Martti Nurmi

Prospective Randomized Trial of Interferon Alfa-2a Plus Vinblastine Versus Vinblastine Alone in Patients With Advanced Renal Cell Cancer

PURPOSE The combination of interferon alfa-2a (IFNalpha2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNalpha2a plus VLB versus VLB alone in patients with advanced renal cell cancer. PATIENTS AND METHODS We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNalpha2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNalpha2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNalpha2a at 18 million units per injection, the dose was reduced to 9 million units. RESULTS Median survival was 67.6 weeks for the 79 patients receiving IFNalpha2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P =.0049). Overall response rates were 16. 5% for patients treated with IFNalpha2a plus VLB and 2.5% for patients treated with VLB alone (P =.0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported. CONCLUSION The combination of IFNalpha2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNalpha2a for these patients.

Prolactin and prolactin receptors are expressed and functioning in human prostate.

Prolactin is widely expressed in different tissues, and it is presumed to have both local and systemic actions. In males it is known to influence reproductive functions but the significance and mechanisms of prolactin action in male accessory reproductive tissues are poorly understood. Here we show that prolactin acts as a direct growth and differentiation factor for human prostate, as measured by changes in DNA synthesis and epithelial morphology of organ cultures. Furthermore, we report the expression in human prostate of a short prolactin receptor form in addition to the long form, based upon ligand cross-linking studies and RT-PCR analysis of mRNA expression. The highest density of prolactin receptors was detected in the secretory epithelial cells by immunohistochemistry. Finally, we report that prolactin is locally produced in human prostate epithelium, as evidenced by marked prolactin immunoreactivity in a significant portion of prostate epithelial cells, with parallel expression of prolactin mRNA in human prostate. Collectively, these data provide significant support for the existence of an autocrine/paracrine loop of prolactin in the human prostate and may shed new light on the involvement of prolactin in the etiology and progression of neoplastic growth of the prostate.

Activation of signal transducer and activator of transcription 5 in human prostate cancer is associated with high histological grade.

We have recently identified signal transducer and activator of transcription 5 (Stat5) as a critical survival factor for prostate cancer cells. We now report that activation of Stat5 is associated with high histological grade of human prostate cancer. Specifically, immunohistochemical analysis demonstrated a strong positive correlation with activation of Stat5 and high Gleason score in 114 human prostate cancers. To investigate the mechanisms underlying constitutive activation of Stat5 in prostate cancer, a dominant-negative mutant of Janus kinase 2 (Jak2) was delivered by adenovirus to CWR22Rv cells. Dominant-negative-Jak2 effectively blocked the activation of Stat5 whereas wild-type Jak2 enhanced activation, indicating that Jak2 is the main kinase that phosphorylates Stat5 in human prostate cancer cells. A ligand-induced mechanism for activation of Stat5 in prostate cancer was suggested by the ability of prolactin (Prl) to stimulate activation of both Jak2 and Stat5 in CWR22Rv human prostate cancer cells and in CWR22Rv xenograft tumors. In addition, Prl restored constitutive activation of Stat5 in five of six human prostate cancer specimens in ex vivo long-term organ cultures. Finally, Prl protein was locally expressed in the epithelium of 54% of 80 human prostate cancer specimens with positive correlation with high Gleason scores and activation of Stat5. In conclusion, our data indicate that increased activation of Stat5 was associated with more biologically aggressive behavior of prostate cancer. The results further suggest that Jak2 is the principal Stat5 tyrosine kinase in human prostate cancer, possibly activated by autocrine/paracrine Prl.

Increased expression of cyclooxygenase-2 and nitric oxide synthase-2 in human prostate cancer

Abstract Cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase-2 (NOS-2) each have an important role in angiogenesis. The expression of these genes was investigated in human prostate cancer by immunohistochemistry, the expression of COX-1 and COX-2 being confirmed by mRNA analysis. Prostate cancer specimens from 12 patients were compared to control prostates from 13 patients operated on for bladder carcinoma. The intensity of COX-2 and NOS-2 immunostaining was significantly stronger in prostate cancer cells than in the non-malignant glandular epithelium of the control prostates. COX-2 and NOS-2 were clearly also expressed in the lesions of prostatic intraepithelial neoplasia (PIN) in control prostates. COX-2 was detected in the muscle fibres of the hyperplastic stroma of some control prostates. No significant difference was detected in COX-1 expression between control and cancer prostates. These results indicate that the expression of COX-2 and NOS-2 is elevated in prostatic adenocarcinoma and in PIN.

Risk factors for mortality and morbidity related to radical cystectomy

To evaluate the risk factors for mortality and morbidity related to radical cystectomy (RC) in a medium‐sized academic centre, and to analyse the rate and trends of perioperative morbidity and mortality, as although complications related RC to are lower in modern than historic series, RC is still associated with marked risks.

Associations between Serum Testosterone Fall and Cognitive Function in Prostate Cancer Patients

Data on the association between cognition and testosterone levels in elderly men are inconclusive. Androgen deprivation therapy is commonly used in the treatment of prostate cancer with the aim of achieving castration levels of serum testosterone. The study group comprised 26 elderly men (mean age 65 years) with newly diagnosed prostate cancer. Cognitive testing was done at baseline and at 6 and 12 months on androgen deprivation therapy. Cognitive performances were evaluated using verbal, visuomotor, and memory tests as well as tests of processing speed and attention. Castration levels of testosterone were achieved in all patients by 6 months. Significant associations between cognitive performances and testosterone decline were documented: visuomotor slowing, slowed reaction times in some attentional domains including working memory and impaired hit rate in a vigilance test, impaired delayed recall and recognition speed of letters, but improvement in object recall. The results suggest selective associations between testosterone decline and cognition. Documentation of cognitive performance with changes in serum testosterone levels has substantial implications for informed patient support in prostate cancer.

Increased Expression of FGF-8 Isoforms and FGF Receptors in Human Premalignant Prostatic Intraepithelial Neoplasia Lesions and Prostate Cancer

Fibroblast growth factor 8 (FGF-8) is implicated in growth of prostate cancer. Alternative splicing of the human FGF-8 gene potentially allows coding for four protein isoforms (a, b, e, and f). These isoforms differ in their binding to FGF receptors (FGFR) and in their mitogenic and transforming capacity in transfection assays. Here, we used RT-PCR and immunohistochemistry to study the expression of FGF-8 and FGFR isoforms in human prostate cancer (n = 31). Nonmalignant prostate specimens from cystoprostatectomies (n = 24) were examined as controls. Most prostate cancer samples and some control prostates also contained prostatic intraepithelial neoplasia (PIN) lesions. FGF-8a and e were expressed at significantly higher frequencies in prostate cancer (FGF-8a, 55%; FGF-8e, 45%) than in control samples (FGF-8a, 17%, p = 0.0052; FGF-8e, 8%, p = 0.0031). On the contrary, FGF-8b was found at an equal frequency in prostate cancer (55%) and in control prostates (50%). Furthermore, a combination of two or three FGF-8 isoforms (a, b, and/or e) was also expressed at a higher frequency in prostate cancer than in control samples (45% and 8%, respectively, p = 0.0031). Immunohistochemistry with an antibody recognizing all FGF-8 isoforms was more strongly immunoreactive in prostate cancer cells and PIN lesions than in normal-type epithelium. The receptor splicing variants FGFR1IIIc and FGFR2IIIc, which are activated by FGF-8, were found both in prostate cancer and control samples. Interestingly, immunoreactivity for FGFR1 and FGFR2 was much stronger in prostate cancer cells and PIN than in normal epithelium. These results demonstrate, for the first time, that FGF-8 isoforms and their receptors FGFR1IIIc and FGFR2IIIc are expressed at an increased level not only in prostate cancer but also in premalignant PIN lesions. These data suggest that FGF-8 may have an important autocrine role in the development of human prostate cancer. In addition to FGF-8b, the FGF-8 isoforms a and e may be involved in this process.

Radiologic diagnosis of renal colic: the role of plain films, excretory urography and sonography

The accuracy of plain films, excretory urography and ultrasound for the clinical work-up of renal colic for detecting urinary calculi was evaluated prospectively in 49 patients. Excretory urography was the most sensitive and specific test. Plain films and sonography each had a sensitivity of approximately 60%, but combined yielded a sensitivity of 80%; specificity did not improve. A diagnostic algorithm where sonography was performed first followed by an excretory urography in case of a negative sonography was highly sensitive (93%) and rather specific (79%). This algorithm appears also to have a good cost-benefit rate.

Functional imaging of localized prostate cancer aggressiveness using 11C-acetate PET/CT and 1H-MR spectroscopy.

We assessed the ability of 11C-acetate PET/CT, MRI, and proton MR spectroscopy (1H-MRS) to image localized prostate cancer and detect its aggressiveness, using qualitative and quantitative approaches. Methods: Twenty-one patients with untreated localized prostate cancer, diagnosed using transrectal ultrasound-guided biopsy, were prospectively enrolled. Cancer laterality was based on the percentage of cancer and the highest Gleason score determined from biopsies. In addition to PET/CT, 3-dimensional 1H-MRS of the entire prostate volume using a quantitative approach was performed. The imaging and histologic findings of 8 patients undergoing subsequent prostatectomy were compared on a sextant level. For each lobe and sextant, standardized uptake values (SUVs) and (choline + creatine + polyamines)–to–citrate (CCP/C) ratios were obtained from 11C-acetate PET/CT and 1H-MRS, respectively. The visual and quantitative findings on PET/CT and MRI data were compared with cancer laterality and aggressiveness based on the Gleason score and with prostate-specific antigen (PSA) velocity and international risk group classification. Results: The sensitivity, specificity, and accuracy, on a lobar level using visual analysis, of 11C-acetate PET/CT were 80%, 29%, 71%, respectively, and 89%, 29%, 79%, respectively, using contrast-enhanced MRI. The sensitivity and accuracy of 11C-acetate PET/CT decreased to 64% and 63% and specificity increased to 62% when sextant analysis was performed. The agreement between prostate cancer laterality based on biopsy findings and visual interpretation of 11C-acetate PET/CT and contrast-enhanced MRI was similar at 71%. The mean SUV maximum and CCP/C maximum for the dominant tumor lesion were 5.5 and 1.48, respectively, and did not differ significantly from values in the nondominant lobe. The dominant-lesion SUVs or CCP/C values were not associated with histologically determined prostate cancer aggressiveness, nor did PSA velocity correlate with the SUV or CCP/C values from the entire gland. Conclusion: 11C-acetate PET/CT, MRI, and 1H-MRS enable detection of localized prostate cancer with comparable and limited accuracy but fail to provide information on cancer aggressiveness.

Estradiol and cognition during androgen deprivation in men with prostate carcinoma

The adverse effects of hormonal manipulation in prostate carcinoma need to be established in view of its increasing use as an adjuvant treatment. This prospective study investigated the association of androgen deprivation‐induced estradiol decline with cognition in prostate carcinoma.