High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary diffuse large B-cell CNS lymphoma (MARTA): a single-arm, phase 2 trial.

BACKGROUND: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL. METHODS: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m2 (day 1), intravenous cytarabine 2 g/m2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete. FINDINGS: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications. INTERPRETATION: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials. FUNDING: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg.

Non-Invasive Intracranial Pressure Monitoring.

(1) Background: Intracranial pressure (ICP) monitoring plays a key role in the treatment of patients in intensive care units, as well as during long-term surgeries and interventions. The gold standard is invasive measurement and monitoring via ventricular drainage or a parenchymal probe. In recent decades, numerous methods for non-invasive measurement have been evaluated but none have become established in routine clinical practice. The aim of this study was to reflect on the current state of research and shed light on relevant techniques for future clinical application. (2) Methods: We performed a PubMed search for "non-invasive AND ICP AND (measurement OR monitoring)" and identified 306 results. On the basis of these search results, we conducted an in-depth source analysis to identify additional methods. Studies were analyzed for design, patient type (e.g., infants, adults, and shunt patients), statistical evaluation (correlation, accuracy, and reliability), number of included measurements, and statistical assessment of accuracy and reliability. (3) Results: MRI-ICP and two-depth Doppler showed the most potential (and were the most complex methods). Tympanic membrane temperature, diffuse correlation spectroscopy, natural resonance frequency, and retinal vein approaches were also promising. (4) Conclusions: To date, no convincing evidence supports the use of a particular method for non-invasive intracranial pressure measurement. However, many new approaches are under development.

Early clinical experience with the p48MW HPC and p64MW HPC flow diverters in the anterior circulation aneurysm using single anti-platelet treatment.

BACKGROUND: The p64MW HPC and p48MW HPC flow diverters have reduced thrombogenicity due to hydrophilic coating. The purpose of this study was to evaluate its safety and efficacy in Mongolian patients under single antiplatelet therapy (SAPT) with prasugrel. MATERIALS AND METHODS: We performed a retrospective review of patients enrolled into our prospectively maintained database to identify all patients treated with either the p48MW HPC or p64MW HPC under SAPT. We recorded baseline demographics, aneurysm size and location, procedural complications, angiographic and clinical results. RESULTS: 24 patients, (female = 21, 87.5%), age 48.2 ± 11.6 years (range 25-63) underwent treatment of 30 aneurysms with either p64MW HPC or p48MW HPC. All aneurysms were saccular with dome width 8.2 ± 6.5 (range 1.6-26.0 mm) and dome height 7.6 ± 6.7 (range 1.6-30.0 mm). None of the aneurysms were previously treated. The average PRU was 54.6 ± 31.2 (range 1-127) on pre-operative VerifyNow testing. Angiographic follow-up was available for 13 patients (17 aneurysms), 183 ± 36 days post-procedure, at which point 64.7% of aneurysms (n = 11/17) were completely occluded and 11.8% (n = 2/17) had only neck remnants resulting in 76.5% of aneurysms being adequately occluded A single intra-operative complication (4.2%) occurred however all patients were mRS ≤1 at last follow-up. There were two post-operative complications neither of which resulted in permanent neurological morbidity. There were no instances of post-operative aneurysmal rupture or delayed parenchymal haemorrhage. The overall mortality was 0%. CONCLUSION: The efficacy and safety of p64MW HPC coated devices under SAPT is similar to uncoated flow diverters that require DAPT.

Endovascular Treatment of Posterior Circulation Saccular Aneurysms With the p64 Flow Modulation Device: Mid-and Long-Term Results in 54 Aneurysms From a Single Center.

Objective: Flow diverter (FD) stents have become one of the most common tools for treating intracranial aneurysms; however, their role in treating posterior circulation aneurysms is still discussed with controversy. In this study, we evaluated the safety and effectiveness of p64 FD for the treatment of saccular, unruptured aneurysms in the posterior circulation over a long-term follow-up period in a single center. Methods: From our prospectively maintained database, we retrospectively identified patients who underwent treatment of an intracranial saccular aneurysm arising from the posterior circulation with ≥1 p64 FD implanted or attempted between October 2012 and December 2019. Aneurysms could have been treated with prior or concomitant saccular treatment (e.g., coiling, intra-aneurysmal flow diversion). Aneurysms with parent vessel implants other than p64, fusiform aneurysms, and dissections were excluded. Peri- and postprocedural complications, clinical outcome, and clinical and angiographic follow-up results were evaluated. Results: In total, 54 patients (45 female, 9 male; mean age 55.1 years) with 54 intracranial aneurysms met the inclusion criteria. In 51 cases (94.4%), one p64 was implanted; in 2 cases (3.7 %), two p64s were implanted; in one case, deployment of the p64 was not feasible. Procedural complications occurred in 3.7% and postprocedural complications in 9.3 %, respectively. Hemorrhagic complications occurred in 2/54 patients (3.7%), thereof one fatal parenchymal hemorrhage. Ischemic complications were observed in 5/54 patients (9.3%). Early, mid-term, and long-term angiographic follow-up examinations showed complete or near-complete aneurysm occlusion, defined according to the O'Kelly -Marotta (OKM) scale as OKM C + D in 56, 75.6, and 82.9 %, respectively. Asymptomatic side vessel occlusions occurred in 3.8%, each during the first follow-up. Conclusions: The implantation of a p64 FD is a safe and effective device for endovascular treatment of posterior circulation saccular aneurysms with a high success rate and low morbi-mortality.

Endovascular Treatment of Anterior Circulation Aneurysms With the p64 Flow Modulation Device: Mid- and Long-Term Results in 617 Aneurysms From a Single Center.

BACKGROUND: Flow diverters have become an important tool in the treatment of intracranial aneurysms, especially when dealing with difficult-to-treat or complex aneurysms. The p64 is the only fully resheathable and mechanically detachable flow diverter available for clinical use. OBJECTIVE: To evaluate the safety and effectiveness of p64 for the treatment of intracranial saccular unruptured aneurysms arising from the anterior circulation over a long-term follow-up period. METHODS: We retrospectively reviewed our prospectively maintained database to identify all patients who underwent treatment for an intracranial saccular (unruptured or beyond the acute hemorrhage phase) aneurysm arising from the anterior circulation with ≥1 p64 between December 2011 and December 2019. Fusiform aneurysms and dissections were excluded. Aneurysms with prior or concomitant saccular treatment (eg, coiling and clipping) were included. Aneurysms with parent vessel implants other than p64 were excluded. Anatomic features, intraprocedural complications, clinical outcome, as well as clinical and angiographic follow-ups were all recorded. RESULTS: In total, 530 patients (388 females; median age 55.9 yr) with 617 intracranial aneurysms met the inclusion criteria. The average number of devices used per aneurysm was 1.1 (range 1-3). Mean aneurysm dome size was 4.8 mm (range 1-27 mm). Treatment-related morbimortality was 2.4%. Early, mid-term, and long-term angiographic follow-up showed complete or near-complete aneurysm occlusion in 76.8%, 89.7%, and 94.5%, respectively. CONCLUSION: Treatment of intracranial saccular unruptured aneurysms of the anterior circulation using p64 is a safe and effective treatment option with high rate of occlusion at long-term follow-up and low morbimortality.

Initial experience with the novel p64MW HPC flow diverter from a cohort study in unruptured anterior circulation aneurysms under dual antiplatelet medication.

OBJECTIVE: p64MW HPC is a new low-profile flow diverter with reduced thrombogenicity due to hydrophilic coating. The purpose of this study was to evaluate its safety and efficacy in Mongolian patients under dual antiplatelet therapy. METHODS: Consecutive patients with unruptured anterior circulation aneurysms were prospectively enrolled. All patients received aspirin and clopidogrel before and six months after the procedure, followed by lifelong aspirin medication. High platelet reactivity (VerifyNow) did not trigger further action. The safety and efficacy endpoints were clinical outcome and aneurysm occlusion. RESULTS: In 29 patients (26 female, median age 57 years), 46 aneurysms (neck width 3.3 mm, fundus diameter 3.7 mm, median) were treated. Dual platelet function inhibition was confirmed in eight patients (28%). The response to Clopidogrel was between 100 and 239 P2Y12 reaction units (VerifyNow) in 13 patients (45%). Non-response to at least one drug was found in 8 of 29 patients (28%). One collapsed p64MW HPC required balloon angioplasty. No other periprocedural thrombus formation occurred. Postprocedural MRI revealed lesions with diffusion restriction in 3 of 29 patients. Digital subtraction angiography after three months for 42 of 46 (91%) aneurysms showed an adequate aneurysm occlusion in 25 (60%). Distal p64MW HPC migration of 3 implants was retreated with another p64MW HPC. Follow-up digital subtraction angiography of 26 of 46 (57%) aneurysms after six months showed adequate aneurysm occlusion in 22 (85%). Significant in-stent stenosis or thrombosis, morbidity or mortality was not encountered. CONCLUSION: p64MW HPC implantation in patients under dual antiplatelet therapy with or without dual platelet function inhibition has a low procedural complication rate. The early aneurysm occlusion rate is high.

Clinical Diffusion Mismatch to Select Pediatric Patients for Embolectomy 6 to 24 Hours After Stroke: An Analysis of the Save ChildS Study.

OBJECTIVE: To determine whether thrombectomy is safe in children up to 24 hours after onset of symptoms when selected by mismatch between clinical deficit and infarct. METHODS: A secondary analysis of the Save ChildS Study (January 2000-December 2018) was performed, including all pediatric patients (<18 years) diagnosed with arterial ischemic stroke who underwent endovascular recanalization at 27 European and United States stroke centers. Patients were included if they had a relevant mismatch between clinical deficit and infarct. RESULTS: Twenty children with a median age of 10.5 (interquartile range [IQR] 7-14.6) years were included. Of those, 7 were male (35%), and median time from onset to thrombectomy was 9.8 (IQR 7.8-16.2) hours. Neurologic outcome improved from a median Pediatric NIH Stroke Scale score of 12.0 (IQR 8.8-20.3) at admission to 2.0 (IQR 1.2-6.8) at day 7. Median modified Rankin Scale (mRS) score was 1.0 (IQR 0-1.6) at 3 months and 0.0 (IQR 0-1.0) at 24 months. One patient developed transient peri-interventional vasospasm; no other complications were observed. A comparison of the mRS score to the mRS score in the DAWN and DEFUSE 3 trials revealed a higher proportion of good outcomes in the pediatric compared to the adult study population. CONCLUSIONS: Thrombectomy in pediatric ischemic stroke in an extended time window of up to 24 hours after onset of symptoms seems safe and neurologic outcomes are generally good if patients are selected by a mismatch between clinical deficit and infarct. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for children with acute ischemic stroke with a mismatch between clinical deficit and infarct size, thrombectomy is safe.

The p48 MW flow modulation device for treatment of unruptured, saccular intracranial aneurysms: a single center experience from 77 consecutive aneurysms.

BACKGROUND: The p48 MW Flow Modulation Device (phenox, Bochum Germany) is a low profile flow diverter stent (FDS), designed for implantation into intracranial arteries with a diameter of less than 3.5 mm. OBJECTIVE: To evaluate the safety and efficacy of the p48 MW FDS in the treatment of unruptured aneurysms located at intracranial arteries with less than 3.5 mm diameter based on a retrospective analysis from a single tertiary neurovascular center. METHODS: A prospectively maintained database was retrospectively reviewed to identify all cases of intracranial saccular aneurysms treated electively with the p48 MW device. Records were made of basic demographics, aneurysmal characteristics, interventional procedures, adverse events, clinical outcomes and occlusion rates on angiographic follow-ups. RESULTS: A total of 77 aneurysms and 74 patients were included. The mean size of the treated aneurysms was 3.5 ± 2.4 mm and the mean aspect ratio was 1.3 ± 0.4. A total of 80 endovascular procedures were performed with a total of 12 (15%) adverse events leading to two (2.5%) permanent morbidities/mortalities. Technical issues were encountered in 3 (3.9%) cases. Adequate occlusion of the treated aneurysm was recorded in 55.6% and 63.9% on the first and latest available DSA follow-ups, respectively. There were no cases of side-branch occlusion. CONCLUSIONS: The p48 MW is an easy-to-use implant with very good safety margins. Side branch occlusion and significant in-stent stenosis are infrequently encountered. The time from implantation to sufficient aneurysm occlusion takes longer than with FDS with lower porosity.

Does Device Selection Impact Recanalization Rate and Neurological Outcome?: An Analysis of the Save ChildS Study.

Background and Purpose- The recent Save ChildS study provides multicenter evidence for the use of mechanical thrombectomy in children with large vessel occlusion arterial ischemic stroke. However, device selection for thrombectomy may influence rates of recanalization, complications, and neurological outcomes, especially in pediatric patients of different ages. We, therefore, performed additional analyses of the Save ChildS data to investigate a possible association of different thrombectomy techniques and devices with angiographic and clinical outcome parameters. Methods- The Save ChildS cohort study (January 2000-December 2018) analyzed data from 27 European and United States stroke centers and included all pediatric patients (<18 years), diagnosed with arterial ischemic stroke who underwent endovascular recanalization. Patients were grouped into first-line contact aspiration (A Direct Aspiration First Pass Technique [ADAPT]) and non-ADAPT groups as well as different stent retriever size groups. Associations with baseline characteristics, recanalization rates (modified Treatment in Cerebral Infarction), complication rates, and neurological outcome parameters (Pediatric National Institutes of Health Stroke Scale after 24 hours and 7 days; modified Rankin Scale and Pediatric Stroke Outcome Measure at discharge, after 6 and 24 months) were investigated. Results- Seventy-three patients with a median age of 11.3 years were included. Currently available stent retrievers were used in 59 patients (80.8%), of which 4×20 mm (width×length) was the most frequently chosen size (36 patients =61%). A first-line ADAPT approach was used in 7 patients (9.6%), and 7 patients (9.6%) were treated with first-generation thrombectomy devices. In this study, a first-line ADAPT approach was neither associated with the rate of successful recanalization (ADAPT 85.7% versus 87.5% No ADAPT) nor with the complication rate or the neurological outcome. Moreover, there were no associations of stent retriever sizes with rates of recanalization, complication rates, or outcome parameters. Conclusions- Our study suggests that neurological outcomes are generally good regardless of any specific device selection and suggests that it is important to offer thrombectomy in eligible children regardless of technique or device selection. Registration- URL: https://www.drks.de/; Unique identifier: DRKS00016528.

Feasibility, Safety, and Outcome of Endovascular Recanalization in Childhood Stroke: The Save ChildS Study.

Importance: Randomized clinical trials have shown the efficacy of thrombectomy of large intracranial vessel occlusions in adults; however, any association of therapy with clinical outcomes in children is unknown. Objective: To evaluate the use of endovascular recanalization in pediatric patients with arterial ischemic stroke. Design, Setting, and Participants: This retrospective, multicenter cohort study, conducted from January 1, 2000, to December 31, 2018, analyzed the databases from 27 stroke centers in Europe and the United States. Included were all pediatric patients (<18 years) with ischemic stroke who underwent endovascular recanalization. Median follow-up time was 16 months. Exposures: Endovascular recanalization. Main Outcomes and Measures: The decrease of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) score from admission to day 7 was the primary outcome (score range: 0 [no deficit] to 34 [maximum deficit]). Secondary clinical outcomes included the modified Rankin scale (mRS) (score range: 0 [no deficit] to 6 [death]) at 6 and 24 months and rate of complications. Results: Seventy-three children from 27 participating stroke centers were included. Median age was 11.3 years (interquartile range [IQR], 7.0-15.0); 37 patients (51%) were boys, and 36 patients (49%) were girls. Sixty-three children (86%) received treatment for anterior circulation occlusion and 10 patients (14%) received treatment for posterior circulation occlusion; 16 patients (22%) received concomitant intravenous thrombolysis. Neurologic outcome improved from a median PedNIHSS score of 14.0 (IQR, 9.2-20.0) at admission to 4.0 (IQR, 2.0-7.3) at day 7. Median mRS score was 1.0 (IQR, 0-1.6) at 6 months and 1.0 (IQR, 0-1.0) at 24 months. One patient (1%) developed a postinterventional bleeding complication and 4 patients (5%) developed transient peri-interventional vasospasm. The proportion of symptomatic intracerebral hemorrhage events in the HERMES meta-analysis of trials with adults was 2.79 (95% CI, 0.42-6.66) and in Save ChildS was 1.37 (95% CI, 0.03-7.40). Conclusions and Relevance: The results of this study suggest that the safety profile of thrombectomy in childhood stroke does not differ from the safety profile in randomized clinical trials for adults; most of the treated children had favorable neurologic outcomes. This study may support clinicians' practice of off-label thrombectomy in childhood stroke in the absence of high-level evidence.

The use of flow diverters to treat small (≤5 mm) ruptured, saccular aneurysms.

BACKGROUND: There is limited published literature on the use of flow diverting stents (FDS) to treat ruptured intracranial aneurysms in the acute stage. We present our experience of using FDS to treat small (≤5 mm) ruptured aneurysms. METHODS: We retrospectively identified all patients with ≤5 mm ruptured aneurysms treated exclusively with FDS between February 2009 and February 2016. We recorded demographic data, the Hunt and Hess score, aneurysm location and size, therapeutic intervention, immediate angiographic and clinical result, and clinical and radiological follow-up information. RESULTS: We identified seven patients (four females) with average age 59.8 ± 10 years (range 48-75). The average aneurysm fundus size was 2.7 ± 0.76 mm (range 1-4 mm). The average time from ictus to treatment was 6.3 days (range 1-14 days) and there were no cases of repeat rupture prior to treatment or intraoperative rupture. Angiographic follow-up was available in five patients. At initial follow-up, aneurysms (100%) were completely occluded raymond roy classification 1 (RRC 1). None of the aneurysms re-ruptured following treatment. Clinically, six patients were discharged with good functional outcome modified Rankin Score (mRS ≤2). There were no mortalities. CONCLUSION: The use of FDS to treat small, ruptured, saccular aneurysms is feasible; however, the use of FDS should not be considered first-line treatment. Further studies are required to determine the safety and efficacy of the use of FDS in the acute situation.

The value of whole lesion ADC histogram profiling to differentiate between morphologically indistinguishable ring enhancing lesions-comparison of glioblastomas and brain abscesses.

BACKGROUND: Morphologically similar appearing ring enhancing lesions in the brain parenchyma can be caused by a number of distinct pathologies, however, they consistently represent life-threatening conditions. The two most frequently encountered diseases manifesting as such are glioblastoma multiforme (GBM) and brain abscess (BA), each requiring disparate therapeutical approaches. As a result of their morphological resemblance, essential treatment might be significantly delayed or even ommited, in case results of conventional imaging remain inconclusive. Therefore, our study aimed to investigate, whether ADC histogram profiling reliably can distinguish between both entities, thus enhancing the differential diagnostic process and preventing treatment failure in this highly critical context. METHODS: 103 patients (51 BA, 52 GBM) with histopathologically confirmed diagnosis were enrolled. Pretreatment diffusion weighted imaging (DWI) was obtained in a 1.5T system using b values of 0, 500, and 1000 s/mm2. Whole lesion ADC volumes were analyzed using a histogram-based approach. Statistical analysis was performed using SPSS version 23. RESULTS: All investigated parameters were statistically different in comparison of both groups. Most importantly, ADCp10 was able to differentiate reliably between BA and GBM with excellent accuracy (0.948) using a cutpoint value of 70 × 10-5 mm2 × s-1. CONCLUSIONS: ADC whole lesion histogram profiling provides a valuable tool to differentiate between morphologically indistinguishable mass lesions. Among the investigated parameters, the 10th percentile of the ADC volume distinguished best between GBM and BA.