Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease.

Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6(-/-) mice received allogeneic non-T cell-depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6(-/-) recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6(-/-) recipients' liver. When mice received 0.5 x 10(6) allogeneic T cells with T cell-depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6(-/-) than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6(-/-) T-cell proliferation. We therefore assessed the response of WT or Gas6(-/-) ECs to tumor necrosis factor-alpha. Lymphocyte transmigration was less extensive through Gas6(-/-) than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

Whole-body 3D T1-weighted MR imaging in patients with prostate cancer: feasibility and evaluation in screening for metastatic disease.

PURPOSE: To develop and assess the diagnostic performance of a three-dimensional (3D) whole-body T1-weighted magnetic resonance (MR) imaging pulse sequence at 3.0 T for bone and node staging in patients with prostate cancer. MATERIALS AND METHODS This prospective study was approved by the institutional ethics committee; informed consent was obtained from all patients. Thirty patients with prostate cancer at high risk for metastases underwent whole-body 3D T1-weighted imaging in addition to the routine MR imaging protocol for node and/or bone metastasis screening, which included coronal two-dimensional (2D) whole-body T1-weighted MR imaging, sagittal proton-density fat-saturated (PDFS) imaging of the spine, and whole-body diffusion-weighted MR imaging. Two observers read the 2D and 3D images separately in a blinded manner for bone and node screening. Images were read in random order. The consensus review of MR images and the findings at prospective clinical and MR imaging follow-up at 6 months were used as the standard of reference. The interobserver agreement and diagnostic performance of each sequence were assessed on per-patient and per-lesion bases. RESULTS: The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher with whole-body 3D T1-weighted imaging than with whole-body 2D T1-weighted imaging regardless of the reference region (bone or fat) and lesion location (bone or node) (P < .003 for all). For node metastasis, diagnostic performance (area under the receiver operating characteristic curve) was higher for whole-body 3D T1-weighted imaging (per-patient analysis; observer 1: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P = .006 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging; observer 2: P = .006 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P = .006 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging), as was sensitivity (per-lesion analysis; observer 1: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P < .001 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging; observer 2: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P < .001 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging). CONCLUSION: Whole-body MR imaging is feasible with a 3D T1-weighted sequence and provides better SNR and CNR compared with 2D sequences, with a diagnostic performance that is as good or better for the detection of bone metastases and better for the detection of lymph node metastases.

CD34/QBEND10 immunostaining in bone marrow biopsies: an additional parameter for the diagnosis and classification of myelodysplastic syndromes.

CD34/QBEND10 immunostaining has been assessed in 150 bone marrow biopsies (BMB) including 91 myelodysplastic syndromes (MDS), 16 MDS-related AML, 25 reactive BMB, and 18 cases where RA could neither be established nor ruled out. All cases were reviewed and classified according to the clinical and morphological FAB criteria. The percentage of CD34-positive (CD34 +) hematopoietic cells and the number of clusters of CD34+ cells in 10 HPF were determined. In most cases the CD34+ cell count was similar to the blast percentage determined morphologically. In RA, however, not only typical blasts but also less immature hemopoietic cells lying morphologically between blasts and promyelocytes were stained with CD34. The CD34+ cell count and cluster values were significantly higher in RA than in BMB with reactive changes (p&lt;0.0001 for both), in RAEB than in RA (p=0.0006 and p=0.0189, respectively), in RAEBt than in RAEB (p=0.0001 and p=0.0038), and in MDS-AML than in RAEBt (p&lt;0.0001 and p=0.0007). Presence of CD34+ cell clusters in RA correlated with increased risk of progression of the disease. We conclude that CD34 immunostaining in BMB is a useful tool for distinguishing RA from other anemias, assessing blast percentage in MDS cases, classifying them according to FAB, and following their evolution.

Granulocyte-macrophage colony-stimulating factor elicits bone marrow-derived cells that promote efficient colonic mucosal healing.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy is effective in treating some Crohn's disease (CD) patients and protects mice from colitis induced by dextran sulfate sodium (DSS) administration. However, its mechanisms of action remain elusive. We hypothesized that GM-CSF affects intestinal mucosal repair. METHODS: DSS colitic mice were treated with daily pegylated GM-CSF or saline and clinical, histological, and inflammatory parameters were kinetically evaluated. Further, the role of bone marrow-derived cells in the impact of GM-CSF therapy on DSS colitis was addressed using cell transfers. RESULTS: GM-CSF therapy reduced clinical signs of colitis and the release of inflammatory mediators. GM-CSF therapy improved mucosal repair, with faster ulcer reepithelialization, accelerated hyperproliferative response of epithelial cells in ulcer-adjacent crypts, and lower colonoscopic ulceration scores in GM-CSF-administered mice relative to untreated mice. We observed that GM-CSF-induced promotion of mucosal repair is timely associated with a reduction in neutrophil numbers and increased accumulation of CD11b(+) monocytic cells in colon tissues. Importantly, transfer of splenic GM-CSF-induced CD11b(+) myeloid cells into DSS-exposed mice improved colitis, and lethally irradiated GM-CSF receptor-deficient mice reconstituted with wildtype bone marrow cells were protected from DSS-induced colitis upon GM-CSF therapy. Lastly, GM-CSF-induced CD11b(+) myeloid cells were shown to promote in vitro wound repair. CONCLUSIONS: Our study shows that GM-CSF-dependent stimulation of bone marrow-derived cells during DSS-induced colitis accelerates colonic tissue repair. These data provide a putative mechanism for the observed beneficial effects of GM-CSF therapy in Crohn's disease.

Progenitor cell therapy for heart disease.

Many cell types are currently being studied as potential sources of cardiomyocytes for cell transplantation therapy to repair and regenerate damaged myocardium. The question remains as to which progenitor cell represents the best candidate. Bone marrow-derived cells and endothelial progenitor cells have been tested in clinical studies. These cells are safe, but their cardiogenic potential is controversial. The functional benefits observed are probably due to enhanced angiogenesis, reduced ventricular remodeling, or to cytokine-mediated effects that promote the survival of endogenous cells. Human embryonic stem cells represent an unlimited source of cardiomyocytes due to their great differentiation potential, but each step of differentiation must be tightly controlled due to the high risk of teratoma formation. These cells, however, confront ethical barriers and there is a risk of graft rejection. These last two problems can be avoided by using induced pluripotent stem cells (iPS), which can be autologously derived, but the high risk of teratoma formation remains. Cardiac progenitor cells have the advantage of being cardiac committed, but important questions remain unanswered, such as what is the best marker to identify and isolate these cells? To date the different markers used to identify adult cardiac progenitor cells also recognize progenitor cells that are outside the heart. Thus, it cannot be determined whether the cardiac progenitor cells identified in the adult heart represent resident cells present since fetal life or extracardiac cells that colonized the heart after cardiac injury. Developmental studies have identified markers of multipotent progenitors, but it is unknown whether these markers are specific for adult progenitors when expressed in the adult myocardium. Cardiac regeneration is dependent on the stability of the cells transplanted into the host myocardium and on the electromechanical coupling with the endogenous cells. Finally, the promotion of endogenous regenerative processes by mobilizing endogenous progenitors represents a complementary approach to cell transplantation therapy.

Early stage primary bone lymphoma - a retrospective, multicenter rare cancer network (rcn) study

Purpose: Primary bone lymphoma (PBL) accounts for less than 1% of all malignant lymphomas, and 4-5% of all extra-nodal lymphomas. In this study, the disease profile, outcome, and prognostic factors were assessed in patients with stage I and II PBL.Patients and Methods: Thirteen Rare Cancer Network (RCN) institutions enrolled 116 consecutive patients with PBL treated between 1987 and 2008 in this study. Inclusion criteria were age > 16 years, stage I and II, minimum 6 months follow-up and a biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). Eighty-seven patients underwent chemoradiotherapy (CXRT), 15 radiotherapy (RT) without (13) or with (2) surgery, 14 chemotherapy (CXT) without (9) or with (5) surgery. Median RT dose was 40 Gy (range: 4-60). The median number of CXT cycles was 6 (range: 2-8). Median follow-up was 41 months (range: 6-242).Results: The overall response rate at the end of treatment was 91% (CR 74%, PR 17%). Local recurrence or progression was observed in 12 (10%) patients, and systemic recurrence in 17 (15%). Causes of death included disease progression in 21, unrelated in 5, CXT-related toxicity in 1, and second primary cancer in 2 patients. The 5-yr overall survival (OS), lymphoma-specific survival (LSS), and local control (LC) were 76%, 78% and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for OS were age <50 years (P=0.008), international prognostic index (IPI) score ≤1 (P=0.009), high grade histology (P=0.04), CXRT (P=0.05), CXT (P=0,0004), complete response (CR) (P<0.0001), number of CXT cycles ( ≥6 ) (P=0.01), and RT dose > 40 Gy (P=0.005). All above-mentioned parameters were also significant for LSS except for age and number of chemotherapy cycles. For LC, only CR and stage I were favorable factors. In multivariate analysis, IPI score, RT dose, complete response, and chemotherapy were independently influencing the outcome (OS and LSS). Complete response at the end of treatment was the only predicting factor for LC. Six patients developed grade 3 or more toxicities, according to Common Terminology Criteria for Adverse Events (CTCAE) V3.0.Conclusion: This large multicenter study confirms the relatively good prognosis of early stage PBL treated with combined CXRT. Local control was excellent, while systemic failures were rare. An adequate dose of RT (40 Gy or more) and complete CXT regime (≥ 6 cycles) were associated with better outcome.

Clinical factors associated with trabecular bone score.

Dual-energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) is the reference standard for diagnosing osteoporosis but does not directly reflect deterioration in bone microarchitecture. The trabecular bone score (TBS), a novel grey-level texture measurement that can be extracted from DXA images, predicts osteoporotic fractures independent of BMD. Our aim was to identify clinical factors that are associated with baseline lumbar spine TBS. In total, 29,407 women ≥50yr at the time of baseline hip and spine DXA were identified from a database containing all clinical results for the Province of Manitoba, Canada. Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Multiple linear regression and logistic regression (lowest vs highest tertile) was used to define the sensitivity of TBS to other risk factors associated with osteoporosis. Only a small component of the TBS measurement (7-11%) could be explained from BMD measurements. In multiple linear regression and logistic regression models, reduced lumbar spine TBS was associated with recent glucocorticoid use, prior major fracture, rheumatoid arthritis, chronic obstructive pulmonary disease, high alcohol intake, and higher body mass index. In contrast, recent osteoporosis therapy was associated with a significantly lower likelihood for reduced TBS. Similar findings were seen after adjustment for lumbar spine or femoral neck BMD. In conclusion, lumbar spine TBS is strongly associated with many of the risk factors that are predictive of osteoporotic fractures. Further work is needed to determine whether lumbar spine TBS can replace some of the clinical risk factors currently used in fracture risk assessment.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. CONCLUSIONS: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.

Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.

Suggestive linkage to chromosome 1q for bone mineral apparent density in Brazilian sister adolescents.

OBJECTIVE: To investigate linkage to chromosome 1q and 11q region for lumbar spine, femoral neck and total body BMD and volumetric BMD in Brazilian sister adolescents aged 10-20-year-old and 57 mothers. METHODS: We evaluated 161 sister pairs (n=329) aged 10-20 years old and 57 of their mothers in this study. Physical traits and lifestyle factors were collected as covariates for lumbar spine (LS), femoral neck (FN) and total body (TB) BMD and bone mineral apparent density (BMAD). We selected nine microsatellite markers in chromosome 1q region (spanning nearly 33cM) and eight in chromosome 11q region (spanning nearly 34cM) to perform linkage analysis. RESULTS: The highest LOD score values obtained from our data were in sister pairs LS BMAD analysis. Their values were: 1.32 (P<0.006), 2.61 (P<0.0002) and 2.44 (P<0.0004) in D1S218, D1S2640 and D1S2623 markers, respectively. No significant LOD score was found with LS and FN BMD/BMAD in chromosome 11q region. Only TB BMD showed significant linkage higher than 1.0 for chromosome 11q region in the markers D11S4191 and D11S937. DISCUSSION/CONCLUSIONS: Our results provided suggestive linkage for LS BMAD at D1S2640 marker in adolescent sister pairs and suggest a possible candidate gene (LHX4) related to adolescent LS BMAD in this region. These results reinforce chromosome 1q21-23 as a candidate region to harbor one or more bone formation/maintenance gene. In the other hand, it did not repeat for chromosome 11q12-13 in our population.

Evaluating bone marrow metastasis of neuroblastoma with iodine-123-MIBG scintigraphy and MRI.

Of 10 patients with neuroblastoma who had both 123I-MIBG scintigraphy and MRI at diagnosis, four presented with bone marrow metastasis that was diagnosed by both imaging modalities and confirmed by bone marrow biopsy and smears. This report focuses on the follow up of the four patients with bone marrow metastasis. MIBG scintigraphy and MRI were concordant in two patients, a case of normalization and a case of relapse in the seventh dorsal vertebra confirmed by surgical biopsy. The last two patients presented a normalized MIBG scan for marrow infiltration after chemotherapy but persistent abnormal MRI signal of several vertebrae, suggesting marrow infiltration, up to 27 mo after the end of chemotherapy in one case. In the second patient, MRI bone marrow aspect returned to normal 4 mo after the end of chemotherapy. Bone marrow biopsy remained negative in these two MIBG-negative patients. These cases suggest that in presence of complete normalization of the MIBG scan after chemotherapy, the persistence of a hypointense signal on bone marrow on T1WI does not necessarily indicate persistence of disease but may be due to delayed normalization. Therefore, attention must be paid to the delay of signal normalization on MRI (which can be as long as more than 2 yr after the end of chemotherapy) in order to avoid false-positive interpretation.

Early Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study

PURPOSE/OBJECTIVE(S): Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas, and 4-5% of all extranodal lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with stage I and II PBL. MATERIALS/METHODS: Between 1987 and 2008, 116 consecutive patients with PBL treated in 13 RCNinstitutions were included in this study. Inclusion criteriawere: age.17 yrs, PBLin stage I and II, andminimum6months follow-up. The median agewas 51 yrs (range: 17-93).Diagnosticwork-up included plain boneXray (74%of patients), scintigraphy (62%), CT-scan (65%),MRI (58%), PET (18%), and bone-marrow biopsy (84%).All patients had biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). The histopathological type was predominantly diffuse large B-cell lymphoma (78%) and follicular lymphoma (6%), according to theWHOclassification. One hundred patients had a high-grade, 7 intermediate and 9 low-gradeNHL. Ninety-three patients had anAnn-Arbor stage I, and 23 had a stage II. Seventy-seven patients underwent chemoradiotherapy (CXRT), 12 radiotherapy (RT) alone, 10 chemotherapy alone (CXT), 9 surgery followed by CXRT, 5 surgery followed by CXT, and 2 surgery followed by RT. One patient died before treatment.Median RT dosewas 40Gy (range: 4-60).Themedian number ofCXTcycleswas 6 (range, : 2-8).Median follow-upwas 41months (range: 6-242). RESULTS: Following treatment, the overall response rate was 91% (CR 74%, PR 17%). Local recurrence was observed in 12 (10%) patients, and systemic recurrence in 17 (15%) patients. Causes of death included disease progression in 16, unrelated disease in 6, CXT-related toxicity in 1, and secondary cancer in 2 patients. The 5-yr overall survival (OS), disease-free survival (DFS), lymphoma- specific survival (LSS), and local control (LC) were 76%, 69%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for survival were: age\50 years (p = 0.008), IPI score #1 (p = 0.009), complete response (p\0.001), CXT (p = 0.008), number of CXT cycles $6 (p = 0.007), and RT dose . 40 Gy (p = 0.005). In multivariate analysis age, RT dose, complete response, and absence of B symptoms were independent factors influencing the outcome. There were 3 patients developing grade 3 or more (CTCAE.V3.0) toxicities. CONCLUSIONS: This large multicenter study, confirms the relatively good prognosis of early stage PBL, treated with combined CXRT. Local control was excellent, and systemic failure occurred infrequently. A sufficient dose of RT (. 40 Gy) and complete CXT regime (. 6 cycles) were associated with a better outcome. Combined modality appears to be the treatment of choice.

Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.

BACKGROUND: The Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth. METHODOLOGY AND PRINCIPAL FINDINGS: To study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD), characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia. SIGNIFICANCE: Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) and oligoarthritis.

A 24-year-old woman who had sinus histiocytosis with massive lymphadenopathy (SHML, Rosai-Dorfman disease) also had oligoarthritis. We found only four previously reported cases of SHML with clinical joint disease. The clinical picture may suggest rheumatoid arthritis or a spondylarthropathy with peripheral joint involvement. SHML should be considered routinely among the differential diagnoses in young patients with arthritis and large lymphadenopathies. There is no consensus regarding the treatment. In our patient, conventional disease-modifying antirheumatic drugs followed by 3 months of adalimumab then 3 months of etanercept had no effect on the symptoms.

Determinants of methicillin-susceptible Staphylococcus aureus native bone and joint infection treatment failure: a retrospective cohort study.

BACKGROUND: Although methicillin-susceptible Staphylococcus aureus (MSSA) native bone and joint infection (BJI) constitutes the more frequent clinical entity of BJI, prognostic studies mostly focused on methicillin-resistant S. aureus prosthetic joint infection. We aimed to assess the determinants of native MSSA BJI outcomes. METHODS: Retrospective cohort study (2001-2011) of patients admitted in a reference hospital centre for native MSSA BJI. Treatment failure determinants were assessed using Kaplan-Meier curves and binary logistic regression. RESULTS: Sixty-six patients (42 males [63.6%]; median age 61.2 years; interquartile range [IQR] 45.9-71.9) presented an acute (n = 38; 57.6%) or chronic (n = 28; 42.4%) native MSSA arthritis (n = 15; 22.7%), osteomyelitis (n = 19; 28.8%) or spondylodiscitis (n = 32; 48.5%), considered as "difficult-to-treat" in 61 cases (92.4%). All received a prolonged (27.1 weeks; IQR, 16.9-36.1) combined antimicrobial therapy, after surgical management in 37 cases (56.1%). Sixteen treatment failures (24.2%) were observed during a median follow-up period of 63.3 weeks (IQR, 44.7-103.1), including 13 persisting infections, 1 relapse after treatment disruption, and 2 super-infections. Independent determinants of treatment failure were the existence of a sinus tract (odds ratio [OR], 5.300; 95% confidence interval [CI], 1.166-24.103) and a prolonged delay to infectious disease specialist referral (OR, 1.134; 95% CI 1.013-1.271). CONCLUSIONS: The important treatment failure rate pinpointed the difficulty of cure encountered in complicated native MSSA BJI. An early infectious disease specialist referral is essential, especially in debilitated patients or in presence of sinus tract.