tbuckley/cabot-search huggingface dataset:
Multidose oxygen therapeutic for radiation sensitization treatment of glioblastoma multiforme.
Authors: David Brown Wilson, Jason Lickliter, Evan Unger, Olivia Longacre
Journal: Journal of Clinical Oncology (2014)

TPS2112 Background: NuvOx is running a Phase 1b/2 evaluation of dodecafluoropentane emulsion (2% DDFPe) as a radiation sensitizer administered intravenously prior to radiation treatment (RT) in Glioblastoma (GBM) patients. Pre-clinically, DDFPe has been shown to increase tumor pO2 concentration of hypoxic solid tumors with an increase in survival. An NDA for DDFPe was previously to the FDA and considered safe and effective as an imaging agent in over 2200 patients. Subsequently DDFP was found to have 200 times the oxygen carrying capacity relative to hemoglobin, which led to the hypothesis that relatively low doses of DDFPe would be safe and effective at reversing hypoxic conditions and improve the effectiveness of the standard fractionated RT in post-resected GBM patients. Methods: This study is intended to determine the safe and effective therapeutic dose for fractionated radiation treatment of GBM. The dosing schedule begins at 0.05cc/kg and escalates to 0.35 cc/kg. The study is in two parts; the first part being dose optimization and the second will be expansion at the optimal dose to include enough patients to establish progression free survival statistics at 6 months post-treatment. Tumor hypoxia will be measured using Tissue Oxygen Level Dependent MRI at proscribed points during the course of therapy along with other molecular, hematologic and biochemical markers indicative of hypoxia. The FDA has granted the right of reference to the NDA submission as an imaging agent and provided guidance for the development strategy for DDFPe as an oxygen therapeutic. Elevated tumor pO2 provides a background for more efficient RT in solid tumors. Data will be presented regarding the status of enrollment, residual tumor size and relative oxygenation during treatment, changes in tumor size, as well as hematologic, and other indicators of safety and efficacy as a consequence of DDFPe administration. Ethics Committee approval was granted as of the preparation of this abstract and dosing will begin very soon. The intent of this presentation is to delve further into the study design as well as present data regarding the pharmacokinetic parameters and biomarker determination reflecting tumor oxygenation data collected thus far.
Site variation in assessment of biomarkers on biopsy specimens in patients with metastatic disease.
Authors: Jennifer J. Griggs, Thomas Braun, Dawn Marie Severson, Elizabeth Marie Layhe, David H. Gorski, Tara M. Breslin, Norah Lynn Henry
Journal: Journal of Clinical Oncology (2017)

224 Background: Clinical practice guidelines in patients with metastatic breast cancer recommend assessment of biomarkers—estrogen receptors (ER), progesterone receptors (PR), and HER2—on metastatic lesions. The purpose of this study was to identify factors associated with assessment of these biomarkers in patients who had undergone confirmatory biopsies. We were particularly interested in variation between treatment sites. Methods: Eligible patients were those diagnosed with metastatic breast cancer who had undergone a confirmatory biopsy and who were part of the Michigan Breast Oncology Quality Initiative (MiBOQI) registry, a statewide registry of 25 health systems. Analyses investigated associations between assessment of ER, PR, HER2 and treating center, disease, clinical and non-clinical factors. Results: Between 2006 and 2015, 805 patients had a confirmatory biopsy. Of these, 66% had ER, 63% had PR, 62% had HER2, and 57% had all three assessed on the biopsy specimen. In bivariate analysis, characteristics associated with assessment of biomarkers were earlier stage and hormone receptor-positive primary tumors, private or military insurance, white race, longer time since initial diagnosis, and bone only, liver only, lung only, chest wall, skin, and lymph nodes, and multiple sites of metastases. Younger age was positively associated with assessment of HER2. Biomarker assessment also varied significantly between treatment sites and increased over time. In multivariate analyses, time since diagnosis of the primary (p &lt; 0.001) and treatment site (p &lt; 0.001) remained significant. With the exception of ER (p = 0.09), performance of biomarkers increased significantly over time. Conclusions: Across 25 health systems in a quality improvement collaborative, the proportion of patients with metastatic disease who underwent a confirmatory biopsy increased over time. Nonetheless, treatment site continued to be independently associated with the odds of having biomarkers assessed on biopsy specimens. Our findings suggest that there are opportunities for improvement to provide guideline-concordant care in patients treated in diverse settings.
A phase Ib trial of erlotinib (E) in combination with docetaxel (D) and carboplatin (C) in untreated ovarian, fallopian tube and primary peritoneal cancers
Authors: P. Vasey, S. Kaye, J. Paul, G. Rustin, R. Wilson, J. P. Guastalla, E. Pujade-Lauraine, M. Gore, H. Gabra, K. Carty
Journal: Journal of Clinical Oncology (2004)

5017 Background: Epidermal growth factor receptor (HER1/EGFR) overexpression occurs in over 50% of advanced epithelial ovarian carcinomas (EOC) and is associated with poor prognosis. Erlotinib (Tarceva™, a highly potent reversible HER1/EGFR tyrosine-kinase inhibitor) has exhibited additive antitumor activity in combination with platinum and taxane chemotherapy preclinically, and single agent activity in heavily pretreated patients (pts). In pts with EOC, D with C has a tolerable safety profile, similar efficacy as paclitaxel with C, and is an acceptable first-line option (Vasey ASCO 2002). This dose-escalation trial evaluated the safety and tolerability of E with DC. Methods: Pts with chemonaive disease who had undergone surgery received i.v. D (75mg/m2) and C (AUC 5) every 3 weeks for 6 cycles in combination with daily oral E (50–100mg). After 6 cycles, pts could continue with E alone (150mg/d) until tumor progression. Safety and tumor response were primary and secondary endpoints, respectively. Dose limiting toxicity (DLT) was defined according to NCI-CTC 2.0 criteria in cycle 1+2. Results: 39 pts (median age 59 years; stage III/IV EOC) have been treated (median 5 cycles). 1/12 pts in Cohort 1 (50mg E + DC) had a drug-related DLT (plantar-palmar erythrodysethesia [PPE]). In Cohort 2, 4/12 pts on 100mg E with DC had significant skin toxicity (intolerable grade 2 or 3 rash) and 1 pt had grade 3 diarrhea despite loperamide treatment. The dose of E was reduced to 75mg/d in Cohort –2, and so far only 1/12 pts has had a DLT (grade 3 diarrhea). Antitumor activity was noted in all cohorts. Pharmacokinetic analyses will determine E exposure and interaction with DC. Conclusions: The combination of 100mg E with standard doses of DC exceeded the maximum tolerated dose. Expansion of Cohort –2 is ongoing with escalation of E from 75 to 100mg/day in cycle 2 in suitable pts. # # Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Amgen; Aventis Aventis; Roche Pharmaceuticals
Phase II study of AZD2171 for the treatment of patients with myelodysplastic syndromes.
Authors: Shannon Eileen O'Mahar, Alcee Jumonville, Patrick J. Flynn, Alvaro Moreno-Aspitia, Charles Erlichman, Betsy LaPlant, Mark Juckett
Journal: Journal of Clinical Oncology (2012)

6570 Background: Inhibition of vascular endothelial growth factor receptors (VEGFR) can block growth and trigger apoptosis in neoplastic cells. AZD2171 (cediranib) is a highly potent, orally bioavailable, VEGFR-1/2 inhibitor. We conducted a phase II study of the efficacy of AZD2171 for the treatment of MDS. Methods: Adults with MDS (IPSS Int-2 or High) were eligible if they exhibited adequate organ function and ECOG 0-2. The primary endpoint was proportion of responses according to the IWG criteria assessed at one and every 3 months. Prior investigation of cediranib at 45 mg daily in patients with acute leukemia demonstrated toxicity concerns and therefore, the starting dose of this study was lowered to 30 mg daily. Results: A total of 16 pts with MDS (median age 73 years) were enrolled at a 30 mg starting dose, and all were evaluable. Median baseline marrow blasts were 12.0 % (range 2-18); 3 pts (18.8 %) had low, 6 (37.5 %) intermediate, and 7 (43.8 %) had high risk cytogenetics. Prior therapy included azacitidine (n=7), decitabine (n=2), cytarabine (n=2), erythropoietin-stimulating agents (ESAs) (n=2), lenalidomide (n=1), or none (n=6). Patients were treated for a median of two 28-day cycles (range 1 to 11). There were no confirmed responses. Patients with baseline blasts &gt; 5% showed no significant reduction in the blast count at 4 and 12 weeks. Median OS was 4.7 mo (95% CI: 2.6 – 11.6). Median TTP was 3.8 mo (95% CI: 1.7 – 10.8). Grade 4 hematological adverse events at least possibly related to cediranib were neutropenia (n=2) and thrombocytopenia (n=4). Grade 3 hematological adverse events at least possibly related to study treatment included: neutropenia (n=3), thrombocytopenia (n=2), and anemia (n=2). Grade 3 non-hematological adverse events included fatigue (n=4), dyspnea (n=3), dehydration (n=2), diarrhea (n=2), nausea (n=2), asthenia (n=1), and hypertension (n=1). Hypertension and proteinuria was uncommon with the 30 mg/day dose. Conclusions: With no confirmed response from 16 patients, cediranib was determined to be ineffective at a dose of 30 mg daily in our patient population. Supported by NCI N01-CM62205, NCI P30-CA014520 and the UW Carbone Comprehensive Cancer Center.
Christopher James Lucas
Authors: Viv Lucas
Journal: BMJ (2017)

Christopher James Lucas (“Chris”) served as general duty medical officer to the Coldstream Guards, the Guards Training Depot, and the King’s Troop of the Royal Horse Artillery during his national service from 1950 to 1952. He subsequently trained in general medicine and neurology at University College Hospital and in general psychiatry at St George’s Hospital, London. He then worked …
Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type–Specific Dynamic Logic Models
Authors: Federica Eduati, Victoria Doldàn-Martelli, Bertram Klinger, Thomas Cokelaer, Anja Sieber, Fiona Kogera, Mathurin Dorel, Mathew J. Garnett, Nils Blüthgen, Julio Saez-Rodriguez
Journal: Cancer Research (2017)

Genomic features are used as biomarkers of sensitivity to kinase inhibitors used widely to treat human cancer, but effective patient stratification based on these principles remains limited in impact. Insofar as kinase inhibitors interfere with signaling dynamics, and, in turn, signaling dynamics affects inhibitor responses, we investigated associations in this study between cell-specific dynamic signaling pathways and drug sensitivity. Specifically, we measured 14 phosphoproteins under 43 different perturbed conditions (combinations of 5 stimuli and 7 inhibitors) in 14 colorectal cancer cell lines, building cell line-specific dynamic logic models of underlying signaling networks. Model parameters representing pathway dynamics were used as features to predict sensitivity to a panel of 27 drugs. Specific parameters of signaling dynamics correlated strongly with drug sensitivity for 14 of the drugs, 9 of which had no genomic biomarker. Following one of these associations, we validated a drug combination predicted to overcome resistance to MEK inhibitors by coblockade of GSK3, which was not found based on associations with genomic data. These results suggest that to better understand the cancer resistance and move toward personalized medicine, it is essential to consider signaling network dynamics that cannot be inferred from static genotypes. Cancer Res; 77(12); 3364-75. ©2017 AACR.
Effect of afatinib alone and in combination with dasatinib in triple-negative breast cancer cell lines.
Authors: Mohamed F.K. Ibrahim, Alexandra Canonici, Denis Collins, John Crown, Norma O'Donovan
Journal: Journal of Clinical Oncology (2014)

1128 Background: TNBC is a subtype of breast cancer negative for expression of estrogen and progesterone receptors and lack of HER2 gene amplification. It is associated with poor prognosis and lack of targeted therapies. Therefore, there is a need for identification of new therapies. EGFR, a member of the ErbB family, is frequently overexpressed in TNBC. Furthermore, crosstalk between EGFR and Src kinase signaling has been observed in breast cancer. The aim of this study is to assess the activity of afatinib, an irreversible pan-HER tyrosine kinase inhibitor alone and in combination with dasatinib, a Src inhibitor, in TNBC. Methods: Using proliferation assays, the effect of afatinib was assessed alone and in combination with dasatinib in TNBC cell lines. Combination indexes (CI) at ED50, effective dose of combination that inhibits 50% of growth, were determined using the Chou and Talalay equation. CI < 1 implies synergy and CI > 1 implies antagonism. Results: The 6 TNBC cell lines tested responded to afatinib with IC50 values ranging from 0.02 to 2.44 µM. As previously shown, the TNBC cell lines showed sensitivity to dasatinib with IC50 values ranging from 9.6 nM to 3.1 µM. The HDQ-P1 cell line, classified as belonging to the basal-like 2 subtype of TNBC, showed significant sensitivity to both afatinib (IC50 = 17.5 ± 2.1 nM) and dasatinib (IC50= 16.6 ± 5.3 nM). The combination of afatinib and dasatinib was synergistic in 5 of the 6 TNBC cell lines tested (Table). Conclusions: Our results suggest that afatinib may have activity in TNBC. We also demonstrate that afatinib in combination with dasatinib may be more effective than either agent alone. Effect of afatinib in combination with dasatinib in TNBC cell lines. % growth inhibition Cell lines Subtype Afatinib Dasatinib Afatinib + Dasatinib CI (ED50) HCC1143 Basal-Like 1 1 µM - 30.9 ± 5.6 200 nM - 52.6 ± 3.2 61.9 ± 3.7 N/A HCC1937 Basal-Like 1 1 µM - 53.8 ± 3.1 50 nM - 43.1 ± 1.5 70.0 ± 2.2 0.39 ± 0.09 HDQP1 Basal-Like 2 100 nM - 66.5 ± 2.4 200 nM - 87.1 ± 2.5 91 ± 0.8 0.26 ± 0.05 MDA-MB-231 Mesenchymal stem-like 1 µM - 60.9 ± 10.7 200 nM - 87.6 ± 2.2 89.5 ± 3.0 1.05 ± 0.09 Hs578T Mesenchymal stem-like 1 µM - 15.7 ± 1.9 50 nM - 53.8 ± 1.5 65.5 ± 2.7 0.22 ± 0.04 BT20 Unclassified 1 µM - 36.9 ± 4.1 625 nM - 39.7 ± 1.5 76.9 ± 1.4 0.00 ± 0.00
Mesh implant review is a betrayal, say campaigners
Authors: Bryan Christie
Journal: BMJ (2017)

Campaigners are considering a legal challenge to the Scottish government’s acceptance of a review into the use of transvaginal mesh implants whose conclusions they have condemned as a “whitewash.”

The final report of the review group,1 first set up in 2013, has refused to ban their use in Scotland, to the dismay of hundreds of women who have had serious and painful complications from implant surgery.

The safety of mesh implants has been brought into question by thousands of women around the world, many of whom are taking legal action against manufacturers, including in Scotland.

Last year a jury in …
Cost analysis of high vs. low activity iodine-125 seeds as monotherapy for permanent prostate brachytherapy
Authors: D. J. Perry, R. J. Patel, M. Yudelev, S. R. Keole, A. J. Frazier, C. Zuniga, P. Dalmia
Journal: Journal of Clinical Oncology (2004)

4717 Background: We have previously reported the differences in post-implant parameters for high and low activity I-125 seeds for permanent prostate brachytherapy (PPB). We have also reported similar rates of PSA relapse-free survival (RFS) and GI/GU morbidity. This study is a cost analysis of higher vs. lower activity radioactive seeds used for PPB in the treatment of localized adenocarcinoma of the prostate. Methods: Treatment plans for 174 patients receiving I-125 PPB as monotherapy for localized adenocarcimona of the prostate were reviewed. Pre-treatment planning was performed for all patients using the ASTRO guidelines for PPB. Specific activity (mCi/cc) was determined for prostate volumes which ranged from 13.8 to 71.1 cc. Current prices for individual model 6711 I-125 seeds were obtained from the manufacturer (Oncura). Total seed costs for implants utilizing 0.450 mCi (67 patients) and 0.326 mCi (107 patients) radioactive seeds were compared. Results: The median prostate volumes for patients receiving implants utilizing 0.450 mCi and 0.326 mCi seeds were 40.0 and 41.1 cc respectively. The mean specific activity for both groups was equal (0.87 ± 0.02 mCi/cc). Cost per I-125 seed was $45. The median (mean) number of seeds per cc for 0.450 mCi and 0.326 mCi implants were 1.9 and 2.7 (1.9 ± 0.33 and 2.7 ± 0.43) respectively, resulting in a median of 42 % more seeds required for 0.326 mCi implants. This translated to a median cost of $3,452 per 0.450 mCi implant vs. $4,884 per 0.326 mCi implant, corresponding to a $1,432 price differential per patient based on a median population prostate volume of 40.8 cc. Conclusions: Based upon current prices for I-125 radioactive seeds, there is a significant cost advantage to the use of higher vs. lower activity seeds in PPB for localized adenocarcinoma of the prostate. Previously reported data suggests similar morbidity and PSA RFS between implants utilizing either seed activity. No significant financial relationships to disclose.
HAGE (DDX43) protein expression as an independent biomarker of poor clinical outcome of breast cancer (BC) and potential as a therapeutic target for ER-negative BC.
Authors: Stephen Chan, Tarek M. A. Abdel-Fatah, Stephanie McArdle, Paul Moseley, Catherine Johnson, Andrew R. Green, Ian O. Ellis, Robert Rees
Journal: Journal of Clinical Oncology (2012)

1013 Background: Recently, we have confirmed that HAGE is involved in promoting proliferation as assessed by increased thymidine incorporation and our preliminary results using shRNA to permanently knockdown HAGE expression also suggests the involvement of HAGE in tumor motility and metastasis. In this study we aimed to analyze the expression of HAGE in large well-characterized BC cohorts to determine its relationship with other clinico-pathological parameters and to investigate its prognostic value. Methods: HAGE protein expression was assessed in: a) 40 normal breast tissue (NBT), b) 60 invasive BCs and their matching NBT, c) BC cell lines, d) A series of 1650 consecutive cases of primary BC who treated with adjuvant CMF and/or endocrine therapies. Further validation was performed in 2 independent series of high risk ER- BC: a) 300 ER –BC who did not received any CT and b) 396 ER- BC treated with adjuvant anthracycline (ATC) based CT. Results: The NBT showed negative HAGE expression (HAGE-) throughout. HAGE overexpression (HAGE+) was observed in 10% of BC and was significantly associated with aggressive clinico-pathological features including: ER-, high grade and triple negative phenotypes. Moreover, HAGE+ expression showed an adverse outcome with a 2-4 fold increase in the risk of death, recurrence and metastases (ps&lt;0.00001) compared to HAGE-; ps&lt;0.0001. Using a multivariate Cox regression model including ER status, grade, size and tumour stage, HAGE expression was confirmed as a powerful independent prognostic factor (p&lt;0.0001). The poor clinical outcome of HAGE+ was further confirmed in high risk (NPI&gt;3.4) ER- patients who did not received any CT (p&lt;0.0001). While, adjuvant CT either CMF or ATC had a positive impact on HAGE+/high risk ER- BC as HAGE+ had a similar risk of death, recurrence and distant metastases to HAGE- expression. Conclusions: This is the first report which shows HAGE to be a potential predictor for poor prognosis in BC patients, and may be an attractive novel target for molecular and vaccine therapy for those patients. A prospective trial of adjuvant chemotherapy/vaccine to confirm this finding is warranted.
Annals Story Slam - Finding Cheeky
Authors: Katherine Mayer
Journal: Annals of Internal Medicine (2017)

Web Exclusives4 April 2017Annals Story Slam - Finding CheekyFREEKatherine Mayer, MDKatherine Mayer, MDFrom Cooper University Hospital, Camden, New Jersey.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0036 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Finding Cheeky "Finding Cheeky," by Dr. Katherine Mayer (Duration 5:52)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Cooper University Hospital, Camden, New Jersey.Current Author Address: Katherine Mayer, MD, Cooper University Hospital; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 4 April 2017Volume 166, Issue 7Page: SS1 ePublished: 4 April 2017 Issue Published: 4 April 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Lung cancer screening on YouTube: Difficulty of finding balanced information.
Authors: Juan Alban, Luis Felipe Alban, Amit Khanal, Lawrence Eric Feldman
Journal: Journal of Clinical Oncology (2017)

162 Background: Lung cancer (LC) is the leading cause of cancer mortality in the US, the ACS estimates upwards of 220,000 new cases will be diagnosed this year. Recently, the Center for Medicare/Medicaid Services (CMS) agreed to cover LC screening with low-dose CT for patients however, CMS requires prior documentation of a shared-decision making (SDM) visit between the patient and the referring clinician to inform them about risks of screening. LC Screening programs have begun to use YouTube for patient recruitment, education and marketing of screening. The objective of this study is to shed light on the role of YouTube in lung cancer screening in terms of guidelines, screening options, target population, steps after screening, and risks and benefits of screening. Methods: We searched YouTube.com to identify videos dealing with lung screening using the keywords: lung cancer screening. Videos without sound, uploaded before 2009, longer than 20 minutes, duplicates and videos in a language other than English were excluded. This method yielded 124 videos that fit criteria. Videos were coded for inclusion of LC screening process, risks and benefits of screening, screening guidelines, risk factors for LC, and treatment options after LC diagnosis. Results: 124 videos had a cumulative 262753 views. 38.7% of the videos included no mention of CMS guidelines. Only 30% included any mention of the risks associated with screening; 14% mentioned false positives, 12% radiation; 4% anxiety associated with screening though 92% of all videos sampled were intended for patients. 91% of videos explained the benefits associated with cancer screening however, only 26% explained the actual process of screening. The majority of videos were created by medical institutions (66%). No videos sampled included false information. Conclusions: While most videos highlighted the benefits of LC screening, YouTube can’t serve as a replacement for SDM visits due to inadequate discussion of risks of screening. A substantially low number of videos (30%) discussed the risks of lung cancer screening. Given the high rate of false positives, radiation and anxiety associated with screening, patients need to be made aware of these risks so they can make an informed decision.
A Ph-Negative Myeloproliferative Disorder with JAK2 Mutation Disclosed by Imatinib Therapy in Two Patients with Ph+ CML.
Authors: Emilia Giugliano, Dario Ferrero, Carmen Fava, Chiara Dellacasa, Giovanna Mattioli, Patrizia Scaravaglio, Enrico Gottardi, Stefano Ulisciani, Filomena Daraio, Giuseppe Saglio, Giovanna Rege-Cambrin
Journal: Blood (2006)