tbuckley/cabot-search huggingface dataset:
The Law of Unintended Consequences
Authors: Alan D. Haber
Journal: Annals of Internal Medicine (2016)

On Being a Doctor6 December 2016The Law of Unintended ConsequencesAlan D. Haber, MDAlan D. Haber, MDFrom Fox Chase Cancer Center, Philadelphia, Pennsylvania.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-2840 Audio Reading - “The Law of Unintended Consequences” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Law of Unintended Consequences," by A.D. Haber. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I have never considered myself a cat person. Still, after we adopted Hazel, I quickly came to admire the unique traits encoded in feline DNA. I was particularly impressed by the righting reflex: a cat's ability to land on its feet. My oldest son, a wannabe physicist, once tested this reflex by gently tossing her from ever-lowering heights and ever-increasing degrees of angular velocity. Hazel never resisted and always landed upright—until she didn't. The thud of cat hitting floor awkwardly was unnerving for its unexpectedness. It was a glitch in the Matrix and was the same misgiving I experienced when ... Author, Article, and Disclosure InformationAffiliations: From Fox Chase Cancer Center, Philadelphia, Pennsylvania.Corresponding Author: Alan D. Haber, MD, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111; e-mail, alan.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “The Law of Unintended Consequences” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "The Law of Unintended Consequences," by A.D. Haber. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 6 December 2016Volume 165, Issue 11Page: 824-825KeywordsBiopsyBronchoscopyHealth Insurance Portability and Accountability ActIntensive care unitsPhysicistsReflexesRespiratory failureSepsisStrokeSurgeons ePublished: 6 December 2016 Issue Published: 6 December 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases
Authors: Zhenfan Yang, Qiuli Guo, Yingchun Wang, Kan Chen, Lin Zhang, Ziqiang Cheng, Yanping Xu, Xiaolu Yin, Yu Bai, Sarit Rabbie, Dong-Wan Kim, Myung-Ju Ahn, James Chih-Hsin Yang, Xiaolin Zhang
Journal: Science Translational Medicine (2016)

Non-small-cell lung cancer patients with activating mutations in epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) treatment. Nevertheless, patients often develop central nervous system (CNS) metastases during treatment, even when their extracranial tumors are still under control. In the absence of effective options, much higher doses of EGFR TKIs have been attempted clinically, with the goal of achieving high enough drug concentrations within the CNS. Although limited tumor responses have been observed with this approach, the toxicities outside the CNS have been too high to tolerate. We report the discovery and early clinical development of AZD3759, a selective EGFR inhibitor that can fully penetrate the blood-brain barrier (BBB), with equal free concentrations in the blood, cerebrospinal fluid, and brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer models and prevents the development of BM in nude mice. An early clinical study in patients with BM and LM treated with AZD3759 confirms its BBB-penetrant properties and antitumor activities. Our data demonstrate the potential of AZD3759 for the treatment of BM and LM and support its further clinical evaluation in larger trials.
Incidence of febrile neutropenia in patients with early-stage breast cancer receiving adjuvant FEC-D treatment.
Authors: H. Assi, D. Richard, L. Boyle, M. A. Shaikh, S. A. Bourque
Journal: Journal of Clinical Oncology (2011)

e11520 Background: Adjuvant chemotherapy is associated with serious toxicities such as febrile neutropenia (FN). FEC-D is currently the most common taxane-containing regimen used for early stage breast cancer (ESBC). In clinical practice, clinicians have noted a much higher rate of FN. The aim of the present study was to examine the incidence of FN in women receiving FEC-D for the treatment of ESBC. Secondary aims included reporting hospital admission and length of stay of patients with FN and the potential benefit of using granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis with FEC-D. Methods: Retrospective chart reviews was conducted on all women with breast cancer referred to The Moncton Hospital, Canada between January 2005 and December 2009. The collected data was subsequently entered manually into Microsoft Access, which is used to build the Moncton Hospital Breast Cancer database. The data collected included: patient demographics, staging, hormone receptor status, number of patients treated with FEC-D, FN rate, admission to hospital, length of hospitalization and use of G-CSF. Results: A total of 127 patients were treated with FEC-D. Of these, 41 experienced FN, giving a total incidence of 32%. All of these patients required hospitalization with an average length of stay of 5.78 days. There was no toxic death. Patients who received primary prophylaxis had a lower incidence of FN (10%; 2/21) compared to those who did not receive primary prophylaxis (37%; 39/106). Further analysis of our data revealed that 44% of FN occurred during the FEC treatment while the remaining 56% occurred during the Docetaxel treatment. Conclusions: The incidence of FN in this retrospective analysis of ESBC patients receiving adjuvant FEC-D treatment without primary prophylaxis demonstrates a much higher rate(37%) than the rate initially reported in the PACS-01 study (11.4%). Our observations are consistent with those of other studies which also report high incidences of FN (24% and 29.4%). Patients who received primary prophylaxis in the present study had a lower incidence of FN (10%). Consistent with ASCO guidelines, prophylactic G-CSF should be considered for ESBC patients receiving an adjuvant FEC-D regimen.
The impact of screening for prostate cancer on the development of metastatic disease.
Authors: J. P. Ciezki, C. A. Reddy, P. Kupelian, E. A. Klein
Journal: Journal of Clinical Oncology (2011)

192 Background: Routine screening for prostate cancer (CaP) was first advocated in 1993 in the US. Opponents of screening argue that the implementation of routine screening has not resulted in a meaningful improvement in survival. Since we are essentially unable to cure metastatic disease, the best measure of the efficacy of screening may not be overall survival but instead its ability to lessen the metastatic disease burden of the screened population. We assess the effect of screening on this endpoint. Methods: From 1986-1996, 1,721 patients with CaP were definitively treated with radical prostatectomy (RP) or radiotherapy (RT) at our institution. The cohort was divided into a pre screening era group (1986-1992; PRE, n=575) and a post screening era group (1993-1996; POST, n=1,146). Due to the potential for an imbalance in follow up time between the two groups, all patients were censored at ten years. Kaplan- Meier analysis was used to calculate the ten year metastases free survival rates (MFSR). Cox proportional hazards regression was used to examine if screening era along with disease, treatment, and follow-up characteristics was associated with an increased risk of developing metastatic disease. Results: The median follow up for all patients was 10 yrs (range: 0.1-10), 9.6 yrs (range: 0.1-10) for PRE patients, and 10 yrs (range: 0.1-10) for POST patients. The distribution by NCCN risk classification for the PRE patients was 44% high risk (H), 21% intermediate risk (I) and 28% low risk (L) vs. 36% H, 27% I, and 37% L for the POST patients (p &lt; 0.0001). Within 10 years of treatment, 13% of all patients had developed metastatic disease. The 10 year MFSR for high risk PRE vs POST patients was 58% vs. 82% (p &lt; 0.0001), 79% vs. 93% for I (p &lt; 0.0001), and 90% vs. 98% (p = 0.0001) for L patients. On multivariable analysis, screening era (p &lt; 0.0001, HR = 4.6, 95% CI = 3.4-6.1), T-stage, biopsy Gleason score, and post-treatment PSA testing frequency were significant. Conclusions: Screening for CaP results in a significant decrease in the risk of a patient developing metastatic disease within 10 years of treatment even after controlling for severity of disease. This risk reduction may yield improved quality of life and a cost savings to the medical care system. No significant financial relationships to disclose.
The Pattern Of Cytogenetic Aberrations In CML BC Stratified For Treatment
Authors: Christian Dietz, Lida Kalmanti, Michael Lauseker, Claudia Haferlach, Gudrun Göhring, Brigitte Schlegelberger, Martine Jotterand, Barbara Heinze, Dieter K. Hossfeld, Rüdiger Hehlmann, Andreas Hochhaus, Martin C. Müller, Benjamin Hanfstein, Ulrike Proetel, Annette Schreiber, Stefan W. Krause, Andreas Neubauer, Cornelius F. Waller, Markus Pfirrmann, Joerg Hasford, Wolf-Karsten Hofmann, Hans-Jochem Kolb, Hermann Heimpel, Susanne Saussele, Alice Fabarius
Journal: Blood (2013)
Synergy between Nonmyeloablative Doses of Intravenous Busulfan and Post-Transplantation Cyclophosphamide for Induction of Tolerance to MHC-Compatible Stem Cell Allografts.
Authors: Xiaotao Zhou, Jie Wang, Moshe Y. Levy, Heather Symons, Ephraim J. Fuchs
Journal: Blood (2005)
An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.
Authors: Chadi Nabhan, Leonard G. Gomella, Todd DeVries, James Boyd Whitmore, Mark Walter Frohlich, Daniel J. George
Journal: Journal of Clinical Oncology (2012)

144 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Our previous analyses on the effect of salvage crossover treatment with a product constructed from previously frozen cells (APC8015F) on OS in the control arms of mCRPC studies of sipuleucel-T suggested a positive treatment effect with salvage therapy (George DJ et al. JCO 2011;29:abstr 139). To quantify how treatment with APC8015F might have impacted the OS of the IMPACT study, we performed an exploratory analysis adjusting for the potential bias that salvage APC8015F might have had in estimating the OS advantage of sipuleucel-T. Methods: After objective disease progression, patients (pts) in the control arm were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. A rank-preserving structural failure time (RPSFT) model, as previously described, was applied to adjust the sipuleucel-T treatment effect. Results: In the 512-pt IMPACT study, there was a 4.1-month median improvement in OS (25.8 vs 21.7 months) for sipuleucel-T compared to control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control pts received APC8015F; other post-progression interventions were balanced. Median OS was 23.8 months for control pts receiving APC8015F and 11.6 months for control pts not receiving APC8015F. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control was 18.0 months (HR=0.60, 95% CI: 0.41, 0.95), representing a 7.8-month median improvement in OS in favor of sipuleucel-T. Results from extensions of the RPFST model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: Adjusting for a positive effect of APC8015F in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover.
Patterns of referral for adjuvant radiotherapy after radical prostatectomy in men with prostate cancer: A population-based analysis.
Authors: Harvey Quon, Derek Suderman, Kimi Guilbert, Pascal Lambert
Journal: Journal of Clinical Oncology (2012)

140 Background: Randomized trials have shown improved biochemical disease free survival after adjuvant radiotherapy (ART) in patients with pT3 or margin positive disease after radical prostatectomy for prostate cancer. This study examines the rates of referral to a radiation oncologist for patients with high risk pathologic features after prostatectomy. Also, the impact of the presentation of these randomized trials will be examined. Methods: All men diagnosed in the province of Manitoba with prostate adenocarcinoma between 2003 and 2008 who underwent radical prostatectomy were identified through a central cancer registry database. Manual chart review was performed and detailed demographic and clinico-pathologic data were analyzed to determine their influence on referral to a radiation oncologist within 6 months of surgery. Analysis of referral rates before and after the presentation of 2 randomized trials were also examined. Results: A total of 1080 patient records of men undergoing prostatectomy for prostate cancer were reviewed. Of these, 546 (50.6%) men had at least one high risk pathologic feature. This includes pT2 margin positive disease in 298/546 (54.6%), pT3a in 154/546 (28.2%), and pT3b in 94/546 (17.2%). Multivariable logistic regression was performed adjusting for age, distance from cancer centre, Gleason score, T stage, perineural invasion, and margin status. Gleason score 8-10 (p&lt;0.0001), higher pathologic T stage (p&lt;0.0001), and farther distance (p=0.0028) were associated with referral for ART. Age and margin status were not significantly associated. Men with pT3a (odds ratio 3.35) and pT3b disease (odds ratio 5.32) were more likely to be referred than pT2 margin positive disease (p&lt;0.0001). There were 78/546 (14.3%) patients with a high risk factor who were referred for ART within 6 months of surgery. The rates of referral were not significantly different before and after the presentation of randomized trials (p=0.60). Conclusions: Men with higher pathologic stage (pT3) and grade (Gleason 8-10) are more likely to receive ART. However, referral for ART did not increase significantly after presentation of the randomized trials and remains underutilized.
A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes
Authors: Rajiv Agarwal, Frederick L Locke, Rangesh Kunnavakkam, Koen van Besien, Richard A. Larson, Olatoyosi Odenike, Lucy Godley, Hongtao Liu, Michelle M. Le Beau, Sandeep Gurbuxani, Michael J Thirman, Dorothy A. Sipkins, Carol White, Andrew Artz, Wendy Stock
Journal: Blood (2011)
Improved detection of right colon adenomas with additional retroflexion following two forward-view examinations: a prospective study
Authors: Hyun Lee, Seong Jeon, Hye Park, Seong Yeo
Journal: Endoscopy (2016)

<b>Background and study aims</b> Colonoscopy in the right colon is less effective than in the left colon in screening for colorectal cancer. The aim of this study was to prospectively evaluate the diagnostic value of retroflexion in the right colon. <b>Patients and methods</b> A total of 1020 patients undergoing screening or surveillance colonoscopy were enrolled. After the first cecal intubation, the scope was withdrawn from the cecum to the hepatic flexure in the standard forward view and all identified polyps were resected. A second examination from the cecum to the hepatic flexure was then performed in standard forward view, and finally a third examination of that same segment was conducted in retroflexion. Additionally detected polyps at each examination were removed. The main outcome measures included the proportion of procedures with successful retroflexion, the additional yield for adenoma detection, and the adenoma miss rate. <b>Results</b> Retroflexion was successful in 840 patients (82.4 %). Retroflexion detected a significantly greater proportion of patients with adenomas in the proximal segment than the two standard examinations combined (forward view 25.5 % vs. total examination 27.5 %; <i>P</i> < 0.001). The per-adenoma miss rate of the two standard examinations in the right colon was 10.4 % (52/502), and the per-patient adenoma miss rate was 4.9 % (50/1020). The detection of additional adenomas using retroflexion was associated with age ≥ 55 years, gastroenterologist experience, and the presence of polyps on forward-view examination. <b>Conclusions</b> Colonoscopic retroflexion in the proximal colon resulted in an increased detection of adenomas, even after two consecutive forward-view examinations. Trial registered at Clinical Research Information Service (CRIS): KCT0000725.
Prognostic index for patients with brain metastases from breast cancer: A validation and refinement of the breast-specific graded prognostic assessment (GPA) index.
Authors: H. K. Ahn, S. Lee, J. H. Sohn, S. Park, Y. H. Ham, J. J. Seo, E. Y. Cho, D. H. Nam, J. I. Lee, D. H. Choi, W. Park, S. J. Huh, Y. H. Park, J. S. Ahn, Y. Im
Journal: Journal of Clinical Oncology (2011)

1097 Background: Breast cancer (BC) is the second most common cause of brain metastases (BM). Various prognostic indexes such as RPA to predict survival in BM patients have been developed in patients enrolled in RTOG trials. However, they did not predict BC specific-survival with BM accurately because they had mostly included lung cancer patients. BC specific graded prognostic assessment (GPA) has been developed (Sperduto et al., IJROBP. 2010) and modified (ASCO 2010 abst. #1028) to reflect unique biologic feature of BC. The purpose of this study is to appraise and refine the Sperduto’s BC-specific GPA index (S’ GPA). Methods: We retrospectively investigated 272 patients with BM from BC between 1995 and 2009 at Samsung Medical Center. 173 of 272 patients who had available clinical data with ER, PR, and HER2 status were included. We appraised the S’ GPA index in our cohort. Since treatment with trastuzumab significantly enhanced survival of HER2 overexpressing BC patients with BM, we refined the S’ GPA index as shown in the table. Then, we validated our refined BC-specific GPA index with external patients’ cohort (n=140). Results: Overall median survival time (MST) for 173 patients was 9.4 months. However, Sperduto’s GPA index did not predict survival of BC with BM accurately in our patients’ cohort. The patients with our refined GPA scores of 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 showed significant discrimination in MST with 6.0 (n=22), 8.6 (n=76), 11.4 (n=60), 14.1 (n=15) months (p=0.004), respectively. Our refined GPA index was validated with external patients’ cohort at Yonsei Cancer Center. It did predict survival of BC with BM accurately in validation cohort according to refined GPA scores (p<0.001). Conclusions: The Sperduto’s GPA index was not appraisable for predicting survival of BC with BM in the era of trastuzumab. Refining the BC specific GPA index incorporated with trastuzumab treatment is proposed to be a prognostic tool with better predictive value. The refined BC-specific GPA index. Score 0 0.5 1.0 KPS <70 70-80 90-100 Age >70 <70 No. of brain mets >3 2-3 1 ER/PR ER –ve and PR -ve ER and/or PR +ve HER2 HER2 +ve W/O trastuzumab HER2 -ve HER2 +ve with trastuzumab
Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis
Authors: Wilhem Leconet, Myriam Chentouf, Stanislas du Manoir, Clément Chevalier, Audrey Sirvent, Imade Aït-Arsa, Muriel Busson, Marta Jarlier, Nina Radosevic-Robin, Charles Theillet, Dany Chalbos, Jean-Max Pasquet, André Pèlegrin, Christel Larbouret, Bruno Robert
Journal: Clinical Cancer Research (2016)

Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation. Clin Cancer Res; 23(11); 2806-16. ©2016 AACR.
3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”
Authors: Se Hoon Choi, Young Hye Kim, Luisa Quinti, Rudolph E. Tanzi, Doo Yeon Kim
Journal: Molecular Neurodegeneration (2016)

Alzheimer's disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.
Towards Stopping Imatinib Therapy under the Umbrella of Interferone: Alpha-Interferone Improves Molecular Response in CML Patients with Imatinib Induced Complete Cytogenetic Remission: An Early Observation from a Study of Pegylated Interferone in the Set up of Minimal Residual Disease.
Authors: Izhar Hardan, Ninette Amariglio, Luba Trakhtenbrot, Avichai Shimoni, Maya Koren-Michowitz, Gideon Rechavi, Arnon Nagler
Journal: Blood (2006)