Publications by authors named "Wesley Y Naritoku"

20 Publications

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ACGME Milestones 2.0: why and what's new for cytopathology?

J Am Soc Cytopathol 2021 May 24. Epub 2021 May 24.

Department of Clinical Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California.

Background: Primary stakeholders in the Accreditation Council for Graduate Medical Education (ACGME) Milestones Project are: ACGME, Residency Programs, Residents, Fellowship Programs, Fellows, and Certification Boards. The intent of the Milestones is to describe the educational and professional developmental trajectory of a trainee from the first stages of their postgraduate education through the completion of their clinical training. The Milestones 2.0 project includes changes made based on experience with Milestones 1.0.

Methods: The ACGME solicited volunteers to participate in the development of subspecialty Milestones 2.0. The workgroup was charged with reviewing/making any additions to the four "Harmonized Milestones", developing subspecialty specific milestones for the Patient Care and Medical Knowledge competencies, and creating a supplemental guide. The Milestones were finalized following review of input from an open comment period.

Results: The Cytopathology Milestones 2.0 will go into effect July 2021. They include additional subcompetencies in the 4 harmonized competency areas and cytopathology-specific edits to the patient care and medical knowledge subcompetencies. Although the number of subcompetencies has increased from 18 to 21, within each subcompetency, the number of milestone trajectories has decreased. Additionally, within each subcompetency, the wording has been streamlined. A supplemental guide was created and Milestones 1.0 were compared to 2.0; however, curriculum mapping has been left to programs to develop.

Conclusions: The ultimate goal of the Cytopathology Milestones 2.0 is to provide better real-time documentation of the progress of cytopathology fellows. The expected outcome is to produce highly competent cytopathologists, improving the care they provide, regardless of the program at which they trained.
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http://dx.doi.org/10.1016/j.jasc.2021.04.003DOI Listing
May 2021

Entry of Graduates of US Pathology Residency Programs Into the Workforce: Cohort Data Between 2008 and 2016 Remain Positive and Stable.

Acad Pathol 2020 Jan-Dec;7:2374289520901833. Epub 2020 Feb 6.

The Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.

The pathologist workforce in the United States is a topic of interest to the health-care community as a whole and to institutions responsible for the training of new pathologists in particular. Although a pathologist shortage has been projected, there has been a pervasive belief by medical students and their advisors that there are "no jobs in pathology." In 2013 and again in 2017, the Program Directors Section of the Association of Pathology Chairs conducted surveys asking pathology residency directors to report the employment status of each of their residents graduating in the previous 5 years. The 2013 Program Directors Section survey indicated that 92% of those graduating in 2010 had obtained employment within 3 years, and 94% of residents graduating in 2008 obtained employment within 5 years. The 2017 survey indicated that 96% of those graduating in 2014 had obtained employment in 3 years, and 97% of residents graduating in 2012 obtained positions within 5 years. These findings are consistent with residents doing 1 or 2 years of fellowship before obtaining employment. Stratification of the data by regions of the country or by the size of the residency programs does not show large differences. The data also indicate a high percentage of employment for graduates of pathology residency programs and a stable job market over the years covered by the surveys.
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http://dx.doi.org/10.1177/2374289520901833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005983PMC
February 2020

Report and Recommendations of the Association of Pathology Chairs' Autopsy Working Group.

Acad Pathol 2018 Jan-Dec;5:2374289518793988. Epub 2018 Aug 30.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Autopsy has been a foundation of pathology training for many years, but hospital autopsy rates are notoriously low. At the 2014 meeting of the Association of Pathology Chairs, some pathologists suggested removing autopsy from the training curriculum of pathology residents to provide additional months for training in newer disciplines, such as molecular genetics and informatics. At the same time, the American Board of Pathology received complaints that newly hired pathologists recently certified in anatomic pathology are unable to perform an autopsy when called upon to do so. In response to a call to abolish autopsy from pathology training on the one hand and for more rigorous autopsy training on the other, the Association of Pathology Chairs formed the Autopsy Working Group to examine the role of autopsy in pathology residency training. After 2 years of research and deliberation, the Autopsy Working Group recommends the following:Autopsy should remain a component of anatomic pathology training.A training program must have an autopsy service director with defined responsibilities, including accountability to the program director to record every autopsy performed by every resident.Specific entrustable activities should be defined that a resident must master in order to be deemed competent in autopsy practice, as well as criteria for gaining the trust to perform the tasks without direct supervision.Technical standardization of autopsy performance and reporting must be improved.The current minimum number of 50 autopsies should not be reduced until the changes recommended above have been implemented.
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http://dx.doi.org/10.1177/2374289518793988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117865PMC
August 2018

Evolution of the Pathology Residency Curriculum: Preparing for a Positive Future.

Acad Pathol 2016 Jan-Dec;3:2374289516667746. Epub 2016 Oct 5.

Department of Pathology, Harvard Medical School, Massachusetts General Hospital Boston, MA, USA.

The required medical knowledge and skill set for the pathologist of 2020 are different than in 2005. Pathology residency training curriculum must accordingly change to fulfill the needs of these ever-changing requirements. In order to make rational curricular adjustments, it is important for us to know the current trajectory of resident training in pathology-where we have been, what our actual current training curriculum is now-to understand how that might change in anticipation of meeting the needs of a changing patient and provider population and to fit within the evolving future biomedical and socioeconomic health-care setting. In 2013, there were 143 Accreditation Council for Graduate Medical Education-accredited pathology residency training programs in the United States, with approximately 2400 residents. There is diversity among residency training programs not only with respect to the number of residents but also in training venue(s). To characterize this diversity among pathology residency training programs, a curriculum survey was conducted of pathology residency program directors in 2013 and compared with a similar survey taken almost 9 years previously in 2005 to identify trends in pathology residency curriculum. Clinical pathology has not changed significantly in the number of rotations over 9 years; however, anatomic pathology has changed dramatically, with an increase in the number of surgical pathology rotations coupled with a decline in stand-alone autopsy rotations. With ever-expanding medical knowledge that the graduating pathology resident must know, it is necessary to (1) reflect upon what are the critical need subjects, (2) identify areas that have become of lesser importance, and then (3) prioritize training accordingly.
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http://dx.doi.org/10.1177/2374289516667746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497861PMC
October 2016

The Pathologist Pipeline: Implications of Changes for Programs and Post-Sophomore Fellowships-Program Directors' Section Perspective.

Acad Pathol 2016 Jan-Dec;3:2374289516646117. Epub 2016 May 11.

Department of Pathology and Laboratory Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

A shortage of physicians in the United States has been long projected. Because of predictions of retirement among the aging pathology workforce, there is an anticipated shortage of pathologist as well. To address the pathology workforce shortage among pathologists, the Association of Pathology Chairs assembled a subcommittee of the Association of Pathology Chairs Advocacy Committee to explore ways to identify the strengths, weaknesses, opportunities, and threats to the pathology workforce. One opportunity to encourage strong candidates to pursue pathology as a career is to explore possibility to revisit advanced credit for the post-sophomore fellowship. A survey that was designed to understand the post-sophomore fellowship training better was distributed on the listserv of the Program Directors Section of the Association of Pathology Chairs. A review of the literature on post-sophomore fellowship programs is presented in light of the findings from this survey. Many post-sophomore fellowship programs are run similar to a first-year resident experience, although programs show great diversity in curriculum, including some programs that focus on research. Post-sophomore fellowships attract medical students to the area of pathology and tend to end up in academic and research positions. A second survey of program directors served as an opinion poll of challenging issues that affect residency training. From the second opinion poll, most program directors feel that residents can use additional training to improve the outcome of our future pathologists.
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http://dx.doi.org/10.1177/2374289516646117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497856PMC
May 2016

Identifying the Challenges of "Small" Pathology Residency Programs and Creating Collaborative Solutions.

Acad Pathol 2016 Jan-Dec;3:2374289516643541. Epub 2016 Apr 26.

Department of Pathology, MedStar Georgetown University Hospital, Medical Dental Building, Washington, DC, USA.

The majority of pathology residency training programs in the United States are considered to be small training programs. Small training programs, regardless of specialty, encounter unique challenges that have been documented in the literature. With the implementation of the Next Accreditation System (NAS), and other Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements, adequate personnel and other resources are necessary. An online survey was conducted on the pathology program directors' section listserv to help identify characteristics and challenges of small pathology residency training programs. A discussion group on small pathology residency programs was held at the 2015 Association of Pathology Chairs/Program Directors annual meeting, where the results of the survey were discussed and small breakout groups followed the discussion of the survey. The results of the online survey and discussion groups are discussed in this paper.
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http://dx.doi.org/10.1177/2374289516643541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497919PMC
April 2016

Diagnosis of Basal-Like Breast Cancer Using a FOXC1-Based Assay.

J Natl Cancer Inst 2015 Aug 3;107(8). Epub 2015 Jun 3.

: Interdisciplinary Health Sciences Initiative (TWJ, PSR), Department of Statistics (AQ), Beckman Institute for Advanced Science and Technology (PSR), University of Illinois Cancer Center (PSR), and Department of Surgery, University of Illinois College of Medicine (PSR), University of Illinois at Urbana Champaign, Urbana Champaign, IL; Onconostic Technologies, Inc., Champaign, IL (TR); John Wayne Cancer Institute, Santa Monica, CA (JW); Department of Pathology and Laboratory Medicine, Keck USC/LAC and USC Medical Center/VAGLAHS, Los Angeles, CA (XL, WYN); Departments of Surgery and Obstetrics and Gynecology, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA (BH, XC); Department of Pathology, Carle Foundation Hospital, Urbana, IL (FB); Department of Surgery, Mayo Clinic, Jacksonville, FL (SPB); Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA (CRT); Division of Surgical Oncology, Carle Cancer Center, Urbana, IL (PSR).

Background: Diagnosis of basal-like breast cancer (BLBC) remains a bottleneck to conducting effective clinical trials for this aggressive subtype. We postulated that elevated expression of Forkhead Box transcription factor C1 (FOXC1) is a simple and accurate diagnostic biomarker for BLBC.

Methods: Accuracy of FOXC1 expression in identifying BLBC was compared with the PAM50 gene expression panel in gene expression microarray (GEM) (n = 1992) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 349) datasets. A FOXC1-based immunohistochemical (IHC) assay was developed and assessed in 96 archival formalin-fixed, paraffin-embedded (FFPE) breast cancer samples that also underwent PAM50 profiling. All statistical tests were two-sided.

Results: A FOXC1-based two-tier assay (IHC +/- qRT-PCR) accurately identified BLBC (AUC = 0.88) in an independent cohort of FFPE samples, validating the accuracy of FOXC1-defined BLBC in GEM (AUC = 0.90) and qRT-PCR (AUC = 0.88) studies, when compared with platform-specific PAM50-defined BLBC. The hazard ratio (HR) for disease-specific survival in patients having FOXC1-defined BLBC was 1.71 (95% CI = 1.31 to 2.23, P < .001), comparable to PAM50 assay-defined BLBC (HR = 1.74, 95% CI = 1.40 to 2.17, P < .001). FOXC1 expression also predicted the development of brain metastasis. Importantly, unlike triple-negative or Core Basal IHC definitions, a FOXC1-based definition is able to identify BLBC in both ER+ and HER2+ patients.

Conclusion: A FOXC1-based two-tier assay, by virtue of being rapid, simple, accurate, and cost-effective may emerge as the diagnostic assay of choice for BLBC. Such a test could substantially improve clinical trial enrichment of BLBC patients and accelerate the identification of effective chemotherapeutic options for this aggressive disease.
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http://dx.doi.org/10.1093/jnci/djv148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554196PMC
August 2015

Cytopathology fellowship milestones.

Cancer Cytopathol 2014 Dec 18;122(12):859-65. Epub 2014 Sep 18.

Department of Pathology, Keck School of Medicine, Los Angeles County-University of Southern California Medical Center, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.

The American Society of Cytopathology has provided guidelines for goals and objectives for cytopathology fellows. There are 90 Accreditation Council for Graduate Medical Education-accredited cytopathology fellowship training programs in the United States, each with its own unique curriculum designed to achieve these goals and objectives. The Accreditation Council for Graduate Medical Education cytopathology fellowship milestones were developed to ensure some uniformity in the outcomes of the various skill sets and competencies expected of a graduating cytopathology fellow. The rationale, development, and details of the cytopathology fellowship milestones are described herein.
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http://dx.doi.org/10.1002/cncy.21483DOI Listing
December 2014

Selective pathology fellowships: diverse, innovative, and valuable subspecialty training.

Arch Pathol Lab Med 2014 Apr;138(4):518-25

From the Department of Pathology, University of Virginia Health System, Charlottesville (Dr Iezzoni); the Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, Texas (Drs Ewton and Chévez-Barrios); the Accreditation Council for Graduate Medical Education, Chicago, Illinois (Mr Moore and Ms Thorsen); and the Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles (Dr Naritoku).

Context: Although selective pathology fellowships have a long-standing history of developing trainees with advanced expertise in specific areas of pathology other than those of the American Board of Pathology-certified subspecialties, the widespread interest in this training continues to grow.

Objective: To describe the historical background and current status of selective pathology fellowships, and to provide examples of 3 programs. In addition, Accreditation Council for Graduate Medical Education (ACGME)-accredited programs and nonaccredited programs in Selective Pathology are compared.

Data Sources: ACGME data banks and publicly available online materials were used. Program directors of the fellowships examples in this paper provided program-specific information. Additionally, an online survey of the program directors and program coordinators of ACGME-accredited programs and nonaccredited programs in selective pathology was performed.

Conclusions: There are currently 76 ACGME-accredited selective pathology programs. The programs are distributed between 3 major categories: surgical pathology, focused anatomic pathology, and focused clinical pathology. Although the vast majority of programs are concerned that their funding source may be cut in the next 3 years, most programs will not change the number of fellowship positions in their programs. Program requirements devoted specifically and solely to selective pathology have been developed and are in effect. The value of this training is recognized not only by pathologists, but by clinicians as well, in both academia and private practice. Importantly, the diversity and innovation inherent in selective pathology allow these programs to adeptly address new subspecialty areas and technologic advances in the current and evolving practice of pathology.
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http://dx.doi.org/10.5858/arpa.2013-0454-SADOI Listing
April 2014

Anatomic and clinical pathology boot camps: filling pathology-specific gaps in undergraduate medical education.

Arch Pathol Lab Med 2014 Mar;138(3):316-21

From the Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles (Dr Naritoku); the Department of Laboratory Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York (Dr Vasovic); the Department of Pathology, Albert Einstein College of Medicine, Bronx, New York (Drs Steinberg and Prystowsky); and the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Dr Powell).

Context: The Liaison Committee on Medical Education began an initiative to change medical education across the United States in the early 2000s. With the explosion in medical science knowledge, the need arose to teach selected fundamental information both in a contextual and in an active learning manner.

Objective: To identify ways to address gaps in training and knowledge that became apparent following implementation of learner-centered teaching methods, with devotion of more time to Internet-based learning and less emphasis on face-to-face lecture time. There was a dramatic departure from or de-emphasis of many traditional courses, such as embryology, gross anatomy, microscopic anatomy, and pathology, to the integration of these sciences into system-based active learning courses. This change in medical school curricula produces a medical graduate who hopefully thinks differently but certainly lacks subject-specific knowledge for a variety of medical specialties.

Data Sources: Pathology residency programs have developed "boot camps" for the initial months of residency training both to provide the necessary foundation of pathology-specific medical science and to introduce basic skills and processes required for practice of anatomic pathology and laboratory medicine. The College of American Pathologists Graduate Medical Education Committee sent a questionnaire out on the Program Directors Section Listserv; the results are discussed and 3 boot camp programs are described.

Conclusions: Boot camps have 2 purposes: (1) to teach or strengthen knowledge required to practice pathology and (2) to introduce basic skills and processes that will be used during the practitioner's career.
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http://dx.doi.org/10.5858/arpa.2013-0356-SADOI Listing
March 2014

The pathology milestones and the next accreditation system.

Arch Pathol Lab Med 2014 Mar;138(3):307-15

From the Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles (Dr Naritoku); the Department of Pathology, University of Alabama Birmingham (Dr Alexander); the American Board of Pathology, Tampa, Florida (Dr Bennett and Johnson); the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston (Dr Black-Schaffer); the Hematopathology Division, Joint Pathology Center, Silver Springs, Maryland, and Washington, DC (Dr Brissette); the Department of Pathology, Virginia Commonwealth University Medical Center, Richmond (Dr Grimes); the Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Hoffman); the Department of Pathology, University of Arkansas for Medical Sciences, Little Rock (Dr Hunt); the Department of Pathology, University of Virginia Health System, Charlottesville (Dr Iezzoni); the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha (Dr Kozel); the Department of Pathology, East Carolina University, Greenville, North Carolina (Dr Mendoza); the Department of Pathology, University of Colorado School of Medicine, Aurora (Dr Post); the Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, Texas (Dr Powell); the Department of Molecular Pathology, Cleveland Clinic Foundation, The Pathology and Laboratory Medicine Institute, Cleveland, Ohio (Dr Procop); the Department of Pathology, Albert Einstein College of Medicine, Bronx, New York (Dr Steinberg); and the Accreditation Council for Graduate Medical Education, Chicago, Illinois (Ms Thorsen and Dr Nestler).

Context: In the late 1990s, the Accreditation Council for Graduate Medical Education developed the Outcomes Project and the 6 general competencies with the intent to improve the outcome of graduate medical education in the United States. The competencies were used as the basis for developing learning goals and objectives and tools to evaluate residents' performance. By the mid-2000s the stakeholders in resident education and the general public felt that the Outcomes Project had fallen short of expectations.

Objective: To develop a new evaluation method to track trainee progress throughout residency using benchmarks called milestones. A change in leadership at the Accreditation Council for Graduate Medical Education brought a new vision for the accreditation of training programs and a radically different approach to the evaluation of residents.

Data Sources: The Pathology Milestones Working Group reviewed examples of developing milestones in other specialties, the literature, and the Accreditation Council for Graduate Medical Education program requirements for pathology to develop pathology milestones. The pathology milestones are a set of objective descriptors for measuring progress in the development of competency in patient care, procedural skill sets, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice.

Conclusions: The milestones provide a national standard for evaluation that will be used for the assessment of all residents in Accreditation Council for Graduate Medical Education-accredited pathology training programs.
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http://dx.doi.org/10.5858/arpa.2013-0260-SADOI Listing
March 2014

Phlegmonous gastritis in a patient with myeloid sarcoma: a case report.

Appl Immunohistochem Mol Morphol 2009 Oct;17(5):458-62

Department of Pathology, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, CA 90030, USA.

Phlegmonous gastritis is a rare acute bacterial infection of the gastric wall with an extremely high mortality rate. Early diagnosis is crucial for immediate treatment that could improve the outcomes. Here we report a case in which a patient with underlying chronic myelomonocytic leukemia was diagnosed with phlegmonous gastritis on biopsy. This 57-year-old man presented with shortness of breath and intermittent upper quadrant abdominal pain for 4 days. Laboratory tests showed markedly increased white blood cell. A diagnosis of chronic myelomonocytic leukemia was made based on a peripheral blood smear and flow cytometry. Gastric biopsy showed suppurative inflammation in the submucosal region, prompting the diagnosis of phlegmonous gastritis. The patient was given empirical antibiotic treatment, and the white blood cell decreased dramatically. Surgical intervention was discussed but deferred. Despite continued antibiotics treatment, the patient died. The limited autopsy confirmed the diagnosis of phlegmonous gastritis. Immunohistochemical studies further revealed the occurrence of myeloid sarcoma that involved the gastrointestinal tract.
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http://dx.doi.org/10.1097/PAI.0b013e31819f86e2DOI Listing
October 2009

Unmethylated E-cadherin gene expression is significantly associated with metastatic human prostate cancer cells in bone.

Prostate 2008 Nov;68(15):1681-8

Molecular Pathology Program, Huntington Medical Research Institutes, Pasadena, California 91101, USA.

Background: The concurrent determination of methylation status of E-cadherin gene and E-cadherin protein expression remains scant in metastatic prostate cancer cells in bone, the most prevalent site for metastatic growth. Therefore, the study was undertaken to ascertain the methylation status of E-cadherin gene, a most frequent and known epigenetic mechanism of its regulation, and the protein expression in prostate tissue biopsy specimen.

Methods: The methylation of E-cadherin gene was determined by methylation specific-PCR and the protein expression by immunohistochemical method in the consecutive sections of each prostate tissue biopsy specimen.

Results: The unmethylated E-cadherin gene and homogeneous E-cadherin protein expression was significantly associated with BPH as compared to the primary prostate carcinoma (Fisher's Exact P < 0.001). A significant association was observed between the concurrent methylated gene and markedly reduced expression of the protein in the primary prostate cancer cells as compared to the BPH cells, suggesting methylation-dependent regulation of the gene expression in these cases. In contrast to the primary cancer, a highly significant increase in the frequency of metastatic prostate cancer cells in bone exhibited the concurrent expression of unmethylated gene and homogeneous protein (Fisher's Exact P < 0.001).

Conclusions: The study clearly demonstrated a significant association of the concurrent expression of unmethylated E-cadherin gene and E-cadherin protein with metastatic prostate cancer cells in bone, and that its expression may have a role in the intercellular adhesion in the formation of metastatic lesions in bone.
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http://dx.doi.org/10.1002/pros.20836DOI Listing
November 2008

Overexpression of E-cadherin protein in metastatic breast cancer cells in bone.

Anticancer Res 2007 Nov-Dec;27(6B):3903-8

Gene Therapy Program, Huntington Medical Research Institutes, Pasadena, CA 91101-1830, USA.

Aim: The aim of the present study was to evaluate E-cadherin, whose expression remains poorly understood in the intercellular adhesion of metastatic breast cancer cells in bone, the most prevalent site for metastatic growth.

Materials And Methods: An immunohistochemical staining method was used for the localization of E-cadherin protein in tissue biopsy specimens of normal breast (n = 9) and well- (n = 8), moderately (n = 8) or poorly (n = 14) differentiated invasive primary breast cancer and metastatic breast cancer in bone (n = 17). The expression patterns of E-cadherin were classified as homogeneous (most cells exhibiting positivity), heterogeneous (a few scattered patches of cells with positivity) or negative (cells with undetectable positivity).

Results: Normal breast epithelial cells showed homogeneous overexpression of E-cadherin in all cases. A progressive and statistically significant reduction of E-cadherin expression was detected in the histologically well- to moderately to poorly differentiated breast cancer cells (p < 0.001). The clumps of invasive primary breast cancer cells in CD-31-positive blood vessels exhibited E-cadherin expression. Moreover, as compared to the poorly differentiated breast cancer cells, a significantly increased frequency of the metastatic breast cancer cells in bone exhibited homogeneous expression of E-cadherin in 15 out of 17 and heterogeneous expression in the remaining 2 cases (McNemar Exact p < 0.001). This is the first demonstration of membranous overexpression of E-cadherin on metastatic breast cancer cells in bone; the high frequency of its expression may have a role in the intercellular adhesion of metastatic cells in bone.
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February 2008

Overexpression of E-cadherin and beta-catenin proteins in metastatic prostate cancer cells in bone.

Prostate 2008 Jan;68(1):78-84

Gene Therapy Program, Huntington Medical Research Institutes, Pasadena, California 91101, USA.

Background: The expression of E-cadherin in the intercellular adhesion of metastatic prostate cancer cells in bone, which is the most prevalent site of metastatic growth, remains elusive.

Methods: The aim of the study was to compare the concurrent membranous expression of E-cadherin and beta-catenin proteins, the state which is known to be associated with the cellular adhesion function of E-cadherin, in prostate biopsy tissue specimens by immunohistochemical staining method. The expression patterns of E-cadherin or beta-catenin were classified as homogeneous (most cells exhibiting positively), heterogeneous (a few scattered patches of cells with positivity) or negative.

Results: Benign prostate hyperplasia cells exhibited homogeneous expression of both E-cadherin and beta-catenin in 9 of 11 (82%), whereas the primary prostate cancer cells were homogeneously positive for both proteins only in 4 of 22 (18%) of the cases. The results are similar to those reported in literature. However, in contrast to the primary cancer, a significantly increased frequency of the metastatic prostate cancer cells in bone exhibited homogeneous expression of E-cadherin and beta-catenin in 12 of 17 (71%) of the cases. A statistically significant association was observed between the overexpression of both proteins and the metastatic prostate cancer cells in bone (Fisher's exact P < 0.001).

Conclusions: The result of the study demonstrated for the first time that the membranous overexpression of E-cadherin and beta-catenin are significantly associated with the metastatic prostate cancer cells in bone and that the high frequency of expression suggest their involvement in the intercellular adhesion of the metastatic cells in bone.
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http://dx.doi.org/10.1002/pros.20670DOI Listing
January 2008

Telomerase and markers of cellular proliferation are associated with the progression of cervical intraepithelial neoplasia lesions.

Int J Gynecol Pathol 2007 Jul;26(3):214-22

Gene Therapy Program, Huntington Medical Research Institutes, Pasadena, California 91101, USA.

The expression of the catalytic subunit of telomerase protein (human telomerase reverse transcriptase [hTERT]), which is associated with telomerase activity, was evaluated as a potential marker of the high-grade premalignant cervical intraepithelial neoplasia (CIN 2/3) lesions. For comparison, cases of normal cervical squamous mucosa, low-grade CIN1 lesion, and cervical squamous cell carcinoma were included. The hTERT expression was also compared with Ki-67 and topoisomerase II-alpha (TPII-alpha) to determine the proliferative activity of the hTERT-positive dysplastic cells by a quantitative immunohistochemical staining method and was classified as follows: negative, 5% or less; moderate, 6% to 50%; or high, greater than 50% of the positive cells. The hTERT-positive cells were detected in a patchy pattern in the lower parabasal layers and in much of the basal layer in normal squamous mucosa. A similar frequency of Ki-67- or TPII-alpha-positive cells was observed, with the exception of the basal layer cells that were mostly negative. It is worthy to note that the recognizable intact basal layer cells in cases of CIN lesions were also consistently positive for the expression of hTERT, but rarely for Ki-67 or TPII-alpha. The expression of hTERT was detected in a less patchy pattern at a high or moderate percentage of the dysplastic epithelial cells each in 28.5% of cases of CIN1 lesions. A similar frequency, high and moderate percentage combined, of the TPII-alpha-positive dysplastic cell was also observed. In contrast, a high percentage of the hTERT-positive dysplastic cells were detected as diffuse basal or full-length thickness in 87.5% or 95% of cases of CIN2 or CIN3, respectively. A similar frequency of Ki-67 or TPII-alpha expression was observed in the dysplastic cells of CIN3 lesions. The pattern of hTERT-positive malignant cells in squamous cell carcinoma and dysplastic cells in the high-grade CIN lesions, to a greater extent, and dysplastic cells in the low-grade CIN lesion, to a lesser extent, was distinct from that of the normal cervical squamous mucosa. The results suggest that the progressive increase in the hTERT expression, together with the proliferative activity of the dysplastic epithelial cells of the high-grade CIN lesions, represents an early genetic abnormality in cervical pathogenesis.
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http://dx.doi.org/10.1097/01.pgp.0000250146.44592.d2DOI Listing
July 2007

The autopsy as a performance measure and teaching tool.

Hum Pathol 2007 May 21;38(5):688-695. Epub 2007 Mar 21.

Department of Pathology and Laboratory Medicine, West Los Angeles Veterans Affairs Medical Center, Los Angeles, CA 90073, USA.

A survey of pathology training programs about current operations and attitudes revealed that the autopsy is underused in medical student and pathology resident teaching, is inadequately reported, often does not have a dedicated faculty, is not championed by pathologists or clinicians, is not valued as a performance measure, and is barely used as a resource for medical research. The autopsy can be reestablished as a teaching tool and performance measure, but this will require that the autopsy be recognized as a credible and valuable medical procedure. The autopsy must then be funded; and new sources of both volume and funding, such as incorporating autopsies into payment schedules, into clinical trials, and in pay-for-performance initiatives, must be solicited. Once there is reimbursement for autopsies, pathologists, clinicians, and health care administrators will embrace the autopsy as a new source of revenue and as a valid measure of physician, hospital, and health system performance. Pathologists and the pathology specialty societies must take the lead in the reestablishment of the autopsy and must, at the same time, encourage innovations such as centralization, greater use of Pathology Assistants, and application of molecular techniques. New tools for using the autopsy in medical student teaching should be embraced, and the role of the autopsy in pathology residency programs must be reevaluated.
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http://dx.doi.org/10.1016/j.humpath.2007.01.001DOI Listing
May 2007

LEA-135 expression: its association with a lower risk of recurrence and increased overall survival of patients with lymph node-positive primary invasive breast cancer.

Anticancer Res 2004 Jul-Aug;24(4):2391-400

Gene Therapy Program, Huntington Medical Research Institutes, Pasadena, CA 91101-1830, USA.

A retrospective study was undertaken to determine and compare the prognostic significance of LEA-135 protein expression by immunohistochemistry with other prognostic pathological parameters, with respect to recurrence and overall survival. This study was conducted in freshly-frozen tissue sections from a cohort of 367 patients having primary invasive breast cancer, with axillary lymph node metastasis. The association of LEA-135 expression was compared with estrogen and progesterone receptor status, segmentectomy or radical mastectomy and hormonal therapy or chemotherapy in terms of recurrence or disease-free survival. Pathologic parameters including tumor size, histological tumor type and histological grade, as well as age of patients at the time of initial diagnosis, and the treatments, together with a median follow-up of 8.8 years were contemplated for the study. Among these parameters, tumor size and histological grade were individually and significantly associated with an increased probability of recurrence (log rank p<0.001 in both cases) and short survival (log ranks p<0.001 and p=0.002, respectively), whereas age was only significantly associated with an increased probability of recurrence (log rank p=0.002) by univariate analysis. By multivariate analysis, both tumor size and histological grade remained statistically significant for recurrence (log rank p<0.001 and p=0.013, respectively) and overall survival (log ranks p<0.001 and p=0.016, respectively). Among the prognostic biomarkers, both ER and PR expression were associated with a decreased rate of recurrence (log ranks p<0.001 and p=0.008, respectively) and overall survival (log ranks p<0.001 and p=0.002, respectively) by univariate analysis. By multivariate analysis, only the ER expression remained significantly associated with a decreased recurrence and increased overall survival (log ranks p=0.023 and p=0.002, respectively). Patients with high (>50% positive cells) or moderate (5-50% positive cells) number of LEA-135-positive cells had a lower probability (46%) of recurrence at 10 years after surgery compared to 76% in LEA-135-negative patients (log rank p<0.001) by univariate analysis. Moreover, the probability of overall survival was higher in patients with high or moderate expression of LEA-135 (46% and 47%, respectively) compared to LEA-135-negative patients (24%) by univariate analysis (log rank p=0.009). By multivariate analysis, the association remained statistically significant for recurrence (log rank p<0.001) and survival (log rank p=0.002). However, there was no significant association between LEA-135 and any of the pathological parameters, age, hormone receptor status, the mode of surgery or the form of therapy (chemo- and/or hormonal) received by this cohort of patients. The results show that an improved prognosis was directly associated with the density of LEA-135-positive cancer cells, while loss of LEA-135 expression was associated with an aggressive phenotype of cancer cells during breast cancer progression. Thus, LEA-135 expression can be implicated as a significant and independent biomarker to identify and distinguish high- from low-risk patients with lymph node-positive invasive breast cancer for an aggressive treatment. Moreover, according to the present results, LEA-135 expression appears to be associated with the tumor cells that have retained certain normal biological characteristics, leading to their lack of aggressiveness and hence a better prognosis.
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September 2004

LEA.135 expression: identifies low-risk patients with breast ductal carcinoma in situ.

Anticancer Res 2002 Sep-Oct;22(5):2933-7

Department of Pathology, USC Keck School of Medicine, Los Angeles, CA, USA.

The expression of a cell surface-associated sialoglycoprotein (LEA.135), which has been shown to be significantly associated with decreased incidence of recurrence and increased overall survival of patients with primary invasive breast carcinoma, was evaluated in a retrospective study to identify subsets of patients with breast ductal carcinoma in situ (DCIS) who are at high risk of subsequently developing invasive breast carcinoma. The study was carried out by an immuno-histochemical method on formalin-fixed and paraffin-embedded tissue sections from 63 patients initially with DCIS. Pathological parameters such as DCIS histological type, nuclear grade, as well as time and type of recurrence (either a second DCIS or the diagnosis of locally invasive breast carcinoma) together with follow-up in years were available for the cohort of patients. A comparison of recurrence was made of patients whose tumor cells exhibited LEA.135 expression (24 +/- 8% recurring by 7 years), compared with those patients whose specimens showed the absence of LEA.135 expression (41 +/- 10% recurring by 7 years). A statistically significant univariant association between LEA.135 expression and the absence of recurrence of DCIS or development of locally invasive breast carcinoma was observed, suggesting a favorable prognostic significance of LEA. 135 expression (log-rank p = 0.032). It is worthy of mention that none of the LEA. 135-positive patients developed recurrence as DCIS or locally invasive breast carcinoma (0.24 +/- 0.08) after 5 years of the initial diagnosis of DCIS, whereas those from LEA. 135-negative progressively increased their recurrence at 5 years (0.30 +/- 0.09), 7 years (0.41 +/- 0.10) and 10 years (0.63 +/- 0.12). The results of this pilot study show that LEA.135 expression is significantly associated with a favorable prognosis of patients with DCIS, leading to a decreased incidence of recurrence.
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February 2003
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