tbuckley/cabot-search huggingface dataset:
Changes of bodyweight and lipids during intermittent maximum androgen blockade (IMAB) in the treatment of advanced prostate cancer
Authors: P. Quarles van Ufford-Mannesse, N. A. Spry, K. Byth, M. P. Berry, L. J. Hayden, E. I. Korbel, H. Woo, H. Gurney
Journal: Journal of Clinical Oncology (2005)

4661 Background: The androgen-depleted state leads to physiological changes. The reversibility of these effects is unknown. Methods: Patients with either recurrent local or advanced disease were treated with a combination of Flutamide 250mg tid and a 3 monthly depot of Leuprolide 22.5mg (MAB) for 9 months. When serum PSA level at 9 months was <4.0 ng/ml, treatment was withheld until PSA reached >20 ng/ml or pretreatment level. This cycle of ON- and OFF-treatment was repeated until disease progression whilst on MAB therapy. Bodyweight, fasting serum lipids and testosterone were measured at set intervals during ON and OFF therapy. Results: 233 patients were enrolled in a prospective multicenter trial. Median follow up was 139 weeks. 229 completed cycle 1 ON-treatment (ON1), 204 cycle 1 OFF-treatment (OFF1), 89 ON2, 63 OFF2, 8 ON3 and 4 patients OFF3. Median duration in OFF1, OFF2 and OFF3 were 53, 28 and 11 weeks, respectively. From baseline until the end of follow-up 47.8% gained weight (26.3% 2–5 kg and 21.5% ≥5 kg). During ON1 51.3% gained ≥2kg. During OFF1 21% of these patients continued to gain ≥ 2kg, 53% stabilized and 26% lost ≥ 2kg. When these patients restarted MAB 46% regained ≥ 2kg, 43% remained stable and 11% lost ≥ 2kg. There were no significant changes in lipids and no correlation between changes in weight and lipids ON and OFF treatment. There was no significant correlation between baseline testosterone level and changes in weight or lipids. Conclusions: Almost 50% of patients gain weight during IMAB. Most weight gain is seen during the first 9 months of treatment. In a quarter of these patients, the weight gain was reversible when MAB was stopped and an additional half of these patients had stabilization of weight. Almost half of these patients regain weight once MAB recommenced. There was no significant change in lipids towards a pro- or anti-atherogenic direction. Baseline testosterone did not to predict for changes in weight or lipids. No significant financial relationships to disclose.
A pediatric phase I trial and pharmacokinetic study of aflibercept (VEGF Trap): A Children's Oncology Group Phase I Consortium study.
Authors: J. R. Park, D. S. Hawkins, M. Ingle, S. C. Borinstein, J. L. Glade Bender, D. Yamashiro, S. Baruchel, A. P. Chen, P. C. Adamson, S. Blaney
Journal: Journal of Clinical Oncology (2010)

9530 Background: Interference with vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability may be beneficial in controlling the growth and metastatic spread of cancer. A pediatric phase I trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of aflibercept. Methods: Cohorts of 3-6 children with refractory solid tumors received aflibercept, administered over 60 minutes every 14 days, at dose levels of 2, 2.5 or 3 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers was performed with the initial dose. Results: 21 eligible patients (pts), 11 males, median (range) age 12.9 (1.9-21.6) yrs with sarcoma (n=5), clear cell sarcoma (n=1), hepatocellular carcinoma (n=2), adenocarcinoma (n=2), embryonal tumors (n=9) or CNS tumors (n=2) were enrolled. Of 18 pts fully evaluable for toxicity, 1/6 receiving 2 mg/kg/dose developed DLT (intra-tumoral hemorrhage) and 2/6 receiving 3 mg/kg/dose developed DLT (pain and tumor/subcutaneous tissue necrosis). None of the 6 pts receiving 2.5 mg/kg/dose developed DLT, defining this as the MTD. Non-dose limiting grade 3 or 4 toxicities included neutropenia, hemoglobin/anemia and limb pain at metastatic disease sites. Four patients had stable disease for a median of 17.4 weeks (range 13.4-29). At the MTD, the median (range) free and bound aflibercept serum concentrations on d8 were 5,110 (3,330-6,020) and 2,070 (1,230-2,690) ng/ml, respectively, while on d15 the median trough free and bound concentrations were 1,971 (991-2,440) and 3,920 (2,100-3,970) ng/ml. Conclusions: The recommended pediatric phase 2 dose of aflibercept is 2.5 mg/kg/dose every 14 days. On target anti-angiogenic effects of tumor necrosis and hemorrhage proved dose limiting, but DLTs did not appear to occur in patients with minimal disease burden. Differences in disease burden may thus underlie the lower MTD observed in pediatric patients relative to the adult recommended phase 2 dose of 4 mg/kg every 14 days. No significant financial relationships to disclose.
A phase II study of sorafenib in combination with bicalutamide in patients with chemo-naive hormone refractory prostate cancer (HRPC)
Authors: E. K. Beardsley, S. L. Ellard, S. J. Holte, S. A. North, E. Winquist, K. N. Chi
Journal: Journal of Clinical Oncology (2008)

16098 Background: Sorafenib is a multi-targeted kinase inhibitor associated with discordant PSA and clinical responses in patients (pts) with HRPC, possibly due to an effect on PSA expression. This trial was conducted to evaluate the effects of androgen receptor blockade using bicalutamide in combination with sorafenib in pts with chemotherapy naïve HRPC. Methods: Multicenter phase 2 study with 2 stage design. Pts had to have a rising PSA > 5, minimal or no symptoms, and not have received bicalutamide in the year prior to study entry. Sorafenib 400 mg was administered orally twice daily with bicalutamide 50 mg PO daily continuously on a 28-day cycle. The primary endpoint was PSA response (≥ 50% decline from baseline) or stable disease ≥ 6 months, with a 40% rate of response/stable disease being considered of interest. Seventeen evaluable pts were to be accrued to the first stage. Pts could continue protocol therapy with rising PSA in the absence of other signs of disease progression. Results: Twenty pts were enrolled in the first stage. Baseline characteristics included: ECOG PS 0:1 in 16:4, median PSA = 29 (range 6.5–410), 6 patients had no clinical metastases, 11 had bone, 9 lymph node and 3 visceral metastases. To date, a median of 3 cycles (range 0–7) has been delivered and 13 pts continue therapy. Related grade 3/4 adverse events included: AST/ALT elevations (6 pts), anorexia (2 pts), fatigue (4 pts), muscle weakness (2 pts), skin rash (2 pts), hand-foot syndrome (8 pts). Treatment was stopped due to AE in 3 pts, PSA progression in 8 pts, and radiologic/symptomatic progression in 2 pts. One pt died of acute pancreatitis considered possibly related to sorafenib during cycle 4. PSA declines of ≥ 30% and ≥ 50% have occurred in 8 (40%) and 7 (35%). Median time to PSA response was 1.0 months (0.9–2.1). Median time to PSA or radiological/symptomatic progression has not been reached. Conclusions: The combination of bicalutamide and sorafenib is well tolerated. Six pts have had a confirmed PSA response or stable disease, meeting the criteria to proceed with the 2nd stage of this study. No significant financial relationships to disclose.
IL-10 and IL-12 expression in breast cancer patients and effect of therapy
Authors: V. S. Rao, A. Alabi, C. E. Dyer, J. Greenman, P. J. Drew
Journal: Journal of Clinical Oncology (2008)

14016 Background: We investigated whether immune system impairment manifested by increased Interleukin-10 (IL-10) and reduced IL-12 levels occur in breast cancer patients and determined the effect of surgery and adjuvant therapy on these cytokine levels. Methods: Blood samples were collected from primary breast cancer patients before surgery, post-operatively and after completion of adjuvant therapy and healthy controls. Serum IL-10 and IL-12 levels and IL-12 level in supernatants from stimulated PBMC (after incubation with S. aureus Cowan's strain I in vitro for 24 hours) were measured by ELISA. IL-10 and IL-12 levels in tumor specimens were ascertained by immunohistochemistry. Results: No significant difference in serum IL-10 (P=0.957) and IL-12 levels (P=0.5) between patients (n=91) and controls (n=31) was detected (Kruskal-Wallis test). Comparison of prognostic factors (size, lymph node involvement, estrogen receptor status and grade) with IL-10 and IL-12 levels did not show any significant association except for grade which was inversely related to serum IL-12 levels (P=0.045; multi-way ANOVA). No difference in IL-12 production capacity of PBMC was detected between patients and controls. Immunohistochemistry revealed appreciable staining for IL-10, but was inconclusive for IL-12. No significant difference in serum IL-10 and IL-12 production capability of PBMC following surgery was detected. However serum IL-12 levels were significantly elevated (P=0.001; Wilcoxon signed rank test). After completion of adjuvant therapy, serum IL-10 levels were not significantly altered, however, there was a trend towards a fall in serum IL-12 ( P=0.06; Wilcoxon signed rank test). Conclusions: Skewing of the immune system towards a Th2 cytokine profile has not been demonstrated in this study. Tumor grade which is reflective of biological aggressiveness was the only prognostic factor which influenced IL-12 levels, suggesting a degree of immune impairment. The rise in serum IL-12 following surgery may indicate a partial skewing of the Th1/Th2 balance which may be beneficial to the host immune system. The fall in serum IL-12 after adjuvant therapy may be a manifestation of the long term impact of these immuno-suppressive regimens on the immune system. No significant financial relationships to disclose.
Sharing hope: Preserving fertility through partnership.
Authors: Ruth Rechis, Emily Eargle, Sarah R. Arvey, Stephanie Nutt, Ashley Koenings, Bree Hemingway
Journal: Journal of Clinical Oncology (2013)

69 Background: Each year about 70,000 individuals aged 15-39 are diagnosed with cancer. Unfortunately, essential cancer treatments often negatively impact an individual’s fertility. The average cost of fertility preservation ranges upwards of $12,000 for women and $1,500 for men and most insurance companies typically do not cover pre-treatment fertility preservation. Not only do these individuals experience a life-threatening cancer diagnosis, they are also faced with the possibility of not having children of their own in the future. The LIVESTRONG Foundation’s Fertile Hope Program provides educational information and timely pre-treatment financial assistance to cancer survivors whose medical treatments present the risk of infertility. Female participants receive the medication at no cost through the Foundation’s partnership with EMD Serono, and all survivors can receive at least a 25% discount, on preservation services at the more than 350 partnering fertility clinics. Methods: LIVESTRONG Navigators implementing this program track all interactions on an ongoing basis. Additionally, in 2012, clients who had been approved for the program within the last 12 months and those who had been approved two or more years ago received an online survey (N=200 and 105 respondents respectively). Results: In 2012, 3,353 individuals (1,537 men and 1,816 women) saved a total of $12,542,114 through this program. Survey respondents indicated that they value the speed of the process and the opportunity to preserve their fertility. Interestingly, respondents noted that they learned about the program through a reproductive doctor, but they learned about fertility-related issues through an oncologist. Finally, respondents indicated that 14 babies have been born as a result of this program. Conclusions: This program has made a unique and measurable change to improve the quality of life of survivors. By providing information and support as well as reducing costs, survivors have the potential to fulfill their aspirations to bear a biological child. Ensuring that providers who share information about fertility-related issues are informed about these types of programs could help to ensure all interested survivors have access to discounted, timely fertility preservation.
A prospective trial of involved field radiation (IFRT) + chemotherapy compared to extended field (EFRT) radiation for favorable Hodgkin disease: Survival differences and implications of mature follow-up for current combined modality therapy
Authors: S. J. Horning, R. T. Hoppe, R. H. Advani, S. Breslin, J. Allen, S. L. Hancock, S. A. Rosenberg
Journal: Journal of Clinical Oncology (2007)

8014 Background: We conducted a prospective randomized trial from 1980–88 comparing IFRT plus VBM (vinblastine, bleomycin, methotrexate) chemotherapy to extended field radiation (EFRT) in patients with favorable stage I-IIIA disease to limit radiation exposure and define an effective treatment regimen that preserved fertility and did not increase the risk of leukemia. Methods: Patients (pt) with favorable, laparotomy-staged disease were defined as those with no bulky mediastinal disease, no or minimal abdominal disease (&lt;5 cm), no or minimal splenic disease, and &lt;1 extranodal site. VBM was given for 6 cycles after 44 Gy IFRT. EFRT was subtotal lymphoid for stage I-IIA and total lymphoid irradiation for I-IIB, IIIA pt. We previously reported (J Clin Oncol 6:1822, 1988) no survival differences in this study. Follow-up was similar for both arms and was further supplemented by an approved SSA Epidemiologic Vital Status Data Record application. Results: 72 pt were randomized, 34 to IFRT + VBM and 38 to EFRT. Median follow-up is 20.8 yr (10.3–25.1) and just 8 pt were censored at &lt;15 yr. Twenty-one yr freedom from progression is 96% for IFRT + VBM vs 74% for EFRT (p= 0.035). A single death at 18 yr was recorded in IFRT + VBM pt (3%) whereas 11 deaths occurred among EFRT pt (29%). Overall survival (OS) at 21 yr is 95% for IFRT + VBM vs 68% for EFRT (p=0.003). As previously reported, fertility was informally assessed, but premature menopause was not observed and both men and women conceived after IFRT + VBM. Conclusion: The reduction of radiation to IFRT, combined with a less toxic chemotherapy in our study, resulted in excellent long-term OS that was significantly superior to EFRT. The survival data with IFRT + VBM also compare favorably with our historical EFRT experience. Moreover, these results have implications for current combined modality therapy where much lower doses of RT, more limited fields and brief chemotherapy should lead to even less late morbidity and mortality. No significant financial relationships to disclose.
Mood state and melanoma outcome in the Multicenter Selective Lymphadenectomy Trial
Authors: J. R. Garreau, M. Faries, X. Ye, D. Morton
Journal: Journal of Clinical Oncology (2009)

9603 Background: Emotional state has been linked to cancer survival, but its influence on the outcome of early melanoma is unclear. The Multicenter Selective Lymphadenectomy Trial (MSLT-I) randomized patients with clinically localized cutaneous melanoma to wide local excision (WEX) plus observation or to WEX plus sentinel lymph node biopsy (SNB). Clinical endpoints included disease-specific and disease-free survival. A substudy of this phase III trial evaluated the impact of mood state on survival, and the impact of recurrence on mood state. Methods: Patients were asked to complete a 65-question form within 6 months of enrollment (baseline) and every 12 months thereafter. This questionnaire measured 6 identifiable mood states (vigor-activity, tension-anxiety, depression, anger-hostility, fatigue-inertia, confusion-bewilderment) of the Profile of Mood States (POMS), a validated mood scale for assessing responses to therapy. Self-reported data from the questionnaires were linked to demographic and clinical variables. Results: Of 2,001 patients accrued to MSLT-I, 1,620 completed the questionnaire at baseline. The baseline distribution of POMS variables was similar in the two treatment arms (data not shown). Patients with more vigor at baseline had a significantly longer disease-free and overall survival ( Table ), even after adjusting for age, tumor thickness, site, and ulceration status (p &lt;0.001). Among 136 patients who completed a questionnaire within 6 months after recurrence, comparison of baseline and post-recurrence responses revealed significant changes in mood state: tension, fatigue and confusion increased, whereas vigor decreased (p = 0.0004, 0.0171, 0.0089, and 0.0028, respectively). Conclusions: Vigor, a measure of energy and optimism, is directly correlated with disease-free and overall survival in early melanoma. The negative impact of recurrence on mood state suggests that SNB as a tool for preventing recurrence might also improve mood state and psychological well-being. Supported by NIH CA29605. [Table: see text] No significant financial relationships to disclose.
Intratumoral conversion of flucytosine to 5-fluorouracil using a novel MLV-based replication-competent retroviral vector carrying the cytosine deaminase gene (Toca 511) in an immune-competent model of glioblastoma.
Authors: J. M. Robbins, D. Ostertag, K. Amundson, T. Buckley, F. E. Lopez, B. Martin, H. E. Gruber, W. Gunzburg, O. Perez, D. J. Jolly
Journal: Journal of Clinical Oncology (2010)

e13541 Background: Patients with the most common and aggressive form of brain cancer, glioblastoma multiforme (GBM) have poor prognosis and few palliative options. Gene therapy approaches using replication-deficient viral vectors have been tried previously for GBM with limited efficacy likely due to poor gene delivery to the tumor. Methods: We used a novel replication-competent retroviral vector (Toca 511) engineered to efficiently deliver a modified cytosine deaminase (CD) prodrug activating gene to glioma cells. We investigated the functionality of Toca 511 using intratumoral delivery in a syngeneic, orthotopic glioma model in immune-competent B6C3F1 mice. Freshly excised tumors were analyzed by quantitative PCR, western, and HPLC. Results: Brain tumors isolated from mice treated with Toca 511 and flucystosine (5FC) had observable expression of CD protein and vector copy numbers per genome that demonstrate efficient tumor infection. Extensive tumor specific viral spread with almost no spread of vector from the site of injection was observed in the first 24 days. Highly efficient intratumoral conversion of the 5FC prodrug into the anticancer drug 5-fluorouracil (5FU) was demonstrated after intraperitoneal or oral dosing with 5FC. Studies with Toca 511 at high and mid dose levels in combination with 5FC resulted in prolonged survival compared to controls (> 5 months, p<0.0036 and <0.0354 respectively) in this syngeneic glioma model. The highest Toca 511 dose level tested yielded no safety related findings in the mice. Conclusions: Toca 511 efficiently delivers a functional CD gene for expression in glioma cells in a syngeneic, orthotopic model in immune-competent mice. Toca 511 increases survival through the delivery of CD gene and subsequent efficient conversion of 5FC into 5FU within the brain tumor with no safety related findings. A phase I ascending dose trial of the safety and tolerability of Toca 511 in combination with 5FC in patients with recurrent GBM is planned for first quarter 2010. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Tocagen, Inc. Tocagen, Inc. Tocagen, Inc.
A phase II trial (N0177) of erlotinib and temozolomide (TMZ) combined with radiation therapy (RT) in glioblastoma multiforme (GBM)
Authors: P. D. Brown, S. Krishnan, J. Sarkaria, W. Wu, P. Mischel, W. H. Yong, R. Arusell, R. B. Jenkins, J. C. Buckner, C. Giannini
Journal: Journal of Clinical Oncology (2008)

2016 Background: EGFR amplification in GBMs is a common occurrence and is associated with treatment resistance. Erlotinib, a selective inhibitor of EGFR, was combined with TMZ and RT in a phase II trial for GBMs. Methods: Adult patients not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) throughout the treatment protocol until progression. Erlotinib alone was delivered for 1 week, then concurrent with TMZ (75 mg mg/m2 daily) and RT (60 Gy), followed by up to 6 cycles of adjuvant TMZ (200 mg/m2, daily x 5d, q28 d). The primary endpoint was survival at 1 year with a planned sample size of 93 patients. Results: 97 eligible patients were accrued with 8 patients over 70 years old. By definition the primary endpoint was successfully met with over half the patients (61%) patients alive at 1 year and a median survival of 15 months. However, there was no sign of benefit when comparing N0177 with the radiation/TMZ arm of EORTC 26981: Recursive partitioning analysis (RPA) III 19 vs. 21 months, RPA IV 15 vs. 16 months, RPA V 8 vs. 10 months respectively (Mirimanoff JCO 2006). Presence of diarrhea and/or rash, EGFRvIII, p53, PTEN, combination EGFR and PTEN, and EGFR amplification status were not significantly (p>.05) predictive of survival. MGMT status was analyzable in only 27% of patients and was not predictive of survival probably due to small sample size. The median survival of patients older than 70 was 4.5 months (p=0.001). Grade 2+ rash (42%) and diarrhea (10%) were frequent adverse events. Conclusions: Although the primary endpoint was successfully met utilizing pre-TMZ era historic controls, there was no sign of benefit compared to TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. Elderly patients did poorly even with combination therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology
The Race Is On
Authors: Jon C. Rittenberger, Tomas Drabek
Journal: Circulation (2015)

I t is hard to believe that the first descriptions of brainwaves, later called electroencephalograms (EEGs), are older than ECGs; both are >100 years old.Significant progress has been made in understanding heart and brain functions with the use of novel invasive and noninvasive technologies that allow detailed mapping of structural and functional connections.However, in extreme situations such as cardiac arrest, we still rely, at least initially, on these "ancient" technologies for a quick diagnosis and guidance for treatment.