Archive for category: Article of the Week

Editorial: The pursuit of purpose: reframing strategies to prevent physician burnout

If there is one virtue that drives surgery residents to toil away in sterile, brightly lit operating rooms for extended hours for the best years of their life, it is the pursuit of purpose. However, these extended hours can also lead to what the WHO has now officially recognized as a medical condition: burnout. In a study in this issue of BJUI, Marchalik et al. [1] use qualitative analysis to elaborate on the prevalence and predictors of burnout among urology residents in the USA and in four European countries. Using an anonymous survey, the authors report a high prevalence of burnout in urology residents in both cohorts, with the European residents (44%) experiencing a higher burden than their US counterparts (38%). Given the recent focus, in the academic as well as general media, on the importance and severe implications of physician burnout, and the recognition of burnout as a disease by WHO, the timing of this publication for concrete organizational action seems propitious, especially since this analysis combines data from two continents with different institutional and educational frameworks, providing more granular data for a particularly immersive surgical specialty with a high rate of burnout.

Most recently, a costconsequence analysis reported that physician burnout costs approximately $4.6 bn each year to the US healthcare system, with a cost of $7600 per‐physician‐per‐year at the institutional level resulting from reduced clinical productivity and turnover [2]. While addressing these economic losses from burnout is important from an organizational and health system point of view, focusing on these alone would be missing the larger picture. It is only when we consider the depersonalization, emotional drainage, and loss of professional and personal accomplishment associated with burnout that we begin to realize the scope of this epidemic. Deservedly, burnout is being recognized as a ‘moral injury’ [3]. And indeed, it is a moral injury: when physicians working under systems that betray their purpose as a healer, the damage is not only professional and systematic, but deeply personal as well.

The constant act of balancing competing demands – the financial interests of the healthcare institutions, looming litigations and ever‐changing documentation requirements – has undermined effective human interactions with patients and diminished the zeal that drives physicians to spend a major part of their youth in training. Journalist Diane Silver defines moral injury as ‘a deep soul wound that pierces a person’s identity, sense of morality, and relationship to society’ [3]. Except in the context of healthcare delivery, this injury extends to deterioration of relationships with patients and fellow physicians. Indeed, burnout among physicians has been demonstrated to be associated with suboptimal patient care [4], and the consequent inability to deliver high‐quality care because of health system deficiencies leads to decline in physician well‐being and professional dissatisfaction [5].

While the urgency of addressing physician burnout is obvious, this study by Marchalik et al. is also valuable as it highlights some of the practices that are protective, revealing lessons that can be implemented. The authors report that burnout was significantly lower among residents who sought mental health services and those who had access to structured mentorship. Unsurprisingly, those who had a caring environment experienced less depersonalization and emotional drainage. This is an instructive lesson for the residency programme directors: if they want their most important human resource to flourish, they need to start building supportive work environments. This could start with pairing interns and residents with dedicated and experienced faculty mentors; these initiatives would facilitate career coaching and provide space where residents feel comfortable seeking information on mental healthcare.

Interestingly, the authors also found a significant doseresponse relationship between the number of non‐medical books residents read per month and decreased rates of burnout. This finding may surprise some healthcare administrators, who have routinely attempted to integrate ‘wellness’ and ‘mindfulness’ into clinical programmes to stimulate physician motivation, without much benefit. However, the positive relationship between non‐medical literature and medicine is an ancient one. Fortunately, in the last few decades, this relationship has witnessed a comeback and an increasing number of trainees are finding solace in their engagement with medical humanities and narrative medicine. These engagements have led to physicians developing emotional intelligence, empathy for patients and colleagues, and an opportunity to examine their role as healers [6]. This insight from the study should be another lesson for medical educators, who can encourage inclusion of reflections on life as a physician.

The epidemic of burnout among surgery residents requires immediate attention. Taking proactive action towards this is not only a matter of preventing economic loss or improving physician productivity, but an urgent ethical issue. All stakeholders – hospital administrators, healthcare policy‐makers, and regional physician leaders – must work together in developing inventive solutions to address the burnout epidemic. This will be essential to realizing the maximal potential of residency and reinstating purpose of clinical work.

References

  1. Marchalik, DGoldman, CCCarvalho, FFL et al. Resident burnout in USA and European urology residents: an international concern. BJU Int 2019124349‐ 56
  2. Han, SShanafelt, TDSinsky, CA et al. Estimating the attributable cost of physician burnout in the United States cost of physician burnout. Ann Intern Med 2019170784‐ 90
  3. Dean, WTalbot, SPhysicians aren’t ‘burning out.’ They’re suffering from moral injury. STAT News 2018. Available at: https://www.statnews.com/2018/07/26/physicians-not-burning-out-they-are-suffering-moral-injury/. Accessed May 29, 2019.
  4. Shanafelt, TDBradley, KAWipf, JEBack, ALBurnout and self‐reported patient care in an internal medicine residency program. Ann Intern Med 2002136358– 67
  5. Friedberg, MWChen, PGBusum, KR et al. Factors affecting physician professional satisfaction and their implications for patient care, health systems, and health policy. Rand Health Q 201431
  6. Bonebakker, VLiterature & medicine: humanities at the heart of health care: a hospital‐based reading and discussion program developed by the Maine humanities council. Acad Med 200378:963– 7

 

Video: Resident burnout in USA and European urology residents

Resident burnout in USA and European urology residents: an international concern

Abstract

Objective

To describe the prevalence and predictors of burnout in USA and European urology residents, as although the rate of burnout in urologists is high and associated with severe negative sequelae, the extent and predictors of burnout in urology trainees remains poorly understood.

Subjects and methods

An anonymous 32‐question survey of urology trainees across the USA and four European countries, analysing personal, programme, and institutional factors, was conducted. Burnout was assessed using the validated abridged Maslach Burnout Inventory. Univariate analysis and multivariable logistic regression models assessed drivers of burnout in the two cohorts.

Results

Overall, 40% of participants met the criteria for burnout as follows: Portugal (68%), Italy (49%), USA (38%), Belgium (36%), and France (26%). Response rates were: USA, 20.9%; Italy, 45.2%; Portugal, 30.5%; France, 12.5%; and Belgium, 9.4%. Burnout was not associated with gender or level of training. In both cohorts, work–life balance (WLB) dissatisfaction was associated with increased burnout (odds ratio [OR] 4.5, P < 0.001), whilst non‐medical reading (OR 0.6, P = 0.001) and structured mentorship (OR 0.4, P = 0.002) were associated with decreased burnout risk. Lack of access to mental health services was associated with burnout in the USA only (OR 3.5, P = 0.006), whilst more weekends on‐call was associated with burnout in Europe only (OR 8.3, P = 0.033). In both cohorts, burned out residents were more likely to not choose a career in urology again (USA 54% vs 19%, P < 0.001; Europe 43% vs 25%, P = 0.047).

Conclusion

In this study of USA and European urology residents, we found high rates of burnout on both continents. Despite regional differences in the predictors of burnout, awareness of the unique institutional drivers may help inform directions of future interventions.

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Residents’ podcast: Resident burnout

Maria Uloko is a Urology Resident at the University of Minnesota Hospital. In this podcast she discusses the following BJUI Article of the month:

Resident burnout in USA and European urology residents: an international concern

Read the full article

Abstract

Objective

To describe the prevalence and predictors of burnout in USA and European urology residents, as although the rate of burnout in urologists is high and associated with severe negative sequelae, the extent and predictors of burnout in urology trainees remains poorly understood.

Subjects and methods

An anonymous 32‐question survey of urology trainees across the USA and four European countries, analysing personal, programme, and institutional factors, was conducted. Burnout was assessed using the validated abridged Maslach Burnout Inventory. Univariate analysis and multivariable logistic regression models assessed drivers of burnout in the two cohorts.

Results

Overall, 40% of participants met the criteria for burnout as follows: Portugal (68%), Italy (49%), USA (38%), Belgium (36%), and France (26%). Response rates were: USA, 20.9%; Italy, 45.2%; Portugal, 30.5%; France, 12.5%; and Belgium, 9.4%. Burnout was not associated with gender or level of training. In both cohorts, work–life balance (WLB) dissatisfaction was associated with increased burnout (odds ratio [OR] 4.5, P < 0.001), whilst non‐medical reading (OR 0.6, P = 0.001) and structured mentorship (OR 0.4, P = 0.002) were associated with decreased burnout risk. Lack of access to mental health services was associated with burnout in the USA only (OR 3.5, P = 0.006), whilst more weekends on‐call was associated with burnout in Europe only (OR 8.3, P = 0.033). In both cohorts, burned out residents were more likely to not choose a career in urology again (USA 54% vs 19%, P < 0.001; Europe 43% vs 25%, P = 0.047).

Conclusion

In this study of USA and European urology residents, we found high rates of burnout on both continents. Despite regional differences in the predictors of burnout, awareness of the unique institutional drivers may help inform directions of future interventions.

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BJUI Podcasts now available on iTunes, subscribe here https://itunes.apple.com/gb/podcast/bju-international/id1309570262

Article of the week: Biparametric vs multiparametric prostate MRI for the detection of PCa in treatment‐naïve patients

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community, and a video produced by the authors. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Biparametric vs multiparametric prostate magnetic resonance imaging for the detection of prostate cancer in treatment-naïve patients: a diagnostic test accuracy systematic review and meta-analysis

Mostafa Alabousi*, Jean-Paul Salameh†‡, Kaela Gusenbauer§, Lucy Samoilov, Ali Jafri**, Hang Yu§ and Abdullah Alabousi††

 

*Department of Radiology, McMaster University, Hamilton, Department of Clinical Epidemiology and Public Health, University of Ottawa, The Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, §Department of Medicine, McMaster University, Hamilton, Department of Medicine, Western University, London, ON, Canada, **Department of Medicine, New York Institute of Technology School of Osteopathic Medicine, Glen Head, NY, USA, and ††Department of Radiology, St Joseph’s Healthcare, McMaster University, Hamilton, ON, Canada

Read the full article

Abstract

Objective

To perform a diagnostic test accuracy (DTA) systematic review and meta‐analysis comparing multiparametric (diffusion‐weighted imaging [DWI], T2‐weighted imaging [T2WI], and dynamic contrast‐enhanced [DCE] imaging) magnetic resonance imaging (mpMRI) and biparametric (DWI and T2WI) MRI (bpMRI) in detecting prostate cancer in treatment‐naïve patients.

Methods

The Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE) were searched to identify relevant studies published after 1 January 2012. Articles underwent title, abstract, and full‐text screening. Inclusion criteria consisted of patients with suspected prostate cancer, bpMRI and/or mpMRI as the index test(s), histopathology as the reference standard, and a DTA outcome measure. Methodological and DTA data were extracted. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)‐2 tool. DTA metrics were pooled using bivariate random‐effects meta‐analysis. Subgroup analysis was conducted to assess for heterogeneity.

Results

From an initial 3502 studies, 31 studies reporting on 9480 patients (4296 with prostate cancer) met the inclusion criteria for the meta‐analysis; 25 studies reported on mpMRI (7000 patients, 2954 with prostate cancer) and 12 studies reported on bpMRI DTA (2716 patients, 1477 with prostate cancer). Pooled summary statistics demonstrated no significant difference for sensitivity (mpMRI: 86%, 95% confidence interval [CI] 81–90; bpMRI: 90%, 95% CI 83–94) or specificity (mpMRI: 73%, 95% CI 64–81; bpMRI: 70%, 95% CI 42–83). The summary receiver operating characteristic curves were comparable for mpMRI (0.87) and bpMRI (0.90).

Conclusions

No significant difference in DTA was found between mpMRI and bpMRI in diagnosing prostate cancer in treatment‐naïve patients. Study heterogeneity warrants cautious interpretation of the results. With replication of our findings in dedicated validation studies, bpMRI may serve as a faster, cheaper, gadolinium‐free alternative to mpMRI.

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Editorial: Dropping the GAD – just a fad?

It is not without irony that, at the very moment that the UK’s National Institute for Health and Care Excellence (NICE) is poised to ratify the recommendation that multiparametric MRI (mpMRI) be introduced into the prostate cancer diagnostic pathway, we are seeking to significantly modify the very intervention on which they are about to provide judgement on [1].

The modification proposed is both compelling and plausible, as it renders the process of imaging the prostate in order to detect and localise clinically significant prostate cancer; simpler, quicker, safer and cheaper. It entails dropping the most complex and time‐consuming component of the three multiparametric sequences, the dynamic (time‐dependent) T1‐weighted gadolinium‐enhanced (GAD) sequence. This was a sequence that was, in the early days of MRI, imbued to have biological significance because it was capable of exploiting the differences in the microvascular architecture and function that we have tended to associate with cancer and non‐cancer in order to discriminate between the two. Or so we thought [2].

The systematic review in this issue of the BJUI by Alabousi et al. [3] explores, via the process of systematic review, whether the omission of the T1‐GAD sequence results in any clinically important reduction in test performance when compared with the full sequence scan comprising traditionally of T2, diffusion and T1‐GAD sequences. It did not.

By any stretch this is a tough analysis to pull‐off, as T1‐GAD sequences are not standardised in terms of acquisition or reporting. Every group seems to manage the dynamic images in a different way. As such they tend to suffer from quality control issues, possibly to a greater extent than the T2 and diffusion sequences. The verification of the signal by biopsy strategy and sampling intensity will have varied across studies, as will the threshold of the definition of clinically significant prostate cancer. These inherent methodological problems are all familiar to readers and issues that are pertinent to any imaging study in the detection of prostate cancer. However, there are two issues that make any current assessment of GAD vs no GAD really problematic. The first is the almost exclusive reliance on single‐centre retrospective data. In the few studies that claim a prospective design no comparative data were available. Studies of this type are typical in the early phase of exploring a clinical question and will, in time, be corrected. The other, largely hidden, hardly discussed and truly problematic issue relates to the manner by which we synthesise an overall risk score from the MRI sequences that we derive. The near ubiquitous use of the Prostate Imaging‐Reporting and Data System (PI‐RADS) scoring system introduces a systematic bias by the manner in which a Boolean form of logic is used to decide on the degree of influence that each sequence has in relation to the overall score. According to the manner by which PI‐RADS is applied, it tends to render the T1‐GAD sequence subordinate (only relevant in a minority of cases), contingent (to T2/diffusion) and disparate (dependent on prostate zone) in the way it is invoked [4]. The result is, that within the PIRADS framework, the T1‐GAD sequence is destined to play a relatively small role in driving the overall summary score of risk. It might, therefore, not be too surprising if its removal made little difference to the overall detection of clinically significant prostate cancer.

So what are the next steps? Clearly this is a very important issue and a simpler, quicker, safer and cheaper MRI would be desirable from multiple perspectives. It would render what is currently a complex intervention that comprises an invasive component into a totally passive image acquisition in which no medically trained health professional need be present. It is almost certainly a pre‐requisite for adoption in resource-poor jurisdictions and for entertaining the role of MRI as a primary population‐based screening test.

It took a large number of randomised trials to get mpMRI accepted into the prostate cancer diagnostic pathway. What is the minimum amount of evidence required to disinvest in one of its key components? In other words how many clinically significant cancers would we tolerate missing in order to offer the less complex test?

A direct (head‐to‐head) non‐inferiority randomised comparative study would, following some of our own recent calculations, require >3000 men to participate, which might just prove a little too challenging. An alternative approach is a study in which men would have lesions declared using a Likert score, thereby making no prior assumptions on the role and utility of any single sequence, by traditional mpMRI (standard) but also by a T2‐diffusion MRI (experimental) with appropriate blinding. Some lesions would be private to either standard or experimental imaging but most, it is likely, would be shared. All would require sampling. The yield, the misses, the test accuracy for each approach, could be calculated with necessary adjustments for the inevitable incorporation and verification biases.

It is interesting to observe that in many parts of the world mpMRI was introduced by clinicians before a large body of evidence was accumulated because they felt it was the right thing to do [5]. It may well be the case that ‘dropping the GAD’ will be subject to the same decision‐making process and precede any definitive judgement based on reliable evidence. Recent activity on PubMed would suggest that this might already have happened [6].

References

  1. National Institute for Health and Care Excellence (NICE). Non‐invasive MRI scan for Prostate Cancer recommended by NICE. Available at: https://www.nice.org.uk/news/article/non-invasive-mri-scan-for-prostate-cancer-recommended-by-nice. Accessed May 2019.
  2. Little, RABarjat, HHare, JI et al. Evaluation of dynamic contrast‐enhanced MRI biomarkers for stratified cancer medicine: how do permeability and perfusion vary between human tumours? Magn Reson Imaging 20184698– 105
  3. Alabousi, MSalameh, JPGusenbauer, K et al. Biparametric vs multiparametric prostate magnetic resonance imaging for the detection of prostate cancer in treatment‐naïve patients: a diagnostic test accuracy systematic review and meta‐analysis. BJU Int 2019124209– 20
  4. Turkbey, BRosenkrantz, ABHaider, MA et al. Prostate Imaging reporting and Data System version 2.1: 2019 update of Prostate Imaging Reporting and Data System version 2. Eur Urol 2019 [Epub ahead of print]. https://doi.org/10.1016/j.eururo.2019.02.033
  5. Ahmed, HUKirkham, AArya, M et al. Is it time to consider a role for MRI before prostate biopsy? Nat Rev Clin Oncol 20096197– 20
  6. Xu, MFang, MZou, J et al. Using biparametric MRI radiomics signature to differentiate between benign and malignant prostate lesions. Eur J Radiol 201911438– 44

 

Video: Biparametric vs multiparametric prostate MRI for the detection of PCa in treatment‐naïve patients: a diagnostic test accuracy systematic review and meta‐analysis

Read the full article

Abstract

Objective

To perform a diagnostic test accuracy (DTA) systematic review and meta‐analysis comparing multiparametric (diffusion‐weighted imaging [DWI], T2‐weighted imaging [T2WI], and dynamic contrast‐enhanced [DCE] imaging) magnetic resonance imaging (mpMRI) and biparametric (DWI and T2WI) MRI (bpMRI) in detecting prostate cancer in treatment‐naïve patients.

Methods

The Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE) were searched to identify relevant studies published after 1 January 2012. Articles underwent title, abstract, and full‐text screening. Inclusion criteria consisted of patients with suspected prostate cancer, bpMRI and/or mpMRI as the index test(s), histopathology as the reference standard, and a DTA outcome measure. Methodological and DTA data were extracted. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)‐2 tool. DTA metrics were pooled using bivariate random‐effects meta‐analysis. Subgroup analysis was conducted to assess for heterogeneity.

Results

From an initial 3502 studies, 31 studies reporting on 9480 patients (4296 with prostate cancer) met the inclusion criteria for the meta‐analysis; 25 studies reported on mpMRI (7000 patients, 2954 with prostate cancer) and 12 studies reported on bpMRI DTA (2716 patients, 1477 with prostate cancer). Pooled summary statistics demonstrated no significant difference for sensitivity (mpMRI: 86%, 95% confidence interval [CI] 81–90; bpMRI: 90%, 95% CI 83–94) or specificity (mpMRI: 73%, 95% CI 64–81; bpMRI: 70%, 95% CI 42–83). The summary receiver operating characteristic curves were comparable for mpMRI (0.87) and bpMRI (0.90).

Conclusions

No significant difference in DTA was found between mpMRI and bpMRI in diagnosing prostate cancer in treatment‐naïve patients. Study heterogeneity warrants cautious interpretation of the results. With replication of our findings in dedicated validation studies, bpMRI may serve as a faster, cheaper, gadolinium‐free alternative to mpMRI.

 

 

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Article of the week: A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community, and a video produced by the authors. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome

Alberto Martini*, Joanna Wang*, Nicholas M. Brown*, Shivaram Cumarasamy*, John P. Sfakianos*, Ardeshir R. Rastinehad*, Kenneth G. Haines III, Nils Peter Wiklund*, Sujit S. Nair* and Ashutosh K. Tewari*

 

Departments of *Urology and Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA

 

Read the full article

Abstract

Objective

To investigate the genomic features of tertiary pattern 5 (TP5) on radical prostatectomy specimens in an effort to explain the poor clinical outcomes associated with this disease subtype.

Patients and methods

Data from 159 men with Gleason Grade Group (GGG) 3 or 4 were considered. All patients had Decipher diagnostic testing with transcript profiles and single‐channel array normalisation (SCAN)‐normalised expression of coding genes.

The relationship between Decipher and TP5 was investigated by linear and binary logistic regressions. A differential transcriptomic analysis between patients with and without TP5 was performed. The prognostic role of these genes on progression‐free survival (PFS) and overall survival (OS) was evaluated using The Cancer Genome Atlas.

Results

In all, 52/159 (33%) patients had GGG 3–4 with TP5 disease. TP5 was associated with a higher Decipher score (β 0.07, 95% confidence interval [CI] 0.02–0.13; = 0.04) and higher likelihood of falling within the intermediate‐ or high‐risk categories (odds ratio 3.34, 95% CI 1.34–8.35; = 0.01). Analysis of microarray data revealed an 18‐gene signature that was differentially expressed in patients with TP5; 13 genes were over‐ and five under‐expressed in the TP5 cohort.

The overexpression of cyclin dependent kinase inhibitor 2B (CDKN2B), polo‐like kinase 1 (PLK1), or cell division cycle 20 (CDC20) was associated with worse PFS. The group harbouring overexpression of at least one gene had a 5‐year PFS rate of 50% vs 74% in the group without overexpression (P < 0.001).

Conclusions

Our studies have elucidated unique genomic features of TP5, whilst confirming previous clinical findings that patients harbouring TP5 tend to have worse prognosis. This is the first RNA‐based study to investigate the molecular diversity of TP5 and the first correlating CDKN2B to poorer prognosis in patients with prostate cancer.

Read more Articles of the week

Editorial: Transcriptomic signatures for tertiary pattern 5 in prostate cancer

Significant evidence is now emerging and publications have shown that the molecular characterization of tumours represents an important approach to stratifying patients with prostate cancer into appropriate treatments and their responses, helping to inform the next steps in the care pathway of these patients [1]. Understanding the functional role of the genes included in these signatures also gives an insight into the biology of the disease and how it develops and progresses.

BJUI has published papers in the past describing gene signatures that are associated with pathological Gleason score as pathological markers of aggressiveness and their potential role in predicting outcome [2].

The paper by Martini et al. [3] in the current issue of BJUI adds to this important literature. In a cohort of 159 patients, of whom 52 had tertiary pattern 5 (TP5) prostate cancer, Martini et al. showed that TP5 was associated with higher risk categories in the Decipher genomic score. Their study supports the literature showing that patients with TP5 have an elevated likelihood of developing disease after radical prostatectomy and have a poor prognosis [4]. It should be noted, however, that this is a small cohort with few patients defined as having TP5 disease. As prostate cancer is highly heterogeneous and gene expression can also be affected by the patient’s background, additional validation of this finding will be required in independent cohorts.

Additional analysis of the 698 gene by Martini et al. [3] identified a unique RNA signature of 18 genes for the TP5 cohort. A limitation of using the 698 gene previously demonstrated to be related to prostate cancer is that those with TP5 disease may be a unique subset of patients that may be associated with unfamiliar pathological pathways and new genes. An examination of novel genes whose expression pattern is unique to patients with TP5 disease may reveal additional genes.

Martini et al. then used the independent TCGA provisional database to link the expression of these 18 genes with clinical features. Patients harbouring any of the three genes CDKN2B, PLK1 and CDC20 mRNA were found to have worse progression‐free survival. The authors go on to undertake analysis of the 18 genes using the ingenuity network analysis tool identifying pathways involved in the cell cycle, DNA replication and repair, cellular assembly, cell death and survival and gene expression, which would fit with the biology of progressive disease. They also revealed a role in the dedifferentiation process and progression of cells towards anaplasia. They specifically identified CDKN2B, which has previously been associated with tumour suppression but might actually be linked to tumour progression, and identified it for further investigation.

Finally the researchers found that 13 genes out of the 18‐gene TP5 signature are upregulated in tumour lesions with TP5. Following these results they performed a sensitivity analysis in which the expression values of the genes in the cohort with GGG3‐4 and TP5 were compared with those of patients with GGG5 and discovered that these genes were similarly overexpressed in both groups. This finding strengthens the hypothesis that these genes are implicated in the dedifferentiation process of tumour cells, but it also raises the question of whether the pattern of expression of these genes is unique to patients with TP5 only, or whether it is associated with every tumour (primary, secondary or tertiary) that is classified as GGG5. Further research is needed to understand what the clinical significance of this genetic signature is and what pathological process it describes in practice.

This investigation into the functional role of the genes has given an insight into the biology of prostate cancer progression and TP5 disease which might inform a future area of research for novel biomarker panels and therapeutic interventions.

by R. William Watson and Omri Taltsh

References

  1. Cucchiara, VCooperberg, MRDall’Era, MLin, DWMontorsi, FSchalken, JAEvans, CP Genomic markers in prostate cancer decision making. Euro Urol 201873572– 82
  2. Pellegrini, KSanda, MGPatil, DLong, QSantiago‐Jiménez, MTakhar, MErho, NYousefi, K,Davicioni, EKlein, EAJenkins, RBKarnes, RJMoreno, CS Evaluation of a 24‐Gene signature for prognosis of metastatic events and prostate cancer‐specific mortality. BJU Int 2017119961– 7
  3. Martini, AWang, JBrown, NMCumarasamy, SSfakianos, JPRastinehad, ARHaines, KG,Wiklund, NPNair, SSTewari, AK A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome. BJU Int 2019124155– 62
  4. Whittemore, DEHick, EJCarter, MRMoul, JWMiranda‐Sousa, AJSexton, WJ Significance of tertiary Gleason pattern 5 in Gleason score 7 radical prostatectomy specimens. J Urol 2008179:516– 22

 

 

Video: A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome

A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome

by Alberto Martini

Read the full article

Abstract

Objective

To investigate the genomic features of tertiary pattern 5 (TP5) on radical prostatectomy specimens in an effort to explain the poor clinical outcomes associated with this disease subtype.

Patients and methods

Data from 159 men with Gleason Grade Group (GGG) 3 or 4 were considered. All patients had Decipher diagnostic testing with transcript profiles and single‐channel array normalisation (SCAN)‐normalised expression of coding genes.

The relationship between Decipher and TP5 was investigated by linear and binary logistic regressions. A differential transcriptomic analysis between patients with and without TP5 was performed. The prognostic role of these genes on progression‐free survival (PFS) and overall survival (OS) was evaluated using The Cancer Genome Atlas.

Results

In all, 52/159 (33%) patients had GGG 3–4 with TP5 disease. TP5 was associated with a higher Decipher score (β 0.07, 95% confidence interval [CI] 0.02–0.13; = 0.04) and higher likelihood of falling within the intermediate‐ or high‐risk categories (odds ratio 3.34, 95% CI 1.34–8.35; = 0.01). Analysis of microarray data revealed an 18‐gene signature that was differentially expressed in patients with TP5; 13 genes were over‐ and five under‐expressed in the TP5 cohort.

The overexpression of cyclin dependent kinase inhibitor 2B (CDKN2B), polo‐like kinase 1 (PLK1), or cell division cycle 20 (CDC20) was associated with worse PFS. The group harbouring overexpression of at least one gene had a 5‐year PFS rate of 50% vs 74% in the group without overexpression (P < 0.001).

Conclusions

Our studies have elucidated unique genomic features of TP5, whilst confirming previous clinical findings that patients harbouring TP5 tend to have worse prognosis. This is the first RNA‐based study to investigate the molecular diversity of TP5 and the first correlating CDKN2B to poorer prognosis in patients with prostate cancer.

View more videos

 

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