Pineal parenchymal tumor of intermediate differentiation: diagnostic pitfalls and discussion of treatment options of a rare tumor entity

Tumors of the pineal region are uncommon, comprising approximately 0.4-1% of all intracranial tumors in adults in European and American series. Histopathologically, they are a very heterogeneous group of tumors. Of genuine pineal tumors, pineal parenchymal tumors of intermediate differentiation (PPTIDs) are the least frequently found type. In this paper, we report on the case of a patient with an unexpected and difficult-to-diagnose PPTID. A 2.2 x 2.2-cm midline mass within the posterior part of the third ventricle with consecutive obstructive hydrocephalus was found in a 44-year-old man presenting with diplopia and gait disturbances. There was no clear connection of the tumor to the pineal gland. Differential diagnosis included all intraventricular and midline tumors, therefore a biopsy was taken. Preliminary histopathological diagnosis was germinoma or primitive neuroectodermal tumor, and the tissue sample was reexamined by a referential neuropathological institute. Final diagnosis was PPTID. The tumor was then resected through a transventricular/transchoroidal approach. Histopathological examination of tumor specimen confirmed the diagnosis of a PPTID. Postoperatively, the patient received gamma-knife radiosurgery. At 1-year follow-up, there are no signs of tumor regrowth. Diagnosis of pineal parenchymal tumors in general and PPTIDs in particular can be troublesome. Their histopathological features are still being defined, as is the biological behavior of the different tumor entities. Thus, treatment options including surgery, radiation therapy, and chemotherapy remain controversial. We recommend surgical removal of PPTID, preferably in toto whenever the size of the tumor permits that kind of excision.

Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells

The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of inactive to active glucocorticoids. 11beta-HSD1 plays a crucial role in the pathogenesis of obesity and controls glucocorticoid actions in inflammation. Several studies have demonstrated that TNF-alpha increases 11beta-HSD1 mRNA and activity in various cell models. Here, we demonstrate that mRNA and activity of 11beta-HSD1 is increased in liver tissue from transgenic mice overexpressing TNF-alpha, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF-alpha-induced transcription of the 11beta-HSD1 gene (HSD11B1) in HepG2 cells. We found that TNF-alpha acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF-alpha in the proximal promoter region (-180 to +74). Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. Gel shift and RNA interference assays revealed the involvement of mainly C/EBPalpha, but also C/EBPbeta, in basal and only of C/EBPbeta in the TNF-alpha-induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPbeta on the proximal HSD11B1 promoter upon TNF-alpha treatment. In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. To our knowledge, this is the first study showing involvement of p38 MAPK in the TNF-alpha-mediated 11beta-HSD1 regulation, and that TNF-alpha stimulates enzyme activity in vivo.

Tumor suppressor and hepatocellular carcinoma

A few signaling pathways are driving the growth of hepatocellular carcinoma. Each of these pathways possesses negative regulators. These enzymes, which normally suppress unchecked cell proliferation, are circumvented in the oncogenic process, either the over-activity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective. The loss of several key tumor suppressors has been described in hepatocellular carcinoma. Here, we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.

Low-grade endometrial stromal sarcoma with inferior vena cava tumor thrombus and intracardiac extension: radical resection may improve recurrence free survival

BACKGROUND: Endometrial stromal sarcoma (ESS) represents 0.2% of all uterine malignancies. Based on the mitotic activity, a distinction is made between low and high-grade ESS. Although the overall five-year survival rate for low-grade ESS exceeds 80%, about 50% of the patients show tumor recurrence, mostly after a long latency period. Tumor invasion of the great vessels is extremely rare. We describe a patient with advanced low-grade ESS with tumor invasion of the infrarenal aorta and the inferior vena cava. The patient presented with a large tumor thrombus extending from the inferior vena cava into the right atrium. METHODS: Review of literature and identification of 19 patients, including our own case report, with advanced low-grade ESS with invasion of the great vessels and formation of an inferior vena cava tumor thrombus. RESULTS: All 19 patients presented with an abdominal tumor mass and a tumor thrombus protruding into the inferior vena cava. The tumor thrombus extended into the right heart cavities in nine patients reaching the right atrium in four, the right ventricle in three and the pulmonary artery in two patients. There were 5 patients with an advanced primary tumor and 14 patients with an advanced recurrent tumor. Seven patients presented with synchronous metastatic disease and six patients with a pelvic tumor infiltrating the bladder, the rectosigmoid colon or the infrarenal aorta. Mean age at surgery was 45.9+/-12.3 years (median 47, range 25-65 years). Tumor thrombectomy was accomplished by cavatomy or by right atriotomy after installation of a cardiopulmonary bypass. There was no peri-operative mortality and a very low morbidity. Radical tumor resections were achieved in 10 patients. The follow-up for these 10 patients was 2+/-1.3 years (median 2, range 0.3-4.5 years). Nine patients remained recurrence free whereas one patient suffered an asymptomatic local recurrence. CONCLUSIONS: Low-grade ESS is a rare angioinvasive tumor with a high recurrence rate. Resection of an inferior vena cava tumor thrombus, even with extension into the right heart cavities, can be performed safely. Extensive radical surgery is therefore justified in the treatment of advanced tumor manifestations of a low-grade ESS potentially improving recurrence free survival.

[Tumor surveillance after resection of colorectal cancer]

Because recurrent adenocarcinoma of the colon and rectum (CRC) can still be treated with acceptable 5-year survival rates, tumor surveillance plays an important role. Early detection of recurrent disease from CRC allows for effective treatment with intention for cure. This is why, in 2007, an interdisciplinary group modified the popular "FAGAS" criteria, a proposition for surveillance after curative resection of colorectal cancer. Proposed are the 3-monthly follow-up of the tumor marker CEA (carcino embryonic antigen), which, in case of lower sigmoid or rectal cancer, would be completed by rectosigmoidoscopy and endosonography every 6 months. As a major change liver sonography is now proposed to be replaced by annual thoraco-abdominal CT scan. Colonoscopy within the first year after resection has its place in the surveillance due to a high rate of metachronous secondary tumors missed in the initial endoscopy. Once completed it needs not to be repeated for at least 3 years. Only in cases where early stage CRC was been completely resected no schematic surveillance must take place.

TRAIL-induced apoptosis: between tumor therapy and immunopathology

The death ligand members of the tumor necrosis factor (TNF) family are potent inducers of apoptosis in a variety of cell types. In particular, TNF-related apoptosis-inducing ligand (TRAIL) has recently received much scientific and commercial attention because of its potent tumor cell-killing activity while leaving normal untransformed cells mostly unaffected. Furthermore, TRAIL strongly synergizes with conventional chemotherapeutic drugs in inducing tumor cell apoptosis, making it a most promising candidate for future cancer therapy. Increasing evidence indicates, however, that TRAIL may also induce or modulate apoptosis in primary cells. A particular concern is the potential side effect of TRAIL-based tumor therapies in the liver. In this review we summarize some of the recent findings on the role of TRAIL in tumor cell and hepatocyte apoptosis.

Immunological microenvironment in prostate cancer: high mast cell densities are associated with favorable tumor characteristics and good prognosis

BACKGROUND: Number of intratumoral mast cells predicts survival in various cancers. The prognostic significance of such mast cells in surgically treated prostate cancer is unknown. METHODS: Mast cell densities were determined in prostate cancer samples of more than 2,300 hormone-naïve patients using a tissue microarray format in correlation with clinical follow-up data. Mast cells were visualized immunohistochemically (c-kit). All patients were homogeneously treated by radical prostatectomy at a single institution. RESULTS: Mast cells were present in 95.9% of the tumor samples. Median mast cell number on the tissue spot was 9 (range: 0-90; median density: 31 mast cells/mm(2)). High mast cell densities were significantly associated with more favorable tumors having lower preoperative prostate-specific antigen (P = 0.0021), Gleason score (P < 0.0001) and tumor stage (P < 0.0001) than tumors with low mast cell densities. Prostate-specific antigen recurrence-free survival significantly (P = 0.0001) decreased with decline of mast cell density showing poorest outcome for patients without intratumoral mast cells. In multivariate analysis mast cell density narrowly missed to add independent prognostic information (P = 0.0815) for prostate-specific antigen recurrence. CONCLUSION: High intratumoral mast cell density is associated with favorable tumor characteristics and good prognosis in prostate cancer. This finding is consistent with a role of mast cells in the immunological host-defense reaction on prostate cancer. Triggering mast cell activity might expand immunotherapeutic strategies in prostate cancer.

Survival in surgically treated, nodal positive prostate cancer patients is predicted by histopathological characteristics of the primary tumor and its lymph node metastases

BACKGROUND: Histopathological risk factors for survival stratification of surgically treated nodal positive prostate cancer patients are poorly defined as reflected by only one category for nodal metastases. METHODS: We evaluated biochemical recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in 102 nodal positive, hormone treatment-naïve prostate cancer patients (median age: 65 years, range: 45-75 years; median follow-up 7.7 years, range: 1.0-15.9 years) who underwent radical prostatectomy and standardized extended lymphadenectomy. RESULTS: A significant stratification was possible, with the Gleason score of the primary and virtually all nodal parameters favoring patients with better differentiated primaries and metastases, lower nodal tumor burden, and without extranodal extension of metastases. In multivariate analyses, diameter of the largest metastasis (< or =10 mm vs. >10 mm) was the strongest independent predictor for RFS (P < 0.001), DSS (P < 0.001), and OS (P < 0.001) with a more than quadrupled relative risk of cancer related deaths for patients with larger metastases (Hazard ratio: 4.2, Confidence interval: 2.0-8.9; 5-year RFS/DSS/OS: 18%/57%/54%). The highest 5-year survival rates were seen in patients with micrometastases only (RFS/DSS/OS: 47%/94%/94%). CONCLUSION: The TNM classification's current allocation of only one category for nodal metastases in prostate cancers is unsatisfactory since subgroups with significantly different prognoses can be identified. The diameter of the patient's largest metastasis (< or =10 mm vs. >10 mm) should be used for substaging because of its independent prognostic value. The substage "micrometastasis only" is also useful in nodal positive prostate cancer since it designates the subgroup with the most favorable outcome.

Cytotoxic effects of camptothecin and cisplatin combined with tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) in a model of primary culture of non-small cell lung cancer

The cytokine tumor-necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has been shown to preferentially induce apoptosis in cancer cells. A previous study of our group demonstrated that non-small cell lung cancer cell lines can be sensitized to Apo2L/TRAIL-induced apoptosis by chemotherapeutic agents. The aim of the present study was the evaluation of these results in a model of primary culture of non-small cell lung cancer.

Transmembrane tumor necrosis factor alpha is required for enteropathy and is sufficient to promote parasite expulsion in gastrointestinal helminth infection

To study the specific role of transmembrane tumor necrosis factor (tmTNF) in protective and pathological responses against the gastrointestinal helminth Trichinella spiralis, we compared the immune responses of TNF-alpha/lymphotoxin alpha (LTalpha)(-/-) mice expressing noncleavable transgenic tmTNF to those of TNF-alpha/LTalpha(-/-) and wild-type mice. The susceptibility of TNF-alpha/LTalpha(-/-) mice to T. spiralis infection was associated with impaired induction of a protective Th2 response and the lack of mucosal mastocytosis. Although tmTNF-expressing transgenic (tmTNF-tg) mice also had a reduced Th2 response, the mast cell response was greater than that observed in TNF-alpha/LTalpha(-/-) mice and was sufficient to induce the expulsion of the parasite. T. spiralis infection of tmTNF-tg mice resulted in significant intestinal pathology characterized by villus atrophy and crypt hyperplasia comparable to that induced following the infection of wild-type mice, while pathology in TNF-alpha/LTalpha(-/-) mice was significantly reduced. Our data thus indicate a role for tmTNF in host defense against gastrointestinal helminths and in the accompanying enteropathy. Furthermore, they also demonstrate that TNF-alpha is required for the induction of Th2 immune responses related to infection with gastrointestinal helminth parasites.

FDG uptake in giant cell tumor of the tendon sheath in a patient restaged for gastrointestinal stroma tumor (GIST)

A 70-year-old man known for recurrent abdominal gastrointestinal stroma tumor presented with a suspicious peritoneal mass demonstrated by an abdominal CT scan. Whole-body PET showed focal FDG uptake in the right hip, whereas the peritoneal mass was FDG negative. Histologic work-up of the PET positive lesion surprisingly revealed a giant cell tumor of the tendon sheath. The benignity of the peritoneal mass was confirmed by its disappearance in repeated CT scans. In general, focally increased FDG uptake should be subject to further investigations, especially in localizations that are not consistent with typical metastatic pathways of the former primary tumor.

Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim

Apoptotic death of hepatocytes, a contributor to many chronic and acute liver diseases, can be a consequence of overactivation of the immune system and is often mediated by TNFalpha. Injection with lipopolysaccharide (LPS) plus the transcriptional inhibitor D(+)-galactosamine (GalN) or mitogenic T cell activation causes fatal hepatocyte apoptosis in mice, which is mediated by TNFalpha, but the effector mechanisms remain unclear. Our analysis of gene-targeted mice showed that caspase-8 is essential for hepatocyte killing in both settings. Loss of Bid, the proapoptotic BH3-only protein activated by caspase-8 and essential for Fas ligand-induced hepatocyte killing, resulted only in a minor reduction of liver damage. However, combined loss of Bid and another BH3-only protein, Bim, activated by c-Jun N-terminal kinase (JNK), protected mice from LPS+GalN-induced hepatitis. These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases.

EpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins

Specific delivery to tumors and efficient cellular uptake of nucleic acids remain major challenges for gene-targeted cancer therapies. Here we report the use of a designed ankyrin repeat protein (DARPin) specific for the epithelial cell adhesion molecule (EpCAM) as a carrier for small interfering RNA (siRNA) complementary to the bcl-2 mRNA. For charge complexation of the siRNA, the DARPin was fused to a truncated human protamine-1 sequence. To increase the cell binding affinity and the amount of siRNA delivered into cells, DARPin dimers were generated and used as fusion proteins with protamine. All proteins expressed well in Escherichia coli in soluble form, yet, to remove tightly bound bacterial nucleic acids, they were purified under denaturing conditions by immobilized metal ion affinity chromatography, followed by refolding. The fusion proteins were capable of complexing four to five siRNA molecules per protamine, and fully retained the binding specificity for EpCAM as shown on MCF-7 breast carcinoma cells. In contrast to unspecific LipofectAMINE transfection, down-regulation of antiapoptotic bcl-2 using fusion protein complexed siRNA was strictly dependent on EpCAM binding and internalization. Inhibition of bcl-2 expression facilitated tumor cell apoptosis as shown by increased sensitivity to the anticancer agent doxorubicin.