Primary aspergillosis of the sphenoid sinus with pituitary invasion – a rare differential diagnosis of sellar lesions

Summary Aspergillosis belongs to the group of mycotic diseases of paranasal sinuses. The invasive forms, and particularly the fulminant forms, are potentially fatal. Isolated aspergillosis of the sphenoid sinus or the clivus is a difficult diagnosis, since the often misleading clinical manifestations of this rare disease develop late. These patients become apparent by neurological signs such as cavernous sinus syndrome, pseudotumor of the pituitary or the orbit. Diagnosis is often made intra-operatively or on histological examination. We report a case of invasive aspergillosis uniquely involving the sellar area revealed by clinical features suggesting a pseudotumor of the pituitary. Although such lesions are almost always seen in immune suppressed subjects, in our case, the patient was immune competent and had no past history of sinusitis. The question of whether, and when to perform limited or extensive surgery remains an issue for discussion, owing to the rarity of this disease honed by lack of experience. It depends on several factors: the kind of disease, the immunity, the subtype of invasive fungal sinusitis and the degree of tissue invasion.     

Within-gene interaction between c.135 G/A genotypes and RET proto-oncogene germline mutations in HSCR families.

Hirschsprung disease (HSCR) is considered a model for a complex inheritance disorder. Several genes, including the major HSCR-susceptibility RET proto-oncogene, play an aetiological role in the development of HSCR. Genetic linkage analysis in familial HSCR with both long- and short-segment phenotypes has demonstrated a tight linkage to the RET locus, while the phenotype within a HSCR family is characterised by an incomplete penetrance or a variable extension of the aganglionosis. Therefore, additional genetic alterations of RET are postulated in the aetiology or modification of the HSCR phenotype. In this study, the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, were investigated by direct DNA sequencing in a HSCR population. We genotyped the c.135 G/A polymorphism and resolved haplotypes comprising the mutation locus and the c.135 G/A polymorphism. Twenty different mutations were detected in 18 of 76 HSCR patients. In ten families the mutations were inherited from the parents, while only four patients had a positive family history for the disease. Moreover, in all ten families an incomplete penetrance of the HSCR phenotype was observed. We have investigated the effect of the non-mutated wild-type allele as well as the c.135 G/A polymorphism on the phenotype within the HSCR families. Our findings support the notion that both RET alleles are involved in the pathogenesis of a subgroup of HSCR patients in a dose-dependent fashion. Additionally, we have shown a modifying effect of the c.135 G/A polymorphism on the HSCR phenotype within HSCR families.     

Ergebnisse der strukturierten Konsensuskonferenz „Bild gebende Verfahren in der Unfallchirurgie“ und Methodik zur Messung der Akzeptanz unter Tagungsteilnehmern

Existing knowledge and present experience relating to the indications for imaging techniques in trauma surgery were summarised, screened and considered in different ways by representatives of various professional scientific bodies, with the aim of finding what procedures should be implemented as the primary examination techniques after a careful clinical examination when particular posttraumatic situations affecting the knee, foot, ankle, or hand were found. In the course of an interdisciplinary consensus conference the evidence-based recommendations prepared by a panel were discussed and modified, giving rise to statements on the suitability of the given imaging techniques in 28 different clinical situations immediately after a clinical examination, based on scientific evidence and medical consensus. The degree of consensus was measured and carefully documented. These statements were transformed into decision algorithms and presented to doctors working in accident and emergency medicine during a conference on trauma surgery, with the aim of.measuring the acceptance of the statements among those attending the trauma surgery meeting. The remarks made by the participants during the discussion and the results of the acceptance measurements clearly show the need for further discussion among experts.     

Ten novel MSH2 and MLH1 germline mutations in families with HNPCC

Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer-susceptibility syndromes. Germline mutations in mismatch repair genes are associated with the clinical phenotype of HNPCC. We report ten novel germline mutations, three in MSH2 and seven in MLH1. All but one mutation have been found in families fulfilling criteria of the Bethesda guidelines; four of them additionally fulfilled the Amsterdam criteria I or II. Eight mutations were considered pathogenic and predictive diagnostics in healthy family members at risk shall be undertaken; these include five frameshift mutations leading to premature stop codons, in MSH2: c.1672delT (p.S558Xfs) and c.2466_2467delTG (p.C822X) and in MLH1: c.1023delG (p.R341Xfs), c.1127_1128dupAT (p.K377Xfs) and c.1310delC (p.P437Xfs); three mutations leading to splice aberrations, in MSH2: c.1661G>C (r.1511_1661del) and in MLH1: c.677+3A>C (r.589_677del) and c.1990-2A>G predicted to result in a splice site defect. The remaining two mutations are unclassified variants with assumed pathogenicity: one missense mutation in the highly conserved ATPase domain of MLH1 (c.122A>G [p.D41G]) and one in-frame insertion of twelve nucleotides in MLH1 (c.2155_2156insATGTGTTCCACA [p.I719delinsNVFHI]). These two mutations were not found in 102 alleles of healthy control individuals. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IHC) revealed complete loss of expression of the affected protein in the tumor cells from all but three patients. The tumors from the patients with the mutations c.1127_1128dupAT and c.1990-2A>G showed a reduction of expression of the MLH1-protein, rather than complete loss. In the tumor from the patient with the missense mutation c.122A>G [p.D41G] a normal expression of the proteins coded by MLH1 and MSH2 was noticed.     

Gene therapy of malignant tumors

New techniques in molecular biology and increasing insights in the genetic basis of tumorigenesis led to the development of therapeutic agents composed of genetic information. The majority of gene therapy trials is targeted towards cancer therapy. The most frequently used strategy is immunotherapy which comprises transfer of genes encoding cytokines, costimulatory molecules or tumorspecific antigens to enable cells of the immune system to identify and destroy tumor cells. The second important strategy makes use of suicide genes to selectively kill tumor cells. Compensation of genetic defects by the downregulation of activated oncogenes or the restoration of tumor suppressor gene functions is the third concept to revert the malignant phenotype of cancer cells.     

Biological principles for multimodal therapy approaches

Cancer development and progression has been associated with numerous genetic events in tumor cells. Germline mutations of caretaker and gatekeeper genes are responsible for hereditary cancer syndromes. Exogenous factors in conjunction with functional germline variants of a variety of genes may contribute to tumor initiation in sporadic malignant disease. Furthermore, pathways to neoplasia require somatic events in the developing tumor. Acquired or inherited genetic instability permits stepwise tumor progression. The most fearsome aspect of tumor progression is dissemination of tumor cells to draining lymph nodes of the primary or to distant organs, which limits effectiveness of surgical therapy. Cellular heterogeneity of malignant neoplasms has important implications for chemotherapy and radiotherapy. An increasing understanding of the molecular biology of tumors is the prerequisite for improved prediction, prevention and therapy of malignant disease.     

Neurochirurgische Therapie der malignen Gliome

Die malignen Gliome des Gehirns sind durch ihr infiltratives Wachstum gekennzeichnet. Der Mangel an einer Tumorkapsel und die diffuse Ausbreitung von Tumorzellen in das umgebende Hirngewebe erschweren eine radikale Tumorexstirpation. Im Folgenden werden die neurochirurgischen Therapiem?glichkeiten und ihre Grenzen, ein malignes Gliom durch Operation kurativ zu behandeln, aufgezeigt.     

Accumulation of genetic alterations in brain metastases of sporadic breast carcinomas is associated with reduced survival after metastasis.

Tumor progression is characterized by stepwise accumulation of genetic alterations. To identify alterations associated with breast cancer metastasis, an analysis of comparative loss of heterozygosity (LOH) was performed on 38 primary sporadic breast carcinomas and 16 distant metastases. Two loci at 5q21 and 18q21 were chosen because of their reported increased deletion frequency in metastatic tumors. LOH at 17q21, 13q12-13, 17p13.1 and 11q22-23 was analyzed to determine whether there is a specific involvement of these breast cancer-associated gene loci in the metastatic process. Our data show that distant metastases are characterized by markedly increased LOH frequency at all loci examined. In both gene locus groups, significantly more distant metastases are affected by combined LOH. Furthermore, a significantly reduced postmetastatic survival time has been observed in patients with brain metastases affected by synchronous allelic loss at the four breast cancer-associated gene loci. Our results suggest that cumulative LOH of breast cancer-related gene loci is associated with a more aggressive phenotype of metastatic breast tumors.     

Therapy of hematogenous melanoma brain metastases with endostatin.

PURPOSE: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases. EXPERIMENTAL DESIGN: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed. RESULTS: In vitro secretion of endostatin by 2.5 x 10(5) cells within 24 hours was 0.12 +/- 0.03 ng, 4.35 +/- 0.4, and 1.18 +/- 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was <20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 +/- 2.6 versus 13.3 +/- 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 x 10(5) wild-type cells killed the mice within 24 +/- 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals. CONCLUSION: Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.