Publications by authors named "Deborah Smith"

280 Publications

Teaching Medication Calculation: A Contextual Approach.

Nurse Educ 2021 May 11. Epub 2021 May 11.

By Maryann P. Valcourt, PhD, CPNP, and Deborah Smith, RNC, MSN, CNM, Marymount University, Arlington, VA,

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NNE.0000000000001030DOI Listing
May 2021

Fibroblast Growth Factor Receptor 2 Isoforms Detected via Novel RNA ISH as Predictive Biomarkers for Progestin Therapy in Atypical Hyperplasia and Low-Grade Endometrial Cancer.

Cancers (Basel) 2021 Apr 3;13(7). Epub 2021 Apr 3.

School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, Princess Alexandra (PA) Hospital Campus, 37 Kent St., Woolloongabba, Brisbane, Queensland 4102, Australia.

Women with atypical hyperplasia (AH) or well-differentiated early-stage endometrioid endometrial carcinoma (EEC) who wish to retain fertility and/or with comorbidities precluding surgery, are treated with progestin. Clinically approved predictive biomarkers for progestin therapy remain an unmet need. The objectives of this study were to document the overall response rate (ORR) of levonorgestrel intrauterine device (LNG-IUD) treatment, and determine the association of FGFR2b and FGFR2c expression with treatment outcome. BaseScope RNA ISH assay was utilized to detect expression of FGFR2b and FGFR2c mRNA in the diagnostic biopsies of 89 women (40 AH and 49 EEC) treated with LNG-IUD. Detailed clinical follow-up was available for 69 women which revealed an overall response rate (ORR) of 44% (30/69) with a higher ORR seen in AH (64%) compared to EEC (23%). The recurrence rate in women who initially responded to LNG-IUD was 10/30 (33.3%). RNA ISH was successful in 72 patients and showed FGFR2c expression in 12/72 (16.7%) samples. In the 59 women with detailed clinical follow-up and RNA-ISH data, women with tumours expressing FGFR2c were 5-times more likely to have treatment failure in both univariable (HR 5.08, < 0.0001) and multivariable (HR 4.5, < 0.002) Cox regression analyses. In conclusion, FGFR2c expression appears to be strongly associated with progestin treatment failure, albeit the ORR is lower in this cohort than previously reported. Future work to validate these findings in an independent multi-institutional cohort is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13071703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038411PMC
April 2021

Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

Cancer Chemother Pharmacol 2021 May 17;87(5):689-700. Epub 2021 Feb 17.

G1 Therapeutics, Inc., Research Triangle Park, NC, USA.

Purpose: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC).

Methods: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection.

Results: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03.

Conclusion: Integrated PK/PD, safety, and efficacy data support 240 mg/m as the RP2D for trilaciclib. CLINICALTRIALS.

Gov Identifiers: NCT02243150; NCT02499770; NCT02514447.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-021-04239-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026479PMC
May 2021

Client perceptions of the BreastScreen Australia remote radiology assessment model.

BMC Womens Health 2021 Jan 18;21(1):30. Epub 2021 Jan 18.

College of Medicine and Dentistry, James Cook University, Douglas, QLD, 4811, Australia.

Background: Telehealth and teleradiology are increasingly used around the world to facilitate health care provision when the health care provider and clients are separated by distance. The BreastScreen Australia Remote Radiology Assessment Model (RRAM) is an initiative developed to address the challenges of inadequate access to a local radiological workforce in regional Australia. With the growth in telehealth innovations more broadly, the RRAM represents a departure from the traditional onsite model where a radiologist would be co-located with practice staff during assessment clinics. Understanding client satisfaction is an important consideration with new models. This article explores client perceptions of the RRAM including awareness, satisfaction with experiences, confidence in the quality of care being received, and preferences regarding models of service delivery.

Methods: Clients in four BreastScreen services across three Australian states and territories were invited to provide feedback on their experiences of the RRAM. Brief face-to-face interviews based on a survey were conducted at the conclusion of assessment clinic visits. Clients also provided feedback through surveys completed and returned by post, and online.

Results: 144 clients completed the survey regarding their experiences of the RRAM. The majority were aged between 50 and 59 years (55/144, 38.2%). Most had attended a BreastScreen service for either screening or assessment on a total of two to five occasions (85/142, 59.9%) in the past. Nearly all women who attended a RRAM clinic expressed satisfaction with their experience (142/143, 99.3%). Clients were aware that the radiologist was working from another location (131/143, 91.6%) and the majority believed there wouldn't be any difference in the care they received between the RRAM and the onsite model (120/142, 84.5%). Clients generally had no particular preference for either the onsite or RRAM model of service delivery.

Conclusions: Clients' high satisfaction with their clinic experiences, high confidence in care being received, and the majority having no preference for either the onsite or remote model indicates their acceptance of the RRAM. Client acceptance of the model supports continuation of the RRAM at these sites and expansion. Findings may inform future telehealth innovations where key health care team members are working remotely.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12905-020-01163-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812334PMC
January 2021

"From the technology came the idea": safe implementation and operation of a high quality teleradiology model increasing access to timely breast cancer assessment services for women in rural Australia.

BMC Health Serv Res 2020 Nov 30;20(1):1103. Epub 2020 Nov 30.

College of Medicine and Dentistry, James Cook University, QLD, Douglas, 4814, Australia.

Breast cancer is the most commonly diagnosed cancer in Australian women. Providing timely diagnostic assessment services for screen-detected abnormalities is a core quality indicator of the population-based screening program provided by BreastScreen Australia. However, a shortage of local and locum radiologists with availability and appropriate experience in breast work to attend onsite assessment clinics, limits capacity of services to offer assessment appointments to women in some regional centres. In response to identified need, local service staff developed the remote radiology assessment model for service delivery. This study investigated important factors for establishing the model, the challenges and enablers of successful implementation and operation of the model, and factors important in the provision of a model considered safe and acceptable by service providers.

Methods: Semi-structured interviews were conducted with service providers at four assessment services, across three jurisdictions in Australia. Service providers involved in implementation and operation of the model at the service and jurisdictional level were invited to participate. A social constructivist approach informed the analysis. Deductive analysis was initially undertaken, using the interview questions as a classifying framework. Subsequently, inductive thematic analysis was employed by the research team. Together, the coding team aggregated the codes into overarching themes.

Results: 55 service providers participated in interviews. Consistently reported enablers for the safe implementation and operation of a remote radiology assessment clinic included: clinical governance support; ability to adapt; strong teamwork, trust and communication; and, adequate technical support and equipment. Challenges mostly related to technology and internet (speed/bandwidth), and maintenance of relationships within the group.

Conclusions: Understanding the key factors for supporting innovation, and implementing new and safe models of service delivery that incorporate telemedicine, will become increasingly important as technology evolves and becomes more accessible. It is possible to take proposed telemedicine solutions initiated by frontline workers and operationalise them safely and successfully: (i) through strong collaborative relationships that are inclusive of key experts; (ii) with clear guidance from overarching bodies with some flexibility for adapting to local contexts; (iii) through establishment of robust teamwork, trust and communication; and, (iv) with appropriate equipment and technical support.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12913-020-05922-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708244PMC
November 2020

Novel Thienopyrimidine Inhibitors of -Myristoyltransferase with On-Target Activity in Intracellular Amastigotes.

J Med Chem 2020 07 14;63(14):7740-7765. Epub 2020 Jul 14.

Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, U.K. W12 0BZ.

The leishmaniases, caused by species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. -Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (), a compound with modest activity against intracellular amastigotes and excellent selectivity (>660-fold) for NMT over human NMTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383931PMC
July 2020

FGFR2c Mesenchymal Isoform Expression Is Associated with Poor Prognosis and Further Refines Risk Stratification within Endometrial Cancer Molecular Subtypes.

Clin Cancer Res 2020 09 15;26(17):4569-4580. Epub 2020 May 15.

Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, located at the Translational Research Institute, PA Hospital Campus, 37 Kent St Woolloongabba, Brisbane, Queensland, Australia.

Purpose: The two most common molecular subtypes of endometrial cancers, mismatch repair deficient (MMRd) and p53 wild-type (p53wt) comprise the majority of endometrial cancers and have intermediate prognoses where additional risk stratification biomarkers are needed. Isoform switching of FGFR2 from FGFR2b to FGFR2c (normally expressed in mesenchymal cells), has been reported in other solid carcinomas. The objective of this study was to investigate the role of FGFR2c in risk stratification of endometrial cancer.

Experimental Design: We have developed and optimized a BaseScope RNA ISH assay to detect FGFR2c. FGFR2c expression was determined in a preliminary screening cohort of 78 endometrial cancers and a clinically and molecularly annotated Vancouver cohort ( = 465). Cox regression model analyses were performed to assess the prognostic value of FGFR2c.

Results: Univariate and multivariate analyses revealed FGFR2c expression was significantly associated with shorter disease-specific survival (DSS) and progression-free survival (PFS) in endometrioid endometrial cancer (EEC, = 302). Notably, FGFR2c expression was significantly associated with shorter PFS and DSS in patients with grade 3 EECs ( < 0.003 and < 0.002) and the European Society Medical Oncology (ESMO) high-risk group ( < 0.0001 and < 0.002), respectively. Moreover, within the MMRd subtype, FGFR2c expression was significantly associated with shorter PFS ( < 0.048) and DSS ( < 0.001).

Conclusions: FGFR2c expression appears an independent prognostic biomarker in patients with EEC and further discerns the outcomes within grade 3 tumors, ESMO high-risk groups, as well as within the MMRd and p53wt subtypes. FGFR2c inclusion into future molecular subtyping can further refine risk stratification of EEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-4088DOI Listing
September 2020

Ethical Decision Making in Critical Care: Communication, Coordination of Care, and the Practice of the Clinical Nurse Specialist.

Clin Nurse Spec 2020 May/Jun;34(3):93-95

Author Affiliations: Inpatient Palliative Care (Ms Buhagiar), Kaiser Permanente Santa Rosa, California; Senior Nursing Student (Mr Schoenlein), Pacific Lutheran University, Tacoma, Washington; and Inpatient Palliative Care Team (Ms Smith), Kaiser Permanente Redwood City, California.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NUR.0000000000000520DOI Listing
April 2020

Genetic validation of Leishmania genes essential for amastigote survival in vivo using N-myristoyltransferase as a model.

Parasit Vectors 2020 Mar 14;13(1):132. Epub 2020 Mar 14.

Centre for Immunology and Infection, Department of Biology, University of York, York, YO10 5DD, UK.

Background: Proving that specific genes are essential for the intracellular viability of Leishmania parasites within macrophages remains a challenge for the identification of suitable targets for drug development. This is especially evident in the absence of a robust inducible expression system or functioning RNAi machinery that works in all Leishmania species. Currently, if a target gene of interest in extracellular parasites can only be deleted from its genomic locus in the presence of ectopic expression from a wild type copy, it is assumed that this gene will also be essential for viability in disease-promoting intracellular parasites. However, functional essentiality must be proven independently in both life-cycle stages for robust validation of the gene of interest as a putative target for chemical intervention.

Methods: Here, we have used plasmid shuffle methods in vivo to provide supportive genetic evidence that N-myristoyltransferase (NMT) is essential for Leishmania viability throughout the parasite life-cycle. Following confirmation of NMT essentiality in vector-transmitted promastigotes, a range of mutant parasites were used to infect mice prior to negative selection pressure to test the hypothesis that NMT is also essential for parasite viability in an established infection.

Results: Ectopically-expressed NMT was only dispensable under negative selection in the presence of another copy. Total parasite burdens in animals subjected to negative selection were comparable to control groups only if an additional NMT copy, not affected by the negative selection, was expressed.

Conclusions: NMT is an essential gene in all parasite life-cycle stages, confirming its role as a genetically-validated target for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13071-020-3999-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071782PMC
March 2020

Co-existence of leiomyomas, adenomyosis and endometriosis in women with endometrial cancer.

Sci Rep 2020 02 27;10(1):3621. Epub 2020 Feb 27.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Leiomyomas, adenomyosis, and endometriosis are reported to be risk factors for endometrial carcinoma (EC), and adenomyosis and endometriosis also for ovarian carcinoma (OC). We aimed to describe the prevalence of these conditions in EC patients with or without an OC diagnosis, and to investigate their relationship with EC risk and prognostic factors in these patients. We evaluated the co-existence of these three conditions in 1399 EC patients, and compared the prevalence of epidemiological risk factors and tumor prognostic features in patients with each condition versus not. Prevalence of conditions was also assessed in the subset of patients with prior/concurrent OC. The observed coexistence of leiomyomas, adenomyosis and endometriosis significantly deviated from that expected (P = 1.2 × 10). Patients were more likely to: report a younger age at menarche (P = 0.004) if they had leiomyomas; have used oral contraceptives (P = 6.6 × 10) or had ≥2 full-term pregnancies (P = 2.0 × 10) if they had adenomyosis; be diagnosed with EC at younger age (P = 5.0 × 10) if they had endometriosis. Patients with prior/concurrent OC were more likely to be diagnosed at younger age (P = 5.0 × 10), have endometriosis (P = 9.9 × 10), and present with higher stage EC (P = 6.6 × 10). These findings justify further consideration of these gynecologic conditions as independent risk and prognostic factors for EC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59916-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046700PMC
February 2020

Integrating pharmacists into Aboriginal Community Controlled Health Services (IPAC project): Protocol for an interventional, non-randomised study to improve chronic disease outcomes.

Res Social Adm Pharm 2020 10 26;16(10):1431-1441. Epub 2019 Dec 26.

James Cook University, College of Medicine and Dentistry, Division of Tropical Health and Medicine, 1 James Cook Drive, Townsville, QLD, 4811, Australia.

Background: Aboriginal and Torres Strait Islander peoples experience a higher burden of chronic disease yet have poorer access to needed medicines than other Australians. Adverse health outcomes from these illnesses can be minimised with improved prescribing quality. This project aims to improve quality of care outcomes for Aboriginal and Torres Strait Islander adult patients with chronic disease by integrating a pharmacist within primary health care teams in Aboriginal Community Controlled Health Services (ACCHSs).

Methodology: This non-randomised, prospective, pre and post quasi-experimental study, will be pragmatic, community-based and participatory, comparing outcomes and costs using paired patient data. Pharmacists will be integrated at 22 sites for approximately 15 months to conduct patient-related and practice-related activities through 10 core roles: providing medication management reviews, assessing adherence and medication appropriateness, providing medicines information and education and training, collaborating with healthcare teams, delivering preventive care, liaising with stakeholders, providing trnsitional care, and undertaking a drug utilisation review. With patients' consent, de-identified client-level data will be extracted from clinical information systems and pharmacists will record deidentified activity in an electronic logbook. Primary expected outcomes include improvements in biometric indices (glycated haemoglobin, systolic and diastolic blood pressure, lipids, cardiovascular risk, albumin-creatinine ratio) from baseline to end of study. Expected secondary outcomes include improvements in estimated glomerular filtration rate, prescribing indices (appropriateness, overuse and underuse), medication adherence, self-assessed health, and health service utilisation indices. A qualitative assessment of stakeholder and patient perceptions and a cost-effectiveness analysis will be undertaken.

Discussion: Numerous inquiries have recommended evaluating the impact of pharmacists integrated within primary health care settings. This study is the first to explore this impact on the health of Aboriginal and Torres Strait Islander peoples who are medically underserved. Evaluation of innovative integrated workforce models is necessary to address the challenges of delivering quality care together with this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sapharm.2019.12.022DOI Listing
October 2020

A multi-institutional analysis of clinical outcomes and patterns of care of 1p/19q codeleted oligodendrogliomas treated with adjuvant or salvage radiation therapy.

J Neurooncol 2020 Jan 18;146(1):121-130. Epub 2019 Nov 18.

Department of Radiation Oncology, Center for Advanced Medicine, Washington University School of Medicine, 4921 Parkview Place, Campus Box #8224, St. Louis, MO, 63110, USA.

Purpose: Practice patterns vary for adjuvant treatment of 1p/19q-codeleted oligodendroglioma patients. This study evaluates the outcomes of adjuvant (aRT) versus salvage radiation therapy (sRT) in a multi-institutional cohort.

Methods: Oligodendroglioma patients with confirmed 1p/19q codeletion who were treated with RT with or without chemotherapy from 2000 to 2017 at four tertiary centers were retrospectively reviewed. Overall survival (OS), post-RT progression-free survival (PFS), freedom-from-RT (FFRT), and radiation necrosis (RN) rates were determined using Kaplan-Meier analyses. OS1/PFS1 were defined from the initial surgery. OS2/PFS2 were defined from the RT start-date. Multivariable analyses (MVAs) of prognostic factors for OS and PFS were performed with Cox regression.

Results: One hundred eighty-six patients were identified: 124(67%) received aRT and 62(33%) received sRT; of sRT patients, 58% were observed after surgery while 42% received chemotherapy without aRT. The median time from initial diagnosis to sRT was 61 months, and 74% had reoperations before sRT. sRT had longer OS1 than aRT (94% vs. 69% at 10 years, p = 0.03) and PFS1 (10-year PFS of 80% vs. 68%, p = 0.03), though sRT was not associated with significantly different OS1/PFS1 on MVAs. Chemotherapy did not delay sRT compared to observation and had worse PFS2 (42% vs. 79% at 5 years, p = 0.08). Higher RT dose was not associated with improved clinical outcomes but was associated with higher symptomatic RN rate (15% vs. 0% at 2 years, p = 0.003).

Conclusions: Delaying RT for selected oligodendroglioma patients appears safe. Adjuvant chemotherapy does not delay sRT longer than observation and may be associated with worse PFS after RT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-019-03344-3DOI Listing
January 2020

Identification and Development of an Irreversible Monoacylglycerol Lipase (MAGL) Positron Emission Tomography (PET) Radioligand with High Specificity.

J Med Chem 2019 09 16;62(18):8532-8543. Epub 2019 Sep 16.

Department of Clinical Neuroscience, Center for Psychiatry Research , Karolinska Institutet and Stockholm County Council , SE-17176 Stockholm , Sweden.

Monoacylglycerol lipase (MAGL), a serine hydrolase extensively expressed throughout the brain, serves as a key gatekeeper regulating the tone of endocannabinoid signaling. Preclinically, inhibition of MAGL is known to provide therapeutic benefits for a number of neurological disorders. The availability of a MAGL-specific positron emission tomography (PET) ligand would considerably facilitate the development and clinical characterization of MAGL inhibitors via noninvasive and quantitative PET imaging. Herein, we report the identification of the potent and selective irreversible MAGL inhibitor (PF-06809247) as a suitable radioligand lead, which upon radiolabeling was found to exhibit a high level of MAGL specificity; this enabled cross-species measurement of MAGL brain expression (), assessment of in vivo binding in the rat, and nonhuman primate PET imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b00847DOI Listing
September 2019

Microenvironment engineering of osteoblastic bone metastases reveals osteomimicry of patient-derived prostate cancer xenografts.

Biomaterials 2019 11 31;220:119402. Epub 2019 Jul 31.

Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology (QUT), Brisbane, QLD, Australia; Australian Prostate Cancer Research Centre, Queensland (APCRC-Q), QUT, Brisbane, QLD, Australia; Translational Research Institute (TRI), QUT, Brisbane, QLD, Australia; Centre in Regenerative Medicine, IHBI, QUT, Kelvin Grove, QLD, Australia; School of Biomedical Sciences, Faculty of Health, QUT, Brisbane, QLD, Australia. Electronic address:

Representative in vitro models that mimic the native bone tumor microenvironment are warranted to support the development of more successful treatments for bone metastases. Here, we have developed a primary cell 3D model consisting of a human osteoblast-derived tissue-engineered construct (hOTEC) indirectly co-cultured with patient-derived prostate cancer xenografts (PDXs), in order to study molecular interactions in a patient-derived microenvironment context. The engineered biomimetic microenvironment had high mineralization and embedded osteocytes, and supported a high degree of cancer cell osteomimicry at the gene, protein and mineralization levels when co-cultured with prostate cancer PDXs from a lymph node metastasis (LuCaP35) and bone metastasis (BM18) from patients with primary prostate cancer. This fully patient-derived model is a promising tool for the assessment of new molecular mechanisms and as a personalized pre-clinical platform for therapy testing for patients with prostate cancer bone metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2019.119402DOI Listing
November 2019

Treatment Outcomes and Dose Rate Effects Following Gamma Knife Stereotactic Radiosurgery for Vestibular Schwannomas.

Neurosurgery 2019 12;85(6):E1084-E1094

Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York.

Background: Gamma Knife radiosurgery (GKRS; Elekta AB) remains a well-established treatment modality for vestibular schwannomas. Despite highly effective tumor control, further research is needed toward optimizing long-term functional outcomes. Whereas dose-rate effects may impact post-treatment toxicities given tissue dose-response relationships, potential effects remain largely unexplored.

Objective: To evaluate treatment outcomes and potential dose-rate effects following definitive GKRS for vestibular schwannomas.

Methods: We retrospectively reviewed 419 patients treated at our institution between 1998 and 2015, characterizing baseline demographics, pretreatment symptoms, and GKRS parameters. The cohort was divided into 2 dose-rate groups based on the median value (2.675 Gy/min). Outcomes included clinical tumor control, radiographic progression-free survival, serviceable hearing preservation, hearing loss, and facial nerve dysfunction (FND). Prognostic factors were assessed using Cox regression.

Results: The study cohort included 227 patients with available follow-up. Following GKRS 2-yr and 4-yr clinical tumor control rates were 98% (95% CI: 95.6%-100%) and 96% (95% CI: 91.4%-99.6%), respectively. Among 177 patients with available radiographic follow-up, 2-yr and 4-yr radiographic progression-free survival rates were 97% (95% CI: 94.0%-100.0%) and 88% (95% CI: 81.2%-95.0%). The serviceable hearing preservation rate was 72.2% among patients with baseline Gardner-Robertson class I/II hearing and post-treatment audiological evaluations. Most patients experienced effective relief from prior headaches (94.7%), tinnitus (83.7%), balance issues (62.7%), FND (90.0%), and trigeminal nerve dysfunction (79.2%), but not hearing loss (1.0%). Whereas GKRS provided effective tumor control independently of dose rate, GKRS patients exposed to lower dose rates experienced significantly better freedom from post-treatment hearing loss and FND (P = .044).

Conclusion: Whereas GKRS provides excellent tumor control and effective symptomatic relief for vestibular schwannomas, dose-rate effects may impact post-treatment functional outcomes. Further research remains warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyz229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855984PMC
December 2019

Natural history, clinical course and predictors of interval time from initial diagnosis to development of subsequent NSCLC brain metastases.

J Neurooncol 2019 May 14;143(1):145-155. Epub 2019 Mar 14.

Department of Radiation Oncology, Columbia University Irving Medical Center, 622 West 168th Street, BNH B-11, New York, NY, 10032, USA.

Purpose: Non-small cell lung cancer (NSCLC) brain metastases are associated with substantial morbidity and mortality. During recent years, accompanying dramatic improvements in systemic disease control, NSCLC brain metastases have emerged as an increasingly relevant clinical problem. However, optimal surveillance practices remain poorly defined. This purpose of this study was to further characterize the natural history, clinical course and risk factors associated with earlier development of subsequent NSCLC brain metastases to better inform clinical practice and help guide survivorship care.

Methods: We retrospectively reviewed all institutional NSCLC brain metastasis cases treated with radiotherapy between 1997 and 2015. Exclusion criteria included presence of brain metastases at initial NSCLC diagnosis and incomplete staging information. Interval time to brain metastases and subsequent survival were characterized using Kaplan-Meier and multivariate Cox regression analyses.

Results: Among 105 patients within this cohort, median interval time to development of brain metastases was 16 months. Median interval times were 29, 19, 16 and 13 months for Stage I-IV patients, respectively (P = 0.016). Additional independent predictors for earlier development of NSCLC brain metastases included non-adenocarcinomatous histopathology (HR 3.036, P < 0.001), no prior surgical resection (HR 1.609, P = 0.036) and no prior systemic therapy (HR 3.560, P = 0.004). Median survival following intracranial progression was 16 months. Delayed development of brain metastases was associated with better prognosis (HR 0.970, P < 0.001) but not survival following intracranial disease onset.

Conclusions: Collectively, our results provide valuable insights into the natural history of NSCLC brain metastases. NSCLC stage, histology, prior surgical resection and prior systemic therapy emerged as independent predictors for interval time to brain metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-019-03149-4DOI Listing
May 2019

Immuno-PET Imaging to Assess Target Engagement: Experience from Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors.

J Nucl Med 2019 07 7;60(7):902-909. Epub 2019 Feb 7.

Hengrui Therapeutics, Inc., Princeton, New Jersey.

PET imaging with radiolabeled drugs provides information on tumor uptake and dose-dependent target interaction to support selection of an optimal dose for future efficacy testing. In this immuno-PET study of the anti-human epidermal growth factor receptor (HER3) mAb GSK2849330, we investigated the biodistribution and tumor uptake of Zr-labeled GSK2849330 and evaluated target engagement as a function of antibody mass dose. Zr-GSK2849330 distribution was monitored in 6 patients with HER3-positive tumors not amenable to standard treatment. Patients received 2 administrations of Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of Zr-GSK2849330 uptake in tumor tissues was evaluated 2 wk later using increasing doses of unlabeled GSK2849330 in combination with the tracer. Up to 3 PET scans (2 hours post infusion [p.i.] and days 2 and 5 p.i.) were performed after tracer administration. Biodistribution and tumor targeting were assessed visually and quantitatively using SUV. The 50% and 90% inhibitory mass doses (ID and ID) of target-mediated antibody uptake were calculated using a Patlak transformation. At baseline, imaging with tracer showed good tumor uptake in all evaluable patients. Predosing with unlabeled mAb reduced the tumor uptake rate in a dose-dependent manner. Saturation of Zr-mAb uptake by tumors was seen at the highest dose (30 mg/kg). Despite the limited number of patients, an exploratory ID of 2 mg/kg and ID of 18 mg/kg have been determined. In this immuno-PET study, dose-dependent inhibition of tumor uptake of Zr-GSK2849330 by unlabeled mAb confirmed target engagement of mAb to the HER3 receptor. This study further validates the use of immuno-PET to directly visualize tissue drug disposition in patients with a noninvasive approach and to measure target engagement at the site of action, offering the potential for dose selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.118.214726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604691PMC
July 2019

Dual pathways in social evolution: Population genetic structure of group-living and solitary species of kleptoparasitic spiders (Argyrodinae: Theridiidae).

PLoS One 2018 29;13(11):e0208123. Epub 2018 Nov 29.

Department of Ecology and Evolutionary Biology, University of Kansas, Lawrence, Kansas, United States of America.

Group-living behavior is taxonomically widespread but rare in spiders. The conventional view is that the main pathways to group-living in spiders are either sub-social, where extended maternal care leads to prolonged sibling association; or communal living, where individuals aggregate to exploit a common resource. Female egg-sac guarding behavior occurs throughout kleptoparasitic spiders in the subfamily Argyrodinae (Theridiidae), while individuals in group-living species cohabit in the resource rich webs of their host spiders. These attributes fit both sub-social and communal routes to group-living, which offers new insights to study the early stages of social evolution. We investigated whether members of kleptoparasitic groups in natural populations comprise related individuals by comparing the population structure of two group-living species, Argyrodes miniaceus and A. cf. fissifrons, and two solitary species, A. fasciatus and Neospintharus trigonum. We found that: (1) genetic-spatial autocorrelation in group-living species was highest among spiders sharing the same host web and declined steeply with increasing distance, but no significant autocorrelation at any scale for solitary species; (2) there was high relatedness among group members in two cases of group-living species, which indicated relatedness was not an adhesive agent in most of the groups, but no high relatedness in solitary species; and (3) the host web boundary was not the sole predictor of genetic structures in group-living species. These results suggest that population genetic structure in the group-living species is caused by limited dispersal of group members that is favored by ecological conditions, including the nature and size of resources. In contrast, the absence of genetic structuring in populations of solitary species indicates a high level of dispersal with individual interactions unlikely to have fitness benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208123PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264510PMC
April 2019

Risk and prognostic factors for endometrial carcinoma after diagnosis of breast or Lynch-associated cancers-A population-based analysis.

Cancer Med 2018 12 28;7(12):6411-6422. Epub 2018 Nov 28.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

We hypothesized that endometrial carcinoma (EC) patients with a prior cancer diagnosis, after accounting for EC arising after tamoxifen-treated prior breast carcinoma, are more likely to have an underlying genetic basis. We used information from a population-based study to compare measured risk factors, tumor characteristics, survival, and known mismatch repair (MMR) pathogenic variant status for EC subgroups according to prior diagnosis of cancer (none, breast cancer tamoxifen-treated or not, Lynch Syndrome (LS)-associated cancer). Family history of any cancer was increased for EC cases with prior breast cancer, both tamoxifen treated (P = 0.005) and untreated (P = 0.01). EC cases with prior LS-associated cancer more often reported family history of LS-associated cancer (P = 0.04) and breast cancer (P = 0.05). EC patients with a germline pathogenic MMR gene variant were more likely to report a prior cancer than cases with a MMR proficient tumor (P = 0.0001), but more than half (54.5%) of MMR carriers reported no prior cancer. Women developing EC after tamoxifen treatment for breast cancer were significantly more likely to develop EC of malignant mixed mullerian tumor subtype (13.2% vs 2.6%, P = 1.3 × 10 ), present with stage IV disease (8.8% vs 1.2%, P = 1.6 × 10 ), and have poorer survival (HR 1.96; P = 0.001). While report of prior cancer is an indicator of MMR pathogenic variant status, molecular analysis of all ECs at diagnosis is warranted to detect all patients with LS. Results also indicate the importance of longer-term monitoring of women treated with tamoxifen for symptoms of EC, and the need for studies assessing the biological mechanism underlying the poorer prognosis of this subset of EC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.1890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308118PMC
December 2018

A novel model to correlate hydrogel spacer placement, perirectal space creation, and rectum dosimetry in prostate stereotactic body radiotherapy.

Radiat Oncol 2018 Oct 1;13(1):192. Epub 2018 Oct 1.

Department of Radiation Oncology, Columbia University Medical Center, New York, New York, 10032, USA.

Background: The SpaceOAR hydrogel is employed to limit rectal radiation dose during prostate radiotherapy. We identified a novel parameter - the product of angle θ and hydrogel volume - to quantify hydrogel placement. This parameter predicted rectum dosimetry and acute rectal toxicity in prostate cancer patients treated with stereotactic body radiotherapy to 36.25 Gy in 5 fractions.

Methods: Twenty men with low- and intermediate-risk prostate cancer underwent hydrogel placement from 2015 to 2017. Hydrogel symmetry was assessed on the CT simulation scan in 3 axial slices (midgland, 1 cm above midgland, 1 cm below midgland). Two novel parameters quantifying hydrogel placement - hydrogel volume and angle θ formed by the prostate, hydrogel, and rectum - were measured, and the normalized product of θ and hydrogel volume calculated. These were then correlated with perirectal distance, rectum maximum 1-3 cc point doses (rD 1-3 cc), and rectum volumes receiving 80-95% of the prescription dose (rV80-95%). Acute rectal toxicity was recorded per RTOG criteria.

Results: In 50% of patients, hydrogel placement was symmetric bilaterally to within 1 cm of midline in all three CT simulation scan axial slices. Lateral hydrogel asymmetry < 2 cm in any one axial slice did not affect rectum dosimetry, but absence of hydrogel in the inferior axial slice resulted in a mean increase of 171 cGy in the rD 1 cc (p < 0.005). The perirectal distance measured at prostate midgland, midline (mean 9.1 ± 4.3 mm) correlated strongly with rV95 (R 0.6, p < 0.001). The mean hydrogel volume and θ were 10.3 ± 4.5 cc and 70 ± 49°, respectively. Perirectal distance, rV95 and rD 1 cc correlated with hydrogel angle θ (p < 0.01), and yet more strongly with the novel metric θ*hydrogel volume (p < 0.001). With a median follow up of 14 months, no rectal toxicity >grade 2 was observed. Low grade rectal toxicity was observed in a third of men and resolved within 1 month of SBRT. Men who had these symptoms had higher rD 1 cc and smaller θ*hydrogel volume measurements.

Conclusions: Optimal hydrogel placement occurs at prostate midgland, midline. The novel parameter θ*hydrogel volume describes a large proportion of rectum dosimetric benefit derived from hydrogel placement, and can be used to assess the learning curve phenomenon for hydrogel placement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13014-018-1135-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167802PMC
October 2018

The Case for Importance of Voting.

J Natl Med Assoc 2018 Aug;110(4):304

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jnma.2018.07.002DOI Listing
August 2018

A phase 2 study of ofatumumab (Arzerra) in combination with a pan-AKT inhibitor (afuresertib) in previously treated patients with chronic lymphocytic leukemia (CLL).

Leuk Lymphoma 2019 01 19;60(1):92-100. Epub 2018 Jun 19.

a Princess Margaret Cancer Centre/Ontario Cancer Institute , Toronto , ON , Canada.

AKT plays a centralized role in tumor proliferation and survival and is aberrantly activated in chronic lymphocytic leukemia (CLL). In this phase 2 trial, 30 relapsed/refractory CLL patients were treated with combination afuresertib, a novel oral AKT inhibitor, and ofatumumab for 6 months, followed by afuresertib maintenance for 12 months. We aimed to achieve deeper and more durable responses, without requiring long-term continuous treatment. Treatment was generally well tolerated but respiratory infections were common, with 18% severe requiring hospitalization. Hematologic toxicities were manageable (grade 3-4 neutropenia 39%). At a median follow-up of 13.4 months, overall responses were 50% (complete responses 3.6%). Median progression-free survival was 8.5 months and overall survival 34.8 months. Combination therapy with ofatumumab and afuresertib is active and well tolerated, but does not appear to lead to durable responses and may not provide additional benefit over single-agent ofatumumab in relapsed/refractory CLL. Novel agent combinations are currently undergoing intense investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2018.1468892DOI Listing
January 2019

Koebner phenomenon: Consideration when choosing fractionation for breast irradiation.

Adv Radiat Oncol 2018 Apr-Jun;3(2):108-110. Epub 2017 Dec 12.

Department of Radiation Oncology, Columbia University Medical Center, New York, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.adro.2017.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000185PMC
December 2017

Velocity-based Adaptive Registration and Fusion for Fractionated Stereotactic Radiosurgery Using the Small Animal Radiation Research Platform.

Int J Radiat Oncol Biol Phys 2018 11 4;102(4):841-847. Epub 2018 May 4.

Department of Radiation Oncology, Columbia University Medical Center, New York, New York. Electronic address:

Purpose: To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP).

Methods And Materials: C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification. Two arms were compared: Arm 1, where we performed 3 individual MRI-to-CBCT fusions using rigid registration, contouring GTVs on each, and Arm 2, where the authors performed MRI-to-CBCT fusion and contoured GTV on the first CBCT followed by Velocity-based adaptive registration. The first CBCT and associated GTV were exported from MuriPlan (Xstrahl Life Sciences) into Velocity (Varian Medical Systems, Inc, Palo Alto, CA). In Arm 1, the second and third CBCTs were exported similarly along with associated GTVs (Arm 1), while in Arm 2, the first (prone) CBCT was fused separately to the second (prone) and third (supine) CBCTs, performing deformable registrations on initial CBCTs and applying resulting matrices to the contoured GTV. Resulting GTVs were compared between Arms 1 and 2.

Results: Comparing GTV overlays using repeated MRI fusion and GTV delineation (Arm 1) versus those of Velocity-based CBCT and GTV adaptive fusion (Arm 2), mean deviations ± standard deviation in the axial, sagittal, and coronal planes were 0.46 ± 0.16, 0.46 ± 0.22, and 0.37 ± 0.22 mm for prone-to-prone and 0.52 ± 0.27, 0.52 ± 0.36, and 0.68 ± 0.31 mm for prone-to-supine adaptive fusions, respectively.

Conclusions: Velocity-based adaptive fusion of CBCTs and contoured volumes allows for efficient fSRS planning using a single MRI-to-CBCT fusion. This technique is immediately implementable on current SARRP systems, facilitating advanced preclinical treatment paradigms using existing clinical treatment planning software.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.04.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202197PMC
November 2018

Energy expenditure of rugby players during a 14-day in-season period, measured using doubly labelled water.

Eur J Appl Physiol 2018 Mar 20;118(3):647-656. Epub 2018 Jan 20.

Institute for Sport, Physical Activity and Leisure, Leeds Beckett University, G19 Fairfax Hall, Headingley Campus, Leeds, LS6 3QN, UK.

Criterion data for total energy expenditure (TEE) in elite rugby are lacking, which prediction equations may not reflect accurately. This study quantified TEE of 27 elite male rugby league (RL) and rugby union (RU) players (U16, U20, U24 age groups) during a 14-day in-season period using doubly labelled water (DLW). Measured TEE was also compared to estimated, using prediction equations. Resting metabolic rate (RMR) was measured using indirect calorimetry, and physical activity level (PAL) estimated (TEE:RMR). Differences in measured TEE were unclear by code and age (RL 4369 ± 979; RU 4365 ± 1122; U16, 4010 ± 744; U20, 4414 ± 688; U24, 4761 ± 1523 Kcal day). Differences in PAL (overall mean 2.0 ± 0.4) were unclear. Very likely differences were observed in RMR by code (RL 2366 ± 296; RU 2123 ± 269 Kcal day). Differences in relative RMR between U20 and U24 were very likely (U16, 27 ± 4; U20, 23 ± 3; U24, 26 ± 5 Kcal kg day). Differences were observed between measured and estimated TEE, using Schofield, Cunningham and Harris-Benedict equations for U16 (187 ± 614, unclear; - 489 ± 564, likely and - 90 ± 579, unclear Kcal day), U20 (- 449 ± 698, likely; - 785 ± 650, very likely and - 452 ± 684, likely Kcal day) and U24 players (- 428 ± 1292; - 605 ± 1493 and - 461 ± 1314 Kcal day, all unclear). Rugby players have high TEE, which should be acknowledged. Large inter-player variability in TEE was observed demonstrating heterogeneity within groups, thus published equations may not appropriately estimate TEE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00421-018-3804-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805815PMC
March 2018

Clinical and molecular characteristics of gliosarcoma and modern prognostic significance relative to conventional glioblastoma.

J Neurooncol 2018 Apr 20;137(2):303-311. Epub 2017 Dec 20.

Department of Radiation Oncology, Columbia University Medical Center, 622 West 168th Street, CHONY North B11, New York, NY, 10032, USA.

Gliosarcoma is a rare histopathologic variant of glioblastoma traditionally associated with a poor prognosis. While gliosarcoma may represent a distinct clinical entity given its unique histologic composition and molecular features, its relative prognostic significance remains uncertain. While treatment of gliosarcoma generally encompasses the same standardized approach used in glioblastoma, supporting evidence is limited given its rarity. Here, we characterized 32 cases of gliosarcoma and retrospectively evaluated survival relative to 451 glioblastoma patients diagnosed during the same era within the same institution. Overall, we identified 22 primary gliosarcomas, representing 4.7% of WHO Grade IV primary glioblastomas, and 10 secondary gliosarcomas. With median age of 62, patients were predominately Caucasian (87.5%) and male (65.6%). Tumors with available molecular profiling were primarily MGMT-unmethylated (87.5%), IDH-1-preserved (100%) and EGFR wild-type (100%). Interestingly, while no significant median survival difference between primary gliosarcoma and glioblastoma was observed across the entire cohort (11.0 vs. 14.8 months, p = 0.269), median survival was worse for gliosarcoma specifically among patients who received modern temozolomide-based (TMZ) chemoradiotherapy (11.0 vs. 17.3 months, p = 0.006). Matched-pair analysis also trended toward worse median survival among gliosarcomas (11.0 vs. 19.6 months, log-rank p = 0.177, Breslow p = 0.010). While adjuvant radiotherapy (HR 0.206, p = 0.035) and TMZ-based chemotherapy (HR 0.531, p = 0.000) appeared protective, gliosarcoma emerged as a significantly poor prognostic factor on multivariate analysis (HR 3.27, p = 0.012). Collectively, our results suggest that gliosarcoma may still portend worse prognosis even with modern trimodality therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-017-2718-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297205PMC
April 2018

Improving the Patient Experience in the Urology Office: An Evidence-Based Tool Kit to Impact Staff Perception Of Patient Satisfaction.

Urol Nurs 2016 Nov-Dec;36(6):289-96

Researchers evaluated the effectiveness of an educational intervention, which included use of an evidence-based tool kit for healthcare providers to improve patient satisfaction. Findings demonstrated improved staff perceptions of their actions influencing patient experiences, use of standardized patient care processes, and increased patient experience scores.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2018

ER and PR expression and survival after endometrial cancer.

Gynecol Oncol 2018 02 6;148(2):258-266. Epub 2017 Dec 6.

Population Health Department QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Electronic address:

Objective: To measure association between endometrial carcinoma ER and PR status and endometrial cancer (EC) survival, accounting for inter-observer variation.

Methods: The intensity and proportion of tumor cell expression of ER and PR in ECs were assessed independently and semi-quantitatively by two pathologists using digital images of duplicate tumor tissue microarrays (TMAs). Cases with inconsistent initial assessment were reviewed and final scoring agreed. The association between overall and EC-specific survival and hormone receptor expression (intensity, proportion and combined) was assessed using Cox regression analysis. The C-index was used to evaluate model discrimination with addition of ER and PR status.

Results: Tumor ER and PR analysis was possible in 659 TMAs from 255 patients, and in 459 TMAs from 243 patients, respectively. Initial ER and PR scoring was consistent in 82% and 80% of cases, respectively. In multivariate analyses decreased ER and PR expression was associated with increased tumor-related mortality. Associations reached statistical significance for ER proportion score (P=0.05), ER intensity score (P=0.003), and PR combined score (P=0.04). Decreased expression of combined ER/PR expression was associated with poorer EC-specific survival than decreased expression of either hormone receptor alone (P=0.005). However, hormone receptor status did not significantly improve mortality prediction in individual cases.

Conclusion: ER and PR expression combined, using cut-points that capture variation in scoring and across cores, is significantly associated with EC-specific survival in analyses adjusting for known prognostic factors. However, at the individual level, ER and PR expression does not improve mortality prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2017.11.027DOI Listing
February 2018