Estrogen and Progesterone Therapy and Meningiomas

Meningiomas are common intracranial tumors with female predominance. Their etiology is still poorly documented. The role of sexual hormones has long been evoked, and data have been conflicting across studies. However, a dose-dependent relationship between the incidence and growth of meningiomas and hormonal treatment with the progestin cyproterone acetate (CPA) has recently been established. CPA- associated meningiomas seem to be mainly located in the anterior and middle skull base, are more likely to be multiple; may harbor P1K3CA mutations in up to 1/3 of cases and are favored by a longer duration of treatment. A similar but lower risk of meningiomas has been recently reported with the use of chlormadinone acetate and nomegestrol acetate as progestin treatments. Concerning hormonal replacement therapy (HRT) in menopausal patients, evidence from epidemiological studies seem to favor an increased risk of meningiomas in treated patients although a recent study failed to show an increased growth of meningiomas in HRT treated vs. non treated patients. Until larger studies are available, it seems wise to recommend avoiding HRT in patients with meningiomas. Evidence from published data does not seem to support an increased risk of meningiomas with oral contraceptive (OC) use. Data are too scarce to conclude on fertility treatments. Based on studies demonstrating the expression of hormonal receptors in meningiomas, therapies targeting these receptors have been tried but have failed to show an overall favorable clinical outcome in meningioma treatment.

Impact of Maximizing Css/MIC Ratio on Efficacy of Continuous Infusion Meropenem Against Documented Gram-Negative Infections in Critically Ill Patients and Population Pharmacokinetic/Pharmacodynamic Analysis to Support Treatment Optimization

Introduction: optimal treatment of Gram-negative infections in critically ill patients is challenged by changing pathophysiological conditions, reduced antimicrobial susceptibility and limited therapeutic options. The aim of this study was to assess the impact of maximizing Css/MIC ratio on efficacy of continuous infusion (CI) meropenem in treating documented Gram-negative infections in critically ill patients and to perform a population pharmacokinetic/pharmacodynamic analysis to support treatment optimization.Materials and Methods: Classification and regression tree (CART) analysis was used to identify whether a cutoff of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) (Css/MIC) ratio correlated with favorable clinical outcome. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. The probability of target attainment (PTA) of the identified Css/MIC ratio was calculated by means of Monte Carlo simulations. Cumulative fraction of response (CFRs) were calculated against common Enterobacterales, P. aeruginosa and A. baumannii as well.Results: a total of 74 patients with 183 meropenem Css were included. CART analysis identified a Css/MIC ratio ≥4.63 as cutoff value significantly associated with favorable clinical outcomes. Multivariate regression analysis confirmed the association [OR (95%CI): 20.440 (2.063–202.522); p < 0.01]. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that, across different classes of renal function, dosages of meropenem ranging between 0.5 and 2 g q6h over 6 h (namely by CI) may grant PTAs of Css/MIC ratios ≥4.63 against susceptible pathogens with an MIC up to the EUCAST clinical breakpoint of 2 mg/L. The CFRs achievable with these dosages were very high (>90%) against Enterobacterales across all the classes of renal function and against P. aeruginosa among patients with CLCR < 30 ml/min/1.73 m2, and quite lower against A. baumannii.Discussion: our findings suggest that Css/MIC ratio ≥4.63 may be considered the pharmacodynamic target useful at maximizing the efficacy of CI meropenem in the treatment of Gram-negative infections in critically ill patients. Dosages ranging between 0.5 g q6h and 2 g q6h by CI may maximize the probability of favorable clinical outcome against meropenem-susceptible Gram-negative pathogens among critically ill patients having different degrees of renal function.

Point-of-care ultrasound in cardiorespiratory arrest (POCUS-CA): narrative review article

The POCUS-CA (Point-of-care ultrasound in cardiac arrest) is a diagnostic tool in the Intensive Care Unit and Emergency Department setting. The literature indicates that in the patient in a cardiorespiratory arrest it can provide information of the etiology of the arrest in patients with non-defibrillable rhythms, assess the quality of compressions during cardiopulmonary resuscitation (CPR), and define prognosis of survival according to specific findings and, thus, assist the clinician in decision-making during resuscitation. This narrative review of the literature aims to expose the usefulness of ultrasound in the setting of cardiorespiratory arrest as a tool that allows making a rapid diagnosis and making decisions about reversible causes of this entity. More studies are needed to support the evidence to make ultrasound part of the resuscitation algorithms. Teamwork during cardiopulmonary resuscitation and the inclusion of ultrasound in a multidisciplinary approach is important to achieve a favorable clinical outcome.

Correlation between immune-related adverse events and therapeutic effects of nivolumab in patients with malignant pleural mesothelioma

Background Nivolumab is used for the treatment of malignant pleural mesothelioma (MPM). However, immune-related adverse events (irAEs) occur in patients treated with nivolumab. Several studies have reported the correlation between irAEs and therapeutic effects of immune checkpoint inhibitor, but none have reported the correlation in MPM. Here we report a retrospective study which shows the correlation between irAEs and therapeutic effects of nivolumab in patients with MPM. Methods This study included patients treated with nivolumab at Tokushima University Hospital from February 2009 to September 2021. We retrospectively reviewed the medical records to evaluate the several clinical factors, such as the presence or absence of irAEs, their severities, progression-free survival (PFS), overall survival (OS) or objective response to the treatment. Results Eleven patients received treatment with nivolumab. Objective response rate was 18.2% and the disease control rate was 90.9%. Median PFS was 6.8 months (95% confidence interval, 1.3 to 11.9 months) and median OS was 15.2 months (95% confidence interval, 8.9 to 21.5 months). IrAEs occurred in eight patients (72.7%), and grade ≥ 2 irAEs occurred in six patients (54.5%). PFS and OS were significantly longer in the grade ≥ 2 irAEs group than in grade < 2 irAEs group (median PFS 13.6 vs. 3.8 months, p = 0.0093; median OS not reached vs. 8.6 months, p = 0.0108). Conclusions This is the first study to report the correlation between irAEs and therapeutic effects in patients with MPM. Because the presence of irAEs may be associated with a favorable clinical outcome, early detection and appropriate management of irAEs will increase the therapeutic benefits to patients.

Predictors of favorable outcome after endovascular thrombectomy for acute ischemic stroke due to large vessel occlusion in young patients

Background Mechanical thrombectomy (MT) became a standard of care for patients with acute ischemic stroke (AIS) with its efficacy demonstrated by meta-analysis and randomized studies. Although ischemic stroke is associated more with older patients, it may also have devastating neurological effects on young patients. Purpose To present our experience with stroke patients aged <50 years treated with endovascular means and to evaluate clinical and procedural factors associated with outcome and mortality. Material and Methods This study was conducted on 34 young stroke patients treated with MT. Clinical features including baseline results, radiological imaging, procedural details, and outcome results were documented and evaluated. Recanalization was assessed according to the TICI score. The clinical condition was evaluated after three months using mRS. Mortality rate was calculated. Results The rate of successful recanalization (TICI ≥2c) was 79% (27/34). Symptomatic intracranial hemorrhage (sICH) was observed in 5 (15%) patients. After 90 days, the mortality rate was 12%. Favorable clinical outcome (mRs 0–2) was regained in 65% of the patients whereas satisfactory clinical outcome was seen in 85%. Poor clinical outcome (mRs >2) was observed in 9 (23.7%) patients. Conclusion In conclusion, the results of this study demonstrate that MT for AIS in young patients is feasible and provides an excellent rate of arterial recanalization and high rate of favorable outcomes. Statistical analysis showed that shorter time from onset to arrival and reperfusion, successful recanalization and absence of hemorrhagic transformation are the predictors of favorable clinical outcome and overall survival rate.

Abstract 1122‐000049: Safety and Efficacy of Daily Intra‐Arterial Endovascular Therapy for Refractory Cerebral Vasospasm Following Subarachnoid Hemorrhage

Introduction : Delayed cerebral ischemia (DCI) and cerebral infarction (CI) due to vasospasm is a major cause of death and disability after aneurysmal subarachnoid hemorrhage (aSAH). Transluminal balloon angioplasty (BA) and super‐selective intra‐arterial (IA) infusion of vasodilators are considered for refractory vasospasm. We examined the safety and efficacy of repeated daily IA treatment in vasospasm. Methods : We reviewed records a single center of vasospasm treatment for aSAH from 2016 through 2019. Primary endpoints were rate of cerebral infarctions and safety related to daily treatments. Secondary endpoints were mortality and favorable clinical outcome at hospital discharge defined as modified Rankin scale of scores 0–2. Results : Of 426 patients with SAH, 197 were aneurysmal with 79 with DCI. Forty‐five out of 79 underwent IA treatment, of which 14 underwent 1 or 2 treatments (Group 1) and 31 underwent ≥3 treatments (Group2). Incidence of CI were similar (Group 1: 42.8%; Group 2: 54.8%, p = 0.45) Good clinical outcomes at discharge were seen in 36% in Group 1 and 16% in Group 2 (p = 0.15). Mortality was 7% in group 1 and 26% in group 2 (p = 0.17). Conclusions : Complications including vessel dissection, systemic hypotension and seizures did not increase with repeated treatments. CI was not noted to differ, but the outcomes were worse in group 2 which may relate to severity of SAH rather than DCI.

P.205 Association Between Vein of Galen Aneurysmal Malformation and Hirayama Disease: A Clue into Pathophysiology?

Background: Hirayama Disease (HD) is a rare disorder consisting of insidious onset of unilateral weakness and atrophy of the forearm and intrinsic hand muscles. Vein of Galen aneurysmal malformations (VGAMs) are rare congenital cerebral vascular malformations, consisting of high-flow arteriovenous shunting between a persistent median prosencephalic vein and arterial feeders. Methods: 14 years old boy known for VGAM presented with left-sided HD. His cervical MRI revealed enlarged epidural with anterior, left-ward displacement of the posterior dura and spinal cord. He underwent surgical treatment by laminotomies, along with tenting of an autologous duroplasty to the overlying laminae. Results: We decided to combine epidural venous plexus coagulation with posterior duraplasty and dural fixation using tenting suture which led to a favorable clinical outcome has not been previously proposed in the literature. We hypothesize that in this context, an abnormal vasculature could also predispose to posterior epidural venous plexus engorgement, anterior dural displacement in cervical flexion, and microvascular changes in the anterior spinal arterial circulation, leading to the progressive anterior horn cell ischemia that lead to the clinical phenotype of HD. Conclusions: The association between HD and VGAM in this patient may provide clues with regard to the pathophysiology of HD.

Accuracy and Prognostic Role of NCCT-ASPECTS Depend on Time from Acute Stroke Symptom-onset for both Human and Machine-learning Based Evaluation

Purpose We hypothesize that the detectability of early ischemic changes on non-contrast computed tomography (NCCT) is limited in hyperacute stroke for both human and machine-learning based evaluation. In short onset-time-to-imaging (OTI), the CT angiography collateral status may identify fast stroke progressors better than early ischemic changes quantified by ASPECTS. Methods In this retrospective, monocenter study, CT angiography collaterals (Tan score) and ASPECTS on acute and follow-up NCCT were evaluated by two raters. Additionally, a machine-learning algorithm evaluated the ASPECTS scale on the NCCT (e-ASPECTS). In this study 136 patients from 03/2015 to 12/2019 with occlusion of the main segment of the middle cerebral artery, with a defined symptom-onset-time and successful mechanical thrombectomy (MT) (modified treatment in cerebral infarction score mTICI = 2c or 3) were evaluated. Results Agreement between acute and follow-up ASPECTS were found to depend on OTI for both human (Intraclass correlation coefficient, ICC = 0.43 for OTI < 100 min, ICC = 0.57 for OTI 100–200 min, ICC = 0.81 for OTI ≥ 200 min) and machine-learning based ASPECTS evaluation (ICC = 0.24 for OTI < 100 min, ICC = 0.61 for OTI 100–200 min, ICC = 0.63 for OTI ≥ 200 min). The same applied to the interrater reliability. Collaterals were predictors of a favorable clinical outcome especially in hyperacute stroke with OTI < 100 min (collaterals: OR = 5.67 CI = 2.38–17.8, p < 0.001; ASPECTS: OR = 1.44, CI = 0.91–2.65, p = 0.15) while ASPECTS was in prolonged OTI ≥ 200 min (collaterals OR = 4.21,CI = 1.36–21.9, p = 0.03; ASPECTS: OR = 2.85, CI = 1.46–7.46, p = 0.01). Conclusion The accuracy and reliability of NCCT-ASPECTS are time dependent for both human and machine-learning based evaluation, indicating reduced detectability of fast stroke progressors by NCCT. In hyperacute stroke, collateral status from CT-angiography may help for a better prognosis on clinical outcome and explain the occurrence of futile recanalization.

Retrospective evaluation of intravenous fosfomycin in multi-drug resistant infections at a tertiary care hospital in Lebanon

Introduction: Fosfomycin has re-emerged as a possible therapeutic alternative for the treatment of resistant bacterial pathogens. Its main mechanism of action is the inhibition of the initial step of cell wall synthesis and is active against both Gram-positive and Gram-negative bacteria. However, its clinical effectiveness against multidrug resistant bacteria remains largely unknown. Therefore, we aim to evaluate the clinical and microbiological effectiveness of intravenous fosfomycin as well as its safety in a tertiary care teaching hospital in Lebanon. Methodology: This is a retrospective chart review of adult patients who had presented to the hospital and were treated with intravenous fosfomycin for at least 24 hours for any type of infection between 2014 and 2019. Results: Among 31 episodes treated with intravenous fosfomycin, 68% had an overall favorable clinical response. In 84% of the episodes, fosfomycin was administered in combination with other antibiotics, commonly tigecycline. Of those with available cultures at end of therapy, 73% achieved microbiological success. No relapse was documented within 30 days of completion of therapy. In the episodes secondary to resistant pathogens, the rates of favorable clinical outcome and microbiological success at the end of therapy were 71% and 73%, respectively. Fosfomycin resistance developed in two cases and mild adverse events occurred in 65% of the episodes during the course of treatment. Conclusions: Fosfomycin is a safe and effective option in the treatment of multi-drug resistant infections. Nevertheless, careful stewardship is important to maintain its efficacy and to reduce the risk of selection of antimicrobial resistance.

HBeAg Levels Vary across the Different Stages of HBV Infection According to the Extent of Immunological Pressure and Are Associated with Therapeutic Outcome in the Setting of Immunosuppression-Driven HBV Reactivation

HBeAg is a marker of HBV-activity, and HBeAg-loss predicts a favorable clinical outcome. Here, we characterize HBeAg-levels across different phases of HBV infection, their correlation with virological/biochemical markers and the virological response to anti-HBV therapy. Quantitative HBeAg (qHBeAg, DiaSorin) is assessed in 101 HBeAg+ patients: 20 with acute-infection, 20 with chronic infection, 32 with chronic hepatitis and 29 with immunosuppression-driven HBV-reactivation (HBV-R). A total of 15/29 patients with HBV-R are monitored for >12 months after starting TDF/ETV. qHBeAg is higher in immunosuppression-driven HBV-R (median[IQR]:930[206–1945]PEIU/mL) and declines in chronic hepatitis (481[28–1393]PEIU/mL, p = 0.03), suggesting HBeAg production, modulated by the extent of immunological pressure. This is reinforced by the negative correlation between qHBeAg and ALT in acute infection (Rho = −0.66, p = 0.006) and chronic hepatitis (Rho = −0.35; p = 0.05). Interestingly, qHBeAg strongly and positively correlates with qHBsAg across the study groups, suggesting cccDNA as a major source of both proteins in the setting of HBeAg positivity (with limited contribution of integrated HBV-DNA to HBsAg production). Focusing on 15 patients with HBV-R starting TDF/ETV, virological suppression and HBeAg-loss are achieved in 60% and 53.3%. Notably, the combination of qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL at HBV-R is the only factor predicting no HBeAg loss (HBeAg loss: 0% with vs. 72.7% without qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL, p = 0.03). In conclusion, qHBeAg varies over the natural course of HBV infection, according to the extent of immunological pressure. In the setting of HBV-R, qHBeAg could be useful in predicting the treatment response under immunosuppression.