MSD Patients Research Articles

Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model

BackgroundMultiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD.MethodsTo test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive).ResultsAfter 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain.ConclusionsOur results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.

Allogeneic hematopoietic cell transplantation for older patients with AML with active disease. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70-79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n = 58), 10/10 HLA-MUD (n = 228), and Haplo (n = 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p < 0.01) and presented the combination female donor to male recipient (p < 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2-74.3) and 47.6% (95% CI 33.1-60.8) for MSD, 43% (95% CI 35.8-49.9), and 37.5% (95% CI 30.7-44.4) for MUD, and 25.9% (95% CI 15.8-37.2), and 26.5% (95% CI 16.3-37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19-40.9), for MUD it was 30.2% (95% CI 23.9-36.7), and for MSD 34.9% (95% CI 22-48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6-55.6) for Haplo recipients, 32.2% (95% CI 26-33.1) for MUD and 17.5% (95% CI 8.4-29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3-48.5) for MSD, 29.6% (95% CI 23.2-36.2) for MUD, and 19.2% (95% CI 10.7-29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23-11.61, p < 0.001) and MUD (HR 3.21, 95% CI 1.48-0.6.94, p = 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98-0.6.56, p < 0.001, and HR 2.3, 95% CI 1.37-0.3.88, p = 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31-0.3.84, p = 0.003, and HR 1.64, 95% CI 1.04-0.2.60, p = 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07-2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted.

Treosulfan Based Haploidentical Αß T Cell Depleted HSCT Represents a Curative Alternative in Pediatric and Adult Patients with Transfusion Dependent Thalassaemia

Background: Quality of life remains severely compromised in patients suffering from Transfusion Dependent Thalassemia (TDT) despite optimal supportive care. HSCT with a MSD, the current curative option, achieving a 92.1% 2y-OS in children and 84.4% in adults (EBMT registry). Unfortunately, availability of MDs is limited, so that haploidentical HSCT is increasingly explored. Methods: 13 TDT patients (median age: 11 years; range: 2-23) received either a CD3 +/CD19 + (n=4; all class II/III) or αß/CD19 + (n=10; 7 class II, II/III) T-haplo-HSCT and were compared with 8 TDT-patients (7 class II, II/III, III) receiving a BM graft from a MSD (median age: 11 years; range: 4-22). Indication for T-haplo HSCT patients was severe iron overload/ transfusion-associated complications. All patients received an identical conditioning regimen consisting of treosulfan, thiotepa, fludarabine (FTT) and ATG-Grafalon, with the only difference in the timing of ATG (upfront in T-haplo-HSCT, prior to d0 in MSD-HSCT). Immunosuppression (IST) was maintained for a minimum of 180 days consisting of calcineurin inhibitors (mainly tacrolimus) and MMF. Results: The OS and DFS for MSD and T-haplo-HSCT was 100%/100% and 100%/92%, respectively (Table 1). The median follow-up was 30 months for MSD (range 4-72) and 38 months for T-haplo-HSCT (range 4-86). Neutrophil engraftment was achieved after a median of 31 days for MSD patients and 17 days for T-haplo-HSCT with a median of 5 x 10 8 TNC/kg (range: 3.28-7.88) and 15 x 10 6 CD3 +/CD19 + or αβ/CD19 + depleted CD34 + cells/kg (range: 9.2-24.2), respectively. One patient received two T-haplo HSCT, due to primary graft failure partly due to a major AB0 incompatibility. A mixed chimerism was observed in 3/7 MSD-HSCT (median 92%; range 27.5-100%) and in T-haplo-HSCT in 2/13 patients (median 99%; range: 45.3 -100%). Transfusion independence was achieved in all MSD and in all but one T-haplo patient. In MSD and in T-haplo-HSCT, IST was terminated after a median of 173 days and 226 days (range: 112-347), respectively. MSD patients reached CD4 counts &amp;gt;50/µl on day +43 (median; range: 25-125) and T-haplo-HSCT patients on day +114 (median; range: 33-173). The treosulfan-based conditioning regimen was well tolerated with no VOD/SOS observed in this high-risk population. No case of acute or chronic Graft-versus-Host disease (GvHD) was observed in the MSD population. In T-haplo-HSCT, 3 patients experienced grade I acute GvHD (skin) which resolved with prednisolone and in 2 cases with additional extracorporeal photopheresis. Only the oldest patient experienced mild chronic skin GvHD, which resolved by day +580. No severe infectious complications occurred despite a prolonged chimerism-triggered weaning of the IST. Conclusions: Independent of donor availability, graft rejection and iron-overload related organ damage (VOD/SOS) are major pitfalls in transplanting advanced stage TDT patients. Treosulfan demonstrated to be an excellent alternative to busulfan in this setting reflected in the safety and efficacy data of this pilot series. Overall, outcomes of T-haplo-HSCT in TDT are very encouraging with a competitive OS, so that a transplant indication in pediatric and AYA TDT patients lacking a MD is feasible.

Impact of holistic, patient-centric yoga & naturopathy-based lifestyle modification program in patients with musculoskeletal disorders: A quasi-experimental study

BackgroundMusculoskeletal disorders (MSD) are one of the leading causes of disability and decreased well-being globally. This study investigates the role of a 10-day holistic, person-centric yoga & naturopathy based lifestyle intervention model (HOPE-YN) in improving musculoskeletal health, vitality, strength, flexibility, pain, and treatment satisfaction among MSD patients. MethodsThis quasi-experimental study included 57 participants with varying MSD, aged between 29 and 65, who underwent a 10-day HOPE-YN program that included interventions like diet, yoga, massage, etc. Additionally, each patient received a holistic consultation focused on holistic dimensions of health and healing. Except for STS and TUG, which were measured at the baseline and 10th day, the Musculoskeletal-related Health Quality (MSK-HQ), the Visual Analog Scale for Health, Vitality, and Pain, weight, sit-to-stand (STS) and time-up-and-go (TUG) tests, and the visit-specific patient satisfaction questionnaire (VSQ-9) were measured at the baseline, 10th day, and 1 month post intervention. ResultsThe study was completed by 50 participants (76 % females), with the majority of the participants reporting having osteoarthritis and rheumatoid arthritis. Statistically significant improvement (P < 0.001) was observed in MSK-HQ, health, vitality, pain, STS, and TUG scores at the end of 10 days and one month after the intervention(P < 0.001). Females were found to have higher treatment satisfaction compared to males (P = 0.008). Treatment satisfaction was associated with improvements in vitality (P = 0.02), TUG (P = 0.03) and STS scores (P = 0.04). ConclusionHOPE-YN program was found to be beneficial in managing MSD and may improve adherence to lifestyle programs. The findings need to be validated through robust clinical trials.

Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency

Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine‐generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA‐approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose‐ and time‐dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.

Impact of Donor Type in Patients with Acute Myeloid Leukemia Given Allogeneic Hematopoietic Cell Transplantation after Low-Dose TBI Based Regimen: A Study from the Acute Leukemia Working Party of the EBMT and Eurocord

Backround. Low-dose total body irradiation (TBI)-based nonmyeloablative conditioning regimens are widely used in acute myeloid leukemia (AML) patients in first or second complete remission (CR) at the time of transplantation. With these regimens the burden for tumor eradication relies mostly on immune-mediated graft-versus-leukemia (GVL) effects that can be impacted by donor type. Here we assessed the impact of donor type in a large cohort of AML patients transplanted in CR after low-dose TBI-based nonmyeloablative conditioning regimens.Methods. Inclusion criteria included >= 18 years of age, de novo or secondary AML in CR1 or CR2, transplantation between 2004 and 2015, conditioning with fludarabine + 2 Gy TBI with or without pre- or post-transplant cyclophosphamide, no in vitro or in vivo T cell depletion of the graft (besides post-transplant cyclophosphamide), and either an HLA-matched sibling donor (MSD), a 10/10 HLA-matched unrelated donor (MUD), an HLA-haplo-identical donor (Haplo) or a single or double umbilical cord blood (CBT).Results. Data from 1357 patients receiving grafts from MSD (n=594), MUD (n=442), Haplo (n=77) or given single or double CBT (n=244) were included. The proportion of patients transplanted in CR1 was 87%, 80%, 66% and 60% in MSD, MUD, Haplo and CBT groups, respectively (P<0.001) while median patient age at transplantation was 58, 63, 57 and 55 years, respectively (P<0.001). The proportion of patients with secondary AML was 16%, 22%, 21% and 20% in MSD, MUD, Haplo and CBT groups (P=0.04). Median follow-up was 49, 25, 17 and 48 months, respectively (P<0.001). Graft rejection occurred in 2% of each MSD and MUD recipients, 7% of haplo patients and 8% of CBT recipients (P<0.001). Grade III-IV acute GVHD was more frequent in CBT (16%) than in MUD (9%), haplo (8%) or MSD (7%) recipients (P<0.001). In contrast, chronic GVHD was less frequent in CBT (27%) and in haplo (30%) patients than in MSD (50%) and MUD (52%) recipients (P<0.001). Two-year OS and GRFS were 60% and 30% in MSD patients, 56% and 41% in CBT recipients, 54% and 24% in MUD recipients, and 42% and 35% in haplo patients, respectively (P=0.02 for OS and P=0.03 for GRFS ; Figure 1). Two-year incidences of relapse and nonrelapse mortality (NRM) were 33% and 12% in MSD patients, 29% and 20% in MUD recipients, 34% and 17% in CBT recipients, and 37% and 21% in haplo patients, respectively (P=0.7 for relapse and P<0.001 for NRM). In multivariate analyses, in comparison to MSD patients, each other donor type was associated with a significantly higher NRM. Interestingly, CBT was associated with a higher incidence of grade III-IV acute GVHD (HR 2.9, P=0.001) but a lower incidence of chronic GVHD (HR=0.4, P<0.001) than MSD resulting in a significantly worse GVHD-free relapse free survival (GRFS) the first 100 days (HR=1.5, P=0.02) but significantly better GRFS beyond day 100 (HR=0.6, P=0.001). Finally, there was a suggestion for lower OS in haplo patients (HR 1.5, P=0.08). Factors associated with worse OS included intermediate and adverse-risk cytogenetics and secondary AML. AML relapse, GVHD and infections were the primary causes of death of 24%, 6% and 4% of MSD recipients, 21%, 7% and 7% of MUD recipients, 22%, 5% and 14% of haplo recipients, and 25%, 8% and 5% of CBT recipients, respectively.Conclusions. In this large cohort of AML patients transplanted in CR following low-dose TBI-based nonmyeloablative conditioning regimen there were no significant differences in OS and LFS between MSD, MUD and UCB while there was a suggestion for lower LFS and OS with haplo due to a higher incidence of death from infection. Since this regimen relies nearly exclusively on GVL effects for tumor eradication, our data suggest that the intensity of GVL effects is comparable with these four donor types. Further studies including more haplo patients are needed to confirm these results. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau. Mohty:Sanofi: Honoraria, Speakers Bureau.

Transplant Outcomes with Fludarabine and Melphalan in High Risk AML Patients By Donor Types

Background: Fludarabine and melphalan (FM) reduced intensity conditioning regimen has been widely used for allogeneic stem cell transplantation (allo-SCT) in AML patients not eligible for more ablative regimens. In this study, we looked into a contemporary group of high risk AML patients treated with FM and updated their outcome expectation by donor type. Methods: We included 292 AML patients who had first allo-SCT between January 2010 and December 2019 if their donors were haploidential (haplo, n=142) or matched related sibling (MSD, n=49) or matched unrelated donor (MUD, n=101) and their conditioning regimen was intravenous melphalan given as 100 mg/m2 or 140 mg/m2 in addition to fludarabine. Graft versus host disease (GvHD) prophylaxis was either tacrolimus and methotrexate (n=91) or tacrolimus with post-transplant cyclophosphamide (PTCy) +/- Mycophenolate mofetil (n=201). The primary outcome was relapse-free survival (RFS) defined as time to relapse or death whichever happened first. Secondary outcomes was overall survival (OS). Results: The median age was younger in haplo transplants compared with MDS or MUDs (50 vs. 63)(Table 1). There were more patients in first or second complete remission with count recovery (CR1/2) in haplo group compared with MSD (29%) and MUD (37%) but that did not reach significance (p=0.22). High risk disease risk by European Leukemia Net (ELN), advance group, was also distributed similarly between donor groups (21% in MSD, 32% in MUD and 24% in haplo, p=0.5). Hematopoietic comorbidity index (HCT-CI) &amp;gt;2 was frequent in all donor groups (43% in MSD, 46% MUD and 36% haplo, p=0.4). Hematopoietic stem cell source and GvHD prophylaxis differed by donor as expected; all haplo patients but 15 had bone marrow (BM, 89%) while 2% of MSD and 26% of MUD had BM. GvHD prophylaxis was PTCy in all haplo patients but half of the MUD patients (49%) and some of the MSD also received PTCy (20%). The median follow-up of 143 survivors was 24 months (range, 1 to 102 months). RFS at 2 years was 41.6% (95% confidence interval (CI) 35.5%- 47.6%) and OS was 48.6% (95% CI=42.1%-54.7%). Outcome estimates by donor types are presented in table 2. Considering the haplo patients were younger, we also analyzed RFS for older patients aged &amp;gt;50 and &amp;gt;60 separately (Figure). Causes of death was mostly relapse in all donor types; 54.2% in MSD, 40.4% in MUD and 44.7% in haplo. Cox regression model for RFS revealed that CR1/2 or CR without count recovery (CRi/p) were favorable prognostic variables compared with advanced disease (hazard ratio (HR)=0.35, 95%CI=0.25-0.51, p&amp;lt;0.001 and HR=0.65, 95%CI=0.44-0.96, p=0.03) but ELN adverse risk (HR=1.91, 95%CI=1.37-2.65, p&amp;lt;0.001) and HCT-CI&amp;gt;2 (HR=1.62, 95%CI=1.17-2.23, p=0.003) were poor prognostic markers. Age &amp;gt;50 was not a prognostic factor for RFS. Conclusion: FM remains to be an effective conditioning regimen that is leading to similar RFS after transplant with different donor types. Despite smaller sample size, even older haploidentical patients had RFS that was not significantly different compared with older MSD and MUD patients. However, relapse remains to be the major reason of failure in patients with high risk features including disease status not in CR with count recovery at allo-SCT and/or adverse ELN risk. Innovative strategies either with more ablative regimens or post-transplant maintenance or integration of cellular therapy options are needed to improve outcomes for those AML patients. Disclosures Oran: Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Ciurea:Kiadis Pharma: Current equity holder in publicly-traded company, Research Funding. Mehta:Incyte: Research Funding; Kadmon: Research Funding; CSL Behring: Research Funding. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Popat:Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Pfizer: Other: Served on advisory board; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy; Kite: Other: Served on advisory board. Champlin:Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents &amp; Royalties; Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy.

A systematic review and meta-analysis of published cases reveals the natural disease history in multiple sulfatase deficiency.

Multiple Sulfatase Deficiency (MSD, MIM#272200) is an ultra-rare lysosomal storage disorder arising from mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE). FGE is necessary for the activation of sulfatases, a family of enzymes that are involved in the degradation of sulfated substrates such as glycosaminoglycans and sulfolipids. SUMF1 mutations lead to functionally impaired FGE and individuals with MSD demonstrate clinical signs of single sulfatase deficiencies, including metachromatic leukodystrophy (MLD) and several mucopolysaccharidosis (MPS) subtypes. Comprehensive information related to the natural history of MSD is missing. We completed a systematic literature review and a meta-analysis on data from published cases reporting on MSD. As available from these reports, we extracted clinical, genetic, biochemical, and brain imaging information. We identified 75 publications with data on 143 MSD patients with a total of 53 unique SUMF1 mutations. The mean survival was 13 years (95% CI 9.8-16.2 years). Seventy-five clinical signs and 11 key clusters of signs were identified. The most frequently affected organs systems were the nervous, skeletal, and integumentary systems. The most frequent MRI features were abnormal myelination and cerebral atrophy. Individuals with later onset MSD signs and survived longer than those with signs at birth. Less severe mutations, low disease burden and achievement of independent walking positively correlated with longer survival. Despite the limitations of our approach, we were able to define clinical characteristics and disease outcomes in MSD. This work will provide the foundation of natural disease history data needed for future clinical trial design.

Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification.

Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular sulfatases by oxidizing a conserved cysteine in the active site of sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all sulfatases. As the majority of sulfatases are localized to the lysosome, loss of sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.

Surgical treatment of metastatic spine disease: an update on national trends and clinical outcomes from 2010 to 2014

BACKGROUND CONTEXTMetastatic spine disease (MSD) is becoming more prevalent as medical treatment for cancers advance and extend survival. More MSD patients are treated surgically to maintain neurological function, ambulation, and quality of life. PURPOSEThe purpose of this study was to use a large, nationally representative database to examine the trends, patient outcomes, and health-care resource utilization associated with surgical treatment of MSD. DESIGNThis was an epidemiologic study using national administrative data from the Nationwide Readmissions Database (NRD). PATIENT SAMPLEAll patients in the NRD from 2010 to 2014 who underwent spinal surgery were included in the study. OUTCOME MEASURESMortality, blood transfusion, complications, length of stay, cost, and discharge location during index hospitalization as well as hospital readmission and revision surgery within 90-days of surgery were analyzed. METHODSInternational Classification of Diseases, Ninth Revision, (ICD-9) codes was used to identify patients of interest within the NRD from 2010 to 2014. Patients were separated into two cohorts – those with MSD and those without. Trends for surgical treatment of MSD were assessed and outcomes measures for both cohorts were analyzed and compared. RESULTSThe number of surgical treatments for MSD increased from 6,007 in 2010 to 7,032 in 2014 (p-trend<.0001) which represented a 17.1% increase. During index hospitalization, MSD patients had an increased risk of mortality (odds ratio [OR]=3.22, 95% confidence interval [CI]: 2.85–3.63, p<.0001), blood transfusion (OR=2.93, 95% CI: 2.66–3.23, p<.0001), any complication (OR=1.24, 95% CI: 1.18–1.31, p<.0001), and discharge to skilled nursing facility (OR=1.51, 95% CI:1.41–1.61, p<.0001). MSD patients had longer average length of stay (13.05 vs. 4.56 days, p<.0001) and cost ($49,421.75 vs. $26,190.37, p<.0001) during index hospitalization. Furthermore, MSD patients had an increased risk of hospital readmission (OR=2.82, 95% CI: 2.68–2.96, p<.0001), readmission for surgical site infection (OR=2.38, 95% CI: 2.20–2.58, p<.0001), and readmission with neurologic deficits (OR=1.62, 95% CI: 1.27–2.06, p<.0001) despite a decreased risk of revision fusion (OR=0.71, 95% CI: 0.53–0.96, p=.026). CONCLUSIONSThe number of MSD patients who undergo surgical treatments is increasing. Not only do these patients have worse outcomes during index hospitalization, but they are also at an increased risk of hospital readmission for surgical site infection and neurologic complications. These findings stress the need for multidisciplinary perioperative treatment plans that mitigate risks and facilitate quick, effective recovery in these unique, at-risk patients.

L’arthroplastie totale chez les patients porteurs d’une dysplasie musculo-squelettique est liée à un risque accrue d’infection du site opératoire

IntroductionMusculoskeletal dysplasias (MSD) are inherited conditions of abnormal cartilage and bone development and remodeling which include, amongst others, multiple epiphyseal dysplasia (MED), spondyloepiphyseal dysplasia (SED), achondroplasia, and hypochondroplasia. The aim of this study was to compare patient characteristics and in-hospital complications between MSD and non-MSD patients undergoing total joint arthroplasty (TJA). HypothesisMSD patients undergoing TJA are at increased risk of in-hospital postoperative complications and mortality compared to non-MSD patients. Materials and methodsThe Nationwide Inpatient Sample (NIS) from the years 2005 to 2014 was used for this retrospective cohort study. International Classification of Diseases, Clinical Modifications (ICD-9-CM) procedure codes identified primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures and were used to separate MSD and non-MSD patients. Patients with trauma or malignancy as primary diagnoses, non-elective procedures, revision procedures, and concurrent bilateral surgeries were excluded. Patients were compared using linear regression or multivariate logistic regression analysis to control for confounders. All statistical analyses were performed taking into account the NIS sampling scheme and associated sampling weights. ResultsA total of 1,255 patients comprised the MSD group and 8,027,181 patients the non-MSD group. MSD patients were younger than non-MSD patients (50.9 vs 65.8 years, p<0.001), with less comorbidities including: hypertension (40.2% vs 64.5%, p<0.001), coronary artery disease (5.5% vs 12.9%, p<0.001), diabetes mellitus (9.4% vs 19.0%, p<0.001), and hypothyroidism (7.8% vs 14.7%, p=0.002). MSD patients had higher risks of surgical site infection (0.8% vs 0.2%; OR, 4.16; 95% CI, 1.03–16.75; p=0.044), and perioperative hemorrhage (2.1% vs 0.7%; OR, 3.20; 95% CI, 1.32–7.76; p=0.010). DiscussionMSD patients undergoing TJA were younger with less co-morbidity compared to non-MSD patients, and had no significant difference in overall perioperative medical and surgical complication rates. However, they are at increased risk for surgical site infection and perioperative hemorrhage possibly due to the anatomical complexity encountered. Level of evidenceIII, Retrospective Cohort.

Patients with musculoskeletal dysplasia undergoing total joint arthroplasty are at increased risk of surgical site Infection

IntroductionMusculoskeletal dysplasias (MSD) are inherited conditions of abnormal cartilage and bone development and remodeling which include, amongst others, multiple epiphyseal dysplasia (MED), spondyloepiphyseal dysplasia (SED), achondroplasia, and hypochondroplasia. The aim of this study was to compare patient characteristics and in-hospital complications between MSD and non-MSD patients undergoing total joint arthroplasty (TJA). HypothesisMSD patients undergoing TJA are at increased risk of in-hospital post-operative complications and mortality compared to non-MSD patients. Materials and methodsThe Nationwide Inpatient Sample (NIS) from the years 2005 to 2014 was used for this retrospective cohort study. International Classification of Diseases, Clinical Modifications (ICD-9-CM) procedure codes identified primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures and were used to separate MSD and non-MSD patients. Patients with trauma or malignancy as primary diagnoses, non-elective procedures, revision procedures, and concurrent bilateral surgeries were excluded. Patients were compared using linear regression or multivariate logistic regression analysis to control for confounders. All statistical analyses were performed taking into account the NIS sampling scheme and associated sampling weights. ResultsA total of 1,255 patients comprised the MSD group and 8,027,181 patients the non-MSD group. MSD patients were younger than non-MSD patients (50.9 vs. 65.8 years, p<0.001), with less comorbidities including: hypertension (40.2% vs. 64.5%, p<0.001), coronary artery disease (5.5% vs. 12.9%, p<0.001), diabetes mellitus (9.4% vs. 19.0%, p<0.001), and hypothyroidism (7.8% vs. 14.7%, p=0.002). MSD patients had higher risks of surgical site infection (0.8% vs. 0.2%; OR, 4.16; 95% CI, 1.03–16.75; p=0.044), and perioperative hemorrhage (2.1% vs. 0.7%; OR, 3.20; 95% CI, 1.32–7.76; p=0.010). DiscussionMSD patients undergoing TJA were younger with less co-morbidity compared to non-MSD patients, and had no significant difference in overall perioperative medical and surgical complication rates. However, they are at increased risk for surgical site infection and perioperative hemorrhage possibly due to the anatomical complexity encountered. Level of EvidenceIII, Retrospective Cohort.

Aerobic training enhances cognition and functional status in depressive multiple sclerosis patients. A case-control study. Pilot study

Multiple sclerosis (MS) is a complex disease manifested by a wide range of symptoms. Depression is one of the most important problems in individuals with MS. Depressive symptoms are strictly associated with lower quality of their life. Recent studies suggest that aerobic training (AT) alleviates depressive symptoms. Therefore, the aims of this study were to study the effects of aerobic training (AT) on depression, cognition and functional status in 2 groups of multiple sclerosis (MS) patients: with depression syndrome (MS-D) and without depression (MS). Moreover, we analyzed the mean delta values with their confidence intervals and examined the changes in baseline values using covariance analysis. A sample of 31 individuals with MS and 28 MS-D performed 30 minutes of AT using lower-extremity ergometer 3 × 10 min. per day with 60 min. break for 6 weeks. Both groups were matched for age and sex. All examined parameters were assessed before and after the series of AT using the Montreal Cognitive Assessment (MoCA), the Beck Depression Inventory (BDI), Activity Daily Living Scale (ADL) and the Expanded Disability Status Scale (EDSS). We analyzed the dropout rate as a measure of feasibility. In both groups, the AT sessions induced a significant improvement in reducing depression (BDI) and cognition impairment (MoCA). However, the changes observed in MS-D patients were significantly greater than those observed in MS patients, especially in the BDI and MoCA. There were no statistically significant correlations of EDSS, MOCCA, BDI, ADL and age or gender. AT appears to be effective easy tool in improving cognition and functional status in patients with MS. This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS.

Impact of Donor Type in Patients with AML Given Allogeneic Hematopoietic Cell Transplantation After Low-Dose TBI-Based Regimen.

Purpose: We assessed the impact of donor type in acute myeloid leukemia (AML) patients transplanted with 2 Gy total body irradiation (TBI)-based nonmyeloablative conditioning regimen.Patients and Methods: Data from 1,715 adult patients, with AML in CR1 or CR2 were included in this retrospective survey.Results: Donors consisted either of HLA-matched sibling donors (MSD, n = 701), 10/10 HLA-matched unrelated donors (MUD, n = 611), HLA-haploidentical donors (haplo, n = 112) or single or double umbilical cord bloods (CBT, n = 291). Chronic graft-versus-host disease (GVHD) was less frequent in CBT (28%) and in haplo (30%) patients than in MSD (50%) and MUD (51%) recipients (P < 0.001). Two-year incidence of relapse was 32%, 30%, 34%, and 34% in MSD, MUD, CBT and haplo patients, respectively (P = 0.7). Two-year overall (OS) and GVHD-free relapse-free survival (GRFS) were 59% and 29% in MSD patients, 56% and 39% in CBT recipients, 53% and 23% in MUD recipients, and 43% and 37% in haplo patients, respectively. In multivariate analyses, MUD patients had lower GRFS than MSD patients beyond day 100 (HR 1.3, P = 0.001) while CBT was associated with a better GRFS than MSD beyond day 100 (HR 0.6, P = 0.002).Conclusions: In this large cohort of AML patients transplanted following low-dose TBI-based conditioning, the relapse incidence was not affected by donor type suggesting that the intensity of GVL effects might be comparable with these four transplant approaches. Furthermore, CBT was associated with better GRFS beyond day 100 than MSD while the opposite was observed for MUD. Clin Cancer Res; 24(12); 2794-803. ©2018 AACR.

Myelodysplastic syndromes and iron metabolism

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis in bone marrow and cytopenias in peripheral blood. In patients with MDS, iron overload is frequent due to red blood cell transfusions and ineffective erythropoiesis. Dysplastic erythroblasts in MDS secrete humoral factors such as erythroferrone, which suppress hepatic expression of hepcidin. Hepcidin is the key regulator of systemic iron homeostasis, and suppression of hepcidin expression leads to an increase in iron absorption from the intestines, exacerbating systemic iron overload. Patients with MDS with ring sideroblasts (MDS-RS) are prone to iron overload, with most harboring splicing factor 3B subunit 1 (SF3B1) mutations in hematopoietic cells. SF3B1 mutations may induce ring sideroblasts by downregulating ATP binding cassette subfamily B member 7, which exports iron-sulfur clusters from the mitochondria to the cytoplasm. Iron overload in MDS causes hepatic dysfunction, diabetes, cardiac failure, and atherosclerosis, whereas excess iron may suppress normal hematopoiesis. Though randomized control studies are lacking, results from retrospective and cohort studies indicate that iron chelation therapy is appropriate for lower-risk MSD patients with transfusion-related iron overload, although it is not recommended for higher-risk MSD patients with short life expectancy.

An Improved Features of Health Screening Test System for Malaysian Social Security Organisation (SOCSO) Programme

The purpose of this paper is to improve the features of Health Screening Test System (HSTS) on Social Security Organization (SOCSO) program as physical evaluation for musculoskeletal disable workers (MSDs). SOCSO existing functional testing system are not suitable because of the evaluation was recorded manually peg board too high for Asian people. The occupational therapist whose involve in all the procedures is just doing the judgment in times to determine the capability of the patients. The functional capacity evaluation (FCE) technique is based on the functional range of motion evaluation that consist of positional tolerance respecting to time-motion testing on HSTS peg board and it is by referring to the original work movement. The main features of HSTS are able to measure speed, acceleration and evaluation of SOCSO’s patients for returning to work based on SOCSO’s requirement. In order to validate the accuracy of the proposed model, HSTS is used to evaluate the patient’s positional tolerance and then the result would be compare over the time frame which is Method Time Measurement (MTM) standard. This method is able to provide information and feedback for therapies as a status of patients. It is found that the proposed model is superior in getting the accurate time test for patient’s movements besides practicable and suitable for physical evaluation on MSD patients.

PC0006 Impact of physician preferences for homeopathic or conventional medicines on patients with muskuloskeltal disorders: Results from the EPI3-MSD cohort

BackgroundMusculoskeletal disorders (MSDs) are a leading reason for consultation in primary care. As these disorders tend to become chronic, available treatments are largely symptomatic in nature explaining in part the...

Natriuretic Peptides as Well as Endothelin, and Not Troponin Are of Value in Early Diagnosis of Acute Cardiotoxicity in Children Undergoing Hematopoietic Stem Cell Transplantation

The incidence of cadiotoxicity (CT) has been estimated at 5–10% of adult patients following hematopoietic stem cell transplantation (HSCT), but it is unknown in patients undergoing HSCT in childhood. Recent studies showed several biochemical markers as potentially useful for early detection of CT: Atrial Natriuretic Peptide (ANP) secreted by the atria in response to stretch as a result of an increased left atrial pressure, N-terminal fragment of Brain Natriuretic Peptide (NT-proBNP) produced by ventricles in response to ventricular dilatation and increased wall stress, cardiac Troponin I (TnI) the thin-filament contractile protein released to the circulation after myocardial injury and Endothelin 1 (ET-1) a vasoconstrictor peptide synthesized in the vasculature and by the endothelial cells and ventricular myocytes. The aim of the study was to assess the frequency and significance of elevated NT-proBNP, ANP, ET-1 and TnI plasma levels and their correlation to echocardiographic parameters of left ventricular function: shortening fraction (FS) and ejection fraction (EF) in children in early postransplant period. Patients: A total number of 31 consecutive children (22 boys and 9 girls) with median age of 9.6 years (range 0–18), treated with HSCT were included in the study: 12 autologous (aHSCT), 9 unrelated donor (MUD HSCT) and 10 family donor (MSD HSCT) transplantations were performed. The control group consisted of 14 healthy children, with median age of 10.9 years.Methods: The plasma levels of NT-proBNP, ANP and ET-1 were measured in transplanted patients on days −7, 0, +7, +14 by the Electrochemiluminescent Immunoassay (Biomedica) and TnI by the Immunoassay (Abbot). SF and EF were assessed by echocardiography prior to HSCT and about day +30 and +100 after transplantation. The same tests were performed in the control group. Results: Baseline echocardiographic parameters were within the normal range in all patients included in the study. In comparison with a control group, a trend to decrease median SF and EF values was observed on day +30 (FS > 28% and EF > 55%). In transplanted patients median ET-1 plasma levels were elevated in all analyzed time points when compared to controls (p< 0.05); median NT pro-BNP plasma concentrations were significantly elevated from days −7 to +7 (p< 0.05) and median ANP plasma concentrations on day +7 (p< 0.05). Median levels of TnI did not differ between analyzed and control groups. No correlation was found between elevated biochemical marker levels and echocardiographic parameters evaluated on days +30 and +100 after HSCT. According to the type of transplant, in aHSCT patients ET-1 plasma level elevation was observed in 4 analyzed time points (p< 0.05), while in MUD transplant recipients on day +7 only and in MSD transplant recipients on day +14 only. NT pro-BNP and ANP plasma levels were elevated in MUD transplant recipients on days 0,+7, +14 (p<0.05), in MSD patients on day +7, while in aHSCT patients no difference was found, when compared to controls. The levels of TnI did not differ between patients and controls in any transplant type. Statistically significant correlation was found between ANP level on day +14 and EF on day +100 in MUD patients and in aHSCT patients (r = −0.9 and r = −0.78 respectively).Conclusions: Elevation of natriuretic peptides (ANP, NT-proBNP) levels may indicate the risk of cardiotoxicity, especially in unrelated transplant recipients. ET-1 plasma concentration is elevated mainly in children following autologous transplantation. The value of measuring TnI levels in the assessment of CT in children following HSCT is low. Further studies are necessary to confirm the role of natriuretic peptides and ET-1 as markers of acute CT regarding the type of transplant.

Outcome of Hematopoietic Cell Transplant from HLA-Matched Siblings Compared to a Volunteer Unrelated Donors Matched for HLA-A, B, C, DRB1, and DQB1 Alleles.

Hematopoietic cell transplantation from an HLA-matched unrelated donor (URD) is an alternative when an HLA-matched sibling donor (MSD) is not available. Matching of donor HLA alleles is associated with improved outcome after unrelated HCT compared to mismatching. Whether HLA matching can result in outcomes similar to those observed after HLA-identical sibling HCT remains an important question. We compared clinical outcomes after HCT in 704 recipients with HLA-A, B, C, DRB1, DQB1 allele matched URD and 1211 recipients of HLA-identical MSD. Patients received myeloablative conditioning for treatment of AML, ALL, CML, or MDS. The two groups were similar in phase of disease (advanced: acute leukemia>CR1, CML>CP,MDS>RA; early: all others), source of stem cells, age, and patient CMV serology. Male patients with a female donors occurred more frequently in the MSD group (27%) relative to the URD group (18%), and MSD were more often CMV-seropositive (52%) than URD (29%). Multivariable regression models were fit for the endpoints overall survival (OS), acute graft-vs-host disease (GVHD), and relapse, adjusting for each of the factors listed above. Overall, 350 (50%) of URD and 597 (49%) of MSD recipients survive for a median of 7.1 years follow-up (range 0.1–15.2), leading to an adjusted hazard ratio (HR) for mortality of 1.16 (confidence interval (CI), 1.00–1.34, p=.05). The relative risk was similar among pediatric (<18 years) and adult patients (interaction test, p>0.90), but there was a suggestion that the risk differed according to phase of disease (interaction test, p=0.07). In particular, the adjusted HR in early disease phase was 1.39 (CI, 1.08–1.78, p=.01) compared to 1.09 (CI, 0.91–1.30, p=0.37) in advanced phase. Grades II–IV GVHD occurred in 83% of URD and 67% of MSD patients, for an adjusted odds ratio (OR) of 2.37 (CI, 1.84–3.06, p<0.0001), while grades III–IV GVHD occurred in 25% and 18% of recipients, respectively (adjusted OR=1.98 (CI, 1.52–2.57, p<0.0001)). As with mortality, there was a suggestion that the difference in GVHD between URD and MSD differed according to disease phase (p=0.07 for grades II–IV, p=0.04 for grades III–IV). The OR for grades II–IV GVHD was 2.79 (CI, 1.94–4.01, p<0.0001) among patients with early phase disease and 1.99 (CI, 1.38–2.88, p=0.0003) among those with advanced phase, while OR for grades III–IV GVHD was 2.58 (CI, 1.75–3.80, p<0.0001) among early phase and 1.59 (CI, 1.10–2.30, p=0.01) among advanced phase patients. Relapse was observed in 25% of unrelated recipients compared to 29% of sibling recipients (HR=0.88; CI, 0.72–1.08; p=0.22). The association of relapse with donor type was not significantly affected by disease phase (interaction test, p=0.84). When an unrelated donor is matched for HLA-A, B, C, DRB1, and DQB1 with the recipient, survival after HCT is similar to that with an HLA-identical sibling donor for patients with advanced disease despite the increased incidence of severe GVHD. Mortality is higher in the URD group for patients with early disease phase. While the difference in mortality for early disease phase may reflect the importance of alloreactivity among patients with few other competing risks for mortality, selection bias for patients with unfavorable prognostic features also may contribute to higher mortality in the URD group.

Reduced-Intensity Allogeneic Transplantation after Failure of Autologous Transplantation: A Prospective Multi-Center CALGB Study.

Relapse of malignancy (RM) remains the most important cause of treatment failure following high-dose chemotherapy and autologous hematopoietic transplantation (AHCT). Allogeneic transplantation (allo-HCT) can salvage some patients who relapse or develop MDS following AHCT. However, myeloablative allo-HCT has been associated with a prohibitive transplant-related mortality (TRM) in such patients. CALGB study 100002 prospectively assessed the safety of reduced-intensity allo-HCT (RICT) in patients who failed prior AHCT. Eligibility required the development of RM or MDS > 6 months following AHCT for a hematologic malignancy and an available HLA-identical sibling (MSD) or 9/10 locus matched related donor, or a 10/10 matched unrelated donor. Between Dec 02 and Mar 06, 82 patients were registered from 11 CALGB centers. Patient characteristics: median age = 51 (17–70); male-63%; diagnoses - NHL 30%, HD 26%, MM 18%, MDS 16%, AML 8%, CLL 2%; donor - MSD 43%, MUD 55%, 9/10 MRD 2%. Median time between AHCT and RICT was 2.6 yrs (0.6–5.7 yrs). Preparative regimen for patients with MSD was fludarabine 30 mg/m2/d x 5 d, busulfan (i.v.) 3.2 mg/kg/d x 2 d. For patients without MSD rabbit ATG (Thymoglobulin ®) 2.5mg/kg/d x 4 d was added. PBSC 2–8 x 106 CD34+ cells/kg was used as the graft. GVHD prophylaxis consisted of tacrolimus tapering at d +90 and methotrexate 5 mg/m2 x 3 doses for MSD patients. For non-MSD patients, tacrolimus was tapered starting d +180, a fourth dose of methotrexate and MMF (d 0 to d +60) were added. Primary endpoint was TRM at 6 months. For 56 patients with > 6 months post-RICT follow-up (median follow-up 1.3 yrs), 6 month TRM was 8.7% (MSD patients 4.2%, non-MSD patients 9.3%). Total cumulative TRM was 14.3% (MSD 16.7%, non-MSD 12.5%). Reported cumulative rates of II–IV and III–IV acute GVHD are 28.2% and 11.8% respectively. Chimerism studies were performed centrally on peripheral blood (PB) specimens. The percentage of patients from MSD patients who achieved full (> 90%) donor T-cell (CD3) chimerism in PB on day 30, 60, 90 and 180 post transplant are 15, 40, 47, 57 and 60% respectively. In contrast, for non-MSD patients the corresponding rates are 78, 68, 86 and 91 % respectively. Both MSD and non-MSD patients achieved full (>90%) donor chimerism in myeloid cells by d 30 in > 80% of patients. This study observed a <10% 6-month TRM for RICT following AHCT failure in the multi-center, co-operative group setting. Also, the use of a more potent GVHD prophylaxis regimen seems to enable TRM rates for non-MSD patients to approximate those seen for MSD patients. MSD patients achieve slower onset of full-donor chimerism in T-cells with this regimen. A successor study will assess means of increasing early T-cell chimerism in the MSD patients.