Urogenital Tumors Research Articles

Clinical implementation of high precision radiotherapy for urogenital tumors. Controlling dosimetric and geometric uncertainties

In this thesis a number of aspects of conformal radiotherapy of urogenital tumors have been studied to improve their planning and delivery process. The aims of the study are threefold. First, three-dimensional (3D) data on target delineation, organ motion, and patient setup are analyzed to incorporate into the planning of the treatment of bladder and prostate cancer. The data on bladder delineation uncertainties are obtained from the 3D variation in a multiobserver study, organ motion is quantified by analyzing bladder volumes at different moments during treatment, while the data on setup uncertainties of bladder patients are extracted from portal imaging. The results showed that organ motion is the most important uncertainty during radiotherapy of bladder cancer. As part of a quality assurance procedure of a prostate trial, delineation of the various volumes and treatment planning were compared in the participating institutions. Differences in delineation of the prostate between different observers are small. However, differences in delineation of the rectum greatly influenced the calculated risk of rectal complications. Therefore, applying a stricter definition of delineation of organs-at-risk is needed to retrieve more reliable trial results. Next, a mathematical model for the rectal wall has been developed, incorporating stretching due to variable rectal filling and neighboring structures. The application of the model yields accurate dose distributions in the rectal wall without delineating the inner surface of the rectum. This approach reduces both the workload and variations due to inaccurate delineation of the rectal wall. A second tool has been developed to take into account the additional dose resulting from acquiring electronic portal images used for patient setup verification. In this formalism beam weights and wedge angles of the treatment fields are adjusted in such a way that the dose and dose homogeneity in the PTV are preserved. Finally, the impact of an extensive in vivo dosimetry program on the delivery of conformal treatments of bladder and prostate cancer patients has been assessed. Analysis of measurements performed on more than 500 patients revealed that during the first years a number of relatively large, up to 7%, systematic errors were traced by in vivo dosimetry. In the later period it was possible to trace minor imperfections, even smaller than 1%, using statistical analysis of the results.

Does hypercoagulability awaken dormant tumor cells in the host?

Does hypercoagulability awaken dormant tumor cells in the host?

Evaluation of nuclear matrix protein-22 as a clinical diagnostic marker for bladder cancer

Objectives. To evaluate prospectively the prognostic power of urinary nuclear matrix protein-22 (NMP-22) for bladder cancer in Taiwanese screening and surveillance settings. Methods Single voided urine samples were obtained from 68 healthy individuals, 303 patients with benign urothelial diseases, and 28 patients with urogenital tumors. The NMP-22 levels in the urine samples were measured using enzyme-linked immunosorbent assay methods. Results The median NMP-22 level in healthy individuals and patients with benign and malignant disease was 5.9, 4.8, and 7.4 U/mL, respectively. The positive NMP-22 rate in healthy individuals and patients with benign and malignant disease was 4.4%, 17.2%, and 50%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value was 50%, 82.8%, 21.2%, and 94.7%, respectively, using 7.5 U/mL as the cutoff value. Conclusions Our data demonstrated that NMP-22 is not a good diagnostic tool for screening or follow-up surveillance of bladder cancer owing to its low sensitivity and positive predictive value. Nevertheless, it could be adopted as a tool to rule out the possibility or risk of developing bladder cancer because of its high negative predictive value in our study.

Urothelial Mesh - A New Technique of Cell Culture on Biomaterials

Urogenital malformations, trauma or tumours may demand surgical reconstruction in children. Cell culture is an important technology in biomaterial research and tissue engineering. Tissue-engineering of urothelial organs is of interest in children, because the number of complications and re-operations may be reduced. Actually, monolayer cultures of urothelium are used for tissue engineering and biocompatibility testing. A culture system that more closely mimics the physiologic environment of the urothelium would be of interest. The aim of this study was to determine the biological and mechanical characteristics of urothelial mesh cultured in vitro. Meshes containing urothelium, lamina propria, and submucosal tissue were generated using a skin mesh graft cutter. Meshes were cultured in 6-well plates, on collagen I/III, polydioxanone/polylactic acid and silicone matrices. Cell morphology was examined by inversion microscopy, histology, and scanning electron microscopy. It was compared to urothelium cultured by methods reported in the literature. To define the basic mechanical properties, meshes were extended longitudinally by a servohydraulic testing machine and strain diagrams generated. Urothelium was reproducibly cultured from meshes. Cell growth could be induced onto fibrillary collagen, polydioxanone-polylactic acid matrices and shaped polyurethane surfaces. Cells formed confluent layers of flat cells, resembling native urothelium. The meshes have unique mechanical properties, allowing for stable fixation, surgical handling and mechanical stimulation. Meshes can be used for cell culture on biomaterials. They maintain epithelial-stromal integrity and mechanic stability. The small size of tissue bridges allows in vitro culture for long periods with many potential advantages for tissue engineering and biologic research. Applications are possible both in vitro and in vivo.

Low frequency of human polyomavirus BKV and JCV DNA in urothelial carcinomas of the renal pelvis and renal cell carcinomas

Human polyomaviruses BKV and JCV establish a persistent infection in the kidney and possess oncogenic potential in experimental animal models. Their possible involvement in the pathogenesis of human urogenital tumors has been suggested by several studies but is not conclusively resolved. For the present study, highly sensitive quantitative TaqMan PCR assays were developed to detect BKV and JCV DNA sequences in matched pairs of human tumors and surrounding normal tissue. Samples from 55 patients with renal pelvic urothelial carcinomas and from 83 patients with renal cell carcinomas of all histologic subtypes were investigated. Human polyomavirus DNA was detected in renal pelvis samples with a frequency of 16% (BKV) and 15% (JCV), and in kidney samples with a frequency of 1% (BKV) and 23% (JCV), respectively. However, viral sequences were not present more often in tumors than in normal tissue. There was no integration of the potentially oncogenic viral large T-antigen in the tumors, and the viral concentration of both BKV and JCV was not higher in DNA extracted from tumors compared to normal tissue. These data provide no evidence for a causative role of the human polyomaviruses BKV and JCV in the development of tumors of the renal pelvis and the kidney.

Otarine herpesvirus-1: a novel gammaherpesvirus associated with urogenital carcinoma in California sea lions ( Zalophus californianus)

The incidence of neoplasia in California sea lions (CSLs) is considered to be unusually high. Electron microscopic examination of some of these urogenital tumours revealed the presence of virions with typical herpes-like structure. While current attempts to cultivate this virus have not been successful, molecular studies employing DNA extracted from tumour tissues allowed both the classification of the agent and its identification in tumours and archived tissue samples. Two genome fragments generated using degenerate primers in PCR demonstrated highest identities with other mammalian gammaherpesviruses. Phylogenetic analysis showed that this novel virus, tentatively designated Otarine herpesvirus-1 (OtHV-1), grouped with members of the gammaherpesvirus subfamily and was distinct from PHV-2, a previously described pinniped gammaherpesvirus. An OtHV-1 specific PCR was established and used to investigate the presence of this virus in CSL tissues. PCR of DNA isolated from animals with these tumours, demonstrated that this virus was present in 100% (16/16) of tumours. Furthermore, DNA extracted from archived brain and muscle tissues was also positive in 29% (4/14) and 50% (7/14) of cases examined. This preliminary study provides evidence to support the hypothesis that the presence of this novel gammaherpesvirus is a factor in the development of urogenital carcinoma in CSLs.

Solitary fibrous tumor of renal pelvis

A 70-year-old Japanese man was referred because of a right renal mass of 2 years in duration. Imaging studies, including magnetic resonance imaging, revealed an ovoid mass, with relatively abundant vascularity, in the right renal pelvis. Right radical nephrectomy was done and a tumor measuring 6.0 x 4.5 x 4.0 cm was found in the renal pelvis. Solitary fibrous tumor (SFT) was highly suspected by histology. Immunohistochemical study using a monoclonal antibody directed against the human hematopoietic progenitor cell antigen (CD34) stain confirmed SFT. This is the first case of SFT of the renal pelvis. Although SFT is extremely rare in urogenital organs, this tumor must be included in the differential diagnosis when we encounter urogenital tumors consisting of mesenchymal elements.

Pseudosarcomatous myofibroblastic tumor and myosarcoma of the urogenital tract.

Abstract Objective.—Pseudosarcomatous myofibroblastic tumors (PMTs) of the urogenital tract are rare but distinctive lesions. Despite their benign behavior, they are frequently misinterpreted as leiomyosarcomas and rhabdomyosarcomas in preoperative biopsies and even in resected specimens because of their atypical spindle-cell features. Precise diagnosis of PMTs is important to avoid unnecessary radical therapy. We analyzed urogenital myoid tumors to clarify which of their characteristics are useful for the differential diagnosis. Methods.—We evaluated 7 urogenital myoid tumors consisting of 3 PMTs, 2 leiomyosarcomas, and 2 rhabdomyosarcomas. We studied the expression of various immunohistochemical muscle-cell markers including desmin, muscle-specific actin, α-smooth muscle actin, high-molecular-weight caldesmon, and myogenin. Results.—Desmin, muscle-specific actin, and α-smooth muscle actin were noted variably in all tumor types, whereas high-molecular-weight caldesmon was expressed only in leiomyosarcoma...

Anaplastic lymphoma kinase expression in inflammatory pseudotumors.

Anaplastic lymphoma kinase (ALK), a hallmark of anaplastic large cell lymphoma, has recently been implicated in the genesis of some inflammatory pseudotumors (inflammatory myofibroblastic tumors) in children and young adults. The aim of this study was to determine the frequency of its expression among inflammatory pseudotumors, and to characterize the clinicopathologic features of the positive cases. Sixty-one cases of inflammatory pseudotumors were retrieved from the surgical pathology archives and consultation files. Paraffin sections were immunostained with the antibody ALK1. The patients ranged in age from 0.5 to 79 years (median age, 50 years), with 10 patients (16.4%) younger than 20 years. Five cases (8.2%) were ALK+, including two of six urogenital inflammatory myofibroblastic tumors, none of eight pulmonary inflammatory pseudotumors, three (one adrenal, one small bowel, one liver) of 31 extrapulmonary inflammatory pseudotumors, none of nine hepatic/splenic inflammatory pseudotumors expressing follicular dendritic cell markers and harboring Epstein-Barr virus, and none of seven inflammatory pseudotumors of the lymph node. When only those patients 40 years or younger were considered, the ALK positivity rate became 21.7% (five of 23). All five ALK+ cases occurred in young patients aged 0.5 to 37 years, who were alive and well at 3.5 to 17 years. The tumors exhibited a spectrum of histologic features typical of inflammatory pseudotumors/myofibroblastic tumors, but there was at least focal nuclear atypia. Immunostaining for ALK produced fibrillary or granular cytoplasmic staining in the neoplastic cells, sometimes with cell membrane accentuation. This study confirms that ALK is implicated in a proportion of inflammatory pseudotumors, and is generally associated with a favorable outcome. The results also support the heterogeneity of inflammatory pseudotumors, with the follicular dendritic cell/Epstein-Barr virus-positive cases and those occurring in lymph nodes representing different biologic entities.

METALLOTHIONEIN EXPRESSION IN RENAL CELL CARCINOMA: SUBCELLULAR LOCALIZATION AND PROGNOSTIC SIGNIFICANCE

We investigated the immunohistochemical localization of metallothionein (MT) in renal cell carcinoma and determined the potential role of MT expression as a possible prognostic variable for tumor proliferation and progression. Tumor tissue blocks from 70 patients with renal cell carcinoma who underwent radical or partial nephrectomy were investigated. Mean followup plus or minus standard error was 36 +/- 3 months. Immunohistochemical testing was performed by the avidin-streptavidin method using a monoclonal mouse antiMT antibody. MT staining intensity in samples was evaluated semiquantitatively. The subcellular distribution of MT was also determined. Staining characteristics were compared with the clinicopathological results. MT immunostaining was found in 39 of 70 tumors (55.7%) and subcellulary MT was localized in the cytoplasm, nucleus and cell membrane. The survival of patients with MT immunostaining was significantly worse than that of those with MT negative results (p = 0.02). A significant relationship of higher tumor grade and MT staining intensity was observed in grades I and III (p = 0.01), and grades II and III (p = 0.02) tumors. No association was found of MT expression and pathological stage. Sarcomatoid tumors showed significantly higher MT expression than clear cell, papillary, granular or chromophobe tumors (p = 0.02, 0.001, 0.01 and 0.01, respectively). MT expression was not an independent prognostic variable. MT over expression seems to be associated with malignant behavior and poor prognosis in renal cell carcinoma. Therefore, MT expression may be considered a useful marker of less differentiated and more aggressive renal cell carcinoma.

Ludwig Rehn (1849-1930)--pioneering findings on the aetiology of bladder tumours.

One hundred and six years ago, the surgeon Ludwig Rehn from Frankfurt am Main held a pioneering lecture in Berlin about the possible origins of bladder tumours. He thereby gave the decisive impulse for cancer research in general and specifically for the investigation of aetiological factors involved in the development of urogenital tract tumours. Thereafter, this resulted in an intensified scientific discussion addressing this issue. Although the detailed evaluation of the causes finally contributing to tumour growth is still ongoing, the work of Ludwig Rehn on bladder tumours among aniline workers considerably promoted the establishment of urology as a specialised field within German clinical medicine and is therefore a milestone in the history of medicine.

Mechanisms of drug resistance in chemotherapy for urogenital carcinoma.

Cancer chemotherapy is the principal approach for urogenital cancers. However, the acquisition of resistance to anticancer agents is a critical factor that limits the successful treatment of malignancies. The multidrug resistant (MDR) phenotype has been widely recognized in cancer chemotherapy in urogenital tumors and the mechanisms underlying MDR have also been extensively studied. One of the principle mechanisms in MDR is caused by the overexpression of P-glycoprotein (P-gp), encoded by the multidrug resistance gene (MDR1). It functions as an ATP-dependent active efflux pump of chemotherapeutic agents in human cancer cells. Recently, other drug resistance proteins, including multidrug resistance-associated protein (MRP1) and cMOAT (or MRP2), were also identified from multidrug resistant cells. A functional analysis of MRP1 has shown that MRP1 may have the potential to act as a transporter of glutathione conjugates, which has been known as a central detoxification pathway in anticancer agents. Furthermore, several other resistance-related proteins (e.g. glutathione S-transferase, metallothionein, thioredoxin, topoisomerase I, II, O6-alkylguanine-DNA methyltransferase, etc.) have been found to be up- or down-regulated in resistant cells and these molecules are believed to contribute to the resistant phenotype as well. Based on the molecular characteristics identified in MDR, several experimental and clinical approaches have been studied to overcome MDR. One of these strategies is to reverse MDR by using such P-gp inhibitors as verapamil and cyclosporine A. In this review, we summarize the recent advances in MDR-related molecules and clinical trials to circumvent MDR in urogenital carcinomas.

Two different forms of p53 localized differently within cells of urogenital tumours

We analyzed the subcellular localization of p53 in prostate and bladder carcinoma cells. Using laser scanning microscopy and PAb1620, a monoclonal antibody recognizing the wildtype conformation of p53, and another monoclonal antibody directed against the mutant conformation of the protein (PAb240), we found two different subsets of p53 within the same cell. The wildtype subgroup was found in the nucleolus, whereas the mutant protein was confined to the nucleus. The results obtained by immunofluorescence were verified by Western blot analysis and immunoprecipitation. Thus, our findings demonstrate an unusual subcellular localization pattern of p53 in prostate and bladder cancer cells which may indicate another mechanism of inactivation of p53.

Malignant melanoma of the mucous membranes: a review of 119 cases.

Melanomas arising from the mucous membranes lining the respiratory, digestive, and genitourinary tracts are rare. Women are more commonly affected than are men, mainly because there is no male counterpart for vulvovaginal lesions. The mainstay of therapy is surgery, with little current use of adjuvant modalities in primary therapy. These lesions usually are advanced at initial presentation; consequently, the prognosis is poor, with 5-year survivals well below 50% in most series. One hundred and nineteen patients with primary mucosal melanoma were reviewed. They represented 1.1% of the 10,393 melanoma patients seen at Duke University between 1970 and 1995. All data were obtained from the patients' clinic charts and computerized databases. There were 43 tumors arising from the head and neck region, 46 from the urogenital tract, and 30 from the anorectum. A female predominance was observed, with a female-to-male ratio of 2.7:1. All but five of the patients underwent resection with curative intent. Regional or distant metastases, or both, were encountered in 36 patients at the time of presentation. In patients with head and neck and urogenital tumors, local recurrences accounted for most of the treatment failures, whereas systemic recurrences were more common with tumors arising in the anorectum. The age and gender of the patient, anatomic site of origin of the tumor, clinical stage at initial presentation, and ulceration of the primary all clearly affected prognosis. Overall, the probabilities of being alive 1, 5, and 10 years after diagnosis were 80%, 29%, and 15%, respectively. Widely accepted classification systems are needed so that results from separate institutions can be compared adequately. Multi-institutional trials could help in delineating standardized therapeutic protocols and in establishing the potential roles of emerging modalities in the treatment of this subtype of melanoma.

Intratumoral vascularity as a prognostic factor in cancers of the urogenital tract.

INTRODUCTION A POSITIVE correlation of increasing intratumoral microvessel density (IMD) with various measures of tumour aggressiveness has been reported for a long list of solid tumours arising at multiple body sites. This list includes not only cancers of the breast, head and neck, lung, skin, stomach, colon, rectum, bone marrow, and central nervous system, but also those arising in the prostate, bladder, ovary, cervix, endometrium and testis. In most of these studies increasing IMD was found to have independent prognostic significance when compared to traditional prognostic markers by multivariate analysis. These reports are derived from numerous independent medical centres located around the world and these, as well as other evidence supporting the importance of tumour vascularity in the growth and spread of cancer, have been recently extensively reviewed [l]. Also, recent work, especially for prostate carcinoma, suggests that the assessment of IMD may first achieve widespread practical application in urogenital tract tumours. This review will focus on those studies of urogenital tract tumours wherein measuring tumour angiogenesis has been useful as a prognostic factor.

Assessment of urinary gonadotropin in solid carcinomas other than gynecological tumors

To the already long list of existing tumor markers, a new marker has been recently added, the urinary gonadotropin peptide (UGP). This marker is determined in the urine of cancer patients and is considered to be particularly specific for ovarian carcinomas. The purpose of our study was to assess the specificity of UGP in a variety of malignancies other than ovarian carcinomas, e.g., breast, colonic, lung, and urogenital tumors (n = 50 each). The tumors were compared with benign lesions of the same organs. Urine samples of 50 healthy donors served as controls. The 450 urine samples were tested in duplicate using the UGP EIA-kit from Ciba Corning Diagnostics. All tumors were staged and histologically classified. For normalization in all samples, creatinine levels were determined. UGP was found in all tested tumors, however, with very low sensitivity of 20% in urogenital tumors, 46% in lung, and 30% or 27% in colon and breast carcinomas, respectively. The specificity of UGP was comprised between 100% (breast) and 88%. Clearly elevated UGP-concentrations were seen in postmenopausal women. A comparison of UGP with the optimal markers for each tumor system showed that UGP is not superior to these markers. However, we can confirm UGP as being an optimal marker for gynecological carcinomas. © 1996 Wiley-Liss, Inc.

Basic fibroblast growth factor as a candidate tumor marker for renal cell carcinoma.

The present investigation was conducted to determine serum levels of basic fibroblast growth factor (FGF) by enzyme immunoassay in patients with various urogenital tumors. Renal cell carcinoma had a higher tendency (28 of 52, 53.8%) toward increased serum levels of basic FGF than any of the other urogenital tumors, and increased serum basic FGF was detected more frequently in patients with advanced renal cell carcinoma. Analysis of histological pattern indicated that renal cell carcinoma with a solid or tubular component is more likely to produce basic FGF. However, no significant difference was seen between the percentage of clear cell type tumor patients with increased serum basic FGF (50.0%) and the percentage of granular cell type tumor patients with increased serum basic FGF (66.7%). Five of 8 patients with renal cell carcinoma who underwent selective renal venous sampling before nephrectomy showed increased serum basic FGF in the renal vein from the affected kidney. After resection of the affected kidney to remove the cancer, serum basic FGF disappeared within 2 weeks. However, residual huge tumor or postoperative disease prolonged the increased levels of basic FGF in 2 patients, indicating that basic FGF is produced from and secreted by tumor tissue itself. These findings suggest that serum basic FGF can be useful in the diagnosis, and in evaluating the prognosis, of patients with renal cell carcinoma.

CLINICAL-EVALUATION OF SERUM BASIC FETOPROTEIN AS A MARKER IN UROGENITAL MALIGNANT-TUMORS

Serum basic fetoprotein (BFP) and other markers were assessed for use in urogenital malignant tumors. Useful in gastric, hepatic, pancreatic and mammary carcinomas, BFP is not very organ specific. Studies of its marker efficiency in urogenital tumors seem fitting. 190 untreated urogenital cancer patients were studied. Serum BFP was examined by EIA using a MoAb and compared with seven non-specific other cancer markers. Serum BFP efficiency in renal cell carcinoma was higher than TPA and lower than IAP and did not correlate with either; in seminoma it was lower than AFP and similar to beta-hCG; in prostatic carcinoma it was lower than PSA and higher than PAP and showed a comparatively stronger correlation with PSA. In three cancers it increased with tumor stage. Indispensable in diagnosing testicular tumors, some marker are, unlike BFP in our study, not effective in assessing and monitoring seminoma and are less efficient in the diagnosis of early prostatic carcinoma. A combination assay involving BFP and these antigens would be useful.

Sequential Changes in Stem Cell Markers in Peripheral Blood and Leukapheresis Samples after Injections of Recombinant Human Granulocyte Colony-stimulating Factor in Patients with Urogenital Malignant Solid Tumors: A Preliminary Study

In order to evaluate the mobilization effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on peripheral blood stem cells (PBSCs), rhG-CSF was given to patients with urogenital malignancy before chemotherapy. Markers for the stem cells, such as colony forming unit-granulocyte/macrophage (CFU-GM) and burst forming unit-erythrocyte (BFU-E), were sequentially monitored in peripheral blood and leukapheresis samples. Five patients, including a 13-year-old boy, were given 5 micrograms/kg rhG-CSF subcutaneously: the pediatric case for four consecutive days and the adult cases for six consecutive days (53-72 years of age). None of the patients had received chemotherapy within the four weeks prior to the start of the rhG-CSF series. PBSC collections were performed on the fifth day in the pediatric case and on the fifth and seventh days in the adult cases. Progenitor cells were monitored by methyl-cellulose cell culture techniques. CFU-GM on day 5 of the rhG-CSF series in peripheral blood increased 14- to 53-fold compared with samples taken immediately before the series. CFU-GM in the leukapheresis products on day 5 was greatest (70 x 10(3)/kg) in the pediatric case and least (14 x 10(3)/kg) in the oldest patient's case. The totals of the CFU-GM collected by two phereses in the adult cases were 21-73 x 10(3)/kg and the totals of CD34 positive cells were 0.6 to 1.4 x 10(6)/kg. The data suggest rhG-CSF to induce sufficient PBSCs for bone marrow rescue into the peripheral blood without any preceding chemotherapy. The patient's age may, however, be a contributory factor in using this method.

Bone Marrow Immunoscintigraphy versus Conventional Bone Scintigraphy in the Diagnosis of Skeletal Métastasés in Urogenital Malignancies

Bone marrow immunoscintigraphy using a 99mTc-labelled anti-NCA-95 monoclonal antibody and conventional bone scintigraphy with 99mTc-methylene-diphosphonate were compared in the diagnosis of skeletal metastases in 58 patients with urogenital tumours. In 13 patients with metastatic disease, bone marrow immunoscintigraphy proved to be superior to bone scintigraphy, detecting 431 metastatic lesions on immunoscans as compared to 261 lesions on bone scans. However, on a patient-by-patient basis bone marrow immunoscintigraphy did not demonstrate a clinical advantage over conventional bone scanning, as in this study no patient was identified with metastatic disease still confined to the marrow space, with bone scintigraphy and bone X-ray being normal.