Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation.

IMPORTANCE: Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG. OBJECTIVE: To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies. INTERVENTIONS: Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution. MAIN OUTCOMES AND MEASURES: The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA postintervention status. Safety outcomes included all severe autologous HSCT-related complications. RESULTS: Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment- or MG-related deaths. CONCLUSIONS AND RELEVANCE: Autologous HSCT results in long-term symptom- and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.

Autologous stem cell transplantation for stiff person syndrome: two cases from the Ottawa blood and marrow transplant program.

IMPORTANCE: Stiff person syndrome (SPS) is a rare neurological disease causing significant functional disability for patients and presenting a therapeutic challenge for clinicians. Autologous hematopoietic stem cell transplantation (auto-HSCT) has been used successfully to remit autoimmune-mediated neurological diseases. We report 2 cases of severe SPS treated with auto-HSCT, a novel therapy for this disease. OBSERVATIONS: Two anti-glutamic acid decarboxylase antibody-positive patients with SPS had an autologous hematopoietic stem cell graft collected and stored. Subsequently, the patients underwent auto-HSCT. Both patients achieved clinical remission with sustained, marked improvement in symptoms and a return to premorbid functioning, now more than 2.5 and 4.5 years after the procedure. CONCLUSIONS AND RELEVANCE: Stiff person syndrome represents a novel indication for auto-HSCT. The resolution of clinical manifestations of SPS despite the persistence of anti-glutamic acid decarboxylase antibodies following auto-HSCT suggests that the antibody does not play a direct role in pathogenesis of SPS.

A 15-year analysis of early and late autologous hematopoietic stem cell transplant in relapsed, aggressive, transformed, and nontransformed follicular lymphoma.

Autologous stem cell transplant (ASCT) has been shown to be an effective treatment for follicular lymphoma (FL). We explored our experience in ASCT for FL among all patients treated over a 15-year period from diagnosis through their entire treatment history including relapse post ASCT. All patients who underwent an unpurged ASCT for relapsed, advanced FL between June 1990 and December 2000 were analyzed. After salvage therapy they received melphalan/etoposide/total body irradiation, BCNU, etoposide, cytarabine, melphalan (BEAM), or cyclophosphamide BCNU etoposide (CBV) as conditioning for the ASCT. One hundred thirty-eight patients with a median age of 48 years and a median follow-up of 7.6 years were analyzed. The majority were of the subtype grade 1, nontransformed (FL-NT), having had 1 prior chemotherapy. The progression-free (PFS) and overall survival (OS) of the FL-NT at 10 years were 46% and 57%, respectively, and at 5 years for the transformed (FL-T) were 25% and 56%, respectively, of which only the PFS was significantly different (P=.007). The median OS from diagnosis was 16 years for the FL-NT. ASCT positively altered the trend of shorter remissions with subsequent chemotherapies, and there was no difference in OS between those who had 1, 2, or >2 chemotherapies prior to ASCT. Salvage therapy for relapse post ASCT was effective (OS>1 year) in a third of patients. Unpurged ASCT is an effective tool in the treatment of relapsed, aggressive FL-NT and FL-T, is superior to retreatment with standard chemotherapy, is effective at various stages of treatment, is likely to have a beneficial influence on the natural history of this disease, and the disease is amenable to salvage therapy post-ASCT relapse.

Determining lead sources in Mexico using the lead isotope ratio.

OBJECTIVE: Lead poisoning can, in some cases, be traced to a specific route or source of exposure on the basis of the individual's blood lead isotope ratio. To assess the major source of lead exposure among women residing in Mexico City, we compared blood, ceramic, and gasoline lead isotope ratios. MATERIAL AND METHODS: The study population, randomly selected from participants of a large trial, (1/1996-12/1996) comprised of 16 women whose lead levels exceeded 10 micrograms/dl and who reported using lead-glazed ceramics. Lead isotope ratios were performed on a Perkin Elmer 5000 Inductively Coupled Plasma Mass Spectrometer (ICP-MS) interfaced with a Perkin Elmer HGA-600MS Electrothermal Vaporization System (ETV). RESULTS: The isotope ratios (206Pb/204Pb, 207Pb/204Pb, and 208Pb/204Pb) of both the blood specimens and their corresponding ceramic specimens were highly correlated, with r = 0.9979, r2 = 0.9958, r = 0.9957, r2 = 0.9915 and r = 0.9945, r2 = 0.9890 values for the three isotope ratios, respectively, suggesting that the lead exposure most likely resulted from the use of these ceramic. Measurements of lead isotope ratios from leaded gasoline in use at the time of blood sampling, differed from those in blood and ceramics. CONCLUSIONS: Determining lead isotope ratios can be an efficient tool to identify a major source of lead exposure and to support the implementation of public health prevention and control measures. This paper is available too at: http://www.insp.mx/salud/index.html.

Determining lead sources in Mexico using the lead isotope ratio

OBJECTIVE: Lead poisoning can, in some cases, be traced to a specific route or source of exposure on the basis of the individual's blood lead isotope ratio. To assess the major source of lead exposure among women residing in Mexico City, we compared blood, ceramic, and gasoline lead isotope ratios. MATERIAL AND METHODS: The study population, randomly selected from participants of a large trial, (1/1996-12/1996) comprised of 16 women whose lead levels exceeded 10 æg/dl and who reported using lead-glazed ceramics. Lead isotope ratios were performed on a Perkin Elmer 5000 Inductively Coupled Plasma Mass Spectrometer (ICP-MS) interfaced with a Perkin Elmer HGA-600MS Electrothermal Vaporization System (ETV). RESULTS: The isotope ratios (206Pb/204Pb, 207Pb/204Pb, and 208Pb/204Pb) of both the blood specimens and their corresponding ceramic specimens were highly correlated, with r=0.9979, r²=0.9958, r=0.9957, r²=0.9915 and r=0.9945, r²=0.9890 values for the three isotope ratios, respectively, suggesting that the lead exposure most likely resulted from the use of these ceramic. Measurements of lead isotope ratios from leaded gasoline in use at the time of blood sampling, differed from those in blood and ceramics. CONCLUSIONS: Determining lead isotope ratios can be an efficient tool to identify a major source of lead exposure and to support the implementation of public health prevention and control measures.

Temperature-induced formation of a non-native intermediate state of the all beta-sheet protein CD2.

Domain 1 of the cell adhesion protein CD2 (CD2-1) has an all beta-structure typical of proteins belonging to the immunoglobin superfamily. It has a remarkable ability to fold as a native monomer or a metastable intertwined dimer. To understand the origin of structural rearrangements of CD2-1, we have studied equilibrium unfolding of the protein using various biophysical spectroscopic techniques. At temperatures above approx 68 degrees C, a partially folded state of CD2-1 (H state) with a distinct secondary structure, involving largely exposed aromatic and hydrophobic residues and a substantially perturbed tertiary structure, is observed. In contrast, an unfolded state (D state) of CD2-1 with random-coil-like secondary and tertiary structures is observed in 6 M GuHCl. This partially folded high-temperature state has increased negative molar ellipticity at 222 nm in far-ultraviolet CD spectra, implying formation of a non-native helical conformation. The existence of this non-native high-temperature intermediate is consistent with relatively high intrinsic helical propensities in the primary sequence of CD2-1. This conformational flexibility may be important in the observed domain swapping of CD2-1.