Purpose To assess the applicability of active surveillance in patients with intermediate risk prostate cancer, we compared the survival outcomes of patients with low risk and intermediate risk ...disease. Materials and Methods Active surveillance was offered to all patients with low risk (cT1-T2b and Gleason score 6 and prostate specific antigen 10 ng/ml or less) and select intermediate risk disease (age greater than 70 years with cT2c or prostate specific antigen 15 ng/ml or less, or Gleason score 3+4 or less). Data from November 1995 to May 2013 were extracted from a prospectively collected database. The primary outcome was metastasis-free survival, and secondary outcomes were overall survival, cause specific survival and treatment-free survival. Results A total of 213 intermediate risk and 732 low risk cases were identified. Median age was 72 years (IQR 67.3, 76.8) in the intermediate risk cohort and 67 years (IQR 60.6, 71.9) in the low risk group. Median followup was comparable (6.7 years for intermediate risk vs 6.5 years for low risk). Gleason 7 disease comprised 60% of the intermediate risk cohort. The 15-year metastasis-free, overall, cause specific and treatment-free survival rates were inferior in the intermediate risk group (metastasis-free survival HR 3.14, 95% CI 1.51–6.53, p=0.001, 82% for intermediate risk vs 95% for low risk). On further evaluation the estimated 15-year metastasis-free survival for cases of Gleason 6 or less with prostate specific antigen less than 10 ng/ml was 94%, Gleason 6 or less with prostate specific antigen 10 to 20 ng/ml was 94%, Gleason 3+4 with prostate specific antigen 20 ng/ml or less was 84% and Gleason 4+3 with prostate specific antigen 20 ng/ml or less was 63%. Conclusions These data support the use of active surveillance in low risk and intermediate risk cases of Gleason 6 but not Gleason 7 prostate cancer. Multiparametric magnetic resonance imaging and novel biomarkers might be vital in detecting favorable Gleason 7 disease.
Programmed death ligand-1 (PD-L1) immunohistochemistry is used to guide treatment decisions regarding the use of checkpoint immunotherapy in the management of urothelial carcinoma of the bladder and ...hypopharyngeal (HP) squamous cell carcinoma. With increasing PD-L1 testing options, a need has arisen to assess the analytical comparability of diagnostic assays in order to develop a more sustainable testing strategy. Using tissue microarrays, PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was manually scored in 197 cases and 27 cases of bladder and HP cancer, respectively. Three commercial kits (Ventana SP263, Ventana SP142, Dako 22C3) and 1 platform-independent test (Cell Signalling Technologies E1L3N) were utilized. Across the 3 commercially available clones, 14% and 74% of urothelial carcinomas were positive and negative, respectively, whereas 7% and 78% of HP carcinomas were positive and negative, respectively. Twelve percent of bladder and 15% HP cases showed discrepant PD-L1 classification results. Regardless of the scoring algorithm used, E1L3N provided comparable PD-L1 staining results. Fleiss’ kappa and intraclass correlation coefficient (ICC) analyses demonstrated substantial agreement among all antibody clones (k=0.639 to 0.791) and excellent reliability among SP263, 22C3, and E1L3N antibodies (ICC, 0.929 to 0.949) in TC staining. Compared with the other 3 clones, SP142 TC staining was lower with only moderate correlation (ICC, 0.500 to 0.619). Generally, the reliability of immune cell staining was lower compared with TC staining (ICC, 0.519 to 0.866). Our results demonstrate good analytic comparability of all 4 antibodies. The results are encouraging and support growing optimism in the pathology and oncology communities concerning strategies in PD-L1 assay use.
Radiotherapy (RT) for breast cancer improves survival, but poses risk to the heart, resulting from a linear relationship between RT dose and heart disease. This review presents studies worldwide ...reporting heart doses from whole breast RT after 2014 to update a previous systematic review (Taylor et al, Int J Radiat Oncol Biol Phys, 2015) in order to determine patterns of current heart dosimetry among varying RT regimens. Studies published between January 2014 and September 2017 were included if they reported whole heart dose based on whole breast RT technique or treatment position and had a sample size of ≥ 20 patients. Studies reporting brachytherapy, proton RT only, or boost to tumor bed were excluded. Among 99 studies, whole heart dose was reported by 231 regimens. The mean heart dose for left-sided breast cancer, reported by 84 studies (196 regimens), was 3.6 Gy, compared with a review of those previously reported (5.4 Gy). Regimens employing breathing control in any position had a significantly lower mean heart dose (1.7 Gy) compared with regimens without breathing control (4.5 Gy) (P < .0001). The mean heart dose varied significantly between continents (P < .0001), with heterogeneity reported among countries within Europe (P = .04) although not within other continents. On average, the mean heart dose steadily decreased between 2014 (4.6 Gy) and 2017 (2.6 Gy) (P = .003). Other heart dose parameters including the mean dose to the left anterior descending artery were reported by 80 left-sided regimens, and the mean left anterior descending artery dose was 12.4 Gy.
Tumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune ...gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profıle and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies.
It is not clear to what extent the age of diagnosis and the attained age impact on cancer mortality rates in men with newly diagnosed prostate cancer. We estimated annual prostate cancer mortality ...rates and 20-year survival rates according to the age of diagnosis, race, grade and time since diagnosis using data from the Surveillance, Epidemiology and End-Results (SEER) program. We identified 116,796 prostate cancer patients diagnosed between 1992 and 1997 and followed them for 20 years. There were 21,896 deaths from prostate cancer. We calculated actuarial survival rates and annual prostate cancer mortality rates by age of diagnosis and by tumor grade. The risk of a man dying of prostate cancer was 17% for men diagnosed before age 70 and was 21% for those diagnosed after age 70. The mean annual prostate cancer mortality rate calculated over the 20-year period post-diagnosis was 1.5%. The annual rate increased from 0.9% for those diagnosed below age 60 to 2.1% for those diagnosed above age 70. For men with Gleason score ≥ 7 prostate cancer, the annual prostate cancer mortality rate peaked 2–3 years after diagnosis and then declined. For men diagnosed with Gleason score ≤ 6 prostate cancer, the annual prostate cancer mortality rate continued to rise 20 years after diagnosis and peaked after age 85. This suggests that high-grade prostate cancers are aggressive from the outset, but that low-grade prostate cancers may enter a state of dormancy and reactivate as the patient ages.
Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing ...to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated radiation treatment. One miR candidate found to be upregulated by ionizing radiation was miR-95, the enforced expression of which promoted radiation resistance in a variety of cancer cells. miR-95 overexpression recapitulated an aggressive phenotype including increased cellular proliferation, deregulated G2-M checkpoint following ionizing radiation, and increased invasive potential. Using combined in silico prediction and microarray expression analyses, we identified and validated the sphingolipid phosphatase SGPP1, an antagonist of sphingosine-1-phosphate signaling, as a target of miR-95 that promotes radiation resistance. Consistent with this finding, cell treatment with FTY720, a clinically approved small molecule inhibitor of S1P signaling, sensitized miR-95 overexpressing cells to radiation treatment. In vivo assays extended the significance of these results, showing that miR-95 overexpression increased tumor growth and resistance to radiation treatment in tumor xenografts. Furthermore, reduced tumor necrosis and increased cellular proliferation were seen after radiation treatment of miR-95 overexpressing tumors compared with control tumors. Finally, miR-95 expression was increased in human prostate and breast cancer specimens compared with normal tissue. Together, our work reveals miR-95 expression as a critical determinant of radiation resistance in cancer cells.
Prostate cancer is the second most frequently diagnosed non-skin cancer in men worldwide. Patient outcomes are remarkably heterogeneous and the best existing clinical prognostic tools such as ...International Society of Urological Pathology Grade Group, pretreatment serum PSA concentration and T-category, do not accurately predict disease outcome for individual patients. Thus, patients newly diagnosed with prostate cancer are often overtreated or undertreated, reducing quality of life and increasing disease-specific mortality. Biomarkers that can improve the risk stratification of these patients are, therefore, urgently needed. The ideal biomarker in this setting will be non-invasive and affordable, enabling longitudinal evaluation of disease status. Prostatic secretions, urine and blood can be sources of biomarker discovery, validation and clinical implementation, and mass spectrometry can be used to detect and quantify proteins in these fluids. Protein biomarkers currently in use for diagnosis, prognosis and relapse-monitoring of localized prostate cancer in fluids remain centred around PSA and its variants, and opportunities exist for clinically validating novel and complimentary candidate protein biomarkers and deploying them into the clinic.
Active surveillance (AS) for prostate cancer (PCa) relies on regular PSA tests and surveillance biopsies. Compliance rates with biopsies vary but the subsequent impact on oncologic outcomes is not ...known. The objective of this study was to determine whether non-compliance with the confirmatory biopsy negatively impacts PCa-specific outcomes.
A retrospective analysis was performed on a prospective single-arm cohort of men enrolled in AS for PCa between 1995 and 2018 with a median follow-up of 9.1 years. A total of 1,275 patients were enrolled and 1,043 patients had a minimum of three years of follow-up and were included in the analysis. Patients were stratified by compliance with a confirmatory biopsy within 24 months of enrollment in AS. The primary outcome was recurrence-free survival (RFS). Secondary outcomes included metastatic-free survival (MFS), and cause-specific survival (CSS).
A total of 1,275 patients were enrolled and 1,043 patients had a minimum of three years of follow-up and were included in the analysis, of which 425 were treated for localized PCa. Patients non-compliant with the confirmatory biopsy had higher rates of recurrence post-treatment (19% versus 12%, HR=1.64, 95% CI 1.19-2.26, p=0.003) and metastases (7% versus 2%, HR=3.56, 95% CI 1.8-7.0, p=0.0003) even after accounting for age, PSA, and Grade Group (GG). CSS was not significantly different between the two groups. The results were consistent even in the subset of patients with GG 1 at study entry.
Non-compliance with a confirmatory biopsy compromises the control of PCa in men followed on AS. Patients and physicians should be aware of the importance of adhering to protocol for men on AS.
Radiation dermatitis is a common adverse effect of radiotherapy (RT) in breast cancer patients. Although radiation dermatitis is reported by either the clinician or the patient, previous studies have ...shown disagreement between clinician-reported outcomes (CROs) and patient-reported outcomes (PROs). This review evaluated the extent of discordance between CROs and PROs for radiation dermatitis. Studies reporting both clinician and patient-reported outcomes for external beam RT were eligible. Nine studies met the inclusion criteria for the systematic review, while 8 of these studies were eligible for inclusion in a meta-analysis of acute and late skin toxicities. We found an overall agreement between CROs and PROs of acute skin colour change, fibrosis and/or retraction, and moist desquamation (p > 0.005). Reporting of late breast pain, breast edema, skin colour change, telangiectasia, fibrosis and/or retraction and induration/fibrosis alone (p > 0.005) were also in agreement between clinicians and patients. Our meta-analysis revealed a greater reporting of acute breast pain by patients (RR = 0.89, 95% CI 0.87–0.92, p < 0.001), greater reporting of acute breast edema by physicians (RR = 1.80, 95% CI 1.65–1.97, p < 0.001) and a greater reporting of late breast shrinkage by patients (RR = 0.61, 95% CI 0.44–0.86, p = 0.005). However, our review was limited by the discrepancies between PRO and CRO measurement tools as well as the absence of standard time points for evaluation of radiation dermatitis. Given potential discrepancies between CROs and PROs, both measures should be reported in future studies. Ultimately, we advocate for the development of a single tool to assess symptoms from both perspectives.
•Patient- and clinician-reported outcomes generally demonstrated high levels of agreement.•Patients reported more acute breast pain and late breast shrinkage than clinicians.•Clinicians reported more acute breast edema than patients.•The measurement tools and time points at which radiotherapy side effects were assessed varied considerably across studies.•Standardized reporting of radiotherapy side effects by clinicians and patients could impact future symptom management.
Men with BRCA1 or BRCA2 gene mutations are at increased risk of developing breast cancer and may have an indication for breast cancer screening using mammography. Since breast cancer is often viewed ...as a woman’s disease, visibilizing and understanding men’s experience of having a BRCA mutation and specifically, of screening for breast cancer through mammography, were the objectives of this research study.
The theoretical framework of interpretive phenomenology guided the process of data collection, coding, and analysis. Phenomenology is both a philosophy and research method which focuses on understanding the nature of experience from the perspectives of people experiencing a phenomenon, the essence of and commonalities among people’s experiences, and the ways in which people experience the world through their bodies. Data were collected via in-depth interviews with a purposive sample of 15 male participants recruited from the Male Oncology Research and Education (MORE) Program.
This article reports findings about participants’ use of gender-specific language to describe their breasts, awareness of the ways in which their bodies changed overtime, and experiences of undergoing mammograms.
This study is the first to describe men with BRCA’s perceptions of their breasts and experiences of mammography in a high-risk cancer screening clinic. This study sheds light on an under-researched area—breasts and masculinities—and could potentially lead to improved clinical understanding of men’s embodied experiences of BRCA, as well as suggestions for improving the delivery of male breast cancer screening services.
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