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1.
Eur J Haematol ; 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898589

RESUMO

OBJECTIVES: Despite major advances in treatment options for multiple myeloma (MM), patients refractory to the main drug classes and those with aggressive, especially extramedullary disease, still face a dismal outcome. For these patients, effective therapeutic options are urgently warranted. METHODS: In this retrospective study, we report on the safety and efficacy of the intensive combination regimen of pomalidomide plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (Pom-PACE) in patients with relapsed refractory MM (RRMM) or plasma cell leukemia (PCL). A study population of 20 consecutive patients treated with Pom-PACE at two academic centers was included for analysis. All patients had to have a confirmed relapse according to International Myeloma Working Group criteria and adequate organ function prior to the start of therapy. Data were collected by reviewing medical charts. Exploratory analyses were performed with regard to efficacy and safety. RESULTS: Patients were heavily pretreated with a median number of four prior therapies (range: 1-10). All patients were exposed to immunomodulators, proteasome inhibitors, and alkylating agents, 80% were double-class refractory, 40% were triple-class refractory. Extramedullary MM or PCL were present in 15 patients (75%). Overall response rate (ORR) was 68%, with 31% achieving at least a very good partial response. Responses were achieved rapidly with an ORR of 64% after one cycle. Median progression-free survival was 8.9 months (0.92-not reached [NR]) and median overall survival was 11.8 months (3-40.6). Pom-PACE was associated with significant toxicity. All evaluable patients experienced Grade 4 hematological toxicity. However, no treatment related mortality was observed. CONCLUSION: Pomalidomide-PACE was able to induce rapid responses in heavily pretreated, aggressive RRMM with a manageable toxicity profile and therefore offers an effective salvage regimen and a potential bridging strategy to further treatment options such as chimeric antigen receptor T-cell therapy.

2.
Ann Hematol ; 102(2): 349-358, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36564535

RESUMO

Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.


Assuntos
Janus Quinases , Policitemia Vera , Humanos , Hidroxiureia/uso terapêutico , Futilidade Médica , Nitrilas/uso terapêutico , Policitemia Vera/diagnóstico , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Pirimidinas/uso terapêutico , Janus Quinases/uso terapêutico
3.
BMC Cancer ; 22(1): 735, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35790913

RESUMO

BACKGROUND: The therapeutic armamentarium in multiple myeloma has been significantly broadened by proteasome inhibitors, highly efficient means in controlling of multiple myeloma. Despite the developments of therapeutic regimen in treatment of multiple myeloma, still the complete remission requires a novel therapeutic strategy with significant difference in outcomes. Proteasome inhibitors induce autophagy and ER stress, both pivotal pathways for protein homeostasis. Recent studies showed that the IRE1α-XBP1 axis of the unfolded protein response (UPR) is up-regulated in multiple myeloma patients. In addition, XBP1 is crucial for the maintenance of viability of acute lymphoblastic leukemia (ALL). RESULTS: We analyzed the efficacy of targeting IRE1α-XBP1 axis and autophagy in combination with proteasome inhibitor, ixazomib in treatment of multiple myeloma. In this present study, we first show that targeting the IRE1α-XBP1 axis with small molecule inhibitors (STF-083010, A106) together with the ixazomib induces cell cycle arrest with an additive cytotoxic effect in multiple myeloma. Further, we examined the efficacy of autophagy inhibitors (bafilomycin A, BAF and chloroquine, CQ) together with ixazomib in multiple myeloma and observed that this combination treatment synergistically reduced cell viability in multiple myeloma cell lines (viable cells Ixa: 51.8 ± 3.3, Ixa + BAF: 18.3 ± 7.2, Ixa + CQ: 38.4 ± 3.7) and patient-derived multiple myeloma cells (Ixa: 59.6 ± 4.4, Ixa + CQ: 7.0 ± 2.1). We observed, however, that this combined strategy leads to activation of stress-induced c-Jun N-terminal kinase (JNK). Cytotoxicity mediated by combined proteasome and autophagy inhibition was reversed by addition of the specific JNK inhibitor JNK-In-8 (viable cells: Ixa + BAF: 11.6 ± 7.0, Ixa + BAF + JNK-In-8: 30.9 ± 6.1). CONCLUSION: In this study we showed that combined inhibition of autophagy and the proteasome synergistically induces cell death in multiple myeloma. Hence, we consider the implication of pharmaceutical inhibition of autophagy together with proteasome inhibition and UPR-directed therapy as promising novel in vitro treatment strategy against multiple myeloma.


Assuntos
Mieloma Múltiplo , Inibidores de Proteassoma , Apoptose , Autofagia , Benzamidas , Linhagem Celular Tumoral , Endorribonucleases , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Proteínas Serina-Treonina Quinases , Piridinas , Pirimidinas
4.
Ann Hematol ; 101(12): 2655-2663, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36269400

RESUMO

Molecular diagnostics moves more into focus as technology advances. In patients with myeloproliferative neoplasms (MPN), identification and monitoring of the driver mutations have become an integral part of diagnosis and monitoring of the disease. In some patients, none of the known driver mutations (JAK2V617F, CALR, MPL) is found, and they are termed "triple negative" (TN). Also, whole-blood variant allele frequency (VAF) of driver mutations may not adequately reflect the VAF in the stem cells driving the disease. We reasoned that colony forming unit (CFU) assay-derived clonogenic cells may be better suited than next-generation sequencing (NGS) of whole blood to detect driver mutations in TN patients and to provide a VAF of disease-driving cells. We have included 59 patients carrying the most common driver mutations in the establishment or our model. Interestingly, cloning efficiency correlated with whole blood VAF (p = 0.0048), suggesting that the number of disease-driving cells correlated with VAF. Furthermore, the clonogenic VAF correlated significantly with the NGS VAF (p < 0.0001). This correlation was lost in patients with an NGS VAF <15%. Further analysis showed that in patients with a VAF <15% by NGS, clonogenic VAF was higher than NGS VAF (p = 0.003), suggesting an enrichment of low numbers of disease-driving cells in CFU assays. However, our approach did not enhance the identification of driver mutations in 5 TN patients. A significant correlation of lactate dehydrogenase (LDH) serum levels with both CFU- and NGS-derived VAF was found. Our results demonstrate that enrichment for clonogenic cells can improve the detection of MPN driver mutations in patients with low VAF and that LDH levels correlate with VAF.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Calreticulina/genética , Calreticulina/metabolismo , Frequência do Gene , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética
5.
Blood ; 134(21): 1832-1846, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31511238

RESUMO

Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Animais , Humanos , Camundongos , Mutação
6.
Ann Hematol ; 100(12): 2943-2956, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34390367

RESUMO

Myeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing-associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN.


Assuntos
Antígenos CD34/genética , Transtornos Mieloproliferativos/genética , Transcriptoma , Regulação Neoplásica da Expressão Gênica , Humanos , Policitemia Vera/genética , Mielofibrose Primária/genética , Trombocitemia Essencial/genética
7.
Mol Carcinog ; 59(1): 87-103, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31691359

RESUMO

Hypereosinophilia (HE) is caused by a variety of disorders, ranging from parasite infections to autoimmune diseases and cancer. Only a small proportion of HE cases are clonal malignancies, and one of these, the group of eosinophilia-associated tyrosine kinase fusion-driven neoplasms, is sensitive to tyrosine kinase inhibitors, while most subtypes lack specific treatment. Eosinophil functions are highly dependent on actin polymerization, promoting priming, shape change, and infiltration of inflamed tissues. Therefore, we investigated the role of the actin-binding protein lymphocyte cytosolic protein 1 (LCP1) in malignant and nonmalignant eosinophil differentiation. We use the protein kinase C-ß (PKCß) selective inhibitor enzastaurin (Enza) to dephosphorylate and inactivate LCP1 in FIP1L1-platelet-derived growth factor receptor α (PDGFRA)-positive Eol-1 cells, and this was associated with reduced proliferation, metabolic activity, and colony formation as well as enhanced apoptosis and impaired migration. While Enza did not alter FIP1L1-PDGFRA-induced signal transducer and activator of transcription 3 (STAT3), STAT5, and ERK1/2 phosphorylation, it inhibited STAT1Tyr701 and AKTSer473 (but not AKTThr308 ) phosphorylation, and short hairpin RNA knockdown experiments confirmed that this process was mediated by LCP1 and associated mammalian target of rapamycin complex 2 (mTORC2) activity loss. Homeobox protein HoxB8 immortalized murine bone marrow cells showed impaired eosinophilic differentiation upon Enza treatment or LCP1 knockdown. Furthermore, Enza treatment of primary HE samples reduced eosinophil differentiation and survival. In conclusion, our data show that HE involves active LCP1, which interacts with mTOR and triggers mTORC2 activity, and that the PKCß inhibitor Enza as well as targeting of LCP1 may provide a novel treatment approach to hypereosinophilic disorders.


Assuntos
Síndrome Hipereosinofílica/tratamento farmacológico , Indóis/farmacologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas dos Microfilamentos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Idoso , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Síndrome Hipereosinofílica/metabolismo , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico
8.
Ann Hematol ; 98(12): 2703-2709, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748924

RESUMO

Philadelphia negative (Ph-neg) myeloproliferative neoplasms (MPN) are a heterogenous group of clonal stem cell disorders. Approved treatment options include hydroxyurea, anagrelide, and ruxolitinib, which are not curative. The concept of synthetic lethality may become an additional therapeutic strategy in these diseases. In our study, we show that DNA repair is altered in classical Ph-neg MPN, as analyzed by gene expression analysis of 11 genes involved in the homologous recombination repair pathway (HRR), the non-homologous end-joining pathway (NHEJ), and the single-strand break repair pathway (SSB). Altogether, peripheral blood-derived cells from 57 patients with classical Ph-neg MPN and 13 healthy controls were analyzed. LIG3 as an essential part of the SSB was significantly lower expressed compared to controls in all three entities (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)). In addition, while genes of other DNA-repair pathways showed-possibly compensatory-increased expression in ET (HRR, NHEJ) and PV (NHEJ), MF samples displayed downregulation of all genes involved in NHEJ. With regard to the JAK2 mutational status (analyzed in ET and MF only), no upregulation of the HRR was detected. Though further studies are needed, based on these findings, we conclude that synthetic lethality may become a promising strategy in treating patients with Ph-neg MPN.


Assuntos
Reparo do DNA , DNA de Neoplasias , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Proteínas de Neoplasias , Transcrição Gênica , Adulto , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Cromossomo Filadélfia
9.
Blood ; 127(23): 2841-6, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27060169

RESUMO

The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed ß subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance.


Assuntos
Células-Tronco Adultas/fisiologia , Proliferação de Células/genética , Células-Tronco Hematopoéticas/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células-Tronco Adultas/metabolismo , Animais , Divisão Celular/genética , Células Cultivadas , Feminino , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
10.
Recent Results Cancer Res ; 212: 87-108, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30069626

RESUMO

Bosutinib is one of the five tyrosine kinase inhibitors which are currently approved for the treatment of chronic myeloid leukemia. By its dual inhibition of Src and ABL kinase and also targeting further kinases, it creates a unique target portfolio which also explains its unique side effect profile. The approval of bosutinib in 2013 made the drug available for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. As initially the first-line clinical trial comparing bosutinib with imatinib in CML patients in chronic phase did not reach its primary endpoint and therefore the product was not licensed for first-line therapy, a second first-line trial, the so-called BFORE study, was performed and just recently the promising results have been published predicting a quick expansion of the existing label. In comparison with the other approved TKIs, bosutinib harbors a distinct side effect profile with only very few cardiovascular and thromboembolic events and minimal long-term safety issues with most adverse events happening during the first months of treatment. On the other hand, gastrointestinal side effects are very common (e.g., diarrhea rates in more than 80% of the patients) with bosutinib surprising some of the investigators during the early clinical trials evaluating bosutinib. Until then, several approaches have been used to face this problem resulting in extensive supportive efforts (such as early loperamid treatment) as well as new trials testing alternative dosing strategies with early dose adjustment schedules. This article reports preclinical and clinical data available for bosutinib both in hematologic diseases such as CML or ALL and solid tumours as well as other diseases and envisions future perspectives including additional patient groups in which bosutinib might be of clinical benefit.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Humanos
13.
Blood ; 122(10): 1741-5, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23894152

RESUMO

Local hypoxia in hematopoietic stem cell (HSC) niches is thought to regulate HSC functions. Hypoxia-inducible factor-1 (Hif-1) and Hif-2 are key mediators of cellular responses to hypoxia. Although oxygen-regulated α-subunits of Hifs, namely Hif-1α and Hif-2α, are closely related, they play overlapping and also distinct functions in nonhematopoietic tissues. Although Hif-1α-deficient HSCs lose their activity on serial transplantation, the role for Hif-2α in cell-autonomous HSC maintenance remains unknown. Here, we demonstrate that constitutive or inducible hematopoiesis-specific Hif-2α deletion does not affect HSC numbers and steady-state hematopoiesis. Furthermore, using serial transplantations and 5-fluorouracil treatment, we demonstrate that HSCs do not require Hif-2α to self-renew and recover after hematopoietic injury. Finally, we show that Hif-1α deletion has no major impact on steady-state maintenance of Hif-2α-deficient HSCs and their ability to repopulate primary recipients, indicating that Hif-1α expression does not account for normal behavior of Hif-2α-deficient HSCs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Animais , Proliferação de Células , Sobrevivência Celular , Feminino , Deleção de Genes , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Masculino , Camundongos
14.
Stem Cells ; 32(6): 1390-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24496882

RESUMO

Adult hematopoiesis depends on rare multipotent hematopoietic stem cells (HSCs) that self-renew and give rise to progenitor cells, which differentiate to all blood lineages. The strict regulation of the fine balance between self-renewal and differentiation is essential for normal hematopoiesis and suppression of leukemia development. HSCs and progenitor cells are commonly assumed to reside within the hypoxic BM microenvironment, however, there is no direct evidence supporting this notion. Nevertheless, HSCs and progenitors do exhibit a hypoxic profile and strongly express Hif-1α. Although hypoxia signaling pathways are thought to play important roles in adult HSC maintenance and leukemogenesis, the precise function of Hif-dependent signaling in HSCs remains to be uncovered. Here we discuss recent gain-of-function and loss-of-function studies that shed light on the complex roles of hypoxia-signaling pathways in HSCs and their niches in normal and malignant hematopoiesis. Importantly, we comment on the current and often contrasting interpretations of the role of Hif-dependent signaling in stem cell functions.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Leucemia/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/genética , Animais , Hipóxia Celular/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leucemia/patologia
15.
Medicine (Baltimore) ; 102(49): e36532, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38065882

RESUMO

Thyroid cancers are among the most common endocrine cancers. An inflammation is associated with many stages of cancer. Therefore, in this study, we aimed to evaluate whether it has a prognostic significance inflammation marker. Neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio, systemic inflammation response, systemic immune-inflammation index, and neutrophils to lymphocytes and platelets ratio (N/LP) in patients diagnosed with thyroid cancer in the internal medicine outpatient clinic and operated between March 1, 2017 and May 1, 2022 were evaluated retrospectively. Three hundred forty patients were diagnosed with thyroid cancer; 275 (80.9%) of them were women and the mean age was 44.6 ±â€…13.5 years. Multifocality (P = .02) was significant in patients with invasion. High N/LP ratio (odds ratio: 1.4, 95% confidence interval: 1.0-2.0, p: 0.003) and high invasion (odds ratio: 0.2, 95% confidence interval: 0.1-0.4, P < .01) was found to be significant in patients with tumor size ≥2 cm. There is a relationship between multifocality and invasion, and the risk of invasion increases as the tumor size increases in thyroid cancer. The N/LP ratio was significant as it could be a new marker in showing the relationship between thyroid cancer and its prognosis. Further studies are needed in which the prognosis is followed up, longer-term, more comprehensive, and confounding factors are excluded.


Assuntos
Linfócitos , Neoplasias da Glândula Tireoide , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Prognóstico , Estudos Transversais , Estudos Retrospectivos , Linfócitos/patologia , Neoplasias da Glândula Tireoide/patologia , Neutrófilos/patologia , Inflamação/patologia
16.
Front Oncol ; 13: 1277453, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37941547

RESUMO

Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We confirmed continuous shortening of telomere length (TL) by imetelstat treatment but observed emergence and expansion of a KRAST58I mutated clone during the patient's clinical course. In order to investigate the molecular mechanisms involved in the imetelstat treatment response, we generated induced pluripotent stem cells (iPSC) from this patient. TL of iPSC-derived hematopoietic stem and progenitor cells, which was increased after reprogramming, was reduced upon imetelstat treatment for 14 days. However, while imetelstat reduced clonogenic growth of the patient's primary CD34+ cells, clonogenic growth of iPSC-derived CD34+ cells was not affected, suggesting that TL was not critically short in these cells. Also, the propensity of iPSC differentiation toward megakaryocytes and granulocytes was not altered. Using human TF-1MPL and murine 32DMPL cell lines stably expressing JAK2V617F or CALRdel52, imetelstat-induced reduction of viability was significantly more pronounced in CALRdel52 than in JAK2V617F cells. This was associated with an immediate downregulation of JAK2 phosphorylation and downstream signaling as well as a reduction of hTERT and STAT3 mRNA expression. Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable.

17.
J Med Biochem ; 41(4): 491-496, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36381073

RESUMO

Background: COVID-19 may affect many endocrine tissues as well as thyroid gland and hypothalamus-pituitary-thyroid axis. It has been shown that COV D-19 infection suppresses thyroid hormones in some studies and causes subacute thyroiditis in the others so that its effects are still not fully known. The aim of our study is to retrospectively evaluate thyroid functions, clinical findings, biochemical and inflammatory markers in PCR positive patients infected with COVID-19; and to evaluate the relationship between abnormal thyroid function tests (TFT) and clinical and laboratory findings and whether it has potential prognostic significance. Methods: The data of patients aged 18 years and older, 201 patients who applied to Mersin City Training and Research Hospital due to COVID-19 infection between 1st of March and 1st of April in 2021 and received inpatient treatment were evaluated retrospectively. Results: Large TFT (TSH, T3, T4, anti-TPO) and laboratory data of 201 patients with mild, moderate or severe pneumonia on CT were scanned retrospectively. 121 (60.2%) of the patients were male, mean age was 51.9 ± 14.6 years, and the most common comorbid disease was hypertension in 65 (32.3%) patients. Conclusions: It has been determined that the deterioration in TFTs is associated with LDH and D-dimer which are indicators of cell and endothelial damage, duration of hospitalization, clinical severity, and having mutant strains and it has been concluded that low TSH can be used as a prognostic indicator in COVID-19 patients. Further studies with healthy control groups, quantitative RT-PCR tests, histological and pathological correlations, and long-term follow-up are needed.

18.
Lancet Haematol ; 9(11): e810-e821, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36328040

RESUMO

BACKGROUND: Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma. METHODS: This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32), and dexamethasone (20 mg orally on days 1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, and 32-33). Isatuximab was given as 10 mg/kg intravenously on days 1, 8, 15, 22, and 29 of cycle 1 and on days 1, 15, and 29 of cycles 2 and 3. The primary endpoint was minimal residual disease (MRD) negativity assessed by flow cytometry, in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT03617731. FINDINGS: Between Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related. INTERPRETATION: Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma. FUNDING: Sanofi and Bristol Myers Squibb (Celgene).


Assuntos
Mieloma Múltiplo , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Lenalidomida/uso terapêutico , Bortezomib/efeitos adversos , Mieloma Múltiplo/terapia , Quimioterapia de Indução , Dexametasona , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
19.
Blood Adv ; 5(17): 3373-3376, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477817

RESUMO

The molecular causes of myeloproliferative neoplasms (MPNs) have not yet been fully elucidated. Approximately 7% to 8% of the patients carry predisposing genetic germline variants that lead to driver mutations, which enhance JAK-STAT signaling. To identify additional predisposing genetic germline variants, we performed whole-exome sequencing in 5 families, each with parent-child or sibling pairs affected by MPNs and carrying the somatic JAK2 V617F mutation. In 4 families, we detected rare germline variants in known tumor predisposition genes of the DNA repair pathway, including the highly penetrant BRCA1 and BRCA2 genes. The identification of an underlying hereditary tumor predisposition is of major relevance for the individual patients as well as for their families in the context of therapeutic options and preventive care. Two patients with essential thrombocythemia or polycythemia vera experienced progression to acute myeloid leukemia, which may suggest a high risk of leukemic transformation in these familial MPNs. Our study demonstrates the relevance of genetic germline diagnostics in elucidating the causes of MPNs and suggests novel therapeutic options (eg, PARP inhibitors) in MPNs. Furthermore, we uncover a broader tumor spectrum upon the detection of a germline mutation in genes of the DNA repair pathway.


Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Proteína BRCA1/genética , Reparo do DNA/genética , Células Germinativas , Humanos , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética
20.
Stem Cell Reports ; 16(11): 2768-2783, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34678208

RESUMO

Calreticulin (CALR) mutations are driver mutations in myeloproliferative neoplasms (MPNs), leading to activation of the thrombopoietin receptor and causing abnormal megakaryopoiesis. Here, we generated patient-derived CALRins5- or CALRdel52-positive induced pluripotent stem cells (iPSCs) to establish an MPN disease model for molecular and mechanistic studies. We demonstrated myeloperoxidase deficiency in granulocytic cells derived from homozygous CALR mutant iPSCs, rescued by repairing the mutation using CRISPR/Cas9. iPSC-derived megakaryocytes showed characteristics of primary megakaryocytes such as formation of demarcation membrane system and cytoplasmic pro-platelet protrusions. Importantly, CALR mutations led to enhanced megakaryopoiesis and accelerated megakaryocytic development in a thrombopoietin-independent manner. Mechanistically, our study identified differentially regulated pathways in mutated versus unmutated megakaryocytes, such as hypoxia signaling, which represents a potential target for therapeutic intervention. Altogether, we demonstrate key aspects of mutated CALR-driven pathogenesis dependent on its zygosity, and found novel therapeutic targets, making our model a valuable tool for clinical drug screening in MPNs.


Assuntos
Calreticulina/genética , Mutação da Fase de Leitura , Células-Tronco Pluripotentes Induzidas/metabolismo , Megacariócitos/metabolismo , Transtornos Mieloproliferativos/genética , Calreticulina/metabolismo , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Citometria de Fluxo , Perfilação da Expressão Gênica/métodos , Humanos , Megacariócitos/ultraestrutura , Microscopia Eletrônica de Transmissão , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trombopoese/genética
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