bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized multicenter phase II trial of navcap (vinorelbine and capecitabine) versus navcap followed by weekly docetaxel as first line treatment in HER-2/neu negative metastatic breast cancer patients: updated results.
Authors: Ghosn M , Farhat FS , Kattan JG , Hanna C , Younes F , Haddad N , Aftimos P , Nasr F , Moukaddem W , Chahine G
Published: December 2010

Abstract #6116

Background: Capecitabine (C), vinorelbine (V) and docetaxel (D) are effective in the 1st line treatment of metastatic breast cancer (MBC). Based on the efficacy and the tolerability of Navcap (M. Ghosn et al. Antican Res 2006) and Navcap followed by docetaxel in MBC (M. Ghosn et al. Can Chemother Pharmacol 2008), we initiated a randomized phase II study. Primary Objective: To compare the objective response rate (ORR) of 8 cycles of Navcap vs. 4 cycles of Navcap followed by 12 weekly Docetaxel in the 1st line setting of MBC. Methods: Patients (pts) with measurable disease, no prior chemotherapy in MBC and Her-2/neu negative are eligible. All pts will receive Navcap (V 25 mg/m2 on d1 & d8 as IV push and C 825 mg/m2 bid D1-14 q3w) for 4 cycles. Pts progressing under treatment with Navcap are withdrawn and receive Docetaxel as 2nd line treatment. Pts responding or stable after completing 4 cycles of Navcap are randomized to: Arm A (4 Navcap) or Arm B (12 weekly Docetaxel 25 mg/m²/week). Results: From July 2004 to June 2008, a total of 110 pts were enrolled. At the time of this analysis 78 pts had completed the first 4 cycles of Navcap with an ORR of 55% (CR 13%) and a stable disease of 19%. 20 pts (26%) were excluded from randomization due to PD. 58 pts were randomized: Arm A: 30 pts and Arm B: 28 pts. Patient characteristics are summarized in table 1. All pts were evaluable for response with objective response rates of 70% & 78% in Arms A and B respectively. The median TTP & overall survival are 10 & 34 months in Arm A; 11 & 34 months in Arm B. Statistical comparison for efficacy & survival outcomes will be done once all pts are randomized & long term follow-up is available. All pts were evaluable for toxicity. The majority of adverse events were mild. Arm A: Gr 4 neutropenia (3%), Gr 3 anemia (6%). Arm B: Gr 3-4 anemia (9.6%), Gr 3 leukopenia (4.8%) & Gr 2 alopecia (14.3%). Conclusions: These preliminary results show that Navcap confirms its high response rate in 1st line treatment for HER-2/neu negative MBC. By the date of the meeting all pts will be randomized and will have completed their treatment. Mature data will be presented accordingly. (Protocol initiated & coordinated by the Cancer Research Group/Collaborative Group, Beirut–Lebanon).   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6116.
A multicenter phase II trial of weekly paclitaxel (wPC) and epirubicin (E) in first line metastatic breast cancer (MBC) and pronostic impact of VEGF level.
Authors: Abadie S , Capitain O , Delva R , Maillart P , Soulié P , Bourbouloux E , Levy C , Delozier T , Campone M , Morin Meschin M , Delecroix V , Ollivier J , Boux de Casson F , Poirier A , Berger V , Fumoleau P , Gamelin E
Published: December 2010

Abstract #6122

Background : wPC and E are effective in the treatment of MBC. The main objective was to determine the efficacy of combined induction with wPC and E followed by consolidation with wPC. Secondary objective were to determine tolerance survivals and characterize antiangiogenic PC activity and predictive values of plasmatic neurotrophic and endothelial factors, in terms of neurotoxicity and efficacy.  Methods : patients (pts) with RECIST measurable metastasis were recruited from april 2004 to may 2006 : ages (18-75 y) PS≤2, prior neoadjuvant adjuvant chemotherapy (NA-A CT) was permited if >6 month. 3 cycles [wPC 80 mg/m² (D1, D8, D15, reinduction D28) and epirubicine 100 mg/m² D15], were followed by wPC (no week rest). VEGF, IL6, IL6SR, BDNF were measured in plasma at baseline and C2. Evaluation was performed after 3 induction cycles and every 3 month. A Simon optimal two-stage design was performed with 13 objective responses, allowing to accrue 25 more patients (28 responses expected).  Results : 54 patients: median age 58.5 (30-75); 81% had surgery, 53.7% radiotherapy and 40.7% had NA-A CT, 46.3% hormonotherapy. Metastatic sites were nodes (36) lung (36) liver (28) bone (23). 100% PC and 90% E dose were administered at C2 and C3. 49 patients were evaluable for response; 3 patients withdrawn for taxol hypersensitivity, 1 early death (GIII asthenia and dyspnea), 1 investigator's decision. ITT analysis was performed: 33 responses (ORR: 61 %) Median OS was 30 months. During induction, 16 grade III, 27 grade IV and 3 febrile neutropenia were reported. There were 13 serious adverse events.  Consolidation was mainly associated with neurotoxicity n=28 (20pts), GIII (n=1; 3.6%) GIV (n=1; 3.6%), astenia n=26 (18pts) ), GIII n=1; 3.8% GIV n=1; 3.8%and onycholysis n=15 (13pts) ), GIII n=2 ; 13.4% GIV n=1; 6.7%.  High initial VEGF plasma levels were correlated with poor survival s (PFS, OS) with an univariate cox model (OR=1.954, 95%CI 0.944-4.043, p=0.071 ; HR 4.437, 95%CI 1.731-11.371, p=0.0019). Thresholds were determined. No correlation were observed between neurotoxicity and IL6, IL6SR and BDNF plasma levels.  Conclusion : Despite the significant but manageable haematologic toxicity, PC + E showed a high efficacy. VEGF plasma levels are predictive of the outcome and should be tested as antiangiogenic drugs targeting factors.This work was supported in part by BMS.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6122.
A dose-finding and pharmacokinetic study of I.V. vinflunine in combination with doxorubicin as first line treatment of metastatic breast cancer.
Authors: Machiels J , Chollet P , Taleb A , Baurain J , Humblet Y , Mazzeo F , Zaman K , Kasiborski F , Bauer J
Published: December 2010

Abstract #6124

Background: VFL is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class. In a phase II study in anthracycline and taxane pretreated MBC patients (pts), an ORR of 30% observed. Given activity shown by DXR or VFL in MBC, we conducted a phase I study of the combination, define maximum tolerated dose (MTD), recommended dose (RD), safety (NCI CTC 2.0), PK interaction and efficacy (Recist).  Methods: 2 schedules investigated (VFL D1 with DXR D1, every 3 weeks and VFL Ds 1 and 8, with DXR Ds 1 and 8, every 3 weeks). Eligibility: Pts with MBC, previously untreated for metastatic disease; could have received adj/neoadjuvant with anthracycline-containing regimen, cumulative doses < 250 mg/m² for DXR, 450 mg/m² for EPI. Dose escalation used 3+3 design; PK samples were obtained for VFL and DXR to investigate potential interaction.    Results: 32 patients were enrolled (15 patients in schedule 1 and 17 in schedule 2) and received escalating doses of VFL and DXR.  In schedule 1, 2 dose levels (DL) were investigated; At DL VFL250/DXR50, 8 pts were treated with 6 patients evaluable for DLT, where 2 DLTs were identified consisting of neutropenia < 0.1x109/l > 3 days and a neutropenic infection; then this DL was considered MTD; at the DL VFL250/DXR40, 7 pts were treated without developing DLTs then considered RD. 73 cycles were administered (median 6); Most frequent haematological toxicity was neutropenia, gr 3 in 1 pt and gr 4 in 11 pts. Main non-haematological adverse events were: nausea 80%, fatigue 73.3%, constipation 40%, vomiting 40%, anorexia 33.3%, stomatitis 20%, dyspnea 13.3%. Clinical activity: 7 pts (46.7%) had PR, and 4 pts (26.7%) SD. No PK interaction was detected.  In schedule 2, at DL VFL150/DXR25, 6 of 9 pts were evaluable in whom 2 Gr 4 neutropenia > 7 days occurred, (DL considered as MTD). In the DL below VFL120/DXR25, 6 of 8 pts were evaluable, only 1 Gr 4 neutropenia > 7 days occurred, (DL considered RD). A total of 89 cycles (median 6) were administered; neutropenia was the main haematological toxicity, with Gr ¾ in 14 pts (82.4%); main non-haematological toxicities: fatigue 82.4%, constipation 76.5%, nausea 76.5%, vomiting 64.7%, stomatitis 41.2%, dyspnea 41.2%, anorexia 35.3%; no episode of Gr 4 occurred.  Among 17 treated pts, 8 (47.1%) had PR and 6 (35.3%) SD. PK analysis ongoing.  Conclusion: RD for schedule 1 is VFL250/DXR40 on day 1, Q3W, for schedule 2, VFL120/DXR25 on days 1 and 8, Q3W. Overall VFL/DXR combination is feasible and toxicity was manageable, where haematological toxicity was frequent but reversible. Promising antitumour activity was detected.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6124.
Optimal treatment and prognosis of breast cancer after Hodgkin's disease: analysis of 143 cases.
Authors: Cutuli B , Tunon de Lara C , Livi L , Baron M , Levy C , Kerbrat P , Provencio M , Gonzague-Casabianca L , Mege A , Lemanski C , Delva C
Published: December 2010

Abstract #6153

Background   Breast cancer (BC) is the most frequent second malignancy in women treated for Hodgkin's disease (HD), but there are few specific data on these tumors. This study assesses histopathological features, locoregional and systemic treatments as well as prognostic factors of these secondary BC.  Material and methods:  127 women treated for HD in 9 centers subsequently developed 143 BC. Median age at HD diagnosis was 25 years. HD stages were I, II, III and IV in 28%, 49%, 16% and 7%. Radiotherapy (RT) alone was used in 44 cases and chemotherapy (CT) + RT in 83 cases. Twelve patients relapsed and had a new treatment by RT (3), CT (5) or both (4).  Results:  First BC occurred after 18-year median interval (<10 years: 11%; 10-20 years: 49%; >20 years: 40%). TNM classification (126/143) showed 23 mammographically detected T0 (18%), 54 T1 (43%, 40 T2 (32%) and 9 T3T4 (7%). 129 tumors were infiltrating carcinoma (IC) and 14 (10%) DCIS. Twenty-four (17%) tumors were multifocal. Five patients had metastasis at diagnosis; 135 tumors were operated (121 IC and 14 DCIS): 57 (42%) by conservative surgery (40 with RT) and 78 (58%) by mastectomy (5 with RT). Axillary dissection (AD) and SNB were performed in 74% and 23% of the cases. Median tumor size for IC was 19 mm. Axillary nodal involvement (ANI) was found in 28% of IC (pN1-3 : 22%; pN>3 : 6%). ER and PgR were positive in 57% and 49%.  43 (39%) tumors were SBR III (high grade). Chemotherapy (CT) and hormonotherapy (HT) were performed in 47% and 42% of IC. With a 5-year median FU, 17 patients (12%) developed local recurrences (LR) and 35 (30%) had metastases. Significant metastasis predictive factors were ANI and SBR III; 12 (10%) women developed a third cancer.  5 and 10-year overall survival (OS) rates were 69% and 53%, and disease-specific survival (DSS) rates 72% and 62%. 5-year DSS rates were 79% for T0T1 versus 44% for pT2T3T4 (p=0.0068) and 81% for pN0 versus 65% for pN+ (p=0.0012).  Conclusion  Young women (especially 15-25 years) treated for HD should be carefully monitored by mammography, ultrasound and maybe MRI in order to detect early occurrence of BC. The prognosis of small lesions (pTis/pT1) is excellent and conservative treatment often feasible. This study is still ongoing, with 200 planned cases. Optimal adjuvant treatment options will be discussed and compared with a former series including 133 cases (Radiotherapy and Oncology, 2001, 59: 247-255).

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6153.
Effect of tibolone on breast cancer recurrence: LIBERATE trial bone sub-study.
Authors: Bundred NJ , Kenemans P , Beckmann MW , Foidart J , Kubista E , von Schoultz B , Sismondi P , Vassilopoulou-Sellin R , Yip C , Egberts J , Planellas Gomez JV , el Galta R , van Os SC
Published: December 2010

Abstract #66

LIBERATE, a randomized, placebo controlled, double blind trial studied the effect of tibolone (Livial), a tissue selective hormone replacement therapy (HRT) on breast cancer (BC) recurrence, aiming to demonstrate non-inferiority of treatment compared to placebo. In the LIFT trial of osteoporotic women, tibolone prevented BC development.  Design and Method: Women with surgically treated BC (T1-3, N0-2, M0) within the last 5 years complaining of vasomotor symptoms, were randomly assigned to tibolone 2.5mg daily or placebo treatment for a maximum of 5 years. Adequate sample size was estimated to be >1500 in each arm. A bone mineral density (BMD) sub-study of 724 patients (454 Caucasian; 270 Asian) was enrolled utilizing DXA scanning at baseline and 2 years.  Results: Between 2002 and 2004, 3,148 women were randomized in 31 countries; 1579 to tibolone and 1569 to placebo. Mean age at randomization was 52.7 years (28.0-75.0) and mean time since surgery was 2.1 years. In total 58% of women recruited were node positive and 78% ER positive. The trial closed prematurely in July 2007, with a median follow-up of 3.1 years (0.01-4.99) per patient, because an increased risk of BC recurrence occurred on tibolone HR 1.40 (1.14-1.70; p<0.001); 15.2% (237/1556) women on tibolone recurred compared to 10.7% (165/1542) on placebo. Risk for distant recurrence on tibolone was HR 1.38 (95% CI 1.09-1.74 p=0.007).  Aromatase inhibitor (AI) users had the highest risk of recurrence on tibolone HR 2.42 (1.01-5.79) compared to tamoxifen treated women HR 1.25 (0.98-1.59). Compared to ER positive cancers HR 1.56 (1.22-2.01), ER negative cancer had no increased risk of recurrence HR 1.15 (0.73-1.80). No differences in mortality occurred between groups.  At entry to the bone sub-study, 298 (43%) women had normal BMD, 313 (45%) osteopenia (T-score between -1 and -2.5) and 81 (11.7%) osteoporosis. Low body mass index (<0.001), Asian race (p<0.001) and old age at menarche predicted for low bone mass after 2 years. Tibolone increased BMD by 3.5% at the lumbar spine and 2.9% at the hip compared to placebo (both p<0.001) and reduced fracture rate in the Caucasian (p=0.036) but not the Asian population. Women with normal BMD (before or at day 1) had increased recurrence on tibolone 15.1% (21/139) compared to placebo 6.9% (11/159) p=0.036, whereas no increased BC recurrence was seen in women with low BMD; 7.5% (15/201) on tibolone and 6.7% (13/193) on placebo.  Conclusion: HRT after breast cancer treatment increases BC recurrence especially in AI treated patients. Risk of BC recurrence is elevated in BC women with normal BMD (compared to low) who take HRT.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 66.
Local-regional recurrence with and without radiation after neoadjuvant chemotherapy and mastectomy for T3N0 breast cancer patients.
Authors: Nagar H , Mittendorf EA , Strom EA , Perkins G , Oh JL , Tereffe W , Woodward W , Gonzalez-Angulo A , Hunt K , Buchholz T , Yu T
Published: December 2010

Abstract #74

Purpose: The goal of this study was to compare the local-regional recurrence (LRR) risk in patients with clinical T3N0 breast cancer who were treated with neoadjuvant chemotherapy (NeoChemo) and mastectomy (Mastx) according to the use of adjuvant radiation (RT).  Methods: Clinicopathologic data from 164 patients with clinical T3N0 breast cancer who received NeoChemo and Mastx from 1985 to 2004 were retrospectively reviewed. In this cohort, 121 (74%) patients received adjuvant radiation (RT) while 43 (26%) patients did not. The median number of axillary lymph nodes (LN) dissected was 15. After NeoChemo, 54% of patients (n=89) had no pathologically involved lymph nodes at the time of surgery (ypLN-) while 46% (n=75) had at least 1 lymph node pathologically positive (ypLN+). Actuarial rates were calculated using Kaplan-Meier analysis and compared using log-rank test. Cox proportional hazards models were fit to determine the association of RT with the risk of LRR after adjustment for other patient and disease characteristics.  Results: At a median follow-up of 77 months, 17 of the 164 patients had a LRR. For all patients, the 5-year local-regional control rates (5-yr LRC) were 90%. The 5-yr LRC for those who received RT (n=121) was 95% and for those who did not received RT (n=43) was 76% (p = 0.002), with a higher proportion of the patients who received RT having pathologically involved LN (+RT 53% vs –RT 23%, p=0.002).  Among the entire cohort, the 5-yr LRC was 85% for patients with ypLN+ disease and 94% for patients with ypLN- disease (p=0.093). In patients with ypLN+, the 5-yr LRC with no RT (n=11) was 47% and with RT (n=64) was 92% (p<0.001). In patients with ypLN-, the 5-yr LRC with no RT (n=32) was 86% and with RT (n=57) was 98% (p=0.063). Patients who had tumors with high nuclear grade had worse 5-yr LRC (Grade low 100%, intermediate 97%, high 81%, p=0.023). The presence of lymphovascular invasion, close/positive margin, or estrogen receptor status did not statistically correlate with LRC. In a Cox regression model, patients with tumor exhibiting high nuclear grade (Hazard Ratio (HR) 5.0, 95% Confidence Interval (CI) 1.6-15.4), ypLN+ (HR 6.6, 95% CI 2.0-22.1) and no adjuvant RT (HR 7.6, 95% CI 2.4-24.0) had increased risk of LRR.  Conclusions: Post mastectomy adjuvant RT appears to improve LRC in clinical T3N0 breast cancer patients treated with neoadjuvant chemotherapy and mastectomy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 74.
Integrated meta-analysis on 6402 patients with early breast cancer receiving neoadjuvant anthracycline-taxane +/- trastuzumab containing chemotherapy.
Authors: von Minckwitz G , Kaufmann M , Kümmel S , Fasching P , Eiermann W , Blohmer J , Costa SD , Sibylle L , Dietmar V , Untch M
Published: December 2010

Abstract #79

Background: An integrated meta-analysis on individual data has been performed on 7 prospective neoadjuvant trials containing doxorubicin (A) or epirubicin (E), docetaxel (D) or paclitaxel (P) (with or without trastuzumab (H)) conducted by the German Breast Group and the AGO Breast Group.  Methods: Patients (Pts) with operable or locally advanced, non-metastatic breast cancer were included in trials between 1998 and 2002: GeparDo (dose-dense (dd) AD +/- tamoxifen (Tam), N=248), GeparDuo (ddAD+Tam vs AC-D+Tam;N=904), AGO 1 (EP vs ddE-ddP;N=666), Gepartrio-Pilot (DAC+/-vinorelbine/capecitabine(NX);N=284), and between 2003 and 2007: GeparTrio (DACx6 vs DACx8; DACx6 vs DAC-NX;N=2072); Prepare (EC-P vs ddE-ddP-CMF;N=733) and GeparQuattro (EC-D vs EC-DX vs EC-D-X;+H if HER2+),N=1495). Pathological complete response (pCR) is defined as no invasive residuals in the breast and lymphnodes (ypT0/is,ypN0).  Results: Overall 1200 (18.7%) out of 6402 pts (13.7% before and 21.2% after 2003) had a pCR at surgery. pCR-rates according to treatment groups were: conventional dosed (N=5007): 20.1% vs dose-dense (N=1395): 13.9% (p<.0001); docetaxel-based (N=5003): 19.9% vs. paclitaxel based (N=1399): 14.4% (p<.0001); HER 2 negative (N=2342): 18.4% vs HER2 pos treated w/o trastuzumab (N=684): 22.6% vs HER2 pos treated with trastuzumab (N=446): 39.9% (p<.0001). pCR rates according to predictive factors were: age < 50 yrs (N=3152): 21.7% vs >= 50 yrs (N=3248): 15.9% (p<.0001); tumor size <= 5cm (N=4763): 20.6% vs > 5cm (N=1358): 14.1% (p<.0001); T-stage 1-3 (N=5611): 16.8% vs T4 (N=735): 12.2% (p=0.0065); node-neg (N=2784): 21.3% vs node-pos (N=3354): 17.2% (p=0.0009); ductal or other (N=5346): 20.5% vs lobular (N=781): 8.6% (p<.0001); grade 1 or 2 (N=3544): 12.2% vs grade 3 (N=2362): 27.1% (p<.0001); hormone receptor (HR) pos (N=3890): 11.3% vs neg (N=1912): 34.6% (p<.0001), HR and HER2 (triple) neg (N=1516): 32.5% vs non-triple neg (w/o pts treated with trastuzumab) (N=2782): 4.0% (p<.0001). Multivariate analysis revealed HR (OR 3.2 (95% CI: 2.7-3.8); p<.0001), grade (OR 1.8 (1.5-2.2); p<.0001), tumor type (OR 1.7 (1.2-2.3); p=0.001), HER2 (OR 2.2 (1.8-2.5); p<.0001), dose dense vs standard therapy (OR 1.3 (1.1-1.7); p=0.0076), age (OR 1.3 (1.2-1.6); p=0.0001), and tumor size (OR 1.5 1.2-1.9); p=0.0006) as significant predictors of pCR. Breast conservation was achieved in 64.8% (65.5% before 2003 and 64.4% after 2003 despite increase in pCR rate). Patients achieving a pCR had a mastectomy in 17.1%.  Conclusions: Findings of this meta-analysis might be used to better select patients and treatment for the neoadjuvant approach and development of new strategies to further improve pCR and breast conservation rate.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 79.
Pegylated liposomal doxorubicin (PLD) plus docetaxel significantly improves time to progression (TTP) compared with docetaxel (D) monotherapy in patients with advanced breast cancer (ABC) treated with adjuvant anthracycline: results from a randomized phase 3 study.
Authors: Sparano J , Makhson A , Semiglazov V , Tjulandin S , Balashova O , Bondarenko I , Bogdanova N , Chatikhine V , Zhuang S , Xiu L , Yuan Z , Rackoff W
Published: December 2010

Abstract #80

Background: Earlier studies have showed that PLD (DOXIL®/CAELYX®) has comparable efficacy but is significantly less cardiotoxic than conventional doxorubicin for the treatment of ABC. We sought to determine whether women with ABC who had relapsed at least 1 year after prior adjuvant anthracycline would derive clinical benefit from the addition of PLD to D without an increase in cardiac toxicity.  Methods: 751 pts were randomly assigned to receive either D 75 mg/m2 (N=373) or PLD 30 mg/m2 followed by D 60 mg/m2 (N=378) on Day 1 every 21 days. Treatment was to continue until disease progression or the occurrence of unacceptable toxicity. The primary endpoint was TTP and secondary endpoints were overall survival (OS), objective response rate (ORR), cardiac and overall safety. The analysis for TTP was planned after approximately 485 events and for final OS after 485 deaths.  Results: This prespecified TTP analysis was performed after 555 TTP events. Median TTP was increased from 7.0 months for D, to 9.8 months for the PLD+D (HR=0.65; 95% CI 1.41, 2.35; P=0.000001), and the ORR was also significantly improved for the PLD+D (26% vs. 35% P=0.0085). OS was similar between the two arms at the time of this interim analysis with 374 (50%) total deaths (HR=1.06; 95% CI 0.86;1.30). Both groups received a median of 6 cycles. Grade 3/4 neutropenia was reported in 66% and 65% of pts on PLD+D arm and D arm, respectively; the incidence of pts with febrile neutropenia was 7% and 6%, respectively, and the overall incidence of pts with grade 3-4 drug-related adverse events was 74% and 66%, respectively. There was no increase in cardiac toxicity, as determined by reported cardiac adverse events or LVEF measurements in the PLD+D arm compared with the D arm. Congestive heart failure was reported in 3 (1%) pts in the PLD+D arm and 4 (1%) pts in the D arm. Grade 3/4 hand-foot syndrome (HFS) and stomatitis were reported for 24% and 11% of PLD+D pts and infrequently in the D group (1% and 1%, respectively).  Discussion: Treatment with PLD+D combination results in statistically significant improvement of TTP and ORR compared with D among pts with ABC without an increased risk of cardiac toxicity. Additional follow-up is needed to determine the impact of the combination on OS. HFS and stomatitis occurred more often in pts treated with PLD+D therapy. The addition of PLD to a D-based regimen is a safe and effective option for pts with ABC previously treated with adjuvant anthracycline regimens.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 80.
A phase I study of vandetanib and metronomic chemotherapy in advanced breast cancer.
Authors: Mayer EL , Isakoff SJ , Hannagan K , Savoie J , Beckman J , Klement G , Gelman R , Winer EP , Burstein HJ
Published: December 2010

Abstract #906

Background: Vandetanib (V) is an oral tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptors 2 and 3 and epidermal growth factor receptor. Metronomic chemotherapy, continuous low-dose oral cyclophosphamide and methotrexate (CM), has activity in combination with anti-angiogenic treatments. We sought to define the safety and tolerability of all-oral combination therapy with V and CM in advanced breast cancer.  Patients and Methods: Eligible patients (pts) had stage IV breast cancer; measurable disease was not required and stable brain metastases were acceptable. Up to 4 prior chemotherapy regimens were allowable, as was prior bevacizumab. Pts with systemic anticoagulation or QTc abnormalities were excluded. Three sequential dose escalation cohorts of approximately 8 pts were enrolled. All pts received CM (C 50 mg PO qd, M 2.5 mg PO d1-2 q week), and V in 3 dose-escalation cohorts: 100 mg qd (Cohort 1), 200 mg qd (Cohort 2), and 300 mg qd (Cohort 3). Pts received V + CM until progression or unacceptable toxicity; dose adjustments were made for treatment related toxicity. The primary endpoint was safety and toxicity of the regimen; secondary endpoints included response rate, non-invasive vascular analysis of hypertension, and platelet proteomics.  Results: 24 pts (median age 49 years) entered the study. 83% had visceral disease, 92% had received prior chemotherapy for metastatic disease (median number of regimens, 2), and 38% had received prior bevacizumab. Median cycles of therapy completed was 2 (range 1-8); median number of weeks on study was 8 (range 2-33). Toxicities in Cohorts 1 and 2 were generally manageable, and most commonly consisted of diarrhea, nausea, fatigue, abnormal hepatic function, and hyperglycemia. Despite fewer cycles of drug exposure, increased toxicity was observed in Cohort 3, including 3 episodes of dose limiting toxicity (mucositis/rash, 1; abnormal hepatic function, 2). One-third of pts required V dose reduction, and 21% of pts came off study for toxicities including cerebrovascular event (1), pulmonary embolus (1), rash (1), abnormal hepatic function (1), and myocarditis (1). Moderate hypertension was observed in 42% of pts, with a single grade 3 event. Of the 20 response-evaluable pts, 2 (10%, 95% CI 1.2 – 31.7 %) demonstrated partial response, one lasting over 30 weeks, and 3 had stable disease > 24 wks (15%, 95% CI 3.2 – 37.9%). Results from correlative vascular hypertension analyses and platelet proteomics will be presented.  Conclusions: The all-oral regimen of V + CM was tolerable at a maximum dose of V 200 mg qd. Dose-limiting toxicity was seen in the V 300 mg cohort. Modest clinical activity in this heavily pretreated population was observed, and supports further investigation of this anti-angiogenic regimen in advanced breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 906.
Pathobiology: when the tumor is the target.
Authors: Richardson A , Carey L
Published: December 2010

Abstract #ES-5

Breast cancer evaluation and treatment has benefited markedly from expanding understanding of the anatomic and molecular mechanisms that control cell growth and metastasis. Traditional staging has been augmented by genomic-based assays, targetable differences among tumors have emerged, and the future holds promise that we will be able to individualize and optimize treatment based upon identifiable tumor and host characteristics. This education session will:  - Review molecular pathways relevant to breast cancer development and growth  - Discuss how genomics has expanded our understanding of breast cancer biology and behavior  - Examine how modern molecular biology is applied clinically

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-5.
A Modified Sesamol Derivative Inhibits Progression of Atherosclerosis
Authors: Ying Zhekang , Kherada Nisharahmed , Kampfrath Thomas , Mihai Georgeta , Simonetti Orlando , Desikan Rajagopal , Selvendiran Karuppaiyah , Sun Qinghua , Ziouzenkova Ouiliana , Parthasarathy Sampath , Rajagopalan Sanjay
Published: December 2010

Objective—

Sesamol, a phenolic component of lignans, has been previously shown to reduce lipopolysaccharide-induced oxidative stress and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. In the present study, we synthesized a modified form of sesamol (INV-403) to enhance its properties and assessed its effects on atherosclerosis.

Methods and Results—

Watanabe heritable hyperlipidemic rabbits were fed with high-cholesterol chow for 6 weeks and then randomized to receive high-cholesterol diet either alone or combined with INV-403 (20 mg/kg per day) for 12 weeks. Serial MRI analysis demonstrated that INV-403 rapidly reduced atherosclerotic plaques (within 6 weeks), with confirmatory morphological analysis at 12 weeks posttreatment revealing reduced atherosclerosis paralleled by reduction in lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, INV-403 improved vascular function (decreased constriction to angiotensin II and increased relaxation to acetylcholine), reduced systemic and plaque oxidative stress, and inhibited nuclear factor–κB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IκBα phosphorylation via inhibition of IκB kinase 2 (IKK2).

Conclusion—

INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor–κB signaling.
A skeletochronological study of age, growth and longevity of Rana macrocnemis populations from four locations at different altitudes in Turkey
Authors: Kutrup Bilal , Özdemir Nurhayat , Bülbül Ufuk , Çakır Emel
Published: December 2010

We examined life-history traits such as population age structure, growth and
longevity of Iranian Long-Legged frogs (Rana macrocnemis) from 4 different
locations at different altitudes in Turkey by skeletochronology performed on
the phalanges. The maximum lifespan was 5 years in Maçka (350 m a.s.l.), 6
years in Hıdırnebi (1430 m a.s.l.), 8 years in Sarıkamış (2276 m a.s.l.) and
10 years in Ovit (2850 m a.s.l.). Age at sexual maturity of both males and
females was 2-3 years in the Maçka, Hıdırnebi and Sarıkamış populations,
while 3-4 years for males and 3-5 years for females in the Ovit population.
In all populations, males and females did not exhibit any differences in
terms of mean age and SVL except for Sarıkamı¸s where the males were
significantly larger than the females. A positive correlation was observed
between age and SVL for both sexes in all populations except for the males
of the Maçka population.
Is the imperilled spur-thighed tortoise (Testudo graeca) native in Sardinia? Implications from population genetics and for conservation
Authors: Vamberger Melita , Corti Claudia , Stuckas Heiko , Fritz Uwe
Published: December 2010

Using mtDNA sequences and 12 microsatellite loci, we compare populations of Testudo graeca from Sardinia and North Africa. The observed pattern of almost no differentiation combined with reduced variation in the Sardinian population is consistent with introduction in prehistoric or historic times from what is now Tunisia and neighbouring Algeria. Furthermore, in the light of the recently published recommendation to eradicate the non-native T. graeca from Italy, we review recent studies on the archaeological and fossil record, on the phylogeography and population genetics of the three other chelonian species occurring in Sardinia (Emys orbicularis, T. hermanni, T. marginata). We conclude that the extant Sardinian populations of all four species are not native. However, they are and should be safeguarded under EC law (Council Regulation No 338/97 on the Protection of Species of Wild Fauna and Flora; Flora Fauna Habitat Directive: Appendix IV, Art. 12) because they serve as a back-up for the declining mainland populations. Moreover, these populations constitute an important part of the human-shaped natural heritage of the Mediterranean.
Low levels of genetic diversity among morphologically distinct populations of an enigmatic montane frog from Mexico (Craugastor uno: Craugastoridae)
Authors: Streicher Jeffrey , Meik Jesse , Smith Eric , Campbell Jonathan
Published: December 2010

Craugastor uno is a direct-developing frog endemic to high-elevation pine-oak
forests of the Sierra Madre del Sur in Mexico. The species was described
from a single female specimen collected in the state of Guerrero, but
otherwise remains poorly known. It is listed as endangered by the IUCN and
some authors have considered it extinct. A recent report expanding the range
to include montane localities in the state of Oaxaca has been disputed.
Herein we describe variation in a group of 7 C. uno specimens that includes
males, females, and juveniles collected from 1972 to 2004. We compared
individuals from localities in the states of Guerrero and Oaxaca using
morphology and several genetic markers. Molecular analyses revealed C. uno
exhibits little genetic variation at the loci sampled. Our findings suggest
that while the Guerrero and Oaxaca populations have diverged only recently
from one another, they appear to be presently isolated and may be
distinguished by several distinct quantitative and qualitative morphological
traits. We also report multilocus genetic evidence of this putative
isolation in the form of regional segregation among haplotypes. However, at
this time we refrain from revising the taxonomy owing to our small sample
size and limited geographic coverage.
RNA extraction from sauropsids blood: evaluation and improvement of methods
Authors: Chiari Ylenia , Galtier Nicolas
Published: December 2010

Advanced, transcriptome-based molecular techniques require the use of RNA of high quality and quantity. RNA extraction from nucleated blood of endangered non-model organisms is still problematic due to insufficient starting material or physico-chemical differences between samples from different organisms. Here we evaluate, validate, and suggest modifications to two protocols used for RNA extraction on animals with nucleated red cells such as birds, crocodilians, and turtles.
Definition of South China Sea Monsoon Onset and Commencement of the East Asia Summer Monsoon*
Authors: Wang B. , LinHo  , Zhang Yongsheng , Lu M-M.
Published: December 2010

The climatological mean summer monsoon onset in the South China Sea (SCS) is a remarkably abrupt event. However, defining onset dates for individual years is noticeably controversial. The controversies and complications arise primarily from a number of factors: the intermittent southward intrusion of cold fronts into the northern SCS, the bogus onset in late April before the establishment of tropical monsoons over Indochina, and active intraseasonal oscillation. In this paper, a simple yet effective index, USCS, the 850-hPa zonal winds averaged over the central SCS (5°–15°N and 110°–120°E), is proposed for objectively defining the SCS monsoon onset. This onset index depicts not only the sudden establishment of the tropical southwesterly monsoon over the SCS but also the outbreak of the rainy season in the central-northern SCS.

In this paper the East Asian summer monsoon (EASM) is defined as the broadscale summer monsoon over East Asia and the western North Pacific region (0°–40°N, 100°–140°E). It is shown that the seasonal transition of EASM can be objectively determined by the principal component of the dominant empirical orthogonal mode of the 850-hPa zonal winds, UEOF1. It is found that the local index USCS represents UEOF1 extremely well; thus, it can be used to determine both the SCS onset and the commencement of the broadscale EASM. The result suggests that the SCS summer monsoon onset indeed signifies the beginning of the summer monsoon over East Asia and the adjacent western Pacific Ocean. Evidence is also provided to show the linkage between the two salient phases of EASM: the local onset of the SCS monsoon and the local onset of the mei-yu (the rainy season in the Yangtze River and Huai River basin and southern Japan).
A Consolidated CLIPER Model for Improved August–September ENSO Prediction Skill
Authors: Lloyd-Hughes Benjamin , Saunders Mark A. , Rockett Paul
Published: December 2010

A prime challenge for ENSO seasonal forecast models is to predict boreal summer ENSO conditions at lead. August–September ENSO has a strong influence on Atlantic hurricane activity, Northwest Pacific typhoon activity, and tropical precipitation. However, summer ENSO skill is low due to the spring predictability barrier between March and May. A “consolidated” ENSO–climatology and persistence (CLIPER) seasonal prediction model is presented to address this issue with promising initial results. Consolidated CLIPER comprises the ensemble of 18 model variants of the statistical ENSO–CLIPER prediction model. Assessing August–September ENSO skill using deterministic and probabilistic skill measures applied to cross-validated hindcasts from 1952 to 2002, and using deterministic skill measures applied to replicated real-time forecasts from 1900 to 1950, shows that the consolidated CLIPER model consistently outperforms the standard CLIPER model at leads from 2 to 6 months for all the main ENSO indices (3, 3.4, and 4). The consolidated CLIPER August–September 1952–2002 hindcast skill is also positive to 97.5% confidence at leads out to 4 months (early April) for all ENSO indices. Optimization of the consolidated CLIPER model may lead to further skill improvements.
An Observational Study of Cold Season–Banded Precipitation in Northeast U.S. Cyclones
Authors: Novak David R. , Bosart Lance F. , Keyser Daniel , Waldstreicher Jeff S.
Published: December 2010

A climatological and composite study of banded precipitation in the northeast United States during the cold season (October–April) is presented. Precipitation systems in the northeast United States in April 1995 and from October 1996 to April 2001 that exhibited greater than 25.4 mm (1 in.) of rainfall, or 12.7 mm (0.5 in.) liquid equivalent, were identified as cases for study. A total of 111 cases were identified during this period, of which 88 had available radar data. Of these cases, 75 exhibited banded structure whereas 13 did not. A band classification scheme was developed from a subset of study cases. Application of the classification scheme to the 88 cases revealed that banded cases can exhibit a variety of banded events during their evolution. Single-banded events were the most common (48), followed by transitory (40), narrow cold frontal (36), multi (29), and undefined (9). Further investigation of the single-banded events highlighted banded structure in the comma-head portion of storms, with 81% of these events exhibiting a majority of their length in the northwest quadrant of the surface cyclone.

Composites were calculated for cases exhibiting single-banded events in the northwest quadrant of the surface cyclone and for nonbanded cases to distinguish synoptic and mesoscale flow regimes associated with banded events and nonbanded cases. The banded composite was marked by cyclogenesis and the development of a closed midlevel circulation. This flow configuration was associated with deformation and strong midlevel frontogenesis northwest of the surface cyclone center, which coincided with the mean band position. The nonbanded composite exhibited a much weaker cyclone located in the confluent entrance region of an upper-level jet. The absence of a closed midlevel circulation in the nonbanded composite limited deformation and associated frontogenesis northwest of the surface cyclone. Cross-section analysis through the respective composite frontogenesis maxima showed that the banded composite frontal zone exhibited stronger and deeper frontogenesis and weaker conditional stability than the nonbanded composite frontal zone.

Case studies from the northeast United States confirm the composite results, highlighting the importance of deep-layer frontogenesis coincident with weak conditional stability. These results are in qualitative agreement with the Sawyer–Eliassen equation, which predicts that the frontogenetical response will be enhanced (reduced) in the presence of small (large) moist symmetric stability.
Columbia Gorge Gap Winds: Their Climatological Influence and Synoptic Evolution
Authors: Sharp Justin , Mass Clifford F.
Published: December 2010

This paper quantifies the impact of the Columbia Gorge on the weather and climate within and downstream of this mesoscale gap and examines the influence of synoptic-scale flow on gorge weather. Easterly winds occur more frequently and are stronger at stations such as Portland International Airport (KPDX) that are close to the western terminus of the gorge than at other lowland stations west of the Cascades. In the cool season, there is a strong correlation between east winds at KPDX and cooler temperatures in the Columbia Basin, within the gorge, and over the northern Willamette River valley. At least 56% of the annual snowfall, 70% of days with snowfall, and 90% of days with freezing rain at KPDX coincide with easterly gorge flow.

Synoptic composites were created to identify the large-scale patterns leading to strong winds, snowfall, and freezing rain in the gorge. These composites showed that all gorge gap flow events are associated with a high-amplitude 500-mb ridge upstream of the Pacific Northwest, colder than normal 850-mb temperatures over the study region, and a substantial offshore sea level pressure gradient force between the interior and the northwest coast. However, the synoptic evolution varies for different kinds of gorge weather events. For example, the composite of the 500-mb field for freezing rain events features a split developing in the upstream ridge with zonal flow at midlatitudes, while for easterly gap winds accompanied by snowfall, there is an amplification of the ridge.
Training in Counseling Psychology
Authors: Ridley Charles R. , Mollen Debra
Published: December 2010

This Major Contribution, consisting of four articles, critically evaluates the status of training in counseling psychology, especially at the entry level, and offers a model for moving the field forward. In this first article, we provide a rationale for the contribution, laying the foundation for the subsequent three articles. Specifically, we ask the questions, Do training programs in counseling psychology produce the desired results? and Is the prevailing paradigm of training effective in developing counselor competence? Then we report on the research showing a disappointing relationship among training, experience, and expertise. We conclude by inviting the profession to engage in honest self-reflection about the status and future direction of training in counseling psychology.
A Framework of Search Engine Use for Travel Planning
Authors: Fesenmaier Daniel R. , Xiang Zheng , Pan Bing , Law Rob
Published: December 2010

Search engines have become one of the primary tools for travel planning and, as such, have become an important element in the marketing efforts of destination marketing organizations. Recently, it has been demonstrated that because of the dynamic relationships among search engine providers, the tourism industry, and travelers, it is essential that destination marketing organizations understand how search engines are used by travelers within the travel planning process. This study proposed a three-stage model that provides a framework for examining how online travelers use search engines and how different aspects of the travel planning process shape this use. The model was evaluated based on a national survey of American online travel planners, and the findings provide significant insight into the role of search engines for travel planning. The implications of the study for search engine marketing are discussed as well as several challenges for future research.
Chasing Science: Children’s Brains, Scientific Inquiries, and Family Labors
Authors: Rapp Rayna
Published: December 2010

Over the last three decades, an escalating portion of U.S. school children has been classified for special education; those with diagnoses entitled to services now number 15 percent of all public school pupils. At the same time, American scientists have focused increasingly on juvenile brains, studying what one psychiatric epidemiologist labeled ‘‘social incapacities.’’ This article reports on the laboratory labors of two scientific groups: neuroscientists who scan children’s brains in search of resting state differences according to diagnosis and psychiatric epidemiologists who look to epigenetics to distinguish differential diagnostic populations. The article focuses on the medicalization of childhood differences and the harmonies and discordances between what researchers and parents understand to be at the root of children’s learning and social capacities.
Indicators for Follow-Up of Multidisciplinary Teamwork in Care Processes
Authors: Deneckere Svin , Robyns Nathalie , Vanhaecht Kris , Euwema Martin , Panella Massimiliano , Lodewijckx Cathy , Leigheb Fabrizio , Sermeus Walter
Published: December 2010

In order to study the impact of interventions on multidisciplinary teamwork in care processes, relevant indicators need to be defined. In the present study, the authors performed a Delphi survey of a purposively selected expert panel consisting of scientific researchers and hospital managers. Thirty-six experts from 13 countries participated. Each participant rated a list of team indicators on a scale of 1–6. Consensus was sought in two consecutive rounds. The content validity index (CVI) varied from 8% to 92%. A final list of 19 indicators was generated: 5 on team context/structure, 8 on team process, and 6 on team outcomes. Most relevant team indicators were as follows: “team relations,” “quality of team leadership,” “culture/climate for teamwork,” “team perceived coordination of the care process,” and “team vision.” Scientific researchers and hospital managers that want to study and improve multidisciplinary teamwork in care processes should primarily focus on these team indicators.
Sex differences in friendship expectations: A meta-analysis
Authors: Hall Jeffrey A.
Published: December 2010

Friendship expectations are prescriptive normative behaviors and highly valued qualities in ideal same-sex friends. This paper reports the results of five meta-analyses of sex differences from 37 manuscripts (36 samples, N = 8825). A small difference favoring females was detected in overall friendship expectations ( d = .17). Friendship expectations were higher for females in three of four categories: symmetrical reciprocity (e.g., loyalty, genuineness; d = .17), communion (e.g., self-disclosure, intimacy; d = .39), solidarity (e.g., mutual activities, companionship; d = .03), but agency (e.g., physical fitness, status; d = -.34) was higher in males. Overall expectations and symmetrical reciprocity showed small effect sizes. Medium effect sizes for communion favoring females and for agency favoring males support predictions of evolutionary theory.
A Cross-National Investigation of Student Intentions to Pursue a Sales Career
Authors: Karakaya Fahri , Quigley Charles , Bingham Frank
Published: December 2010

Previous studies related to student selection of a sales career indicate that their perception of sales as a career is generally negative. Numerous reasons have been offered for this negative view, including negative perceptions of attributes associated with sales jobs and salespeople. This study examines the perceptions of negative and positive attributes of sales jobs and salespeople held by students in three nations and the impact these perceptions have on their feelings about selling. The impact that their feelings have on their intentions to pursue a career in sales is also investigated. The examination of students’ intention to select sales as a career in the United States, Switzerland, and Turkey identified several underlying dimensions of sales jobs, salespeople, and their feelings about selling. Study findings indicate that perceptions of a sales job and of salespeople influence their feelings toward selling. As expected, students’ feelings toward selling are positively related to their intention to pursue a sales career. However, their career intentions are significantly affected by their enrollment in a sales course, nationality, gender, and academic major. Several explanations are offered for these differences, and educational and training implications are discussed.