Total Dose Levels Research Articles

Abstract CT231: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer

Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of estrogen receptor (ER)+ breast cancer (BC). However, many patients (pts) relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms. Furthermore, mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen can mediate resistance. Therefore, next generation ER targeting agents with robust activity in both wild type and mutant ER tumors are needed. GDC-0810 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader that induces tumor regression in tamoxifen-sensitive and resistant ER+ BC xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2-) locally advanced or metastatic BC (progressing after ≥ 6 months on endocrine therapy; ≤ 2 prior chemotherapies) to determine the safety, pharmacokinetic (PK) and recommended phase II dose (RP2D) of GDC-0810. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples, CT scans, and when feasible, paired pre and on-study tumor biopsies were obtained. Results: Forty-one pts (median # of prior therapies: 4) were enrolled at 5 total daily dose levels (100-800 mg) and 2 regimens: once (QD) or twice (BID) daily given orally with and without fasting. Increases in GDC-0810 exposure were dose-dependent. The common treatment-related adverse events (AEs) were grade 1/2 diarrhea (63%), fatigue (46%), nausea (44%), flatulence (24%), vomiting (22%), and anemia (22%). Diarrhea was mostly Grade 1, intermittent in nature, and manageable with dose modifications, dietary adjustments, and treatment with PRN loperamide. There was one dose limiting toxicity of Grade 3 diarrhea at 800 mg QD (fasting). 600 mg QD given with food was determined to be single agent R2PD. Complete/near complete (>90%) suppression of FES uptake was observed in 90% of pts with FES-PET scans, including 5 pts with known ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-study biopsies. At a median follow-up of 8 months 13 of 31 (42%) pts on study achieved stable disease > 6 months while 10 pts remain active on study with followup < 6 months. Conclusions: GDC-0810 has a tolerable safety profile to date, with predictable PK, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER+ BC. A phase IIa study of GDC-0810 is ongoing in postmenopausal women with ER+ (HER2-) advanced or metastatic BC who have been previously treated with an aromatase inhibitor, including tumors with ESR1 mutations (clinicaltrials.gov NCT01823835). Citation Format: Maura Dickler, Aditya Bardia, Ingrid Mayer, Eric Winer, Peter Rix, Jeff Hager, Meng Chen, Iris Chan, Edna Chow-Maneval, Carlos Arteaga, Jose Baselga. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT231. doi:10.1158/1538-7445.AM2015-CT231

<formula formulatype="inline"><tex Notation="TeX">$1/f$</tex></formula> Noise Model for NPN Bipolar Junction Transistors Based on Radiation Effect

Radiation-induced current gain and $1/f$ noise degradations in NPN bipolar junction transistors are due to accumulation of oxide-trapped charges and interface states at the surface of the device. Based on an available model of base surface current of NPN bipolar junction transistors, a simplified model is presented with some approximations at low total dose level, which can explain the degradation mechanisms of the current gain. Based on the theory of carrier number fluctuation and the simplified model of base surface current, a $1/f$ noise model is developed, which can be used to explain the $1/f$ noise degradation induced by the radiation at low total dose level. The model suggests that the gain and $1/f$ noise degradations can be attributed to the same physical origin, and these two kinds of degradations are the result of accumulation of oxide-trapped charges and interface states. The radiations were performed in a ${\rm Co}^{60}$ source at a dose rate of 10 rad(Si)/s up to a total dose of 70 krad(Si). The degradations of the current gain and $1/f$ noise are compared, and the relationship between $1/f$ noise and the current gain is given, which accords well with the experimental results. Compared to the current gain, the $1/f$ noise parameter is more sensitive, so it may be used to evaluate the radiation resistance capability of bipolar junction transistors.

Glyburide transport across the human placenta.

To estimate the magnitude of transplacental transfer of glyburide in women with gestational diabetes mellitus (GDM). A prospective, observational study was conducted on women with GDM on glyburide therapy. On delivery admission, the glyburide dose and time of last dose were recorded. Immediately postdelivery, maternal and umbilical venous blood samples were obtained and the concentrations of glyburide were determined by high-performance liquid chromatography-mass spectrometry with a limit of detection of 0.25 ng/mL. Nineteen patient dyads were analyzed. The mean total daily maternal glyburide dose was 6.6±6.3 mg per day and the mean time between last dose and sampling was 13.3±6.5 hours. The mean maternal serum glyburide level at birth was 15.4±20.8 ng/mL, whereas the mean umbilical glyburide level was 7.5±8.2 ng/mL, which showed a statistical correlation (r=0.72, P<.01). There were statistically significant relationships between total maternal glyburide dose (1.25-20 mg per day) and maternal glyburide levels (0.93-70.71 ng/mL; r=0.46, P≤.01) and between total maternal glyburide dose and umbilical glyburide levels (0.95-32.41 ng/mL; r=0.43, P≤.01) However, we observed wide variability in maternal and umbilical glyburide levels at both extremes of the total glyburide dose. Seventy-nine percent of cord samples (15/19) had glyburide levels less than 10 ng/mL (the limit of detection reported in earlier studies) and 37% (7/19) were higher than the corresponding maternal samples. Transplacental transfer of glyburide is highly variable among patients, corroborating ex vivo placental perfusion studies showing a transport-mediated glyburide efflux from the fetal to the maternal circulation. In most neonates (79%), glyburide levels were below 10 ng/mL. III.

How Safe Are Reduced Doses per Fraction in Target Volumes of 2&lt;sup&gt;nd&lt;/sup&gt; to 4&lt;sup&gt;th&lt;/sup&gt; Order in the Simultaneous Integrated Boost Irradiation Technique in Head and Neck Carcinoma Patients?

Aim: The simultaneous irradiation of target volumes of different total dose levels using intensity modulated radiotherapy leads to reduced doses per fraction and longer treatment times in target volumes of 2nd to 4th order. Does the thereby caused reduced biological effectiveness induce an increased recurrence risk? The current work deals with the problem of recurrences of patients with head and neck carcinomas treated either with an intensitiy (IMRT) or with a volumetric modulated (VMAT) irradiation technique. Methods: From October 2002 to September 2014, 699 patients with carcinomas of the head and neck were irradiated using IMRT or VMAT. The median follow up of the patients was 21.9 months (2 to 145 months). Primary tumor regions (1st order target volume) of 565 patients were treated with doses per fraction of 2 Gy. Accordingly, further 133 target volumes of the primary tumor received reduced doses per fraction. In 1 patient, the lymphatic drainage was treated solely without irradiation of the primary region. For the lympatic drainage, 854 1st order target volumes were treated with a dose per fraction of 2 Gy. Reduced doses per fraction were applied to further 1780 target volumes. Results: 54 of 699 patients developed a recurrence in the primary tumor region after radio-(chemo) therapy, 4 patients developed a recurrence of the primary tumor and a unilateral recurrence of the lymphatic drainage, 2 patients a recurrence of the primary tumor and a bilateral lymph node recurrence. 18 patients showed an isolated unilateral recurrence and additionally 2 patients a bilateral recurrence of the lymphatic drainage. 619 patients stayed recurrence free. In primary tumor regions, receiving a dose per fraction of 2 Gy 55 patients (9.7%) developed a recurrence, whereas in target volumes receiving a reduced dose per fraction 5 patients (3.8%) developed a recurrence (p nd to 4th order was not increased due to reduced doses per fraction deposited by means of a simultaneous integrated boost technique. Therefore, the simultaneous irradiation of target volumes with different dose levels is safely applicable within one treatment plan.

The effect of interface trapped charge on threshold voltage shift estimation for gamma irradiated MOS device

The ionizing radiation affects the silicon-based electronic devices and leads to the build-up of trapped hole in the oxide and an increase in trap density at the Si–SiO2 interface. These defects cause degradation of device parameters such as threshold voltage shifts, sub-threshold swing and etc. Although the effect of oxide charges on the threshold voltage shift in MOS devices is dominant, accurate estimation requires for modeling of the interface trapped charge effect. In this work, the effect of interface trapped charge on threshold voltage shift in an N-channel MOS transistor device, irradiated at different total ionization doses, was estimated considering proton transport model in gate oxide. The analytical model calculations consider the time dependent buildup of trapped holes and interface trap charges. Furthermore, we used ATLAS as a numerical semiconductor simulation code which only allows modeling oxide trapped charge to calculate the variation of threshold voltage shift with TID without considering the interface trap. Computational results were compared with experimental results at several doses and gate biases. According to the experimental results, ATLAS overestimates threshold voltage shift within 30% approximately. The results based on considering proton transport mechanism in analytical model, showed significantly better agreement with experimental results for total dose level up to 2.87 krad at several different biases. Overall results indicated that considering interface trap charges modeling, substantially improves the accuracy of the threshold voltage shift estimation.

Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS): A Phase 1 Study

Background: Most adults with AML or high-risk MDS will ultimately require salvage therapy. However, the likelihood of achieving a complete remission (CR) with standard salvage regimens is often 15-20% or less. Emerging data suggest that pre-treatment (“priming”) with a hypomethylating agent such as decitabine can sensitize AML cells to chemotherapeutics, prompting a dose-escalation study of MEC preceded by decitabine-priming in relapsed/refractory AML and high-risk MDS.Methods: This single arm study aimed to estimate the maximum tolerated dose (MTD) of decitabine-primed MEC in adults ≥18 years with relapsed/refractory high-risk MDS (>10% blasts) or AML requiring first or subsequent salvage therapy. Previous treatment with hypomethylating agents or MEC (but not the combination) was acceptable. Trial participation required a treatment-related mortality (TRM) score of <9.2, corresponding to an expected TRM of 4% with standard induction chemotherapy. Patients with post-transplant relapse were eligible if graft-versus host disease was well controlled. Excluded were patients with concomitant illness with expected survival <1 year, and active, uncontrolled infection. Cohorts of 6-12 patients were assigned to 1 of 3 total dose levels of decitabine (20mg/m2 for 5, 7, or 10 days) followed by MEC (mitoxantrone 8mg/m2/day x 5 days; etoposide 100 mg/m2/day x 5 days; cytarabine 1 g/m2/day x 5 days) after a break of 5 days. In the case of persistent leukemia, patients were eligible for re-induction provided all non-hematologic toxicities had resolved to grade <2. Patients achieving a CR or CR with incomplete platelet recovery (CRp) could receive 2 additional cycles of decitabine-MEC given at doses identical to those used during induction. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days.Results: 30 patients, median age 55 (range: 19-72) years, with primary refractory disease (n=13), first relapse (n=16), or second relapse (n=1) with median duration of prior CR of 4 (range: 1-19) months were enrolled and received a median of 1 (range: 1-3) cycles of therapy. During dose escalation, 1 DLT occurred at each the 2nd and 3rd tested dose level after cycle 1 (septic shock with multi-organ failure in both), identifying a 10-day course of decitabine together with standard dose MEC as the MTD. A total of 12 patients received therapy at the MTD level. 9/30 patients achieved a CR (30%). This CR rate compared favorably relative to a historic control population with patient matching based on duration of prior remission and number of prior salvage therapies (Blood 1996; 88:756), with an observed/expected CR ratio of 1.9. 5 additional patients achieved a CRp, and 1 achieved a CR with incomplete count recovery (CRi) for an overall response rate of 15/30 (50%). Furthermore, 4 patients achieved a morphologic leukemia-free state, 8 had refractory disease, and 3 died before a response was assessed. Of the 15 patients who achieved a remission, 3 remain on study, 9 were taken off protocol to pursue further intensive consolidation therapy including hematopoietic cell transplantation, and 3 have died after a median CR duration of 68 days. In the 15 responders, the median response duration was 68 days (range 0-437), with 6 of these responses ongoing. Overall survival of these 15 patients was longer (median of 211 [range: 59-484] days) than that for patients who failed to achieve remission but lived at least 29 days (i.e. did not experience TRM) (median of 110 [range: 30-303] days). Six patients died within 28 days of treatment initiation for a TRM rate of 20%: 4 from infection, 1 from intracranial hemorrhage, and 1 from unknown cause. Besides grade 3-4 cytopenias, cough, fatigue, nausea and infection/neutropenic fever were the most common adverse events.Conclusion: Decitabine-primed MEC is feasible, well tolerated, and has anti-leukemic activity in relapsed/refractory AML and high-risk MDS. A phase 2 study based on these findings has been initiated. DisclosuresOff Label Use: Off-label use of some of the study drugs for either AML or high-risk MDS.

Accounting for neutron exposure in the Japanese atomic bomb survivors.

The Japanese atomic bomb survivors that were directly exposed to both γ rays and neutrons have been followed by the Radiation Effects Research Foundation (RERF). The estimation of the γ-ray risks requires some adjustment for the greater biological effect of the neutrons per unit dose. Because the small neutron doses and the predominant γ-ray doses are highly correlated, the neutron relative biological effectiveness (RBE) cannot be reliably estimated from the survivors' data and information from radiobiology must be invoked. As data became available on neutron doses, RERF has used a constant neutron RBE value of 10, even though radiobiological studies indicate that the RBE values appear to have considerably larger values at low doses. The approximation RBE = 10 assumes that if the RBE is variable it takes roughly this value in the range of total dose most relevant for linear risk estimation, namely about 1 Gy. We consider some possible RBE functions to explain the correct use and the impact of a dose-dependent RBE. However, we do not advocate any particular choice or even that a variable RBE be employed. Rather we show that the assumed neutron RBE, within a wide range of choices, is far less important to the outcome of risk assessment of the RERF data than generally believed. Some of these misperceptions have been related to the consideration of variable RBE functions, and without due attention to the fact that in the case of the A-bomb survivors' data, the mixed field of neutrons and γ rays must be considered. Therefore, the RBE value of neutrons is much lower than the RBE in pure neutron fields that are used in radiobiological experiments. Thus, applying the pure neutron field RBE to the mixed-field A-bomb radiation can lead to an overestimation of the actual neutron RBE for moderate total dose levels of 1 Gy by a factor of more than four. While in a pure neutron exposure the RBE depends on the neutron dose, in the mixed field it depends on both components of exposure, and in particular, we show that in the RERF setting the RBE depends mainly on the accompanying γ-ray dose.

Ovarian responsiveness in women receiving fertility treatment after methotrexate for ectopic pregnancy: a systematic review and meta-analysis.

Does previous methotrexate (MTX) treatment for ectopic pregnancy (EP) have an effect on ovarian response in women receiving fertility treatment? MTX treatment for EP does not seem to affect subsequent fertility treatment. MTX is commonly used to treat EPs that are diagnosed early. Previous studies have reported conflicting results about its effect on subsequent fertility treatments. This systematic review and meta-analysis included a total of 329 patients who had participated in 7 observational studies. A search of the MEDLINE, EMBASE and PUBMED databases was conducted to identify studies about fertility treatments after MTX treatment for EP, published in English or French up to December 2013. Studies were eligible for inclusion only if they compared indicators of ovarian responsiveness during ART in the cycles before and after an injection of MTX for EP. The primary outcome measure was the number of oocytes retrieved. Secondary outcomes included the basal serum FSH level, duration of stimulation, total gonadotrophin dose and serum E2 level on the day of hCG triggering. The mean number of oocytes retrieved during the cycles before and after the MTX treatment did not differ significantly (P = 0.4). The comparisons before and after MTX treatment of the basal plasma FSH level, the duration of stimulation, the total gonadotrophin dose used for stimulation and the estradiol level on the day ovulation was triggered did not find any significant differences. The literature on this topic is sparse, with few studies and even fewer of high methodological quality. These results indicate that MTX to treat EP in infertile patients does not have any negative effect on their subsequent fertility treatment, but further studies should be performed before this result can be considered definitive. This work received support from the Department of Gynecology and Obstetrics, La Conception Hospital, Marseille, France. The authors have no competing interests to declare. N/A.

A Randomized, Open-Label, Non-Inferiority Study of Intravenous Iron Isomaltoside 1,000 (Monofer) Compared With Oral Iron for Treatment of Anemia in IBD (PROCEED)

OBJECTIVES:In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA).METHODS:This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of −0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response.RESULTS:Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was −0.37 (95% confidence interval (CI): −0.80, 0.06) with P=0.09 in the full analysis set (N=327) and −0.45 (95% CI: −0.88, −0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of −4.4 (95% CI: −7.4, −1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67% oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP).CONCLUSIONS:We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose–response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD.

Radiation testing of the AeroForm co2-based breast tissue expander implant

BackgroundTissue expanders are used in breast reconstruction after mastectomy to stretch the remaining tissue to create space for placement of permanent breast implants. The AeroForm™ Tissue Expander, developed by AirXpanders™ Inc., contains electronic components designed to activate the release of carbon dioxide from an internal reservoir to inflate the expander. Breast cancer patients who undergo mastectomy and tissue expander/implant-based breast reconstruction may require radiation therapy at doses up to 50–60 Gy while the expander is in place. The ionizing radiation used in postmastectomy radiation therapy interacts with electronic components in medical implants, which may cause degradation in performance above certain levels. Most commercial electronic components used in medical devices, such as complementary metal-oxide semiconductor or bipolar integrated circuits can withstand radiation levels in the 50 Gy range without any performance degradation. Beyond this level, the performance may still be sufficient to guarantee functionality, but this needs to be confirmed at the system and electronic circuit level. We assessed the impact of radiation levels up to 75 Gy on 32 AeroForm™ Tissue Expanders (AirXpanders, Inc., Palo Alto, CA USA) and on the associated internal printed circuit assemblies.FindingsThe electronics inside the AeroForm™ Tissue Expander implant continued to function properly after exposure to radiation levels up to 75 Gy, which is well above the maximum total dose level typically used in postmastectomy radiation therapy.ConclusionsStandard postmastectomy radiation therapy doses do not damage or affect the functionality of the AeroForm™ Tissue Expander.

Differences in supratentorial white matter diffusion after radiotherapy – new biomarker of normal brain tissue damage?

Introduction. Therapy-induced injury to normal brain tissue is a concern in the treatment of all types of brain tumours. The purpose of this study was to investigate if magnetic resonance diffusion tensor imaging (DTI) could serve as a potential biomarker for the assessment of radiation-induced long-term white matter injury. Material and methods. DTI- and T1-weighted images of the brain were obtained in 19 former radiotherapy patients [nine men and 10 women diagnosed with astrocytoma (4), pituitary adenoma (6), meningioma (8) and craniopharyngioma (1), average age 57.8 (range 35–71) years]. Average time from radiotherapy to DTI scan was 4.6 (range 2.0–7.1) years. NordicICE software (NIC) was used to calculate apparent diffusion coefficient maps (ADC-maps). The co-registration between T1 images and ADC-maps were done using the auto function in NIC. The co-registration between the T1 images and the patient dose plans were done using the auto function in the treatment planning system Eclipse from Varian. Regions of interest were drawn on the T1-weighted images in NIC based on isocurves from Eclipse. Data was analysed by t-test. Estimates are given with 95% CI. Results. A mean ADC difference of 4.6(0.3;8.9)× 10−5 mm2/s, p = 0.03 was found between paired white matter structures with a mean dose difference of 31.4 Gy. Comparing the ADC-values of the areas with highest dose from the paired data (dose > 33 Gy) with normal white matter (dose < 5 Gy) resulted in a mean dose difference of 44.1 Gy and a mean ADC difference of 7.87(3.15;12.60)× 10−5 mm2/s, p = 0.003. Following results were obtained when looking at differences between white matter mean ADC in average dose levels from 5 to 55 Gy in steps of 10 Gy with normal white matter mean ADC: 5 Gy; 1.91(−1.76;5.58)× 10−5 mm2/s, p = 0.29; 15 Gy; 5.81(1.53;10.11)× 10−5 mm2/s, p = 0.01; 25 Gy; 5.80(2.43;9.18)× 10−5 mm2/s, p = 0.002; 35 Gy; 5.93(2.89;8.97)× 10−5 mm2/s, p = 0.0007; 45 Gy; 4.32(−0.24;8.89)× 10−5 mm2/s, p = 0.06; 55 Gy; −4.04(−14.96;6.89)× 10−5 mm2/s, p = 0.39. Conclusion. The results indicate that the structural integrity of white matter, assessed by ADC-values based on DTI, undergoes changes after radiation therapy starting as early as total dose levels between 5 and 15 Gy.

Occupational Radiation Exposure and the Vascular Interventionalist

In this month’s EJVES the paper by Patel and colleagues 1 provides an in-depth analysis of the occupational radiation exposure relevant to vascular interventionalists measured in the operating environment.The paper provides detailed information regarding the risks from performing EVAR and TEVAR and highlights an important point e that vascular interventionalists need to pay due regard to the radiation risks to themselves and their team and find methods to reduce this risk. The extrapolated dose quoted in this article is concerning. Moreover, arterial specialists are becoming ever more ambitious and procedures more and more complex with longer screening times and radiation exposure as a result. The dose may well be set to rise dramatically in the coming years, underlining the importance of compliance with standard radiation safety measures. While radiation protection training and adherence is vital, it is probably undervalued by those that learnt their trade in the operating theatre of old. These points are well documented in Patel’s article, but the levels of total body effective radiation dose to operating staff during endovascular procedures that may occur with more frequent and more complex practice is worrying and means that simple measures to protect staff are not enough. Technological advancements in low-dose imaging championed by the major companies in this field are a big step in reducing radiation dose while maintaining the necessary imaging quality to perform complex procedures. At the same time, it is vital that we continue to embrace new imaging techniques to reduce the need for repeated digital subtraction angiogram sequences. Fusion of pre- or intraoperative cross-sectional imaging is clearly effective in reducing operator dose, 2 and other imaging technologies such as intravascular ultrasound may compliment these approaches. Integration of new catheter technologies that allow the operator to be removed from the radiation source, such as robotic catheter systems are gaining favour in many centres both for vascular intervention (Magellan, Hansen Medical, Mountain View, CA, USA) and cardiac electrophysiological ablation. These systems allow the operator to navigate through the vascular tree from a workstation removed from the radiation source. The only occupational radiation exposure encountered in robotically assisted procedures is therefore in the delivery of the intervention itself. 3 As experience grows these systems will play a vital role in dose reduction for the operator. The ultimate goal must be to do away with radiation all together and find novel methods to track endovascular tools without the use of radiation, or, at least in the meantime, reducing the operator dose significantly. 4 This paper highlights a growing problem for vascular interventionalists. Simple steps to reduce exposure are vital but may not be enough and we must look to integrate cutting-edge imaging modalities, robotic technology, and tool tracking systems to reduce operator exposure in the future.

60Co gamma radiation effect on AlGaN/AlN/GaN HEMT devices

The testing techniques and experimental methods of the 60Co gamma irradiation effect on AlGaN/AlN/GaN high electron mobility transistors (HEMTs) are established. The degradation of the electrical properties of the device under the actual radiation environment are analyzed theoretically, and studies of the total dose effects of gamma radiation on AlGaN/AlN/GaN HEMTs at three different radiation bias conditions are carried out. The degradation patterns of the main parameters of the AlGaN/AlN/GaN HEMTs at different doses are then investigated, and the device parameters that were sensitive to the gamma radiation induced damage and the total dose level induced device damage are obtained.

Single event effect of 3D H-gate SOI NMOS devices in total dose ionizing

The single event effect of H-gate SOI NMOS devices in total dose ionizing are studied by means of numerical simulation. By analyzing the mobility degradation in the simulation process, the corrected mobility Lombardi model due to degradation at interfaces is obtained. As the simulated transfer characteristic curves of SOI transistor agree well with the experimental data, the single event effect of H-gate SOI NMOS devices in total dose ionizing is simulated by this corrected model. Results shows that the maximum drain currents of devices under the same conditions are slight increasing, but the transistors get a significant increase in the drain collected charge with increasing total dose level.

Conversion from Twice (Prograf) to Once Daily Administration of Tacrolimus (Advagraf) Regimen in Renal or Liver Transplant Recipients; An Open Multicenter Trial

Introduction: “Non-adherence” is an important factor for both acute and chronic rejection and later graft-loss. A new formulation of tacrolimus (Tac) is available that is dosed once daily (OD). OD dosing has been shown to increase adherence. The aims were to assess the change in total Tac dose and trough level at baseline and after conversion from BID to OD dosing in kidney (ktx) and liver recipients (ltx) and how this affected patient self reported adherence. Methods: 241 recipients (mean age 51 y) were included from 23 centres. 224 (205 ktx, 14 ltx and 5 ltx+ktx) completed the study. The patients had stable graft function and were at least 6 months after transplantation. Mean time to conversion was 5.3 and 8.0 years for ktx and ltx. The patients were converted from Tac BID to OD on a 1:1 mg ratio. The patients also filled out a questionnaire at 3 months. Results: 2 patients died, 6 were changed back to Prograf and 9 were withdrawn. No patient had a rejection episode after the conversion. The mean Tac daily dose remained unchanged from visit 1 and after 3 months (3.9±2.0 and 3.9±2.1mg). In 140 patients (62%) the dose was unchanged, 35 (16%) had a lower dose, and 49 (22%) had a higher dose at 3 months. The mean Tac level was significantly lower after conversion. The through level decreased from 6.33±1.8 to 5.60±1.7 ng/ml, p< 0.0001. 141 (63%) of patients had a lower and 83 (37%) had a higher level. The questionnaire showed that 31% “sometimes” forgot their immunosuppressive medication and 19% stated that the conversion helped to improve their compliance. 55% experienced the conversion “for the better”. Conclusions: Conversion from Prograf to Advagraf was safe and well tolerated. Mean daily Tac dose remained the same but trough level was significantly lower after conversion

Rational design of an immunoconjugate for selective knock-down of leukemia-specific E2A–PBX1 fusion gene expression in human Pre-B leukemia

The t(1;19)(q23;p13) is one of the most common chromosomal translocations in acute lymphoblastic leukemia (ALL) and results in production of the transforming oncoprotein E2A-PBX1. Here we first report a novel, biomarker-guided biotherapy strategy for personalized treatment of t(1;19)(+) ALL. A supervised interrogation of the gene expression profiles of primary leukemic cells from a cohort of 207 children with high risk B-lineage ALL identified up-regulated CD19 gene expression as a biomarker for t(1;19)(+) ALL. A disulfide-linked immunoconjugate of a 5-amino-modified 24 mer phosphorothioate anti-sense E2A-PBX1 oligonucleotide (AON) with a mAb specific for a CD19 receptor (αCD19-AON) was prepared as a CD19-directed and leukemia-specific biotherapeutic agent against E2A-PBX1(+) B-lineage ALL. Treatment of E2A-PBX1(+) leukemia cells with low nanomolar concentrations of αCD19-AON resulted in selective depletion of E2A-PBX1 transcripts and caused apoptotic destruction and abrogation of clonogenic growth. Subcutaneously administered αCD19-AON at a total dose level of 93 nmol kg(-1) delivered over 14 days using a micro-osmotic pump more than doubled the leukemia-free survival time of SCID mice in a xenograft model of E2A-PBX1(+) human B-lineage ALL (82.0 ± 1.9 days vs. 37.0 ± 0.1 days, P < 0.0001). Both the AON moiety and the targeting CD19-specific mAb moiety were required for the in vitro as well as in vivo anti-leukemic activity of αCD19-AON. The observed in vitro and in vivo anti-leukemic potency of the αCD19-AON immunoconjugate provides the first preclinical proof-of-principle that t(1;19)(+) high risk B-lineage ALL can be treated with leukemia-specific biotherapeutic agents that knock-down E2A-PBX1 expression.

Does higher starting dose of FSH stimulation with letrozole improve fertility preservation outcomes in women with breast cancer?

To evaluate the efficacy of ovarian stimulation with higher doses of gonadotropins in fertility preservation (FP) cycles with the intention to maximize the likelihood of future pregnancies. Retrospective (secondary analysis). Academic medical centers. Low-dose (LD, 150 IU; n = 34) versus high-dose (HD, >150 IU; n = 117) FSH start in 151 patients with breast cancer (BCa) undergoing ovarian stimulation for embryo cryopreservation with letrozole (LE) before cancer treatment. None. FP cycle outcomes. Mean total FSH dose (2,037 ± 679 IU vs. 1,128 ± 381 IU) and FSH level on trigger day (21.1 ± 8.9 vs. 10.6 ± 4.5 mIU/mL) were higher in the HD group, confirming the receipt of higher-dose FSH. There was no difference in other patient characteristics. Despite the larger number of follicles >17 mm in diameter in the HD group (5.0 ± 2.0 vs. 3.4 ± 1.4), neither peak E(2) (498.0 ± 377.5 vs. 397.9 ± 320.3), number of oocytes (13.3 ± 8.7 vs. 12.3 ± 8.0), nor number of embryos (6.3 ± 4.7 vs. 5.4 ± 3.8) were significantly different from the LD group. Of those undergoing frozen embryo transfer (ET), live birth rate (LBR)/ET trended higher in the LD (9/15) compared with HD (2/11) group, with 2.1 ± 0.8 vs. 1.9 ± 0.3 embryos transferred, respectively. Higher-dose FSH stimulation in LE cycles does not improve outcomes and may be associated with lower LBR. Our findings may support minimal stimulation in young noninfertile women with BCa.

Preliminary assessment of ecological exposure of adult residents in Fukushima Prefecture to radioactive cesium through ingestion and inhalation

ObjectiveThis study aims to estimate the ecological exposure of adult residents of Fukushima Prefecture to 134cesium (Cs) and 137Cs through ingestion and inhalation between July 2 and July 8, 2011.MethodsFifty-five sets of meals with tap water, each representing one person’s daily intake, were purchased in local towns in Fukushima Prefecture. Locally produced cow’s milk (21 samples) and vegetables (43 samples) were also purchased. In parallel, air sampling was conducted at 12 different sites using a high-volume sampler. Nineteen sets of control meals were collected in Kyoto in July 2011. 134Cs and 137Cs levels in the samples were measured using a germanium detector.ResultsRadioactivity was detected in 36 of the 55 sample meals from Fukushima, compared with one of 19 controls from Kyoto. The median estimated dose level (μSv/year) was 3.0, ranging from not detectable to 83.1. None of the cow’s milk (21) or vegetable (49) samples showed levels of contamination above the current recommended limits (Bq/kg) of 200 for milk and 500 for vegetables. The total effective dose levels by inhalation were estimated to be <3 μSv/year at nine locations, but samples at three other locations close to the edge of the 20-km radius from the crippled nuclear power plant showed higher levels of contamination (μSv/year): 14.7 at Iitate, 76.9 at Namie, and 27.7 at Katsurao.ConclusionsLevels of exposure to 134Cs and 137Cs in Fukushima by ingestion and inhalation are discernible, but generally within recommended limits.Electronic supplementary materialThe online version of this article (doi:10.1007/s12199-011-0251-9) contains supplementary material, which is available to authorized users.

Radiation-induced shallow trench isolation leakage in 180-nm flash memory technology

The effects of total ionizing dose (TID) irradiation on the inter-device and intra-device leakage current in a 180-nm flash memory technology are investigated. The positive oxide trapped charge in the shallow trench isolation (STI) oxide is responsible for the punch-through leakage increase and punch-through voltage decrease. Nonuniform radiation-induced oxide trapped charge distribution along the STI sidewall is introduced to analyze the radiation responses of input/output (I/O) device and high voltage (HV) device. At low dose level, the inversion near the STI corner caused by the trapped charge occurs more easily due to the lower doping concentration in this region, which gives rise to the subthreshold hump effect. With total dose level increase, more charge at deep region of the STI oxide is accumulated, predominating the intra-device off-state leakage current. It has been discussed that the STI corner scheme and substrate doping profile play important roles on influencing the device’s performance after radiation.

SU-E-J-07: A Preliminary Study on Optimal Dose-Allocation Parameters for Low-Dose Cone-Beam CT

Purpose: Cone-beam CT (CBCT) is widely used for providing image guidance in radiotherapy and interventional procedures. Due to the patient safety concern involved in repetitive CBCT scans, significant effort has been devoted to possibly lowering imaging dose in CBCT. For a given total dose, it is also important to investigate how image quality can be affected by dose allocations over projection views and by image-reconstruction algorithms. In this work, we investigate quantitatively how image quality changes resulted from different combinations of dose-allocation parameters and some existing reconstruction algorithms. Methods: We performed simulation studies by using a numerical phantom containing structures ofdifferent contrast levels. We also acquired real data of a Catphan phantom (The Phantom Laboratory, Salem, NY) by using the on-board imaging system (Varian Medical Systems, Palo Alto, CA). At three different total dose levels, we allocated each of them to different numbers of views ranging from 120 to 650. For each allocation scheme we applied the FDK and ASD-POCS algorithms to obtain reconstructed images. A set of quantitative metrics were used to evaluate image quality based on relevant tasks. Results: Preliminary results showed that for total dose levels under study, both FDK and ASD-POCS algorithms yield images with comparable quality when a large number of views are considered and that images reconstructed by the ASD-POCS from smaller number of views generally exhibit higher quality. Overall, for each given total dose level the ASD-POCS algorithm yields images of comparable or higher quality than does the FDK algorithm. Conclusions: We demonstrated that CBCT image quality can be optimized for a fixed total dose by choosing an appropriate combination of dose- allocation parameters and reconstruction algorithm. This finding may potentially be used for improving current CBCT image quality and for designing innovative, low-dose CBCT imaging protocols.