Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity.

Mitochondria are dynamic organelles that continually move, fuse and divide. The dynamic balance of fusion and fission of mitochondria determines their morphology and allows their immediate adaptation to energetic needs, keeps mitochondria in good health by restoring or removing damaged organelles or precipitates cells in apoptosis in cases of severe defects. Mitochondrial fusion and fission are essential in mammals and their disturbances are associated with several diseases. However, while mitochondrial fusion/fission dynamics, and the proteins that control these processes, are ubiquitous, associated diseases are primarily neurological disorders. Accordingly, inactivation of the main actors of mitochondrial fusion/fission dynamics is associated with defects in neuronal development, plasticity and functioning, both ex vivo and in vivo. Here, we present the central actors of mitochondrial fusion and fission and review the role of mitochondrial dynamics in neuronal physiology and pathophysiology. Particular emphasis is placed on the three main actors of these processes i.e. DRP1,MFN1-2, and OPA1 as well as on GDAP1, a protein of the mitochondrial outer membrane preferentially expressed in neurons. This article is part of a Special Issue entitled: Mitochondria & Brain.

[Doublehit lymphomas -  review of the literature and case report]. / Lymfomy se dvema zásahy -  prehled literatury a kazuistika.

UNLABELLED: Blymphocytes are cells of the immune system responsible for the antibody  mediated immune response. As estimated, a human body can produce as much as 1011 specific antibodies. There are no specific genes coding for every individual antibody in the human genome. Discrepancy between the huge diversity of antibodies and limited coding capacity of the genome is solved by combination of unique arrangement of genetic information for immunoglobulin and unique genetic and somatic processes providing this wide spectrum of antibodies. On one side, these mechanisms represent a life protecting source of a wide spectrum of antibodies but at the same time, they can be life threatening by raising the risk of a serious tumor disease, the B cell lymphoma. Double hit lymphomas represent a specific group of B cell lymphomas often featuring concurrent rearrangements of BCL2 and MYC genes. Activation of the MYC oncogene, typical for Burkitt lymphoma (BL), causes strong stimulation of cell proliferation. High activity of BCL 2, typical for follicular lymphoma, induces resistance to apoptosis. Concurrent damage of regulation of apoptosis and proliferation is probably responsible for the typical clinical manifestation of double hit lymphomas - aggressive course, resistance to conventional chemotherapy, high-risk of early relapse, short overall survival, frequent extranodal and central nervous system involvement. Recently, these lymphomas have attracted a strong attention of researchers as they provide sharp insights into processes of lymphocytes maturing and lymphomas development and highlight the double edged nature of mechanisms allowing the antibody broad diversity. CASE REPORT: Fifty  three year  old man was diagnosed with B cell lymphoma unclassifiable with features intermediate between diffuse large B cell lymphoma (DLBCL) and BL, based on morphology and immunophenotype. Fluorescent in situ hybridization analysis revealed double hit lymphoma diagnosis as the tumor cells bear t(14;18) translocation concurrently with the MYC gene rearrangement. The patient died five months after dia-gnosis.

Clinical impact of PAI 1 4G/5G gene polymorphism in colorectal carcinoma patients.

Plasminogen activator ihnibitor (PAI 1) belongs to the plasminogen activator system, which is part of the metastatic cascade and significantly contributes to invasive growth and angiogenesis of malignant tumors. Its plasma level is normally low but 4G/4G homozygotes have higher concentrations of PAI 1. This genotype may be associated with worse prognosis and proximal location of colorectal cancer than 5G/5G homozygotes. In our prospective evaluation we examined plasma level PAI 1 (using photometric microplate method ELISA) pre-surgery and, subsequently, 6-8 weeks later, from 80 patients. For the PAI 1 rs1799889 -675 4G/5G polymorphism test the PCR amplification was used.Analysis of collected data was confirmed that significantly higher plasma levels of PAI 1 were found in patients before starting therapy, which decreased (p=0.004) after initiation of treatment. Patients with higher plasma level PAI 1 before (p=0.013) and after therapy (p=0.004) had significantly shorter survival. We found no relationship between polymorphisms of PAI 1 (-675 4G/5G) in relation to stage, survival or tumor location. PAI 1 is useful as a negative marker of prognosis and could be advantageous when planning adjuvant treatment of patients with colorectal carcinoma. Although opinions on the importance of polymorphisms of PAI 1 in relation to the prognosis are not uniform, it does seem that their role in the prognosis of patients with colorectal cancer is not essential.

[Histiocytic sarcoma]. / Histiocytární sarkom.

Histiocytic sarcoma is a neoplasm arising from the histiocytes. Histiocytic neoplasms are among the rarest malignancies of lymphatic tissues. Occurs in less than 1% of all malignancies affecting lymph nodes and soft tissues [1,2]. The exact incidence of histiocytic sarcoma has not been described so far. In this article, we report three patients with HS, who were treated at the departement of Internal medicine, haematology and oncology, Faculty Hospital Brno. Despite the fact that all these patients had the same disease, the treatment effects differ depending on the stage of the disease at the time of diagnosis.

Extensive Al amyloidosis presenting with recurrent liver hemorrhage and hemoperitoneum: case report and literature review.

BACKGROUND: Spontaneous hepatic bleeding is a rare but potentially life-threatening complication of primary systemic amyloidosis. Although the liver is a common site of amyloid deposition, clinical presentation is usually mild or absent. CASE: We report a case of a female patient, who had been repeatedly surgically revised because of liver rupture and hemoperitoneum. Initially, the computed tomography finding was interpreted as liver hemangioma. However, based on liver biopsy, the diagnosis had to be changed to primary systemic amyloidosis, and the patient was referred to our hematooncology department. Due to a considerably advanced disease, the patient was eligible only for palliative chemotherapy with cyclophosphamide and dexamethasone, which could not deflect the course of rapidly progressing liver destruction. CONCLUSION: The cause behind ruptured and bleeding liver does not always need to be hemangioma but rather amyloidosis. In cases of advanced disease and in patients with contraindications for aggressive treatment, the outlook for complete hematological and organ treatment response is very limited. An early diagnosis is of utmost importance. Although liver biopsy brings the definite results, screening for monoclonal protein in serum or urine, leading to a search for AL amyloidosis, may be sufficient for diagnosis. The presence of some of the warning signs (B-symptoms such as fevers or subfebrile temperatures, fatigue, weight loss; and paraneoplastic laboratory findings such as elevated C-reactive protein and erythrocyte sedimentation rate) should raise suspicion of a lymphoproliferative disease.

[Our experience in treatment of multicentric plasma-cell Castleman disease associated with vasculitis manifestations - case report and literature review]. / Nase zkusenosti s lécbou multicentrické plazmocelulární Castlemanovy choroby s projevy vaskulitidy - popis prípadu a prehled literatury.

Castleman disease is a rare idiopathic non-neoplastic lymphoproliferative disorder with 2 clinical (unicentric and multicentric) and 3 histomorphological (hyaline-vascular, plasma-cell and mixed) forms identified. The case report given here describes the 3-year experience with therapy in a patient, male born 1961, diagnosed with multicentric plasma-cell Castleman disease (HIV and HHV-8 negative) with the finding of generalized lymphadenopathy and splenomegaly. During first line treatment (R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, 3 cycles in total, 12/2008-2/2009) the development of bilateral upper and lower limb edemas with clinical manifestation of vasculitis occurred and a restaging computed tomography (CT) examination revealed a stable finding of the lymphadenomegaly. Greater success was achieved with thalidomide regimen (CTD: cyclophosphamide, thalidomide, dexamethasone, 10 cycles, 3/2009-1/2010) leading to reduction in the size of the hypervascularized lymph nodes (almost by 50%) as well as their radiopharmaceutical (fluorodeoxyglucose) uptake as seen on a combined positron emission tomography and computed tomography (PET/CT) scan imaging. Thalidomide was given daily at doses between 100 and 200 mg. We returned to the CTD regimen again in April 2010 after a short period of monoclonal antibody tocilizumab treatment (400 mg intravenous in 2-week intervals with 50% dose reduction due to a limited supply of the drug, 5 doses in total) during which edemas reoccurred with a CT scan finding of stable lymphadenomegaly. However, the renewed regimen with thalidomide was stopped after 2.5 cycles due to adverse effects of thalidomide (neuropathy) and corticoids (Cushing syndrome). In September 2010, after enrollment in the Celgenes Compassionate Use Program we were able to start treating the patient with the derivative of thalidomide, lenalidomide, at a dosage of 25 mg on days 1-21 in a 28-day cycle, 15 cycles in total (10/2010-12/2011). The monotherapy with lenalidomide was very well tolerated by the patient without any effects of myelotoxicity, thromboembolism or relapses of edemas and vasculitis, additionally now with apparent improvement of fatic disorder and the patients motor abilities. Thus, lenalidomide represents an attractive alternative agent for patients with Castleman disease after rituximab and cytostatics failures. It has a favourable safety profile and could be therefore considered for administering in first line treatment.

[The role of PET-CT in decision making on the treatment of localized nodular form of pulmonary AL-amyloidosis]. / Prínos PET-CT vysetrení pro rozhodování o lécbe lokalizované nodulární formy plicní AL-amyloidózy.

Depending on the extent of organism affected, there is a systemic (amyloid is deposited in the interstitial space of multiple tissues and organs) and localized (amyloid is deposited in one or a few solitary lesions) form of amyloidosis. Localized forms of amyloidosis have a significantly better prognosis than the systemic ones. The respiratory tract might be affected by diffuse interstitial involvement, associated with systemic AL-amyloidosis, as well as localised involvement of respiratory tract (localised laryngotracheobronchial amyloidosis) or pulmonary parenchyma called nodular form of localized pulmonary amyloidosis. Tracheobronchial form may affect larynx and bronchial tree, and forms plaques or nodules in the epithelium of the respiratory tract. Nodular form causes spherical or irregular lesions in the pulmonary parenchyma, indistinguishable from pulmonary parenchyma metastases. We describe a two-year follow up of a patient with nodular form of pulmonary amyloidosis. The patient had multiple lesions in both lungs, clearly visible on HRCT (High Resolution Computer Tomography) that intensively accumulated fluorodeoxyglucose (FDG) during the first PET-CT. At the time of diagnosis, the largest lesion SUV for FDG accumulation was 8.2. Histochemical analysis showed that amyloid consisted of the light λ chains, i.e. AL-amyloid. Investigations to detect a systemic form of amyloidosis, if present, were negative. The patient had no monoclonal immunoglobulin either in the urine or serum (negative immunofixation) and had normal levels of free light chains in the serum. Her symptoms were previously suggestive of the Sjögrens syndrome. However, the rheumatologist consulted at the time of diagnosis of the nodular form of pulmonary amyloidosis did not find any signs of an active systemic connective tissue disorder. CRP was repeatedly normal. When systemic AL-amyloidosis was excluded, we decided to only monitor lesion development with no treatment intervention. The patient had 3 PET-CTs. CT showed that no lesions enlarged, some lesions decreased in size slightly. It should be emphasized that follow-up PET-CTs did not show increased FDG accumulation. We assume that the increased FDG accumulation in pulmonary lesions seen during the first PET-CT was due to the activity of the cells that formed this amyloid and that this activity spontaneously ceased, leading to normalization of FDG accumulation in pulmonary nodules. PET-CT is useful for monitoring of the development of pulmonary nodular amyloidosis. Normalization of originally increased FDG accumulation in amyloid lesions suggests cessation of the process of amyloid formation and is a positive prognostic sign.

[Lenalidomide induced therapeutic response in a patient with aggressive multi-system Langerhans cell histiocytosis resistant to 2-chloro-deoxyadenosine and early relapsing after high-dose BEAM chemotherapy with autologous peripheral blood stem cell transplantation]. / Lenalidomid indukoval lécebnou odpoved u pacienta s agresivní multisystémovou formou histiocytózy z Langerhansových bunek (LCH), rezistentní ke 2-chlorodeoxyadenosinu a casne relabující po vysokodávkované chemoterapii BEAM s autologní transplantací kmenových hemopoetických bunek.

Adult Langerhans cell histiocytosis (LCH) usually follows a favorable course. Very rarely, however, multi-system (multi-organ) LCH difficult to manage either with traditional first line treatment (vinblastine, mercaptopurine, prednisone or etoposide) or 2-chlorodeoxyadenosine occurs. In these patients, other treatment modalities have to be used. We describe a patient with LCH manifesting with generalized lymphadenopathy and infiltrating the pulmonary parenchyma and skin. The disease activity was always associated with B-symptoms (weight loss, subfebrile states, night sweats). Histological investigations repeatedly showed higher proliferation activity than that usual in adult patients with LCH. Expression of Ki-67 proliferation marker was up to 30% and there were 8-10 cells in mitosis in the microscope viewing field. Therefore, therapy started with the application of stimulation regimen (cyclophosphamide 2 g/m2 on day 1 and etoposide 200 mg/m2 on days 1-3) followed by collection of peripheral blood stem cells. Then, treatment with 2-chlorodeoxyadenosine, the first 3 cycles as monotherapy of 5 mg/m2 SC on days 1-5 in 28-day cycles, the next 3 cycles in combination with cyclophosphamide 150 mg/m2 on days 1-5 and methylprednisolone 250 mg on days 1-5, was used. However, the disease relapsed 2 months after completion of the therapy. This early relapse was treated with 4 cycles of CHOEP chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone). Following the 4th cycle of CHOEP, high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, melphalan) with autologous stem cell transplantation were administered. According to the follow-up PET-CT examination, this treatment resulted in complete disease remission. However, the disease relapsed again in the lymph nodes, lungs, skin and bones 5 months after the high-dose chemotherapy. The progression was documented on PET-CT scanning. Lenalidomide 25 mg daily for 21 days in 28-day cycles with dexamethasone 20 mg once a week were administered as the 4th line treatment. After the 4th cycle of lenalidomide, PET-CT was performed, where the CT component suggested a significant reduction (more than 50%) in the size of the lymph nodes and the PET component showed substantial reduction in fluorodeoxyglucose accumulation in the affected lymph nodes as well as in the bone lesions. HRCT showed disappearance of pulmonary nodules. During the treatment, CRP levels declined and hemoglobin rose from 110 to 141 g/l, i.e. partial remission was achieved after 4 cycles. Etoposide (100 mg IV) was added to lenalidomide and dexamethasone on days 22, 23 and 24 of the above mentioned 28-day cycle. The added etoposide further intensified treatment response. In all, 11 cycles of this chemotherapy were given, resulting in complete remission confirmed by follow-up PET-CT. The achieved remission was consolidated using allogeneic bone marrow transplantation after FLAMSA reduced intensity conditioning without amsacrine. Four months after allogeneic transplantation, the patient has been relapse free. Herein we presented treatment response of highly aggressive LCH to lenalidomide. The used four cycles led to partial remission only and with the combination of lenalidomide, dexamethasone and etoposide the treatment response was further intensified to complete remission.

[Six-year follow-up of a patient with multiple angiomatosis involving skeleton, thoracic and abdominal cavities and the gut wall]. / Sestileté sledování pacienta s mnohocetnou angiomatózou postihující skelet, brisní i hrudní dutinu a stenu trávicí trubice.

BACKGROUNDS: Multiple angiomatosis is a rare disease causing angiomatous lesions in multiple organs and tissues with a risk of life-threatening haemorrhage. OBSERVATION: A young man was diagnosed with multiple angiomatosis at the age of 28 after two years of back and abdominal pain. Laparotomy revealed multiple spongy lesions mostly within the retroperitoneal space. Also, an involvement of the gut wall, bones and mediastinum was evident. After 6 years of treatment, the disease has been stabilized. Bone pain ceased with a significant contribution of zoledronate. Using CT and MR imaging, the effectiveness of antiangiogenic drugs was evaluated. Furthermore, treatment response was evaluated using laboratory values for coagulation and blood count, as angiomatous proliferation is known to be associated with disseminated intravascular coagulation and anaemia. RESULTS: Baseline laboratory examination revealed elevated D-dimer (more than 20 µg/mL), low fibrinogen (1.4 g/L), and the presence of fibrin monomers. After treatment with 6 mil. IU of interferon-alpha thrice weekly, there was only partial improvement in D-dimer (17.2 µg/mL) and fibrinogen (1.5 g/L) concentrations but fibrin monomers remained positive. After thalidomide (100 mg daily), D-dimer decreased to 6.1 µg/mL and fibrinogen levels increased to 1.9 g/L with the disappearance of fibrin monomers. CT scanning showed significant regression of angiomatous lesions. Progressive neuropathy was the reason to lower the dose of thalidomide by half and this caused D-dimer to rise again. Switching to lenalidomide 10 mg daily led to an increase in D-dimer to 10.8 µg/mL and decrease in haemoglobin concentration to 124 g/L. Fibrin monomers became positive again. Combined therapy with thalidomide (50 mg/day) and lenalidomide (10 mg days 1-21 in 28-day cycles) has led to stabilisation of the disease. Median concentration of haemoglobin increased to 131 (84-141) g/l. The median of D-dimer decreased to 9.3 (8.0-17) µg/mL. CONCLUSION: Thalidomide in the dose of 100 mg daily led to better stabilisation of the disease than interferon-alpha. However, lowering the dose because of adverse effects failed to be effective sufficiently. Lenalidomide 10 mg daily was well-tolerated but insufficient to improve D-dimer and haemoglobin concentrations. Therefore, for further treatment we have decided to use the combination of lenalidomide and thalidomide in doses of 10 mg and 50 mg, respectively because both drugs have desirable antiangiogenic activities with different adverse effect profiles. On this therapy, the patients disease has been stable for 9 months.

Clinical significance of the plasminogen activator system in relation to grade of tumor and treatment response in colorectal carcinoma patients.

Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, and together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. In our project we examined the expression of uPA, uPAR, PAI 1 and PAI 2 in tumor tissue and we also studied the plasma levels of PAI 1 before and after the initiation of therapy in patients with colorectal carcinoma in relationship to grade of tumor and the treatment response. In our prospective evaluation we included 80 patients treated for adenocarcinoma of the colon and rectum. Analysis of collected data revealed statistically significant evidence of a relationship between the level of PAI 1 in plasma before treatment and grade of the tumor, which increases with tumor grade (p=0.025). We demonstrated that there exists a statistically significant relationship between the expression of PAI 2 (p<0.001) and uPAR (p=0.031) and grade of tumor. We also confirmed a statistically significant relationship between soluble levels of PAI 1 before treatment and therapeutic response (p=0.021). In our group of patients the expression of uPA, uPAR, PAI 1 and 2 in tumor tissue in relation to response to treatment was also assessed. Our results suggest that the greater expression of these parameters in tumor tissue is linked to a worse response to therapy. In conclusion, PAS factors help as a prognostic indicators and could also act as a predictive factor in colorectal carcinoma.

[Successful treatment of Erdheim-Chester disease by 2-chlorodeoxyadenosine-based chemotherapy. Two case studies and a literature review]. / Uspesná lécba Erdheimovy-Chesterovy nemoci chemoterapií obsahující 2-chlorodeoxyadenosin. Popis dvou prípadu a prehled literatury.

INTRODUCTION: Erdheim-Chester disease is an extremely rarely occuring condition and thus an optimal treatment is not known. Two new cases have been diagnosed in our centre in 2008 and 2009. Both patients had diabetes insipidus, B symptoms (subfebrile to febrile states) and pain in long bones of lower limbs. CASE STUDIES: Imaging showed high accumulation of fluorodeoxyglucose as well as Tc-pyrophosphate in long bones of lower as well as upper limbs, aortic wall thickening with periaortic fibrosis and perirenal fibrosis. In addition, one of the patients had multiple lesions in the brain. 2-chlorodeoxyadenosine 5 mg/m2 s.c. and cyclophosphamide 150 mg/m2 administered on days 1 to 5 in 28-day cycles were selected for the treatment of both patients. Dexamethasone 24 mg/day for 5 days was added to this treatment in the second patient. Six cycles of the treatment were planned. Both patients were prescribed bisphosphonates--zoledronate and clodronate, respectively. Treatment effect was assessed with PET-CT and MR. Following treatment completion, brain infiltrates were reduced to a small residuum in the first patient who did not anymore complain of leg pain. However, there was no reduction in fluorodeoxyglucose accumulation in bone lesions and thus treatment response was assessed as partial remission. This patient is currently receiving a second line treatment and treatment follow-up is 26 months from the diagnosis. Repeated PET-CTs in the second patient showed a significant reduction in accumulation of fluorodeoxyglucose in all pathological lesions. Febrile states and pain in long bones as well as pathological fatigue ceased after the treatment. Increased CPR and fibrinogen gradually returned to their normal levels. This response is assessed as complete remission. This patient's follow-up is 16 months from the diagnosis. CONCLUSION: Administration of 2-chlorodeoxyadenosine (5 mg/m2 s.c.) + cyclophosphamide (150 mg/m2 intravenously) and dexamethasone (24 mg/day) led to partial remission in one patient; nearly complete remission of CNS infiltrates but persistent elevation of fluorodeoxyglucose accumulation in bone lesions. Complete remission with a significant reduction in accumulation of fluorodeoxyglucose in all disease lesions with normalization of originally increased inflammatory markers and disappearance of all symptoms of the disease was achieved in the second patient.

[Plasminogen activator system and its clinical significance in patients with a malignant disease]. / Plazminogen aktivátor systém a jeho klinický význam u pacientu s nádorovým onemocnením.

Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, a serine protease participating in the activation of matrixmetaloproteinases, latent elastases, growth factors and cytokines involved in the degradation of extracellular matrix elements. Together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI-1, PAI-2, PAI-3 and protease nexin), it forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. Plasminogen activator inhibitor 1 inhibits uPA-dependent invasiveness of some cancer cell lines. The vitronectin-PAI-1 complex inhibits migration of smooth muscle cells by binding alpha(v)beta3 integrin to vitronectin. PAI-1 or its deficiency interferes with signalling pathways such as PI3K/Akt and JAK/STAT and it is included in the processes of maintaining the integrity of the endothelial cells and thereby regulation of cell death. PAI-1 affects apoptosis by reducing cell adhesion and functioning of intracellular signalling pathways. The individual components of PAS undoubtedly play an important role in angiogenesis and metastasising of malignant tumours. In the near future, results of published studies with various types of cancer could be reflected in diagnostic and therapeutic algorithms and, at the same time, could serve as the goal for targeted therapies.

[Castleman disease]. / Castlemanova choroba.

BACKGROUNDS: Castleman disease is a rare non-clonal lymphoproliferative disorder with the etiopathogenesis not yet thoroughly clarified. Clinically, either unicentric (localized) or multicentric (generalized) forms are recognized while, histopathologically, hyaline-vascular, plasma-cell and mixed variants of the disease exist. These types vary one from another in their clinical courses and, importantly, in methods of therapeutic management. While the unicentric hyaline-vascular form usually manifests as benign growth of a single lymph node and treatment response to complete surgical excision reaches up to 100%, the multicentric plasmocellular variant is an aggressive disease with generalized symptoms, laboratory abnormalities and the need for systemic therapy. AIM: The paper provides an overview of information on Castleman disease from its clinical and histopathological signs to diagnostic and therapeutic options. It deals with the role of cytokines and HHV-8 virus infection in the disease pathophysiology and is supplied with ample pictorial documentation of radiographic findings including ultrasonography, computed tomography and hybrid imaging by positron emission tomography (PET) in combination with simultaneously taken full-body computed tomography (CT) scans, the so called PET/CT. We also present photographs of histological specimens taken from an HIV and HHV-8 negative patient with the plasmocellular multicentric form. CONCLUSIONS: Consequent to its low incidence, Castleman disease is often misdiagnosed or diagnosed with a delay. Therefore, it is always necessary to include this rare condition in differential diagnostics of lymphadenopathy, microcytic anemia as well as B-symptoms (night sweats, fevers and weight loss). In conclusion, we also stress the significance of full-body PET/CT scanning during staging and treatment response evaluation.

[Partial regression of CNS lesions of Erdheim-Chester disease after treatment with 2-chlorodeoxadenosine and their full remission following treatment with lenalidomide]. / Parciální regrese lozisek Erdheimovy-Chesterovy nemoci v CNS po lécbe 2-chlorodeoxyadenosinem a jejich kompletní vymizení prn lécbe lenalidomidem.

INTRODUCTION: Erdheim-Chester disease is a very rare syndrome affecting adult population. It typically causes hyperostosis of long bones, retroperitoneal fibrosis and widening of the aortic wall. Patients frequently suffer from disease-associated fevers and pain in the lower limbs. No guidelines are available for the treatment of this rare ailment. Therefore, we describe our experience with lenalidomide in a patient with poor treatment response to 2-chlorodeoxyadenosine. CASE: Diabetes insipidus and neurological problems developing over 4 years were the first signs of the disease. The disease was diagnosed from histology of the bone marrow extracted from the ilium. At diagnosis, the patient had multiple infiltrates in the brain, widened wall of the thoracic and abdominal aorta, fibrotic changes to retroperitoneum and typical hyperostosis of the long bones of lower limbs with high accumulation of technetium pyrophosphate as well as fluorodeoxyglucose. First line treatment involved 2-chlorodeoxyadenosine 5 mg/m2 s.c. for 5 consecutive days every 28 days. There was no clear treatment response identifiable on the MR scan of the brain following the third cycle and thus 4th-6th cycle consisted of 2-chlorodexyadenosine 5 mg/m2 + cyclophosphamide 150 mg/m2 + dexamethasone 24 mg day 1-5 every 28 days. After the 6th cycle, MR showed partial regression of the brain lesions. PET-CT showed an increased accumulation of fluorodeoxyglucose in bone lesions. Second line treatment involved lenalidomide 25 mg/day days 1-21 every 28 days. Lenalidomide tolerance was excellent; the number of neutrophils and thrombocytes was within the physiological range throughout the treatment period. Follow-up MR showed complete remission of the brain lesions, while follow-up PET-CT showed further increase in fluorodeoxyglucose accumulation in the bones of lower limbs. CONCLUSION: Treatment with 2-chlorodeoxyadenosine-based regimen provided partial remission of Erdheim-Chester disease lesions in the brain, while treatment with lenalidomide resulted in complete remission of these lesions. Fluorodeoxyglucose continues to accumulate in the long bones of lower limbs. We are unable to elucidate the reasons for complete remission of the disease in the brain as per the MR and its progression in the long bones according to PET-CT. Further testing of lenalidomide in the treatment of this disease is required to support further use of this perspective treatment option.

[Lymphoma-like course in aggressive adult multisystem Langerhans cell histiocytosis and the benefit of PET/CT imaging in evaluation of diffuse metabolic activity of lung parenchyma]. / Lymfomu podobný prubeh agresivní multisystémové histiocytózy z Langerhansoých bunek v dospelosti a prínos PET/CT vysetrení pri hodnocení difuzní metabolické aktivity v plicním parenchymu.

The case report given here describes an unusual case of a 35-year-old otherwise healthy male diagnosed with aggressive form of Langerhans cell histiocytosis initially taking course under the form of lymphoma with expressed B symptoms (night sweats, fever and weight loss) and generalized peripheral lymphadenopathy. Also present were productive cough and perianal itching. The diagnosis was determined from lymph node and perianal skin biopsies. Furthermore, by a typical finding on HRCT (high-resolution computed tomography), pulmonary involvement was confirmed the gradual development of which we succeeded to document through a series of several HRCT and PET/CT scans from its initial florid phase characterized by disseminated nodularities up to the terminal phase with the decline of activity and development of cystic formations. After the collection of peripheral blood stem cells, the planned patient's therapy started which in all consisted of three monotherapy cycles with cladribine followed by three cycles of combined chemotherapy (cladribine + cyclophosphamide + methylprednisolone) and complemented with curative radiotherapy of the perianal area. This treatment put the disease into complete remission. However, in two months the initial B-symptoms occurred again, along with the pulmonary symptomatology, perianal pruritus and newly also hip bone pains. The suspected LCH relapse was proved histologically by lymph node biopsy and confirmed at a restaging PET/CT examination which also showed disease dissemination into the hip bones. Consequently, an aggressive form of the disease with early relapse had been the case, which was indicated for administering 4 cycles of CHOEP (cyclophosphamide + doxorubicin + vincristine + etoposide + prednisone) as salvage regimen completed in March 2010 with autologous peripheral blood stem cell transplantation after high-dose BEAM (carmustine + etoposide + cytarabine + melphalan) chemotherapy. Thus, the generalized involvement of nodes doesn't always need to be malignant lymphoma or metastatic dissemination of a tumour but also LCH may be the case. The presence of B symptoms may very likely stand for an aggressive form of the disease course. Histological evaluation of the proliferative characteristic (given by Ki-67 immunohistochemical proliferative index marker and also morphologically by the number of mitosis) may draw attention to an aggressive form of this disease. However, therapy with cladribine (2-chlorodeoxyadenosine) which proves beneficial in classic forms of LCH, in cases of highly aggressive forms of LCH doesn't need to have the same effect as in LCH with low proliferative activity, which conforms to the present experience in the treatment of indolent and aggressive lymphomas. In our study, the hybrid PET/CT imaging proved high sensitivity in evaluating the activity of the disease, including its early relapse. We are presenting here a new method for description and evaluation of diffuse increased activity of pulmonary parenchyma by means of PET/CT examination and for using this method within the framework of monitoring the curative response.

[Treatment of AL-amyloidosis--results from one clinic and review of published experience with new agents (bortezomib, thalidomide and lenalidomide) in AL-amyloidosis]. / Lécba AL-amyloidózvy--výsledky jednoho pracoviste a prehled publikovanych zkuseností s novými léky (bortezomibem, thalidomidem a lenalidomidem) u AL-amyloidózy.

PATIENTS: Fifteen patients with light chain deposits in the form of AL-amyloidosis and 2 patients with light chain deposition as amorphous matter (light chain deposition disease) were treated at our clinic as of 1999. Median age at the diagnosis was 63 (34-77) years. The light chain deposition caused: nephrotic syndrome in 12 (70%) patients, renal insufficiency with reduced filtration in 4 (23%) patients, cardiomyopathy in 4 (23%) patients, hepatosplenomegaly in 2 (12%) patients, manifest coagulopathy in 2 (12%) patients, periorbital hematoma in 2 (12%) patients, visceral and somatic neuropathy in 2 (12%) patients. Treatment with high-dose dexamethasone in combination with adriamycin and vincristine (VAD) or cyclophosphamide (CAD orjust CD) was used in 11 patients. In 4 patients, therapy was completed with high-dose chemotherapy and autologous transplantation; complete haematological and organ treatment response was achieved in all 4 patients with remission lasting 113+, 87+, 50, 45+ months. Of the remaining 7 patients in whom high-dose dexamethasone therapy was not completed with high-dose chemotherapy, 3 achieved complete haematological remission (CR) and very good partial remission (VGPR), with 2 patients achieving complete organ treatment response. Organ response in the third patient cannot be assessed due to the short evaluation period. PR with no organ treatment response was achieved in other 2 patients and 2 patients died during the treatment. Therapy with prednisone and alkylating cytostatics was used in 2 patients with serious organ damage, both patients died after a short period of time due to the disease and thus treatment response cannot be evaluated. Combination of thalidomide, dexamethasone and cyclophosphamide (CTD) was used in 4 patients. Two of these patients did not complete full 2 cycles, one for unmanageable thalidomide-associated constipation, the other died. Two patients underwent a total of 5 and 6 cycles of this treatment with PR effect and plateau after the previous decline of monoclonal immunoglobulin concentrations. Treatment combination of bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) was used in three patients. In one patient (6 completed CTD cycles with the PR result) this combination led to complete haematological remission, complete remission was also achieved in the second patient and the application of 2 CVD cycles led to CR in the third (5 CTD cycles with PR result). Just one of the 3 female patients has been followed up for more than 12 months and so it is possible to evaluate organ treatment response in this patient; nephrotic syndrome ceased, meaning that organ CR has been achieved. CONCLUSION: Early diagnosis (before severe organ damage occurs) enables administration of aggressive treatment (high-dose chemotherapy and autologous transplantation) with the outlook of complete haematological and organ treatment response. New drugs thalidomide and bortezomib further expand treatment armamentarium; according to our limited experience and published information, bortezomib may be considered as very effective and well tolerated agent suitable, in combination, for patients with the diagnosis of AL-amyloidosis.

[Diabetes insipidus followed, after 4 years, with dysarthria and mild right-sided hemiparesis--the first clinical signs of Erdheim-Chester disease. Description and depiction of a case with a review of information on the disease]. / Diabetes insipidus, následovaný po 4 letech dysartrií a lehkou pravostrannou hemiparézou--první klinické príznaky Erdheimovy-Chesterovy nemoci. Popis a zobrazení prípadu s prehledem informací o této nemoci.

In 2004, diabetes insipidus was the first clinical sign of Erdheim-Chester disease in our patient. Following introduction of substitution therapy with adiuretin, the patient had no further health complaints for four years until 2008 when he gradually developed dysarthria and, consequently, movement disorder in the form of mild right hemiparesis. The first CNS CT scan (2004) did not reveal any pathology. The first pathological MRI of the brain in 2006 - thickening of pituitary stalk by pathological infiltration to 4-5 mm. During the following year, further infiltrates were detected in the CNS. The number and size of CNS infiltrates increased gradually on MRIs performed repeatedly up to 2008. Erdheim-Chester disease has become suspected based on PET-CT examination at the end of 2008. CT showed irregular structure of the skeleton with noticeable sclerotic foci in otherwise osteoporotic bone structure; changes were the most evident in the long bones of lower limbs, in the pelvic bones, skull and arms, while only one vertebra was affected from within the entire spine. Finding ofthickened aortic wall (up to 8 mm) as another pathological circumstance was consistent with the Erdheim-Chester disease-associated changes described as coated aorta. CT scan revealed clear fibrotic changes in the area of retroperitoneum. Applied fluorodeoxyglucose has accumulated in the bone foci described on CTscans as well as in the thickened wall ofthe thoracic and abdominal aorta (SUV 3.6). Tc-pyrophosphonate skeleton scintigraphy showed the same bone foci as PET-CT. Full body MRI showed pathological signal from the bone marrow of the above mentioned locations, particularly during STIR imagining, where there was clear abnormal signal corresponding to accumulated histiocytes, the higher signal of which was well-differentiated from the normal bone marrow. Measurement of bone mineral density with DEXA confirmed reduced density in lumbar vertebrae to the average value of - 2.7 SD (the lowest value was -3.1SD). The disease is associated with elevated inflammatory parameters: leucocytosis, thrombocytosis, elevated CRP and fibrinogen levels. Diagnosis was verified following histological assessment ofiliac bone marrow, where focal infiltrations with foamy histiocytes of typical immunophenotype (CD68+, CD1a-, S100-) were confirmed. Treatment was initiated with chemotherapy consisting of 2g/m2 of cyclophosphamide on day 1 and 200 mg/m2 of etoposide IV infusion on days 1-3, and followed by administration of 5 microg/kg of G-CSF and collection of haematopoietic peripheral blood stem cells (PBSC). PBSC collection was followed by 5-day administration of 5 mg/m2/day of 2-chlorodeoxyadenosine (Litac) administered to the patient at monthly intervals.

[Pulmonary segmentectomy for tumour]. / Plicní segmentektomie pro nádor.

BACKGROUND: An analysis of outcome data of pulmonary segmentectomy focused on local efficacy in primary non small cell lung cancer and true or seeming lung metastasis. PATIENTS AND METHODS: Miscellaneous series of twenty patients treated with classical open procedure involving individuals with primary or metachronous non small cell lung cancer, solitary pulmonary metastasis of extrapulmonary cancer and/or benign pulmonary lesions, lung metastasis mimicing. Thirteen patients after segmentectomy because of malignancy are separated into a group of 7 cases with NSCLC up to 20 mm in diameter, and a group of 6 persons with solitary pulmonary opacity up to 38 mm treated previously surgically for extrapulmonary cancer. Both without enlargement of hilar and/or mediastinal lymphatics proven on preoperative CT imaging. Third part of the group collects benign pulmonary lesions: chondrohamartoma, pneumonitis and pulmonary infarct. Persons involved through a ten years period are followed up at 3 (4)-months intervals. RESULTS: No perioperative and thirty day mortality was registered. Six cases of distant recurrence were recorded, three in NSCLC and three in extrapulmonary cancer patients. Five patients died within the follow-up period, three of them through the general progression of the oncological disease. Two deaths were non-cancer related. One R1 disease was discovered in a patient with primary lung adenocarcinoma. No local recurrence was recorded in both cancer series with median age of 63 yrs (range 45-79 yrs) and median duration of follow up 35 months. CONCLUSION: Lung segmentectomy seems to accomplish local control of early stage non small cell lung cancer and pulmonary metastasis of extrapulmonary cancer in selected patients.

[The use of galactomannan detection in diagnosing invasive aspergillosis in hemato-oncological patients]. / Vyuzití detekce galaktomananu pro diagnostiku invazivní aspergilózy u hematoonkologických nemocných.

UNLABELLED: PREMISES AND OBJECTIVES: Timely diagnosis is of critical importance for the prognosis of invasive aspergilosis (IA) patients. Over recent years, IA detection of galactomannan using the ELISA method has assumed growing importance. The objective of the study was to analyse the usability of the method in current clinical practice of a hemato-oncological ward. PATIENTS AND METHODS: From May 2003 to October 2006, blood samples were taken from patients at IA risk to detect galactomannan (GM) in serum using the ELISA method. The patients who underwent the tests were classified by the probability of IA presence on the basis of the results of conventional diagnostic methods and section findings. RESULTS: A total of 11,360 serum samples from 911 adult patients were tested for GM presence. IA (probable/proven) was diagnosed in 42 (4.6%) of them. The rates of sensitivity, specificity, positive and negative predictive value of galactomannan detection for IA diagnosis in our ward were, respectively, 95.2%, 90.0%, 31.5% and 99.7%. The principal causes of the limited positive predictive value of the test were the high percentage of false-positive test results (mainly caused by concomitant administration of some penicillin antibiotics or Plasma-Lyte infusion solution), as well as the fact that a large percentage of patients we examined fell within the group of patients with hematological malignity with a very low prevalence of IA. CONCLUSION: GM detection in serum is associated with high sensitivity and excellent negative predictive value in IA diagnosis in hemato-oncological patients. Knowledge and elimination of possible causes of false-positive results as well as focusing the screening on patients at greatest risk of infection are necessary for an even better exploitation of the test.

[Treatment of multiple angiomatosis involving the skeleton and the abdominal and thoracic cavities with interferon alpha, thalidomide and zoledronate]. / Lécba mnohocetné angiomatózy postihující skelet, brisní i hrudní dutinu interferonem alpha, thalidomidem a zoledronátem.

Multiple angiomatosis is a very rare disease formed by histologically benign angiomas spreading beyond single organ or tissue. In the case reported herein, hemangiomas affected several vertebrae of a young man and spread through his peritoneal cavity projecting to his stomach and causing recurrent hematemesis. Also affected was the mediastinum. The patient suffered from bone pain and digestive problems. Initial treatment involved 2 drugs with antiangiogenic effect: interferon alpha (initial dose of6 million units 3 times a week, later reduced to 3 million units 3 times a week due to adverse effects) and zoledronate (4 mg i.v. every 28 days). Even though the therapy eliminated bone pain after 2 months, CT check at a later stage showed but little regression of the mass of the angiomas in the abdominal cavity and the mediastinum. Substantial reduction in the mass of the angiomas to merely residual quantity, i.e. partial remission of the disease, was achieved only after the addition of 100 mg/day thalidomide (Myrin) to the above mentioned doses of interferon and zoledronate administered on a regular basis. However, the disease recurred after the therapy was interrupted, and the above triple combination therapy has had to be restored. Maintenance therapy will succeed to repeated achievement of remission of angiomas. A very good therapeutic effect was recorded for combined interferon alpha, thalidomide and zoledronate in this specific case of multiple angiomatosis.