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CDKN2A FISH analysis of Ewing sarcoma. Cytogenet
Before treatment, 7 patients (47%) were transfusion
9. Scheinin I, Myllykangas S, Borze I, Bohling T, Knuutila S,
dependent (mean requirement 5.9 units over six
Saharinen J. CanGEM: mining gene copy number changes
months, range 0–21); 6 had platelet counts < 100×109/L
in cancer. Nucleic Acids Res Epub 2007 Oct 11.
(mean 157×109/L, range 32–487×109/L). All non-
10. Panani AD. Cytogenetic and molecular aspects of
Philadelphia negative chronic myeloproliferative disor-
splenectomized patients had palpable splenomegaly
ders: clinical implications. Cancer Lett 2007;255:12-25.
11. Espinet B, Puigdecanet E, Florensa L, González L, Salido
After low dose thalidomide ±prednisolone the over-
M, Bellosillo B, et al. Array comparative genomic
hybridization reveals an absence of recurrent genomic
all transfusion requirements were unchanged (mean 6.0
copy number changes in essential thrombocythemia.
units/six months), 3 out of 7 (43%) transfusion-depend-
Abstract 0098. Haematologica (EHA Annual Meeting
ent patients had a fall in transfusion requirement after
thalidomide, 2 became transfusion independent.
However, 3 patients progressed and required transfu-sion. There was no significant rise in mean platelet
Low-dose thalidomide in myelofibrosis
counts (157×109/L pre-treatment, 184×109/L post-treat-ment). Splenomegaly was reduced by more than 50%in 4 out of 13 (31%) patients. Median white cell count
Allogeneic stem cell transplant is the only potentially
curative treatment for myelofibrosis, but is often pre-
Overall responses according to EUMNET criteria
cluded by advanced age, poor performance status or
were: no complete responses, five major responses
copathologies.1 Increased marrow angiogenesis occurs
(33%), one moderate response (7%), and five minor
in myelofibrosis and greater neovascularization corre-
responses (33%). Four patients (27%) had no response.
lates with poorer prognosis,2 stimulating interest in
Median time to peak response was 7.5 weeks (range
thalidomide therapy. Doses of 100-400mg daily
2–15 weeks). Seven patients both had a response and
reduced transfusion requirement and splenomegaly in
did not stop thalidomide early because of adverse
some patients, but were poorly-tolerated.3 Low-dose
effects; the median response duration was 16 weeks
thalidomide starting at 50mg daily with/without a
(4–95 weeks). For 3 patients, response was lost when
tapering dose of prednisolone is reported to be well-tol-
prednisolone stopped at week 12. The 2 patients not
treated with prednisolone demonstrated a minor and
We investigated 15 patients treated with low-dose
no response respectively. Five out of 13 patients (38%)
thalidomide (50 mg daily) for myelofibrosis in our cen-
were positive for the JAK2V617F
mutation and were
ters. The study was approved by the ethics committee at
indistinguishable from negative patients.9
St Thomas’ Hospital. All patients met consensus criteria
Four patients (27%) developed grade 1/2 peripheral
for myelofibrosis.6 Clinical parameters are summarized
neuropathy; 2 grade 1/2 constipation while somno-
in Table 1. Median follow-up was eight months.
lence was reported in one patient. No proven throm-
All patients initially received oral thalidomide 50 mg
boembolism occurred, but one patient with pneumonia
daily. Thirteen patients also received oral prednisolone
and marked leukocytosis died following an uncon-
at 30-60 mg (0.5-1mg/kg) daily; tapered over 12 weeks.
firmed pulmonary embolism. There was no neutrope-
Responses were confirmed according to European
nia or increased myeloproliferation. One patient expe-
Myelofibrosis Network (EUMNET) criteria;7 the
rienced weight gain and folliculitis ascribed to steroids.
International Working Group consensus criteria8 were
Eleven patients had stopped thalidomide by the end of
not used since no patient had repeated bone marrows.
the study due to: lack/loss of hematologic response
Table 1. Patients’ characteristics and responses.
ET: essential thrombocytosis; PV: polycythemia vera; F: female; M: male; HU: hydroxycarbamide (hydroxyurea); IFN
α; EPO: erythropoietin.
Lille score: Dupriez et al., 1996. EUMNET response criteria: Barosi et al., 2005.
(n=6), neuropathy (n=3), development of an unrelatedmalignancy (glioblastoma) (n=1), reduced-intensity
1. Cervantes F. Modern management of myelofibrosis Br J
This is the first study to use internationally agreed
response criteria for myelofibrosis (the EUMNET crite-
2. Mesa RA, Hanson CA, Rajkumar SV, Schroeder G, Tefferi
ria) to evaluate response to thalidomide and pred-
A. Evaluation and clinical correlations of bone marrow
nisolone. Overall, 40% of patients achieved major or
angiogenesis in myelofibrosis with myeloid metaplasia.
moderate responses by EUMNET criteria. All respons-
3. Elliott MA, Mesa RA, Li CY, Hook CC, Ansell SM, Levitt
es began within the first 12 weeks of treatment, sug-
RM, et al. Thalidomide treatment in myelofibrosis with
gesting that thalidomide could be stopped if there is no
myeloid metaplasia. Br J Haematol 2002;117:288-96.
4. Mesa RA, Steensma DP, Pardanani A, Li CY, Elliott M,
response by this time. Among responders, the median
Kaufmann SH, et al. A phase 2 trial of combination low-
response duration was 16 weeks. Three patients lost
dose thalidomide and prednisone for the treatment of
their responses when prednisolone was withdrawn at
myelofibrosis with myeloid metaplasia. Blood 2003; 101:
12 weeks. The 2 patients not treated with prednisolone
5. Marchetti M, Barosi G, Balestri F, Viarengo G, Gentili S,
appeared to have a less favourable response.
Barulli S, et al. Low-dose thalidomide ameliorates cytope-
Our results are consistent with those of phase II tri-
nias and splenomegaly in myelofibrosis with myeloid
als.4 In the Mesa trial,4 40% became transfusion inde-
metaplasia: a phase II trial J Clin Oncol 2004;22:424-31.
6. Barosi G, Ambrosetti A, Finelli C, Grossi A, Leoni P,
pendent, 75% had a >50% rise in platelet count, and
Liberato NL, et al. The Italian Consensus Conference on
19% had a >50% reduction in spleen size. In the
Diagnostic Criteria for Myelofibrosis with Myeloid
Marchetti trial,5 39% became transfusion independent,
Metaplasia. Br J Haematol 1999;104:730-7.
7. Barosi G, Bordessoule D, Briere J, Cervantes F, Demory JL,
22% had a >50x109/L rise in platelet count, and 19%
Dupriez B, et al. Response criteria for myelofibrosis with
had a >50% reduction in spleen size.
myeloid metaplasia: results of an initiative of the
The relative importance of thalidomide and pred-
European Myelofibrosis Network (EUMNET). Blood
nisolone when used in combination is unclear, but
8. Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly
prednisolone seems to be partly responsible for
JT, et al. International Working Group (IWG) consensus
responses. Case reports suggest that corticosteroids
criteria for treatment response in myelofibrosis with
have efficacy as monotherapy in myelofibrosis.9
myeloid metaplasia, for the IWG for Myelofibrosis
Research and Treatment (IWG-MRT). Blood 2006;108:
However, our response rates are similar to those
obtained with thalidomide monotherapy (median 100
9. Jack FR, Smith SR, Saunders PW. Idiopathic myelofibrosis:
mg/d). Three of our patients experienced a loss of clin-
anaemia may respond to low-dose dexamethasone. Br J
ical response when prednisolone was stopped consis-tent with other studies4 and 2 patients not treated withprednisolone showed a poorer performance.
Our data confirms that low-dose thalidomide with
Increased cortical bone mineralization in imatinib
treated patients with chronic myelogenous
prednisolone is effective treatment for myelofibrosis,
leading to transfusion independence, improvement inthrombocytopenia and reduction in spleen size in somepatients. We recommend assessment of thrombotic risk
Imatinib mesylate (Glivec®, Gleevec™, Novartis
and thromboprophylaxis for high-risk patients. Low-
International AG) and the second generation ABL tyro-
dose thalidomide is not effective in all patients, and
sine kinase inhibitors have markedly improved the out-
responses are often not sustained after withdrawal of
come of patients with chronic myeloid leukemia (CML).
More patients are receiving treatment with these
inhibitors for prolonged periods of time and experience
Robert Weinkove,1 John T. Reilly,2 Mary Frances McMullin,3
with imatinib now exceeds five years. The immediate
Natasha J. Curtin,4 Deepti Radia,1 and Claire N. Harrison1
side effects are usually mild and manageable. There have
1Department of Haematology, St Thomas’ Hospital, London;
been recent reports on the long-term side effects associ-
2Department of Haematology, Royal Hallamshire Hospital,
ated with prolonged use of imatinib.1-3 Berman and co-
Sheffield; 3Department of Haematology, Belfast City Hospital,
workers found that imatinib treated patients had
Belfast; 4Department of Haematology Queen Elizabeth Hospital,
hypophosphatemia, lower osteocalcin levels and higher
parathyroid hormone levels.2 Subsequent studies con-
Acknowledgments: we wish to thank Drs. N. Ketley and J. Ropner
firmed the observation of hypophosphatemia in patients
receiving imatinib.4-8 The authors concluded that ima-tinib may affect bone remodeling and if left untreated,
Correspondence: Claire Harrison, Department of Haematology, St
chronic hypophosphatemia may result in impaired bone
Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust
mineralization, rickets, and osteomalacia.2
London SE1 7EH, UK. Phone: international +44.207.1882742.
We, therefore, investigated bone mineral density
Fax: international +44.207.1882728.
E-mail: [email protected]
(BMD) in imatinib treated CML patients and healthycontrols. All imatinib treated CML patients at
Citation: Weinkove R, Reilly JT, McMullin MF, Curtin NJ, Radia
Sahlgrenska University Hospital were identified of
D, Harrison CN. Low-dose thalidomide in myelofibrosis.
whom 17 fulfilled the study inclusion criteria: (i) imatinib
Haematologica 2008; 93:1100-1101.
treatment duration ≥24 months, and (ii) first chronic
phase of the disease with complete cytogenetic remis-sion. The inclusion criteria were set to minimize the con-founding effect of leukemia and to allow time for a pos-
Méthodes Séparatives : synthèse et étude de nouvelles phases stationnaires pour la chromatographie liquide et l'électrophorèse capillaire Extrait du L' Institut des Sciences Moléculaires - Université Bordeaux - CNRS Méthodes Séparatives : synthèse et étude de nouvelles phases stationnaires pour la chromatographie liquide et l'électrophorèse capillaire Date de mise
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