred only in patients with LVI. Staining for Ki-67 may help detect high-risk patient. RH followed by adjuvant therapy in high-risk patients resulted in 100% 5-year survival, but is associated with morbidity. No significant financial relationships to disclose.
A phase I/II study of a multivalent dendritic cell vaccine in patients with metastatic melanoma
Authors: I. Gorin, M. Prince, J.-J. Grob, M.-T. Leccia, T. Lesimple, E. Ferriès, N. Bercovici, E. Tartour, R. Taylor, C. Robert
Journal: Journal of Clinical Oncology (2005)

2542 Background: Vaccination with dendritic cells (DC), designed to express tumor antigens, is considered to be a possible strategy to elicit anti-tumour immune responses. Effective vaccines that mediate clinical responses in cancer patients may require generation of broad specific cytotoxic T lymphocytes directed against multiple epitopes. Allogeneic lysates from tumor cell lines are an attractive source of antigens as they contain multiple known and unknown tumor associated antigens (TAA). Methods: This is a multicentre, randomised, blinded phase I/II study in patients (pts) with stage IV (AJCC) metastatic melanoma. Safety was the primary objective; immune response (IR) and clinical response, using RECIST criteria, were secondary objectives. Patients were randomised to receive either non matured or matured DC loaded with lysate from 3 melanoma cell lines. DC were obtained from monocytes cultured with IL-13 and GM-CSF and, as required, matured with a bacterial extract and IFN-γ. Six immunizations of ∼2.0 x 107 lysate-loaded DC were administered subcutaneously and intradermally every 4 weeks. Blood samples were collected before each vaccination and IR to lysate or peptides derived from TAA were monitored by proliferation assay and ELISPOT assay for IFN-γ secretion after in vitro stimulation. Results: Sixty melanoma pts were included; 49 received at least one immunisation. No serious adverse events (AE) related to vaccination were observed. The most frequent AE related to treatment was injection site reaction. Increases or inductions in IR to the tumor lysate or TAA-derived peptides were detected after vaccination in one third of evaluable pts, demonstrating immunogenicity of the DC vaccine. A preliminary analysis of the data indicates no pts achieved an overall objective response, although 4 disease stabilisations were observed at week 12. Conclusions: In this phase I/II study vaccination with lysate-loaded DC, matured or not, was well tolerated. Increased IR to tumor lysate or TAA peptides were observed indicating that lysate-loaded DC may induce anti-tumor immune responses, even in patients with advanced metastatic disease. Further clinical studies will be conducted in patients with less advanced disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration IDM S.A.
Brachial plexus syndrome (BPS) due to primary or locally recurrent breast cancer (BC)
Authors: A. S. Braverman, B. S. Kamenova, D. Efiom-Ekaha, C. Sohn
Journal: Journal of Clinical Oncology (2005)

748 Backround: BC-associated BPS has been ascribed to radiation (RT) plexopathy but may also be associated with primary or locally recurrent BC. BPS often causes severe pain and/or disability. Methods: We retrospectively surveyed all our BC pts, including 580 with locally advanced BC (LABC), for those meeting criteria for BPS: 1) Intractable homolateral arm pain, without cervical spine or humerus metastases; and/or, 2) Arm &/or hand weakness and hyporeflexia. Pts meeting these criteria were evaluated for associated untreated primary tumors or local recurrences, and for the responses of their BPS to RT or chemotherapy (CT). Results: 29 pts met these criteria for BPS. Narcotic analgesia was required by 16/29. Motor deficits, were present in 23/29, and were incapacitating in 10/29. Arm edema developed synchronously with BPS symptoms in 17/29, and was severe in 8/29. BPS presented in association with untreated, LABC in 7/29 pts; 4/7 had matted or fixed axillary nodes, 2 supraclavicular nodes (SCN), and 3 chest wall (CW) invasion. BPS presented 7–180 months (median 31) after prior treatment of 22/29 pts’ primary BC. Prior treatment included mastectomy in 16/22, tumorectomy in 6/22, RT in 13/22 and (CT) in 20/22. Nine of these 22 pts had 4–18 nodes involved by tumor, but 5/9 had refused RT. When their BPS presented, 19/22 pts had recurred locally: 13/19 on the upper CW, 13/22 in SCN, and 4 at both sites. Two of 3 pts without local recurrence had received RT. 22 pts with BPS and associated local tumor masses were treated; partial or complete responses occurred to RT in 6/8, and to CT in 9/17. The overall response rate was 14/17 (82%). Remission duration ranged from 2–60 months, (median 10 months.) Untreated or unresponsive pts had incapacitating arm weakness and intractable pain. Conclusions: BPS is most frequently associated with local recurrences of BC, in SCN or the upper chest wall. Prompt RT or CT can durably alleviate BPS. No significant financial relationships to disclose.
Effects of G-CSF on circulating tumor cells (CTC) and CA 27.29 in breast cancer patients
Authors: P. Hepp, B. Rack, A. Schneider, M. Rezai, H. Tesch, T. Beck, U. Söling, W. Lichtenegger, M. W. Beckmann, W. Janni
Journal: Journal of Clinical Oncology (2009)

11027 Background: Some recent publications indicated that the use of G-CSF could be connected to an increase in CTC as well as elevated levels of tumor markers such as CA 27.29. In the SUCCESS Trial CTC and CA27.29 are examined before and after adjuvant chemotherapy (CHT) in 3754 breast cancer patients (pts). Methods: The SUCCESS Trial is a phase III trial comparing FEC-Docetaxel vs. FEC-Doc-Gemcitabine regime and 2 vs. 5 years of treatment with zoledronate in patients with primary breast cancer (BC) (N+ or high risk). Blood samples are taken before and after CHT. CTC were assessed with the CellSearchSystem (Veridex, Warren, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labeled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish epithelial cells and leukocytes. CA27.29 has been measured with ST AIA-PACK Ca27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Tessenderlo, Belgium). The cutoff for CA27.29 is 32 U/ml and &gt;1 cell for the CTC analysis. Patients were grouped to CTC/CA27.29 raise or no raise and 1 to 6 cycles with G-CSF or no G-CSF at all. Results: Data on 1510 pts are available for CTC analysis. 745 pts (49%) received at least one course of G-CSF. 117 pts (8%) showed an increase in CTC after CHT. In this group 52 (3%) pts received G-CSF and 65 (4%) did not. 693 pts with stable or decreased CTC received G-CSF (46%) and 700 did not (46%). There was no significant difference (p=0.29). The analysis of CA27.29 is based on the data of 2556 pts. 1252 pts (49%) received at least one course of G-CSF. 338 pts (13%) exceeded the threshold for CA27.29 only after CHT. In this group 209 pts (8%) received G-CSF and 129 (5%) did not. 1043 pts with stable or decreased CA27.29 received G-CSF (41%) and 1175 did not (46%). This difference was highly significant (p&lt;0.0001). Conclusions: No evidence can be provided for a significant correlation between an increase in the number of CTC and the application of G-CSF over CHT. Nevertheless the results on CA27.29 showed a highly significant correlation between the administration of G-CSF and elevated CA27.29 levels directly after CHT. This could be a possible explanation for the often observed increase of tumor markers after CHT. [Table: see text]
Correlation of the topography of <i>KIT</i> exon 11 mutation with primary GIST location and predictive value for PFS in patients with advanced GIST: Results from the BFR14 randomized phase III trial of the French Sarcoma Group.
Authors: J. Blay, N. Bin Bui, P. A. Cassier, F. Duffaud, A. Adenis, F. Bertucci, J. Dhomont, J. Emile, P. Bringuier, A. Le Cesne
Journal: Journal of Clinical Oncology (2010)

10019 Background: There is a substantial level of heterogeneity within KIT exon 11 mutations (mut) in GIST The impact of this heterogeneity on clinical presentation and outcome of advanced GIST treated with imatinib was investigated in the BFR14 series. Methods: Among the 434 pts included, 107 had GIST with KIT exon 11, and had not been randomized to the Stop arms. We analyzed the topography (from codons 549 to 581) of the mut, their nature (deletion, missense, insertion...) and lengthes. 4 groups of mut were found in n=101 tumors in which a description was available. Results: The 4 groups (G) were: G1 whose first mutated codon was <555 (n=16, 15%), G2 whose first mutated codon was from 555 to 559, excluding those in G3 (n=40, 37%), G3 composed of the deletion of C557 and C558 only, i.e.WK deletion, (n=22, 20%), G4 whose first mutated codon was 560 and beyond (n=23, 21%). The most frequent point (pt) mutations were on 557, 559, and 560 (n=4, 9, and 8 respectively) : pt mut on 559 were observed almost only on non-gastric non-bowel sites (p=0.0001), while mut on 560 were most often observed on bowel sites (p=0.04). G4 mut were more frequent in bowel sites (39% vs 13%), while G1 mut were more frequent in gastric GIST (20% vs 10%) (p=0.04) No correlation with sex, site of mets, met size, age were observed. PFS was differed significantly in the 4 groups: median PFS was not reached.(G1), 22 mos (G2), 55 mos (G23) and 58 mos (G4) respectively. OS was not significantly different in the 4 groups. Neither the length of the mut (from 1 to 20 codons), type of mut, nor individual point mut correlated to PFS or OS. Using Cox model, including all parameters described in Van Glabbeke et al JCO 2005;23:5795, only gastric site and G2 mutations were retained as independent prognostic factors for PFS. PS and PMN count>5.0G/L were the only independent factors for OS. Conclusions: The site of mutation on KIT exon 11 varies according to the primary site of GIST and is an independent prognostic factor for PFS. These results deserve confirmation in other prospective series in advanced GIST and may be worth exploring in adjuvant series. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Novartis, Pfizer, PharmaMar, Roche GlaxoSmithKline, Novartis, Pfizer, PharmaMar, Roche Novartis, Pfizer, PharmaMar Novartis, Pfizer
Clinical profile and outcome of patients with breast cancer and bone marrow metastasis (BMM) at the Brazilian National Cancer Institute (INCA).
Authors: L. M. Soares, D. G. Candido Reis, R. Dienstmann, M. D. Gaui, P. S. Faria, D. Herchenhorn
Journal: Journal of Clinical Oncology (2010)

e11515 Background: Breast cancer (BC) is the second most common cancer in the world. Advanced disease is associated with worse prognosis, especially when visceral metastasis are diagnosed. The objective of this study is to evaluate the clinical characteristics and outcome of pts with BC and BMM. Methods: Retrospective chart review of clinical data from pts with BC and histopathological confirmation of BMM treated at the Brazilian National Cancer Institute between 1996 and 2008. Results: Clinical data was available from 88 consecutive pts. All pts had cytopenias, and this was the clinical indication for the BM biopsy. Median age at diagnosis of BC was 53y (33-72); median interval between BC and BMM diagnosis was 35 months (0-85). Infiltrating ductal carcinoma represented 84.4% of cases, infiltrating lobular carcinoma 8.8%, mucinous carcinoma 5.5%, and mixed tumor histology 1%; histological grade I 3.3%, 22.2% in II and III in 15.5% (59% not rated); hormone receptor was positive in 64.4%, negative in 23.3%; stage at diagnosis: 35.5% stage IV, 32.2% IIIB, 36.6% IIIA, 5.5% IIB, 4.4% II. When BMM was diagnosed, 90% had bone metastasis, 36.6% had liver metastasis, 26.6% skin, 10% pleural/lung, 10% central nervous system. Most pts received treatment after the diagnosis of BMM: 31% chemotherapy, 8.8% endocrine therapy, 18.8% chemo and endocrine therapy. Median overall survival after the BMM diagnosis: 16 weeks (0-480). Conclusions: BMM was associated with advanced disease and poor overall survival. No significant financial relationships to disclose.
Evaluation of safety, tolerability, and activity: A registry for temsirolimus-treated patients with advanced or metastatic renal cell carcinoma (aRCC) in the usual health care setting
Authors: H. F. Pelz, G. Krekeler, L. Bergmann, J. Roigas, T. Steiner, P. A. Loeschmann, M. Kosch
Journal: Journal of Clinical Oncology (2009)

e16127 Background: In November 2007, temsirolimus (TEMS) was approved in the EU for the first-line treatment of patients with aRCC who have at least 3 of 6 prognostic risk factors. A pivotal study had demonstrated significantly increased overall survival with TEMS in poor risk aRCC compared to the former standard Interferon (10.9 mo vs 7.3 mo). A pre-registration compassionate use program (CUP) for patients with aRCC confirmed the known safety profile of TEMS. However, the low incidence of reported serious adverse events (SAE) even in the CUP (8 SAE during about 2,200 applications) reflects the low level of spontaneous SAE reporting in oncology. To better identify the true safety profile of newly approved drugs, collection of data on pharmacovigilance in the post-approval period is essential. Hence, a noninterventional trial appears to be adequate. Methods: To prospectively evaluate TEMS in the usual health care setting we started a registry for TEMS-treated patients with aRCC. Primary objective is the evaluation of TEMS´s safety profile. Secondary objectives include the tolerability and activity of TEMS as well as the profile, comorbidity and characteristics of patients and sequence of systemic therapies in aRCC. Inclusion criteria: histologically confirmed aRCC treated with TEMS, written informed consent by the patient. Results: With regulatory and ethic committee's notification the registry started in Germany in January 2008. The registry is set up and managed by Wyeth´s medical department in collaboration with a scientific advisory board. Up to the December 15, 2008, 124 centers have recruited 130 patients. Preliminary documentation is available for 68 patients (57 male, 11 female), median age 65.8 yrs (43.2 –86.7), median Karnofsky index 75%. 32 pts experienced 90 AE, including 15 pts with 40 SAE (16 of them considered related, 24 not related by the treating physician). Conclusions: To further evaluate the safety, tolerability and efficacy of TEMS in the post-approval period and also due to the low level of spontaneously reported SAE in oncology Wyeth started a registry for TEMS-treated patients in aRCC. Updated results will be presented. [Table: see text]