Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. PROCEDURE: We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. Individual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. RESULTS: The incidence of VTE was 5.1%. Extremes of weight at diagnosis (<5th or >95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. CONCLUSION: We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.

Microscopic characterisation of photodetectors used in the hadron calorimeter of the Compact Muon Solenoid experiment.

The Hybrid Photodetector (HPD) is a hybrid unit with a single accelerating gap between a common photocathode and an array of PIN diodes. Customised HPDs with 19 channels were used to detect scintillation light from hadron calorimeter in the Compact Muon Solenoid (CMS) experiment. In this paper, we present results on radiation damage studies carried out on the used HPDs in the outer hadron (HO) and the end-cap hadron (HE) calorimeter of the CMS experiment operating at CERN. The calorimeter is made of alternating layers of scintillating tiles and metals, such as brass or iron. The scintillating light was transmitted to the HPDs by means of optical fibres. Due to excessive exposure to scintillation light and ionising radiation during data taking at the Large Hadron Collider, the performance of the HPDs was expected to degrade significantly in the HE detector. Independent studies on radiation damage of these used photosensors were important to assess the degradation in the performance of the calorimeter. Microscopic scans of relative photon detection efficiencies for two HPDs (one each from HO and HE detector) were made using micron resolution optical scanner. The scanner was specially designed and built for microscopic characterisation of photosensors. Imprints of each fibre (∼1 mm in diameter) on the photocathode with varying damage within the same pixel of the HPD were observed. The localised damage of the photocathode was determined to vary with the amount of scintillation (or calibration) light transmitted by optical fibres to the HPD.

Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade.

Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM.

The wide-ranging clinical implications of the short telomere syndromes.

There is an increasing number of inherited disorders in which excessive telomere shortening underlies the molecular defect, with dyskeratosis congenita (DC) being the archetypal short telomere syndrome. DC is classically described as a mucocutaneous triad of oral leukoplakia, nail dystrophy and abnormal skin pigmentation. However, excessive telomere shortening can affect almost any organ system, so the clinical manifestations are protean, including developmental delay, cerebellar hypoplasia, exudative retinopathy, aplastic anaemia, acute myeloid leukaemia, idiopathic pulmonary fibrosis, idiopathic hepatic cirrhosis, head and neck cancer and dental abnormalities, and may be multi-systemic. Undiagnosed patients may be seen by essentially any medical subspecialist. Correct diagnosis is important to ensure appropriate management, and for initiating investigations to identify affected family members. Treatment is often supportive, with transplantation offering cure for pulmonary fibrosis or bone marrow failure. Higher rates of mortality and morbidity with transplantation often require regimen alterations, underscoring the need for correct diagnosis. Short telomeres result from mutations in genes essential for telomere maintenance (e.g. genes encoding subunits of the telomerase enzyme complex). Disease severity reflects not only the severity of the defect, but also the inheritance of short telomeres, giving rise to incomplete penetrance and genetic anticipation. Attendees of the inaugural Australian Short Telomere Syndrome Conference were updated on the current scientific and clinical understanding of these disorders, and discussed the best approach for management of these patients in the Australian context. This review will include recommendations from the conference and aims to increase awareness of short telomere disorders.

Utility of next-generation sequencing technologies for the efficient genetic resolution of haematological disorders.

Next-generation sequencing (NGS) has now evolved to be a relatively affordable and efficient means of detecting genetic mutations. Whole genome sequencing (WGS) or whole exome sequencing (WES) offers the opportunity for rapid diagnosis in many paediatric haematological conditions, where phenotypes are variable and either a large number of genes are involved, or the genes are large making sanger sequencing expensive and labour-intensive. NGS offers the potential for gene discovery in patients who do not have mutations in currently known genes. This report shows how WES was used in the diagnosis of six paediatric haematology cases. In four cases (Diamond-Blackfan anaemia, congenital neutropenia (n = 2), and Fanconi anaemia), the diagnosis was suspected based on classical phenotype, and NGS confirmed those suspicions. Mutations in RPS19, ELANE and FANCD2 were found. The final two cases (MYH9 associated macrothrombocytopenia associated with multiple congenital anomalies; atypical juvenile myelomonocytic leukaemia associated with a KRAS mutation) highlight the utility of NGS where the diagnosis is less certain, or where there is an unusual phenotype. We discuss the advantages and limitations of NGS in the setting of these cases, and in haematological conditions more broadly, and discuss where NGS is most efficiently used.

Reduced incidence of second solid tumors in survivors of childhood Hodgkin's lymphoma treated without radiation therapy.

BACKGROUND: We assessed the risk of developing second malignancies in children treated for Hodgkin's lymphoma (HL), the majority of whom received chemotherapy only. PATIENTS AND METHODS: The development of second malignancies in children with HL, treated between 1960 and 1999, was assessed. Results were obtained by both chart review and linkage with a centralized cancer registry. Tumor incidence was compared for patients treated with and without radiotherapy (RT) and with the general population. Risk factors for developing second tumors were assessed by multivariate analysis. RESULTS: Of 142 childhood HL patients, 63 had received RT and 79 had not. Overall survival was similar for both groups. Fourteen patients developed second solid tumors, 12 who had received RT and 2 treated with chemotherapy only (P <0.001), with a 30-year cumulative incidence of 24.7% [95% confidence interval (CI) 7.27-47.4] and 5.8% (95% CI 0-58.9), respectively (P = 0.01). The standardized incidence ratio for second solid tumors was 236 (95% CI 112.2-359.0) versus 43.6 (95% CI 0-103.9), respectively. Multivariate analysis showed treatment with RT was the only significant risks factor for developing second solid tumors. CONCLUSIONS: Children with HL without RT have a substantially lower incidence of second tumors than those treated with RT.

Measurement of the nucleon strange-antistrange asymmetry at next-to-leading order in QCD from NuTeV Dimuon data.

We present a new measurement of the difference between the nucleon strange and antistrange quark distributions from dimuon events recorded by the NuTeV experiment at Fermilab. This analysis is the first to use a complete next to leading order QCD description of charm production from neutrino scattering. Dimuon events in neutrino deep inelastic scattering allow direct and independent study of the strange and antistrange content of the nucleon. We find a positive strange asymmetry with a significance of 1.6sigma. We also report a new measurement of the charm mass.

Inclusive double-pomeron exchange at the fermilab tevatron p p collider.

We report results from a study of events with a double-Pomeron exchange topology produced in p p collisions at sqrt[s]=1800 GeV. The events are characterized by a leading antiproton and a large rapidity gap on the outgoing proton side. We find that the differential production cross section agrees in shape with predictions based on Regge theory and factorization, and that the ratio of double-Pomeron exchange to single diffractive production rates is relatively unsuppressed as compared to the O(10) suppression factor previously measured in single diffractive production.

Search for Kaluza-Klein graviton emission in pp collisions at square root[s] = 1.8 TeV using the missing energy signature.

We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 pb(-1) of ppmacr; collisions at sqrt[s]=1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a (3+1+n)-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for n=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.

Search for pair production of scalar top quarks in R-parity violating decay modes in pp collisions at square root of s=1.8 TeV.

We present the results of a search for pair production of scalar top quarks (t(1)) in an R-parity violating supersymmetry scenario in 106 pb(-1) of pp collisions at square root of s=1.8 TeV collected by the Collider Detector at Fermilab. In this mode each t(1) decays into a tau lepton and a b quark. We search for events with two tau's, one decaying leptonically (e or mu) and one decaying hadronically, and two jets. No candidate events pass our final selection criteria. We set a 95% confidence level lower limit on the t(1) mass at 122 GeV/c(2) for Br(t(1)-->tau b)=1.

Search for lepton flavor violating decays of a heavy neutral particle in p(-)p collisions at sqrt[s]=1.8 TeV.

We report on a search for a high mass, narrow width particle that decays directly to emu, etau, or microtau. We use approximately 110 pb(-1) of data collected with the Collider Detector at Fermilab from 1992 to 1995. No evidence of lepton flavor violating decays is found. Limits are set on the production and decay of sneutrinos with R-parity violating interactions.

Central pseudorapidity gaps in events with a leading antiproton at the fermilab tevatron pp collider.

We report a measurement of the fraction of events with a large pseudorapidity gap deltaeta within the pseudorapidity region available to the proton dissociation products X in p+p-->p+X. For a final state p of fractional momentum loss xi(p) and 4-momentum transfer squared t(p) within 0.063 is found to be 0.246+/-0.001 (stat)+/-0.042 (syst) [0.184+/-0.001 (stat)+/-0.043 (syst)]. Our results are compared with gap fractions measured in minimum bias pp collisions and with theoretical expectations.

Search for the supersymmetric partner of the top quark in dilepton events from pp collisions at square root of s=1.8 TeV.

We have searched for pair production of the supersymmetric partner of the top quark (stop) in 107 pb(-1) of pp collisions at square root of s=1.8 TeV collected by the Collider Detector at Fermilab (CDF). Each stop is assumed to decay into a lepton, bottom quark, and supersymmetric neutrino. Such a scenario would give rise to events with two leptons, two hadronic jets, and a substantial imbalance of transverse energy. No evidence of such a stop signal has been found. We exclude stop masses in the region (80

Search for associated production of Upsilon and vector boson in pp collisions at sqrt[s]=1.8 TeV.

We present a search for associated production of the Upsilon(1S) and a vector boson in 83 pb(-1) of ppmacr; collisions at sqrt[s]=1.8 TeV collected by the CDF experiment in 1994-1995. We find no evidence of the searched signal in the data, and set upper limits to the production cross sections.

Search for long-lived charged massive particles in pp collisions at square root s = 1.8 TeV.

We report a search for the production of long-lived charged massive particles in a data sample of 90 pb(-1) of square root[s]=1.8 TeV pp collisions recorded by the Collider Detector at Fermilab. The search uses the muonlike penetration and anomalously high ionization energy loss signature expected for such a particle to discriminate it from backgrounds. The data are found to agree with background expectations, and cross section limits of O(1) pb are derived using two reference models, a stable quark and a stable scalar lepton.

Search for a W' boson decaying to a top and bottom quark pair in 1.8 TeV pp collisions.

We report the results of a search for a W' boson produced in pp; collisions at a center-of-mass energy of 1.8 TeV using a 106 pb(-1) data sample recorded by the Collider Detector at Fermilab. We observe no significant excess of events above background for a W' boson decaying to a top and bottom quark pair. In a model where this boson would mediate interactions involving a massive right-handed neutrino (nu(R)) and have standard model strength couplings, we use these data to exclude a W' boson with mass between 225 and 536 GeV/c(2) at 95% confidence level for M(W')>>M(nu(R)) and between 225 and 566 GeV/c(2) at 95% confidence level for M(W')

Search for new physics in photon-lepton events in pp collisions at sqrt[s] = 1.8 TeV.

We present the results of a search in pp collisions at sqrt[s] = 1.8 TeV for anomalous production of events containing a photon and a lepton (e or mu), both with large transverse energy, using 86 pb(-1) of data collected with the Collider Detector at Fermilab during the 1994-1995 collider run at the Fermilab Tevatron. The presence of large missing transverse energy (E(T)), additional photons, or additional leptons in these events is also analyzed. The results are consistent with standard model expectations, with the possible exception of photon-lepton events with large E(T), for which the observed total is 16 events and the expected mean total is 7.6+/-0.7 events.

Search for nu(mu)-->nu(e) and nu(mu)-->nu(e) oscillations at NuTeV.

Limits on nu(mu)-->nu(e) and nu(mu)-->nu(e) oscillations are extracted using the NuTeV detector with sign-selected nu(mu) and nu(mu) beams. In nu(mu) mode, for the case of sin(2)2alpha = 1, Delta(m)(2)>2.6 eV(2) is excluded, and for Delta(m)(2)>>1000 eV(2), sin(2)2alpha>1.1 x 10(-3). The NuTeV data exclude the high Delta(m)(2) end of nu(mu)-->nu(e) oscillation parameters favored by the LSND experiment without the need to assume that the oscillation parameters for nu and nu are the same. We present the most stringent experimental limits for nu(mu)(nu(mu))-->nu(e)(nu(e)) oscillations in the large Delta(m)(2) region.

Diffractive dijet production at sqrt[s] = 630 and 1800 GeV at the Fermilab Tevatron.

We report a measurement of the diffractive structure function F(D)(jj) of the antiproton obtained from a study of dijet events produced in association with a leading antiproton in pp collisions at sqrt[s] = 630 GeV at the Fermilab Tevatron. The ratio of F(D)(jj) at sqrt[s] = 630 GeV to F(D)(jj) obtained from a similar measurement at sqrt[s] = 1800 GeV is compared with expectations from QCD factorization and other theoretical predictions. We also report a measurement of the xi ( x-Pomeron) and beta ( x of parton in Pomeron) dependence of F(D)(jj) at sqrt[s] = 1800 GeV. In the region 0.035

Upsilon production and polarization in p p macro collisions at square root of s = 1.8 TeV.

We report on measurements of the Upsilon(1S), Upsilon(2S), and Upsilon(3S) differential cross sections (d(2)sigma/dp(T)dy)(/y/<0.4), as well as on the Upsilon(1S) polarization in p p macro collisions at square root of s = 1.8 TeV using a sample of 77+/-3 pb(-1) collected by the collider detector at Fermilab. The three resonances were reconstructed through the decay Upsilon-->mu(+)mu(-). The measured angular distribution of the muons in the Upsilon(1S) rest frame is consistent with unpolarized meson production.