tbuckley/cabot-search huggingface dataset:
Soluble VEGF-A and lymphangiogenesis in metastatic malignant melanoma patients
Authors: C. Soubrane, R. Mouawad, V. Sultan, J. Spano, D. Khayat, O. Rixe
Journal: Journal of Clinical Oncology (2006)

8049 Background: Vascular endothelial growth factor (VEGF-A) and its circulating form (sVEGF-A) play a major role in tumor progression and angiogenesis. However, the clinical implications of circulating VEGF-A in metastatic malignant melanoma patients and its role in tumor-associated lymphangiogenesis and lymphatic metastasis remained unclear. Objectives: The aim of this study is to evaluate the potential role of circulating VEGF-A levels in lymphangiogenesis and its usefulness in metastatic malignant melanoma patients. Methods and Patients: using a sensitive enzyme-linked immunosorbent assays, VEGF-A level was measured in sera of 65 patients treated by biochemotherapy with a fully documented history of disease in comparison with 30 healthy controls. Results: A wide range (0- 566 pg/ml) of pretreatment sVEGF-A level was detected in the serum of MMM patients and the median level (40.5 pg/ml) was significantly higher (p=0.0007) than that of healthy donors (7.5 pg/ml). Age, gender and LDH were not associated with sVEGF-A levels. Regarding tumor burden, median pretreatment sVEGF-A level was higher in patients with high tumor burden (n= 40) as compared to patients with low tumor burden (n=25). Furthermore, the most surprising finding of our study was that patients with only lymph node metastasis (n=23) had a significantly (p= 0.021) higher median sVEGF-A levels (45.7 pg/ml) as compared to the 42 patients with different metastatic sites (16.6 pg/ml). Conclusion: these results suggest that sVEGF-A levels may predict lymph node metastasis in metastatic malignant melanoma patients. In addition, it may be promising targets for new therapeutic strategies in melanoma disease. No significant financial relationships to disclose.
Comparing and validating simple measures of patient-reported peripheral neuropathy (PRPN) for NCCTG Clinical Trials: A pooled analysis of 2,440 patients (pts)
Authors: H. Liu, A. D. Tan, A. Grothey, P. L. Schaefer, J. C. Buckner, C. L. Loprinzi, R. F. Morton, J. A. Sloan
Journal: Journal of Clinical Oncology (2008)

9534 Background: The introduction of new anti-cancer therapies which cause pts to incur PN has required the development of new methods to assess this treatment outcome. This study compared and validated alternative methods of assessing PRPN in a series of North Central Cancer Treatment Group (NCCTG) clinical trials. Methods: Data were combined from 5 NCCTG trials (2440 pts) that used single- item questions scaled 0–100 relating to numbness and tingling respectively in fingers and toes to measure PN. Patient quality of life (QOL) was assessed using UNISCALE, Symptom Distress Scale (SDS), Profile of Mood States (POMS), Brief Pain Inventory (BPI) and Subject Global Impression of Change (SGIC). Associations between items were tested using Bland-Altman method and correlation. Wilcoxon tests compared QOL scores between pts with PN (score >40) vs. no PN. Change in PN and QOL was compared with a 20-point change defined as clinically meaningful. Minimal important differences (MID) were estimated using both anchor-based approach and distribution-based methods. Results: At baseline, the proportion of PRPN was 11% (numbness) and 10% (tingling); and 18% on each at last assessment. The correlation between PN items at baseline and last assessment was 0.8, with an average difference of <1 point on the 100-point scale. The MID estimate of SGIC in overall QOL, Physical Condition and Emotional State were 24, 21, 25 for numbness (respectively); and 19, 18, 17 for tingling (respectively). The distribution-based MID estimate was 12 for both PN items. Pts with substantial PN reported an average of 10 points lower QOL, mood and worse SDS and a 20 point-deficit in the BPI interference items. Pts with ≤20 points worsening in PN reported significant declines in SDS (p<0.001), worst pain (p<0.02), but not in POMS (p=0.64) or overall QOL (p=0.86). Conclusions: The two PN items for numbness and tingling were redundant. Anchor-based MID methods produced larger and inconsistent estimates relative to the distribution-based methods. Evidence of criterion validity and responsiveness indicates that these simple measures of PN can be used successfully in cancer clinical trials. No significant financial relationships to disclose.
Phase I/II trial of interferon α2b and ATRA-IV in the treatment of patients with advanced renal cancer
Authors: D. M. Nanus, S. Boorjian, M. I. Milowsky, D. M. Coll, M. Cobham, J. Kaplan, G. E. Shelton, J. Melia, D. P. Petrylak, L. J. Gudas
Journal: Journal of Clinical Oncology (2005)

4606 Background: We previously reported the safety of combining IFN α2b (IFN) with low dose (15 mg/m2 TIW) liposome-encapsulated all-trans retinoic acid (ATRA-IV) in patients (pts) with renal cancer (RC) (Cancer 2002;95:1220). ATRA-IV possesses increased and prolonged serum retinoid levels compared to oral ATRA. We conducted a phase I/II trial of higher-dose weekly ATRA-IV in combination with IFN in pts with advanced RC. Methods: Pts had histologically confirmed advanced RC, measurable disease and a KPS of ≥60%. In the phase I study, cohorts of 3–6 pts were treated with weekly ATRA-IV (dose levels: 60, 75, and 90 mg/m2) and IFN (3 million units (MU), escalated weekly to 5 and 7 MU, Mon-Fri) to establish any dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Ten pts have been treated on the phase II trial. Pts completing 8 weeks of therapy were evaluable for response. Serum RA pharmacokinetics were determined using high-performance liquid chromatography (HPLC) on weeks 1 and 8 and peripheral blood lymphocytes (PBMCs) were obtained to measure changes in gene expression. Results: Toxicity: 1 of 6 pts treated at the 75 mg/m2 dose level experienced Grade 3 leukopenia, requiring cessation of treatment. Three pts were treated at the 90 mg/m2 dose level without a DLT establishing ATRA-IV at 90 mg/m2 as the MTD. To date, no pt from the phase II arm has experienced any Grade 3/4 toxicity. Response: In 20 pts evaluable for response, 5 (25%) have demonstrated a major response (1 complete response in a pt with lung-only metastases and 4 partial responses). 5 additional pts (25%) have experienced stable disease, lasting 16+, 12, 10, 9+, and 2+ months. HPLC analysis demonstrate no significant difference between weeks 1 and 8 in serum RA pharmacokinetics. Correlative studies on PBMCs are in progress. Conclusions: The combination of ATRA-IV administered once a week with IFN is well tolerated and possesses anti-tumor activity in pts with advanced RC. The sustained increased serum RA concentrations support use of the liposomal delivery system. We are currently evaluating whether in vivo expression of RA inducible genes, including retinoic acid receptor RARβ, correlates with clinical response. No significant financial relationships to disclose.
p53 expression predicts poorer survival in African-American women with breast cancer
Authors: K. A. Dookeran, K. Ferrer, M. Sekosan, E. Sciupokiene, X. Gao, Y. Wang, B. Lukaszczyk, L. Diaz de Leon, R. de la Torre, H. A. Zaren
Journal: Journal of Clinical Oncology (2005)

9635 Background: Outcome disparities for African-American (AA) women with breast cancer, including late stage presentation & poorer survival, may in part be due to biologically aggressive tumors. We hypothesized that survival would be worse for AA women with breast tumors which demonstrate abnormal p53 tumor suppressor gene function. Methods: Tumors from 188 consecutive AAs were evaluated for abnormal nuclear accumulation of p53 protein with IHC, using monoclonal antibodies DO-7 & Pab 1801 on paraffin embedded tissue, at the SHCC MBCCOP, in Chicago. Staining was scored on the UK Receptor Group, 0–8 system, with ≥2 as positive, & slides were read by 2 blinded pathologists. Disease-free survival (DFS), distant-disease free survival (DDFS), & overall survival (OS) were computed by the Kaplan-Meier method & correlated with p53 expression. Univariate analyses were performed with the use of a two-sided log-rank test & multivariate analysis was performed with the use of the Cox proportional-hazards model. Results: A total of 72 cases (39.6%) were positive with D07 IHC, 47 cases (27%) were positive with 1801 IHC, & 42 cases (30.2%) were positive for both D07 & 1801 IHC. The mean follow-up was 48 months & young age, high AJCC stage, high tumor grade & negative ER status, were all significantly correlated with p53 expression & poorer survival. p53 expression with 1801 IHC was significantly correlated with DFS, DDFS, & OS. For DFS, 44 events occurred, Hazard Ratio (HR)=2.63, 95% Confidence Interval (95% CI)=1.43–4.85, p=0.002; for DDFS, 34 events occurred, HR=2.68, 95% CI=1.33–5.41, p=0.006; and for OS, 25 events occurred, HR=2.93, 95% CI=1.31–6.55, p=0.009. Multivariate analysis demonstrated that independent predictors for DFS were p53 expression (HR=2.04, 95% CI=1.08–3.85, p=0.027), stage (HR=3.0, 95% CI=1.57–5.73, p=0.0008) & PR status (HR=0.46, 95% CI=0.23–0.95, p=0.036); for DDFS, p53 expression (HR=2.46, 95% CI=1.21–5.0, p=0.012) & stage (HR=3.26, 95% CI=1.58–6.71, p=0.001); and for OS, p53 expression (HR=2.69, 95% CI=1.19–6.10, p=0.017) & stage (HR=2.75, 95% CI=1.22–6.23, p=0.014). Conclusions: Abnormal nuclear accumulation of p53 protein independently predicts poorer survival & agressive biology in AA women with breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Avon Foundation, NCI
Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: Results of a phase I trial.
Authors: David Azria, Xavier Rebillard, Nathalie Coux, Marta Jarlier, Rodolphe Thuret, Carmen Llacer-Moscardo, Marie Charissoux, Stephane Culine
Journal: Journal of Clinical Oncology (2013)

150 Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d with subsequent dose levels of 7.5 and 10 mg/d. The primary endpoint was the determination of the maximum tolerated dose (MTD). Dose escalation was implemented according to the continual reassessment method (CRM). Results: Fifteen patients were enrolled and 14 were assessable for toxicity and response. Significant toxicities were demonstrated at the 7.5 and 10 mg/d dose levels. Dose-limiting toxicity (DLT) occurred in two patients at dose level 7.5 mg/d and characterized by a grade 3 diarrhea and a grade 3 hydronephrosis due to dehydration and kidney lithiasis. DLT also occurred in two patients at dose level 10 mg/d (grade 3 diarrhea and grade 3 laryngopharyngeal infection). The MTD was reached at 7.5 mg/day (dose-level II). The recommended dose of RAD001 was 5 mg/d. After a median follow-up of 22 months, 12 patients are alive, 1 is dead (not related to cancer) and 2 patients had relapsed. Conclusions: Concomitant hormone-radiotherapy and everolimus is well-tolerated with mucositis, hypercholesterolemia, and urinary disorders. The recommended phase-II trial dose of everolimus in this combined setting is 5 mg/day. Clinical trial information: NCT00943956.
Assessment of time from cytoreductive nephrectomy (CN) to initiation of targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Winston Vuong, Mark Chang, Nora Ruel, Joann Hsu, Courtney Carmichael, Robert A. Figlin, Sumanta Kumar Pal
Journal: Journal of Clinical Oncology (2014)

540 Background: For patients (pts) with de novo mRCC, the initiation of TT typically occurs at a window of 4-6 weeks following CN. Although this practice is thought to mitigate impaired wound healing, bleeding and other complications (cx) in the perioperative period potentially related to antiangiogenic TT, there is limited data to support this practice. Methods: An institutional database including over 670 pts with RCC was interrogated. Pts with de novo mRCC who had received CN and subsequent TT were identified. When available, demographic data, Charlson comorbidity index (CCI), body mass-index (BMI) and surgical data (estimated blood loss [EBL], intraoperative cx, etc.) were recorded. ICD-9 codes recorded up to 90 days following CN were evaluated; newly applied diagnoses with possible relationship to surgery were considered to be potential postoperative cx. For continuous variables, the Spearman correlation test was used to determine associations with time to TT. For categorical variables, Kaplan-Meier analyses were conducted to determine if time to TT varied across subgroups. Results: Of 270 pts with mRCC, 79 pts received cytoreductive nephrectomy. Of these, 36 pts received TT as an initial treatment strategy (others received IL-2, IFN or chemotherapy), and 30 pts had a documented date of TT initiation. Two pts were removed given receipt of preoperative TT, resulting in a total of 28 pts in the current analysis. Median time to TT was 46 days (range, 28-93). Median overall survival for the overall cohort was 17.2 months. No association was found between age, BMI, CCI, number of sites of metastasis and time to TT. Time to TT did not vary by race (Caucasian v other) or class of TT (VEGF-directed therapy v mTOR inhibitor). Furthermore, EBL and the frequency of intraoperative cx did not vary by time to TT. The most frequently encountered postoperative cx included pleural effusion, pain, fatigue and nausea. Conclusions: With the caveat of our small sample size, the lack of an association between operative cx and time to TT suggests that an abbreviated timeframe between CN and TT may be entertained. These findings warrant exploration in larger series and/or prospective validation.
Correlation between lymphocyte counts and response to outpatient intravenous interleukin-2 preceded by famotidine in metastatic melanoma.
Authors: W. Quan, K. N. Donkor, F. M. Quan
Journal: Journal of Clinical Oncology (2011)

8585 Background: Increased numbers of peripheral blood lymphocytes have been seen in patients receiving high-dose continuous and bolus infusion Interleukin-2 (IL-2) regimens. The toxicity of high-dose IL-2 due to a “capillary leak” syndrome requires in-patient administration of such regimens. Daily intravenous doses of IL-2 of 18-21.6 MIU/m2 over 15-30 minutes have been developed to attempt to lessen toxicity of this therapy. Famotidine may increase Interleukin-2 internalization by the IL-2 receptor on lymphocytes (Tsunoda, 1992). Previously, we have shown that patients with metastatic melanoma may be treated safely with outpatient intravenous Interleukin-2 preceded by intravenous famotidine daily for 3-5 days (Quan et al, 2003; Quan et al, 2010). The current study involves 17 patients with metastatic melanoma. Methods: Thirteen patients with stage IV melanoma received IL-2 18 MIU/m2 intravenously (IV) preceded by famotidine 20 mg IV daily for 3 days for six consecutive weeks. Four patients with metastatic melanoma received IL-2 21.6 MIU/m2 IV preceded by famotidine 20 mg IV daily for four days every 3 weeks. Peripheral blood lymphocyte counts were measured on the first day of each week of IL-2 therapy for all patients. Student’s t-test was used to compare the highest lymphocyte counts in responding patients vs. non-responders. Results: Four patients experienced either a complete (2) or partial (2) response. Thirteen patients were non-responders. The median lymphocyte count achieved in the responding patients was 4750/mm3 (range: 3100-5314/mm3) compared to the median of 2400/mm3 (range: 1500-4949/mm3) in the non-responders (p = 0.008). Conclusions: Peripheral blood lymphocyte numbers are significantly higher in patients with metastatic melanoma responding to outpatient intravenous Interleukin-2 preceded by famotidine than in non-responders. Further studies using flow cytometry and lymphocyte cytoxicity assays are currently being done.
5-year outcome for women randomised in a phase III trial comparing doxorubicin (A) and cyclophosphamide (C) with doxorubicin and docetaxel (D) as primary medical therapy of breast cancer: An Anglo-Celtic Cooperative Oncology Group Study
Authors: T. R. Evans, A. Yellowlees, I. Devine, H. M. Earl, D. A. Cameron, A. W. Hutcheon, R. E. Coleman, J. P. Crown, R. C. Leonard, J. L. Mansi
Journal: Journal of Clinical Oncology (2008)

540 Background: To compare the disease-free (DFS) and overall survival (OS), at a median follow up of 80 months, of women with primary or locally advanced breast cancer randomised to receive either doxorubicin and cyclophosphamide (AC) or doxorubicin and docetaxel (AD) as primary chemotherapy. Methods: Eligible patients (pts) with histologically-proven breast cancer with primary tumors > 3cm, inflammatory, or locally advanced disease, and no evidence of metastases, were randomised to receive a maximum of 6 cycles of either A (60 mg/m2) plus C (600 mg/m2) i/v every 3 weeks, or A (60 mg/m2) plus D (75 mg/m2) i/v every 3 weeks followed by surgery on completion of chemotherapy. Clinical and pathologic responses have previously been reported. Time to relapse, site of relapse, and all-cause mortality were recorded. The primary objective of this updated analysis was to determine the DFS and OS, which were assessed using stratified log-rank methods. Results: 363 pts were randomised to AC (n = 180) or AD (n = 183). Complete clinical and pathologic response rates were 17% and 24% for AC and 20% and 21% for AD (p = 0.42, 0.61, respectively). The number of pts with positive axillary lymph nodes at surgery was 61% (AC) and 66% (AD) (p = 0.28). The number of pts with pathologic complete response in the breast and negative axillary nodes at surgery was 16% for AC and 12% for AD. At a median follow-up of 80 months, there is no significant difference between AC and AD for DFS (p = 0.28), OS (p = 0.74), or for relapse site. The median DFS/OS were not estimable; the 25th percentile for DFS (OS) (75% of pts relapse free [alive]) was 20 (40) months and 25 (50) months for AC and AD, respectively. The 5-year DFS (95% CI) was 53% (47%-60%) for AC and 58% (52%-65%) for AD; 5-year OS (95% CI) was 67% (60%-74%) for AC and 71% (64%-78%) for AD. Site of relapse were local only (26%), distant only (56%), and both local and distant (18%). Distant relapse sites included bone (37%), liver (15%), lung (15%), pleura (7%), and soft tissue (2%). 92% of deaths were due to metastatic breast cancer. Conclusions: At a median follow-up of 80 months, our data do not suggest a DFS or OS benefit for simultaneous AD over AC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis sanofi-aventis
Changes in cardiovascular signaling proteins during doxorubicin treatment in children with high-risk ALL.
Authors: T. L. Miller, S. E. Lipshultz, R. E. Scully, D. Sawyer, S. R. Lipsitz, L. B. Silverman, H. Smith, J. M. Henkel, V. I. Franco, L. L. Cushman, S. E. Sallan
Journal: Journal of Clinical Oncology (2011)

9551 Background: Signaling proteins sensitive to cardiac changes may help predict late cardiac effects of doxorubicin (DOX) in children treated for acute lymphoblastic leukemia (ALL). We assessed changes in such proteins during therapy and their associations with biomarkers of cardiac injury and echocardiograms. Methods: Cardiotrophin-1 (CT-1), neuregulin-1 (NRG-1), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) were assayed post-hoc from available serum samples taken before, during, and after treatment in 90 DOX treated patients from the Dana-Farber Cancer Institute Childhood ALL Consortium Protocol 95-01. This was compared to echocardiograms, cardiac troponin-T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) previously assayed from the same samples. Associations between changes over time in any two variables were quantified by Spearman's correlation coefficients. Results: Mean CT-1 at baseline (800.5 pg/ml; n=74) decreased mid treatment (206.0 pg/ml; n=61) and post treatment (19.1 pg/ml; n=58) (P<0.001). Mean NRG-1 at baseline (17.9 pg/ml; n=84) decreased mid treatment (13.5 pg/ml; n=88) and post treatment (7.7 pg/ml; n=75) (P<0.001). Mean VEGF at baseline (145.4 pg/ml; n=89) and mid treatment (176.8 pg/ml; n=56) remained stable but increased post treatment (291.6 pg/ml; n=52) compared to baseline (P=0.002) and mid treatment (P=0.003). Mean IL-6 at baseline (32.3 pg/ml; n=90) decreased mid treatment (9.2 pg/ml; n=86) but increased post treatment (21.5 pg/ml; P<0.001). Changes in IL-6 correlated with hsCRP levels during therapy (Spearman coefficient=0.41, P<0.001). Changes in NRG-1 correlated marginally with z scores for left ventricular (LV) mass (0.30, P=0.08), LV end diastolic dimension (0.33, P=0.06), and LV end posterior wall thickness (0.29, P=0.09). No other significant associations were found. Conclusions: Decreases in CT-1 and NRG-1 during treatment may reflect increased cardiac apoptosis and decreased LV mass and function. Increases in IL-6 and VEGF could suggest DOX-related inflammation and angiogenesis. These results support the need for future research on the role of these proteins.