tbuckley/cabot-search huggingface dataset:
Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor
Authors: A. Jimeno, D. S. Hong, S. Hecker, R. Clement, R. Kurzrock, L. A. Pestano, A. Hiscox, R. A. Leos, D. L. Kirkpatrick, S. G. Eckhardt, R. S. Herbst
Journal: Journal of Clinical Oncology (2009)

3542 Background: PX-866 is an orally available nanomolar pan-inhibitor of PI-3K whose administration results in antitumor activity and pathway (AKT, S6 and mTOR) inhibition in animal models. Loss of PTEN and/or PI 3K mutations have been associated with enhanced susceptibility to PX-866. PX-866 is being evaluated in a phase 1 clinical trial to determine the MTD, and measure safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in PBMCs and tumor tissue in patients with solid tumors. Methods: Patients with advanced metastatic cancers receive PX-866 orally once daily for 5 of 7 days for 2 weeks in a 28-day cycle. Dose levels of 0.5, 1, 2, 3, 4.5, 6, 8, and 10 mg are planned. PK and PD samples are collected days 1, 2, 5, 8, 12, and 15 of cycle one and days 1 and 12 of cycle two. A PD assay has been developed that utilizes flow cytometry to test the inhibition of S6RP and mTOR in PBMC. Once the MTD of this PX-866 schedule of administration has been identified, an expansion cohort is planned to investigate tumor PD events and correlate tumor and PBMC endpoints with efficacy. Results: Four cohorts (0.5, 1, 2, 3 mg) comprising 12 patients (age 42–74, median PS 1) have completed accrual, with the 4.5 mg cohort actively enrolling. The total number of cycles to date is 30 (median 2, range 1–5+). Abdominal discomfort and mild diarrhea have been possibly associated with PX-866. No drug-related severe adverse events or dose-limiting toxicities have occurred. Of the 6 patients treated in the first 2 cohorts, 3 previously progressing patients had stable disease (SD) as best response and were on study for 105, 147 and 162+ (still active) days. Two patients (squamous cell skin cancer and melanoma) had decrease in pain allowing discontinuation of analgesics. Proof-of-concept PD studies in PBMCs evidenced a dose dependent inhibition of both p-S6RP and p-mTOR levels. Conclusions: PX-866 is a novel oral PI-3K inhibitor that is undergoing development in a clinical trial with built-in PD endpoints. PX-866 has shown to have a mild side effect profile while inducing stabilization of disease in previously progressing cancer patients. Oral PX-866 provides target inhibition even at low drug doses and inhibition is maintained for an extended time following the last dose. Updated clinical, PK and PD results will be presented. [Table: see text]
Effective detection of the epidermal growth factor receptor mutation in pathologic specimens of non-small cell lung cancer patients by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR Clamp
Authors: S. Hoshi, S. Aoyagi, C. Kono, Y. Amano, Y. Yamada, T. Yamaguchi, C. Ogawa, N. Suzuki, Y. Sano, T. Nukiwa
Journal: Journal of Clinical Oncology (2006)

20113 Background: EGFR mutations link to the responsiveness to gefitinib, so it is important to get result of EGFR mutations more rapidly and sensitively. Methods: We screened 14 trans-bronchial lung biopsy (TBLB) specimens of non-small cell lung cancer (NSCLC) patients; 10 patients responded to gefitinib and 4 patients did not respond to gefitinib. We examined exons 18 through 21 (the area of the EGFR gene coding for the tyrosine kinase domain) both by the PNA-LNA PCR clamp method and the conventional sequence method. Results: We found five different mutations in 9 patients of 10 who responded to gefitinib by the PNA-LNA PCR clamp method, but only in 7 patients by the conventional sequence method. Detected mutations were the point mutation of exon 18(719S) and exon 21(858R), deletions of exon 19 (E746-A750del (nt2235–2249), E746-A750del (nt2236–2250), L747-E749del A750P). All 4 patients who did not respond to gefitinib were not detected any EGFR mutations either by the PNA-LNA PCR clamp method or by the conventional sequence method. We could get result for 2 days by the PNA-LNA PCR method, but by 7 days by the conventional sequence method routinely. Conclusions: The PNA-LNA PCR clamp method is more sensitive and rapid than the conventional sequence method. The detected EGFR mutations have good relation to gefitinib response. No significant financial relationships to disclose.
Pharmacokinetics of oral deforolimus (AP23573, MK-8669)
Authors: G. J. Fetterly, M. M. Mita, C. D. Britten, E. Poplin, W. D. Tap, A. Carmona, L. Yonemoto, C. L. Bedrosian, E. H. Rubin, A. W. Tolcher
Journal: Journal of Clinical Oncology (2008)

14555 Background: Deforolimus is a non-pro drug rapamycin analog which specifically inhibits mTOR. Intravenous deforolimus has shown promising anti-tumor activity in a variety of malignancies. We tested the safety and tolerability of oral deforolimus in a comprehensive phase I study. A PK model was developed to characterize the concentration-time profile of deforolimus following oral administration on different dosing schedules. Subsequently the PK results were compared to historical IV data. Our data show oral deforolimus to be bioavailable, with a safety and tolerability profile similar to IV deforolimus. Methods: The trial was an open label dose-finding study for adults with advanced/refractory solid tumors. Tolerability and anti-tumor results are reported in a companion abstract. Seven dosing regimens (QDx4 qd and bid QW, QDx5 QW± a loading dose, QDx6 QW, QDx21 Q28D, and QDx28) were investigated. Multiple PK samples were taken on Days 1, 15 and 21 of a 28 day cycle. Trough samples were collected on Days 2, 4, 8, 11, 15, 16 and 22. Deforolimus levels were determined by LC/MS/MS. PK modeling was performed using WinNonLin®. Results: A 2-compartment PK model incorporating a lag time for absorption best described deforolimus PK in the 129 evaluable patients of the 147 who received treatment. Following oral administration, deforolimus has a rapid exponential decline followed by a slower linear phase of elimination. Cmax occurred at 2–3 hours; the median terminal half life is 35–70 hours. Mean estimated AUC and Cmax increased in a less than dose-proportional manner. Absolute bioavailability derived from prior IV data was ∼20%. AUCs (μg*hr/mL) at MTD over a cycle are shown below for six regimens. Conclusions: Oral deforolimus has a comparable half life to the IV form and exhibits similar nonlinear PK behavior (JCO 2005 23, 16S: 3043). A 40 mg QDx5/week schedule offers a high cumulative AUC while maintaining convenience and tolerability. This schedule has been selected for further evaluation in SUCCEED: a global phase 3 trial in patients with metastatic sarcomas. Dosing Cohort (n) Mean AUC0–28 days SD QD×21 15mg (11) 17.9 11.9 QD×28 10mg (13) 14.6 8.8 QD×4 50mg qw (12) 31.2 14.1 QD×5 60 loading/30 mg qw (7) 25.8 9.8 QD×5 qw 40mg (20) 34.6 16.6 QD×6 qw 30mg (13) 36.3 18.6 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ariad Ariad, Cognigen Corporation ARiad Ariad
Italian observational trial of appraisal and comparison by geriatric assessment instruments. Use of high potency opioids for cancer pain control and quality of life in elderly people
Authors: G. Ferrero, G. Porcile, P. Pronzato, C. Naso, A. Gozza, M. Galliano, U. Folco, C. Caroti
Journal: Journal of Clinical Oncology (2005)

8164 Background: Pain is probably under-recognized and under-treated in the Elderly with advanced cancer disease but, the effect of a therapy with high potency opioids is not studied so much in geriatric age people.To evaluate efficacy and tollerability of escalating doses of Transdermal Fentanyl (TTS-F) with Immediate Release Oral Morphine (IROM) as rescue medication,for treatment of moderate-severe cancer pain we have started a Multicentric Observational Analysis in four cancer centres of north-western Italy.Studies of oncological palliation using valid measures of quality of life,show that patients may be willing to accept some side effects of treatment, as long as they gain relief from tumor-related symptoms. Methods: -TIQ (Therapy Impact Questionnaire) -VAS (Visual Analogic Scale): 0 to 10 -Toxicity (WHO criteria) -Geriatric Assessment for pts aged>70 yrs (only at time 0): CIRS (Comorbility Index) IADL/ADL (Instrumental Activities Daily Living/Activities Daily Living) Patients characteristics -149 pts -Total Median Age: 66 yrs (range 38–86) -Median ECOG PS: 1 (range 0–2) -Elderly (>70 yrs): 65 Pain Starting situation -Median starting VAS: 5.5 (range 3–9) -TIQ: depression 68 pts, cachexia 50 pts, dispnoea 37 pts -CIRS (Comorbidity index): comorbidity were present among 56 pts. TTS-Fentanyl starting dose:25 mcg/h every 72 h (range 25–50 mcg) plus IROM 10 mg every 4–6 hours for breakthrough pain present in 38 pts Results: -Quickly pain VAS downloading during first two weeks of treatment (median VAS 1) -Analgesic doses were not significantly increased after two months and not exceeded WHO grade 2 -IROM rescue was similar to that observed for the overall population -TIQ, ADL and IADL were not influenced by therapy Conclusions: TTS-F plus Rescue-IROM offers durable long term maintenance pain relief wild acceptable toxicity also in elderly people, is particularly useful for cancer pts with compliance problems and may be considered as first-line treatment for moderate/severe cancer pain. The results on pts. QoL and the positive test of collaboration in Italian Regions are encouraging and justify a territorial planning of this program. No significant financial relationships to disclose.
Risk factors for low bone mineral density (BMD) in pediatric sarcoma survivors
Authors: H. Ahn, S. C. Kaste, T. Liu, C. A. Billups, M. M. Hudson, S. L. Spunt
Journal: Journal of Clinical Oncology (2006)

9059 Background: The incidence of and risk factors for low BMD in patients treated for sarcoma in childhood is unknown. Methods: Retrospective medical record review of 99 patients with pediatric sarcoma diagnosed between 12/82 and 2/03 who had undergone QCT evaluation more than 1 year after completion of treatment. Low BMD was defined as &gt;1.5 standard deviations below the mean. A Z-test was used to assess whether BMD was lower in our patient population than in the normal reference population. Logistic regression was used to examine factors predictive of low BMD. Risk factors analyzed included demographic variables, tumor features, treatment exposures, endocrine/renal dysfunction, and health habits. Results: Twenty-six of the 99 sarcoma survivors (26%) had low BMD. The mean (−0.8) and median (−0.75) QCT Z-scores were significantly lower than those of the normal reference population (mean and median = 0, p&lt;0.0001). Factors associated with lower BMD included young age at sarcoma diagnosis (p=0.044) or at QCT measurement (p=0.001), greater weight at diagnosis (p=0.045), non-lower extremity tumor site (p=0.023), higher cumulative cyclophosphamide dose (p=0.007), smaller size at QCT measurement [height (p=0.018), weight (p=0.012)], and low serum creatinine [at diagnosis (p=0.033), at QCT measurement (p=0.014)]. Gender, race, ifosfamide/methotrexate/etoposide exposure, radiotherapy, endocrinopathy, and health habits were not predictive of low BMD. Conclusions: Survivors of childhood sarcoma are at high risk for low BMD. Risk factors include young age, non-lower extremity tumor site, and high cumulative cyclophosphamide exposure. Prospective studies are needed to confirm these risk factors, and to guide implementation of effective screening guidelines and therapeutic measures. No significant financial relationships to disclose.
Microrna-551b Is Preferentially Expressed In Hematopoietic Stem and Multipotent Progenitor Cells and High Expression In Acute Myeloid Leukemia Is An Independent Prognostic Factor For Relapse and Poor Survival
Authors: David C. de Leeuw, Fedor Denkers, Peter J. Valk, Gerrit Jan Schuurhuis, Gert J. Ossenkoppele, Linda Smit
Journal: Blood (2013)
Survival of non-small cell lung cancer (NSCLC) patients in a randomized trial as predicted by the FDG-PET standardized uptake value (SUV).
Authors: K. Y. Gulenchyn, T. Farncombe, D. E. Maziak, G. E. Darling, A. A. Driedger, A. Hendler, C. Marriott, F. Raymond, L. Ehrlich, M. N. Levine
Journal: Journal of Clinical Oncology (2010)

7076 Background: Patients with NSCLC who are being considered for surgery undergo staging with imaging tests to detect spread of the cancer and avoid unnecessary surgery. However, after intended curative surgery, the 5-year survival for stage I disease is only 50%. Tests to identify NSCLC patients with a high risk of recurrence after surgery could be used to select those who might receive adjuvant therapy. FDG PET-CT is used to stage NSCLC. The uptake of FDG by tumor cells reflects tumor proliferation and is measured by the SUV. A number of studies reported that the SUV is prognostic in NSCLC but many of these studies were retrospective, small in size, and did not adjust for important confounding factors including performance status. Methods: A randomized trial was conducted in which patients with stage I-IIIA NSCLC on the basis of chest radiography and thoracic CT and who had a tumor considered to be resectable were allocated to PET-CT or conventional staging (abdominal CT and bone scan). All patients also had cranial imaging using CT or magnetic resonance imaging. The primary outcome was correct upstaging. The last patient was entered in August 2007 and the trial results were recently published (Ann Intern Med 2009;151;221-228). We conducted a secondary planned analysis to determine whether the SUV of the primary lung lesion was prognostic for survival, adjusting for known prognostic factors in a Cox multivariable model. Results: In the trial, 170 patients were allocated to PET-CT and 1 withdrew prior to PET. Characteristics were: mean age 67, 51% male, ECOG: 0 (59%), 1 (37%), 2 (4%); stage I (78%), II (12%), IIIA (10%). See Table for results for the 163 patients with ECOG = 0 or 1. Conclusions: In our prospective study, the SUV was prognostic of poor survival in patients with early-stage NSCLC who underwent surgical resection, even after adjusting for tumor stage and performance status. Stage Deaths (%) Median SUV dead/alive Hazard ratio (95% CI) per unit increase in SUV Unadjusted Adjusted† I 32/128 (25) 12/6.2 1.06 (1.02, 1.11)* 1.08 (1.02, 1.14)* II 10/18 (56) 14/8.8 1.05 (0.96, 1.13) 1.06 (0.97, 1.15) IIIA 11/17 (65) 14/14 * p < 0.01 † Adjusted for ECOG, age, gender, PET machine No significant financial relationships to disclose.
Cataracts among elderly prostate cancer patients receiving androgen deprivation therapy (ADT) in the United States.
Authors: J. Beebe-Dimmer, K. A. Schwartz, K. Cetin, H. Morgenstern, C. Yee, M. Bartoces, V. B. Shahinian, J. Fryzek, J. F. Acquavella
Journal: Journal of Clinical Oncology (2010)

e15068 Background: Approximately one-third of all prostate cancer patients receive some form of ADT. Side effects have been reported in patients receiving ADT, including metabolic abnormalities such as weight gain, dyslipidemia and insulin resistance. As cataracts have been linked to these components of the metabolic syndrome, an increased risk of cataract may be another adverse consequence of ADT use. Methods: Using data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we estimated the risk of cataract associated with ADT use among 64,988 prostate cancer patients aged 66 years and older diagnosed between 1996 and 2003 (with claims through 2006). Exposure to ADT was defined as having received at least one dose of a gonadotropin-releasing hormone (GnRH) agonist or orchiectomy within the first 6 months of prostate cancer diagnosis. The outcome measure was a first claim of either cataract diagnosis or surgery identified in Medicare claim files using the appropriate ICD-9 or CPT-codes. A Cox proportional hazards model was used to generate a hazard ratio (HR) associated with type of ADT. Results: Approximately 50% of prostate cancer patients had received some form of ADT within 6 months of diagnosis: 1.5% underwent an orchiectomy and 47.2% received GnRH agonists. Overall, ADT use was associated with a small increase in cataract risk (adjusted HR = 1.11, 95% CI=1.08-1.15). Cataract risk associated with GnRH agonist treatment was similar for patients with no cataract history prior to prostate cancer diagnosis (HR=1.14, 95% CI=1.10-1.19) and patients with a history of cataract (HR=1.08, 95% CI=1.03-1.12). Alternatively, orchiectomy was associated with cataract development only among patients with no prior history of cataract (HR=1.18, 95% CI=1.00-1.39). Conclusions: This is the first systematic investigation of the association between ADT and cataract. Our results suggest a modest elevation in risk of cataract among ADT users. However, the estimated risk is small and could be due to uncontrolled bias. Further study, preferably prospective in design, is needed to provide additional evidence to support or refute these findings. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, MedImmune Amgen Amgen Amgen
Infection of Capuchin Monkeys (&lt;italic&gt;Cebus albifrons&lt;/italic&gt;) With &lt;italic&gt;Herpesvirus saimiri&lt;/italic&gt;&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: H Rabin, G R Pearson, W C Wallen, R H Neubauer, J L Cicmanec, T W Orr
Journal: JNCI Journal of the National Cancer Institute (1975)

Herpesvirus saimiri (HVS) induced persistent, clinically inapparent infections of long-term duration in capuchin monkeys (Cebus albifrons). The infections were characterized by development of antibody to HVS-associated antigens and recovery of low levels of virus-genome-carrying lymphocytes in the peripheral blood. Peripheral lymphocyte counts remained in low-normal to normal ranges and no physical signs of lymphoma were evident. Prednisolone treatment caused immunosuppression in one monkey; this was accompanied by a progressive loss of humoral antibody to HVS-associated antigens, but neoplastic disease did not develop.
Financial burden among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Ryan David Nipp, Anne C. Kirchhoff, Douglas Beaty Fair, Karen Kuhlthau, Kelly Hyland, Giselle Katiria Perez, Gregory T. Armstrong, Paul C. Nathan, Kevin C. Oeffinger, Wendy M. Leisenring, Elyse R. Park
Journal: Journal of Clinical Oncology (2015)

233 Background: Cancer diagnosis and treatment can be associated with crippling financial burden, but whether this extends long-term into survivorship is unknown. We sought to examine survivors’ out-of-pocket (OOP) medical costs and their effects. Methods: From May 2011-April 2012, we surveyed a randomly selected sample of cancer survivors from the Childhood Cancer Survivor Study to assess survivors’ 1) financial distress, 2) monetary insecurity and 3) cost-motivated health behavior in the past year. We estimated the proportion of survivors with high OOP costs (≥10% of their annual household income). To determine associations between high OOP costs and the 3 outcomes of financial burden noted above, we used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for each of the outcomes, adjusting for sex, marital status, insurance, employment and income. Results: Of 1,101 mailed surveys, we received 698 (63% response) with a median age of 39 years (range 25-60) and 31 years from diagnosis (range 23-42). 9.3% (n=54) reported high OOP costs. Survivors with high OOP costs were more likely to report financial distress, monetary insecurity and cost-motivated health behavior. Conclusions: Adult survivors of childhood cancer may experience high OOP costs, resulting in significant financial burden. Our findings suggest that survivors’ OOP burdens not only influence their financial distress and monetary insecurities, but may also negatively impact their health behavior. [Table: see text]
Immune response induced by irradiated B16F0 vaccine diminish melanoma lung metastasis in mouse model
Authors: Ling Geng
Journal: Cancer Research (2008)

2848  Background and Purpose: Melanoma has had a rising incidence in the United States over the past years. The aim of this study is to develop a novel protocol of stimulating immune response of melanoma carrying mice by irradiating and then surgical remove tumor to reduce melanoma metastatic disease.Methods:B16F0, mouse melanoma, in cell culture were irradiated with 25 Gy and incubated for 0, 6, and 24 hours, and then the cells growth on histological slides were fixed for CRT (calreculin), a potential immunogenicity of tumor cells, immunofluorescence staining. According to CRT expression following radiation from experiment 1, 1x 106 irradiated B16F0 cells were injected subcutaneously into the back neck of C57 mouse at 6 hours after 25 Gy. Control group were only received medium injection. 12 days after irradiated B16F0 vaccine injection, 0.8 x10 untreated B16F0 cells were implanted subcutaneously into the right hind limb on control and vaccine injection C57BL6/J mice. Tumor growth delay study were performed, and meanwhile B16F0 tumor tissues from control and vaccine injection mice were sampled for tumor-infiltrating lymphocytes (TIL) assay with whole mount histology technique for CD8+ T cell (cytotoxic T lymphocyte) detection. 0.5 x 106 B16F0 cells in 50 μl of medium were injected into the small previous made skin pouch on the right lateral abdomen of C57 mice. B16 F0 tumors (about 5-6 mm in diameter) of the irradiation + surgical remove group (6 mice) at 6 days after implantation were irradiated with 25 Gy. 300 ng of interleukin 2 was injected subcutaneously near tumor for the irradiation + surgical remove group at day 3 and 4 after irradiation. The tumor surgical remove group (5 mice) received shamed irradiation. The tumors were removed by surgery at day 5 after irradiation or shamed irradiation. 0.25 x 106 untreated B16F0 were injected each mouse through tail vein. The mice were sacrificed at day 12 after tail vein injection and the lungs were sampled for surface B16F0 nodes count. Results: CRT strongly expressed on the cell membrane surface of B16F0 after 25 Gy, 6 hours point had maximum expression. Irradiated B16F0 vaccine caused 5-7 days tumor growth delay comparing with the control group. The CD8+ T cell IHF staining showed that tumor infiltrating lymphocytes significantly appeared in B16F0 tumor tissues after irradiated B16F0 vaccine injection but control B16F0 tumor tissues had very few of CD8 + T cells positive staining. The counting of B16F0 nodes on lung surface resulted respectively the irradiation + surgical remove group: 4.2 ± 2.7, surgical remove group: 53.2 ± 9.5, and control group: 93.2 ± 17.1. Conclusion:Irradiated B16F0 vaccine can induce immune response that diminishes melanoma lung metastasis in mouse model.