Heterogeneous suppression of experimentally induced colon cancer metastasis in rat liver lobes by inhibition of extracellular cathepsin B.

Metastatic rat colon cancer cells but not normal rat hepatocytes showed activity of cathepsin B on their plasma membranes. Activity was visualized in living cells with a new fluorogenic substrate, [Z-Arg]2-cresyl violet, and confocal microscopy. When these cancer cells were injected into the portal vein of rats, the animals developed tumors in the liver in a heterogeneous fashion. Three- to four-fold more tumors were found in the small caudate lobe than in the other three large lobes of the liver. Oral treatment with a selective water-soluble inhibitor of extracellular cathepsin B, Mu-Phe-homoPhe-fluoromethylketone, resulted in 60% reduction of the number of tumors and 80% reduction of the volume of tumors in the three large lobes whereas tumor development was not affected in the small caudate lobe. This study supports the conclusions that (a) extracellular cathepsin B plays a crucial but complex role in liver colonisation by rat colon carcinoma cells in vivo, (b) its selective inhibition suppresses tumor growth heterogeneously in the liver and (c) the caudate lobe of the liver is a relatively large risk factor for tumor development.

In vivo inhibition of cysteine proteinases delays the onset of growth of human pancreatic cancer explants.

An animal model was used to study the effects of oral treatment with a small molecular selective inhibitor of cysteine proteinases, Z-Phe-Arg-fluoromethylketone (Z-Phe-Arg-FMK) on primary tumour development. Poorly differentiated rapidly growing and moderately differentiated slowly growing human pancreatic tumours were implanted in the neck of nude mice that were orally treated or not with the inhibitor. Growth rates of the tumours were determined during 38 days after implantation. The poorly differentiated tumours were not affected by treatment with the inhibitor. Development of the moderately differentiated tumours was inhibited significantly by Z-Phe-Arg-FMK treatment. Moreover, the amount of stroma was increased and the volume of cancer cells was reduced in the moderately differentiated tumours that had grown in the treated animals. Reduction in size of the tumours was not achieved by reduction in growth rate but in a delay of the onset of growth. It is concluded that cysteine proteinases play a transient role at the start of tumour development only when cancer cells are surrounded by stroma as was the case in the moderately differentiated but not in the poorly differentiated pancreatic tumours. However, this role of cysteine proteinases can easily be taken over by other proteinases.

Testicular microlithiasis, a premalignant condition: prevalence, histopathologic findings, and relation to testicular tumor.

OBJECTIVES: To perform a retrospective analysis concerning the prevalence of testicular microlithiasis (TM). In patients with TM, the association of TM with testicular tumor, histopathologic findings, and follow-up were studied. METHODS: During a 6-year period at the Central Military Hospital or the University Medical Center in Utrecht, The Netherlands, ultrasonography of the testis was performed in 1535 patients. Patient records, ultrasound images, and histopathologic specimens were reviewed. Follow-up was performed in patients with TM. RESULTS: In 63 patients (4.1%), with a mean age of 35.4 years (range 19 to 74), TM was diagnosed at ultrasonography. In 29 of these patients (46%), a concomitant testicular tumor was diagnosed. A statistically significant correlation was found between TM and the presence of a testicular tumor (P <0.001; chi-square test). No significant correlation was found concerning the respective positions of the TM and the tumor in the testis, type of calcification, and histologic type of the tumor. In 34 patients, TM was found without a malignancy at diagnosis (mean age 39.2 years; range 19 to 69). Follow-up was possible in 31 patients. During the follow-up period (median 61.8 months), 1 patient developed a testicular tumor. CONCLUSIONS: A correlation was found between TM and testicular tumor. Because an increasing number of studies have reported patients with TM who developed a testicular tumor, TM should be regarded as a premalignant condition, which necessitates follow-up. Urologists should consider testis biopsy in patients with TM.

Reduced specificity of 5-ALA induced fluorescence in photodynamic diagnosis of transitional cell carcinoma after previous intravesical therapy.

OBJECTIVE: Photodynamic diagnosis (PDD) for the detection of bladder cancer has become a diagnostic tool in several hospitals. Several studies have reported different rates of false positive biopsies using 5-aminolevulinic acid induced fluorescence. In this study we evaluated the effect of previous intravesical therapy on the false positive biopsy rate. METHODS: Two hours prior to endoscopy 1.5g ALA dissolved in 50ml 1.4% NaHCO(3) solution was instilled intravesically. For fluorescence excitation a blue light source (D-light, Karl Storz) was used. Under white and fluorescence light guidance, tumor locations were recorded, cold cup biopsies were taken and tumors were resected. Patients were divided into 3 groups, last intravesical therapy (IVT) less than 6 months prior to PDD, last IVT longer than 6 months before PDD and no previous IVT. RESULTS: In total 917 biopsies were taken in 249 procedures of fluorescent and non-fluorescent areas. White light endoscopy revealed 270 and PDD 378 of in total 390 tumors, resulting in a sensitivity of 97% and specificity of 49% for PDD. Pathologic evaluation considered 270 fluorescent biopsies as false positive. The rate of false positive biopsies was 25.7% in the group No IVT, 30.6% in the group PDD-IVT >6 months, whereas in the group "within 6 months after intravesical therapy" the rate was 39.6% (p<0.025). When premalignant lesions such as dysplasia II are considered tumor the difference between the groups is even more significant (p<0.001). CONCLUSIONS: The procedure has a high sensitivity for superficial bladder cancer and decreases the number of overlooked lesions. Recent intravesical therapy results in significantly more false positive fluorescent biopsies. Since patient outcome might predominantly be determined by the early detection and subsequent treatment of (pre)malignant tissue we suggest that PDD is justified even shortly after intravesical therapy.