Publications by authors named "David Nicol"

97 Publications

Features and Management of Late Relapse of Nonseminomatous Germ Cell Tumour.

Eur Urol Open Sci 2021 Jul 7;29:82-88. Epub 2021 Jun 7.

Department of Urology, Royal Marsden Hospital, London, UK.

Background: Late relapse (LR) of nonseminomatous germ cell tumour (NSGCT) is uncommon, with limited data published. LR is defined as relapse occurring after a disease-free interval of 2 yr.

Objective: To review features of NSGCT LR in a UK tertiary centre.

Design Setting And Participants: A total of 3064 patients were referred from January 2005 to December 2017. We identified patients who experienced LR after initial pathology demonstrated NSGCT and reviewed data for their original and LR presentation and management.

Outcome Measurements And Statistical Analysis: Outcomes included time to LR measured from the date of diagnosis, and overall survival.  This was assessed using  Cox proportional Hazards modelling, with stratification or adjustment for potential confounders.

Results And Limitations: We identified 101 patients with LR; the median time to LR was 96 mo. Forty-three patients (42.6%) experienced relapse after 10 yr. Univariable log-rank testing revealed that the median time to LR was significantly shorter for patients who had not received induction chemotherapy (iCTx; 54 mo, 95% confidence interval [CI] 48-108) than for those who did (112 mo, 95% CI 84-186;  = 0.04). Patients who had received iCTx were less likely to have elevated tumour markers (36% vs 46%) and more likely to undergo initial surgical resection at LR compared to CTx-naïve patients. Postpubertal teratoma (PPT), yolk sac, and dedifferentiated elements predominated for patients with iCTx exposure, whereas active GCT or fibrosis predominated in postchemotherapy resections for CTx-naïve patients at LR. Forty-one men underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) as part of their initial treatment for metastatic disease. Of these, 20 experienced LR in the retroperitoneum, with 18 undergoing repeat RPLND as part of their LR management. Fifteen of the repeat RPLND histopathology specimens had a PPT component. There have been 23 deaths overall; survival was worse for patients presenting with symptoms (13/36, 33%) and those receiving CTx and no surgery (10/17, 59%) at LR.

Conclusions: When LR of NSGCT occurs, it is frequently after an extended interval and is later among patients with prior iCTx, with PPT predominating. The high frequency of LR within the retroperitoneum following PC-RPLND reinforces the need for good-quality PC-RPLND.

Patient Summary: We reviewed data for patients who had a late relapse of testicular cancer. We found that patients who did not receive chemotherapy as the first treatment for their initial diagnosis had a shorter time to relapse. Our results highlight the importance of long-term follow-up for testicular cancer.
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http://dx.doi.org/10.1016/j.euros.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317789PMC
July 2021

Factors that influence patients' views on treatment decision-making in localised kidney cancer.

Transl Androl Urol 2021 Jun;10(6):2824-2827

King's College London, Faculty of Life Sciences and Medicine, Translational and Oncology Research (TOUR), London, UK.

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http://dx.doi.org/10.21037/tau-20-1317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261443PMC
June 2021

The 'hub and spoke model' for the management of surgical patients during the COVID-19 pandemic.

Int J Health Plann Manage 2021 Sep 27;36(5):1397-1406. Epub 2021 May 27.

The Royal Marsden NHS Foundation Trust Hospital, London, UK.

During the on-going COVID-19 pandemic a number of key public health services have been severely impacted. These include elective surgical services due to the synergetic resources required to provide both perioperative surgical care whilst also treating acute COVID-19 patients and also the poor outcomes associated with surgical patients who develop COVID-19 in the perioperative period. This article discusses the important principles and concepts for providing important surgical services during the COVID-19 pandemic based on the model of the RMCancerSurgHub which is providing surgical cancer services for a population of approximately 2 million people across London during the pandemic. The model focusses on creating local and regional hub centres which provide urgent treatment for surgical patients in an environment that is relatively protected from the burden of COVID-19 illness. The model extensively utilises the extended multidisciplinary team to allow for a flexible approach with core services delivered in 'clean' sites which can adapt to viral surges. A key requirement is that of a clinical prioritisation process which allows for equity in access within and between specialties ensuring that patients are treated on the basis of greatest need, while at the same time protecting those whose conditions can safely wait from exposure to the virus. Importantly, this model has the ability to scale-up activity and lead units and networks into the recovery phase. The model discussed is also broadly applicable to providing surgical services during any viral pandemic.
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http://dx.doi.org/10.1002/hpm.3243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239827PMC
September 2021

Selection of metastasis competent subclones in the tumour interior.

Nat Ecol Evol 2021 07 17;5(7):1033-1045. Epub 2021 May 17.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
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http://dx.doi.org/10.1038/s41559-021-01456-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611703PMC
July 2021

Recommendations to Balance Benefits and Risks Of Thromboprophylaxis and to Avoid Central Venous-access Devices During First-line Chemotherapy in Men with Metastatic Germ Cell Tumors: The European Association Of Urology Testicular Cancer Panel Position in 2021.

Eur Urol 2021 07 12;80(1):4-6. Epub 2021 Mar 12.

Department of Urology Medipol Mega, Istanbul Medipol University, Istanbul, Turkey.

Men with metastatic germ cell tumors undergoing chemotherapy are at high risk of venous thromboembolic events and low risk of bleeding. A central venous-access device should be avoided whenever possible. Thromboprophylaxis may be prescribed after balancing the risks and benefits for each individual patient.
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http://dx.doi.org/10.1016/j.eururo.2021.02.032DOI Listing
July 2021

The role of CT chest in screening for asymptomatic COVID-19 infection in self-isolating patients prior to elective oncological surgery: findings from a UK Cancer Hub.

Br J Radiol 2021 Jan 26;94(1117):20200994. Epub 2020 Nov 26.

Department of Radiology, The Royal Marsden NHS Foundation Trust, London, UK.

Objectives: In accordance with initial guidance from the Royal College of Surgeons and Royal College of Radiologists, we evaluated the utility of CT of the chest in the exclusion of asymptomatic COVID-19 infection prior to elective cancer surgery on self-isolating patients during the pandemic.

Methods: All surgical referrals without symptoms of COVID-19 infection in April and May 2020 were included. Patient records were retrospectively reviewed. Screening included CT chest for major thoracic and abdominal surgery. CTs were reported according to British Society of Thoracic Imaging guidelines and correlated with reverse transcriptase polymerase chain reaction (RT-PCR) and surgical outcomes.

Results: The prevalence of RT-PCR confirmed COVID-19 infection in our screened population was 0.7% (5/681). 240 pre-operative CTs were performed. 3.8% (9/240) of CTs were reported as abnormal, only one of which was RT-PCR positive. 2% (5/240) of cases had surgery postponed based on CT results. All nine patients with CTs reported as abnormal have had surgery, all without complication.

Conclusion: The prevalence of asymptomatic COVID-19 infection in our screened population was low. The pre-test probability of CT chest in asymptomatic, self-isolating patients is consequently low. CT can produce false positives in this setting, introducing unnecessary delay in surgery for a small proportion of cases.

Advances In Knowledge: Self-isolation, clinical assessment and RT-PCR are effective at minimising COVID-19 related surgical risk. The addition of CT chest is unhelpful. Our data have particular relevance during the second wave of infection and in the recovery phase.
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http://dx.doi.org/10.1259/bjr.20200994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774707PMC
January 2021

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study.

Gut 2021 06 27;70(6):1053-1060. Epub 2020 Aug 27.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK

Objective: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic.

Design: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval.

Results: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%.

Conclusions: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.
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http://dx.doi.org/10.1136/gutjnl-2020-321650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447105PMC
June 2021

Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study.

Lancet Oncol 2020 08 20;21(8):1035-1044. Epub 2020 Jul 20.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK; National Cancer Registration and Analysis Service, Public Health England, London, UK; Department of Clinical Genetics, Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Background: During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2.

Methods: In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008-17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013-16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I-III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1-6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred.

Findings: Across England in 2013-16, an average of 6281 patients with stage I-III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1-3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3-8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14 873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22 635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type.

Interpretation: Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(20)30392-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116538PMC
August 2020

Prostate-specific membrane antigen expression in melanoma metastases.

J Cutan Pathol 2020 Dec 6;47(12):1115-1122. Epub 2020 Jul 6.

Department of Academic Surgery, Melanoma and Sarcoma, The Royal Marsden NHS Foundation Trust, London, UK.

Background: Prostate-specific membrane antigen (PSMA) is a prostatic epithelial protein that is used as a radiotracer (68Ga-PSMA-11) for prostate cancer staging. PSMA-PET/CT (positron emission tomography/computed tomography) performed for prostate cancer has been observed to detect melanoma metastases. The aim of this study was to investigate the performance of PSMA immunohistochemistry on resected melanoma metastases to explore its use as a diagnostic imaging biomarker for melanoma.

Methods: A total of 41 specimens with stage III/IV melanoma were stained with PSMA immunohistochemistry. All specimens required both disease and control regions. Two pathologists scored the specimens and a receiver operating characteristic (ROC) curve was plotted. Western blot and multiplex immunofluorescence were also performed.

Results: The area under the ROC curve was 0.82, suggesting that PSMA has excellent discriminatory power in melanoma metastases. Sensitivity is 82.9% and specificity 73.2%. Immunohistochemistry and Western blot reveal that PSMA staining in melanoma consistently and most intensely occurs in tumor neovasculature. Multiplex immunofluorescence shows that melanocytes may also weakly express PSMA.

Conclusion: The performance of PSMA immunohistochemistry in melanoma metastases contrasts with that reported in prostate cancer studies. This study indicates that PSMA shows promise for use as a novel biomarker in melanoma and justifies further research in the clinical setting with potential as a PET/CT radiotracer and intraoperative fluorescence marker for melanoma.
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http://dx.doi.org/10.1111/cup.13774DOI Listing
December 2020

Transition from open and laparoscopic to robotic pancreaticoduodenectomy in a UK tertiary referral hepatobiliary and pancreatic centre - Early experience of robotic pancreaticoduodenectomy.

HPB (Oxford) 2020 11 1;22(11):1637-1644. Epub 2020 Apr 1.

HPB Surgical Unit, Dept. of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0HS, UK; Surgery and Oncology, The Royal Marsden Hospital, 203 Fulham Road, London, SW3 6JJ, UK. Electronic address:

Background: Pancreaticoduodenectomy is performed using an open technique (OPD) as the gold standard. An increase in those performed laparoscopically (LPD) and robotically (RPD) are now reported. We compared the short-term outcomes of RPD cases with LPD and OPD.

Methods: A retrospective review of a prospectively collected database was undertaken of our first consecutive RPD, our first LPD and consecutive OPD cases. Those requiring venous and/or arterial resection were excluded.

Results: RPD (n = 25) had longer median operating times (461 (IQR 358-564) mins) than LPD (n = 41) (330 (IQR 262.5-397.5) mins) and OPD (n = 37) (330 (IQR 257-403) mins, p < 0.0001). Estimated blood loss and transfusion requirement was less after RPD and LPD compared to OPD (p = 0.012 and p < 0.0001 respectively). No RPD cases required conversion to open operation compared to 24.4% of LPD. Morbidity was comparable with a Clavien Dindo score ≥3 in 20.00%, 24.39% and 18.92% for RPD, LPD and OPD respectively (p = 0.83). Post-operative pancreatic fistula rates were seen in 16.00%, 29.27% and 21.62% of our RPD, LPD and OPD cohorts respectively (p = 0.81). 90-day mortality was seen in 0.97% of the total cohort. Length of hospital stay (LOS) was shorter for RPD compared to both LPD (p = 0.030) and OPD (p = 0.002).

Conclusion: RPD is safe to perform with comparable outcomes to LPD and OPD. Further evidence is provided that a randomised controlled trial for PD techniques is required.
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http://dx.doi.org/10.1016/j.hpb.2020.03.008DOI Listing
November 2020

A Decision Analysis Evaluating Screening for Kidney Cancer Using Focused Renal Ultrasound.

Eur Urol Focus 2021 Mar 14;7(2):407-419. Epub 2019 Sep 14.

Cambridge Centre for Health Services Research, University of Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge, UK; Health Economics Group, Norwich Medical School, University of East Anglia, Norwich, UK. Electronic address:

Background: Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value.

Objective: To determine (1) whether current evidence suggests that screening is potentially cost-effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps.

Design, Setting, And Participants: A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted.

Intervention: A single focused renal ultrasound scan compared with standard of care (no screening).

Outcome Measurements And Statistical Analysis: Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum.

Results And Limitations: Given a prevalence of RCC of 0.34% (0.18-0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08-0.25%), screening 60-yr-old women resulted in an ICER of £37327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was <£30000/QALY as long as the prevalence of RCC was ≥0.25% for men and ≥0.2% for women at age 60yr. Given the willingness to pay a threshold of £30000/QALY (€37 878/QALY), the population-expected values of perfect information were £194 million (€244 million) and £97 million (€123 million) for 60-yr-old men and women, respectively. The expected value of perfect parameter information suggests that the prevalence of RCC and stage shift associated with screening are key research priorities.

Conclusions: Current evidence suggests that one-off screening of 60-yr-old men is potentially cost-effective and that further research into this topic would be of value to society.

Patient Summary: Economic modelling suggests that screening 60-yr-old men for kidney cancer using ultrasound may be a good use of resources and that further research on this topic should be performed.
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http://dx.doi.org/10.1016/j.euf.2019.09.002DOI Listing
March 2021

Expert Elicitation to Inform a Cost-Effectiveness Analysis of Screening for Renal Cancer.

Value Health 2019 09 31;22(9):981-987. Epub 2019 May 31.

Cambridge Centre for Health Services Research, University of Cambridge, Institute of Public Health, Cambridge, UK.

Background: Population screening for renal cell carcinoma (RCC) using ultrasound has the potential to improve survival outcomes; however, a cost-effectiveness analysis (CEA) has yet to be performed. Owing to the lack of existing evidence, we performed structured expert elicitation to derive unknown quantities to inform the CEA.

Objective: To elicit the cancer stage distribution (proportion of individuals with each stage of cancer) for different RCC screening scenarios and the annual transition probabilities for undiagnosed disease becoming diagnosed in the National Health Service.

Methods: The study design and reporting adhered to the Reporting Guidelines for the Use of Expert Judgement in Model-Based Economic Evaluations. The elicitation was conducted face-to-face or via telephone between each individual expert and the facilitator, aided by online material. For multinomial data, Connor-Mosimann and modified Connor-Mosimann distributions were fitted for each expert and for all experts combined using mathematical linear pooling.

Results: A total of 24 clinical experts were invited, and 71% participated (7 urologists, 6 oncologists, 4 radiologists). The modified Connor-Mosimann distribution provided the best fit for most elicited quantities. Greater uncertainty was noted for the elicited transition probabilities compared with the elicited stage distributions.

Conclusion: We performed the first expert elicitation of RCC screening parameters, crucial information that will inform the CEA of screening. In addition, the elicited quantities may enable future health economic evaluations assessing the value of diagnostic tools and pathways in RCC.
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http://dx.doi.org/10.1016/j.jval.2019.03.018DOI Listing
September 2019

Urothelial carcinoma arising from the transplanted kidney: A single-center experience and literature review.

Clin Transplant 2019 06 23;33(6):e13559. Epub 2019 Apr 23.

Department of Urology, Imperial College Healthcare NHS Trust, London, UK.

Urothelial carcinoma (UC) is a malignancy predominantly arising in the bladder. Upper tract UC (UUC) is uncommon, accounting only for 5-10% of the cases. High incidence of neoplasms is associated with immunosuppressive therapy; thus, UCs of the transplanted grafts often lead to a more aggressive treatment, in order to withdraw completely the immunosuppression. It significantly affects the patient quality of life, meaning return to dialysis, along with the worse life expectancy. We present our single-institution experience of this rare malignancy in two mid-age kidney transplant recipients, with UCs successfully treated with radical nephroureterectomy: G3 pT3 N0 + G3 pT1 N0 in the first patient and G3 pT2 N0 in the second one. We also review the previous literature focusing on stage of presentation and treatment for the affected kidney transplant patients.
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http://dx.doi.org/10.1111/ctr.13559DOI Listing
June 2019

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.

Nat Genet 2018 05 16;50(5):682-692. Epub 2018 Apr 16.

The Institute of Cancer Research, London, UK.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials.
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http://dx.doi.org/10.1038/s41588-018-0086-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372064PMC
May 2018

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Cell 2018 04 12;173(3):581-594.e12. Epub 2018 Apr 12.

Department of Pathology, University College London Hospitals, London WC1E 6DE, UK.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
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http://dx.doi.org/10.1016/j.cell.2018.03.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938365PMC
April 2018

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

Cell 2018 04 12;173(3):595-610.e11. Epub 2018 Apr 12.

Department of Scientific Computing, the Francis Crick Institute, London NW1 1AT, UK.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
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http://dx.doi.org/10.1016/j.cell.2018.03.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938372PMC
April 2018

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Cell 2018 04 12;173(3):611-623.e17. Epub 2018 Apr 12.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
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http://dx.doi.org/10.1016/j.cell.2018.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927631PMC
April 2018

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

Cancer Cell 2018 04 22;33(4):649-663.e4. Epub 2018 Mar 22.

The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8 to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
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http://dx.doi.org/10.1016/j.ccell.2018.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904288PMC
April 2018

Two-years Postradiotherapy Biopsies: Lessons from MRC RT01 Trial.

Eur Urol 2018 06 4;73(6):968-976. Epub 2018 Jan 4.

Institute of Cancer Research and Royal Marsden Hospitals, Sutton and London, UK. Electronic address:

Background: The importance of 2-yr postradiotherapy prostate biopsy status remains uncertain.

Objective: To assess the value of 2 year post treatment biopsies in a randomised trial of radiotherapy dose escalation.

Design, Setting, And Participants: Between 1998 and 2001, 843 men with localised prostate cancer were randomised to receive either control-64Gy or escalated-74Gy conformal radiotherapy (CFRT) in the MRC RT01 trial in combination with 3-6-mo neoadjuvant androgen deprivation therapy. Prostate biopsies were planned at 2 yr from start of CFRT in suitable men.

Outcome Measurements And Statistical Analysis: Prostate biopsy results and prostate-specific antigen (PSA) levels performed at 2 yr post-CFRT were evaluated with long-term biochemical progression free survival (bPFS) and overall survival. Outcome measures were timed from the 2-yr biopsy using a landmark approach.

Results And Limitations: A 2-yr biopsy was performed in 312/843 patients. One hundred and seventy-seven patients were included in the per-protocol group with median follow-up of 7.8 yr from biopsy. Median PSA at biopsy was 0.5ng/ml. Sixty-four bPFS events were reported: 46/145 (32%) in patients with negative, 6/18 (33%) suspicious, and 12/14 (86%) positive biopsies. A positive biopsy was prognostic of worse bPFS, going forward, compared with negative and suspicious biopsies, hazard ratio (HR)=4.81 (95% confidence interval [CI]: 2.50-9.26, p<0.001). The estimate for survival was HR=1.58 (95% CI: 0.52-4.78, p=0.42). PSA values at 2 yr between 1.01ng/ml and 2.09ng/ml were also associated with subsequent PSA failures (HR=2.71, 95% CI: 1.98-3.71), bPFS events (HR=2.45, 95% CI: 1.81-3.32), and prostate cancer-specific survival (HR=2.87, 95% CI: 1.08-7.64) compared with PSA ≤1.0ng/ml.

Conclusions: Two-year postradiotherapy prostate biopsies have limited value in patients with PSA control but both positive biopsy and higher PSA status are strongly associated with future bPFS events. A policy of selected biopsy may provide an opportunity for early salvage interventions.

Patient Summary: Routine 2-yr postradiotherapy biopsy is not recommended but can be considered in selected patients with unfavourable post-treatment prostate-specific antigen levels who are suitable for early salvage treatments.
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http://dx.doi.org/10.1016/j.eururo.2017.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954168PMC
June 2018

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

PLoS Genet 2017 Sep 25;13(9):e1007001. Epub 2017 Sep 25.

Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.
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http://dx.doi.org/10.1371/journal.pgen.1007001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628936PMC
September 2017

Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma.

Sci Rep 2017 08 4;7(1):7342. Epub 2017 Aug 4.

Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, 138669, Singapore, Republic of Singapore.

Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach.
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http://dx.doi.org/10.1038/s41598-017-07191-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544702PMC
August 2017

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.

Immunity 2017 04 11;46(4):577-586. Epub 2017 Apr 11.

Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK.

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.
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http://dx.doi.org/10.1016/j.immuni.2017.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437702PMC
April 2017

Paratesticular Sarcoma: Typical Presentation, Imaging Features, and Clinical Challenges.

Urology 2017 Feb 14;100:163-168. Epub 2016 Sep 14.

Department of Radiology, Royal Marsden NHS Foundation Trust, London, United Kingdom.

Objective: To describe the major imaging features, together with clinical data, of paratesticular sarcomas.

Materials And Methods: A retrospective analysis was performed of available imaging and clinical data of 77 consecutive cases of paratesticular sarcoma referred to the soft tissue sarcoma center at the Royal Marsden hospital between January 2006 and January 2015.

Results: Of the total cases, 87% had been referred postoperatively, 43% of which had been imaged preoperatively and 24% of which required re-resection due to incomplete initial excision. On imaging, abnormal fat was present in 73% of paratesticular liposarcomas, with solid or enhancing components indicating high-grade tumors. Leiomyosarcomas and rhabdomyosarcomas were all purely solid masses.

Conclusion: Paratesticular sarcomas are rare, and lack of awareness may compromise treatment and outcome. They may be mistaken for common clinical problems such as inguinal hernias and epididymal cysts. Surgery for these presumed diagnoses may result in inadequate clearance and an increased risk of recurrence. A low threshold for imaging atypical paratesticular masses is needed, as this may better inform management.
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http://dx.doi.org/10.1016/j.urology.2016.09.005DOI Listing
February 2017

Clean intermittent self-catheterization does not appear to be effective in the prevention of urethral stricture recurrence.

Scand J Urol 2016 1;50(1):71-3. Epub 2015 Oct 1.

b Department of Urology , Princess Alexandra Hospital , Brisbane , Australia.

Objective: The aim of this study was to assess the effect of clean intermittent self-catheterization (CISC) on stricture recurrence.

Materials And Methods: The incidence of stricture recurrence was assessed retrospectively in a group of 126 new patients treated endoscopically for urethral stricture in a general urological setting between 1994 and 2001, of whom 31 performed twice-weekly CISC and 95 did not. Stricture recurrence was defined as recurrent symptomatic stricture requiring further operative intervention following initial intervention. The mean follow-up available was 25 months (range 1-132 months).

Results: Of the 126 patients assessed, 60 (47.6%) developed recurrent stricture and required an average of 3.13 endoscopic retreatments each during the follow-up period. There was no significant difference (chi-squared p = 0.46) between the number of stricture recurrences in those performing CISC (13-41.9%) and those not performing CISC (47-49.5%).

Conclusion: CISC does not appear to prevent medium-term stricture recurrence.
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http://dx.doi.org/10.3109/21681805.2015.1086888DOI Listing
December 2016

Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution.

Nat Commun 2015 Mar 19;6:6336. Epub 2015 Mar 19.

Genomic analysis of tumour development, Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain.

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.
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http://dx.doi.org/10.1038/ncomms7336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383019PMC
March 2015

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Nat Genet 2015 Apr 2;47(4):367-372. Epub 2015 Mar 2.

Department of Radiation Oncology, University of Toronto, Toronto, Canada.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
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http://dx.doi.org/10.1038/ng.3221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380509PMC
April 2015

Lessons learnt in the management of primary invasive penile cancer in an Australian tertiary referral centre: clinical outcomes with a minimum 48 months follow-up study.

Korean J Urol 2015 Feb 30;56(2):125-30. Epub 2015 Jan 30.

Department of Urology, The Royal Marsden Hospital, London, UK.

Purpose: To report on lessons learnt in the management of primary invasive penile cancer in a major tertiary hospital in Australia.

Materials And Methods: Medical records for all patients who underwent surgery for primary invasive penile cancer between January 2000 and January 2011 were obtained. Patient demographics, clinical status of inguinal node, cancer stage and clinical outcomes were reviewed. All patients were followed up for a minimum of 48 months postoperative unless patient deceased within the first 48 months from the time of penile cancer surgery.

Results: Over the 11-year period, a total of 23 cases of invasive penile cancer were identified. Partial penectomy was the most common form of organ preserving surgery and the majority of patients have pT1b disease. Of the 9 patients with clinically palpable inguinal nodes, 7 patients were diagnosed with pN3 disease following inguinal lymphadenectomy. The Kaplan-Meier cancer-specific survival at 72 months showed decreasing survival based on tumour stage (83% in pT1, 79% in pT2, and 64% in pT3 disease) and nodal disease (100% in node negative, 50% in superficial inguinal lymphadenopathy, and 38% in patients with deep inguinal and/or pelvic lymphadenopathy) (p=0.082). The Kaplan-Meier cancer-specific survival revealed statistically significant difference in survival outcome in patients with local recurrence vs. systemic metastasis disease (33% vs. 17%, p=0.008).

Conclusions: The presence of high risk features such as tumour stage, lymph node involvement and distant metastasis carries a significant higher risk of death and tumour recurrence in patients with penile cancer and inguinal lymph node metastasis.
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http://dx.doi.org/10.4111/kju.2015.56.2.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325116PMC
February 2015
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