Charge-State-Dependent Energization of Suprathermal Ions During Substorm Injections Observed by MMS in the Magnetotail.

Understanding the energization processes and constituent composition of the plasma and energetic particles injected into the near-Earth region from the tail is an important component of understanding magnetospheric dynamics. In this study, we present multiple case studies of the high-energy (≳40 keV) suprathermal ion populations during energetic particle enhancement events observed by the Energetic Ion Spectrometer (EIS) on NASA's Magnetospheric Multiscale (MMS) mission in the magnetotail. We present results from correlation analysis of the flux response between different energy channels of different ion species (hydrogen, helium, and oxygen) for multiple cases. We demonstrate that this technique can be used to infer the dominant charge state of the heavy ions, despite the fact that charge is not directly measured by EIS. Using this technique, we find that the energization and dispersion of suprathermal ions during energetic particle enhancements concurrent with (or near) fast plasma flows are ordered by energy per charge state (E/q) throughout the magnetotail regions examined (~7 to 25 Earth radii). The ions with the highest energies (≳300 keV) are helium and oxygen of solar wind origin, which obtain their greater energization due to their higher charge states. Additionally, the case studies show that during these injections the flux ratio of enhancement is also well ordered by E/q. These results expand on previous results which showed that high-energy total ion measurements in the magnetosphere are dominated by high-charge-state heavy ions and that protons are often not the dominant species above ~300 keV.

Autogenous and efficient acceleration of energetic ions upstream of Earth's bow shock.

Earth and its magnetosphere are immersed in the supersonic flow of the solar-wind plasma that fills interplanetary space. As the solar wind slows and deflects to flow around Earth, or any other obstacle, a 'bow shock' forms within the flow. Under almost all solar-wind conditions, planetary bow shocks such as Earth's are collisionless, supercritical shocks, meaning that they reflect and accelerate a fraction of the incident solar-wind ions as an energy dissipation mechanism1,2, which results in the formation of a region called the ion foreshock3. In the foreshock, large-scale, transient phenomena can develop, such as 'hot flow anomalies'4-9, which are concentrations of shock-reflected, suprathermal ions that are channelled and accumulated along certain structures in the upstream magnetic field. Hot flow anomalies evolve explosively, often resulting in the formation of new shocks along their upstream edges5,10, and potentially contribute to particle acceleration11-13, but there have hitherto been no observations to constrain this acceleration or to confirm the underlying mechanism. Here we report observations of a hot flow anomaly accelerating solar-wind ions from roughly 1-10 kiloelectronvolts up to almost 1,000 kiloelectronvolts. The acceleration mechanism depends on the mass and charge state of the ions and is consistent with first-order Fermi acceleration14,15. The acceleration that we observe results from only the interaction of Earth's bow shock with the solar wind, but produces a much, much larger number of energetic particles compared to what would typically be produced in the foreshock from acceleration at the bow shock. Such autogenous and efficient acceleration at quasi-parallel bow shocks (the normal direction of which are within about 45 degrees of the interplanetary magnetic field direction) provides a potential solution to Fermi's 'injection problem', which requires an as-yet-unexplained seed population of energetic particles, and implies that foreshock transients may be important in the generation of cosmic rays at astrophysical shocks throughout the cosmos.

Transient, small-scale field-aligned currents in the plasma sheet boundary layer during storm time substorms.

We report on field-aligned current observations by the four Magnetospheric Multiscale (MMS) spacecraft near the plasma sheet boundary layer (PSBL) during two major substorms on 23 June 2015. Small-scale field-aligned currents were found embedded in fluctuating PSBL flux tubes near the separatrix region. We resolve, for the first time, short-lived earthward (downward) intense field-aligned current sheets with thicknesses of a few tens of kilometers, which are well below the ion scale, on flux tubes moving equatorward/earthward during outward plasma sheet expansion. They coincide with upward field-aligned electron beams with energies of a few hundred eV. These electrons are most likely due to acceleration associated with a reconnection jet or high-energy ion beam-produced disturbances. The observations highlight coupling of multiscale processes in PSBL as a consequence of magnetotail reconnection.

Electron-scale measurements of magnetic reconnection in space.

Magnetic reconnection is a fundamental physical process in plasmas whereby stored magnetic energy is converted into heat and kinetic energy of charged particles. Reconnection occurs in many astrophysical plasma environments and in laboratory plasmas. Using measurements with very high time resolution, NASA's Magnetospheric Multiscale (MMS) mission has found direct evidence for electron demagnetization and acceleration at sites along the sunward boundary of Earth's magnetosphere where the interplanetary magnetic field reconnects with the terrestrial magnetic field. We have (i) observed the conversion of magnetic energy to particle energy; (ii) measured the electric field and current, which together cause the dissipation of magnetic energy; and (iii) identified the electron population that carries the current as a result of demagnetization and acceleration within the reconnection diffusion/dissipation region.

Ewing Sarcoma tumor cells express CD34: implications for autologous stem cell transplantation.

The significance of tumor cell contamination in marrow and peripheral blood stem cell (PBSC) collections of patients with solid tumors remains controversial. Various methods have been developed to purge tumor cells from autologous stem cell products, including CD34+ selection. PBSC harvests from patients with Ewing family of tumors (EFT) were analyzed for contaminating tumor cells prior and after CD34+ selection using reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC) analyzes. The expression of CD34 was studied by RT-PCR and FC in 14 primary tumors and 13 PBSC harvests, respectively. Tumor cells were identified in the harvests by both methods. In two patients, contaminating tumor cells were evident by RT-PCR only after positive selection. FC analysis confirmed a higher level of tumor cells in the CD34+ fraction. In an attempt to explore this finding, expression of CD34 was detected in 93% of primary tumors and 67% of contaminated harvests. As CD34 is expressed on EFT cells, these cells may be enriched following CD34+ selection of harvests, although the total number of tumor cells is reduced. Other methods of purging, rather than CD34+ selection, should be explored in patients with EFT undergoing autologous stem cell transplantation.

Tumor cells are present in stem cell harvests of Ewings sarcoma patients and their persistence following transplantation is associated with relapse.

BACKGROUND: Tumor cells frequently contaminate autologous stem cell products in a variety of malignancies, but their clinical significance remains controversial. We retrospectively monitored tumor contamination in stem cell harvests from patients with Ewing family of tumors (EFT) all harboring the specific translocation EWS-FLI-1 that characterize these tumors. PROCEDURE: Twenty- seven harvests from 11 patients were included in the study. In addition, 6 and 19 bone marrow (BM) or peripheral blood (PBL) samples were available before and after transplantation, respectively, for RT-PCR and nested PCR analyzes. RESULTS: All 11 patients had contaminating tumor cells in their harvests. All samples prior to transplantation were RT-PCR positive. Two out of the 11 patients who underwent transplantation died of complications. Out of the remaining nine patients, two are alive and well 68 and 84 months from diagnosis, and are the only patients with no detectable tumor cells in their samples after transplantation. One of these patients harbored contaminating tumor cells in only one of the two harvests collected. Seven patients relapsed after transplant, and in four patients BM/PBL samples were available prior to the clinical relapse. All these samples harbored contaminating tumor cells. CONCLUSIONS: We suggest a possible correlation between the amount of contaminating cells in the harvest and relapse after transplantation. Quantitative RT-PCR studies of the chimeric transcripts are underway to explore this issue.

Association between telomerase activity and outcome in patients with nonmetastatic Ewing family of tumors.

PURPOSE: Telomerase is considered a molecular marker for malignancy. The aim of this study was to determine telomerase activity (TA) as a prognostic factor at diagnosis and as a marker for minimal residual disease during therapy and follow-up in nonmetastatic Ewing family of tumors (EFT). PATIENTS AND METHODS: Primary tumor specimens and 97 peripheral blood (PBL) samples from 31 EFT patients were analyzed for TA by the Telomeric Repeat Amplification Protocol (TRAP assay). The telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) gene expression was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and telomere length was determined by Southern blotting. The presence of the EFT chimeric transcripts was analyzed by RT-PCR. Correlations with progression-free survival were evaluated. RESULTS: At diagnosis, TA in primary tumors did not correlate with outcome. During therapy and follow-up, highly significant correlation was observed between high TA in PBL samples and adverse prognosis (P <.0001). None of the patients harboring low TA progressed, with a long follow-up (median, 60 months) and a progression-free survival (PFS) of 100%. In nine patients, high TA actually could predict relapse, long before overt clinical relapse. The group of patients with high TA and positive RT-PCR had the most adverse outcome; PFS of 20% (P =.0025). TA was found to be a better prognostic factor than RT-PCR and histopathologic response at surgery. CONCLUSION: The results suggest that TA is a significant prognostic variable, superior to the established clinical prognostic parameters during therapy and tumor surveillance. It could be used in combination with RT-PCR for a new risk classification.

Molecular cytogenetic parameters in Ewing sarcoma.

To evaluate possible genomic instability and possible random aneuploidy, we applied comparative genomic hybridization and fluorescence in situ techniques, and evaluated telomerase activity in 16 cases of Ewing sarcoma (EWS) and compared the results to 7 controls. Common secondary aberrations (gains of chromosomes 8 and 12) were found in the study group. There was a direct correlation between the detection of random aneuploidy and development of tumor relapse (P = 0.0047). Other detectable abnormal parameters (secondary) and high telomerase activity were also more common among the cases with relapse but did not reach a statistical significance (probably because of the small sample size). In EWS, the detection of random aneuploidy seems to be a sensitive parameter in the prediction of tumor relapse.

Optic pathway glioma: correlation of imaging findings with the presence of neurofibromatosis.

BACKGROUND AND PURPOSE: Despite the benign histology of optic pathway glioma (OPG) (low-grade astrocytoma), its biological behavior is unpredictable, and it is unclear whether specific morphologic or anatomic patterns may be predictive of prognosis. It is also unclear whether OPG associated with neurofibromatosis (NF) is a distinct entity from non-NF-OPG. Our purpose was to describe the MR imaging features of OPG, compare the findings between patients with and those without NF, and identify prognostic imaging signs. METHODS: MR examinations of 91 patients with OPG (47 with NF and 44 without) were reviewed at presentation and during follow-up. The images were evaluated for size and extension of tumor, and imaging parameters. Statistical bivariate analysis was used to compare the patients with and those without NF, and Pearson correlation was used to evaluate the correlation between the different imaging parameters and prognosis. Kappa values were calculated to determine intraobserver and interobserver variability. RESULTS: The most common site of involvement in the NF group was the orbital nerve (66%), followed by the chiasm (62%). In the non-NF group, the chiasm was the most common site of involvement (91%); the orbital nerves were involved in only 32%. Extension beyond the optic pathway at diagnosis was uncommon in the NF group (2%) but frequent in the non-NF group (68%). In the NF group, the tumor was smaller and the original shape of the optic pathways was preserved (91% vs. 27% in the non-NF group). The presence of cystic components was significantly more common in the non-NF patients (66% vs. 9% in the NF group). During follow-up, half the NF patients remained stable, in contrast to 5% of the non-NF group. No statistical correlation was found between imaging features and biological behavior of the tumor. CONCLUSION: NF-OPG is a separate entity from non-NF-OPG, with different imaging features and prognosis, thereby warranting a specific diagnostic, clinical, and therapeutic approach.

Effect of P-glycoprotein expression on outcome in the Ewing family of tumors.

This study was designed to determine the prognostic significance of multidrug resistance, mediated by P-glycoprotein (Pgp) expression, in Ewing sarcoma. The clinical and laboratory features, treatment protocol, and outcome of 75 patients with Ewing sarcoma or peripheral neuroectodermal tumor treated between 1972 and 1997 were reviewed. Pgp expression was tested with the monoclonal antibody JSB-1. Thirty-four (64%) of the 53 tissue samples from untreated patients stained positive for Pgp. Progression-free and overall survival were 44 and 59%, respectively, in patients with negative findings, and 28 and 41% in those with positive findings; neither difference was significant. Of the 12 relapsed patients, 6 (50%) expressed more Pgp after chemotherapy than at diagnosis and 4 (33%) expressed less. Within these subgroups, 5 out of 6 and 3 out of 4 died from the disease. No correlation was found between Pgp and known prognostic factors of Ewing tumors. Pgp expression is probably an intrinsic factor of Ewing tumors but has no correlation to prognosis.

Treatment of alpha-fetoprotein secreting hepatoblastoma by response of serum alpha-fetoprotein levels: a new concept.

Hepatoblastoma, the commonest primary malignant liver tumor in infants and children, is usually associated with elevated serum alpha-fetoprotein (AFP) levels. The authors sought to determine if AFP levels can be used to modify treatment, thereby avoiding the wait for formal imaging studies and prolonged suboptimal treatment and limiting the use of effective but toxic chemotherapy. From April 1984 to December 1997, 8 children were diagnosed with AFP-secreting hepatoblastoma. Serum AFP levels were measured weekly. If AFP levels failed to improve, or increased on at least 2 successive examinations, the chemotherapy protocol was changed. When an excellent response was achieved, less toxic chemotherapy was substituted. Six patients (75%) were disease-free for at least 2 years, some with high-risk or metastatic disease. Two patients died. Six of the 7 nonmetastatic patients (86%) remain disease-free (only one had a resectable tumor). Chemotherapy changes resulted in reduced AFP levels in 7 patients. This study supports the use of AFP monitoring to modify treatment in hepatoblastoma responding to therapy with less toxic drugs and the use of nonstandard therapy when suboptimal responses are obtained.

Methotrexate treatment protocols and the central nervous system: significant cure with significant neurotoxicity.

Methotrexate can influence the central nervous system through several metabolic toxic pathways. These effects can be categorized as immediate, acute to subacute, or chronic neurologic syndromes. The acute to subacute syndrome occurs frequently in acute lymphoblastic leukemia treatment protocols, generally manifesting with focal neurologic signs and changes seen on magnetic resonance imaging and single photon emission computed tomography. While in some patients the neurotoxicity is transient and benign and allows for continuation of chemotherapy, in others it can be quite severe and debilitating, leading to permanent neurologic deficits. The need to modify the treatment protocols when neurotoxicity appears is not fully established. It is also unknown whether the use of sufficient amounts of leucovorin can overcome the toxic effects of the drug.

Visual pathway tumors and hydrocephalus.

The authors evaluated the impact of hydrocephalus on the clinical picture of children with visual pathway tumor (VPT) with or without neurofibromatosis (NF). Charts of children with VPT treated in the authors' center since 1985 were retrospectively reviewed, and those with hydrocephalus were selected and summarized. Thirty-five children with VPT were found, of whom 20 had NF. Hydrocephalus was found in 4 children with NF (20%) and in 5 without NF (33.3%). In 6 of the children, ventricular dilatation with signs of acute increased intracranial pressure already existed at the time of diagnosis and the hydrocephalus was shunted at this time. In the other 3 children, all with NF, the hydrocephalus resulted from slowly developing aqueductal stenosis, leading in 2 to severe visual acuity deterioration. The results suggest that in children with VPT and NF, hydrocephalus, and especially hydrocephalus resulting from aqueductal stenosis, is more frequent than in the general population of NF patients, and less frequent than in VPT patients without NF. The possibility of the indolent development of hydrocephalus should be borne in mind while following children with NF. The optic nerve, when already involved with a glioma, is more vulnerable to increased pressure. Thus, in children with VPT and NF, any ventricular dilatation should lead to a consideration of early shunting.

Apparently unrelated clones shown by spectral karyotyping to represent clonal evolution of cryptic t(10;11)(p13;q23) in a patient with acute monoblastic leukemia.

The accurate genetic classification of acute leukemia is of the utmost clinical importance for treatment stratification. In the present study, we report on a young girl with aggressive acute monoblastic leukemia (AML) (M5b) with skin, lymph node, and bone marrow involvement, in whom cytogenetic analysis revealed three clones with different secondary chromosomal changes. Two clones had the secondary +8 and del(9q) aberrations, with the der(11)t(1;11) in the second one; the third clone was apparently unrelated to the others, and had add(7)(p?21),-13,+22. Using the spectral karyotyping (SKY) technique, we found that all three clones originated from a common clone that harbored the hidden primary t(10;11)(p13;q23) or its derivatives, suggesting clonal evolution. The first clone had the balanced t(10;11), the second had its derivative, der(10)t(10;11), and the third had the other derivative, der(11)t(10;11). On fluorescence in situ hybridization (FISH), MLL gene splitting, with translocation of its centromeric portion to 10p, and deletion of its telomeric portion, was demonstrated. In conclusion, the detection of the very poor prognostic t(10;11) aberration in AML, was possible by complementing the traditional cytogenetic analysis with SKY and FISH.

Subacute central nervous system degeneration in a child: an unusual manifestation of ifosfamide intoxication.

A 5-year-old child with desmoplastic small round-cell tumor was treated with a protocol of very-high-dose, short-term chemotherapy, containing HD-CAV (cyclophosphamide, doxorubicin, vincristine, and mesna), ifosfamide, and etoposide. Two days after the initiation of ifosfamide, he exhibited new-onset lethal encephalopathy manifested by subacutely progressive cerebellar and then temporal and frontocortical degeneration leading to a vegetative state and eventually to death. A full work-up, including brain biopsy, was negative, excluding infections and metabolic or vascular causes. Ifosfamide is known to be capable of causing acute encephalopathy that can be severe but is generally reversible. This child showed a very atypical progressive, lethal course of ifosfamide toxicity. The possibility of this complication should be considered when high-dose ifosfamide treatment is planned for children.

Improved outcome in childhood B-cell lymphoma with the intensified French LMB protocol.

BACKGROUND: During the last 20 years, 120 children with B cell lymphoma were treated at the National Pediatric Hematology/Oncology Center of Israel. Until 1986, 63 patients received an institutional protocol (BMC), and thereafter 57 patients received a modified French LMB protocol. We report the results of a retrospective analysis comparing the results of these two protocols. PROCEDURE: Patient characteristics were similar in both groups except for stage of disease and lactate dehydrogenase (LDH) levels. Significantly more patients in the LMB group had higher stage disease, and the LDH levels also were higher (<600 microg/ml). RESULTS: Fifty-four of fifty-seven children on the modified LMB protocol are alive, disease-free, with an overall event-free survival of 94% (median follow-up of 73 months). Event-free survival for stages I, II, and III patients is 100%, and for stage IV 77%, whereas the overall event-free survival was 58% among 63 children treated previously, and for stage IV patients only 10%. Severe marrow suppression and neutropenic enterocolitis were the major complications of this intensive protocol. CONCLUSIONS: Intensive chemotherapy with a modified LMB protocol and modern supportive care result in a high cure rate of childhood B cell lymphoma even in patients with advanced disease.

Tc-99m MIBI to evaluate children with Ewing's sarcoma.

PURPOSE: Tc-99m MIBI has been used increasingly to evaluate benign and malignant tumors because of its tumor-seeking properties and ability to provide an imaging assessment of multiple-drug resistance. This study investigated the clinical utility of Tc-99m MIBI in the management of Ewing's sarcoma in children. METHODS: Thirteen Tc-99m MIBI studies in nine (six male, three female) patients ages 6.5 to 20 years (mean, 13.4 years) with Ewing's sarcoma were reviewed. All patients had imaging studies at diagnosis, and four had follow-up studies during or after therapy. Scintigraphy was evaluated for Tc-99m MIBI uptake within the tumor and in metastases, which other imaging modalities had shown to be present in four patients. Scintigraphic results were correlated with the clinical course in all patients and with tumor P-glycoprotein status in six patients. RESULTS: Tc-99m MIBI accumulated in 6 of 9 primary tumors and did not accumulate in one recurrent tumor. No metastases showed Tc-99m MIBI uptake. The presence or absence of Tc-99m MIBI uptake at diagnosis or after therapy carried no prognostic significance. Tc-99m MIBI was present in the two tumors that were P-glycoprotein positive and in only one of four tumors that were P-glycoprotein negative. CONCLUSION: Tc-99m MIBI imaging does not appear to be useful in Ewing's sarcoma.