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BACKGROUND & AIMS: Vedolizumab is indicated for the treatment of chronic pouchitis in the European Union. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements. METHODS: EARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab efficacy and safety in adults with chronic pouchitis. Centrally read endoscopic and histologic evaluation was performed at baseline, Week (W)14, and W34. Ulcer count, adapted Simple Endoscopic Score for Crohn's Disease in the pouch, and Pouchitis Disease Activity Index histologic component were evaluated. Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 were compared by MH status at W14. RESULTS: Following treatment, mean (standard deviation) number of ulcers in vedolizumab-treated patients reduced from 15.1 (16.4) to 5.0 (4.9) at W14 and 2.7 (3.2) at W34 versus placebo-treated patients with corresponding values of 11.8 (11.3), 13.4 (18.4), and 9.7 (13.8) (vedolizumab vs placebo difference [95% confidence interval]: W14: -8.4 [-14.3 to -2.6]; W34: -7.0 [-12.0 to -2.0]). More patients receiving vedolizumab versus placebo achieved reduction in ulcerated pouch surface area (W14: 52.4% vs 20.0%; difference, 32.4 percentage points [p.p] [9.7, 51.4]; W34: 52.1% vs 12.9%; difference, 40.2p.p [15.6, 60.3]), absence of ulceration (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), Simple Endoscopic Score for Crohn's Disease remission (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), and MH (W14: 16.7% vs 2.5%; difference, 14.2p.p [1.9, 26.4]). Patients with MH at W14 had higher rates of Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 than those without. CONCLUSIONS: Vedolizumab induced endoscopic improvements in patients with chronic pouchitis, which was associated with improved outcomes at W34, particularly in patients achieving MH at W14. (ClinicalTrials.gov number, NCT02790138.).
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PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.
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Voluntarios Sanos , Hialuronoglucosaminidasa , Infusiones Subcutáneas , Humanos , Hialuronoglucosaminidasa/administración & dosificación , Hialuronoglucosaminidasa/efectos adversos , Masculino , Femenino , Adulto , Adulto Joven , Persona de Mediana Edad , Inmunoglobulinas/administración & dosificación , Inmunoglobulinas/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , AdolescenteRESUMEN
Introduction: Planning cranioplasty (CPL) in patients with suspected or proven post-traumatic hydrocephalus (PTH) poses a significant management challenge due to a lack of clear guidance. Research question: This project aims to create a European document to improve adherence and adapt to local protocols based on available resources and national health systems. Methods: After a thorough non-systematic review, a steering committee (SC) formed a European expert panel (EP) for a two-round questionnaire using the Delphi method. The questionnaire employed a 9-point Likert scale to assess the appropriateness of statements inherent to two sections: "Diagnostic criteria for PTH" and "Surgical strategies for PTH and cranial reconstruction." Results: The panel reached a consensus on 29 statements. In the "Diagnostic criteria for PTH" section, five statements were deemed "appropriate" (consensus 74.2-90.3 %), two were labeled "inappropriate," and seven were marked as "uncertain."In the "Surgical strategies for PTH and cranial reconstruction" section, four statements were considered "appropriate" (consensus 74.2-90.4 %), six were "inappropriate," and five were "uncertain." Discussion and conclusion: Planning a cranioplasty alongside hydrocephalus remains a significant challenge in neurosurgery. Our consensus conference suggests that, in patients with cranial decompression and suspected hydrocephalus, the most suitable diagnostic approach involves a combination of evolving clinical conditions and neuroradiological imaging. The recommended management sequence prioritizes cranial reconstruction, with the option of a ventriculoperitoneal shunt when needed, preferably with a programmable valve. We strongly recommend to adopt local protocols based on expert consensus, such as this, to guide patient care.
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Purpose: The VERSIFY phase 3 trial in patients with Crohn's disease (CD) treated with vedolizumab was the first to include a substudy that used a standardized magnetic resonance enterography (MRE) protocol to assess features of transmural inflammation (bowel edema and wall thickness) and extramural disease activity (enlarged lymph nodes). Patients and Methods: Patients received intravenous vedolizumab (300 mg) at weeks 0 (baseline), 2, and 6, and then every 8 weeks for 26 or 52 weeks. Post hoc analyses included a subpopulation with a Magnetic Resonance Index of Activity score of ≥7 in at least one bowel segment at baseline and at least one postbaseline MRE assessment. Changes in transmural inflammation, including intramural bowel edema and wall thickness, were evaluated. Patient-level and segment-level analyses were performed. Results: MRE images were evaluated in 27 patients with 83 evaluable bowel segments at baseline and week 26, and 13 patients with 38 evaluable segments at baseline, week 26, and week 52. At baseline, all patients had bowel wall edema and wall thickness of >3 mm in at least one bowel segment. The proportion of patients with edema decreased at weeks 26 (17/27 [63.0%]) and 52 (4/13 [30.8%]) and the proportion with bowel wall thickness of >3 mm decreased at weeks 26 (25/27 [92.6%]) and 52 (10/13 [76.9%]). Conclusion: In patients with CD treated with vedolizumab for 26 and 52 weeks, the number of patients, and bowel segments, with MRE-detected transmural inflammation was reduced. These results highlight the impact of vedolizumab on components of transmural inflammation in CD and demonstrate that using MRE in CD multicenter clinical trials is feasible. Trial Registration: ClinicalTrials.gov NCT02425111, April 23, 2015, http://www.clinicaltrials.gov NCT02425111; EU Clinical Trials Register EudraCT 2014-003509-13, https://www.clinicaltrialsregister.eu.
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This study explored short- and mid-term functional outcomes in patients undergoing decompressive hemicraniectomy (DHC) due to space-occupying cerebral infarction and asked whether there is a potentially harmful effect of a priorly performed endovascular treatment (EVT). Medical records were screened for patients requiring DHC due to space-occupying cerebral infarction between January 2016 and July 2021. Functional outcomes at hospital discharge and at 3 months were assessed by the modified Rankin Scale (mRS). Out of 65 patients with DHC, 39 underwent EVT before DHC. Both groups, i.e., EVT + DHC and DHC alone, had similar volumes (280 ± 90 mL vs. 269 ± 73 mL, t-test, p = 0.633) and proportions of edema and infarction (22.1 ± 6.5% vs. 22.1 ± 6.1%, t-test, p = 0.989) before the surgical intervention. Patients undergoing EVT + DHC tended to have a better functional outcome at hospital discharge compared to DHC alone (mRS 4.8 ± 0.8 vs. 5.2 ± 0.7, Mann-Whitney-U, p = 0.061), while the functional outcome after 3 months was similar (mRS 4.6 ± 1.1 vs. 4.8 ± 0.9, Mann-Whitney-U, p = 0.352). In patients initially presenting with a relevant infarct demarcation (Alberta Stroke Program Early CT Score ≤ 5), the outcome was similar at hospital discharge and after 3 months between patients with EVT + DHC and DHC alone. This study provided no evidence for a harmful effect of EVT before DHC in patients with space-occupying brain infarction.
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Ectopic pituitary neuroendocrine tumors (PitNET)/adenomas are rare and diagnostically challenging extra-sellar tumors. Previous studies have demonstrated the impact of epigenomic analyses in the diagnostics of sellar neoplasms and characterized the close relationship of epigenomic signatures and cellular origins of PitNET/adenomas. As of today, little is known about the pathogenesis of ectopic PitNET/adenomas, and epigenomic analyses have not been performed in these rare tumors. We report on the clinical course of an 81-year-old patient with sphenoid ectopic sparsely granulated corticotroph PitNET/adenoma and deploy genome-wide DNA methylation analysis to compare its methylation profile to a reference cohort of sellar neoplasms. Genome-wide methylation analysis revealed an epigenomic profile analogous to reference sellar corticotroph PitNET/adenomas, and the copy number variation profile showed loss of chromosomes 18 and 22. The methylation profile shows concordance with sellar corticotroph PitNET/adenomas suggesting a common cellular origin and confirming the reliability of methylation analyses as a diagnostic method in these rare tumors. This is the first data suggesting that epigenetic profiles of ectopic PitNET/adenoma do not differ from their sellar counterparts.
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BACKGROUND: Vedolizumab is an anti-α4ß7 integrin antibody used to treat moderate to severe ulcerative colitis (UC) and Crohn's disease (CD). This post hoc analysis of patient-reported outcomes (PROs) from the VISIBLE 1 (NCT02611830) and 2 (NCT02611817) phase 3 studies evaluated onset of treatment effect on patient-reported symptoms during 6-week vedolizumab induction. METHODS: Patient-reported stool frequency (SF) and rectal bleeding (RB) (UC Mayo score), and SF and abdominal pain (AP) in CD were collected via electronic diary from VISIBLE patients receiving one or more open-label intravenous (IV) vedolizumab induction doses (weeks 0 and 2). PRO data were analyzed using descriptive statistics. RESULTS: Data from 994 patients (UC 383, CD 611) showed mean ratings for all PROs declined consistently week-on-week from baseline through week 6, with early onset of improvement. By week 2, 22% of patients with UC reported RB improvement (≥1-point reduction in RB subscore, 7-day mean), rising to 45% by week 6. By week 6, 18% of patients with UC achieved SF improvement (SF subscore 0; 21% antitumor necrosis factor alpha [anti-TNFα] naive, 13% anti-TNFα experienced). SF improvement in patients with CD (reduction of ≥3 stools, 7-day mean) was achieved by 32% at week 6 (34% anti-TNFα naive, 30% anti-TNFα experienced). Fewer patients with CD reported severe/moderate AP at week 6 (5.1%/28.5%) than baseline (14.6%/61.5%). SF decline appeared greater and faster for anti-TNFα-naive vs. anti-TNFα-experienced patients (UC and CD). CONCLUSION: Results indicate early onset of patient-reported UC and CD symptom improvement during vedolizumab IV induction in VISIBLE 1 and 2.
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Anticuerpos Monoclonales Humanizados , Colitis Ulcerosa , Enfermedad de Crohn , Humanos , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Quimioterapia de Inducción , Factor de Necrosis Tumoral alfa , Medición de Resultados Informados por el Paciente , Fármacos Gastrointestinales/efectos adversos , Resultado del Tratamiento , Inducción de RemisiónRESUMEN
BACKGROUND: Clinical observations indicated that vaccine-induced immune thrombosis with thrombocytopenia (VITT)-associated cerebral venous sinus thrombosis (CVST) often has a space-occupying effect and thus necessitates decompressive surgery (DS). While comparing with non-VITT CVST, this study explored whether VITT-associated CVST exhibits a more fulminant clinical course, different perioperative and intensive care unit management, and worse long-term outcome. METHODS: This multicenter, retrospective cohort study collected patient data from 12 tertiary centers to address priorly formulated hypotheses concerning the clinical course, the perioperative management with related complications, extracerebral complications, and the functional outcome (modified Rankin Scale) in patients with VITT-associated and non-VITT CVST, both with DS. RESULTS: Both groups, each with 16 patients, were balanced regarding demographics, kind of clinical symptoms, and radiological findings at hospital admission. Severity of neurological symptoms, assessed with the National Institute of Health Stroke Scale, was similar between groups at admission and before surgery, whereas more patients with VITT-associated CVST showed a relevant midline shift (≥ 4 mm) before surgery (100% vs. 68.8%, p = 0.043). Patients with VITT-associated CVST tended to undergo DS early, i.e., ≤ 24 h after hospital admission (p = 0.077). Patients with VITT-associated CVST more frequently received platelet transfusion, tranexamic acid, and fibrinogen perioperatively. The postoperative management was comparable, and complications were evenly distributed. More patients with VITT-associated CVST achieved a favorable outcome (modified Rankin Scale ≤ 3) at 3 months (p = 0.043). CONCLUSIONS: Although the prediction of individual courses remains challenging, DS should be considered early in VITT-associated CVST because an overall favorable outcome appears achievable in these patients.
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Trombosis de los Senos Intracraneales , Trombocitopenia , Trombosis , Humanos , Estudios Retrospectivos , Trombosis de los Senos Intracraneales/etiología , Trombosis de los Senos Intracraneales/cirugía , Trombosis/complicaciones , Trombocitopenia/inducido químicamente , Progresión de la EnfermedadRESUMEN
In the perioperative management of patients with glioblastoma (GBM), physicians face the question of whether and when to administer prophylactic or therapeutic anticoagulation (AC). In this study, we investigate the effects of the timing of postoperative heparinization on thromboembolic events (TE) and postoperative hemorrhage (bleeding, PH) as well as the interactions between the two in the context of an underlying intracerebral malignancy. For this retrospective data analysis, 222 patients who underwent surgery for grade IV glioblastoma, IDH-wildtype (2016 CNS WHO) between 01/01/2014 and 31/12/2019 were included. We followed up for 12 months. We assessed various biographical and clinical data for risk factors and focused on the connection between timepoint of AC and adverse events. Subgroup analyses were performed for pulmonary artery embolism (PE), deep vein thrombosis, and postoperative intracranial hemorrhage (PH) that either required surgical intervention or was controlled radiologically only. Statistical analysis was performed using Mann-Whitney U-Test, Chi-square test, Fisher's exact test and univariate binomial logistic regression. p values below 0.05 were considered statistically significant. There was no significant association between prophylactic AC within 24 h and more frequent major bleeding (p = 0.350). AC in patients who developed major bleeding was regularly postponed by the physician/surgeon upon detection of the re-bleeding; therefore, patients with PH were anticoagulated significantly later (p = 0.034). The timing of anticoagulant administration did not differ significantly between patients who experienced a thromboembolic event and those who did not (p = 0.634). There was considerable overlap between the groups. Three of the six patients (50%) with PE had to be lysed or therapeutically anticoagulated and thereafter developed major bleeding (p < 0.001). Patients who experienced TE were more likely to die during hospitalization than those with major bleeding (p = 0.022 vs. p = 1.00). Prophylactic AC within 24 h after surgery does not result in more frequent bleeding. Our data suggests that postoperative intracranial hemorrhage is not caused by prophylactic AC but rather is a surgical complication or the result of antithrombotic therapy. However, thromboembolic events worsen patient outcomes far more than postoperative bleeding. The fact that bleeding may occur as a complication of life-saving lysis therapy in the setting of a thromboembolic event should be included in this cost-benefit consideration.
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Glioblastoma , Embolia Pulmonar , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/etiología , Tromboembolia Venosa/diagnóstico , Anticoagulantes/efectos adversos , Estudios Retrospectivos , Glioblastoma/complicaciones , Glioblastoma/cirugía , Hemorragias Intracraneales/complicaciones , Hemorragia Posoperatoria/tratamiento farmacológico , Embolia Pulmonar/tratamiento farmacológicoRESUMEN
Sometimes cranioplasty is necessary to reconstruct skull bone defects after a neurosurgical operation. If an autologous bone is unavailable, alloplastic materials are used. The standard technical approach for the fabrication of cranial implants is based on 3D imaging by computed tomography using the defect and the contralateral site. A new approach uses 3D surface scans, which accurately replicate the curvature of the removed bone flap. For this purpose, the removed bone flap is scanned intraoperatively and digitized accordingly. When using a design procedure developed for this purpose creating a patient-specific implant for each bone flap shape in short time is possible. The designed skull implants have complex free-form surfaces analogous to the curvature of the skull, which is why additive manufacturing is the ideal manufacturing technology here. In this study, we will describe the intraoperative procedure for the acquisition of scanned data and its further processing up to the creation of the implant.
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PURPOSE: In absence of comprehensive data collection on traumatic brain injury (TBI), the German Society for Neurosurgery (DGNC) and the German Society for Trauma Surgery (DGU) developed a TBI databank for German-speaking countries. METHODS: From 2016 to 2020, the TBI databank DGNC/DGU was implemented as a module of the TraumaRegister (TR) DGU and tested in a 15-month pilot phase. Since its official launch in 2021, patients from the TR-DGU (intermediate or intensive care unit admission via shock room) with TBI (AIS head ≥ 1) can be enrolled. A data set of > 300 clinical, imaging, and laboratory variables, harmonized with other international TBI data collection structures is documented, and the treatment outcome is evaluated after 6- and 12 months. RESULTS: For this analysis, 318 patients in the TBI databank could be included (median age 58 years; 71% men). Falls were the most common cause of injury (55%), and antithrombotic medication was frequent (28%). Severe or moderate TBI were only present in 55% of patients, while 45% suffered a mild injury. Nevertheless, intracranial pathologies were present in 95% of brain imaging with traumatic subarachnoid hemorrhages (76%) being the most common. Intracranial surgeries were performed in 42% of cases. In-hospital mortality after TBI was 21% and surviving patients could be discharged after a median hospital stay of 11 days. At the 6-and 12 months follow-up, a favorable outcome was achieved by 70% and 90% of the participating TBI patients, respectively. Compared to a European cohort of 2138 TBI patients treated in the ICU between 2014 and 2017, patients in the TBI databank were already older, frailer, fell more commonly at home. CONCLUSION: Within five years, the TBI databank DGNC/DGU of the TR-DGU could be established and is since then prospectively enrolling TBI patients in German-speaking countries. With its large and harmonized data set and a 12-month follow-up, the TBI databank is a unique project in Europe, already allowing comparisons to other data collection structures and indicating a demographic change towards older and frailer TBI patients in Germany.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Masculino , Humanos , Persona de Mediana Edad , Femenino , Sistema de Registros , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/terapia , Resultado del Tratamiento , Alemania/epidemiologíaRESUMEN
BACKGROUND: Approximately half the patients with ulcerative colitis who undergo restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) will subsequently have pouchitis, and among those patients, one fifth will have chronic pouchitis. METHODS: We conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab in adult patients in whom chronic pouchitis had developed after undergoing IPAA for ulcerative colitis. Patients were assigned (in a 1:1 ratio) to receive vedolizumab intravenously at a dose of 300 mg or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All the patients received concomitant ciprofloxacin from weeks 1 to 4. The primary end point was modified Pouchitis Disease Activity Index (mPDAI)-defined remission (an mPDAI score of ≤4 and a reduction from baseline of ≥2 points in the mPDAI total score; scores range from 0 to 12, with higher scores indicating more severe pouchitis) at week 14. The mPDAI is based on clinical symptoms and endoscopic findings. Other efficacy end points included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction from baseline of ≥2 points in the mPDAI score) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of ≤6 and a reduction from baseline of ≥3 points; scores range from 0 to 18, with higher scores indicating more severe pouchitis) at weeks 14 and 34. The PDAI is based on clinical symptoms, endoscopic findings, and histologic findings. RESULTS: Among the 102 patients who underwent randomization, the incidence of mPDAI-defined remission at week 14 was 31% (16 of 51 patients) with vedolizumab and 10% (5 of 51 patients) with placebo (difference, 21 percentage points; 95% confidence interval [CI], 5 to 38; P = 0.01). Differences in favor of vedolizumab over placebo were also seen with respect to mPDAI-defined remission at week 34 (difference, 17 percentage points; 95% CI, 0 to 35), mPDAI-defined response at week 14 (difference, 30 percentage points; 95% CI, 8 to 48) and at week 34 (difference, 22 percentage points; 95% CI, 2 to 40), and PDAI-defined remission at week 14 (difference, 25 percentage points; 95% CI, 8 to 41) and at week 34 (difference, 19 percentage points; 95% CI, 2 to 37). Serious adverse events occurred in 3 of 51 patients (6%) in the vedolizumab group and in 4 of 51 patients (8%) in the placebo group. CONCLUSIONS: Treatment with vedolizumab was more effective than placebo in inducing remission in patients who had chronic pouchitis after undergoing IPAA for ulcerative colitis. (Funded by Takeda; EARNEST ClinicalTrials.gov number, NCT02790138; EudraCT number, 2015-003472-78.).
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Colitis Ulcerosa , Fármacos Gastrointestinales , Reservoritis , Proctocolectomía Restauradora , Adulto , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ciprofloxacina/administración & dosificación , Ciprofloxacina/uso terapéutico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/cirugía , Reservoritis/tratamiento farmacológico , Reservoritis/etiología , Enfermedad Crónica , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Proctocolectomía Restauradora/efectos adversos , Método Doble Ciego , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Administración Intravenosa , Quimioterapia CombinadaRESUMEN
BACKGROUND: Vedolizumab (VDZ) is an anti-α 4 ß 7 integrin monoclonal antibody approved for inflammatory bowel disease treatment. VDZ serum and antidrug antibody (ADA) concentrations may be used for treatment optimization. In this article, the results of 5 commercial assays (Grifols, Immundiagnostik, Progenika, Sanquin, and Theradiag) measuring VDZ concentration and ADA were compared with those of the reference assays used in VDZ clinical studies. Our findings will assist clinicians in interpreting commercial assay results in the context of VDZ clinical trial data. METHODS: VDZ-treated patient samples were used to evaluate the agreement between commercial assays and the reference VDZ serum concentration assay, based on linear regression, Bland-Altman, and qualitative agreement analyses. VDZ ADAs were detected using qualitative assays. Specificity, selectivity, accuracy, and precision were assessed using serum samples from healthy donors or patients with IBD (VDZ serum concentration <0.5 mcg/mL) spiked with VDZ, with/without other biologics (identical sample sets per assay). RESULTS: All assays were specific and selective for VDZ. Overall, the commercial assay results for VDZ-spiked samples correlated well with those of the reference serum concentration assay (R 2 ≥ 0.98). Compared with the Immundiagnostik and Theradiag assays, the Grifols, Sanquin, and Progenika assays had the best reference assay agreement (based on regression analysis, Bland-Altman plots, and qualitative agreement [Cohen's kappa ≥0.92]). All immunogenicity assays detected VDZ ADAs; only the reference assay detected VDZ ADAs in the presence of 15 mcg/mL VDZ, advising caution with commercial ADA assays if VDZ is present. CONCLUSIONS: All 5 commercial assays are suitable for VDZ therapeutic monitoring and ADA testing. However, the absolute values from the reference assays and the different commercial assays were not comparable, indicating that the same assay must be used for repeated monitoring of VDZ serum concentrations.
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Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Estudios Retrospectivos , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: It is suspected that microbiome-derived trimethylamine N-oxide (TMAO) may enhance platelet responsiveness and accordingly be thrombophilic. The purpose of this prospective observational study is to evaluate TMAO in patients with subarachnoid hemorrhage (SAH) and compare it with a control group. A secondary aim was to investigate TMAO in the cerebrospinal fluid (CSF) from SAH patients. This should provide a better understanding of the role of TMAO in the pathogenesis of SAH and its thrombotic complications. METHODS: The study included patients with diagnosed spontaneous SAH recruited after initial treatment on admission and patients with nerve, nerve root, or plexus disorders serving as controls. Blood samples were gathered from all patients at recruitment. Additionally, sampling of SAH patients in the intensive care unit continued daily for 14 days. The CSF was collected out of existing external ventricular drains whenever possible. RESULTS: Thirty-four patients diagnosed with SAH, and 108 control patients participated in this study. Plasma TMAO levels at baseline were significantly lower in the SAH group (1.7 µmol/L) compared to the control group (2.9 µmol/L). TMAO was detectable in the CSF (0.4 µmol/L) and significantly lower than in plasma samples of the SAH group at baseline. Plasma and CSF TMAO levels correlated positively. The TMAO levels did not differ significantly during the observation period of 15 days. CONCLUSIONS: Although we assumed that patients with higher TMAO levels were at higher risk for SAH a priori, plasma TMAO levels were lower in patients with SAH compared with control subjects with nerve, nerve root, or plexus disorders on admission to the hospital. A characteristic pattern of plasma TMAO levels in patients with SAH was not found.
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Hemorragia Subaracnoidea , Humanos , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/terapia , Metilaminas , Estudios ProspectivosRESUMEN
RATIONALE: Aneurysmal subarachnoid hemorrhage (SAH) has high morbidity and mortality. While the primary injury results from the initial bleeding cannot currently be influenced, secondary injury through vasospasm and delayed cerebral ischemia worsens outcome and might be a target for interventions to improve outcome. To date, beside the aneurysm treatment to prevent re-bleeding and the administration of oral nimodipine, there is no therapy available, so novel treatment concepts are needed. Evidence suggests that inflammation contributes to delayed cerebral ischemia and poor outcome in SAH. Some studies suggest a beneficial effect of anti-inflammatory glucocorticoids, but there are no data from randomized controlled trials examining the efficacy of glucocorticoids. Therefore, current guidelines do not recommend the use of glucocorticoids in SAH. AIM: The Fight INflammation to Improve outcome after aneurysmal Subarachnoid HEmorRhage (FINISHER) trial aims to determine whether dexamethasone improves outcome in a clinically relevant endpoint in SAH patients. METHODS AND DESIGN: FINISHER is a multicenter, prospective, randomized, double-blinded, placebo-controlled clinical phase III trial which is testing the outcome and safety of anti-inflammatory treatment with dexamethasone in SAH patients. SAMPLE SIZE ESTIMATES: In all, 334 patients will be randomized to either dexamethasone or placebo within 48 h after SAH. The dexamethasone dose is 8 mg tds for days 1-7 and then 8 mg od for days 8-21. STUDY OUTCOME: The primary outcome is the modified Rankin Scale (mRS) at 6 months, which is dichotomized to favorable (mRS 0-3) versus unfavorable (mRS 4-6). DISCUSSION: The results of this study will provide the first phase III evidence as to whether dexamethasone improves outcome in SAH.
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Isquemia Encefálica , Accidente Cerebrovascular , Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Estudios Prospectivos , Resultado del Tratamiento , Accidente Cerebrovascular/complicaciones , Isquemia Encefálica/complicaciones , Isquemia Encefálica/tratamiento farmacológico , Infarto Cerebral/complicaciones , Inflamación/complicaciones , Dexametasona/uso terapéutico , Vasoespasmo Intracraneal/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
A threshold-based classification of cerebral vasospasm needs reference values for intracranial vessel diameters on digital subtraction angiography (DSA). We aimed to generate adjusted reference values for this purpose by retrospectively analyzing angiograms and potential influencing factors on vessel diameters. Angiograms of the anterior circulation were evaluated in 278 patients aged 18−81 years. The vessel diameters of 453 angiograms (175 bilateral) were gathered from nine defined measuring sites. The effect sizes of physical characteristics (i.e., body weight and height, body mass index, gender, age, and cranial side) and anatomical variations were calculated with MANOVA. Segments bearing aneurysms were excluded for the calculation of reference values. Adjusted vessel diameters were calculated via linear regression analysis of the vessel diameter data. Vessel diameters increased with age and body height. Male and right-sided vessels were larger in diameter. Of the anatomical variations, only the hypoplastic/aplastic A1 segment had a significant influence (p < 0.05) on values of the anterior cerebral artery and the internal carotid artery with a small effect size (|ω2| > 0.01) being excluded from the reference values. We provide gender-, age-, and side-adjusted reference values and nomograms of arterial vessel diameters in the anterior circulation.
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BACKGROUND: Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) has been extensively investigated, but the impact of collateralization remains unclear. We investigated the predictive value of collateral activation for delayed cerebral ischemia (DCI)-related infarctions and functional outcome. METHODS: Data from 43 patients with CVS (January 2014 to August 2021) were evaluated for the angiographic presence of leptomeningeal and ophthalmic collaterals (anterior falcine artery (AFA), supratrochlear artery (STA), dorsal nasal artery (DNA)) on internal carotid artery angiograms. Vasospasm-related infarction and the modified Rankin Scale (mRS) score after six months were chosen as the endpoints. RESULTS: 77% of the patients suffered from DCI-related infarctions. In 233 angiograms (at hospitalization, before spasmolysis, after six months), positive vessel signs were observed in 31 patients for STA, 35 for DNA, and 31 for AFA. The STA sign had the highest positive (84.6%) and negative (85.7%) predictive value for unfavorable outcome (mRS 4-6) in patients aged ≥50 years. DNA and AFA signs were not meaningful predictors for either endpoint. Leptomeningeal collaterals showed a positive Pearson's correlation with the STA sign in 87.5% (p = 0.038) without providing any prediction for either endpoint. CONCLUSIONS: The STA sign is associated with clinical outcome in patients with CVS after SAH aged ≥50 years, and was correlated with the occurrence of leptomeningeal collaterals.
RESUMEN
Background: Cerebral vasospasm (CVS) continues to account for high morbidity and mortality in patients surviving the initial aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only drug known to reduce delayed cerebral ischemia (DCI), but it is believed not to affect large vessel CVS. Milrinone has emerged as a promising option. Our retrospective study focused on the effectiveness of the intra-arterial application of both drugs in monotherapy and combined therapy. Methods: We searched for patients with aneurysmal SAH, angiographically confirmed CVS, and at least one intra-arterial pharmacological angioplasty. Ten defined vessel sections on angiograms were assessed before and after vasodilator infusion. The improvement in vessel diameters was compared to the frequency of DCI-related cerebral infarction before hospital discharge and functional outcome reported as the modified Rankin Scale (mRS) score after 6 months. Results: Between 2014 and 2021, 132 intra-arterial interventions (144 vascular territories, 12 bilaterally) in 30 patients were analyzed for this study. The vasodilating effect of nimodipine was superior to milrinone in all intradural segments. There was no significant intergroup difference concerning outcome in mRS (p = 0.217). Only nimodipine or the combined approach could prevent DCI-related infarction (both 57.1%), not milrinone alone (87.5%). Both drugs induced a doubled vasopressor demand due to blood pressure decrease, but milrinone alone induced tachycardia. Conclusions: The monotherapy with intra-arterial nimodipine was superior to milrinone. Nimodipine and milrinone may be used complementary in an escalation scheme with the administration of nimodipine first, complemented by milrinone in cases of severe CVS. Milrinone monotherapy is not recommended.