A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials. METHODS: We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE). RESULTS: IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively. CONCLUSION: Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.

Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021.

BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the voting results from APCCC 2021. DESIGN, SETTING, AND PARTICIPANTS: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making.

Utility of machine learning of apparent diffusion coefficient (ADC) and T2-weighted (T2W) radiomic features in PI-RADS version 2.1 category 3 lesions to predict prostate cancer diagnosis.

PURPOSE: To evaluate if machine learning (ML) of radiomic features extracted from apparent diffusion coefficient (ADC) and T2-weighted (T2W) MRI can predict prostate cancer (PCa) diagnosis in Prostate Imaging-Reporting and Data System (PI-RADS) version 2.1 category 3 lesions. METHODS: This multi-institutional review board-approved retrospective case-control study evaluated 158 men with 160 PI-RADS category 3 lesions (79 peripheral zone, 81 transition zone) diagnosed at 3-Tesla MRI with histopathology diagnosis by MRI-TRUS-guided targeted biopsy. A blinded radiologist confirmed PI-RADS v2.1 score and segmented lesions on axial T2W and ADC images using 3D Slicer, extracting radiomic features with an open-source software (Pyradiomics). Diagnostic accuracy for (1) any PCa and (2) clinically significant (CS; International Society of Urogenital Pathology Grade Group ≥ 2) PCa was assessed using XGBoost with tenfold cross -validation. RESULTS: From 160 PI-RADS 3 lesions, there were 50.0% (80/160) PCa, including 36.3% (29/80) CS-PCa (63.8% [51/80] ISUP 1, 23.8% [19/80] ISUP 2, 8.8% [7/80] ISUP 3, 3.8% [3/80] ISUP 4). The remaining 50.0% (80/160) lesions were benign. ML of all radiomic features from T2W and ADC achieved area under receiver operating characteristic curve (AUC) for diagnosis of (1) CS-PCa 0.547 (95% Confidence Intervals 0.510-0.584) for T2W and 0.684 (CI 0.652-0.715) for ADC and (2) any PCa 0.608 (CI 0.579-0.636) for T2W and 0.642 (CI 0.614-0.0.670) for ADC. CONCLUSION: Our results indicate ML of radiomic features extracted from T2W and ADC achieved at best moderate accuracy for determining which PI-RADS category 3 lesions represent PCa.

Effect of phase of enhancement on texture analysis in renal masses evaluated with non-contrast-enhanced, corticomedullary, and nephrographic phase-enhanced CT images.

OBJECTIVE: To compare texture analysis (TA) features of solid renal masses on renal protocol (non-contrast enhanced [NECT], corticomedullary [CM], nephrographic [NG]) CT. MATERIALS AND METHODS: A total of 177 consecutive solid renal masses (116 renal cell carcinoma [RCC]; 51 clear cell [cc], 40 papillary, 25 chromophobe, and 61 benign masses; 49 oncocytomas, 12 fat-poor angiomyolipomas) with three-phase CT between 2012 and 2017 were studied. Two blinded radiologists independently assessed tumor heterogeneity (5-point Likert scale) and segmented tumors. TA features (N = 25) were compared between groups and between phases. Accuracy (area under the curve [AUC]) for RCC versus benign and cc-RCC versus other masses was compared. RESULTS: Subjectively, tumor heterogeneity differed between phases (p < 0.01) and between tumors within the same phase (p = 0.03 [NECT] and p < 0.01 [CM, NG]). Inter-observer agreement was moderate to substantial (intraclass correlation coefficient = 0.55-0.73). TA differed in 92.0% (23/25) features between phases (p < 0.05) except for GLNU and f6. More TA features differed significantly on CM (80.0% [20/25]) compared with NG (40.0% [10/25]) and NECT (16.0% [4/25]) (p < 0.01). For RCC versus benign, AUCs of texture features did not differ comparing CM and NG (p > 0.05), but were higher for 20% (5/25) and 28% (7/25) of features comparing CM and NG with NECT (p < 0.05). For cc-RCC versus other, 36% (9/25) and 40% (10/25) features on CM had higher AUCs compared with NECT and NG images (p < 0.05). CONCLUSION: Texture analysis of renal masses differs, when evaluated subjectively and quantitatively, by phase of CT enhancement. The corticomedullary phase had the highest discriminatory value when comparing masses and for differentiating cc-RCC from other masses. KEY POINTS: • Subjectively evaluated renal tumor heterogeneity on CT differs by phase of enhancement. • Quantitative CT texture analysis features in renal tumors differ by phases of enhancement with the corticomedullary phase showing the highest number and most significant differences compared with non-contrast-enhanced and nephrographic phase images. • For diagnosis of clear cell RCC, corticomedullary phase texture analysis features had improved accuracy of classification in approximately 40% of features studied compared with non-contrast-enhanced and nephrographic phase images.

Importance of phase enhancement for machine learning classification of solid renal masses using texture analysis features at multi-phasic CT.

OBJECTIVE: To compare machine learning (ML) of texture analysis (TA) features for classification of solid renal masses on non-contrast-enhanced CT (NCCT), corticomedullary (CM) and nephrographic (NG) phase contrast-enhanced (CE) CT. MATERIALS AND METHODS: With IRB approval, we retrospectively identified 177 consecutive solid renal masses (116 renal cell carcinoma [RCC]; 51 clear cell [cc], 40 papillary, 25 chromophobe and 61 benign tumors; 49 oncocytomas and 12 fat-poor angiomyolipomas) with renal protocol CT between 2012 and 2017. Tumors were independently segmented by two blinded radiologists. Twenty-five 2-dimensional TA features were extracted from each phase. Diagnostic accuracy for 1) RCC versus benign tumor and 2) cc-RCC versus other tumor was assessed using XGBoost. RESULTS: ML of texture analysis features on different phases achieved mean area under the ROC curve (AUC [SD]), sensitivity/specificity for 1) RCC vs benign = 0.70(0.19), 96%/32% on CM-CECT and 0.71(0.14), 83%/58% on NG-CECT and; 2) cc-RCC vs other = 0.77(0.12), 49%/90% on CM-CECT and 0.71(0.16), 22%/94% on NG-CECT. There was no difference in AUC comparing CECT to NCCT (p = 0.058-0.54) and no improvement when combining data across all three phases compared single-phase assessment (p = 0.39-0.68) for either outcome. AUCs decreased when ML models were trained with one phase and tested on a different phase for both outcomes (RCC;p = 0.045-0.106, cc-RCC; < 0.001). CONCLUSION: Accuracy of machine learning classification of renal masses using texture analysis features did not depend on phase; however, models trained using one phase performed worse when tested on another phase particularly when associating NCCT and CECT. These findings have implications for large registries which use varying CT protocols to study renal masses.

Blue nevus-like and blue nevus-associated melanoma: a comprehensive review of the literature.

BACKGROUND: Malignant blue nevus, blue nevus-associated melanoma and blue nevus-like melanoma are all terms used to describe malignant melanomas arising from, in association with, or resembling blue nevi. This review is aimed at summarizing the available literature to reduce the confusion surrounding this rare malignancy, and aid the surgeon in choosing further diagnostic or therapeutic measures. METHODS: We conducted a search of Medline, Embase, Science Direct, Scopus and the Cochrane Library for all full text articles published in English that reported on a malignant melanoma arising from, in association with, or resembling a blue nevus. RESULTS: We identified 91 cases that fit the criteria above. The mean age at diagnosis was 45 years, with a slight male predominance (males: 48; females: 43). Metastatic cases were reported in 55% (n = 50), of which 16 were metastatic at the time of diagnosis, 16 developed metastases within the first year and 18 within 5 years of initial diagnosis. The mean Breslow thickness was 6.8 mm at the time of diagnosis (n = 39). CONCLUSIONS: The histological criteria for diagnosing this malignancy are very poorly defined, and may contribute to the substantial confusion surrounding the terminology. There is no consensus on which prognostic indicators predictive of outcome in 'conventional' malignant melanoma are applicable to blue nevus-like melanoma/blue nevus-associated melanoma. However, two larger case series have demonstrated a significant association between Breslow thickness (or largest tumour dimension when non-epidermal) and recurrence-free survival, as well as rate of local recurrence, but larger studies are needed to confirm this.

Secondary Merkel Cell Carcinoma Arising From a Graft Donor Site.

Merkel cell carcinoma (MCC) is a highly aggressive cutaneous neuroendocrine tumour that is increasing in incidence. We report a case of a 92-year-old white man on long-term immunosuppression for temporal arteritis who presented with a Merkel cell tumour on his left cheek. A wide local excision was performed and the defect was reconstructed with a full-thickness skin graft. Four years later, the patient re-presented with a Merkel cell tumour arising from the right supraclavicular donor site. To our knowledge, this is the first report of a recurrence of MCC into a donor site. This has important implications as a reminder of planning fresh surgical instruments and needle inoculation for reconstruction if there is any clinical suspicion of MCC to prevent iatrogenic spread.

Repurposing Metformin as Therapy for Prostate Cancer within the STAMPEDE Trial Platform.

Metformin is a safe, well-tolerated, inexpensive treatment that can be given in addition to current standard-of-care therapies for prostate cancer. Its use might mitigate the deleterious side effects of castration and exert an additional anticancer effect. It will be incorporated in the STAMPEDE trial platform in summer 2016. This will test its true utility as a repurposed treatment for men with high-risk locally advanced or metastatic prostate cancer at first presentation.

Health-related quality of life in pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer following treatment with the specific endothelin A receptor antagonist zibotentan (ZD4054).

PURPOSE: Zibotentan (ZD4054) is a specific endothelin A receptor antagonist in clinical development for the treatment of hormone-resistant prostate cancer (HRPC). In a Phase II trial in patients with pain-free or mildly symptomatic metastatic HRPC, zibotentan was well tolerated with a promising signal for prolonged overall survival compared with placebo. As part of this trial, the impact of zibotentan compared with placebo on health-related quality of life (HRQoL) was assessed. METHODS: Patients were randomized to receive once-daily oral zibotentan 10 or 15 mg, or matching placebo. Patients were allocated to one of two questionnaires; the Functional Assessment of Cancer Therapy-Prostate (FACT-P) or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), supplemented by PR25, specific for prostate cancer. Questionnaires were completed at baseline and every 4 weeks until disease progression when study treatment was discontinued. RESULTS: Compliance with questionnaire completion was >90% (286 of 312 patients) of the intention-to-treat population at baseline. Of baseline completers who were available for assessment (i.e., had not clinically progressed), 89% (164 of 184) and 83% (73 of 88) completed questionnaires at 12 and 24 weeks, respectively. HRQoL scores from both questionnaires were high at baseline and remained high throughout the study, with scores being similar in the zibotentan and placebo groups. However, some floor and ceiling effects were seen in the EORTC QLQ-C30 questionnaire. CONCLUSIONS: High-baseline HRQoL scores were maintained throughout treatment with zibotentan. The FACT-P instrument was selected to further assess the impact of zibotentan on HRQoL in the Phase III clinical trial program.

The West Midlands Bladder Cancer Prognosis Programme: rationale and design.

OBJECTIVE To describe the rationale and design of the Bladder Cancer Prognosis Programme (BCPP), and to demonstrate the capability of this design. METHODS There is a need to understand the determinants of bladder cancer to help reduce recurrence, progression, morbidity, mortality and related costs. We previously showed that lifestyle factors are important for determining the risk of bladder cancer, but little is known about their importance in determining the risk of recurrence or progression after diagnosis. Also, histopathological factors alone provide only crude prognostication; the analysis of molecular markers represents a method for refinement but research in this area has not been useful in informing therapeutic decisions or prognostication. The BCPP is a prospective longitudinal cohort study of all patients with newly diagnosed bladder cancer within the West Midlands (UK), investigating the influence of lifestyle factors on recurrence and progression, health-related quality of life, the predictive effect of a panel of molecular markers on recurrence or progression, and the establishment of Europe's largest comprehensive bladder cancer bio-repository. It also incorporates the first randomized clinical trial on the efficacy of selenium and vitamin E on bladder cancer. The numbers and proportions of eligible patients recruited, questionnaires completed and specimens obtained were all recorded. RESULTS Since December 2005, 771 patients have been recruited (68% of eligible patients) and of these, 331 are currently being followed up by questionnaires. We have obtained blood, urine and tumour tissues from 92%, 80% and 80% of patients, respectively. CONCLUSIONS The design of the BCPP has allowed this study to be incorporated into routine clinical work throughout the West Midlands, achieving high levels of recruitment, and data and specimen collection. This might represent a model for the future investigation of urological and other malignancies.

Flucloxacillin reduces stiffness following flexor tendon repair.

To determine the benefit of antibiotic prophylaxis on postoperative mobility in flexor tendon repairs, case notes of 72 flexor tendon injuries in twenty four patients were analyzed retrospectively (2001-2003). Only patients with non-contaminated injuries from sharp instruments in flexor zone 2 were included in the study; 57% were male, average age was 31 years, and 24% were smokers. The majority of injuries were caused by metal blades (45%). Most tendons were repaired with modified Kessler technique (69%). Twenty-five percent received intravenous flucloxacillin or co-amoxiclav perioperatively. Reduced total active motion (TAM, found in 25% of patients more than 7 weeks after surgical repair) significantly complicated patients without perioperative intravenous flucloxacillin cover. The use of intravenous perioperative flucloxacillin is a plausible adjunct in surgery to prevent postoperatively reduced mobility.

Dendritic cell immunotherapy for urological cancers using cryopreserved allogeneic tumour lysate-pulsed cells: a phase I/II study.

OBJECTIVE: To assess the feasibility, toxicity and immunogenicity of dendritic cell (DC)-based immunotherapy in patients with advanced urological cancers. PATIENTS AND METHODS: Patients with hormone-refractory prostate cancer (11) and metastatic renal cell carcinoma (five) received 1-3 x 10(6) intradermal allogeneic tumour lystate-pulsed DCs fortnightly for six vaccinations then monthly until disease progression. Intradermal keyhole limpet haemocyanin was injected near the DCs as the adjuvant. DC vaccine was prepared from buffy coats, then lysate-pulsed, cryopreserved in aliquots, and tested for phenotypic expression and activity in an allogeneic mixed lymphocyte reaction before clinical use. RESULTS: There was no evidence of significant toxicity from vaccine or adjuvant. Delayed-type hypersensitivity skin testing and biopsy revealed a cellular infiltrate to intradermal re-challenge to tumour lysate and adjuvant in almost all patients. In addition, there was increased expression of T helper type 1 cytokines, interferon-gamma-expressing T cell by ELISPOT analysis, but also interleukin-10 in a few patients. Vaccination resulted in a reduction in the level of prostate-specific antigen (PSA) in one patient, a reduction in PSA velocity in a further man and an increased PSA doubling time in six. Two of five patients with renal cell carcinoma had stabilization of disease. CONCLUSION: The cryopreservation and repeated administration of DC vaccine was feasible and not toxic. There was evidence of induction of both humoral and cellular immunity to vaccine and adjuvant in most patients. The use of sequential aliquots of identical cryopreserved vaccine will ensure quality control and greatly facilitate future clinical studies in terms of consistency of vaccine administered and the provision of primed DCs for in vitro assessment of response.