Martin Susani

PROSPECTIVE EVALUATION OF PROSTATE CANCER DETECTED ON BIOPSIES 1, 2, 3 AND 4: WHEN SHOULD WE STOP?

PURPOSE We evaluated biochemical parameters and pathological features, as well as biopsy related morbidity of prostate cancer detected on biopsies 2, 3 and 4 in men with total serum prostate specific antigen (PSA) between 4 and 10 ng./ml. These features were compared to those detected on prostate biopsy 1. MATERIALS AND METHODS In this prospective European Prostate Cancer Detection study 1,051 men with total PSA between 4 and 10 ng./ml. underwent transrectal ultrasound guided sextant biopsy and 2 additional transition zone biopsies. All patients in whom biopsy samples were negative for prostate cancer underwent biopsy 2 after 6 weeks. If also negative, biopsies 3 and even 4 were performed at 8-week intervals. Those patients with clinically localized cancer underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either biopsy 1 or 2 and clinically organ confined disease who agreed to undergo radical prostatectomy were compared. RESULTS Cancer detection rates on biopsies 1, 2, 3 and 4 were 22% (231 of 1,051), 10% (83 of 820), 5% (36 of 737) and 4% (4 of 94), respectively. Overall, of the patients with clinically localized disease, which was 67% of cancers detected, 86% underwent radical prostatectomy and 14% opted for watchful waiting or radiation therapy. Overall, 58.0%, 60.9%, 86.3% and 100% of patients had organ confined disease on biopsies 1, 2, 3 and 4, respectively. Despite statistically significant differences in regard to multifocality (p = 0.009) and cancer location (p = 0.001), including cancer on biopsy 2 showing a lower rate of multifocality and a more apico-dorsal location, there were no differences in regard to stage (p = 0.2), Gleason score (p = 0.3), percent Gleason grade 4/5 (p = 0.2), serum PSA and patient age between biopsies 1 and 2. However, cancer detected on biopsies 3 and 4 had a significantly lower Gleason score (p = 0.001 and 0.001), lower rate of grade 4/5 (p = 0.02), and lower volume (p = 0.001 and 0.001) and stage (p = 0.001), respectively. CONCLUSIONS Despite differences in location and multifocality, pathological and biochemical features of cancer detected on biopsies 1 and 2 were similar, suggesting comparable biological behaviors. Cancer detected on biopsies 3 and 4 had a lower grade, stage and volume compared with that on biopsies 1 and 2. Morbidity on biopsies 1 and 2 was similar, whereas biopsies 3 and 4 had a slightly higher complication rate. Therefore, biopsy 2 in all cases of a negative finding on biopsy 1 appears justified. However, biopsies 3 and 4 should only be obtained in select patients with a high suspicion of cancer and/or poor prognostic factors on biopsy 1 or 2.

Tissue Ablation in Benign Prostatic Hyperplasia with High Intensity Focused Ultrasound

The safety and effectiveness of tissue ablation by coagulative necrosis with high-intensity focused ultrasound (HIFU) applied through a rectal probe to 36 patients with symptomatic benign prostatic hyperplasia (BPH) was investigated in a phase II clinical trial. Overall, HIFU treatment was well tolerated, the mean hospital stay being 1.1 days. Negative side effects were transient urinary retention in 32/36 patients, hematuria in 2 patients and hematospermia resolving after 3-4 weeks (n = 15). After 3 months the maximum flow rate/s (Qmax) increased from 9.0 +/- 3.9 to 14.4 +/- 7.0 ml/s, the median flow rate/s (QM90) from 4.9 +/- 2.4 to 7.6 +/- 4.17 ml/s; the postvoid residual volume decreased from 128 +/- 88 to 57 +/- 35 ml and the AUA symptom score from 25.5 +/- 5 to 13.2 +/- 4.4. In conclusion, it was shown that tissue ablation in patients with symptomatic BPH using HIFU is safe and dramatically reduces both obstructive and irritative symptoms and leads to a significant increase in uroflow and a decrease in postvoid residual volume.

Tyrosine Kinases Expressed in Vivo by Human Prostate Cancer Bone Marrow Metastases and Loss of the Type 1 Insulin-Like Growth Factor Receptor

An important biological feature of prostate cancer (PCa) is its marked preference for bone marrow as a metastatic site. To identify factors that may support the growth of PCa in bone marrow, expression of receptor and nonreceptor tyrosine kinases by androgen-independent PCa bone marrow metastases was assessed. Bone marrow biopsies largely replaced by PCa were analyzed using reverse transcriptase-polymerase chain reaction amplification with degenerate primers that amplified the conserved kinase domain. Sequence analyses of the cloned products demonstrated expression of multiple kinases. Expression of the receptor and nonreceptor tyrosine kinases, alpha platelet-derived growth factor receptor and Jak 1, respectively, was confirmed by immunohistochemistry. In contrast, the type 1 insulin-like growth factor receptor, thought to play a role in PCa development, was lost in metastatic PCa. These results implicate several specific growth factors and signaling pathways in metastatic androgen-independent PCa and indicate that loss of the type 1 insulin-like growth factor receptor contributes to PCa progression.

Incidence of testicular microlithiasis

In adults polytopic intratubular calcifications of the testes are rare. Known as testicular microlithiasis, they manifest themselves in a characteristic echo pattern on sonography with high-frequency transducers (5 to 10 MHz). This consists of multiple echogenic specks in an otherwise normal testicular parenchyma. In a retrospective analysis of 1,710 testicular sonograms of adults, bilateral intratesticular microliths were found in 11 cases (0.6%). In 5 of them, the microliths were associated with a testicular tumor. One patient with a tumor in the contralateral testis had undergone radiotherapy and another one presented with hypogonadism. Four patients with noncontributory histories presented with varicocele or epididymal cyst. Sonographic findings were confirmed histologically in 6 patients. Multiple intratubular calcifications were found in all of them. The pathogenesis of testicular microliths is still poorly understood. Their clinical relevance is unclear, but their incidence in adults appears to be higher than reported in the literature.

Expression of aquaporins and PAX-2 compared to CD10 and cytokeratin 7 in renal neoplasms: a tissue microarray study

Diagnostic use of antibodies against aquaporin water channel proteins and PAX-2, a nuclear transcription factor in renal development, was tested in 202 renal neoplasms, using tissue microarray technique. Immunohistochemistry for aquaporin-1, aquaporin-2, PAX-2, CD10, and cytokeratin 7 was performed on 102 clear cell renal cell carcinomas, 44 papillary renal cell carcinomas (among them 34 type 1 and 10 type 2), 24 chromophobe renal cell carcinomas, three collecting duct carcinomas (carcinomas of the collecting ducts of Bellini), and 29 oncocytomas. Aquaporin-1 expression was found in clear cell renal cell carcinomas and papillary renal cell carcinomas of both types (78 and 73%, respectively), but not in chromophobe renal cell carcinomas, collecting duct carcinomas, and oncocytomas. Aquaporin-2 expression was not seen in any of the tested tumors. PAX-2 and CD10 was found in the majority of clear cell renal cell carcinomas (88 and 85%, respectively) but only in few papillary renal cell carcinomas, chromophobe renal cell carcinomas and oncocytomas. Decrease or loss of aquaporin-1 and PAX-2 was shown in higher grades compared to lower grades of clear cell renal cell carcinomas (P<0.0001 and <0.0245, respectively). Cytokeratin 7 was rarely seen in clear cell renal cell carcinomas, type 2 papillary renal cell carcinomas, and oncocytomas, but was found in the majority of type 1 papillary renal cell carcinomas (97.1%) and chromophobe renal cell carcinomas (88%). Aquaporin-1 and PAX-2 expression was found to correlate with nuclear grading for clear cell renal cell carcinomas but not for papillary renal cell carcinomas. No correlation of tumor stage and aquaporin-1 and PAX-2 expression was seen. Aquaporin-1 and PAX-2 are reliable markers for clear cell renal cell carcinomas of lower grades but not for higher grades. CD10 expression remains stable, independent of nuclear grading.

Morphology of tissue destruction induced by focused ultrasound.

The effect of high-intensity focused ultrasound (HIFU) ablation on the morphology of prostatic, renal and testicular tissue was studied by light and electron microscopy. Specimens were obtained in 21 patients 1 h to 10 weeks after lesioning. Histological findings showed consistent coagulative necrosis with precisely defined, sharp margins to normal tissue. Lesion size and position correlated well with the assumed target zones, suggesting that HIFU permits therapeutic tissue ablation.

Renal tumour size measured radiologically before surgery is an unreliable variable for predicting histopathological features: benign tumours are not necessarily small

To compare histopathological findings as a function of radiological tumour size, as published data suggest that small renal tumours are often benign and large tumours are renal cell cancer (RCC).

Tissue ablation in benign prostatic hyperplasia with high-intensity focused ultrasound.

In a phase I clinical trial the morphological impact and safety of high intensity focused ultrasound administered transrectally for tissue ablation in prostates from 22 patients undergoing subsequent prostatectomy were evaluated. Location and size of the tissue lesions correlated well with the predefined target area and revealed sharply delineated coagulative necrosis in all cases. Intervening tissues, such as the rectal wall and posterior prostate capsule, were invariably intact. In a subsequent phase II clinical trial the effectiveness of transrectal high intensity focused ultrasound as a novel minimally invasive treatment modality for 50 patients with symptomatic benign prostatic hyperplasia was determined. The maximum urinary flow rate (ml. per second) increased from 8.9 +/- 4.1 to 12.7 +/- 6.4 at 3 months in 44 patients, 12.4 +/- 5.6 at 6 months in 33 and 13.1 +/- 6.5 at 12 months in 20. During the same period the post-void residual volume (ml) decreased from 131 +/- 120 to 48 +/- 41, 59 +/- 42 and 35 +/- 30, respectively, and the American Urological Association symptom score (points) decreased from 24.5 +/- 4.7 to 13.3 +/- 4.4, 13.4 +/- 4.7 and 10.8 +/- 2.5, respectively. These data demonstrate that transrectal high intensity focused ultrasound is capable of inducing coagulative necrosis in the human prostate via a transrectal approach while preserving intervening and adjacent tissue. A 47% (+4.2 ml. per second) improvement in uroflowmetry and a 53% (-13.7 points) decrease in the American Urological Association symptom score 1 year after treatment clearly prove that transrectal high intensity focused ultrasound is a novel and safe minimally invasive treatment option for benign prostatic hyperplasia.

Transperineal radiofrequency interstitial tumor ablation of the prostate: Correlation of magnetic resonance imaging with histopathologic examination

OBJECTIVES Radiofrequency (RF) energy has recently been employed to destroy human tissue in vivo. The purpose of this study was to investigate the safety of this approach in localized carcinoma of the prostate (CaP) and specifically, the predictability of lesions obtained with radiofrequency interstitial tumor ablation (RITA). METHODS Using RITA, a total of 21 lesions were induced in 10 patients with localized CaP (mean age 70.4 years). RF was delivered transperineally under transrectal ultrasound (TRUS) guidance. All patients underwent endorectal magnetic resonance imaging (MRI) before and after treatment. Radical prostatectomy was performed in all patients 1 to 7 days after RITA. Three of the patients were treated with local anesthesia only. The predictability of the thermal lesion was assessed by correlating the findings of intraoperative TRUS, pre- and post-RITA endorectal MRI, and the histologic examination of the specimen. RESULTS Postoperatively, patients were catheterized for an average of 1.8 days (1 to 3 days). Lesions of 2 x 2 x 2 cm were targeted. Average lesion diameters obtained on MRI were 2.08 +/- 0.23 x 2.09 +/- 0.36 x 2.28 +/- 0.21 cm. Average lesion diameters defined by coagulative necrosis at histologic examination were 2.20 +/- 0.23 x 2.10 +/- 0.31 x 2.38 +/- 0.14 cm. There were no statistically significant differences (P = 0.377) between average lesion volume on MRI (5.37 +/- 1.83 cm3) and average lesion volume at histology (5.86 +/- 1.63 cm3). No complications or adverse events were noted. CONCLUSIONS In this Phase I study, RITA was shown to be safe and feasible, and to result in lesions that were predictable in size and location. MRI accurately visualized and verified the area of coagulative necrosis as documented at histology. The procedure is technically simple and can even be performed under local anesthesia.

Perimodiolar Electrodes in Cochlear Implant Surgery

Perimodiolar-positioned cochlear implant electrodes have been developed in order to bring the electrode contacts as close as possible to the spiral ganglion cells, which are the target of electrostimulation. This results in lower electrical thresholds, higher dynamic ranges and less channel interaction when compared with normal implant electrodes which are usually located peripherally within the scala tympani. In this study we evaluated 4 different types of perimodiolar electrode: the Clarion Preformed electrode, the Clarion Preformed electrode with positioner, the Nucleus Contour electrode and the Med-El Perimodiolar Combi 40 electrode. These devices require different approaches to achieve a perimodiolar electrode position. The electrodes were inserted in fresh human temporal bones. After processing these bones with the electrodes in situ by employing a sawing, grinding and polishing technique, the inner ear structures as well as the electrode positions could be evaluated in detail. All electrode types studied had a more or less perimodiolar position; however, each type produced a certain amount of trauma to cochlear structures which is discussed in relation to mechanical properties. Further human temporal bone studies with improved perimodiolar cochlear implant electrodes are necessary in order to find an optimized type of electrode.Perimodiolar-positioned cochlear implant electrodes have been developed in order to bring the electrode contacts as close as possible to the spiral ganglion cells, which are the target of electrostimulation. This results in lower electrical thresholds, higher dynamic ranges and less channel interaction when compared with normal implant electrodes which are usually located peripherally within the scala tympani. In this study we evaluated 4 different types of perimodiolar electrode: the Clarion Preformed electrode, the Clarion Preformed electrode with positioner, the Nucleus Contour electrode and the Med-El Perimodiolar Combi 40 electrode. These devices require different approaches to achieve a perimodiolar electrode position. The electrodes were inserted in fresh human temporal bones. After processing these bones with the electrodes in situ by employing a sawing, grinding and polishing technique, the inner ear structures as well as the electrode positions could be evaluated in detail. All electrode types studied had a more or less perimodiolar position; however, each type produced a certain amount of trauma to cochlear structures which is discussed in relation to mechanical properties. Further human temporal bone studies with improved perimodiolar cochlear implant electrodes are necessary in order to find an optimized type of electrode.