The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

Idiopathic hypereosinophilic syndrome: a new cause of vasculitis of the central nervous system.

Idiopathic hypereosinophilic syndrome (IHES) is a primary haematological condition characterised by persistent, otherwise unexplained hypereosinophilia sufficient to cause organ damage. Various neurological complications are reported, but very few have mentioned CNS pathology and none has included CNS vasculitis. Our objective here is to report IHES as a new cause of histopathologically confirmed CNS vasculitis. A 39-year-old man presented with a relapsing sub-acute encephalopathy, with severe headaches, confusion and drowsiness, myoclonus, ataxia and papilloedema. He had a history of nephrotic syndrome 18 years earlier, stable for the past 5 years on low-dose corticosteroids and low-dose tacrolimus (2 mg bd); lichen planus, and (15 years previously) aloplecia totalis. On admission, he had a marked peripheral eosinophilia (up to 9.1 × 10(9)/dL), which­it subsequently became clear­had been intermittently present for 16 years. After extensive investigation, biopsies of brain and bone marrow confirmed diagnoses of cerebral vasculitis, with lymphocytic and macrophage (but not eosinophilic) cellular infiltration of blood vessel walls, and IHES. CNS vasculitis can therefore now be added to the list of neurological complications of IHES. A dramatic and sustained neurological improvement, and likewise of the eosinophilia, following treatment with corticosteroids and cyclophosphamide, emphasises the tractability of this newly described form of CNS vasculitis.

A method for the preparation of highly purified adeno-associated virus using affinity column chromatography, protease digestion and solvent extraction.

Recombinant adeno-associated virus (AAV) is becoming the vector of choice for many gene therapy protocols. There has been much recent progress made toward increasing AAV titres but a continuing problem in using AAV has been that it is relatively difficult to concentrate and purify. Traditional methods, such as caesium chloride (CsCl) gradients, have drawbacks, notably extended purification times and the ability to process only limited volumes. Where the target cells of interest require a high multiplicity of infection (MOI), or to complete in vivo experiments, there is a requirement for both the production of high titre and a large volume of virus. This is laborious to obtain using traditional methods. A simple technique is described here for purifying AAV, involving affinity chromatography, protease digestion and solvent extraction that retains both the high yields and titres obtained using CsCl gradients. In addition, this technique displays a fast throughput and may be used to purify AAV from larger volumes than CsCl gradients. The high yield and purity of these virus preparations has allowed us to achieve good levels of expression in the target cell types tested. The purification technique described here will be applicable to any protocol that requires high titre, high purity recombinant AAV (rAAV).

Artefactual elevation of an automated white cell count following femoral vein puncture.

We report the novel occurrence of an erroneous automated total and differential white blood cell count on a blood sample obtained by traumatic femoral venepuncture, caused by contamination of the blood sample with subcutaneous adipose tissue. The erroneous counts were observed on a Bayer-Technicon H2 analyser while counts on a Coulter GenS, were much less affected. Characteristic scatter plots from both instruments are illustrated.

An extremely delayed cytogenetic response to interferon-alpha in a patient with chronic myeloid leukaemia.

In chronic myeloid leukaemia (CML), treatment with interferon alpha IFN-alpha results in loss of the Ph' chromosome in a significant proportion of patients. Most cytogenetic responses occur early at a median of 9 months after initiation of treatment and failure to detect a cytogenetic response within a predetermined period may be a reason for IFN-alpha withdrawal. We report a patient in whom IFN-alpha dosage was initially severely limited by bone marrow suppression but in whom continuing treatment led to a first cytogenetic response only after 53 months. Increasing Ph' negativity over a further 2 years was associated with improving haematological tolerance which permitted IFN-alpha dose escalation and complete cytogenetic remission was achieved at 7 years after diagnosis. This remission has been sustained and has thus followed the most delayed cytogenetic response to IFN-alpha so far reported.