Polypharmacy in Parkinson's disease: risks and benefits with little evidence.

Polypharmacy is common practice in Parkinson's disease. Medical treatment targeting the dopaminergic system alone may include up to five different compounds: L-DOPA (in combination with a DOPA decarboxylase inhibitor), a catechol-O-methyltransferase (COMT) and a monoamine oxidase (MAO-B) inhibitor and a dopamine agonist. Particular motor and non-motor symptoms may require additional specific therapeutics, such as drugs aimed at tremor control and to treat depression, dementia and orthostatic and autonomic dysfunction. No prospective studies have yet been performed with regard to the efficacy or the long-term benefit of combining such different treatments in Parkinson's disease and retrospective analyses are sparse. We thus tried to compile the available evidence for polypharmacy strategies in Parkinson's disease and devised an expert opinion statement.

Insight into the incidence of acute aortic dissection in the German region of Berlin and Brandenburg.

BACKGROUND: Stanford acute type A aortic dissection (ATAAD) is a potentially lethal condition. Epidemiology studies show a statistical incidence in Europe of approximately 2-16 cases/100,000 inhabitants/year. In Germany, the estimated incidence (here subsumed under "thoracic aortic dissection" with 4.63 cases/100,000 inhabitants/year) is mainly extracted from medical death certificates by the German Federal Statistical Office. The prehospital incidence of ATAAD deaths is largely unknown. Since patients often die in the pre-hospital setting, the incidence of ATAAD is therefore likely to be higher than current estimates. MATERIAL AND METHODS: For the period from 2010 to 2014, we retrospectively analyzed all in-hospital ATAAD data from two of the largest cardiac surgical centers that treat ATAAD in the Berlin-Brandenburg region. In addition, autopsy reports of all forensic medicine institutes and of one large pathological provider in the region were analyzed to identify additional non-hospitalized ATAAD patients. Based on these findings, the regional incidence of ATAAD was calculated. RESULTS: In addition to in-hospital ATAAD patients (n=405), we identified additional 145 lethal ATAAD cases among 14,201 autopsy reports. The total of 550 ATAAD cases led to an estimated incidence of 11.9 cases/100,000 inhabitants/year for the whole Berlin-Brandenburg region. Arterial hypertension, pre-existing aortic dilatation, and hereditary connective tissue disorder were found in, respectively, 62.7%, 10%, and 1.8% of patients. CONCLUSION: ATAAD is more frequent than previously reported. Our results show that when patients who die outside of cardiac surgery centers are included, the incidence of ATAAD significantly exceeds the rate reported by the Federal Statistical Office.

Persisting hepatitis E virus infection leading to liver cirrhosis despite recovery of the immune system in an HIV-infected patient.

Chronic hepatitis E has been described several times in strongly immunosuppressed HIV-patients. We describe the persistence of HEV-infection in an HIV-patient despite a restored immune response. This case demonstrates that HEV-infection can persist in formerly immunosuppressed individuals irrespective of the current immune status. Persisting HEV-infection can lead to chronic inflammation and liver cirrhosis. Physicians should be aware of the possibility of chronic hepatitis E even in patients that are not any longer immunocompromised. However, ribavirin is an efficient treatment option.

[Microkeratome and excimer laser-assisted endothelial keratoplasty (MELEK)]. / Mikrokeratom- und Excimer-Laser-gestützte endotheliale Keratoplastik (MELEK).

INTRODUCTION: Descemet's stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK) have become well established procedures for the treatment of endothelial pathologies. In the last years the field of lamellar corneal surgery has further developed in terms of preparation of the lamellae as well as of implantation. PATIENTS AND METHODS: A modified form of the "ultrathin DSAEK" (UT-DSAEK) is the "microkeratome and excimer laser-assisted endothelial keratoplasty" (MELEK). In this new technique a corneal graft is prepared by a single cut of a microkeratome followed by a stromal excimer-laser thinning and smoothing. The purpose of the present report is to describe this new technique and present first clinical results. RESULTS: In this prospective clinical study 18 patients (76 ± 11 years) underwent a MELEK. The BCVA increased from 0.25 ± 0.1 preoperatively to one month postoperatively was 0.33 ± 0.21 (decimal, n = 12), after three months 0.51 ± 0.23 (n = 8) and after six months 0.80 ± 0.16 (n = 4). The average thickness of the residual stromal lamella before laser ablation was 173 ± 42 µm, after ablation 111 ± 15 µm. The central corneal thickness decreased from 704 µm to 639 µm, the thickness of the transplant decreased from 114 µm to 106 µm six months postoperatively. CONCLUSION: The ultrathin "microkeratome and excimer laser-assisted endothelial keratoplasty" (MELEK) is a new and safe technique in the field of lamellar keratoplasty. In the future it could have the potential to combine the advantages of DSAEK and DMEK for the treatment of endothelial pathologies.

[Therapy refractory blepharoconjunctivitis in a 90 year old patient]. / Therapierefraktäre Blepharokonjunktivitis bei einer 90-jährigen Patientin.

Sebaceous gland carcinoma can clinically mimic benign conditions such as chalazion and blepharoconjunctivitis. This carcinoma should be histologically excluded for every unilateral, recalcitrant chalazion and every unilateral, therapy refractory blepharitis. Autosomal dominant Muir-Torre syndrome should be considered in patients who develop sebaceous gland carcinoma of the ocular adnexa. In this case, the sebaceous gland carcinoma is combined with visceral carcinoma.

Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936.

Polymerase chain reaction (PCR) assessment of clonal T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements is an important diagnostic tool in mature T-cell neoplasms. However, lack of standardized primers and PCR protocols has hampered comparability of data in previous clonality studies. To obtain reference values for Ig/TCR rearrangement patterns, 19 European laboratories investigated 188 T-cell malignancies belonging to five World Health Organization-defined entities. The TCR/Ig spectrum of each sample was analyzed in duplicate in two different laboratories using the standardized BIOMED-2 PCR multiplex tubes accompanied by international pathology panel review. TCR clonality was detected in 99% (143/145) of all definite cases of T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, peripheral T-cell lymphoma (unspecified) and angioimmunoblastic T-cell lymphoma (AILT), whereas nine of 43 anaplastic large cell lymphomas did not show clonal TCR rearrangements. Combined use of TCRB and TCRG genes revealed two or more clonal signals in 95% of all TCR clonal cases. Ig clonality was mostly restricted to AILT. Our study indicates that the BIOMED-2 multiplex PCR tubes provide a powerful strategy for clonality assessment in T-cell malignancies assisting the firm diagnosis of T-cell neoplasms. The detected TCR gene rearrangements can also be used as PCR targets for monitoring of minimal residual disease.

Activation-induced cytidine deaminase (AID) is expressed in normal spermatogenesis but only infrequently in testicular germ cell tumours.

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes in antigen-dependent B-cell maturation. SHM is not restricted to immunoglobulin gene loci, raising the possibility of a function for AID in other cell types. In this study, it is shown that AID is expressed in spermatocytes in the human testis. AID was mostly cytoplasmic but nuclear AID was also observed in a proportion of cells, in keeping with the DNA deamination model of AID function. Intratubular germ cell neoplasia unclassified (IGCNU), the precursor lesion of testicular cancers, was AID-negative. Seminomas also lacked AID expression. Nuclear and cytoplasmic AID expression was observed in three of 32 mixed non-seminomatous germ cell tumours. The results provide evidence for a physiological role for AID outside the immune system. AID expression in spermatocytes points to a role in meiosis. It remains uncertain whether AID may also contribute to the genetic aberrations characteristically found in testicular germ cell tumours. The consistent absence of detectable AID expression in atypical spermatogonia of IGCNU and its rare expression in germ cell tumours suggest that continued expression of AID is not involved in the pathogenesis of germ cell tumours.

[Immunohistochemical characterization of salivary gland tumors with tissue micro-arrays]. / Immunphänotypische Charakterisierung von Speicheldrüsentumoren unter Verwendung von Gewebe-Micro-Arrays.

Systematic analysis of gene expression in salivary gland tumors is necessary to identify genes associated with specific tumor types. From the salivary gland register of the University Hospital Hamburg-Eppendorf sufficient samples of various tumors were available to generate Tissue Micro-Arrays (TMA). In light of the considerable heterogeneity of salivary gland tumors, this study was aimed at evaluating the suitability of TMA in salivary gland diagnostics and research. Epithelial antigens are not sufficient for a tumor-type-specific characterization. Myoepithelial markers are suitable for distinguishing biphasic tumor types from purely epithelial tumors. The detection of amylase in acinic cell carcinomas, and the detection of steroid hormone receptors in these and other malignant salivary gland tumors particularly in combination with the expression of transcription factors, oncogenes and proliferation associated antigens result in characteristic expression profiles. These may prove to be valuable for further investigations, especially on the molecular level.

[Salivary duct carcinoma]. / Speichelgangkarzinome.

This tutorial focuses on salivary duct carcinoma (SDC), a rare, high grade neoplasm mainly of major salivary glands. The clinical course of these tumors is characterised by extended local disease, early distant metastasis, and poor outcome. The morphology of SDC is reminiscent of breast ductal carcinomas and may occasionally cause diagnostic problems. In spite of mimicry with ductal carcinoma in situ of the breast and an in situ component, that is evident in most tumors by immunohistology with antibodies directed against high molecular weight cytokeratins (Ck), SDC is always an invasive carcinoma. By immunohistology, most tumors show reactivity with antibodies directed against Ck 7, Ck 8/18 and Ck 19 whereas a morphologically indistinguishable subgroup expresses Ck 5/6 in tumor cells in addition to residual basal epithelia. Carcinoembryonic antigen, GCDFP-15 and androgen receptor are other helpful markers in routine diagnosis of SDC. Prostate-specific antigen is detectable in some cases. Abnormal p53 expression seems to indicate an adverse prognosis. Expression of c-erbB2, the over-expression of which is associated with a poor prognosis, may form the basis for a targeted therapeutic approach for selected cases of SDC.

Alpha-fetoprotein-positive carcinoma of the pancreas: a case report.

We report on the case of a 19-year-old male with an alpha-fetoprotein (AFP)-producing acinar cell carcinoma of the pancreas. Tumour markers other than AFP were normal. Because of inoperability, a combined radiochemotherapy was initiated with a hyperfractionated dose of 44.8 Gy. Initially, the tumour showed a good response to irradiation and 5-fluorouracil (5-FU) application, and therapy showed sufficient local control. After combined radio-chemotherapy, AFP levels declined from about 3000 ng/ml (reference area: 0-7 ng/ml) to 18 ng/ml, but increased when widespread metastasis appeared. The patient died 18 months after the initial therapy due to general tumour progression. Originally, AFP was thought to be specific to hepatocellular carcinoma and germ cell tumours. Rarely has it been reported in other malignancies. Rare cases of acinar cell carcinomas of the pancreas were found to express AFP. Our patient is the youngest reported in the literature to date. When present, AFP expression is useful for diagnosis and as a marker for monitoring therapeutic response and recurrence of the disease.

[Myoepthelial tumors of salivary glands]. / Myoepitheliale Tumoren der Kopfspeicheldrüsen.

This tutorial focuses on myoepithelial tumors of salivary glands, an entity with heterogeneous cytomorphology and inconsistent immunophenotype. Moreover, the clinical course cannot be predicted reliably from cytomorphological and immunophenotypic analysis. This heterogeneity causes problems in routine diagnostic, so that diagnosis ultimately rests on conventional histology. In a representative series of myoepitheliomas and malignant myoepitheliomas, antibodies against cytokeratins 5/6, S 100 protein and vimentin produced the most consistent reactivity profile. Staining for cytokeratins 5/6 is a useful addition to the established immunohistologic marker panel in the work-up of myoepitheliomas, because of its reliable expression in most cases and because it may underline the epithelial nature of the lesion. Comparative genomic hybridisation (CGH) profiles of myoepitheliomas and myoepithelial carcinomas showed no chromosomal aberration in less than 50% of myoepithelial carcinomas, so that CGH is of limited help in a given case. In a case that was represented in three separately localized manifestations of the disease that differed in their CGH profiles, gross genetic aberrations suggest to be acquired during tumor progression and should raise the suspicion of malignancy. Thus, diagnosis of myoepithelial tumors of salivary glands has to rest on morphological grounds with support of a restricted panel of immunohistologic markers.

Amelanotic malignant melanoma of the esophagus: case report.

We present the case of a primary malignant esophageal melanoma arising in a 75-year-old male, initially diagnosed as anaplastic squamous cell carcinoma. After resection of the tumor, histological work-up was indicative of a marked morphological heterogeneity, resembling a focally amelanotic primary malignant melanoma. Primary malignant melanomas of the esophagus are exceptionally rare. An exact preoperative diagnosis is critical with respect to the appropriate therapeutic strategy. Clinicopathological features of this entity with a brief review of the literature are presented.

Black oesophagus: a rare disorder with potentially fatal outcome. A forensic pathological approach based on five autopsy cases.

Black oesophagus is a rare pathological condition of unknown aetiology characterised by a full length, circumferential black discolouration of the entire oesophageal mucosa. The disease is sporadically encountered during upper gastrointestinal endoscopy. We used conventional histology, enzyme histochemistry and immunohistology to examine five autopsy cases (four males, one female; age range 43-86 years) of black oesophagus. On microscopical examination, the esophageal mucosa was entirely necrotic with demarcation by a leukocytic infiltrate in the upper submucosa. This infiltrate was dominated by neutrophilic granulocytes and scattered macrophages lacking haemosiderin deposits, placing the noxious mucosal injury in a time frame of approximately 24-72 h prior to death. Black oesophagus was established as the immediate cause of death in one case due to desanguination from the oesophagus and significantly contributed to the fatal outcome in a second case. Apart from a history of chronic alcohol consumption in four cases, no other pre-existing pathological or debilitating conditions could be established. The remarkably consistent pathomorphological picture of the disease seems to be the result of impaired microcirculation of the oesophageal mucosa due to prolonged hypotension of variable aetiology. The diagnosis of black oesophagus requires exclusion of other causes such as ingestion of caustic materials and should be based on histological examination.

[Intra-abdominal fibromatosis after appendectomy as cause for ileus]. / Intraabdominale Fibromatose nach Appendektomie als Ursache rezidivierender Ileuszustände.

Aggressive intraabdominal fibromatosis is a rare response to surgical trauma. Characteristic is the local destroying growth. Only an operation in the purpose of R0-resection ends in cure. We report on a 29-year-old man, who developed intraabdominal fibromatosis as reaction to surgical trauma 19 years after appendectomy and subsequent to several relaparotomies due to adhesions. A huge conglomeratumor which included the ileum and the colon acsendens resulted in bowel obstruction and ileus. Complete surgical removal of the tumor lead after a primary complicated course to recovery.

[Undifferentiated salivary gland carcinomas]. / Undifferenzierte Karzinome der Speicheldrüsen.

Undifferentiated salivary gland carcinomas may be divided into small cell and large cell types. Among large cell undifferentiated carcinomas, lymphoepithelial carcinomas have to be distinguished, the latter of which are endemic in the Arctic regions and southern China where virtually all cases of these tumors are associated with the Epstein-Barr virus (EBV). Association with EBV may also be observed in sporadic cases, and detection of EBV gene products may aid their diagnosis. Immunohistology may be employed to resolve the differential diagnosis of undifferentiated salivary gland carcinomas, comprising malignant lymphomas, amelanotic melanomas, Merkel cell carcinomas, and adenoid cystic carcinomas, in particular in small biopsy materials. Because of the rarity of undifferentiated salivary gland carcinomas, the differential diagnosis should always include metastases of undifferentiated carcinomas arising at other primary sites, particularly when expressing the thyroid transcription factor-1 (TTF-1).

[Salivary gland lymphomas]. / Lymphome der Kopfspeicheldrüsen.

This tutorial focuses on malignant lymphomas and inflammatory conditions as potential precursors of primary malignant lymphomas in salivary glands. Salivary glands display a mucosa-associated lymphoid tissue and are often associated with intra- and periglandular lymph nodes. Inflammation of the glands may variably produce duct ectasia, lymphoepithelial lesions, atrophy, and fibrosis. Primary lymphomas of the salivary glands may develop on the basis of autoimmune sialadenitis and comprise most frequently marginal zone lymphomas, less often monocytoid lymphomas or other lymphoma entities. In a large proportion of cases, lymphoma infiltrates are attributable to extraglandular lymphomas either as a leukemic infiltrate with diffuse enlargement or as a localized manifestation of primary nodal non-Hodgkin lymphomas. Diagnosis is based on conventional histology and immunohistology.

Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease: detection of the virus in lymphomas but not in adenocarcinomas.

Epstein-Barr virus (EBV) is associated with several lymphoid and epithelial human malignancies. The latter include gastric adenocarcinomas, while sporadic colorectal adenocarcinomas (CRCs) have been reported to be EBV-negative. Recently, increased numbers of EBV-infected B lymphocytes have been detected in intestinal mucosal samples affected by ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD). Both CRC and colorectal non-Hodgkin's lymphoma (NHL) are recognized complications of inflammatory bowel disease (IBD), but it is unclear to what extent EBV contributes to the development of these neoplasms. Seventeen cases of IBD-associated CRC and nine cases of IBD-associated colorectal NHL were therefore studied for the presence of EBV by in situ hybridization. EBV-positive cases were further studied for the expression of the EBV-encoded nuclear antigen (EBNA) 2 and the latent membrane protein (LMP) 1 of EBV by immunohistochemistry. Four out of seven cases of colorectal NHL associated with UC were shown to be EBV-positive. In addition, two of two colorectal NHLs developing in patients with CD were EBV-positive. Of the EBV-positive lymphomas, three displayed a pattern of EBV latent gene expression consistent with type I latency (EBNA2(-)/LMP1(-)), two a type II pattern (EBNA2(-)/LMP1(+)), and one a type III pattern (EBNA2(+)/LMP1(+)). These findings suggest that EBV infection is involved in the pathogenesis of a proportion of colorectal NHLs developing in IBD. Iatrogenic immunosuppression may contribute to the development of these lymphomas. By contrast, all 17 IBD-associated CRCs were EBV-negative, including a case of CRC occurring synchronously with an EBV-positive NHL. In conjunction with previous reports on sporadic CRCs, this suggests that EBV is not involved in the pathogenesis of CRC.

["Problem-based learning--inflammation and transplantation": an integrated, subject-centred course in the clinical section of the medical curriculum at the medical school of the University of Muenster]. / Problemorientiertes Lernen--Entzündungsmedizin & Transplantation: ein integrierter, themenzentrierter Kurs im klinischen Studienabschnitt an der Medizinischen Fakultät der Westfälischen Wilhelms-Universität (WWU) Münster.

Conventional medical curricula present information pertinent to chronic inflammatory diseases, infectious diseases and transplantation, via systematic lectures and courses in medical specialties without any integrated approach. The authors report on a 3-week model course that attempts to provide students with an overview of clinical presentation, diagnostics, and therapy of representative disease entities with particular emphasis on the interdisciplinary approach to these problems in hospital practice. In addition to problem-based learning in small groups, the model course comprises interdisciplinary concept lectures, practical demonstrations of specific diagnostic procedures, and bedside teaching. In the meantime, the course "Problem-Based Learning--Inflammation and Transplantation" has been held twice successfully as a mandatory course in the clinical part of the curriculum at the Muenster Medical School.