Regular Dose Research Articles

Trajectories of Alcohol Use and Related Harms for Managed Alcohol Program Participants over 12Months Compared with Local Controls: A Quasi-Experimental Study.

Investigate changes in alcohol use and related harm using the first multisite, controlled, longitudinal study of Managed Alcohol Programs (MAPs). MAPs provide regular doses of alcohol, accommodation, social supports and healthcare to unstably housed people with alcohol dependence. A multisite, quasi-experimental, longitudinal study was conducted in day centres, shelters and residential programs for unstably housed people. There were 59 MAP participants from six Canadian cities and 116 local controls. Self-reported alcohol consumption and harms were assessed at 0-2, 6 and 12 months. Liver function test results were accessed for MAP participants. Both groups had similar reductions in mean drinks per day (MAP: -8.11; controls: -8.54 controls, P < 0.001) and days drinking per month (MAP: -2.51 days, P < 0.05; control: -4.81 days, P = 0.0001) over 6--12 months. Both reduced non-beverage alcohol consumption. MAP participants reported significantly fewer harms at both 0-2 and 6 months than controls. MAP participants had similar total consumption to controls, but spread out over more days (25.41 versus 19.64 days per month, P = 0.001). After leaving a MAP, participants' liver status deteriorated, with increases in both aspartate transaminase and bilirubin levels. MAP sites with effective policies on outside drinking drank less and had fewer harms. MAP participants drank less hazardously than controls, especially with effective management of non-MAP drinking. Reductions in alcohol use and harms occurred for both groups, although MAP participants reported fewer harms at 0-6 months. Departing an MAP was associated with deterioration in liver status. Although providing stable housing, MAPs did not worsen health or increase alcohol use.

The impact of Vancomycin loading dose on the emergency department in Saudi Arabia: a multicenter cohort study

Background: The emergency department (ED) is a crowded area with complex workflow. Broad spectrum antibiotics given within the first hour of recognizing sepsis have proven to lower the mortality rate. Initiating optimal dose of Vancomycin to attain targeted serum level is an important role of emergency physicians and pharmacists. Objective: To evaluate the efficacy and safety of Vancomycin loading dose (VLD) (25-35 mg/kg) in reaching the targeted Vancomycin serum trough level compared to regular dose (15-20 mg/kg) in ED. Study design and settings: A multicenter, retrospective, cohort study. Methods: The study was carried out in four hospitals in Saudi Arabia; patients who received VLD were matched in a 1:1 fashion based on age category and diagnosis suspected in the ED. Inclusion criteria were age ≥14 years, diagnosed with serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and microbiology culture confirmed MRSA. Exclusion criteria were missing weight, SCr, or Vancomycin trough level, patient on dialysis therapy/continuous renal replacement therapies, and concomitant use of nephrotoxic drugs at ED. Results: Over the 1-year study period, a total of 3,746 patients were prescribed Vancomycin in the ED. 232 patients received VLD matched to 232 patients received regular dose. Mean dose were 25.3 mg/kg (±4.3) and 13.7 mg/ kg (±2.6) for VLD and regular dose groups, respectively. The targeted Vancomycin trough level was significantly reached with the VLD group within 24 hours post-initial dose vs regular dose [18.7 (±3.2) vs. 11.6 (±4.3), respectively, p < 0.0001]. No difference in SCr value was noted post-Vancomycin initial dose between VLD and regular dose groups [1.5 (± 1.5) vs. 1.4 (± 1.8), respectively, p = 0.735]. Nephrotoxicity incident was higher with VDL (33, 14.2%) compared to regular dose, but the difference was not significant (22, 9.5%, p = 0.117). Conclusion: VLD has a rapid effect in reaching the targeted Vancomycin serum trough level compared to regular dose with a low rate of nephrotoxicity effect. The finding supports the use of VLD in patients admitted to ED who were suspected to have serious infections caused by MRSA.

Is specific anti-factor Xa activity measurement a way to predict relevant bleeding in non-valvular atrial fibrillation (NVAF) patients?

Anti-Xa direct oral anticoagulants (DOACs) are first line therapy for stroke prevention in NVAF patients. There is no need of regular anticoagulation monitoring and dose reduction may be indicated in patients showing a high bleeding risk. However, we still estimate 2 to 5% of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) in NVAF patients. Thereupon, we must identify other bleeding risks such as biological overdose. The goal of this study was to investigate specific anti-Xa activity measurement as a mean to predict bleeding complications in NVAF patients. One hundred and forty-six patients (either on apixaban or rivaroxaban) were enrolled from 2017 to 2019. The DOACs measurements were performed the day of inclusion. We determined an overdose and therapeutic underdose thresholds according to expected anti-Xa plasma range levels filled in the European heart rhythm association guide use of DOACs. MB, CRNMB and minor bleedings and strokes occurring during the follow up (up to 3 years) were recorded. We analysed the correlation between therapeutic overdose and the studied endpoints. To this day, the statistical analyses are still being conducted. The first results show that among the 146 patients, more or less 14% were considered overdosed. Moreover, a statistical trend was found between overdosed patients and MB or CRNMB. In routine clinical practice, anti-Xa activity measurement could be used to predict bleeding risk in a selected population in order to adapt doses or to consider a change of molecule.

Vaccination rate and adherence of tick-borne encephalitis vaccination in Germany

BackgroundTick-borne encephalitis (TBE) is an arboviral infection of the central nervous system. As there is no causal treatment of TBE, disease prevention by vaccination is especially important. Immunization consists of a three-dose primary vaccination schedule, followed by regular booster doses. In Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute recommends TBE vaccination for all those at high risk of contracting TBE. This includes individuals living in, traveling to and/or working in risk areas, and being exposed to ticks. To our knowledge, there are currently no reliable data on TBE vaccination rates in Germany available. MethodsThis retrospective cohort study based on anonymized German health claims data was conducted to determine vaccination rates of TBE primary immunization in 2012 to 2015 by federal state, compliance with the vaccination schedule, and TBE vaccination uptake for the 2011 birth cohort. Vaccination protection rates for each federal state were simulated based on a compartmental model. ResultsVaccination rates of an initiated primary immunization ranged from about 3% in the southern federal states to <1% in the northern federal states. Across all federal states, compliance with the vaccination schedule decreased with each subsequent vaccination. Slightly higher TBE vaccination uptake was determined in the 2011 birth cohort, as compared to the German school entry health examination statistics in 2017. Simulated vaccination protection rates for each federal state ranged from 10% in Hamburg to 51% in Baden-Wuerttemberg. ConclusionsWhile there was an overall low vaccination uptake and a discrepancy between areas of high vs. low TBE risk, this study also indicates a concerning decline in vaccination compliance. Vaccinating physicians should address the importance of adherence upon initiation of TBE vaccination.

Vaccination Strategies for Minimizing Loss of Life in COVID-19 in a Europe Lacking Vaccines

Aim and Background: We aimed at identifying vaccination strategies that minimize loss of life in the COVID-19 pandemic. COVID-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.Methods: Based on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established “one dose fits all” approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, COVID-19 case and death rates similar to Europe in late January 2021 is used.Results: When the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100’000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30’000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.Conclusion: Protecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics.

Ecology and Economics of Oil Production

Nowadays, the world is facing the depletion of developed reserves and the exploitation of fields with poor reservoir features. These factors are forcing oil producers to use low-capacity high-head electric centrifugal submersible pump units (ESP). The use of such ESP in oil production causes pump temperature to rise to about a hundred degrees centigrade. Increasing the temperature strength of the cable line used as part of the ESP reduces the number of failures in terms of the electrical component. In order to reduce the number of ESP failures due to cable line fusing, oil producers started using cable lines with operating temperatures of over 200оС. Increasing the temperature strength of the cable line used as part of the ESP leads to a partial decrease in failures due to a reduction in the electric resistance of the “cable-motor” system. Meanwhile, failures of ESPs due to salt deposition in the pump stages started to grow. In the absence of any theoretical insight into the salt deposition phenomenon, ESP manufacturers started providing oil producers with various devices to protect pump stages from salt deposition. However, it soon became clear that these devices (containers with chemical salts) show no tangible results in terms of salt deposition elimination; hence, over the past few years, oil production enterprises have been maintaining the proper operation of ESPs by the regular dosing of chemicals to the pump suction or by hydrochloric acid treatment. Investigation of the failed ESP units has reliably ascertained the following: formation and effect of high temperature in and around the centrifugal pump; effect of the pump’s high temperature on the adjacent cable line; application of cable lines with high operating temperatures leads to salt deposition in the centrifugal pump chamber; salt deposition accompanies temperature deformation of the cable line’s insulation; acid treatment does not protect the ESP unit against salt deposition; acid treatment may result in the wear of a flow string; Therefore, solution of the salt deposition problem should start with an investigation of the dependence of a centrifugal pump’s temperature on the oil reservoir’s working parameters. The solution of many oil production problems and a reduction in oil recovery costs can only be achieved by means of ESP control automation. The described revolutionary studies of ESP operation in oil recovery will lay the foundation for a complete robotization of oil production.

A bivalent cyclic RGD–siRNA conjugate enhances the antitumor effect of apatinib via co-inhibiting VEGFR2 in non-small cell lung cancer xenografts

The vascular endothelial growth factor receptor 2 (VEGFR2) is considered to be a pivotal target for anti-tumor therapy against angiogenesis of non-small cell lung cancer (NSCLC). However, effective and low-toxicity targeted therapies to inhibit VEGFR2 are still lacking. Here, biRGD–siVEGFR2 conjugate comprising murine VEGFR2 siRNA and [cyclo(Arg-Gly-Asp-D-Phe-Lys)-Ahx]2-Glu-PEG-MAL (biRGD) peptide which selectively binds to integrin αvβ3 receptors expressing on neovascularization endothelial cell was synthesized. The anti-tumor activity and renal toxicity of biRGD–siVEGFR2 or its combination therapy with low-dose apatinib were investigated on NSCLC xenografts. The immunogenicity of biRGD–siVEGFR2 was also evaluated in C57BL/6J mice. In vivo, intravenously injected biRGD–siVEGFR2 substantially inhibited NSCLC growth with a marked reduction of vessels and a down-regulation of VEGFR2 in tumor tissue. Furthermore, biRGD–siVEGFR2 in combination with low-dose apatinib achieved powerful anti-tumor effect with less nephrotoxicity compared with the regular dose of apatinib. Besides, no obvious immunogenicity of biRGD–siVEGFR2 was found. These findings demonstrate that biRGD–siVEGFR2 conjugate can be used as a new candidate for the treatment of NSCLC and its combination therapy with apatinib may also provide a novel strategy for cancer treatment in clinic.

Cryptogenic Cirrhosis, An Ambiguity of a Diagnosis: A Case Report of Progressive Cirrhosis of Undetermined Cause

Cirrhosis is the result of chronic liver disease due to a variety of causes. It is deemed to be cryptogenic when the leading cause cannot be identified despite extensive laboratory, radiological and pathological investigations. The prevalence of cryptogenic cirrhosis diagnosis has been dramatically reduced in recent years due to the advanced achievement in diagnostic medicine, whereby it is attributed to only about less than 5% of cirrhosis cases. Here, we present a case of a 16-year-old boy with nonsignificant family history, was not taking any regular medication, and presented with progressive intermittent jaundice for a few years due to liver cirrhosis. Although an extensive investigation has been done, the etiology of the cirrhotic liver was still unknown. He had no features to support nonalcoholic steatohepatitis. He was in Child’s Grade B and prophylactically treated with a regular dose of propranolol to prevent portal hypertension complication while waiting for a liver transplant. This case report served the objective of showing that despite the advances in medical diagnostic techniques, cryptogenic cirrhosis is still used as a diagnosis in cases of chronic liver disease of unknown etiology.

Thyroxine Accelerates Functional Recovery in a Rat Model of Sciatic Nerve Crush.

To see how thyroxine affects the sensory and motor function of a damaged sciatic nerve in male rats. Forty adult male Wistar rats were allocated to four groups, 10 individuals each. Then, crush injury was done on the right sciatic nerve in all the groups using a vessel clamp. In thyroxine-treated groups and after the crush, the rats were given regular doses of thyroxine (5 and 10 ?g/kg) for one week intraperitoneally. Negative control group was treated intraperitoneally with distilled water as a vehicle. In sham operated group, only surgical procedures were performed without nerve crush. Then, behavioral, histological, and morphometric parameters were assessed at the regeneration time. After one week of treatment with thyroxine, the motor function improved significantly following a sciatic nerve crush (P ? 0.05). Also, morphometric parameters and sensory restoration improved in thyroxine-treated groups. Findings of this study showed that neuro-protective effects of thyroxine can be due to the stimulatory effects of thyroxine in myelin sheath formation and increasing the expression of SCG10 protein which is required for the development of growth cones.

Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis.

Alcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating factor (G-CSF) has been shown to favorably modulate the intrahepatic immune milieu and stimulate the regenerative potential of the liver. Initial studies have shown encouraging results with G-CSF in patients with severe alcoholic hepatitis. It has also been found to help steroid nonresponsive patients. There is, however, a need for careful selection of patients, regular dose monitoring and close observation for adverse events of G-CSF. In this review, we analyze the basis of the potential benefits, clinical studies, cautions and challenges in the use of G-CSF in alcoholic hepatitis.

Gas Chromatography-Mass Spectrometry Analysis of Bioactive Compounds of Iraqi Truffle Terfezia claveryi (Ascomycetes), Synthesis of Silver Nanoparticles, and Appraisal of Its Biological Activities.

Microwave-assisted extraction (MAE) is a highly selective method that reduces the time and number of solvents used, has high efficiency, and is environmentally friendly. This study aimed to evaluate the antioxidant, anticancer, and antibacterial activities of Iraqi Terfezia claveryi desert truffle extract and silver nanoparticles by MAE using water and hexane as extraction solvents. Chemical compositions were identified by gas chromatography-mass spectrometry. Silver nanoparticles were characterized by field emission scanning electron microscopy. Antioxidant activity was assessed with the 2,2-diphenyl-1-picrylhydrazyl method. Antibacterial activity was evaluated against four types of pathogenic bacteria, and anticancer activity was also assessed. The T. claveryi hexane extract showed approximately 18 bioactive compounds, with an antioxidant half-maximal inhibitory concentration of 6.896 μg/mL. This extract also had significant antibacterial action against Escherichia coli and Pseudomonas aeruginosa. A cytotoxicity test of the hexane extract showed moderate toxicity against hepatocellular carcinoma mouse (HCAM) liver cancer cells. Acridine orange/ ethidium bromide staining showed apoptosis and DNA damage in HCAM cells treated with the hexane extract. The results of this study suggest that components of the T. claveryi wild desert truffle could have important nutrition functions that might support the immune system in fighting liver diseases when taken in daily regular doses.

Continuous versus extended antipsychotic dosing in schizophrenia: Less is more

Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but—past acute phase treatment—it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects.

How biocompatible haemodialysers can conquer the need for systemic anticoagulation even in post-dilution haemodiafiltration: a cross-over study.

BackgroundWhile systemic anticoagulation is most widely used in haemodialysis (HD), contraindications to its use might occur in particular settings. The Solacea™ haemodialyser with an asymmetric triacetate membrane claims improved biocompatibility and has already shown promising results when used in combination with only half dose of anticoagulation. To quantify the performance of the Solacea™ when further decreasing anticoagulation to zero, fibre blocking was assessed by micro-computed tomography (micro-CT).MethodsTen maintenance HD patients underwent six dialysis sessions at midweek using a Solacea™ 19H dialyser, consecutively in pre-dilution haemodiafiltration (pre-HDF), HD and post-dilution HDF (post-HDF). After the first three sessions with only a quarter of their regular anticoagulation dose (one-quarter), the last three sessions were performed without anticoagulation (zero). Dialyser fibre blocking was quantified in the dialyser outlet potting using a 3D micro-CT scanning technique post-dialysis.ResultsEven in case of reduced (one-quarter) anticoagulation, the relative number of open fibres post-dialysis was almost optimal, i.e. 0.96 (0.87–0.99) with pre-HDF, 0.99 (0.97–0.99) with HD and 0.97 (0.92–0.99) with post-HDF. Fibre patency was mildly decreased for pre-HDF and HD when anticoagulation was decreased from one-quarter to zero, i.e. to 0.76 (0.61–0.85) with pre-HDF (P = 0.004) and to 0.80 (0.77–0.89) with HD (P = 0.013). Comparing the results for zero anticoagulation, post-HDF [i.e. 0.94 (0.82–0.97)] performed as well as HD and pre-HDF.ConclusionsThe Solacea™ dialyser provides promising results for use in conditions where systemic anticoagulation is contraindicated. Post-HDF, although inducing haemoconcentration in the dialyser, is equally effective for fibre patency in case of zero anticoagulation as pre-HDF and HD when using Solacea™.

Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial

Despite limited evidence, non-daily dosing of statins is recommended for managing muscle symptoms associated with statin therapy. We assessed the tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients having muscle symptoms associated with atorvastatin therapy. A parallel-group, outcome-assessment-blinded, randomized controlled clinical trial was conducted at Colombo South Teaching Hospital, Sri Lanka. Patients with muscle pain, tenderness or cramps alone or in combination for ≥2 weeks while on daily atorvastatin for ≥1 month, with no alternative cause, were recruited. Patient's regular atorvastatin dose was given every-other-day to those in intervention group (IG) and daily to those in control group (CG). Primary outcomes were assessed at 24 weeks and included composite of myalgia and myositis, LDL-cholesterol level and percentage reduction of LDL-cholesterol from baseline. Number recruited was 49 to IG (women:79.6%; mean-age:60.6 ± 8.7years) and 52 to CG (women:73.1%; mean-age:61.7 ± 9.8years). Mean atorvastatin dose per day was 8.6 mg (SD = 4 mg) and 17.6 mg (SD = 8.4 mg) in IG and CG, respectively. Composite of myalgia and myositis at 24 weeks was 79.6% in IG and 69.2% in CG (OR = 1.7, 95% CI 0.7–4.3; p = 0.234). IG failed to show noninferiority for mean LDL-cholesterol (difference:0.31 mmol/L; upper limit 97.5% CI:0.61 mmol/L; p for noninferiority = 0.989) and for mean percentage reduction of LDL-cholesterol from baseline (difference:3.13%; upper limit 97.5% CI:15.5%; p for noninferiority = 0.718). At 24 weeks, mean creatine kinase and discomfort due to muscle symptoms (assessed with Visual Analogue Scale) were not different between the two groups. Findings of this study do not favor every-other-day atorvastatin as an option for managing patients with muscle symptoms associated with atorvastatin therapy.

A room with a green view: the importance of nearby nature for mental health during the COVID-19 pandemic.

The COVID‐19 pandemic and its global response have resulted in unprecedented and rapid changes to most people’s day‐to‐day lives. To slow the spread of the virus, governments have implemented the practice of physical distancing (“social distancing”), which includes isolation within the home with limited time spent outdoors. During this extraordinary time, nature around the home may play a key role in mitigating against adverse mental health outcomes due to the pandemic and the measures taken to address it. To assess whether this is the case, we conducted an online questionnaire survey (n = 3,000) in Tokyo, Japan, to quantify the association between five mental health outcomes (depression, life satisfaction, subjective happiness, self‐esteem, and loneliness) and two measures of nature experiences (frequency of greenspace use and green view through windows from home). Accounting for sociodemographic and lifestyle variables, we found that the frequency of greenspace use and the existence of green window views from within the home was associated with increased levels of self‐esteem, life satisfaction, and subjective happiness and decreased levels of depression, anxiety, and loneliness. Our findings suggest that a regular dose of nature can contribute to the improvement of a wide range of mental health outcomes. With the recent escalation in the prevalence of mental health disorders, and the possible negative impacts of the COVID‐19 pandemic on public mental health, our findings have major implications for policy, suggesting that urban nature has great potential to be used as a “nature‐based solution” for improved public health.

“Low Dose Ganciclovir for Cytomegalovirus Reactivation after Allogeneic HSCT Is a Feasible Option with Same Efficacy and Less Toxicity Than Regular Dose”

Background: Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) occurs in approximately 70% of seropostive patients. CMV reactivation is associated with higher non-relapse mortality (NRM) and worse overall survival (OS). Although preemptive therapy effectively prevents CMV disease, toxicity of ganciclovir (GCV), valganciclovir (VGCV), and foscarnet is a major concern. While GCV 5 mg/kg BID (regular dose) is the most commonly used regimen, some series have suggested that a lower dose (5mg/kg QD, lower dose) could be an option. Objectives: To compare two different regimens of ganciclovir (regular vs. lower dose) for preemptive CMV therapy. Patients and Methods: This was an observational, retrospective study in adult patients who underwent HSCT between April 2007 and April 2020 in two centers. Doses of ganciclovir were determined at the discretion of the transplant physician. The primary endpoint was CMV clearance (rate and time to) between the two preemptive strategies. Results: We analyzed 118 consecutive patients. The median age was 50 years, acute leukemia was the most frequent underlying disease (59%), and most patients received transplants from alternative donors (matched unrelated in 32% and haploidentical in 36%), after reduced-intensity conditioning regimens (76%), with peripheral blood as the source of stem cells (73%). T-cell depletion was performed in 31% (ATG in 29%, alemtuzumab in 2%). In total there were 174 CMV reactivations: 124 (71%) were treated with the regular dose, and 50 (29%) in an outpatient setting with low dose. The median time to CMV clearance was similar between regular and low dose of GCV (15 days vs. 18 days, respectively, p=0.88). The cumulative incidence (CI) of CMV clearance at 30 days was 83% in the regular dose and 88% in the lower dose (p=0.82). By multivariate analysis, correcting for the differences between the groups, the GCV regimen did not influence the time to CMV clearance (hazard ratio 0.94, 95% confidence interval 0.70 - 1.26). On the other hand, hematologic toxicity was more frequent in the regular dose, with more cases of both grade 3-4 neutropenia (59% vs. 33%, respectively, p=0.002) and thrombocytopenia (77% vs. 48%, respectively, p&amp;lt;0.0001). Ten patients had CMV disease and were treated with GCV 5mg/kg BID for 21 days. Conclusion: Our findings suggest that the use of GCV once daily was safe, less toxic, and may be less expensive, considering that most patients will receive the regimen in an outpatient basis. These data should be confirmed in a prospective trial. Disclosures No relevant conflicts of interest to declare.

Efficacy and Safety of Venetoclax Combinations in t(11;14) Multiple Myeloma: Real World Data Collected from 7 Hungarian Centers

Background. Myeloma patients reaped immense benefit from the introduction of new classes of drugs over the last decades. This improvement, however, was much less marked in patients with translocation 11;14 [t(11;14)], a group in which immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) - the two most important pillars of current myeloma care - are less effective. This subgroup of patients used to be known for their relatively slow pace of progression often experiencing long plateau phases following autologous stem cell transplantation (ASCT), whereas at the same time t(11;14) is also disproportionately prevalent in difficult to treat clinical entities such as plasma cell leukemia or AL amyloidosis. Venetoclax, a selective bcl-2 inhibitor first approved for CLL was investigated for the treatment of relapsed myeloma patients and although it failed to show benefit for myeloma patients as a whole, t(11;14) patients showed exceptional responses, thus paving the way towards the first genetically targeted treatment in myeloma. As a result, its off label use is on the rise, even though clinicians have to face unanswered questions regarding the right dosage and therapy length, as well as the potential for adverse events (AEs), especially infections. Real world data could help elucidate its optimal use, but is as of yet very limited. Aims and methods. We addressed all Hungarian centers treating myeloma to evaluate the efficacy and safety of venetoclax, collecting data about the treatment duration, AEs, dose modifications and treatment discontinuations, and analysed response rates as well as progression free survival (PFS). Results. 33 patients were reported from 7 Hungarian sites. After the initial analyses, we identified two distinct rationales for venetoclax treatment. 22 patients were relapsed and heavily pretreated with an average of 4.5 prior lines; here venetoclax was chosen as ultimum refugium. In this group, combination partners were bortezomib-dexamethasone (VelDex) in 14 patients, 5 had dexamethasone only, one VRd, one DRd and one Kd. Considering the highly pretreated nature of this group, the overall response rate was a remarkably high 95% with 40.9% partial, 31.8% very good partial, and 22.7% complete responses. Treatment mostly continued until progression. The median PFS and OS calculated from venetoclax initiation were 299 and 437 days. The most common AEs were cytopenias and infections reported in 8 and 6 patients with 1 fatal infection. In the second group, 11 patients received venetoclax after a suboptimal initial response (6 PR, 4 SD, 1 PD) to their first line IMiD+PI combination with the goal of further tumor elimination preceding ASCT. Remarkably, although the length of venetoclax treatment was short - median 2 cycles -, all 11 patients deepened their response to at least VGPR and 7 to CR. 9 patients had ASCT converting 2 further VGPRs into CR, so at the end of the planned protocol 10 of the 11 patients had CR. Venetoclax was combined with VelDex in 9 and VTD in 2 cases, the one year PFS and OS were 91 and 100%, with no venetoclax related AEs reported. An important aspect of our analysis was the question of venetoclax dosing, as the appropriate dose in this indication is not yet clear. Reflecting this uncertainty, as well as funding difficulties with this off-label drug, only one patient received 800 mg dose as seen in the Bellini trial; one received 600 mg daily, with all others taking 400 mg or less. To counteract this lower daily dose available, some centers employed a combination with clarithromycin, a strong CYP3A inhibitor known to increase venetoclax serum levels two- to threefold. Where available, serum venetoclax levels were monitored to ensure serum levels comparable to regular dosing. Another point to emphasize is that 5 patients in the relapsed, and another 2 in the frontline group had deletion 17p, usually resulting in refractoriness to standard treatments. Among these patients however, 5 reached VGPR, 1 PR, and only one progressed on venetoclax treatment. Some responses proved lasting especially in the frontline group. Conclusion. Our results highlight the importance of targeted treatments in multiple myeloma. We experienced lasting responses in quadruple-refractory patients. In the newly diagnosed group where the depth of pre-ASCT response has a big impact on PFS, venetoclax may have a role converting suboptimal responses into CRs by eliminating residual disease. Figure Disclosures Illés: Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria. OffLabel Disclosure: venetoclax use in t(11;14) myeloma which is not yet licensed

The use of ketamine in the management of refractory cancer pain in a palliative care unit.

Ketamine has been used as an adjuvant to opioid therapy for the management of refractory cancer pain but the current evidence is insufficient to draw any conclusions regarding its efficacy. We aimed to assess the response to ketamine in patients with refractory cancer pain treated in an oncology palliative care unit. Patients with refractory cancer pain despite opioid dose escalation were selected for a trial of parenteral ketamine infusion according to a local protocol. The medical records of those patients treated between January 2004 and December 2018 were retrospectively reviewed. The primary endpoint of the study was a favorable response to ketamine, defined as a reduction in regular opioid dose with no increase in pain intensity or a reduction in pain intensity by ≥2 points on the numerical rating scale (NRS) with a stable regular opioid dose. The secondary endpoint was adverse events associated with ketamine. Among the 70 patients, mean pain score on NRS improved from 7.0 to 4.0 after ketamine (P<0.001). Forty-nine patients had a reduction of pain score by ≥2 points on NRS, 33 had ≥50% reduction in pain intensity. The median decrease in regular opioid dose was 25.5%, and the mean difference was -133.2 mg (P=0.002). A favorable response to ketamine was observed in 52 patients (74.3%). The use of more than one coanalgesic (odds ratio 3.451; 95% CI: 1.087-10.960; P=0.036) was associated with a favorable response to ketamine on multivariate analysis. Adverse events were mostly mild, with the commonest being drowsiness (45.7%), hypertension (34.3%) and nightmares (25.7%). Only five and three patients required temporary suspension and early termination of ketamine infusion respectively. These data demonstrated the efficacy and safety of ketamine in a population of patients with refractory cancer pain. The use of more than one coanalgesic was associated with a favorable response to ketamine. Further large and multicentered studies are warranted to confirm these data.

Pertussis (Keuchhusten)

Pertussis wird durch das gramnegative Bakterium Bordetella pertussis verursacht. Die Krankheitsmanifestationen reichen von unspezifischem Husten bis zu lebensbedrohlichen Verläufen mit Hyperleukozytose und respiratorischer Insuffizienz, v.a. bei jungen Säuglingen. Die Diagnose basiert auf klinischer Symptomatik und mikrobiologischen Nachweisverfahren. Die Therapie besteht aus Makrolidantibiotika; bei Apnoen kann Koffein versucht werden. Die Inzidenz beträgt 10–40 Fälle/100.000 Bevölkerung und Jahr, bei Säuglingen ist sie am höchsten (ca. 50), gefolgt von Jugendlichen (30–35). Mehr als 50 % der in den ersten 5 Lebensmonaten an Pertussis erkrankten Kinder werden hospitalisiert. Die Impfprävention umfasst Grundimmunisierung und regelmäßige Auffrischimpfungen mit azellulären Impfstoffen. Um schwere Verläufe bei jungen Säuglingen zu verhindern, ist die Impfung schwangerer Frauen am erfolgversprechendsten. Säuglinge geimpfter Mütter sollen zeitgerecht ab dem Alter von 2 Monaten für den Eigenschutz immunisiert werden.

42 Poster Discussion - Tumor drug exposure is positively correlated with an improved outcome, in patients with advanced solid tumors, upon treatment with a high dose intermittent sunitinib regimen

Background: Innovative strategies for the clinical use of multitargeting tyrosine kinase inhibitors (TKIs), like sunitinib, are needed to fully exploit their antitumor activity. The inhibitory activity of these drugs depends on the tumor drug concentration, its affinity for kinases and kinase activity in tumor cells. Their broader inhibitory capacity at high concentrations might be essential for optimal suppression of tumor growth and induction of apoptosis. In a recent phase I trial NCT02058901, we administered high dose intermittent sunitinib 300 mg once a week and 700 mg once every two weeks, to patients with advanced tumors. This strategy resulted in higher peak plasma concentrations compared to regular dosing of sunitinib, without drug accumulation and with promising clinical benefit. We hypothesized that these plasma concentrations subsequently lead to higher tumor drug concentrations. Here, we determined tumor- and skin tissue drug concentrations of patients participating in this trial and related them to the plasma concentrations and clinical outcome.