tbuckley/cabot-search huggingface dataset:
Phase-1 study of isophosphoramide mustard (IPM)-lysine in advanced cancers
Authors: R. Gale, A. Van Vugt, L. Rosen, L. Chang, P. Lorusso, M. Valdivieso, L. Malburg, R. Struck, L. Morgan
Journal: Journal of Clinical Oncology (2006)

9524 Background: IPM is a bi-functional alkylator which cross-links DNA through G:C base-pairs resulting in irreparable 7-atom inter-strand cross-links. IPM is the active moiety of ifosfamide (IFOS), a pro-drug of IPM. IPM is active in diverse cancer models but is unstable. We stabilized IPM with lysine (IPM-lysine; ZIO-201). ZIO-201 was active in pre-clinical models including human cancer cell lines, human-mouse xenografts and cancers resistant to cyclophosphamide (CPA) and IFOS. Because ZIO-201 is not metabolized to acrolein or chloroacetaldehyde, bladder and CNS toxicities are unlikely. Methods: Phase-1 trial in subjects with advanced cancers. ZIO-201 was given daily for 3 consecutive d at a starting dose of 30 mg/me 2 /d every 3 w. Neither mesna nor IV hydration were given. 11 dose levels were studied in 18 subjects up to 795 mg/me 2 /d; dose-escalation continues. Data on the 1st 15 subjects are available for analysis. Results: Median age was 59 y (range, 18–70 y); 10 subjects were male. Diagnoses included colorectal cancer (N=5), sarcoma (N=3) and 1 subject each with gastric, lung, bladder, prostate, ovary and thyroid cancers and mesothelioma. 7 had extensive and 8, limited disease. All subjects received extensive prior therapy. Median N cycles was 2 (range, 1–13). Toxicities ≥ grade-2 occurring in &gt; 20% of subjects included anemia (N subjects=4) and diverse GI complaints (N=4). 4 of 8 subjects receiving doses &gt; 445 mg/me2/d had transient proximal renal tubular acidosis. There was no hemorrhagic cystitis or CNS toxicity. 1 subject with mesothelioma had stable disease &gt; 13 mo. Pharmacokinetic studies at 595 mg/me 2 /d showed a t max = 13 min (SD ± 9 min), C max = 44.7 μg/mL (SD ± 34.1 μg/mL), t 1/2 = 35 min (SD ± 7 min) and AUC 0-∞ = 1.68 mg·min/ml (SD ± 1.26 mg·min/ml). Conclusions: These data suggest a possible role for ZIO-201 in IFOS-sensitive cancers (especially sarcoma and lymphoma). ZIO-201 may also be active in CPA and IFOS-resistant cancers. Comparable or greater efficacy with less toxicity is expected. [Table: see text]
Abstract 14359: Systemic to Pulmonary Collateral Flow Increases as a Fraction of Aortic Flow After Fontan Completion
Authors: Kevin K Whitehead, Matthew A Harris, Andrew C Glatz, Yoav Dori, Marc S Keller, Jonathan J Rome, Mark A Fogel
Journal: Circulation (2011)

Background:  We recently described a method of quantifying systemic to pulmonary collateral (SPC) flow in patients with superior (S2) and total (S3) cavopulmonary connections using magnetic resonance phase contrast velocity mapping (PC-MRI). We wished to examine changes in physiology and SPC flow from S2 to S3 by comparing serial PC-MRI data. We hypothesized that SPC flow decreases after S3 compared to S2.   Methods:  We retrospectively reviewed MRI data to identify patients who had collateral flow quantified at both S2 and S3. SPC flow, systemic blood flow (Qs = total caval flow), and pulmonary blood flow (Qp = total pulmonary vein flow) were quantified as previously described. Fenestration flow was quantified in S3 by the difference in flow in the Fontan baffle above and below the fenestration.   Results:  We identified 10 patients who had SPC flow quantified at 0.3±0.4 yrs before and 0.6±0.3 yrs after S3. Indexed SPC flow was 1.2±0.6 L/min/m2 at S2 and 1.7±09 L/min/m2 at S3 (p=0.06). This represented a significantly higher fraction of aortic flow in S3 compared to S2 (35±13% vs. 28±12%, p=0.04). As a result, while indexed aortic flow did not change (4.4±0.7 L/min/m2 at S2 vs. 4.5 L/min/m2 at S3), there was a significant decrease in Qs from 3.2±0.8 L/min/m2 at S2 to 2.8±0.6 L/min/m2 at S3 (p=0.04). Fenestration flow averaged 46±32% of the inferior vena caval (IVC) flow at S3, with a decrease in right to left shunt from 1.7 at S2 to 0.5 L/min/m2 at S3 (p   Conclusions:  Indexed SPC flow does not appear to decrease significantly in the short term after S3 and trends toward increasing. While the indexed aortic flow does not change, SPC flow expressed as a fraction of aortic flow increases significantly at S3, resulting in a significantly lower Qs at S3.
Palbociclib — Taking Breast-Cancer Cells Out of Gear
Authors: Lisa A. Carey, Charles M. Perou
Journal: New England Journal of Medicine (2015)

Palbociclib is a first-in-class inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). In some but not all cell types, these proteins regulate the transition from the G1 phase to the S phase of the cell cycle. CDK4 and CDK6 regulate proliferation in some types of epithelial cells, including estrogen-receptor–positive luminal cells.1 In estrogen-receptor–positive breast cancers, estrogen induces CDK4 and CDK6 activity, leading to hyperphosphorylation of RB (the gene encoding retinoblastoma protein) and promotion of cell-cycle traversal; this is the rationale for testing CDK4 and CDK6 inhibitors in estrogen-receptor–positive breast cancer.In this issue of the Journal, Turner and . . .
Abstract 16820: Human Vascular Pericytes and Cardiac Stem Cells for Specialized Stimulation of Neovascularization and Cardiomyogenesis of the Infarcted Heart
Authors: Kathryn Mitchell, Rajesh Katare, Marco Meloni, Federica Riu, Rosa Russo, Miriam Gubernator, Antonio P Beltrami, Paolo Madeddu
Journal: Circulation (2012)

Background:  Both vascular and myocardial cells are essential for effective cardiac repair. Here, we investigate whether co-transplantation of adventitial pericytes (APs) from saphenous vein leftovers of patients undergoing coronary artery bypass graft (CABG) surgery and c-Kit+ cardiac stem cells (CSCs) from transplantation donor hearts could synergistically improve cardiac recovery in a mouse model of acute myocardial infarction (MI).   Methods  &   Results:  Viability and purity of cell preparations were verified before transplantation. SCID-beige immuno-deficient mice were subjected to operative MI and randomly allocated to peri-infarct injection of APs, CSCs, APs+CSCs (each at 300000/heart) or vehicle (V) (n=10 per group). As previously shown, APs improved pressure indexes (dP/dtmax [mean±SE]: 4250±142 vs 3828±78 mmHg in V, p=0.02), and both volumetric (LVESV: 35±8 vs 87±1 μ l, p   Conclusions:  These data indicate that, in addition to their angiocrine activity, APs enhance recovery of the ischemic heart by attracting endogenous CSCs via an as yet unidentified paracrine mechanism; this AP-evoked host response appears to be robust since co-therapy of APs and CSCs does further improve AP therapy alone.
New on the Menu: Genetically Modified Salmon
Authors: Rebecca Voelker
Journal: JAMA (2016)

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Pharmacokinetics (PK), safety and tolerability of atrasentan (ABT-627, ATN) in combination with docetaxel (DOC) in men with hormone refractory prostate cancer (HRPC)
Authors: D. P. Petrylak, S. G. Mohile, G. Shelton, R. A. Carr, J. Steinberg, D. Sleep, J. Melia, M. J. Rieser, D. Nanus, M. I. Milowsky
Journal: Journal of Clinical Oncology (2006)

14512 Background: ATN (Xinlay) is an oral selective endothelin A receptor antagonist in Phase III clinical development for the treatment of HRPC. ATN is extensively metabolized by oxidation and glucuronidation. In vitro, CYP3A is the predominant isozyme involved in oxidative metabolism of ATN and DOC; ATN inhibits CYP3A with an IC50 of ∼3 μM (15-fold the mean plasma Cmax for 10 mg/d ATN). Methods: 11 men with HRPC received DOC 75 mg/m 2 by 1-h IV infusion on day (D) 1 of each 21-D cycle (C), and ATN 10 mg po qd starting D8C1 and prednisone(Pred) 5 mg orally twice daily.Three oral doses of dexamethasone 8 mg were administered starting 12 hours before DOC. On coadministration days, ATN was taken at the start of the DOC infusion. PK were to be determined over 24 h following DOC alone (D1C1) and in combination with ATN (D1C2), and following ATN alone (D20C1) and in combination with DOC (D1C2). Plasma concentrations of ATN and DOC were determined using a validated LC/MS/MS method. Results: Preliminary PK results are summarized (N = 10, mean ± SD) in the table below. Some patients (pts) had D1C2 PK performed D1C4 (N = 4), D1C5 (N = 3) or not at all (N = 1). No unexpected adverse events (AE) were observed. One subject experienced neutropenic fever related to DOC. This resolved with treatment and ATN/DOC was resumed. Efficacy: 3/5 DOC naive and 2/6 DOC resistant pts had a &gt;50% post treatment PSA decline. One DOC resistant pt demontrated post treatment calcicfication of liver metastases accompanied by a &gt;45% PSA decline. Conclusions: No PK interaction was observed between ATN and DOC when coadministered at full standard single agent dosages implying 10 mg QD ATN did not alter CYP3A4 activity in gut or liver. Treatment with ATN/DOC was well tolerated and demonstrated activity in DOC resistant pts, further justifying a planned Southwest Oncology Group phase III study comparing ATN/DOC/Pred to DOC/Pred. [Table: see text] [Table: see text]
A phase I study of sonepcizumab (S), a humanized monoclonal antibody to sphingosine-1-phosphate (S1P), in patients with advanced solid tumors.
Authors: M. S. Gordon, R. Just, L. S. Rosen, A. Dorr
Journal: Journal of Clinical Oncology (2010)

2560 Background: S1P is a bioactive lipid that signals through G-protein coupled receptors to activate downstream processes associated with cancer, including angiogenesis and tumor cell proliferation, metastasis, and survival. Sonepcizumab has high affinity for S1P and acts as a molecular sponge to reduce S1P signaling which, in nonclinical models, inhibits tumor growth. Methods: We performed a phase I study of single-agent S administered weekly by 90 min IV infusions (decreasing to 30 min as tolerated). The primary objective was to determine safety and dose-limiting toxicities (DLTs). Secondary endpoints included PK and PD activity as measured by changes in cytokines, lymphocyte counts, tumor size, and plasma S1P levels. Dose levels were 1, 3, 10, 17, and 24 mg/kg with an extension phase of 6 patients at 24 mg/kg. Results: Twenty-eight pts received S. The median age was 66 years (range 51-82); M/F 16/12. Cancer types were ovarian (5 pts), renal (4), colorectal (4), breast (2), prostate (2), melanoma (2), head and neck (2), and other (7). All pts received prior systemic therapy. 7 patients did not meet DLT evaluable criteria based on early discontinuation without experiencing a DLT. No DLTs and no drug-related SAEs were reported. Infusion reactions occurred in 3 of 9 patients at 24 mg/kg but not at lower doses. There were 27 Grade ≥ 3 adverse events with 2 recorded as related to study drug (1 anemia, 1 vomiting). PK data show an average half-life over 4 days with significant interpatient variability. S1P plays a role in lymphocyte trafficking. At the 24 mg/kg dose, there was an average 37% decrease in absolute lymphocyte counts 1 hr post infusion. Other PD results are pending. 8 pts have had stable disease for ≥ 2 mo including 1 with carcinoid (15+ mo) and 1 with adenoid cystic (8+ mo), treated with 3 and 17 mg/kg, respectively. Conclusions: S given to pts with advanced cancer is well tolerated at doses up to 24 mg/kg weekly with some pts experiencing long-term stable disease. Decreased lymphocyte counts suggest biologic activity of S in humans. Phase II trials are planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lpath, Inc. Lpath, Inc. Lpath, Inc.
Barriers to the practice of cancer genetic by primary care providers
Authors: M. E. Wood, A. Stockdale, B. S. Flynn
Journal: Journal of Clinical Oncology (2004)

6149 Background: Genetic testing is available for genes associated with cancer risk (BRCA1/2, MLH1/MSH2, etc). Results of testing has implications for risk assessment, cancer screening and prevention options. Often patients first seek counseling from their primary care provider (PCP). We report preliminary data from a study which seeks to understand the needs of PCPs regarding the practice of cancer genetics. Methods: Three major activities comprise this study. 1.In-depth interviews with 30–60 PCPs, serving a culturally and economically diverse group of patients in urban, rural and suburban settings in order to document PCPs' understanding of cancer genetics and barriers to the practice of cancer genetics in primary care settings. 2. A survey will be administered to 1422 PCPs in the above practice settings to provide a generalizable assessment of attitudes towards the practice of cancer genetics. 3. An expert panel, comprised of primary care providers and experts in cancer genetics, will use the data collected from PCPs to formulate standards for PCP knowledge and make recommendations for educational interventions designed to assist physicians in meeting those standards. Results: 18 physician interviews have been performed in individuals from all three sites and all specialties. Medical school graduation ranges from 1963–98. Themes emerging from these interviews suggest: -Lack of training in genetics even for recent graduates -Lack of confidence in interpretation of cancer family history and referral for genetic counseling and testing. Referrals often at the request of the patient -Cancer family history commonly focuses on cancers for which screening can be increased (breast, colon, etc) -PCPs may recommend against counseling and testing due to lack of trust in technology (interpretation of test results) and discrimination. PCPs are concerned about cost of testing and unaware of insurance coverage for testing -PCPs lack understanding of psychosocial issues regarding genetic testing. Conclusions: Preliminary results suggest that PCPs are commonly uninformed regarding options for genetic counseling and testing for cancer risk. No significant financial relationships to disclose.
A phase I trial of scutellaria barbata (BZL101) for metastatic breast cancer
Authors: A. T. Perez, H. S. Shaw, G. F. Fleming, D. L. Hershman, S. Franco, C. L. Shapiro, K. Neal, I. Cohen, M. Tagliaferri, D. Tripathy
Journal: Journal of Clinical Oncology (2008)

1099 Background: BZL101 is an aqueous extract from herba Scutellaria Barbata. BZL101 demonstrates in vitro growth inhibitory effects on human breast cancer cell lines and does not inhibit the growth of normal human mammary epithelium. In a murine xenograft model, oral and intraperitoneal administration of BZL101 inhibited tumor formation without any observed toxicity. Treatment of breast cancer cells with BZL101 leads to sustained inhibition of glycolysis, as evident from the decreased enzymatic activities within the glycolytic pathway and inhibition of lactate production. Because tumor cells primarily rely on glycolysis for energy production (Warburg effect), targeting this pathway may lead to novel cytotoxic agents with less toxicity than the currently available treatments. We are conducting an open-label, dose escalation, phase I trial of BZL101 for MBC to determine the MTD. Methods: Eligible patients have histologically confirmed MBC and measurable disease. Patients can not receive any other anticancer treatment on trial. Three patients are enrolled at each dose level and treated for 28 days. If toxicity is acceptable, 3 additional patients are enrolled to a higher dose until the MTD is reached. The primary endpoints are safety and toxicity and tumor response defined by RECIST. Results: 14 patients have been enrolled. The mean number of prior treatments for metastatic disease was 3.6. There have been no SAEs attributable to BZL101. There was one grade 4 AE for AST elevation attributed to BZL101. All other BZL101 related AEs were grade 1 and 2 of which the most frequent were: diarrhea (29%), nausea (14%), headache (14%) and ALT increase (14%). 5 patients were evaluable for response and one patient had stable disease for 8 months with radiographic evidence of tumor shrinkage. Conclusions: BZL101 has a favorable tolerability profile and encouraging clinical activity for the treatment of MBC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bionovo, Inc. Bionovo, Inc Bionovo, Inc.
Retinoblastoma survivors face raised risk of serious health problems, study finds
Authors: Zosia Kmietowicz
Journal: BMJ (2016)

Adults who were treated for retinoblastoma as children face a small increased risk of chronic health problems in later life, a US study has found.1

Previous research on the long term health effects of treatment for retinoblastoma have been small and have focused primarily on specific problems, such as eye problems or new cancers. To provide a more comprehensive review a team led by Danielle Novetsky Friedman, of Memorial Sloan Kettering Cancer Center in New York City, assessed the long term medical problems of 470 …
Association of Oxygen Target and Growth Status With Increased Mortality in Small for Gestational Age Infants
Authors: Michele C. Walsh, Juliann M. Di Fiore, Richard J. Martin, Marie Gantz, Waldemar A. Carlo, Neil Finer
Journal: JAMA Pediatrics (2016)

saturation group.It is known that SGA infants have higher mortality and worse outcomes compared with AGA infants of the same gestation. 3Furthermore, growth restriction has been shown to increase the risk of pulmonary hypertension in the setting of bronchopulmonary dysplasia. [4]5][6] These reports mirror our finding of bronchopulmonary dysplasia as a leading mortality cause in the SGA cohort.We view these analyses as hypothesis generating.These results must be confirmed in other oxygen targetting studies.An important opportunity to do this is in the planned Neonatal Oxygenation Prospective Meta-analysis, which includes data from 4800 infants with a prespecified analysis by growth status.We speculate that SGA infants may experience hypoxia in utero that destabilizes respiratory control or affects pulmonary vascular resistance, increasing vulnerability to lower saturation targets.
The use of radiation for stage I seminoma: Analysis of the National Cancer Database.
Authors: Nikhil Waingankar, Elizabeth Handorf, Marc C. Smaldone, Elizabeth R. Plimack, Yu-Ning Wong, Mohammed Haseebuddin, Eric M. Horwitz, Robert G. Uzzo, Alexander Kutikov
Journal: Journal of Clinical Oncology (2015)

385 Background: Primary radiotherapy has historically been the preferred treatment for stage I seminoma. However, there is emerging consensus that observation or primary chemotherapy may be preferred in order to reduce overtreatment and risk of secondary malignancy. Hypothesizing that the use of radiotherapy has decreased in the modern era, our objective was to assess temporal practice patterns in stage I seminoma using a large national cancer registry. Methods: The National Cancer Database (NCDB) was queried for all patients diagnosed with stage I seminoma from 1998 to 2011. Temporal trends for receipt of systemic chemotherapy, radiation, and observation (defined as no treatment) were assessed. Following adjustment for patient, demographic, and clinicopathologic characteristics, generalized estimating equations were used to assess for associations between covariates and receipt of primary radiotherapy. Results: Of the 34,251 patients identified with stage I seminoma in the NCDB, 20,627 were treated with radiation (60.2%), 2,278 were treated with chemotherapy (6.7%), and 11,346 were managed with observation (33.1%). Radiation use significantly declined from 73.5% in 1998 to 29.6% in 2011 (p&lt;0.0001), while utilization of chemotherapy (1.9% to 16.5%, p&lt;0.0001) and observation (24.6% to 53.9%, p&lt;0.0001) increased. Following adjustment, age categories 30−39 years (OR 1.06 [CI 1.01−1.13]) and 40−49 years (OR 1.10 [CI 1.03−1.17]), and stage T2 (OR 1.25 [CI 1.17−1.32]) and T3 (OR 1.21 [CI 1.04−1.41]) were associated with increased utilization of radiotherapy. Uninsured patients (OR 0.78 [CI 0.71−0.86]) and those with Medicaid (OR 0.82 [CI 0.73−0.92]) or Medicare (OR 0.62 [CI 0.55−0.69]) were less likely to undergo primary radiotherapy, while those with non-Medicare/Medicaid government insurance were more likely to receive radiation (OR 1.40 [CI 1.13-1.75]). Conclusions: In the largest known cohort of patients with Stage I seminoma reported to date, these data demonstrate that utilization of radiation therapy for stage I seminoma is on the decline. Coinciding with shifts in evidence−based guidelines, observation is now the most commonly employed management strategy for patients with Stage I seminoma.
Relative Solvolytic Reactivities of Chloromethyl Ether and Bls(chloromethyl)ether
Authors: R. W. Nichols, R. F. Merritt
Journal: JNCI Journal of the National Cancer Institute (1973)

The solvolytic rate ratio of bis(chloromethyl)ether and chloromethyl ether is = 1 :5,000 in methanol. As the medium becomes more ionizing, the rate differential approaches 106 in 25% dimethylformamide- 75% water. Solvolytic reactivity cannot be the only factor contributing to carcinogenicity.