From Meaningful Outcomes to Meaningful Change Thresholds: A Path to Progress for Establishing Digital Endpoints.

This paper examines the use of digital endpoints (DEs) derived from digital health technologies (DHTs), focusing primarily on the specific considerations regarding the determination of meaningful change thresholds (MCT). Using DHTs in drug development is becoming more commonplace. There is general acceptance of the value of DHTs supporting patient-centric trial design, capturing data outside the traditional clinical trial setting, and generating DEs with the potential to be more sensitive to change than conventional assessments. However, the transition from exploratory endpoints to primary and secondary endpoints capable of supporting labeling claims requires these endpoints to be substantive with reproducible population-specific values. Meaningful change represents the amount of change in an endpoint measure perceived as important to patients and should be determined for each digital endpoint and given population under consideration. This paper examines existing approaches to determine meaningful change thresholds and explores examples of these methodologies and their use as part of DE development: emphasizing the importance of determining what aspects of health are important to patients and ensuring the DE captures these concepts of interest and aligns with the overarching endpoint strategy. Examples are drawn from published DE qualification documentation and responses to qualification submissions under review by the various regulatory authorities. It is the hope that these insights will inform and strengthen the development and validation of DEs as drug development tools, particularly for those new to the approaches to determine MCTs.

Are patient-reported outcome instruments for ankylosing spondylitis fit for purpose for the axial spondyloarthritis patient? A qualitative and psychometric analysis.

OBJECTIVES: Several patient-reported outcome (PRO) instruments have been validated in AS. This study aims to evaluate several measurement properties of such PROs in a broad axial SpA (axSpA) population, including both AS and non-radiographic axSpA (nr-axSpA) subpopulations. METHODS: PROs assessed were total and nocturnal back pain, patient global assessment of disease activity, BASDAI, BASFI and the 36-item Short Form Health Survey. A literature review and both clinician and patient qualitative interviews provided information on instrument content validity. Reliability (test-retest and internal consistency), construct validity (PROs, clinical-outcome correlations and known-groups validity) and PRO responsiveness were assessed. Data from the RAPID-axSpA trial (NCT01087762) investigating certolizumab pegol efficacy in axSpA, including relevant subpopulations, were utilized. RESULTS: Concepts identified for the broad axSpA population by both clinician and patient interviews were consistent with those identified through literature review of AS. All PROs demonstrated reliability in the RAPID-axSpA population (n = 325), with test-retest intraclass correlation coefficients and internal consistency Cronbach's α >0.8. Validity was supported by agreement between PROs and clinician-rated measures; except for the 36-item Short Form Health Survey Mental Components Summary, correlations between PROs and physician global assessment of disease activity ranged from 0.28 to 0.42 for week 0 and from 0.53 to 0.65 for week 24. PRO measures showed good sensitivity to change (effect size >0.8) at weeks 12 and 24 for responders. No variations in measurement properties were noted between the subpopulations. CONCLUSION: This study indicates that both content validity and measurement properties of PRO instruments utilized in AS are preserved in the broad axSpA population.

Comparative effectiveness of frame-based, frameless, and intraoperative magnetic resonance imaging-guided brain biopsy techniques.

OBJECTIVE: To compare the diagnostic yield and safety profiles of intraoperative magnetic resonance imaging (MRI)-guided needle brain biopsy with 2 traditional brain biopsy methods: frame-based and frameless stereotactic brain biopsy. METHODS: A retrospective analysis was performed of 288 consecutive needle brain biopsies in 277 patients undergoing stereotactic brain biopsy with any of the 3 biopsy methods at Brigham and Women's Hospital from 2000-2008. Variables including age, sex, history of radiation and previous surgery, pathology results, complications, and postoperative length of hospital stay were analyzed. RESULTS: Over the course of 8 years, 288 brain biopsies were performed. Of these, 253 (87.8%) biopsies yielded positive diagnostic tissue. Young age (<40 years old) and history of brain radiation or surgery were significant negative predictors for a positive biopsy diagnostic yield. Excluding patients with prior radiation or surgeries, no significant difference in diagnostic yield was detected among the 3 groups, with frame-based biopsies yielding 96.9%, frameless biopsies yielding 91.8%, and intraoperative MRI-guided needle biopsies yielding 89.9% positive diagnostic yield. Serious adverse events occurred 19 biopsies (6.6%). Intraoperative MRI-guided brain biopsies were associated with less serious adverse events and the shortest postoperative hospital stay. CONCLUSIONS: Frame-based, frameless stereotactic, and intraoperative MRI-guided brain needle biopsy techniques have comparable diagnostic yield for patients with no prior treatments (either radiation or surgery). Intraoperative MRI-guided brain biopsy is associated with fewer serious adverse events and shorter hospital stay.

Surgery for intractable epilepsy due to unilateral brain disease: a retrospective study comparing hemispherectomy techniques.

BACKGROUND: Hemispherectomy is a surgical procedure used to treat medically intractable epilepsy in children with severe unilateral cortical disease secondary to acquired brain or congenital lesions. The major surgical approaches for hemispherectomy are anatomic hemispherectomy, traditional functional hemispherectomy, and peri-insular hemispherotomy. We describe the epilepsy outcome, including the need for reoperation, after hemispherectomy in patients with brain malformations or acquired brain lesions who underwent hemispherectomy for refractory epilepsy. METHODS: We conducted a retrospective observational study at Children's Hospital Boston. Cases were ascertained from a research database of patients who underwent epilepsy surgery from 1997 to 2011. Data were obtained from electronic medical records and office charts. Outcome after surgery was defined as improvement in seizures (quantity and severity) represented by the Engel classification score measured at last follow-up, with a minimum of 12 months of follow-up. The need for reoperation for completion of hemispheric disconnection. We also examined whether placement of ventriculoperitoneal shunt was required after hemispherectomy was a secondary outcome. RESULTS: We identified 36 patients who underwent hemispherectomy for severe, medically intractable epilepsy. Group 1 (n = 14) had static acquired lesions, and group 2 (n = 22) had malformations of cortical development. Mean age at surgery for group 1 was 9 years (S.D. 5.5) and 2.77 years for group 2 (S.D. 4.01; P < 0.001). The seizure outcome was good in both groups (Engel score I for 25, II for three, III for six, and IV for two patients) and did not differ between the two groups. In group 1, five patients underwent anatomic hemispherectomy (one had prior focal resection), four underwent functional hemispherectomy, and five underwent peri-insular hemispherotomy; none required a second procedure. In group 2, a total of 14 patients had anatomic hemispherectomy (of these, three had had limited prior focal resection), five had functional hemispherectomy, and three had peri-insular hemispherotomy. Among the patients in group 2 who had had functional hemispherectomy, one required reoperation to complete the disconnection and one required peri-insular hemispherotomy because of persistent seizures. In group 1, three patients underwent a ventriculoperitoneal shunt, and from these patients two underwent anatomic hemispherectomy and one had functional hemispherectomy. In group 2, 12 patients had ventriculoperitoneal shunt, and all of them had anatomic hemispherectomy as a first or second procedure. CONCLUSION: Seizure outcome after hemispherectomy is good in patients with acquired lesions and with developmental malformations. Although the seizure outcome was similar in the three procedures, the complication rate was higher with anatomic hemispherectomy than with the more recent functional hemispherectomy and peri-insular hemispherotomy. The group with cortical malformations generally had surgery at a younger age; two patients with malformations of cortical development who underwent functional hemispherectomy required second surgeries. The need for reoperation in these cases may reflect the anatomic complexity of developmental hemispheric malformations, which may lead to incomplete disconnection.

Immediate titanium mesh cranioplasty for treatment of postcraniotomy infections.

OBJECTIVE: Postcraniotomy infections have generally been treated by debridement of infected tissues, disposal of the bone flap, and delayed cranioplasty several months later to repair the resulting skull defect. Debridement followed by retention of the bone flap has also been advocated. Here we propose an alternative operative strategy for the treatment of postcraniotomy infections. METHODS: Two patients presenting with clinical and radiographic signs and symptoms of postcraniotomy infections were treated by debridement, bone flap disposal, and immediate titanium mesh cranioplasty. The patients were subsequently administered antibiotics, and their clinical courses were followed. RESULTS: The patients treated in this fashion did not have recurrence of their infections during 3-year follow-up periods. CONCLUSIONS: Surgical debridement, bone flap disposal, and immediate titanium mesh cranioplasty may be a suitable option for the treatment of postcraniotomy infections. This treatment strategy facilitates the eradication of infectious sources and obviates the risks and costs associated with a second surgical procedure.

Somatic activation of AKT3 causes hemispheric developmental brain malformations.

Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.

Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia.

OBJECTIVE: The most common neurological symptom of tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) is early life refractory epilepsy. As previous studies have shown enhanced excitatory glutamatergic neurotransmission in TSC and FCD brains, we hypothesized that neurons associated with these lesions may also express altered γ-aminobutyric acid (GABA)(A) receptor (GABA(A)R)-mediated inhibition. METHODS: Expression of the GABA(A)R subunits α1 and α4, and the Na(+)-K(+)-2Cl(-) (NKCC1) and the K(+)-Cl(-) (KCC2) transporters, in human TSC and FCD type II specimens were analyzed by Western blot and double label immunocytochemistry. GABA(A) R responses in dysplastic neurons from a single case of TSC were measured by perforated patch recording and compared to normal-appearing cortical neurons from a non-TSC epilepsy case. RESULTS: TSC and FCD type IIb lesions demonstrated decreased expression of GABA(A)R α1, and increased NKCC1 and decreased KCC2 levels. In contrast, FCD type IIa lesions showed decreased α4, and increased expression of both NKCC1 and KCC2 transporters. Patch clamp recordings from dysplastic neurons in acute slices from TSC tubers demonstrated excitatory GABA(A)R responses that were significantly attenuated by the NKCC1 inhibitor bumetanide, in contrast to hyperpolarizing GABA(A)R-mediated currents in normal neurons from non-TSC cortical slices. INTERPRETATION: Expression and function of GABA(A)Rs in TSC and FCD type IIb suggest the relative benzodiazepine insensitivity and more excitatory action of GABA compared to FCD type IIa. These factors may contribute to resistance of seizure activity to anticonvulsants that increase GABAergic function, and may justify add-on trials of the NKCC1 inhibitor bumetanide for the treatment of TSC and FCD type IIb-related epilepsy.

Alternative splicing of CHEK2 and codeletion with NF2 promote chromosomal instability in meningioma.

Mutations of the NF2 gene on chromosome 22q are thought to initiate tumorigenesis in nearly 50% of meningiomas, and 22q deletion is the earliest and most frequent large-scale chromosomal abnormality observed in these tumors. In aggressive meningiomas, 22q deletions are generally accompanied by the presence of large-scale segmental abnormalities involving other chromosomes, but the reasons for this association are unknown. We find that large-scale chromosomal alterations accumulate during meningioma progression primarily in tumors harboring 22q deletions, suggesting 22q-associated chromosomal instability. Here we show frequent codeletion of the DNA repair and tumor suppressor gene, CHEK2, in combination with NF2 on chromosome 22q in a majority of aggressive meningiomas. In addition, tumor-specific splicing of CHEK2 in meningioma leads to decreased functional Chk2 protein expression. We show that enforced Chk2 knockdown in meningioma cells decreases DNA repair. Furthermore, Chk2 depletion increases centrosome amplification, thereby promoting chromosomal instability. Taken together, these data indicate that alternative splicing and frequent codeletion of CHEK2 and NF2 contribute to the genomic instability and associated development of aggressive biologic behavior in meningiomas.

Imaging of human mesenchymal stromal cells: homing to human brain tumors.

Human mesenchymal stromal cells (hMSC) can be used as a drug delivery vehicle for the treatment of GBM. However, tracking the migration and distribution of these transplanted cells is necessary to interpret therapeutic efficacy. We compared three labeling techniques for their ability to track the migration of transplanted hMSC in an orthotopic mouse xenograft model. hMSC were labeled with three different imaging tags (fluorescence, luciferase or ferumoxide) for imaging by fluorescence, bioluminescence or magnetic resonance imaging (MRI), respectively. hMSC were labeled for all imaging modalities without the use of transfection agents. The labeling efficacy of the tags was confirmed, followed by in vitro and in vivo migration assays to track hMSC migration towards U87 glioma cells. Our results confirmed that the labeled hMSC retained their migratory ability in vitro, similar to unlabeled hMSC. In addition, labeled hMSC migrated towards the U87 tumor site, demonstrating their retention of tumor tropism. hMSC tumor tropism was confirmed by all three imaging modalities; however, MRI provides both real time assessment and the high resolution needed for clinical studies. Our findings suggest that ferumoxide labeling of hMSC is feasible, does not alter their migratory ability and allows detection by MRI. Non invasive tracking of transplanted therapeutic hMSC in the brain will allow further development of human cell based therapies.

Neurosurgery certification in member societies of the WFNS: global overview.

OBJECTIVE: To determine the complexity and diversity of the neurosurgery certification and recertification process in member societies of the World Federation of Neurosurgical Societies. MATERIAL AND METHODS: A 13-item survey was sent to 88 national and regional societies that are members of the World Federation of Neurosurgical Societies. Variables included in the survey covered a wide range of aspects pertaining to the certification process achieved by cognitive and oral examinations. The data received from 40 responding societies (response rate 45%) were tabulated, and an individual and comparative (global) analysis was performed for all categories, including eligibility and requirements for certification, examination components, use of computer-assisted technology and imaging, performance, validation of foreign degrees, recertification, and maintenance of certification. RESULTS: We present here the global analysis, which is comparative of all participating societies. Although there is high variability in the structure of certification programs worldwide, performance in knowledge-based examinations is similar. Recertification and maintenance of certification are still under development in many societies. CONCLUSION: With the onset of globalization, we anticipate that efforts will be made in the future to obtain homogeneity in the structure of certification, recertification, and in criteria for international reciprocity of postgraduate neurosurgical training. Peer-Review Article.

Neurosurgery certification in member societies of the WFNS: Africa and the Middle East.

BACKGROUND: This study sought to compare objectively the complexity and diversity of the certification process in neurological surgery in member societies of the World Federation of Neurosurgical Societies (WFNS) in the African and Middle Eastern regions. METHODS: This report centers on two geographic regions: Africa and the Middle East. We provide a subgroup analysis based on the responses provided to the 13-item survey sent in Part I of this study. The data received were analyzed, and three Regional Complexity Scores (RCS) were designed. To compare national board experience, eligibility requirements to access the certification process, and the obligatory nature of the examinations, a RCS-Organizational score was created (RCS-O, 20 points maximum). To analyze the complexity of the examination, a RCS-Components was designed (RCS-C, 20 points maximum). The sum of both is presented in a global RCS (RCS-G). In addition, a descriptive summary of the certification process per responding society is also provided. RESULTS: Based on the data provided by our RCS system, the highest RCS-G was obtained by South Africa (19 of 40 points), followed by Egypt (18 of 40 points), countries of the Gulf Neurosurgical Society (16 of 40 points), and the Neurosurgical Society of East and Central Africa (16 of 40 points). CONCLUSIONS: This grading system allows societies to compare their process of certification within their continental region and worldwide, potentially identifying aspects for further improvement or development.

Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus.

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD). A total of 35 patients with suspected iNPH patients were evaluated with ELD. CSF was collected in the beginning of the test, and the concentrations of total tau, ptau(181), Aß(42), NFL, TNF-α, TGFß1, and VEGF were analysed by ELISA. Twenty-six patients had a positive ELD result-that is, their gait symptoms improved; 9 patients had negative ELD. The levels of all analyzed CSF biomarkers were similar between the groups and none of them predicted the ELD result in these patients. Contrary to expectations lumbar CSF TNF-α concentration was low in iNPH patients.

Neurosurgery certification in member societies of the World Federation of Neurosurgical Societies: Asia.

OBJECTIVE: To objectively compare the complexity and diversity of the certification process in neurological surgery in member societies of the World Federation of Neurosurgical Societies. METHODS: This study centers in continental Asia. We provide here an analysis based on the responses provided to a 13-item survey. The data received were analyzed, and three Regional Complexity Scores (RCS) were designed. To compare national board experience, eligibility requirements for access to the certification process, and the obligatory nature of the examinations, an RCS-Organizational score was created (20 points maximum). To analyze the complexity of the examination, an RCS-Components score was designed (20 points maximum). The sum of both is presented in a Global RCS score. Only those countries that responded to the survey and presented nationwide homogeneity in the conduction of neurosurgery examinations could be included within the scoring system. In addition, a descriptive summary of the certification process per responding society is also provided. RESULTS AND CONCLUSION: On the basis of the data provided by our RCS system, the highest global RCS was achieved by South Korea and Malaysia (21/40 points) followed by the joint examination of Singapore and Hong-Kong (FRCS-Ed) (20/40 points), Japan (17/40 points), the Philippines (15/40 points), and Taiwan (13 points). The experience from these leading countries should be of value to all countries within Asia.

Reduced allergy and immunoglobulin E among adults with intracranial meningioma compared to controls.

Meningioma, the most frequent tumor in the central nervous system, has few recognized risk factors. We explored the role of allergies in a population-based case-control consortium study of meningioma in five geographic areas. We also studied serum levels of a marker of atopic allergy (IgE) in a subset of study participants, a first for a study on meningioma. Participants (N = 1,065) with surgically resected, pathologically confirmed meningioma and controls (N = 634) selected via random-digit dialing were recruited and interviewed. Cases were less likely than controls to report history of physician-diagnosed allergy [odds ratio (OR) = 0.64; 95% confidence interval (95% CI): 0.51-0.80]. Also, cases (N = 295) had lower total serum IgE than controls [N = 192; OR = 0.85, 95% CI: 0.75-0.98 for each unit of Ln(IgE)]. Similar to glioma and cancers at several other sites, meningioma appears to have an inverse relationship with history of allergies and a biomarker of atopic allergy. As some common opposing predisposition or developmental processes for allergy and meningioma may exist, further research into immune processes that can affect the incidence and natural history of meningioma is warranted.