Publications by authors named "Laura Wood"

290 Publications

Opposing roles of the immune system in tumors.

Science 2021 09 16;373(6561):1306-1307. Epub 2021 Sep 16.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1126/science.abl5376DOI Listing
September 2021

Insights into the origins of pancreatic cancer.

Nature 2021 Sep 15. Epub 2021 Sep 15.

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http://dx.doi.org/10.1038/d41586-021-02435-4DOI Listing
September 2021

International migration of unaccompanied minors: trends, health risks, and legal protection.

Lancet Child Adolesc Health 2021 Aug 17. Epub 2021 Aug 17.

Institute for Global Health, UCL, London, UK.

The global population of unaccompanied minors-children and adolescents younger than 18 years who migrate without their legal guardians-is increasing. However, as data are not systematically collected in any region, if collected at all, little is known about this diverse group of young people. Compared with adult migrants, unaccompanied minors are at greater risk of harm to their health and integrity because they do not have the protection provided by a family, which can affect their short-term and long-term health. This Review summarises evidence regarding the international migration and health of unaccompanied minors. Unaccompanied minors are entitled to protection that should follow their best interests as a primary consideration; however, detention, sometimes under the guise of protection, is a widespread practice. If these minors are provided with appropriate forms of protection, including health and psychosocial care, they can thrive and have good long-term outcomes. Instead, hostile immigration practices persist, which are not in the best interests of the child.
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http://dx.doi.org/10.1016/S2352-4642(21)00194-2DOI Listing
August 2021

Familial Adenomatous Polyposis-associated Traditional Serrated Adenoma of the Small Intestine: A Clinicopathologic and Molecular Analysis.

Am J Surg Pathol 2021 Jul 8. Epub 2021 Jul 8.

Department of Pathology, Johns Hopkins School of Medicine Department of Pathology, Sol Goldman Pancreatic Cancer Research Center Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University of Medicine, Baltimore, MD.

Familial adenomatous polyposis (FAP) is an inherited cancer predisposition syndrome associated with numerous gastrointestinal tract adenomatous polyps, as well as gastric fundic gland polyps and pyloric gland adenomas in the upper gastrointestinal tract. While colonic FAP-associated traditional serrated adenomas (TSAs) have been reported in a few studies, small bowel FAP-associated adenomas with TSA morphology have not been characterized. This study describes the clinicopathologic and molecular findings of this type of adenoma in the small bowel of patients with FAP. We reviewed small bowel adenomas in 45 consecutive FAP patients to identify adenomas with zones showing slit-like serrations, cells with eosinophilic cytoplasm, ectopic crypt formation, and vesicular nuclei. Sporadic small bowel adenomas from 51 consecutive patients were also reviewed for adenomas with the same features. Of the 177 polyps from 45 FAP patients and 60 polyps from 51 nonsyndromic patients, 18 TSAs from 9 FAP patients (20%) and 10 TSAs from the sporadic group (19.6%) were identified. FAP patients presented at a younger age than nonsyndromic patients (median: 43 vs. 66; P=0.0048). FAP-associated TSAs were asymptomatic and smaller than sporadic TSAs (median size: 0.6 vs. 2.5 cm; P=0.00006). Immunostaining for β-catenin and testing for BRAF and KRAS mutations were performed in a subset of the cohort. Nuclear β-catenin was seen in 1 FAP-associated TSA and 3 nonsyndromic TSAs. All TSAs (FAP-associated and nonsyndromic) showed wild-type BRAF, while KRAS mutations were identified only in the nonsyndromic setting. In summary, small bowel FAP-associated and sporadic TSAs share a similar morphology, and the BRAF-serrated pathway does not contribute to their pathogenesis.
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http://dx.doi.org/10.1097/PAS.0000000000001770DOI Listing
July 2021

Healthcare access for migrant children in England during the COVID-19 pandemic.

BMJ Paediatr Open 2020 16;4(1):e000705. Epub 2020 Jul 16.

Centre for the Health of Women, Children and Adolescents, Institute for Global Health, University College London, London, UK.

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http://dx.doi.org/10.1136/bmjpo-2020-000705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372171PMC
July 2020

Microperimetry Hill of Vision and Volumetric Measures of Retinal Sensitivity.

Transl Vis Sci Technol 2021 06;10(7):12

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford Biomedical Research Centre, Oxford, UK.

Purpose: Mean retinal sensitivity is the main output measure used in microperimetry. It is, however, of limited use in patients with poor vision because averaging is weighted toward zero in those with significant scotomas creating an artificial floor effect. In contrast, volumetric measures avoid these issues and are displayed graphically as a hill of vision.

Methods: An open-source program was created to manipulate raw sensitivity threshold data files obtained from MAIA microperimetry. Thin plate spline interpolated heat maps and three-dimensional hill of vision plots with an associated volume were generated. Retrospective analyses of microperimetry volumes were undertaken in patients with a range of retinal diseases to assess the qualitative benefits of three-dimensional visualization and volumetric measures. Simulated pathology was applied to radial grid patterns to investigate the performance of volumetric sensitivity in nonuniform grids.

Results: Volumetric analyses from microperimetry in RPGR-related retinitis pigmentosa, choroideremia, Stargardt disease, and age-related macular degeneration were analyzed. In simulated nonuniform testing grids, volumetric sensitivity was able to detect differences in retinal sensitivity where mean sensitivity could not.

Conclusions: Volumetric measures do not suffer from averaging issues and demonstrate superior performance in nonuniform testing grids. Additionally, volume measures enable detection of localized retinal sensitivity changes that might otherwise be undetectable in a mean change.

Translational Relevance: As microperimetry has become an outcome measure in several gene-therapy clinical trials, three-dimensional visualization and volumetric sensitivity enables a complementary analysis of baseline disease characteristics and subsequent response to treatment, both as a signal of safety and efficacy.
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http://dx.doi.org/10.1167/tvst.10.7.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196404PMC
June 2021

Early detection of pancreatic cancer using DNA-based molecular approaches.

Nat Rev Gastroenterol Hepatol 2021 07 7;18(7):457-468. Epub 2021 Jun 7.

Departments of Pathology & Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Due to its poor prognosis and the late stage at which it is typically diagnosed, early detection of pancreatic cancer is a pressing clinical problem. Advances in genomic analysis of human pancreatic tissue and other biospecimens such as pancreatic cyst fluid, pancreatic juice and blood have opened the possibility of DNA-based molecular approaches for early detection of pancreatic cancer. In this Review, we discuss and focus on the pathological and molecular features of precancerous lesions of the pancreas, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, which are target lesions of early detection approaches. We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. We highlight the latest discoveries related to genetic heterogeneity and multifocal neoplasia in precancerous lesions. In addition, we review specific approaches, challenges and clinically available assays for early detection of pancreatic cancer using DNA-based molecular techniques. Although detection and risk stratification of precancerous pancreatic neoplasms are difficult problems, progress in this field highlights the promise of molecular approaches for improving survival of patients with this disease.
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http://dx.doi.org/10.1038/s41575-021-00470-0DOI Listing
July 2021

Pathology of intraductal papillary mucinous neoplasms.

Langenbecks Arch Surg 2021 May 28. Epub 2021 May 28.

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21212, USA.

Background: Intraductal papillary mucinous neoplasms (IPMNs) represent a unique opportunity to treat and prevent a curable neoplasm before it has the chance to progress to incurable cancer. This prospect, however, has to be balanced with the real risk of over treating patients with lesions that would, in fact, never progress during the life of the patient.

Purpose: Informed clinical decisions in the treatment of IPMNs are first and foremost based on a deep understanding of the pathology of these lesions.

Conclusions: Here we review the pathology of IPMNs, with an emphasis on the clinical relevance of the important features that characterize these lesions.
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http://dx.doi.org/10.1007/s00423-021-02201-0DOI Listing
May 2021

Cell of Origin Influences Pancreatic Cancer Subtype.

Cancer Discov 2021 03;11(3):660-677

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, California.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell-derived and acinar cell-derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution. SIGNIFICANCE: Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134763PMC
March 2021

Low Luminance Visual Acuity and Low Luminance Deficit in Choroideremia and RPGR-Associated Retinitis Pigmentosa.

Transl Vis Sci Technol 2021 02;10(2):28

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Introduction: Choroideremia and RPGR-associated retinitis pigmentosa (RP) are two distinct inherited rod-cone degenerations, where good visual acuity (VA) is maintained until late disease stages, limiting its usefulness as a disease marker. Low luminance VA and low luminance deficit (standard VA minus low luminance VA) may be more sensitive visual function measures.

Methods: Standard VA was obtained using Early Treatment Diabetic Retinopathy Study letter charts (Precision Vision, Bloomington, IL, USA). Low luminance VA was assessed using a 2.0-log unit neutral density filter, with the same chart setup, without formal dark adaptation. Mean central retinal sensitivity was assessed using MAIA microperimetry (Centervue SpA, Padova, Italy). Optical coherence tomography imaging was attained with Heidelberg Eye Explorer software (Heidelberg Engineering, Heidelberg, Germany).

Results: Twenty-four male participants with confirmed pathogenic RPGR mutations, 44 male participants with confirmed pathogenic CHM mutations, and 62 age-matched controls underwent clinical assessment prior to clinical trial recruitment. Low luminance VA was significantly reduced in both disease groups compared to controls. The low luminance deficit correlated with microperimetry retinal sensitivity and ellipsoid zone width. Eleven participants with moderate VA had poor low luminance VA (subsequently a large low luminance deficit), no detectable microperimetry sensitivity, and severely constricted ellipsoid zone widths.

Conclusions: Low luminance VA and subsequently low luminance deficit are useful markers of central macular visual function in both choroideremia and RPGR-associated RP, when standard VA is preserved.

Translational Relevance: Low luminance visual acuity and low luminance deficit are useful vision measures in two distinct rod-cone degenerations and may be useful in other retinal degenerations.
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http://dx.doi.org/10.1167/tvst.10.2.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900861PMC
February 2021

The Dual Epidemics of 2020: Nursing Leaders' Reflections in the Context of Whole Person/Whole Systems.

Nurs Adm Q 2021 Jul-Sep 01;45(3):243-252

Rutgers Cancer Institute of New Jersey & RWJBH Oncology Services, and Rutgers School of Nursing, New Brunswick, New Jersey (Dr Hayes); Boston Children's Hospital, Boston, Massachusetts (Dr Wood); Boston Medical Center, Boston, Massachusetts (Dr Gaden); William F. Connell School of Nursing, Boston College, Chestnut Hill, Massachusetts (Dr Gennaro); Dana-Farber Cancer Institute, Boston, Massachusetts (Dr Gross); Tufts Medical Center and Tufts Children's Hospital, and Tufts Medical School, Boston, Massachusetts (Ms Hudson-Jinks); Brigham and Women's Faulkner Hospital, Boston, Massachusetts (Ms Loescher); Beth Israel Deaconess Medical Center, Boston, Massachusetts (Dr Maurer); Mittelman Family Foundation, Boston, Massachusetts (Ms Mittelman); Brigham and Women's Hospital, Boston, Massachusetts (Dr Pearson); College of Natural, Behavioral, and Health Sciences, Simmons University, Boston, Massachusetts (Dr Sharp-McHenry); College of Nursing and Health Sciences, University of Massachusetts Boston, Boston (Dr Thompson); and School of Nursing, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts (Dr Van Pelt).

The Greater Boston Nursing Collective, a consortium composed of university nursing deans and chief nursing officers within academic medical centers and specialty hospitals in Boston, Massachusetts, was formed in 2014. Since the group's inception, our mission has been to create and reinforce whole-person/whole-system healing environments to improve the health of all communities. Through our collaboration in navigating the dual epidemics of COVID-19 and structural racism within our respective organizations, and across the United States and the world, we share experiences and lessons learned. Our common mission is clearer than ever: to create safe and joyful work environments, to protect the dignity of those we are privileged to serve, and to generate policies to advance health equity to rectify societal forces that have shaped this dual epidemic. We are humbled by the many who persist despite limited rest and respite, and whose stories, innovations, and leadership we are honored to witness and share. They have defined our generation, just as nurses in earlier crises have done: leading through service to others as our purpose and privilege.
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http://dx.doi.org/10.1097/NAQ.0000000000000475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168929PMC
June 2021

Organoids in cancer research: a review for pathologist-scientists.

J Pathol 2021 Jul 19;254(4):395-404. Epub 2021 May 19.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

The use of three-dimensional (3D) culture models for cancer research has expanded greatly in recent years, with studies in almost every tumor type addressing a wide variety of research questions. Multiple distinct 3D culture approaches are now available, each with its own advantages and disadvantages, as well as most effective applications. In this review, we focus on one of these 3D culture models, organoids, in which multicellular units are isolated from primary or metastatic tumors and cultured in extracellular matrix gels. Organoids can be studied in acute cultures for short times after isolation, or passaged and biobanked for long-term use. We define this model system and describe some key studies in which organoid culture models were used to investigate cellular strategies and molecular mechanisms driving cancer initiation and progression, highlighting research questions for which this model is particularly well suited. In addition, as interest in implementing organoid systems continues to expand, we discuss key considerations in developing a new organoid research program. Our goal is to demonstrate the power and utility of organoid models and provide guidance for investigators who are considering implementation of these models in their own research programs. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5684DOI Listing
July 2021

Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis.

J Pathol 2021 Jul 21;254(3):279-288. Epub 2021 May 21.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Epigenetic alterations are increasingly recognized as important contributors to the development and progression of pancreatic ductal adenocarcinoma. 5-hydroxymethylcytosine (5hmC) is an epigenetic DNA mark generated through the ten-eleven translocation (TET) enzyme-mediated pathway and is closely linked to gene activation. However, the timing of alterations in epigenetic regulation in the progression of pancreatic neoplasia is not well understood. In this study, we hypothesized that aberrant expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) and subsequent global 5hmC alteration are linked to early tumorigenesis in the pancreas. Therefore, we evaluated alterations of 5hmC and TET1 levels using immunohistochemistry in pancreatic neoplasms (n = 380) and normal ducts (n = 118). The study cohort included representation of the full spectrum of precancerous lesions from low- and high-grade pancreatic intraepithelial neoplasia (n = 95), intraductal papillary mucinous neoplasms (all subtypes, n = 129), intraductal oncocytic papillary neoplasms (n = 12), and mucinous cystic neoplasms (n = 144). 5hmC and TET1 were significantly downregulated in all types of precancerous lesion and associated invasive pancreatic ductal adenocarcinomas compared with normal ductal epithelium (all p < 0.001), and expression of 5hmC positively correlated with expression of TET1. Importantly, downregulation of both 5hmC and TET1 was observed in most low-grade precancerous lesions. There were no clear associations between 5hmC levels and clinicopathological factors, thereby suggesting a common epigenetic abnormality across precancerous lesions. We conclude that downregulation of 5hmC and TET1 is an early event in pancreatic tumorigenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5682DOI Listing
July 2021

Clinical applications of microperimetry in RPGR-related retinitis pigmentosa: a review.

Acta Ophthalmol 2021 Mar 29. Epub 2021 Mar 29.

Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.

Microperimetry, or fundus-tracked perimetry, is a precise static-automated perimetric technique to assess central retinal function. As visual acuity only deteriorates at a late disease stage in RPGR-related retinitis pigmentosa (RP), alternative markers for disease progression are of great utility. Microperimetry assessment has been of critical value as an outcome measure in a recently reported phase I/II gene therapy trial for RPGR-related RP, both in terms of detecting safety and efficacy signals. Here, we performed a review of the literature. We describe the principles of microperimetry before outlining specific parameters that may be useful as outcome measures in clinical trial settings. The current state of structure-function correlations between short-wavelength autofluorescence, optical coherence tomography and adaptive optics in RPGR-related retinitis pigmentosa are also summarized.
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http://dx.doi.org/10.1111/aos.14816DOI Listing
March 2021

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Laboratory Reference Ranges and Testing Intervals Work Group.

Clin Cancer Res 2021 May 9;27(9):2416-2423. Epub 2021 Feb 9.

Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population.

Experimental Design: Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation.

Results: In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria.

Conclusions: Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102342PMC
May 2021

Pancreatic cancer pathology viewed in the light of evolution.

Cancer Metastasis Rev 2021 Feb 8. Epub 2021 Feb 8.

Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA.

One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This "evolutionary view" creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.
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http://dx.doi.org/10.1007/s10555-020-09953-zDOI Listing
February 2021

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review.

Ophthalmic Physiol Opt 2021 03 6;41(2):213-223. Epub 2021 Jan 6.

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Purpose: The measurement of standard visual acuity (VA) is the most well-known part of any ophthalmic examination to indicate visual function. Despite this, it is insensitive in detecting early disease changes. Therefore, other visual function tests have been developed including low luminance VA (LLVA) and low luminance deficit (LLD). This scoping literature review aims to summarise the current published applications of LLVA and LLD assessments to evaluate their utility as clinical markers and research outcome measures in a variety of ophthalmic conditions.

Recent Findings: Sixty-five peer-reviewed publications were included. LLVA was pioneered for use in geographic atrophy, a subtype of age-related macular degeneration, which remains the mainstay of its clinical application. However, other studies have reported additional useful applications in inherited retinal diseases including rare maculopathies and rod-cone dystrophies. Although there are some variations in testing methodology, use of the standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter is the most popular approach. The optimal testing luminance is still to be defined.

Summary: Overall, LLVA is an earlier clinical marker of change in central retinal function than standard VA. It has been shown to be a risk factor for disease progression and a better indicator of a patient's level of everyday visual function. It is inexpensive and simple to implement using readily available standard ophthalmic equipment.
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http://dx.doi.org/10.1111/opo.12775DOI Listing
March 2021

Implementing a human factors approach to RCA : Tools, processes and strategies.

J Healthc Risk Manag 2021 Jul 19;41(1):31-46. Epub 2020 Dec 19.

Department of Human Factors and Behavioral Neurobiology, Embry-Riddle Aeronautical University, Daytona Beach, FL, 32115, USA.

Root Cause Analysis and Action (RCA ) guidelines offer fundamental improvements to traditional RCA. Yet, these guidelines lack robust methods to support a human factors analysis of patient harm events and development of systems-level interventions. We recently integrated a complement of human factors tools into the RCA process to address this gap. These tools include the Human Factors Analysis and Classification System (HFACS), the Human Factors Intervention Matrix (HFIX), and a multiple-criterion decision tool called FACES, for selecting effective HFIX solutions. We describe each of these tools and illustrate how they can be integrated into RCA to create a robust human factors RCA process called HFACS-RCA . We also present qualitative results from an 18-month implementation study within a large academic health center. Results demonstrate how HFACS-RCA can foster a more comprehensive, human factors analysis of serious patient harm events and the identification of broader system interventions. Following HFACS-RCA implementation, RCA team members (risk managers and quality improvement advisors) also experienced greater satisfaction in their work, leadership gained more trust in RCA findings and recommendations, and the transparency of the RCA process increased. Effective strategies for overcoming implementation barriers, including changes in roles, responsibilities and workload will also be presented.
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http://dx.doi.org/10.1002/jhrm.21454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213862PMC
July 2021

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture.

Am J Surg Pathol 2020 Dec 4. Epub 2020 Dec 4.

Department of Pathology, The University of Pittsburgh, Pittsburgh, PA.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.
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http://dx.doi.org/10.1097/PAS.0000000000001637DOI Listing
December 2020

Desmin and CD31 immunolabeling for detecting venous invasion of the pancreatobiliary tract cancers.

PLoS One 2020 30;15(11):e0242571. Epub 2020 Nov 30.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Although venous invasion (VI) is a poor prognostic factor for patients with pancreatobiliary tract cancers, its histopathologic characteristics have not been well described. We evaluated the patterns of VI and the added benefit provided by CD31, desmin, and dual CD31‒desmin immunolabeling for identification of VI. We included 120 surgically resected pancreatobiliary tract cancer cases-59 cases as a test set with known VI and 61 cases as a validation set without information of VI. VI was classified into three patterns: intraepithelial neoplasia-like (IN-like), conventional, and destructive. Hematoxylin and eosin (H&E) staining and CD31, desmin, and dual CD31‒desmin immunolabeling were performed. Foci number and patterns of VI were compared with the test and validation sets. More foci of VI were detected by single CD31 (P = 0.022) than H&E staining in the test set. CD31 immunolabeling detected more foci of the conventional pattern of VI, and desmin immunolabeling detected more foci of the destructive pattern (all, P < 0.001). Dual CD31‒desmin immunolabeling identified more foci of VI (P = 0.012) and specifically detected more foci of IN-like (P = 0.045) and destructive patterns (P < 0.001) than H&E staining in the validation set. However, dual CD31‒desmin immunolabeling was not helpful for detecting the conventional pattern of VI in the validation set. Patients with VI detected by dual CD31‒desmin immunolabeling had shorter disease-free survival (P <0.001) than those without VI. VI detected by dual CD31‒desmin immunolabeling was a worse prognostic indicator (P = 0.009). More foci of VI could be detected with additional single CD31 or dual CD31‒desmin immunolabeling. The precise evaluation of VI with dual CD31‒desmin immunolabeling can provide additional prognostic information for patients with surgically resected pancreatobiliary tract cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242571PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703967PMC
January 2021

The Impact of Clinical and Pathological Features on Intraductal Papillary Mucinous Neoplasm Recurrence After Surgical Resection: Long-Term Follow-Up Analysis.

Ann Surg 2020 Nov 17. Epub 2020 Nov 17.

Department of Surgery, Hepatobiliary and Pancreatic Surgery Section of the Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, MD.

Objective: This study aimed to identify risk factors for recurrence after pancreatic resection for intraductal papillary mucinous neoplasm (IPMN).

Summary Background Data: Long-term follow-up data on recurrence after surgical resection for IPMN are currently lacking. Previous studies have presented mixed results on the role of margin status in risk of recurrence after surgical resection.

Methods: A total of 126 patients that underwent resection for noninvasive IPMN were followed for a median of 9.5 years. Dedicated pathological and radiological reviews were performed to correlate clinical and pathological features (including detailed pathological features of the parenchymal margin) with recurrence after surgical resection. In addition, in a subset of 32 patients with positive margins, we determined the relationship between the margin and original IPMN using driver gene mutations identified by next-generation sequencing.

Results: Family history of pancreatic cancer and high-grade IPMN was identified as risk factors for recurrence in both uni- and multivariate analysis (adjusted hazard ratio 3.05 and 1.88, respectively). Although positive margin was not significantly associated with recurrence in our cohort, the size and grade of the dysplastic focus at the margin were significantly correlated with recurrence in margin-positive patients. Genetic analyses showed that the neoplastic epithelium at the margin was independent from the original IPMN in at least 9 of 32 cases (28%). The majority of recurrences (74%) occurred after 3 years, and a significant minority (32%) occurred after 5 years.

Conclusion: Sustained postoperative surveillance for all patients is indicated, particularly those with risk factors such has family history and high-grade dysplasia.
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http://dx.doi.org/10.1097/SLA.0000000000004427DOI Listing
November 2020

Dual diagnosis theater: A pilot drama therapy program for individuals with serious mental illness and substance use disorder.

Schizophr Res 2021 04 12;230:95-97. Epub 2020 Nov 12.

UMass Memorial Health Care/University of Massachusetts Medical School, 55 N Lake Ave, Worcester, MA 01655, United States. Electronic address:

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http://dx.doi.org/10.1016/j.schres.2020.11.008DOI Listing
April 2021

Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic mutations predominantly in low-grade regions.

Gut 2021 May 7;70(5):928-939. Epub 2020 Oct 7.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Objective: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression.

Design: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples.

Results: Our multiregion whole exome sequencing identified , a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs.

Conclusion: Hotspot mutations in occur at high prevalence in IPMNs. Unique among pancreatic driver genes, mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.
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http://dx.doi.org/10.1136/gutjnl-2020-321217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262510PMC
May 2021

Gastric cancer following pancreaticoduodenectomy: Experience from a high-volume center and review of existing literature.

Surg Open Sci 2020 Oct 16;2(4):32-40. Epub 2020 Aug 16.

Johns Hopkins Hospital, Department of Surgery, Hepatobiliary and Pancreatic Surgery Section of the Division of Surgical Oncology, Baltimore, MD, USA.

Background: Prolonged survival of patients after pancreaticoduodenectomy can be associated with late complications due to altered gastrointestinal anatomy. The incidence of gastric cancer is increasingly reported. We set out to examine our experience with gastric cancer as a late complication after pancreaticoduodenectomy with a focus on incidence, risk factors, and outcomes.

Methods: We queried our prospectively collected institutional database for patients that developed gastric cancer after pancreaticoduodenectomy and conducted a systematic review of the literature.

Results: Our database revealed 6 patients who developed gastric cancer following pancreaticoduodenectomy, presenting with a mean age of 62.2 years and an even sex distribution. All of those patients underwent pancreaticoduodenectomy for malignant indications with an average time to development of metachronous gastric cancer of 8.3 years. Four patients complained of gastrointestinal discomfort prior to diagnosis of secondary malignancy. All of these cancers were poorly differentiated and were discovered at an advanced T stage (≥ 3). Only half developed at the gastrointestinal anastomosis. Four underwent surgery with a curative intent, and 2 patients are currently alive (mean postgastrectomy survival = 25.5 months). In accordance with previous literature, biliopancreatic reflux from pancreaticoduodenectomy reconstruction, underlying genetic susceptibility, and adjuvant therapy may play a causative role in later development of gastric cancer.

Conclusion: Long-term survivors after pancreaticoduodenectomy who develop nonspecific gastrointestinal complaints should be evaluated carefully for complications including gastric malignancy. This may serve as an opportunity to intervene on tumors that typically present at an advanced stage and with aggressive histology.
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http://dx.doi.org/10.1016/j.sopen.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486455PMC
October 2020

The Critical Role of the Oncology Nurse as a Partner in the Management of Patients With Advanced Kidney Cancer: Toxicity Management, Symptom Control, and Palliative Care.

Cancer J 2020 Sep/Oct;26(5):460-463

The treatment of advanced renal cell carcinoma has changed dramatically since 2005 with the approval of 12 regimens including oral, intravenous, and combination strategies. These approvals have changed the treatment paradigm for these patients and developed new challenges and a critical role for oncology nurses to ensure that the treatment plan and adverse events are managed effectively. The majority of these regimens include an oral anticancer drug, which requires patients and their caregivers to understand the medication, the potential adverse events, the importance of medicine adherence, and the importance of early and ongoing education with the oncology team to maximize clinical outcomes. The evolution of the role of the nurse in meeting this need and its critical contribution to the comprehensive care of the kidney cancer patient will be reviewed.
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http://dx.doi.org/10.1097/PPO.0000000000000476DOI Listing
September 2021

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma.

Clin Genitourin Cancer 2020 12 5;18(6):429-435. Epub 2019 Dec 5.

Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Introduction: Ipilimumab plus nivolumab has been approved for intermediate- and poor-risk metastatic renal cell carcinoma (RCC). However, the activity in non-clear cell RCC (nccRCC) is unknown.

Patients And Methods: Patients from Cleveland Clinic and the University of Texas Southwestern who had received ipilimumab plus nivolumab for metastatic nccRCC from October 2017 to May 2019 were retrospectively identified. Ipilimumab plus nivolumab was administered in accordance with the CHECKMATE 214 trial. Imaging was obtained at baseline and every 12 weeks. The baseline patient characteristics, objective response per Response Evaluation Criteria in Solid Tumors, version 1.1, and treatment-related adverse events (TRAEs) per Common Terminology Criteria for Adverse Events, version 5.0, were analyzed.

Results: Eighteen patients were identified. The median age was 59 years (range, 32-81 years), 77.8% were men, and the Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (50%). The median treatment duration was 2.4 months (range, 0.7-12.3 months). The non-clear cell histologic types included 6 papillary, 5 chromophobe, 3 unclassified, 2 adenocarcinoma of renal origin, 1 translocation, and 1 medullary. Most had an intermediate (66%) or poor (22%) International Metastatic Database Consortium risk. The best objective response included 6 partial responses (PRs; 33.3%) and 3 with stable disease (16.7%). Of the patients with a PR, the median time to the best response was 3.0 months, and median duration of the PR was 4.3 months. The median progression-free survival was 7.1 months. All-grade TRAEs were noted in 11 patients (61.1%) and included colitis (22%), hepatotoxicity (16%), rash (11%), and fatigue (11%). Eleven patients (61%) had TRAEs requiring high-dose glucocorticoids (> 40 mg of prednisone equivalent daily).

Conclusions: Ipilimumab plus nivolumab demonstrated objective responses and notable toxicity in patients with nccRCC.
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http://dx.doi.org/10.1016/j.clgc.2019.11.012DOI Listing
December 2020

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Service de Pathologie, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
August 2020

Binocular Visual Function in a Pre-Presbyopic Patient with Uniocular Cataract Undergoing Cataract Surgery with a Multifocal Intraocular Lens.

Clin Ophthalmol 2020 16;14:2001-2009. Epub 2020 Jul 16.

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Background/aim: An increasing number of pre-presbyopic patients are undergoing uniocular cataract extraction. We aim to compare the binocular status of subjects with uniocular cataracts, implanted either with a multifocal or a monofocal intraocular lens (IOL).

Materials And Methods: Subjects were recruited from outpatient ophthalmology clinics and randomized to an IOL type. Corrected and uncorrected LogMAR distance visual acuity (VA) and near and intermediate VA using the Radner reading test were completed. The binocular tests included the Worth Four Dot Test, fixation disparity, TNO stereoacuity and foveal suppression assessment. In addition to the near activity vision questionnaire. The trial was closed early because the chosen multifocal lens had been superseded by newer models. We report two subjects, one receiving the multifocal IOL and a monofocal IOL control with the most comparable baseline characteristics.

Results: Both subjects experienced uncomplicated cataract surgery, showing clinically significant improved corrected distance VA, 0.06 LogMAR and -0.16 LogMAR in the monofocal and multifocal IOL, respectively. The multifocal subject had 30 seconds of arc stereoacuity indicating normal binocular vision. Only gross binocular single vision with no stereopsis was found in the monofocal IOL subject. The latter subject also had reduced near vision quality-of-life questionnaire results.

Conclusion: This two-patient case series demonstrates greater binocular near ability, with the multifocal IOL, in the pre-presbyopic patient undergoing uniocular cataract surgery. The case series highlights the need, and methodology for investigating further the functional and quality-of-life benefits of implanting multifocal IOLs in pre-presbyopic patients, those in their twenties and thirties, undergoing uniocular cataract surgery.
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http://dx.doi.org/10.2147/OPTH.S254532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371563PMC
July 2020

A nontargeted approach to determine the authenticity of Ginkgo biloba L. plant materials and dried leaf extracts by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and chemometrics.

Anal Bioanal Chem 2020 Oct 5;412(25):6969-6982. Epub 2020 Aug 5.

National Institute of Metrology, Quality and Technology (INMETRO), Xerém, Duque de Caxias, RJ, 25250-020, Brazil.

The lack of stringent regulations regarding raw materials for herbal supplements used for medicinal purposes has been a constant challenge in the industry. Ginkgo biloba L. leaf extracts attract consumers because of the supposed positive effect on mental performance and memory. Supplements are produced using dried leaf materials and standardized leaf extracts such as EGb 761. Adulteration of Ginkgo biloba L. plants and extracts are becoming more and more common practice due to economically driven motivation from increasing demand in the market and the high cost of raw materials and production. Reinforcement in quality control (QC) to avoid adulterations is necessary to ensure the efficacy of the supplements. In this study, liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was used with principal component analysis (PCA) as an unsupervised exploratory method to analyze, identify, and evaluate the adulterated Ginkgo biloba L. plant materials and dried leaf extracts using the PCA scores and loadings obtained and compound identification.
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http://dx.doi.org/10.1007/s00216-020-02830-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953348PMC
October 2020

The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go.

Mod Pathol 2020 12 23;33(12):2544-2563. Epub 2020 Jul 23.

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The publication of the "Pan-Cancer Atlas" by the Pan-Cancer Analysis of Whole Genomes Consortium, a partnership formed by The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), provides a wonderful opportunity to reflect on where we stand in our understanding of the genetics of pancreatic cancer, as well as on the opportunities to translate this understanding to patient care. From germline variants that predispose to the development of pancreatic cancer, to somatic mutations that are therapeutically targetable, genetics is now providing hope, where there once was no hope, for those diagnosed with pancreatic cancer.
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http://dx.doi.org/10.1038/s41379-020-0629-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375585PMC
December 2020
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