Detection of metallic objects on digital radiographs with convolutional neural networks: A MRI screening tool.

INTRODUCTION: Screening for metallic implants and foreign bodies before magnetic resonance imaging (MRI) examinations, are crucial for patient safety. History of health are supplied by the patient, a family member, screening of electronic health records or the picture and archive systems (PACS). PACS securely store and transmits digital radiographs (DR) and related reports with patient information. Convolutional neural networks (CNN) can be used to detect metallic objects in DRs stored in PACS. This study evaluates the accuracy of CNNs in the detection of metallic objects on DRs as an MRI screening tool. METHODS: The musculoskeletal radiographs (MURA) dataset consisting of 14.863 upper extremity studies were stratified into datasets with and without metal. For each anatomical region: Elbow, finger, hand, humerus, forearm, shoulder and wrist we trained and validated CNN algorithms to classify radiographs with and without metal. Algorithm performance was evaluated with area under the receiver-operating curve (AUC), sensitivity, specificity, predictive values and accuracies compared with a reference standard of manually labelling. RESULTS: Sensitivities, specificities and area under the ROC-curves (AUC) for the six anatomic regions ranged from 85.33% (95% CI: 78.64%-90.57%) to 100.00% (95% CI: 98.16%-100.00%), 75.44% (95% CI: 62.24%-85.87%) to 93.57% (95% CI: 88.78%-96.75%) and 0.95 to 0.99, respectively. CONCLUSION: CNN algorithms classify DRs with metallic objects for six different anatomic regions with near-perfect accuracy. The rapid and iterative capability of the algorithms allows for scalable expansion and as a substitute MRI screening tool for metallic objects. IMPLICATIONS FOR PRACTICE: All CNNs would be able to assist in metal detection of digital radiographs prior to MRI, an substantially decrease screening time.

Long-term results in children with AML: NOPHO-AML Study Group--report of three consecutive trials.

In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.

Unexpected medical coincidences require systematic and careful strategies: an example.

In a cohort of 14 children with identical cardiac xenografts, two boys developed acute myeloid leukaemia 11 and 16 months respectively after the operation. A dedicated working group designed a scheme intending to take care of all aspects of the situation. This article focuses on preferred strategies towards patients, relatives, government, and the media. We did not find any substantial evidence supporting the association between bovine xenografts and two cases of acute myeloid leukaemia.

[Children with cancer--great progress, a lot of good news and some disappointments]. / Barn med kreft--store fremskritt, mange gleder og noen skuffelser.

Each year, between 125 and 150 children under the age of 15 develop cancer in Norway. More than half of the children are less than five years of age at diagnosis. The malignancy is often of an embryonal origin and the disease spectrum very different from that in adults. Our progress in understanding and treating childhood malignancies is one of the success stories in paediatrics and in cancer biology and management. In the Nordic countries, about three of four children with cancer are cured, but the progress is different in different disease groups. For some malignancies, survival is close to 100%, while progress for other types have been much slower. However, cancer is still the main cause of death in children above one year of age who die of a disease. The progress has its price. The treatment is often intensive, with great morbidity and a definite mortality. Late effects are also of great concern. A more specific therapy targeted against the malignant cell, with less damage to normal cells, has long been our goal. Progress in recent years in the understanding of the malignant cells has now given the first definite examples that such targeted therapy may soon become a reality.

CD99 signals caspase-independent T cell death.

Death signaling by Fas and TNF receptors plays a major role in the control of activated mature T cells. However, the nature of the death receptors, which may be used by the immune system to control T cells that have not acquired susceptibility to Fas ligand or TNF, is not established. In this study, we demonstrate that engagement of distinct epitopes on CD99 rapidly induces T cell death by a novel caspase-independent pathway. A new mAb to these CD99 epitopes, Ad20, induces programmed cell death of transformed T cells as determined by morphological changes, phosphatidylserine exposure on the cell surface, and uptake of propidium iodide. In general, ligation of CD99 induced kinetically faster and more profound death responses as compared with the impact of anti-Fas and TNF-related apoptosis-inducing ligand (TRAIL). Ad20-induced programmed cell death was observed with seven of eight T cell lines examined, and notably, only two of these were distinctly responsive to anti-Fas and TRAIL. CD99-mediated death signaling proceeded independently of functional CD3, CD4, CD45, and p56(lck), revealed distinctions from CD47-mediated T cell death responses, and was not influenced by interference with CD47 signaling. In contrast to the effect on transformed T cell lines, Ad20-induced death responses were not observed with normal peripheral T cells. Thus, our data suggest that CD99 is linked to a novel death pathway that may have biologic relevance in control of early T cells.

[Folling's disease]. / Føllings sykdom.

Norway is a small country and we have few examples of medical scientists that has discovered and cultivated unknown territory. One very good example is the man who discovered the first link between metabolic disease and brain development. Asbjørn Følling was born in 1888 and discovered "his disease" (phenylketonuria = PKU) in 1934. This article gives a description of his life, discovery and work.

A randomized trial of 13-Cis retinoic acid in children with advanced neuroblastoma after high-dose therapy.

One hundred and seventy-five children with Stage 3 or 4 neuroblastoma who had obtained a good response to conventional therapy were randomly allocated to 13-Cis retinoic acid at a dose of 0.75 mg/kg/day or placebo for up to 4 years. Toxicity was mild but no advantage in event-free survival was shown for the children receiving retinoic acid.

CD47 signals T cell death.

Activation-induced death of T cells regulates immune responses and is considered to involve apoptosis induced by ligation of Fas and TNF receptors. The role of other receptors in signaling T cell death is less clear. In this study we demonstrate that activation of specific epitopes on the Ig variable domain of CD47 rapidly induces apoptosis of T cells. A new mAb, Ad22, to this site induces apoptosis of Jurkat cells and CD3epsilon-stimulated PBMC, as determined by morphological changes, phosphatidylserine exposure on the cell surface, uptake of propidium iodide, and true counts by flow cytometry. In contrast, apoptosis was not observed following culture with anti-CD47 mAbs 2D3 or B6H12 directed to a distant or closely adjacent region, respectively. CD47-mediated cell death was independent of CD3, CD4, CD45, or p56lck involvement as demonstrated by studies with variant Jurkat cell lines deficient in these signaling pathways. However, coligation of CD3epsilon and CD47 enhanced phosphatidylserine externalization on Jurkat cells with functional CD3. Furthermore, normal T cells required preactivation to respond with CD47-induced apoptosis. CD47-mediated cell death appeared to proceed independent of Fas or TNF receptor signaling and did not involve characteristic DNA fragmentation or requirement for IL-1beta-converting enzyme-like proteases or CPP32. Taken together, our data demonstrate that under appropriate conditions, CD47 activation results in very rapid T cell death, apparently mediated by a novel apoptotic pathway. Thus, CD47 may be critically involved in controlling the fate of activated T cells.

Intensified treatment of acute childhood lymphoblastic leukaemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of 2648 patients diagnosed between 1981 and 1996. Nordic Society of Paediatric Haematology and Oncology (NOPHO)

In a multinational, population-based study from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2648 children below 15 y of age were diagnosed with acute lymphoblastic leukaemia (ALL) in the years 1981-1996. The annual incidence was 3.9/100000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification of therapy, based on multidrug chemotherapy including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. For children with non-B-cell ALL (n=2602), the event-free survival (p-EFS) increased from 0.53+/-0.02 (diagnosed 7/81-6/86) to 0.67+/-0.02 (7/86-12/91) to 0.78+/-0.02 (1/92-12/96). The corresponding p-EFS values at 5 y were 0.57, 0.70 and 0.78, respectively. The main improvements were seen in the group of children with non-high risk leukaemia, with 5-y p-EFS values increasing from 0.60 to 0.76 and 0.85 for the three periods. In high-risk patients, progress has been moderate, especially in children with high white blood cell values at diagnosis. During the last 5-y period, only 10% of the patients received cranial irradiation in first remission while 90% of the patients received high doses of cytostatic infusions (methotrexate isolated or combined with cytarabinoside) and multiple intrathecal injections of methotrexate as CNS-adjusted treatment without any indication of an increased CNS relapse rate.

The TCR-binding region of the HLA class I alpha2 domain signals rapid Fas-independent cell death: a direct pathway for T cell-mediated killing of target cells?

TCR binding to an MHC class I/peptide complex is a central event in CTL-mediated elimination of target cells. In this study, we demonstrate that specific activation of the TCR-binding region of the HLA-A2 class I alpha2 domain induces apoptotic cell death. mAbs to this region rapidly induced apoptosis of HLA-A2-expressing Jurkat E11 cells, as determined by morphologic changes, phosphatidylserine exposure on the cell surface, and propidium iodide uptake. In contrast, apoptosis was not induced following culture with mAbs directed to other regions of the class I molecule. Death signaling by class I molecules is apparently dependent on coreceptor activation, as apoptosis is also signaled by HLA-A2 molecules, where the intracytoplasmic residues were deleted. HLA class I alpha2-mediated cell death appeared to proceed independent of the Fas pathway. Compared with apoptotic signaling by Fas ligation, HLA class I alpha2-mediated responses displayed a faster time course and could be observed within 30 min. Furthermore, class I alpha2-induced cell death did not involve observable DNA fragmentation. The apoptotic response was not affected significantly by peptide inhibitors of IL-1beta converting enzyme (ICE)-like proteases and CPP32. Taken together, activation of the TCR-binding domain of the class I alpha2 helix may result in apoptotic signaling apparently dependent on a novel death pathway. Thus, target HLA class I molecules may directly signal apoptotic cell death following proper ligation by the TCR.

Cure of infantile myofibromatosis with severe respiratory complications without antitumour therapy.

UNLABELLED: The prognosis of infantile myofibromatosis (IMF) depends on the organs involved: the prognosis is very poor if vital viscera are affected, but excellent if there is no visceral involvement. We report the case of a boy presenting with a pathological fracture at the age of 6 weeks. Progressive osteolytic lesions in the whole skeleton until the age of 8 months led to respiratory failure due to a softened thoracic wall requiring mechanical ventilation for 11 months. No pulmonary, laryngeal or other visceral involvement was found. In spite of the rapidly progressing disease and serious complications only supportive therapy was given. The lesions subsided gradually leaving slight deformities but normal function. At the age of 3.5 years the boy has an excellent quality of life. CONCLUSION: This case illustrates that even in progressing, complicated multifocal infantile myofibromatosis (without visceral involvement) the lesions can resolve without antitumour treatment if high quality intensive care is supplemented.

[A global challenge in the debate on priorities]. / En globaL utfordring i prioriteringsdebatten.

The authors discuss and summarise an international report, "Investing in Health Research and Development", which considers research needs based on an analysis of the burden of disease, measured mainly in terms of Disability Adjusted Life Years (DALYs). The report is to be accompanied by a 10-volume series called Global Burden of Disease and Injury Series. One of the authors (Lie) was a member of the committee that published the report. Another (Godal) headed the secretariat that supported the committee in its work. The report and the accompanying books of background material are expected to be useful in the years to come for funding agencies and governments, both in rich and in poor countries, when deciding what should be supported by way of research and how the health services should be organised. The authors discuss the content of the report and its possible implications for colleagues, research, international development assistance agencies, and health service planners in Norway.

[Immune thrombocytopenic purpura in children--controversy and consensus. How much investigation and treatment is meaningful?]. / Immuntrombocytopenisk purpura hos barn--kontroverser og konsens. Hvor mye utredning og behndling er meningsfull?

Immune thrombocytopenic purpura (ITP) is a postinfectious thrombocytopenia with a general tendency to bleed. The disease is often self-limiting in children, but the risk of intracranial haemorrhage has led to some controversy about indications and intensities of treatment. In nearly all cases of intracranial haemorrhage documented in the literature since 1970, the platelet count was 15 x 10(9)/l) or lower and was observed in less than 1% of the patients. In typical cases of acute ITP no extensive laboratory investigation is required. Indications for treatment depend more on clinical bleeding symptoms than on platelet count. Up to now there is no proven difference in efficacy between steroids and immunoglobulins. In 10-25% the disease becomes chronic, but spontaneous remission can occur after many years. Management of the chronic form has to be adjusted to the individual patient. Continuous steroid treatment for more than three weeks is contraindicated. Splenectomy should be avoided if at all possible because the risk of sepsis after splenectomy is comparable with the risk of life-threatening bleeding.

A population-based study of 272 children with acute myeloid leukaemia treated on two consecutive protocols with different intensity: best outcome in girls, infants, and children with Down's syndrome. Nordic Society of Paediatric Haematology and Oncology (NOPHO).

From July 1984 the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) have registered all children with acute myeloid leukaemia (AML) and treated them on two consecutive protocols of different intensity (NOPHO-84 and NOPHO-88). We probably have information on every child with this diagnosis in our region. We found an annual incidence of AML of 0.7 new cases per 100,000 children < 16 years of age. We observed a distinct peak of incidence in the first 2 years of life. Children with Down's syndrome accounted for 13% of all cases. Eighty of 105 cases treated on NOPHO-84 achieved remission (78%). In NOPHO-88, 100/118 patients entered remission (85%). The overall event-free survival (p-EFS) for the two studies was 0.32 for NOPHO-84 and 0.42 for NOPHO-88. The majority of relapses occurred within 2 years of diagnosis. When looking for prognostic factors the strongest significant adverse factor found was male sex. Children with Down's syndrome (n = 35) had a very favourable outcome if they received therapy according to protocol, and infants (n = 26) had a superior outcome compared to children 1-2 years or > 10 years of age at diagnosis.

Role of the TCR binding region of the HLA class I alpha 2 domain in regulation of cell adhesion and proliferation.

In addition to Ag presentation for T cell surveillance, MHC molecules have been implicated in mediating regulatory signals. We have assessed biologic responses following engagement of the TCR accessible region of the HLA class I alpha 2 domain. mAbs directed to this domain specifically induced cell aggregation of normal hematopoietic and leukemic cells. The functional consequences were unique since other mAbs reactive with HLA class I residues outside the TCR binding domain did not induce cell aggregation. The adhesion response required ATP, mRNA, protein, and actin synthesis and did not depend on LFA-1/ICAM interactions. Cell aggregation was also induced when all but four of the intracytoplasmic residues of the class I molecule were deleted, indicating that transduction of signals leading to cell adhesion does not require this portion of the molecule. mAbs directed to HLA class I alpha 2 amino acid residues within the TCR binding domain were also able to inhibit proliferation of normal mitogen-stimulated T cells. Growth inhibition correlated with down-regulated expression of CD25, CD28, and CD95, suggesting that reduced transduction of costimulatory signals is involved. Although HLA class I signals inducing cell aggregation required engagement of positions within the TCR binding region, growth inhibitory signals could be generated through positions both within and adjacent to this domain. Taken together, engagement of specific positions within the TCR binding domain of the class I alpha 2 helix results in active cellular responses. Thus, this region may be directly involved in signal transduction following CTL recognition of target cells.

RG1, a new murine monoclonal antibody recognizing a "supertypic" determinant on HLA-A molecules.

Monomorphic and polymorphic anti-HLA monoclonal antibodies (mAb) are valuable reagents for assessment of the structural and functional importance of different class I determinants. We have generated a new mAb, RG1, reacting with an epitope variably expressed on normal and leukemic hematopoietic cells of different lineages. Immunoprecipitation of the RG1 antigen disclosed a bimolecular complex characteristic of class I proteins. The RG1 epitope was expressed on an HLA-A2 transfected cell line but not on cells transfected with HLA-E, -F or -G molecules. MAb reactivity with reference B-lymphoblastoid cell lines and HLA typing of RG1 reactive and unreactive cells demonstrated that the epitope was expressed in conjunction with defined HLA-A molecules. Cells expressing HLA-A2, -A24(9) and -A68(28) proteins were brightly stained with RG1 whereas mAb binding to HLA-A1, -A11 and a split of A3 molecules was significantly lower. In contrast, the RG1 epitope was apparently not expressed on HLA-A23(9), -A25(10), -A26(10), -A29(19), -A30(19), -A31(19), -A32(19), -A33(19) and some HLA-A3 molecules. Based on class I alpha sequence data, these results suggest that the RG1 epitope is localized to a region of the alpha 2 helix accessible to the T cell receptor for antigen on cytotoxic T lymphocytes. Lys in position 144 and His in position 151 are apparently critical for RG1 binding.

[Screening of newborn infants in Norway for severe metabolic disease]. / Screening av nyfødte i Norge for alvorlig metabolsk sykdom.

The objective of neonatal screening for phenylketonuria and congenital hypothyroidism is early diagnosis and initiation of treatment to prevent brain damage and mental retardation. We present the results of the Norwegian national neonatal screening programme for phenylketonuria and congenital hypothyroidism. Screening for phenylketonuria based on serum phenylalanine determinations started in 1967 and covered the whole country in 1978. National screening for congenital hypothyroidism started in 1979. One hundred children with phenylketonuria and 280 children with a strong indication of congenital hypothyroidism have been detected up to 1 October 1994. Screening-related challenges and principles of treatment are discussed.