Median Initial Dose Research Articles

Radiotherapy as Part of Treatment Strategies in Nasal Cavity and Paranasal Sinus Malignancies.

Modern intensity-modulated radiotherapy (IMRT) is frequently applied to treat patients with nasal cavity and paranasal sinus (NC/PNS) malignancies. One hundred and four patients who underwent radiotherapy (RT) between 1994 and 2020 were recognized. This analysis compared conventional-radiotherapy (CRT) and image-guided IMRT outcomes for NC/PNS malignancies. The median follow-up was 69 months. Eighty-eight patients (85%) were managed with image-guided IMRT. The median initial radiation dose was 65 Gy, with 68 Gy applied for patients treated with primary RT versus 63 Gy applied for adjuvant therapy (p=0.1). The 5-year locoregional control (LRC) was 85%. The locoregional recurrence rate was 18% following IMRT versus 31% in the 2D/3D-conventional RT group (p=0.09). Moreover, IMRT was associated with a lower inner-ear toxicity rate (8% vs. 20%, respectively; p=0.045). IMRT appears to be linked with higher LRC and lower inner-ear acute toxicities compared to conventional RT.

Safety and efficacy outcomes in immune checkpoint inhibitor (ICI)-treated metastatic urothelial carcinoma (mUC) patients (pts) requiring treatment interruption (TI) due to immune-related adverse events (irAEs).

411 Background: Most patients (pts) with metastatic urothelial carcinoma (mUC) will receive immune checkpoint inhibitors (ICI) at some point during treatment. As such, understanding of immune-mediated toxicity is integral to optimal patient management. We describe the clinical characteristics, treatment, and outcomes of ICI-treated mUC pts who experienced irAEs requiring treatment interruption (TI). Methods: ICI-treated mUC pts who developed > grade 2 (per CTCAEv5) irAEs leading to >2 week TI were retrospectively reviewed. Patient-, disease-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per CTCAEv5. Time to treatment interruption (TTI), treatment-free interval (TFI), time to next treatment (TTNT), and duration of response (DoR) were assessed descriptively. Results: Of 200 ICI-treated mUC pts, 18 (9%) experienced irAEs necessitating TI. 12 (43%) were male; median age at diagnosis was 72.5 (range, 45-80); 15 (83%) had KPS > 80. 8 (44%) had pure UC histology, 14 (78%) had prior cystectomy or nephroureterectomy, and 11 (61%) received platinum-based chemotherapy in the perioperative setting. 4 (22%) received 1L platinum-based Tx for mUC. ICI therapy was distributed evenly between atezolizumab (50%, n = 9) and pembrolizumab (50%, n = 9). Median TTI was 6.5 months (mos) (range, 1-19). The most common irAEs were dermatitis (22%, n = 4), colitis (17%, n = 3), and transaminitis (17%, n = 3); the majority were grade 2 (72%, n = 13). No grade 4/5 events occurred. 14 pts (78%) were treated with methylprednisolone and/or prednisone. Median initial prednisone-equivalent steroid dose was 45 mg/day (range, 30-1,250) with a median steroid duration of 42 days (range, 4-198). ICI were held and later re-challenged in 10 pts (56%), permanently discontinued in 7 pts (39%), and transitioned to a subsequent Tx in 1 pt (5%). Of 10 pts re-challenged with ICI, 7 (70%) experienced an irAE upon re-challenge (4 with recurrent irAEs, 3 with new irAEs); ICI was permanently discontinued in 3 of these pts. For pts receiving subsequent Tx, median TFI was 1 month (range, 0-12) and median TTNT was 5 mos (range, 2-31). Median DoR among all pts with initial response to ICI therapy was 15.5 mos (range, 2-52). Of 7 pts who permanently discontinued ICI and received no further Tx, 6 (86%) demonstrated an ongoing sustained therapy response with median DoR of 22.5 mos (range, 12-52). Conclusions: In this cohort, ICI-treated mUC pts who developed irAEs requiring treatment interruption had a high rate of subsequent irAEs upon ICI re-challenge. Importantly, pts who discontinue ICI due to irAE can have durable responses off treatment, consistent with data from other cancers.

Use of Alfentanil in Palliative Care.

Alfentanil is used for chronic pain relief in palliative care. However, there is a dearth of data on its use. For this reason, a decision was made to review the use of alfentanil in palliative care. Retrospective study was carried out in a palliative care service. The files of patients who received alfentanil as an intravenous or subcutaneous continuous infusion for pain relief, between January 2018 and April 2019. In total, 111 patients received alfentanil out of 113 admissions. Of them, 56 were male, and the median age was 70 years. The median number of days on alfentanil was 6 (range 1 to 129). The most frequent primary reasons for switching to alfentanil was uncontrolled pain in 52 (46%) patients and renal impairment in 24 (21%) patients. The median 24-h initial dose of alfentanil was 4 mg (1–20), and the median final 24-h dose of alfentanil was 5 mg (1–60), (p < 0.001). The initial 24-h median number of rescue doses was 2 (0–8), and the final median number of rescue doses was 1 (0 to 8), (p = 0.025). In 56 patients who were on alfentanil for at least 7 days, the dose decreased in 3 (5%), remained stable in 10 (18%) and increased in 43 (77%). The patient on alfentanil for 129 days maintained the same dose throughout that period. Alfentanil can be a useful second-line opioid. The induction of tolerance does not seem to be particularly rapid with alfentanil.

A retrospective, observational study of perampanel in refractory and super-refractory status epilepticus

IntroductionThe outcomes of administration of Perampanel (PER) which is a β-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor antagonist for the treatment of refractory status epilepticus (RSE) and Super-refractory (SRSE) were previously reported in small cohort studies and case reports. We report efficacy and side effect results of an observational cohort of 75 patients treated with PER for RSE and SRSE. MethodsThis was a single-center, retrospective, observational study of patients with RSE admitted to the neurocritical care unit between April 2017 and September 2019 who received treatment with PER. The primary outcome was the occurrence of a definite response to PER, which was defined as clear resolution of the ictal pattern and/or seizures within 72 h of delivery of PER which was the last administered antiseizure medication (ASM). Secondary outcomes included the percentage of patients other response types (partial responder or non-responder), as well as the rate of adverse effects. ResultsA total 75 patients were included in our analysis. PER was initiated as the median sixth ASM at a median initial dose of 12 mg. For the primary outcome, 31 (41.3%; 95% confidence interval 31.0%–53.0%) patients were classified as a definite responder. Seven patients (9.3%) experienced an adverse effect that was attributed to PER, with the most common being sedation in four patients. ConclusionsIn our retrospective cohort of RSE, we observed a definite response rate of 41.3% within 72 h of PER initiation. PER was well tolerated with few documented adverse effects. Further prospective studies are needed to confirm the role of PER in treating patients with RSE.

Lower vancomycin trough levels in adults undergoing unrelated cord blood transplantation

Vancomycin (VCM) is frequently used for neutropenic patients undergoing cord blood transplantation (CBT). We retrospectively examined the relationship between VCM trough levels and the efficacy and toxicity in 122 adult patients undergoing CBT in our institute. The median initial dose of VCM based on body weight was 9.1 mg/kg/dose (range, 6.0–22.6 mg/kg/dose). The median initial trough level of VCM for all patients was 4.50 µg/mL (range, 1.20–24.05 µg/mL), at a median of 3 days (range, 2–6 days) after VCM administration. The cumulative incidence of acute kidney injury (AKI) was 19% at 30 days after VCM administration. A higher median trough level of VCM during the first 7 days was significantly associated with the development of AKI in the multivariate analysis (Hazard ratio: 1.28, p = .026). These data suggest that a lower VCM trough level may be safe in adult patients undergoing CBT under therapy with nephrotoxic drugs.

Ketamine for pain control of snake envenomation in Guinea: A case series

Snakebite envenomation is a global health crisis and is classified as a Category A neglected tropical disease by the World Health Organization (WHO). Snakebite envenomations account for a significant amount of morbidity and morbidity in tropical and subtropical regions. Recently, publications have illustrated the potential for snake envenomations causing post-traumatic stress disorder (PTSD) in a significant number of patients. Ketamine is on the WHO's list of essential medications and is used for a variety of pharmacologic applications including anesthesia and acute pain management. To date it has not been assessed for pain control in snakebite envenomations. Twelve patients who presented with severe pain secondary to Bitis, Causus, and Atractaspis envenomations were treated with low-dose intravenous ketamine. The patients included 7 males and 5 females with a median age of 37.5 (range 14–64) and a median presentation time of 5.75 h (range 5 min–96 h) after the initial bite occurred. Ten envenomations were presumed to have been caused by Bitis species resulting in extensive swelling and blistering of the affected extremities. One envenomation was presumedC. maculatus causing local swelling and pain. One envenomation was a presumed Atractaspis species causing significant local pain with minimal swelling. All patients expressed having significant pain but could not express the degree of their pain using an analogue pain scale. An initial median dose of 5 mg of ketamine (range 2.5–15 mg) was administered intravenously for pain control. Every patient expressed decreased pain and felt more comfortable within 1 min after administration of ketamine. Nine of the twelve patients only required a single dose. There were no adverse side effects. Ketamine appears to be an effective means of pain control for those suffering from painful envenomations. With minimal risk of significant side effects at acute pain management doses and the average cost per effective dose averaging between US$0.03–0.06, this may provide a cheap, safe, and effective solution for Sub-saharan Africa and other resource-limited settings. Controlled studies need to be done to critically assess our observations.

Ruxolitinib in children with steroid-refractory acute graft-versus-host disease: A retrospective multicenter study of the pediatric group of SFGM-TC.

We conducted a national multicenter retrospective study in France to evaluate the efficacy and tolerance of ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplant. Patients were recruited from the 15 pediatric transplantation centers. Transplanted patients were eligible if they met the following criteria: aged ≤ 18 years at transplantation, receiving a myeloablative allogeneic hematopoietic stem cell transplant, having an aGVHD of grade ≥2, and treated with ruxolitinib for steroid-refractory aGVHD. Twenty-nine patients received ruxolitinib for steroid-refractory aGVHD. Six patients achieved a complete response at day 28 after the start of treatment but finally 19 patients (65.5%) achieved a complete response (CR) with a median delay of 41 days (5-93 days). Two patients had a partial response. All patients who achieved CR or partial response discontinued corticosteroid treatment. Eight patients showed treatment failure. The overall response rate was 72.4%. Twenty-three of 29 patients were alive at a median follow-up of 685 days (177-1042 days) after the hematopoietic stem cell transplantation. Viral replication was observed in 41.4% of cases. We did not observe severe hematological adverse events and cytopenia requiring a modification of ruxolitinib doses always resolved. The median initial dose of ruxolitinib was 12.6mg/m2 /day with an important range. We could not demonstrate any relationship between initial dose and effectiveness. Ruxolitinib may constitute a promising second-line treatment for children with steroid-refractory aGVHD that should be validated in a prospective large-scale pharmacokinetic and efficacy trial.

Optimal oral cyclosporin dosing with concomitant posaconazole post allogeneic stem cell transplantation

Cyclosporin is an immunosuppressive agent in allogeneic hematopoietic stem cell transplantation and its metabolism is strongly affected by concomitant drugs, including posaconazole which is now extensively used as anti-fungal prophylaxis post-allograft. We undertook a retrospective audit of 29 patients undergoing their first allograft who were receiving posaconazole at the time of transition from intravenous to oral cyclosporin. This group had a median initial oral cyclosporin dose of 2.58 mg/kg bd (range 1.75–3.95) and high incidence of cyclosporin-related toxicity was noted, requiring significant dose reductions such that by day 60 the media dose was 1.60 mg/kg bd (range 0.86–3.33). We subsequently amended our dosing protocol and analyzed a further 20 patients specifying an initial oral cyclosporin dose of 2.25 mg/kg bd and found this had little impact on toxicity or requirement for dose reductions. Starting doses of no greater than 2 mg/kg bd appear optimal to prevent toxicity in allograft recipients receiving concomitant posaconazole.

Evaluation of dosing and safety outcomes of low-dose prophylactic warfarin in children after cardiothoracic surgery.

Prophylactic warfarin with an International Normalized Ratio (INR) goal of 1.5 to 2.0 is one antithrombotic therapy utilized in children after cardiothoracic surgery (CTS); published sources suggest a dose of 0.1 mg/kg per day to achieve this goal. However, few studies have evaluated dosing in this population. The purpose of this study was to evaluate dosing and safety outcomes in children receiving warfarin after CTS. A descriptive, retrospective review was conducted to evaluate warfarin dosing and INR outcomes in patients 18 years of age or younger who underwent CTS and received prophylactic warfarin with an INR goal of 1.5 to 2.0 from January 2014 through December 2018. The primary objective was to determine the median initial warfarin dose. Secondary objectives included identifying the percentage of documented INR values that were outside the therapeutic range, the percentage of patients with therapeutic INRs at discharge, and the 30-day readmission rate. Twenty-six patients were included in the review. The median initial warfarin dosage was 0.07 mg/kg/d (interquartile range [IQR], 0.05-0.10 mg/kg/d). Of the total of 177 INR values collected during the entire study period, 67 (37.9%) were therapeutic, 64 (36.2%) were subtherapeutic, and 46 (26.0%) were supratherapeutic. Eighteen patients (69.2%) had at least 1 supratherapeutic INR at any point during the study period, most frequently on days 2 through 4 of therapy. At discharge, 11 patients (42.3%) had therapeutic INRs. Four patients (15.4%) were readmitted within 30 days, with bleeding documented in 2 patients during their readmission. The majority of patients received an initial warfarin dose less than that specified in published recommendations but still had a supratherapeutic INR at least once during the study period. When initiating warfarin after CTS, a dosage of <0.1 mg/kg per day and frequent monitoring may be needed to achieve an INR goal of 1.5 to 2.0.

Treatment of status epilepticus with zonisamide: A multicenter cohort study of 34 patients and review of literature

IntroductionWe present a summary of clinical cases of oral zonisamide (ZNS) used to treat refractory and super-refractory episodes of status epilepticus (SE). MethodsZonisamide administration in SE was identified in the clinical records of patients treated in Frankfurt and Marburg between 2011 and 2017. ResultsZonisamide was administered during a total of 37 SE episodes in 34 patients with a mean age of 58.7 ± 17.8 years, 21 of them were female (61.7%). The median latency from the onset of SE to administration of ZNS was 6.3 days. Patients had already undergone unsuccessful treatment with a median of three other antiseizure drugs (ASDs).The median initial dose of ZNS was 100 mg/d, titrated to a median maintenance dose of 400 mg/d. Patients underwent ZNS treatment for a median period of 7 days. Zonisamide was the final drug administered in 9 of 37 (24.3%) episodes, with a clinical effect attributed to ZNS observed in 6 of 37 (16.2%) episodes. An effect attributed to ZNS was observed in 5 out of 30 episodes of refractory SE (RSE) and in one out of 7 episodes of super-refractory SE (SRSE). Possible negative side effects of ZNS were observed in two patients (one patient each with ataxia and skin rash). The mortality rate in hospitalized patients was 10.4% (n = 4). ConclusionThe rate of SE resolution attributed to ZNS treatment (16.2%) can be considered relevant, particularly since ZNS treatment tends to be administered only after several other options have been tried, and has a treatment latency of over six days. Zonisamide may therefore be considered as an alternative oral treatment option in RSE and SRSE.

P131: Practice patterns of emergency department physicians administering naloxone for patients with suspected opioid overdose

Introduction: Naloxone is recommended for reversing opioid-associated respiratory depression. There is wide variability in emergency department (ED) practice patterns regarding naloxone use, dosing, and observation time post-administration. This study describes the naloxone practice patterns of ED physicians managing suspected opioid overdose patients. Methods: A retrospective chart review was conducted of adult patients (≥ 18 years) presenting to an academic tertiary care centre (consisting of two EDs with an annual census 150,000 visits) in 2017 with suspected opioid overdose who were administered naloxone in the ED. Patients were identified electronically and the following information was abstracted from patient charts: demographics, naloxone dosage and infusion initiation, disposition data, indications for naloxone administration, response to therapy, and adverse effects. Variability in initial and total dose was examined. Initial dose was also compared in those with cardiorespiratory compromise (CPR given, respiratory rate &lt; 8, or desaturation below 89%) using independent samples median tests. Data was analyzed using standard descriptive statistics. Results: 113 patients met inclusion criteria. Indications for naloxone administration were: level of consciousness (50.5%), respiratory depression (4.0%), miosis (1.0%), a combination of factors (19.8%), or undocumented (24.8%). Median initial dose was 0.40 mg (IQR: 0.20-0.40 mg). Median total naloxone administered in the ED was 0.48 mg (IQR: 0.35-1.2 mg). The initial dose resulted in a response in 43.1% of patients, with 36.0% of responding patients later experiencing subsequent respiratory depression. 31% of patients received a naloxone infusion. Initial dose in patients with cardiopulmonary compromise was significantly different only comparing patients who received CPR versus those who did not (median 0.40 mg; IQR: 0.20-0.80 mg; P = 0.019). Four patients experienced emesis following naloxone. Median length of ED stay was 7.0 hours (IQR: 4.0-9.5 hours), and median hospital length of stay was 3.0 days (IQR: 1.0-5.0 days). Median ED observation time prior to discharge was 4.0 hours (IQR: 2.0-8.0 hours). Ultimate disposition home, to the ward, or to the intensive care unit was 47.1%, 42.2%, and 9.8% respectively (1.0% deceased). Conclusion: The dose and usage of naloxone by ED physicians in this study is variable. Further prospective studies are needed to determine the effective naloxone dosing strategy.

High Concentration of Vancomycin in Children with Central Diabetes Insipidus: A Retrospective Case Series

Although the high concentration of vancomycin (VCM) has the potential to cause acute kidney injury and ototoxicity, there were no studies focused on its pharmacokinetics in children with central diabetes insipidus (CDI). We, therefore, evaluated the pharmacokinetic indices of VCM in children with CDI diagnosed and treated at Ehime University Hospital between January 2008 and December 2019. Five patients with CDI administered VCM, were retrospectively reviewed. VCM median initial dose, trough value, clearance (CL) and half-life (t1/2) were 42.0 mg/kg/day (range, 18.8 mg/kg/day-60.0 mg/kg/day), 34.5 mg/L (range, 12.5 mg/L-182 mg/L), 6.54 mL/min (range, 1.57-47.1 mL/min), and 7.11 hr (range, 3.35 hr -38.5 hr), respectively. VCM trough values were high in cases of untreated or inadequately treated CDI. Our results suggest that the decrease in CL and the increase in the volume of distribution caused by CDI and sepsis could result in an extended VCM t1/2 and a higher VCM trough value in patients with CDI.

Retrospective analysis of infliximab and adalimumab treatment in a large cohort of juvenile dermatomyositis patients

BackgroundAnti-TNF treatment may be useful for the treatment of patients with refractory juvenile dermatomyositis (JDM). The aim of this study was to describe the use of infliximab and adalimumab therapy in juvenile dermatomyositis as an adjunctive treatment.MethodsSixty children recruited to the UK JDM Cohort and Biomarker Study that had received at least 3 months of anti-TNF treatment (infliximab or adalimumab) were studied. Childhood Myositis Assessment Scale (CMAS), Manual Muscle Testing (MMT8) and physician’s global assessment (PGA) were recorded. Skin disease was assessed using the modified skin disease activity score (DAS). Data were analysed using Friedman’s test for repeated measures analysis of variance.ResultsCompared to baseline, there were improvements at 6 and 12 months in skin disease (χ2(2) = 15.52, p = 0.00043), global disease (χ2(2) = 8.14, p = 0.017) and muscle disease (CMAS χ2(2) = 17.02, p = 0.0002 and MMT χ2(2) = 10.56, p = 0.005) in infliximab patients. For patients who switched from infliximab to adalimumab, there was improvement in global disease activity (χ2(2) = 6.73, p = 0.03), and trends towards improvement in CMAS, MMT8 and modified DAS. The median initial prednisolone dose was 6 [0–10] mg, and final was 2.5 [0–7.5] mg (p < 0.0001). Fifty-four per cent of patients had a reduction in the number and/or size of calcinosis lesions. Twenty-five per cent switched their anti-TNF treatment from infliximab to adalimumab. 66.7%of the switches were to improve disease control, 26.7% due to adverse events and 6.6% due to patient preference. A total of 13.9 adverse reactions occurred in 100 patient-years, of which 5.7 were considered serious.ConclusionReductions in muscle and skin disease, including calcinosis, were seen following treatment with infliximab and adalimumab.

Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients

BackgroundIn the field of palliative care, morphine is known to be effective for alleviating dyspnea in cancer patients. However, little is known regarding the safety and efficacy of morphine therapy for refractory dyspnea as palliative care in advanced heart failure (HF) patients. MethodsWe retrospectively reviewed consecutive advanced HF patients who were referred to the Palliative Care Team at our institution and administered morphine for refractory dyspnea during hospitalization between September 2013 and December 2018. We investigated the details of morphine usage, vital signs, an 11-point quantitative symptom scale, and adverse events at baseline, 24 h, and 72 h after the start of treatment. ResultsMorphine was administered for refractory dyspnea in 43 advanced HF patients [mean age: 73.5 years, male: 28 (65%), New York Heart Association functional class IV: 43 (100%), median left ventricular ejection fraction: 25%, median B-type natriuretic peptide level: 927 pg/ml, concurrent intravenous inotrope: 33 (77%)]. Median initial dose of morphine was 5 mg/day in both oral and intravenous administration and median duration of administration was 5 days. Significant decreases in an 11-point quantitative symptom scale [7 (5, 9) vs. 2 (1, 6); p < 0.01, (data available in 8 patients)] and respiratory rate (22.2 ± 6.1 vs. 19.7 ± 5.2 breaths per minute; p < 0.01) were observed 24 h after the start of morphine administration. Meanwhile, oxygen saturation, blood pressure, and heart rate were not significantly altered after treatment (NS). Common adverse events were delirium (18%) and constipation (8%); however, no lethal adverse event definitely related to morphine therapy occurred during treatment. ConclusionsThis single-center retrospective study revealed the clinical practice of morphine therapy and suggested that morphine therapy might be feasible for refractory dyspnea as palliative care in advanced HF patients.

Vancomycin Pharmacokinetics in Obese Patients with Sepsis or Septic Shock.

Obese patients with sepsis or septic shock may have altered vancomycin pharmacokinetics compared with the general population that may result in improper dosing or inadequate drug concentrations. The objective of this study was to characterize vancomycin pharmacokinetics in obese patients with sepsis or septic shock, and to develop a novel pharmacokinetic dosing model based on pharmacokinetic-pharmacodynamic target requirements. Prospective observational pharmacokinetic study. Large quaternary academic medical center. Sixteen obese (body mass index [BMI] 30kg/m2 or higher) adults with sepsis and either a gram-positive bacteremia or requiring vasopressor support (septic shock), who were receiving vancomycin between November 2016 and June 2018, were included. Patients were excluded if they were receiving renal replacement therapy or extracorporeal membrane oxygenation, treatment for central nervous system infections, pregnant, or receiving vancomycin for surgical prophylaxis. Four blood samples per patient were collected following a single dose of vancomycin: one peak serum vancomycin level (within 1-2hrs of infusion completion), two random levels during the dosing interval, and one trough level (within 30-60min of the next dose) were measured. A population pharmacokinetic model was developed to describe vancomycin concentrations over time. Simulations to determine optimal dosing were performed using the pharmacokinetic model with different ranges of creatinine clearance (Clcr ) and different vancomycin daily doses. Median age of the patients was 62years; median BMI was 36.1kg/m2 , Acute Physiology and Chronic Health Evaluation II score was 26, and Sequential Organ Failure Assessment score was 11. Eleven patients (69%) had an acute kidney injury. Median initial vancomycin dose was 15mg/kg; median vancomycin trough concentration was 17mg/L. A one-compartment model best characterized the pharmacokinetics of vancomycin in obese patients with sepsis or septic shock. Volume of distribution was slightly increased in this population (0.8L/kg) compared with the general population (0.7L/kg). Only Clcr effect on drug clearance was found to be significant (decrease in the objective function value by 16.4 points), confirming that it is a strong predictor of vancomycin clearance. To our knowledge, this study provides the first population-based pharmacokinetic model in obese patients with sepsis or septic shock. The nomograms generated from this pharmacokinetic model provide a simplified approach to vancomycin dosing in this patient population.

Carbon Ion Beam Reirradiation in Recurrent High-Grade Glioma.

BackgroundPatients with recurrent glioma after prior radiotherapy have a poor prognosis. Carbon ion beam radiotherapy offers highly conformal dose distributions and more complex biological radiation effects eventually resulting in optimized normal tissue sparing and improved outcome. The aim of this study was to analyze toxicity, local control and overall survival after reirradiation of recurrent high-grade glioma with carbon ion radiotherapy.MethodsBetween 10/2015 and 12/2018, 30 patients (median age: 59 years) with recurrent high-grade glioma were reirradiated with carbon ion beams and retrospectively analyzed. Diagnosis of recurrent glioma was based on magnetic resonance imaging. Thirteen patients had repeated resection prior to reirradiation and 24 patients underwent additional chemotherapy. The median initial radiation dose was 60 Gy and the median time interval between the initial and repeated radiotherapy was 10 months. The reirradiation dose was 45 Gy (relative biological effectiveness) applied in 15 fractions. All patients received regular follow-up imaging after reirradiation. Kaplan-Meier estimation, log rank test and Cox regression analysis were used for statistical assessment.ResultsApplying common toxicity criteria, there were no grade 5 or 4 adverse events, while 8 patients showed grade 3 adverse events. The median follow-up after reirradiation was 11 months and the median overall survival after diagnosis of recurrent high-grade glioma was 13 months. The 6-, 12- and 24-month overall survival rates after diagnosis of recurrent high-grade glioma were 76%, 50% and 19%, respectively. Upon multivariate Cox regression analysis, a Ki67 score of the initial tumor histology of less than 20% was prognostic. Repeated resection or chemotherapy for the recurrent disease did not result in significantly prolonged survival.ConclusionCarbon ion reirradiation in recurrent high-grade glioma is safe and feasible. No radiation-associated grade 4 toxicities were documented and treatment was tolerated well.

Therapeutic Efficacy and Safety of Methotrexate in Moderate-to-Severe Atopic Dermatitis: A Retrospective Study of Korean Patients at Tertiary Referral Hospital.

BackgroundMethotrexate (MTX) has been prescribed to suppress atopic dermatitis (AD) symptoms and flares in moderate-to-severe cases.ObjectiveThe purpose of this study was to evaluate the therapeutic efficacy and safety of MTX as well as the suppressive activity of MTX to reduce flares in moderate-to-severe AD patients.MethodsPatients with moderate-to-severe AD who were treated with MTX at the Chonnam National University Hospital were retrospectively studied.ResultsTotal 102 patients (79 males, 23 females) with a median age of 22.0±10.3 years were studied. The median initial dose of MTX was 10.3±2.6 mg/week, and the MTX-weekly dose was increased by 2.5 to 5 mg at an interval of 2 to 4 weeks to a maximum dose of 17.5±2.7 mg/week. The median maintenance dose was 11.7±2.1 mg/week; the median duration of treatment with MTX was 34.0±38.8 weeks. The initial response was noted after 5.8±3.7 weeks. Of the 102 patients, 60.8% (62/102) showed successful treatment response and 39.2% (40/102) showed mild or no improvement. MTX therapy effectively suppressed the frequency of AD flares by more than 50% in 71.1% (32/45) of the patients who responded among the MTX responders group. The most common adverse events were transient liver abnormality (5.9%, 6/102) and gastrointestinal discomfort (3.9%, 4/102), but no serious adverse events occurred.ConclusionOur results reveal that MTX is a relatively safe drug to control moderate-to-severe AD with satisfactory therapeutic efficacy and inhibitory activity against AD flares.

Argatroban et thrombopénie induite par l’héparine : observatoire des modalités de prescription et d’utilisation en France

A survey of prescribing practices was carried out in France to ensure that argatroban was used appropriately during the first 18months after it obtained marketing authorization for anticoagulation in adults with heparin-induced thrombocytopenia (HIT). This observational study was proposed to public and private hospitals with at least 2 orders of argatroban. All patients who received at least one argatroban injection during the study period had to be included. Their demographic characteristics, the pathology causing heparin treatment, the indication of treatment with argatroban, as well as available real-life clinical and biological monitoring data were retrospectively collected. In the 23 participating centers, the drug was prescribed mainly by the following hospital units: surgery and intensive care (79.3%) (of which 18.3% cardiovascular), nephrology/hemodialysis (14.8%) and internal medicine (5.9%). Among the 169 patients included, with median age of 68 years, 118 (69.8%) had renal impairment (creatinine clearance <90mL/min). The HIT probability scoring and diagnostic tests used differed widely between the centers. The reasons for prescribing the drug were mainly suspected HIT (51.5%), declared confirmed HIT (21.3%) or a history of HIT (14.8%). Seventy-three(73) patients (43.2%) had thrombotic symptoms or a systemic reaction initially. The median initial dose prescribed was 0.5μg/kg/min (ranging from 0.05 to 4.42) and doses >2μg/kg/min were used during hemodialysis. More than half of the patients (58.6%) had no clinical complications. Most of the serious adverse reactions were hemorrhagic (11/12). This study illustrates the complexity of treatment for HIT and the need to be familiar with and follow guidelines on the management of HIT, especially for susceptible patients treated in intensive care units.

Consistency of Dosing of Turoctocog Alfa Pegol (N8-GP) throughout the Pathfinder Clinical Trials: Implications for Recommendations for Effective Prophylaxis, Bleed Resolution, and Perioperative Management

Introduction: Replacement factor VIII (FVIII) products have been administered to achieve desired FVIII levels for bleed treatment, perioperative management, or routine prophylaxis. Individual variability in pharmacokinetics (PK) has resulted in dosing ranges, rather than fixed doses. N8-GP (ESPEROCT®) is an extended half-life recombinant FVIII product. The pathfinder trials evaluated routine prophylaxis and bleed treatment in previously treated adolescents/adults (pathfinder 2) and children (pathfinder 5) with severe hemophilia A and perioperative management of major surgery (pathfinder 3). Methods: Adolescents/adults (aged ≥12 y) were administered 50 IU/kg N8-GP every 4 days (Q4D) as routine prophylaxis in the main phase; alternative weekly dosing was explored in 2 extension phases. For the on-demand treatment arm, patients were to be given 20 to 70 IU/kg, depending on bleed severity and desired FVIII levels. Children (aged &amp;lt;12 y) on prophylaxis were administered a target of 60 (50-75) IU/kg N8-GP twice weekly. For surgery, a pre-trial test dose of 50 IU/kg was administered with PK assessment and then dosing in the study was to achieve desired FVIII suggested by World Federation of Hemophilia guidelines. Results: Pathfinder 2 enrolled 186 patients (46 from the US) with 128 (69%) completing the second extension phase encompassing 785 patient-years (66,577 exposure days) with 2,758 treated bleeds. On-demand patients (n=12) treated for a total of 37 patient-years of exposure reported 1,270 (46%) bleeds. In the main phase, 105 of 175 adolescents/adults on prophylaxis (50 IU/kg Q4D) experienced 436 bleeds with a median annualized bleeding rate (ABR) of 1.2. Through the study (mean 3.5 years), 177 adolescents/adults on doses of ~52 IU/kg Q4D had a median ABR of 0.99 and mean (95% CI) FVIII trough levels of 3.1 (2.6-3.4) IU/dL. Treatment of bleeding through extension 1 is described in Table; the median dose for mild/moderate bleeds was 42 IU/kg. For participants who were in the on-demand arm, the median initial dose was 28 IU/kg, with 88.4% of bleeds treated with a single dose. In subjects receiving prophylaxis, the median initial dose matched the prophylaxis dose (52 IU/kg), and 76% of bleeds received a single dose. For 15 severe bleeds, the median total dose was 111 IU/kg per episode. Pathfinder 5 enrolled 68 children (34 aged 0-5 y, 34 aged 6-11 y), 95% previously on prophylaxis; 62 completed the extension, amounting to 306 patient-years (32,138 exposure days) with mean exposure of 4.5 years. Overall, 55 patients (81%) reported 330 bleeds; most were traumatic (67%). Median ABR in the main phase (0.48 years) was 2.0 and through the entire study was 0.8 with mean (95% CI) FVIII trough activity of 1.9 (1.6-2.5) IU/dL. The mean prophylaxis dose was 64.7 IU/kg at a mean interval of 3.5 days, likely reflecting rounding the targeted 60 IU/kg twice weekly dose. For 70 bleeds in the main phase, 88% of bleeds were treated with 1 to 2 injections; median utilization for bleeds was 68 IU/kg (Table). Pathfinder 3 evaluated 45 surgeries in 33 adolescents/adults; 96% were reported as excellent/good efficacy. Median preoperative dose mirrored test dose (52 IU/kg) with median total dose per surgery of 702 IU/kg (until 14 days post-surgery). Postoperative dosing was at ~24-hour intervals with the number of doses and treatment duration dependent on procedure (Table). Conclusion: The pathfinder trials demonstrate effective prophylaxis was achieved with very consistent prophylaxis dosing for both adolescents/adults (~50 IU/kg Q4D) and children (~65 IU/kg twice weekly). Bleeds were generally treated for patients on prophylaxis with a single prophylactic dose (~50 or ~65 IU/kg). Dosing intervals in severe bleeding and surgery were ~24 hours, including in children. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wheeler:uniQure: Membership on an entity's Board of Directors or advisory committees; BioMarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Lentz:Novo Nordisk Inc.: Consultancy, Honoraria, Research Funding. Clausen:Novo Nordisk A/S: Employment. Cooper:Novo Nordisk Inc.: Employment.

Real-World Analysis of Ruxolitinib Treatment Patterns and Outcomes Among Patients with Myelofibrosis

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, cytopenias, and poor survival. Ruxolitinib (RUX) is the only approved treatment for Intermediate or High-risk MF. In a previous study, we have shown almost 1 in 3 patients initiating RUX had dose modifications during the first 3 months of treatment (Burton T et al. HemaSphere 2019). The objective of this study was to assess RUX treatment patterns among patients with MF. Methods: This retrospective analysis used administrative claims data from a large US health plan to identify adults (aged ≥ 18 years) with ≥ 1 claim for RUX and ≥ 2 non-diagnostic medical claims for primary (International Classification of Diseases [ICD] 9th or 10th Revision [9/10]: 238.76, D47.4) or secondary MF (ICD-9/10: 289.83, D75.81) from January 1, 2012 to June 30, 2018. The first RUX claim on or after the first MF claim defined the index date. Included patients were continuously enrolled in a commercial or Medicare Advantage health plan for 3 months before the index date (pre-index period) and 6 months on or after the index date (post-index period). Clinical characteristics, MF-related treatments, health care resource utilization (HCRU), and costs were assessed during the pre- and post-index periods. Costs were adjusted to 2018 US dollars using the medical component of the Consumer Price Index. Cohorts were created based on the maximum (max) RUX daily dose observed during the 6-month post-index period: suboptimal max &lt; 30 mg/day (SUB); and optimal max ≥ 30 mg/day (OPT). All variables were analyzed descriptively. Results: Among 495 eligible patients, mean (SD) age was 69.4 (10.3) years; 54.1% were male; and 25% had a primary MF diagnosis code. Median initial RUX dose was 30 mg/day and patients continued with this dose for a mean (SD) of 70.0 (45.8) days. RUX dose was modified for 19.4% of patients during the 6-month post-index period, and the distribution of max RUX daily doses was: &lt; 15 mg (13.7%), 15-29 mg (24.9%), 30-40 mg (55.8%), and &gt; 40 mg (5.7%). Two groups based on max RUX dosing were further analyzed: 191 (38.6%) in the SUB cohort (&lt; 30 mg), and 304 (61.4%) in the OPT cohort (≥ 30 mg). Patients in the SUB cohort were older than patients in the OPT cohort (SUB: mean 70.8 [SD 10.1] years; OPT: mean 68.5 [SD 10.3] years; P = 0.013), but the mean Charlson Comorbidity Index scores did not differ (SUB: mean 1.6 [SD 1.8]; OPT: mean 1.5 [SD 1.8]; P = 0.601). Rates of anemia were higher at baseline for the SUB cohort than the OPT cohort (SUB: 64.9%; OPT: 53%; P = 0.009). During the 6-month post-index period, compared with patients in the OPT cohort, patients in the SUB cohort had a higher proportion of thrombocytopenia (SUB: 31.4%; OPT: 22.7%; P = 0.03). Nearly half (45.5%) the sample used a supportive agent such as an androgen, systemic steroid, or erythropoiesis-stimulating agent during the post-index period (SUB: 48.2%; OPT: 43.8%; P = 0.34). With respect to HCRU and costs, the SUB cohort had a higher proportion of emergency department (ED) visits than the OPT cohort during baseline (SUB: 31.4%; OPT: 23.4%; P = 0.048); and baseline total mean (SD) all-cause costs were USD 18,079 (21,876) overall, USD 18,908 (24,411) for the SUB cohort, and USD 17,559 (20,145) for the OPT cohort (P = 0.523). During the 6-month follow-up period, 31.1% of patients had ≥ 1 ED visit (SUB: 35.1%; OPT: 28.6%; P = 0.131), 22.8% had ≥ 1 inpatient (IP) hospitalization (SUB: 24.6%; OPT: 21.7%; P = 0.455), and total mean (SD) all-cause costs were USD 94,498 (97,391) overall (SUB: USD 93,289 [115,418]; OPT: USD 95,258 [84,315]; P = 0.839). Conclusion: In this study, patients with MF treated with RUX experienced significant disease burden and high costs, regardless of dose. Both anemia and thrombocytopenia were observed along with nearly half of patients using a supportive agent. Given the large proportion of patients with a dose adjustment, suboptimal dosing, and an IP hospitalization, there continues to be a need for additional therapeutic options for patients with MF. Disclosures Parikh: Celgene Corporation: Employment, Equity Ownership. Patel:Celgene Corporation: Employment, Equity Ownership. Sundquist:Optum: Employment, Equity Ownership. Lal:Optum: Employment. Copher:Celgene Corporation: Employment. Gerds:Roche: Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy.