Frontal-striatal tract integrity and depression in older adults with and without multiple sclerosis.

OBJECTIVE: Lower white matter integrity of frontal-subcortical circuitry has been associated with late-life depression in normally aging older adults and with the presence of multiple sclerosis (MS). Frontal-striatal white matter tracts involved in executive, cognitive, emotion, and motor function may underlie depression in older adults with MS. The present study examined the association between depression score and frontal-striatal white matter integrity in older adults with MS and controls. METHODS: Older adults with MS (OAMS) (n = 67, mean age = 64.55 ± 3.89) and controls (n = 74, mean age = 69.04 ± 6.32) underwent brain MRI, cognitive assessment, psychological, and motoric testing. Depression was assessed through the 30-item Geriatric Depression Scale. Fractional anisotropy (FA) was extracted from two bilateral tracts: dorsolateral prefrontal cortex to putamen nucleus (DLPFC-pn) and dorsolateral prefrontal cortex to caudate nucleus (DLPFC-cn). RESULTS: OAMS reported significantly worse (i.e., higher) depression symptoms (ß = .357, p < .001) compared to healthy controls. Adjusted moderation analyses revealed, via group by FA interactions, significantly stronger associations between FA of the left DLPFC-pn tract and total depression (B = - 61.70, p = .011) among OAMS compared to controls. Conditional effects revealed that lower FA of the left DLPFC-pn was significantly associated with worse (i.e., higher) depression symptoms (b = - 38.0, p = .028) only among OAMS. The other three tracts were not significant in moderation models. CONCLUSIONS: We provided first evidence that lower white matter integrity of the left DLPFC-pn tract was related to worse depression in older adults with MS.

Caudate volume and symptoms of apathy in older adults with multiple sclerosis.

BACKGROUND: Apathy is common in multiple sclerosis (MS) and neurological disease, but its presence and underlying brain mechanisms in older adults with MS (OAMS) have not been evaluated. OBJECTIVE: Examine apathy and its association with caudate nuclei volume in OAMS and controls. We hypothesized that compared to controls, OAMS would demonstrate: a) greater apathy; b) stronger associations between apathy and caudate nuclei volumes. METHODS: OAMS (n = 67, mean age = 64.55 ± 3.89) and controls (n = 74, mean age = 69.04 ± 6.32) underwent brain MRI, cognitive assessment, psychological, and motoric testing. Apathy was assessed through the apathy subscale of the 30-item Geriatric Depression Scale. RESULTS: OAMS reported greater apathy compared to controls (ß = 0.281, p = 0.004). Adjusted moderation analyses revealed a significantly stronger association between caudate volume and apathy (left: B = -1.156, p = 0.039, right: B = -1.163, p = 0.040) among OAMS compared to controls. Conditional effects revealed that in adjusted models, lower volume of both the left (b = -0.882, p = 0.037) and right (b = -0.891, p = 0.038) caudate nuclei was significantly associated with greater apathy only among OAMS. CONCLUSION: Caudate nuclei, which are susceptible to adverse MS effects and implicated in mediating cognitive and motor function, may influence the presence and severity of apathy in OAMS.

Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma.

BACKGROUND: For patients with multiple myeloma (MM), each additional line of therapy (LOT) is associated with lower response rates, shorter treatment duration and treatment-free intervals, and increased rates of toxicities and comorbidities. Here, we examine frontline treatment patterns, and attrition rates by LOT among newly diagnosed MM (NDMM) patients in the United States who were eligible or ineligible for autologous stem cell transplant (ASCT). METHODS: Data were identified from three US patient-level databases collectively covering the period January 2000 to September 2018. Patients had an index diagnosis of MM on or after January 1, 2007, medical and prescription insurance coverage at diagnosis, a 1-year look-back period prior to the index diagnosis, no prior malignancies in the 1-year period before index diagnosis, and had received ≥1 LOT. RESULTS: Among patients who did not receive ASCT (non-transplant; n = 22,062), 12,557 (57%) received only 1 LOT and 9505 (43%) received > 1 LOT. Patients receiving only 1 LOT were significantly older, had higher mean Charlson Comorbidity Index (CCI) scores, and higher incidences of comorbidities. Among the 2763 patients receiving ASCT, 2184 received > 1 LOT, and 579 (21%) received only 1 LOT (ie, ASCT was the last treatment). 1682 (61%) patients received induction therapy as frontline treatment, of whom 187 (11%) also received consolidation therapy. The latter group was younger than those who received only induction therapy, had lower mean CCI scores, and comparable or lower incidences of selected comorbidities. The most common frontline therapy for non-transplant and transplant-eligible patients was bortezomib/dexamethasone and bortezomib/lenalidomide/dexamethasone, respectively. Attrition rates across all LOTs were high for non-transplant patients (range, 43-57%) and transplant patients (range, 21-37%). Treatment duration decreased by LOT for non-transplant patients and was consistent across LOTs for transplant patients. CONCLUSIONS: In this analysis, a substantial proportion of patients with NDMM who received frontline therapy did not appear to receive a subsequent LOT. These high attrition rates underscore the need to use the most optimal treatment regimens upfront rather than reserving them for later LOTs in which the clinical benefit may decrease.

Targeting Cognitive Control Deficits With Neuroplasticity-Based Computerized Cognitive Remediation in Patients With Geriatric Major Depression: A Randomized, Double-Blind, Controlled Trial.

Late life major depression (LLD) is often accompanied by cognitive deficits. When patients have specific deficits in cognitive control functions (CCD), they are not only distressing and debilitating, they often predict poor clinical outcomes such as reduced response to SSRI/SNRI antidepressants, increased disability, suicide and all-cause mortality. We recently reported that in an open label trial, our treatment designed to target these specific CCD with neuroplasticity-based computerized cognitive remediation (nCCR) improved depression and CCD in patients who failed to remit with conventional antidepressant treatment. This study tested the hypothesis that in patients with LLD who have failed at least one trial of an SSRI/SNRI antidepressant at an adequate dose for at least 8 weeks, nCCR will improve both depressive symptoms and the CCD associated with poor antidepressant response (i.e. semantic strategy, inhibition of prepotent responses) more than an active control group. Participants were randomized (1:1) to receive either 30 hours/ 4 weeks of neuroplasticity based computerized cognitive remediation (nCCR) designed to target CCD, or the active control condition matched for duration, engagement, reward, computer presentation, and contact with study staff. All participants and raters were blinded. Mixed effects model analysis the time effect (week) (F(1,71.22)=25.2, p<0.0001) and treatment group X time interaction (F(1,61.8)=11.37, p=.002) reached significance indicating that the slope of decline in MADRS was steeper in the nCCR-GD group. Further, the nCCR group improved their semantic clustering strategy(t(28)=9.5; p=.006), as well as performance on the Stroop interference condition, and cognitive flexibility (Trails B). Further, results transferred to memory performance, which was not a function trained by nCCR. clinicaltrials.gov.

Mobility limitations and fear of falling in non-English speaking older Mexican-Americans.

OBJECTIVE: To determine whether older Mexican-Americans who cannot speak and/or understand spoken English have higher rates of mobility limitations or fear of falling than their English-speaking counterparts. DESIGN: We conducted a cross-sectional analysis of 1169 community-dwelling Mexican-Americans aged 72-96 years from the 2000-2001 wave of the Hispanic Established Population for the Epidemiological Study of the Elderly. Mobility limitations were defined as having a Short Physical Performance Battery score ≤9, and fear of falling by participant report of being somewhat, fairly, or very afraid of falling. We determined the rates and odds ratios, for having mobility limitations and fear of falling as a function of English ability in those who were 72-96, <80, and ≥80 years of age. RESULTS: Among participants who were unable to speak and/or understand spoken English 85.7% had mobility limitations and 61.6% were afraid of falling, compared to 77.6% and 57.5%, respectively, of English speakers. Before adjusting for covariates, participants who did not speak and/or understand spoken English were more likely to have mobility limitations (odds ratio: 1.7; 95% CI: 1.3-2.4) but not fear of falling, compared to English speakers. Among those aged ≥80 years, but not those <80 years, who did not speak or understand English were more likely to have mobility limitations (odds ratio: 4.8; 95% CI:2.0-11.5) and fear of falling (odds ratio: 2.0; 95% CI:1.3-3.1). CONCLUSION: Older Mexican-Americans who do not speak or understand spoken English have a higher rate of mobility limitations and fear of falling than their English-speaking counterparts.

Coordination Impairments Are Associated With Falling Among Older Adults.

Background/Study Context: Approximately one third of older adults over the age of 65, and over 40% of those over 80 years, fall each year, leading to fractures, morbidity, and mortality. Annual direct medical costs due to falls in the United States are approximately $19.2 billion. The identification of new treatable risk factors for falls has the potential to advance their prevention and rehabilitation. METHODS: A cross-sectional study of 127 community-dwelling adults aged 67-99 years was conducted. An electronic gait walkway was used to assess gait coordination, measured as the Phase Coordination Index during normal speed walking. A motion capture system was used to assess rhythmic interlimb antiphase ankle coordination, measured as the standard deviation of ankle relative phase. Having fallen in the previous year was self-reported retrospectively. Odds ratios for falling as a function of coordination quartiles were determined using multivariable logistic regression. RESULTS: Adjusting for age, sex, body mass index, number of chronic conditions, Mini-Mental State Examination score, gait speed, and the variability of step length, time, and width, the odds ratios for falling based upon being in the 4th (the poorest) quartiles of gait or ankle coordination were 5.5 (95% confidence interval [CI]: 1.2-24.7) and 8.2 (95% CI: 2.2-31.3), respectively, and 3.7 (95% CI: 1.0-13.8) for the 3rd quartile of gait coordination, compared with the best (the 1st) coordination quartiles. Similar results were found in regression without adjustment for gait characteristics. CONCLUSION: The results support the hypothesis that impaired gait and rhythmic interlimb ankle coordination are associated with a history of falls in the past year. Prospective longitudinal research is needed to determine the possible direction of causality between falls and impaired coordination.

Rhythmic Interlimb Coordination Impairments Are Associated With Mobility Limitations Among Older Adults.

Background/Study Context: Mobility limitations affect more than 25% of adults aged 70 years or older. This study tested the hypothesis that impairments in ankle and shoulder coordination are associated with mobility limitations among older adults. METHODS: his study consisted of conducted a cross-sectional analysis from a sample of community-dwelling older adults (N = 130) aged ≥67 years. Motion capture equipment was used to collect kinematic data during rhythmic antiphase coordination of the right and left: (a) ankles moving in dorsi-plantarflexion; and (b) glenohumeral ("shoulder") moving in flexion-extension while paced by an auditory metronome. Coordination variability was measured as the standard deviation of the relative phase between right and left body segments. Mobility limitations were defined as a score of ≤9 on the Short Physical Performance Battery (SPPB). Odds ratios for mobility limitations as a function of coordination variability quartiles were determined using multivariable logistic regression. RESULTS: Adjusting for age, gender, body mass index, number of chronic conditions and Mini-Mental State Examination score, the odds ratios for mobility limitation (SPPB score ≤9) were 7.38 (95% confidence interval [CI]: 2.20-24.78) and 15.40 (95% CI: 4.31-55.07) for the 3rd and 4th (the poorest) ankle coordination quartiles, respectively, and 6.73 (95% CI: 2.11-21.51) for the 4th shoulder coordination quartile, compared with the best (the 1st) coordination quartiles. CONCLUSION: The results supported the hypothesis that impaired interlimb ankle and shoulder coordination are associated with the manifestation of mobility limitations. These findings indicate the need for further study of the role of coordination impairments as potential contributors to poor mobility among older adults.

The Savvy Caregiver Program: impact of an evidence-based intervention on the well-being of ethnically diverse caregivers.

This article reports on the impact of the Savvy Caregiver Program (SCP) on English-speaking caregivers of Hispanic, Black/African American, and Asian/Pacific Islander descent. Caregivers completed a questionnaire prior to study enrollment, at 6 and 12 months postenrollment. Caregivers in all 3 ethnic groups showed more caregiver competence, reduced depression, greater tolerance for care recipients' memory problems, better management of their overall situation, and improved perception of that situation 6 months and 12 months post-enrollment. The study demonstrates that in the sample studied the SCP was as effective in helping ethnically diverse caregivers as it has shown to be with Caucasian caregivers.

Use of focused computerized cognitive training (Neuroflex) to improve symptoms in women with persistent chemotherapy-related cognitive impairment.

Purpose: Chemotherapy-related cognitive impairment (CRCI) is a distressing and increasingly recognized long-term sequela reported by breast cancer patients following cancer treatment. There is an urgent but unmet clinical need for treatments that improve CRCI. In this context, we proposed the use of a novel cognitive enhancement strategy called Neuroflex to target CRCI experienced by breast cancer survivors. Methods: The primary aim of this pilot study was to evaluate the feasibility and acceptability of Neuroflex, a novel digital cognitive enhancement strategy, in breast and gynecologic cancer survivors with CRCI. Secondary analyses focused on whether improvements in performance on Neuroflex were associated with improvement in subjective cognitive complaints and objective cognitive performance measures. Results: Participants (N = 21) completed an average of 7.42 hours of Neuroflex training per week, an average of 44.5 (±1.01) hours total, and had a 100% completion rate. Participants exhibited significant improvement in self-reported cognitive function as well as significant improvement on tasks of verbal learning and memory and auditory working memory. Participants also exhibited improvement in mood, as well as improvement on a disability assessment. Conclusions: Results demonstrate feasibility and that breast cancer survivors are capable of completing a lengthy and challenging cognitive training program. Secondly, Neuroflex may confer specific cognitive benefits to both self-reported and objective performance. Results strongly support further investigation of Neuroflex in a larger controlled trial to establish efficacy for CRCI symptoms. Further studies may also result in optimization of this digital intervention for women with CRCI.

Assessing the prognostic utility of hematologic response for overall survival in patients with newly diagnosed AL amyloidosis: results of a meta-analysis.

OBJECTIVES: Amyloid light-chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits made up of toxic light chains causing progressive organ dysfunction and death. Recent studies suggest that hematologic response may be an important prognostic indicator of overall survival (OS) in AL amyloidosis. The aim of this study was to evaluate the trial-level association between hematologic complete response (CR) or very good partial response or better (≥ VGPR) and OS in newly diagnosed patients. METHODS: Studies were identified via systematic literature review. Pooled effect estimates were generated by a random-effects model. RESULTS: Nine observational studies reporting hematologic CR or ≥VGPR and OS hazard ratios (HRs) were included in the meta-analysis. Achieving hematologic CR was associated with improved OS (HR, 0.21; 95% confidence interval [CI] 0.13-0.34). Achieving ≥ VGPR was also associated with improved OS (HR 0.21; 95% CI 0.17-0.26). Results of a sensitivity analysis excluding one outlier study revealed no heterogeneity and a better overall HR estimate. Potential limitations of this meta-analysis include the small number of eligible studies (consistent with the rarity of the disease) and inconsistencies in reporting of results. CONCLUSIONS: Overall, our findings support the use of deep hematologic response (CR or ≥VGPR) as a clinical trial endpoint in newly diagnosed AL amyloidosis. This study provides evidence that early hematologic response is a strong patient-level surrogate for long-term OS in patients with AL amyloidosis receiving frontline therapy. Structured data collection of depth of response in future trials will further strengthen these observations.

Real-world treatment patterns, costs, and outcomes in patients with AL amyloidosis: analysis of the Optum EHR and commercial claims databases.

BACKGROUND: This study characterised real-world treatment patterns, clinical outcomes, and cost-of-illness in patients with light-chain (AL) amyloidosis. METHODS: Data were extracted from the US-based Optum® EHR and Clinformatics® Data Mart (claims) databases (2008-2019) for patients newly diagnosed with AL amyloidosis and who initiated anti-plasma cell therapies. Healthcare resource utilisation (HCRU) and related costs were compared across lines of therapy (LOT). Incidences of cardiac and renal failure were evaluated using the Kaplan-Meier method. RESULTS: About 1347 patients (EHR, n = 776; claims, n = 571) were included. Median age was 68 years; 56.8% were male. At initial diagnosis, 33.1% and 15.1% of patients had cardiac and renal failure, respectively. Most patients received bortezomib-containing treatment in LOT1 (69%); bortezomib-cyclophosphamide-dexamethasone was most common (26%). HCRU was similar across LOTs. Mean per-patient-per-month and per-patient-per-LOT costs were $19,343 and $105,944 for LOT1, $19,183 and $95,793 for LOT2, and $16,611 and $128,446 for LOT3, respectively. Costs were primarily driven by anti-plasma cell therapies, outpatient visits, and hospitalisations. The 5-year cardiac and renal failure rates following initial diagnosis were 64.5% and 39.0%, respectively. CONCLUSION: AL amyloidosis is associated with substantial costs and suboptimal outcomes, highlighting the need for new therapeutic approaches to prevent organ deterioration, and reduce disease burden.

[Clinical reasoning in nursing, concept analysis]. / Le raisonnement clinique des infirmières, analyse de concept.

BACKGROUND: Nurses work in situations of complex care requiring great clinical reasoning abilities. In literature, clinical reasoning is often confused with other concepts and it has no consensual definition. AIM: To conduct a concept analysis of a nurse's clinical reasoning in order to clarify, define and distinguish it from the other concepts as well as to better understand clinical reasoning. METHOD: Rodgers's method of concept analysis was used, after literature was retrieved with the use of clinical reasoning, concept analysis, nurse, intensive care and decision making as key-words. RESULTS: The use of cognition, cognitive strategies, a systematic approach of analysis and data interpretation, generating hypothesis and alternatives are attributes of clinical reasoning. The antecedents are experience, knowledge, memory, cues, intuition and data collection. The consequences are decision making, action, clues and problem resolution. CONCLUSION: This concept analysis helped to define clinical reasoning, to distinguish it from other concepts used synonymously and to guide future research.

Comparative efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) without and with daratumumab (D-VTd) in CASSIOPEIA versus VTd in PETHEMA/GEM in transplant-eligible patients with newly diagnosed multiple myeloma, using propensity score matching.

Background: Traditional bortezomib, thalidomide, and dexamethasone (VTd) regimens for patients with newly diagnosed multiple myeloma (NDMM) include doses of thalidomide up to 200 mg/day (VTd-label). Clinical practice has evolved to use a lower dose (100 mg/day) to reduce toxicity (VTd-mod), which was evaluated in the phase III CASSIOPEIA study, without or with daratumumab (D-VTd; an anti-CD38 monoclonal antibody). We used propensity score matching to compare efficacy and safety for VTd-mod and D-VTd with VTd-label. Methods: Patient-level data for VTd-mod and D-VTd from CASSIOPEIA (NCT02541383) and data for VTd-label from the PETHEMA/GEM study (NCT00461747) were analyzed. Propensity scores were estimated using logistic regression, and nearest-neighbor matching procedure was used. Outcomes included overall survival (OS), progression-free survival (PFS), time to progression (TTP), postinduction and posttransplant responses, as well as rate of treatment discontinuation and grade 3/4 peripheral neuropathy. Results: VTd-mod was noninferior to VTd-label for OS, PFS, TTP, postinduction very good partial response or better (≥VGPR) and overall response rate (ORR). VTd-mod was significantly better for posttransplant ≥VGPR and ORR versus VTd-label. VTd-mod safety was not superior to VTd-label despite the lower thalidomide dose. D-VTd was significantly better than VTd-label for OS, PFS, TTP, postinduction and posttransplant ≥VGPR and ORR, and was noninferior to VTd-label for safety outcomes. Conclusions: In transplant-eligible patients with NDMM, D-VTd had superior efficacy compared with VTd-label. Despite a lower dose of thalidomide, VTd-mod was noninferior to VTd-label for safety and was significantly better for posttransplant ≥VGPR/ORR. These data further support the first-line use of daratumumab plus VTd.

Front-line daratumumab-VTd versus standard-of-care in ASCT-eligible multiple myeloma: matching-adjusted indirect comparison.

Aim: To compare daratumumab plus standard-of-care (SoC; bortezomib/thalidomide/dexamethasone [VTd]) and VTd alone with other SoC for transplant-eligible newly diagnosed multiple myeloma. Patients & methods: We conducted an unanchored matching-adjusted indirect comparison of progression-free and overall survival (PFS/OS) with D-VTd/VTd versus bortezomib/lenalidomide/dexamethasone (VRd), bortezomib/cyclophosphamide/dexamethasone (VCd) and bortezomib/dexamethasone (Vd). Results: After matching adjustment, significant improvements in PFS were estimated for D-VTd versus VRd (hazard ratio [HR]: 0.47 [95% CI: 0.33-0.69]), VCd (HR: 0.35 [95% CI: 0.21-0.58]) and Vd (HR: 0.42 [95% CI: 0.28-0.63]). OS was significantly longer with D-VTd versus VRd (HR: 0.31 [95% CI: 0.16-0.57]), VCd (HR: 0.35 [95% CI: 0.14-0.86]) and Vd (HR: 0.38 [95% CI: 0.18-0.77]). No significant PFS/OS differences were seen for VTd versus other SoC. Conclusion: This analysis supports front-line daratumumab for transplant-eligible newly diagnosed multiple myeloma.

Matching-adjusted indirect comparison of efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) as per label compared with modified VTd dosing schedules in patients with newly diagnosed multiple myeloma who are transplant eligible.

Background: The combination of bortezomib, thalidomide, and dexamethasone (VTd) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Although approved labeling for VTd includes an escalating thalidomide dose up to 200 mg daily (VTd-label), a lower fixed dose of thalidomide (100 mg daily; VTd-mod) has become commonplace in clinical practice. To date, no clinical trials comparing VTd-mod with VTd-label have been performed. Here, we compared outcomes for VTd-mod with VTd-label using a matching-adjusted indirect comparison. Methods: VTd-mod data were from NCT02541383 (CASSIOPEIA; phase III) and NCT00531453 (phase II); VTd-label data were from NCT00461747 (PETHEMA/GEM; phase III). To adjust for heterogeneity, baseline characteristics from VTd-label were weighted to match VTd-mod. Outcomes included overall survival (OS), progression-free survival (PFS), postinduction and posttransplant responses, and safety. Results: VTd-mod was noninferior to VTd-label for OS, postinduction overall response rate (ORR), and very good partial response or better (≥VGPR). VTd-mod was significantly better than VTd-label for PFS, posttransplant ORR, and ≥VGPR. VTd-mod was noninferior to VTd-label for safety outcomes, and inferior to VTd-label for postinduction and posttransplant complete response or better. Conclusions: Our analysis supports the continued use of VTd-mod in clinical practice in transplant-eligible NDMM patients.

A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma.

The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29-0.37; P < .001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P < .001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis.

AIM: A systematic literature review and network meta-analysis were conducted to determine the relative efficacy and safety of interventions for treatment-naive chronic lymphocytic leukemia patients, as comparative evidence is scarce. MATERIALS & METHODS: Relative treatment effects of progression-free survival, overall survival and safety outcomes were estimated via network meta-analysis based on data identified via systematic literature review. RESULTS: Ibrutinib was superior in all pairwise comparisons for progression-free survival (probability to be better [P] range: overall population: 69-100%; fludarabine-ineligible population: 69-100%) and overall survival (P range: overall: 89-100%; fludarabine-ineligible: 91-100%) and had the highest probability of being best for all outcomes. CONCLUSION: Ibrutinib provides superior benefit in survival and safety compared with other front-line treatments of chronic lymphocytic leukemia.

Comparative Efficacy of Ibrutinib Versus Obinutuzumab + Chlorambucil in First-Line Treatment of Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison.

INTRODUCTION: Ibrutinib (ibr) monotherapy and the combination of obinutuzumab plus chlorambucil (obi) are approved for previously untreated chronic lymphocytic leukemia (CLL). No trials directly comparing their efficacy are available. Therefore a matching-adjusted indirect comparison (MAIC) was performed to provide insight into their relative efficacy in terms of progression-free survival (PFS) and overall survival (OS). MAIC attempts to adjust for between-trial differences in factors known or suspected to influence treatment effects, to minimize bias. METHODS: A MAIC within a Bayesian framework was conducted using individual patient data from the RESONATE-2 study of ibr versus chlorambucil and published data from the CLL11 study of obi versus chlorambucil. Both studies were conducted in patients ineligible for full-dose fludarabine-based therapy. After matching, the reweighted adjusted relative efficacy measure of ibr versus chlorambucil from RESONATE-2 [hazard ratio (HR), 95% credible interval (CrI)] was compared with that of obi versus chlorambucil from CLL11 for each endpoint, using a Bayesian indirect comparison. RESULTS: Our results suggest that in a population with similar average baseline characteristics to CLL11, ibr would improve PFS and OS outcomes compared to obi. Before matching, the HRs for ibr versus obi were 0.48 [CrI = 0.22-1.02, p(HR <1) = 97%], 0.85 [CrI = 0.44-1.63, p(HR <1) = 69%], and 0.40 [CrI = 0.10-1.54, p(HR <1) = 91%] for PFS by investigator assessment, PFS by independent review committee, and OS, respectively. After matching on all available characteristics the HRs decreased to 0.12 [CrI = 0.02-0.97, p(HR <1) = 98%], 0.24 [CrI = 0.04-1.35, p(HR <1) = 95%], and 0.21 [CrI = <0.01-8.89, p(HR <1) = 79%], respectively. There was a large variance around the treatment effect for OS due to the low number of deaths. CONCLUSION: Our analysis suggests that ibrutinib is highly likely to provide greater PFS benefit than obinutuzumab plus chlorambucil in older or less fit patients with previously untreated CLL. There is also an indication of improvement in OS, albeit with a higher uncertainty due to the low number of events. FUNDING: Janssen-Cilag Ltd.

Impact of novel agents on patient-relevant outcomes in patients with previously untreated chronic lymphocytic leukemia who are not eligible for fludarabine-based therapy.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is an orphan disease that primarily affects the elderly. The majority of symptomatic patients eligible for frontline treatment are unfit for fludarabine based chemoimmunotherapy. Historical treatment includes chlorambucil (Chl), bendamustine/rituximab (BR), and chlorambucil/rituximab/ChlR combination. Clinical guidelines now recommend the use of novel agents, such as ibrutinib (Ibr), in both frontline and relapse settings and other novel agents, such as idelalisib (with rituximab), in relapse settings. Despite compelling clinical results for novel agents, follow-up in clinical trials is relatively short and, thus, the comparative long-term benefits are still unknown. MATERIALS AND METHODS: The authors developed a simulation model to generate treatment specific lifetime estimates of Overall Survival (OS) and Quality Adjusted Life Years (QALYs) for treatment with BR, Chl, ChlR, and Ibr. Two potential clinical scenarios were modelled: with and without novel agents for treating CLL. The model was based on health states relating to first- and second-line progression-free survival (PFS), post-progression survival, and death. RESULTS: Where novel agents were assumed unavailable, mean OS ranged from 5.4-8.5 years and QALYs from 3.5-6.1. Where novel agents were available, the mean OS increased to 10.0 years, with a corresponding increase in QALYs to 7.6. Frontline Ibr use followed by Physician's Choice, including novel agents at relapse, resulted in projected increase in OS of between 18% (1.5 years) and 85% (4.6 years), corresponding to a 25-117% increase in QALYs, compared with currently available traditional therapies. LIMITATIONS: The limitations of this analysis include immature OS data and the assumption of equivalent efficacy across all novel agents in terms of their impact on PFS and OS. CONCLUSIONS: The use of novel agents is predicted to yield substantive gains in predicted lifetime OS and QALY improvements compared to traditional therapies in CLL patients who are ineligible for fludarabine-based chemoimmunotherapy.