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PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity. ispartof: GENETICS IN MEDICINE vol:24 issue:9 pages:1967-1977 ispartof: location:United States status: published

Background Despite increasing commitment to patient engagement in research, evaluation of the impact of these efforts on research processes, products, and teams is limited. Objective To explore the impacts of engaging patients as consultants to research studies by examining the experiences, impacts, and lessons learned from a program facilitating patient engagement at a Veterans Health Administration research center. Design We developed a logic model to articulate the activities being implemented to support patient engagement and their anticipated outcomes. Then, we conducted qualitative, semi-structured interviews with participants in the local Veteran Consulting Network to qualitatively explore these outcomes. Participants Twelve researchers and eleven Veteran patients with experience working on at least one grant or funded study. Approach Interview transcripts were inductively coded using a consensus-based approach. Findings were synthesized using framework analysis and mapped back onto our logic model of expected patient engagement impacts. Key Results Patient engagement improved the perceived quality and relevance of research studies as patient consultants challenged researchers’ assumptions about patient populations and clinical contexts and gave feedback that helped improve the feasibility of proposed grants, readability of study materials, comprehensiveness of study assessments, and cultural sensitivity and relevance of interventions. Patient engagement also had personal benefits to researchers and patients. Researchers reported improved communication skills and higher job satisfaction. Patients reported a sense of purpose and satisfaction from their work with greater awareness of and appreciation for research. Conclusions Engaging patients in research can have multiple benefits to the people and work involved. Our evaluation process can serve as a template for other organizations to plan for and assess the impact of their own patient engagement programs. Creating logic models and updating them based on feedback from program users make engagement goals explicit, help verify expected mechanisms to achieve impact, and facilitate organizational learning.

Background and ObjectivesInternal neurofibromas, including plexiform neurofibromas (PNF), can cause significant morbidity in patients with neurofibromatosis type 1 (NF1). PNF growth is most pronounced in children and young adults, with more rapid growth thought to occur in a subset of PNF termed distinct nodular lesions (DNL). Growth behavior of internal neurofibromas and DNL in older adults is not well documented; yet knowledge thereof is important for patient risk stratification and clinical trial design. The primary objective of this study was to evaluate the long-term growth behavior of internal neurofibromas in adults with NF1. Secondary objectives were to correlate tumor growth behavior with patient-specific, tumor-specific, and patient-reported variables.MethodsIn this prospective cohort study, internal neurofibromas were identified on coronal short TI inversion recovery sequences on baseline and follow-up whole-body MRIs (WBMRIs). Tumor growth and shrinkage were defined as a volume change ≥20%. The association between tumor growth and patient-specific (baseline age, sex, and genotype), tumor-specific (morphology, location, DNL presence on baseline WBMRI, and maximum standardized uptake value on baseline PET imaging), and patient-reported variables (endogenous and exogenous hormone exposure, pain intensity, and quality of life) was assessed using the Spearman correlation coefficient and Kruskal-Wallis test.ResultsOf 106 patients with a baseline WBMRI obtained as part of a previous research study, 44 had a follow-up WBMRI. Three additional patients with WBMRIs acquired for clinical care were included, generating 47 adults for this study. The median age during baseline WBMRI was 42 years (range 18–70). The median time between WBMRIs was 10.4 years. Among 324 internal neurofibromas, 62.8% (56% of PNF and 62.1% of DNL) shrank spontaneously without treatment and 17.1% (17.9% of PNF and 13.8% of DNL) grew. Growth patterns were heterogeneous within participants. Patient-specific, tumor-specific, and patient-reported variables (including endogenous and exogenous hormone exposure) were not strong predictors of tumor growth.DiscussionInternal neurofibroma growth behavior in older adults differs fundamentally from that in children and young adults, with most tumors, including DNL, demonstrating spontaneous shrinkage. Better growth models are needed to understand factors that influence tumor growth. These results will inform clinical trial design for internal neurofibromas.

The coronavirus pandemic increased anxiety and stress and prevented access to health care worldwide; it is unclear how COVID‐19 affected adults with a multisystem genetic disorder such as neurofibromatosis (NF). An anonymous online survey was distributed through an international registry and foundations to adults with NF (June–August 2020) to assess the impact of the pandemic on mental health and NF health care. Six hundred and thirteen adults (18–81 years; M = 45.7) with NF1 (77.8%), NF2 (14.2%), and schwannomatosis (7.8%) provided complete responses. Respondents rated moderate‐to‐high amounts of worry about the impact of COVID‐19 on their emotional (46.3%) and physical health (46.7%), and 54.8% endorsed moderate‐to‐high pandemic‐related stress. Adults with diagnosed/suspected mental health disorders or moderate‐to‐severe NF symptom impact as well as females endorsed higher COVID‐19 stress (ps

ObjectiveTo review and recommend patient-reported outcome (PRO) measures assessing multidimensional domains of quality of life (QoL) to use as clinical endpoints in medical and psychosocial trials for children and adults with neurofibromatosis (NF) type 1, NF2, and schwannomatosis.MethodsThe PRO working group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration used systematic methods to review, rate, and recommend existing self-report and parent-report PRO measures of generic and disease-specific QoL for NF clinical trials. Recommendations were based on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility.ResultsThe highest-rated generic measures were (1) the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales for NF clinical trials for children or for children through adults, (2) the Functional Assessment of Cancer Therapy–General for adult medical trials, and (3) the World Health Organization Quality of Life–BREF for adult psychosocial trials. The highest-rated disease-specific measures were (1) the PedsQL NF1 Module for NF1 trials, (2) the NF2 Impact on Quality of Life Scale for NF2 trials, and (3) the Penn Acoustic Neuroma Quality of Life Scale for NF2 trials targeting vestibular schwannomas. To date, there are no disease-specific tools assessing multidimensional domains of QoL for schwannomatosis.ConclusionsThe REiNS Collaboration currently recommends these generic and disease-specific PRO measures to assess multidimensional domains of QoL for NF clinical trials. Additional research is needed to further evaluate the use of these measures in both medical and psychosocial trials.

ObjectiveAs part of an evaluation of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration patient representative program, we surveyed REiNS members to (1) identify facilitators and barriers to involving patient representatives and (2) understand whether and how involving patient representatives affected recommendations for clinical trial outcomes.MethodsWe administered an anonymous online survey to all REiNS members. Facilitators and barriers to patient representative involvement were solicited using a modified free listing technique; responses were inductively grouped into higher-order categories and ranked based on saliency score (Smith s). Open-ended questions assessed patient representative expectations for engagement, perceived benefits/costs of patient engagement, and patient representative contributions; responses were analyzed using conventional content analysis.ResultsA total of 63/172 (37%) members responded, including 18/30 (60%) patient representatives. Providing sufficient opportunities to meaningfully engage in research tasks and cultivating a respectful, inclusive atmosphere were key facilitators to patient representatives' satisfaction and ability to make an impact. Respondents perceived that patient representatives directly (through their input on research tasks) and indirectly (through effects on other stakeholders' knowledge and communication style) improved the organization's research, leading to selection of more meaningful, relevant, and feasible clinical trial outcome measures. Ongoing challenges to patient engagement include difficulty scheduling meetings and concerns about the level of scientific knowledge patient representatives needed to effectively engage.ConclusionsInvolving patient representatives in REiNS improved perceived quality of neurofibromatosis clinical trial outcome measures. Negotiating sufficient opportunities to engage, fostering an inclusive atmosphere, and navigating time pressures are key to effective patient engagement.

Schwannomatosis (SWN) is a rare tumor suppressor syndrome that predisposes affected individuals to develop multiple schwannomas and, less often, meningiomas. The most common symptom is chronic, severe pain. No medications are broadly effective in treating SWN-associated pain. The clinical trial described in this manuscript is a phase 2, randomized, double-blind, placebo-controlled study investigating the safety and efficacy of tanezumab - a humanized monoclonal antibody that inhibits nerve growth factor - for treatment of SWN-related pain. As the first therapeutic trial for SWN-related pain, it also aims to evaluate trial endpoints, understand recruitment patterns, and improve clinical trial design in this rare disease.The primary objective of this trial is to assess the analgesic efficacy of subcutaneous tanezumab 10 mg in subjects with SWN who continue pre-existing pain therapy (excluding non-steroidal anti-inflammatory drugs). The secondary objective is to assess safety in this population. Exploratory objectives include assessment of pain features, quality of life, and predictive biomarkers.The study is comprised of four periods (pre-treatment, double-blind treatment, single-arm treatment, safety follow-up) across 10 months with a delayed-start trial design to allow all participants to receive tanezumab. Forty-six participants will be enrolled and randomized 1:1 to receive either tanezumab or placebo subcutaneously in the double-blind treatment period; all participants receive tanezumab during the single-arm treatment period.This study is the first therapeutic trial for SWN patients and targets a biological driver of SWN-related pain. It aims to establish a model for future pain studies in SWN and other rare diseases.NCT04163419 on ClinicalTrials.gov.

Diagnosis of rare, genetic diseases is challenging, but conceptual frameworks of the diagnostic process can be used to guide benchmarking and process improvement initiatives. Using the National Academy of Medicine diagnostic framework, we assessed the extent of, and reasons for diagnostic delays and diagnostic errors in schwannomatosis, a neurogenetic syndrome characterized by nerve sheath tumors and chronic pain. We reviewed the medical records of 97 people with confirmed or probable schwannomatosis seen in two U.S. tertiary care clinics. Time-to-event analysis revealed a median time from first symptom to diagnosis of 16.7 years (95% CI, 7.5-26.0 years) and median time from first medical consultation to diagnosis of 9.8 years (95% CI, 3.5-16.2 years). Factors associated with longer times to diagnosis included initial signs/symptoms that were intermittent, non-specific, or occurred at younger ages (p

PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS. ispartof: GENETICS IN MEDICINE vol:23 issue:8 pages:1506-1513 ispartof: location:United States status: published

Introduction\ud \ud Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction.\ud \ud \ud \ud Methods\ud \ud A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori.\ud \ud \ud \ud Results\ud \ud 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity.\ud \ud \ud \ud Conclusions\ud \ud Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.

Objective UK national guidelines recommend pancreatic enzyme replacement therapy (PERT) in pancreatic cancer. Over 80% of pancreatic cancers are unresectable and managed in non-surgical units. The aim was to assess variation in PERT prescribing, determine factors associated with its use and identify potential actions to improve prescription rates. Design RICOCHET was a national prospective audit of malignant pancreatic, peri-ampullary lesions or malignant biliary obstruction between April and August 2018. This analysis focuses on pancreatic cancer patients and is reported to STROBE guidelines. Multivariable regression analysis was undertaken to assess factors associated with PERT prescribing. Results Rates of PERT prescribing varied among the 1350 patients included. 74.4% of patients with potentially resectable disease were prescribed PERT compared to 45.3% with unresectable disease. PERT prescription varied across surgical hospitals but high prescribing rates did not disseminate out to the respective referring network. PERT prescription appeared to be related to the treatment aim for the patient and the amount of clinician contact a patient has. PERT prescription in potentially resectable patients was positively associated with dietitian referral (p = 0.001) and management at hepaticopancreaticobiliary (p = 0.049) or pancreatic unit (p = 0.009). Prescription in unresectable patients also had a negative association with Charlson comorbidity score 5–7 (p = 0.045) or >7 (p = 0.010) and a positive association with clinical nurse specialist review (p = 0.028). Conclusion Despite national guidance, wide variation and under-treatment with PERT exists. Given that most patients with pancreatic cancer have unresectable disease and are treated in non-surgical hospitals, where prescribing is lowest, strategies to disseminate best practice and overcome barriers to prescribing are urgently required.

PurposeThe coronavirus disease 2019 (COVID-19) pandemic has had unprecedented impact on the provision of medical care for genetic disorders. The purpose of this study was to assess the effects of the pandemic on neurofibromatosis (NF) care and research.MethodsSixty-three United States NF clinics were surveyed to identify the impact of the pandemic on clinician role, patient volume, continuity of guideline-driven surveillance, research protocols, and use of (and satisfaction with) telehealth for the delivery of NF care.ResultsFifty-two clinic directors or their representatives completed the survey (83% response rate). About 2/3 of the clinics reported a greater than 50% decrease in the number of available patient appointments, and modified clinical surveillance and research protocols. Fifty-one clinics (98%) newly instituted telehealth during the pandemic. Barriers to telehealth prior to the pandemic were insurance reimbursement concerns and lack of infrastructure. Since telehealth was initiated, high provider satisfaction was reported with ease of use. The most common area of concern was related to inability to perform a physical examination.ConclusionResults show marked impacts on NF care and research since the beginning of the pandemic, with potential long-term changes related to the introduction (or adoption) of telehealth for clinical care.

ObjectiveTo assess the reliability and variability of digital calipers, 3D photography, and high-frequency ultrasound (HFUS) for measurement of cutaneous neurofibromas (cNF) in patients with neurofibromatosis type 1 (NF1).BackgroundcNF affect virtually all patients with NF1 and are a major source of morbidity. Reliable techniques for measuring cNF are needed to develop therapies for these tumors.MethodsAdults with NF1 were recruited. For each participant, 6 cNF were assessed independently by 3 different examiners at 5 different time points using digital calipers, 3D photography, and HFUS. The intraclass correlation coefficient (ICC) was used to assess intrarater and interrater reliability of linear and volumetric measurements for each technique, with ICC values >0.90 defined as excellent reliability. The coefficient of variation (CV) was used to estimate the minimal detectable difference (MDD) for each technique.ResultsFifty-seven cNF across 10 participants were evaluated. The ICC for image acquisition and measurement was >0.97 within and across examiners for HFUS and 3D photography. ICC for digital calipers was 0.62–0.88. CV varied by measurement tool, linear vs volumetric measurement, and tumor size.ConclusionsHFUS and 3D photography demonstrate excellent reliability whereas digital calipers have good to excellent reliability in measuring cNF. The MDD for each technique was used to create tables of proposed thresholds for investigators to use as guides for clinical trials focused on cNF size. These criteria should be updated as the performance of these end points is evaluated.

Objective To understand diagnostic communication preferences of patients with schwannomatosis, a rare disease. Methods Eighteen adults with schwannomatosis from across the United States participated in semi-structured phone interviews about their diagnostic experiences. Interview transcripts were inductively coded using thematic analysis. Results We identified three elements of effective diagnostic communication: education (particularly about etiology, prognosis, and treatment options); psychological support (to cope with the new diagnosis and any prior diagnostic harms); and efforts to develop therapeutic alliance (i.e. feelings of collaboration, trust, and social-emotional rapport). Poor communication was characterized by inadequate or jargon-heavy explanations, perceived disinterest in or disbelief of symptoms, and lack of partnership. Effective communication helped people feel informed and cope with their condition; poor communication could cause significant psychological distress. Conclusions During diagnosis, patients need education and psychosocial support; the presence of therapeutic alliance between clinicians and patients facilitates this assistance. Diagnostic communication that includes these elements helps patients proactively engage in healthcare decision-making and connect with appropriate treatments. Practice Implications When disclosing a rare disease diagnosis, clinicians should meaningfully educate patients about the disorder and acknowledge diagnosis-related psychosocial stressors. Approaching diagnosis empathetically and collaboratively helps foster therapeutic alliance. Referrals for psychological and genetic counseling are often warranted.

Obwohl in einigen Landern das individuelle Risiko fur diabetische Spatkomplikationen rucklaufig ist, muss aufgrund der Vielzahl der betroffenen Menschen von einem weiteren Anstieg von Patienten mit Diabetes mellitus und Nierenerkrankungen gerechnet werden. Das Vorhandensein einer Niereninsuffizienz erhoht das Risiko fur komplizierte Hypoglykamien deutlich. Der HbA1c-Zielwert ist daher in Abhangigkeit von Komorbiditat und Therapiesicherheit individuell einzustellen. Erschwerend kommt hinzu, dass bei Patienten mit fortgeschrittener Niereninsuffizienz der HbA1c-Wert falsch-niedrig ist. Die Nieren tragen auf vielfaltige Weise zur Glukosehomoostase bei. Die SGLT2(„sodium-glucose cotransporter 2“)-Hemmung stellt ein vielversprechendes neues Wirkprinzip dar; fur den klinischen Alltag ist bedeutsam, Art und Dosis der antidiabetischen Therapie an den jeweiligen Grad der Niereninsuffizienz anzupassen. Bei nierentransplantierten Patienten ist mit dem Auftreten eines NODAT („new-onset diabetes after transplantation“) zu rechnen. Entsprechende Screeninguntersuchungen sind ratsam.

People living with medically unexplained symptoms (MUS) often have poor quality of life and health outcomes. Many struggle to engage with and trust in healthcare systems. This qualitative study examined how experiences with institutions influence perceptions of medical care for MUS by applying the theoretical framework of institutional betrayal to narratives of U.S. military Veterans living with Gulf War Illness (GWI). Institutional betrayal refers to situations in which the institutions people depend upon for safety and well-being cause them harm. Experiences of institutional betrayal both during active military service and when first seeking treatment appeared to shape perceptions of healthcare in this sample. Veterans expressed the belief that the military failed to protect them from environmental exposures. Veterans' concerns regarding subsequent quality of healthcare were intrinsically linked to a belief that, despite official documentation to the contrary, the predominant paradigm of both the U.S. Department of Defense and the U.S. Department of Veterans Affairs (VA) is that GWI does not exist. Veterans reported that providers are not adequately trained on treatment of GWI and do not believe Veterans' descriptions of their illness. Veterans reported taking up self-advocacy, doing their own research on their condition, and resigning themselves to decrease engagement with VA healthcare or seek non-VA care. The study's findings suggest institutional level factors have a profound impact on perceptions of care and the patient-provider relationship. Future research and policy aimed at improving healthcare for people living with MUS should consider the concept of institutional betrayal.

The patient reported outcomes measurement information system (PROMIS) provides clinicians and researchers access to reliable, validated measures of physical, mental, and social well-being. The use of PROMIS can facilitate comparisons among clinical subpopulations and with the U.S. general population. We report on the first study using PROMIS measures in patients with neurofibromatosis (NF). Eighty-six adult patients (mean age = 44; 55% female; 87% white; 50% NF1, 41% NF2 and 9% schwannomatosis) completed a battery of PROMIS computerized adaptive tests (CATs). Across all PROMIS instruments, mean scores for each CAT were between 48.97 and 52.60, which is within ±0.5 SD of the U.S. general population norms. However, scores were distributed across a broad range for each PROMIS measure (±3 SDs). Clinically meaningful scores (defined >1 SD impairment) were observed in 20% (pain interference), 17% (pain behavior), 16% (physical function), 16% (anxiety), 16% (depression), 15% (satisfaction with social roles), 13% (fatigue), 6% (anger), and 5% (satisfaction with discretionary social activities) of the sample. All PROMIS measures were highly interrelated in bivariate analysis (P ≤ .001). There were no differences in PROMIS scores by disease type (NF1, NF2 and schwannomatosis), or self reported learning disabilities, or compared with the US population. Scores suggest a broad continuum of symptoms and functioning in patients with NF that is not affected by NF type, as well as interrelation among the physical and psychosocial domains as measured by PROMIS. PROMIS measures may be useful in clinical practice to monitor changes in symptoms and functioning over time, as well as in clinical trials to determine patient reported changes during drug and psychosocial clinical trials.

Objective: Tumors and other disease complications of neurofibromatosis (NF) can cause pain and negatively affect physical functioning. To document the clinical benefit of treatment in NF trials targeting these manifestations, patient-reported outcomes (PROs) assessing pain and physical functioning should be included as study endpoints. Currently, there is no consensus on the selection and use of such measures in the NF population. This article presents the recommendations of the PRO group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration for assessing the domains of pain and physical functioning for NF clinical trials. Methods: The REiNS PRO group reviewed and rated existing PRO measures assessing pain intensity, pain interference, and physical functioning using their systematic method. Final recommendations are based primarily on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility for clinical trials. Results: The REiNS PRO group chose the Numeric Rating Scale–11 (≥8 years) to assess pain intensity, the Pain Interference Index (6–24 years) and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale (≥18 years) to evaluate pain interference, and the PROMIS Physical Functioning Scale to measure upper extremity function and mobility (≥5 years) for NF clinical trials. Conclusions: The REiNS Collaboration currently recommends these PRO measures to assess the domains of pain and physical functioning for NF clinical trials; however, further research is needed to evaluate their use in individuals with NF. A final consensus recommendation for the pain interference measure will be disseminated in a future publication based on findings from additional published research.

Objective:To test, within a single-blind randomized controlled trial, the feasibility, acceptability, efficacy, and durability of a mind–body program (the Relaxation Response Resiliency Program for neurofibromatosis [3RP-NF]) vs an attention placebo control (Health Enhancement Program for NF [HEP-NF]), both delivered via group videoconferencing.Methods:Sixty-three patients completed baseline assessments and were randomized. Primary outcomes were physical health and psychological quality of life (QoL), measured by the WHOQOL-BREF (World Health Organization QoL abbreviated instrument). Secondary outcomes were social relations and environment QoL, depression, anxiety, pain intensity, and pain interference.Results:Sixty-three participants completed the intervention (100%) and 52 the 6-month follow-up (82.5%). Acceptability was 4.1 (5-point scale). Patients in the 3RP-NF showed greater improvement in physical health QoL (7.69; 95% confidence interval [CI]: 0.29–15.10; p = 0.040), psychological QoL (5.57; 95% CI: 0.17–11.34; p = 0.056), social relations QoL (10.95; 95% CI: 1.57–20.31; p = 0.021), environment QoL (8.02; 95% CI: 2.57–13.48; p = 0.005), and anxiety (−2.32; 95% CI: −3.96 to 0.69; p = 0.006) compared to those in HEP-NF, and gains were maintained at follow-up. Patients in the 3RP-NF did not improve more than those in HEP-NF on depression, with both groups showing improvement. Patients in the 3RP-NF with baseline pain ≥5 of 10 showed improvement in pain intensity from baseline to posttest (1.30; 95% CI: −2.26 to −0.34; p = 0.009) with effects maintained at follow-up; this improvement was not greater than that in HEP-NF. There were more treatment responders in the 3RP-NF group (p < 0.05).Conclusions:The 3RP-NF delivered via videoconferencing was highly feasible and accepted by patients, and resulted in sustained improvement in QoL.Classification of evidence:This study provides Class II evidence that for patients with NF, a mind–body program is superior to an attention placebo control in improving QoL.

To explore health-related quality of life (HRQoL) reported by individuals with neurofibromatosis type 2 (NF2) and to assess for correlations between HRQoL and objective measures of disease manifestations.Prospective observational study.Seven international NF2 centers.Eighty-one individuals with NF2, 73 adults (18 years) and 8 children/adolescents (10-17 years).Quality of life was measured by Short Form-36 (SF-36) norm-based scores. Objective clinical measures were hearing (categorized by word-recognition scores), facial function (categorized by the House-Brackmann scale) and the volume of subjects' larger vestibular schwannoma (VS).At baseline, adults showed significant deficits in all but two subscales of the SF-36 compared with age- and gender-adjusted United States population norms. In linear regression models including age, gender, inheritance status, hearing, facial weakness and VS volume, demographic and functional measures showed no relationship to any SF-36 subscale. Larger baseline VS volume was significantly related to reduced physical role performance, reduced mental health, and increased pain (p 0.05). In bivariate analysis, previous VS surgery was not significantly associated with baseline HRQoL; receipt of VS surgery or tumor growth during the observation period was not significantly associated with changes in HRQoL.NF2 patients report reduced HRQoL in physical, social, and mental domains, but this was not significantly related to objective measures of hearing or facial functioning. Larger baseline VS volume negatively impacted patient-reported HRQoL whereas VS surgery or tumor growth did not. Future studies should explore the relationship between tumor volume and HRQoL and psychosocial factors that may moderate this relationship.

Purpose Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. Patients and Methods Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. Results Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell–derived factor 1α (P = .037 and .025, respectively). Conclusion Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.

Menschen mit Typ-2-Diabetes steht in der Regel eine grose Bandbreite an Antidiabetika zur Verfugung. Fur Patienten mit eingeschrankter Nierenfunktion ist die Auswahl jedoch begrenzt, da die Pharmakokinetik unterschiedlicher Substanzen durch die renale Funktionsstorung verandert werden kann. So ist hier der Abbau exogenen Insulins verzogert. Basierend auf einer erhohten Insulinresistenz besteht gleichzeitig ein erhohter Insulinbedarf. Diese Dysbalancen lassen eine allgemeine Dosisempfehlung kaum zu. Vielmehr sollte die Therapie mit einer niedrigen Insulindosis begonnen und nach Bedarf auftitriert werden. GLP-1-Rezeptoragonisten weisen hingegen kein intrinsisches Hypoglykamierisiko auf und stellen daher eine mogliche Alternative fur Patienten mit Niereninsuffizienz dar. Die Datenlage zu den GLP-1-Rezeptoragonisten verdeutlicht jedoch auch Unterschiede innerhalb dieser Substanzklasse. So werden Lixisenatid und Exenatide glomerular filtriert, die Substanzen Liraglutid, Albiglutid und Dulaglutid hingegen nicht. Haufige gastrointestinale Nebenwirkungen sowie vereinzelte Berichte von schwerwiegenden Nebenwirkungen nach Anwendung von Exenatide bei Patienten mit Nephropathie verlangen eine strikte Uberwachung und wenn notig eine konservative Dosisanpassung durch den Arzt.

Introduction: Critical limb ischemia (CLI) is associated with a prothrombotic diathesis that involves a complex balance between the coagulation and fibrinolytic systems. Knowledge of this is essential when considering revascularization procedures but is often overlooked. The aim of this review is to summarize the available literature and provide an overview of the effects of lower limb angioplasty and open surgical revascularization on coagulation, fibrinolysis, and platelet activation. Methods: A MEDLINE and EMBASE search was conducted between 1973 and 2014 for articles relating to the effects of revascularization for patients with CLI on the fibrinolytic and coagulation pathways. Studies with a small cohort of patients (Results: Many of the studies included in this analysis had small cohorts. Multiple markers were assessed across the published literature including von Willebrand factor, tissue factor, prothrombin fragments 1 and 2, platelets, soluble platelet selectin, plasminogen activator inhibitor 1, tissue plasminogen activator, and thrombin–antithrombin complex. Percutaneous intervention causes an exaggerated prothrombotic and a disturbed fibrinolytic effect. Surgery seems to cause a similar prothrombotic derangement with reduced fibrinolysis and platelet hyperactivity, but this appears to be maintained for a considerable amount of time postoperatively. Conclusion: There is a sparse amount published on the effects of the coagulation and fibrinolytic systems in patients undergoing intervention for CLI. Much of these studies are small, historical, and completely heterogeneous, making it difficult to draw meaningful conclusions. The literature does identify a prothrombotic state in patients with CLI, which appears to be exacerbated by any form of intervention and prolonged in those having surgery. Understanding this may allow us to tailor the intervention offered to patients and prevent limb loss.

BACKGROUND Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are related genetic tumor predisposition syndromes caused by distinct germline pathogenic variants on chromosome 22. Both conditions are characterized by the presence of cranial, peripheral, and/or spinal nerve schwannomas. The long-term growth behavior of schwannomas is unknown but knowledge thereof would help guide patient surveillance and selection for treatment and improvement of clinical trial design. Whole-body MRI (WBMRI) can detect whole-body schwannoma burden in a single image acquisition session. METHODS 12 NF2 and 10 SWN patients who underwent a WBMRI between 2007-2010 underwent a repeat WBMRI between 2018-2019. Schwannomas were segmented on short tau inversion recovery (STIR) sequences. Tumor volume was calculated using a three-dimensional tumor quantification software (3DQI). Tumor growth and shrinkage were defined as a volume change ≥ 20% over the entire study period. RESULTS Median time between scans was 10 years. A total of 103 schwannomas (46 NF2-associated, 57 SWN-associated) were analyzed. In both NF2 and SWN, 50% of tumors grew. Median growth was 88.3% in NF2 and 100.4% in SWN. All growing NF2-associated schwannomas grew in the setting of exposure to systemic therapy whereas only one growing SWN-associated tumor had been treated systemically. Excluding resected tumors, 19.4% of schwannomas shrank. Median shrinkage was 48.5% in NF2 and 37.4% in SWN. All shrinking NF2-associated tumors had been treated with systemic therapy whereas none of the shrinking SWN-associated tumors had been. 19 new tumors (7 NF2-associated, 12 SWN-associated) developed in 8 patients. CONCLUSIONS Half of NF2- and SWN-associated schwannomas grow significantly over a decade. In NF2 patients, growth occurs despite systemic treatment whereas, in SWN patients, schwannomas may shrink spontaneously without treatment. These findings may suggest a more aggressive tumor phenotype in NF2. Continued patient enrollment and correlation of MRI findings with functional outcomes and hormone exposure history are ongoing.

BACKGROUND: Telehealth allows for evaluation and management to be delivered over long distances, which may particularly benefit patients with rare neurological diseases. METHODS: We performed a retrospective cohort study of patients receiving telehealth-based care in our NF clinic, and used ArcGIS to calculate driving distance and time from patients home to clinic. RESULTS: 109 patients (70 female, median age: 37 years) had telehealth visits from May 2016-March 2018, eighteen (17%) of whom had multiple telehealth visits. Patient diagnosis was 33% NF1, 42% NF2, 8% Schwannomatosis, and 17% other, compared to our clinic population of 58% NF1, 31% NF2, 6% Schwannomatosis and 5% other. Only 7 patients (6%) were pediatric, compared to 15% pediatric population in our NF clinic. Telehealth visit indication was 62% routine follow up, 26% new test result follow up, 6% evaluation of a new problem, and 6% on-therapy follow up. The plan developed by telehealth visits included 24% new radiology ordered, 7% new medication ordered, 18% new specialty consultation ordered, and 51% no change in previous plan. Telehealth saved patients a median round trip drive of 108 miles (IQR 388 miles) and a median driving time of 170 minutes (IQR 292 minutes). CONCLUSIONS: Telehealth improved NF specialty care through more accessible routine follow up, and urgent evaluation of new symptoms in 6% of patients. Telehealth visits led to new testing, referrals, or medications in 49% of cases, showing that telehealth fulfills a distinct need for services while saving patients time and travel. Adult patients were overrepresented among telehealth cases compared to our general clinic volume, suggesting that in-person examination of children may be preferred by NF providers or families. Given difficulties in access to specialty care, telehealth offers an opportunity to extend care for patients with rare neurological diseases who live at a distance from specialty centers.

Objective Assess patient-reported outcomes (PRO) for hearing and tinnitus relative to clinical hearing assessment in people with neurofibromatosis 2 (NF2) associated hearing loss. Study design Prospective, open label, phase-II clinical trial with PRO administered pre-, post-, and after treatment. Setting Three tertiary referral centers. Patients Fourteen patients with NF2, median age of 30 years (range, 14-79 yr) and progressive hearing loss (median baseline word recognition score, 60%; range, 13-82%). Half of these patients achieved objective hearing response (word recognition score improved beyond the 95% critical difference versus baseline). Intervention Bevacizumab 7.5 mg/kg was administered every 3 weeks for 48 weeks, followed by surveillance for 24 weeks off-drug. Main outcome measures Speech, spatial, and qualities of hearing scale (SSQ) and tinnitus reaction questionnaire (TRQ) to assess hearing difficulties in life situations and tinnitus related distress. Results Patient-reported speech understanding and auditory quality improved with bevacizumab treatment and were significantly correlated with word recognition scores, but not pure tone threshold average. There was no change in spatial perception after treatment. Reduction in tinnitus distress after treatment with bevacizumab did not reach statistical significance. Conclusion Participants had reductions in hearing difficulty during treatment with bevacizumab, suggesting that patients subjectively experience hearing-related benefit mirroring clinical hearing assessments. We suspect the lack of significant reduction in tinnitus distress is related to small sample size and low intensity of distress in our sample. These data highlight the usefulness of PRO measures to assess benefits of treatment in the setting of NF2-associated hearing loss.

Schwannomatosis has been linked to germline mutations in the SMARCB1 and LZTR1 genes, and is frequently associated with pain. In a cohort study, we assessed the mutation status of 37 patients with clinically diagnosed schwannomatosis and compared to clinical data, whole body MRI (WBMRI), visual analog pain scale, and Short Form 36 (SF-36) bodily pain subscale. We identified a germline mutation in LZTR1 in 5 patients (13.5%) and SMARCB1 in 15 patients (40.5%), but found no germline mutation in 17 patients (45.9%). Peripheral schwannomas were detected in 3 LZTR1-mutant (60%) and 10 SMARCB1-mutant subjects (66.7%). Among those with peripheral tumors, the median tumor number was 4 in the LZTR1 group (median total body tumor volume 30 cc) and 10 in the SMARCB1 group (median volume 85cc), (P=.2915 for tumor number and P = .2289 for volume). mutation was associated with an increased prevalence of spinal schwannomas (100% vs 41%, P = .0197). The median pain score was 3.9/10 in the LZTR1 group and 0.5/10 in the SMARCB1 group (P = .0414), and SF-36 pain-associated quality of life was significantly worse in the LZTR1 group (P = .0106). Pain scores correlated with total body tumor volume (rho = 0.32471, P = .0499), but not with number of tumors (rho = 0.23065, P = .1696). We found no significant difference in quantitative tumor burden between mutational groups, but spinal schwannomas were more common in LZTR1-mutant patients. Pain was significantly higher in LZTR1-mutant than in SMARCB1-mutant patients, though spinal tumor location did not significantly correlate with pain. This suggests a possible genetic association with schwannomatosis-associated pain.

Das neue orale Antidiabetikum Empagliflozin ist ein selektiver Inhibitor des aktiven natriumabhangigen Glukosecotransporters SGLT2 (sodium glucose linked transporter 2) zur insulinunabhangigen Kontrolle des Blutzuckers bei Typ-2-Diabetes mellitus, der seit Mai 2014 in den Landern der Europaischen Union zugelassen ist. Die SGLT2-Inhibition ist ein neuer Therapieansatz zur Blutzuckersenkung durch Hemmung der Glukosereabsorption in der Niere mit erhohter Glukoseausscheidung uber den Harn. Die Senkung des Nuchtern- und des postprandialen Blutzuckers erfolgt unabhangig von Insulinwirkung und Insulinsekretion sowie unabhangig vom Ausmas der Insulinresistenz und des Betazellfunktionsverlustes. Es besteht kein substanzeigenes Hypoglykamierisiko. Zusatzlich fuhrt die SGLT2-Inhibition mit Empagliflozin zur Gewichtsabnahme und Blutdrucksenkung. Dieser Ubersichtsartikel erlautert das Wirkprinzip der SGLT2-Inhibition und fasst klinische Daten zu Empagliflozin in der Monotherapie, den oralen Kombinationstherapien (einschlieslich gepoolter Daten) und den Kombinationstherapien mit Insulin zusammen. Der primare Studienendpunkt war die HbA1c-Anderung. In den sieben dargestellten Studien und in der gepoolten Analyse war die mittlere HbA1c-Senkung mit Empagliflozin (10 bzw. 25 mg/Tag) klinisch relevant und statistisch signifikant versus Placebo und dem Sulfonylharnstoff Glimepirid. Je nach Studie und Dosis lagen die mittleren placebokorrigierten HbA1c-Senkungen nach 24 Wochen Therapie mit Empagliflozin bei bis zu 0,9 %.

Neurofibromatosis 1 (NF1) is a genetic disorder in which patients are at significantly increased risk for developing malignant peripheral nerve sheath tumors (MPNST) and malignant gliomas (brain cancer). We sought to develop a measure for assessing perceived risk of developing MPNST and brain cancer among patients with NF1 and to examine patients' perceived risk of developing these cancers. We assessed 112 NF1 patients' perceived risk of developing MPNST and brain cancer using an 8-item scale we developed that yielded two subscales in a principal component analysis (PCA). Linear regression models examined factors associated with perceived risk of malignancy. 33.9 % and 47.3 % of patients disagreed that having NF1 placed them at increased risk for MPNST and brain cancer, respectively. The PCA of the perceived risk items yielded a 2-factor solution with an MPNST and a brain subscale (total scale α = 0.90). Level of anxiety was the primary factor associated with perceived risk for both cancers. A significant proportion of NF1 patients underestimate their risk of developing MPNST and brain cancer. Perceived risk was associated with emotional distress, in particular anxiety. Clinicians should actively communicate with NF1 patients about their elevated cancer risk.

Background Our primary aim was to assess the ability of a non-profit foundation-sponsored clinic network to facilitate access to specialized care for patients with neurofibromatoses (NF), a group of neurogenetic disorders including NF1, NF2, and schwannomatosis (SWN). Our secondary aim was to identify how our findings in NF could be applied more broadly to other rare diseases. Methods We retrospectively reviewed aggregate data on patient volume reported by specialty NF clinics in a nonprofit network from 2008 to 2015. We classified clinics as high or low volume for disease type (NF1 and NF2/schwannomatosis) and pediatric/adult care. We compared clinic-level data to self-reported patient-level data from a large online patient registry. Results Between 2008 and 2015, the number of certified NF clinics grew from 32 to 50, and annual patient volume rose from 6776 to 10,245 patients (13% of the total estimated U.S. NF patient population). For patient registry participants (n = 4476), the median driving distance to the nearest network clinic was 51.3 miles. Driving distances to reach high-volume centers were elevated for adults compared to children (295.8 vs. 67.9 miles), and schwannomatosis and NF2 patients compared to NF1 patients (310.9 vs. 368.1 vs. 161.7 miles). Of registry participants reporting their location of care (n = 2271), only 43.2% received care in a network specialty clinic, with especially low rates of attendance in the Southwest and Far West. Conclusions While the number of certified NF clinics and volume of patients seen in these clinics has increased, many NF patients still do not attend specialty clinics and/or travel a significant distance for care. Geographic access to care is more limited for adults, patients with rarer conditions, and patients in the Western U.S. Potential measures to improve access to specialty care for people living with NF and other rare diseases are discussed.

Determining health literacy level is an important prerequisite for effective patient education. We assessed multiple dimensions of health literacy and sociodemographic predictors of health literacy in patients with neurofibromatosis. In 86 individuals with a confirmed diagnosis of neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), or schwannomatosis, we assessed health literacy status using two HL tools-the adapted functional, communicative, and critical health literacy scale (adapted FCCHL) and health literacy assessment using talking touchscreen technology (Health LiTT). Factor analyses of the adapted FCCHL in NF patients showed factor structure and psychometric properties similar to pilot work in other patient populations. As a group, patients with NF had moderate scores on the Health LiTT and moderate to high scores on the adapted FCCHL, with the highest score on the functional health literacy subscale. Patients with NF1, those with lower education and those with learning disabilities had lower scores on Health LiTT; in multivariate analysis, learning disability and education remained significant predictors of HealthLiTT scores. Only lower education was associated with lower adapted FCCHL scores. Results suggest utilizing health literacy tools in NF patients is feasible and could provide physicians with valuable information to tailor health communication to subpopulations with lower health literacy levels.

NF1, NF2, and Schwannomatosis are incurable tumor suppressor syndromes associated with poor quality of life. The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an NF adapted, 8-week group mind body skills based intervention, the relaxation response resiliency program (3RP) aimed at improving resiliency and increasing satisfaction with life. Patients seen at MGH’s Neurofibromatosis Clinic were offered participation if they described difficulties coping to a treating physician. Participants completed measures of life satisfaction, resiliency, stress, mood, lifestyle, pain, post-traumatic growth and mindfulness at baseline and after completing the 3RP program. The intervention had relative feasible enrollment rate (48 % rate, 32 out of 67 of patients signing the informed consent form). However, out of the 32 patients who signed the informed consent, only 20 started the study (62.5 %) and only 16 completed it (50 %), suggesting problems with feasibility. The main reason cited for non-participation was burden of travel to the clinic. The intervention was highly acceptable, as evidenced by an 80 % completion rate (16/20). Paired t tests showed significant improvement in resiliency, satisfaction with life, depression, stress, anxiety, mindfulness and post traumatic growth, with effect sizes ranging from 0.73–1.33. There was a trend for significance for improvement in somatization and sleepiness (p = 0.06), with effect sizes of 0.54–0.92 respectively. Statistically nonsignificant improvement was observed in all other measures, with effect sizes small to medium. In sum, the 3RP was found to be relatively feasible, highly acceptable and preliminary efficacious in decreasing symptom burden in this population, supporting the need of a randomized controlled trial.

Background Appendicectomy for acute appendicitis in children may be performed in specialist centres by paediatric surgeons or in general surgery units. Service provision and outcome of appendicectomy in children may differ between such units. Methods This multicentre observational study included all children (aged less than 16 years) who had an appendicectomy at either a paediatric surgery unit or general surgery unit. The primary outcome was normal appendicectomy rate (NAR). Secondary outcomes included 30-day adverse events, use of ultrasound imaging and laparoscopy, and consultant involvement in procedures. Results Appendicectomies performed in 19 paediatric surgery units (242 children) and 54 general surgery units (461 children) were included. Children treated in paediatric surgery units were younger and more likely to have a preoperative ultrasound examination, a laparoscopic procedure, a consultant present at the procedure, and histologically advanced appendicitis than children treated in general surgery units. The unadjusted NAR was significantly lower in paediatric surgery units (odds ratio (OR) 0·37, 95 per cent confidence interval 0·23 to 0·59; P < 0·001), and the difference persisted after adjusting for age, sex and use of preoperative ultrasound imaging (OR 0·34, 0·21 to 0·57; P < 0·001). Female sex and preoperative ultrasonography, but not age, were significantly associated with normal appendicectomy in general surgery units but not in paediatric surgery units in this adjusted model. The unadjusted 30-day adverse event rate was higher in paediatric surgery units than in general surgery units (OR 1·90, 1·18 to 3·06; P = 0·011). When adjusted for case mix and consultant presence at surgery, no statistically significant relationship between centre type and 30-day adverse event rate existed (OR 1·59, 0·93 to 2·73; P = 0·091). Conclusion The NAR in general surgery units was over twice that in paediatric surgery units. Despite a more severe case mix, paediatric surgery units had a similar 30-day adverse event rate to general surgery units. Service provision differs between paediatric and general surgery units.

BACKGROUND Neurofibromas affect 40–50% of neurofibromatosis type 1 (NF1) patients and can cause significant morbidity and mortality. They grow more rapidly during childhood and adolescence but studies in adults are limited by their retrospective nature and follow-up time < 3 years. The long-term natural history of neurofibromas remains unknown. No guidelines exist on the need and frequency of surveillance imaging for patients. Whole-body MRI (WBMRI) can detect whole-body tumor burden, including internal neurofibromas. METHODS 17 adult NF1 patients who underwent WBMRI between 2007–2010 (Scan 1) underwent repeat WBMRI between 2018–2019 (Scan 2). Internal neurofibromas were segmented on short tau inversion recovery (STIR) sequences and tumor volume was calculated using a computerized volumetry and three-dimensional segmentation software. Circumscribed tumors were defined as discrete; invasive tumors or those involving multiple nerves were defined as plexiform. Tumor growth and shrinkage were defined as volume change ≥ 20% over the entire study period. RESULTS Median patient age was 43 years during Scan 1 and 53 years during Scan 2. Median time between Scan 1 and 2 was 9 years. A total of 140 neurofibromas were assessed. 24% of tumors grew by a median 63% (6.8% per year). 54% of tumors spontaneously decreased in volume by a median 60% (7% per year) without treatment. On a per-patient basis, 18% of patients had overall tumor growth and 41% overall tumor shrinkage. 8 new tumors developed in 7 patients. 16 tumors resolved entirely without medical or surgical intervention. Growth behavior did not correlate with discrete or plexiform morphology. CONCLUSION A subset of internal neurofibromas in adult NF1 patients grow significantly over a long-term period, suggesting that continued monitoring of these patients may be warranted. Surprisingly, more than half of neurofibromas shrink spontaneously without intervention. Continued patient enrollment and correlation of imaging findings with functional outcomes are underway.

Objectives: Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity. Methods: The REiNS PRO group selected core endpoint domains important to assess in NF. The members developed criteria to rate PRO measures, including patient characteristics, psychometric properties, and feasibility, and utilized a systematic process to evaluate PROs for NF clinical trials. Within the subdomain of pain intensity, the group reviewed the Numerical Rating Scale-11 (NRS-11), the Visual Analogue Scale, and the Faces Pain Scale-Revised using this process. Results: Based on the review criteria, each of these pain intensity scales is brief, reliable, valid, and widely used. However, the NRS-11 was given the highest rating for use in NF clinical trials due to recommendations from pain experts and other consensus groups, its extensive use in research, strong psychometric data including sensitivity to change, and excellent feasibility in ages $8 years. Conclusions: The systematic review criteria and process are effective for identifying appropriate PRO measures and provide information utilized by the REiNS Collaboration to achieve consensus regarding PROs in NF clinical trials. Neurology® 2013;81 (Suppl 1):S6–S14

The aim of this study was to review the literature on quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis, and to identify the specific aspects of quality of life that were studied and reported in this population. We also set out to report predictors of quality of life. Published research reports were included if they described quality of life in this population and met methodological quality according to a list of predefined criteria. Eight studies (7 in NF1, 1 in NF2, 0 in schwannomatosis), conducted between 2001 and 2013, met inclusion criteria. The methodological quality of the eight studies was mostly high according to ratings by predefined criteria. Most studies reported that patients with NF experience decreased quality of life when compared to the general population. Visibility and disease severity were strong predictors of skin-specific quality of life in NF1 patients. However, the majority of findings regarding predictors of quality of life were weak or inconclusive. Given the decreased quality of life in NF patients, it is important to examine more comprehensively the psychosocial factors in this population, especially in patients with NF2 and schwannomatosis. Mind body interventions that address these domains may provide comprehensive and efficacious long term treatment.

Aims The goal of this study was to compare the long-term safety and efficacy of the basal insulin analogue, insulin degludec with insulin glargine (both with insulin aspart) in Type 1 diabetes, over a 2-year time period. Methods This open-label trial comprised a 1-year main trial and a 1-year extension. Patients were randomized to once-daily insulin degludec or insulin glargine and titrated to pre-breakfast plasma glucose values of 3.9–4.9 mmol/l. Results The rate of nocturnal confirmed hypoglycaemia was 25% lower with insulin degludec than with insulin glargine (P = 0.02). Rates of confirmed hypoglycaemia, severe hypoglycaemia and adverse events, and reductions in glycated haemoglobin and fasting plasma glucose were similar between groups. Despite achieving similar glycaemic control, insulin degludec-treated patients used 12% less basal and 9% less total daily insulin than did insulin glargine-treated patients (P

Insulin degludec (IDeg) ist ein neues lang wirksames Basalinsulin. Aufgrund des stabilen, flachen Wirkprofils von IDeg kommt es zu einer gleichmasigen Verteilung des blutzuckersenkenden Effekts uber 24 h, wobei die Wirkung uber 24 h hinausgeht. Fur IDeg wurde ein umfassendes Phase-3-Studienprogramm, in dem mehr als 4200 Patienten mit Typ-1-Diabetes und Typ-2-Diabetes in unterschiedlichen Erkrankungsstadien mit IDeg behandelt wurden, durchgefuhrt. Zur Basis-Bolus-Therapie mit IDeg liegen 2 Phase-3-Studien vor, die im Vergleich zu Insulin glargin ein signifikant geringeres Risiko fur nachtliche Hypoglykamien bei Patienten mit Typ-1- bzw. Typ-2-Diabetes zeigen. Auserdem wurde die Rate der Gesamthypoglykamien bei der Therapie des Typ-2-Diabetes mit IDeg signifikant reduziert. IDeg stellt einen Fortschritt im Bereich der Diabetes-Therapie dar, da im Vergleich zu Insulin glargin bei mindestens gleich guter Effektivitat (HbA 1c -Reduktion) weniger Hypoglykamien (insbesondere nachtliche) auftraten.

Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis-associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. © 2016 Wiley Periodicals, Inc.

As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy.The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood-onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype.A total of 180 SRS questionnaires were completed in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21 y, range 4-63 y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9 y, range 4-22 y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p0.001) and various seizure variables (p0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism.Our data show that in TSC and childhood-onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific in these conditions.