Academic literature on the topic '85th regiment'

ABSTRACT OBJECTIVES The purpose of this study was to assess the appropriateness of weight-based dosing of continuous intravenous infusion of fentanyl in overweight/obese versus normal-weight children admitted to the pediatric intensive care unit (PICU). METHODS This retrospective, pilot study included 5- to 12-year-old children admitted to the PICU over a 2-year period who received continuous intravenous infusion fentanyl for ≥ 4 days. The overweight/obese group included children with a body mass index (BMI) ≥ 85th percentile, while the control group included children with BMI < 85th percentile. The primary objective was to compare the number of fentanyl continuous intravenous infusion dosage changes required per day to achieve adequate sedation between groups. Secondarily, opioid withdrawal symptoms following the discontinuation of fentanyl and concomitant sedative/analgesic regimens were analyzed between groups. Student t tests and chi-square analyses were performed as appropriate, with an a priori alpha of p≤0.05. RESULTS Sixteen normal-weight and 15 overweight/obese patients with 18 and 16 individual infusions were identified, respectively. No statistical difference was found between groups for the number of dosage changes per day, 0.92 versus 0.69 (p=0.16). Five patients in each group experienced withdrawal (p=0.71). The total number of concomitant bolus doses received was greater in the overweight/obese group but did not reach statistical significance. CONCLUSIONS There was a numerical, but statistically nonsignificant difference in the number of sedative/analgesic bolus doses and dosing changes per day between groups. Larger studies are warranted to determine the optimal dosing strategy for continuous intravenous infusion fentanyl in overweight/obese children.

Abstract Abstract 2278 Poster Board II-255 Obesity has become a pandemic in the US, affecting both children and adults. In the adult population, evidence suggests that obesity has an adverse impact on outcomes of hematopoietic stem cell transplant for various malignancies. We investigated the influence of obesity on children undergoing unrelated cord blood transplant utilizing data from the Cord Blood Transplant Study. To our knowledge, no data exists on the effect obesity has on key prognostic indicators for cord blood transplant for malignant diseases in children. There were 191 patients '18 years of age with malignant diseases prospectively enrolled on a National Heart Lung Blood Institute (NHLBI) sponsored cord blood transplant study between 1999 and 2003. Data set was obtained after signed agreement with the NHLBI and local IRB approval. All patients received myeloablative preparative regimens with either total body irradiation and cyclophosphamide (N=172) or busulfan and melphalan (N=19). In addition, all patients received anti-thymocyte globulin as part of their conditioning regimens. Graft versus host disease (GVHD) prophylaxis included cyclosporine and prednisone. Children were classified into groups according to body mass index (BMI) percentile. Normal weight was defined as BMI between the 5th and 85th percentile, overweight between the 85th and 95th percentile, obesity above 95th percentile for age and gender according to the Center for Disease Control and Prevention (CDC) guidelines. For the overall survival (OS) and disease free survival (DFS), the Cox regression model was used to test the effect of BMI while controlling for age, gender, performance status (<90 versus ≥90), HLA match (≤4/6 versus ≥5/6 HLA match), total nucleated cell count (TNC) per kg infused and CMV status. For neutrophil and platelet engraftment, transplant related mortality (TRM), grade II-IV acute GVHD, and chronic GVHD, competing risks regression analyses were used to test effect of BMI while controlling for other covariates. The median age was 7.59 years (range 2.07 – 17.90) with 113 (59%) male. 160 patients (84%) had a performance status of ≥90. 51 patients (27%) had acute myelogenous leukemia (AML), 109 patients (57%) had acute lymphoblastic leukemia (ALL) and 30 patients (16%) had other malignant diseases. 119 patients (62%) received a cord blood unit matched at 3/6 or 4/6 HLA antigens and 72 patients (38%) received a cord blood unit matched at 5/6 or 6/6 HLA antigens. The median TNC per kg infused was 5.2 × 107/kg (range 0.15-80.9 × 107/kg). Of the 191 total patients who were classified by their BMI percentiles, 117 patients (61%) were normal weight, 35 patients (18%) were overweight and 39 patients (20%) were obese. The two groups were not significantly different in sex distribution (p=0.25), diagnosis (p=0.13), performance status (p=0.91), median TNC received (p=0.49) or CMV status (p=0.47). Obese patients were significantly younger with a median age of 5.7 years compared to 8.9 years in normal weight children (p=0.002). Time to neutrophil and platelet engraftment, TRM, risk of grade II-IV acute GVHD, DFS and OS were not significantly different in overweight or obese patients compared to normal weight patients. There was a trend towards increased risk of chronic GVHD in obese patients (p=0.045) compared to normal weight patients. In conclusion, obesity has no significant effect on multiple outcomes after unrelated cord blood transplant in children with malignant diseases. Disclosures: No relevant conflicts of interest to declare.

521 Background: DPD deficiency is a pharmacogenetic syndrome associated with dose-limiting toxicity to fluoropyrimidines. Oncologists are expected to recognize and diagnose this syndrome, as toxicities could be fatal. Over 40 single nucleotide polymorphisms (SNPs) and deletions have been identified within the DPYD gene. IVS14+1G>A (DPYD*2A) is the most common (40-50%) and best studied of these SNPs. Yet, it showed a median sensitivity of 30% and is absent in Japanese, Korean and African Americans. Overall, the data on DPYD testing is insufficient to provide enough guidance to diagnose DPD deficiency. Herein we describe our experience with germline pharmacogenomics in patients with DPD deficiency. Methods: Between 2011 and 2015, 35 patients with gastrointestinal malignancies were tested for DPYD mutations; 17 were tested after developing toxicities to treatment and 18 were tested prior to treatment. IVS14+1G>A (DPYD*2A) was tested in all patients. DPYD c.85T>C (DPYD*9A), DPYD c.1679T>G (DPYD*13A), DPYD c.-1590T>C, and DPYD c.2846A>T were tested in 24 patients (69%) only. We explored the association between DPYD mutations and fluoropyrimidine-related toxicity using Fisher’s exact test. Results: Median age was 60 years, 43% were male, 80% were Caucasian and 20% were African American. Capecitabine-based regimens (71%) and 5-Fluorouracil-based regimens (29%). 14 out of 35 patients (40%) had DPYD mutations. Grade 3 toxicities were encountered in 64% of patients with DPYD mutation and 48% of patients with no DPYD mutation. In patients who received full dose fluoropyrimidines (57% of patients with DPYD mutation and 81% of patients with no DPYD mutation), DPYD mutations were associated with a significantly higher rate of grade 3 diarrhea (p=0.026). In patients with DPYD mutation, 2 (14%) had DPYD*A2 mutation and 12 (86%) had DPYD*9A mutation. Conclusions: In patients treated with fluoropyrimidines, the rate of grade 3 diarrhea was significantly higher in patients with mutated DPYD gene. Testing for DPYD*2A alone to diagnose DPD deficiency is suboptimal. Testing for other DPYD mutation variants including DPYD*9A provides a more comprehensive approach. These data should further be validated in prospective clinical trials.

Abstract Background Anti-thymocyte globulin (ATG) is used as prophylaxis against graft-versus-host-disease (GVHD). Dosing regimens for ATG are weight-based and largely empiric. An ideal dose of ATG would prevent severe GVHD yet maintain graft-versus-tumor effect and allow for adequate immune reconstitution to prevent severe infections. Previous studies suggest ATG dose reduction from 7.5 mg/kg to 6 mg/kg is associated with decreased risk of infections (Hamadani et al, Blood, 2009), while further decrease to 2.5 mg/kg is associated with a higher risk of GVHD (Mohty et al, Blood 2003). The targets of ATG, recipient T-cells post-cytotoxic therapy and T-cells in the stem cell graft, are not a function of recipient weight. Furthermore, current dosing strategies do not account for patient specific factors. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the first day of ATG administration would interact with the amount of ATG administered to influence transplant outcomes. Methods We retrospectively analyzed 135 patients who received rabbit ATG (Thymoglobulin¨) for GVHD prophylaxis after allo-HCT between 1/1/2005 and 12/31/2013. All dosing was based on recipient weight and changes over the 8 years reflect programmatic changes in dosing strategies. Of these, 24 patients (18%) received 10 mg/kg ATG, 43 patients (32%) received 7.5 mg/kg ATG, and 68 patients (50%) received 5 mg/kg ATG. Additional GVHD prophylaxis included calcineurin inhibitor and methotrexate for ablative conditioning and calcineurin inhibitor and mycophenolate mofetil for reduced intensity conditioning. Disease and treatment-related characteristics are summarized in Table 1. Results The median follow-up from day of transplant was 26.4 months (range 1.1 to 97.3). The 100-day cumulative incidence of grade II-IV acute GVHD was 20%, 13% and 6% in the in 5 mg/kg, 7.5 mg/kg and 10 mg/kg groups, respectively, p = 0.36. The 2-year cumulative incidence of chronic GVHD in the 3 groups was 57%, 58%, and 52%, respectively, p = 0.88. Severity of chronic GVHD, per NIH consensus criteria, was lower with higher doses of ATG (24% vs. 17% vs 0%, respectively, p = 0.026). There was no difference in the 2-year overall survival for patients who received 5 mg/kg, 7.5 mg/kg, or 10 mg/kg (60% vs 51% vs 46%, respectively, p = 0.39). However, infectious complications were significantly higher with higher doses of ATG (1% vs 9% vs 17%, p = 0.026). Similarly, invasive fungal infections increased with higher doses of ATG (0% vs. 0% vs. 8%, p = 0.009). The median total amount of ATG given was 568 mg (range 127.7 to 1342.6). Multivariate analyses using the cox-proportional hazard model showed no significant impact of total amount of ATG (HR= 1.024, p = 0.12) or CIBMTR disease risk (HR= 1.65, p = 0.06) on overall survival. The median peripheral blood ALC on the day of ATG administration was 11.5 x 102/μL (range 0.0 - 58.14). The interaction of total ATG and ALC was a favorable predictor for overall survival (HR= 1.12, p = 0.05). For ALC at the 15th percentile (1.9 x 102/μL), increasing total ATG was associated with higher risk of death. For ALC at the 85th percentile (26.6 x 102/μL), increasing total ATG was associated with lower risk of death (Figure 1). Conclusions Our study validates previous findings that increasing dose of ATG increases risk of infection. Novel findings show that decreasing dose of ATG increases severity of chronic GVHD. In addition, we show the recipient ALC on the day of transplant interacts significantly with the total amount of ATG and influences overall survival. Future studies to optimize ATG dosing based on ALC are warranted to further improve the therapeutic window of ATG. Table 1. Variable 5 mg/kg 7.5 mg/kg 10 mg/kg Regimen Reduced-Intensity 63% 74% 100% Ablative 37% 26% 0% Donor Matched 96% 86% 100% Mismatched 4% 14% 0% Stem Cell Source Peripheral Blood 91% 70% 83% Bone Marrow 9% 30% 17% Primary Disease Acute Leukemia 38% 37% 41% Myeloid Disorder 44% 17% 21% Lymphoid Disorder 17% 23% 38% Other 1% 23% 0% Figure 1. Figure 1. Disclosures Off Label Use: Antithymocyte globulin for prophylaxis for graft-versus-host disease..

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH) is life-threatening disorder of immune dysregulation involving macrophage and T-cell activation resulting in massive cytokine release causing multi-organ dysfunction. Similar release of cytokine products from fat tissue is associated with obesity-related insulin resistance. Our case presentation is an example of HLH and insulin resistance, two conditions with overlapping pathophysiology, occurring simultaneously. Clinical Presentation: A 17-year-old male, with no history of hyperglycemia, underwent renal transplant due dysplastic kidneys. He received 500mg IV methylprednisolone during surgery followed by a prednisone taper starting at 70mg daily. Serum glucoses post-transplant ranged from 97 to 129 mg/dL. Three weeks post-transplant he was admitted for fever and dehydration. BMI on admission was the 85th percentile. Serum glucose was 371 mg/dL without ketosis. He started on insulin therapy, requiring 60 units per day (0.8 units/kg). It was suspected his new-onset diabetes was due to his immunosuppressant regimen (prednisone 50mg daily, tacrolimus) and/or acute illness. With persistent fevers and negative infectious workup, there was concern for HLH. The diagnosed was confirmed with ferritin level of 65,962 ng/mL (27-265), hemoglobin 6.5 gm/dL, platelets 88,000, triglycerides 765 mg/dL, soluble IL-2 receptor 2,717 u/mL (45 - 1,105). For HLH treatment, he received methylprednisolone 800 mg daily x 3 doses. During this time his insulin requirements increased to 188 units per day (3.6 units/kg). He was transitioned to dexamethasone 20mg daily. His insulin requirements increased over the next 72 hours to 388 units per day (5.2 units/kg). He was found to be positive for Ehrlichiosis, a known precipitant of HLH. Doxycycline therapy was initiated for a 14 day course. One week into his doxycycline course his ferritin had decreased to 999 ng/mL. He remained on dexamethasone 20 mg daily but developed severe hypoglycemia to 29 mg/dL with altered mental status. All insulin therapy was held. Fasting glucoses over the next 4 days ranged from 94-154 mg/dL and post-prandial glucoses 116-288 mg/dL. He discharged home with only short acting insulin for glucoses above 250 mg/dL, which he did not require. Case Lessons: Cytokine release from macrophages is implicated in the pathology of both HLH and insulin resistance associated with obesity. Glucocorticoids used to treat HLH can also exacerbate insulin resistance. Providers should be aware of the risk of hyperglycemia and large insulin requirements in patients with HLH, and the potential for rapid reduction of insulin needs as HLH is successfully treated.

The presence of a charge over a company’s property will reduce the likelihood of an unsecured creditor obtaining payment, or at least a substantial dividend, in the insolvency of the company. The prudent unsecured creditor will bear this in mind in assessing whether to advance credit to a company, and at what level. For this reason a system of charges registration has long been employed, initially with a separate scheme for England and Wales and another for Scotland, in order that unsecured creditors can be aware of the presence of charges. This system has recently been revised and simplified and a single scheme now applies in the UK with effect from 6 April 2016. Charges created by UK companies prior to that date remain subject to the previous regime.