Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial. Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600-700 mg/m 2 , given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles. Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1 * 03:03 and/or HLA-C * 07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1-2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients. Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients Rekeland et al. Intravenous Cyclophosphamide in ME/CFS responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.

the etiology and pathogenesis of Myalgic encephalomyelitis/chronic fatigue Syndrome (Me/cfS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4-3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1-2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3-2.2], p nc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by medically unexplained fatigue, post-exertional malaise and a variety of additional symptoms, such as chronic pain, sleep disturbances and cognitive difficulties. ME/CFS is diagnosed on clinical grounds alone, and different sets of criteria specify the mandatory symptoms as well as recommendations for the exclusion of differential diagnoses 1-3 . The specificity and validity of different diagnostic criteria have been questioned, yet there is no agreement on the level of heterogeneity in ME/CFS, and there is no consensus on how to categorize different subgroups 4-8 .The pathogenesis and etiology of ME/CFS are unknown, with several models having been proposed 9 . One central hypothesis states that autoimmunity is part of the pathophysiology 10,11 . ME/CFS has been reported to be partly heritable 12,13 , consistent with a multifactorial etiology dependent on both genetic and environmental factors. This is the prevailing model for a vast number of diseases, including established autoimmune diseases (AID). Several publications report immunological alterations among ME/CFS patients, e.g. changes in natural killer (NK) cell function 14,15 , cytokine levels 16,17 , and DNA methylation patterns consistent with immune dysregulation 18 . Some of these findings have failed to reproduce in other studies, which could be due to differences in methodology, the complexity and heterogeneity of ME/CFS, and lack of power due to small sample sizes 19 . Resultingly, the autoimmunity hypothesis warrants further evaluation. A characteristic feature of AID is genetic association with certain human leukocyte antigen (HLA) alleles 20 . Thus, a thorough inve...

The two imprinting syndromes Temple syndrome (TS14) and Prader-Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation-sensitive MLPA-kit detecting deletions and methylation aberrations in chromosomal region 14q32. TS14 was confirmed in 3 out of 143 patients (2.1%). In comparison, PWS was also confirmed in three patients. Brief clinical descriptions of the TS14 patients are presented. Temple syndrome is presumably underdiagnosed, and should be considered when testing children for PWS.