OBJECTIVES:To investigate whether nurse navigator-led triaging of high-risk patients may reduce prostate cancer (PCa) diagnosis and treatment times using an in-house bespoke PRostate cancer diAGnosis and MAnagement Triage In the Clinial care pathway (PRAGMATIC) triaging system, as locally advanced/metastatic disease should be diagnosed and treated rapidly, and UK targets allow 28 days for diagnosis, and 62 days to commence treatment. PATIENTS AND METHODS:We reviewed diagnosis and treatment timelines for patients undergoing 28/62-day investigation for suspected PCa at a tertiary unit in a 3-month period (2022). We then introduced nurse navigator-led triaging of urgent referrals and evaluated a subsequent 3-month period (2024), with streamlining for rapid investigation and treatment based on prostate-specific antigen, magnetic resonance imaging (MRI) staging, and histology. We hypothesised nurse navigator-led triaging would improve investigation and treatment times for high-risk localised, or locally advanced, or metastatic PCa. RESULTS:A total of 165 and 327 consecutive patients were on the 28/62-day PCa pathway in the pre- (2022) and post-nurse navigator-led (2024) triaging periods, respectively. The median time from referral to first appointment (8 vs 4 days), MRI (12 vs 6 days), MRI result (26 vs 17 days), biopsy decision (25 vs 16 days), biopsy procedure (48 vs 22 days), biopsy result communication (64 vs 44 fays), and prostate-specific membrane antigen positron emission tomography computed tomography staging scan (87 vs 56 days) was reduced following nurse navigator triaging of high-risk cases (all P < 0.001). The median time from referral to treatment for Gleason Grade Group ≥3, or T3, or ≥N1, or ≥M1 disease (104 vs 70 days; 49/75 [65.3%] vs 72/128 [56.3%] patients), and for M1b disease (47 vs 27 days; 15/75 [20%] vs 32/128 [25%] patients), was reduced (P < 0.05). CONCLUSIONS:Nurse navigator-led triaging and stratification of the most clinically urgent suspected PCa cases was associated with improved imaging, biopsy diagnosis, and treatment times for the highest-risk patients.

Background: Detection of metastatic disease is important to inform prostate cancer management. Objectives: Evaluate local and distant staging by initial 18F-PSMA-1007 PET in primary and secondary prostate cancer. Design, Setting, and Participants: We retrospectively identified a consecutive series of 18F-PSMA-1007 PET scans from the date of introduction of 18F-PSMA-1007 PET in September 2019 until April 2022 at a single UK tertiary referral center. Our protocol was registered in advance (OSF registration ID: KTE3R). Results: We identified 1335 PSMA-PET scans, from 1220 men. Across 623 initial scans for primary staging, we observed PSMA-PET avidity in 97.6% cases positive for local disease, 29.5% for nodal disease, and 26.5% for metastatic disease. PSMA-PET identified a 13.2% absolute increase in nodal lesions compared with MRI and a 24.0% absolute increase in metastatic lesions compared with MRI marrow. The sensitivity for detection of local disease among 79 patients who had radical prostatectomy was 96.2% for PSMA-PET vs 89.4% for multiparametric MRI. Across 612 scans for secondary staging, we observed PSMA-PET positive avidity in 51.2% of cases for local recurrence, 46.6% for nodal disease, and 43.0% for metastatic disease. When evaluated by the PSA range for patients receiving secondary staging, using the PSA values of 0.2 to 0.49, 0.5 to 0.99, 1 to 1.99, and ≥ 2 ng/mL, PSMA-PET scans were positive in 57.8%, 75.0%, 83.8%, and 95.5% of cases, respectively. PSMA-PET identified a 26.2% absolute increase in metastatic lesions compared with MRI marrow or other skeletal MRI (n = 61) and a 14.7% absolute increase in metastatic lesions compared with the bone scan (n = 42). Conclusion: 18F-PSMA-1007 PET identifies a higher number of nodal and metastatic lesions compared with conventional cross-sectional imaging. However, the high number of indeterminate lesions and stage migration necessitates discussion of 18F-PSMA-1007 PET imaging within a multidisciplinary team and places a higher burden on these teams.

Purpose/Objective(s) Hypoxia is a common characteristic of solid tumors, including non-small cell lung cancer (NSCLC). Hypoxia is associated with increased resistance to cell death, thus rendering it resistant to standard cancer treatment such as radiotherapy and chemotherapy. Surgical intervention is the primary approach of treatment for NSCLC patients in whom tumor is resectable. However, whether baseline tumour hypoxia affects overall survival and disease progression of patients with NSCLC following surgical management remains unclear. The hypothesis of this retrospective study is that surgical outcomes are worse with the presence of baseline hypoxia, as measured by radiotracer fluoromisonidazole (F-MISO) uptake detected by hypoxia-positron emission tomography/computed tomography (PET-CT), in NSCLC patients who underwent surgical resection during the ATOM trial (NCT02628080) at a single institution. Materials/Methods We only selected participants from the ATOM trial who did not receive atovaquone prior to surgical intervention. We then extracted data such as patient demographics, stage of cancer at time of surgery, presence of baseline hypoxia (defined as tumor-to-blood ratio (TBR) 1.4 greater than 1.5 mL), overall survival (OS) at 1 and 3 years, and 1-year progression free survival (PFS). Kaplan-Meier survival analysis for time from surgery to death was compared between patients with or without baseline hypoxia and the p-value was calculated with log-rank test. Results A total of 26 trial participants from the ATOM study were included in this analysis. The majority were male (n = 19, 73.1%), with a mean age of 69.3 years. Three, ten, four, and nine patients were in stages 1-4 NSCLC, respectively. Fourteen patients had baseline hypoxia whilst 12 patients did not. The 1- and 3-year OS for patients with baseline hypoxia were 86% and 71%, respectively. For those without baseline hypoxia, OS at 1 and 3 years were 92% and 83%, respectively. One-year PFS for patients with baseline hypoxia was 55%; those without hypoxia had 1-year PFS of 80%. Using Kaplan-Meier analysis, there was no statistically significant difference when comparing both groups (p = 0.63). Conclusion Patients with baseline hypoxia tend to have worse surgical outcomes compared to those without baseline hypoxia. However, the Kaplan Meier survival analysis demonstrated that the difference in survival is not statistically significant. A larger sample size from multi-center studies in the future is warranted to investigate this further.

Background: It is important to investigate, diagnose and commence treatment for locally advanced and metastatic prostate cancer quickly to optimise treatment outcomes. Since the introduction of national 2-week wait and 31/62-day targets in the United Kingdom for investigation of suspected prostate cancer over 2 decades ago, the clinical pathway has become increasingly complex. This may lead to some patients with the most clinically significant disease having the rapidity of their diagnosis and commencement of treatment compromised by resource use in diagnosing less significant, or clinically insignificant, disease. Methods: We will conduct a retrospective review of timelines for diagnosis and commencement of treatment for all men referred to a tertiary unit for investigation of suspected prostate cancer on the 2-week wait pathway in a 3-month period in 2023. In parallel, we will introduce triaging of all new 2-week wait referrals in a prospective 3-month period, with a dedicated nurse navigator streamlining patients for the most rapid investigation and treatment, based on pre-specified risk criteria including PSA, pre-biopsy mpMRI findings including TNM staging, and histology results. We hypothesise that this bespoke triaging system, above and beyond the 2-week wait and 2022 Faster Diagnostic Pathway guidance issued by NHS England, will improve timings for investigation and commencement of treatment for the most clinically significant prostate cancer cases. Conclusions: The use of in-house criteria for triaging and stratification of the most clinically urgent and significant prostate cancer cases, identified by a nurse specialist navigator, may improve clinical outcomes for patients with greatest need for rapid prostate cancer imaging, diagnosis and treatment.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study did not receive any funding.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:We have registered an actionable review of the entire 2-week wait and 28/62-day prostate cancer diagnosis and treatment pathway at our Institution (Oxford University Hospitals NHS Foundation Trust). This registered QIP (OUH reference number 8381) aims to allow all those engaged in the various multiple steps of the 2-week wait and 28/62-day pathway to triage the highest risk cases for the most rapid diagnosis and treatment, whilst simultaneously safeguarding against undue delay for lower-risk cases as an unintended consequence.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present work are contained in the manuscript.

Irreversible electroporation (IRE) is a recent and minimally invasive method of partial prostate ablation. However, knowledge of the essential landmarks of prostate anatomy is crucial to achieving safe and effective partial ablation by IRE. High-quality imaging of the prostate is essential before the procedure. The individual morphological pattern of the prostate must be taken into account and detailed mapping with measurement of the lesion is necessary to determine optimal needle placement. The entire tumour volume must be covered while ensuring the safety of critical anatomical structures such as the rectum, urethra, nerve bundles and sphincter muscle.

Objectives Primary objectives: to determine whether local anaesthetic transperineal prostate (LATP) biopsy improves the detection of clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology (ISUP) Grade Group ≥2 disease (i.e., any Gleason pattern 4 disease), compared to transrectal ultrasound‐guided (TRUS) prostate biopsy, in biopsy‐naïve men undergoing biopsy based on suspicion of csPCa. Secondary objectives: to compare (i) infection rates, (ii) health‐related quality of life, (iii) patient‐reported procedure tolerability, (iv) patient‐reported biopsy‐related complications (including bleeding, bruising, pain, loss of erectile function), (v) number of subsequent prostate biopsy procedures required, (vi) cost‐effectiveness, (vii) other histological parameters, and (viii) burden and rate of detection of clinically insignificant PCa (ISUP Grade Group 1 disease) in men undergoing these two types of prostate biopsy. Patients and Methods The TRANSLATE trial is a UK‐wide, multicentre, randomised clinical trial that meets the criteria for level‐one evidence in diagnostic test evaluation. TRANSLATE is investigating whether LATP biopsy leads to a higher rate of detection of csPCa compared to TRUS prostate biopsy. Both biopsies are being performed with an average of 12 systematic cores in six sectors (depending on prostate size), plus three to five target cores per multiparametric/bi‐parametric magnetic resonance imaging lesion. LATP biopsy is performed using an ultrasound probe‐mounted needle‐guidance device (either the ‘Precision‐Point’ or BK UA1232 system). TRUS biopsy is performed according to each hospital's standard practice. The study is 90% powered to detect a 10% difference (LATP biopsy hypothesised at 55% detection rate for csPCa vs 45% for TRUS biopsy). A total of 1042 biopsy‐naïve men referred with suspected PCa need to be recruited. Conclusions This trial will provide robust prospective data to determine the diagnostic ability of LATP biopsy vs TRUS biopsy in the primary diagnostic setting.

INTRODUCTION AND OBJECTIVE: Recent studies have shown the superiority of PSMA-PET in staging of prostate cancer compared to conventional cross-sectional imaging. To date, most PSMA-PET scans have been performed for secondary prostate cancer and use a Gallium-68 ligand. Our objectives were to quantify local and distant staging by 18F PSMA PET in primary PCa. METHODS: We identified retrospectively a consecutive series of 18F PSMA-PET scans which we interrogated using a prospectively registered protocol (OSF registration ID: KTE3R). All PET scans were performed for staging of prostate cancer at a single UK tertiary referral centre, from the date of introduction of PSMA PET in September 2019 until August 2021. For primary staging, we compared PSMA PET to MRI and prostatectomy histology (for T and N staging), and MRI Marrow (for M staging). RESULTS: We identified 820 PSMA PET scans from 765 men, of which 354 were for primary staging. The mean age was 69.0 years (SD[7.4 years), and D'Amico risk classification was: 0.3% low risk; 72.0% intermediate risk; 27.7% high risk. We observed PSMA PET avidity in 96.9% of cases for local disease, 33.1% for nodal disease, and 32.5% for metastatic disease. PSMA PET identified local disease similar to MRI (96.6% versus 96.9%, respectively), and identified 14.72% more nodal lesions than MRI, and 27.2% more metastatic lesions than MRI Marrow (Figure 1). Some 47 men underwent radical prostatectomy after both PSMA-PET and MRI, of which all had positive histology. The sensitivity of PSMA-PET was 97.8% versus 93.6% with MRI for any primary lesion. A total of 21 of these patients had lymph node dissection, of which two had positive histology. The sensitivity of PSMA-PET for any nodal disease was 50% versus 0% with MRI. Narrow slice MRI was used to corroborate skeletal lesions in 14 PSMA PET scans. None of the PSMA PET scans were positive on Narrow slice MRI, indicating an estimated false-positive rate for skeletal lesions of at least 6.7% (14 false positives versus 195 negative PSMA PET scans). CONCLUSIONS: 18F PSMA-PET adds value over MRI in identification of local disease as well as nodal and distant metastatic spread. However, there is a notable estimated false-positive rate of at least 6.7%. Source of Funding: None

INTRODUCTION AND OBJECTIVE: Covid-19 caused major disruptions to cancer diagnosis and treatment. We aimed to evaluate the longitudinal disruption to prostate cancer management. METHODS: We completed a prospective service evaluation from 01/09/2019 to 31/08/2021 of all referrals, investigations, and treatments for prostate cancer at a single centre. The first UK Covid-19 lockdown occurred from 23/03/20 to 04/07/2020: monthly data for the time period before, during, and after the first UK lockdown were compared using ANOVA and Tukey HSD. RESULTS: We identified 4501 patients for inclusion. There was a profound decrease in all aspects of prostate cancer management during the first lockdown period. For pre-lockdown, lockdown, and postlockdown periods respectively, the mean monthly rates were: 256 v 125 v 363 PSA tests (p=0.0003);86 v 40 v 79 two-week-wait referrals (p=0.0005);62 v 18 v 54 MRI imaging for possible cancer (p<0.0001);32 v 15 v 36 diagnoses (p=0.002);17 v 9 v 14 prostatectomies (p=0.06). In the period after the first lockdown, despite the previous drop, we did not observe an increase in the number of referrals, MRI imaging, diagnoses, or treatment required (including active monitoring, chemotherapy, radiotherapy, prostatectomy, and palliative care) in comparison to pre-lockdown levels (all p>0.05). However, interestingly, we did see an increase in the number of PSA tests performed (p=0.04), which continued through the two subsequent UK lockdowns. CONCLUSIONS: To our knowledge, this is the first study to provide an overview of the impact of COVID-19 national lockdowns on the whole prostate cancer management pathway - from initial referral to final treatment. Despite the disruption to prostate cancer management during the first UK Covid-19 lockdown leading to a decrease in referrals, diagnoses and treatment in the context of reduced PSA testing, we have not seen a subsequent increase in these numbers after lockdown despite a rise in PSA testing. The rise in the number PSA tests performed post-lockdown may suggest a degree of compensatory PSA observation in the community. (Figure Presented).

Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is of interest to help develop novel hypoxia modifiers and guide radiation treatment planning. Yet, the optimal post-injection (p.i.) timing of hypoxic imaging remains questionable. Therefore, we investigated the correlation between hypoxia-related quantitative values in FMISO-PET acquired at 2 and 4 h p.i. in patients with non-small cell lung cancer (NSCLC). Patients with resectable NSCLC participated in the ATOM clinical trial (NCT02628080) which investigated the hypoxia modifying effects of atovaquone. Two-hour and four-hour FMISO PET/CT images acquired at baseline and pre-surgery visits (n = 58) were compared. Cohort 1 (n = 14) received atovaquone treatment, while cohort 2 (n = 15) did not. Spearman’s rank correlation coefficients (ρ) assessed the relationship between hypoxia-related metrics, including standardised uptake value (SUV), tumour-to-blood ratio (TBR), and tumour hypoxic volume (HV) defined by voxels with TBR ≥ 1.4. As the primary imaging-related trial endpoint used to evaluate the action of atovaquone on tumour hypoxia in patients with NSCLC was change in tumour HV from baseline, this was also assessed in patients (n = 20) with sufficient baseline 2- and 4-h scan HV to reliably measure change (predefined as ≥ 1.5 mL). Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. In tumours overall, strong correlation (P < 0.001) was observed for SUV max ρ = 0.87, SUV mean ρ = 0.91, TBR max ρ = 0.83 and TBR mean ρ = 0.81 between 2- and 4-h scans. Tumour HV was moderately correlated (P < 0.001) with ρ = 0.69 between 2- and 4-h scans. Yet, in tumour subregions, the correlation of HV decreased from the centre ρ = 0.71 to the edge ρ = 0.45 (P < 0.001). SUV, TBR, and HV values were consistently higher on 4-h scans than on 2-h scans, indicating better tracer-to-background contrast. For instance, for TBR max , the mean, median, and interquartile range were 1.9, 1.7, and 1.6–2.0 2-h p.i., and 2.6, 2.4, and 2.0–3.0 4-h p.i., respectively. Our results support that FMISO-PET scans should be performed at 4 h p.i. to evaluate tumour hypoxia in NSCLC. Trial registration: ClinicalTrials.gov, NCT02628080. Registered 11/12/2015, https://clinicaltrials.gov/ct2/show/NCT02628080 .

Background Tumour hypoxia promotes an aggressive tumour phenotype and enhances resistance to anticancer treatments. Following the recent observation that the mitochondrial inhibitor atovaquone increases tumour oxygenation in NSCLC, we sought to assess whether atovaquone affects tumour subregions differently depending on their level of hypoxia. Methods Patients with resectable NSCLC participated in the ATOM trial (NCT02628080). Cohort 1 ( n = 15) received atovaquone treatment, whilst cohort 2 ( n = 15) did not. Hypoxia-related metrics, including change in mean tumour-to-blood ratio, tumour hypoxic volume, and fraction of hypoxic voxels, were assessed using hypoxia PET imaging. Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. Results Atovaquone-induced reduction in tumour hypoxia mostly occurred in the inner and outer tumour subregions, and to a lesser extent in the centre subregion. Atovaquone did not seem to act in the edge subregion, which was the only tumour subregion that was non-hypoxic at baseline. Notably, the most intensely hypoxic tumour voxels, and therefore the most radiobiologically resistant areas, were subject to the most pronounced decrease in hypoxia in the different subregions. Conclusions This study provides insights into the action of atovaquone in tumour subregions that help to better understand its role as a novel tumour radiosensitiser. Trial registration : ClinicalTrials.gov, NCT0262808. Registered 11th December 2015, https://clinicaltrials.gov/ct2/show/NCT02628080

ABSTRACTBackgroundMRI, bone scan, and CT staging is recommended in the staging of prostate cancer. However, prostate-specific membrane antigen positron emission tomography (PSMA PET) could be superior in detection of local and distant prostate cancer cells. Most PSMA PET scans for prostate cancer are performed with a Gallium-68 ligand, with the Fluorine-18 (18F) ligand being introduced more recently. Methods: We will conduct a retrospective review of electronic patient records for all consecutive patients who underwent preoperative 18F-PSMA PET scan for prostate cancer from its introduction at our centre in 2019. We will compare PET scans with other imaging modalities and evaluate its use in diagnosis and management decisions for prostate cancer.ConclusionsUnderstanding the role of 18F-PSMA PET in diagnosis and management could influence the diagnostic pathway of primary and secondary prostate cancer.Trial registrationNot applicable.

Abstract Purpose: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non–small cell lung cancer (NSCLC). Patients and Methods: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. Results: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change −28% [95% confidence interval (CI), −58.2 to −4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, −6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%–74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. Conclusions: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Background: In this article we share our experience of creating a digital pathology (DP) supraregional germ cell tumour service, including full digitisation of the central laboratory. Methods: DP infrastructure (Philips) was deployed across our hospital network to allow full central digitisation with partial digitisation of two peripheral sites in the supraregional testis germ cell tumour network. We used a survey-based approach to capture the quantitative and qualitative experiences of the multidisciplinary teams involved. Results: The deployment enabled case sharing for the purposes of diagnostic reporting, second opinion, and supraregional review. DP was seen as a positive step forward for the departments involved, and for the wider germ cell tumour network, and was completed without significant issues. Whilst there were challenges, the transition to DP was regarded as worthwhile, and examples of benefits to patients are already recognised. Conclusion: Pathology networks, including highly specialised services, such as in this study, are ideally suited to be digitised. We highlight many of the benefits but also the challenges that must be overcome for such clinical transformation. Overall, from the survey, the change was seen as universally positive for our service and highlights the importance of engagement of the whole team to achieve success.

Background Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity.Methods In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells.Results The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2–8 weeks following vaccination, possibly indicating an inflammatory response in the target organ.Conclusions An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab.Trial registration The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063).

Tumor hypoxia confers profound resistance to radiation. An emerging strategy to tackle hypoxia is by reprogramming tumor metabolism. The antimalarial drug atovaquone inhibits oxidative phosphorylation (OXPHOS) and preclinically has been shown to reduce tumor cell oxygen consumption and alleviate tumor hypoxia resulting in radiosensitization. We conducted a translational clinical trial to determine whether atovaquone reduces tumor hypoxia in patients with non-small cell lung cancer (NSCLC). Patients with NSCLC scheduled for surgical resection were recruited sequentially into two cohorts. Cohort 1 received oral atovaquone 750mg bd until the day before surgery. Cohort 2 received no treatment. Tumor hypoxia imaging with 18F-FMISO or 18F-FAZA PET-CT was undertaken at baseline and repeated just prior to resection. Tumor hypoxic volume (HV) was defined using tumor-to-blood tracer uptake ratio ≥1.4, with ≥10% reduction in HV classed a response to treatment. Patients with <1.5 mL HV at baseline were deemed not evaluable for HV analysis and were replaced. Perfusion CT (pCT) and shMOLLI T1 map MRI were undertaken at the same timepoints to assess for changes in tumor perfusion and biochemistry, respectively. An inter-cohort comparison of hypoxia metagene expression signatures obtained by RNA sequencing was conducted from multiple regions per resected tumor. Adverse event monitoring (CTCAE v4.0) was performed until surgery. Forty-six patients were recruited with 30 (15 per cohort) evaluable for paired HV analysis. Patient and tumor characteristics were similar between cohorts. Median duration of atovaquone treatment between imaging timepoints was 12 days. The median change in HV in atovaquone-treated patients was -28% (95% CI: -58.2, -4.4), with 11 (73.3%) patients classed as responders. In contrast, the median change in untreated patients was +15.5% (95% CI: -6.5, +35.5). Using linear regression with pre-surgery HV as outcome adjusting for cohort and baseline HV and tumor volume (log-transformed), the expected geometric mean HV was 60% (95% CI: 30%, 70%) lower for treated patients (p = 0.004). Transcriptomic analysis revealed significantly decreased expression of multiple hypoxia metagene signatures in treated tumors. Altered expression of OXPHOS related pathways was also observed suggesting wider metabolic reprogramming. pCT and MRI results did not show altered tumor perfusion or suggest change in cellularity, respectively, in keeping with an OXPHOS-dependent mechanism of action. No adverse events related to atovaquone were reported. This the first clinical study to investigate whether an OXPHOS inhibitor reduces tumor hypoxia. The data presented supports our pre-clinical finding that atovaquone rapidly reduces tumor hypoxia through decreased oxygen consumption in NSCLC. We will shortly commence phase I clinical testing combining atovaquone with radical chemoradiotherapy in NSCLC.

Purpose Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. Methods and Materials Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. Results 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA=0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). Conclusions 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.

Purpose: We evaluated interreader agreement with PI-RADS (R) (Prostate Imaging Reporting and Data System) version 2 for detection of prostate cancer. Materials and Methods: We searched MEDLINE (R), Embase (R) and the Cochrane Library between 2015 and June 3, 2019 to identify original research reporting interreader agreement in the use of PI-RADS version 2. Quality of the retrieved studies was assessed by 2 independent reviewers using the Guidelines for Reporting Reliability and Agreement Studies. Pooled k for PI-RADS version 2 was calculated, and a head-to-head comparison with version 1 was performed for the available studies. Subgroup analysis was performed according to zonal anatomy (peripheral or transitional zone), cutoff value (4 or higher, or 3 or higher) and specific imaging sequences (T2-weighted, diffusion-weighted and dynamic contrast enhanced). Meta-regression analysis was performed to assess the cause of study heterogeneity. Results: A total of 30 studies (4,095 patients) were included. Pooled k of PI-RADS version 2 was 0.61 (95% CI 0.55-0.67). In 4 studies evaluating head-to-head comparisons PI-RADS versions 1 and 2 showed similar pooled k values (0.61, 95% CI 0.33-0.90 vs 0.68, 95% CI 0.57-0.79; p=0.61). Substantial interreader agreement was noted with a cutoff of 4 or higher (kappa=0.61) and moderate agreement was observed with a cutoff of 3 or higher (kappa=0.57), peripheral zone (kappa=0.64), transitional zone (kappa=0.49) and the 3 magnetic resonance imaging sequences (kappa 0.42-0.58). Difference in reader experience was the single significant factor affecting study heterogeneity (p=0.01). Conclusions: PI-RADS version 2 provides substantial interreader agreement in overall scoring in patients with suspicious prostate cancer, with a similar level of agreement to version 1.