TUXEDO: A phase I/II trial of cetuximab with chemoradiotherapy in muscle-invasive bladder cancer.

OBJECTIVE: To assess feasibility and preliminary efficacy of adding cetuximab to standard chemoradiotherapy for muscle-invasive bladder cancer. PATIENTS AND METHODS: TUXEDO was a prospective, single-arm, open-label, phase I/II trial conducted in six UK hospitals. Cetuximab was administered with an initial loading dose of 400mg/m2 on day 1 of week -1, and then 7-weekly doses of 250mg/m2 . Radiotherapy schedule was 64Gy/32F with day 1 mitomycin C (12g/m2 ) and 5-fluorouracil (500mg/m2 /day) over days 1-5 and 22-26. Patients with T2-4aN0M0 urothelial cancer and a performance status (PS) of 0-1 were eligible. Prior neoadjuvant therapy was permitted. The phase I primary outcome was impact on radiotherapy treatment completion and toxicity experienced during treatment. The phase II primary outcome was local control at three-months post-treatment. ISRCTN identifier: 80733590. RESULTS: Between Sept-2012 and Oct-2016, 33 patients were recruited; 7 in phase I, 26 in phase II. Three patients in phase II were subsequently deemed ineligible and received no trial therapy. Eight patients discontinued cetuximab due to adverse effects. Median age of patients was 70.1 years (range 60.6-75.1), 20 were PS 0, 27 male and 26 had already received neoadjuvant chemotherapy. In phase I, all patients completed planned radiotherapy, with no delays or dose reductions. Of the 30 evaluable patients in phase II, 25 had confirmed local control 3-months post treatment (77%, 95% CI: 58-90). During the trial there were 18 serious adverse events. The study was halted due to slow accrual. CONCLUSION: Phase I data demonstrate it is feasible and safe to add cetuximab to chemoradiotherapy. Exploratory analysis of phase II data provides evidence to consider further clinical evaluation of cetuximab in this setting.

Spontaneous CD4+ and CD8+ T-cell responses directed against cancer testis antigens are present in the peripheral blood of testicular cancer patients.

Cancer/testis antigen (CTAg) expression is restricted to spermatogenic cells in an immune-privileged site within the testis. However, these proteins are expressed aberrantly by malignant cells and T-cell responses against CTAgs develop in many cancer patients. We investigated the prevalence, magnitude and phenotype of CTAg-specific T cells in the blood of patients with testicular germ cell tumors (TGCTs). CD8+ and CD4+ T-cell responses against MAGE-A family antigens were present in 44% (20/45) of patients' samples assayed by ex vivo IFN-γ ELISPOT. The presence of MAGE-specific CD8+ T cells was further determined following short-term in vitro expansion through the use of pMHC-I multimers containing known immunogenic peptides. Longitudinal analysis revealed that the frequency of MAGE-specific T cells decreased by 89% following orchidectomy suggesting that persistence of tumor antigen is required to sustain CTAg-specific T-cell immunity. Notably, this decrease correlated with a decline in the global effector/memory T-cell pool following treatment. Spontaneous T-cell immunity against CTAg proteins therefore develops in many patients with testicular cancer and may play an important role in the excellent clinical outcome of patients with this tumor subtype.

Cytokines as effectors and predictors of responses in the treatment of bladder cancer by bacillus Calmette-Guérin.

The most effective intravesical treatment of non-muscle-invasive bladder cancer is instillation of live Mycobacterium bovis bacillus Calmette-Guérin (BCG). BCG stimulates the release of cytokines, contributing directly or indirectly to its effectiveness. However, the function of specific cytokines is not well understood. We have undertaken a nonsystematic review of primary evidence regarding cytokine detection, activation and response in BCG patients. Cytokines IL-2, IL-8 and TNF-α appear to be essential for effective BCG therapy and nonrecurrence, while IL-10 may have an inhibitory effect on BCG responses. IL-2, IL-8, TRAIL and TNF-α are potentially predictive of response to BCG. Alterations in genes encoding cytokines may also affect responses. There are significant data showing the association of certain cytokines with successful BCG treatment, and which may be useful predictive markers. Isolating those cytokines mediating efficacy may hold the key to ameliorating BCG's side effects and improving efficacy and patient compliance.

A Rare Case of Ipsilateral Scrotal Recurrence of Testicular Cancer After Radical Orchidectomy.

A lump in the testicle, painful or painless, could represent testicular cancer. Testicular cancer can be subdivided into germ-cell testicular cancer and sex cord-stromal tumors. A majority of testicular neoplasms are germ cell tumors (GCTs). GCTs are broadly divided into seminomatous and non-seminomatous germ cell tumors (NSGCTs) due to differences in natural history and treatment. Removal of the testis, also known as a radical orchidectomy, is often offered as part of the treatment for testicular cancer, which may be followed by additional medical treatment. It is not very common to have a recurrence of testicular cancer in the scrotum after a radical orchidectomy, and it is even rare to find this scrotal recurrence on the same side. An extensive literature review showed only one recorded case of scrotal recurrence of NSGCTs after orchidectomy but on the contralateral side. Here, we report the first case of scrotal recurrence of NSGCT after radical inguinal orchidectomy on the same side in a man who had orchidopexy in childhood. It is still unclear why testicular cancer could recur in the scrotum after a radical orchidectomy.

The detection and upgrade rates of prostate adenocarcinoma following transperineal template-guided prostate biopsy - a tertiary referral centre experience.

INTRODUCTION: We aim to present transperineal template-guided prostate biopsy (template biopsy) outcomes at a tertiary referral centre. Furthermore, to identify the detection rate of prostate cancer in those with a previous negative transrectal ultrasound guided prostate biopsy and the upgrade rate of those on active surveillance for Gleason 3 + 3 = 6 prostate adenocarcinoma. MATERIAL AND METHODS: We conducted a prospective study of 200 consecutive men who underwent template biopsy over a 22-month period in a tertiary referral centre, using a standard 24 region template prostate biopsy technique. Indications and histology results, as well as complications, were recorded. RESULTS: Median age was 67 years and median PSA was 10 ng/mL. Overall detection rate was 47%. 39.5% of cases with previous negative transrectal biopsies were found to have prostate adenocarcinoma. 47.5% of cases on active surveillance for Gleason 3 + 3 = 6 prostate adenocarcinoma were upgraded. The most frequent complication was acute urinary retention at a rate of 12.5%, however, the use of a single prophylactic dose of tamsulosin was found to be beneficial, with 13 cases needed to treat to prevent one episode. CONCLUSIONS: Template biopsies are safe and efficacious with an overall detection rate of 47% in the present series. Due to the high detection rate, one must consider template biopsy following one negative transrectal biopsy where there is persistent clinical suspicion. Furthermore, those considering active surveillance for Gleason 3 + 3 = 6 disease should be offered template biopsy to confirm the grade of their disease.

Design of an improved surgical instrument for the removal of bladder tumours.

The aim of this work was to design an add-on instrument that could potentially decrease the recurrence of non-muscle invasive bladder cancer. The current surgical approach permits spilled tumour cells to disseminate within the bladder, re-implant and cause tumour recurrence. An add-on instrument has been designed in the form of an opening cone intended to provide space for surgery and yet reduce tumour cell spillage and dissemination. A prototype was manufactured using the shape memory metal Nitinol which was activated using an electrical current to facilitate opening and supplemented with latex to provide a sealed environment. The prototype was tested in comparable surgical conditions utilising porcine bladder wall and blue dye to simulate tumour cells. It was demonstrated that the vast majority of dye was retained within the device, supporting the proposed aim.

Urologist led one-stop testicular clinic: the UK 'gold standard'.

Prompt diagnosis and early treatment for testicular cancer is vital. To help with this a one-stop, urologist run, testicular clinic with testicular ultrasound scanning as an integral part of the clinic format was introduced to investigate patients in an efficient and timely manner. The aim of this study was to assess the feasibility and efficiency of running a one-stop testicular clinic. A prospectively collected electronic database of all patients attending a one-stop testicular clinic at a busy university hospital was interrogated over a 6-year period. Only new referral males, above the age of 15 years old were included. Case notes were reviewed retrospectively. A total of 1757 patients were found with a median age of 36. 6.3 % had a suspicious ultrasound scan and overall 5.6 % were found to have malignancy histologically. In addition a significant proportion of men with a history of testicular maldescent went on to develop testicular cancer (p < 0.01). Median time from referral to clinic and clinic to orchidectomy for suspected testicular cancers was 9 and 5 days respectively (95 % CI). Some of the benefits of a urologist run one-stop testicular clinic include: timely diagnosis and treatment, early reassurance with normal investigations, the discovery of clinically unsuspecting malignancy and the increase in teaching opportunities. These collective benefits must improve patient experience and benefit the department as a whole. A urologist led one-stop testicular clinic should be regarded as the gold standard.

Pharmacological management of metastatic boney pain.

Many malignancies metastasise to the skeleton. This often results in a relatively unique pain process, which dramatically affects a patient's quality of life. With one in three members of the population likely to develop cancer at some stage in their lives, the prevalence of bone metastases is high. Despite the large financial investment on therapies for these patients, treatment is still suboptimal. In this article, the various treatments available are reviewed. Opiates and bisphosphonates, the mainstays in current practise, are covered in detail, and evolving therapies that may shape future management are also discussed.