ABSTRACT
BACKGROUND: The COVID-19 pandemic, while unfortunately notable for immense strain and death throughout the world, has also shown great promise in the development of medical countermeasures. As the global scientific community shifted almost entirely towards vaccines, diagnostics and therapeutics, new trial designs most significantly adaptive platform trials, began to be used with greater speed and broader reach. These designs allowed for deploying and investigating new therapeutics, repurposing currently existing therapeutics and flexibly removing or adding additional medications as data appeared in real-time. Moreover, public-private sector partnering occurred at a level not seen before, contributing greatly to the rapid development and deployment of vaccines. OBJECTIVES: To provide a brief overview of the advances in preventative and therapeutic medical countermeasure development for COVID-19. METHODS: A narrative review of relevant major medical countermeasure trials was conducted using the date range February 2020-December 2022, representing the period of greatest productivity in research to investigate COVID-19. RESULTS: Among the most influential trial designs are the adaptive platform designs, which have been applied to the development of initial COVID-19 antivirals, monoclonal antibodies, repurposing of existing immunomodulatory therapy and assisted in the disproof of ineffective medical therapies. Some of the most prominent examples include the REMAP-CAP, RECOVERY and TOGETHER trials. CONCLUSIONS: Adaptive platform trial designs hold great promise for utility in future pandemics and mass casualty events. Additionally, public-private sectoring is essential for rapid medical countermeasure development and should be further enhanced for future biopreparedness.
Subject(s)
COVID-19 , Medical Countermeasures , Vaccines , Humans , COVID-19/prevention & control , Pandemics/prevention & control , Research DesignABSTRACT
PURPOSE OF REVIEW: The worldwide SARS-CoV-2 pandemic has taken a heavy toll on ICUs worldwide. This review expounds on lessons learned for ICU preparedness during the pandemic and for future mass casualty events. RECENT FINDINGS: In the 21st century, there have already been several outbreaks of infectious diseases that have led to mass casualties creating ICU strain, providing multiple opportunities for hospitals and hospital systems to prepare their ICUs for future events. Unfortunately, the sheer scale and rapidity of the SARS-CoV-2 pandemic led to overwhelming strain on every aspect of ICU disaster preparedness. Yet, by analyzing experiences of hospitals throughout the first 7 months of the current pandemic in the areas of infection control, equipment preparedness, staffing strategies, ICU spatial logistics as well as acute and postacute treatment, various important lessons have already emerged that will prove critical for successful future ICU preparedness. SUMMARY: Preemptive planning, beginning with the early identification of staffing resources, supply chains and alternative equipment sources, coupled with strong infection control practices that also provide for the flexibility for evolving evidence is of utmost importance. However, there is no single approach that can be applied to every health system.
Subject(s)
COVID-19/epidemiology , Infection Control/organization & administration , Intensive Care Units/organization & administration , Pandemics , HumansABSTRACT
BACKGROUND: Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements. Emerging immunotherapies targeting Programmed Death Ligand 1 (PD-L1) and immune-suppressing T cells (Tregs) may benefit metaplastic breast cancer patients, which are typically chemo-resistant and do not express hormone therapy targets. METHODS: We evaluated the immunohistochemical expression of PD-L1 and FOXP3, and the extent of tumour infiltrating lymphocytes (TILs) in a large cohort of metaplastic breast cancers, with survival data. RESULTS: Metaplastic breast cancers were significantly enriched for PD-L1 positive tumour cells, compared to triple-negative ductal breast cancers (P < 0.0001), while there was no significant difference in PD-L1 positive TILs. Metaplastic breast cancers were also significantly enriched for TILs expressing FOXP3, with FOXP3 positive intra-tumoural TILs (iTILs) associated with an adverse prognostic outcome (P = 0.0226). Multivariate analysis identified FOXP3 iTILs expression status as an important independent prognostic factor for patient survival. CONCLUSIONS: Our findings indicate the clinical significance and prognostic value of FOXP3, PD-1/PD-L1 checkpoint and TILs in metaplastic breast cancer and confirm that a subset of metaplastics may benefit from immune-based therapies.
Subject(s)
B7-H1 Antigen/biosynthesis , Biomarkers, Tumor/immunology , Breast Neoplasms/pathology , Forkhead Transcription Factors/biosynthesis , Adult , Aged , Breast Neoplasms/immunology , Female , Humans , Immune Checkpoint Inhibitors , Lymphocytes, Tumor-Infiltrating/immunology , Metaplasia , Middle AgedABSTRACT
Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to â¼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Mutation , Neoplasms, Complex and Mixed/genetics , Antigens, CD/analysis , Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/classification , Breast Neoplasms/pathology , Cadherins/analysis , Class I Phosphatidylinositol 3-Kinases/genetics , Cross-Sectional Studies , Epithelial-Mesenchymal Transition , ErbB Receptors/analysis , Female , Genetic Predisposition to Disease , Humans , Keratins/analysis , Metaplasia , Middle Aged , Neoplasm Grading , Neoplasms, Complex and Mixed/chemistry , Neoplasms, Complex and Mixed/classification , Neoplasms, Complex and Mixed/pathology , Neurofibromin 1/genetics , PTEN Phosphohydrolase/genetics , Phenotype , Tumor Burden , Tumor Suppressor Protein p53/geneticsABSTRACT
The role of pathologists is to provide diagnostic, prognostic and predictive data to enable clinical colleagues to manage patients optimally. Current histo/anatomical pathology is predominantly morphology-based, with the addition of biomarkers, applied largely through immunohistochemistry, fluorescence in-situ hybridization (FISH) and a limited range of polymerase chain reaction (PCR)-based molecular tests. The desire to apply genomics to the clinical care of patients has been facilitated by the human genome project and subsequently by high-throughput technologies known collectively as massive parallel sequencing (MPS, also referred to as next-generation sequencing, NGS). The use of MPS to identify mutations/variants and tissue RNA expression profiles for diagnosis, prognostication and targeted therapy stratification is now a reality in many clinical specialities. If histopathologists are considered experts in solid tumour pathology, MPS potentially falls within their scope; however, it challenges our predominant morphology-based paradigm. This review summarizes and comments on the current and future state of play of MPS for the practising histopathologist. It will focus on somatic mutations in solid tumours and will challenge histopathologists to take further leadership roles in this area.
Subject(s)
High-Throughput Nucleotide Sequencing/methods , Neoplasms/genetics , High-Throughput Nucleotide Sequencing/trends , Humans , Pathologists , Pathology/methods , Pathology/trendsABSTRACT
AIMS: The proliferation marker Ki67 has been extensively investigated as a prognostic factor in breast cancer, but has not gained widespread clinical acceptance. Phosphohistone H3 is a new immunohistochemical marker for quantifying mitoses; however, there is limited information on its prognostic value in breast cancer. In this study, we performed a head-to-head comparison of Ki67 and phosphohistone H3 to establish the marker with the greatest prognostic value. METHODS AND RESULTS: Tissue microarrays from 108 breast cancer patients were immunohistochemically stained for Ki67 and phosphohistone H3. Our results showed that phosphohistone H3 had a greater prognostic value than Ki67 in a multivariable model that adjusted for traditional prognostic variables in breast cancer. Phosphohistone H3 staining was a stronger predictor of survival at 5 years after diagnosis [hazard ratio (HR) 4.35, P < 10(-5) ] than Ki67 (HR 2.44, P = 0.004), and better separated the risk of death in patients aged >45 years. Importantly, phosphohistone H3 consistently showed strong unequivocal staining, in contrast to the variable staining intensities associated with Ki67. CONCLUSIONS: Our study suggests that phosphohistone H3 staining is a stronger and more robust prognostic indicator than Ki67 staining in breast cancer patients, and has the potential for use in routine diagnostic laboratories.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Histones/analysis , Ki-67 Antigen/analysis , Adult , Aged , Breast Neoplasms/mortality , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Phosphorylation , Prognosis , Proportional Hazards Models , Tissue Array AnalysisABSTRACT
BACKGROUND: Existing ethics guidance and regulatory requirements emphasize the need for pregnancy-specific safety and efficacy data during the development of vaccines in health emergencies. Our objective was to conduct a systematic review of vaccine clinical trials during active epidemic periods. METHODS: We searched for Phase II and Phase III vaccine clinical trials initiated during the H1N1 influenza, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Zika, and Ebola virus disease (EVD) outbreaks from 2009 to 2019. Data were extracted from clinical trial protocols identified in the following registries: ClinicalTrials.gov, Pan African Clinical Trial Registry (PACTR), and all primary registries indicated by the World Health Organization's International Clinical Trials Registry Platform (ICTRP). Published studies from registered clinical trials were located through PubMed. Data was extracted on eligibility criteria and pregnancy outcomes. Data from this study is available in the Center for Open Science Data Repository: https://osf.io/nfk2p/?view_only=47deb3b206724af9b46c9c0c0083a267. RESULTS: We identified 96 vaccine clinical trial protocols and included 84 in analysis. 5 records were excluded in screening for irrelevant abstracts, 7 were excluded in full-text assessment (1 for a therapeutic drug trial, 3 for enrolling elderly adults only, 3 for enrolling children/adolescents only). There were no eligible trials for MERS-CoV or Zika virus vaccines. Overall, 8 protocols explicitly included pregnant people; of these, 3 were completed trials with published results. Incidental pregnancies and outcomes of pregnant participants were reported in 2 studies, 10 studies reported serious adverse events related to pregnancy without mentioning total incidental pregnancies. A total of 411 recorded pregnancy outcomes were reported, with 293 from the 3 pregnancy-eligible studies with results. 71 serious adverse events pertaining to pregnancy were reported from all clinical trials with results. CONCLUSION: Pregnant people are underrepresented in vaccine clinical trials conducted during outbreaks, resulting in underreporting of pregnancy-related outcomes and a lack of protection for pregnant people and neonates from infectious diseases.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human , Middle East Respiratory Syndrome Coronavirus , Vaccines , Zika Virus Infection , Zika Virus , Adolescent , Adult , Aged , Child , Female , Humans , Infant, Newborn , Pregnancy , Disease Outbreaks , Influenza, Human/prevention & control , Zika Virus Infection/prevention & control , Clinical Trial Protocols as TopicABSTRACT
OBJECTIVE: Endometrial cancer, in developed countries, is the most common malignancy of the female genital tract. Surgery and radiotherapy are successful in many patients but systemic and recurrent diseases have no consistently effective treatments, and for high grade advanced disease the prognosis is poor. The study investigated characteristics of adrenomedullin in endometrial cancer to assist in identifying targets for developing treatments. METHODS: Endometrial samples of women with and without cancer, and the Ishikawa cell line were used to investigate adrenomedullin mRNA regulation, peptide expression, adrenomedullin secretion and effects of adrenomedullin on VEGF secretion. RESULTS: Expression of adrenomedullin mRNA was upregulated compared to that in healthy post-menopausal endometria. Adrenomedullin secretion was increased by cobalt chloride in this study. Secretion was reduced by the naturally-occurring compounds, (-)-epigallocatechin gallate (EGCG) and 3,4',5-trihydroxystilbene (resveratrol), which we have previously demonstrated to also suppress VEGF secretion in endometrial tumour tissue. We noted, for the first time, that adrenomedullin enhanced VEGF secretion from tumour cells. CONCLUSIONS: Increased adrenomedullin expression may result in amplifying both tumorigenic and angiogenic activities. A substantial impact on growth of tumours may result in vivo as a consequence of the synergism between adrenomedullin and VEGF. Adrenomedullin, which has altered cellular characteristics in tumour compared to healthy tissue, offers an understudied target with potential to modify endometrial cancer behaviour, complementing other treatments.
Subject(s)
Adenocarcinoma/metabolism , Adrenomedullin/metabolism , Biomarkers, Tumor/metabolism , Endometrial Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Vascular Endothelial Growth Factor A/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adrenomedullin/antagonists & inhibitors , Adrenomedullin/genetics , Biomarkers, Tumor/genetics , Case-Control Studies , Catechin/analogs & derivatives , Catechin/metabolism , Cell Line, Tumor , Cobalt/metabolism , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Female , Humans , Neoplasm Grading , RNA, Messenger/metabolism , Resveratrol , Stilbenes/metabolism , Up-RegulationABSTRACT
Importance: The 2017-2018 influenza season in the US was marked by a high severity of illness, wide geographic spread, and prolonged duration compared with recent previous seasons, resulting in increased strain throughout acute care hospital systems. Objective: To characterize self-reported experiences and views of hospital capacity managers regarding the 2017-2018 influenza season in the US. Design, Setting, and Participants: In this qualitative study, semistructured telephone interviews were conducted between April 2018 and January 2019 with a random sample of capacity management administrators responsible for throughput and hospital capacity at short-term, acute care hospitals throughout the US. Main Outcomes and Measures: Each participant's self-reported experiences and views regarding high patient volumes during the 2017-2018 influenza season, lessons learned, and the extent of hospitals' preparedness planning for future pandemic events. Interviews were recorded and transcribed and then analyzed using thematic content analysis. Outcomes included themes and subthemes. Results: A total of 53 key hospital capacity personnel at 53 hospitals throughout the US were interviewed; 39 (73.6%) were women, 48 (90.6%) had a nursing background, and 29 (54.7%) had been in the occupational role for more than 4 years. Participants' experiences were categorized into several domains: (1) perception of strain, (2) effects of influenza and influenza-like illness on staff and patient care, (3) immediate staffing and capacity responses to influenza and influenza-like illness, and (4) future staffing and capacity preparedness for influenza and influenza-like illness. Participants reported experiencing perceived strain associated with concerns about preparedness for seasonal influenza and influenza-like illness as well as concerns about staffing, patient care, and capacity, but future pandemic planning within hospitals was not reported as being a high priority. Conclusions and Relevance: The findings of this qualitative study suggest that during the 2017-2018 influenza season, there were systemic vulnerabilities as well as a lack of hospital preparedness planning for future pandemics at US hospitals. These issues should be addressed given the current coronavirus disease 2019 pandemic.
Subject(s)
Capacity Building , Change Management , Civil Defense/organization & administration , Disaster Planning/methods , Disease Outbreaks , Influenza, Human , COVID-19/epidemiology , COVID-19/prevention & control , Capacity Building/methods , Capacity Building/organization & administration , Disease Outbreaks/prevention & control , Disease Outbreaks/statistics & numerical data , Health Workforce/organization & administration , Humans , Influenza, Human/epidemiology , Influenza, Human/prevention & control , Influenza, Human/therapy , Personnel Management/methods , Qualitative Research , SARS-CoV-2 , Seasons , Severity of Illness Index , United States/epidemiologyABSTRACT
BACKGROUND: New Zealand Maori have a poorer outcome from breast cancer than non-Maori, yet prognostic data are sparse. The objective of this study was to quantify levels of prognostic factors in a cohort of self-declared Maori and European breast cancer patients from Christchurch, New Zealand. METHODS AND RESULTS: Clinicopathological and survival data from 337 consecutive breast cancer patients (27 Maori, 310 European) were evaluated. Fewer tumours were high grade in Maori women than European women (p = 0.027). No significant ethnic differences were detected for node status, tumour type, tumour size, human epidermal growth factor receptor, oestrogen and progesterone receptor (ER/PR) status, or survival.In addition, tumour and serum samples from a sub-cohort of 14 Maori matched to 14 NZ European patients were analyzed by immunohistochemistry and enzyme linked immunosorbent assay for molecular prognostic factors. Significant correlations were detected between increased grade and increased levels of hypoxia inducible factor-1 (HIF-1α), glucose transporter-1 (GLUT-1), microvessel density (MVD) and cytokeratins CK5/6 (p < 0.05). High nodal status correlated with reduced carbonic anhydrase IX (CA-IX). Negative ER/PR status correlated with increased GLUT-1, CA-IX and MVD. Within the molecular factors, increased HIF-1α correlated with raised GLUT-1, MVD and CK5/6, and CK5/6 with GLUT-1 and MVD (p < 0.05). The small number of patients in this sub-cohort limited discrimination of ethnic differences. CONCLUSIONS: In this Christchurch cohort of breast cancer patients, Maori women were no more likely than European women to have pathological or molecular factors predictive of poor prognosis. These data contrast with data from the North Island NZ, and suggest potential regional differences.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/ethnology , Breast Neoplasms/metabolism , Adult , Aged , Cohort Studies , Ethnicity , Female , Humans , Immunohistochemistry/methods , Middle Aged , New Zealand , Population Groups , Prognosis , Treatment Outcome , White PeopleABSTRACT
BACKGROUND: The current coronavirus disease 2019 pandemic is causing significant strain on ICUs worldwide. Initial and subsequent regional surges are expected to persist for months and potentially beyond. As a result of this, as well as the fact that ICU provider staffing throughout the United States currently operate at or near capacity, the risk for severe and augmented disruption in delivery of care is very real. Thus, there is a pressing need for proactive planning for ICU staffing augmentation, which can be implemented in response to a local surge in ICU volumes. METHODS: We provide a description of the design, dissemination, and implementation of an ICU surge provider staffing algorithm, focusing on physicians, advanced practice providers, and certified registered nurse anesthetists at a system-wide level. RESULTS: The protocol was designed and implemented by the University of Pittsburgh Medical Center's Integrated ICU Service Center and was rolled out to the entire health system, a 40-hospital system spanning Pennsylvania, New York, and Maryland. Surge staffing models were developed using this framework to assure that local needs were balanced with system resource supply, with rapid enhancement and expansion of tele-ICU capabilities. CONCLUSIONS: The ICU pandemic surge staffing algorithm, using a tiered-provider strategy, was able to be used by hospitals ranging from rural community to tertiary/quaternary academic medical centers and adapted to meet specific needs rapidly. The concepts and general steps described herein may serve as a framework for hospital and other hospital systems to maintain staffing preparedness in the face of any form of acute patient volume surge.
ABSTRACT
INTRODUCTION: Circulating biomarkers have been increasingly used in the clinical management of breast cancer. The present study evaluated whether RNAs and a protein present in the plasma of patients with breast cancer might have utility as prognostic biomarkers complementary to existing clinical tests. PATIENTS AND METHODS: We performed microarray profiling of small noncoding RNAs in plasma samples from 30 patients with breast cancer and 10 control individuals. Two small noncoding RNAs, including microRNA (miR)-923, were selected and quantified in plasma samples from an evaluation cohort of 253 patients with breast cancer, using droplet digital polymerase chain reaction. We also measured cancer antigen (CA) 15-3 protein levels in these samples. Cox regression survival analysis was used to determine which markers were associated with patient prognosis. RESULTS: As independent markers of prognosis, the plasma levels of miR-923 and CA 15-3 at the time of surgery for breast cancer were significantly associated with prognosis, irrespective of treatment (Cox proportional hazards, P = 3.9 × 10-3 and 1.9 × 10-9, respectively). After building a multivariable model with standard clinical and pathological features, the addition of miR-923 and CA 15-3 information into the model resulted in a significantly better predictor of disease recurrence in patients, irrespective of treatment, compared with the use of clinicopathological data alone (area under the curve at 3 years, 0.858 vs. 0.770 with clinicopathological markers only; P = .017). CONCLUSION: We propose that the plasma levels of miR-923 and CA 15-3, combined with standard clinicopathological predictors, could be used as a preoperative, noninvasive estimate of patient prognosis to identify which women might need more aggressive treatment or closer surveillance after surgery for breast cancer.
Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/surgery , Cell-Free Nucleic Acids/blood , Neoplasm Recurrence, Local/epidemiology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Breast Neoplasms/blood , Breast Neoplasms/pathology , Case-Control Studies , Cell-Free Nucleic Acids/metabolism , Disease-Free Survival , Female , Gene Expression Profiling , Healthy Volunteers , Humans , Kaplan-Meier Estimate , Liquid Biopsy/methods , Mastectomy , MicroRNAs/blood , Middle Aged , Mucin-1/blood , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/prevention & control , Oligonucleotide Array Sequence Analysis , Predictive Value of Tests , Prognosis , ROC Curve , Risk Assessment/methodsABSTRACT
Genetic analysis of breast tumor core needle biopsies may provide early diagnostic information that is useful to direct subsequent clinical management. We report metaphase comparative genomic hybridization (CGH) analysis of 42 core needle biopsies prospectively sampled from invasive ductal breast carcinomas of 41 patients, and show that recurrent chromosomal copy number changes are associated with histologically defined tumor features. As far as is known, this is the first time CGH profiles from diagnostic breast tumor core needle biopsies have been reported in association with pathological data in such detail. A comparison of Grade 1 (n = 7), Grade 2 (n = 16), and Grade 3 tumors (n = 19) revealed a chromosomal copy number gain involving 8q22 that was associated with higher grade (1/7 vs. 16/19, respectively) and therefore altered cell differentiation status. CGH results were validated using tumor touch imprints prepared from a subgroup from the same sample set (n = 18) by fluorescence in situ hybridization (FISH) and two probes selected from regions of interest within 8p21 and 8q22. Overall concordance between CGH and FISH for 8p21 and 8q22 imbalances was 9/18 (50%) and 12/18 (67%), respectively. When FISH and CGH data were combined, and tumors classified according to better defined resected tumor histology available for 34cases, 19/19 Grade 3 tumors showed 8q22 gain compared with 0/6 Grade 1 tumors and 4/9 Grade 2 tumors. Further comprehensive studies are required to verify the biological significance of this association and its potential to facilitate early clinicopathological assessment of breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
Subject(s)
Breast Neoplasms/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 8 , Biopsy, Needle , Breast Neoplasms/pathology , Cohort Studies , Humans , In Situ Hybridization, Fluorescence , Neoplasm Invasiveness , Nucleic Acid HybridizationABSTRACT
Invasive ductal carcinomas of the breast (IDC) are routinely assessed on hematoxylin and eosin stained paraffin sections, with limited use of immunohistochemistry (IHC). Most IDC are regarded as a single diagnostic entity, IDC of no special type (IDC-NST), which is subdivided further only by grading. However, recent research suggests that there is high clinical relevance in differentiating IDC subtypes. Here, we ascertain whether tumor histology alone can predict basal or luminal cell phenotype in high-grade IDC-NST, and whether IHC and molecular characteristics are associated with the observed morphologies. A total of 29 grade 3 IDC-NST samples were studied, 10 tumors from a selected pilot cohort A and 19 tumors from an unselected validation cohort B. Along with histopathological assessment, the expression of ESR1, PGR, ERBB2 (HER-2), the basal/myoepithelial marker TP73L (p63), cytokeratins 5/6 (KRT5/6) and 14 (KRT14), and the luminal-specific cytokeratins 8/18 (KRT 8/18) and 19 (KRT19) was assessed by IHC. Hierarchical cluster analysis of clinicopathological variables and, separately, microarray expression profiles showed that the phenotypically distinctive basaloid and luminal tumors of cohort A fell into two main groups, defined by heterogeneous or uniformly positive expression of KRT8/18. The 38 genes differentially expressed between these two classes included ERBB2, KRT8, and six other genes previously associated with ERBB2-positive or luminal phenotypes. Tumor histology was not predictive for validation cohort B, but quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed two molecularly defined clusters that again aligned with the KRT8/18 staining phenotypes. Metaphase comparative genomic hybridization revealed 10q, 16q, and 20q copy-number imbalances that associated recurrently with KRT8/18 staining patterns.
Subject(s)
Breast Neoplasms/genetics , Keratin-18/genetics , Keratin-8/genetics , Neoplasm Invasiveness/genetics , Adult , Aged , Cohort Studies , DNA, Complementary , Female , Humans , Middle Aged , Nucleic Acid Hybridization , Oligonucleotide Array Sequence Analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND: Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)-α signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients. MATERIALS AND METHODS: We reduced ESR1 (gene encoding the ER-α protein) mRNA levels using small interfering RNA in ER+ MCF7 breast cancer cells and assayed for transcriptional changes using Affymetrix HG U133 Plus 2.0 arrays. We also compared 1034 ER+ and ER- breast tumors from publicly available microarray data. The principal components of ER activity generated from these analyses and from other published estrogen signatures were compared with ESR1 expression, ER-α IHC, and patient survival. RESULTS: Genes differentially expressed in both analyses were associated with ER-α IHC and ESR1 mRNA expression. They were also significantly enriched for estrogen-driven molecular pathways associated with ESR1, cyclin D1 (CCND1), MYC (v-myc avian myelocytomatosis viral oncogene homolog), and NFKB (nuclear factor kappa B). Despite their differing constituent genes, the principal components generated from these new analyses and from previously published ER-associated gene lists were all associated with each other and with the survival of patients with breast cancer treated with endocrine therapies. CONCLUSION: A biomarker of ER-α pathway activity, generated using ESR1-responsive mRNAs in MCF7 cells, when used alongside ER-α IHC and ESR1 mRNA expression, could provide a method for further stratification of patients and add insight into ER pathway activity in these patients.
Subject(s)
Breast Neoplasms/metabolism , Estrogen Receptor alpha/metabolism , Gene Expression Profiling , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Carrier Proteins , Estrogen Receptor alpha/genetics , Female , Humans , Immunohistochemistry , MCF-7 Cells , Practice Guidelines as Topic , RNA Interference , RNA, Messenger/metabolism , RNA, Small Interfering , Receptors, Estrogen , Signal Transduction , Tissue Array AnalysisABSTRACT
Tumours of perivascular epithelioid cells (PEComas) are being increasingly reported at visceral and somatic sites. Both benign and malignant variants have been identified, although clinical follow-up is often limited, which prevents meaningful predictions of behavior. We report the case of a malignant soft tissue PEComa with histologically confirmed regional lymph node metastases and radiologically confirmed pulmonary metastases. The light microscopic appearance and immunohistochemical profile (HMB-45, smooth muscle actin positive) and electron microscopic appearance support perivascular epithelioid cell differentiation.
Subject(s)
Carcinoma/secondary , Epithelioid Cells/pathology , Soft Tissue Neoplasms/pathology , Aged , Carcinoma/metabolism , Carcinoma/pathology , Epithelioid Cells/metabolism , Humans , Immunohistochemistry , Lung Neoplasms/secondary , Lymphatic Metastasis/pathology , Male , Microscopy, Electron, Transmission , Soft Tissue Neoplasms/metabolismABSTRACT
Breast core biopsy is one of the major nonoperative methods of diagnosis. Increasingly, there is also a need to provide prognostic data to facilitate timely patient management. We present the results from 500 patients with invasive breast carcinoma, who underwent core biopsy followed by a therapeutic surgical procedure. Grade and type of the invasive and in situ carcinoma, together with the presence or absence of vascular invasion, were determined in both biopsy and definitive surgical excision and the results compared. There was 67% agreement with overall grade (kappa value 0.48), with scores for tubule formation, pleomorphism, and mitotic scoring achieving values of 82%, 73%, and 58%, respectively. Only 60% of grade 1 and 2 carcinomas showed concordance, but 84% of grade 3 tumors showed agreement between core and excision results. Tumor typing, vascular invasion, and grading of ductal carcinoma in situ had agreement values of 74%, 69%, and 65%, respectively. The major problem with assessing prognostic factors on needle biopsy specimens is undersampling of the most informative areas. However, in those patients in whom preoperative assessment of prognostic factors is most likely to be beneficial, i.e., those with grade 3 carcinomas, a high level of agreement was achieved in this large study.