Biomedical subjects
Publications and source records attributed to Ingo Kausch.
We present a rare case of mesonephroid adenocarcinoma arising from mesonephroid metaplasia of the urinary bladder. For the first time, the unique histopathologic features in this patient provide evidence for the theory that vesical mesonephroid adenocarcinoma might be a highly aggressive metaplastic variant of urothelial carcinoma that should be treated accordingly.
OBJECTIVES: To determine whether clusterin immunoreactivity of muscle-invasive bladder carcinoma can predict disease-related survival of patients treated by radical cystectomy. METHODS: Multi-tissue arrays were constructed from 132 tumors and stained immunohistochemically using a mouse monoclonal antibody (clone 7D1). Positive clusterin staining was defined as immunoreactivity in more than 10% of tumor cells. We also studied tumor proliferation (Ki-67 antigen), p53, and Her2 expression. Immunoreactivity was compared with disease-related survival. Univariate and multivariate analyses were performed. RESULTS: Positive immunohistochemical clusterin expression was found in 25% of the tumors. On univariate analysis, clusterin immunoreactivity (P = 0.048), tumor stage (P = 0.011), nodal status (P = 0.0001), sex (P = 0.039), Ki-67 antigen index (P = 0.011), and Her2 expression (P = 0.020) were significantly associated with disease-related survival. On multivariate analysis, tumor stage (P = 0.01), nodal status (P = 0.0001), Ki-67 antigen (P = 0.0001), and Her2 expression (P = 0.001) were identified as significant independent predictive factors; clusterin expression missed the level of statistical significance by only a narrow margin (P = 0.058). CONCLUSIONS: Although clusterin immunoreactivity showed only a trend towards an independent prognostic relevance in this study, we conclude that it may be used, in addition to conventional and other immunohistochemical prognosticators, as a supplementary tool to provide more prognostic information in patients undergoing cystectomy for muscle-invasive bladder cancer.
In total, 70-80% of newly diagnosed bladder cancers are confined to the mucosa and staged as Ta, T1 or carcinoma in situ according to the 2002 tumor, lymph nodes and metastasis classification. The standard treatment for these nonmuscle-invasive bladder cancers is transurethral tumor resection with or without adjuvant intravesical chemotherapy or intravesical immunotherapy and subsequent follow-up. Diagnosis and follow-up of nonmuscle-invasive bladder cancer offers two main problems. First, approximately 10-20% of all tumors are not seen in standard cystoscopy. Additionally, frequently repeated follow-up cystoscopies are bothersome for the patient. As an adjunct to standard cystoscopy, fluorescence-guided cystoscopy has demonstrated significantly higher tumor detection rates and optimized patient treatment in recent Phase III studies. Second, routinely performed urine cytology is characterized by high specificity but low sensitivity. Today, several urine tests are available that may increase diagnostic accuracy and potentially prolong intervals of follow-up cystocopy. Owing to rather high recurrence rates after transurethral tumor resection in most tumors and high progression rates in poorly differentiated tumors, adjuvant intravesical chemotherapy or intravesical immunotherapy has gained widespread use in patients with nonmuscle-invasive bladder cancer. Only a few further immunomodulatory drugs, such as recombinant cytokines, have shown significant clinical effectiveness. Additional approaches, such as photodynamic therapy with different photosensitizers and thermotherapy in combination with intravesical chemotherapy, have been evaluated in Phase III studies.
OBJECTIVE: Overexpression of KIT (CD117), a tyrosine kinase receptor, has been reported in a variety of tumors, some of which are susceptible to therapy with imatinib mesylate. Our aim was to analyze KIT expression immunohistochemically in renal cell carcinomas (RCCs) and in oncocytomas. METHODS: Routinely processed, paraffin-embedded specimens from 61 RCCs and 13 renal oncocytomas were investigated immunohistochemically. Cytoplasmic and membrane-bound KIT staining of tumor cells was determined semiquantitatively. A subset of cases was additionally analyzed for point mutations of c-kit exon 17 by peptide nucleic acid-mediated nested polymerase chain reaction-clamping. RESULTS: All cases of oncocytomas and chromophobe RCCs showed membrane-bound KIT positivity, while about three-quarters of cases showed cytoplasmic reactivity. All other types of RCC were found KIT negative. Within the group of chromophobe RCCs, negative cytoplasmatic KIT reactivity was significantly correlated with advanced tumor stage (pT > or = 2; p = 0.036). Analysis of c-kit exon 17 revealed no 'gain-of-function' mutation like the codon 816 Asp-->Val mutation (D816V). CONCLUSIONS: KIT expression is a hallmark of oncocytoma and chromophobe RCC. Since all other types of RCC were found to be KIT negative, immunohistochemical KIT reactivity may be used as an additional diagnostic criterion to distinguish chromophobe RCC from other RCC types. KIT reactivity and the absence of c-kit mutation D816V in chromophobe RCC justify speculations that imatinib mesylate therapy could be effective in patients with advanced disease.
OBJECTIVE: To evaluate the prognostic impact of p16 immunoreactivity in minimally invasive transitional cell bladder carcinomas (stage T1). METHODS: Multi-tissue-arrays containing 73 samples of T1 bladder carcinomas were stained immunohistochemically for p16. Additionally, p53 and Ki-67 antigen expression were examined. A multivariate analysis including other prognostically relevant factors like tumor grade and sub-stage was performed. RESULTS: Loss of p16 expression occurred in 54% of cases and was significantly associated with reduced progression-free (p=0.018 by univariate analysis), but not with recurrence-free survival (p=0.341). Median Ki-67 antigen and p53 index were 51% (range, 1-93%) and 10% (range, 0-100%), respectively. Both indices correlated significantly (p=0.041 and p=0.024, respectively) with recurrence-free, but not with progression-free survival. Also tumor grade was significantly associated with tumor recurrence (p=0.006). By multivariate analysis, tumor grade (p=0.008) was identified as an independent predictor of tumor recurrence, whereas p16 expression (p=0.009) was identified as an independent predictor of tumor progression. CONCLUSION: According to our data, there is a significant correlation between loss of p16 expression and tumor progression in patients with minimally-invasive bladder cancer. Immunohistochemical p16 staining may therefore represent a useful tool of providing additional information on the clinical outcome of these patients.
We report the case of a papillary urothelial carcinoma associated with osteoclast-like giant cells. A 60-year old woman presented with hematuria. A papillary neoplasm was detected by cystoscopy and removed transurethrally. Histological examination revealed a papillary urothelial carcinoma (grade I) associated with multiple stromal giant cells, which displayed morphological, ultrastructural and immunohistochemical characteristics of osteoclast-like giant cells. The formation of osteoclast-like giant cells in association with urothelial bladder carcinoma is a rare event, of which only six cases have been reported in the Anglo-American literature. It may cause diagnostic problems because primary giant cell tumor, giant cell carcinoma and foreign body stromal reaction have to be considered. Immunohistochemistry and electron microscopy may help to rule out these differential diagnoses.
OBJECTIVE: To evaluate the effects of suppressing the expression of Ki-67 (expressed in proliferating cells) by antisense oligonucleotides (asON) directed against Ki-67 (which specifically inhibit the proliferation of tumour cells and tumour growth in cell culture and in subcutaneous murine tumour models) on the growth, cell viability and angiogenic activity of a preclinical renal cell carcinoma (RCC) severe combined immunodeficiency disease (SCID) mouse model. MATERIALS AND METHODS: Human RCC cells (SK-RC-35) were incubated with asON and control ON in the presence of a cationic lipid in monolayer cell culture. To test Ki-67 as a target for antitumour therapy in more complex models, asON were administered to three-dimensional RCC (SK-RC-35) spheroid cultures and to SCID mice bearing subcutaneous SK-RC-35 xenografts. For animal studies, 1 x 10(6) SK-RC-35 cells were implanted subcutaneously. Subsequently, asON or ON were injected intraperitoneally daily for 14 days at 10 mg/kg/day. Tumour size, weight and status of metastasis were documented daily and after death, respectively. The number of apoptotic cells, Ki-67-positive cells and the microvessel density in tumour sections was determined immunohistochemically. Quantitative reverse transcription-polymerase chain reaction of Ki-67 mRNA was also assessed for the tumours. RESULTS: Treatment of RCC cells with asON resulted in a specific inhibition of cell growth in monolayer and spheroid cell culture. Systemic administration of Ki-67-directed asON significantly decreased tumour growth (P = 0.009) in SCID mice. Immunohistochemical staining of tumour specimens showed stronger inhibition of Ki-67-positive cells in asON-treated tumours (mean 27.8%) than in controls (mean 42.5-57%). Furthermore, there were about twice as many apoptotic cells after asON treatment. There was no significant difference among treatment groups for microvessel density. CONCLUSION: These results indicate that Ki-67 represents a suitable antiproliferative target, and that asON are a potent agent inhibiting tumour growth and apoptosis, but not tumour vascularization, in human RCC.
E-cadherin is a transmembrane glycoprotein involved in intercellular adhesion. Abnormal (i.e., lost or decreased) expression of E-cadherin has been linked to invasiveness of many malignant tumors, including bladder carcinomas. To our knowledge, studies analyzing the prognostic impact of E-cadherin immunoreactivity especially in minimally invasive transitional cell bladder carcinomas (stage pT1) have not been published in the Anglo-American literature. In the present study, we immunostained 69 cases of pT1 transitional cell bladder carcinomas for E-cadherin using multitissue arrays. The results were compared with p53 and Ki-67 antigen immunoreactivity, clinicopathological parameters and the patients' outcome. E-cadherin immunoreactivity, which was found abnormal in 42% of cases, correlated significantly with substage (pT1a/pT1b; p=0.029) and p53 index (p=0.041) and tendentiously with Ki-67 antigen index (p=0.089) and age (p=0.07). By univariate Cox regression analysis, abnormal E-cadherin immunostaining correlated significantly (p=0.005) with early tumor recurrence, but not with early tumor progression (p=0.168). In a multivariate analysis, this parameter was identified, besides tumor grade (p=0.002), as an independent predictor of recurrence-free survival (p=0.016). Concerning tumor progression, age was identified as the single independent prognostic parameter (p=0.041), but E-cadherin immunoreactivity displayed a tendentious independent predictive value in this respect (p=0.071). We conclude from our data that immunohistochemical E-cadherin staining may provide additional prognostic information in patients with pT1 bladder carcinomas.
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In this paper, results from current randomized and other relevant studies on cytokine and vaccine therapy of kidney cancer in the adjuvant setting and in metastatic disease are reviewed. Improvement of medical therapy of kidney cancer is required since the relative 5-year survival of kidney cancer is only 62%. In the adjuvant setting, cytokine monotherapy (interferon [IFN]-alpha or interleukin [IL]-2) is not effective in improving progression-free or overall survival. Recently, an autologous kidney cancer cell vaccine has been shown to reduce the risk of tumor progression following radical nephrectomy for organ-confined or locally advanced kidney cancer in a randomized Phase III study. There were only a few vaccine-related side effects. Presently, this is the only promising approach for the adjuvant treatment of kidney cancer following nephrectomy. In metastatic kidney cancer patients with the tumor-bearing kidney in situ, a combination of radical nephrectomy plus IFN-alpha is more effective than IFN-alpha alone. In metastatic kidney cancer without the option of operative removal of the primary tumor and/or metastases, cytokines such as IFN-alpha, IL-2 and IL-12 and their combinations result in response rates of 10-30%, but the 5-year overall survival is less than 10%. Furthermore, the ideal dose, administration and combination of different agents are yet to be defined. Vaccine therapy of metastatic kidney cancer has been investigated only in Phase I and II studies with limited clinical benefit. Based on the current literature there is a clear need for new approaches in metastatic kidney cancer.
The Ki-67 protein is tightly regulated and depends on the proliferative status of a cell. It is present in the nuclei of proliferating cells but absent in resting cells. Since transformation of malignant cells is frequently associated with high cell proliferation and since proliferation is tightly associated with the Ki-67 protein labeling index, this antigen may represent a potential target for cancer therapy. In the present study we determined the ability of a phosphorothioate antisense oligodeoxyribonucleotide (ODN) targeted against Ki-67 mRNA to inhibit tumor cell proliferation specifically in cell culture, in multicellular 3-dimensional spheroids (MCS) and in subcutaneous murine tumor models. Antisense treatment of 1 myeloid and different epithelial tumor cell lines in suspension and monolayer culture, respectively, resulted in specific reduction of Ki-67 mRNA and protein, inhibition of proliferation and increased apoptotic cell death. Multicellular human bladder carcinoma spheroids lost their 3-dimensional structure and underwent cell death after incubation with antisense oligonucleotides. The growth of subcutaneous syngeneic prostatic (p = 0.05) and transitional cell tumors (p = 0.001) in immunocompetent mice was significantly inhibited in antisense-treated animals. From these findings we conclude that antisense inhibition of Ki-67 protein expression may be a rational approach in anticancer therapy.
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Modulation of gene expression using antisense oligonucleotides has advanced from the laboratory to the clinic. Numerous companies can, at least partially, attribute their success to the development of antisense techniques, and one antisense drug is currently on the market. Antisense compounds have been used in clinical trials that included patients with urologic tumors, mostly directed at proliferation- or apoptosis-related targets. Furthermore, therapeutic inhibition of many new identified genes is being investigated in preclinical tests. This review provides a contemporary overview of current preclinical and clinical antisense oligonucleotide concepts for the treatment of urologic tumors.
We report on the clinical, morphologic, immunohistochemical, ultrastructural, and molecular cytogenetic features of a primitive neuroectodermal tumor (PNET) primarily arising in the urinary bladder. An 81-year-old man presented with lymphedema of the lower extremities, fatigue, and urge incontinence. Radiographically, a tumor filling the entire cavity of the urinary bladder and extending into the pelvic and retroperitoneal tissue was noted. Histology of tumor biopsies showed a highly cellular, focally necrotic small round-cell tumor with numerous mitoses and occasional rosette-like structures. The tumor cells displayed significant immunoreactivity for neuron-specific enolase (NSE) and the MIC2 gene product (CD99). Dense-core granules were detectable by electron microscopy. A molecular cytogenetic analysis using comparative genomic hybridization (CGH) revealed gains of the chromosomes 3p, 6, 8q, 12, 17q, and 21q. The patient died two weeks after diagnosis. To the best of our knowledge, this is the fifth reported case of a PNET of the urinary bladder, and the first that includes a molecular cytogenetic analysis based on CGH.
Effective treatments are needed urgently for metastatic disease in bladder, prostate, and renal cell cancer. In the past few years, several new approaches for treating these conditions have been proposed, including gene therapy. A number of different strategies have been developed to accomplish urologic cancer gene therapy. Genetic immunomodulation strategies attempt to activate immune defense mechanisms against tumor cells by transfer of tumor antigens, cytokine genes, or strongly immunogenic cell surface molecules. In this review, we illustrate the recent developments in immune gene therapy.
BACKGROUND: Due to their variable clinical course, there is a need for new prognostic parameters in minimally invasive (stage T1) bladder carcinomas. MATERIALS AND METHODS: Using multitissue arrays, protein expression and gene copy numbers of topoisomerase (TOP2alpha), HER2 and p53 were investigated by immunohistochemistry and by fluorescence in situ hybridization (FISH) in 73 T1 tumors. The results were compared with tumor recurrence and progression. RESULTS: The median TOP2alpha and p53 index was 21% (range, 3-59%) and 7% (range, 0-93%), respectively. HER2 overexpression (score 3+) was detected in 9 cases (12%). High TOP2alpha and p53 indices and HER2 overexpression were significantly associated with earlier tumor recurrence, but not with earlier tumor progression. While TOP2alpha and p53 gene amplification was detected in no case, 5 cases (8%) showed HER2 gene amplification, which was related to HER2 3+ score in 4 cases. Loss of TOP2alpha, HER2 and p53 gene was observed in 4 (8%), 8 (13%) and 6 cases (12%), respectively. By univariate analysis, TOP2alpha index (p=0.0267), HER2 score (p =0.028) and p53 index (p=0.0188) were significantly and loss of TOP2alpha gene (p=0.0575) tendentially correlated with tumor recurrence, while loss of HER2 gene (p=0.069) and loss of p53 gene (p=0.0587) were tendentially correlated with tumor progression. In a multivariate analysis, which also included tumor grade and T1 substage, TOP2alpha index (p=0.043) and p53 index (p=0.02) were identified as independent predictors of tumor recurrence and loss of p53 gene (p=0.012) and T1 substage (p=0.029) as independent predictors of tumor progression. CONCLUSION: Immuno-histochemical TOP2alpha and p53 staining as well as FISH analysis of p53 gene copy numbers and T1 substaging are helpful means of providing additional information on the biological behavior of T1 transitional cell carcinomas.