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Background: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients., Methods: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI., Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m 2 and nab-paclitaxel 125 mg/m 2 . In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9-8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (>222 days) with 80% sensitivity and 85% specificity., Conclusion: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion.

Background: Besides spinal complications, intracranial hematoma or abscess may occur after neuraxial block. Risk factors and outcome remain unclear., Objective: This review evaluates characteristics, treatment and recovery of patients with intracranial complications after neuraxial block., Evidence Review: We systematically searched MEDLINE, Embase and the Cochrane Library from their inception to May 2020 for case reports/series, cohort studies and reviews of intracranial hematoma or abscess associated with neuraxial block. Quality of evidence was assessed using the critical appraisal of a case study checklist by Crombie., Findings: We analyzed 232 reports, including 291 patients with hematoma and six patients with abscess/empyema. The major part of included studies comprised single case reports with a high risk of bias. Of the patients with hematoma, 48% concerned obstetric patients, the remainder received neuraxial block for various perioperative indications or pain management. Prior dural puncture was reported in 81%, either intended (eg, spinal anesthesia) or unintended (eg, complicated epidural catheter placement). Headache was described in 217 patients; in 101 patients, symptoms resembled postdural puncture headache (PDPH). After treatment, 11% had partial or no recovery and 8% died, indicating the severity of this complication. Intracranial abscess after neuraxial block is seldom reported; six reports were found., Conclusion: Diagnosis of intracranial hematoma is often missed initially, as headache is assumed to be caused by cerebrospinal hypotension due to cerebrospinal fluid leakage, known as PDPH. Prolonged headache without improvement, worsening symptoms despite treatment or epidural blood patch, change of headache from postural to non-postural or new neurological signs should alert physicians to alternative diagnoses., Competing Interests: Competing interests: MdQ: received payments for lectures from Johnson & Johnson Medical Devices Companies. MWH: executive section editor, Pharmacology with Anesthesia & Analgesia, and section editor, Anesthesiology, with Journal of Clinical Medicine; furthermore, he served as consultant for Euro-cept BV and received honoraria for lectures from CSL Behring in the past., (© American Society of Regional Anesthesia & Pain Medicine 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)