Diagnostic Imaging in the Evaluation of Asymptomatic Microhematuria: Systematic Review and Meta-analysis.

PURPOSE: Microhematuria is a highly prevalent condition with a low associated risk of urothelial and upper tract malignancy. The AUA Guidelines recently changed recommendations for imaging favoring renal ultrasound for low- and intermediate-risk patients with microhematuria. We summarize the diagnostic test characteristics of computed tomography urography, renal ultrasound, and magnetic resonance urography in comparison with surgical pathology for the diagnosis of upper urinary tract cancer in microhematuria and gross hematuria patients. MATERIALS AND METHODS: This study is a systematic review and meta-analysis using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines from evidence collected for the 2020 AUA Microhematuria Guidelines report, including studies assessing imaging following diagnosis of hematuria published from January 2010 through December 2019. RESULTS: The search identified 20 studies which reported the prevalence of malignant and benign diagnoses in relation to imaging modality, of which 6 were included in the quantitative analysis. For the detection of renal cell carcinoma and upper urinary tract carcinoma in patients with microhematuria and gross hematuria, computed tomography urography had a sensitivity of 94% (95% CI, 84%-98%) and a specificity of 99% (95%CI, 97%-100%) with a certainty of evidence rating of very low and low, respectively when 4 studies were pooled. In comparison, ultrasound demonstrated a sensitivity ranging from 14%-96% (low certainty of evidence) and a specificity of 99%-100% in 2 studies (moderate certainty of evidence), while magnetic resonance urography demonstrated a sensitivity of 83% and specificity of 86% in 1 study with a low certainty of evidence. CONCLUSIONS: In a limited data set for each individual imaging modality, computed tomography urography appears the most sensitive imaging modality for the diagnostic evaluation of microhematuria. Future studies will be needed to evaluate the clinical and health system financial impacts of the change in guideline recommendations from computed tomography urography to renal ultrasound in evaluating low- and intermediate-risk patients with microhematuria.

Molecular Biomarker Testing for the Diagnosis of Diffuse Gliomas.

CONTEXT.­: The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. OBJECTIVE.­: To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. DESIGN.­: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, "What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?" Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus. RESULTS.­: Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs. CONCLUSIONS.­: Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management.

The AUA/SUFU Guideline on Adult Neurogenic Lower Urinary Tract Dysfunction: Treatment and Follow-up.

PURPOSE: The clinician treating patients with neurogenic lower urinary tract dysfunction (NLUTD) needs to balance a variety of factors when making treatment decisions. In addition to the patient's urologic symptoms and urodynamic findings, other issues that may influence management options of the lower urinary tract include cognition, hand function, type of neurologic disease, mobility, bowel function/management, and social and caregiver support. This Guideline allows the clinician to understand the options available to treat patients, understand the findings that can be seen in NLUTD, and appreciate which options are best for each individual patient. This allows for decisions to be made with the patient, in a shared decision-making manner, such that the patient's quality of life can be optimized with respect to their bladder management. MATERIALS AND METHODS: A comprehensive search for studies assessing patients undergoing evaluation, surveillance, management, or follow-up for NLUTD was conducted from January 2001 through October 2017 and was rerun in February 2021 to capture newer literature. The primary search returned 20,496 unique citations. Following a title and abstract screen, full texts were obtained for 3,036 studies. During full-text review, studies were primarily excluded for not meeting the PICO criteria. One hundred eight-four primary literature studies met the inclusion criteria and were included in the evidence base. RESULTS: This guideline was developed to inform clinicians on the proper evaluation, diagnosis, and risk stratification of adult patients with NLUTD and the non-surgical and surgical treatment options available. Additional statements on urinary tract infection and autonomic dysreflexia were developed to guide the clinician. CONCLUSIONS: NLUTD patients may undergo non-surgical and surgical treatment options depending on their level of risk, symptoms, and urodynamic findings. Appropriate follow-up, primarily based on their risk stratification, must be maintained after treatment.

The AUA/SUFU Guideline on Adult Neurogenic Lower Urinary Tract Dysfunction: Diagnosis and Evaluation.

PURPOSE: The clinician treating patients with neurogenic lower urinary tract dysfunction (NLUTD) needs to balance a variety of factors when making treatment decisions. In addition to the patient's urologic symptoms and urodynamic findings, other issues that may influence management options of the lower urinary tract include cognition, hand function, type of neurologic disease, mobility, bowel function/management, and social and caregiver support. This Guideline allows the clinician to understand the options available to treat patients, understand the findings that can be seen in NLUTD, and appreciate which options are best for each individual patient. This allows for decisions to be made with the patient, in a shared decision-making manner, such that the patient's quality of life can be optimized with respect to their bladder management. MATERIALS AND METHODS: A comprehensive search for studies assessing patients undergoing evaluation, surveillance, management, or follow-up for NLUTD was conducted from January 2001 through October 2017 and was rerun in February 2021 to capture newer literature. The primary search returned 20,496 unique citations. Following a title and abstract screen, full texts were obtained for 3,036 studies. During full-text review, studies were primarily excluded for not meeting the PICO criteria. One hundred eight-four primary literature studies met the inclusion criteria and were included in the evidence base. RESULTS: This guideline was developed to inform clinicians on the proper evaluation, diagnosis, and risk stratification of patients with NLUTD and the non-surgical and surgical treatment options available. Additional statements on urinary tract infection and autonomic dysreflexia were developed to guide the clinician. This Guideline is for adult patients with NLUTD and pediatric NLUTD will not be discussed. CONCLUSIONS: NLUTD patients should be risk-stratified as either low-, moderate-, high-, or unknown-risk. After diagnosis and stratification, patients should be monitored according to their level of risk at regular intervals. Patients who experience new or worsening signs and symptoms should be reevaluated and risk stratification should be repeated.

Executive Summary: Screening for Lung Cancer: Chest Guideline and Expert Panel Report.

BACKGROUND: Low-dose chest CT screening for lung cancer has become a standard of care in the United States, in large part because of the results of the National Lung Screening Trial (NLST). Additional evidence supporting the net benefit of low-dose chest CT screening for lung cancer, and increased experience in minimizing the potential harms, has accumulated since the prior iteration of these guidelines. Here, we update the evidence base for the benefit, harms, and implementation of low-dose chest CT screening. We use the updated evidence base to provide recommendations where the evidence allows, and statements based on experience and expert consensus where it does not. METHODS: Approved panelists reviewed previously developed key questions using the Population, Intervention, Comparator, Outcome format to address the benefit and harms of low-dose CT screening, and key areas of program implementation. A systematic literature review was conducted using MEDLINE via PubMed, Embase, and the Cochrane Library on a quarterly basis since the time of the previous guideline publication. Reference lists from relevant retrievals were searched, and additional papers were added. Retrieved references were reviewed for relevance by two panel members. The quality of the evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations, Assessment, Development and Evaluation approach. Meta-analyses were performed where appropriate. Important clinical questions were addressed based on the evidence developed from the systematic literature review. Graded recommendations and ungraded statements were drafted, voted on, and revised until consensus was reached. RESULTS: The systematic literature review identified 75 additional studies that informed the response to the 12 key questions that were developed. Additional clinical questions were addressed resulting in seven graded recommendations and nine ungraded consensus statements. CONCLUSIONS: Evidence suggests that low-dose CT screening for lung cancer can result in a favorable balance of benefit and harms. The selection of screen-eligible individuals, the quality of imaging and image interpretation, the management of screen-detected findings, and the effectiveness of smoking cessation interventions can impact this balance.

Screening for Lung Cancer: CHEST Guideline and Expert Panel Report.

BACKGROUND: Low-dose chest CT screening for lung cancer has become a standard of care in the United States, in large part because of the results of the National Lung Screening Trial (NLST). Additional evidence supporting the net benefit of low-dose chest CT screening for lung cancer, and increased experience in minimizing the potential harms, has accumulated since the prior iteration of these guidelines. Here, we update the evidence base for the benefit, harms, and implementation of low-dose chest CT screening. We use the updated evidence base to provide recommendations where the evidence allows, and statements based on experience and expert consensus where it does not. METHODS: Approved panelists reviewed previously developed key questions using the Population, Intervention, Comparator, Outcome format to address the benefit and harms of low-dose CT screening, and key areas of program implementation. A systematic literature review was conducted using MEDLINE via PubMed, Embase, and the Cochrane Library on a quarterly basis since the time of the previous guideline publication. Reference lists from relevant retrievals were searched, and additional papers were added. Retrieved references were reviewed for relevance by two panel members. The quality of the evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Meta-analyses were performed when enough evidence was available. Important clinical questions were addressed based on the evidence developed from the systematic literature review. Graded recommendations and ungraded statements were drafted, voted on, and revised until consensus was reached. RESULTS: The systematic literature review identified 75 additional studies that informed the response to the 12 key questions that were developed. Additional clinical questions were addressed resulting in seven graded recommendations and nine ungraded consensus statements. CONCLUSIONS: Evidence suggests that low-dose CT screening for lung cancer can result in a favorable balance of benefit and harms. The selection of screen-eligible individuals, the quality of imaging and image interpretation, the management of screen-detected findings, and the effectiveness of smoking cessation interventions can impact this balance.

Microhematuria: AUA/SUFU Guideline.

PURPOSE: Patients presenting with microhematuria represent a heterogeneous population with a broad spectrum of risk for genitourinary malignancy. Recognizing that patient-specific characteristics modify the risk of underlying malignant etiologies, this guideline sought to provide a personalized diagnostic testing strategy. MATERIALS AND METHODS: The systematic review incorporated evidence published from January 2010 through February 2019, with an updated literature search to include studies published up to December 2019. Evidence-based statements were developed by the expert Panel, with statement type linked to evidence strength, level of certainty, and the Panel's judgment regarding the balance between benefits and risks/burdens. RESULTS: Microhematuria should be defined as ≥ 3 red blood cells per high power field on microscopic evaluation of a single specimen. In patients diagnosed with gynecologic or non-malignant genitourinary sources of microhematuria, clinicians should repeat urinalysis following resolution of the gynecologic or non-malignant genitourinary cause. The Panel created a risk classification system for patients with microhematuria, stratified as low-, intermediate-, or high-risk for genitourinary malignancy. Risk groups were based on factors including age, sex, smoking and other urothelial cancer risk factors, degree and persistence of microhematuria, as well as prior gross hematuria. Diagnostic evaluation with cystoscopy and upper tract imaging was recommended according to patient risk and involving shared decision-making. Statements also inform follow-up after a negative microhematuria evaluation. CONCLUSIONS: Patients with microhematuria should be classified based on their risk of genitourinary malignancy and evaluated with a risk-based strategy. Future high-quality studies are required to improve the care of these patients.

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

CONTEXT: - In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: - To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN: - The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS: - Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS: - The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes ( ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.

The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer.

BACKGROUND: TBX3 is a T-box transcription factor repressor that is elevated in metastatic breast cancer and is believed to promote malignancy of tumor cells, possibly by promoting cell survival and epithelial-mesenchymal transition. METHODS: The relative expression of TBX3 was assessed in the 21T cell lines which were derived from an individual patient and represent three distinct stages of breast cancer progression: 21PT, atypical ductal hyperplasia; 21NT, ductal carcinoma in situ; and 21MT-1, invasive mammary carcinoma. Two different isoforms of TBX3 (TBX3iso1 and TBX3iso2) were overexpressed to evaluate cell survival/colony forming ability, growth, and invasion in the ductal carcinoma in situ-like 21NT cell line using an in vitro Matrigel model of cancer progression. In addition, TBX3 expression was knocked down to evaluate the effects of downregulating TBX3 on the invasive mammary carcinoma-like 21MT-1 cell line. Finally, PCR array profiling was used to assess alterations in gene expression due to TBX3 overexpression in the 21NT cells. RESULTS: TBX3 is abundant in the invasive 21MT-1 cell line, while being minimally expressed in the non-invasive 21NT and 21PT cell lines. Overexpression of either TBX3iso1 or TBX3iso2 in 21NT cells resulted in increased cell survival/colony forming ability, growth vs. apoptosis and invasion in Matrigel. In contrast, short hairpin RNA-mediated knockdown of TBX3 in the 21MT-1 cells resulted in smaller colonies, with a more regular, less dispersed (less infiltrative) morphology. Array profiling of the 21NT TBX3 iso1 and iso2 transfectants showed that there are common alterations in expression of several genes involved in signal transduction, cell cycle control/cell survival, epithelial-mesenchymal transition and invasiveness. CONCLUSIONS: Overall, these results indicate that TBX3 (isoform 1 or 2) expression can promote progression in a model of early breast cancer by altering cell properties involved in cell survival/colony formation and invasiveness, as well as key regulatory and EMT/invasiveness-related gene expressions.

Human 21T breast epithelial cell lines mimic breast cancer progression in vivo and in vitro and show stage-specific gene expression patterns.

Early breast cancer progression involves advancement through specific morphological stages including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive mammary carcinoma (IMC), although not necessarily always in a linear fashion. Observational studies have examined genetic, epigenetic and gene expression differences in breast tissues representing these stages of progression, but model systems which would allow for experimental testing of specific factors influencing transition through these stages are scarce. The 21T series cell lines, all originally derived from the same patient with metastatic breast cancer, have been proposed to represent a mammary tumor progression series. We report here that three of the 21T cell lines indeed mimic specific stages of human breast cancer progression (21PT-derived cells, ADH; 21NT-derived cells, DCIS; 21MT-1 cells, IMC) when grown in the mammary fat pad of nude mice, albeit after a year. To develop a more rapid, readily manipulatable in vitro assay for examining the biological differences between these cell lines, we have used a 3D Matrigel system. When the three cell lines were grown in 3D Matrigel, they showed characteristic morphologies, in which quantifiable aspects of stage-specific in vivo behaviors (ie, differences in acinar structure formation, cell polarization, colony morphology, cell proliferation, cell invasion) were recapitulated in a reproducible fashion. Gene expression profiling revealed a characteristic pattern for each of the three cell lines. Interestingly, Wnt pathway alterations are particularly predominant in the early transition from 21PTci (ADH) to 21NTci (DCIS), whereas alterations in expression of genes associated with control of cell motility and invasion phenomena are more prominent in the later transition of 21NTci (DCIS) to 21MT-1 (IMC). This system thus reveals potential therapeutic targets and will provide a means of testing the influences of identified genes on transitions between these stages of pre-malignant to malignant growth.

Distinct karyotypes in three breast cancer cell lines --21PTCi, 21NTCi, and 21MT-1 --derived from the same patient and representing different stages of tumor progression.

Three breast carcinoma cell lines --21PTCi, 21NTCi, and 21MT-1 --all originating from a 36-year-old woman with metastatic breast cancer, have been characterized previously as stably representing different stages of progression: (nontumorigenic [21PTCi]; tumorigenic, nonmetastatic [21NTCi]; and tumorigenic, weakly metastatic [21MT-1]). These cell lines were investigated for cytogenetic characteristics using G-banding and spectral karyotyping. All three cell lines have multiple chromosome aberrations, but they differ in the types of rearrangements and breakpoints. 21PTCi cells have a modal number (mn) of 56, with 55 types of aberrations, including 16 numeric and 39 structural. 21NTCi cells have a mn of 56, with 70 types of aberrations, including 19 numerical and 51 structural. Finally, 21MT-1 cells have a mn of 54, with 43 types of aberrations, including 14 numerical and 29 structural. The most common rearrangements differ in each cell line [i.e., der(X)t(X;3), der(4)t(1;4), del(6q) and der(19)t(17;19)(q11.2;q13.4) in 21PTCi; der(4)t(1;4), der(12)t(12;15) and -16 in 21NTCi; and der(1)t(1;10), +5, der(6)t(6;7), der(11)t(11;13), -20, and der(20)t(20;21) in 21MT-1]. This cytogenetic result is consistent with previous findings in that the three cell lines represent different stages of tumor progression. We hypothesize that the cytogenetic changes in these cell lines may be related to their distinct biologic characteristics. These three cell lines, with their different karyotypes and biologic characteristics, provide a vital tool for further study of the genetic and epigenetic events involved in transitions between premalignant and malignant phenotypes.