Anthony A. Amato

Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib

PURPOSE To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. PATIENTS AND METHODS Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). RESULTS Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. CONCLUSION Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Myoblast Transfer in the Treatment of Duchenne's Muscular Dystrophy

BACKGROUND Myoblast transfer has been proposed as a technique to replace dystrophin, the skeletal-muscle protein that is deficient in Duchennes muscular dystrophy. Donor myoblasts injected into muscles of affected patients can fuse with host muscle fibers, thus contributing their nuclei, which are potentially capable of replacing deficient gene products. Previous controlled trials involving a single transfer of myoblasts have been unsuccessful. METHODS We injected donor muscle cells once a month for six months to the biceps brachii muscles of one arm of each of 12 boys with Duchennes muscular dystrophy. The opposite arms served as sham-injected controls. In each procedure 110 million cells donated by fathers or brothers were transferred. The patients were randomly assigned to receive either cyclosporine or placebo. Strength was measured by quantitative isometric muscle testing. Six months after the final myoblast transfer, the presence of dystrophin was assessed with the use of peptide antibodies specific to the deleted exons of the dystrophin gene. RESULTS There was no significant difference in muscle strength between arms injected with myoblasts and sham-injected arms. In one patient, 10.3 percent of muscle fibers expressed donor-derived dystrophin after myoblast transfer. Three other patients also had a low level of donor dystrophin (< 1 percent); eight had none. CONCLUSIONS Myoblasts transferred once a month for six months failed to improve strength in patients with Duchennes muscular dystrophy. The value of exon-specific peptide antibodies in the interpretation of myoblast-transfer results was demonstrated in a patient with Duchennes muscular dystrophy who had a high percentage of donor-derived dystrophin. Specific variables affecting the efficiency of myoblast transfer need to be identified in order to improve upon this technique.

119th ENMC international workshop: Trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands

Department of Neurology, University Medical Center, Heidelberg laan 100, Utrecht, CX 3584, The Netherlands Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA The Walton Centre for Neurology and Neurosurgery, Liverpool, UK Department of Rheumatology, King’s College Hospital, London, UK Rheumatology Unit, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden King’s Neurosciences Centre, King’s College Hospital, London, UK Institute of Rheumatology, Prague, Czech Republic Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands Department of Clinical Neurosciences, Guy’s, King’s and Thomas’ School of Medicine, London, UK

Distinctive patterns of microRNA expression in primary muscular disorders

The primary muscle disorders are a diverse group of diseases caused by various defective structural proteins, abnormal signaling molecules, enzymes and proteins involved in posttranslational modifications, and other mechanisms. Although there is increasing clarification of the primary aberrant cellular processes responsible for these conditions, the decisive factors involved in the secondary pathogenic cascades are still mainly obscure. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs regulated during the degenerative process of muscle to gain insight into the specific regulation of genes that are disrupted in pathological muscle conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major muscular disorders in humans [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis]. Although five miRNAs were found to be consistently regulated in almost all samples analyzed, pointing to possible involvement of a common regulatory mechanism, others were dysregulated only in one disease and not at all in the other disorders. Functional correlation between the predicted targets of these miRNAs and mRNA expression demonstrated tight posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy. Together with direct mRNA–miRNA predicted interactions demonstrated in DMD, some of which are involved in known secondary response functions and others that are involved in muscle regeneration, these findings suggest an important role of miRNAs in specific physiological pathways underlying the disease pathology.

Interferon-α/β–mediated innate immune mechanisms in dermatomyositis

Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement‐mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon‐α/β were highly overexpressed, and immunohistochemistry for the interferon‐α/β inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon‐α, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon‐α/β inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus. Ann Neurol 2005;57:664–678

A Phase I/II trial of MYO-029 in Adult Subjects with Muscular Dystrophy

Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO‐029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb‐girdle muscular dystrophy).

Clinical spectrum of chronic acquired demyelinating polyneuropathies.

A number of presentations of chronic demyelinating polyneuropathy have been identified, each distinguished by its phenotypic pattern. In addition to classic chronic inflammatory demyelinating polyneuropathy (CIDP), which is characterized clinically by symmetric proximal and distal weakness and sensory loss, several regional variants can be recognized: multifocal motor neuropathy (MMN: asymmetric and pure motor), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (asymmetric, sensory, and motor), and distal acquired demyelinating symmetric (DADS) neuropathy (symmetric, distal, sensory, and motor). There are also temporal, pathological, and disease‐associated variants. This review describes a clinical scheme for approaching the chronic acquired demyelinating polyneuropathies that leads to a rational use of supportive laboratory studies and treatment options. In addition, we propose new diagnostic criteria for CIDP that more accurately reflect current clinical practice.

Guillain-Barré syndrome and Fisher syndrome: case definitions and guidelines for collection, analysis, and presentation of immunization safety data.

ames J. Sejvara,∗, Katrin S. Kohla, Jane Gidudua, Anthony Amatob, Nandini Bakshic, Roger Baxterc, ale R. Burwend, David R. Cornblathe, Jan Cleerbout f, Kathryn M. Edwardsg, Ulrich Heiningerh, ichard Hughes i, Najwa Khuri-Bulos j, Rudolf Korinthenbergk, Barbara J. Lawl, Ursula Munrom, elena C. Maltezoun, Patricia Nello,1, James Oleskep, Robert Sparksq, Priscilla Velentgasr, atricia Vermeers, Max Wiznitzer t, The Brighton Collaboration GBS Working Group2

Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: Impact of a dose-modification guideline

The frequency, characteristics and reversibility of bortezomib‐associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose‐modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1·3 mg/m2 (days 1, 4, 8, 11, eight 21‐d cycles, then days 1, 8, 15, 22, three 35‐d cycles); bortezomib was held, dose‐reduced or discontinued depending on peripheral neuropathy severity, according to a protocol‐specified dose‐modification guideline. Overall, 124/331 patients (37%) had treatment‐emergent peripheral neuropathy, including 30 (9%) with grade ≥3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade ≥3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose‐modification guidelines. Of patients with grade ≥2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade ≥2 peripheral neuropathy. Bortezomib‐associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.

Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.

PURPOSE To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. PATIENTS AND METHODS Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. CONCLUSION Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.