Extracorporeal photochemotherapy in patients with Cutaneous T Cell Lymphomaor Graft-vs-Host Disease

Extracorporeal photokjemoterapi (ECP) har blitt akseptert som behandling av enkelte T celle medierte tilstander, som kutant T celle lymfom (CTCL) og Graft-vs-Host disease (GVHD). Ved CTCL responderer omtrent halvparten av pasientene på behandlingen. Det finnes imidlertid ingen gode prediktive markører for respons, og en slik markør ville naturlig nok være av stor nytte. I Paper I har vi evaluert responsraten ved ECP hos pasienter med CTCL som har blitt behandlet på St. Olavs Hospital, i tillegg til å undersøke flere andre potensielle prediktive markører. 7 av 16 pasienter ble klassifisert som respondere på ECP-behandling. Hverken T celle klonalitet eller noen av serummarkørene som ble undersøkt kunne benyttes som prediktiv markør før behandlingsstart, men det kan se ut til at forandringer i enkelte av markørene etter 6 måneders behandling korrelerer med klinisk respons evaluert etter 12 måneders behandling. Virkningsmekanismen til ECP ved CTCL er fortsatt ikke kjent. ECP induserer apoptose av lymfocytter. Inntil nylig har man trodd at monocytter ikke går i apoptose av behandlingen, men heller aktiveres og differensieres til umodne dendrittceller (DC). Disse er effektive fagocytter og presenterer fagocytert tumor antigen til immunforsvaret. Slik har man trodd at en cytolytisk tumorspesifikk immunrespons settes i gang. I Paper II har vi undersøkt hvordan ECP påvirker monocytter og umodne DC når det gjelder indusering av apoptose samt evne til å differensiere etter behandling. Vi fant at både lymfocytter, monocytter og umodne DC går i apoptose innen 72 timer etter ECP-behandling. Siden de også har en redusert evne til å differensiere etter ECP er det sannsynlig at den terapeutiske effekten av ECP heller skyldes in vivo mekanismer som følge av infusjon av apoptotiske celler, fremfor infusjon av monocytter som er indusert til å differensiere til umodne DC. Monocytter og DC som ble bestrålt med 30Gy gamma bestråling, dvs doser som induserer apoptose av lymfocytter, ser ut til å være uaffisert av denne behandlingen når det gjelder overlevelse og evne til differensiering. GVHD oppstår når allogene effektor T celler fra en donor angriper mottakeren. Det er foreslått at ECP trigger visse toleransemekanismer, som hemming av pro-inflammatoriske cytokiner, stimulering av regulatoriske T celler (Treg) og produksjon av anti-inflammatoriske cytokiner. Det kan imidlertid virke paradoksalt at den samme behandlingen skal sette i gang en tumorspesifikk, cytolytisk immunrespons mot lymfomceller hos den ene pasientgruppen, mens den fører til økt regulatorisk aktivitet hos GVHD pasienter. I Paper III har vi sammenlignet den relative andelen av sirkulerende Treg celler hos pasienter med CTCL eller GVHD. Vi fant her at CTCL pasientene har nær dobbelt så høy forekomst av Treg celler i sirkulasjon, sammenlignet med GVHD og normal kontroller. I tillegg undersøkte vi også om det var en målbar forandring av cytokiner i serum før og etter ECP. Før behandling var det anti-inflammatoriske cytokinet TGF-β i gjennomsnitt tre ganger høyere hos GVHD pasientene, sammenlignet med CTCL. Begge pasientgruppene hadde en liten, men signifikant økning av TGF-β etter behandling. Disse resultatene kan tolkes som en forbedret Treg funksjon som resultat av behandlingen. Økt TGF-β kan indikere høy Treg aktivering hos GVHD pasientene, mens en forhøyet relativ andel Treg celler hos CTCL pasientene kan tolkes som en respons som muligens er involvert i nedregulering av lymfom celleneExtracorporeal photochemotherapy (ECP) has been accepted as a standard therapy in certain T cell mediated conditions, such as cutaneous T cell lymphomas (CTCL) and Graft-vs-Host Disease (GVHD). In CTCL approximately one half of these patients respond to the treatment. However, predictive criteria for selecting patients who will respond to ECP are mainly lacking. In Paper I, we have evaluated the response rate to ECP in CTCL patients treated at St. Olavs Hospital, as well as investigated several potential predictive markers. Seven out of 16 patients evaluated were classified as responders to ECP. Neither T cell clonality nor any of the serum markers assessed pre-treatment could reliably predict the response to ECP treatment. However, the individual relative changes in some of the serum markers assessed during 6 months of ECP treatment coherently displayed correlation to the clinical response as evaluated after 12 months of ECP treatment. The mechanism of effect in ECP therapy is somewhat unclear. ECP has been shown to induce apoptosis in lymphocytes. Until recently the prevailing opinion has been that the monocytes were mainly not affected by this treatment, but rather were activated and differentiated into immature dendritic cells (DC), capable to phagocytize apoptotic CTCL-cells, and initiate a cytolytic tumour specific immune response. In Paper II we have tried to elucidate the effect of ECP on monocytes and immature DC, and followed the ability of the cells to differentiate and survive post treatment. We found that lymphocytes, monocytes and immature DC become apoptotic within 72 hours when treated with ECP. Since monocytes and immature DC seem to have a reduced ability to differentiate after ECP treatment, it is likely that the therapeutic effect of ECP is caused by in vivo effects of reinfused apoptotic cells, rather than by infusion of monocytes induced to differentiate into immature DC. Monocytes and DC treated with 30Gy gamma irradiation, i.e. doses that induce apoptosis in lymphocytes, were unaffected regarding survival and ability to differentiate post-treatment. GVHD is mainly mediated by allogeneic effector T cells recognizing the transplant recipient as foreign. ECP is reported to be triggering certain tolerance mechanisms, such as inhibition of pro-inflammatory cytokines, stimulation of regulatory T cells (Treg) and production of anti-inflammatory cytokines. It may, however, seem like a paradox that ECP initiates a tumour specific, cytolytic response against lymphoma cells in one condition, whereas it increases the regulatory function in another. In Paper III we have compared the relative levels of circulating Treg cells in patients with CTCL or GVHD. We found that the relative amount of Treg cells was twice as high in CTCL compared to GVHD and healthy controls. In addition, we investigated whether there were any measurable changes in serum cytokine levels during ECP therapy. Pre-treatment, the anti-inflammatory cytokine TGF-β was on average 3 times higher in GVHD than in CTCL. Both patient groups had a small, but significant increase in TGF-β after treatment. Our results indicate a strengthened Treg function as a result of ECP. Elevated TGF-β may indicate high Treg activation in GVHD, whereas an increased number of Treg cells in CTCL could be interpreted as a response that possibly is involved in down-regulating the lymphoma cells

Post-traumatic epidural tension pneumocephalus: a case report

Abstract Introduction: Pneumocephalus is usually a self-limiting condition commonly associated with neurosurgical interventions, head and facial trauma. In contrast, tension pneumocephalus is extremely rare, and considered a neurosurgical emergency. Case presentation: We present a rare case of post-traumatic epidural tension pneumocephalus in a 30-year-old white man who deteriorated rapidly after a blunt head trauma. Imaging revealed a large, right temporoparietal epidural pneumocephalus with mass effect, most likely arising from a small defect in the mastoid sinus. A pre-existing mucocele was also suspected. Emergency burr hole evacuation was performed and he experienced full recovery, but more invasive treatment was eventually needed to resolve the condition. Conclusions: Epidural tension pneumocephalus is a rare and potentially life-threatening condition, but treatable with the right management. To the best of our knowledge, a post-traumatic tension pneumocephalus caused by a pre-existing mucocele has not been reported in the literature

Inter-and Intraobserver Agreement of Morphological Grading for Central Lumbar Spinal Stenosis on Magnetic Resonance Imaging

Abstract Study Design Validation study of a morphological grading system for central lumbar spinal stenosis. Objective To evaluate and validate the inter- and intraobserver agreement of a morphological grading system for central lumbar spinal stenosis on magnetic resonance imaging between neurosurgeons and radiologists. Methods Two neurosurgeons and two radiologists independently assessed the morphological grading of lumbar spinal stenosis on pretreatment magnetic resonance imaging of 84 patients. Inter- and intrarater agreements were calculated by comparing the observers' evaluations level to level on the grading method. The results of both clinicians were compared with the assessment of both radiologists. Results On axial magnetic resonance images, 189 lumbar disk levels were evaluated for the grade of stenosis. The interobserver agreement between the clinicians was substantial. The interobserver agreement between clinician 1 and both radiologists was substantial, and it was moderate between clinician 2 and both radiologists. The clinicians' intraobserver agreement was almost perfect, and the radiologists' intraobserver agreement was substantial. Conclusions The interobserver agreement of this morphological grading for lumbar spinal stenosis was high between both the clinicians and radiologists, whereas the intraobserver agreement was almost perfect. Experienced clinicians may safely evaluate lumbar magnetic resonance images using this morphological grading for central lumbar spinal stenosis.publishedVersio

Confusion with cerebral perfusion pressure in a literature review of current guidelines and survey of clinical practise.

Background: Cerebral perfusion pressure (CPP) is defined as the difference between the mean arterial pressure (MAP) and the intracranial pressure (ICP). However, since patients with traumatic brain injury (TBI) are usually treated with head elevation, the recorded CPP values depends on the zero level used for calibration of the arterial blood pressure. Although international guidelines suggest that target values of optimal CPP are within the range of 50 – 70 mmHg in patients with TBI, the calibration of blood pressure, which directly influences CPP, is not described in the guidelines. The aim of this study was to review the literature used to support the CPP recommendations from the Brain Trauma Foundation, and to survey common clinical practice with respect to MAP, CPP targets and head elevation in European centres treating TBI patients. Methods: A review of the literature behind CPP threshold recommendations was performed. Authors were contacted if the publications did not report how MAP or CPP was measured. A short questionnaire related to measurement and treatment targets of MAP and CPP was sent to European neurosurgical centres treating patients with TBI. Results: Assessment methods for CPP measurement were only retrieved from 6 of the 11 studies cited in the TBI guidelines. Routines for assessment of CPP varied between these 6 publications. The 58 neurosurgical centres that answered our survey reported diverging routines on how to measure MAP and target CPP values. Higher CPP threshold were not observed if blood pressure was calibrated at the heart level (p = 0.51). Conclusions: The evidence behind the recommended CPP thresholds shows no consistency on how blood pressure is calibrated and clinical practice for MAP measurements and CPP target values seems to be highly variable. Until a consensus is reached on how to measure CPP, confusion will prevail

Long-Term Results After Surgery for Degenerative Cervical Myelopathy

BACKGROUND AND OBJECTIVES: Degenerative cervical myelopathy (DCM) is a frequent cause of spinal cord dysfunction, and surgical treatment is considered safe and effective. Long-term results after surgery are limited. This study investigated long-term clinical outcomes through data from the Norwegian registry for spine surgery. METHODS: Patients operated at the university hospitals serving Central and Northern Norway were approached for long-term follow-up after 3 to 8 years. The primary outcome was change in the Neck Disability Index, and the secondary outcomes were changes in the European Myelopathy Scale score, quality of life (EuroQoL EQ-5D); numeric rating scales (NRS) for headache, neck pain, and arm pain; and perceived benefit of surgery assessed by the Global Perceived Effect scale from 1 year to long-term follow-up. RESULTS: We included 144 patients operated between January 2013 and June 2018. In total, 123 participants (85.4%) provided patient-reported outcome measures (PROMs) at long-term follow-up. There was no significant change in PROMs from 1 year to long-term follow-up, including Neck Disability Index (mean 1.0, 95% CI −2.1-4.1, P = .53), European Myelopathy Scale score (mean −0.3, 95% CI −0.7-0.1, P = .09), EQ-5D index score (mean −0.02, 95% CI −0.09-0.05, P = .51), NRS neck pain (mean 0.3 95% CI −0.2-0.9, P = .22), NRS arm pain (mean −0.1, 95% CI −0.8-0.5, P = .70), and NRS headache (mean 0.4, 95% CI −0.1-0.9, P = .11). According to Global Perceived Effect assessments, 106/121 patients (87.6%) reported to be stable or improved (“complete recovery,” “much better,” “slightly better,” or “unchanged”) at long-term follow-up compared with 88.1% at 1 year. Dichotomizing the outcome data based on severity of DCM did not demonstrate significant changes either. CONCLUSION: Long-term follow-up of patients undergoing surgery for DCM demonstrates persistence of statistically significant and clinically meaningful improvement across a wide range of PROMs

Inter-and Intraobserver Agreement of Morphological Grading for Central Lumbar Spinal Stenosis on Magnetic Resonance Imaging

Study Design Validation study of a morphological grading system for central lumbar spinal stenosis. Objective To evaluate and validate the inter- and intraobserver agreement of a morphological grading system for central lumbar spinal stenosis on magnetic resonance imaging between neurosurgeons and radiologists. Methods Two neurosurgeons and two radiologists independently assessed the morphological grading of lumbar spinal stenosis on pretreatment magnetic resonance imaging of 84 patients. Inter- and intrarater agreements were calculated by comparing the observers’ evaluations level to level on the grading method. The results of both clinicians were compared with the assessment of both radiologists. Results On axial magnetic resonance images, 189 lumbar disk levels were evaluated for the grade of stenosis. The interobserver agreement between the clinicians was substantial. The interobserver agreement between clinician 1 and both radiologists was substantial, and it was moderate between clinician 2 and both radiologists. The clinicians’ intraobserver agreement was almost perfect, and the radiologists’ intraobserver agreement was substantial. Conclusions The interobserver agreement of this morphological grading for lumbar spinal stenosis was high between both the clinicians and radiologists, whereas the intraobserver agreement was almost perfect. Experienced clinicians may safely evaluate lumbar magnetic resonance images using this morphological grading for central lumbar spinal stenosis

Inter-and Intraobserver Agreement of Morphological Grading for Central Lumbar Spinal Stenosis on Magnetic Resonance Imaging

Abstract Study Design Validation study of a morphological grading system for central lumbar spinal stenosis. Objective To evaluate and validate the inter- and intraobserver agreement of a morphological grading system for central lumbar spinal stenosis on magnetic resonance imaging between neurosurgeons and radiologists. Methods Two neurosurgeons and two radiologists independently assessed the morphological grading of lumbar spinal stenosis on pretreatment magnetic resonance imaging of 84 patients. Inter- and intrarater agreements were calculated by comparing the observers' evaluations level to level on the grading method. The results of both clinicians were compared with the assessment of both radiologists. Results On axial magnetic resonance images, 189 lumbar disk levels were evaluated for the grade of stenosis. The interobserver agreement between the clinicians was substantial. The interobserver agreement between clinician 1 and both radiologists was substantial, and it was moderate between clinician 2 and both radiologists. The clinicians' intraobserver agreement was almost perfect, and the radiologists' intraobserver agreement was substantial. Conclusions The interobserver agreement of this morphological grading for lumbar spinal stenosis was high between both the clinicians and radiologists, whereas the intraobserver agreement was almost perfect. Experienced clinicians may safely evaluate lumbar magnetic resonance images using this morphological grading for central lumbar spinal stenosis

Patients with moderate and severe traumatic brain injury: impact of preinjury platelet inhibitor or warfarin treatment

Objective We aimed to examine the effect of preinjury antithrombotic medication on clinical and radiologic neuroworsening in traumatic brain injury (TBI) and study the effect on outcome. Methods A total of 184 consecutive patients ≥50 years old with moderate and severe TBI admitted to a level 1 trauma center were included. Neuroworsening was assessed clinically by using the Glasgow Coma Scale (GCS) score and radiologically by using the Rotterdam CT score on repeated time points. Functional outcome was assessed with the Glasgow Outcome Scale Extended 6 months after injury. Results The platelet inhibitor group (mean age, 77.3 years; n = 43) and the warfarin group (mean age, 73.2 years; n = 20) were significantly older than the nonuser group (mean age, 63.7 years; n = 121; P ≤ 0.001). In the platelet inhibitor group 74% and in the warfarin group, 85% were injured by falls. Platelet inhibitors were not significantly associated with clinical or radiologic neuroworsening (P = 0.37–1.00), whereas warfarin increased the frequency of worsening in GCS score (P = 0.001–0.028) and Rotterdam CT score (P = 0.004). In-hospital mortality was higher in the platelet inhibitor group (28%; P = 0.030) and the warfarin group (50%; P < 0.001) compared with the nonuser group (13%). Platelet inhibitors did not predict mortality or worse outcome after adjustment for age, preinjury disability, GCS score, and Rotterdam CT score, whereas warfarin predicted both mortality and worse outcome. Conclusions In this study of patients with moderate and severe TBI, preinjury platelet inhibitors did not cause neuroworsening or predict higher mortality or worse outcome. In contrast, preinjury warfarin caused neuroworsening and was an independent risk factor for mortality and worse outcome at 6 months. Hence, fall prevention and liberal use of computed tomography examinations is important in this patient group.acceptedVersion© 2018. This is the authors’ accepted and refereed manuscript to the article. Locked until 07.03.2019 due to copyright restrictions. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0

Patients with moderate and severe traumatic brain injury: impact of preinjury platelet inhibitor or warfarin treatment

Objective We aimed to examine the effect of preinjury antithrombotic medication on clinical and radiologic neuroworsening in traumatic brain injury (TBI) and study the effect on outcome. Methods A total of 184 consecutive patients ≥50 years old with moderate and severe TBI admitted to a level 1 trauma center were included. Neuroworsening was assessed clinically by using the Glasgow Coma Scale (GCS) score and radiologically by using the Rotterdam CT score on repeated time points. Functional outcome was assessed with the Glasgow Outcome Scale Extended 6 months after injury. Results The platelet inhibitor group (mean age, 77.3 years; n = 43) and the warfarin group (mean age, 73.2 years; n = 20) were significantly older than the nonuser group (mean age, 63.7 years; n = 121; P ≤ 0.001). In the platelet inhibitor group 74% and in the warfarin group, 85% were injured by falls. Platelet inhibitors were not significantly associated with clinical or radiologic neuroworsening (P = 0.37–1.00), whereas warfarin increased the frequency of worsening in GCS score (P = 0.001–0.028) and Rotterdam CT score (P = 0.004). In-hospital mortality was higher in the platelet inhibitor group (28%; P = 0.030) and the warfarin group (50%; P < 0.001) compared with the nonuser group (13%). Platelet inhibitors did not predict mortality or worse outcome after adjustment for age, preinjury disability, GCS score, and Rotterdam CT score, whereas warfarin predicted both mortality and worse outcome. Conclusions In this study of patients with moderate and severe TBI, preinjury platelet inhibitors did not cause neuroworsening or predict higher mortality or worse outcome. In contrast, preinjury warfarin caused neuroworsening and was an independent risk factor for mortality and worse outcome at 6 months. Hence, fall prevention and liberal use of computed tomography examinations is important in this patient group

Comparative effectiveness of microdecompression and laminectomy for central lumbar spinal stenosis: Study protocol for an observational study

Introduction: This observational study is designed to test the equivalence between the clinical effectiveness of microdecompression and laminectomy in the surgical treatment of central lumbar spinal stenosis. Lumbar spinal stenosis is the most frequent indication for spinal surgery in the elderly, and as the oldest segment of the population continues to grow its prevalence is likely to increase. However, data on surgical outcomes are limited. Open or wide decompressive laminectomy, often combined with medial facetectomy and foraminotomy, was formerly the standard treatment. In recent years a growing tendency towards less invasive decompressive procedures has emerged. At present, many spine surgeons perform microdecompression for central lumbar spinal stenosis. Methods and analysis: Prospectively registered treatment and outcome data are obtained from the Norwegian Registry for Spine Surgery. The primary outcome measure is change in Oswestry disability index between baseline and 12-month follow-up. Secondary outcome measures are changes in health-related quality of life measured by the Euro-Qol-5D between baseline and 12-month follow-up, perioperative complications, and duration of surgical procedures and length of hospital stay. Ethics and dissemination: The study has been evaluated and approved by the regional committee for medical research in central Norway and all participants provided written informed consent. The findings of this study will be disseminated through peer-reviewed publications