How to Manage the Initiation of Apomorphine Therapy Without Antiemetic Pretreatment: A Review of the Literature

Introduction Pretreatment with the antiemetic trimethobenzamide has been recommended practice in the United States (US) to address the risk of nausea and vomiting during initiation of apomorphine treatment. However, trimethobenzamide is no longer being manufactured in the US, and despite the recent update to the US prescribing information, there may be uncertainty regarding how to initiate apomorphine. Methods To better understand why antiemetic pretreatment was recommended and if it is necessary when initiating apomorphine therapy, we performed a literature review of subcutaneous apomorphine therapy initiation with and without antiemetic pretreatment in patients with PD. Results Three studies were identified as providing relevant information on antiemetic prophylaxis with initiation of injectable apomorphine. The first study demonstrated that nausea was significantly more common in patients who received 3-days of trimethobenzamide pretreatment compared with those who did not, while the primary endpoint of second study found no significant effect on the binary incidence of nausea and/or vomiting on Day 1 of apomorphine treatment. In the third study, which used a slow titration scheme for apomorphine, transient nausea was reported in just 23.1% of the antiemetic nonusers. Conclusions Based on the reviewed trials and our clinical experience, we suggest that subcutaneous apomorphine therapy can be initiated using a slow titration scheme without antiemetic pretreatment

Integrated Active Fire Retrievals and Biomass Burning Emissions Using Complementary Near-Coincident Ground, Airborne and Spaceborne Sensor Data

Ground, airborne and spaceborne data were collected for a 450 ha prescribed fire implemented on 18 October 2011 at the Henry W. Coe State Park in California. The integration of various data elements allowed near coincident active fire retrievals to be estimated. The Autonomous Modular Sensor-Wildfire (AMS) airborne multispectral imaging system was used as a bridge between ground and spaceborne data sets providing high quality reference information to support satellite fire retrieval error analyses and fire emissions estimates. We found excellent agreement between peak fire radiant heat flux data (less than 1% error) derived from near-coincident ground radiometers and AMS. Both MODIS and GOES imager active fire products were negatively influenced by the presence of thick smoke, which was misclassified as cloud by their algorithms, leading to the omission of fire pixels beneath the smoke, and resulting in the underestimation of their retrieved fire radiative power (FRP) values for the burn plot, compared to the reference airborne data. Agreement between airborne and spaceborne FRP data improved significantly after correction for omission errors and atmospheric attenuation, resulting in as low as 5 difference between AquaMODIS and AMS. Use of in situ fuel and fire energy estimates in combination with a collection of AMS, MODIS, and GOES FRP retrievals provided a fuel consumption factor of 0.261 kg per MJ, total energy release of 14.5 x 10(exp 6) MJ, and total fuel consumption of 3.8 x 10(exp 6) kg. Fire emissions were calculated using two separate techniques, resulting in as low as 15 difference for various specie

Consensus of German Transplant Centers on Hematopoietic Stem Cell Transplantation in Fanconi Anemia

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative therapy for the severe hematopoietic complications associated with Fanconi anemia (FA). In Germany, it is estimated that 10–15 transplants are performed annually for FA. However, because FA is a DNA repair disorder, standard conditioning regimens confer a high risk of excessive regimen-related toxicities and mortality, and reduced intensity regimens are linked with graft failure in some FA patients. Moreover, development of graft-versus-host disease is a major contributing factor for secondary solid tumors. The relative rarity of the disorder limits HSCT experience at any single center. Consensus meetings were convened to develop a national approach for HSCT in FA. This manuscript outlines current experience and knowledge about HSCT in FA and, based on this analysis, general recommendations reached at these meetings

Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000

Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457)

Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia

Trials with 2nd generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but associated with risk of Cytokine Release Syndrome (CRS). Instead, we studied use of donor Epstein Barr virus-specific T-cells (EBV CTL) transduced with a 1st generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi- center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric ALL. Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10-4) post-1st SCT, or prophylactically post-2nd SCT. An initial cohort showed poor expansion/persistence. We next investigated EBV-directed vaccination to enhance expansion/persistence. 11 patients were treated. No CRS, neurotoxicity or GVHD was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de-novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Whilst CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range 0-28) days without vaccination compared to 56 (range 0-221) days with vaccination (P=0.06). This study demonstrates feasibility of such multi-center studies and the potential for enhancing persistence with vaccination.Leukemia accepted article preview online, 27 January 2017. doi:10.1038/leu.2017.39

N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson\u27s Disease: Preliminary Clinical and Cell Line Data.

BACKGOUND: The purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine (NAC) in Parkinson\u27s disease (PD). METHODS: The overarching goal of this pilot study was to generate additional data about potentially protective properties of NAC in PD, using an in vitro and in vivo approach. In preparation for the clinical study we performed a cell tissue culture study with human embryonic stem cell (hESC)-derived midbrain dopamine (mDA) neurons that were treated with rotenone as a model for PD. The primary outcome in the cell tissue cultures was the number of cells that survived the insult with the neurotoxin rotenone. In the clinical study, patients continued their standard of care and were randomized to receive either daily NAC or were a waitlist control. Patients were evaluated before and after 3 months of receiving the NAC with DaTscan to measure dopamine transporter (DAT) binding and the Unified Parkinson\u27s Disease Rating Scale (UPDRS) to measure clinical symptoms. RESULTS: The cell line study showed that NAC exposure resulted in significantly more mDA neurons surviving after exposure to rotenone compared to no NAC, consistent with the protective effects of NAC previously observed. The clinical study showed significantly increased DAT binding in the caudate and putamen (mean increase ranging from 4.4% to 7.8%; p CONCLUSIONS: The results of this preliminary study demonstrate for the first time a potential direct effect of NAC on the dopamine system in PD patients, and this observation may be associated with positive clinical effects. A large-scale clinical trial to test the therapeutic efficacy of NAC in this population and to better elucidate the mechanism of action is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT02445651

How to manage the initiation of apomorphine therapy without antiemetic pretreatment: A review of the literature

Introduction: Pretreatment with the antiemetic trimethobenzamide has been recommended practice in the United States (US) to address the risk of nausea and vomiting during initiation of apomorphine treatment. However, trimethobenzamide is no longer being manufactured in the US, and despite the recent update to the US prescribing information, there may be uncertainty regarding how to initiate apomorphine. Methods: To better understand why antiemetic pretreatment was recommended and if it is necessary when initiating apomorphine therapy, we performed a literature review of subcutaneous apomorphine therapy initiation with and without antiemetic pretreatment in patients with PD. Results: Three studies were identified as providing relevant information on antiemetic prophylaxis with initiation of injectable apomorphine. The first study demonstrated that nausea was significantly more common in patients who received 3-days of trimethobenzamide pretreatment compared with those who did not, while the primary endpoint of second study found no significant effect on the binary incidence of nausea and/or vomiting on Day 1 of apomorphine treatment. In the third study, which used a slow titration scheme for apomorphine, transient nausea was reported in just 23.1% of the antiemetic nonusers. Conclusions: Based on the reviewed trials and our clinical experience, we suggest that subcutaneous apomorphine therapy can be initiated using a slow titration scheme without antiemetic pretreatment