Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

A biomimetic tissue from cultured normal human urothelial cells: analysis of physiological function.

The urinary bladder and associated tract is lined by the urothelium. Once considered as just an impermeable epithelium, it is becoming evident that the urothelium not only functions as a volume-accommodating urinary barrier but has additional roles, including sensory signaling. Lack of access to normal human urothelium has hampered physiological investigation, and although cell culture systems have been developed, there has been a failure to demonstrate that normal human urothelial (NHU) cells grown in vitro retain the capacity to form a functional differentiated urothelium. The aim of this study was to develop a biomimetic human urothelium from NHU cell cultures. Urothelial cells isolated from normal human urothelium and serially propagated as monolayers in serum-free culture were homogeneous and adopted a proliferative, nondifferentiated phenotype. In the presence of serum and physiological concentrations of calcium, these cells could be reproducibly induced to form stratified urothelia consisting of basal, intermediate, and superficial cells, with differential expression of cytokeratins and superficial tight junctions. Functionally, the neotissues showed characteristics of native urothelium, including high transepithelial electrical resistance of >3,000 Omega.cm(2), apical membrane-restricted amiloride-sensitive sodium ion channels, basal expression of Na(+)-K(+)-ATPase, and low diffusive permeability to urea, water, and dextran. This model represents major progress in developing a biomimetic human urothelial culture model to explore molecular and functional relationships in normal and dysfunctional bladder physiology.

The efficacy of a range of contact media as coupling agents in extracorporeal shockwave lithotripsy.

OBJECTIVE: To determine if the nature of the coupling agent normally used between the lithotripter and the patient affects the stone fragmentation rate during extracorporeal shock wave lithotripsy. MATERIALS AND METHODS: A jig designed to hold 'phantom' 10-mm stones at the focal point was fixed against the shock wave delivery point of an electromagnetic lithotripter (Dornier Compact, Germany). A layer of either petroleum jelly (Vaseline, Cheeseborough-Ponds Ltd, London, UK) ultrasonography jelly, a eutectic mixture of local anaesthetic (EMLA) cream, Instillagel (Farco-Pharma, Cologne, Germany) or a commercial water-soluble lubricating jelly was placed between the jig and shockwave head, and the number of shock waves required to fragment the stones was recorded. RESULTS: Significantly more shock waves were required to fragment stones when petroleum jelly was used as the coupling agent than with all the other agents under test, whereas significantly fewer shock waves were required when using Instillagel or lubricating jelly than for all other agents. CONCLUSION: The coupling agent used in water-free lithotripsy can affect the stone fragmentation rate and should not be considered inert. Ultrasonography jelly is probably the optimum agent available for use as a lithotripsy coupling agent.

Radioimmunoassay for quantifying antibody to N. Gonorrhoeae in human sera.

A radioimmunoassay has been developed for the serodiagnosis of gonorrhoea. When 382 human sera from acutely infected and well documented control subjects were assayed by this procedure, 90% were diagnosed correctly, 5% were diagnosed incorrectly, and in 5% the results were indecisive.

Susceptibility of rabbits immunized with Mycobacterium bovis (BCG) or Mycobacterium phlei to Shigella keratoconjunctivitis.

Vaccination of rabbits with mycobacteria increased their resistance to eye infection with Shigella flexneri. However, the severity of keratoconjunctivitis was not reduced in the vaccinated animals.

Correlation between pathogenicity of Shigella and intraperitoneal survival in mice.

Phagocytosis of virulent and avirulent strains of Shigella and Escherichia coli in the mouse peritoneum was studied. A direct correlation between bacterial virulence and resistance to phagocytosis by peritoneal phagocytes was demonstrated. Virulent strains were less readily cleared and were able to multiply to a limited extent within the peritoneal cavity. An epimerase-deficient, rough mutant of S. flexneri 2a was highly susceptible to phagocytosis. Restoration of the cell wall structure in these mutants resulted in a significant increase in their resistance to phagocytosis. Susceptibility to phagocytosis in smooth S. flexneri was age-dependent. Cells from 16-hr cultures were more resistant to removal from the peritoneum than were cells from 48- and 72-hr cultures.

Chemoprophylaxis of Shigella flexneri keratoconjunctivitis in rabbits.

Chloramphenicol, chlortetracycline, streptomycin, and sulfisoxazole prevented keratoconjunctivitis in rabbit eyes infected with Shigella flexneri. The route of administration of the agent and the dose were important variables in controlling the infectious process. This assay system appears to be a useful technique for the in vivo evaluation of chemotherapeutic agents.