IgG1 pan-neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality.

OBJECTIVES: We aimed to define the clinical and serological characteristics of pan-neurofascin antibody-positive patients. METHODS: We tested serum from patients with suspected immune-mediated neuropathies for antibodies directed against nodal/paranodal protein antigens using a live cell-based assay and solid-phase platform. The clinical and serological characteristics of antibody-positive and seronegative patients were then compared. Sera positive for pan-neurofascin were also tested against live myelinated human stem cell-derived sensory neurons for antibody binding. RESULTS: Eight patients with IgG1-subclass antibodies directed against both isoforms of the nodal/paranodal cell adhesion molecule neurofascin were identified. All developed rapidly progressive tetraplegia. Cranial nerve deficits (100% vs 26%), autonomic dysfunction (75% vs 13%) and respiratory involvement (88% vs 14%) were more common than in seronegative patients. Four patients died despite treatment with one or more modalities of standard immunotherapy (intravenous immunoglobulin, steroids and/or plasmapheresis), whereas the four patients who later went on to receive the B cell-depleting therapy rituximab then began to show progressive functional improvements within weeks, became seronegative and ultimately became functionally independent. CONCLUSIONS: IgG1 pan-neurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically classified patient group.

Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy.

Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.

Porphyric neuropathy.

Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta-aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality.

Burden of Treatment-Induced Peripheral Neuropathy in Patients with Multiple Myeloma in Sweden.

INTRODUCTION: Treatment-induced peripheral neuropathy (TIPN) is a complication of multiple myeloma (MM) treatment. OBJECTIVE: This real-world, retrospective study used electronic medical record (EMR) data from 3 Swedish clinics to assess the occurrence and economic burden of TIPN in patients with MM. METHODS: Eligible patients had an MM diagnosis in the Swedish Cancer Registry between 2006 and 2015 and initiated treatment during that period. Follow-up was until last EMR visit, death, or study end (April 2017). The current analyses included patients receiving bortezomib, lenalidomide, carfilzomib, or thalidomide at any treatment line. To discern healthcare resource utilization (HCRU) and costs associated with TIPN from other causes, patients with TIPN were matched with those without on baseline characteristics, treatment, and line of therapy. All analyses were descriptive. RESULTS: Overall, 457 patients were included; 102 (22%) experienced TIPN. Patients experiencing TIPN during first-line treatment mostly received bortezomib-based regimens (n = 48/57 [84%]); those with TIPN during second- and third/fourth-line treatment mostly received lenalidomide/thalidomide-based regimens (19/31 [61%], 8/14 [57%], respectively). Patients with TIPN had higher HCRU/costs than those without TIPN (mean differences in hospital outpatient visits: 5.2, p = 0.0031; total costs per patient-year: EUR 17,183, p = 0.0007). CONCLUSIONS: Effective MM treatments associated with a reduced incidence of TIPN could result in decreased healthcare expenditure.

History of lower-limb complications and risk of cancer death in people with type 2 diabetes.

BACKGROUND: Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes. METHODS: We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models. RESULTS: Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th-75th percentile, 4.7-5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3-6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21-1.94), p = 0.0004], PAD [1.32 (1.02-1.70), p = 0.03] or neuropathy (1.41 (1.11-1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers. CONCLUSIONS: PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.

Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in U.S. Adults : A Prospective Cohort Study.

BACKGROUND: Growing evidence indicates that peripheral neuropathy (PN) is common even in the absence of diabetes. However, the clinical sequelae of PN have not been quantified in the general population. OBJECTIVE: To assess the associations of PN with all-cause and cardiovascular mortality in the general adult population of the United States. DESIGN: Prospective cohort study. SETTING: NHANES (National Health and Nutrition Examination Survey), 1999 to 2004. PARTICIPANTS: 7116 adults aged 40 years or older who had standardized monofilament testing for PN. MEASUREMENTS: Cox regression to evaluate the associations of PN with all-cause and cardiovascular mortality after adjustment for demographic and cardiovascular risk factors, overall and stratified by diabetes status. RESULTS: The overall prevalence of PN (±SE) was 13.5% ± 0.5% (27.0% ± 1.4% in adults with diabetes and 11.6% ± 0.5% in adults without diabetes). During a median follow-up of 13 years, 2128 participants died, including 488 of cardiovascular causes. Incidence rates (per 1000 person-years) of all-cause mortality were 57.6 (95% CI, 48.4 to 68.7) in adults with diabetes and PN, 34.3 (CI, 30.3 to 38.8) in adults with PN but no diabetes, 27.1 (CI, 23.4 to 31.5) in adults with diabetes but no PN, and 13.0 (CI, 12.1 to 14.0) in adults with no diabetes and no PN. In adjusted models, PN was significantly associated with all-cause mortality (hazard ratio [HR], 1.49 [CI, 1.15 to 1.94]) and cardiovascular mortality (HR, 1.66 [CI, 1.07 to 2.57]) in participants with diabetes. In those without diabetes, PN was significantly associated with all-cause mortality (HR, 1.31 [CI, 1.15 to 1.50]), but the association between PN and cardiovascular mortality was not statistically significant after adjustment (HR, 1.27 [CI, 0.98 to 1.66]). LIMITATION: Prevalent cardiovascular disease was self-reported, and PN was defined by monofilament testing only. CONCLUSION: Peripheral neuropathy was common and was independently associated with mortality in the U.S. population, even in the absence of diabetes. These findings suggest that decreased sensation in the foot may be an underrecognized risk factor for death in the general population. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute of the National Institutes of Health.

Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial.

Importance: Oxaliplatin-based chemotherapy is associated with debilitating peripheral sensory neuropathy (PSN) for patients with stage III colon cancer. Objective: To assess disease-free survival (DFS) and long-lasting PSN in patients treated with 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. Design, Setting, and Participants: An open-label, multicenter, phase 3 randomized clinical trial of 1313 Asian patients with stage III colon cancer was conducted investigating the noninferiority of 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. From August 1, 2012, to June 30, 2014, participants were randomized to the 2 treatment groups. Data were analyzed from July 2017 to June 2018. Interventions: Patients were randomized to receive 3 or 6 months of adjuvant chemotherapy. The choice of chemotherapy regimen, with the drugs modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX), was at the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was DFS. Secondary end points included the evaluation of PSN for up to 3 years and overall survival. Results: Of the 1313 patients (651 were women and mean age was 66 [range, 28-85] years) enrolled and randomized, 22 were not treated because 10 were unable to begin treatment within 2 weeks of enrollment, 7 withdrew their consent, and 5 were not treated for various other reasons. Of 1291 patients treated (650 in the 3-month arm and 641 in the 6-month arm), 969 (75%) received the chemotherapy drug CAPOX. The hazard ratio (HR) for DFS of the 3-month arm compared with the 6-month arm was 0.95 (95% CI, 0.76-1.20). Hazard ratios were 1.07 (95% CI, 0.71-1.60) and 0.90 (95% CI, 0.68-1.20) for the drugs mFOLFOX6 and CAPOX, and 0.81 (95% CI, 0.53-1.24) and 1.07 (95% CI, 0.81-1.40) for patients with low-risk disease (TNM classification stages T1-3 and N1) and high-risk disease (stages T4 or N2), respectively. The rates of any grade of PSN lasting for 3 years in the 3-month vs 6-month treatment arms were 9.7% vs 24.3% (P < .001). Incidence of PSN lasting for 3 years was significantly lower for patients treated with CAPOX than for patients treated with mFOLFOX6 in both the 3-month (7.9% vs 15.7%; P = .04) and 6-month arms (21.0% vs 34.1%; P = .02). Conclusions and Relevance: The incidence of long-lasting PSN was significantly lower for 3 months than for 6 months of therapy, and significantly lower for treatment with the drug CAPOX than with mFOLFOX6. Since the shortened therapy duration did not compromise outcomes, a 3-month course of CAPOX may be the most appropriate treatment option, particularly for patients with low-risk disease. Trial Registration: UMIN Clinical Trials Registry: UMIN000008543.

Polymorphisms in the promotor region of the CRBN gene as a predictive factor for peripheral neuropathy in the course of thalidomide-based chemotherapy in multiple myeloma patients.

Thalidomide is commonly used in treatment of multiple myeloma (MM). This study aimed to analyse the influence of clinical and molecular factors - single nucleotide polymorphisms (SNPs) of the CRBN gene: rs6768972 and rs1672753, on the risk of adverse effects (AEs) of thalidomide-based chemotherapy in patients with MM. The study group included 82 patients receiving CTD (thalidomide, cyclophosphamide, dexamethasone) as first line treatment. The intensity of haematological and non-haematological AEs was assessed according to the Common Terminology Criteria for Adverse Events v4.03. Multivariate analysis showed that patients with the CRBN CC genotype (rs1672753) had more than a 14-fold higher risk of peripheral polyneuropathy compared to patients with other variants of the investigated SNP [odds ratio (OR) = 14·29]. Carriers of this genotype were burdened with significantly (about 17-fold) higher risk of diarrhoea during treatment (OR = 16·67). The presence of CRBN AA (rs6768972) or TT (rs1672753) genotypes was associated with about 333-fold and 250-fold lower risk of constipation in the course of therapy (OR = 0·003; OR = 0·004, respectively). Selected CRBN SNPs may be useful in assessing the probability of AEs in the form of peripheral polyneuropathy and gastrointestinal motility disorders associated with the use of thalidomide in patients with MM.

Noninfectious Neurologic Complications after Allogeneic Hematopoietic Stem Cell Transplantation.

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be associated with neurologic complications, data on noninfectious etiologies are scanty. Therefore, we analyzed the incidence, clinical characteristics, risk factors, and influence on outcomes of noninfectious neurologic complications (NCs) in 971 consecutive patients with hematologic malignancies undergoing allo-HSCT at our center between January 2000 and December 2016. We evaluated NCs affecting the central nervous system (CNS) and peripheral nervous system (PNS). The median duration of follow-up of survivors was 71 months (range, 11 to 213 months). A total of 467 patients received a matched sibling donor (MSD) transplant, 381 received umbilical cord blood (UCB), 74 received a haploidentical transplant, and 49 received a matched unrelated donor (MUD) transplant. One hundred forty-nine (15.3%) NCs were documented at a median of 78 days after transplantation (range, 5 days before to 3722 days after). The cumulative incidence risk of developing NC was 7.5% (95% confidence interval, 6% to 8.2%) at day +90 and 13% at 5 years. The 5-year cumulative incidence of NCs was 10.8% after MSD allo-HSCT and 15.3% after alternative donor (UCB, MUD, haploidentical) allo-HSCT (P = .004). There were 101 (68%) CNS complications, including encephalopathy, n = 46 (31%); headache, n = 20 (13%); stroke, n = 15 (10%); seizures, n = 9 (6%), posterior reversible encephalopathy syndrome, n = 6 (4%), and myelopathy, n = 5 (3%). PNS complications (32%) included neuropathies, n = 25 (17%), and myopathies and neuromuscular junction disorders, n = 23 (17%), with 17% of the total PNS complications being immune-related. In multivariable analysis, donor type other than MSD, age ≥40 years, development of acute graft-versus-host disease (GVHD) grade II-IV (hazard ratio [HR], 3.3; P < .00001), and extensive chronic GVHD (HR, 3.2; P = .0002) were independently associated with increased risk of NCs. The 5-year overall survival (OS) was 21% in patients who developed NCs and 41% for those who did not (P < .0001). This difference in OS was observed in patients developing CNS NCs, but not in those developing PNS complications. In conclusion, our study reveals NCs as a frequent and heterogeneous complication that, when affecting CNS, is associated with poor prognosis following allo-HSCT.

Dementia complicating type 2 diabetes and the influence of premature mortality: the Fremantle Diabetes Study.

AIMS: To investigate risk factors for, and the influence of premature mortality on, dementia complicating type 2 diabetes. METHODS: Participants with type 2 diabetes in the community-based observational Fremantle Diabetes Study Phase 1 (n = 1291, mean age 64.0 years) were followed from 1993 to 1996 to end-June 2012. Incident dementia was identified from validated health databases. Dementia risk was assessed using Cox proportional hazards modelling supplemented by competing risk regression modelling in the total cohort and sub-groups defined by age of diabetes onset as mid-life (< 65 years) or late-life (≥ 65 years). RESULTS: During mean ± SD follow-up of 12.7 ± 5.9 years, 717 participants (55.5%) died and 180 (13.9%) developed dementia. Overall, few risk factors predicted incident dementia and most predicted time to death. In mid-life diabetes, incident dementia was predicted by diabetes duration, cerebrovascular disease, schizophrenia, antipsychotic medication and the APOE ε4 allele. In late-life diabetes, risk factors were peripheral neuropathy, lack of exercise, lower fasting serum glucose, no antihypertensive therapy and the APOE ε4 allele. Competing risk analysis showed age to be a positive predictor compared with the inverse association in Cox models that suggested survivor bias in an older community-based cohort. CONCLUSIONS: Dementia in type 2 diabetes is multifactorial. An association with diabetes duration, independent of most possible confounders, suggests that one or more unmeasured processes specific to diabetes may be implicated in the pathogenesis. The risk factors for dementia were also associated with an increased risk of death. This suggests that recently reported improvements in mortality in type 2 diabetes may be accompanied by reductions in dementia incidence.

Efficacy of Nab-Paclitaxel Plus Gemcitabine and Prognostic Value of Peripheral Neuropathy in Patients with Metastatic Pancreatic Cancer.

Background/Aims: The combination of nab-paclitaxel and gemcitabine (nab-P/Gem) is widely used for treating metastatic pancreatic cancer (MPC). We aimed to evaluate the therapeutic outcomes and prognostic role of treatment-related peripheral neuropathy in patients with MPC treated with nab-P/Gem in clinical practice. Methods: MPC patients treated with nab-P/Gem as the first-line chemotherapy were included. All 88 Korean patients underwent at least two cycles of nab-P/Gem combination chemotherapy (125 and 1,000 mg/m2, respectively). Treatment-related adverse events were monitored through periodic follow-ups. Overall survival and progression-free survival were estimated by the Kaplan-Meier method, and the Cox proportional hazards regression linear model was applied to assess prognostic factors. To evaluate the prognostic value of treatment-related peripheral neuropathy, the landmark point analysis was used. Results: Patients underwent a mean of 6.7±4.2 cycles during 6.3±4.4 months. The median overall survival and progression-free survival rates were 14.2 months (95% confidence interval [CI], 11.8 to 20.3 months) and 8.4 months (95% CI, 7.1 to 13.2 months), respectively. The disease control rate was 84.1%; a partial response and stable disease were achieved in 30 (34.1%) and 44 (50.0%) patients, respectively. Treatment-related peripheral neuropathy developed in 52 patients (59.1%), and 13 (14.8%) and 16 (18.2%) patients experienced grades 2 and 3 neuropathy, respectively. In the landmark model, at 6 months, treatment-related peripheral neuropathy did not have a significant correlation with survival (p=0.089). Conclusions: Nab-P/Gem is a reasonable choice for treating MPC, as it shows a considerable disease control rate while the treatment-related peripheral neuropathy was tolerable. The prognostic role of treatment-related neuropathy was limited.

The role of bortezomib in newly diagnosed diffuse large B cell lymphoma: a meta-analysis.

Although the survival rate of diffuse large B cell lymphoma (DLBCL) has increased with years, there are still patients who do not achieve complete remission or who relapse, especially patients with activated B cell-like (ABC) DLBCL. Bortezomib, a proteasome inhibitor, has shown activity in diffuse large B cell lymphoma, especially in the subtype of ABC DLBCL. We conducted a meta-analysis to compare the efficacy and adverse events in bortezomib-containing regimens with standard R-CHOP regimen in treating DLBCL. Our results show that comparing to standard R-CHOP regimen, bortezomib-containing regimen could not prolong the survival in patients with ABC DLBCL. And patients who received bortezomib had a trend of higher risk with peripheral neuropathy, although there is no significant statistical difference.

Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial.

OBJECTIVES: The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. METHODS: In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. RESULTS: Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. CONCLUSIONS: MTX may be effective and safe for remission-maintenance in AAV. TRIAL REGISTRATION: clinicaltrials.gov NCT00751517.

Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT).

BACKGROUND: In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. PATIENTS AND METHODS: Patients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). RESULTS: In the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤ I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). CONCLUSIONS: nab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤ I in many patients (median ≈ 1 month) NCT00844649.

Bortezomib- and thalidomide-induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study.

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.

Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus.

AIMS: Identifying individuals with diabetes at high risk of cardiovascular disease (CVD) remains challenging. We aimed to establish whether peripheral neuropathy (PN) is associated with incident CVD events and to what extent information on PN may improve risk prediction among individuals with type 2 diabetes. METHODS: We obtained data for individuals with type 2 diabetes, and free of CVD, from a large primary care patient cohort. Incident CVD events were recorded during a 30-month follow-up period. Eligible individuals had complete ascertainment of cardiovascular risk factors and PN status at baseline. The association between PN and incident CVD events (non-fatal myocardial infarction, coronary revascularisation, congestive cardiac failure, transient ischaemic attack and stroke) was evaluated using Cox regression, adjusted for standard CVD risk factors. We assessed the predictive accuracy of models including conventional CVD risk factors with and without information on PN. RESULTS: Among 13 043 eligible individuals, we recorded 407 deaths from any cause and 399 non-fatal CVD events. After adjustment for age, sex, ethnicity, systolic blood pressure, cholesterol, body mass index, HbA1c, smoking status and use of statin or antihypertensive medication, PN was associated with incident CVD events (HR 1.33; 95% CI 1.02 to 1.75, p=0.04). The addition of information on PN to a model based on standard CVD risk factors resulted in modest improvements in discrimination for CVD risk prediction and reclassified 6.9% of individuals into different risk categories. CONCLUSIONS: PN is associated with increased risk for a first cardiovascular event among individuals with diabetes.

Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia.

Bortezomib frequently produces severe treatment-related peripheral neuropathy (PN) in Waldenström's macroglobulinemia (WM). Carfilzomib is a neuropathy-sparing proteasome inhibitor. We examined carfilzomib, rituximab, and dexamethasone (CaRD) in symptomatic WM patients naïve to bortezomib and rituximab. Protocol therapy consisted of intravenous carfilzomib, 20 mg/m2 (cycle 1) and 36 mg/m(2) (cycles 2-6), with intravenous dexamethasone, 20 mg, on days 1, 2, 8, and 9, and rituximab, 375 mg/m(2), on days 2 and 9 every 21 days. Maintenance therapy followed 8 weeks later with intravenous carfilzomib, 36 mg/m(2), and intravenous dexamethasone, 20 mg, on days 1 and 2, and rituximab, 375 mg/m(2), on day 2 every 8 weeks for 8 cycles. Overall response rate was 87.1% (1 complete response, 10 very good partial responses, 10 partial responses, and 6 minimal responses) and was not impacted by MYD88(L265P) or CXCR4(WHIM) mutation status. With a median follow-up of 15.4 months, 20 patients remain progression free. Grade ≥2 toxicities included asymptomatic hyperlipasemia (41.9%), reversible neutropenia (12.9%), and cardiomyopathy in 1 patient (3.2%) with multiple risk factors, and PN in 1 patient (3.2%) which was grade 2. Declines in serum IgA and IgG were common. CaRD offers a neuropathy-sparing approach for proteasome inhibitor-based therapy in WM. This trial is registered at www.clinicaltrials.gov as #NCT01470196.

Pain in end-stage renal disease: a frequent and neglected clinical problem.

Pain is a major health problem in end-stage renal disease (ESRD) affecting half of the dialysis patients; most of them experience a moderate to severe degree of pain. Nevertheless, the impact of chronic pain and its consequences are often underestimated. Sources of pain related to the uremic environment are renal bone disease (osteitis fibrosa cystica, amyloidosis, osteomalacia), osteoarthritis, calcific uremic arteriolopathy and peripheral neuropathy. Moreover, comorbid conditions such as ischemic peripheral artery disease, diabetic neuropathy, osteopenia/ osteoporosis (due to long-standing hypertension, diabetes, or old age) result in various kinds of pain. Also the primary kidney disease (e.g. autosomal dominant polycystic kidney disease (ADPKD)) as well as performance of hemodialysis or peritoneal dialysis are important causes of pain. Potential consequences of persistent pain are disturbed sleep, weakened memory/attention, altered mood (anxiety and depressive disorder), impotence, poorer physical state, less social activities and consideration of withdrawal from dialysis. Consequently the health-related-quality of life (HRQOL) is diminished, associated with a higher morbidity and mortality. In the therapy of pain the WHO three-step analgesic ladder adapted for ESRD, was shown to be effective in dialysis patients. Of fundamental importance are various forms of non-pharmacological strategies including electrotherapy. Recently the so-called high tone external muscle stimulation (HTEMS) was very effective in the management of neuropathic pain in ESRD patients.