Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy.

Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (≥30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with ≥30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with ≥30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC.

[Dementia with argyrophilic grains]. / Demenz mit argyrophilen Granula.

Dementia with argyrophilic grains (AG) is a neuropathologically defined potentially dementing disease of advanced age which was first described by H. and E. Braak in 1987. It is often combined with histopathological signs of Alzheimer's disease but has nevertheless to be considered as a distinct entity since pure bona fide cases have been reported. Clinically it may resemble either Alzheimer's or Pick's disease; it is almost exclusively confined to patients older than 60 years and progresses slowly but relentlessly. Repeatedly prominent behavioral disorders were pointed out. Useful therapeutic regimens are not available at present but acetylcholinesterase inhibitors have proven effective in some cases and amantadines as well as dopamine agonists hold some promise from a theoretical perspective, too. The diagnosis can be ascertained only by histopathological examination. For the clinician it is important to know that this disease is to be considered as an additional and differential diagnosis of both Alzheimer's disease and the frontotemporal dementias. It must be counted among the tauopathies. This review is supplemented by a detailed case report.

ErbB-2/HER-2 protein expression, serum tumour necrosis factor-alpha (TFM-alpha) and soluble tumour necrosis factor receptor-2 (TNFR-2) concentrations in human carcinoma of the uterine cervix.

The expression of erbB-2 protein (by immunohistochemistry), serum TNF-alpha, soluble TNF-receptor 2 (sTNFR-2, ELISA) concentrations and mitogenic (LPS, ConA, PHA) induced TNF-alpha production of the peripheral blood mononuclear cells (PBMNC) were studied in 91 (UICC Stage 1: 39, Stage 2: 33, Stage 3: 14, Stage 4: 5) patients with carcinoma of the uterine cervix. During a follow-up period of seven years 30 patients died (Stage 4: 5, Stage 3: 12, Stage 2: 11, Stage 1: 2). ErbB-2 protein expression was significantly more frequent in patients with UICC Stages 3-4 (14/19), and in those with fatal outcomes (14/30, p < 0.0001, chi-square test). Serum TNF-alpha (2.70 +/- 0.69 pg/ml) and sTNFR-2 (3.85 +/- 1.05 ng/ml) concentrations were significantly lower in cancer patients (p < 0.0001, Mann-Whitney test) as compared to 64 age-matched control women (TNF-alpha: 4.32 +/- 0.36, TNFR-2: 4.85 +/- 0.82). The mitogenic induced TNF-alpha production of PBMNC was also significantly less with all the three mitogens applied (LPS: 35.24 +/- 8.84, ConA: 26.28 +/- 7.81, PHA: 20.48 +/- 7.04 pg/l million of cells/24 hours, p < 0.0001) as compared to the controls (LPS: 65.33 +/- 8.82, ConA: 51.00 +/- 8.87, PHA: 41.80 +/- 9.01). Serum TNF-alpha, sTNFR-2 concentrations and the mitogenic induced TNF-alpha production of PBMNC was significantly decreased in patients with erbB-2 positivity as compared to those with negativity. In conclusion the expression of the oncoprotein and the lower levels of the members of the TNF system seem to be poor prognostic parameters in patients with carcinoma of the uterine cervix.

Calcium-sensing receptor A986S polymorphism in human rectal cancer.

BACKGROUND AND AIMS: In vivo and in vitro experiments show the protective role of calcium ions (Ca2+) against colorectal cancer. The calcium-sensing receptor (CaSR) detects extracellular Ca2+ concentration. An association between the CaSR A986S polymorphism and serum calcium in healthy adults has been reported. Subjects with AA genotype had lower serum concentrations of Ca2+ than other genotypes. The expression of erbB-2, epidermal growth factor receptor (EGFR), p53, and ras in colorectal cancer has been suggested to have diagnostic and prognostic significance. PATIENTS AND METHODS: We investigated the relationship between the CaSR A986S polymorphism and the expression of erbB-2, EGFR, p53, and ras as well as the UICC stage in 56 patients with rectal cancer. RESULTS: The occurrence of the genotype AA was not different in cancer patients and in 112 controls. In the presence of the coexpression of major oncogenes, patients with genotype AA were in significantly higher UICC stages than in the case of AS genotype. During the follow-up period AA genotype showed a tendency for poor prognosis. CONCLUSIONS: Our observation raises the possibility that genetic alterations of CaSR influence the pathogenesis of rectal cancer.

[The role of estrogen receptor, vitamin D receptor and calcium receptor genotypes in the pathogenesis of colorectal cancer]. / Osztrogén-, D-vitamin- és kalcium-érzékeló receptorok genotípusainak szerepe a colorectalis daganatok patogenezisében.

In this study, the Xbal polymorphisms of the estrogen-, the Bsml polymorphism of the vitamin D- as well as the A986S polymorphism of the calcium-sensing receptor genes were investigated in 56 patients with colorectal cancer. The expression of erbB-2, epidermal growth factor receptor, ras, p53 and their relationship to estrogen-, vitamin D- and calcium-sensing receptor genotypes were also studied. In subjects exhibiting XX genotype of the estrogen receptor gene or bb genotype of the vitamin D receptor gene, erbB-2 expression was significantly lower compared to those with xx, Xx or BB, Bb (6/56 and 11/56 vs. 31/56 and 26/56; p = 0.0043 and 0.041). The presence of the XX alleles of estrogen receptor gene significantly correlated with the overexpression of the epidermal growth factor receptor expression in tumors, whereas in xx and Xx genotypes, significantly higher expression was seen (7/56 vs. 30/56; p = 0.049). Analyzing the combinations of the two gene allelic variants, we have found XXbb genotype to be associated with a significantly lower erbB-2 expression, compared to other combinations (Xxbb, XxBb, XXBb) (2/7 vs. 7/7, 4/5, 4/5; p = 0.0011). Patients with AA calcium-sensing receptor genotype were in higher UICC stages at the time of discovery of their disease than those with AS genotype. The AA allelic variant of the calcium-sensing gene was more frequent among patients with colorectal cancer compared to controls (36/56 vs. 36/112; p = 0.0004). Our observations raise the possibility that estrogen-, and vitamin D receptor gene polymorphisms accompanied with variable oncogene expression might influence the pathogenic processes resulting in the development of colorectal cancer. The A986S polymorphism of calcium-sensing receptor might also be a prognostic marker of the disease.

Locoregional recurrence in patients with anastomotic leakage after anterior resection for rectal carcinoma.

OBJECTIVE: Anastomotic leakage is a serious complication after anterior resection for rectal carcinoma. It is controversial whether anastomotic leakage influences the rate of locoregional recurrence and therefore survival. PATIENTS AND METHODS: The data of 940 patients with invasive rectal carcinoma stage I-III treated by curative anterior resection from 1978 to 1996 at the Department of Surgery of the University of Erlangen were analysed. Patients who received neoadjuvant or adjuvant treatment were excluded as well as patients who died postoperatively. 89 out of 814 patients (10.9%) developed an anastomotic leakage after anterior resection. RESULTS: The rate of locoregional recurrence during the first five postoperative years of all patients was 13.6%. In patients with anastomotic leakage the rate of locoregional recurrence was 22.0%, significantly higher than in patients without anastomotic leakage which was 12.5%, (P=0.018). On multivariate Cox regression analysis anastomotic leakage was shown to be an independent risk factor for locoregional recurrence (relative risk: 1.7, CI 95%: 1.02-2.75, P=0.042). Also cancer-related survival was influenced significantly by anastomotic leakage in univariate analysis as well as in multivariate analysis (relative risk: 1.6, CI 95%: 1.1-2.2, P=0.017). CONCLUSION: Anastomotic leakage after anterior resection for rectal carcinoma is a risk factor for locoregional recurrence and decreases cancer-related survival.

Vitamin D receptor gene BsmI polymorphism correlates with erbB-2/HER-2 expression in human rectal cancer.

Apart from the regulation of calcium metabolism, 1, 25-dihydroxyvitamin D(3) plays an essential role in cell proliferation and differentiation in several tissues. The vitamin D receptor (VDR) gene shows polymorphisms in humans that appear to be clinically significant in some pathological conditions. In the present study, the BsmI polymorphism of the VDR gene was studied in 59 Caucasian patients with rectal cancer (mean follow-up: 48 months). The relationship between VDR genotypes and the expression of oncogenes as well as their influence on survival were also investigated. VDR polymorphism was examined in tumor and normal mucosa cells by PCR technique. The expression of erbB-2/HER-2, p53, ras and epidermal growth factor receptor (EGFR) was also detected by immunohistochemistry and protein blotting. The presence of the VDR B allele significantly correlated with the overexpression of the erbB-2 oncogene. There was no difference in the VDR genotype between cancer and normal mucosal cells. Coexpression of erbB-2, pan-ras, p53 and EGFR internal and external domains was significantly higher in cancer cells than in normal mucosa. There was no significant correlation between VDR genotypes and age, gender, tumor infiltration depth, number and site of lymph node metastases and lymphatic or blood vessel infiltration. The VDR genotype alone did not influence survival. Overexpression of erbB-2 and EGFR was associated with a poor prognosis. In patients expressing only one oncogene in cancer cells, the presence of the VDR B allele showed a tendency to a poor prognosis. In conclusion, VDR gene BsmI polymorphism might affect the development and prognosis of rectal cancer by influencing erbB-2 oncogene expression.

Lobular carcinoma of the breast in an 85-year-old man.

The present study describes a case of the extremely rare histological picture of a lobular carcinoma of the male breast. The 85-year-old patient presented with a tumour in a very advanced stage. The results of genetic studies excluded Klinefelter's syndrome, but a new gene mutation affecting the BRCA1 gene (breast cancer gene 1) was found in the patient.

Elevated serum TNF-alpha level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients.

AIMS: The aim of the study was to analyse the role of tumour necrosis factor-alpha (TNF-alpha) in insulin resistance and endothelial dysfunction in patients with different types of obesity. PATIENTS AND METHODS: Fasting serum TNF-alpha immunoreactive concentration (enzyme-linked immunosorbent assay, ELISA) and bioactivity (L929 cell cytotoxicity assay), endothelin-1 and C-peptide levels (radioimmunoassay, RIA) were measured in 15 patients with android- and 13 patients with gynoid-type obesity and 15 lean healthy controls with normal glucose tolerance and blood pressure. RESULTS: Significantly (P<0.01) higher TNF-alpha concentration (8.92 +/- 0.44 pg/ml) and bioactivity (3.12 +/- 0.48 U/ml) were found in patients with android obesity as compared to patients with gynoid obesity (7.01 +/- 0.30 pg/ml, 0.97 +/- 0.11 U/ml) and to the lean controls (6.88 +/- 0.26 pg/ml, 0.88 +/- 0.08 U/ml). Serum endothelin-1 (5.38 +/- 0.30 pg/ml) and C-peptide levels (4.82 +/- 0.71 ng/ml) were also significantly higher (P < 0.01) in patients with android-type obesity than in controls (3.89 +/- 0.43 pg/ml, 1.46 +/- 0.25 ng/ml, respectively). In patients with gynoid-type obesity, only the C-peptide levels proved to be significantly higher (2.84 +/- 0.29 ng/ ml). Endothelin-1 levels, although were found to be slightly higher, did not differ statistically from in controls (4.56 +/- 0.31 pg/ml). There were significant positive linear correlations only in patients with android-type obesity between TNF-alpha, body mass index (BMI), serum endothelin-1 and C-peptide levels. CONCLUSIONS: TNF-alpha may be one of the factors contributing to insulin resistance and vascular dysfunction in patients with android obesity.

Improvements in staging of gastric carcinoma from using the new edition of TNM classification.

AIMS: To recognize possible advantages of the 5th edition of TNM of gastric carcinoma in comparison to the former edition. METHODS: Data from Erlangen Cancer Center for 898 patients with gastric carcinoma treated surgically by total or subtotal gastrectomy with en bloc lymphadenectomy were analysed. RESULTS: The prognostic significance of TNM has been improved by the new edition as demonstrated by the likelihood ratio test. In addition, uncertainties of method in the pathological classification of regional lymph-node metastasis inherent in the 4th edition can now be avoided. CONCLUSION: The changes in the TNM classification introduced by the 5th edition are justified by data from the Erlangen Cancer Center, have methodic advantages in determining the N classification, and lead to an improvement in estimation of outcome.

Predictive value of nuclear beta-catenin expression for the occurrence of distant metastases in rectal cancer.

PURPOSE: Adenomatous polyposis coli protein, glycogen synthetase kinase-3-beta, T cell transcription factor/lymphoid enhancer-binding factor, and beta-catenin modulate cell differentiation and proliferation via the expression of effector genes. It has recently been postulated that beta-catenin is a potent oncogene of sporadic colorectal carcinogenesis and a prognostic tumor marker. Our aim was to investigate whether the nuclear overexpression of beta-catenin, possibly caused by mutations in exon 3 of beta-catenin (CTNNB1), is correlated with distant metastatic spread or disease-free survival in rectal carcinoma. METHODS: Immunohistochemical analysis was performed with an anti-beta-catenin-monoclonal antibody on paraffin sections of two groups of patients (n = 2 x 77) with rectal carcinoma curatively treated by surgery alone. The patients selected were all free of local disease, to exclude surgical influence. Patient groups were matched for age, gender, International Union Against Cancer stage, and year of operation (1982 to 1991) and differed only in subsequent metachronous distant metastatic spread. Follow-up was prospective (median, 9.6 years). Three staining patterns were defined: membranous (normal), diffuse cytoplasmic (pathologic), and intense nuclear staining (pathologic). When intense nuclear staining was defined, the specimen was microdissected. Then, DNA was isolated, polymerase chain reaction-amplified, and sequenced to detect mutations in exon 3. RESULTS: Nuclear overexpression of beta-catenin correlated neither with distant metastatic spread (chi-squared, 0.37; P = 0.79) nor with disease-free survival (log-rank with trend, P = 0.62). No mutations were found in the area of the serine/threonine-kinase glycogen synthetase kinase-3-beta-phosphorylation site in exon 3 (CTNNB1) of beta-catenin. CONCLUSION: Although beta-catenin seems to play an important role in early colorectal carcinogenesis, its value as a prognostic marker is questionable. It must be assumed that metastatic ability is determined by other factors than the disturbance of the beta-catenin T cell transcription factor/lymphoid enhancer-binding factor cascade and that other mechanisms might cause the observed nuclear translocation of beta-catenin.

DCC protein as a predictor of distant metastases after curative surgery for rectal cancer.

PURPOSE: The aim of this study was to determine the value of DCC (deleted in colorectal cancer) protein for predicting metachronous distant metastases after curative surgery for rectal cancer. The DCC protein--for which a gene has been located on chromosome 18q--has recently been reported to have a prognostic value in colorectal cancer. This finding might have implications for treatment of International Union Against Cancer Stage II rectal carcinoma, in which distant metastases will develop in 14 percent of patients despite optimal surgery. METHODS: Paraffin-embedded tissues from 85 patients who developed distant metastases, but no local recurrence, after curative surgery for rectal cancer were matched with 85 samples from patients who remained disease-free. Matching criteria were tumor stage, age, gender, and date of surgery. Expression of DCC protein was assessed using immunohistochemistry. End points of follow-up were recurrence of disease and death. Mean follow-up was 9.6 years. No patient received either local or systemic adjuvant therapy. RESULTS: The DCC protein was found to be expressed in 64.9 percent of tumor samples. Nonexpression of DCC protein had an negative influence on survival (P = 0.03). For all tumor stages together, sensitivity of the test for subsequent occurrence of distant metastases was 42 percent and specificity was 71 percent. In Stage II cancers, the positive predictive value was 19 percent, and the negative predictive value was 88 percent. CONCLUSIONS: Our results confirm that DCC protein is a useful prognostic marker in patients with rectal carcinomas, but the positive predictive value of DCC protein for occurrence of metachronous metastases does not appear to be sufficient to justify adjuvant therapeutic measures in Stage II rectal cancer.

Influence of surgery on metachronous distant metastases and survival in rectal cancer.

PURPOSE: Total mesorectal excision (TME) and other technical surgical factors reduce local recurrence rate in rectal cancer. Scientific evidence of the positive effect of optimal surgery on survival is locking. Whether a reduction in the incidence of distant metastases can be achieved with optimal surgery is uncertain. We examine the effects of the quality of surgery, as reflected by local recurrence rate, on survival and the incidence of initial distant metastases. PATIENTS AND METHODS: Between 1974 and 1991, 1,581 consecutive patients who underwent curative resection (RO) for rectal carcinoma were monitored for recurrence and survival. TME was introduced in 1985. No patient received adjuvant radiotherapy or chemotherapy. The median follow-up time was greater than 13 years. RESULTS: The local recurrence rate decreased from 39.4% to 9.8% during the study period (P < .0001). The observed 5-year survival rate improved from 50% to 71% (P < .0001). Three hundred six patients with local recurrence had a significantly lower observed 5-year survival rate (P < .0001). A total of 1,285 patients had no local recurrence, but 275 of them developed distant metastases (International Union Against Cancer [UICC] stage I, 8%; stage II, 16%; stage III, 40%). Better-quality surgery had no effect on the incidence of initial distant metastases, which remained constant (P = .44). CONCLUSION: Quality of surgery is an independent prognostic factor for survival in rectal cancer, but has no influence on initial occurrence of distant metastases. Local recurrence cannot be considered an outcome criterion of adjuvant treatment without consideration of the surgeon as a risk factor.

[Beta-catenin expression and its significance for metastasis in curatively operated rectum carcinoma]. / Beta-Catenin Expression und ihre Bedeutung für die Metastasierung beim kurativ operierten Rektumkarzinom.

Two selected groups of 77 patients each (matched for age, sex, UICC stage and year of surgery) were compared. All patients were curatively operated on for rectal cancer by surgery alone. All remained locally disease-free, differing only in distant metachronous metastatic spread. beta-Catenin expression was investigated using immunohistochemical methods. Overexpression of nuclear beta-catenin was not correlated with disease-free survival or distant metachronous metastasis. Thus, this potential oncogen cannot be used as a prognostic marker in rectal cancer. Additionally, in four cases of intense nuclear staining, after DNA isolation and sequencing of exon 3, which encodes for the GSK-3 beta phosphorylation site, no mutations could be detected.

[Advantages and limitations of intraoperative mechanical autotransfusion in al prostatectomies]. / Möglichkeiten und Grenzen der intraoperativen maschinellen Autotransfusion (MAT) bei radikalen Prostatektomien.

UNLABELLED: Intraoperative autotransfusion (MAT), preoperative autologous blood donation, and preoperative normovolaemic haemodilution are three different methods to avoid homologous blood transfusion during surgical procedures. The controversial use of MAT via cell saver in tumour surgery as well as contamination of the operative field with urine illustrate the particular difficulties of autologous blood transfusion in connection with radical prostatectomy. We investigated changes in the osmotic resistance of the retransfused red blood cells (RBC), bacterial contamination, changes in coagulation parameters, and the presence of tumour cells. PATIENTS AND METHODS: After written informed consent, 24 patients who presented for radical prostatectomy were randomly allocated to either a group that used MAT or a group that used homologous transfusion. The patients received "balanced anaesthesia" with midazolam, fentanyl, atracurium, and nitrous oxide/oxygen. The analysed parameters from the preoperative period to the 3rd postoperative day are shown in Table 1. The Haemonetics 3 Plus Cell Saver was used for autotransfusion. RESULTS: Our results showed that the haematologic parameters, coagulation factors, and serum chemistry did not differ between the two groups (Tables 2-4). However, there were significant differences during the investigated period. The osmotic resistance of the salvaged RBCs was higher than that preoperatively. Furthermore, there were no tumour cells in the autologous salvaged RBCs. CONCLUSION: Our results showed no decrease in the quality of the autotransfused RBCs, urine was not retransfused; and there were no significant differences between the groups postoperatively. Although there were no tumour cells in the salvaged blood, the possibility of blood irradiation is discussed. We concluded that because of the risk of infection of homologous blood products, MAT is a safe possibility to reduce the amount of homologous blood transfusion required in connection with radical prostatectomy.

Pathological features of rectal cancer after preoperative radiochemotherapy.

The standard therapy for rectal carcinoma is surgical, however, preoperative radiochemotherapy will play an increasing role especially in locally advanced disease. To estimate the prognosis and the effect of radiochemotherapy the postradiochemotherapeutical pathological features are important to assess. We examined the surgical specimens of 17 patients after preoperative radiochemotherapy to estimate and grade the histological reactions. A proposal for a grading system for tumor regression (not yet available in the literature) has also been described. All but one of the carcinomas showed different degrees of tumor regression. A total regression was not observed after standardised pathological work up. In only one case a locally curative resection was not possible. We think that preoperative radiochemotherapy is able to reduce tumor mass thus achieving operability in non-curatively operable cases. We recommend standards of pathological work up and regression grading for further studies comparing surgery and radiochemotherapy of rectal carcinoma.

Is local excision of pT1-ampullary carcinomas justified?

We propose that local excision of carcinomas of the ampulla of Vater is justifiable under the following conditions: when the tumour is limited to the ampulla of Vater as diagnosed by pre-operative endoluminal sonography (uT1) and UICC-staging (pT1); and when it is graded G1 or G2 and there is no lymphatic infiltration and the tumour is completely resected (R0). Under these conditions peri-operative morbidity and mortality were significantly reduced compared with more extensive surgery. There was no local recurrence of tumour in our study and long-term survival rates were comparable with Whipple's procedure. This implies that lymphatic spread is limited in localized disease and the feasibility of the proposed procedure may therefore be analogous to localized resections in other malignant tumours, e.g. carcinoma of the rectum.