Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors ...is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms 'BRAF,' 'mutation,' and 'cancer/tumor.' These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression.
The Tumor-Node-Metastasis (TNM) classification on cancer staging, jointly developed by the American Joint Commission on Cancer (AJCC) and the Union for International Cancer Control (UICC), has been ...updated to its 8th edition with two contemporaneous versions published by the AJCC and UICC. While the goal of the AJCC and UICC is to have identical TNM staging systems, differences exist between these two publications including in the staging of urologic cancers. Among several new facets in the AJCC staging manual, a select few of greater import include an expanded section on imaging, presentation of levels of evidence for significant changes, and endorsement of risk assessment models that pass the AJCC quality criteria such as in prostate cancer. The updates for urologic cancers in the AJCC stage categories can be grouped into: (1) newly defined TNM categories and prognostic stage groupings, (2) clarifications and refinements of previously defined categories, and (3) more systematic and expanded presentation of prognostic factors. Changes are harmonized with the current reporting and treatment guidelines. Contributions from genitourinary pathology are evident in the AJCC classification from many of the International Society of Urological Pathology (ISUP) consensus conferences on prostate, kidney, testicular, and penile neoplasms that addressed staging issues and the timely publication of the 4th edition of the World Health Organization (WHO) classification of urinary and male genital organ tumors. New grading approaches for penile (WHO/ISUP grade), prostate (Grade group), and kidney (WHO/ISUP nucleolar grade) cancers were adopted in the AJCC system. Many of these updates in the AJCC staging manual are also included in the 8th UICC TNM edition. In an effort to achieve the optimal staging recommendations for urologic cancers, updates in the 8th TNM edition were generated through the acquisition of best evidences, tapping interdisciplinary resources including consensus recommendations, and enhanced data analysis.
In this report, we explain the seminal changes in the 8th edition of the Tumor-Node-Metastasis staging system for urologic cancers. Major stage category definitional changes are in Tumor-Node-Metastasis classifications of testicular, penile, and prostate cancer which improve patient stratification for prognosis and management.
Refining the standards that provide the best possible staging system is a never-ending process. The 8th edition continues in that tradition with a more focused attempt to incorporate nonanatomic factors into staging. This approach is most evident in staging of prostate cancers where nonanatomic factors including grade of tumor and serum prostate specific antigen levels significantly impact American Joint Committee on Cancer prognostic stage group assignment whereby which even some organ-confined cancers may be classified as stage III cancer.
A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial ...carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.
Abstract Context The clinical significance of positive surgical margins (PSMs) in radical prostatectomy (RP) specimens and the management of affected patients remain unclear. Objective To address ...pitfalls in the pathologic interpretation of margin status; provide an update on the incidence, predictors, and long-term oncologic implications of PSMs in the era of robot-assisted laparoscopic RP (RALRP); and suggest a practical evidence-based approach to patient management. Evidence acquisition A systematic review of the literature was performed in April 2013 using Medline/PubMed, Web of Science, and Scopus databases and the Cochrane Database of Systematic Reviews. Studies focusing on PSMs in RP pertinent to the objectives of this review were included. Particular attention was paid to publications within the last 5 yr and those concerning RALRP. Evidence synthesis A total of 74 publications were retrieved. Standardized measures to overcome variability in the pathologic interpretation of surgical margins have recently been established by the International Society of Urological Pathology. The average rate of PSMs in contemporary RALRP series is 15% (range: 6.5–32%), which is higher in men with a more advanced pathologic stage and equivalent to the rate reported in prior open and laparoscopic prostatectomy series. The likelihood of PSMs is strongly influenced by the surgeon's experience irrespective of the surgical approach. Technical modifications using the robotic platform and the role of frozen-section analysis to reduce the margin positivity rate continue to evolve. Positive margins are associated with a twofold increased hazard of biochemical relapse, but their association with more robust clinical end points is controversial. Level 1 evidence suggests that adjuvant radiation therapy (RT) may favorably affect prostate-specific antigen recurrence rates, but whether the therapy also affects systemic progression, prostate cancer–specific mortality, and overall survival remains debatable. Conclusions Although positive margins in prostate cancer are considered an adverse oncologic outcome, their long-term impact on survival is highly variable and largely influenced by other risk modifiers. Adjuvant RT appears to be effective, but further study is required to determine whether early salvage RT is an equivalent alternative.
Abstract Context Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). Objective To understand the ...mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. Evidence acquisition PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants , and AR alterations . Papers published before 1990 were excluded from the review, and only English-language papers were included. Evidence synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC. Patient summary We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non–AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.
Management of bladder cancer (BC) is primarily driven by stage, grade, and biological potential. Knowledge of each is derived using clinical, histopathological, and radiological investigations. This ...multimodal approach reduces the risk of error from one particular test, but may present a staging dilemma when results conflict. Multiparametric magnetic resonance imaging (mpMRI) may improve patient care through imaging of the bladder with better resolution of the tissue planes than computed tomography and without radiation exposure.
To define a standardized approach to imaging and reporting mpMRI for BC, by developing a VI-RADS score.
We created VI-RADS (Vesical Imaging-Reporting And Data System) through consensus using existing literature.
We describe standard imaging protocols and reporting criteria (including size, location, multiplicity, and morphology) for bladder mpMRI. We propose a five-point VI-RADS score, derived using T2-weighted MRI, diffusion-weighted imaging, and dynamic contrast enhancement, which suggests the risks of muscle invasion. We include sample images used to understand VI-RADS.
We hope that VI-RADS will standardize reporting, facilitate comparisons between patients, and in future years, will be tested and refined if necessary. While we do not advocate mpMRI for all patients with BC, this imaging may compliment pathology or reduce radiation-based imaging. Bladder mpMRI may be most useful in patients with non–muscle-invasive cancers, in expediting radical treatment or for determining response to bladder-sparing approaches.
Magnetic resonance imaging (MRI) scans for bladder cancer are becoming more common and may provide accurate information that helps improve patient care. Here, we describe a standardized reporting criterion for bladder MRI. This should improve communication between doctors and allow better comparisons between patients.
Magnetic resonance imaging (MRI) scans for bladder cancer are becoming more common and may provide accurate information that helps improve patient care. Here, we describe a standardized reporting criterion for bladder MRI. This should improve communication between doctors and allow better comparisons between patients.
Variants and new entities of bladder cancer Lopez‐Beltran, Antonio; Henriques, Vanessa; Montironi, Rodolfo ...
Histopathology,
January 2019, Volume:
74, Issue:
1
Journal Article
Peer reviewed
Pathological evaluation of bladder cancer typically reveals great tumour heterogeneity, and therefore the common observation of urothelial carcinoma exhibiting a wide variety of histopathological ...patterns is not surprising. Some of these patterns are so distinctive that they have been recognised as specific variants of urothelial carcinoma. Classifications have recently been revised in the 2016 World Health Organisation (WHO) classification of tumours of the urinary system and male genital organs. The current WHO classifications clarify terminological issues and provide better definition criteria, but also incorporate some new entities. Many of these variants have important prognostic or therapeutic implications worth knowing by the urologist and oncologist, but also represent diagnostic challenges in daily pathology practice. This review will discuss the features of variants of urothelial carcinoma in the context of our current clinical practice. Histological variations and new entities of bladder cancer not included in the current WHO classification of urothelial tumours will be briefly discussed.
Abstract Context Prostate cancer (PCa) is the most common cancer in the adult male, and benign prostatic hyperplasia (BPH) represents the most frequent urologic diagnosis in elderly males. Recent ...data suggest that prostatic inflammation is involved in the pathogenesis and progression of both conditions. Objective This review aims to evaluate the available evidence on the role of prostatic inflammation as a possible common denominator of BPH and PCa and to discuss its possible clinical implication for the management, prevention, and treatment of both diseases. Evidence acquisition The National Library of Medicine Database was searched for the following Patient population, Intervention, Comparison, Outcome (PICO) terms: male, inflammation, benign prostatic hyperplasia, prostate cancer, diagnosis, progression, prognosis, treatment, and prevention. Basic and clinical studies published in the past 10 yr were reviewed. Additional references were obtained from the reference list of full-text manuscripts. Evidence synthesis The histologic signature of chronic inflammation is a common finding in benign and malignant prostate tissue. The inflammatory infiltrates are mainly represented by CD3+ T lymphocytes (70–80%, mostly CD4), CD19 or CD20 B lymphocytes (10–15%), and macrophages (15%). Bacterial infections, urine reflux, dietary factors, hormones, and autoimmune response have been considered to cause inflammation in the prostate. From a pathophysiologic standpoint, tissue damage associated with inflammatory response and subsequent chronic tissue healing may result in the development of BPH nodules and proliferative inflammatory atrophy (PIA). The loss of glutathione S-transferase P1 (GSTP1) may be responsible in patients with genetic predisposition for the transition of PIA into high-grade intraepithelial neoplasia (HGPIN) and PCa. Although there is growing evidence of the association among inflammatory response, BPH, and PCa, we can only surmise on the immunologic mechanisms involved, and further research is required to better understand the role of prostatic inflammation in the initiation of BPH and PCa. There is not yet proof that targeting prostate inflammation with a pharmacologic agent results in a lower incidence and progression or regression of either BPH or PCa. Conclusions Evidence in the peer-reviewed literature suggested that chronic prostatic inflammation may be involved in the development and progression of chronic prostatic disease, such as BPH and PCa, although there is still no evidence of a causal relation. Inflammation should be considered a new domain in basic and clinical research in patients with BPH and PCa.
Staging of bladder cancer Magers, Martin J; Lopez‐Beltran, Antonio; Montironi, Rodolfo ...
Histopathology,
January 2019, Volume:
74, Issue:
1
Journal Article
Peer reviewed
Urothelial carcinoma of the urinary bladder is a heterogeneous disease with multiple possible treatment modalities and a wide spectrum of clinical outcome. Treatment decisions and prognostic ...expectations hinge on accurate and precise staging, and the recently published American Joint Committee on Cancer (AJCC) Staging Manual, 8th edition, should be the basis for staging of urinary bladder tumours. It is unfortunate that the International Union Against Cancer (UICC) 8th edition failed to incorporate new data which is considered in the AJCC 8th edition. Thus, the AJCC 8th edition is the focus of this review. Several critical changes and clarifications are made by the AJCC 8th edition relative to the 7th edition. Although the most obvious changes in the 8th edition are in the N (i.e. perivesical lymph node involvement now classified as N1) and M (i.e. M1 is subdivided into M1a and M1b) categories, several points are clarified in the T category (e.g. substaging of pT1 should be attempted). Further optimisation, however, is required. No particular method of substaging pT1 is formally recommended. In this review, these modifications are discussed, as well as points, which require further study and optimisation.
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