MMM is a chronic myeloproliferative disorder accompanied by an intense bone marrow stromal reaction that includes collagen fibrosis, osteosclerosis, and angiogenesis. The molecular pathogenesis of MMM has not been fully characterized despite the recent discovery of an activating JAK2 mutation (JAK2V617F) in approximately half of the patients. Conventional drug therapy in MMM not improves survival and is used for palliative purposes only. Myocet™ is a proprietary liposomal formulation of doxorubicin designed to enhance delivery of the drug to tumor cells and reduce side effects while maintaining equivalent anti-tumor efficacy. Moreover liposomes are avidly removed from circulation by the macrophages of the RES or MPS and are taken up in the spleen, liver and bone marrow were show both a cytotoxic and anti-angiogenic activity We thus designed a phase II study for patients with primary MMM. The treatment program consisted of 25 mg total dose of Myocet™ given I.V. every two weeks for six months. Study eligibility criteria included a histologically confirmed diagnosis of MMM, platelet count ≥ 100 × 109/L, and neutrophil count ≥ 1 × 109/L, PS ≤ 2, LVEF > 50%, normal liver and renal function. 8 patients (median age, 66 years; range, 60–73) were enrolled to the trial. Median duration of disease prior to protocol treatment was 45 months (range, 24–144). All pts (100%) had received prior therapy for MMM, including thalidomide 3 (37%), hydroxyurea 8 (100%), interferon 2 (25%)), anagrelide 2 (25%), and erythropoietin 8 (100%). 3 patients (37%) were RBC transfusion-dependent and 1 had severe constitutional symptoms (night sweats or disease related fever). Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were 10 cm BCM (median, range 6 to 30), 8.5 × 109/L (3–36.2), 250 × 109/L (160–950), 151.1 × 106/L (1.9–356), and 680 U/L (316–868), respectively. 8/8 pts had JAK2 V617F mutation. In addition, pre-treatment and post-treatment quantitative assessment by real-time quantitative polymerase chain reaction (RQ-PCR) of WT1 transcripts in the peripheral blood were performed and the values were expressed as WT1 copies every 104 copies of ABL. 7/8 pts are evaluable for response and toxicity (i.e., received six months of therapy) 1 pt discontinued because of progression. Clinico-hematologic responses have been observed in 7/7 (100%) pts and were evaluated according to European Myelofibrosis Network criteria These include 1 CR, 5 Major Response,1 Minor Response 1 of 3 transfusion-dependent pts have become transfusion independent. The median time to response was 12 weeks (range, 4 to 18). Therapy has been well tolerated. Only a Grade 3 thrombocytopenia was seen. Striking WT1 gene expression levels in samples that were obtained after treatment were found to be significantly lower (median 480 range 210–520) than those before (median 1000, range 560–1230) (P < .0001, Mann-Whitney U test) The median post-treatment follow up at the time of this writing was 10 months (range 8–13) We conclude that Myocet has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile.
Recently, a JAK2V617F mutation has been described in the majority of patients with polycythemia vera (PV), and in a subset of patients with essential thromocythemia (ET) and idiopathic myelofibrosis (IMF). Similarly, PRV-1 has been found overexpressed in many of these patients. The aim of the study was to correlate PRV-1 and WT1 expression with the presence of JAK2 mutation in order to establish whether these markers identify the same subset of patients. Using a Real Time PCR we studied the expression level of PRV1 and WT1 in 330 patients including 26 IMF, 156 PV, 122 ET, 16 HES. 10 familiar forms of PV were included. In addition a control group of 50 healthy subject and 60 reactive conditions were studied All the patients were analyzed for the presence of JAK2 mutation using the ABI Prims 3100 genetic analyzer. We found that JAK2 mutation was present in 50 % of IMF, 93% of PV and 55% of ET and 6% of HES. PRV-1 was increased in 84% of IMF, 98% of PV and 90% of ET and it was not increased in HES. WT1 was increased in 99% of IMF, 45% of PV and 42% of ET and 100% of HES. No mutations of JAK2 were detected in normal subjects or in reactive conditions. Both WT1 and PRV1 were expressed at low levels in normal subject (for PRV1 the mean value of 2-Delta Delta Ct was 2,05; range 0,05–5,46; for WT1 mean value WT1 copies/104 ABL copies of 4; range 0–20). The mean value of WT1 copies/104 ABL copies in IMF was 306 (p=0,00004 compared to normal controls), in PV was 156 (p=0,0001), in ET was 202 (p=0,0002) and in HES was 161 (p=0,0004). PRV1 mean value in IMF was 144 expressed as 2−Delta Delta Ct, and it was 423 in PV and 290 in ET. Moreover the correlation between the three markers allowed to establish that both WT1 and PRV1 were higher in JAK2 mutated samples when compared to wild type JAK2 with a p value of 0,001 for WT1 and 0,004 for PRV1. In spite of these we were able to identify a subset of patients affected by IFM characterized by increased values of PRV1 and WT1 but not by JAK2 mutation (34%) and a small subset 15% characterized only by WT1 overexpression. Only 5% of PV and 35% of ET patients expressed only PRV-1 but not JAK2 mutation and WT1 expression. HES patients overexpressed WT1 but not PRV1 and only one patient presented the JAK2 mutation. Finally 10 patients affected by familiar form of PV were studied. All the subjects showed normal PRV-1 expression but high level of WT1 transcript and 9 out of 10 presented the JAK2 mutation. This study demonstrates that the combination of all these markers is probably useful for a correct diagnosis of these patients but further studies are required to stratify these patients and to better classify them according to the presence of molecular lesions.
ABSTRACT. Mesangioproliferative or membranoproliferativa glomerulonephritis; as the changes in bone marrow, which contributes to the development of severe anemia associated with thrombocytopenia are observed in animals with leishmaniasis canine visceral (LCV). The aim was to determine the relation between morphometric macroscopic and microscopic changes of kidney and bone marrow (BM) with the number of amastigotes of Leishmania sp in BM. Forty-seven dogs of different ages and sexes, naturally 2 infected with Leishmania sp were evaluated and grouped according to the number of Leishmania sp/mm in BM: low load, moderately low load, moderately high load and high load. Macroscopic morphometric parameters were measured in kidney: length, width and thickness; microscopic parametrec: number of
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