3rd Administration Research Articles

Cross-Cultural Adaptation of the Administration Instructions of the Developmental Test of Visual Perception 3rd Edition for isiZulu-Speaking Children

Introduction: Visual perceptual skills are vital for developing academic skills and contribute to language development and socio-cultural participation. The Developmental Test of Visual Perception 3rd Edition evaluates visual perceptual skills but is only available in English. lsiZulu is the most spoken language in South Africa (24,4%), with English being the fourth. Therefore, the English version of the Developmental Test of Visual Perception 3rd Edition cannot be described as a universally authentic assessment instrument in this context. Methodology: This study aimed to translate and cross-culturally adapt the Developmental Test of Visual Perception 3rd Edition administration instructions into isiZulu using a five-stage qualitatively driven multimethod sequen tial design. Qualitative feedback on the functional, cultural and conceptual equivalence was obtained at various intervals. Results: This study demonstrated a methodology for translating and cross-culturally adapting the administration instructions of the Developmental Test of Visual Perception 3rd Edition into isiZulu to advance the authenticity of the assessment within the South African context. The isiZulu version was found to be functionally, culturally and conceptually equivalent. Conclusion: This research has demonstrated a framework upon which the cross-cultural adaptations of other assessment instruments and other languages in South Africa can be based. Implications for practice • The rigorous methodology demonstrated in this research can be used as a framework to guide other studies in the translation and cross-cultural adaptation of other assessment instruments and into other languages. • This study demonstrated that multiple contributors from various backgrounds are necessary to ensure equivalence during the process of translation and cross-cultural adaptation. However, an emphasis is placed on the value of including occupational therapists with clinical experience when translating and cross-culturally adapting assessment instruments intended to be used within the field of occupational therapy. • Through the rigorous method used to translate and cross-cultural adapt the DTVP-3, this study enhanced its authenticity as an assessment instrument within the South African context. Having isiZulu administration instructions available could provide equal opportunity to children who may not be as proficient in English as in isiZulu. • Once a distribution agreement has been reached with ProEd Inc., the original publisher and licence holder, the isiZulu administration instructions of the DTVP-3 will be made available for use in South Africa with isiZulu-speaking children.

Active Ascent Does Not Alter Cognitive Performance Compared To Passive Ascent To 3600 m

PURPOSE: Cognitive performance is known to decrease following acute exposure to high altitude (HA) but it is unknown whether active ascent affects that response. The purpose of this study was to examine changes in cognitive performance following active and passive ascent to 3600 m. METHODS: Forty-one healthy unacclimatized Soldiers (n = 41, mean ± SD; age = 26 ± 5 yr; body weight = 83.5 ± 11.6 kg; VO2max = 47.9 ± 5.5 ml · kg−1 · min−1) were tested at sea level (SL) in Ft. Leonard Wood, MO, flown to Taos Ski Valley, NM (2845 m) where they arrived around 1400 and then either hiked (n = 21; 5.0 km, 15.5% mean grade) or were driven (n = 20; 30-min drive) to a HA ski patrol facility located at 3600 m where they resided for the next 4 days. Energy expenditure during ascent was measured using an ankle accelerometer (Actical, Respironics, Inc.). Six cognitive modules (simple reaction time (SRT), match to sample (M2S), mathematical processing (MTH), procedural reaction time (PRO), simultaneous spatial processing (SPD) and simple reaction time 2 (SR2)) were administered using the Automated Neuropsychological Assessment Metrics in the morning (~0900) four times at SL, and following ~19 h at HA (HA2), and ~ 43 h at HA (HA3). All cognitive modules demonstrated no difference between the third (am) and fourth (pm) administrations at SL so the 3rd administration was used for the baseline record. RESULTS: The active group expended a greater (P < 0.05) amount of energy (745 ± 435 kcal) than the passive group (55 ± 10 kcal) during ascent. There were no differences in cognitive performance between groups so data were combined. The SRT decreased (P < 0.05) from SL (203 ± 28) to HA2 (192 ± 34) and increased (P < 0.05) from HA2 to HA3 (204 ± 29). PRO decreased (P < 0.05) from SL (97.5 ± 13.7) to HA2 (91.2 ± 14.9) and increased (P < 0.05) from HA2 to HA3 (96.1 ± 11.3). The SRT2 decreased (P < 0.05) from SL (195 ± 29) to HA2 (179 ± 46) and remained unchanged from HA2 to HA3 (188 ± 34). There were no changes in M2S, MTH, and SPD from SL to HA2 or HA3. CONCLUSION: Active compared to passive ascent did not impact cognitive performance at HA but reaction time whether simple, procedural, or repeated decreased on HA2. Both SRT and PRO recovered on HA3 but SR2, a measure of cognitive fatigue, did not recover. Authors’ views not official U.S. Army or DoD policy. Funding: USAMRDC

FiD: a smartphone application for anxiety assessment: two weeks study

Anxiety disorders affect approximately one in six people, causing significant problems in their quality of life and that of their families with a significant percentage of mentally ill people not showing compliance with treatment or not receiving appropriate treatment. Research data therefore reveal the need to develop new and effective interventions that will improve the compliance and therapeutic management of the mentally ill. Because of the recent technological advancement, the field of electronic mental health applications (MHapps) offers unique opportunities which can contribute to self-management of mental health problems and patient compliance, as well as to development of preventive and therapeutic interventions. Mental health applications (MHapps) offer a unique opportunity for expanding availability and quality of treatment of mental health disorders, however few applications have been carefully assessed so far making their effectiveness questionable. The present study investigated the effect of MHapp FiD (Feel-Identity) on anxiety- an innovative electronic prototype application-in a sample of adults over a two-week period. Participants made daily use of the application, based on self-monitoring and self-recording in accordance with the Cognitive Behavioural Therapy protocol, with feedback interventions being fully automated. In order to investigate anxiety levels, the STAI questionnaire (State & Trait Anxiety Inventory) was administered over three different time periods: before the use of MHapp FiD, following the first week after its use, and following the second week after its use. The results between the 3 groups of application usage, showed a statistically significant decrease of the average TRAIT anxiety levels between the 1st and the 3rd administration, i.e., after two weeks of application usage, equal to -3.020 units (Mean Difference = -3.020, p-value = 0.006 <0.01), and a statistically significant drop of the average total anxiety levels, between the administration of the 2nd and the 3rd administration, i.e., over the second week of application usage, equal to -5.388 units (Mean Difference = -5.388, p-value = 0.029 <0.05). Τhere was no statistically significant difference as to the average STATE anxiety levels. The results showed a correlation between the daily use of the FiD application and the reduction of anxiety, providing a promising perspective for dissemination of the application in clinical populations with the addition of more functions and interventions.

Therapeutic Effect of Statins and LPS Antibody on Proinflammatory Mediator and Biochemical Markers of Sepsis Rat Model Induced by E. coli

This study aims to determine the effect of statins and LPS antibodies administration combined with E. coli intraperitoneal injection toward proinflammatory mediators (TNF-?, hs-CRP, PCT, and MDA) urea, BUN, and creatinine) and liver function (SGPT, SGOT, and total bilirubin) in sepsis rats. This study used 30 male white rats (Rattus novergicus strain Wistar) divided into 6 groups induced by E. coli bacteria combined with statins, LPS antibody (Ab-LPS), and a combination of statins+Ab-LPS. Examination of proinflammatory mediators (TNF-?, hs-CRP, PCT, and MDA) was carried out by the ELISA method through the examination of biochemical markers namely renal function (urea, BUN, and creatinine) and liver function (SGPT, SGOT, and total bilirubin) were analyzed by using the autoanalyzer. The data obtained were statistically analyzed using the T-test. The result shows that E. coli+statins gave significant changes on the MDA level at 0th hour administration and TNF-? and hs-CRP at 3rd hour administration. The E. coli+Ab-LPS treatment showed significant changes at the 0th hour administration for MDA, creatinine, and total bilirubin and at the 3rd hour administration for MDA. The E. coli+statins+Ab-LPS treatment showed significant changes in MDA, creatinine, and total bilirubin at 0th hour administration and on creatinine and total bilirubin at 3rd hour administration.

SAT-LB91 Asparaginase Induced Severe Hypertriglyceridemia Requiring Multiple Plasmapheresis Sessions

Background: Asparaginase (ASP) is an essential component of chemotherapy for acute T-cell lymphoblastic lymphoma (T-ALL). Hypertriglyceridemia (HTG) is a known side effect of ASP therapy in children and adults (incidence up to 67 and 12.5%, respectively). The mechanism of HTG is multifactorial and involves lipoprotein lipase (LPL) suppression. Acute pancreatitis can occur in 13% of patients. There are no treatment guidelines currently available for ASP-induced HTG. Clinical Case: A 33 year old male with history of prediabetes, HTG and T-ALL being treated with CALGB 10403 chemotherapy protocol (vincristine, methotrexate, cytarabine and pegylated-ASP) presented to the ED with acute onset abdominal pain radiating to the back with associated nausea. He denied alcohol use. Home medications included fenofibrate, metformin and atorvastatin. His TG level prior to initiating chemotherapy was 454 mg/dL (ref range < 150) with an HbA1C of 6.5%. Upon presentation; TG level was 11,650 mg/dL, lipase was 563 U/L (13-60) with CT abdomen findings suggestive of mild pancreatitis. He was treated in the ICU with insulin drip at 0.05 - 0.1 unit/kg/hr with repeat TG level 6,490 mg/dL after 48 hours. He eventually required 5 serial plasmapheresis sessions over a 10 day hospital course in order to achieve a goal TG level under 500 mg/dL. Conclusion: ASP is part of standard multiagent chemotherapy for patients with ALL however poses the risk of developing severe HTG. This side effect may be explained by multiple mechanisms including increased synthesis of very low-density lipoprotein (VLDL), decreased LPL activity as a result of an increase in the apoCIII/apoCII ratio, and increase in serum chylomicrons. Studies have shown patients who had extreme HTG had a higher frequency of ApoE3/4 phenotype, suggesting that screening for ApoE polymorphism may identify patients at high risk for developing this. HTG secondary to ASP is often asymptomatic, with severe elevations in TG levels observed around 10 days after the 3rd administration of ASP and resolving 2-3 weeks after drug discontinuation. There are no treatment guidelines for ASP-associated HTG as there is no single typical clinical course. Management for severe HTG includes insulin infusion and plasmapheresis. Insulin rapidly activates LPL leading to mean TG reduction of 50% within the first 24 hours as compared to 66% reduction after single plasmapheresis therapy. However, there is paucity of data regarding the appropriate insulin dose and whether there is a linear dose-response in TG level reduction. Further studies are required to develop standard treatment guidelines for ASP-induced HTG which may help alleviate serious complications such as acute pancreatitis. Reference: Tozuka et al “Characterization of hypertriglyceridemia induced by L-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma.” Annals of Clinical & Laboratory Science 1997

Real-World Utilization and Safety of Daratumumab Rapid Infusion Administered in a Community Setting: A Retrospective Observational Study

Introduction: Daratumumab (dara), a CD38-directed monoclonal antibody, was first FDA approved as monotherapy in 2015 for the treatment of patients with relapsed refractory multiple myeloma (RRMM) and has subsequently received approval for combination therapy for RRMM and newly diagnosed transplant ineligible MM1. In clinical trials, median durations of 16 mg/kg infusions for the 1st, 2nd, and subsequent infusions were ~7, 4, and 3 hours, respectively. In 2019, FDA approved split-dosing of the first 16 mg/kg dose and some institutions, including Florida Cancer Specialists &amp; Research Institute (FCS), have also implemented a dara rapid infusion [RI] protocol in which patients can receive dara RI (≤90 minutes infusion duration) after having received ≥2 prior dara doses without any infusion reactions (IRs) and with pre-medications as per institutional guidelines. The objective of this study was to better understand the utilization and IRs observed among patients who received dara RI in routine care. Methods: A retrospective longitudinal cohort design was employed using electronic medical records (EMR) from FCS. The FCS network consists of nearly 100 cancer centers in Florida including ≥200 physicians. Adult patients with MM (ICD-9-CM: 203.xx; ICD-10-CM: C90.xx) who received ≥1 completed dara RI as part of the first dara regimen (index date) received in routine clinical care (i.e. not participation in a clinical trial) between 11/16/2015 and 03/15/2019 (study period) were included. Infusions were considered rapid if they were 1) administered ≥5 days apart (to exclude split-doses), 2) received ≥90% of ordered dose, and 3) had a duration of ≤110 minutes (to allow for variability in recording time in the EMR). RIs were identified from structured fields of FCS EMR, however, to obtain information on IRs, data were abstracted from unstructured fields. Baseline demographic and clinical characteristics at index date were described. This analysis includes interim safety results from a sample of RI patients whose data were abstracted in time for analysis. Abstraction is ongoing for the full RI cohort. IRs were defined as a) an event that occurred within 24 hours of the start of a dara infusion and was reported in the medical chart as directly attributed to the infusion, but was not explicitly stated as an IR, or b) was explicitly stated in the medical chart as an IR to a dara infusion. The frequency and types of IRs were described. Results: A total of 541 patients received a dara regimen during the study period, among whom 168 (31.1%) received RI in their first dara regimen and were included in this analysis, Table 1. Mean age (standard deviation [SD]) at index date was 71.8 (8.9) years and 75 (44.6%) were female; mean time (SD) from initial MM diagnosis to index date was 3.4 (4.2) years. ECOG was 0 or 1-2 for the majority of patients (28.0% and 64.3%, respectively). Utilization of RI increased over time with few RIs occurring prior to 2017 (10.1%). Most RIs were administered for the 3rd or later infusion (89.3%). On average, the first RI occurred around the 12th infusion with an average (SD) duration of 92.8 (8.8) minutes. The most common regimens were dara monotherapy (34.5%), followed by dara + pomalidomide (31.0%), and dara + lenalidomide (14.3%). In the safety analysis (n=142 patients with abstracted information available at the time of this analysis), 35.9% (n=51/142) experienced at least one IR at any time during dara treatment, including RI and non-RI administrations. The most common IRs (i.e. IRs that occurred in at least 10% of patients) experienced by patients at any time during dara treatment included nausea (11.3%) and chills (10.6%). Among RI administrations, 3 patients (2.1%) experienced at least one IR and all occurred on the first administration of dara where data indicate that dara RI may have been administered. No IR was observed among patients receiving RI for the 3rd administration or later. Conclusion: This retrospective study provides real-world evidence on the utilization and safety of dara RI at community-based oncology clinics. In this study, the frequency of IRs among RI administrations was low with no IRs reported when RI was initiated for the 3rd dara administration or later, which suggests that RI is well tolerated. Disclosures Lafeuille: Analysis Group: Employment, Other: Janssen contracted with Analysis group . Romdhani:Analysis Group: Employment, Other: Janssen contracted with Analysis group . Paramasivam:Analysis Group: Employment, Other: Janssen contracted with Analysis group . Zhu:Janssen Scientific Affairs, LLC: Other: contractor for Janssen. Gunawardena:Janssen: Employment, Equity Ownership. Maiese:Janssen: Employment, Equity Ownership.

Novel mRNA-Based Therapy Reduces Toxic Galactose Metabolites and Overcomes Galactose Sensitivity in a Mouse Model of Classic Galactosemia.

Classic galactosemia (CG) is a potentially lethal inborn error of galactose metabolism that results from deleterious mutations in the human galactose-1 phosphate uridylyltransferase (GALT) gene. Previously, we constructed a GalT-/- (GalT-deficient) mouse model that exhibits galactose sensitivity in the newborn mutant pups, reduced fertility in adult females, impaired motor functions, and growth restriction in both sexes. In this study, we tested whether restoration of hepatic GALT activity alone could decrease galactose-1 phosphate (gal-1P) and plasma galactose in the mouse model. The administration of different doses of mouse GalT (mGalT) mRNA resulted in a dose-dependent increase in mGalT protein expression and enzyme activity in the liver of GalT-deficient mice. Single intravenous (i.v.) dose of human GALT (hGALT) mRNA decreased gal-1P in mutant mouse liver and red blood cells (RBCs) within 24h with low levels maintained for over a week. Repeated i.v. injections increased hepatic GalT expression, nearly normalized gal-1P levels in liver, and decreased gal-1P levels in RBCs and peripheral tissues throughout all doses. Moreover, repeated dosing reduced plasma galactose by 60% or more throughout all four doses. Additionally, a single intraperitoneal dose of hGALT mRNA overcame the galactose sensitivity and promoted the growth in a GalT-/- newborn pup.

Vocational Curriculum Implementation of the Three Years Program of Electronics Engineering

This study analysed the implementation of the Indonesian Qualification Framework based vocational curriculum in the three years program of an electronics engineering, Faculty of Engineering, Universitas Negeri Jakarta. The analysis was focused on lecturers and students’ views. This evaluation used the model of Context, Input, Process, Product by involving 49 students in the 3rd semester, 6 lecturers, and administration staff. The findings showed that the implemented learning activities using the new curriculum paradigm are reliable. The context analysis indicated the correlation between lecturers’ competence and qualification and the goals of the study program. The input analysis showed that the lecturer's assignment was appropriate and correspond with lecturers’ subject and education background. The process analysis revealed that the learning process was in accordance with the lectures’ planning. In addition, the practicum activities were reportedly consistent with the academic calendar. The product analysis, in the form of courses distribution each semester, suggested that the needs for improvement to fit the new curriculum paradigm design.

Effects of recurrent sevoflurane anesthesia on cognitive functions with streptozotocin induced Alzheimer disease.

We aimed to investigate the effects of recurrent sevoflurane anesthesia on cognitive functions in Alzheimer Disease. Rats were divided into 4 groups as followed: control (Group C), sevoflurane (Group S), Alzheimer's (Group A) and Alzheimer's + sevoflurane (Group AS)]. Cognitive functions were evaluated with Radial Arm Maze Test (RAMT). Alzheimer model was created by administering 3 mg/kg (10 μl) STZ. Sevoflurane was administered to S and AS groups. Serum samples and hippocampus tissues were analyzed. In RAM test, the entry-exit data were significantly decreased in A and AS groups. After the 2nd and 3rd administration of anesthesia, the numbers were significantly decreased in Group S. Glial-fibrillary-acidic protein levels were significantly higher in AS compared to the C and S groups. The brain tissue caspase 3 activity was less than 1% in all rats in the Group C, 3 % in 2 rats and 1 % in 1 rat in the Group AS. In A and AS group, serum catalase, myeloperoxidase and ferroxidase activities were found to be higher than in the other groups and myeloperoxidase activity was higher in the AS than in the A Group. Serum native thiol, total thiol and disulfide levels were found to be significantly different in the A and AS groups. Sevoflurane anesthesia negatively affected the cognitive functions (Tab. 5, Fig. 10, Ref. 51).

Pretransplantation Myeloablative Conditioning Regimen with Intravenous Busulfan Dose Adjustment for Older Patients with Hematologic Malignancies

Pretransplantation Myeloablative Conditioning Regimen with Intravenous Busulfan Dose Adjustment for Older Patients with Hematologic Malignancies

Abstract LB-202: Liver microvascular injury and thrombocytopenia of antibody-calicheamicin conjugates: mechanism and monitoring

Abstract Gemtuzumab ozogamicin (Mylotarg, GO) and inotuzumab ozogamicin (IO) are antibody-drug conjugates (ADCs) comprised of different humanized monoclonal antibodies (against CD33 and CD22 antigen, respectively) and of the same acid-labile linker and calicheamicin payload. GO and IO are developed for the treatment of acute myeloid leukemia and acute lymphoblastic leukemia, respectively. Adverse events reported with these 2 drugs in patients include thrombocytopenia and liver toxicity, which is characterized by increases in serum aminotransferases and bilirubin along with occasional cases of sinusoidal obstruction syndrome (SOS). The platelet and liver effects were seen in patients with conjugates targeting unrelated antigens and are likely target-independent. Since the specific mechanisms of these toxicities remain elusive, an investigative study was performed in cynomolgus monkeys with a non-binding ADC containing the same linker and payload as GO and IO, PF-0259, with the objectives to investigate the mechanism for thrombocytopenia, characterize the liver injury and identify potential safety biomarkers. Cynomolgus monkeys were dosed intravenously with PF-0259 at 6 mg/m2/dose once every 3 weeks for up to 3 doses and were necropsied 48 hours after the 1st administration (Day 3) or 3 weeks after the 3rd administration (Day 63). PF-0259 induced acute thrombocytopenia (up to 86% reduction in platelet count) in monkeys with nadirs on Days 3-4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver samples from animals necropsied on Day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on Day 63 showed variable endothelial cell recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with AST levels and liver microscopic changes, suggesting that HA could be a sensitive diagnostic marker of the liver microvascular injury. In conclusion, this work has demonstrated that target-independent damage to liver SECs was responsible for acute thrombocytopenia (through platelet sequestration in the liver) and development of early SOS in monkeys. The translation of these observations to humans has not been evaluated. We further hypothesize that this toxicity mechanism may operate for other types of non-calicheamicin based ADCs in patients where adverse events of thrombocytopenia, increased liver enzymes and liver microvascular disorders (including nodular regenerative hyperplasia) have been observed. Citation Format: Magali Guffroy, Hadi Falahatpisheh, Kathleen Biddle, John Kreeger, Leslie Obert, Karen Walters, Richard Goldstein, Germaine Boucher, Timothy Coskran, William Reagan, Danielle Sullivan, Sharon Sokolowski, Richard Giovanelli, Hans-Peter Gerber, Martin Finkelstein, Nasir Khan. Liver microvascular injury and thrombocytopenia of antibody-calicheamicin conjugates: mechanism and monitoring. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-202.

Mobilization of Human Immature Hematopoietic Progenitors after Combinatory Use of Bortezomib and Immunomodulatory Drugs

Introduction: Combination of proteasome inhibitor (PI) bortezomib and immunomodulatory drugs (IMiDs), lenalidomide or thalidomide, have revealed superior outcomes in multiple myeloma (MM) over their single use. PI and IMiDs possess their direct anti-tumor activity as well as exert the indirect pleiotropic biological effects by modulating immune response, cytokine production, cell adhesion molecule, anti-apoptotic factors, cell cycle regulators. We recently found that circulating immature granulocytes and erythrocytes/megakaryocytes frequently appeared in peripheral blood (PB) in patients treated with bortezomib and IMiDs. In this study, we tested whether this effect is derived from PI, IMiDs or combination, and tried to understand its underlying mechanism to further understand their combinatory effects to normal hematopoiesis.Patients & Methods: 47 patients aged 37 - 81 years with newly diagnosed or relapsed/refractory MM were enrolled into this study. PB or bone marrow (BM) samples were collected from 7 patients treated with bortezomib/lenalidomide/dexamethasone (VRD), 15 with bortezomib/thalidomide/dexamethasone (VTD), 6 with bortezomib/dexamethasone (BD), 19 with lenalidomide/dexamethasone (RD) regimen. Clonogenic progenitor assay (CFU-C) was performed using PB samples. Change in expression level of adhesion molecules on mobilized immature cells was analyzed with flowcytometric (FCM) analysis. We counted 250 differential WBC in May-Giemsa-stained PB smears under the microscope every other day after start of chemotherapy.Result: In PB analysis, a significant fraction of immature myeloid or erythro-megakaryocyte cells was morphologically documented in 16 out of 22 (73%) patients treated with VTD/VRD, but never in the patients treated with BD or RD (n=22). During the time course, circulating immature hematopoietic cells gradually increased after the commencement of VRD or VTD therapy, and reached to a peak on a median of 12 days (range, 4 - 24 days), which was documented after 2nd or 3rd administration of bortezomib in the most patients. In these patients, a mean peak percentage of immature cells per WBC was 2.6% (0 - 6.5%) during VRD/VTD therapy. We also performed FCM analyses to confirm mobilization of immature hematopoietic progenitors in peripherally during VRD/VTD therapy. Number of mobilized CD34+ cells was statistically higher in the VRD/VTD group than that in BD/RD group (0.070% vs. 0.017%, p=0.041). We extended an analysis of change in expression of adhesion molecules on mobilized immature cells in PB mononuclear cells, since down-regulation of these molecules resulted in release of stem/progenitor cells from marrow and mobilization into the circulation. We found a significant decrease in mean fluorescence intensity (MFI) of CXCR-4 expressed on PB CD34+ cells in VRD/VTD group compared with that in BD/RD groups (11.1 vs 15.2, p=0.033). Number of CFU-cells (CFU-C) increased after 2nd or 3rd administration of bortezomib during VRD/VTD therapy compared to that before therapy (Figure), which was coincided with the appearance of immature cells in PB. A number of CFU-C derived from 100,000 PB mononuclear cells was increased up to 45 in VRD/VTD group compared to 11 in BD/RD group (p=0.021).Discussion: In this study, we unexpectedly found a transient mobilization of the immature hematopoietic progenitors in the majority of patients who received concurrently PI and IMiDs, but not in the patients treated with either alone. IMiDs promote degradation of IKZF1, which regulate GATA-1 and PU.1, critical transcription factors for erythroid and granuloid lineage, resulting in a suppression of erythropoiesis and granulocyte maturation arrest with accumulation of immature granulocyte progenitors in the BM. In contrast, PI downregulate expressions such as CXCL-12/CXCR-4 and VLA-4/VCAM-1 by which hematopoietic progenitors anchor to BM microenvironments. Therefore, we hypothesize that accumulated immature progenitors in marrow by treatment with IMiDs, can be quickly released into peripherally by concurrent administration of bortezomib. It is still unknown whether the mechanism of mobilization effect is linked to their anti-myeloma effect. Thus, our observations provided the unexpected biological effects of these drugs. Combinatory use of new drugs should be carefully evaluated to maximize their benefit or prevent possible adverse events. [Display omitted] DisclosuresAkashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

SAT0356 The Therapeutic Efficacy of the Novel Uricosuric Agent UR-1102 for Hyperuricemia and Gout

BackgroundControl of blood uric acid is important for the treatment of gout. The clinical potential of a selective uric acid transporter 1 (URAT1) inhibitor as a drug for hyperuricemia and...

Ipilimumab-induced hypophysitis in melanoma patients.

8568 Background: Ipilimumab (Ipi) is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for the treatment of metastatic melanoma (MM) and currently under investigation in the adjuvant setting. Methods: Retrospective analysis of patients treated with ipi between June 2006 and September 2011 in our department in Marseille. As some patients are still blinded in trials, the exact number of patient under ipi is unknown. We present a minimal percentage (&gt;%) assuming that the 120 patients received ipi. Results: A total of 120 patients were treated: 76 stages IV MM, from which 16 in the BMS clinical trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3 or 10mg/kg IV dosage, while stages III MM were randomly assigned to receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12 patients (&gt;10%): 2/76 patients with stage IV MM (&gt;2. 6 %) and 10/44 patients with stage III MM (&gt;22.7). Diagnosis was performed at the 1st, 3rd and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients (33.3%). Clinical symptoms included headaches (n=11; 91.6%), asthenia (n=7; 58.3%) and decreased libido (n=2; 1.6%). Adrenal, thyroidal and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7 patients (58.3%). MRI changes were observed in 7 patients (58.3%): pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids supplementation was required in 11 patients and thyroidian supplementation in 4 patients. Clinical symptoms regressed within one week in 8 patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only if clinicians are aware of these unspecific signs. Only MRI can make diagnosis in some patients without clinical and/or biological signs. Our data suggest that it develops especially for 10mg/kg dosage, after the third administration, and that the rate could be higher in patients with a normal immune system (adjuvant treatment), than in metastatic ones. Hormonal supplementation usually controls the disease.

Abstract 5687: Development of glutathione pegylated liposomal doxorubicin (2B3-101) for the treatment of brain cancer

Abstract Treatment options for brain cancer are limited and overall prognoses are poor. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is essentially based on the already marketed pegylated liposomal doxorubicin (Doxil), with an additional glutathione (GSH) coating to safely enhance delivery across the blood-brain barrier. In a GLP safety study 2B3-101 was administered by intravenous bolus injection on days 1, 15 and 29 to Wistar rats at 1.75, 3.5 and 7 mg/kg. Doxil (7 mg/kg), empty GSH-PEG-liposomes, and vehicle were included, resulting in 6 groups (10 animals/sex/group). Additional animals were allowed 4 weeks of recovery or were used for toxicokinetic analysis. From observations during the in-life part of the study, as well as after histopathological investigations, no major differences were noted between 2B3-101 and Doxil at 7 mg/kg q14dx3. No treatment-related changes in the brain were observed neither after repeated 2B3-101 exposure, nor after treatment with empty GSH-PEG liposomes. In addition, 2B3-101 did not result in doxorubicin-related toxicity in heart tissue. After 1st and 3rd administration of 7 mg/kg, plasma AUC values were 10-44% higher for Doxil when compared to 2B3-101, while C0 values were considered similar for both drug substances. Apparent half-lives for Doxil were 36.1 and 32.6 hours in males and females after the 3rd administration, respectively. For 2B3-101 these values were slightly shorter at 30.0 and 28.8 hours in males and females, respectively. The doxorubicin brain/plasma ratio showed retention of both 2B3-101 and Doxil after repeated doses, where 2B3-101 resulted in significantly higher doxorubicin retention in the brain 2 weeks after the 3rd administration (p&amp;lt;0.02). A modified Irwin test in male Wistar rats (n=8 per group) showed no neurobehavioral effects and no effects of 2B3-101 on body temperature after administration of 1.75 mg/kg, 3.5 mg/kg and 7 mg/kg. Also, empty GSH-PEG liposomes and Doxil did not result in neurobehavioral effects and effects on body temperature. Efficacy of GMP grade 2B3-101 at the maximum tolerated dose was confirmed in mice with intracranial U87 xenografts; compared to saline 10 mg/kg q4dx4 and 18 mg/kg q8dx2 showed a survival benefit of up to 60%, where 18 mg/kg q8dx2 seemed superior. In addition, in mice carrying subcutaneous MDA-MB-231 xenografts it was shown that 10 mg/kg q4dx3 2B3-101 and Doxil both produced significant anti-tumor activity, were well tolerated, and gave similar weight loss profiles. In conclusion, the therapeutic benefit and predictable safety profile of clinical-scale 2B3-101 was successfully demonstrated in preclinical studies. A clinical trial to determine the safety, tolerability and pharmacokinetics of 2B3-101 in patients with solid tumors and brain metastases or recurrent malignant glioma was initiated in June 2011. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5687. doi:1538-7445.AM2012-5687

Immunological evaluation of personalized peptide vaccination in refractory small cell lung cancer

Since the prognosis of small cell lung cancer (SCLC) remains poor, development of new therapeutic approaches, including immunotherapies, would be desirable. In the current study, to evaluate immunological responses in refractory SCLC patients, we conducted a small scale phase II clinical trial of personalized peptide vaccination (PPV), in which vaccine antigens are selected based on pre-existing host immunity. Ten refractory SCLC patients, who had failed to respond to chemo- and/or chemoradiotherapies (median number of regimens, 2.5; median duration, 20.5 months), were enrolled. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher antigen-specific humoral responses were subcutaneously administered (weekly for six consecutive weeks and then bi-weekly thereafter). PPV was terminated before the 3rd administration in four patients because of rapid disease progression, whereas the remaining six patients completed at least one cycle (six times) of vaccinations. Peptide-specific immunological boosting was observed in all of the six patients at the end of the first cycle of vaccinations, with their survival time of 25, 24.5 (alive), 10 (alive), 9.5, 6.5, and 6 months. Number of previous chemotherapy regimens and frequency of CD3(+) CD26(+) cells in peripheral blood were potentially prognostic in the vaccinated patients (hazard ratio [HR] = 2.540, 95% confidence interval [CI] = 1.188-5.431, P = 0.016; HR = 0.941, 95% CI = 0.878-1.008, P = 0.084; respectively). Based on the feasible immune responses in refractory SCLC patients who received at least one cycle (six times) of vaccinations, PPV could be recommended for a next stage of larger-scale, prospective clinical trials.

Robust thermoregulatory overcompensation, rather than tolerance, develops with serial administrations of 70% nitrous oxide to rats

Changes in typical whole-animal dependent variables following drug administration represent an integral of the drug's pharmacological effect, the individual's autonomic and behavioral responses to the resulting disturbance, and many other influences. An archetypical example is core temperature ( T c ), long used for quantifying initial drug sensitivity and tolerance acquisition over repeated drug administrations. Our previous work suggested that rats differing in initial sensitivity to nitrous oxide (N 2O)-induced hypothermia would exhibit different patterns of tolerance development across N 2O administrations. Specifically, we hypothesized that rats with an initially insensitive phenotype would subsequently develop regulatory overcompensation that would mediate an allostatic hyperthermic state, whereas rats with an initially sensitive phenotype would subsequently compensate to a homeostatic normothermic state. To preclude confounding due to handling and invasive procedures, a valid test of this prediction required non-invasive thermal measurements via implanted telemetric temperature sensors, combined direct and indirect calorimetry, and automated drug delivery to enable repeatable steady-state dosing. We screened 237 adult rats for initial sensitivity to 70% N 2O-induced hypothermia. Thirty highly sensitive rats that exhibited marked hypothermia when screened and 30 highly insensitive rats that initially exhibited minimal hypothermia were randomized to three groups ( n=10 each/group) that received: (1) twelve 90-min exposures to 70% N 2O using a classical conditioning procedure, (2) twelve 90-min exposures to 70% N 2O using a random control procedure for conditioning, or (3) a no-drug control group that received custom-made air. Metabolic heat production (via indirect calorimetry), body heat loss (via direct calorimetry) and T c (via telemetry) were simultaneously quantified during N 2O and control gas administrations. Initially insensitive rats rapidly acquired (3rd administration) a significant allostatic hyperthermic phenotype during N 2O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N 2O inhalation in the 4th and 5th sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11th and 12th N 2O administrations. The major mechanism for hyperthermia was a brisk increase in metabolic heat production. However, we obtained no evidence for classical conditioning of thermal responses. We conclude that the degree of initial sensitivity to N 2O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N 2O administrations, but that initially insensitive and sensitive animals eventually converge to similar (and substantial) magnitudes of within-administration hyperthermia mediated by hyper-compensatory heat production.

Urban (re-) organization in Late Roman Palestine and the early Rabbinic guild: The Tosefta on the city and classification of space

Over the latter half of the 2nd century and into the 3rd century, urban institutions and administration figured ever more prominently in the organization and governance of Roman Palestine. In this context, the consolidation of the earliest guild of rabbinic masters took hold, and their Mishnah and its supplement, Tosefta, were composed. When compared with correlative passages in the more utopic Mishnah, traditions in Tosefta show decidedly greater interest in the urban setting and its constituent institutions as the territory for meaningful, ordered, human activity. Tosefta superimposes over Mishnah's utopic mapping of a world centred on one city, an "ideal" Jerusalem, a complementary mapping in which meaningful human action and interaction is centred upon one's "local city." In this respect, one might characterize Tosefta as "diasporizing" Mishnah's mapping of an ideal world centred upon a single Temple-city.

A Comparison Between Methadone and Buprenorphine of Curative effect on Human of Heroin Dependence

目的 对比研究美沙酮口服液和丁丙诺啡对海洛因依赖者替代疗效,评价脱瘾效果.方法 采用随机分组将120病例分为美沙酮组80人和丁丙诺啡组40人,两组分别设置递减法给药方案,单盲法进行1疗程10次脱瘾治疗,以自编21项戒断症状观察积分表(ows)记录症状变化,以t检验比较2组OWS得分.结果 美沙酮治疗组0WS得分(7.01±6.26～21.40±10.57)比丁丙诺啡组得分(12.25±10.26～32.79±11.97)变化小;在治疗初期(第2、3次给药)得分低于丁丙诺啡组,P＜0.01,有极显著性差异;治疗后期(第9次给药)得分也低于丁丙诺啡组,P＜0.05,有显著性差异;治疗中期(第4～8次给药)2组0WS积分差异则无显著性差异,p＞0.05;此外2组在OWS量表中主要症状出现率也有一定差异.结论 美沙酮口服液替代法在剂量调整,快速缓解戒断症状,停药反应等方面优于丁丙诺啡替代法。

Amylinergic control of food intake

Amylin is a pancreatic B-cell hormone that plays an important role in the regulation of nutrient fluxes. As such, amylin reduces food intake in laboratory animals and man, slows gastric emptying and it reduces postprandial glucagon secretion. Amylin deficiency which occurs concomitantly to insulin deficiency in diabetes mellitus, may therefore contribute to some of the major derangements associated with this disorder (hyperphagia, excessive glucagon secretion, accelerated rate of gastric emptying). The described actions of amylin all seem to depend on a direct effect of amylin on the area postrema (AP). As to amylin's satiating effect, the physiological relevance of this action is underlined by studies involving specific amylin antagonists and amylin-deficient mice. In the AP, amylin seems to modulate the anorectic signal elicited by CCK. Subsequent to AP activation, the amylin signal is conveyed to the forebrain via distinct relay stations. Within the lateral hypothalamic area, amylin diminishes the expression of orexigenic neuropeptides such as orexin and MCH. Whether these effects contribute to amylin's short term satiating action remains to be determined. Recent studies suggest that amylin may also play a role as a long-term, lipostatic signal, especially when other feedback systems to the brain are deficient. Obese, leptin-resistant Zucker rats which are hyperinsulinemic and hyperamylinemic, were chronically infused with the amylin antagonist AC 187. AC 187 significantly elevated food intake in obese Zucker rats while having no effect in lean controls. This indicates that at least under certain conditions, chronic blockade of endogenous amylin action may lead to an increase in food intake and/or body weight. As mentioned, the site and mechanism of action for peripheral amylin to reduce food intake seems to be well established. It is less clear how centrally administered amylin reduces food intake although it is well known that 3rd ventricular administration of amylin produces a very strong and long-lasting anorectic action. Amylin receptors have been described in various hypothalamic nuclei but the endogenous ligand of these receptors remains to be investigated. The same holds true as to the physiological relevance of the anorectic effect seen after central amylin administration.