Daratumumab as Single Agent in Relapsed/Refractory Myeloma Patients: A Retrospective Real-Life Survey.

BACKGROUND: The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who received at least three prior lines of therapy, including proteasome inhibitor and immunomodulatory agent. A retrospective multicentric study was designed to evaluate feasibility, tolerability, and efficacy of daratumumab in monotherapy in RRMM. METHODS: This study included 44 consecutive RRMM patients that underwent daratumumab monotherapy after a median number of four prior therapies (range 2-9). Patients were treated in seven Sicilian centers, as part of Sicilian Myeloma Network and three Calabrian centers outside of controlled clinical trials from August 2016 through July 2020. RESULTS: The regimen was well tolerated with few grade 3-4 haematological and rare non-haematological adverse events, such as pneumonia. Definitive discontinuation was due to disease progression in 25 (57%) patients. Since three patients did not complete at least one full cycle, a total of 41 patients was evaluated for response. Overall response rate was 37%, and the disease control rate (stable disease or better) was high (73%). The best achieved responses within 6 months were very good partial remission or better (27%), partial remission (10%), minimal response (14%) and stable disease (22%). After a median follow up of 7.8 months, median progression free survival (PFS) was 7.2 months and overall survival (OS) 7.8 months. Univariate analysis showed that patients with PR or better after 6 months of therapy had longer median PFS and OS (respectively 29.5 vs 3.6 months, p=0.0001 and 30.6 vs 3.9 months p=0.0001), confirmed by multivariate analysis. Furthermore, standard cytogenetic risk and biochemical relapse type had prolonged median PFS, but not OS (respectively unreached vs 2.6, p=0.03 and 23.9 vs 6.2, p=0.05) in both univariate and multivariate analysis. Additionally, univariate analysis showed that patients treated with carfilzomib-lenalidomide-dexamethasone prior to daratumumab had significantly shorter PFS compared to pomalidomide-dexamethasone (3.4 months vs 9.3 months, p=0.03), that multivariate analysis failed to confirm. CONCLUSIONS: Our findings indicate that daratumumab as single agent is safe and well-tolerated regimen in real-life, associated to prolonged PFS and OS in responding patients. No new safety signals were identified.

BCR-ABL1 Doubling-Times and Halving-Times May Predict CML Response to Tyrosine Kinase Inhibitors.

In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene's expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation.

Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib.

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.

Mesenchymal stem cells as adjuvant therapy for limb lengthening in achondroplasia.

Staged leg lengthening allows achondroplastic dwarfs to reach nearly normal height, but it takes long periods of external fixation and it can be burdened by delayed unions. Between 2009 and 2013, eight achondroplastic dwarfs showed delayed unions in the callus formation during femoral lengthening stages in our institute. We performed in-situ injections of bone marrow-derived stem cell concentrates. Patients underwent monthly clinical and radiographic assessment for determination of the healing rate. All eight patients showed an improvement in the regenerated bone, with an average healing index of 23.1 days/cm (range: 18.7-23.8 days/cm). The complete recovery of the delayed consolidation took on an average of 5.2 months (range: 2-10 months). The use of cellular therapy in these patients could represent an innovative application.

High BCR-ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib.

Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses.Experimental Design: We correlated BCR-ABL/GUSIS and BCR-ABL/ABL transcripts at diagnosis with the outcome-defined by the 2013 European LeukemiaNet recommendations-of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR-ABL/GUSIS and BCR-ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS).Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings," 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (P < 0.001), FFS (P < 0.001), and EFS (P < 0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates.Conclusions: Our data suggest that high BCR-ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189-98. ©2017 AACR.

A population-based study of chronic myeloid leukemia patients treated with imatinib in first line.

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

Monosegmental vs bisegmental pedicle fixation for the treatment of thoracolumbar spine fractures.

INTRODUCTION: The anatomy and biomechanics of the thoracolumbar spine place these segments at high risk of trauma injuries. Treatment options are either conservative or surgical, and there is a lack of consensus about the right indications. International scientific publications agree only on basic surgical principles: vertebral stability, deformity correction, protection of neurological structures and fast functional recovery. The most commonly used approach is the posterior approach, which allows the best management of most vertebral fracture patterns. The aim of this study was to compare clinical and radiological outcomes of monosegmental stabilisation with those of bisegmental stabilisation and fusion in the treatment of traumatic thoracolumbar spine fractures. MATERIALS AND METHODS: This retrospective clinical and radiological study evaluated 48 consecutive patients treated with monosegmental (Group M; n=14) or bisegmental (Group B; n=34) posterior pedicular instrumentation for thoracolumbar fractures. Fractures were classified by the new AO Spine TLIC system. Average follow-up was 30 months. Clinical outcomes in both groups were statistically compared. Radiological outcomes were evaluated in terms of vertebral anterior body height restoration and correction of the kyphotic deformity. RESULTS: Radiographical results showed no statistically significant difference between the two groups in vertebral body height restoration and correction of the kyphotic deformity. The mean postoperative somatic vertebral anterior body height in Group M was 25.8±4.52mm and in Group B it was 24.43±4.27mm. In Group M the mean postoperative kyphotic deformity was 11.10±5.71°, in Group B it was 9.09±4.93°. CONCLUSIONS: The results of this study confirm the validity of short and very short instrumentation for the treatment of well-selected type A and B vertebral fractures. In C type fractures correct surgical indication must be evaluated on an individual basis.

Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials.

Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008-2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43-86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score ≥7), and 140 (50.2%) had creatinine clearance ≤70 ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS ≥7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity <80% were independently associated with shorter PFS. Grade III or IV neutropenia, thrombocytopenia, and anaemia were observed in 25.9%, 15.4%, and 15.1% of patients, respectively. Twenty-four patients (8.6%) had severe infections. BR is also an effective and safe regimen for untreated CLL patients, outside of controlled clinical trials.

Sagittal balance in adolescent idiopathic scoliosis: radiographic study of spino-pelvic compensation after surgery.

STUDY DESIGN: Radiographic retrospective study of a consecutive series of 76 patients with adolescent idiopathic scoliosis (AIS) undergoing posterior only surgical correction and fusion. OBJECTIVE: To evaluate the sagittal profile changes in a population of adolescent idiopathic scoliosis after posterior only surgical correction. Although the relationship between pelvic indexes and sagittal profile is well known, little has been published about the sagittal profile changes after posterior surgery in adolescent idiopathic scoliosis. METHODS: Radiological data of 76 AIS patients were analyzed by an independent observer to compare pelvic indexes and spino-pelvic parameters before and at the last follow-up after surgical posterior correction. All patients underwent a posterior only surgical correction by using different anchor techniques (all screws or hybrid construct), but the same derotation correction maneuver (C-D technique). The collected data were analyzed, on AP and LL radiographic views of the entire spine in the upright position, from the same independent observer and using the same Impax software analysis. We collected for each patient on latero-lateral X-rays the following data: pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), thoracic kyphosis (TK), C7 plumb line (C7PL) and spino-sacral angle (SSA). All data were analyzed using a D'Agostino-Pearson normality test and the comparison between the groups was performed with a student's t test. RESULTS: The mean pelvic incidence (PI) of the cohort was 48.89° (± 11.24), with a mean Cobb angle for the main curve of 60.13° (± 13.6). The mean value of residual scoliosis after surgery was 28.18° (± 13.22) with an average improvement of the curve in the frontal plane of 53.2 %. The amount of curve correction of the primary scoliosis curve was statistically significant (p < 0.0001). In the evaluation of the whole group after surgery, we observed an increasing amount of PT (average delta value 2.38°) with a statistical significance (p = 0.0034). If we compare the mean ideal PT value (11.09°) with the pre- and post-operative mean true PT values, we found statistical significance only for the post-operative difference (p = 0.0014). In the general assessment, C7PL seems to remain stable after surgery, and in particular it remains negative. In Lenke 1 group, there was a mean PI value of 50.54° (± 11.45) which is higher than the one reported in the global assessment. Also in this subgroup, we observed a reduction in the mean SS values, with consequent increase in the PT values, as in the general assessment. The C7PL tends to move posteriorly after surgery and this difference is statistically significant. In Lenke 1 group we found a strong statistical significance between pre- and post-surgery data for the Cobb primary curve and for the C7PL, which continues to remain negative. The C7PL remains relatively stable only in the normokyphotic group, while it tends to move behind in the other three groups (Lenke 3, hyperkyphosis and hypokyphosis). CONCLUSIONS: In our series of 76 adolescent affected by AIS, we reported mean PI values of 48.9° with a mean pre-operative PT of 11.51°. After surgery we observed an increase in the PT mean value, about three degrees higher than the ideal value, meaning that there was some compensatory mechanism. Patients affected by AIS showed a slight posterior imbalance and the intervention of scoliosis correction seems to cause a slight further posterior imbalance, especially in Lenke 1 type curves and in patients with hypokyphosis. The clinical significance of this slight imbalance must be carefully evaluated. Further studies are necessary to better establish which could be the best surgical strategy to obtain an optimal spinal sagittal balance.

Subtrochanteric fracture non-unions with implant failure managed with the "Diamond" concept.

BACKGROUND: Subtrochanteric femoral non-unions in the setting of failed metalwork pose a challenging clinical problem. This study assessed the clinical outcome of patients treated according to the principles of the "Diamond" concept. METHODS: Between 2007 and 2011 all patients presented with a subtrochanteric atrophic aseptic non-union in the setting of metalwork failure (broken cephalomedullary reconstruction nail), and treated in a single tertiary referral unit were included to this study. The hypertrophic and the non-unions of pathologic fractures were excluded. The revision strategy was based on the "Diamond concept"; optimisation of the mechanical and the biological environment (implantation of growth factor (rhBMP-7), scaffold (RIA bone graft from contralateral femur) and concentrated mesenchymal stem cells (MSCs) harvested from the iliac crest). The minimum follow up was 26 months (16-48). RESULTS: Fourteen patients met the inclusion criteria. A specific sequence of metalwork failure was noted with initial breakage of the distal locking screws followed by nail breakage at the lag screw level. The intraoperative examination of the removed nails revealed no gross structural damage indicative of inappropriate drilling at the time of the initial intramedullary nailing. Varus mal-alignment was present in the majority of the cases, with an average of 5.2 degrees (0-11). The average time to distal locking screw failure was 4.4 months (2-8.5) and nail failure was 6.5 months (4-10). The time to union after the revision surgery was 6.8 months (5-12). Complications included two deaths in elderly patients (due to unrelated causes), one pulmonary embolism, one myocardial infarction, one below the knee deep vein thrombosis and one blade plate failure that required further revision with double plating and grafting. CONCLUSION: Varus mal-alignment must be avoided in the initial stabilisation of subtrochanteric fractures. Distal locking screw failure is predictive of future fracture non-union and nail breakage. In the absence of sepsis, a single stage procedure based on the "Diamond concept" that simultaneously optimizes the mechanical and biological environment is a successful method for managing complex subtrochanteric atrophic non-unions with failed metalwork.

Cement leakage: safety of minimally invasive surgical techniques in the treatment of multiple myeloma vertebral lesions.

PURPOSE: To evaluate and address the safety of vertebroplasty (VP) and kyphoplasty (KP) in terms of rate and type of cement leakage in the treatment of Multiple Myeloma (MM) vertebral fractures. METHODS: A total number of 37 treated vertebrae were evaluated post-operatively by using standard X-rays and CT scan looking for a cement leakage. VP was done using a monoportal approach in all cases (18 treated levels, group A), while KP was done using a monopedicular approach in 9 levels (group B1) and using a bipedicular approach in the remaining 10 levels (group B2). A computed tomography was used to establish the presence of any cement leakage and to determine its localization. RESULTS: Vertebral augmentation through VP and KP provides immediate pain relief and an improvement of the quality of life of patients affected by MM but it is gravated by high risk of cement leakage. Cement extravasation occurred in 27.7% of total VP procedures and in 21.05% of total KP procedures, but considering the whole number of treated levels, it was more common in multi-level VP and in bipedicular KP, in which a higher quantity of cement was employed. CONCLUSIONS: KP procedure in these patients is slightly less risky but we suggest doing it with a monopedicular approach. It's mandatory to use an high viscosity cement and we suggest not to use an amount of PMMA over 2 cc and a previous treatment with bone marrow transplant is related to a lower risk of cement leakage.

Plasma and drainage fluid levels of soluble receptor activator of nuclear factor-kB (sRANK), soluble receptor activator of nuclear factor-kB ligand (sRANKL) and osteoprotegerin (OPG) during proximal humerus fracture healing.

Fracture healing is an ordered process that restores the structural integrity of the bone. Soluble receptor activator of nuclear factor-kB (sRANK), its ligand (sRANKL) and osteoprotegerin (OPG) are involved in bone remodelling, thus they may play a role in fracture repair. OPG, soluble RANK and RANKL levels were measured in plasma and in drainage fluid, collected from pre-surgery phase to healing in ten patients of both genders (age range 26-65 years) with proximal humerus fracture needing osteosynthesis. All patients showed fracture healing. No significant modifications in the concentrations of sRANKL and OPG were observed, while sRANK showed a significant increase in drainage fluid 24 hours post-surgery compared with intra-surgery time. OPG levels were higher in plasma and drainage fluid than sRANK and sRANKL at each time point. Since there are no published data about sRANK involvement in fracture healing, our study represents the first preliminary indication about a local increase of this marker concentration immediately after surgery.

Ectodermal dysplasia treated with one-step surgical rehabilitation: a case report.

Ectodermal dysplasia (ED) comprises a large heterogeneous group of inherited disorders that are characterized by primary defects in the skin, hair, nails, eccrine glands and teeth. The most characteristic findings are the reduced number of teeth. All rehabilitative programmes involve proper evaluation of skeletal relationships. Prosthetic-implantological treatment at the end of bony growth can be used. In this article a case of ED treated with Le Fort I for maxillary advancement, femur homografts, implants' insertion and immediate loading is described. In December 2007, a 38-year-old female was referred to the Maxillofacial Department of Galeazzi Hospital (Milan, Italy) who had a diagnosis of ED. Twelve implants were inserted in one-step surgical procedure. No implant was lost and all are stable. The occlusion is stable after 15 months of follow-up. The results indicate that the one-step oral rehabilitation can be performed in adults who are affected by ED. Also, this significantly reduces the time of oral and facial rehabilitation.

One-step oral rehabilitation by means of implants' insertion, Le Fort I, grafts, and immediate loading.

PURPOSE: In the last decade, several investigators have reported that autologous and homologous fresh frozen bones are effective materials to restore alveolar ridges before insertion of dental implants. Recently, we have used femur homograft derived from living donors. Here, we reported a 1-step oral rehabilitation of the severely resorbed maxilla by means of implants' insertion, Le Fort I osteotomy for maxillary advancement, grafts, and immediate loading. METHODS: Patients were treated with 1-step oral rehabilitation. Age, sex, implant length and diameter, tooth site, loading, and grafts were the investigated variables. Implant failure and peri-implant bone resorption were considered as predictors of clinical outcome. Kaplan-Meier algorithm and Cox regression were then performed to detect those variables statistically associated with the clinical outcome. RESULTS: Eighty-four implants were inserted in 11 patients. Implants were inserted to replace 22 incisors, 21 cuspids, 20 premolars, and 21 molars. The mean follow-up was 17 months. Two of 84 implants were lost (ie, survival rate = 97.6%), and no differences were detected among the studied variables. By using the 82 fixtures processed with Kaplan-Meier and Cox regression, only implant site has an impact on clinical outcome, and molars have a worse outcome than incisors. CONCLUSION: One-step oral rehabilitation can be used in selected patients. It significantly shortened the time of rehabilitation without adverse effects. Femur homograft derived from living donors is a valuable material for grafting jaw: it is safer, cheap, and available in programmed amounts and avoids a second operation field.

Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain.

BACKGROUND: The efficacy and safety of the association of celecoxib [a selective cyclooxygenase-2 (COX-2) inhibitor] and pregabalin (commonly used to control neuropathic pain), compared with monotherapy of each, were evaluated for the treatment of chronic low-back pain, a condition known to be due to neuropathic as well as nociceptive pain mechanisms. MATERIALS AND METHODS: In this prospective randomized trial, 36 patients received three consecutive 4-week treatment regimes, randomly assigned: celecoxib plus placebo, pregabalin plus placebo, and celecoxib plus pregabalin. All patients were assessed by using a visual analogue scale (VAS, 0-100 mm) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale by an investigator blinded to the administered pharmacological treatment. RESULTS: Celecoxib and pregabalin were effective in reducing low-back pain when patients were pooled according to LANSS score. The association of celecoxib and pregabalin was more effective than either monotherapy in a mixed population of patients with chronic low-back pain and when data were pooled according to LANSS score. Adverse effects of drug association and monotherapies were similar, with reduced drug consumption in the combined therapy. CONCLUSIONS: Combination of celecoxib and pregabalin is more effective than monotherapy for chronic low-back pain, with similar adverse effects.

Combined Diagnostic Tool for joint prosthesis infections.

While diagnosing infection of a joint prosthesis often requires a multi-modal approach, evaluation of combined multiple diagnostics is still a rather subjective process. Based on the known sensitivity and specificity of commonly performed tests for joint prosthesis infection, we developed the Combined Diagnostic Tool, a software program that automatically allows the Combined Tests Index (CTI) to be calculated. The CTI indicates, in a given subject, the relative probability of a combined series of positive tests being true compared to negative tests. CTI values above 1 indicate a progressively higher chance of a prosthesis being infected and vice versa. Double-blind, prospective evaluation of CTI, compared to intra-operative cultural and histological findings, was performed in a consecutive cohort of 36 patients. 21 patients had positive intra-operative findings for infection. All of them had a pre-operative CTI >1 (range: 8.8 to 5552.6; mean: 711 +/- 1298). 15 patients had negative intra-operative results. All had a CTI <1 (range: 0.00013 - 0.297; mean 0.074 +/- 0.099). The difference in CTI between the two groups was statistically significant (p = 0.04). Our results show that the Combined Tests Index may be a useful indicator for differential diagnosis of prosthetic infection.

Porcine models in spinal research: calibration and comparative finite element analysis of various configurations during flexion-extension.

This study was conducted to develop and calibrate a detailed 3-dimensional finite element model of the porcine lumbar spine and to compare this model with various configurations in flexion and extension. Computed tomography scans obtained from the L4-L5 lumbar segment of a Landrace x Large White pig were used to generate a solid volume. The various passive components were characterized by using a step-by-step calibration procedure in which the material properties of the anatomic structures were modified to match the corresponding in vitro data set-points retrieved from the literature. The range of motion of the totally assembled intact model was assessed under a 10-Nm flexion-extension moment and compared with data from a bilateral complete and hemifacetectomy configuration. In addition, the results from our porcine model were compared with published data regarding range of motion in a human finite element model in order to predict the configuration of the porcine model that most closely represented the human spine. Both the intact and hemifacetectomy configurations of the porcine model were comparable to the human spine. However, qualitative analysis of the instantaneous axis of rotation revealed a dissimilarity between the intact porcine model and human spine behavior, indicating the hemifacetectomy configuration of the porcine model as the most appropriate for spinal instrumentation studies. The present 3-dimensional finite element porcine model offers an additional tool to improve understanding of the biomechanics of the porcine spine and to decrease the expense of spinal research.

Biomechanics of the lumbar spine after dynamic stabilization.

Target of the study was to predict the biomechanics of the instrumented and adjacent levels due to the insertion of the DIAM spinal stabilization system (Medtronic Ltd). For this purpose, a 3-dimensional finite element model of the intact L3/S1 segment was developed and subjected to different loading conditions (flexion, extension, lateral bending, axial rotation). The model was then instrumented at the L4/L5 level and the same loading conditions were reapplied. Within the assumptions of our model, the simulation results suggested that the implant caused a reduction in range of motion of the instrumented level by 17% in flexion and by 43% in extension, whereas at the adjacent levels, no significant changes were predicted. Numerical results in terms of intradiscal pressure, relative to the intact condition, predicted that the intervertebral disc at the instrumented level was unloaded by 27% in flexion, by 51% in extension, and by 6% in axial rotation, while no variations in pressure were caused by the device in lateral bending. At the adjacent levels, a change of relative intradiscal pressure was predicted in extension, both at the L3/L4 level, which resulted unloaded by 26% and at the L5/S1 level, unloaded by 8%. Furthermore, a reduction in terms of principal compressive stress in the annulus fibrosus of the L4/L5 instrumented level was predicted, as compared with the intact condition. These numerical predictions have to be regarded as a theoretical representation of the behavior of the spine, because any finite element model represents only a simplification of the real structure.