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5.
JMM Case Rep ; 5(10): e005168, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30479782

RESUMO

INTRODUCTION: Cryptococcosis in immunocompetent adults is a rare disease in Europe, mostly induced by members of the Cryptococcus gattii species complex. The diagnosis can be challenging due to its rarity, unspecific symptoms and long symptomless latency. CASE PRESENTATION: A 49-year-old woman with a three weeks history of headache was admitted to the hospital due to discrete ataxia and impaired vision. Cranial magnetic resonance imaging (MRI) showed a contrast-enhancing mass in the cerebellum. Further investigations detected a slight leukocytosis and a single subpleural nodule in the right inferior lung lobe. The cerebral lesion was surgically removed, and a direct frozen section only showed an unspecific inflammation. In the course of her admission she developed non-treatable cerebral edema and died ten days after surgical intervention. Histopathological examination of the surgical specimen and postmortem evaluation of the lung and the cerebrum demonstrated fungal elements. Molecular identification of the fungal elements in formalin-fixed paraffin-embedded tissue lead to the diagnosis of cryptococcosis induced by C. gattii sensu lato. Molecular genetic analysis identified the involved cryptococcal species as genotype AFLP6/VGII, recently described as Cryptococcus deuterogattii, which is known to be endemic to the west-coast of Canada and the USA. Additional heteroanamnestic information revealed that she had spent her holidays on Vancouver Island, Canada, two years before disease onset, indicating that infection during this stay seems to be plausible. CONCLUSION: Cryptococcosis due to C. deuterogattii is a rarely encountered fungal disease in Europe, not particularly associated with immunodeficiency, and infection is likely to be contracted in endemic areas. Due to its rarity, long symptomless latency, unspecific symptoms and misleading radiological features the diagnosis can be challenging. Physicians need to be aware of this differential diagnosis in immunocompetent patients, as early adequate therapy can be lifesaving.

6.
Pathologe ; 39(Suppl 2): 315-318, 2018 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-30374757

RESUMO

In 2014, two advisory committees (one each for myeloid and lymphoid neoplasms) of about 100 pathologists, hematologists, oncologists, and geneticists met in Chicago to revise the WHO diagnostic criteria. The goal was to define disease entities that should be modified, removed, or added based on new insights. In particular, to improve a biologically meaningful classification, a number of new molecular genetic markers were included, which had proved to be of diagnostic and/or prognostic relevance. The resulting differentiated diagnostic procedure is a challenge for the hematopathologist. Not only is it necessary to pool the information from a multimodal diagnostic process and to compare the results of morphology, immunophenotyping, and clinical information. It is also essential to integrate the techniques of fluorescence in situ hybridization and next generation sequencing into the diagnostic process. Hematopathological diagnostics have become more labor-intensive and cost-intensive as a result of this further differentiation.


Assuntos
Linfoma , Transtornos Mieloproliferativos , Chicago , Humanos , Hibridização in Situ Fluorescente , Organização Mundial da Saúde
7.
Leukemia ; 32(10): 2189-2202, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29654265

RESUMO

Many cases of AML are associated with mutational activation of receptor tyrosine kinases (RTKs) such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK, as an essential gene in multiple subtypes of AML, and observed that AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Interrogation of downstream pathways identified mTORC1-mediated suppression of autophagy and subsequent stabilization of leukemogenic drivers such as mutant FLT3 as important RET effectors. Accordingly, genetic or pharmacologic RET inhibition impaired the growth of FLT3-dependent AML cell lines and was accompanied by upregulation of autophagy and FLT3 depletion. RET dependence was also evident in mouse models of AML and primary AML patient samples, and transcriptome and immunohistochemistry analyses identified elevated RET mRNA levels and co-expression of RET and FLT3 proteins in a substantial proportion of AML patients. Our results indicate that RET-mTORC1 signaling promotes AML through autophagy suppression, suggesting that targeting RET or, more broadly, depletion of leukemogenic drivers via autophagy induction provides a therapeutic opportunity in a relevant subset of AML patients.


Assuntos
Autofagia/genética , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-ret/genética , Animais , Linhagem Celular Tumoral , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Imuno-Histoquímica/métodos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , Transdução de Sinais/genética , Transcriptoma/genética , Tirosina Quinase 3 Semelhante a fms/genética
9.
Pneumologie ; 72(7): 503-506, 2018 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-29466812

RESUMO

Acquired resistances to tyrosine kinase inhibitors in non-small cell lung cancer develop after 9 - 12 month. In 60 % of the cases these resistances arise because of a secondary EGFR-T790 M resistance mutation. This report is describing the case of a patient who developed parallel two different mechanisms of resistance: A T790 M resistance mutation and a transformation into a small cell neuroendocrine cancer. Under therapy with Osimertinib and chemotherapy with carboplatin and etoposide the tumor responsed partially.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas , Compostos de Anilina , Antineoplásicos/farmacologia , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Carcinoma Neuroendócrino/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Mutação , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
10.
Acta Physiol (Oxf) ; 222(3)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29152859

RESUMO

AIM: In vivo vascular smooth muscle cell (VSMC) EGF receptor (EGFR) contributes to acute angiotensin II (AII) effects on vascular tone and blood pressure. The ubiquitously expressed EGFR has been implicated in vascular remodelling preceding end-organ damage by pharmacological inhibition, and AII signalling in cultured vascular cells is partly EGFR-dependent. However, the role of VSMC-EGFR in vivo during AII-induced pathophysiological processes is not known. METHODS: This study assesses the in vivo relevance of VSMC-EGFR during chronic AII challenge without further stressors, using a mouse model with inducible, VSMC-specific EGFR knock out (VSMC-EGFR-KO). In these mice functional and structural vascular, renal and cardiac effects or biomarkers were investigated in vivo and ex vivo. RESULTS: Vascular smooth muscle cell-EGFR-KO prevented AII-induced media hypertrophy of mesenteric arteries, renal arterioles and the aorta, VSMC ERK1/2-phosphorylation as well as the impairment of vascular compliance. Furthermore, induction of vascular fibrosis, creatinineamia, renal interstitial fibrosis as well as the increase in fractional water excretion was prevented. AII-induced increase in systolic blood pressure was mitigated. By contrast, endothelial dysfunction, induction of vascular inflammatory marker mRNA and albuminuria were not inhibited. Cardiac and cardiomyocyte hypertrophy were also not prevented by VSMC-EGFR-KO. CONCLUSION: Vascular smooth muscle cell-EGFRs are relevant for pathological AII action in vivo. Our data show in vivo and ex vivo the necessity of VSMC-EGFR for AII-induced structural and functional vascular remodelling, not including endothelial dysfunction. Hereby, VSMC-EGFR gains importance for complete AII-induced renal end-organ damage succeeding vascular remodelling.


Assuntos
Angiotensina II/farmacologia , Receptores ErbB/deficiência , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Animais , Hipertrofia , Camundongos , Camundongos Knockout , Músculo Liso Vascular/patologia , Túnica Média/patologia
12.
Transpl Infect Dis ; 16(6): 988-92, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25179757

RESUMO

In both conditions, post-transplant lymphoproliferative disorder (PTLD) and hemophagocytic lymphohistiocytosis (HLH), infection with Epstein-Barr virus (EBV) is a key mechanism: almost all PTLD in allogeneic stem cell transplantation (alloSCT) is caused by EBV-related neoplastic lymphoproliferation, and secondary HLH is most frequently triggered by EBV infection. Therefore, concomitant EBV-driven PTLD and HLH early after alloSCT require an approach to eliminate EBV and balance immune activation simultaneously. We report on a patient who developed simultaneous PTLD and signs of HLH on day 64 after alloSCT. Treatment was comprised of stopping cyclosporine, short-course dexamethasone, and 3 courses of rituximab. The patient showed full recovery and complete remission of lymphadenopathy. This result indicates that immediate reduction in EBV-carrying B cells by rituximab, suppression of general inflammation, and parallel support of reconstitution of long-term T-cell function, might be an appropriate therapeutic approach in this rare situation.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Linfo-Histiocitose Hemofagocítica/complicações , Transtornos Linfoproliferativos/virologia , Transplante de Células-Tronco/efeitos adversos , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Rituximab , Adulto Jovem
13.
Bone Marrow Transplant ; 49(2): 179-84, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24292520

RESUMO

The Janus-activated kinase 1 (JAK1) and JAK2 inhibitor ruxolitinib is effective in decreasing symptomatic splenomegaly and myelofibrosis (MF)-related symptoms. However, allogeneic hematopoietic cell transplantation (HCT) remains the only curative option. We evaluated the impact of ruxolitinib on the outcome after HCT. A cohort of 14 patients (median age 58 years) received a subsequent graft from related (n=3) and unrelated (n=11) donors after a median exposure of 6.5 months to ruxolitinib. At HCT, MF risk for survival according to the International Prognostic Scoring System was intermediate-2 or high risk in 86% of patients. Under ruxolitinib, MF-related symptoms were ameliorated in 10 (71.4%) patients and the palpable spleen reduced by a median of 41% in 7 (64%) of 11 patients with splenomegaly. Engraftment occurred in 13 (93%) patients. Acute GvHD grade-III occurred in 2 (14%) patients. Median follow-up was 9 months. Survival, EFS and treatment-related mortality were 78.6, 64 and 7%, respectively. Through the anti-JAK-mediated reduction in both cytokines and splenomegaly as well as improvement in performance status, ruxolitinib might improve outcome after allogeneic HCT in patients with MF. The downregulation of inflammatory cytokines might have a beneficial impact on graft failure and acute GvHD.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Mielofibrose Primária/terapia , Pirazóis/uso terapêutico , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Prognóstico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/farmacologia , Pirimidinas
16.
Orthopade ; 41(6): 482-7, 2012 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-22699758

RESUMO

Paget's osteodystrophia deformans is a monoostotic or polyostotic disease of the skeletal system with increased bone remodelling, structural modifications and skeletal deformation, typically arranged like a chessboard. The unusual case of a patient is described who had suffered from generalized Paget's disease of the bone for 14 years and also developed progressive myopathy and a behavioural variant frontotemporal dementia. Further cytogenetic diagnostics revealed a point mutation in the valosin-containing protein (VCP, p97) gene on chromosome 9p13-p12 consistent with the finding of inclusion body myopathy with early onset Paget's disease and frontotemporal dementia (IBMPFD syndrome). A causal therapy of this disease is not known. Conservative treatment with bisphosphonate therapy, intensive physiotherapeutic exercise and psychotherapeutic treatment was performed to retard the progression of the disease.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 9 , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/genética , Osteíte Deformante/diagnóstico , Osteíte Deformante/genética , Mutação Puntual , Fosfatase Alcalina/sangue , Biópsia , Osso e Ossos/patologia , Terapia Combinada , Diagnóstico por Imagem , Demência Frontotemporal/patologia , Demência Frontotemporal/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/terapia , Osteíte Deformante/patologia , Osteíte Deformante/terapia , Proteína com Valosina
17.
J Transplant ; 20102010.
Artigo em Inglês | MEDLINE | ID: mdl-20936157

RESUMO

We report here a case of acute lymphoblastic leukemia in remission presenting a late-onset bilateral hydronephrosis probably due to polyoma BK virus-induced proliferation of bladder endothelium on both ostii. The diagnosis was made virologically by BK virus Polymerase Chain Reaction (PCR) detection in the absence of any other bladder disease. Awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor.

18.
J Clin Pathol ; 62(1): 84-8, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18755714

RESUMO

BACKGROUND: MicroRNAs have recently taken centre stage as short non-coding RNAs that regulate mRNA expression. AIM/METHODS: To assess the feasibility of using microRNA techniques on routinely processed tissues, the accessibility of two representative microRNAs was examined by real-time quantitative PCR in 86 human formalin-fixed paraffin-embedded (FFPE) samples from liver, breast, bone marrow, lymphatic tissues and colon. Murine liver was used to analyse the influence of fixation time and different fixatives. RESULTS: High-quality microRNA was successfully extracted from routinely processed formalin-fixed tissues, resembling PCR amplification results from snap-frozen material analysed in parallel. While fixation time did not affect microRNA accessibility, non-buffered formalin or fixative supplements such as glutaraldehyde influenced PCR results. Storage of human tissues for up to 7 years did not cause a significant deterioration of microRNA. However, microRNA quality in human archival material following routine processing 10-20 years ago was decreased. Oxidation by ambient air during storage and fixation in non-buffered formalin is a possible reason for loss of microRNA quality. CONCLUSION: The assessment of microRNAs in readily obtained formalin-fixed paraffin-embedded samples is a highly promising tool in molecular pathology when similarly treated samples are analysed. Therefore, microRNA analyses will gain wider acceptance as an adjunct to morphological tissue assessment in routine pathology and retrospective studies.


Assuntos
MicroRNAs/análise , Animais , Estudos de Viabilidade , Fixadores , Formaldeído , Perfilação da Expressão Gênica/métodos , Humanos , Fígado/química , Camundongos , MicroRNAs/genética , Inclusão em Parafina , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Tempo , Bancos de Tecidos , Fixação de Tecidos/métodos
19.
Histol Histopathol ; 22(4): 365-72, 2007 04.
Artigo em Inglês | MEDLINE | ID: mdl-17290346

RESUMO

Scant knowledge exists concerning lineage-restricted mixed chimerism (mCh) after allogeneic peripheral blood stem cell transplantation (PSCT) in patients with chronic idiopathic myelofibrosis (CIMF). Following a sex-mismatched PSCT, a combined immunopheno- and genotyping by fluorescence in-situ hybridization (FISH) was performed on sequential bone marrow (BM) biopsies at standardized intervals. Results were compared with PCR analysis of corresponding peripheral blood samples in five patients. According to FISH, pretransplant specimens revealed a gender congruence of more than 99%, while in the first three months the total BM exhibited a persistent fraction of host cells (30% to 40%) with a tendency to decline after about one year. It is noteworthy that the majority of endothelial cells maintained a recipient origin, whereas CD34+ progenitors and especially CD61+ megakaryocytes exhibited only very few host-derived cells. In keeping with the prevalence of donor cells in the hematopoietic compartment, PCR analysis of peripheral blood cells displayed a non-significant degree of mCh. In conclusion, according to FISH and PCR analysis, successful PSCT in CIMF results in an almost complete chimeric (donor-derived) state of the hematopoietic cell population. The non-transplantable stromal compartment includes the vascular endothelium with a predominance of recipient cells. The minimal mCh of this population implies probably a donor-derived origin (endothelial progenitor cells).


Assuntos
Hematopoese/fisiologia , Mielofibrose Primária/terapia , Transplante de Células-Tronco , Células-Tronco/patologia , Quimeras de Transplante , Antígenos CD34/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Genótipo , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Transplante Homólogo
20.
Acta Haematol ; 115(1-2): 97-101, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16424657

RESUMO

Repeatedly performed bone marrow biopsies were studied in 30 patients with chronic idiopathic myelofibrosis (CIMF) by fluorescence in situ hybridization to detect and quantify trisomy 8 anomaly during the evolution of disease. For the establishment of threshold values we used negative and positive control specimens. At least 500 cells were evaluated in each specimen and only nuclei with three distinctive signals were regarded as positive. According to the controls, 27 patients revealed false-positive signals ranging from 0 to 1.2% (0.88 +/- 1.12). On the other hand, 3 patients showed an incidence of more than 6.5% (up to 10.1%) in the initial prefibrotic as well as advanced fibro-osteosclerotic stages of CIMF. In conclusion, trisomy 8 has been demonstrated already in the prodromal stages of CIMF and therefore is not limited to classical fibro-osteosclerotic manifestations.


Assuntos
Células da Medula Óssea/patologia , Medula Óssea/patologia , Núcleo Celular/patologia , Cromossomos Humanos Par 8 , Mielofibrose Primária/patologia , Trissomia , Biópsia , Doença Crônica , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
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