The association of urinary interferon-gamma inducible protein-10 (IP10/CXCL10) levels with kidney allograft rejection

Background

Interferon-gamma inducible protein-10 (IP-10/CXCL10) is a chemokine involved in the alloimmune response against kidney allograft. We aimed to investigate the association of urinary CXCL10 protein levels with rejection in renal transplant patients.

Methods

A total of 273 urine samples from (biopsy-proven) rejection and non-rejection patients and controls were included in this study. CXCL10 levels were analyzed for association with rejection.

Results

The data showed statistically significant differences in the CXCL10 levels between rejection vs. non-rejection (p?<?0.001). Among the rejection groups, statistically significant differences for CXCL10 levels were found between ACR vs. NAD (p?<?0.001), ACR vs. BLR (p?=?0.019) and AVR vs. NAD (p?=?0.009). Receiver Operating Characteristic (ROC) curve analysis of CXCL10 showed an area under the curve (AUC) of 0.74 with 72% sensitivity and 71% specificity at 27.5 pg/ml between rejection and non-rejection group. Kaplan–Meier curve analysis among different levels of CXCL10 showed a better rejection-free graft survival in patients with <100 pg/ml when compared to >200 pg/ml (38?±?6 vs. 12?±?1.0 weeks; log-rank p?<?0.001) and 100–200 pg/ml (38?±?6 vs. 22?±?9 weeks; log-rank p?=?0.442) concentration.

Conclusion

The results indicate significantly increased levels of CXCL10 protein in the urine at the time of allograft rejection. This association of urinary CXCL10 protein levels with rejection could provide an additional tool for the non-invasive monitoring of allograft rejection.

     

IL-17 Contributes to the Development of Chronic Rejection in a Murine Heart Transplant Model

Background

Although interleukin-17 (IL-17) has been reported to participate in the pathogenesis of infectious, autoimmune and allergic disorders, the precise role in allograft rejection remains uncertain. This study illustrates that IL-17 contributes to the pathogenesis of chronic allograft rejection.

Result

Utilizing a murine heterotopic heart transplant model system, IL-17-deficient recipient mice had decreased allograft inflammatory cell recruitment, decreased IL-6, MCP-1, and KC production, and reduced graft coronary artery disease (GCAD). Intragraft gamma delta (γδ) T cells appear to be the predominant source of IL-17 production.

Conclusion

Therefore, IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.     

OR18 Identification of anti-endothelial non–HLA antibodies in kidney allograft rejection

Aim

The endothelium is the initial point of contact between the donor allograft and the transplant recipient’s immune system and therefore is a likely source for the identification of novel non-HLA Ab associated with rejection. The goal of this study was to identify novel anti-endothelial non-HLA Ab associated with kidney allograft rejection.

Infliximab for Treatment of Granulomatous Disease in Patients with Common Variable Immunodeficiency

Purpose

Eight to 22 % of common variable immunodeficiency (CVID) patients exhibit granulomas of the lungs, spleen, liver, and/or skin. Granulomas can be the most medically significant day-to-day problem for CVID patients. Currently, there are limited options for treatment of granulomas associated with CVID.

Methods

We treated five patients with CVID who exhibited significant clinical symptoms secondary to granulomas with infliximab. The patients were selected and treated based solely on clinical need and were not otherwise controlled or blinded to the therapy. After obtaining baseline studies (labs, spirometry, radiology) and excluding infection, they were treated with infliximab 5 mg/kg at week 0, 2, 6 and every 4 weeks thereafter.

Results

Post treatment improvements were seen in all 5 patients with significant clinical responses observed for both visceral and cutaneous granulomata. Four of the five patients were maintained on infliximab for 5 to 18 months (mean 9.4 months) without adverse reaction or increased susceptibility to infection. One patient completed 6 months of therapy with improvement of respiratory parameters but discontinued infliximab due to joint stiffness and rash that she attributed to the medication.

Conclusion

In our series, infliximab (5 mg/kg monthly) was an effective treatment for cutaneous and visceral granulomas in patients with CVID.     

IL-1 Receptor Accessory Protein-Ig/IL-1 Receptor Type II-Ig Heterodimer Inhibits IL-1 Response More Strongly than Other IL-1 Blocking Biopharmaceutical Agents

Introduction

Interleukin (IL)-1 is a key orchestrator of inflammation and IL-1 inhibitors are expected to be promising pharmaceutical agents for such pathologies. IL-1 is bound to the complex of two receptor components with much higher affinity than with either receptor component alone.

Materials and Methods

We examined the effect of a heterodimer of IL-1 receptor accessory protein (Acp)-immunoglobulin (Ig) and IL-1R type II (IL1R2)-Ig named AcP-Ig/IL1R2-Ig heterodimer, and compared its effects with other IL-1 inhibitors reported previously.

Results and Discussion

Our results demonstrated that the rat AcP-Ig/IL1R2-Ig heterodimer (IC50?=?1.95 pM) inhibited IL-1 response to a greater extent than IL1RA (IC50?=?1,935 pM), Acp-IL1R type I (IL1R1)-Ig homodimer (IC50?=?73.7 pM) and Acp-IL1R2-Ig homodimer (IC50?=?72.8 pM). Moreover, human AcP-Ig/IL1R2-Ig heterodimer (IC50?=?0.14 pM) inhibited it to a greater extent than Acp-IL1R1-Ig homodimer (IC50?=?4.48 pM) and strongly inhibited responses of both IL-1?? and IL-1??.

Conclusions

The AcP-Ig/IL1R2-Ig heterodimer, which is similar to the original extracellular structure of the Acp/IL1R1 complex, may inhibit the IL-1 response more vigorously than other IL-1 blocking biopharmaceutical agents.     

The Challenge of Treating Early-Stage Rheumatoid Arthritis: The Contribution of Mixed Treatment Comparison to Choosing Appropriate Biologic Agents

Background

Use of biologic drugs is approved for treatment in rheumatoid arthritis (RA), both in established disease and at the early stage of RA (ERA). Identification of ERA and an early therapeutic strategy would lead to greater clinical improvement. Only a few indirect comparisons of the efficacy of different biologic agents in established RA have been performed and, to date, no studies reporting direct comparisons have been performed in ERA.

Objective

The aim of this study was to compare, by use of a mixed treatment comparison (MTC), the efficacy profiles of biologic agents in ERA.

Methods

An extensive literature search was performed to identify results of randomized, controlled trials (RCTs) evaluating biologic agents at licensed doses to treat patients affected by ERA. The primary end points for the analysis were the American College of Rheumatology 20 % improvement (ACR20), ACR50, and ACR70 responses from baseline to various times of follow-up. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses. The MTC results are reported as the relative risk of a response for every single treatment coadministered with methotrexate, versus methotrexate plus placebo, which was used as a comparator in all RCTs.

Results

Ten scientific papers met the study inclusion criteria and were included in the analysis. Data on the use of infliximab, adalimumab, etanercept, abatacept, golimumab, and rituximab were included. No studies reported on the use of certolizumab pegol or tocilizumab in ERA. All biologic agents coadministered with methotrexate proved to be more efficacious than methotrexate plus placebo in inducing ACR20, ACR50, and ACR70 responses. The biologic agent characterized by the highest probability of inducing an ACR70 response was adalimumab (33.28 %). Etanercept was the biologic agent with the highest probability of inducing ACR20 and ACR50 responses, in comparison with all other biologic agents, with probability rates of 62.95 and 37.1 %, respectively.

Conclusion

In our analysis, adalimumab proved to be the biologic agent with the highest probability of inducing an ACR70 response in patients affected by ERA, while etanercept was the biologic agent with the highest probability of inducing ACR50 and ACR20 responses.

     

IDO-Competent-DCs Induced by IFN-γ Attenuate Acute Rejection in rat Liver Transplantation

Purpose

We established a stable rat model of liver transplantation using Sprague-Dawley rats and Wistar rats in order to investigate the role of the IDO gene in acute rejection after rat liver transplantation.

Methods

IDO gene expression and IDO enzyme activity were quantified in liver syngeneic grafts and allografts using microdialysis-HPLC. Liver allografts were evaluated for IDO expression by histopathology. We measured liver function-related biomarkers in liver allografts which were re-infused with untreated or IFN-γ-treated dendritic cells (DCs).

Results

We found a significant increase in IDO gene expression and IDO enzyme activity in liver allografts compared the sham and syngeneic graft groups. There was a significant correlation between the number of IDO-positive cells and severity of acute rejection. IDO gene expression and enzyme activity was upregulated in the IFN-γ-treated DC group within 7 days after transplantation compared to the untreated DC group and survival rates were significantly improved.

Conclusions

Our results suggested that IDO gene expression correlates with the severity of acute rejection and that IFN-γ-induced IDO-positive DCs may attenuate acute rejection and catalyze local tryptophan metabolism via IDO enzyme expression, leading to immune tolerance after liver transplantation.     

Histopathologic changes in anti-angiotensin II type 1 receptor antibody-positive kidney transplant recipients with acute rejection and no donor specific HLA antibodies

Objective

To determine the association of antibodies against angiotensin II type 1 receptor (AT1R Ab) and histopathologic changes seen in patients with kidney allograft rejection and negative donor specific HLA antibodies (DSA).

Efficacy, Pharmacokinetics, Safety, and Tolerability of Flebogamma® 10% DIF, a High-Purity Human Intravenous Immunoglobulin, in Primary Immunodeficiency

Background

Flebogamma® 10% DIF represents an evolution of intravenous immune globulin from the previous 5% product to be administered at higher rates and with smaller infusion volumes. Pathogen safety is enhanced by the combination of multiple methods with different mechanisms of action.

Objective

The objective of this study as to evaluate the efficacy, pharmacokinetics, and safety of Flebogamma® 10% DIF for immunoglobulin replacement therapy in primary immunodeficiency diseases (PIDD).

Methods

Flebogamma® 10% DIF was administered to 46 subjects with well-defined PIDD at a dose of 300–600 mg/kg every 21–28 days for 12 months.

Results

Serious bacterial infection rate was 0.025/subject/year. Half-life in serum of the administered IgG was approximately 35 days. No serious treatment-related adverse event (AE) occurred in any patient. Most of the potentially treatment-related AEs occurred during the infusion, accounting for 20% of the 601 infusions administered.

Conclusions

Flebogamma® 10% DIF is efficacious and safe, has adequate pharmacokinetic properties, and is well-tolerated for the treatment of PIDD.     

Plasma YKL-40 is elevated in patients with recurrent atrial fibrillation after catheter ablation

Aim

To study plasma YKL-40 in patients with atrial fibrillation (AF) treated with radiofrequency (RF) catheter ablation and to assess the predictive role of plasma YKL-40 and its changes after restoration of sinus rhythm (SR).

Methods

Forty-six patients (mean age 55 years, range 31–81) with paroxysmal/persistent AF were treated with RF catheter ablation; Holter monitoring for 14 days was performed before ablation and after 3 months. Recurrent symptomatic AF or atrial tachycardia >10 min was considered failure, and the patients were offered a second ablation session. YKL-40 was determined in plasma samples taken prior to ablation and at follow-up visits up to 12 months after ablation.

Results

After a maximum of two ablations, 19 patients (41%) had SR without recurrence of AF after 12 months. The patients with no recurrence of AF had significantly lower baseline plasma levels of YKL-40 prior to ablation compared to patients with recurrence of AF (31 vs. 62 μg/l, P = 0.029). Plasma YKL-40 was not an independent predictor of recurrence of AF after ablation. No significant changes in plasma YKL-40 levels were seen from baseline to follow-up at 12 months.

Conclusion

In patients with paroxysmal or persistent AF treated with catheter ablation, high plasma YKL-40 before ablation is associated with recurrence of AF.     

Clinical Experience With an L-Proline–Stabilized 10 % Intravenous Immunoglobulin (Privigen®): Real-Life Effectiveness and Tolerability

Purpose

This retrospective study evaluated the effectiveness and tolerability in clinical practice of an L-proline–stabilized 10 % intravenous immunoglobulin (IVIG; Privigen®) in patients with primary (PID) or secondary immunodeficiency (SID).

Methods

Patients from 6 centers in Europe and the US were treated with individually determined regimens of Privigen® for ≥3 months. Serum immunoglobulin G (IgG) trough levels, annualized rates of infection, hospitalization and antibiotics use, and the incidence of adverse events (AEs) were analyzed.

Results

Of 72 patients, three infants with severe combined immunodeficiency (SCID) were analyzed separately. The remaining 69 patients (52.2 % male; median age 38 years [range: 0.1–90.0]) with PID (82.6 %) or SID (17.4 %) received a mean (±standard deviation) Privigen® dose of 532?±?250 mg/kg/month resulting in trough serum IgG levels of 407–1,581 mg/dL (median: 954 mg/dL). Ten patients (14.5 %) experienced 11 serious bacterial infections over 22.0?±?15.0 months of treatment (0.087 events/patient/year, upper one-sided 99 % confidence interval: 0.170), the most common being pneumonia (11.6 %). The rates for any infection and hospitalization were 1.082 events/patient/year and 3.63 days/patient/year, respectively. Two patients with severe disease accounted for 303 of 460 hospital days. Across all 72 patients, 13 (18.1 %) patients experienced AEs, including 10 (13.9 %) patients with AEs at least possibly related to Privigen®, including headache (8.3 %), fever, and chills (2.8 % each). No related serious AEs were reported. One infant with SCID died due to severe viral infection.

Conclusions

Despite the heterogeneous population, effectiveness and tolerability of Privigen® in clinical practice closely matched those reported in clinical studies.     

Systemic Therapy for Colorectal Cancer: Patterns of Chemotherapy and Biologic Therapy Use in Nationally Representative US Claims Database

Background

Treatment strategies for colorectal cancer (CRC) are highly variable. The aim of this study is to examine the patterns of chemotherapy and biologic therapy use for CRC patients in a national medical claims database.

Methods

A retrospective and observational analysis was performed using the i3 Innovus claims database to identify healthcare services consumed by patients aged 18 years and older, diagnosed with CRC between 1 January 2005 and 30 June 2009 in commercial health plans.

Results

Of 9,876 subjects diagnosed with CRC, fluorouracil (23.5 %) and capecitabine (10.0 %) were the dominant first-line monotherapies, followed by bevacizumab (3.2 %) and oxaliplatin (2.9 %). The most common combination regimen at first line and first and second line was FOLFOX (fluorouracil, leucovorin, and oxaliplatin; more than 25 %). The combinations FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab (14.2 %) and FOLFOX plus bevacizumab (13.9 %) were significantly more frequent in third and successive lines of CRC therapy than other regimens (χ² = 191.2; P < 0.01). Additionally, the average annualized cost of CRC treatment for all patients was $US66,452, and the adjusted analysis demonstrated that patients receiving FOLFOX-A (FOLFOX + avastin) or FOLFIRI-A (FOLFIRI + avastin) had higher costs for CRC treatment.

Conclusions

With the exception of a sizeable portion of patients on monotherapy, the treatment patterns for CRC were largely consistent with National Comprehensive Cancer Network (NCCN) guidelines.     

Efficacy and Safety of IgPro20, a Subcutaneous Immunoglobulin,in Japanese Patients with Primary Immunodeficiency Diseases

Purpose

Intravenous (IVIG) and subcutaneous (SCIG) immunoglobulin infusions are widely used for the treatment of patients with primary immunodeficiency (PID) worldwide. This prospective, multicenter, open-label, single-arm Phase III study evaluated the efficacy, tolerability, and safety of IgPro20 (Hizentra®; L-proline–stabilized 20 % human SCIG) in adult and pediatric Japanese patients with PID.

Methods

Patients received three IVIG infusions at 3–4-week intervals followed by a dose-equivalent switch to weekly SCIG infusions. A 12-week wash-in/wash-out period was followed by a 12-week SCIG efficacy period. The primary efficacy endpoint was the comparison of total serum IgG trough levels during the IVIG and SCIG efficacy periods by calculating the geometric mean ratio (GMR).

Results

The GMR of IgG trough levels on SCIG versus IVIG was 1.09 (2-sided 90 % confidence interval: 1.06–1.13). No serious bacterial infections were reported. Eleven patients (52.4 %) had infectious episodes with an overall rate of 2.98 infections/patient/year; 7 patients (33.3 %) missed school/work/daycare due to infection (3.48 days/patient/year). Sixteen patients (76.2 %) were treated with antibiotics for an adverse event (AE; 47.6 %) or prophylaxis (23.8 %), resulting in 167.42 days/patient/year of antibiotic use. During SCIG treatment, 24 patients (96.0 %) had 269 AEs (0.461 AEs per/infusion) including local reactions as the most common AE (20 patients, 80.0 %). Local tolerability of IgPro20 was assessed as “very good” or “good” after 85.4 % of SCIG infusions. One patient (4.0 %) experienced a serious AE of moderate severity (bacterial infection) that was considered unrelated to study medication.

Conclusion

IgPro20 was effective and well tolerated in Japanese patients with PID.     

Immunoglobulin Dosage and Switch from Intravenous to Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Hypogammaglobulinemia: Decreasing Dosage Does Not Alter Serum IgG Levels

Objective

The impact of reducing immunoglobulin dosage while switching from intravenous to subcutaneous replacement therapy was evaluated.

Methods

Sixty-five patients with primary hypogammaglobulinemia on stable intravenous replacement therapy were included in a monocentric longitudinal trial. IgG trough levels were measured at baseline and during 1 year following the switch to the subcutaneous route.

Results

Mean IgG trough level after 12 months of subcutaneous therapy was increased by 5.4% (8.37–8.82 g/l, p?=?0.3), while immunoglobulin dosage had been reduced by 28.3% (151–108 mg/kg/week, p?<?0.0001). For the patients with the lowest serum IgG level upon intravenous infusions, serum IgG level rose by 37% (5.33–7.33 g/l, p?=?0.003), while mean immunoglobulin dosage was reduced by 36% (170–109 mg/kg/week, p?=?0.04).

Conclusion

The present study shows that sustained serum IgG levels can be achieved after switching towards subcutaneous replacement despite using reduced immunoglobulin doses.     

Prevalence of bifid mandibular canals in panoramic radiographs: a maxillofacial surgical scope

Purpose

The present study aims to estimate the prevalence of bifid mandibular canals in patients treated at the Dental Clinic of the Federal University of Paraná, Brazil.

Methods

The sample consisted of 3,024 panoramic radiographs from male (n = 1,155) and female (n = 1,869) patients (mean age 30 years). An experienced radiologist analyzed the panoramic radiographs according to the study of Langlais et al. (J Am Dental Assoc 110:923–926, 1985), which classifies bifid mandibular canals into four different types.

Results

Sixty patients (1.98 %) presented bifid mandibular canals. Specifically, 50 patients revealed bifid mandibular canals type I, while 10 patients revealed bifid mandibular canals type II. All the variations were unilateral. In addition, statistically significant results were not observed for gender distribution.

Conclusion

The present findings indicate a low prevalence of morphologic alterations of the mandibular canal in the studied population. However, the present outcome highlights the clinical relevance of investigating the radiologic morphology of the mandibular canal prior to surgical interventions.     

Glucocorticoid Receptor-Beta Up-Regulation and Steroid Resistance Induction by IL-17 and IL-23 Cytokine Stimulation in Peripheral Mononuclear Cells

Purpose

Most asthmatic patients have well controlled symptoms with regular treatment, but some require much higher doses of inhaled and oral corticosteroids, or in rare cases fail to respond; these patients may present Th-17 cell infiltration and associated cytokines (IL-17A and -F) in the airways, sputum and peripheral blood. Because glucocorticoid receptor-beta (GR-beta) is associated with corticosteroid resistance, we investigated whether Th-17 associated cytokines induce steroid insensitivity in PBMCs via GR-beta up-regulation.

Methods

GR-alpha, GR-beta, GILZ and IL-6 expression were analyzed in PBMCs stimulated with IL-2/IL-4, IL-17A/IL-17F and IL-23 cytokines by quantitative RT-PCR. Dexamethasone-inhibition of PHA-induced proliferation and Dexamethasone-induced apoptosis were determined by either ³H-thymidine or CFSE-labelled cells and by Annexin-V staining and flow cytometry.

Results

IL-17 and IL-23 cytokines significantly increased GR-beta expression. IL-2/IL-4 significantly decreased GR-alpha expression without affecting GR-beta. IL17, IL-23 and IL2?+?4 stimulations significantly hampered Dexamethasone-inhibition of proliferation (Dex EC₅₀ for: IL-17A?+?F?=?251 nM; IL-23?=?435 nM; IL2?+?4?=?950 nM; Medium?=?90 nM). IL2?+?4 and IL17A?+?F but not IL-23, significantly hampered Dexamethasone-induced apoptosis (1400 and 320 nM Dex, respectively). Dexamethasone’s trans-activation of GILZ and trans-repression of NF-kB-driven IL-6 expression were both inhibited by IL2?+?4; IL17?+?IL23 antagonized Dex trans-repression in PBMC from asthmatics.

Conclusions

GR-beta up-regulation by IL-17/IL-23 cytokines is associated with induced steroid insensitivity in PBMCs, observed as diminished Dexamethasone’s effects on cell proliferation, apoptosis and gene regulation. Steroid resistance induced by IL-2/IL-4 was associated with decreased GR-alpha expression. This study supports the possibility that Th-17 lymphocytes and associated cytokines play a role in the mechanism of steroid hypo-responsiveness in severe asthmatics.     

Nuclear factor-κB activation inhibitor attenuates ischemia reperfusion injury and inhibits Hmgb1 expression

Objective and design

To investigate the effects of nuclear factor-κB activation inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) on cardiac ischemia reperfusion injury in a transplantation model.

Methods

Hearts of C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipient. Some mice were administrated intraperitoneally with DHMEQ (8 mg/kg) 1 h before reperfusion. For inhibition of Hmgb1, mice were treated with glycyrrhizin at 250 mg/kg prior to reperfusion.

Results

DHMEQ decreased cardiomyocyte apoptosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by DHMEQ treatment. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with DHMEQ treatment (IR+DHMEQ: 58.6 ± 5.75 ml/min; IR: 25.9 ± 4.1 ml/min; P < 0.05). Furthermore, DHMEQ suppressed high mobility group protein (Hmgb1) expression. And the Caspase 3 activity, the number of TUNEL-positive cardiomyocytes and infiltrated neutrophil in cardiac allograft were markedly decreased with Hmgb1 inhibitor treatment.

Conclusions

Nuclear factor-κB activation inhibitor DHMEQ attenuates ischemia reperfusion injury in a cardiac transplantation model and it may be a suitable agent for the protection of the cardiac against ischemia reperfusion injury.     

Delta neutrophil index (DNI) as a novel diagnostic and prognostic marker of infection: a systematic review and meta-analysis

Objective

Delta neutrophil index (DNI) representing the number of immature granulocytes is an emerging marker used in diagnosis of infections and prediction of mortality in infected patients. The present study evaluated the diagnostic accuracy of DNI as a predictive and prognostic factor in infected patients.

Methods

We performed a PubMed search on January 1st, 2017 and identified studies that evaluated DNI as either a predictive or prognostic factor in infected patients. Studies with appropriate information to construct 2 × 2 contingency tables were extracted. We calculated pooled sensitivity and specificity. Meta-analysis of the multivariate logistic regression data set was performed to assess whether DNI functions as an independent factor.

Results

Overall, 12 articles fulfilled the inclusion criteria and a total of 499 cases and 9549 controls were examined. As a predictive factor of infection, DNI’s pooled sensitivity was 0.67 (95% CI 0.62–0.71, I ² = 86.0%) and pooled specificity was 0.94 (95% CI 0.94–0.95, I ² = 92.8%). Area under the receiver operating characteristics (ROC) curve was 0.89. As a prognostic factor for death in infected patients, DNI’s pooled sensitivity was 0.70 (95% CI 0.56–0.81, I ² = 0.0%) and pooled specificity was 0.78 (95% CI 0.73–0.83, I ² = 26.6%). Area under the ROC curve was 0.84. Meta-analysis of the multivariate logistic regression data set showed insignificant results.

Conclusions

DNI is a potentially useful diagnostic tool and predicts mortality among infected patients and should be more widely used in the clinical practice.

     

Trajectories of Perceived Emotional and Physical Distress in Patients with an Implantable Cardioverter Defibrillator

Background

Little is known about the course of emotional and physical distress in patients with an implantable cardioverter defibrillator (ICD).

Purpose

We examined (1) trajectories of emotional and physical distress in the first 18 months postimplantation and (2) predictors of these trajectories, including demographical, clinical, and personality factors.

Methods

Dutch patients with an ICD (N?=?645) completed measures on anxiety, depression, somatic symptoms, and perceived disability at the time of implantation, and 2, 12, and 18 months postimplantation. Measures on Type D personality (tendency to inhibit the expression of negative emotions) and anxiety sensitivity (tendency to fear anxiety-related sensations) were also completed at baseline.

Results

Latent class analysis (LatentGOLD) identified six to seven distinct trajectories, varying largely in overall levels of distress, and remaining relatively stable after a small initial decline. Multinomial regression showed that Type D personality and anxiety sensitivity were the most prominent predictors, particularly of trajectories that reflected higher distress levels. Cardiac resynchronization therapy and coronary artery disease also increased the risk for distress, whereas ICD indication and shocks did not.

Conclusions

The course of emotional and physical distress may be relatively stable after ICD implantation. In clinical practice, identification of patients with high risk of higher levels of emotional and physical distress may be warranted; as such, patients with high levels of anxiety sensitivity or a Type D personality should be identified and offered behavioral support.     

Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial

Background

Although the use of bortezomib alone and in combination with steroids has shown efficacy in AL amyloidosis, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT.

Methods

This was a single-center, prospective, randomized controlled trial comparing induction therapy consisting of two BD cycles followed by HDM/SCT (BD?+?HDM/SCT) with HDM/SCT alone in the treatment of patients with newly diagnosed AL amyloidosis. The hematological and organ responses of the patients were assessed every three months post HDM/SCT.

Results

Fifty-six patients newly diagnosed with renal (100%), cardiac (57.1%), liver (7.1%), or nervous system (8.9%) AL amyloidosis were enrolled in this study; 28 patients were assigned to each arm. Two patients died within 100 days of HDM/SCT (3.6% treatment-related mortality). The overall hematologic response rates in the BD?+?HDM/SCT arm and HDM/SCT arm at three, six and twelve months were 78.5% versus 50%, 82.1% versus 53.5% and 85.7% versus 53.5%, respectively. In the BD?+?HDM/SCT arm, 15 (53.5%) patients achieved a hematologic response after BD and before HDM/SCT. An intention-to-treat analysis revealed a higher rate of complete remission in the BD?+?HDM/SCT arm at both 12 and 24 months (67.9% and 70%, respectively) than with the HDM/SCT-only therapy (35.7% and 35%, respectively, P?=?0.03). After a median follow-up of 28 months, the survival rates at 24 months post-treatment start were 95.0% in the BD?+?HDM/SCT group and 69.4% in the HDM/SCT alone group (P?=?0.03).

Conclusions

Our preliminary data suggest that the outcome of treating AL amyloidosis with BD induction and HDM/SCT was superior to the outcome of the HDM/SCT treatment alone.

Trial registration

This trial has been registered at clinicaltrials.gov with the number NCT01998503.