Publications by authors named "Patricia A Spears"

33 Publications

Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO-Friends of Cancer Research Joint Research Statement.

Clin Cancer Res 2021 May 9;27(9):2394-2399. Epub 2021 Feb 9.

American Society of Clinical Oncology, Alexandria, Virginia.

Purpose: Restrictive clinical trial eligibility criteria (EC) limit the number of patients who can enroll and potentially benefit from protocol-driven, investigational treatment plans and reduce the generalizability of trial results to the broader population. Following publication of expert stakeholder recommendations for broadening EC in 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research () convened working groups to produce additional recommendations and analyze the potential impact on clinical trials using real-world data.

Experimental Design: Multistakeholder working groups were appointed by an ASCO- leadership group to propose recommendations for more inclusive EC related to: washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status.

Results: The four working groups, ASCO Board of Directors, and leadership support the recommendations included in this statement to modernize EC related to washout periods, concomitant medications, prior therapies, laboratory references ranges and test intervals, and performance status to make trial populations more inclusive and representative of cancer patient populations.

Conclusions: Implementation of the recommendations is intended to result in greater ease of determining patient eligibility. Increased opportunities for patient participation in research will help address longstanding underrepresentation of certain groups in clinical trials and produce evidence that is more informative for a broader patient population. More patients eligible will also likely speed clinical trial accrual..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3852DOI Listing
May 2021

Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline.

J Clin Oncol 2021 May 28;39(13):1485-1505. Epub 2021 Jan 28.

Herbert Irving Comprehensive Cancer Center at Columbia University, New York, NY.

Purpose: To develop guideline recommendations concerning optimal neoadjuvant therapy for breast cancer.

Methods: ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and provide recommended care options.

Results: A total of 41 articles met eligibility criteria and form the evidentiary basis for the guideline recommendations.

Recommendations: Patients undergoing neoadjuvant therapy should be managed by a multidisciplinary care team. Appropriate candidates for neoadjuvant therapy include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy. Neoadjuvant therapy can also be used to reduce the extent of local therapy or reduce delays in initiating therapy. Although tumor histology, grade, stage, and estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) expression should routinely be used to guide clinical decisions, there is insufficient evidence to support the use of other markers or genomic profiles. Patients with triple-negative breast cancer (TNBC) who have clinically node-positive and/or at least T1c disease should be offered an anthracycline- and taxane-containing regimen; those with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy. Carboplatin may be offered to patients with TNBC to increase pathologic complete response. There is currently insufficient evidence to support adding immune checkpoint inhibitors to standard chemotherapy. In patients with hormone receptor (HR)-positive (HR-positive), HER2-negative tumors, neoadjuvant chemotherapy can be used when a treatment decision can be made without surgical information. Among postmenopausal patients with HR-positive, HER2-negative disease, hormone therapy can be used to downstage disease. Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy in combination with anti-HER2-positive therapy. Patients with T1aN0 and T1bN0, HER2-positive disease should not be routinely offered neoadjuvant therapy.Additional information is available at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.03399DOI Listing
May 2021

Clinical Utility and User Perceptions of a Digital System for Electronic Patient-Reported Symptom Monitoring During Routine Cancer Care: Findings From the PRO-TECT Trial.

JCO Clin Cancer Inform 2020 10;4:947-957

Mayo Clinic, Scottsdale, AZ.

Purpose: There is increasing interest in implementing digital systems for remote monitoring of patients' symptoms during routine oncology practice. Information is limited about the clinical utility and user perceptions of these systems.

Methods: PRO-TECT is a multicenter trial evaluating implementation of electronic patient-reported outcomes (ePROs) among adults with advanced and metastatic cancers receiving treatment at US community oncology practices (ClinicalTrials.gov identifier: NCT03249090). Questions derived from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) are administered weekly by web or automated telephone system, with alerts to nurses for severe or worsening symptoms. To elicit user feedback, surveys were administered to participating patients and clinicians.

Results: Among 496 patients across 26 practices, the majority found the system and questions easy to understand (95%), easy to use (93%), and relevant to their care (91%). Most patients reported that PRO information was used by their clinicians for care (70%), improved discussions with clinicians (73%), made them feel more in control of their own care (77%), and would recommend the system to other patients (89%). Scores for most patient feedback questions were significantly positively correlated with weekly PRO completion rates in both univariate and multivariable analyses. Among 57 nurses, most reported that PRO information was helpful for clinical documentation (79%), increased efficiency of patient discussions (84%), and was useful for patient care (75%). Among 39 oncologists, most found PRO information useful (91%), with 65% using PROs to guide patient discussions sometimes or often and 65% using PROs to make treatment decisions sometimes or often.

Conclusion: These findings support the clinical utility and value of implementing digital systems for monitoring PROs, including the PRO-CTCAE, in routine cancer care.
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http://dx.doi.org/10.1200/CCI.20.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768331PMC
October 2020

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

J Clin Oncol 2020 12 14;38(34):4120-4129. Epub 2020 Oct 14.

Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.
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http://dx.doi.org/10.1200/JCO.20.01382DOI Listing
December 2020

Direct-to-Consumer Advertising for Cancer Centers and Institutes: Ethical Dilemmas and Practical Implications.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-11

University of Hawai'i Cancer Center, Honolulu, HI.

In the United States, many cancer centers advertise their clinical services directly to the public. Although there are potential public benefits from such advertising, including increased patient awareness of treatment options and improved access to care and clinical trials, there is also potential for harm through misinformation, provision of false hope, inappropriate use of health care resources, and disruption in doctor-patient relationships. Although patient education through advertising is appropriate, misleading patients in the name of gaining market share, boosting profits, or even boosting trial accrual is not. It is critical that rigorous ethical guidelines are adopted and that oversight is introduced to ensure that cancer center marketing supports good patient care and public health interests. Patients with cancer have been identified as an especially vulnerable population because of fears and anxiety related to their diagnosis and the very real need to identify optimal sources of care. Cancer organizations have a fiduciary duty and a moral and legal obligation to provide truthful information to avoid deceptive, inaccurate claims associated with treatment success. In this article, actionable recommendations are provided for both the oncologist and the cancer center's marketing team to promote ethical marketing of services to patients with cancer. This tailored guidance for the oncology community includes explicit communication on (1) ensuring fair and balanced promotion of cancer services, (2) avoiding exaggeration of claims in the context of reputational marketing, (3) providing data and statistics to support direct and implied assertions of treatment success, and (4) defining eligible patient groups in the context of marketing for research. These recommendations for cancer centers are designed to promote ethical quality marketing information to patients with cancer.
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http://dx.doi.org/10.1200/EDBK_279963DOI Listing
March 2020

Performance Measures Based on How Adults With Cancer Feel and Function: Stakeholder Recommendations and Feasibility Testing in Six Cancer Centers.

JCO Oncol Pract 2020 03 19;16(3):e234-e250. Epub 2020 Feb 19.

Department of Health Policy and Management, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Purpose: Patient-reported outcome measures (PROMs) that assess how patients feel and function have potential for evaluating quality of care. Stakeholder recommendations for PRO-based performance measures (PMs) were elicited, and feasibility testing was conducted at six cancer centers.

Methods: Interviews were conducted with 124 stakeholders to determine priority symptoms and risk adjustment variables for PRO-PMs and perceived acceptability. Stakeholders included patients and advocates, caregivers, clinicians, administrators, and thought leaders. Feasibility testing was conducted in six cancer centers. Patients completed PROMs at home 5-15 days into a chemotherapy cycle. Feasibility was operationalized as ≥ 75% completed PROMs and ≥ 75% patient acceptability.

Results: Stakeholder priority PRO-PMs for systemic therapy were GI symptoms (diarrhea, constipation, nausea, vomiting), depression/anxiety, pain, insomnia, fatigue, dyspnea, physical function, and neuropathy. Recommended risk adjusters included demographics, insurance type, cancer type, comorbidities, emetic risk, and difficulty paying bills. In feasibility testing, 653 patients enrolled (approximately 110 per site), and 607 (93%) completed PROMs, which indicated high feasibility for home collection. The majority of patients (470 of 607; 77%) completed PROMs without a reminder call, and 137 (23%) of 607 completed them after a reminder call. Most patients (72%) completed PROMs through web, 17% paper, or 2% interactive voice response (automated call that verbally asked patient questions). For acceptability, > 95% of patients found PROM items to be easy to understand and complete.

Conclusion: Clinicians, patients, and other stakeholders agree that PMs that are based on how patients feel and function would be an important addition to quality measurement. This study also shows that PRO-PMs can be feasibly captured at home during systemic therapy and are acceptable to patients. PRO-PMs may add value to the portfolio of PMs as oncology transitions from fee-for-service payment models to performance-based care that emphasizes outcome measures.
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http://dx.doi.org/10.1200/JOP.19.00784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069703PMC
March 2020

Proposing a Bill of Rights for Patients With Cancer.

JCO Oncol Pract 2020 03 10;16(3):121-123. Epub 2020 Feb 10.

Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.

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http://dx.doi.org/10.1200/JOP.19.00705DOI Listing
March 2020

Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of the Cancer Care Ontario Guideline.

J Clin Oncol 2019 08 17;37(22):1965-1977. Epub 2019 Jun 17.

11Kimmel Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: To update the American Society of Clinical Oncology endorsement of the Cancer Care Ontario recommendations on the Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer.

Methods: Two phase III trials-the Trial Assigning Individualized Options for Treatment (TAILORx) in women with hormone receptor-positive, node-negative tumors and the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) trial-provided the evidence for this update.

Updated Recommendations: Shared decision making between clinicians and patients is appropriate for adjuvant systemic therapy for breast cancer. For patients older than age 50 years and whose tumors have Onco DX recurrence scores less than 26, and for patients age 50 years or younger whose tumors have Onco DX recurrence scores less than 16, there is little to no benefit from chemotherapy. Clinicians may offer endocrine therapy alone for these patients. For patients age 50 years or younger with recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy. Patients with recurrence scores greater than 30 should be considered candidates for chemoendocrine therapy. Based on informal consensus, the Panel recommends that oncologists may offer chemoendocrine therapy to patients with Onco DX scores of 26 to 30.The MammaPrint assay could be used to guide decisions on withholding adjuvant systemic chemotherapy in patients with hormone receptor-positive lymph node-negative breast cancer and in select patients with lymph node-positive cancers. In both patients with node-positive and node-negative disease, evidence of clinical utility of the MammaPrint assay was only apparent in those determined to be at high clinical risk; the Panel thus did not recommend use of MammaPrint assay in patients determined to be at low clinical risk. Remaining recommendations from the 2016 ASCO guideline endorsement are unchanged.Additional information is available at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.19.00948DOI Listing
August 2019

Clinical Development of Novel Drug-Radiotherapy Combinations.

Clin Cancer Res 2019 03 29;25(5):1455-1461. Epub 2018 Nov 29.

Radiation Oncology, NIHR University College London Hospitals Biomedical Research Centre, University College London Cancer Institute, University College London, London, United Kingdom.

Radiotherapy is a fundamental component of treatment for the majority of patients with cancer. In recent decades, technological advances have enabled patients to receive more targeted doses of radiation to the tumor, with sparing of adjacent normal tissues. There had been hope that the era of precision medicine would enhance the combination of radiotherapy with targeted anticancer drugs; however, this ambition remains to be realized. In view of this lack of progress, the FDA-AACR-ASTRO Clinical Development of Drug-Radiotherapy Combinations Workshop was held in February 2018 to bring together stakeholders and opinion leaders from academia, clinical radiation oncology, industry, patient advocacy groups, and the FDA to discuss challenges to introducing new drug-radiotherapy combinations to the clinic. This article summarizes the themes and action points that were discussed. Intelligent trial design is required to increase the number of studies that efficiently meet their primary outcomes; endpoints to be considered include local control, organ preservation, and patient-reported outcomes. Novel approaches including immune-oncology or DNA-repair inhibitor agents combined with radiotherapy should be prioritized. In this article, we focus on how the regulatory challenges associated with defining a new drug-radiotherapy combination can be overcome to improve clinical outcomes for patients with cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397668PMC
March 2019

Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

Clin Cancer Res 2018 11 23;24(21):5292-5304. Epub 2018 Jul 23.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.

Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy. We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures. The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ER features. Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214737PMC
November 2018

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.

J Clin Oncol 2018 07 30;36(20):2105-2122. Epub 2018 May 30.

Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore; Lisa M. McShane, National Cancer Institute, Bethesda, MD; M. Elizabeth Hale Hammond, Intermountain Healthcare and University of Utah School of Medicine, Salt Lake City, UT; Kimberly H. Allison, Stanford University School of Medicine, Stanford; Patrick Fitzgibbons, St Jude Medical Center, Fullerton; Michael F. Press, University of Southern California, Los Angeles, CA; Brittany E. Harvey and Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA; John M.S. Bartlett, Ontario Institute for Cancer Research; Wedad Hanna, Sunnybrook Health Sciences Centre and Women's College Hospital, Toronto, Ontario, Canada; Michael Bilous, Western Sydney University and Australian Clinical Laboratories, Sydney, New South Wales, Australia; Ian O. Ellis, The University of Nottingham, Nottingham; Mitchell Dowsett, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Robert B. Jenkins, Mayo Clinic, Rochester, MN; Patricia A. Spears, Cancer Information and Support Network, Raleigh, NC; Gail H. Vance, Indiana University School of Medicine, Indianapolis, IN; and Giuseppe Viale, University of Milan and Istituto Europeo di Oncologia, Milan, Italy.

Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0; average HER2 copy number < 4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 4.0 and < 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. Find additional information at www.asco.org/breast-cancer-guidelines .
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http://dx.doi.org/10.1200/JCO.2018.77.8738DOI Listing
July 2018

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.

Arch Pathol Lab Med 2018 11 30;142(11):1364-1382. Epub 2018 May 30.

Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; Lisa M. McShane, National Cancer Institute, Bethesda, Maryland; M. Elizabeth Hale Hammond, Intermountain Healthcare and University of Utah School of Medicine, Salt Lake City; Kimberly H. Allison, Stanford University School of Medicine, Stanford, California; Patrick Fitzgibbons, St Jude Medical Center, Fullerton, California; Michael F. Press, University of Southern California, Los Angeles; Brittany E. Harvey and Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, Virginia; John M.S. Bartlett, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Wedad Hanna, Sunnybrook Health Sciences Centre and Women's College Hospital, Toronto, Ontario, Canada; Michael Bilous, Western Sydney University and Australian Clinical Laboratories, Sydney, Australia; Ian O. Ellis, The University of Nottingham, Nottingham, United Kingdom; Mitchell Dowsett, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Robert B. Jenkins, Mayo Clinic, Rochester, Minnesota; Patricia A. Spears, Cancer Information and Support Network, Raleigh, North Carolina; Gail H. Vance, Indiana University School of Medicine, Indianapolis; and Giuseppe Viale, University of Milan and Istituto Europeo di Oncologia, Milan, Italy.

Purpose.—: To update key recommendations of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline.

Methods.—: Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations.

Recommendations.—: Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in >10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended workup for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥2.0; average HER2 copy number <4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥4.0 and <6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results.
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http://dx.doi.org/10.5858/arpa.2018-0902-SADOI Listing
November 2018

A National Study of the Use of Asymptomatic Systemic Imaging for Surveillance Following Breast Cancer Treatment (AFT-01).

Ann Surg Oncol 2018 Sep 17;25(9):2587-2595. Epub 2018 May 17.

Wisconsin Surgical Outcomes Research Program, Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA.

Background: Although not guideline recommended, studies suggest 50% of locoregional breast cancer patients undergo systemic imaging during follow-up, prompting its inclusion as a Choosing Wisely measure of potential overuse. Most studies rely on administrative data that cannot delineate scan intent (prompted by signs/symptoms vs. asymptomatic surveillance). This is a critical gap as intent is the only way to distinguish overuse from appropriate care.

Objective: Our aim was to assess surveillance systemic imaging post-breast cancer treatment in a national sample accounting for scan intent.

Methods: A stage-stratified random sample of 10 women with stage II-III breast cancer in 2006-2007 was selected from each of 1217 Commission on Cancer-accredited facilities, for a total of 10,838 patients. Registrars abstracted scan type (computed tomography [CT], non-breast magnetic resonance imaging, bone scan, positron emission tomography/CT) and intent (cancer-related vs. not, asymptomatic surveillance vs. not) from medical records for 5 years post-diagnosis. Data were merged with each patient's corresponding National Cancer Database record, containing sociodemographic and tumor/treatment information.

Results: Of 10,838 women, 30% had one or more, and 12% had two or more, systemic surveillance scans during a 4-year follow-up period. Patients were more likely to receive surveillance imaging in the first follow-up year (lower proportions during subsequent years) and if they had estrogen receptor/progesterone receptor-negative tumors.

Conclusions: Locoregional breast cancer patients undergo asymptomatic systemic imaging during follow-up despite guidelines recommending against it, but at lower rates than previously reported. Providers appear to use factors that confer increased recurrence risk to tailor decisions about systemic surveillance imaging, perhaps reflecting limitations of data on which current guidelines are based. ClinicalTrials.gov Identifier: NCT02171078.
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http://dx.doi.org/10.1245/s10434-018-6496-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475883PMC
September 2018

In silico Predicted Glucose-1-phosphate Uridylyltransferase (GalU) Inhibitors Block a Key Pathway Required for Listeria Virulence.

Mol Inform 2018 07 8;37(6-7):e1800004. Epub 2018 Mar 8.

Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.

Peptidoglycan walls of gram positive bacteria are functionalized by glycopolymers called wall teichoic acid (WTA). In Listeria monocytogenes, multiple enzymes including the glucose-1-phosphate uridylyltransferase (GalU) were identified as mandatory for WTA galactosylation, so that the inhibition of GalU is associated with a significant attenuation of Listeria virulence. Herein, we report on a series of in silico predicted GalU inhibitors identified using structure-based virtual screening and experimentally validated to be effective in blocking the WTA galactosylation pathway in vitro. Several hits such as C04, a pyrimidinyl benzamide, afforded promising experimental potencies. This proof-of-concept study opens new perspectives for the development of potent and selective GalU inhibitors of high interest to attenuate Listeria virulence. It also underscores the high relevance of using molecular modeling for facilitating the identification of bacterial virulence attenuators and more generally antibacterials.
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http://dx.doi.org/10.1002/minf.201800004DOI Listing
July 2018

Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011.

JAMA Intern Med 2017 10;177(10):1452-1459

George Washington University School of Medicine, Washington, DC.

Importance: Potential research participants may assume that randomized trials comparing new interventions with older interventions always hypothesize greater efficacy for the new intervention, as in superiority trials. However, antibiotic trials frequently use "noninferiority" hypotheses allowing a degree of inferior efficacy deemed "clinically acceptable" compared with an older effective drug, in exchange for nonefficacy benefits (eg, decreased adverse effects). Considering these different benefit-harm trade-offs, proper informed consent necessitates supplying different information on the purposes of superiority and noninferiority trials.

Objective: To determine the degree to which the study purpose is explained to potential participants in randomized clinical trials of antibiotics and the degree to which study protocols justify their selection of noninferiority hypotheses and amount of "clinically acceptable" inferiority.

Design And Setting: Cross-sectional analysis of study protocols, statistical analysis plans (SAPs), and informed consent forms (ICFs) from clinical study reports submitted to the European Medicines Agency. The ICFs were read by both methodologists and patient investigators.

Main Outcomes And Measures: Protocols and SAPs were used as the reference standard to determine prespecified primary hypothesis and record rationale for selection of noninferiority hypotheses and noninferiority margins. This information was cross-referenced against ICFs to determine whether ICFs explained the study purpose.

Results: We obtained trial documents from 78 randomized trials with prespecified efficacy hypotheses (6 superiority, 72 noninferiority) for 17 antibiotics conducted between 1991 and 2011 that enrolled 39 407 patients. Fifty were included in the ICF analysis. All ICFs contained sections describing study purpose; however, none consistently conveyed study hypothesis to both methodologists and patient investigators. Methodologists found that 1 of 50 conveyed a study purpose. Patient investigators found that 11 of 50 conveyed a study purpose, 7 accurately and 4 inaccurately compared with the reference standard. Seventy-one of 72 noninferiority trial protocols or SAPs provided no rationale for selection of noninferiority hypothesis. None provided a clinical rationale for the chosen amount of decreased efficacy.

Conclusions And Relevance: Patients were not accurately informed of study purpose, which raises questions regarding the ethics of informed consent in antibiotic trials. Noninferiority and superiority trials entail different benefit-harm trade-offs that must be conveyed for ethical informed consent.
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http://dx.doi.org/10.1001/jamainternmed.2017.3820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710221PMC
October 2017

Reply to L.B. Marks et al.

J Clin Oncol 2017 04 9;35(11):1258-1259. Epub 2017 Jan 9.

Abram Recht, Beth Israel Deaconess Medical Center, Boston, MA; Elizabeth A. Comen, Memorial Sloan Kettering Cancer Center, New York, NY; Richard E. Fine, The West Clinic Comprehensive Breast Center, Germantown, TN; Gini F. Fleming, University of Chicago Medical Center, Chicago, IL; Patricia H. Hardenbergh, Shaw Regional Cancer Center, Edwards, CO; Alice Y. Ho, Memorial Sloan Kettering Cancer Center, New York, NY; Clifford A. Hudis, American Society of Clinical Oncology, Alexandria, VA; E. Shelley Hwang, Duke University Medical Center, Durham, NC; Jeffrey J. Kirshner, Hematology-Oncology Associates of Central New York, East Syracuse, NY; Monica Morrow, Memorial Sloan Kettering Cancer Center, New York, NY; Kilian E. Salerno, Roswell Park Cancer Institute, Buffalo, NY; George W. Sledge Jr, Stanford University Medical Center, Palo Alto, CA; Lawrence J. Solin, Albert Einstein Healthcare Network, Philadelphia, PA; Patricia A. Spears, North Carolina State University, Raleigh, NC; Timothy J. Whelan, McMaster University, Hamilton, Ontario, Canada; Mark R. Somerfield, American Society of Clinical Oncology, Alexandria, VA; and Stephen B. Edge, Roswell Park Cancer Institute, Buffalo, NY.

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http://dx.doi.org/10.1200/JCO.2016.71.3966DOI Listing
April 2017

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

Pract Radiat Oncol 2016 Nov - Dec;6(6):e219-e234. Epub 2016 Sep 19.

Roswell Park Cancer Institute, Buffalo, NY.

A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT).

Methods: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data.

Recommendations: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.
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http://dx.doi.org/10.1016/j.prro.2016.08.009DOI Listing
March 2017

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

J Clin Oncol 2016 12 30;34(36):4431-4442. Epub 2016 Sep 30.

Abram Recht, Beth Israel Deaconess Medical Center, Boston, MA; Elizabeth A. Comen, Alice Y. Ho, Clifford A. Hudis, Monica Morrow, Memorial Sloan Kettering Cancer Center; New York; Jeffrey J. Kirshner, Hematology Oncology Associates of Central New York, East Syracuse; Kilian E. Salerno and Stephen B. Edge, Roswell Park Cancer Institute, Buffalo, NY; Richard E. Fine, West Clinic Comprehensive Breast Center, Germantown, TN; Gini F. Fleming, University of Chicago Medical Center, Chicago, IL; Patricia H. Hardenbergh, Shaw Regional Cancer Center, Edwards, CO; E. Shelley Hwang, Duke University Medical Center, Durham; Patricia A. Spears, North Carolina State University, Raleigh, NC; George W. Sledge Jr, Stanford University Medical Center, Palo Alto, CA; Lawrence J. Solin, Albert Einstein Healthcare Network, Philadelphia, PA; Mark R. Somerfield, American Society of Clinical Oncology, Alexandria, VA; and Timothy J. Whelan, Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada.

Purpose A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.
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http://dx.doi.org/10.1200/JCO.2016.69.1188DOI Listing
December 2016

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

Ann Surg Oncol 2017 Jan 19;24(1):38-51. Epub 2016 Sep 19.

Roswell Park Cancer Institute, Buffalo, NY, USA.

Purpose: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT).

Methods: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data.

Recommendations: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.
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http://dx.doi.org/10.1245/s10434-016-5558-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179596PMC
January 2017

Listeria monocytogenes wall teichoic acid decoration in virulence and cell-to-cell spread.

Mol Microbiol 2016 09 10;101(5):714-30. Epub 2016 Mar 10.

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27606, USA.

Wall teichoic acid (WTA) comprises a class of glycopolymers covalently attached to the peptidoglycan of gram positive bacteria. In Listeria monocytogenes, mutations that prevent addition of certain WTA decorating sugars are attenuating. However, the steps required for decoration and the pathogenic process interrupted are not well described. We systematically examined the requirement for WTA galactosylation in a mouse oral-virulent strain by first creating mutations in four genes whose products conferred resistance to a WTA-binding bacteriophage. WTA biochemical and structural studies indicated that galactosylated WTA was directly required for bacteriophage adsorption and that mutant WTA lacked appreciable galactose in all except one mutant - which retained a level ca. 7% of the parent. All mutants were profoundly attenuated in orally infected mice and were impaired in cell-to-cell spread in vitro. Confocal microscopy of cytosolic mutants revealed that all expressed ActA on their cell surface and formed actin tails with a frequency similar to the parent. However, the mutant tails were significantly shorter - suggesting a defect in actin based motility. Roles for the gene products in WTA galactosylation are proposed. Identification and interruption of WTA decoration pathways may provide a general strategy to discover non-antibiotic therapeutics for gram positive infections. © 2016 John Wiley & Sons Ltd.
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http://dx.doi.org/10.1111/mmi.13353DOI Listing
September 2016

Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.

J Clin Oncol 2013 Nov 7;31(31):3997-4013. Epub 2013 Oct 7.

Antonio C. Wolff, Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore; Lisa M. McShane, National Cancer Institute, Bethesda, MD; M. Elizabeth H. Hammond, University of Utah School of Medicine and Intermountain Healthcare, Salt Lake City, UT; David G. Hicks, University of Rochester Medical Center, Rochester, NY; Mitch Dowsett, Royal Marsden Hospital, London, United Kingdom; Kimberly H. Allison, Stanford University Medical Center, Stanford; Patrick Fitzgibbons, St Jude Medical Center, Fullerton; Michael F. Press, University of Southern California, Los Angeles, CA; Donald C. Allred, Washington University School of Medicine, St Louis, MO; John M.S. Bartlett, Ontario Institute for Cancer Research; Wedad Hanna, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada; Michael Bilous, University of Western Sydney and Healthscope Pathology, Sydney, New South Wales, Australia; Robert B. Jenkins, Mayo Clinic, Rochester, MN; Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA; Soonmyung Paik, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; Edith A. Perez, Mayo Clinic, Jacksonville, FL; Patricia A. Spears, North Carolina State University, Raleigh, NC; Gail H. Vance, Indiana University Medical Center, Indianapolis, IN; Giuseppe Viale, University of Milan, European Institute of Oncology, Milan, Italy; and Daniel F. Hayes, University of Michigan Comprehensive Cancer Care Center, Ann Arbor, MI.

Purpose: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.

Methods: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing.

Results: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations.

Recommendations: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. This guideline was developed through a collaboration between the American Society of Clinical Oncology and the College of American Pathologists and has been published jointly by invitation and consent in both Journal of Clinical Oncology and the Archives of Pathology & Laboratory Medicine.
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http://dx.doi.org/10.1200/JCO.2013.50.9984DOI Listing
November 2013

Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.

Arch Pathol Lab Med 2014 Feb 7;138(2):241-56. Epub 2013 Oct 7.

Antonio C. Wolff, Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore; Lisa M. McShane, National Cancer Institute, Bethesda, MD; M. Elizabeth H. Hammond, University of Utah School of Medicine and Intermountain Healthcare, Salt Lake City, UT; David G. Hicks, University of Rochester Medical Center, Rochester, NY; Mitch Dowsett, Royal Marsden Hospital, London, United Kingdom; Kimberly H. Allison, Stanford University Medical Center, Stanford; Patrick Fitzgibbons, St Jude Medical Center, Fullerton; Michael F. Press, University of Southern California, Los Angeles, CA; Donald C. Allred, Washington University School of Medicine, St Louis, MO; John M.S. Bartlett, Ontario Institute for Cancer Research; Wedad Hanna, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada; Michael Bilous, University of Western Sydney and Healthscope Pathology, Sydney, New South Wales, Australia; Robert B. Jenkins, Mayo Clinic, Rochester, MN; Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA; Soonmyung Paik, National Surgical Adjuvant Breast and Bowel Project, Pitsburgh, PA; Edith A. Perez, Mayo Clinic, Jacksonville, FL; Patricia A. Spears, North Carolina State University, Raleigh, NC; Gail H. Vance, Indiana University Medical Center, Indianapolis, IN; Giuseppe Viale, University of Milan, European Institute of Oncology, Milan, Italy; and Daniel F. Hayes, University of Michigan Comprehensive Cancer Care Center, Ann Arbor, MI.

Purpose: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.

Methods: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing.

Results: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations.

Recommendations: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.
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http://dx.doi.org/10.5858/arpa.2013-0953-SADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086638PMC
February 2014

Extrauterine listeriosis in the gravid mouse influences embryonic growth and development.

PLoS One 2013 14;8(8):e72601. Epub 2013 Aug 14.

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.

Gravid mice and other rodents inoculated with Listeria monocytogenes typically fail to clear an intrauterine infection and either succumb or expel their intrauterine contents. We took advantage of this property to investigate the effects of an extrauterine infection on parameters of pregnancy success. Pregnant mice were selected for our study if they showed no clinical signs of listeriosis following oral inoculation at 7.5 gestational days (gd), and had no detectable intrauterine colony forming units (cfu) at near term (18.5 gd). The range of oral doses employed was 10⁶-10⁸ cfu per mouse for two listerial serotype strains (4nonb and 1/2a). At all doses, inoculation resulted in a decrease in average near-term (18.5 gd) fetal weight per litter compared to sham inoculated controls. Additionally, embryonic death (indicated by intrauterine resorptions) was exhibited by some inoculated mice but was absent in all sham inoculated animals. In parallel experiments designed to detect possible loss of placental function, gravid uteruses were examined histopathologically and microbiologically 96 h after oral inoculation. Placental lesions were associated with high (> 10⁶), but not low (< 10²) or absent intrauterine cfu. In vitro, mouse embryonic trophoblasts were indistinguishable from mouse enterocytes in terms of their sensitivity to listerial exposure. A model consistent with our observations is one in which products (host or bacterial) generated during an acute infection enter embryos transplacentally and influences embryonic survival and slows normal growth in utero.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072601PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743821PMC
March 2014

In vitro properties of a Listeria monocytogenes bacteriophage-resistant mutant predict its efficacy as a live oral vaccine strain.

Infect Immun 2011 Dec 19;79(12):5001-9. Epub 2011 Sep 19.

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA.

A Listeria monocytogenes glcV mutation precludes the binding of certain listerial phages and produces a profound attenuation characterized by the absence of detectable mutants in the livers and spleens of orally inoculated mice. In vitro, we found that the mutant formed plaques on mouse enterocyte monolayers as efficiently as the parent but the plaques formed were smaller. Intracellular growth rate determinations and examination of infected enterocytes by light and fluorescence microscopy established that the mutant was impaired not in intracellular growth rate but in cell-to-cell spreading. Because this property is shared by other immunogenic mutants (e.g., actA mutants), our glcV mutant was tested for vaccine efficacy. Oral immunization with the mutant and subsequent oral challenge (22 days postvaccination) with the parent revealed a ca. 10,000-fold increase in protection afforded by the mutant compared to sham-vaccinated controls. The glcV mutant did not stimulate innate immunity under the dose and route employed for vaccination, and an infectivity index time course experiment revealed pronounced mutant persistence in Peyer's patches. The immunogenicity of the glcV mutant compared to an isogenic actA mutant reference strain was next tested in an experiment with a challenge given 52 days postvaccination. Both mutant strains showed scant vital organ infectivity and high levels of protection similar to those seen using the glcV mutant in the 22-day postvaccination challenge. Our results indicate that oral administration of a profoundly attenuated listerial mutant can safely elicit solid protective immunity.
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http://dx.doi.org/10.1128/IAI.05700-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232665PMC
December 2011

Factors associated with the acquisition and severity of gestational listeriosis.

PLoS One 2010 Sep 27;5(9):e13000. Epub 2010 Sep 27.

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.

Gravid mammals are more prone to listeriosis than their nongravid counterparts. However, many features of the disease in gravid animals are not well defined. We determined, in mice, that increased susceptibility to lethal infection following oral inoculation begins surprisingly early in pregnancy and extends through embryonic development. Pregnancy did not demonstrably increase the spread of listeriae from the intestine to the liver and spleen in the initial 96 h period post inoculation. Consequently, it appeared that gravid animals were competent to contain an enteric infection, but in those instances where escape did occur, a lethal outcome was more likely. Interestingly, colonic colonization level and prevalence, measured 96 h post inoculation, was significantly higher in gravid individuals. In terms of human risk factors for listeriosis, our results suggest that the window of listeriosis susceptibility afforded by pregnancy may be open longer than previously appreciated. Our results also suggest that while gravid animals are competent to contain an enteric infection, enteric carriage rate may be more of a factor in defining disease incidence than previously considered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013000PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946334PMC
September 2010

Adaptation in a mouse colony monoassociated with Escherichia coli K-12 for more than 1,000 days.

Appl Environ Microbiol 2010 Jul 14;76(14):4655-63. Epub 2010 May 14.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

Although mice associated with a single bacterial species have been used to provide a simple model for analysis of host-bacteria relationships, bacteria have been shown to display adaptability when grown in a variety of novel environments. In this study, changes associated with the host-bacterium relationship in mice monoassociated with Escherichia coli K-12 over a period of 1,031 days were evaluated. After 80 days, phenotypic diversification of E. coli was observed, with the colonizing bacteria having a broader distribution of growth rates in the laboratory than the parent E. coli. After 1,031 days, which included three generations of mice and an estimated 20,000 generations of E. coli, the initially homogeneous bacteria colonizing the mice had evolved to have widely different growth rates on agar, a potential decrease in tendency for spontaneous lysis in vivo, and an increased tendency for spontaneous lysis in vitro. Importantly, mice at the end of the experiment were colonized at an average density of bacteria that was more than 3-fold greater than mice colonized on day 80. Evaluation of selected isolates on day 1,031 revealed unique restriction endonuclease patterns and differences between isolates in expression of more than 10% of the proteins identified by two-dimensional electrophoresis, suggesting complex changes underlying the evolution of diversity during the experiment. These results suggest that monoassociated mice might be used as a tool for characterizing niches occupied by the intestinal flora and potentially as a method of targeting the evolution of bacteria for applications in biotechnology.
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http://dx.doi.org/10.1128/AEM.00358-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901717PMC
July 2010

Identification and characterization of two Bordetella avium gene products required for hemagglutination.

Infect Immun 2010 Jun 29;78(6):2370-6. Epub 2010 Mar 29.

James Madison University, Harrisonburg, Virginia 22807, USA.

Bordetella avium causes bordetellosis in birds, a disease similar to whooping cough caused by Bordetella pertussis in children. B. avium agglutinates guinea pig erythrocytes via an unknown mechanism. Loss of hemagglutination ability results in attenuation. We report the use of transposon mutagenesis to identify two genes required for hemagglutination. The genes (hagA and hagB) were adjacent and divergently oriented and had no orthologs in the genomes of other Bordetella species. Construction of in-frame, unmarked mutations in each gene allowed examination of the role of each in conferring erythrocyte agglutination, explanted tracheal cell adherence, and turkey poult tracheal colonization. In all of the in vitro and in vivo assays, the requirement for the trans-acting products of hagA and hagB (HagA and HagB) was readily shown. Western blotting, using antibodies to purified HagA and HagB, revealed proteins of the predicted sizes of HagA and HagB in an outer membrane-enriched fraction. Antiserum to HagB, but not HagA, blocked B. avium erythrocyte agglutination and explanted turkey tracheal ring binding. Bioinformatic analysis indicated the similarity of HagA and HagB to several two-component secretory apparatuses in which one product facilitates the exposition of the other. HagB has the potential to serve as a useful immunogen to protect turkeys against colonization and subsequent disease.
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http://dx.doi.org/10.1128/IAI.00140-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876549PMC
June 2010

A Listeria monocytogenes mutant defective in bacteriophage attachment is attenuated in orally inoculated mice and impaired in enterocyte intracellular growth.

Infect Immun 2008 Sep 16;76(9):4046-54. Epub 2008 Jun 16.

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA

A Listeria monocytogenes bacteriophage was used to identify a phage-resistant Tn917 insertion mutant of the mouse-virulent listerial strain F6214-1. The mutant was attenuated when it was inoculated orally into female A/J mice and failed to replicate efficiently in cultured mouse enterocytes. Phage binding studies indicated that the mutant had a cell surface alteration that precluded phage attachment. All phenotypes associated with the mutation could be complemented in trans by a single open reading frame (ORF) that corresponded to the ORF interrupted by the Tn917 insertion. The complementation effected was, in all cases, at a level indistinguishable from that of the parent. The Tn917 insertion interrupted a gene that is predicted to encode a group 2 glycosyl transferase (provisionally designated glcV). A similar glcV gene is present in Listeria welshimeri and Listeria innocua and in some serotypes of L. monocytogenes. We speculate that the loss of the glcV product results in a defective phage receptor and that this alteration coincidentally influences a feature of the normal host-pathogen interaction required for virulence. Interestingly, the glcV lesion, while preventing phage attachment, did not alter the mutant's ability to bind to cultured mouse enterocyte monolayers. Rather, the mutation appeared to alter a subsequent step in intracellular replication measured by a reduction in plaque-forming efficiency and plaque size. In vivo, the mutant was undetectable in the liver and spleen 48 h after oral inoculation. The mutation is significant in part because it is one of the few that produce attenuation when the mutant is delivered orally.
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http://dx.doi.org/10.1128/IAI.00283-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519439PMC
September 2008

Influence of pregnancy on the pathogenesis of listeriosis in mice inoculated intragastrically.

Infect Immun 2003 Sep;71(9):5202-9

College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA.

Pregnancy increases the risk of listeriosis, a systemic disease caused by Listeria monocytogenes. However, there is incomplete agreement on the reasons for this increased risk. We examined two features of listeriosis in gravid and nongravid female mice following intragastric (gavage) inoculation, namely, (i) disease severity (measured by lethality) and (ii) listerial infectivity (measured by liver and spleen colonization levels up to 120 h postinoculation). Two listerial strains of differing serotype (1/2a and 4nonb) were initially employed. Neither strain produced a lethal infection in nonpregnant female mice (dose range, 10(6) to 10(9) CFU/mouse), and only the 4nonb strain produced lethalities in pregnant mice (dose range, 10(6) to 10(8) CFU/mouse). The 4nonb strain also produced a higher level of liver and spleen colonization than the 1/2a strain following gavage administration. (The two strains showed similar levels of colonization if parenterally administered.) Both strains were equally capable of binding to and forming plaques upon cultured mouse enterocytes. The ability of the 4nonb strain to produce a lethal infection in pregnant animals did not correlate with an increased incidence or level of liver and spleen colonization over that in nonpregnant females. However, the lethality rate did correlate well with the rate at which embryos and their surrounding decidual covering became infected, suggesting that intrauterine infection could be responsible for the increased disease severity in the gravid females.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC187305PMC
http://dx.doi.org/10.1128/iai.71.9.5202-5209.2003DOI Listing
September 2003