tbuckley/cabot-search huggingface dataset:
The use of biologic therapy in the treatment of unresectable appendiceal neoplasms
Authors: R. T. Shroff, B. T. King, P. Pathak, L. A. Lambert, M. J. Overman, R. A. Wolff, P. F. Mansfield, J. L. Chase, A. Ohinata, C. Eng
Journal: Journal of Clinical Oncology (2008)

15546 Background: Peritoneal dissemination of appendiceal neoplasms (AN) is traditionally treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with a reported median 10-yr overall survival (OS) of 50–60%. Treatment options are limited for those who are not optimal candidates for CRS. We have previously shown that systemic chemotherapy may help in selected patients (Shapiro et al; ASCO GI, 2007); however, the role for biologic agents has not been characterized in these poor prognosis patients. Increased vascular endothelial growth factor (VEGF) expression in tissue specimens has recently been associated with poor prognosis. The purpose of this study was to evaluate the role of biologic agents in patients who were not candidates for cytoreduction. Methods: A retrospective observational cohort study was conducted of AN pts who received systemic chemotherapy with anti-VEGF (bevacizumab) or anti-epidermal growth factor receptor-targeted therapy (cetuximab, panitumumab, or gefitinib) between January 2000 and July 2007. The type of systemic chemotherapy and biologic therapy, response rate (RR), progression-free survival (PFS) and overall survival (OS) were determined. RR was a composite of either radiological or clinical response. Results: A total of 41 pts (M:F - 23:18) were evaluable for response; median age = 53 yrs (range: 41–78). Thirty-five pts had prior CRS and/or HIPEC. Response rates were 71.4% among those who received 1st line therapy (n=28), and 53.8% among those who received 2nd line therapy (n=13). The majority of 1st line pts received combination chemotherapy with 5-fluorouracil (86%) or platinum-based (75%) therapy. Thirty-two pts (78%) received bevacizumab as the biologic therapy of choice. There were no complete responders. After a median follow up of 26.1 mos, the median PFS was 9.8 mos after 1st line and 4.7 mos after 2nd line therapy. The median OS was 56 mos. Conclusions: Treatment options for patients with appendiceal neoplasms who are not candidates for CRS/HIPEC are limited. The addition of biologic therapy to systemic chemotherapy may provide added benefit in response and survival. Initiation of a quality of life analysis is planned. No significant financial relationships to disclose.
A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation
Authors: J. J. Hwang, J. L. Marshall, S. Malik, H. Chun, T. Ahmed, P. A. Pilia
Journal: Journal of Clinical Oncology (2006)

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m 2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m 2 . Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m 2 . No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m 2 administered Q7D, and dose escalation continues. [Table: see text]
Recurrent intragenic rearrangement mutations in the tumor suppressor gene <i>BRCA1</i>: Prevalence results from 12,272 patients at high risk for breast and/or ovarian cancers and methods of biochemical analysis
Authors: B. C. Hendrickson, T. Judkins, A. M. Deffenbaugh, K. Pyne, B. E. Ward, T. Scholl
Journal: Journal of Clinical Oncology (2004)

9533 Background: Rearrangement mutations may represent 5–10% of clinically significant variants in the BRCA1 tumor suppressor gene. Several of these mutations occur recurrently in unrelated families or in specific ethic groups. Previously, we described a multiplexed PCR based method that accurately and efficiently detects several of these recurrent mutations (Nielsen et al; Proc ASCO 2002). Inclusion of this assay as part of a comprehensive genetic analysis for hereditary breast cancer in 12,272 patients revealed the prevalence of five rearrangement mutations in a predominantly North American sample set. Methods: Genomic DNA, isolated from whole blood, was inoculated into a multiplexed PCR assay that detects the previously characterized deletions of BRCA1 exons 8–9, 13, 14–20, 22 and a duplication of exon 13. Results: Clinical testing identified 1,646 patients (13.4%) with clinically significant mutations, 43 (2.6%) being rearrangements detected by the assay. The duplication of exon 13 was identified in 36 patients (2.2% of mutation carriers), making this the most prevalent non-Ashkenazi BRCA1 mutation in our test population. The deletions of exon 22 and exons 14–20 were found in four and three patients, respectively. No occurrences of the deletions of exons 8–9 or exon 13 were identified in this group. Conclusions: Mutation-specific, as well as more generalized methods to detect large rearrangement mutations improve the sensitivity of clinical tests to determine breast/ovarian cancer risk. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Genetics
Low bone density in premenopausal women at high risk for breast cancer
Authors: A. P. O'Dea, M. Thirunavu, J. Nydegger, J. R. Klemp, B. F. Kimler, C. J. Fabian
Journal: Journal of Clinical Oncology (2009)

1532 Background: Tamoxifen when used in the high estrogen milieu of premenopausal women may reduce bone density. However, the proportion of premenopausal women at increased risk for breast cancer who have low bone density and are likely to take tamoxifen is unknown. Methods: Premenopausal women attending a high-risk clinic were invited to take part in an ongoing prospective study assessing bone mineral density (BMD) loss. Women on bisphosphonates or those previously treated with selective estrogen receptor modulators were excluded. BMD was measured by DEXA, serum 25-hydroxyvitamin D (25OHD) by chemiluminescence, and information on risk factors for osteoporosis and breast cancer was obtained by questionnaire. Results: 106 premenopausal women were entered between April and October 2008. Median age was 42 (range 23–57), median body mass index (BMI) was 25 kg/m 2 (range 15–44). All but two were Caucasian. 13% had a prior biopsy with atypical hyperplasia (AH) or in situ carcinoma, 36% had a family history of osteoporosis, 56% took calcium supplements, and 47% took vitamin D supplements. Median sun exposure was 480 minutes per month, the majority with sunscreen. Median serum 25OHD was 34 ng/ml. Five had deficiency (&lt; 20 ng/mL), and 45 women deficiency or insufficiency (&lt; 32 ng/mL). Seven subjects ages 31 to 48 had evidence of low BMD (T-score of less than -1.0 in the spine or hip.) One woman with low BMD by DEXA had a 25OHD level &lt; 32 ng/ml. Women with low BMD had lower BMIs (median of 22 vs. 25 kg/m 2 , p = 0.020) than women with normal bone density. There was no difference in history of vitamin D and calcium supplement use, and low 25OHD levels did not explain the low T-scores. Information on vitamin D receptor polymorphisms associated with BMD loss is pending. Importantly, 21% of women with a prior biopsy demonstrating AH or in situ carcinoma had evidence of bone density loss compared to 4% of women without such a biopsy (p = 0.048). Conclusions: Premenopausal women with a history of AH or in situ carcinoma are most likely to take tamoxifen for primary prevention and in our ongoing study have a high enough incidence of low bone density to make baseline assessment by DEXA a consideration, particularly for those with predisposing factors such as low BMI and lack of sun exposure. No significant financial relationships to disclose.
Abstract 175: Vasopressin Maintains Robust Organ Blood Flow During Resuscitation from Hemorrhagic Shock
Authors: Raúl J Gazmuri, Herbert K Whitehouse, Alvin Baetiong, Karla Whittinghill, Jeejabai Radhakrishnan
Journal: Circulation (2014)

Background: We have reported beneficial hemodynamic and survival effects of vasopressin (VP) infusion in swine models of hemorrhagic shock (HS), and attributed the effects to increases in peripheral vascular resistance. However, VP may also exert a minor effect on venous return. In the present study we used fluorescent microspheres to measure the effects of VP on blood flow to organs of interest during HS produced by liver laceration (LL). Methods: Forty male domestic pigs (32.3 to 40.3 kg) had their left lateral liver lobe lacerated with a sharpened steel, X-shaped 5 cm blade clamp. Thirty-two pigs received a second LL in the same lobe 7.5 minutes later and 24 pigs received a third LL in the left medial lobe at 15 minutes from the first LL. Pigs were randomized 1:1 to receive an infusion of VP (0.04 U/kg•min-1) or vehicle intraosseously starting 7 minutes after the first LL until the end of the experiment (240 min). Microspheres were injected into the left ventricle at baseline (BL) and during HS at times shown in the Table. Results: At 60 minutes of HS, VP infusion was associated with higher aortic blood pressure and lower cardiac index (both NS) along with overall reductions in blood flow to various organs (Table) coincident with a statistically significant reduction in heart rate (157±43 vs 184±29 min-1; p≤0.05). At 120 and 180 minutes of HS, the heart rate was only mildly reduced (NS). The aortic pressures remained high but without a reduction in cardiac index. Organ blood flows were all comparable or higher with VP than in control pigs attaining statistical significance for renal cortical blood flow. Conclusion: Contrary to the expected hemodynamic effects of VP redistributing blood flow away from “non-vital organs,” we observed a robust hemodynamic effect that adequately perfused vital and “non-vital” organs during HS without deterioration over time. Early and sustained VP infusion could represent a highly effective intervention for hemodynamic stabilization during severe HS.
Influenza Vaccination in Patients With Chronic Heart Failure
Authors: Orly Vardeny, Brian Claggett, Jacob A. Udell, Milton Packer, Michael Zile, Jean Rouleau, Karl Swedberg, Akshay S. Desai, Martin Lefkowitz, Victor Shi, John J.V. McMurray, Scott D. Solomon
Journal: JACC Heart Failure (2015)
A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK/ZK to determine clinical benefit on progression-free survival (PFS) in high LDH pts
Authors: P. Major, T. Trarbach, H. Lenz, D. Kerr, K. Pendergrass, J. Douillard, B. Chen, D. Laurent, C. Jacques, E. Van Cutsem
Journal: Journal of Clinical Oncology (2006)

3529 Background: PTK/ZK is an oral, antiangiogenic inhibitor of tyrosine kinase signaling of all known vascular endothelial growth factor receptors (VEGFR). PTK/ZK in combination with FOLFOX4 has been investigated in first line (CONFIRM 1[C1]) and second line (CONFIRM 2 [C2]) mCRC pts. Methods: In both trials, pts were randomized to receive PTK/ZK or placebo. Since high LDH and poor performance status (PS) have been shown to indicate poor prognosis in mCRC, pts were stratified by baseline serum LDH (≤ or &gt; 1.5 X ULN) and PS (0, 1–2), yielding 4 strata per trial. Exploratory analysis of the high LDH strata in C1 indicated that these pts may derive the most benefit from PTK/ZK treatment. The purpose of this pre-planned meta-analysis of C1 and C2 is to determine whether the treatment effect of C1 and C2 are consistent. Results: Both trials showed strikingly similar results. High LDH pts comprise approximately 30% of the total pt population. PTK/ZK seems to have the same strong effect on PFS in high LDH pts in both 1st and 2nd line mCRC with a HR for PFS of 0.67 (p =0.010) for C1 and 0.63 (p &lt; 0.001) for C2 (N=250 and N=316, respectively). The safety profile of PTK/ZK was highly consistent. The most frequent grade 3/4 AEs attributable to PTK/ZK were hypertension, diarrhea, fatigue, nausea, vomiting and dizziness. Increases in AEs associated with antiangiogenic therapy such as bowel perforations and bleeding complications were not observed in the PTK/ZK arms of both trials. In the meta-analysis, PTK/ZK effect on PFS is moderate in the overall population (HR 0.85, p-value 0.005). In contrast, the effect on PFS is strong and clinically meaningful in the high LDH population (HR 0.65, p-value &lt; 0.001, N=566). Conclusion: This meta-analysis is the largest study of poor prognosis pts with high serum LDH in metastatic colorectal cancer. These data suggest that PTK/ZK significantly improves PFS in high LDH pts. Further evaluation of PTK/ZK in this pt population is planned. [Table: see text]
Abstract 17129: Prevalence and Correlation of Abnormal Flow Reserve by Stress Cmr and Coronary Artery Plaque by Cardiac CTA in Symptomatic Patients With Diabetes
Authors: Yasmin S Hamirani, Michael Salerno, Yang Yang, Christopher M Kramer, Jamieson Bourque
Journal: Circulation (2014)

Introduction: Patients with diabetes mellitus (DM) and angina have high morbidity and mortality after negative stress cardiac imaging, and myocardial perfusion reserve (MPR) measures provide additional prognostic information. We aimed to determine the association of abnormal MPR with the extent of coronary artery disease (CAD) in symptomatic diabetics. Method: Symptomatic diabetics age 18-85 without known CAD referred for stress imaging were included. Quantitative stress CMR and coronary CT angiography (CTA) were performed. Plaque distribution was characterized by “segment score” (max score of 16). Plaque severity was graded as 0=none; 1≤30%; 2=30-50%; 3=50-75%; 4≥75%. Plaque scores were summed across all segments into a “total plaque score” (max= 64). Quantitative CMR perfusion analysis was performed using Fermi deconvolution. Patients were stratified by MPR <2 and ≥2. Data were compared using Kruskal-Wallis and Fisher’s Exact testing. Result: Complete data were available in 39 patients. Median age was 5...
Off-label drug use is associated with raised risk of adverse events, study finds
Authors: Michael McCarthy
Journal: BMJ (2015)

The off-label use of prescription drugs was associated with a 44% increase in the risk of adverse drug events and an even greater risk, 54%, when the off-label use was not backed by strong scientific evidence, Canadian researchers have reported in a new study.1 Off-label prescribing is common, with one US study finding that about a fifth of doctors’ prescriptions were for off-label use.2

In the new study, researchers reviewed the primary medical records of a prospective cohort of more than 46 000 adult patients in Quebec who received around 150 000 new prescriptions and were tracked over six years from January 2005 to 2010. The researchers used the Canadian federal health department’s drug approval database to classify prescriptions as “on-label” or …
Computed Tomography Screening for Lung Cancer
Authors: Joshua A. Roth, Scott D. Ramsey
Journal: JAMA (2016)

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Abstract #5445: Biomarker analysis by gene expression profiling of tumor and skin biopsies from a Phase I clinical study with the CDK inhibitor PHA-793887
Authors: Giuseppe Locatelli, Roberta Bosotti, Marina Ciomei, Wilma Pastori, Matteo Bertolotti, Emanuela Scacheri, Angela Scaburri, Enrico Pesenti, Thierry De Baere, Jean-Charles Soria, Vladimir Lazar, Antonella Isacchi
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

PHA-793887 is a potent inhibitor of the kinase activity of CDK2, CDK1, CDK4, CDK5, CDK7, CDK9 and GSK3\#946; currently in clinical development. As inactivation of these kinases is expected to affect cell cycle progression and transcriptional regulation, during preclinical studies the transcriptional effects of the drug were analyzed by microarrays and RT-QPCR in order to better characterize its mechanism of action. A major outcome of this approach was the identification of a panel of 58 genes, including several genes reported in literature as transcriptionally regulated by Cdk2, that were found to be modulated after treatment both in xenograft tumors and in mouse skin. This gene signature therefore represents a potential pharmacodynamic biomarker of PHA-793887 activity in tumors and as well as in skin, used as surrogate tissue. A phase I dose escalation study was recently conducted on this molecule to evaluate its safety profile together with additional pharmacokinetic, biomarker and efficacy assessments. Here we report the analysis of the 58 gene signature modulation in skin biopsies of 7 patients treated with PHA-793887 in the clinical trial, and show that the signature is in effect modulated in patients, with a trend in dose-response correlation. The effects of PHA-793887 treatment on tumor biopsies from the same patients were also analyzed by microarrays with the aim to better interpret and characterize its pharmacological effects. Using a non-supervised hierarchical cluster analysis a possible correspondence emerges between transcriptional gene regulation and patients permanence on treatment, suggesting that changes in gene expression profiles after PHA-793887 administration reflect the pharmacological response rather than correlate with the dose/exposure parameters. Although the number of available samples limits the statistical significance of the analysis, these data suggest that changes in gene expression profiles after PHA-793887 are indicative of its activity not only in vitro but also in a clinical setting.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5445.
Prevalence and predictors of online patient access to electronic medical records among patients with cancer.
Authors: Andrew L Laccetti, Jingsheng Yan, Jennifer Cai, Samantha Gates, Yang Xie, Simon Craddock Lee, David E. Gerber
Journal: Journal of Clinical Oncology (2013)

35 Background: Although the impact of patient access to health records and providers has not been well studied in cancer populations, these applications are now widely employed at cancer centers nationwide. Understanding implications of this practice in cancer patients is critical as patient-reported symptoms may be more likely to represent medical emergencies and test results may be more likely to represent major clinical developments. Methods: Retrospective analysis of enrollment in and use of MyChart, an internet-based patient portal for the EPIC electronic medical record, among patients seen at the Harold C. Simmons Cancer Center at UT Southwestern Medical Center. Predictors of MyChart use were analyzed through univariate and multivariate regression models. Results: A total of 6,495 patients enrolled in MyChart (2006-2012). Mean age was 60 ± 13 years, and 67% were female. The number of patients enrolling per year increased more than five-fold - 181 in 2006 to 1,146 in 2012. The total number of MyChart log-ins was 707,746. Per patient, median total log-ins was 57 (range 1-10,347). In a multivariate model, increased MyChart use was associated with male gender (p=0.01) and with cancer type (p&lt;0.001), with highest rates among patients with genitourinary and upper aerodigestive malignancies. The most common MyChart activities were review of laboratory and radiology results (35%), communicating with providers (34%) [including messaging (29%) and medical advice request (5%)], and appointment scheduling/canceling (18%). Eighty-nine percent of log-ins occurred Monday-Friday. Login-times were 8a-5p (72%), 5p-11p (17%), and 11p-8a (11%). Approximately 32% of messaging (40% of medical advice requests) occurred outside clinic hours. Conclusions: Patient use of an internet-based patient health portal at an NCI-designated cancer center increased dramatically in recent years. The most common activities were viewing of test results and messaging with providers. A substantial proportion of messaging, particularly advice requests, occurred outside clinic hours. Further study of this technology is needed to understand its impact on patient safety, patient/provider satisfaction, and quality of care.