Infusion Regimen Research Articles

Chronic intermittent convection-enhanced delivery of vigabatrin to the bilateral subthalamic nucleus in an acute rat seizure model

Targeted intracerebral drug delivery is an attractive experimental approach for the treatment of drug-resistant epilepsies. In this regard, the subthalamic nucleus (STN) represents a focus-independent target involved in the remote modulation and propagation of seizure activity. Indeed, acute and chronic pharmacological inhibition of the STN with vigabatrin (VGB), an irreversible inhibitor of GABA transaminase, has been shown to produce antiseizure effects. This effect, however, is lost over time as tolerance develops with chronic, continuous intracerebral pharmacotherapy. Here we investigated the antiseizure effects of chronic intermittent intra-STN convection-enhanced delivery of VGB in an acute rat seizure model focusing on circumventing tolerance development and preventing adverse effects. Timed intravenous pentylenetetrazol (PTZ) seizure threshold testing was conducted before and after implantation of subcutaneous drug pumps and bilateral intra-STN cannulas. Drug pumps infused vehicle or VGB twice daily (0.4 µg) or once weekly (2.5 µg, 5 µg) over three weeks. Putative adverse effects were evaluated and found to be prevented by intermittent compared to previous continuous VGB delivery. Clonic seizure thresholds were more clearly raised by intra-STN VGB compared to myoclonic twitch. Both twice daily and once weekly intra-STN VGB significantly elevated clonic seizure thresholds depending on dose and time point, with responder rates of up to 100% observed at tolerable doses. However, tolerance could not be completely avoided, as tolerance rates of 40–75% were observed with chronic VGB treatment. Results indicate that the extent of tolerance development after intermittent intra-STN VGB delivery varies depending on infusion dose and regimen.

Are We Dosing Correctly? Population Pharmacokinetic Modeling of Cefepime, Piperacillin-Tazobactam, and Meropenem in Individuals with Cystic Fibrosis

Abstract Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. The management of these infections becomes increasingly complex due to decreased antimicrobial susceptibility and inadequate pharmacokinetic/pharmacodynamic (PK/PD) characterization of the most commonly used antimicrobial agents in this population. Methods One hundred fifty-five pediatric and adult participants receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK (PopPK) analysis was conducted using nonlinear mixed effects modeling in NONMEM, and clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) for different dosing regimens. Multiple targets, defined as percentage of a 24-h time period that the free drug concentration exceeds the MIC (fT> MIC), were selected based on prior studies of beta-lactam antibiotics. Results Preliminary PopPK modeling results show that lean body weight, creatinine clearance, daily dose, mode of administration (standard vs. extended infusion), and age affect PK parameters, with varying effects by drug. As anticipated, extended or continuous infusions resulted in higher PTA (Table 1). In the cefepime group, the 3-h infusion regimen achieved higher PTAs than the 0.5-h regimen across all age groups. Estimated breakpoints (in which ≥ 90% of patients are expected to achieve a PK/PD target) were 2-4 fold higher in pediatric participants receiving a 3-h infusion vs. 0.5-h infusion, based on age and target fT> MIC. In the meropenem group, increased creatinine clearance led to reduced PTA, and in the piperacillin-tazobactam group, total daily dose and interval were the principal drivers of PTA. Conclusions To our knowledge, this is the largest PopPK study to date of these antimicrobials in individuals with CF. Clinicians should incorporate local antibiograms with these PopPK models to determine optimal dosing in patients with CF, since standard dosing regimens may fail to achieve specific PK/PD targets. This population may also benefit from beta-lactam therapeutic drug monitoring.

Stable IL‐2 Nano‐Assembly for Improved Anti‐Tumor Effect

AbstractInterleukin 2 (IL‐2) is the first approved immune therapeutic drug to treat cancer, however various off‐target effects and intolerable dose‐related toxicities induced by high‐dose intravenous infusion regimens result in a large proportion of patients require dose reduction, preventing the widespread adoption of this treatment. To address these issues, a novel IL‐2 nano‐assembly formulation (nano‐IL‐2) is developed using distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐n‐[methoxy (polyethylene glycol)‐2000] (PEG2000‐DSPE), which is durably stable due to the high binding affinity (10–8 m level) of two components and hardly induces vascular leak or inflamed injury at the injection site. Besides, nano‐IL‐2 exerts excellent solubility, lymph‐targeting property, prolonged and stable serum IL‐2 concentration ranges, and much lower toxicities compared to commercial formulation. Monotherapy of nano‐IL‐2 shows optimal capability to control the growth of murine melanoma and colon cancer. Collectively, the present study provides a novel design strategy for lymph‐targeting IL‐2 formulation which is more suitable for subcutaneous administration with higher safety concern.

A comparative analysis of tranexamic acid dosing strategies in traumatic major hemorrhage.

Tranexamic acid (TXA) is a life-saving treatment for traumatic hemorrhage, but the optimal dosing regimen remains unknown. Different doses and treatment strategies have been proposed, including single bolus, repeated bolus, or bolus plus infusion. The aim of this study was to determine the effect of different TXA dosing strategies on clinical outcomes in bleeding trauma patients. Secondary analysis of a perpetual cohort study from a UK Level I trauma center. Adult patients who activated the local major hemorrhage protocol and received TXA were included. The primary outcome was 28-day mortality. Secondary outcomes were 24-hour mortality, multiple organ dysfunction syndrome, venous thromboembolism, and rotational thromboelastometry fibrinolysis. Over an 11-year period, 525 patients were included. Three dosing groups were identified: 1 g bolus only (n = 317), 1 g bolus +1 g infusion over 8 hours (n = 80), and 2 g bolus (n = 128). Demographics and admission physiology were similar, but there were differences in injury severity (median Injury Severity Score, 25, 29, and 25); and admission systolic blood pressure (median Systolic Blood Pressure, 99, 108, 99 mm Hg) across the 1-g, 1 g + 1 g, and 2-g groups. 28-day mortality was 21% in each treatment group. The incidence of multiple organ dysfunction syndrome was significantly higher in the bolus plus infusion group (84%) vs. 1 g bolus (64%) and 2 g bolus (62%) group, p = 0.002, but on multivariable analysis was nonsignificant. Venous thromboembolism rates were similar in the 1-g bolus (4%), 2 g bolus (8%) and bolus plus infusion groups (7%). There was no difference in rotational thromboelastometry maximum lysis at 24 hours: 5% in both the 1-g and 2-g bolus groups vs. 4% in bolus plus infusion group. Clinical outcomes and 24-hour fibrinolysis state were equivalent across three different dosing strategies of TXA. Single bolus administration is likely preferable to a bolus plus infusion regimen. Therapeutic/Care Management; Level III.

Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.

Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For β-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

Intraoperative Insulin Infusion Regimen versus Insulin Bolus Regimen for Glucose Management during CABG Surgery: A Randomized Clinical Trial

Background and Aim: The stress induced by surgery disrupts the delicate balance between hepatic glucose production and glucose utilization in the body. Despite the significance of intraoperative glycaemic control for diabetic patients, limited attention has been given to this aspect. Two methods for administering insulin to manage glucose levels during surgery exist. This study aimed to compare intraoperative glucose levels in diabetic patients undergoing Coronary Artery Bypass Graft (CABG) surgery using either insulin infusion or the bolus method. Method: This was a Randomized Clinical Trial (RCT). Seventy diabetic patients aged 40 or older scheduled for CABG surgery were enrolled in the trial. They were randomly assigned, using block randomization, to receive intraoperative insulin via either infusion or the bolus method. The primary outcome measure was intraoperative glucose levels. Subsequent insulin unit requirements and intraoperative potassium levels were secondary outcomes. Data was monitored throughout the CABG procedure and recorded at six different checkpoints. Results: Male patients constituted the majority in both groups, with no significant differences in the preoperative characteristics of patients, including HbA1c levels and comorbidities. The infusion regimen demonstrated a statistically significant reduction in glucose levels (-19.12 mg/dL, 95% CI: -27.68 to -10.55, P<0.001, Cohen's d=1.06) compared to the bolus regimen. The total insulin units administered in the infusion group were 480 units, as opposed to 600 units in the bolus group (P=0.001, Cohen's d=0.85). Importantly, no cases of hypoglycemia or hyperkalemia were reported among the patients. Conclusion: Intraoperative glucose control using insulin was effective for CABG patients with diabetes. However, the infusion regimen exhibited statistically superior results compared to the bolus regimen. Clinical Trials Registry and Registration Number: The trial received approval from the Ethics Committee on 2/1/2019/2020 and was registered on Clinicaltrials.gov under ID: NCT04824586.

Clinical Syndrome of Seizures, Headache, and Visual Blurring in Metastatic Carcinoma Colon

AbstractA 51-year-old lady diagnosed as a case of metastatic carcinoma colon stage IV involving lung and left adrenal metastasis was initiated with palliative chemotherapy with FOLFOX-6 chemotherapy infusion regimen that consisted of 5-flurouracil, calcium leucovorin, and oxaliplatin and injection bevacizumab was added to cycle seven of FOLFOX-6 chemotherapy. After 2 months of initiating bevacizumab, she was presented with one episode of generalized tonic clonic seizure, headache, and visual blurring of 2 days duration and magnetic resonance imaging brain T2 fluid-attenuated inversion recovery image revealed subcortical white matter edema in bilateral frontoparietal, occipital, left temporal lobes (Fig. 1A and B), and hyperintense edema with effacement of folia in both cerebellum with nodular areas of contrast enhancement suggestive of posterior reversible encephalopathy syndrome.

Role of Crystalloids in the Perioperative Setting: From Basics to Clinical Applications and Enhanced Recovery Protocols.

Perioperative fluid management, a critical aspect of major surgeries, is characterized by pronounced stress responses, altered capillary permeability, and significant fluid shifts. Recognized as a cornerstone of enhanced recovery protocols, effective perioperative fluid management is crucial for optimizing patient recovery and preventing postoperative complications, especially in high-risk patients. The scientific literature has extensively investigated various fluid infusion regimens, but recent publications indicate that not only the volume but also the type of fluid infused significantly influences surgical outcomes. Adequate fluid therapy prescription requires a thorough understanding of the physiological and biochemical principles that govern the body's internal environment and the potential perioperative alterations that may arise. Recently published clinical trials have questioned the safety of synthetic colloids, widely used in the surgical field. A new clinical scenario has arisen in which crystalloids could play a pivotal role in perioperative fluid therapy. This review aims to offer evidence-based clinical principles for prescribing fluid therapy tailored to the patient's physiology during the perioperative period. The approach combines these principles with current recommendations for enhanced recovery programs for surgical patients, grounded in physiological and biochemical principles.

Safety and feasibility of 120 min rapid infusion regimen of daratumumab in patients with multiple myeloma

Safety and feasibility of 120 min rapid infusion regimen of daratumumab in patients with multiple myeloma

PPARγ-dependent hepatic macrophage switching acts as a central hub for hUCMSC-mediated alleviation of decompensated liver cirrhosis in rats

BackgroundDecompensated liver cirrhosis (DLC), a terminal-stage complication of liver disease, is a major cause of morbidity and mortality in patients with hepatopathies. Human umbilical cord mesenchymal stem cell (hUCMSC) therapy has emerged as a novel treatment alternative for the treatment of DLC. However, optimized therapy protocols and the associated mechanisms are not entirely understood.MethodsWe constructed a DLC rat model consistent with the typical clinical characteristics combined use of PB and CCL4. Performing dynamic detection of liver morphology and function in rats for 11 weeks, various disease characteristics of DLC and the therapeutic effect of hUCMSCs on DLC in experimental rats were thoroughly investigated, according to ascites examination, histopathological, and related blood biochemical analyses. Flow cytometry analysis of rat liver, immunofluorescence, and RT-qPCR was performed to examine the changes in the liver immune microenvironment after hucMSCs treatment. We performed RNA-seq analysis of liver and primary macrophages and hUCMSCs co-culture system in vitro to explore possible signaling pathways. PPARγ antagonist, GW9662, and clodronate liposomes were used to inhibit PPAR activation and pre-exhaustion of macrophages in DLC rats’ livers, respectively.ResultsWe found that changing the two key issues, the frequency and initial phase of hUCMSCs infusion, can affect the efficacy of hUCMSCs, and the optimal hUCMSCs treatment schedule is once every week for three weeks at the early stage of DLC progression, providing the best therapeutic effect in reducing mortality and ascites, and improving liver function in DLC rats. hUCMSCs treatment skewed the macrophage phenotype from M1-type to M2-type by activating the PPARγ signaling pathway in the liver, which was approved by primary macrophages and hUCMSCs co-culture system in vitro. Both inhibition of PPARγ activation with GW9662 and pre-exhaustion of macrophages in DLC rats’ liver abolished the regulation of hUCMSCs on macrophage polarization, thus attenuating the beneficial effect of hUCMSCs treatment in DLC rats.ConclusionsThese data demonstrated that the optimal hUCMSCs treatment effectively inhibits the ascites formation, prolongs survival and significantly improves liver structure and function in DLC rats through the activation of the PPARγ signaling pathway within liver macrophages. Our study compared the efficacy of different hUCMSCs infusion regimens for DLC, providing new insights on cell-based therapies for regenerative medicine.

Individualized antibiotic dosage regimens for patients with augmented renal clearance.

Objectives: Augmented renal clearance (ARC) is a state of enhanced renal function commonly observed in 30%-65% of critically ill patients despite normal serum creatinine levels. Using unadjusted standard dosing regimens of renally eliminated drugs in ARC patients often leads to subtherapeutic concentrations, poor clinical outcomes, and the emergence of multidrug-resistant bacteria. We summarized pharmaceutical, pharmacokinetic, and pharmacodynamic research on the definition, underlying mechanisms, and risk factors of ARC to guide individualized dosing of antibiotics and various strategies for optimizing outcomes. Methods: We searched for articles between 2010 and 2022 in the MEDLINE database about ARC patients and antibiotics and further provided individualized antibiotic dosage regimens for patients with ARC. Results: 25 antibiotic dosage regimens for patients with ARC and various strategies for optimization of outcomes, such as extended infusion time, continuous infusion, increased dosage, and combination regimens, were summarized according to previous research. Conclusion: ARC patients, especially critically ill patients, need to make individualized adjustments to antibiotics, including dose, frequency, and method of administration. Further comprehensive research is required to determine ARC staging, expand the range of recommended antibiotics, and establish individualized dosing guidelines for ARC patients.

Oxytocin: physiology, pharmacology, and clinical application for labor management

Oxytocin is a peptide hormone that plays a key role in regulating the female reproductive system, including during labor and lactation. It is produced primarily in the hypothalamus and secreted by the posterior pituitary gland. Oxytocin can also be administered as a medication to initiate or augment uterine contractions. To study the effectiveness and safety of oxytocin, previous studies have randomized patients to low- and high-dose oxytocin infusion protocols either alone or as part of an active management of labor strategy along with other interventions. These randomized trials demonstrated that active management of labor and high-dose oxytocin regimens can shorten the length of labor and reduce the incidence of clinical chorioamnionitis. The safety of high-dose oxytocin regimens is also supported by no associated differences in fetal heart rate abnormalities, postpartum hemorrhage, low Apgar scores, neonatal intensive care unit admissions, and umbilical artery acidemia. Most studies reported no differences in the cesarean delivery rates with active management of labor or high-dose oxytocin regimens, thereby further validating its safety. Oxytocin does not have a predictable dose response, thus the pharmacologic effects and the amplitude and frequency of uterine contractions are used as physiological parameters for oxytocin infusion titration to achieve adequate contractions at appropriate intervals. Used in error, oxytocin can cause patient harm, highlighting the importance of precise administration using infusion pumps, institutional safety checklists, and trained nursing staff to closely monitor uterine activity and fetal heart rate changes. In this review, we summarize the physiology, pharmacology, infusion regimens, and associated risks of oxytocin.

Long-lasting responses with chemotherapy followed by T-cell therapy in recurrent or metastatic EBV-related nasopharyngeal carcinoma.

Refractory or metastatic nasopharyngeal carcinoma (NPC) patients have a poor prognosis due to the lack of effective salvage treatments and prolonged survival by means of combination chemotherapy being described only for a minority of younger patients with oligometastatic disease. Targeting the Epstein - Barr virus (EBV) proteins expressed in NPC cells has been shown to be a feasible strategy that could help control systemic disease. Between 2011 and 2014, 16 patients with recurrent/metastatic EBV-NPC received first-line chemotherapy (CT) followed by 2 doses of autologous cytotoxic EBV specific T-lymphocytes (15-25 x 107 total cells/dose, 2 weeks apart), based on our previous studies showing the feasibility and efficacy of this infusion regimen. Cumulative overall survival (OS) and median OS were analysed in the whole population and according to specific clinical and biological parameters. All patients received the planned T-cell therapy schedule, 9 after reaching partial (n=5) or complete (n=4) disease remission with CT, and 7 after failing to obtain benefit from chemotherapy. No severe adverse events were recorded. Patients who received cytotoxic T-lymphocytes (CTLs) had a cumulative 10-year OS of 44%, with a median OS of 60 months (95% CI 42-62). Patients responding to CT, with oligometastatic disease (<3 disease sites), and plasma EBV-DNA <1000 copies/mL had a better outcome. Autologous EBV-specific CTLs transplanted following conventional first-line CT demonstrated promising efficacy with several patients obtaining long-lasting disease control. The rationale provided by this study, with the crucial role likely played by the timing of CTL administration when trying to induce synergy with conventional treatment needs to be confirmed in a prospective controlled trial.

Management of Severe Hemophilia A: Low-Dose Prophylaxis vs. On-Demand Treatment.

Prophylactic clotting factor infusion regimens to prevent bleeding and joint deformity has become the standard of care in severe hemophilia A patients. To assess low-dose factor prophylaxis in our population as an alternative approach to managing severe hemophilia A. A prospective cohort study that included 68 hemophilia A patients divided into two groups, i.e., Prophylaxis and on-demand. The two groups were compared for annualized bleeding rate (ABR), hospitalization, units of factor VIII (FVIII) infused, or plasma products transfused, i.e., fresh frozen plasma (FFP) and cryoprecipitate (CP), and development of FVIII inhibitors. Of the 68 patients recruited in this study, 25 (36.7%) were in the prophylaxis group, and 43(63.3%) were in the on-demand group. The on-demand group presented a higher median-IQR ABR [8(20-3) vs. 5(10-1.5), p-value 0.024], several hospitalizations (39.7% vs. 0, p-value0.001), and inhibitor development (9.3% vs. 0, p-value 0.289) compared to the prophylaxis group. The prophylaxis approach demonstrated a significant negative correlation of ABR with FVIII prophylaxis (r=-0484, p=value=0.014). Moreover, no hospitalizations or inhibitor development was observed in the prophylaxis group. The estimated annual consumption of FVIII was 328 IU/kg/year in the on-demand group and 1662.6 IU/kg/year in the prophylaxis group. However, a highly significant difference in plasma product utilization was observed between the two groups, i.e., p-value <0.001 and 0.038 for FFP and CP, respectively. Low-dose factor prophylaxis resulted in improved outcomes compared to on-demand treatment in terms of ABR, joint bleeding, hospitalization, and the development of inhibitors. This treatment approach should be adopted as an economically feasible alternative to high-dose Prophylaxis in resource-constrained countries.

Navigating Access and Optimizing Medication Infusions in an Academic Medical Center: A Quality Improvement Study.

(1) Background: The rising prices of medical infusions have resulted in the increased utilization of policies for payors to manage costs. These policies can be disruptive to the continuity of care, and health systems should develop a systematic strategy to address market changes and prevent patient leakage. (2) Methods: A quality improvement study was conducted by an interdisciplinary workstream to assess the current state of infusion services in an academic medical center in the Midwest and to provide recommendations for immediate access improvement and long-term system planning. An organizational assessment of the value stream was completed, which analyzed the available infusion capacity, billing strategy, patient mix/volumes, payor mix, staffing levels, and current policies. The interventions implemented after developing the infusion system strategy were triaging patients to the appropriate site of care to increase infusion capacity and eliminating paper orders in one of the health system's Infusion Centers. (3) Results: Patients receiving medical infusions for oncologic conditions warrant unique considerations in evaluating the Infusion Center's efficiency due to the infusion regimen's length, complexity, and tolerability. The management of the payor site of care also poses a challenge for health systems to triage patients effectively without fragmenting care. (4) Conclusions: An organizational strategy around infusion services must include broad stakeholder representation to address the clinical, operational, and financial challenges to provide timely care to patients.

Biweekly vs Triweekly low dose intravenous ketamine acute series for severe major depression: A case report

BackgroundOne third of the patients with Major Depression Disorder (MDD) fail to respond to conventional antidepressant treatments - treatment resistant depression (TRD). Low-dose IV ketamine (LDIVK) treatment has become a promising solution for these patients. However, infusion regimens for LDIVK acute series have not been standardized yet. Also, evidence is scarce for retrialing LDIVK treatment to manage MDD symptom recurrences. MethodsThis is a case study of a 45-year-old female experiencing MDD TRD, who completed a triweekly and a biweekly acute course (4 week) of LDIVK treatment three years apart. Treatment effectiveness was assessed by comparing baseline to weekly depression severity scores using validated psychiatric scales to determine changes in depression symptoms. Tolerability was assessed by systematically registering side effects through the infusions. ResultsIn both acute series, the patient achieved symptomatic response equivalent to remission. On the triweekly acute course the patient achieved symptom remission by the second week and in the biweekly acute course by the third week. Reported side effects were mild and transient. LimitationsResults of only one patient included in this report and a different number of LDIVK infusions in each acute course, with the triweekly vs biweekly course providing four additional infusions in four weeks. ConclusionsThese results suggest that implementing a triweekly regimen may be well-tolerated and result in a faster treatment response in certain patients, compared to a biweekly regimen. Furthermore, this case also supports the possibility of a ketamine retrial in case of major depressive recurrences.

DIPG-16. ACUTE VERSUS PROLONGED CONVECTION-ENHANCED DELIVERY OF ALISERTIB INTO H3 K27M-MUTANT MODELS OF DIFFUSE MIDLINE GLIOMA

Abstract Convection-enhanced delivery (CED) is a potentially promising strategy to administer therapeutics directly into the brainstem of children harboring H3 K27-altered diffuse midline glioma (DMG). While early-phase clinical trials have demonstrated the safety of this technique, efficacy has yet to be achieved. Here, we describe how different variations of CED may be exploited to extend survival in a DMG murine patient-derived orthotopic xenograft model. Either 1-day (8 µL/hr) or 7-day (1 µL/hr) continuous CED infusions were performed to deliver an equivalent volume of the aurora kinase inhibitor alisertib to the mouse brainstem. Bioluminescence and magnetic resonance images were acquired to monitor tumor progression, validate CED catheter positioning, and analyze infusion-related imaging changes. Both infusion regimens significantly prolonged survival versus control (median survival benefit of 6.5 and 8 days, p=0.03 and p=0.01, for 1-day and 7-day CED, respectively). Postmortem examination of brains revealed no signs of tissue necrosis, cavitary lesions, or cellular (inflammatory) infiltrate at the site of infusion. However, the tumor parenchyma surrounding the cannula tract was markedly hypocellular in treated animals. Alisertib induced a robust increase in H3 K27 trimethylation along with decreased H3 K27M and Ki-67. Our findings indicate that CED of alisertib is well tolerated and effective, in both the acute and prolonged setting, underscoring the potential of this approach in the management of DMG.

Pre-operative sciatic nerve block vs postoperative surgeon-placed perineural stump catheter for prevention of phantom limb pain after below-knee amputation.

Pre-operative sciatic nerve block vs postoperative surgeon-placed perineural stump catheter for prevention of phantom limb pain after below-knee amputation.

P402 PROSTHETIC MECHANICAL VALVE THROMBOSIS: THE EXPERIENCE OF SALAM CENTRE FOR CARDIAC SURGERY (EMERGENCY NGO)

Abstract Mechanical heart valve (MHV) replacement in patients with rheumatic valve disease is common in Africa. MHV requires long–life anticoagulation (OAT) and managing this can be difficult. Prosthetic valve thrombosis (VT) is a pathological entity characterized by thrombus formation on the prosthetic structures, with subsequent prosthesis dysfunction. Salam Centre for Cardiac Surgery was built in Khartoum Sudan by Emergency NGO. Since April 2007 high–quality and free–of–charge medical and cardio–surgical treatment has been offered to patients. More than 10000 cardiac surgery, 80% of which for MHV replacement, were performed. The aim of the work is to analyze the characteristics of patients with VT, the risk factors and clinical follow–up. From Aug 1, 2018 to Nov 30, 2022, 287 VT involving 237 patients were collected.The incidence is 1.36% p/y. The most relevant risk factor was the interruption of anticoagulant therapy and irregular INR control (N. 142; 49,5%). In 101 cases (35,2%) a clinical factor (infection, pregnancy, eosinophilia, heart failure) was the main cause of VT. The diagnosis, suspected with the Transthoracic Echo and confirmed with fluoroscopy, was done at the OPD visit (32,4%) in asymptomatic or at triage for symptomatic patients (67,6%). 236 patients were admitted to Salam Centre.The treatments of choice were thrombolysis, performed with 2 different protocols, fast and low dose–slow infusion (Alteplase 25 mg./6 hrs), followed by Triple Therapy (TT) (Warfarin, LMWH and Aspirin) (N.189–65,8%), TT alone (N.44– 15,3%) or Warfarin and Aspirin (N.54–18,8%). 210 events (73,2%) ended with unblocked valve,24 events ended with the death of the patient (8,3%); low dose/slow infusion regimen had less deaths. Thrombolysis was more effective (unblockage 79,9%). Warfarin and Aspirin and not admission to Salam Centre were linked to less unblokage and high mortality rate. Conclusions The incorrect conduct of OAT represents the most relevant risk factor for VT.Many are the underlying causes, from economic and social factors to insufficient patient awareness. MOH intervention to offer free of charge INR check, but also patient education must be improved. VT is caused also by intercurrent clinical events such as pregnancy, infection. Eosinophilia represents a chapter that deserves a detailed study.Patients with history of VT must be followed by a dedicated clinic that aims to increase patient loyalty in order to intercept risk factors as early as possible.

Efficacy of avelumab in the treatment of oncourological malignances. Results of registration studies and own experience

Background. In the JAVELIN Bladder 100 trial, 1st line maintenance with avelumab in combination with best supportive care significantly increased (9.2 months) overall survival compared to best supportive care in patients with locally advanced or metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy: 29.7 months versus 20.5 months, respectively. Trial results led to inclusion of avelumab into the international guidelines as a standard of care with the highest level of evidence. Combined therapy with avelumab + axitinib in patients with previously untreated metastatic renal cell carcinoma showed higher progression-free survival and objective response rate compared to sunitinib in all IMDC (International Metastatic Renal Cancer Database Consortium) groups. Avelumab + axitinib is one of the immuno-oncology combinations with proven effectiveness for progression-free survival and objective response rate.Aim. To evaluate the effectiveness of avelumab in treatment of oncological urological diseases in routine clinical practice. Materials and methods. At the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology - branch of the National Medical Research Radiology Center, 12 patients with locally advanced inoperable and metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy in combination with gemcitabine received maintenance avelumab therapy. Median follow-up was 10 months. Primary endpoints were overall survival from the start of avelumab maintenance therapy and safety.Combined therapy with avelumab + axitinib was administered in 18 patients with metastatic renal cell carcinoma. Median follow-up was 9 (3-16) months. Overall survival, progression-free survival, response rate and safety in the overall population and according to IMDC groups were evaluated.Results. At data cut-off (March 2023) with median follow-up of 10 months, overall survival was 100 %, progression-free survival was 66.7 % (among patients who received more than 3 infusions - 100 %). Progression-free survival was higher in patients with tumors of the lower urinary tract compared to upper (72.5 % versus 60 %), complete response to induction platinum-based chemotherapy compared to partial response and stable disease (100 % versus 66.7 %) and presence of metastases in the lymph nodes only compared to visceral and bone metastases (100 % versus 66.7 %). Adverse events were observed in 4 (66.7 %) patients.Among 18 patients who received avelumab + axitinib, complete response was observed in 2 (11.1 %) patients, partial response in 6 (33.3 %) patients, stable disease in 9 (50 %) patients, disease progression in 1 (5.6 %) patient. Response to therapy was observed in patients of all prognosis groups; for large (&gt;5 cm) metastases in the lungs, soft tissues, lymph nodes and bones response was observed 3 months after treatment start. Overall survival for this follow-up duration was 100 %, progression-free survival was 96.4 ± 11.2 %. Adverse events were observed in 8 (44.4 %) patients, and in 6 (75 %) of them they were grade I—II and did not require infusion regimen correction or axitinib dose reduction.Conclusion. Avelumab maintenance therapy in the 1st line is the standard of care for patients with locally advanced and metastatic urothelial cancer without disease progression during 1st line platinum-based chemotherapy. Maintenance therapy allows to achieve better overall survival and progression-free survival irrespective of the choice of platinum regimen (cisplatin or carboplatin), response to platinum-based chemotherapy, number of chemotherapy cycles, tumor localization and advancement.Experience of the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology confirms results of the JAVELIN Bladder 100 trial on the effectiveness of avelumab maintenance therapy in routine clinical practice. Combination drug therapy with avelumab and axitinib in patients with metastatic renal cell carcinoma is an effective and safe treatment method which allows to achieve fast objective response and has good tolerability in patients irrespective of IMDC group or metastasis location. Effectiveness and favorable safety profile of avelumab + axitinib combination were proven in the context of routine clinical practice.