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OBJECTIVES: To analyze whether primary metastatic spread occurs behind the lumbar vessels and whether removal is necessary for accurate staging in diagnostic retroperitoneal lymph node dissection, because dissection of lymphatic tissue behind the lumbar vessels is a challenging maneuver. METHODS: One hundred thirty-nine patients were included in our study. Twenty-nine patients with clinical Stage I tumor underwent laparoscopic staging lymph node dissection, including removal of the lymph nodes behind the lumbar vessels. Sixty-four patients with Stage II testicular cancer were retrospectively examined by computed tomography to determine the localization of the enlarged lymph nodes in relation to the lumbar vessels. On the basis of these results, 49 patients with clinical Stage I underwent laparoscopic lymph node dissection within the same template but without dissection of the lymphatic tissue behind the lumbar vessels. RESULTS: In the first group, 10 of 29 patients had pathologic Stage IIA tumors, with positive nodes exclusively ventral to the lumbar vessels. In group 2, 39 patients with solitary metastatic lesions had enlarged lymph nodes, which were always ventral to the lumbar vessels. Only in 3 of 25 patients with multiple metastases was one enlarged node found behind the lumbar vessels. In group 3, no tumor recurrence either before or behind the lumbar vessels could be found in 46 patients after a mean follow-up of 27.8 months. CONCLUSIONS: On the basis of these data, we believe that primary lymphatic metastatic spread in testicular cancer always occurs ventral to the lumbar vessels. Therefore, the removal of lymphatic tissue behind the lumbar vessels for diagnostic procedures is not necessary.

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Conventional cytogenetic analysis of prostatic carcinoma (PC) is characterized by inefficient growth of tumor cells during in vitro culture, leading to a lack of aberrant karyotypes in many of investigated tumors. In this study we have combined a modified short-term tissue culture method for conventional banding analysis and comparative genomic hybridization (CGH) to examine genetic changes in PC, and to evaluate the effect of the in vitro culture on chromosomal changes by comparing results of the two methods. Cytogenetic analysis was performed on 34 PCs using both, conventional and molecular methods. Tumor tissues were obtained predominantly from untreated primary tumors from 48 patients. For karyotyping all tumor samples were short-term cultured using a feeder layer technique. Additionally DNA from uncultured tumor material from 17 of those patients was isolated and screened for copy number changes using CGH. Conventional banding analysis: clonal aberrations were detected in 65% of the tumor samples. Most of the chromosomal findings were numerical changes, including loss of chromosomes Y (32%), 18, 19 and 21 (each 12%). Less frequent, trisomy of chromosome 7 and monosomy of chromosomes 9, 12 and 22 (each 9%) was found. Additionally an inversion of chromosome 9p and a deletion at chromosome 7q was found in two cases. In 35% no clonal aberrations could be detected. CGH: DNA copy number changes were detected in 65% of the analyzed tumors. Predominantly losses of DNA sequences were found. The most common losses were found at chromosome regions 13q21q33 (29%), 6q11q23 (24%), 16q, and 18 (each 18%), and the most common gains at 19 (18%). In six tumors no copy number changes were found. Both methods showed a similar aneuploidy rate, suggesting that the feeder layer technique is quite a suitable method for in vitro culture of PC cells. However, the two techniques produced substantially differing results for most of the tumor samples, and in some cases the discrepancies are quite striking. Therefore eventual culture effects need to be taken into account when comparing results from conventional cytogenetics and CGH. Some contrary findings from the two methods are discussed.

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Actinomycosis of the urogenital tract is rare and predominantly an infectious disease of horses, cattle, swine, and humans. This case report describes isolated actinomycosis of the hydrocele wall presenting as an inflamed right-sighted hydrocele.

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Interleukin-6 (IL-6) is a pleiotropic cytokine that interacts with its receptor in prostate cells, thus regulating proliferative response and differentiation. It also activates the human androgen receptor in prostate cancer cell lines. In order to assess the significance of these findings in vivo, the expression of key elements of the IL-6 signalling pathway, IL-6 and its receptor, was investigated in tissue samples obtained on radical prostatectomy from prostate cancer patients. IL-6 immunohistochemistry was performed on 17 frozen prostate cancer specimens. IL-6 receptor immunostaining was evaluated in 21 paraffin-embedded prostate tumour specimens. In both groups, adjacent areas of high-grade prostatic intraepithelial neoplasia and benign tissue were also investigated. In benign prostatic epithelium, IL-6 was localized predominantly in basal cells, whereas in prostate cancer tissues more IL-6-positive glandular cells were identified. No IL-6 expression was detected in stromal cells on immunohistochemistry, although IL-6 protein was measured in the supernatants obtained from cultured stromal cells by ELISA. IL-6 receptor was expressed in benign prostatic tissue in both epithelial and stromal cells. Furthermore, IL-6 receptor expression was observed in all tumour specimens investigated and the majority of Gleason patterns analysed had more than 50% of cells showing a positive reaction. IL-6 and IL-6 receptor expression patterns in high-grade prostatic intraepithelial neoplasia lesions were similar to those observed in tumour tissues. Taken together, the results of the present study imply that there are paracrine and autocrine IL-6 loops in benign and neoplastic prostate.

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PURPOSE: We report the long-term oncological efficacy and morbidity of laparoscopic retroperitoneal lymph node dissection for testicular carcinoma. MATERIALS AND METHODS: From August 1992 to September 1999, 73 consecutive patients underwent laparoscopic retroperitoneal lymph node dissection with modified unilateral template dissection. All lumbar vessels within the template were routinely transected in the initial 29 cases only. Patients with positive lymph nodes received 2 cycles of chemotherapy. RESULTS: Operative time ranged from 150 to 630 minutes (mean 221) in our most recent 28 cases. All but 2 operations were completed as planned for a conversion rate of 2.7%. Minor intraoperative complications developed in only 6.8% of cases. In our last 44 patients there was no major and only 1 minor (2.3%) postoperative complication. Mean postoperative hospitalization was 3.3 days. Ejaculation was preserved in all patients. Lymph nodes were positive in 19 cases (26%). Mean followup in 47 patients with pathological stage I disease was 43.3 months (range 7 to 84). We noted 1 retroperitoneal recurrence due to false-negative histological findings but there were no other relapses. At a mean followup of 42.7 months (range 6 to 86) 17 patients with pathological stage II carcinoma treated with 2 cycles of adjuvant chemotherapy were also free of disease. CONCLUSIONS: In our hands laparoscopic retroperitoneal lymph node dissection has not only proved its surgical efficiency, but also its oncological efficacy. Patient satisfaction is high. During long-term followup of more than 3 years not a single recurrence developed due to surgical failure.

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A number of studies revealed that high expression of the proto-oncogene bcl-2 correlated with poor prognosis or resistance to chemotherapy in some tumors but predicted a favorable clinical course in other neoplasias. In these studies, however, different immunologic techniques for Bcl-2 detection were used, raising the question of whether the methods applied were comparable. Using chronic lymphocytic leukemia (CLL) cells, the aims of our study were as follows: (1) to determine the reproducibility of Bcl-2 semiquantitation by immunocytochemistry, flow cytometry, or immunoblotting; (2) to study the agreement between results obtained by these methods; and (3) to examine the association between Bcl-2 expression in tumor cells of 99 patients with CLL and clinical parameters. We found that determination of Bcl-2 expression by immunocytochemistry was reproducible and the results were comparable with those of flow cytometry and immunoblotting. In the patient collective examined, Bcl-2 expression did not reflect the extent of tumor mass, but higher levels were found more often in patients with progressive disease.

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Growth hormone (GH) and placental lactogen (PL) gene transcription patterns in testicular germ cell tumors (GCT) and normal testicular tissue were comparatively investigated to identify GH/PL gene products associated with the development of GCT. This was done by nondiscriminative reverse transcriptase-polymerase chain reaction (RT-PCR), amplifying all major transcripts of any of the 5 GH/PL genes--GH-N(ormal), GH-V(ariant), PL-A, PL-B, PL-L(ike)--and subsequent analytical restriction enzyme analyses of 5'-end radioactively labeled cDNA. Surprisingly, all nonseminomatous GCT (NSGCT; n = 9) expressed GH-N, PL-A/B, and PL-L transcripts (9 of 9). Seminoma (n = 7) showed a distinctly unique pattern of GH-N and PL-A/B. GH-V products, which are hallmarks of the normal healthy testis, were not detected in any testicular cancer specimen (0 of 16). The fact that both seminomatous and NSGCT showed alterations in the same gene cluster indicates a pathogenetic relationship. Two choriocarcinoma cell lines of conceptus origin, BeWo and JAR, clearly differing from the male counterparts, exhibited a placental-derived pattern of PL-A/B and GH-V. Obviously, profound differences exist between conceptus and male germ cell GH/PL gene cluster transcription. In summary, the unique testicular pattern of GH/PL gene expression changes significantly and in directed ways with malignancy. Loss of GH-V gene expression in testicular GCT compared with normal testis and loss (seminoma) or mutation (NSGCT) of PLL gene products might have significance in terms of the relationship between these tumors and for testicular GCT development.

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BACKGROUND: 2',2' -difluorodeoxycytidine (dFdC, gemcitabine) is a pyrimidine antimetabolite with antineoplastic activity against a wide range of solid tumors. The immunosuppressive activities of this compound have not been described to date. METHODS: The in vitro effects on activated T lymphocytes were studied with a lymphocyte colony-forming assay in a microagar culture system. Heart transplantations were performed in the fully allogeneic Lewis/ Brown Norway combination. dFdC was administered once daily at various dosages from the time of surgery until day 50. RESULTS: Phytohemagglutinin-induced lymphocyte proliferation was inhibited 50% by dFdC at a concentration of 3.25+/-0.9 nmol/L. Allografts of untreated animals survived for 7.5 (7-8) days and those with 25, 50, and 75 microg/kg body weight dFdC for 7.3 (7-8), 9.3 (8-10), and 16.3 (10-38) days, respectively. Treatment with 100 or 125 microg/kg body weight of dFdC, however, prolonged allograft survival until day 152.8 (129-178). Dose-dependent leukopenia was the main toxicity. CONCLUSIONS: DFdC is a new immunosuppressive agent that can successfully prevent cardiac rejection in a rat transplantation model.

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Mast cells in the bilateral testicular biopsies of 30 patients with a 'mixed atrophy' of seminiferous tubules were analysed. Seven biopsies from vasectomized patients served as controls. With regard to their characteristic location within testicular tissue, two groups of mast cells could be distinguished, in both control and infertile patients: 'interstitial' mast cells (located between Leydig and other interstitial cells as well as in the vicinity of blood vessels) and 'peritubular' mast cells (located in the close proximity of the tubular lamina propria or incorporated in the lamina propria itself). Morphometric data indicated a significant increase in the number and volume of mast cells in infertile patients when compared with controls. In the biopsies of infertile patients that were analysed both 'interstitial' and 'peritubular' mast cells showed a significant increase in their number and volume, although it appeared that 'peritubular' mast cells increased at a higher rate than 'interstitial' mast cells. A significant negative correlation was found between the following variables: volume and number of mast cells, testis volume and the status of spermatogenesis evaluated by Johnsen's scoring. It was concluded that the increased presence of mast cells is closely associated with an impairment of spermatogenesis.

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Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the nonsteroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention.

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In this study, cytogenetic and fluorescence in situ hybridization analyses were performed on 22 sporadic, unilateral primary renal cell tumors. The tumors were classified according to cell types, growth patterns, and grades of malignancy. A feeder layer technique was used for the cell culture of 13 clear-cell carcinomas, 4 chromophilic carcinomas, 3 chromophobe carcinomas, 1 oncocytoma, and 1 spindle-shaped pleomorphic carcinoma. Eighty-six percent (19/22) of renal tumors showed clonal abnormalities. The most frequent finding in the 15 male patients was loss of chromosome Y (9/15). In 3/15, it was the only observed aberration. The second most visible aberration was regional loss or entire loss of chromosome 9, which was detected in 36% (8/22) of the cases. Four cases showed loss of chromosome 9 and 4 cases a deletion of the short arm with breakpoints on 9p11 and 9p21. Loss of 3p material was observed in 32% (7/22) of the cases but only in 2/13 patients with clear-cell carcinoma. Gain of chromosome 12 or 12p was observed in 27% (6/22). In 23% (5/22) of the patients, gain of whole or partial chromosomes 2, 5, and 7 was found. Less-frequent findings were loss of chromosomes 8, 14, and 21; gain of chromosome 16; and structural abnormalities of chromosome 1 (each 18%; 4/22). Only some of the karyotypes described as typical for the various renal tumor types were confirmed. In contrast with previous reports, chromosome 3 and 9 aberrations did not allow differentiation between tumor types in our study.

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PURPOSE: We investigated laparoscopic retroperitoneal lymphadenectomy after chemotherapy for stage IIB testicular carcinoma in terms of operative feasibility, overall morbidity and tumor control. MATERIALS AND METHODS: Between February 1995 and April 1998, 24 patients underwent laparoscopic retroperitoneal lymphadenectomy following initial chemotherapy for stage IIB (2 to 5 cm.) solitary or unilateral lymph node metastases. Mean tumor diameter was 2.4 cm. before and 1.1 cm. after chemotherapy. Laparoscopic retroperitoneal lymphadenectomy was performed in all patients, including those with complete remission. RESULTS: Laparoscopic retroperitoneal lymphadenectomy could be completed as planned in all patients and there was no need for conversion to open surgery. Operative time was 150 to 300 minutes (mean 240). Blood loss was minimal and no blood transfusions were required. The only postoperative complications were chylous ascites (5 patients) which resolved with conservative management (low fat diet) and a small asymptomatic lymphocele. Histological examination revealed necrosis in 71%, mature teratoma in 25% and active tumor in 4% of patients. Antegrade ejaculation was preserved in all patients. Mean postoperative hospital stay was 4 days, return to normal activities between 1 and 3 weeks, and time to complete recovery between 5 and 10 weeks. All patients were well without evidence of disease at a mean followup of 24.4 months. CONCLUSIONS: Laparoscopic retroperitoneal lymphadenectomy after chemotherapy proved feasible in select patients presenting with solitary or unilateral lymph node metastases and was associated with a low morbidity. Tumor control was not compromised by the laparoscopic approach.

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BACKGROUND: Ductal carcinoma in situ (DCIS) in the male breast is a rare disease that to the authors' knowledge has been investigated to date only in small numbers. Compared with DCIS in the female breast, distinct clinical and morphologic differences have been suggested. METHODS: The files of the Armed Forces Institute of Pathology (AFIP) were searched for cases of pure DCIS and DCIS associated with invasive carcinoma (DCISAIC) in male patients. A total of 280 cases of pure DCIS and 759 invasive mammary tumors were identified; 114 cases (including 84 pure DCIS and 30 DCISAIC) were studied for this preliminary report. All cases were reviewed and classified according to specific subtypes (papillary, cribriform, solid, micropapillary, and comedo) and grades of DCIS. Basic clinical data were extracted from the patients' charts. RESULTS: Men with pure DCIS presented at a median age of 65 years, with a typically nodular, retroareolar, partially cystic mass that frequently was associated with a nipple discharge. The median duration of symptoms was 2 months for patients with pure DCIS and 6 months for patients with DCISAIC. Histologically, the predominant appearance of DCIS (in 74% of cases) was that of a papillary carcinoma often with a superimposed cribriform pattern. Intraductal extension beyond the main papillary lesion was common. It is interesting to note that the pure DCIS cases in this series were uniformly of either low or intermediate grade; high grade or comedocarcinomas were only observed within the group of DCISAIC. No significant morphologic differences between pure DCIS and DCISAIC were encountered, although DCISAIC did show relatively more cellular atypia with more frequent necrosis compared with pure DCIS. CONCLUSIONS: DCIS in the male breast is a distinct lesion that occurs at an older age and displays a significantly different distribution of morphologic subtypes compared with its female counterpart. It presents most frequently as an intraductal papillary carcinoma, and less commonly as a nonpapillary cribriform, solid, or micropapillary DCIS. In the current study the majority of pure DCIS cases were low grade (AFIP Grade 1) with occasional cases displaying necrosis (AFIP Grade 2); high grade pure DCIS appears to be a rare lesion in the male breast. In contrast, DCIS associated with invasive carcinoma more frequently is of higher grade.

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Proliferative and secretory responses in androgen-sensitive prostate cancer LNCaP cells are regulated by steroid and peptide hormones and by differentiation-promoting substances. In the present study, we evaluated whether peripheral blood monocytes that exhibit anti-tumour activity in haematopoietic and solid tumours influence growth and secretion in the LNCaP cell line. For this purpose, LNCaP cells were incubated with monocyte-conditioned medium (MCM), and proliferation as well as expression of androgen receptor (AR) and secretion of prostate-specific antigen (PSA) were assessed. Conditioned medium from monocytes reduced proliferation in a dose-dependent manner. Incubation with 40% MCM caused a 50% reduction in cell proliferation. AR protein decreased by 70% and PSA levels in supernatants from LNCaP cells were reduced by approximately 80% following treatment with MCM. We focused on the contribution of two major products of activated monocytes, prostaglandin E2 and interleukin 1beta (IL-1beta), to the MCM modulatory action. LNCaP cells treated with prostaglandin E2 showed neither a reduction in proliferation nor a down-regulation of AR and PSA levels. The effects of MCM on cellular proliferation, AR protein and PSA secretion were abolished by pretreatment of MCM with a neutralizing anti-IL-1beta antibody. In addition, recombinant IL-1beta was able to replace MCM for the inhibition of proliferation and down-regulation of AR and PSA proteins. LNCaP cells were shown to express the IL-1beta receptor type 1, which transduces IL-1beta signal. Our findings reveal that monocyte-derived IL-1beta inhibits the proliferation of androgen-responsive prostate tumour cells and reduces AR and PSA levels.

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BACKGROUND: Monoclonal antibodies B1 and B3 react with Lewis(y) and related carbohydrate antigens, which are abundant in many solid tumors. These antibodies, when conjugated to a toxin, have been used to target a variety of cancers. Treatment options for advanced prostate cancer are very limited, and there is a need to develop new therapies. In this study, we have asked whether antibodies B1 and B3 react with metastatic lesions from human prostatic carcinoma. METHODS: Indirect streptavidin-biotin peroxidase immunohistochemistry was performed on formalin-fixed specimens from prostate cancer metastases. A total of 6 lymph node metastatic samples from patients who did not receive endocrine treatment and specimens of 14 distant metastases from patients who failed hormonal therapy were obtained. RESULTS: Of the samples, 6 lymph node and 11 distant metastases stained for B1. In the case of B3 staining, 6 lymph node and 10 distant metastatic lesions were positive. In about half of these metastatic samples, more than 40% of cells were immunoreactive with either antibody. Two metastatic samples stained neither for B1 nor for B3 antibody. In general, B1 staining intensity was stronger in samples in which more than 40% of cells were positive. CONCLUSIONS: Our results suggest that B1 and B3 immunoconjugates could be applied to target a substantial percentage of prostate cancer metastases.

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Collecting duct carcinoma (CDC) is a rare variant of carcinoma of the kidney with aggressive behaviour. CDC arise from the epithelium of the ducts of Bellini in the distal nephron. A CDC in a 53-year old male patient is characterised both by cytogenetic analysis and comparative genomic hybridisation (CGH). The cytogenetic analysis shows a biclonal karyotype 47,XY,+3[2]/40-44,XY,-12[3], -22[4][cp5]/46,XY[42]. Loss of DNA sequences detected by CGH involves chromosome 1, 2, 9, 11 and 18. Gain of DNA sequences affect chromosome 16 and 20. The characterisation of a CDC in this study represents an additional contribution to the poorly explored CDC.

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A 24 year old woman presented with a painless fusiform mass in her right index finger. Exploration showed an enlargement of the nerve by fibrofatty tissue and microsurgical intraneural dissection was done. Histological examination identified the lesion as a lipofibromatous hamartoma of the nerve, which is both rare and benign. There are different options for treatment of this lesion.

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Retinoids modulate several cell functions and especially inhibit the growth of tumor cells. Their biological activity is mediated by retinoic acid receptors (RARs), of which three subtypes (alpha, beta, gamma) have been identified. In human neuroblastoma (NB) reduced endogenous RAR-gamma expression was suggested to diminish the sensitivity for retinoids, to promote proliferation, and to contribute to the malignant phenotype. To correlate receptor selectivity with in vitro activity, we analysed the effect of six synthetic retinoids with selectivity for human RAR-alpha/beta/gamma on the human LAN-5 NB cell line and compared it with the natural compound all-trans-retinoic acid (ATRA). Apoptosis was determined by flow-cytometry using terminal-deoxynucleotidyl transferase to end-label DNA fragments in situ in apoptotic cells. The antagonist for RAR-beta/gamma CD2665 as well as the selective agonists for RAR-alpha CD336 and RAR-beta CD2019 were less effective in growth inhibition than ATRA. In contrast, the synthetic RAR-gamma selective agonists CD437 and CD2325 induced a concentration- and time-dependent antiproliferative effect, which was similar or even more pronounced than ATRA. In contrast to ATRA, the adition of CD437 and CD2325 did not induce morphological changes typical of NB cell maturation but resulted in morphological features consistent with the occurrence of programmed cell death. Flow-cytometric analysis showed that in contrast to ATRA the addition of CD 437 and CD 2325 results in progressive time-dependent increase of apoptotic cells (25.9% and 57.7% after 72 hours). In conclusion, our study demonstrates RAR-gamma selectively binding retinoids dramatically suppress NB cell growth, primarily by inducing programmed cell death rather than by cell differentiation. Since advanced or disseminated NB tumors endogenously express low levels of RAR-gamma and lack of apoptosis is involved in tumor progression, RAR-gamma selectively binding retinoids may be more appropriate retinoids for clinical trials in NB.

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BACKGROUND: Endocrine therapy for prostate cancer aims to reduce the levels of circulating androgen or to inhibit androgen action by blocking the androgen receptor in the prostate, or both. Studies in various animal and human prostate cancer models suggested that there may be a downregulation of androgen receptor during prostate cancer progression. Recent work, however, showed androgen receptor expression in all stages of prostate cancer. The presence of mutant androgen receptors in a portion of prostate cancers and receptor activation in the absence of androgen or in the presence of low androgen concentrations is discussed within this context. METHODS: This review attempts to summarize the literature on androgen receptor expression in vitro and in vivo, as well as structural and functional alterations and communication between androgen signal transduction cascade and other signaling pathways. CONCLUSIONS: Prostate tumors adapt to an environment with low androgen supply by using a hyperactive androgen receptor. The mechanisms involved are mutations of the androgen receptor generating receptors with broadened activation spectrum, increased receptor expression, and activation by interaction with other signaling pathways.

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