Christopher L. Brooks

Subcontinental versus suboceanic mantle, II. NdSrPb isotopic comparison of continental tholeiites with mid-ocean ridge tholeiites, and the structure of the continental lithosphere

Abstract Nd-Sr-Pb isotopic measurements for continental flood basalts from the Deccan traps and dolerites from Tasmania show that variations in these basalts are related to continental crust contamination in agreement with Faure et al.s [3] conjecture for Antarctic basalts. The source of these basalts have peculiar depleted characters and it is proposed that such a source is the layered continental lithosphere.

Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients

This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.

Isotopic and trace element constraints on the genesis of the Faeroe lava pile

Abstract Basaltic lavas from the Faeroe Islands form three stratigraphic series which define two geochemical groups. Both the lower and middle series are LREE enriched ((La/Yb) e.f. : 2–3) and are characterized by convex LREE profiles; in contrast, the upper series comprises both depleted ((La/Yb) e.f. : 0.45–0.6) and enriched lavas. This twofold geochemical division is also evident from the incompatible trace elements such as Zr, Nb, Hf and Ta and the compatible trace elements Cr, Ni, Sr and Y. Nd-Sr-Pb isotopic measurements show that the basalts are contaminated by crustal materials, implying the presence of Precambrian sialic basement underneath the Faeroes block, a conclusion supported by geophysical data [35,36]. The uncontaminated end-members, for the LREE-depleted basalts ( 87 Sr/ 86 Sr) 0 ∼ 0.7026 and eNd 0 + 10 and for the LREE-enriched basalts ( 87 Sr/ 86 Sr) 0 ∼ 0.7034 and eNd 0 + 9, require two different mantle source regions thus posing serious problems for petrogenetic models such as dynamic partial melting which have been proposed for the Faeroes. We interpret the LREE-depleted basalts as partial melts of the oceanic asthenosphere whilst the LREE-enriched basalts may result either from the partial melting of deep mantle blobs or of the subcontinental lithosphere during upwelling of the asthenosphere.

Assessment of consistency in contouring of normal-tissue anatomic structures

The purpose of this work is to estimate the uncertainty in the manual contouring of normal anatomical structures. The heart, esophagus, and spinal cord were contoured manually on six sets of computed tomography images by six dosimetrists whose experience ranged from 1 year to over 15 years. To determine the differences between inter‐ and intraobserver variations, each data set was contoured by one of the dosimetrists five times and once each by the five other dosimetrists. The magnitude of the discrepancies in delineating the contours was assessed. Intradosimetrist contouring discrepancies were as follows: esophagus, average 0.3 cm and maximum 2.9 cm; heart, average 0.5 cm and maximum 7.6 cm; and spinal cord, average 0.1 cm and maximum 0.7 cm. Interdosimetrist contouring discrepancies were as follows: esophagus, average 0.4 cm and maximum 3.1 cm; heart, average 0.7 cm and maximum 8.1 cm; and spinal cord, average 0.2 cm and maximum 0.9 cm. Significant discrepancies can occur when normal anatomic structures are contoured manually. Interdosimetrist discrepancies are typically slightly greater than intradosimetrist discrepancies. The magnitude of the discrepancies does not appear to be correlated to the experience of the dosimetrist.

TREATMENT PLANNING FOR LUNG CANCER: TRADITIONAL HOMOGENEOUS POINT-DOSE PRESCRIPTION COMPARED WITH HETEROGENEITY-CORRECTED DOSE-VOLUME PRESCRIPTION

PURPOSE To quantify the differences in doses to target volumes and critical thoracic structures calculated by traditional homogeneous point-dose prescription and heterogeneity-corrected volume-dose prescription. METHODS AND MATERIALS Between 1998 and 2001, 30 patients with inoperable Stage I/II non-small-cell lung cancer underwent radiation treatment planning at our institution. A commercially available convolution/superposition- based algorithm was used. Three treatment plans were calculated for each patient using identical beam geometries: one plan was generated by traditional homogeneous point-dose prescription, a second by the traditional method with heterogeneity correction, and a third by heterogeneity-corrected volume-dose prescription that would cover 95% of the planned target volume (PTV). Target volume coverage, isocenter dose, and dose uniformity in the second and third plans were compared. RESULTS The PTV, clinical target volume (CTV), and isocenter calculated by the heterogeneity-corrected volume-dose method were equivalent to those calculated by the traditional homogeneous point-dose method with heterogeneity correction. The fraction of the PTV covered by heterogeneity-corrected volume-dose prescription was significantly greater than the fraction covered by traditional homogeneous point-dose prescription with heterogeneity correction (p = 0.05). The dose prescribed using the traditional method would have been delivered to less than 90% of the PTV in 14 of 30 patients. There was no significant difference in the maximum and minimum doses to the PTV, the CTV, or the isocenter calculated by the traditional homogeneous method with heterogeneity correction and the heterogeneity-corrected volume-dose method. There was also no significant difference in the planned volume of lung receiving greater than 20 Gy as calculated by these two methods. CONCLUSION When compared with traditional homogeneous radiation treatment planning, heterogeneity-corrected methods produce equivalent PTV, CTV, and isocenter doses while providing superior PTV coverage.

SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia.

While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin‐3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38− BCR‐ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)‐IL3 fusion proteins SL‐401 (DT388‐IL3) and SL‐501 (DT388‐IL3[K116W]) could eradicate these stem cells. SL‐401 and SL‐501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI‐resistant KBM5‐STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL‐401 and SL‐501 decreased the absolute numbers of viable CD34+/CD38−/CD123+ CML progenitor cells by inducing apoptosis. IL3‐targeting agents reduced clonogenic growth and diminished the fraction of primitive long‐term culture‐initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI‐resistant CML blast crisis. These data suggest that the DT‐IL3 fusion proteins, SL‐401 and SL‐501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent

Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.

Intensity-Modulated Radiation Therapy with Noncoplanar Beams for Treatment of Prostate Cancer in Patients with Bilateral Hip Prosthesis-A Case Study

Megavoltage photon intensity-modulated radiation therapy (IMRT) is typically used in the treatment of prostate cancer at our institution. Approximately 1% to 2% of patients with prostate cancer have hip prostheses. The presence of the prosthesis usually complicates the planning process because of dose perturbation around the prosthesis, radiation attenuation through the prosthesis, and the introduction of computed tomography artifacts in the planning volume. In addition, hip prostheses are typically made of materials of high atomic number, which add uncertainty to the dosimetry of the prostate and critical organs in the planning volume. When the prosthesis is bilateral, treatment planning is further complicated because only a limited number of beam angles can be used to avoid the prostheses. In this case study, we will report the observed advantages of using noncoplanar beams in the delivery of IMRT to a prostate cancer patient with bilateral hip prostheses. The treatment was planned for 75.6 Gy using a 7-field coplanar approach and a noncoplanar arrangement, with all fields avoiding entrance though the prostheses. Our results indicate that, compared with the coplanar plan, the noncoplanar plan delivers the prescribed dose to the target with a slightly better conformality and sparing of rectal tissue versus the coplanar plan.

A reappraisal of the Rb-Sr systematics of early Archaean gneisses from Hebron, Labrador

Abstract A re-investigation of the Rb-Sr isotope systematics of early Archaean granodiorite gneisses from Hebron, northern Labrador, confirms the existence of early Archaean crust in that area, but has failed to corroborate both the high degree of coherence and the high initial87Sr/86Sr reported by Barton [1]. Instead, marked geological scatter is observed in the data for both slabbed gneisses and large bulk samples, a scatter unequivocally due to the development of secondary whole-rock isochrons at ∼ 1800 Ma. Regression analysis of the new data gives very large uncertainties in the age and initial87Sr/86Sr because of this secondary disturbance, viz. 3645−470+875 Ma and 0.702+0.005−0.009. We interpret the previous indications of high initial87Sr/86Sr at 3600 Ma as due to chance. The Hebron data cannot be distinguished from similar populations of geologically-disturbed Rb-Sr results from the Uivak I gneisses to the north [5] and the Amitsoq grey gneisses [6]. This supports a field-based contention that the so-called “Hebron gneisses” are both lithologic and stratigraphic equivalents of the Uivak I gneisses.

The interleukin-3 receptor CD123 targeted SL-401 mediates potent cytotoxic activity against CD34 CD123 cells from acute myeloid leukemia / myelodysplastic syndrome patients and healthy donors.

Diseases with clonal hematopoiesis such as myelodysplastic syndrome and acute myeloid leukemia have high rates of relapse. Only a small subset of acute myeloid leukemia patients are cured with chemotherapy alone. Relapse in these diseases occurs at least in part due to the failure to eradicate leukemic stem cells or hematopoietic stem cells in myelodysplastic syndrome. CD123, the alpha chain of the interleukin-3 receptor heterodimer, is expressed on the majority of leukemic stem cells and myelodysplastic syndrome hematopoietic stem cells and in 80% of acute myeloid leukemia. Here, we report indiscriminate killing of CD123+ normal and acute myeloid leukemia / myelodysplastic syndrome cells by SL-401, a diphtheria toxin interleukin-3 fusion protein. SL-401 induced cytotoxicity of CD123+ primary cells/blasts from acute myeloid leukemia and myelodysplastic syndrome patients but not CD123− lymphoid cells. Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia. SL-401 significantly prolonged survival of leukemic mice in acute myeloid leukemia patient-derived xenograft mouse models. In addition to primary samples, studies on normal cord blood and healthy marrow show that SL-401 has activity against normal hematopoietic progenitors. These findings indicate potential use of SL-401 as a “bridge-to-transplant” before allogeneic hematopoietic cell transplantation in acute myeloid leukemia / myelodysplastic syndrome patients.