[Papillary tumors - therapeutic concepts]. / Papillentumoren - therapeutische Konzepte.

Papillary tumors originate from the various structures of the ampulla of Vater; therefore, these rare tumors represent a heterogeneous group of tumor entities. Intestinal differentiated adenomas are the most common benign lesions, whereas intestinal differentiated papillary carcinomas are the most common malignant tumors. Carcinomas with pancreaticobiliary differentiation have a poorer prognosis. Mesenchymal and neuroendocrine tumors are among the least frequent papillary tumors. Diagnosis is performed by side-view upper endoscopy and biopsy. In cases of suspected malignancy a complete staging with computed tomography (CT) and endoscopic ultrasound scanning is indicated to determine local tumor spread.Adenomas are removed by endoscopic snare papillectomy whereas the therapy of choice for papillary carcinomas is pancreatic head resection with systematic lymphadenectomy. Patients with papillary carcinomas are most likely to benefit from adjuvant therapy, which should be determined in an interdisciplinary consensus conference considering the histological differentiation of the tumor.

[Inflammation as molecular target in chondrosarcoma]. / Inflammation als molekulares Target im Chondrosarkom.

Inflammation is a hallmark in the development and progression of malignant tumors. In chondrosarcoma the inflammatory changes are relatively discrete; however, tumor-associated macrophages (TAM) may exert tumor-promoting effects. Interleukin (IL)-1 is an inflammatory cytokine which is produced by TAMs and which leads to the expression of NF-κB-regulated genes in chondrosarcoma cells, such as vascular endothelial growth factor A (VEGF-A). Through IL-1 antagonists and substances, such as curcumin IL-1-induced VEGF-A expression and angiogenesis can be blocked; therefore, IL-1-blockade provides an interesting therapy target for chondrosarcoma.

BRCA1 promoter methylation is a marker of better response to platinum-taxane-based therapy in sporadic epithelial ovarian cancer.

BACKGROUND: The aim of the current study was to investigate the role of BRCA1 promoter methylation as predictive factor of response to platinum-taxane-based therapy in sporadic ovarian cancer. PATIENTS AND METHODS: BRCA1 promoter methylation was analyzed in 42 sporadic epithelial ovarian cancers. The results were validated in a second cohort of 137 ovarian cancer patients. RESULTS: BRCA1 promoter methylation was observed in 35.7 % of patients in the first group and in 33.6 % in the second group. BRCA1 promoter methylation was associated with significant increase in median progression-free survival (PFS) of ovarian cancer patients receiving adjuvant platinum-taxane-based chemotherapy (P = 0.008). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to PFS (HR 0.52; 95 % CI 0.32-0.85, P = 0.009) after adjustment for other prognostic factors. Under the patients with recurrent disease, BRCA1 promoter methylation was associated with significant longer median PFS of 18.5 months in comparison with 12.8 months PFS for patients without BRCA1 promoter methylation. CONCLUSIONS: BRCA1 promoter methylation is predictive for better response to platinum-taxane-based therapy in EOC.

BRCA1 promoter methylation is a marker of better response to anthracycline-based therapy in sporadic TNBC.

The aim of the current study was to investigate the role of BRCA1 gene aberrations in sporadic triple-negative breast cancer (TNBC) and its impact on anthracycline-based therapy. BRCA1 promoter methylation was analyzed in 70 TNBC and compared with the clinical and pathologic characteristics. As a control group, we used 70 patients with non-TNBC. BRCA1 promoter methylation was observed in 65.2 % of patients and was similar in both groups. BRCA1 promoter methylation was associated with decreased intensity of BRCA1 protein expression (P = 0.002) and significant increase of median disease-free survival (DFS) of TNBC patients receiving adjuvant anthracycline-based chemotherapy (P = 0.001). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to DFS (HR 0.224; 95 % CI 0.092-0.546, P = 0.001) in TNBC after adjustment for other prognostic factors. In contrast, in non-TNBC, BRCA1 promoter methylation was not associated with any clinical and pathologic parameters. BRCA1 promoter methylation is a common mechanism of BRCA1 gene aberration in sporadic breast cancer and is predictive for better response to anthracycline-based therapies.

Interlamellar cohesion after corneal crosslinking using riboflavin and ultraviolet A light.

AIMS: Collagen crosslinking treatment of progressive keratoconus using the photosensitiser riboflavin and ultraviolet A light of 370 nm wavelength has been shown to increase significantly the tensile strength of corneal collagen by about 300%. In keratoconus, interlamellar and interfibrillar slippage have been proposed as pathogenetic mechanisms. Therefore, the aim of this study was to assess the impact of collagen crosslinking on the interlamellar cohesive force. METHODS: 72 post mortem porcine eyes were divided into six different treatment groups: the untreated control group, the standard crosslinking group, the hypo-osmolar crosslinking group, the stromal swelling group, the formaldehyde group and the α-amylase group. An anterior 9×4 mm strip of 400 µm thickness was prepared using a lamellar rotating microkeratome. For interlamellar cohesive force measurements a splitting plane was created at 50% depth. Force-distance profiles were recorded using a microcomputer-controlled biomaterial testing machine. RESULTS: The mean interlamellar cohesive force was 0.24 N/mm in the untreated control group, 0.26 N/mm in the standard crosslinking group, 0.25 N/mm in the hypo-osmolar crosslinking group, 0.23 N/mm in hydrated corneas, 0.27 N/mm in the formaldehyde group without statistically significant difference. Only the values of the α-amylase group were statistically significantly lowered by 31.5% to 0.16 N/mm. CONCLUSIONS: Surprisingly, corneal crosslinking does not increase the interlamellar cohesive force. In the α-amylase group the cohesive force was mainly decreased because of the digestion of proteoglycans. Crosslinking seems to stabilise only inter- and intrafibrillar, but not interlamellar cohesion.

[Unilateral papilledema with contralateral loss of vision]. / Einseitiges Papillenödem und kontralateraler Visusverlust.

A 46-year-old woman presented with a 4-day history of headache, dizziness and blurred vision in the left eye and a 1-year history of neck pain. Fundoscopy revealed a pale optic disc in the left eye and a swollen optic disc in the right eye. Furthermore a bilateral anosmia was evident. Cranial magnetic resonance imaging (MRI) showed a mass in the anterior cranial fossa, which was classified as a WHO grade I endotheliomatous meningeoma. A Foster Kennedy syndrome was diagnosed.

[Angiogenesis in cartilage tumors]. / Angiogenese in Knorpeltumoren.

In contrast to normal cartilage, which is avascular, angiogenesis is characteristic of cartilage tumors. In this review, we outline the basic principles of angiogenesis with regard to recent findings on differential morphological and molecular aspects of angiogenesis in cartilage tumors, including enchondromas, conventional chondrosarcomas and dedifferentiated chondrosarcomas. Furthermore, we describe the effects of hypoxia and interleukin-1ß on angiogenic signaling in chondrosarcoma cells.

COX-2 expression in chondrosarcoma: a role for celecoxib treatment?

Chondrosarcomas are resistant to conventional chemo- and radiotherapy. A subset of chondrosarcomas arises secondarily in the benign tumour syndromes enchondromatosis (EC) and multiple osteochondromas (MO), and prevention of tumour development would greatly improve prognosis. We therefore investigated the effect of selective COX-2 inhibition on chondrosarcoma growth. COX-2 expression was studied in central- and peripheral cartilaginous tumours. The effect of COX-2 inhibition was assessed in four high-grade chondrosarcoma cell lines using celecoxib and NS-398 treatment. COX-2 activity (prostaglandin E(2) (PGE(2)) ELISA) and cell viability were measured. The (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo was studied for 8 weeks using a xenograft model of cell line CH2879 in immunoincompetent nude mice. High COX-2 protein expression was mainly found in solitary peripheral chondrosarcoma and in enchondromatosis-related central chondrosarcoma, which was confirmed by qPCR. After 72h of celecoxib treatment, a significant decrease in cell viability was observed in three chondrosarcoma cell lines. In vivo, celecoxib initially slowed tumour growth in chondrosarcoma xenografts; however, after prolonged treatment relapsed tumour growth was observed. Tumour volume was negatively associated with celecoxib serum levels, and seemed smaller in the high-dose prophylactic treatment group. We confirmed the expression of COX-2 in 65% of chondrosarcomas, and COX-2 inhibition by celecoxib diminished cell viability in vitro. The initial response and the decrease in tumour volume with increased celecoxib serum levels in vivo supported a role for celecoxib, although relapsed tumour growth after 6 weeks was worrisome. Also the role of high-dose prophylactic celecoxib in preventing the development of benign and malignant cartilage tumours in EC and MO patients deserves further investigation.

[Unusual myopic fundus alteration]. / Ungewöhnliche myope Fundusveränderung.

A 44-year-old female patient reported a "black dot" which had been in front of the right eye for more than 4 days and which moved together with eye movements. The optical coherence tomography (OCT) image of the right macula showed large cystic cavities and thickening within the retinal pigment epithelium (RPE) near the fovea centralis as well as small bore cystic alterations, which indicated an event in the region of the choroid. Fluorescein angiography and indocyanine green angiography excluded choroidal neovascularization (CNV). The diagnosis revealed a broad superficial choroidal blood vessel mimicking a subretinal hemorrhage.

[Rare neuroendocrine carcinoma of the gall bladder. Coincidental occurrence of an endometrioid ovarian adenocarcinoma]. / Seltenes neuroendokrines Karzinom der Gallenblase. Abgrenzung zur metachronen Koinzidenz mit einem endometrioiden Adenokarzinom des Ovars.

HISTORY AND CLINICAL FINDINGS: The histological investigation of a surgical specimen (after cholecystectomy) from a 73-year-old woman revealed a poorly differentiated carcinoma with glandular structures and a lymph node metastasis. INVESTIGATIONS: Comparative immunochemistry, done to exclude metastatic growth of the previously demonstrated endometrioid ovarian carcinoma, was (1) negative for CK7 and CA125, positive for CK20, chromogranin A and synaptophysin (gall bladder and lymph node metastasis); (2) positive for CK7 and CA125, negative for CK20, chromogranin A and synaptophysin (ovary). DIAGNOSIS: The tumor lesion within the gall bladder and lymph node was classified as a neuroendocrine carcinoma, not a metastasis of the ovarian carcinoma. TREATMENT AND CLINICAL COURSE: The patient underwent another laparotomy with resection of the stump of the cystic duct and the liver parenchyma surrounding the former gall bladder, including dissection of the lymph nodes within the hepatoduodenal ligament. After 14 months another metastasis of the neuroendocrine carcinoma of the gall bladder was found. But for eight years there has been no recurrence of the endometrioid adenocarcinoma of the left ovary. CONCLUSION: Because of the increasing incidence of malignant diseases and second neoplasms there is a growing need for such diagnostic tests as histological and immunohistochemical analysis. This is the first case, according to the available literature, of an endometrioid adenocarcinoma of the ovary concomitant with a neuroendocrine carcinoma of the gall bladder.

PLAG1 activation in lipoblastoma coinciding with low-level amplification of a derivative chromosome 8 with a deletion del(8)(q13q21.2).

Lipoblastoma is a benign uncommon soft-tissue-tumor resembling fetal adipose tissue affecting mainly children under three years of age. In lipoblastoma, the typical cytogenetic changes are clonal rearrangements involving chromosomal region 8q11-->q13. The oncogene PLAG1 (pleomorphic adenoma gene 1) is located within this chromosomal region on band 8q12. Recent reports have demonstrated that in lipoblastoma, the PLAG1 gene is activated by 'promoter-swapping'. Herein, we demonstrate that in lipoblastoma, the PLAG1 gene may also be activated by low-level amplification. We report on a lipoblastoma with the karyotype 48 approximately 50,XX,del(8)(q13q21.2),+del(8)(q13q21.2)x4[cp12]. Subsequent FISH analysis on uncultured tumor cells confirmed this result and demonstrated a low-level amplification of the chromosomal region 8pter-->8q13 and 8q21.2-->8qter. A partial monosomy was seen for the chromosomal region 8q13-->8q21.2. No other gains or losses were observed by CGH analysis. RT-PCR analysis showed that the PLAG1 gene is activated in the tumor sample of the lipoblastoma analyzed, in contrast to normal fatty tissue without PLAG1 expression. In conclusion, our results demonstrate that low-level amplification is a further mechanism of PLAG1 activation in lipoblastomas.

Distribution of sex chromosomes in dysgenetic gonads of mixed type.

In a four-week-old child with female external and internal genitalia but with clitoris hypertrophy chromosome analysis from blood lymphocytes revealed a 46,XY karyotype. No deletion of Y chromosomal sequences was detected by PCR analysis of genomic DNA isolated from peripheral blood leucocytes. Because of the increased risk for gonadal tumours, gonadectomy was performed. Conventional cytogenetic analysis of the left dysgenetic gonad revealed a gonosomal mosaicism with a 45,X cell line in 27 of 50 metaphases. The dysgenetic left gonad demonstrated a significantly higher proportion (P = 0.005) of cells carrying a Y chromosome (46.3%) than the streak gonad from the right side (33.9%). Histomorphological examination of the left gonad revealed immature testicular tissue and rete-like structures as well as irregular ovarian type areas with cystic follicular structures. Interphase FISH analysis of the different tissues of this dysgenetic gonad demonstrated variable proportions of cells with an X and a Y chromosome. Whereas Sertoli cells and rete-like structures revealed a significantly higher proportion of XY cells in relation to the whole section of the dysgenetic gonad (P < 0.0001), almost all granulose-like cells carried no Y chromosome. The proportion of XY/X cells in theca-like cells and Leydig cells was similar to that of the whole dysgenetic gonad. In contrast to these findings, spermatogonia exclusively contained an XY constellation.

[Idiopathic retroperitoneal fibrosis (Ormond's disease)]. / Die idiopathische retroperitoneale Fibrose (Morbus Ormond).

INTRODUCTION: Idiopathic retroperitoneal fibrosis (RPF) represents a rare inflammatory disease, which leads to extensive fibrosis of the retroperitoneal space. In the course of the progressive fibrosis, fibrous tissue compresses the retroperitoneal structures with the development of consecutive ureteral obstruction. Because of the unknown aetiology, no consensus between conservative and surgical treatment exists. CASE REPORT: A 60-year-old patient was admitted to hospital with left-sided flank pain, hydronephrosis, and retroperitoneal tumour. A CT scan-guided biopsy revealed RPF. The hydronephrosis was treated by endoluminal urinary diversion. Under simultaneous administration of steroids, an almost complete regression of the RPF was noted. CONCLUSIONS: First goal in the treatment of RPF is urinary diversion to protect the renal function. A simultaneous therapy with steroids can cause a complete regression of the RPF. Surgical intervention is only recommended in refractory cases.

[Distant metastases on acinic cell carcinoma of the parotid gland after 12 years symptom-free interval]. / Fernmetastasierung eines Azinuszellkarzinoms der Parotis nach 12-jährigem krankheitsfreien Intervall.

Acinic cell carcinoma of parotid gland as cause of distant metastases are rare. The patient was a 60-year-old woman who had in 1993 a acinic cell carcinoma of right parotid gland. Tumour can be resected through total parotidectomy with facial nerve anastomosis and modified radical neck dissection (T (3) N (2b) M (0)). Since the operation the patient has remained symptom-free without any sign of tumour recurrence. After 12 years the patient noted swelling in the region of sternum and biopsy was necessary. Histologically and immunohistochemically the diagnosis of distant metastase on acinic carcinoma of the parotid gland was confirmed.

[Multicentric extra-abdominal fibromatosis: a rare case]. / Multizentrische extraabdominale Fibromatose -- ein seltener Fall.

Extra-abdominal aggressive fibromatosis is a benign fibroblastic neoplasia with an infiltrative nature and a high tendency of local recurrence. Here, we report on a very rare case of multicentric fibromatosis. Low complaints led to considerable size of the tumours. The aim of the multimodal treatment was a limb salvage procedure. Adjuvant radiation therapy and chemotherapy was necessary because of the renunciation of wide resections in favour of the functionality of the limb.

Long-term remission in a patient with carcinoma of unknown primary site.

BACKGROUND: Cancer of unknown primary site also designated as CUP syndrome usually presents as metastatic disease with a poor prognosis and low remission as well as survival rates. CASE: We report a 46-year-old male with para-aortal and left-sided cervical lymph node metastases. Histological examination of a cervical lymph node revealed papillary carcinoma. Despite thorough investigation, no primary tumor was found. The patient was empirically treated with six courses of the FACP regimen (5-fluorouracil, Adriamycin, cyclophosphamide and cisplatin) combined with radiotherapy (40 Gy) and has remained in complete remission for 124 months. CONCLUSION: This case indicates that treatment of a patient with cancer of unknown primary site may be rewarded by a benign course. However, complete cure remains a very rare event in CUP. Remission can be achieved with a platinum-containing regimen combined with radiotherapy.

Spontaneous malignant transformation of conventional giant cell tumor.

Spontaneous malignant transformation of conventional giant cell tumor (GCT) of bone is exceedingly rare. We report on a case of GCT of the iliac crest in a 35-year-old woman with malignant change into a high-grade osteosarcoma 10 years after the first appearance of GCT on a radiograph. Since the patient refused therapy for personal reasons the tumor remained untreated until sarcomatous transformation occurred. Image cytometry showed DNA aneuploidy and a suspiciously high 2c deviation index (2cDI) in the primary bone lesion. A thorough review of the world literature revealed only seven fully documented cases of secondary malignant GCT which matched the definition of a "sarcomatous growth that occurs at the site of a previously documented benign giant cell tumor" and not treated by radiotherapy. These cases as well as the current one suggest that a spontaneous secondary malignant GCT presents as a frankly sarcomatous tumor in the form of an osteosarcoma or malignant fibrous histiocytoma. It usually appears at sites of typical GCTs-often without any recurrent intermediate state-and is diagnosed 3 or more years after the primary bone lesion. The prognosis is poor.

Topotecan (Hycamtin) responsiveness in human renal carcinoma cell lines of the clear cell and papillary types.

BACKGROUND: Since no effective therapeutic approach is yet known for metastatic renal cell carcinoma (RCC), we analyzed the effects of topotecan (Hycamtin), a novel topoisomerase I-inhibitor, in RCC cell lines of the clear cell and papillary/chromophilic types. MATERIALS AND METHODS: The anti-proliferative and apoptosis-inducing effects of topotecan were analyzed in 20 RCC cell lines by MTT-assay and light microscopic apoptosis counting. Moreover, Bcl-2 and Bax expression was investigated by Northern blot and immunocytochemistry while the p53 mutation status was analyzed by DNA sequencing. RESULTS: Exposure to clinically relevant concentrations of topotecan (i.e. < or = 1 microg/ml) resulted in a significant (p<0.05) dose-dependent reduction of cell number in 17 out of 20 RCC cell lines. The reduction of cell number was paralleled by an increase in apoptotic cell death. Papillary/chromophilic RCCs exhibited a significantly (p<0.05) more pronounced responsiveness to topotecan than clear cell RCCs. Moreover, the effects of topotecan proved to be superior to those of 5-fluorouracil (5-FU), an anticancer drug currently used in the therapy of RCCs. No correlation became evident between responsiveness to topotecan and the expression levels of Bcl-2 and Bax. Moreover, the response to topotecan could not be correlated with the p53 mutation status of our RCC cell lines. CONCLUSION: Clinically relevant concentrations of topotecan induced apoptosis in RCC cell lines more effectively than 5-FU. Further testing will show whether topotecan-induced apoptosis can be exploited for the treatment of RCCs in vivo as well.

Deficient activation of CD95 (APO-1/Fas)-mediated apoptosis: a potential factor of multidrug resistance in human renal cell carcinoma.

The pronounced resistance of human renal cell carcinoma (RCC) to anticancer-induced apoptosis has primarily been related to the expression of P-glycoprotein and effective drug detoxification mechanisms. Because the CD95 system has recently been identified as a key mediator of anticancer drug-induced apoptosis, we analysed the contribution of the CD95 system to chemotherapy-induced apoptosis in four newly established RCC cell lines. Here, we demonstrate that all RCC cell lines expressed CD95-receptor and -ligand. Exposure to agonistic anti-CD95 antibodies resulted in induction of apoptosis and significant (P < 0.05) reduction of cell number in three out of four cell lines, indicating that the essential components for CD95-mediated apoptosis were present and functionally intact in the majority of these RCC cell lines. Moreover, treatment of cultures with bleomycin or topotecan, a novel topoisomerase I inhibitor with little substrate affinity for P-glycoprotein, led to induction of apoptosis and significant (P < 0.05) dose-dependent reduction of cell number in all RCC cell lines. Both anticancer drugs also induced upregulation of CD95 ligand expression in all cell lines. Additionally, augmentation of CD95 receptor expression was found in three RCC cell lines, including one p53-mutated cell line, whereas another p53-mutated cell line showed no or only a weak CD95 receptor upregulation after exposure to topotecan or bleomycin, respectively. Despite this upregulation of CD95 receptor and ligand, antagonistic antibodies directed against CD95 receptors or ligands could not inhibit induction of apoptosis by topotecan and bleomycin in any cell line. Thus, although a functionally intact CD95 signalling cascade is present in most RCC cell lines, the anticancer drugs topotecan and bleomycin that induce upregulation of CD95 receptor and ligand fail to effectively activate CD95-mediated apoptosis. This deficient activation of CD95-mediated apoptosis might be an important additional factor for the multidrug resistance phenotype of human RCCs.