Influenza virus infections in patients with malignancies -- characteristics and outcome of the season 2014/15. A survey conducted by the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Medical Oncology (DGHO).

Influenza virus infections (IVI) may pose a vital threat to immunocompromised patients such as those suffering from malignancies, but specific data on epidemiology and outcome in these patients are scarce. In this study, we collected data on patients with active cancer or with a history of cancer, presenting with documented IVI in eight centres in Germany. Two hundred and three patients were identified, suffering from haematological malignancies or solid tumours; 109 (54 %) patients had active malignant disease. Influenza A was detected in 155 (77 %) and Influenza B in 46 (23 %) of patients (genera not determined in two patients). Clinical symptoms were consistent with upper respiratory tract infection in 55/203 (27 %), influenza-like illness in 82/203 (40 %), and pneumonia in 67/203 (33 %). Anti-viral treatment with oseltamivir was received by 116/195 (59 %). Superinfections occurred in 37/203 (18 %), and admission on an intensive care unit was required in 26/203 (13 %). Seventeen patients (9 %) died. Independent risk factors for death were delayed diagnosis of IVI and bacterial or fungal superinfection, but not underlying malignancy or ongoing immunosuppression. In conclusion, patients with IVI show high rates of pneumonia and mortality. Early and rapid diagnosis is essential. The high rate of pneumonia and superinfections should be taken into account when managing IVI in these patients.

[Pathogenesis and molecular pathology of vestibular schwannoma]. / Pathogenese und Molekularpathologie des Vestibularisschwannoms.

Schwannomas are benign Schwann cell-derived tumors of the peripheral nerve sheath often involving the vestibular cranial nerve (vestibular schwannoma). Histologically, they consist of bipolar spindle cells and show a moderate cellularity. Typically, Antoni A regions with a storiform pattern and loose Antoni B regions are intermingled. Verocay bodies are the pathognomonic palisading structures. Malignant transformation is rare. Merlin (schwannomin), the protein product of NF2, is inactivated by mutations, loss of heterozygosity or methylation. Within neurofibromatosis type 2, a germline mutation is present in about half of cases, whereas tumors demonstrate an additional second hit of the NF2 gene. A loss of chromosome 22 or 22q is common. Merlin links the cell membrane with the cytoskeleton and regulates intracellular signaling pathways leading to dysorganization when merlin is inactivated. Loss of merlin activates Rac1 and Ras, and the PAK1, mTORC1, EGFR-Ras-ERK, PI3K-Akt, WNT and Hippo pathways as well as receptor tyrosine kinases. Furthermore, merlin locates to the nucleus and inhibits E3 ubiquitin ligase CRL4DCAF1. Besides biallelic inactivation of NF2 in schwannomas, other genes are involved in the pathogenesis of schwannomatosis-associated schwannomas such as LZTR1, SMARCB1, COQ6 indicating an important role of SWI/SNF chromatin-remodeling complex for schwannoma development. Our own investigations point to deregulation of BAF170, another essential SWI/SNF complex component. Knowledge of mechanisms allows targeted molecular therapy, especially in vestibular schwannomas, using antagonists against mTOR (rapamycin/sirolmus/everolimus), EGFR (lapatinib) or VEGF (bevacizumab), although clinical studies have been in part disappointing so far.

A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling.

Fms-like tyrosine kinase-3 is a commonly mutated gene in acute myeloid leukemia, with about one-third of patients carrying an internal-tandem duplication of the juxtamembrane domain in the receptor (FLT3-ITD). FLT3-ITD exhibits altered signaling quality, including aberrant activation of STAT5. To identify genes affecting FLT3-ITD-mediated STAT5 signaling, we performed an esiRNA-based RNAi screen utilizing a STAT5-driven reporter assay. Knockdowns that caused reduced FLT3-ITD-mediated STAT5 signaling were enriched for genes encoding proteins involved in protein secretion and intracellular protein transport, indicating that modulation of protein transport processes could potentially be used to reduce constitutive STAT5 signaling in FLT3-ITD-positive cells. The relevance of KDELR1, a component involved in the Golgi-ER retrograde transport, was further analyzed. In FLT3-ITD-expressing leukemic MV4-11 cells, downregulation of KDELR1 resulted in reduced STAT5 activation, proliferation and colony-forming capacity. Stable shRNA-mediated depletion of KDELR1 in FLT3-ITD-expressing 32D cells likewise resulted in reduced STAT5 signaling and cell proliferation. Importantly, these cells also showed a reduced capacity to generate a leukemia-like disease in syngeneic C3H/HeJ mice. Together our data suggest intracellular protein transport as a potential target for FLT3-ITD driven leukemias, with KDELR1 emerging as a positive modulator of oncogenic FLT3-ITD activity.

A 45-year-old female with hypokalemic rhabdomyolysis due to VIP-producing composite pheochromocytoma.

The watery diarrhea, hypokalemia and achlorhydria (WHDA) syndrome due to vasoactive intestinal polypeptide (VIP)-producing extra-pancreatic tumors is rare. We report on a 45-year-old woman who suffered from persistent secretory diarrhea for six years and who was admitted to hospital with complaints of muscular weakness and myalgia. Biochemical testing revealed pronounced rhabdomyolysis due to severe hypokalemia. Gastrointestinal evaluation of long-standing diarrhea including endoscopy of the upper and lower gastrointestinal tract and the small intestine did not show any pathologies. An abdominal computed tomography scan revealed a mass of 4 × 5 cm in the left adrenal gland demonstrating a strong uptake in the 123I-labelled metaiodobenzylguanidine scintigraphy. Plasma levels of chromogranin A, calcitonin, parathormone, basal renin and most prominently VIP were increased in line with a increased 24 hour urinary secretion of noradrenaline, dopamine, normetanephrine and vanillymandelic acid. A WDHA (watery diarrhea, hypokalaemia, achlorhydria) syndrome with hypokalemic rhabdomyolysis due to a VIP-producing adrenal tumor was diagnosed that was removed surgically. The histological evaluation demonstrated a composite pheochromocytoma. Diarrhea stopped immediately after surgery together with a normalization of laboratory parameters. In conclusion, this case report focuses on the rare clinical presentation of secretory diarrhea and electrolyte disturbances in combination with hypokalemic rhabdomyolysis which was caused by a VIP-producing composite pheochromocytoma.

[Selective immunoadsorption in neurologic complications of systemic lupus erythematosus]. / Selektive Immunadsorption bei neurologischen Komplikationen eines systemischen Lupus erythematodes.

Vasculitis of the nervous system is a rare cause of multifocal neurologic symptoms and may involve both the central and peripheral nervous systems. Typical symptoms include headache, encephalopathy with cognitive impairment and psychotic symptoms, epileptic seizures, and peripheral neuropathies. Here we report the case of a 71-year-old female presenting with Raynaud's syndrome and paresthesia of the feet. Several weeks later she was admitted to our hospital with a status epilepticus and complex partial seizures. On admission she had mild aphasia, distal paresis of the arms without sensory deficits, and disorientation with hallucinations. Cerebral MRI revealed small, multifocal infarctions in several arterial territories. Multiple cerebral artery stenoses were detected by ultrasound. Examination of the CSF was unremarkable. Serologic tests for autoimmune disorders detected Ro antibodies compatible with systemic lupus erythematosus or Sjögren's syndrome. A sural nerve biopsy revealed ischemic axonal neuropathy. During administration of i.v. methylprednisolone, the symptom progression stopped but dosages could not be tapered due to severe CNS symptoms (mental decline, disorientation, aphasia, hallucinations). Slow but sustained clinical improvement was achieved by immunoadsorption over 3 weeks followed by a combined high-dose immunosuppressive treatment with cyclophosphamide and prednisolone that paralleled a reduction in anti-Ro titers and normalization of cerebral blood flow velocities as detected by repeated transcranial Doppler sonography. Systemic vasculitis may present with multiple neurologic and psychiatric symptoms due to involvement of the central and peripheral nervous systems. After excluding systemic infection, immunosuppressive therapy should be started early. In our case a combination of high-dose methylprednisolone, immunoadsorption with elimination of Ro antibodies, and cyclophosphamide led to the patient's recovery.

Aneurysm of the extracranial carotid artery with spontaneous echo contrast revealed by duplex sonography.

A 56-year old male patient without cerebrovascular disease or risk factors presented with a painless, pulsatile right-sided cervical swelling. Ultrasonography showed a large aneurysm of the right common and internal carotid artery with homogeneous thickening of the vessel wall as well as a parietal thrombus and a dilation of the left common and internal carotid artery with markedly reduced blood flow velocities. In the enlarged lumen of the right internal carotid artery spontaneous echo contrast was apparent with slow, ineffective but orthograde blood flow motions. Ensuing diagnostic procedures revealed multiple aneurysms involving the aorta and its branches. Despite surgical removal of the aneurysm and glucocorticoid therapy, the patient died from a ruptured aneurysm of a coronary artery a few weeks later. Post-mortem examination showed panarteritis consistent with Takayasu's disease. Spontaneous echo contrast is a frequent echocardiographic finding in patients with atrial fibrillation and mitral stenosis, indicating decreased blood flow. This is associated with an increased risk of embolism. In our patient, spontaneous echo contrast indicated severely disturbed haemodynamics due to a large aneurysm of the carotid artery. In the rare case of multiple aneurysms, differential diagnosis should include dissections, infections, and connective tissue diseases. Takayasu's arteritis, however, should also be considered, which usually presents with stenoses, but may be associated with multiple aneurysms of the aorta or its branches. If the diagnostic criteria are present, immunosuppressive treatment should be initiated.

Low-grade fibrosarcoma--report on 39 not otherwise specified cases and comparison with defined low-grade fibrosarcoma types.

AIMS: Low-grade fibrosarcomas are tumours that mainly affect the extremities and trunk of adults of either sex. Among these, low-grade fibromyxoid sarcoma (FMS), hyalinizing spindle cell tumour with giant collagen rosettes (HST) and sclerosing epithelioid fibrosarcoma (SEF) are well-established entities. In this study, our aim was to describe a group of low-grade fibrosarcomatous tumours, which could not be encompassed by these entities. These low-grade fibrosarcomas, not otherwise specified (FNOS) were provisionally designated as 'fibrosarcoma, low-grade fibroblastic type'. METHODS AND RESULTS: In the soft tissue tumour registry we found 39 FNOS (46%), 31 FMS (36%), 11 SEF (13%) and four HST (5%). FNOS occurred in older patients than FMS (mean age 56.3 years versus 33.7 years). They mainly showed fibrous features, but myxoid areas could also be seen. While cells tended to be loosely arranged in the myxoid areas, densely packed sheets with a storiform pattern, fascicular arrangements or regions without a defined growth pattern were observed in the fibrous areas. However, neither whirling nor swirling patterns were found. Arcade-like vessels were not visible; pseudolipoblasts did not occur. FNOS exhibited increased atypia and mitotic count compared with the other sarcomas studied [FNOS, mean value 4.6 mitoses/10 high-power field (HPF); FMS, 0.7/10 HPF). Follow-up data were available in 21 FNOS patients. In seven cases (33.3%), local recurrences were reported. Three patients (14.3%) developed metastases and all of them died of tumour. CONCLUSIONS: The term 'fibrosarcoma, low-grade fibroblastic type' should be used as a diagnosis of exclusion. Further studies should elucidate whether it represents a distinct fibrosarcoma type.

[Tracheal agenesis. A rare cause of respiratory insufficiency in neonates]. / Trachealagenesie. Eine seltene Ursache der respiratorischen Insuffizienz des Neugeborenen.

Tracheal agenesis is a very rare congenital anomaly that occurs isolated or in combination with other anomalies. It presents immediately after birth with an absolute respiratory insufficiency and lack of crying. The immediate precise anatomical classification of the anomaly is crucial in order to decide if surgical therapy is possible. This report describes a newborn boy with tracheal agenesis type II. The diagnosis was confirmed by spiral computed tomography and a selection of the pictures is presented. The treatment was discontinued due to a lack of therapeutical options. Based on this case report we discuss the special situation of this rare anomaly. Interesting information on tracheal agenesis was gathered, the differential diagnosis of respiratory insufficiency of the newborn is summarised and a modified algorithm of the current newborn resuscitation guidelines of the American Heart Association is presented.

[Diplopia and cardiogenic shock]. / Doppelbilder und kardiogener Schock. Eine okuläre Myositis assoziiert mit einer Riesenzellmyokarditis.

Idiopathic giant cell myocarditis is a rare and frequently fatal inflammatory heart disease which leads to congestive heart failure or ventricular arrhythmias. It is often associated with other autoimmune disorders. We report a 39-year-old woman who first presented with diplopia and painful eye movements, the typical clinical picture of orbital myositis. Shortly afterwards, she developed rapidly progressive congestive heart failure due to giant cell myocarditis, which took a fatal course within some weeks. Autopsy confirmed both disorders. This case report underlines the importance of early and repeated monitoring of cardiac function, if orbital myositis is suspected, in order to consider cardiac transplantation, the only efficacious treatment of giant cell myocarditis, in time.

[Differential diagnosis of solitary neurosarcoidosis]. / Differenzialdiagnose der isolierten Neurosarkoidose.

Sarcoidosis is an inflammatory multisystemic disease characterised by noncaseating epithelioid granulomas. The lung is affected in over 90% of patients. According to clinical criteria, the nervous system is involved in 5-9%. However, in autopsy series this number increases to 25%. Solitary involvement of the nervous system without signs of systemic disease is rare and diagnostically cryptic. Due to the wide variety of neurologic symptoms, definite diagnosis of sarcoidosis is possible only by histopathological proof of noncaseating epithelioid granulomas. We report a 51-year-old woman who presented with chronic basal meningitis and involvement of the peripheral and central nervous system due to solitary neurosarcoidosis. Diagnostic procedures and differential diagnosis are discussed.

Potential stem cell therapy and application in neurotrauma.

Traumatic brain injury results from a sudden and external physical insult to the head, which is often accompanied by motor and cognitive impairment. Neurotrauma is characterized not only by focal abnormalities, but rather by multifocal, or even global structural and functional disturbances of the brain network. The impact initially causes necrotic cell death in the underlying tissue, followed by apoptotic cell death in the surrounding tissue due to multiple subsequent events, such as ischemia, excitotoxicity and altered gene expression. These pathological conditions are associated with high morbidity and mortality. Despite the high medical and economical relevance of neurotrauma there are currently no sufficient treatments. Supplementary therapeutic strategies have to be established. Many types of stem cells have the ability to engraft diffusely and become integral members of structures throughout the host CNS. Intrinsic factors appear to derive spontaneously from stem cells and seem to be capable of neuroprotective and/or neuroregenerative functions. Furthermore stem cells can be readily engineered to express specific genes. Such observations suggest that stem cells might participate in reconstructing the molecular and cellular milieu of traumatized brains. In this paper, the state of stem cell research is reviewed and its possible application in neurotrauma will be discussed.

Immunomorphological sequelae of severe brain injury induced by fluid-percussion in juvenile pigs--effects of mild hypothermia.

Severe traumatic brain injury (TBI) often leads to a bad outcome with considerable neurological deficits. Secondary brain injuries due to a rise of intracranial pressure (ICP) and global hypoxia-ischemia are critical and may be reduced in extent by mild hypothermia. A porcine animal model was used to study the effect of severe TBI, induced by fluid percussion (FP; 3.5+/-0.3 atm) in combination with a secondary insult, i.e., temporary blood loss with hypovolemic hypotension. Six-week-old juvenile pigs were subjected to this kind of severe TBI; one group was then submitted to moderate hypothermia at 32 degrees C for 6 h, starting 1 h after brain injury. Animals were killed after 24 h. TBI and hypothermia-associated alterations in the brains were investigated by immunohistochemistry with antibodies against microtubule-associated protein 2 (MAP-2) and beta-amyloid precursor protein (betaAPP). In addition, DNA fragmentation was investigated by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) method. Seven of the 13 normothermic TBI animals developed a secondary increase in ICP (TBI-NT-ICP) after an interval of several hours. None of the animals in the hypothermic trauma (TBI-HT) group exhibited a secondary ICP increase, indicating a protective effect of the treatment. TBI-HT animals showed significantly higher levels of MAP-2 immunoreactivity, lower levels of betaAPP immunoreactivity and less DNA fragmentation than the TBI-NT-ICP animals. Differences between the TBI-HT group and normothermic animals without an ICP increase (TBI-NT) were less marked. A considerable decrease in MAP-2 outside the site of TBI-FP administration was seen only in the TBI-NT-ICP animals. MAP-2 immunohistochemistry was thus a reliable marker of diffuse brain damage. Axonal injury was present in all TBI groups, indicating its special significance in neurotrauma. Thus, severe TBI caused by FP, combined with temporary blood loss, consistently produced traumatic axonal injury and focal brain damage. Mild hypothermia was able to prevent a secondary increase in ICP and its sequelae of diffuse hypoxic-ischemic brain injury. However, hypothermia did not afford protection from traumatic axonal injury.

Neuropathological sequelae of traumatic injury in the brain. An overview.

The identification and interpretation of brain damage resulting from head injury is often not easy. The most obvious structural damage, which is identified post-mortem by neuropathologists, may not be the most reliable alteration with regard to clinico-pathological correlations. For example patients with a fracture of the skull, a severe cerebral contusion or a large intracerebral hematoma that is successfully treated can lead to a complete recovery if no other types of brain damage are present. Thus more subtle forms of pathology, which are often present and some of which can only be identified microscopically, may be more important. It is therefore necessary to get deeper insights into the consequences of brain injury. Though of course not exclusively, this aim can be reached by autopsy. Primary traumatic brain lesions result immediately from mechanical injury. Secondary alterations injuries develop through intracranial and extracranial trauma sequelae, which determine the course and outcome of brain damage. Traumatic brain damage can be classified as focal or diffuse. It may sometimes be difficult to distinguish traumatic from ischemic brain injury. One difference, however, is that the initial events of trauma involve mechanical distortion of the brain. Mechanoporation as traumatic defect in the cell membrane has recently been found to be one of the first steps which leads via ionic influxes to the activation of immediate early genes. Oxygen radicals and cell membrane lipid peroxidation occur also very early. Increased intracellular calcium, activation of phospholipases and calpains furthermore damage the membrane and cytoskeleton and block the axoplasmatic transport, by which delayed cell death can appear. For the description of the extent of traumatically induced brain damage and the possible clinico-pathological correlations it is necessary to take these alterations into consideration as specifically as possible. Neuropathology can contribute to this aim.