MR safety: fast T1 thermometry of the RF-induced heating of medical devices.

Determining the MR compatibility of medical implants and devices is becoming increasingly relevant. In most cases, the heating of conductive implants due to radiefrequency (RF) excitation pulses is measured by fluoroptic temperature sensors in relevant tests for approval. Another common method to determine these heating effects is MR thermometry using the proton resonance frequency. This method gives good results in homogeneous phantoms. However in many cases, technical shortcomings such as susceptibility artifacts prohibit exact proton resonance frequency thermometry near medical implants. Therefore, this work aimed at developing a fast T1-based method which allows controlled MR-related heating of a medical implant while simultaneously quantifying the spatial and temporal temperature distribution. To this end, an inversion recovery snapshot Fast Low-Angle Shot (FLASH) sequence was modified with additional off-resonant heating pulses. With an accelerated imaging method and a sliding-window technique, every 7.6 s a new temperature map could be generated with a spatial in-plane resolution of 2 mm. The temperature deviation from calculated temperature values to reference fluoroptic probe was found to be smaller than 1 K.

Systematic review of the efficacy and safety of fibrinogen concentrate substitution in adults.

BACKGROUND: A sufficient plasma level of fibrinogen is critical for the formation of a fibrin clot and haemostasis in both the perioperative setting and in massive haemorrhage. We assessed the efficacy and safety of fibrinogen concentrate substitution in the perioperative setting and in massive haemorrhage. METHODS: We conducted a systematic literature search for studies conducted on humans and published in either English or German in several databases from 1985 to 2010. In addition, we screened several web sites for assessments on fibrinogen concentrate substitution and conducted a hand search using Scopus. In terms of efficacy, we included all prospective, controlled studies. Concerning safety, we included all prospective studies. RESULTS: We identified two randomised controlled trials and two non-randomised controlled studies, which included a total of 74 patients. The studies indicate that the administration of fibrinogen concentrate is associated with improved clot firmness and reduction in the substitution of other blood products such as red blood cells, fresh frozen plasma and platelet concentrates, as well as decreased post-operative bleeding and drainage volume. In addition, fibrinogen concentrate administration has been reported to be safe with regard to thrombosis and thromboembolic complications, as well as mortality. However, the studies identified were of poor quality. CONCLUSION: In conclusion, the results of the available controlled trials suggest that the administration of fibrinogen concentrate was effective and safe. However, because all studies identified were of inadequate quality, these findings need to be confirmed by randomised controlled trials of sufficient size and long-term follow-up.

Targeted cancer therapies in the twenty-first century: lessons from imatinib.

An increased understanding of the molecular etiology of cancer has enabled the development of novel therapies that are collectively referred to as molecular targeted agents. Unlike the drugs used in conventional chemotherapy, these agents are designed to specifically interfere with key molecular events that are responsible for the malignant phenotype. They hold great promise for widening the therapeutic window, which would provide more effective treatment options as compared with cytotoxic therapies. In addition, the targeted approach that is characteristic of these drugs provides unique opportunities for combination therapies with other anticancer agents that have non-overlapping toxicities. Targeted agents are therefore primed to become invaluable therapeutic tools in the multimodal treatment of cancer. The challenges associated with these novel targeted therapies are distinct from those faced in conventional chemotherapy. These unique challenges include the need to select appropriate pharmacodynamic markers to guide dose and schedule and to identify biomarkers that enable selection of patient populations that are most likely to benefit from the treatment. In addition, although the emergence of resistance to targeted therapies is a problem frequently faced in the clinic, the molecular characterization of resistance mechanisms provides the opportunity to design second-generation therapies or combination therapies aimed at preventing resistance or restoring response. The development of the tyrosine kinase inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). In this article, we discuss the lessons learned from the application of imatinib and other targeted agents in clinical practice and discuss how these insights may guide the development of novel targeted therapies.

The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains.

Bcr-Abl is found in more than 95% of cases with CML. The mechanism of Bcr-Abl-induced transformation is not fully understood. Bcr-Abl is a constitutively active tyrosine kinase with transforming capacity for hematopoietic cells. We demonstrated recently that the Src kinase Hck interacts directly with Bcr-Abl by a kinase-independent mechanism. Moreover, the inhibition of the Hck kinase seems to block some of the transforming effects of Bcr-Abl. To identify the binding domains mediating this interaction of Hck with Bcr-Abl, we co-expressed different plasmid and baculovirus vectors containing mutants or single domains of Bcr-Abl and/or Hck in COS7 and Sf9 cells. At least four independent binding regions for Hck were identified in Bcr-Abl, one in Bcr, one in the region comprising the SH3 and SH2 domain of Abl, one in the SH1 domain of Abl, and one in the C-terminal domain of Abl. In the Hck kinase, deletion of the SH2 and/or the SH3 region abolished binding to Bcr-Abl. In contrast, deletion of the Hck SH1 domain enhanced binding of Hck to Abl and Bcr-Abl. In conclusion, the results indicate that the interaction of Bcr-Abl with Hck is mediated by a novel, complex mechanism that involves multiple domains of Bcr-Abl and the SH2 and SH3 domains of Hck.

Signaling through a novel domain of gp130 mediates cell proliferation and activation of Hck and Erk kinases.

Interleukin-6 (IL-6) induces the activation of the Src family kinase Hck, which is associated with the IL-6 receptor beta-chain, gp130. Here we describe the identification of an "acidic" domain comprising amino acids 771 to 811 of gp130 as a binding region for Hck, which mediates proliferative signaling. The deletion of this region of gp130 (i.e., in deletion mutant d771-811) resulted in a significant reduction of Hck kinase activity and cell proliferation upon stimulation of gp130 compared to wild-type gp130. In addition, d771-811 disrupted the growth factor-stimulated activation of Erk and the dephosphorylation of Pyk2. Based on these findings, we propose a novel, acidic domain of gp130, which is responsible for the activation of Hck, Erk, and Pyk2 and signals cell proliferation upon growth factor stimulation.

Phase I study of Doxil and vinorelbine in metastatic breast cancer.

BACKGROUND: Vinorelbine and Doxil (liposomal doxorubicin) are active chemotherapeutic agents in metastatic breast cancer. A phase I study was designed to evaluate combination therapy. PATIENTS AND METHODS: Thirty women with metastatic breast cancer were enrolled. Dose-limiting toxicity was determined through a dose escalation scheme, and defined for the first treatment cycle, only. Pharmacokinetic studies were performed during the first cycle of treatment. RESULTS: In the first cohort of Doxil 30 mg/m2 day 1 and vinorelbine 25 mg/m2 days 1 and 8, patients experienced severe neutropenia. Vinorelbine administration was changed thereafter to days 1 and 15 of each cycle. Dose limiting toxicity was observed at Doxil 50 mg/m2 and vinorelbine 25 mg/m2. Doxil 40 mg/m2 and vinorelbine 30 mg/m2 was defined as the maximally tolerated dose. Few toxicities (principally neutro penia) were seen at this dose level, with the notable absence of significant nausea, vomiting, or alopecia. Though 63% of patients had received prior anthracycline-based chemotherapy, only one patient developed grade 2 cardiac toxicity. Pharmacokinetic studies revealed prolonged exposure to high doxorubicin concentrations for several days following Doxil administration. CONCLUSIONS: Combination chemotherapy with Doxil and vinorelbine affords treatment with two active drugs in women with metastatic breast cancer, and appears to have a favorable toxicity profile. A schedule of Doxil 40 mg/m2 day 1 and vinorelbine 30 mg/m2 days 1 and 15 given every 28 days is recommended for phase II studies.

Molecular pathogenesis of chronic myeloid leukemia: implications for new therapeutic strategies.

With an annual incidence of about ten in 1,000,000 people, chronic myeloid leukemia (CML) accounts for most cases of myeloproliferative disease and for 20% of all leukemias. While novel therapies such as treatment with interferon-alpha or bone marrow transplantation have successively improved the outcome of CML treatment, hope for future progress in the therapy of CML lies in an almost unique feature of this hematological malignancy. In contrast to many other forms or subforms of leukemias which display a great diversity in chromosomal alterations, most cases (>95%) of CML seem to be caused by an almost invariably found cytogenetic aberration, the so-called Philadelphia chromosome (Ph), resulting in the bcr-abl fusion gene. Its gene product, p210bcr-abl (Bcr-Abl), is believed to be essential for hematopoietic cell transformation and seems to exert its effects by interfering with cellular signal transduction pathways, normally involved in the control of cell death and proliferation. Several partially interacting pathways have been shown to be induced by Bcr-Abl. The role of most of them is still unclear and, as understanding their biological functions should lead to novel therapeutic strategies on a molecular basis, much effort is spent on identifying their precise roles in CML. This review focuses on our current understanding of Bcr-Abl-induced signal transduction and outlines its importance for the biological effects of Bcr-Abl.

Relative loss bounds for single neurons.

We analyze and compare the well-known gradient descent algorithm and the more recent exponentiated gradient algorithm for training a single neuron with an arbitrary transfer function. Both algorithms are easily generalized to larger neural networks, and the generalization of gradient descent is the standard backpropagation algorithm. In this paper we prove worst-case loss bounds for both algorithms in the single neuron case. Since local minima make it difficult to prove worst-case bounds for gradient-based algorithms, we must use a loss function that prevents the formation of spurious local minima. We define such a matching loss function for any strictly increasing differentiable transfer function and prove worst-case loss bounds for any such transfer function and its corresponding matching loss. For example, the matching loss for the identity function is the square loss and the matching loss for the logistic transfer function is the entropic loss. The different forms of the two algorithms' bounds indicates that exponentiated gradient outperforms gradient descent when the inputs contain a large number of irrelevant components. Simulations on synthetic data confirm these analytical results.

Complications of axillary lymph node dissection for carcinoma of the breast: a report based on a patient survey.

BACKGROUND: Axillary lymph node dissection is commonly performed as part of the primary management of breast carcinoma. Its value in patient management, however, has recently been questioned. Few studies exist that document long term complications. METHODS: Four hundred thirty-two patients with Stage I or II breast carcinoma who were free of recurrence 2-5 years after surgery were identified. A cross-sectional survey was conducted to determine the prevalence of long term symptoms and complications as perceived by the patient, and patient and treatment factors that may have predicted complications were determined. Three hundred thirty of the 432 (76%) completed a mailed, self-administered questionnaire. In addition, the medical records of the 330 patients were reviewed. Patient and treatment factors were analyzed with logistic regression. RESULTS: Numbness was reported by 35% of patients at the time of the survey. Pain was noted in 30%, arm swelling in 15%, and limitation of arm movement in 8%. Eight percent reported episodes of infection or inflammation at some point since the diagnosis of breast carcinoma. The majority of symptoms were mild and interfered minimally with daily activities. Younger age (P=0.001) was associated with more frequent reporting of pain. Numbness was more common in younger patients (P=0.004) as well as in those with a history of smoking (P=0.012). There was a positive association of limitation of arm motion with adjuvant tamoxifen therapy (P=0.016). Arm swelling was associated with both younger age (P=0.004) and greater body surface area (P=0.008). Radiation therapy was associated with a higher frequency of infection or inflammation in the arm and/or breast (P=0.001). CONCLUSIONS: Mild symptoms, especially pain and numbness, are common 2-5 years after axillary lymph node dissection. The frequency of inflammation or infection in patients treated with radiation to the breast or chest wall after an axillary lymph node dissection may be greater than previously appreciated. Severe complications or symptoms that have a major impact on daily activities are uncommon. These findings should help health care providers and their patients with breast carcinoma weigh the pros and cons of axillary lymph node dissection.

A review of hereditary breast cancer: from screening to risk factor modification.

The identification of genetic mutations thought to be directly responsible for the development of breast cancer represents a major advance in our understanding of this disease. Mutations in BRCA1 and BRCA2 are thought to be responsible for the majority of inherited breast cancer. Although these mutations account for approximately 5% of breast cancer cases, the identification of these genes will have a profound impact on the way patients and their physicians view breast cancer risk. Genetic testing for BRCA1 and BRCA2 mutations is already available. Interpreting results of genetic tests for these mutations is problematic and the clinical management of women carrying these gene mutations is far from straightforward. The purpose of this paper is to review recent developments in the genetic aspects of breast cancer, including genetic testing, to critically review risk factor modification, and to discuss screening and potential prophylactic measures.

Pharmacokinetics and clinical impact of all-trans retinoic acid in metastatic breast cancer: a phase II trial.

PURPOSE: The purpose of this trial was to evaluate tumor cytoreduction by all-trans retinoic acid (ATRA) in patients with metastatic breast cancer and to characterize the initial pharmacokinetics of this agent. METHODS: The study was a single institution, phase II study. The treatment regimen consisted of ATRA administered orally at a dose of 50 mg/m2 three times a day for 14 consecutive day of a 21-day cycle. Cycles were repeated until disease progression, unacceptable toxicity or patient withdrawal. Plasma samples were obtained following the first dose of ATRA for pharmacokinetic analysis. RESULTS: A total of 17 patients with metastatic breast cancer were enrolled in the study, and 14 completed at least one cycle of therapy and were evaluable for response. One patient achieved a partial response in soft tissue of 4 months duration. Three patients had stable disease for 4, 2, and 2 months duration. The remainder had progressive disease. ATRA was reasonably well tolerated. Pharmacokinetic analysis revealed a high degree of interpatient variability in systemic exposure following the initial dose of ATRA. CONCLUSIONS: We conclude, that in the dose and schedule tested, ATRA does not have significant activity in patients with hormone-refractory, metastatic breast cancer. Future studies should focus on more intensive investigation of those individuals with very high or low ATRA initial systemic exposure in the hope of expanding our understanding of ATRA's clinical pharmacology, ultimately leading to improved efficacy.

The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr.

bcr-abl, the oncogene causing chronic myeloid leukemia, encodes a fusion protein with constitutively active tyrosine kinase and transforming capacity in hematopoietic cells. Various intracellular signaling intermediates become activated and/or associate by/with Bcr-Abl, including the Src family kinase Hck. To elucidate some of the structural requirements and functional consequences of the association of Bcr-Abl with Hck, their interaction was investigated in transiently transfected COS7 cells. Neither the complex formation of Hck kinase with Bcr-Abl nor the activation of Hck by Bcr-Abl was dependent on the Abl kinase activity. Both inactivating point mutations of Hck and dephosphorylation of Hck enhanced its complex formation with Bcr-Abl, indicating that their physical interaction was negatively regulated by Hck (auto)phosphorylation. Finally, experiments with a series of kinase negative Bcr-Abl mutants showed that Hck phosphorylated Bcr-Abl and induced the binding of Grb2 to Tyr177 of Bcr-Abl. Taken together, our results suggest that Bcr-Abl preferentially binds inactive forms of Hck by an Abl kinase-independent mechanism. This physical interaction stimulates the Hck tyrosine kinase, which may then phosphorylate the Grb2-binding site in Bcr-Abl.

Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells.

Chronic myeloid leukemia is characterized by the Philadelphia (Ph1) translocation t(9;22) that generates a hybrid gene, bcr/abl, translated to a Mr210,000 tyrosine kinase (p210bcr/abl) with transforming activity for hematopoietic cells. Hematopoietic cell transformation by p2l0bcr/abl seems to involve activation of the Ras signaling pathway by at least two different signaling intermediates, growth factor receptor-bound protein 2 and Src homology and collagen protein, but additional signaling proteins are likely to be required as well. In an effort to identify additional phosphoproteins activated by p210bcr/abl, we studied the murine, interleukin 3-dependent, myeloid cell line, 32D, and a bcr/abl-transfected, factor-independent subline, 32Dp210. The analysis of whole-cell lysates of 32D and 32Dp210 cells showed that several proteins with a molecular weight of Mr50,000-60,000 were phosphorylated on tyrosine residues in 32Dp210 cells. Because Src family kinases have an apparent molecular weight of Mr50,000-60,000, we asked whether they could become activated by p2l0bcr/abl. Two Src family kinases, p53/56lyn and p59hck, showed a severalfold higher phosphokinase activity in 32Dp210 cells than in 32D cells. Coimmunoprecipitation experiments with anti-Lyn, anti-Hck, and anti-Abl antibodies demonstrated an intracellular association of p210bcr/abl with p53/56lyn and p59hck. Moreover, the phosphokinase activity of p53/56lyn was higher in bcr/abl-positive myeloid cell lines (K562, BV173, and LAMA84) than in the bcr/abl-negative myeloid cell line JOSK-M. In conclusion, the results show that p210bcr/abl induces the activation of at least two Src family kinases, P53/56lyn and p59hck, in myeloid cells. These findings extend the range of potential targets of p210bcr/abl that might mediate its transforming effects.

Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells.

The chimaeric bcr/abl oncogene is detected in virtually all cases of chronic myelogenous leukaemia (CML). It encodes a constitutively active tyrosine kinase of 210 kDalton, p210bcr/abl, which stimulates a variety of cytosolic signalling intermediates. The effects of bcr/abl on the activity of growth factor receptors are less well known. In order to investigate interaction of p210bcr/abl with the receptor tyrosine kinase p145c-kit, we used two myeloid, factor-dependent cell lines, MO7 and 32D, to generate bcr/abl positive sublines, MO7p210 and 32Dp210, by transfection with the bcr/abl gene. Since 32D and 32Dp210 cells did not express p145c-kit, a c-kit retrovirus was used to generate c-kit positive cell lines (32Dkit, 32Dp210kit). In contrast to MO7 and 32Dkit cells, MO7p210 and 32Dp210kit cells were factor independent and did not respond to the growth-promoting effects of recombinant human Steel factor (rhSF). Preincubation with a monoclonal antibody (MAb) neutralizing the binding of SF to p145c-kit did not affect the growth of MO7p210 cells, thus eliminating the possibility of an autocrine SF secretion. 32Dkit cells transfected with bcr/abl containing an inactivating point mutation (Lys-->Arg271) in the Abl kinase domain (32Dp210(Arg271)kit) retained their responsiveness to the effects of rhSF. Immune complex kinase assays showed that the kinase activity of p145c-kit was several-fold higher in MO7p210 and 32Dp210kit cells than in MO7, 32Dkit and 32Dp210(Arg271)kit cells, suggesting that Abl kinase activity was necessary to activate p145c-kit. Co-immunoprecipitation experiments with anti-Kit and anti-Abl MAbs demonstrated that p145c-kit and p210bcr/abl were associated in an intracellular complex in human bcr/abl positive, c-kit positive cell lines (MO7p210; GM/SO). Finally, colony assays with bone marrow from bcr/abl positive CML patients showed that the haemopoietic progenitors of three of four patients did not respond to rhSF. Taken together, the results suggest that p145c-kit can be activated by p210bcr/abl via an Abl-kinase dependent mechanism involving the complex formation of both proteins. These findings could explain some clinical features (basophilia, increase of immature myeloid cells) of chronic-phase CML.

Worst-case quadratic loss bounds for prediction using linear functions and gradient descent.

Studies the performance of gradient descent (GD) when applied to the problem of online linear prediction in arbitrary inner product spaces. We prove worst-case bounds on the sum of the squared prediction errors under various assumptions concerning the amount of a priori information about the sequence to predict. The algorithms we use are variants and extensions of online GD. Whereas our algorithms always predict using linear functions as hypotheses, none of our results requires the data to be linearly related. In fact, the bounds proved on the total prediction loss are typically expressed as a function of the total loss of the best fixed linear predictor with bounded norm. All the upper bounds are tight to within constants. Matching lower bounds are provided in some cases. Finally, we apply our results to the problem of online prediction for classes of smooth functions.

Surgical intervention and heparin-anticoagulation improve prognosis of rhinogenic/otogenic and posttraumatic meningitis.

It is still controversial, whether early surgical removal of infectious material and heparin-anticoagulation to reduce vascular complications will improve outcome in acute meningitis. In the present pilot-study 40 patients with acute or delayed post-traumatic or oto-/rhinogenic purulent bacterial meningitis were analysed for neurological outcome by using the Glasgow outcome score (GOS) and the Tuthill functional score; patients were treated either by early surgical revision of the septic focus (Group 1, within 6 days, n = 15), late surgery (Group 2, later than 6 days, n = 19), or no surgery at all (Group 3, n = 6). All patients, independent of surgical approach, received therapeutic heparin-anticoagulation. Patient groups were otherwise comparable for antibiotic treatment, osmotherapy, microbiology, CSF-findings, CT-scans and prognostic factors. Outcome according to GOS was superior in Group 1 compared with Groups 2/3 (non-significant). Although there was no significant difference on admission in the Tuthill functional score, Group 1 achieved a superior final outcome of 96 points compared with Groups 2 and 3, who gained 72 points (p < 0.01). In addition, Group 1 patients had significantly less intracranial complications (8/15 patients versus 21/25 patients in Groups 2/3, p < 0.01) and were dependent upon respirator treatment for fewer days (10.2 days) than Groups 2/3 (12.5 days, non-significant). In 31 patients CSF-leakage was identified: among these, 17 patients had CSF-leakage, which had not been anticipated by clinical/neuroradiological examinations and revealed only by surgery. The overall mortality in this study population was very low (2.5%), therefore, therapeutic heparin seems to represent an additional favorable treatment measure.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia.

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4-hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.