The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression.

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

[Frequency of spinopelvic alterations in postoperative total hip arthroplasty patients and their association with functional outcomes]. / Frecuencia de alteraciones espinopélvicas en pacientes postoperados de artroplastía total de cadera y su asociación con resultados funcionales.

INTRODUCTION: the analysis of spinopelvic imbalance in patients undergoing total hip arthroplasty has gained significance in recent years, being recognized as a risk factor for instability. Few reports exist regarding the prevalence of spinopelvic alterations in Latin American literature. The aim of this study is to determine the frequency of spinopelvic imbalance in our patients and to associate them with functional outcomes. MATERIAL AND METHODS: 29 patients who underwent total hip arthroplasty using a lateral approach (32 arthroplasties) were included. All patients completed clinical outcome questionnaires preoperatively. Twelve months after surgery, they underwent anteroposterior pelvic and lateral pelvic X-rays, both standing and sitting, and clinical outcome questionnaires were completed. The radiographic parameters examined were: pelvic incidence, lumbar lordosis, sacral slope, anterior pelvic plane and pelvic femoral angle. Functional outcome was assessed with the Harris Hip Score and WOMAC scales. Patients were classified according to their spinopelvic alteration and statistical analysis was performed to identify significant differences between the groups and the correlation with functional outcomes. RESULTS: there was a high frequency of spinopelvic balance alterations (46.8%); 6.2% (n = 2/32) presented isolated spinal stiffness (group 1B), 37.5% (n = 12/29) spinal deformity without spinal stiffness (group 2A) and 3.1% (n = 1/29) spinal deformity associated with stiffness (group 2B). We found no improvement in HHS and WOMAC scores in the groups with spinal stiffness (1B and 2B) (p = 0.98 y 0.15). There is association between spinal stiffness (SS < 10°) and poor functional outcomes (p = 0.02). CONCLUSIONS: the frequency of spinopelvic balance alterations was high. While there was no observed rise in prosthetic dislocations, the existence of spinal stiffness, defined by a SS of less than 10°, was associated to poor outcomes on functional scales.

INTRODUCCIÓN: el análisis de las alteraciones del balance espinopélvico en pacientes sometidos a artroplastía total de cadera ha adquirido importancia en años recientes, siendo reconocido como un factor de riesgo para inestabilidad. Existen pocos reportes de la prevalencia de alteraciones espinopélvicas en literatura latinoamericana. El objetivo de esta investigación es determinar la frecuencia de alteraciones del balance espinopélvico en nuestros pacientes y su asociación con los resultados funcionales. MATERIAL Y MÉTODOS: se incluyeron 29 pacientes intervenidos de artroplastía total de cadera mediante abordaje lateral (32 artroplastías). Todos los pacientes completaron escalas funcionales preoperatoriamente. A los 12 meses de la intervención, se valoró el balance espinopélvico mediante radiografías anteroposterior de pelvis y laterales de pelvis tanto de pie como en sedestación y completaron escalas funcionales. Los parámetros radiográficos valorados fueron: incidencia pélvica, lordosis lumbar, inclinación del sacro (sacral slope), plano pélvico anterior y ángulo pélvico femoral. El estado funcional se valoró con las escalas Harris Hip Score (HHS) y WOMAC. Se clasificó a los pacientes de acuerdo a su alteración espinopélvica y se realizó análisis estadístico para identificar diferencias significativas entre los grupos y la asociación con resultados funcionales. RESULTADOS: encontramos una elevada frecuencia de alteraciones del balance espinopélvico (46.8%); 6.3% (n = 2/32) presentaron rigidez espinal aislada (grupo 1B), 37.5% (n = 12/29) deformidad espinal sin rigidez espinal (grupo 2A) y 3.1% (n = 1/29) deformidad espinal asociada a rigidez (grupo 2B). En los grupos con rigidez espinal (1B y 2B) no hubo mejoría significativa en HHS y WOMAC (p = 0.98 y 0.15). Encontramos asociación entre la presencia de rigidez espinal (SS < 10°) y resultados funcionales subóptimos con valor de p = 0.02. CONCLUSIONES: la frecuencia de alteraciones en el balance espinopélvico fue elevada. A pesar de no verse reflejado en un aumento en la incidencia de luxaciones protésicas, la presencia de rigidez espinal caracterizada por un SS menor a 10° se asoció con resultados subóptimos en las escalas funcionales.

Multiple coronary aneurysms and acute myocardial infarction in a female patient with rhupus: case report and literature review.

Coronary artery aneurysms (CAA) are an infrequent cause of coronary artery disease in both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), most occurring as a result of acute coronary syndromes (ACS). Until now, no cases of CAA have been described in a patient with rhupus syndrome (RhS). Differentiating whether CAA stem from primary vasculitis, atherosclerosis, or a combination of both continues to pose a significant challenge. We present the first described clinical case of a 43-year-old patient with RhS and multiple CAA identified by the presentation of an acute myocardial infarction. The presence of multiple cardiovascular risk factors and the absence of inflammatory findings, both in PET-CT and arterial biopsy, favored an atherosclerotic versus a vasculitic etiology of the CAA. At the time of the aneurysms diagnosis, the patient showed no signs of SLE activity and only moderate RA activity, which underscores the importance of screening for silent coronary aneurysms in these patients, even in subjects exhibiting little apparent activity from their underlying disease. This case also exemplifies the severe impact of atherosclerotic burdens on such patients, demanding vigilance and aggressiveness in its prevention, early diagnosis, and treatment. We hypothesize that RhS could engender an even greater risk of presenting CAA than either SLE or RA on their own, which therefore warrants more careful follow-up in these patients.

[Frecuency of diagnosis of bone lesions in cases of anterior glenohumeral dislocation]. / Frecuencia de diagnóstico de lesiones óseas en luxación glenohumeral anterior.

BACKGROUND: Shoulder dislocation is a common reason for admission in the emergency room. Its recurrence rate may be as high as 96% due to the associated bone lesions. The purpose of this study is to identify the underreporting of lesions comparing those identified in the initial X-ray with those identified in the post-reduction X-ray. MATERIAL AND METHODS: X-rays of 46 patients with suspected anterior glenohumeral dislocation were assessed for diagnostic purposes and to identify the initial bone lesions. After patients had undergone reduction, post-reduction serial bone X-rays (AP, Stryker, Westpoint) were taken and analyzed looking for bone lesions that were initially missed. RESULTS: Bone lesions were identified in 26.1% of the patients based on the initial AP X-rays. In 67.6% of the patients without a pre-reduction fracture a bone lesion was found in the post-reduction serial X-rays. CONCLUSIONS: The underreporting rate of bone lesions was 67.6% comparing the initial AP X-rays with the post-reduction serial bone X-rays.

ANTECEDENTES: Las luxaciones de hombro son motivo común de consulta en las salas de emergencia; presentan un alto índice de recurrencia (hasta 96%) a causa de las lesiones óseas asociadas. El objetivo de este estudio fue identificar un subregistro de lesiones identificadas en radiografía inicial comparada con radiografía postreducción. MATERIAL Y MÉTODOS: Se evaluaron las radiografías de 46 pacientes con sospecha de luxación glenohumeral anterior para diagnóstico e identificación de lesiones óseas iniciales; posteriormente, se realizó reducción y se analizó la serie ósea radiográfica postreducción (AP, Stryker y West Point) para evidenciar lesiones óseas subdiagnosticadas inicialmente. RESULTADOS: Se identificó lesión ósea en 26.1% de los individuos en la radiografía AP en un primer momento; de las personas que no mostraron fractura prerreducción, en 67.6% se encontró lesión ósea en las series radiográficas postreducción. CONCLUSIONES: Se encontró un subdiagnóstico de 67.6% de las lesiones evidentes en la serie ósea postreducción en comparación con la radiografía AP inicial.

Frecuencia de diagnóstico de lesiones óseas en luxación glenohumeral anterior / Frecuency of diagnosis of bone lesions in cases of anterior glenohumeral dislocation

Resumen: Antecedentes: Las luxaciones de hombro son motivo común de consulta en las salas de emergencia; presentan un alto índice de recurrencia (hasta 96%) a causa de las lesiones óseas asociadas. El objetivo de este estudio fue identificar un subregistro de lesiones identificadas en radiografía inicial comparada con radiografía postreducción. Material y métodos: Se evaluaron las radiografías de 46 pacientes con sospecha de luxación glenohumeral anterior para diagnóstico e identificación de lesiones óseas iniciales; posteriormente, se realizó reducción y se analizó la serie ósea radiográfica postreducción (AP, Stryker y West Point) para evidenciar lesiones óseas subdiagnosticadas inicialmente. Resultados: Se identificó lesión ósea en 26.1% de los individuos en la radiografía AP en un primer momento; de las personas que no mostraron fractura prerreducción, en 67.6% se encontró lesión ósea en las series radiográficas postreducción. Conclusiones: Se encontró un subdiagnóstico de 67.6% de las lesiones evidentes en la serie ósea postreducción en comparación con la radiografía AP inicial.

Abstract: Background: Shoulder dislocation is a common reason for admission in the emergency room. Its recurrence rate may be as high as 96% due to the associated bone lesions. The purpose of this study is to identify the underreporting of lesions comparing those identified in the initial X-ray with those identified in the post-reduction X-ray. Material and methods: X-rays of 46 patients with suspected anterior glenohumeral dislocation were assessed for diagnostic purposes and to identify the initial bone lesions. After patients had undergone reduction, post-reduction serial bone X-rays (AP, Stryker, Westpoint) were taken and analyzed looking for bone lesions that were initially missed. Results: Bone lesions were identified in 26.1% of the patients based on the initial AP X-rays. In 67.6% of the patients without a pre-reduction fracture a bone lesion was found in the post-reduction serial X-rays. Conclusions: The underreporting rate of bone lesions was 67.6% comparing the initial AP X-rays with the post-reduction serial bone X-rays.

Bence Jones proteinuria in smoldering multiple myeloma as a predictor marker of progression to symptomatic multiple myeloma.

The diagnosis of smoldering multiple myeloma (SMM) includes patients with a heterogeneous risk of progression to active multiple myeloma (MM): some patients will never progress, whereas others will have a high risk of progression within the first 2 years. Therefore, it is important to improve risk assessment at diagnosis. We conducted a retrospective study in a large cohort of SMM patients, in order to investigate the role of Bence Jones (BJ) proteinuria at diagnosis in the progression to active MM. We found that SMM patients presenting with BJ proteinuria had a significantly shorter median time to progression (TTP) to MM compared with patients without BJ proteinuria (22 vs 88 months, respectively; hazard ratio=2.3, 95% confidence interval=1.4-3.9, P=0.002). We also identified risk subgroups based on the amount of BJ proteinuria: ⩾500 mg/24 h, <500 mg/24 h and without it, with a significantly different median TTP (13, 37 and 88 months, P<0.001). Thus, BJ proteinuria at diagnosis is an independent variable of progression to MM that identifies a subgroup of high-risk SMM patients (51% risk of progression at 2 years) and ⩾500 mg of BJ proteinuria may allow, if validated in another series, to reclassify these patients to MM requiring therapy before the end-organ damage development.

Multiparameter flow cytometry for the identification of the Waldenström's clone in IgM-MGUS and Waldenström's Macroglobulinemia: new criteria for differential diagnosis and risk stratification.

Although multiparameter flow cytometry (MFC) has demonstrated clinical relevance in monoclonal gammopathy of undetermined significance (MGUS)/myeloma, immunophenotypic studies on the full spectrum of Waldenström's Macroglobulinemia (WM) remain scanty. Herein, a comprehensive MFC analysis on bone marrow samples from 244 newly diagnosed patients with an immunoglobulin M (IgM) monoclonal protein was performed, including 67 IgM-MGUS, 77 smoldering and 100 symptomatic WM. Our results show a progressive increase on the number and light-chain-isotype-positive B-cells from IgM-MGUS to smoldering and symptomatic WM (P<.001), with only 1% of IgM-MGUS patients showing >10% B cells or 100% light-chain-isotype-positive B-cells (P<.001). Complete light-chain restriction of the B-cell compartment was an independent prognostic factor for time-to progression in smoldering WM (median 26 months; HR: 19.8, P=0.001) and overall survival in symptomatic WM (median 44 months; HR: 2.6, P=0.004). The progressive accumulation of light-chain-isotype-positive B-cells accompanied the emergence of a characteristic Waldenstrom's phenotype (CD22(+dim) / CD25+ /CD27+ / IgM+) that differed from other B-NHL by negative expression of CD5, CD10, CD11c or CD103. In contrast to myeloma, light-chain-isotype-positive plasma cells in IgM monoclonal gammopathies show otherwise normal antigenic expression. Our results highlight the potential value of MFC immunophenotyping for the characterization of the Waldenström's clone, as well as for the differential diagnosis, risk of progression and survival in WM.

MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström's macroglobulinemia.

We evaluated the MYD88 L265P mutation in Waldenström's macroglobulinemia (WM) and B-cell lymphoproliferative disorders by specific polymerase chain reaction (PCR) (sensitivity ∼10(-3)). No mutation was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas and 9/48 (19%) non-germinal center (GC) diffuse large B-cell lymphomas (DLBCLs). The mutation was absent in all 28 GC-DLBCLs, 13 DLBCLs not subclassified, 35 hairy cell leukemias, 39 chronic lymphocytic leukemias (16 with M-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas and 1 IgM-related neuropathy. Among WM and IgM-MGUS, MYD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P=0.022), more lymphocytosis (24 vs 5%, P=0.006), higher lactate dehydrogenase level (371 vs 265 UI/L, P=0.002), atypical immunophenotype (CD23-CD27+ +FMC7+ +), less Immunoglobulin Heavy Chain Variable gene (IGHV) somatic hypermutation (57 vs 97%, P=0.012) and less IGHV3-23 gene selection (9 vs 27%, P=0.014). These small differences did not lead to different time to first therapy, response to treatment or progression-free or overall survival.

Biomechanical analysis of a new minimally invasive system for osteosynthesis of pubis symphysis disruption.

INTRODUCTION: We analysed the effectiveness of a new percutaneous osteosynthesis system for the treatment of pelvis fractures with rotational instability. METHODS: A pre-clinical cross-sectional experimental study wherein Tile type B1 injuries (open-book fractures) were produced in 10 specimens of fresh human cadavers, including the L4-5 vertebrae, pelvic ring, and proximal third of the femur, keeping intact the capsular and ligamentous structures, is presented in this paper. The physiological mobility of the intact pelvis in a standing position post-injury was compared to that following the performance of a minimally invasive osteosynthesis of the symphysis with two cannulated screws. A specially designed test rig capable of applying loads simulating different weights, coupled with a photogrammetry system, was employed to determine the 3D displacements and rotations in three test cases: intact, injured and fixed. RESULTS: After applying an axial load of 300 N, no differences were observed in the average displacement (mm) of the facet joints of the intact pubic symphysis in comparison to those treated with screws (p >0.7). A statistical difference was observed between the average displacements of the sacroiliac facet joints and pelvises with symphyseal fractures treated with screws after the application of a load (p <0.05). CONCLUSION: The symphyseal setting with two crossed screws appears to be an effective alternative to osteosynthesis in pelvic fractures with rotational instability.

Diseño y desarrollo de un modelo experimental para estudios biomecánicos de fracturas tipo B de Tile del anillo pélvico / Design and development of an experimental model for biomechanical studies of Tile type B1 fracture of the pervic ring

Objetivo: Diseñar un modelo estandarizado y reproducible para la realización de ensayos biomecánicos de fracturas tipo B1 de Tile del anillo pélvico. Metodología: Establecida en dos fases. Fase 1, determinación de requerimientos fundamentales del sistema. Fase 2, diseño, testado y elección de las piezas del modelo experimental. Se empleó una máquina universal de ensayos (MTS- 810), programas de diseño gráfico (Solid Edge Academic), fantomas, rail de carga deslizante y materiales industriales de Fabricación del Sistema de Fijación. Resultados: Se obtuvo un modelo constituido por dos sistemas de anclaje, superior e inferior, que permiten articular la pelvis a la máquina de ensayo tanto proximalmente, a través del sacro y L5, como a nivel distal con ambos fémures. El sistema permitió fijación adecuada de especímenes a máquina de ensayo, mantener la estática postural de bipedestación a la carga y reproductibilidad de lesión B1 de Tile. Conclusión: Es posible diseñar y fabricar un sistema estandarizado de fijación de pelvis humanas a una máquina de análisis de materiales para el estudio biomecánico de las fracturas tipo B1 de Tile del anillo pélvico (AU)

Objetive: The aim of the study is to design a standardized and reproducible procedure for biomechanical testing of Tile B1 fractures of the pelvic ring. Methodology: The methodology for this study was divided in two phases. In the first phase, the requirements to be covered by the system were determined, and in the second one experimental model pieces were designed and chosen. An Universal Testing Machine (MTS-810), Graphic Design Plans Program Software (Solid Edge Academic), Fantomas, Bearing, Sliding Rail and Manufacturing Material Fixing System were used. Results: A specific loading biomechanic system has been created, consisting on an upper and a lower anchor, which allows pelvis ring fix to the test machine both proximally through the sacrum and the last lumbar vertebra, and in terms of both femurs to the database of the testing machine. The procedure make a correct bone fixation, place the pelvis in a stand position, getting to align the upper and lower anterior iliac spines in the same plane and reproduce Tile B1 fracture. Conclusion: It is possible to design and manufacture a simple standard system for determining human pelvis to a testing machine for biomechanical studies of Tile type B1 pelvic ring fractures (AU)