Cytopathic effects and local immune responses in repeated neoadjuvant HSV-tk+ ganciclovir gene therapy for prostate cancer

Objective:Cytopathic effects and local immune response were analyzed histologically in prostatic cancer(PCa)with in situ herpes simplex virus-thymidine kinase(HSV-tk)/ganciclovir(GCV)gene therapy(GT).Methods:Four high-risk PCa patients who received HSV-tk/GCV GT were investigated.After two cycles of intraprostatic injection of HSV-tk and administration of GCV,radical prostatectomy was performed.Formalin-fixed,paraffin-embedded sections were evaluated using immunohistochemistry.PCa with hormone therapy(HT,n=3)or without neoadjuvant therapy(NT,n=4)that were equivalent in terms of risk were also examined as reference.Immunoreactively-positive cells were counted in at least three areas in cancer tissue.Labeling indices(LI)were calculated as percentage values.Results:ssDNA LI in GT increased,indicating apoptosis,as well as tumor-infiltrating lymphocytes and CD68-positive macrophages,compared with their biopsies.GT cases showed significantly higher numbers of single-stranded DNA(ssDNA)LI,CD4/CD8-positive T cells and CD68-positive macrophages including M1/M2 macrophages than HT or NT cases.However,there was no significant difference in CD20-positive B cells among the types of case.There were strong correlations between CD8+T cells and CD68+macrophages(ρ=0.656,p<0.0001)as well as CD4+T cells and CD20+B cells(ρ=0.644,p<0.0001)in PCa with GT.Conclusions:Enhanced cytopathic effect and local immune response might be indicated in PCa patients with HSV-tk/GCV gene therapy.

Recovery of serum testosterone following neoadjuvant and adjuvant androgen deprivation therapy in men treated with prostate brachytherapy

AIM: To investigate the time course of testosterone(T) recovery after cessation of androgen deprivation therapy(ADT) in patients treated with brachytherapy. METHODS: One-hundred and seventy-four patients treated between June 1999 and February 2009 were studied. Patients were divided into a short-term usage group(≤ 12 mo, n = 91) and a long-term usage group(≥ 36 mo, n = 83) according to the duration of gonadotropin-releasing hormone agonist therapy. Median follow-up was 29 mo in the short-term group and was 60 mo in the long-term group.RESULTS: Cumulative incidence rates of T recovery to normal and supracastrate levels at 24 mo after cessationwere 28.8% and 74.6%, respectively, in the long-term usage group, whereas these values were 96.4% and 98.8% in the short-term usage group. T recovery to normal and supracastrate levels occurred significantly more rapidly in the short-term than in the long-term usage group(P < 0.001 and P < 0.001, respectively). Five years after cessation, 22.6% of patients maintained a castrate T level in the long-term usage group. On multivariate analysis, lower T levels(< 10 ng/d L) at cessation of ADT was significantly associated with prolonged T recovery to supracastrate levels in the longterm usage group(P = 0.002). CONCLUSION: Lower T levels at cessation of ADT were associated with prolonged T recovery in the longterm usage group. Five years after cessation of longterm ADT, approximately one-fifth of patients still had castrate T levels. When determining the therapeutic effect, especially biochemical control, we should consider this delay in T recovery.