Posted by rob on April 23, 2011 under Uncategorized | 
A Model of Oscillatory Blood Cell Counts in Chronic Myelogenous Leukaemia.
Bull Math Biol. 2011 Apr 22;
Authors: Drobnjak I, Fowler AC
In certain blood diseases, oscillations are found in blood cell counts. Particularly, such oscillations are sometimes found in chronic myelogenous leukaemia, and then occur in all the derived blood cell types: red blood cells, white blood cells, and platelets. It has been suggested that such oscillations arise because of an instability in the pluri-potential stem cell population, associated with its regulatory control system. In this paper, we consider how such oscillations can arise in a model of competition between normal (S) and genetically altered abnormal (A) stem cells, as the latter population grows at the expense of the former. We use an analytic model of long period oscillations to describe regions of oscillatory behaviour in the S-A phase plane, and give parametric criteria to describe when such oscillations will occur. We also describe a mechanism which can explain dynamically how the transformation from chronic phase to acute phase and blast crisis can occur.
PMID: 21512833 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Interferon-induced sarcoidosis with osseous involvement in a patient with melanoma.
Hell J Nucl Med. 2011 Jan-Apr;14(1):68-69
Authors: Meristoudis G, Tsaroucha A, Ilias I, Giannakopoulos V, Batsakis C, Christakopoulou J
To the Editor: Interferons are widely used in the treatment of both malignant and nonmalignant diseases. One rare complication, attributable to the immunomodulatory effect of interferon (IFN) treatment is the triggering or exacerbation of sarcoidosis. We present the scintigraphic and radiographic imaging findings of a patient that developed sarcoidosis with bone involvement mimicking metastatic disease during the course of adjuvant IFN-alpha treatment for malignant melanoma. A 32 years old woman was diagnosed with a superficial left tibial melanoma, metastatic to the inguinal lymph nodes (Clark level IV; Breslow tumor thickness 1.82mm). Since the primary tumour had more than 0.75mm thickness the patient underwent re-excision of the primary lesion with radioguided sentinel lymph node biopsy, which was positive for micrometastases and subsequently underwent dissection of the lymph nodes of the left groin. She received adjuvant treatment with IFN-alpha. A chest X-ray taken prior to IFN-alpha treatment was unremarkable. Three months later, the patient presented with dry cough and mild dyspnea on exertion. Physical examination was unremarkable; a chest X-ray was inconclusive, with possible left hilar enlargement. Chest computed tomography (CT) showed enlarged mediastinal and hilar lymph nodes as well as a few bilateral small nodules. Pulmonary function tests showed normal spirometry, lung volumes were at lower limit of normal and diffusing capacity was moderately decreased at 79% of predicted. The patient was referred for a gallium-67 citrate ((67)Ga-C) scan, which showed the characteristic “Lambda sign” indicative of sarcoidosis as well as foci of increased accumulation in the right scapula and left iliac bone. A subsequent technetium-99m methylene diphosphonate ((99m)Tc-MDP) scan revealed the same skeletal lesions. Magnetic resonance imaging (MRI) of the thorax and pelvis was concordant with the (67)Ga-C and (99m)Tc-MDP scan findings. The patient’s history of malignant melanoma and the anatomical and functional imaging findings led to the clinical suspicion of osseous metastases. Bronchoaleolar lavage showed lymphocytosis, leukocytosis and macrophages with elevated CD4/CD8 ratio. Moreover, transbronchial needle aspiration lung biopsy revealed non-caseating granulomas whereas bone biopsy of the right scapula was negative for malignancy and showed non-caseating granulomas, consistent with sarcoidosis. Treatment with IFN-alpha was withdrawn; the dyspnea and dry cough subsided within several weeks and three months later the patient had complete clinical remission. Pulmonary function tests were normal and a follow-up MRI after 9 months showed resolution of both hilar lymphadenopathy and osseous lesions. The patient, six years after initial presentation, remains in clinical remission. Thus, a diagnosis of interferon-induced sarcoidosis in melanoma adjuvant treatment was established. It has been recently recognized that IFN-alpha can induce or exacerbate sarcoidosis, presumably through its ability to stimulate the T-helper cell type 1 immune response leading to granuloma formation, which is also involved in the pathogenesis of sarcoidosis, resulting in clinical disease in susceptible individuals. Reported IFN-alpha-induced sarcoidosis occurs from 2 to 168 weeks after starting treatment. The most common organs involved are the lungs, lymph nodes and the skin. After discontinuation of IFN-alpha, and with no other treatment received, the prognosis of sarcoidosis in the vast majority of cases is favourable; for some patients corticosteroids are needed. Most cases of IFN-induced sarcoidosis have been described in patients treated with IFN for chronic hepatitis C; sarcoidosis has also been reported in patients treated with IFN for chronic hepatitis B, renal carcinoma, chronic myelogenous leukaemia, multiple sclerosis, multiple myeloma, and lymphoma. Eleven cases of sarcoidosis have been reported in IFN- treated patients with malignant melanoma. To the best of our knowledge IFN-induced sarcoidosis with bone involvement has not been reported previously. Scintigraphy with (67)Ga-C has the advantage of detecting both pulmonary, with the characteristic lambda and/or panda uptake pattern and extrapulmonary foci of sarcoidosis, assisting diagnosis. Biopsy is mandatory for the diagnosis of the disease. Among the newer functional imaging modalities, fluorine-18 fluoro-deoxyglucose ((18)F-FDG) PET is not useful in diagnosing sarcoidosis, since it shows nonspecific uptake, both pattern and intensity-wise, although it is useful in monitoring disease progression or remission. Although sarcoidosis is a systemic disease, osseous involvement, mostly in the small bones of the hands and feet is relatively uncommon, noted in 5% of patients, although extremes of 1% to 13% have been reported. In some cases sarcoidosis may mimic metastatic dissemination. Although bone scans and MRI are more sensitive than either radiographs or (67)Ga-C scintigraphy in the detection of osseous sarcoidosis, they are also non-specific. In conclusion treatment with IFN-alpha may induce sarcoidosis not only in the lung but also in the skeleton; when restaging patients with malignant diseases it may mimic metastatic bone disease leading to diagnostic pitfalls.
PMID: 21512671 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
(Source: American Journal of Hematology)
More
Posted by rob on under Uncategorized |
AbstractWith the advent of molecularly targeted therapies in the oncology clinic, previously fatal blood cancers have now become chronic diseases. Imatinib, a small molecule tyrosine kinase inhibitor that targets the BCR?ABL fusion protein, dramatically extends survival for patients with chronic myelogenous leukemia and has opened the flood gates for modern “personalized cancer medicine”. Rituximab, a monoclonal antibody with affinity for the CD20 antigen of B?lymphocytes, in an analogous fashion has revolutionized treatment for patients with B?cell lymphomas. Does this paradigm, a rather commonplace approach for the treatment of hematologic malignancies, apply also to acute myelogenous leukemia (AML)? This is an exciting time to be involved in AML research, and an explosion of n…
More
Posted by rob on under Uncategorized |
AbstractAichberger and colleagues recently described an association between nilotinib therapy for chronic myelogenous leukemia (CML) and adverse vascular events, which occurred in 8 (?33%) of their 24 CML patients treated with nilotinib: severe peripheral artery disease (PAD; n=3), less severe PAD (n=1), sudden death (n=1), myocardial infarction (n=1), spinal infarction (n=1) and subdural hematoma (n=1).1 We were intrigued by these observations because of similar events that occurred in two of our patients receiving nilotinib therapy. A female patient developed severe and unrelenting PAD and coronory artery disease (CAD) after approximately 3 years of treatment with nilotinib and the second patient died suddenly after receiving nilotinib therapy for 3 weeks. None of the two patients had …
More
Posted by rob on April 14, 2011 under Uncategorized |
Cytomegalovirus sinusitis in a child with chronic myelogenous leukemia following bone marrow transplantation.
Pediatr Blood Cancer. 2011 Jul 1;56(7):1140-2
Authors: Rayes A, Sahni K, Hanna C, Suryadevara M, Goyal P, Cherrick I
Cytomegalovirus (CMV) is a common opportunistic pathogen. CMV sinusitis has been described in acquired immunodeficiency syndrome (AIDS) patients, but not in other immune compromising conditions. In this report, we describe CMV sinusitis in a child with chronic myelogenous leukemia (CML) following bone marrow transplantation. Pediatr Blood Cancer 2011;56:1140-1142. © 2011 Wiley-Liss, Inc.
PMID: 21488162 [PubMed - in process]
More
Posted by rob on under Uncategorized |
A pyrosequencing-based test for detection and relative quantification of the BCR-ABL1 T315I point mutation.
J Clin Pathol. 2011 Apr 12;
Authors: Schumacher JA, Szankasi P, Bahler DW, Ho AK, Kelley TW
Aims The BCR-ABL1 T315I mutation imparts resistance to tyrosine kinase inhibitors currently available for treatment of chronic myelogenous leukaemia. Thus, quantitative monitoring of the emergence and expansion of T315I-positive subclones may be clinically useful. The goals of this study were to retrospectively review the authors’ experience with Sanger sequencing-based BCR-ABL1 kinase domain mutation testing, paying particular attention to the T315I mutation, and to develop an alternative test for relative quantification of T315I using pyrosequencing. Methods The performance of a new T315I pyrosequencing assay was evaluated. Total RNA was isolated from whole blood and reverse-transcribed. The resulting cDNA was subjected to an initial round of PCR across the BCR-ABL1 breakpoint followed by a second round to amplify the sequence flanking ABL1 codon 315. The final PCR product was pyrosequenced to detect and quantify the T315I point mutation. Additional experiments were carried out to determine the effects of background untranslocated ABL1 on assay sensitivity in samples with low tumour burden. Results The results show that T315I was the most commonly detected kinase domain mutation and was persistent in follow-up testing. All 26 specimens that tested positive by Sanger sequencing for the T315I mutation were also positive using the pyrosequencing test. Relative quantification data derived from pyrosequencing matched the approximate wild-type/mutant ratios found by Sanger sequencing. Serial dilution experiments show sensitivity to 5% mutant allele. The authors also quantitatively assessed the influence of untranslocated ABL1 in the sample background on the assay and found that it occurred at levels not likely to influence performance. Conclusion The described test is useful for detection and relative quantification of the T315I point mutation in chronic myelogenous leukaemia in a sensitive, specific and reproducible manner.
PMID: 21486895 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Prophylaxis and treatment of invasive aspergillosis with voriconazole, posaconazole and caspofungin – review of the literature.
Eur J Med Res. 2011 Apr 28;16(4):145-52
Authors: Karthaus M
Major progress for the management of invasive aspergillosis has come from the introduction of new antifungals since the late 1990s. Although mortality of invasive aspergillosis remains as high as 30-50%. Backbone of management are prophylaxis, early diagnosis and early initiation of antifungals for reduction of invasive aspergillosis related mortality. Randomized trials have been undertaken for the prophylaxis as well as treatment of invasive aspergillosis in the last two decades. Posaconazole is recommended for prophylaxis against aspergillosis in patients treated for acute myelogenous leukemia, myelodysplastic syndrome or patients with graft versus host disease after allogeneic transplantation. Efficacy has been shown for first-line therapy of invasive aspergillosis with voriconazole and liposomal amphotericin B. Gastrointestinal resorption for the azoles posaconazole, voriconazole and itraconazole differ considerably. While oral voriconazole resportion is reduced when taken with food, posaconazole has to be taken with fatty food for optimal intestinal resorption. Beside all advances in the management of invasive aspergillosis important questions remain unresolved. This article reviews the current state of prophylaxis and treatment of invasive aspergillosis and points out clinicians unmet needs.
PMID: 21486728 [PubMed - in process]
More
Posted by rob on under Uncategorized |
Authors: J Lu, Y Ma, N Kong, Z Alipio, C Gao, D S Krause, L E Silberstein
& L Chai (Source: Leukemia)
More
Posted by rob on under Uncategorized |
In this study, we sought to identify targeted PKR activation by Bcr-Abl AS RNA, an anti-sense RNA complementary to the unique mRNA fragments flanking the fusion point of Bcr-Abl, which can be used as an effective anti-leukemia strategy in K562 cells. Moreover, we observed expression of Bcr-Abl AS RNA in K562 cells which resulted in selective apoptosis induction through specific activation of PKR, leading to phosphorylation of eIF2?, global inhibition of protein synthesis, caspase-8 activation and BAX up-regulation. The targeted PKR activation and induced apoptosis were reversed by the PKR inhibitor 2-aminopurine. Taken together, our results indicate that targeted PKR activation led to selective apoptosis induction in K562 cells, which correlated with caspase-8 activity and enhanced ex…
More
Posted by rob on April 1, 2011 under Uncategorized |
ConclusionsDaily oral imatinib at a dose of 340?mg/m2 is well tolerated in children. In addition, imatinib therapy is effective in inducing a high percent of hematologic, cytogenetic and molecular responses, comparable to adults with CML. (This study was registered at ClinicalTrials.gov under identifier NCT00030394.) Pediatr Blood Cancer © 2011 Wiley?Liss, Inc. (Source: Pediatric Blood and Cancer)
More
Posted by rob on under Uncategorized |
Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML) but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKIs), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of imatinib-resistant CML patients (chronic phase, n = 34; accelerated phase [AP], n = 9; and blast phase [BP], n = 4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%); 15 of 19 had advanced CML (AP + BP + second chronic phase). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, P = .03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event…
More
Posted by rob on under Uncategorized |
In theory, it sounds straightforward: Find genetic mutations essential to the growth and survival of the cancer, identify specific inhibitors in the lab, and validate them in human studies. In practice, it is often a complicated path from mutation discovery to a viable targeted therapeutic agent, said Levi Garraway, MD, PhD (DFCI). Several years ago, for example, failure of the first drug in clinical trials designed to block molecular drivers of metastatic melanoma made the BRAF mutation seem a dubious target. And despite last year?s striking results in early phase trials, it seems clear that inhibiting mutant BRAF activity alone cannot eradicate melanoma tumors nor even hold them back for long. ?The good news is that the other kinases in the pathway remain a hot area for drug discovery,…
More
Posted by rob on under Uncategorized |
It is daunting for even the most dedicated scholar of cancer research to track the alphabet soup of promising molecular targets and pathways. But last year a BRAF mutation joined the handful of oncogenes that can be therapeutically targeted by a selective inhibitor. Researchers reported a striking regression of metastatic melanoma tumors.?A major breakthrough,? said an editorial in the New England Journal of Medicine (NEJM), titled ?Melanoma?An Unlikely Poster Child for Personalized Cancer Therapy.? The editorial was published in August alongside the phase I results of one of the experimental inhibitors (RG7204/PLX4032, Roche) by Keith Flaherty, MD (MGH) and his co-investigators.In the trial, 81 percent of the 32 patients in the extension cohort (whose cancers carried the signature BR…
More
Posted by rob on under Uncategorized |
It is daunting for even the most dedicated of scholars to track the alphabet soup of promising molecular targets and pathways. But last year a BRAF mutation joined the handful of oncogenes that can be therapeutically targeted by a selective inhibitor. Researchers reported a striking regression of metastatic melanoma tumors.?A major breakthrough,? said an editorial in the New England Journal of Medicine (NEJM). The editorial, ?Melanoma?An Unlikely Poster Child for Personalized Cancer Therapy,? was published in August alongside the phase I results of one of the experimental inhibitors (RG7204/PLX4032, Roche) by Keith Flaherty, MD (MGH) and his co-investigators.In the trial, 81 percent of the 32 patients in the extension cohort (whose cancers carried the signature BRAF mutation) saw a te…
More
Posted by rob on under Uncategorized |
Abstract As of 2011, the choice of tyrosine kinase inhibitor (TKI) for the patient with newly diagnosed chronic-phase chronic myelogenous
leukemia (CP-CML) is no longer limited to imatinib but can be expanded to include nilotinib and dasatinib. Since 2000, imatinib
has demonstrated remarkable efficacy in the majority of chronic-phase patients. Nilotinib and dasatinib, both more potent
TKIs, are likely to produce quicker and deeper molecular responses, but there are no established criteria for choosing the
best inhibitor for each patient. We now need to establish clearly defined recommendations to address this new stage, in which
individualized therapy in the front-line should become a reality. Likely to be paramount in this setting are assays that directly
assess the effic…
MedWorm Message: Find out about the Doctors 2.0 and You conference in Paris, June 22-23rd. The call is now on for posters and the start-up contest.
More
Posted by rob on under Uncategorized |
SummarySweet syndrome (acute febrile neutrophilic dermatosis) is characterized by a dramatic onset of high fever, neutrophilia and typical skin lesions. About 20 % of patients have an associated malignancy, most commonly hematologic diseases. Chronic and paucisymptomatic manifestations of Sweet syndrome may be misdiagnosed or misinterpreted as harmless, resulting in delayed diagnosis. “Atypical” manifestations are especially suspicious for associated malignancies. This is demonstrated by a 39?year old patient with chronic and afebrile disease who was referred to our clinic only after symptoms had persisted for several months. By that point, an underlying nodular lymphocyte predominant Hodgkin’s lymphoma had already reached an advanced stage. Skin biopsies revealed dermal infiltrates …
More
Posted by rob on under Uncategorized |
Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, and is highly expressed in tumor cells. We have identified NS as a target of oxidative regulation in transformed hematopoietic cells. NS oligomerization occurs in HL-60 leukemic cells and Raji B lymphoblasts that express high levels of c-Myc and have high intrinsic levels of reactive oxygen species (ROS); reducing agents dissociate NS into monomers and dimers. Exposure of U2OS osteosarcoma cells with low levels of intrinsic ROS to hydrogen peroxide (H2O2) induces thiol-reversible disulfide bond-mediated oligomerization of NS. Increased exposure to H2O2 impairs NS degradation, immobilizes the protein within the nucleolus, and results in detergent-insoluble NS. The regulation…
More
Posted by rob on under Uncategorized |
The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces ce…
More
Posted by rob on under Uncategorized |
Patients with chronic myelogenous leukemia (CML) treated with imatinib who remain in complete cytogenetic remission for 2 years have survival rates comparable to the general population. Medscape Medical News (Source: Medscape Today Headlines)
More
