Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables.

PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture.RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.     

Magnetic resonance-guided prostate interventions

We review our experience using an open 0.5-T magnetic resonance (MR) interventional unit to guide procedures in the prostate. This system allows access to the patient and real-time MR imaging simultaneously and has made it possible to perform prostate biopsy and brachytherapy under MR guidance. We review MR imaging of the prostate and its use in targeted therapy, and describe our use of image processing methods such as image registration to further facilitate precise targeting. We describe current developments with a robot assist system being developed to aid radioactive seed placement.     

Complementarity determining regions of an anti-prion protein scFv fragment orchestrate conformation specificity and antiprion activity

The prion protein, PrP, exists in several stable conformations, with the presence of one conformation, PrP(Sc), associated with transmissible neurodegenerative diseases. Targeting PrP by high-affinity ligands has been proven to be an effective way of preventing peripheral prion infections. Here, we have generated bacterially expressed single chain fragments of the variable domains (scFv) of a monoclonal antibody in Escherichia coli, originally raised against purified PrP(Sc) that recognizes both PrP(C) and PrP(Sc). This scFv fragment had a dissociation constant (K(D)) with recombinant PrP of 2 nM and cleared prions in ScN2a cells at 4 nM, as demonstrated by a mouse prion bioassay. A peptide corresponding to the complementarity determining region 3 of the heavy chain (CDR3H) selectively bound PrP(Sc) but had lost antiprion activity. However, synthesis and application of an improved peptide mimicking side chain topology of CDR3H while exhibiting increased protease resistance, a retro-inverso d-peptide of CDR3H, still bound PrP(Sc) and reinstated antiprion activity. We conclude that (1) scFvW226 is so far the smallest polypeptide with bioassay confirmed antiprion activity, and (2) differential conformation specificity and bioactivity can be regulated by orchestrating the participation of different CDRs.     

Management of metastatic prostate cancer: the crucial role of geriatric assessment

Prostate cancer predominantly affects older men, with a median age at diagnosis of 68 years. Due to the increased life expectancy, management of prostate cancer in senior adults (aged >70 years) represents a major public health problem. This patient population may not receive optimal therapy for their disease, if decisions are made based on their chronological age alone. More so than age alone, health status is a major factor affecting individual life expectancy. Comorbidity is the key predictor of health status and should weigh more heavily on the treatment decision than age alone. Other important parameters to consider in senior adults are the degree of dependence in activities of daily living, the nutritional status and the presence or not of a geriatric syndrome. Although clinical trials are rarely designed specifically for senior adults, evidence suggests that healthy senior adults have similar treatment outcomes to their younger counterparts. The urological approach in senior adults with advanced prostate cancer should be fundamentally the same as in younger patients. In hormone-sensitive metastatic prostate cancer, androgen deprivation represents the first-line treatment. In senior adults, care should be given to the increased risk of metabolic syndrome, cardiovascular mortality and bone fracture. In hormone-refractory metastatic prostate cancer, chemotherapy with docetaxel (75 mg/m(2) every 3 weeks) plus low-dose prednisone is the standard and shows the same efficacy in healthy senior adults as in younger patients. The tolerance of docetaxel (3-weekly schedule) has not been specifically studied in vulnerable and frail senior adults. The place of weekly docetaxel in this setting should be further evaluated. Palliative treatments (palliative surgery, radiopharmaceutics, radiotherapy, medical treatments for pain and symptoms, pharmacological palliative therapies) should also be integrated in the global management of these patients. In conclusion, treatment decisions in senior adults should be adapted to health status. Healthy senior adults should be treated the same as younger patients. The development of guidelines for the management of localized and advanced prostate cancer in senior adults is underway.     

Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients

To avoid an unnecessary extend of surgery in primary central nervous system lymphoma (PCNSL), the diagnosis should be suspected after MRI.Pre-treatment MRI examinations of 100 immunologically competent patients with biopsy-proven PCNSL were evaluated. All patients had T2- and T1-weighted images with contrast enhancement. Diffusion-weighted MRI (DW-MRI) was available in 15, proton-MR-spectroscopy (¹H-MRS) in four patients.The number of lesions ranged from one (n=65 patients) to eight (n=1) with a mean of 1.7. The most frequent locations were the cerebral hemispheres (n=66), the basal ganglia (n=27) and the corpus callosum (n=24). In the 65 patients with a solitary lesion, hemispheric lesions were most frequent (n=23) followed by corpus callosum (n=18). Contrast enhancement was found in all but one patient. ¹H-MRS revealed a uniformly pathologic pattern of metabolite concentrations in all patients.Characteristic imaging features of PCNSL are contrast-enhancing lesions with a diameter of at least 15 mm in contact with the subarachnoid space. DW-MRI and proton spectroscopy may aid in differential diagnosis.