Novel strategy: Identifying new markers for demyelination in diabetic distal symmetrical polyneuropathy.

Objective: To develop a novel strategy for identifying acquired demyelination in diabetic distal symmetrical polyneuropathy (DSP). Background: Motor nerve conduction velocity (CV) slowing in diabetic DSP exceeds expectations for pure axonal loss thus implicating superimposed acquired demyelination. Methods: After establishing demyelination confidence intervals by regression analysis of nerve conduction data from chronic inflammatory demyelinating polyneuropathy (CIDP), we prospectively studied CV slowing in 90 diabetic DSP patients with and without at least one motor nerve exhibiting CV slowing (groups A and B) into the demyelination range by American Academy of Neurology (AAN) criteria respectively and 95 amyotrophic lateral sclerosis (ALS) patients. Simultaneously, secretory phospholipase A2 (sPLA2) activity was assessed in both diabetic groups and 46 healthy controls. Results: No ALS patient exhibited CV slowing in more than two motor nerves based on AAN criteria or the confidence intervals. Group A demonstrated a significantly higher percentage of patients as compared to group B fulfilling the above criteria, with an additional criterion of at least one motor nerve exhibiting CV slowing in the demyelinating range and a corresponding F response in the demyelinating range by AAN criteria (70.3 % vs. 1.9 %; p < 0.0001). Urine sPLA2 activity was increased significantly in diabetic groups as compared to healthy controls (942.9 ± 978.0 vs. 591.6 ± 390.2 pmol/min/ml, p < 0.05), and in group A compared to Group B (1328.3 ± 1274.2 vs. 673.8 ± 576.9 pmol/min/ml, p < 0.01). More patients with elevated sPLA2 activity and more than 2 motor nerves with CV slowing in the AAN or the confidence intervals were identified in group A as compared to group B (35.1 % vs. 5.7 %, p < 0.001). Furthermore, 13.5 % of patients in diabetic DSP Group A, and no patients in diabetic DSP Group B, fulfilled an additional criterion of more than one motor nerve with CV slowing into the demyelinating range with its corresponding F response into the demyelinating range by AAN criteria. Conclusion: A combination of regression analysis of electrodiagnostic data and a urine biological marker of systemic inflammation identifies a subgroup of diabetic DSP with superimposed acquired demyelination that may respond favorably to immunomodulatory therapy.

Outcomes for Dostarlimab and Real-World Treatments in Post-platinum Patients With Advanced/Recurrent Endometrial Cancer: The GARNET Trial Versus a US Electronic Health Record-Based External Control Arm.

Background: Patients with advanced or recurrent endometrial cancer (EC) have limited treatment options following platinum-based chemotherapy and poor prognosis. The single-arm, Phase I GARNET trial (NCT02715284) previously reported dostarlimab efficacy in mismatch repair-deficient/microsatellite instability-high advanced or recurrent EC. Objectives: The objective of this study was to compare overall survival (OS) and describe time to treatment discontinuation (TTD) for dostarlimab (GARNET Cohort A1 safety population) with an equivalent real-world external control arm receiving non-anti-programmed death (PD)-1/PD-ligand (L)1/2 treatments (constructed using data from a nationwide electronic health record-derived de-identified database and applied GARNET eligibility criteria). Methods: Propensity scores constructed from prognostic factors, identified by literature review and clinical experts, were used for inverse probability of treatment weighting (IPTW). Kaplan-Meier curves were constructed and OS/TTD was estimated (Cox regression model was used to estimate the OS-adjusted hazard ratio). Results: Dostarlimab was associated with a 52% lower risk of death vs real-world treatments (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.66). IPTW-adjusted median OS for dostarlimab (N=143) was not estimable (95% CI, 19.4-not estimable) versus 13.1 months (95% CI, 8.3-15.9) for real-world treatments (N = 185). Median TTD was 11.7 months (95% CI, 6.0-38.7) for dostarlimab and 5.3 months (95% CI, 4.1-6.0) for the real-world cohort. Discussion: Consistent with previous analyses, patients treated with dostarlimab had significantly longer OS than patients in the US real-world cohort after adjusting for the lack of randomization using stabilized IPTW. Additionally, patients had a long TTD when treated with dostarlimab, suggesting a favorable tolerability profile. Conclusion: Patients with advanced or recurrent EC receiving dostarlimab in GARNET had significantly lower risk of death than those receiving real-world non-anti-PD-(L)1/2 treatments.

Outcomes of dostarlimab versus chemotherapy in post-platinum patients with recurrent/advanced endometrial cancer: data from the GARNET trial and the National Cancer Registration Service in England.

OBJECTIVES: Immune checkpoint inhibitors have emerged as novel treatment options in patients with endometrial cancer. In this study we aimed to compare the survival outcomes of patients with recurrent or advanced endometrial cancer. These patients had received dostarlimab after platinum-based chemotherapy in the single-arm, Phase I GARNET trial. We compared them with a matched indirect real-world cohort. METHODS: The real-world cohort was established using National Cancer Registration and Analysis Service data, with five treatment-specific real-world sub-cohorts identified. To compare clinical outcomes between the GARNET trial and real-world cohorts, we performed matching-adjusted indirect comparisons. We used prognostic variables to create matching scenarios, including scenario 1 that incorporated grade, histology, and platinum-based chemotherapy number; scenario 2 that considered histology and platinum-based chemotherapy number; and scenario 3 that included race/ethnicity, stage at diagnosis, histology, and prior surgery. Overall survival was defined as the time between the first dostarlimab dose or second-line real-world treatment and death. Adjusted hazard ratios for matching-adjusted indirect comparisons were estimated via weighted Cox proportional-hazards models. Progression-free survival, using time-to-next treatment as a proxy for real-world cohorts, was summarized descriptively. RESULTS: Distribution of baseline characteristics that were matched was similar between the GARNET cohort (n=153) and the real-world cohort (n=999). The most common International Federation of Gynecology and Obstetrics (FIGO) stage in both cohorts was stage III/IV (n=88; 57.5% and n=778; 77.9%, respectively), with endometroid histology predominating in the GARNET cohort (n=121; 79.1%) and non-endometrioid the predominant form in the real-world cohort (n=575; 57.6%). The median overall survival for dostarlimab was longer (range 27.1-40.5 months [95% confidence interval (CI) 6.4-non-estimable and 19.4-non-estimable]) both before and after matching for all scenarios compared with the real-world cohort (10.3 months). Across all matching scenarios, patients in the GARNET cohort had a decreased risk of death, with a HR for overall survival of 0.32 (p<0.0001) before matching, as compared with the overall real-world cohort and most treatment-specific real-world cohorts. For all three scenarios, progression-free survival rates at 12 and 18 months were higher for patients on dostarlimab compared with the real-world cohort (0.48 and 0.43 respectively before matching in the GARNET cohort vs 0.28 and 0.16 respectively in the real-world cohort; using time to next treatment as proxy). The effective sample size for scenario 1 was low when compared with the other scenarios (scenario 1: n=18; scenario 2: n=62; scenario 3: n=67). CONCLUSION: In this adjusted indirect dataset, patients with recurrent/advanced mismatch repair deficient/microsatellite instability-high endometrial cancer post-platinum-based chemotherapy who received dostarlimab in the GARNET trial had significantly improved overall survival compared with patients receiving current second-line treatment in England.

Electrodiagnostic profile of conduction slowing in amyotrophic lateral sclerosis.

Objective: Since motor nerve conduction slowing can occur due to loss of large axons, we investigate the conduction slowing profile in amyotrophic lateral sclerosis (ALS) and identify the limits beyond which the diagnosis of exclusive axonal loss is unlikely. Methods: First, using linear regression analysis, we established the range of motor conduction slowing in 76 chronic inflammatory demyelinating polyneuropathy (CIDP) patients. Demyelinating range confidence intervals were defined by assessing conduction velocity (CV), distal latency (DML), and F-wave latency (F) in relation to distal compound muscle action potential (CMAP) amplitude of median, ulnar, fibular, and tibial nerves. Results were subsequently validated in 38 additional CIDP patients. Then, the newly established demyelination confidence intervals were used to investigate the profile of conduction slowing in 95 ALS patients. Results: CV slowing, prolonged DML, and abnormal F were observed in 22.2%, 19.6%, and 47.1% of the studied nerves respectively in ALS patients. When slowing occurred, it affected more than one segment of the motor nerve, suggesting that CMAP amplitude dependent conduction slowing caused by an exclusive loss of large axons is the main mechanism of slowing. No ALS patient had more than 2 nerves with CV slowing in the confidence interval defined by the regression equations or the American Academy of Neurology (AAN) research criteria for CIDP diagnosis. Conclusions: The presence of more than two motor nerves with CV slowing in the demyelinating range defined by the regression analysis or AAN criteria in ALS patients suggests the contribution of acquired demyelination or other additional mechanisms exist in the electrodiagnostic profile of ALS.

Observational study to characterize treatment-resistant depression in Germany, France and the United Kingdom: analysis of real-world data collected through a survey of healthcare professionals.

OBJECTIVE: This study describes treatment patterns, productivity, healthcare resource utilization and previous episodes of depression for patients with treatment-resistant depression (TRD). METHODS: In this cross-sectional study, a quantitative survey was administered to 225 healthcare providers (HCPs) distributed evenly across Germany, France and the UK from July to August 2021. Each HCP was asked to answer based on medical records of five patients with TRD, defined as patients failing to respond to two or more treatments of adequate dose and duration in the same episode of major depressive disorder (MDD), which provided a sample size of 1125 patients. RESULTS: Of the 1125 patients with TRD, 73.2% had two or more previous episodes of MDD, 46.3% had a history of suicidal ideation and 24.8% had attempted suicide. Only 26.8% of patients were employed either full-time or part-time. During the most recent/current TRD episode, 45.5% of patients received five or more lines of treatment, and 46.0% remained on monotherapy. For multiple pharmacological treatments, too many distinct combinations were used to discern trends. Overall, 60.6% of patients had at least one mental health-related hospitalization in the last 12 months; 35.0% had two or more hospitalizations. Half of TRD patients saw a doctor five or more times per year for their depression. CONCLUSIONS: This study addresses the knowledge gap about treatment patterns and healthcare utilization in real-world practice for TRD patients in three European countries. It provides data that potentially could inform treatment guideline development and optimize patient-perceived benefits from the treatment of TRD.

A Retrospective Analysis of the Safety Profile of Intravenous Immunoglobulin in 1176 Patients Receiving Home Infusion Therapy.

OBJECTIVES: This analysis assessed the safety of intravenous immunoglobulin (IVIg) in the treatment of patients with neuroimmunological and immunological disorders in a home-based setting. METHODS: Adverse reactions (ARs) were assessed in a retrospective review of 1176 patients receiving 28,677 home-based IVIg infusions between 1996 and 2013. RESULTS: Of 1176 patients, 648 (55.1%) experienced IVIg-related ARs; 536 (45.6%) were mild, 78 (6.6%) moderate, and 34 (2.9%) severe. Thirty-seven (3.1%) patients were hospitalized because of ARs; of these, headache was most common (51.4%). Mean number of ARs per patient increased from 1.4 (low dose) to 3.6 (high dose). Incidence of ARs increased from 41% in the first 5-year moving average in 2003 to 65% in 2008. The number of ARs correlated with the number of infusions (ρ = 0.24; P < 0.001) and the average IVIg dose (ρ = 0.10; P < 0.001). CONCLUSIONS: Low- and high-dose IVIg were safe and well tolerated with a few serious ARs in patients with neuroimmunological and immunological disorders.

Rescue medication use as a patient-reported outcome in COPD: a systematic review and regression analysis.

BACKGROUND: Reducing rescue medication use is a guideline-defined goal of asthma treatment, however, little is known about the validity of rescue medicine use as a marker of symptoms in chronic obstructive pulmonary disease (COPD). To improve patient outcomes, greater insight is needed into the relationship between rescue medication use and alternative COPD outcomes. METHODS: A systematic search of electronic databases (Embase®, MEDLINE® and Cochrane CENTRAL) was conducted from database start to 26 May, 2015. Studies of bronchodilator therapy with a duration of ≥24 weeks were included if they reported either mean change from baseline (CFB) in rescue medication use in puffs/day or % rescue-free days (%RFD), and at least one other COPD endpoint. Correlation and meta-regression analyses were undertaken to test the association between rescue medication use and other COPD outcomes using weighted means (weights proportional to the sample size of the treatment group) and unweighted means (equal weight for each treatment group). Each association was assessed at 6 months and study end. RESULTS: Forty-six studies involving 46,531 patients provided mean data from 145 treatment groups for evaluation. Changes in both measures of rescue medication use were correlated with changes in trough forced expiratory volume in one second ([FEV1]; Pearson correlation coefficients |r| ≥ 0.63; p < 0.0001) and with St George's Respiratory Questionnaire (SGRQ) score (|r| ≥ 0.70; p < 0.0001) at study end. Change in rescue medication use in puffs/day during the study correlated with annualized rates of moderate/severe exacerbations at 6 months and study end (both r = 0.66; p ≤ 0.0028). CFB in puffs/day was not well correlated with Transition Dyspnoea Index (TDI), but %RFD did correlate with TDI score at 6 months and study end (both r = 0.69; p < 0.0001). The values for CFB in puffs/day corresponding to the proposed minimal clinically important differences for trough FEV1 and SGRQ score were -1.3 and -0.6 puffs/day, respectively. A -1.0 puffs/day CFB in rescue use corresponded to a change of 0.26 events/patient-year in moderate/severe exacerbations. CONCLUSION: This analysis provides clear evidence of associations at a patient group level between rescue medication use and other clinically important COPD outcomes.

Objective response rate is a possible surrogate endpoint for survival in patients with advanced, recurrent ovarian cancer.

OBJECTIVE: Evaluate literature to assess response rate as a surrogate endpoint of survival in ovarian cancer (OC). METHODS: Systematic review consistent with PRISMA criteria, identified randomized, controlled trials reporting overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in recurrent OC. MEDLINE® and Embase® searches (year 2000-March 23, 2015) were augmented by bibliographic screening. Proposed surrogate measures (independent variables) were ORR and disease control rate. True clinical outcomes (dependent variables) were median OS and PFS. Analyses were performed on unweighted and weighted data using correlation analysis, linear regression, and surrogate threshold effect (STE). Smaller STE indicates greater predictive precision with magnitude of STE dependent on variance of prediction. RESULTS: Thirty-nine studies were included for review, representing 9223 platinum-sensitive and resistant patients. Objective response rate (r=0.82; P<0.001) was a better predictor than disease control rate (r=0.58; P<0.001) and strongly correlated with PFS (r=0.85; P<0.0001). Weighted-regression analysis demonstrated that for each 10% increase in ORR, PFS increased by 1.20months and OS by 2.83months. Regression analysis of treatment effects (odds ratio of response, hazard ratio of survival) suggests that a 10% increase in odds ratio of ORR would result in 2.5% reduction in the hazard ratio of OS. Based on weighted data, STE indicated that an ORR of ≥1% is needed to achieve nonzero OS benefit. CONCLUSION: This systematic review supports ORR as a possible surrogate clinical trial endpoint for OS in recurrent OC with at least second-line therapy.

Analysis of the interleukin-1 receptor antagonist gene variable number tandem repeats in ischemic stroke.

BACKGROUND: There is an increasing interest in the role of inflammatory mechanisms contributing to the development of stroke. Recent studies have reported an association between allele 2 of a variable number tandem repeat of the interleukin-1 receptor antagonist (IL1RN) gene in Caucasian patients with ischemic stroke. The purpose of this investigation is to independently confirm these results in our study population. METHODS: We recruited and genotyped 516 Caucasian patients with ischemic stroke and 380 matched controls. Tests of association were performed to estimate odds ratio (OR) for the IL1RN gene variable number tandem repeat polymorphism with case-control status. Genotype frequencies of IL1RN gene were compared by case-control and symptom status using χ2 contingency tables and logistic regression models. RESULTS: No significant association was observed between any of the IL1RN gene genotypes and ischemic stroke. The unadjusted association model a, and the fully saturated model e, adjusted for age, gender, and stroke risk factors demonstrated no significant increase in risk associated with the IL1RN gene 2/2 genotype (a: OR, 1.11; 95% confidence interval [CI], .67-1.89; P=.615; and e: OR, .95; 95% CI, .46-1.94; P=.574). Analyses of genotypic and allelic frequencies of each Trial of Org 10172 in Acute Stroke Treatment subtype with control and pairwise comparison between stroke subtypes did not show any significant differences in their distributions, and all P values were greater than the significance level of .05. CONCLUSION: Our results do not confirm an association between the gene and ischemic stroke in Caucasian patients.

Effects of intrathecal morphine on transcranial electric motor-evoked potentials in adolescents undergoing posterior spinal fusion.

BACKGROUND: Intrathecal morphine (ITM) provides effective analgesia after posterior spinal fusion (PSF). Although most anesthetic drugs have well-characterized effects on evoked potentials, there is little data on the effects of ITM on transcranial electric motor-evoked potentials (tceMEPs). We performed this study to assess the effects of ITM on tceMEPs in the first 30 minutes after administration. We hypothesized that administration of ITM in doses currently used at our institution would not significantly affect mean tceMEP amplitudes and latencies of an ITM study group relative to control patients who did not receive the drug. METHODS: tceMEPs were recorded before ITM injection and 5, 10, 20, and 30 minutes after injection in 14 subjects ages 11 through 18 years undergoing PSF. These recordings were compared to an age-matched control group undergoing PSF in which ITM was not injected. The effects of ITM on tceMEP amplitude and latency were compared between the 2 groups. RESULTS: Fourteen subjects were enrolled in the ITM group and 16 served as controls. There were no significant differences in the baseline mean response amplitudes of the 2 groups for any of the 8 muscles studied. Mean response amplitudes over the 30-minute posttreatment period in the ITM group did not differ significantly from those of the control subjects. Average response amplitudes collapsed across all muscles for each subject were not significantly different during the baseline period (95% CI = -38% to 45%; P = 0.783), nor were they significantly different between the 2 groups during the posttreatment period (95% CI = -30% to 78%; P = 0.640). There also were no significant differences in the mean response latencies of the 2 groups in either the baseline or posttreatment periods. Average response latencies collapsed across all muscles for each subject were 4% larger for the ITM group than for controls during the baseline period (95% CI = -5% to 13%; P = 0.377), and 3% larger for the ITM group than for controls during the posttreatment period (95% CI = -4% to 12%; P = 0.359). CONCLUSIONS: Administration of ITM in doses currently used at our institution did not cause more than a 70% attenuation of mean tceMEP amplitudes or latency changes of an ITM study group relative to control subjects during the 30-minute period after injection. Further studies are required to determine if there are delayed effects after this initial time period.