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

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.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

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.

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

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.

A language-matching model to improve equity and efficiency of COVID-19 contact tracing.

Contact tracing is a pillar of COVID-19 response, but language access and equity have posed major obstacles. COVID-19 has disproportionately affected minority communities with many non-English-speaking members. Language discordance can increase processing times and hamper the trust building necessary for effective contact tracing. We demonstrate how matching predicted patient language with contact tracer language can enhance contact tracing. First, we show how to use machine learning to combine information from sparse laboratory reports with richer census data to predict the language of an incoming case. Second, we embed this method in the highly demanding environment of actual contact tracing with high volumes of cases in Santa Clara County, CA. Third, we evaluate this language-matching intervention in a randomized controlled trial. We show that this low-touch intervention results in 1) significant time savings, shortening the time from opening of cases to completion of the initial interview by nearly 14 h and increasing same-day completion by 12%, and 2) improved engagement, reducing the refusal to interview by 4%. These findings have important implications for reducing social disparities in COVID-19; improving equity in healthcare access; and, more broadly, leveling language differences in public services.

ExPeCT: a randomised trial examining the impact of exercise on quality of life in men with metastatic prostate cancer.

PURPOSE: All patients living with cancer, including those with metastatic cancer, are encouraged to be physically active. This paper examines the secondary endpoints of an aerobic exercise intervention for men with metastatic prostate cancer. METHODS: ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells), was a multi-centre randomised control trial with a 6-month aerobic exercise intervention arm or a standard care control arm. Exercise adherence data was collected via heart rate monitors. Quality of life (FACT-P) and physical activity (self-administered questionnaire) assessments were completed at baseline, at 3 months and at 6 months. RESULTS: A total of 61 patients were included (69.4 ± 7.3 yr, body mass index 29.2 ± 5.8 kg/m2). The median time since diagnosis was 34 months (IQR 7-54). A total of 35 (55%) of participants had > 1 region affected by metastatic disease. No adverse events were reported by participants. There was no effect of exercise on quality of life (Cohen's d = - 0.082). Overall adherence to the supervised sessions was 83% (329 out of 396 possible sessions attended by participants). Overall adherence to the non-supervised home exercise sessions was 72% (months 1-3) and 67% (months 3-6). Modelling results for overall physical activity scores showed no significant main effect for the group (p-value = 0.25) or for time (p-value = 0.24). CONCLUSION: In a group of patients with a high burden of metastatic prostate cancer, a 6-month aerobic exercise intervention did not lead to change in quality of life. Further exercise studies examining the role of exercise for people living with metastatic prostate cancer are needed. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (NCT02453139) on May 25th 2015.

Monkeypox (Mpox) Vaccine Hesitancy Among Mpox Cases: A Qualitative Study.

Human mpox has been an increasing concern in the United States and California since late 2022. While the Jynneos vaccine offers a degree of cross-protection against the disease, vaccine hesitancy is common among those recommended for vaccination. The purpose of this study was to assess vaccine knowledge, facilitators, and barriers to vaccine uptake among individuals previously diagnosed with mpox, or mpox cases, in Santa Clara County, California. In-depth interviews were conducted by public health department staff among mpox cases diagnosed in Santa Clara County between July and September 2022. Responses were analyzed using a grounded theory data analysis approach. Among the 47 participants, 36 (77%) had heard of mpox before diagnosis, and of these, 20 (56%) did not think they were at risk of developing mpox, and 28 (78%) were aware that a vaccine was available. Those who did not receive the vaccine stated vaccine access and availability were the main barriers. Among the six participants not interested in the vaccine, the main hesitancies were lack of perceived risk, stigma of being branded by scarring and labeled gay, and vaccine safety. Overall, the following themes were attributed to reasons for vaccine hesitancy: (a) lack of awareness of the disease and vaccine, including perceived risks; (b) lack of vaccine availability and accessibility; and (c) stigma associated with receiving the vaccine, including being publicly labeled as "gay" and the scarring on forearm potentially seen as branding. We recommend tailoring outreach and educational campaigns to address reasons for mpox vaccine hesitancy.

Genomic Epidemiology and Transmission Dynamics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Congregate Healthcare Facilities in Santa Clara County, California.

BACKGROUND: Outbreaks of SARS-CoV-2 in long-term care facilities (LTCFs) cause significant morbidity and mortality. Mapping viral transmission within and between facilities by combining genomic sequencing with epidemiologic investigations enables targeting infection-control interventions. METHODS: We conducted weekly surveillance of residents and staff in LTCFs in Santa Clara County, California, with ≥1 confirmed COVID-19 case between March and July 2020. Positive samples were referred for whole-genome sequencing. Epidemiological investigations and phylogenetic analyses of the largest outbreaks (>30 cases) were carried out in 6 LTCFs (Facilities A through F). RESULTS: Among the 61 LTCFs in the county, 41 had ≥1 confirmed case during the study period, triggering weekly SARS-CoV-2 testing. The 6 largest outbreaks accounted for 60% of cases and 90% of deaths in LTCFs, although the bed capacity of these facilities represents only 11% of the LTCF beds in the county. Phylogenetic analysis of 196 whole-genome sequences recovered from those facilities showed that each outbreak was monophyletic, with staff and residents sharing a common viral lineage. Outbreak investigations revealed that infected staff members often worked at multiple facilities, and in 1 instance, a staff member infected while working in 1 facility was the likely index case in another. CONCLUSIONS: We detected a pattern of rapid and sustained transmission after a single introduction of SARS-CoV-2 in 6 large LTCF outbreaks, with staff playing a key role in transmission within and between facilities. Infection control, testing, and occupational policies to reduce exposure and transmission risk for staff are essential components to keeping facility residents safe.

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10-9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.

Invadopodia play a role in prostate cancer progression.

BACKGROUND: Invadopodia, actin-rich structures that release metallo-proteases at the interface with extra-cellular matrix, in a punctate manner are thought to be important drivers of tumour invasion. Invadopodia formation has been observed in-vitro and in-vivo in numerous metastatic cell lines derived from multiple tumour types. However, prostate cancer cell lines have not been routinely reported to generate invadopodia and the few instances have always required external stimulation. METHODS: In this study, the invasive potential of primary prostate adenocarcinoma cell lines, which have never been fully characterised before, was investigated both in-vitro invadopodia assays and in-vivo zebrafish dissemination assay. Subsequently, circulating tumour cells from prostate cancer patients were isolated and tested in the invadopodia assay. RESULTS: Retention of E-cadherin and N-cadherin expression indicated a transitional state of EMT progression, consistent with the idea of partial EMT that has been frequently observed in aggressive prostate cancer. All cell lines tested were capable of spontaneous invadopodia formation and possess a significant degradative ability in-vitro under basal conditions. These cell lines were invasive in-vivo and produced visible metastasis in the zebrafish dissemination assay. Importantly we have proceeded to demonstrate that circulating tumour cells isolated from prostate cancer patients exhibit invadopodia-like structures and degrade matrix with visible puncta. This work supports a role for invadopodia activity as one of the mechanisms of dissemination employed by prostate cancer cells. CONCLUSION: The combination of studies presented here provide clear evidence that invadopodia activity can play a role in prostate cancer progression.

Safe provision of systemic anti-cancer treatment for urological cancer patients during COVID-19: a tertiary centre experience in the first wave of COVID-19.

BACKGROUND: Safe provision of systemic anti-cancer treatment (SACT) during the COVID-19 pandemic remains an ongoing concern amongst clinicians. METHODS: Retrospective analysis on uro-oncology patients who continued or started SACT between 1st March and 31st May 2020 during the pandemic (with 2019 as a comparator). RESULTS: 441 patients received SACT in 2020 (292 prostate, 101 renal, 38 urothelial, 10 testicular) compared to 518 patients in 2019 (340 prostate, 121 renal, 42 urothelial, 15 testicular). In 2020, there were 75.00% fewer patients with stage 3 cancers receiving SACT (p < 0.0001) and 94.44% fewer patients receiving radical treatment (p = 0.00194). The number of patients started on a new line of SACT was similar between both years (118 in 2019 vs 102 in 2020; p = 0.898) but with 53.45% fewer patients started on chemotherapy in 2020 (p < 0.001). Overall, 5 patients tested positive for COVID-19 (one asymptomatic, one mild, two moderate, one severe resulting in death). Compared to 2019, 30-day mortality was similar (1.69% in 2019 vs 0.98% in 2020; p = 0.649) whereas 6-month mortality was lower (9.32% in 2019 vs 1.96% in 2020; p = 0.0209) in 2020. CONCLUSION: This study suggests that delivery of SACT to uro-oncology patients during COVID-19 pandemic may be safe in high-incidence areas with appropriate risk-reduction strategies.

Introduction, Transmission Dynamics, and Fate of Early Severe Acute Respiratory Syndrome Coronavirus 2 Lineages in Santa Clara County, California.

We combined viral genome sequencing with contact tracing to investigate introduction and evolution of severe acute respiratory syndrome coronavirus 2 lineages in Santa Clara County, California, from 27 January to 21 March 2020. From 558 persons with coronavirus disease 2019, 101 genomes from 143 available clinical samples comprised 17 lineages, including SCC1 (n = 41), WA1 (n = 9; including the first 2 reported deaths in the United States, with postmortem diagnosis), D614G (n = 4), ancestral Wuhan Hu-1 (n = 21), and 13 others (n = 26). Public health intervention may have curtailed the persistence of lineages that appeared transiently during February and March. By August, only D614G lineages introduced after 21 March were circulating in Santa Clara County.

Epidemiologic Findings from Case Investigations and Contact Tracing for First 200 Cases of Coronavirus Disease, Santa Clara County, California, USA.

In January 2020, Santa Clara County, California, USA, began identifying laboratory-confirmed coronavirus disease among residents. County staff conducted case and contact investigations focused on households and collected detailed case demographic, occupation, exposure, and outcome information. We describe the first 200 test-positive cases during January 31-March 20, 2020, to inform future case and contact investigations. Probable infection sources included community transmission (104 cases), known close contact with a confirmed case-patient (66 cases), and travel (30 cases). Disease patterns across race and ethnicity, occupational, and household factors suggested multiple infection risk factors. Disproportionately high percentages of case-patients from racial and ethnic subgroups worked outside the home (Hispanic [86%] and Filipino [100%]); household transmission was more common among persons from Vietnam (53%). Even with the few initial cases, detailed case and contact investigations of household contacts capturing occupational and disaggregated race and ethnicity data helped identify at-risk groups and focused solutions for disease control.

The impact of a supranetwork multidisciplinary team (SMDT) on decision-making in testicular cancers: a 10-year overview of the Anglian Germ Cell Cancer Collaborative Group (AGCCCG).

BACKGROUND: The germ cell supranetwork multidisciplinary team (SMDT) for the Anglian Network covers a population of 7.5 million. METHODS: We reviewed 10 years of SMDT discussion and categorised them into five domains ((1) overall outcome, (2) chemotherapy regimens-untreated disease and salvage therapy, (3) radiology, (4) pathology and (5) complex cases) to assess the impact of the SMDT. RESULTS: A total of 2892 new cases were reviewed. In the first 5 years, patients with good prognosis disease had poorer survival in low-volume vs high-volume centres (87.8 vs 95.3, p = 0.02), but the difference was no longer significant in the last 5 years (93.3 vs 95.1, p = 0.30). Radiology review of 3206 scans led to rejection of the diagnosis of progression in 26 cases and a further 10 cases were down-staged. There were 790 pathology reviews by two specialised uropathologists, which lead to changes in 75 cases. 18F-fluorodeoxyglucose (18FDG) PET-CT was undertaken during this time period but did not help to predict who would have viable cancer. A total of 26 patients with significant mental health issues who were unable to give informed consent were discussed. CONCLUSION: SMDT working has led to an improvement in outcomes and refining of treatment in patients with germ cell tumours.

Cohort profile: King's Health Partners bladder cancer biobank.

BACKGROUND: Bladder cancer (BC) is the 9th most common cancer worldwide, but little progress has been made in improving patient outcomes over the last 25 years. The King's Health Partners (KHP) BC biobank was established to study unanswered, clinically relevant BC research questions. Donors are recruited from the Urology or Oncology departments of Guy's Hospital (UK) and can be approached for consent at any point during their treatment pathway. At present, patients with bladder cancer are approached to provide their consent to provide blood, urine and bladder tissue. They also give access to medical records and linkage of relevant clinical and pathological data across the course of their disease. Between June 2017 and June 2019, 531 out of 997 BC patients (53.3%) gave consent to donate samples and data to the Biobank. During this period, the Biobank collected fresh frozen tumour samples from 90/178 surgical procedures (of which 73 were biopsies) and had access to fixed, paraffin embedded samples from all patients who gave consent. Blood and urine samples have been collected from 38 patients, all of which were processed into component derivatives within 1 to 2 h of collection. This equates to 193 peripheral blood mononuclear cell vials; 238 plasma vials, 224 serum vials, 414 urine supernatant vials and 104 urine cell pellets. This biobank population is demographically and clinically representative of the KHP catchment area. CONCLUSION: The King's Health Partners BC Biobank has assembled a rich data and tissue repository which is clinically and demographically representative of the local South East London BC population, making it a valuable resource for future BC research.

Evidence for Limited Early Spread of COVID-19 Within the United States, January-February 2020.

From January 21 through February 23, 2020, public health agencies detected 14 U.S. cases of coronavirus disease 2019 (COVID-19), all related to travel from China (1,2). The first nontravel-related U.S. case was confirmed on February 26 in a California resident who had become ill on February 13 (3). Two days later, on February 28, a second nontravel-related case was confirmed in the state of Washington (4,5). Examination of four lines of evidence provides insight into the timing of introduction and early transmission of SARS-CoV-2, the virus that causes COVID-19, into the United States before the detection of these two cases. First, syndromic surveillance based on emergency department records from counties affected early by the pandemic did not show an increase in visits for COVID-19-like illness before February 28. Second, retrospective SARS-CoV-2 testing of approximately 11,000 respiratory specimens from several U.S. locations beginning January 1 identified no positive results before February 20. Third, analysis of viral RNA sequences from early cases suggested that a single lineage of virus imported directly or indirectly from China began circulating in the United States between January 18 and February 9, followed by several SARS-CoV-2 importations from Europe. Finally, the occurrence of three cases, one in a California resident who died on February 6, a second in another resident of the same county who died February 17, and a third in an unidentified passenger or crew member aboard a Pacific cruise ship that left San Francisco on February 11, confirms cryptic circulation of the virus by early February. These data indicate that sustained, community transmission had begun before detection of the first two nontravel-related U.S. cases, likely resulting from the importation of a single lineage of virus from China in late January or early February, followed by several importations from Europe. The widespread emergence of COVID-19 throughout the United States after February highlights the importance of robust public health systems to respond rapidly to emerging infectious threats.

Imaging αvß3 integrin expression in skeletal metastases with 99mTc-maraciclatide single-photon emission computed tomography: detection and therapy response assessment.

PURPOSE: Osteoclast activity is an important factor in the pathogenesis of skeletal metastases and is a potential therapeutic target. This study aimed to determine if selective uptake of 99mTc-maraciclatide, a radiopharmaceutical targeting αvß3 integrin, occurs in prostate cancer (PCa) bone metastases and to observe the changes following systemic therapy. METHODS: The study group comprised 17 men with bone-predominant metastatic PCa who underwent whole-body planar and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging with 99mTc-maraciclatide before (n = 17) and 12 weeks after (n = 11) starting treatment with abiraterone. Tumour to normal bone (T:N) ratios, tumour to muscle (T:M) ratios and CT Hounsfield units (HU) were measured in up to five target metastases in each subject. An oncologist blinded to study scans assessed clinical responses up to 24 weeks using conventional criteria. RESULTS: Before treatment, metastases showed specific 99mTc-maraciclatide accumulation (mean planar T:N and T:M ratios 1.43 and 3.06; SPECT T:N and T:M ratios 3.1 and 5.19, respectively). Baseline sclerotic lesions (389-740 HU) showed lower T:M ratios (4.22 vs. 7.04, p = 0.02) than less sclerotic/lytic lesions (46-381 HU). Patients with progressive disease (PD; n = 5) showed increased planar T:N and T:M ratios (0.29 and 12.1%, respectively) and SPECT T:N and T:M ratios (11.9 and 20.2%, respectively). Patients without progression showed decreased planar T:N and T:M ratios (0.27 and -8.0%, p = 1.0 and 0.044, respectively) and SPECT T:N and T:M ratios (-21.9, and -27.2%, p = 0.3 and 0.036, respectively). The percentage change in CT HU was inversely correlated with the percentage change in SPECT T:M ratios (r = -0.59, p = 0.006). CONCLUSIONS: 99mTc-maraciclatide accumulates in PCa bone metastases in keeping with increased αvß3 integrin expression. Greater activity in metastases with lower CT density suggests that uptake is related to osteoclast activity. Changes in planar and SPECT T:M ratios after 12 weeks of treatment differed between patients with and without PD and 99mTc-maraciclatide imaging may be a potential method for assessing early response.

Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer.

OBJECTIVE: To investigate whether curative prostate cancer (PCa) treatment was received less often by men with both PCa and Type 2 diabetes mellitus (T2DM) as little is known about the influence of T2DM diagnosis on the receipt of such treatment in men with localized PCa. SUBJECTS AND METHODS: The Prostate Cancer database Sweden (PCBaSe) was used to obtain data on men with T2DM and PCa (n = 2210) for comparison with data on men with PCa only (n = 23 071). All men had intermediate- (T1-2, Gleason score 7 and/or prostate-specific antigen [PSA] 10-20 ng/mL) or high-risk (T3 and/or Gleason score 8-10 and/or PSA 20-50 ng/mL) localized PCa diagnosed between 1 January 2006 and 31 December 2014. Multivariate logistic regression was used to calculate the odds ratios (ORs) for receipt of curative treatment in men with and without T2DM. Overall survival, for up to 8 years of follow-up, was calculated both for men with T2DM only and for men with T2DM and PCa. RESULTS: Men with T2DM were less likely to receive curative treatment for PCa than men without T2DM (OR 0.78, 95% confidence interval 0.69-0.87). The 8-year overall survival rates were 79% and 33% for men with T2DM and high-risk PCa who did and did not receive curative treatment, respectively. CONCLUSIONS: Men with T2DM were less likely to receive curative treatment for localized intermediate- and high-risk PCa. Men with T2DM and high-risk PCa who received curative treatment had substantially higher survival times than those who did not. Some of the survival differences represent a selection bias, whereby the healthiest patients received curative treatment. Clinicians should interpret this data carefully and ensure that individual patients with T2DM and PCa are not under- nor overtreated.

Evaluation of treatment response and resistance in metastatic renal cell cancer (mRCC) using integrated 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI); The REMAP study.

BACKGROUND: Tyrosine kinase inhibitors are the first line standard of care for treatment of metastatic renal cell carcinoma (RCC). Accurate response assessment in the setting of antiangiogenic therapies remains suboptimal as standard size-related response criteria do not necessarily accurately reflect clinical benefit, as they may be less pronounced or occur later in therapy than devascularisation. The challenge for imaging is providing timely assessment of disease status allowing therapies to be tailored to ensure ongoing clinical benefit. We propose that combined assessment of morphological, physiological and metabolic imaging parameters using 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) will better reflect disease behaviour, improving assessment of response/non-response/relapse. METHODS/DESIGN: The REMAP study is a single-centre prospective observational study. Eligible patients with metastatic renal cell carcinoma, planned for systemic therapy, with at least 2 lesions will undergo an integrated 18F-FDG PET and MRI whole body imaging with diffusion weighted and contrast-enhanced multiphasic as well as standard anatomical MRI sequences at baseline, 12 weeks and 24 weeks of systemic therapy allowing 18F-FDG standardised uptake value (SUV), apparent diffusion co-efficient (ADC) and normalised signal intensity (SI) parameters to be obtained. Standard of care contrast-enhanced computed tomography CT scans will be performed at equivalent time-points. CT response categorisation will be performed using RECIST 1.1 and alternative (modified)Choi and MASS criteria. The reference standard for disease status will be by consensus panel taking into account clinical, biochemical and conventional imaging parameters. Intra- and inter-tumoural heterogeneity in vascular, diffusion and metabolic response/non-response will be assessed by image texture analysis. Imaging will also inform the development of computational methods for automated disease status categorisation. DISCUSSION: The REMAP study will demonstrate the ability of integrated 18F-FDG PET-MRI to provide a more personalised approach to therapy. We suggest that 18F-FDG PET/MRI will provide superior sensitivity and specificity in early response/non-response categorisation when compared to standard CT (using RECIST 1.1 and alternative (modified)Choi or MASS criteria) thus facilitating more timely and better informed treatment decisions. TRIAL REGISTRATION: The trial is approved by the Southeast London Research Ethics Committee reference 16/LO/1499 and registered on the NIHR clinical research network portfolio ISRCTN12114913 .

Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer.

BACKGROUND: Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa. METHODS: METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London. DISCUSSION: This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place. TRIAL REGISTRATION: EudraCT number 2014-005193-11 . Registered on September 09, 2015.

Association between duration and type of androgen deprivation therapy and risk of diabetes in men with prostate cancer.

Androgen deprivation therapy (ADT) for prostate cancer (PCa) increases risk of type 2 diabetes (T2DM); however the association between types and duration of ADT has not been fully elucidated. We examined how type and duration of ADT affects risk of T2DM. Using data from Prostate Cancer database Sweden (PCBaSe) we investigated risk of T2DM in a cohort of 34,031 men with PCa on ADT; i.e., anti-androgens (AA), orchiectomy, or gonadotropin-releasing hormone (GnRH) agonists compared to an age-matched, PCa-free comparison cohort (n = 167,205) using multivariate Cox proportional hazard regression. T2DM was defined as a newly filled prescription for metformin, sulphonylurea, or insulin in the Prescribed Drug Register. A total of 21,874 men with PCa received GnRH agonists, 9,143 AA and 3,014 underwent orchiectomy. Risk of T2DM was increased in men in the GnRH agonists/orchiectomy group during the first 3 years of ADT [i.e., 1 - 1.5 years HR: 1.61 (95%CI: 1.36 - 1.91)], compared to PCa-free men. The risk decreased thereafter (e.g., 3 - 4 years HR: 1.17 (95% CI: 0.98 - 1.40)). Conversely, no increased risk was seen in men on AA (HR: 0.74 (95%CI: 0.65 - 0.84). The incidence of T2DM per 1,000 person-years was 10 for PCa-free men, 8 for men on AA, and 13 for men on GnRH agonists/orchiectomy. Duration of ADT has a significant impact on risk of T2DM. With the peak after three years of treatment, our data indicates that men on ADT, even for a limited period of time, such as adjuvant to radiotherapy, are at increased risk of T2DM.