Higher Initial Dose Research Articles

Hybrid Thrombolysis for Left Ventricular Assist Device Thrombosis

LVAD thrombolysis can be effective but carries a bleeding risk. Existing data suggest intraventricular (vs peripheral) delivery may reduce bleeding, but is associated with early recurrence. We have developed a novel hybrid thrombolytic approach (hTL) using an initial high dose LV delivery of alteplase followed by a maintenance LV infusion. We studied all patients with durable LVAD pump thrombosis (PT) treated with hTL in our institution between 1/2015 and 9/2019. We report the technique, procedural success and complications. We identified 10 patients with median (IQR) age 56 years (50, 64 years). All had undergone Heartware HVAD implantation. Duration of LVAD support preceding PT was 518 days (172, 920 days). All patients had significant increases in power and haemolysis markers, and were treated initially with heparin and tirofiban (n=9) or heparin alone (n=1). Time to hTL was 3 days (2, 5 days). hTL was done in the cardiac catheterisation laboratory after informed consent. Heparin and tirofiban were stopped in advance. An arterial sheath was placed in a femoral (n=5) or radial (n=5) artery. A pigtail catheter was advanced to the LV under fluoroscopic guidance. Alteplase was infused at 1mg/min and stopped when LVAD power returned to baseline. The pigtail catheter was left in situ, and the alteplase maintenance infusion continued at 1mg/hour to a weight-adjusted maximum. The sheath and catheter were then removed. Median total alteplase dose was 74mg (48, 90mg). There was acute normalisation of pump power in 8 patients, and 6 remained free of thrombosis at 1 year. Among these 6, 3 were bridged to transplant and 3 continue on LVAD support. In the 2 patients with recurrent thrombus (at days 8 and 37), 1 was managed with inotropes and urgent transplant, and 1 died. In the 2 acute non-responders, 1 went for urgent pump exchange and 1 died. There was no procedure-related bleeding or death. Two patients had vascular access site haematoma (both femoral access), and a further 3 patients had minor bleeding not requiring intervention. Three patients developed acute kidney injury probably related to haemolysis. We report a hTL protocol for LVAD thrombosis with 80% initial success, low rate of recurrent thrombosis, and no major bleeding. Interpretation is limited by small group size and retrospective design. These outcomes require comparison with other approaches, ultimately in a randomised trial.

Treatment with Depot Leuprolide Acetate in Girls with Idiopathic Precocious Puberty: What Parameter should be Used in Deciding on the Initial Dose?

Objective:Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose.Methods:Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ≥2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate.Results:Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001).Conclusion:Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ≥36 kg or BMI-SDS ≥1.6 for effective suppression of the HPG axis.

Naloxone dosing in the era of ultra-potent opioid overdoses: a systematic review.

Evaluate the relationship between naloxone dose (initial and cumulative) and opioid toxicity reversal and adverse events in undifferentiated and presumed fentanyl/ultra-potent opioid overdoses. We searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings (1972 to 2018). We included interventional, observational, and case studies/series reporting on naloxone dose and opioid toxicity reversal or adverse events in people >12 years old. A total of 174 studies (110 case reports/series, 57 observational, 7 interventional) with 26,660 subjects (median age 35 years; 74% male). Heterogeneity precluded meta-analysis. Where reported, we abstracted naloxone dose and proportion of patients with toxicity reversal. Among patients with presumed exposure to fentanyl/ultra-potent opioids, 56.9% (617/1,085) responded to an initial naloxone dose ≤0.4 mg compared with 80.2% (170/212) of heroin users, and 30.4% (7/23) responded to an initial naloxone dose >0.4 mg compared with 59.1% (1,434/2,428) of heroin users. Among patients who responded, median cumulative naloxone doses were higher for presumed fentanyl/ultra-potent opioids than heroin overdoses in North America, both before 2015 (fentanyl/ultra-potent opioids: 1.8 mg [interquartile interval {IQI}, 1.0, 4.0]; heroin: 0.8 mg [IQI, 0.4, 0.8]) and after 2015 (fentanyl/ultra-potent opioids: 3.4 mg [IQI, 3.0, 4.1]); heroin: 2 mg [IQI, 1.4, 2.0]). Where adverse events were reported, 11% (490/4,414) of subjects experienced withdrawal. Variable reporting, heterogeneity and poor-quality studies limit conclusions. Practitioners have used higher initial doses, and in some cases higher cumulative naloxone doses to reverse toxicity due to presumed fentanyl/ultra-potent opioid exposure compared with other opioids. High-quality comparative naloxone dosing studies assessing effectiveness and safety are needed.

EVALUATION OF PROTOCOLS FOR RUSH SUBCUTANEOUS IMMUNOTHERAPY WITH STANDARDIZED HOUSE DUST MITE EXTRACTS

Widely accepted loading protocols for rush subcutaneous immunotherapy (rSCIT) have not been established. Our aim was to evaluate the loading protocols of rSCIT. In the low initial dose group (33 patients), the initial dose of standardized house dust mite extract was 1 JAU or less. The target dose at the end of the rush build-up phase was 500 JAU. Next, the initial dose was increased to 10 JAU with the same target dose in the high initial dose group (18 patients). Furthermore, in the modified high initial dosage group (17 patients), the initial dose was 10 JAU but the target dose at the end of the rush phase was 300 JAU. Then, the maintenance dose of 500 JAU was administered at 9 or 10 days after rSCIT initiation. We retrospectively evaluated these protocols. A systemic reaction (SR) occurred in 28 out of 33 (84.8%) patients in the low initial dosage group and in 12 out of 18 (66.7%) patients in the high initial dosage group, on the other hand significantly reduced in 4 out of 17 (23.5%) patients in the modified high-dosage group. The amount of antigen reached 339.3±19.0 JAU in the low initial dosage group and 358.3±24.9 JAU in the high initial dosage group at the end of the rush phase, significantly increased 452.9±20.6 JAU in the modified high-dosage group at 9 or 10 days. In rSCIT using standardized house dust mite extract, lowering the target dose at the end of the rush phase and delaying the administration of the maintenance dose may reduce SR and increase the reached amount of antigen.

Infection-related hospitalization after intensive immunosuppressive therapy among lupus nephritis and ANCA glomerulonephritis patients

Introduction This study aimed to investigate the clinical characteristics, risk factors, and outcomes of infection-related hospitalization (IRH) in patients with lupus nephritis (LN) and ANCA glomerulonephritis after intensive immunosuppressive therapy. Methods Patients diagnosed with LN or ANCA glomerulonephritis who received intensive immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from 2005 to 2014 were enrolled. Demographics, laboratory parameters, immunosuppressive agents, and IRH details were collected. Multivariable Cox regression was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. Results Totally, 872 patients with 806 LN and 66 ANCA glomerulonephritis were enrolled, and 304 (34.9%) patients with 433 episodes of IRH were recorded. ANCA glomerulonephritis patients were more vulnerable to IRH than LN patients (53.0% vs. 33.4%, p = .001). Multivariable Cox regression analysis showed that ANCA glomerulonephritis (HR = 1.62, 95% CI: 1.06–2.49, p = .027), diabetes (HR = 1.82, 95% CI: 1.03–3.22, p = .039) and a higher initial dose of prednisone (HR = 1.01, 95% CI: 1.00–1.02, p = .013) were associated with a higher likelihood of IRH. Higher albumin (HR = 0.96, 95% CI: 0.94–0.98, p < .001), globulin (HR = 0.98, 95% CI: 0.96–0.99, p = .008), and eGFR (HR = 0.99, 95% CI: 0.99–1.00, p < .001), were associated with a lower likelihood of IRH. The rates of transfer to ICU and mortality for ANCA glomerulonephritis patients were higher than those for LN patients (22.9% vs. 1.9%, p < .001, and 20.0% vs. 0.7%, p < .001, respectively). Conclusions ANCA glomerulonephritis patients had a higher risk of IRH and poorer outcome once infected after intensive immunosuppressive therapy than LN patients. More strict control for infection risks is required for ANCA glomerulonephritis patients who undergo intensive immunosuppressive therapy.

Linezolid for the treatment of extensively drug-resistant tuberculosis: a systematic review and meta-analysis.

SETTING: Studies have shown that linezolid (LZD) can be used to treat extensively drug-resistant tuberculosis (XDR-TB).OBJECTIVE: To conduct a systematic review and meta-analysis to assess existing evidence concerning efficacy and safety of LZD for XDR-TB treatment.DESIGN: The MEDLINE@OVID, PubMed, EMBASE, the Cochrane Library, Clinical Trials, Sinomed, CMCI, CNKI, VIP and Wanfang databases were systematically searched for randomised controlled trials, cohort studies, case series or case reports on XDR-TB patients treated with LZD from January 2000 to December 2016. Summary estimates of the rate of sputum culture conversion, treatment success and adverse effects were calculated; data that could not be combined were summarised and described qualitatively. The combined results were examined for heterogeneity, sensitivity and publishing bias.RESULTS: Twenty-two original studies covering a total of 302 patients with XDR-TB fulfilled the inclusion criteria. Pooled estimates for sputum culture conversion and treatment success rates were respectively 93.2% and 67.4% in XDR-TB patients on LZD treatment. The pooled estimates for the rate of myelosuppression, peripheral neuropathy, optic neuritis and adverse reactions of the gastrointestinal tract were respectively 42.5%, 26.0%, 19.0% and 35.0%. Heterogeneity was mostly due to the initial dose of LZD (≤600 mg/d or >600 mg/d), as patients with a high initial dose of LZD were more likely to have myelosuppression (48.4% vs. 24.8%, P = 0.010) and adverse events of the gastrointestinal tract (41.3% vs.15.4%, P = 0.100).CONCLUSION: LZD appears to be effective for XDR-TB, but adverse events are common. An LZD dose of ≤600 mg/d as the initial dose for treating XDR-TB patients is recommended.

Nehézfém- és egyéb toxikus mikroelem-terhelés tartamhatása a főtermés mennyiségére szabadföldi kísérletben

Összefoglalás Dolgozatunkban a Kádár Imre által 1991 tavaszán meszes csernozjom talajon 13 potenciálisan toxikus mikro-/károselem (Al, As, Ba, Cd, Cr, Cu, Hg, Mo, Ni, Pb, Se, Sr és Zn) 0-90-270-810 kg ha−1 szintjeivel beállított szabadföldi tartamkísérlet 1-20. évi főtermés veszteség eredményeit értékeljük. Első megközelítésben, a főtermések relatív termésben kifejezett százalékos terméscsökkenéseit az egyes elemek átlagos fitoxicitása sorrendjében mutattuk be. A 90-270-810 kg ha−1 kezelések átlagában az egyes elemek fitotoxicitása az alábbi sorrendben csökkent: Se &gt; Cr &gt; Cd &gt; Al &gt; Pb &gt; As &gt; Mo &gt; Hg &gt; Cu &gt; Ni &gt; Zn &gt; Ba &gt; Sr. A legkisebb – a kontroll %-ában kifejezett - relatív terméseket, azaz a legnagyobb fitotoxikus hatást a Se, a Cr és a Cd mutattak, míg legkevésbé fitotoxikusnak a Ni, a Zn, a Ba és a Sr bizonyultak. A fitotoxikus évek számát illetően az elemek sorrendje az alábbiak szerint alakult: Se = As &gt; Cr &gt; Cd &gt; Hg &gt; Cu = Zn &gt; Al = Mo &gt; Ni = Pb &gt; Ba = Sr. Legtöbb évben a Se, az As, a Cr és a Cd, míg legkevesebb évben a Ni, a Pb, a Ba és a Sr voltak fitotoxikusak. Átlagos terméscsökkentő hatásukat tekintve a Se, a Cr és a Cd már a 90 kg ha−1 adagtól, a Pb és a Hg a 270 kg ha−1 adagtól, míg az As és a Mo a legnagyobb, 810 kg ha−1 adagtól/adagnál mutatott 10%-nál nagyobb terméscsökkenést a fitotoxikus évek átlagában. Mind a fitotoxikusság mértéke, mind a fitotoxikus évek száma tekintetében, általában, a legnagyobb növényi károsodások az anionos formában kijuttatott elemekhez voltak köthetők, ezen belül is, főleg a nem esszenciális mikroelemekhez. Második megközelítésben, a fitotoxicitás mértékét a kísérleti növények, ill a kísérlet beállítása óta eltelt idő függvényében is nyomon követtük. A kísérleti növények közül legnagyobb terméscsökkenéseket a napraforgó, a spenót és az őszi árpa, míg legkisebbeket a harmadik, a második és az első éves lucerna növényekben kaptunk. Az idő múlásával egyre kisebb terméscsökkenéseket tapasztaltunk, a kísérlet 13. évétől kezdve az átlagos fitotoxicitás mértéke még a 10%-ot sem érte el. Megkülönböztetett figyelemmel kell nyomon kísérni a kadmiumot, amely az idő múlásával egyre kevésbé volt fitotoxikus, viszont még a kísérlet 18. évében is igen nagy könnyen oldható elemtartalmakat mutatott a talaj szántott rétegében.

Serum Metabolomic Profiling Correlated with ISS and Clinical Outcome for Multiple Myeloma Patients Treated with High Dose Melphalan and Autologous Stem Cell Transplantation

Background. The prognosis in multiple myeloma (MM) has improved significantly in the last two decades. However, the outcome after initial high dose melphalan followed by autologous stem cell infusion (ASCT) is very diverse and prognostic markers, based on techniques such as FISH and next generation sequencing have been proposed. Metabolomics, where low molecular weight molecules are detected in body fluids or tissues, is an emerging technique used for diagnostics and prognosis in different cancers. Indeed, as the metabolome is the final down-stream product of the metabolic processes in the organism, it could be highly representative of a disease phenotype. In this study we wanted to examine the metabolomic profile in MM patients treated with ASCT, using nuclear magnetic resonance (NMR) spectroscopy, with the primary aim to determine if possible differences could be correlated to clinical outcome. Patients. MM patients from two Swedish regions, Skåne and Västra Götaland, diagnosed from Jan 2006 to Dec 2016 were identified using the Swedish National Myeloma Registry and ASCT lists from the Sahlgrenska and Lund University Hospitals. Patients with stored serum in the Swedish National Myeloma Biobank, from the time of diagnosis (and pre-treatment), who underwent ASCT as part of the first line therapy were included. A total of 201 patients were included. Clinical data, such as ISS, paraprotein type, high risk cytogenetics, induction therapy, response, progression-free survival (PFS) and overall survival (OS) were obtained from the Swedish National Myeloma Registry or from medical records. Last follow-up was Feb 2019. Methods. Serum samples were analyzed using a 600 MHz 1H NMR spectrometer equipped with a 5 mm BBI room temperature probe. After the 1H NMR data acquisition, peak picking, alignment and integration of the 1D CPMG data was performed in R with an in-house developed script using the speaq-package. The integrated peak data was analyzed using multivariate statistics in SIMCA 14. Principal component analysis was used to check for outliers, followed by discriminant analysis using orthogonal projections to latent structures - discriminant analysis (OPLS-DA) to discriminate between patients with differences in ISS stage and paraprotein type. The validity of the models was judged from R2 and Q2 values compared to permutation tests. Results. As expected, PFS after ASCT differed significantly between the ISS groups. We found that patients with ISS stage III had a significantly different metabolomic profile than stage I patients (Fig 1). Among the most discriminating metabolites were e.g. the amino acids valine, alanine, glutamine and leucine which were higher in the ISS I group. Interestingly, stage I patients had a totally different lipid profile: they had significantly higher levels of apolipoproteins A1 and A2, the total cholesterol level and in most HDL and LDL main fractions compared to stage III patients. Furthermore, IgA patients had a different metabolomic profile compared with IgG patients (Fig 2), where e.g. the level of N-acetylated amino acids were higher in IgA patients. We found no metabolomic correlation with gender, response or high risk cytogenetics. Discussion. We found in this study that the serum metabolomic profile at diagnosis differed in ASCT-treated MM patients with low and high ISS stage. We also found different patterns in patients with IgA vs IgG myeloma. A certain metabolomic pattern could reflect a more aggressive disease and also give potential information on different host factors important for the course of the disease. Together, these findings could form a base for future metabolomic studies of the biology of MM. Figure 1 Disclosures Mellqvist: Amgen, Janssen, Oncopeptides, Sanofi, Sandoz, Takeda: Honoraria.

The Fall Risk with Alpha blockers Given InitiaL dose or Elderly status (FRAGILE) Study.

Background: α-1 adrenergic antagonists are commonly prescribed, but there is question regarding their safety in patients at increased fall risk. Objective: The purpose of the FRAGILE study was to determine the risk for developing adverse drug events (ADEs) in veterans prescribed α-1 blockers. Methods: A single-center, retrospective, observational cohort analysis was conducted of veterans newly initiated on α-1 antagonists. Veterans were categorized into at-risk (patients who met at least 1 of 2 criteria: age 65 or older or high initial dose of α blockade) or control (veterans without either risk factor) groups. The primary outcome was the composite all-cause ADEs, including hospitalizations or emergency department (ED) visits. Secondary outcomes included number of fall-related ADEs and medication discontinuation rates with follow-up for 12 months. Results: A total of 300 veterans were evaluated. There was no significant difference in the composite outcome of all-cause ED visits between at-risk (n = 169) versus control (n = 131) groups (0.81 vs 1.17, P = 0.09) or all-cause hospitalizations (0.28 vs 0.39, P = 0.25). Seventy-three veterans in the at-risk group experienced an all-cause ADE versus 64 in the control group (P = 0.36). No significant differences in secondary outcomes were found. Fall-related side effects occurred in 8% of the total cohort. Conclusion and Relevance: Rates of all-cause or fall-related ADEs were not significantly different. An 8% discontinuation rate resulting from fall-related ADEs and high rates of coadministered medications that could increase fall risk. Pharmacists can play a key role in optimizing α-1 blocker administration.

P2.03-26 Elucidating Mechanisms of Resistance to Targeted Therapies in Mutant EGFR or KRAS Driven Lung Adenocarcinoma Harboring Dual Loss of p53 and RB1

Inactivation of the two canonical tumor suppressors, p53 and RB1, is a genetic hallmark of small-cell lung cancer (SCLC). In contrast, lung adenocarcinomas (LUADs) preferentially harbor alterations in the p16 pathway over RB1. Nonetheless, despite being rare, concurrent loss of p53 and RB1 occurs in a subset of LUADs and this is hypothesized to be necessary for the histological transformation of LUAD to SCLC, observed during treatment with tyrosine kinase inhibitors (TKIs). However, whether the dual loss of p53 and RB1 is sufficient for this histological transformation remains unknown. Furthermore, loss of RB1 in LUADs with EGFR mutations is associated with poor response to TKIs in the absence of SCLC transformation. Here, we aimed to explore how loss of p53/RB1 affects the biology of p16 pathway-altered LUAD, particularly in the context of acquired resistance mechanisms to targeted therapies. Four TP53-mutated LUAD cell lines were used: two EGFR mutation-positive (PC9 and H1975) and two KRAS mutation-positive (H1792 and H358). All these cell lines possess p16 pathway alterations: p16 (CDKN2A) mutations in PC9 and H1975, CDK4 amplification in H1792, and silenced p16 in H358. Inactivation of RB1 was carried out using CRISPR-Cas9 and RB1 knockout monoclonal cells were established. Cell proliferative and clonogenic abilities were assessed. In addition, osimertinib-resistant (PC9 and H1975) and trametinib-resistant (H1792 and H358) cells were generated (initial high dose and/or stepwise dose escalation methods). Acquired resistance mechanisms were evaluated by MSK-IMPACT profiling. Two RB1 knockout clones were established for each cell line. No advantageous effects were observed for proliferative and clonogenic abilities after RB1 knockout. Although loss of p53 and RB1 has been reported to result in lineage shift in prostate cancer through the upregulation of SOX2, deregulation of SOX2 expression was not observed upon RB1 knockout in the TP53-mutant LUAD cells. In addition, although loss of RB1 caused a modest reduction in osimertinib and trametinib sensitivities of H1975 and H358 cells, respectively, no effect was observed in PC9 and H1792 cells. After becoming resistant to osimertinib or trametinib, transformation to SCLC was not observed. Individual resistance mechanisms are currently being assessed by MSK-IMPACT. Dual loss of p53 and RB1 caused no advantageous effects in TP53-mutated and p16 pathway-altered LUAD cells and did not initiate transformation to SCLC as a resistance mechanism to targeted therapies. TP53/RB1 deficiency-related acquired resistance mechanisms to osimertinib or trametinib will be further explored and presented.

Vinca alkaloids, thalidomide and eribulin-induced peripheral neurotoxicity: From pathogenesis to treatment.

Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.

1410Clinical predictors of NT-proBNP response to early initiation of sacubitril/valsartan after hospitalisation for decompensated heart failure: An analysis of the TRANSITION study

Abstract Background NT-proBNP has diagnostic and prognostic value in patients with heart failure (HF). Compared with enalapril, sacubitril/valsartan (S/V) significantly reduced NT-proBNP within 1 week (wk) of administration and reduced HF re-hospitalisation in patients with acute decompensated HF (ADHF) in PIONEER-HF. Identification of predictors of NT-proBNP reduction with S/V could aid prognostication following hospitalisation. Methods TRANSITION (NCT02661217) is an open label study in stabilised ADHF patients with HFrEF that compared S/V initiation pre- versus post-discharge (within 2 wk of discharge). Baseline NT-proBNP was measured at randomisation in both S/V groups (n=950). Clinical predictors of favourable response of NT-proBNP to S/V therapy (defined as reduction to &lt;1000 pg/ml or &gt;30% reduction vs. baseline) were studied at discharge, 4 wk and 10 wk post-randomisation. Results Median NT-proBNP at randomisation was similar in patients with S/V started pre- and post-discharge (1919 vs 1659 pg/ml). In patients receiving S/V in-hospital, NT-proBNP was reduced by 28% at discharge, compared to a 3% reduction in patients receiving optimised standard of care (between group p&lt;0.001). A favorable response was reached in 46% vs 18% patients at discharge, 46% vs 42% at 4 weeks and 51% vs 48% at 10 weeks in pre- vs post-discharge groups. (Figure 1). Predictors of favourable NT-proBNP response to S/V at discharge were hypertension and shorter time from admission to first S/V dose. At 4 wk after randomisation, NT-proBNP was reduced similarly in patients started on S/V pre- and post-discharge. When the two S/V initiation groups were combined, predictors of favorable NT-proBNP response at 4 wk were higher initial dose of S/V (≥49/51 mg b.i.d.), higher baseline levels of NT-proBNP, de novo HF hospitalisation, ACEI/ARB naïve, lower baseline creatinine, no atrial fibrillation (AFib), no prior myocardial infarction (MI). A further reduction in NT-proBNP was seen at 10 wk post-randomisation in patients started on S/V pre- and post-discharge (38% vs 34%, between group p=0.250). Predictors of favourable NT-proBNP response to S/V were similar at 4 wk and 10 wk post-randomisation. Conclusion In-hospital initiation of sacubitril/valsartan shortly after stabilisation was associated with a prompt improvement of NT-proBNP already at discharge, whereas higher baseline levels of NT-proBNP, higher starting dose, absence of AFib and MI history, de novo HF and ACEI/ARB naïve status were associated with favourable NT-proBNP response in the vulnerable phase after discharge. Acknowledgement/Funding The TRANSITION study was funded by Novartis

37. Non-cranial large vessel vasculitis in a 65-year-old woman

IntroductionLarge-vessel vasculitis in older patients is typically associated with giant cell arteritis (GCA) usually presenting with cranial features. GCA can also present with a primarily extra-cranial pattern as large-vessel GCA (LV-GCA).Takayasu arteritis is a large-vessel vasculitis that affects younger females and classically involves the aorta and its major branches. This condition can clinically manifest with claudication of the extremities, impaired peripheral pulsation and systemic symptoms. Features of Takayasu arteritis and LV-GCA can overlap. This case reviews that of a 65-year-old lady with features of non-cranial large-vessel vasculitis and the approach taken to manage her case.Case descriptionA 65-year-old female developed pains affecting the shoulder and forearms over a period of weeks. She additionally noted pins and needles of the affected limbs. Symptoms were worse with use and consistent with claudication. She denied systemic symptoms, headache, visual changes or early morning stiffness.She was referred to the emergency department for assessment. Blood pressure could not be obtained and radial pulses were absent. She was subsequently arranged for further investigation via the vascular team. CT angiogram of the upper limbs demonstrated diffuse significant subclavian and axillary artery stenoses bilaterally with appearances deemed suggestive of underlying vasculitis.She was referred for rheumatological assessment. CRP was 50 and MRA aorta confirmed findings identified on CT scan. Prednisolone was initiated at a dose of 60mg daily for 4 weeks, and was subsequently decreased at an initial rate of 10mg every 2 weeks. Methotrexate was started at a dose of 15mg weekly.Inflammatory markers were noted to improve and CRP decreased to normal range. Despite this, although her paraesthesia resolved, she reported only a modest improvement of her upper limb claudication symptoms.Blood tests were monitored, however shortly after starting methotrexate, ALT significantly increased to 1002 IU/L. Autoimmune and viral hepatitis screen returned negative, US abdomen was suggestive of fatty liver changes but was otherwise unremarkable. Rise in ALT was attributed to methotrexate use and this was stopped, and levels improved. Mycophenolate was thus introduced as an alternative at a dose of 1g BD, but unfortunately resulted in recurrence of raised ALT.At present, she is being managed with prednisolone alone, of which is slowly being reduced. Her case is being additionally reviewed at our local vasculitis centre based at Hammersmith Hospital for consideration of tocilizumab should there be difficulties on steroid reduction.DiscussionTakayasu arteritis is a rare systemic large vessel vasculitis. Incidence is 1-2 per million annually with a female preponderance of 80-90%. Based on ACR classification criteria, the above patient would meet the diagnosis of this condition. Takayasu arteritis would normally be expected for those aged <40 years and has a median onset of 25-30 years. Due to her age, the diagnosis of large vessel vasculitis would be therefore be more consistent with LV- GCA, primarily in the absence of cranial features. Aorta and branch involvement can occur in up to 15% of GCA cases. Histologically, both GCA and Takayasu arteritis share similar findings and cannot be relied upon for diagnostic differentiation. Due to overlap of features, formal diagnostic labelling can be difficult in cases such as the one described.In regards to the management of her case, the general principle was taken of initial high dose prednisolone which has been gradually reduced. Introduction of DMARD therapy was implemented early which would be more typical for Takayasu arteritis rather than GCA. Unfortunately due to deranged ALT attributed initially to methotrexate, and subsequently mycophenolate, she is not currently on any steroid sparing treatment. Studies have demonstrated efficacy of IL-6 inhibition in managing large vessel vasculitis and as mentioned, her case is being reviewed with our local vasculitis centre for consideration of tocilizumab should there be difficulties on prednisolone weaning.Although CRP is now within normal range with treatment, our patient has ongoing claudication symptoms of the upper limbs. It is felt that this is likely due to residual vascular stenotic changes rather than current active vasculitis. As such, following stabilisation of her condition, consideration would be made for vascular surgical intervention in future.Key learning pointsDiagnosis of Takayasu versus giant cell arteritis can present a diagnostic challenge in some older patients due to overlap of typical features. The underlying process of large vessel vasculitis and shared components in both these conditions suggest they are within the same spectrum of disease. We discussed our management approach of high dose prednisolone which would be typically utilised in either diagnosis.In our case, due to drug induced hepatitis from methotrexate and subsequent mycophenolate, current management is with prednisolone alone. In regards to long term steroid sparing therapy, other options including IL-6 inhibition is being considered pending response to current treatment. Vascular surgical intervention for residual stenoses will also be reviewed following stabilisation of underlying inflammation.Conflicts of interestThe authors have declared no conflicts of interest.

RADI-28. UP-FRONT SINGLE SESSION RADIOSURGERY FOR LARGE BRAIN METASTASES - VOLUMETRIC RESPONSES AND OUTCOMES

OBJECTIVE: Patients presenting with large brain metastases (LBM), described in the literature as ≥2.5 cm in maximum diameter or ≥10cm3in volume, pose a management challenge. For patients not compromised by mass effect, corticosteroid therapy followed by SRS allows for efficient, minimal access care that facilitates immediate institution of systemic therapy. METHODS: We performed a volumetric-based analysis in order to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Thirty patients over the age of 18 with systemic cancer and brain metastases (≥2.7cm in greatest diameter or ≥10cm3in volume) who underwent single session SRS were included. Serial tumor volumes, clinical outcomes, and medication requirements were studied. RESULTS: Among 30 patients, 70% of patients had either lung, melanoma, or breast cancer. Median initial tumor size (maximum diameter) was 32mm (range 28–43) and median initial tumor volume was 9.32cm3 (range 1.09–25.31). Median marginal dose was 16Gy (range 12–18). Average percent decrease in tumor volume was 50% on imaging at 4–8 weeks, 60% at 4–6 months, 48% at 6–8 months, and 67% at >8 months compared to initial imaging. Only one patient required a subsequent craniotomy 4 years after SRS for an enlarging cyst which was granulation tissue consistent with radiation effects on pathology. There were no adverse events immediately following SRS. Median corticosteroid use after SRS was 21 days. There was no statistically significant difference in KPS score between treatment day and last follow up, suggesting relative safety and maintenance of function. CONCLUSION: Initial high dose corticosteroid therapy followed by prompt single session SRS is a safe and efficacious method of managing patients with large brain metastases (defined in our study as ≥2.7cm or ≥10cm3), if the clinical condition of the patient is acceptable at presentation.

Abstract 3896: Distinct pharmacokinetics, tissue distribution and CNS penetration of ABI-009 (nab-Sirolimus)

Abstract Background: Activation of the mTOR signaling pathway is frequently observed in multiple types of cancer. The poor solubility and low oral bioavailability of the mTOR inhibitor sirolimus limit its development as an anticancer therapy. ABI-009 (nab-sirolimus) is an injectable nanoparticle form of human albumin-bound sirolimus developed with a proprietary nanoparticle albumin-bound (nab®) technology. Currently, numerous phase 1 and 2 clinical studies are ongoing with ABI-009, including a registrational phase 2 study for the treatment of malignant perivascular epithelioid cell carcinoma (PEComa), and various oncology (bladder cancer, soft-tissue sarcomas, neuroendocrine tumors, colorectal cancer, glioblastoma, and various childhood cancers) as well as in non-oncology indications (pulmonary arterial hypertension (PAH), pediatric epilepsy, and mitochondrial diseases). Several nonclinical studies were conducted to evaluate pharmacokinetics, tissue distribution and in particular, CNS penetration of ABI-009. Methods: Rats were intravenously (IV) administered with a single dose of ABI-009 at 1.7, 9.5, and 17 mg/kg. Blood and organs were collected at 2, 8, 24, 72, and 120 hrs to analyze for sirolimus concentrations. Results: There is a generally linear dose response with sirolimus concentrations in blood, heart, lung, liver, and pancreas following a single dose of IV ABI-009. Sirolimus concentrations in blood and well-perfused organs had high peaks at earlier time points but dropped quickly with time, with the highest concentrations observed in lung. In contrast, sirolimus concentrations in brain rose slowly at first, but maintained at a steady level over time. After 5 days, sirolimus level in the brain was similar to other organs, suggesting substantial and prolonged drug distribution to the brain with ABI-009. Organ/blood ratios of most organs increased with time, with the brain/blood ratios increasing more significantly over time. Higher initial dose of ABI-009 resulted in increased brain/blood ratios. Conclusions: ABI-009 administered IV demonstrated a distinct PK profile compared with oral mTOR inhibitors. The PK of ABI-009 is characterized by higher Cmax and AUC, and rapid tissue distribution. Combined with efficient tumor penetration observed in a xenograft study, results of this study support the potential use of ABI-009 for the treatment of cancers in different organ sites, including lung, brain, liver, and pancreas. These findings also warrant further clinical studies in non-oncology indications including PAH and disorders involving the CNS. Citation Format: Shihe Hou, Anita Schmid, Neil Desai. Distinct pharmacokinetics, tissue distribution and CNS penetration of ABI-009 (nab-Sirolimus) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3896.

LO20: Naloxone dosing for suspected opioid and ultra-potent opioid overdoses: A systematic review

Introduction: Optimizing naloxone dosing in the context of increasing fentanyl and ultra-potent opioid (UPO) prevalence is an important consideration for emergency health care providers. The goal of this systematic review was to evaluate the association between initial and cumulative naloxone doses on effective reversal and adverse events in undifferentiated and fentanyl/UPO overdoses. Methods: We searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings from July to October 2018 and back to 1972. Our search included pertinent indexing terms for UPOs. We included interventional and observational studies reporting on naloxone administration for opioid toxicity reversal in people ≥12 years old. Additionally, we accessed non-traditional evidence sources (case reports and series) given this rapidly changing field. We conducted inclusion screens, data extraction and quality assessments in duplicate. We summarized study characteristics and where reported, analyzed number of patients with clinical response. Response was defined as not receiving further naloxone doses and remaining alive. Results: We included 174 studies (108 case reports and series, 55 observational, 9 interventional) with 26,660 subjects (median age 35.1; 74.2% male). We observed lower response among patients exposed to fentanyl/UPO versus heroin for initial naloxone doses ≤0.4mg (56.8% versus 80.2%) and &amp;gt; 0.4mg (27.0% versus 82.1%). Mean cumulative doses were higher for fentanyl/UPO (2.10 mg, SD 1.80 mg) versus heroin (1.48 mg, SD 1.68 mg) overdoses. In North American studies the median cumulative dose used was higher for fentanyl/UPO versus heroin overdoses. A dose-response curve for fentanyl/UPO studies showed marked variability in doses among responders, indicating heterogeneity. Adverse events reporting was inconsistent; 10% of subjects experienced withdrawal based on studies in which they were reported. Conclusion: This is the first systematic review to summarize proportion of patients with clinical response by naloxone dose provided. While variable reporting, study quality, heterogeneity, and our outcome definitions limit the conclusions we can draw, it appears that higher initial doses and in some cases, higher cumulative naloxone doses were used and may be necessary to reverse toxicity due to fentanyl/UPO compared to other opioids. High-quality prospective studies assessing effectiveness and safety are needed.

An Evaluation of the Incidence of Nephrotoxicity After a Loading Dose of Vancomycin in Patients With Severe Renal Impairment.

Loading doses of vancomycin assist in the rapid achievement of target trough concentrations. Patients with renal dysfunction have been excluded from studies evaluating loading doses. The purpose of this study was to investigate nephrotoxicity related to initial vancomycin dose in patients with severe renal dysfunction. A retrospective cohort study was approved by the Institutional Review Board of a large, academic health system. Adults were included if they received intravenous vancomycin in the emergency department and presented with creatinine clearance < 30mL/min. Chronic dialysis patients were excluded. The primary outcome was incidence of nephrotoxicity after an initial high (>20mg/kg) vs. low (≤20mg/kg) dose of vancomycin. Secondary outcomes included dialysis, vancomycin concentrations, length of stay, in-hospital mortality, and a composite outcome of nephrotoxicity or dialysis. Of the 927 patients included in the analysis, nephrotoxicity occurred in 7.2% and 13.8% of patients in the high- and low-dose groups, respectively (p<0.01). Patients in the high-dose group had a reduced risk of nephrotoxicity (relative risk 0.53; 95% confidence interval 0.35-0.78). The reduction in risk remained after fitting a generalized linear model adjusting for weight, age, sex, initial serum creatinine, diabetes, and chronic kidney disease (relative risk 0.61; 95% confidence interval 0.39-0.93). Limitations of this study include its retrospective design and single-center population. These data suggest that vancomycin loading doses do not increase nephrotoxicity compared with lower doses in patients with severe renal dysfunction. These patients should be included in future studies relating to vancomycin loading doses.

Effect of physostigmine on recovery from septic shock following intra-abdominal infection – Results from a randomized, double-blind, placebo-controlled, monocentric pilot trial (Anticholium® per Se)

PurposeThe cholinergic anti-inflammatory pathway has been shown to be accessible by physostigmine salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. Materials and methodsIn this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The physostigmine group received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. ResultsAdministration of physostigmine salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (−2.37, 95% CI: −5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. ConclusionsTreatment with physostigmine salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. Trial registrationEudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322.

Antiepileptic Drug Use Patterns in Suspect Epileptic Dogs Among Neurology and Emergency Specialists.

This study used a cross-sectional survey designed to inquire about antiepileptic drug (AED) use in newly diagnosed idiopathic epileptic dogs among board-certified emergency and neurology specialists. Results were obtained from 300 completed surveys by 128 board-certified neurologists and 172 board-certified emergency and critical care (ECC) specialists. Case volume was slightly different between groups, with 36% of neurologists and 18% of ECC specialists managing >50 cases of first-time canine seizure patients yearly. The initial AED of choice was similar between the groups, with 66% of neurologists and 64% of ECC specialists using phenobarbital and 16% of neurologists and 26% of ECC specialists using levetiracetam. Although most respondents gave a loading dose of phenobarbital, roughly one-fourth of neurologists did not load the drug versus 6% of ECC specialists. The total loading dose was similar between respondents (16 mg/kg) but varied in administration protocol. Approximately half of neurologists and nearly two-thirds of ECC specialists gave a higher initial dose of levetiracetam than recommended. Almost all the respondents who gave a higher initial dose of levetiracetam used 60 mg/kg IV once. Understanding the common practices in AED use may promote future discussions regarding best practices in the management of canine idiopathic epilepsy.

The efficacy and toxicity of cabazitaxel for treatment of docetaxel-resistant prostate cancer correlating with the initial doses in Japanese patients

BackgroundWe analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC).MethodsWe retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22.5 mg/m2, n = 36) and low (≤20 mg/m2, n = 80) CBZ doses. Factors associated with survival and grade 4 neutropenia were evaluated.ResultsPSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group than in the low-dose group (29 and 14%, P = 0.073). The median PFS time for the all-patient, high- and low-dose groups was 2.8 months (95% confidence interval [CI] 1.9–4.4), 2.1 months (1.2–5.5), and 3.0 months (2.0–4.4), respectively (P = 0.904). The median OS times were 16.3 months (95% CI 9.7–30.9), 30.9 months (11.8–47.4), and 10.2 months (8.6–20), respectively (P = 0.020). In multivariate analyses, PFS was significantly associated with existing bone metastasis at diagnosis (P = 0.005) and OS with PSA > 100 ng/ml (P = 0.007), hemoglobin < 12 g/dl (P = 0.030), and low initial CBZ dose (P = 0.030). Grade 4 neutropenia occurred in 53 patients (45%) and was associated with a low CBZ dose (hazard ratio 0.21, 95% CI 0.08–0.59, P = 0.002).ConclusionsCBZ at a higher initial dose may have similar response rate and response duration, but longer survival duration after treatment with higher toxicity than a lower initial dose for docetaxel-resistant CRPC in Japanese patients.