Translocation of bacterial LPS is associated with self-reported cognitive abilities in men living with HIV receiving antiretroviral therapy.

BACKGROUND: Gut damage allows translocation of bacterial lipopolysaccharide (LPS) and fungal ß-D-glucan (BDG) into the blood. This microbial translocation contributes to systemic inflammation and risk of non-AIDS comorbidities in people living with HIV, including those receiving antiretroviral therapy (ART). We assessed whether markers of gut damage and microbial translocation were associated with cognition in ART-treated PLWH. METHODS: Eighty ART-treated men living with HIV from the Positive Brain Health Now Canadian cohort were included. Brief cognitive ability measure (B-CAM) and 20-item patient deficit questionnaire (PDQ) were administered to all participants. Three groups were selected based on their B-CAM levels. We excluded participants who received proton pump inhibitors or antiacids in the past 3 months. Cannabis users were also excluded. Plasma levels of intestinal fatty acid binding protein (I-FABP), regenerating islet-derived protein 3 α (REG3α), and lipopolysaccharides (LPS = were quantified by ELISA, while 1-3-ß-D-glucan BDG) levels were assessed using the Fungitell assay. Univariable, multivariable, and splines analyses were performed. RESULTS: Plasma levels of I-FABP, REG3α, LPS and BDG were not different between groups of low, intermediate and high B-CAM levels. However, LPS and REG3α levels were higher in participants with PDQ higher than the median. Multivariable analyses showed that LPS association with PDQ, but not B-CAM, was independent of age and level of education. I-FABP, REG3α, and BDG levels were not associated with B-CAM nor PDQ levels in multivariable analyses. CONCLUSION: In this well characterized cohort of ART-treated men living with HIV, bacterial but not fungal translocation was associated with presence of cognitive difficulties. These results need replication in larger samples.

Validation of a robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of navitoclax.

The Bcl-2 family small molecule inhibitor navitoclax is being clinically evaluated to treat multiple cancers including lymphoid malignancies and small cell lung cancer. A sensitive and reliable method was developed to quantitate navitoclax in human plasma using liquid chromatography with tandem mass spectrometry with which to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of navitoclax and the internal standard, navitoclax-d8, was achieved with a Waters Acquity UPLC BEH C18 column using isocratic flow over a 3 min total analytical run time. A SCIEX 4500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of navitoclax. The assay range was 5-5,000 ng/ml and proved to be accurate (89.5-104.9%) and precise (CV ≤ 11%). Long-term frozen plasma stability for navitoclax at -70°C was at least 34 months. The method was applied for the measurement of total plasma concentration of navitoclax in a patient receiving a 250 mg daily oral dose.

The Families First Program to Prevent Child Abuse: Results of a Cluster Randomized Controlled Trial in West Java, Indonesia.

The Families First parenting program is a 10-week paraprofessional-administered adaptation of the Positive Discipline in Everyday Parenting program for West Java, Indonesia. It has not been tested in a randomized controlled trial. The objective was to evaluate the effects of Families First on physical and emotional punishment. We conducted a cluster randomized controlled trial and randomly assigned 20 rural and urban villages in West Java, Indonesia, to intervention or waitlist. Caregivers of children aged 0-7 years in intervention villages received Families First. Between 2017 and 2018, measurements were taken before randomization, immediately post-intervention, and 6 months post-intervention. Primary outcome was presence versus absence of caregiver-reported physical or emotional punishment immediately post-intervention. Intention-to-treat regression models accounted for clustering within villages and were run to compare between groups. Participants and study personnel could not be blinded. There were 374 caregivers in the 10 intervention villages and 362 in the 10 waitlist villages included in the trial and in outcome analyses. The intervention did not result in a lower proportion of intervention families using punishment immediately post-intervention (odds ratio [OR] for physical or emotional punishment immediately post intervention = 1.20 (95% CI 0.79-1.82). There were no significant differences for positive and involved parenting, setting limits, and opinion on discipline, but caregivers in the intervention group had significantly lower odds of using positive discipline (OR = 0.65 (95% CI 0.53-0.80). Families First did not prevent punishment in a setting with low levels of reported punishment but should be tested in a setting with higher levels or among people selected for risk or presence.

Immunotherapy for small cell lung cancer: established applications and novel approaches.

Small cell lung cancer (SCLC) is a devastating disease that has a case fatality rate of more than 90% despite best available treatments. As a result, patients with SCLC are in critical need of improved therapeutic approaches. Immunotherapies, in particular immune checkpoint inhibitors (ICIs), have transformed the treatment of many cancers and are of great interest in SCLC. In recent years, the addition of anti-programmed death ligand 1 (PD-L1) inhibitors to frontline platinum-based chemotherapy in extensive-stage SCLC has improved survival, and combination chemoimmunotherapy is now approved as the standard of care. ICIs are also under investigation in other settings, including as consolidation therapy in limited-stage SCLC following chemoradiation and in combination with chemoradiation. PD-L1 expression and tumor mutational burden are not reliably associated with ICI benefit in SCLC, and predictive biomarkers of ICI response in SCLC are actively sought. Novel immunotherapeutic approaches are under investigation in SCLC. Rational targets and combinations, which stem from investigations of SCLC biology and the immune tumor microenvironment, include combinations with inhibitors of TIGIT or LAG3; targeting alternative signaling pathways, such as DNA damage repair; and co-targeting SCLC-specific tumor antigens, such as fucosyl-GM1 and DLL3. This review summarizes approaches to immunotherapy in SCLC, including current evidence and approvals, as well as key questions and future directions.

Relationships between cognition, function, and quality of life among HIV+ Canadian men.

OBJECTIVE: To estimate the extent to which HIV-related variables, cognition, and other brain health factors interrelate with other HIV-associated symptoms to influence function, health perception, and QOL in older HIV+ men in Canada. DESIGN: Cross-sectional structural equation modelling (SEM) of data from the inaugural visit to the Positive Brain Health Now Cohort. SETTING: HIV clinics at 5 Canadian sites. SUBJECTS: 707 men, age ≥ 35 years, HIV+ for at least one year, without clinically diagnosed dementia. MAIN OUTCOME MEASURES: Five latent and 21 observed variables from the World Health Organization's biopsychosocial model for functioning and disability and the Wilson-Cleary Model were analysed. SEM was used to link disease factors to symptoms, impairments, function, health perception, and QOL with a focus on cognition. RESULTS: QOL was explained directly by depression, social role, health perception, social support, and quality of the environment. Measured cognitive performance had direct effects on activity/function and indirect effects on participation, HP and QOL, acting through self-reported cognitive difficulties and meaningful activities. CONCLUSION: The biopsychosocial model showed good fit, with RMSEA < 0.05. This is the first time the full model has been tested in HIV. All of the domains included in the model are theoretically amenable to intervention and many have evidence-based interventions that could be harnessed to improve QOL.

Trajectory of MS disease course for men and women over three eras.

BACKGROUND: Heterogeneity in disease course exists within multiple sclerosis (MS) subtypes. OBJECTIVE: The objective was to estimate disease course heterogeneity over three distinct onset periods (pre-1995, 1995-2004, and 2005-present) for men and women. METHODS: Group-based trajectory model (GBTM) was used to estimate clusters of patients following stable or unstable disease progression trajectories based on the Expanded Disability Status Scale (EDSS). Inception cohorts were generated from the Montreal Neurological Institute MS Clinic registry. Stable trajectories were defined as an EDSS ⩽3.0 and change ⩽1 point over the study period. Annualized relapse rate (ARR) based on the first 5 years of disease was an explanatory variable. RESULTS: Proportion of women classified as stable was 0% for pre-1995, 69.0% for 1995-2004, and 83.9% post-2005; for men, these proportions were 18.4%, 41.4%, and 53.8%, respectively. Men had lower percentage of stable disease than women in both post-1995 cohorts (chi-square p < 0.0001). ARR was associated with higher disability trajectories in both post-1995 cohort (odds ratios >1.0) but not in the pre-1995 cohort. CONCLUSION: Large proportions of patients remain stable at their initial disability level for at least 15 years. Higher ARR increases the odds of patients being in a higher disability trajectory in the latter cohorts.

How are you? Do people with inflammatory bowel disease experience response shift on this question?

BACKGROUND: As individuals experience changes in their health, they may alter the way they evaluate health and quality of life. The purpose of this study is to estimate the extent to which individuals with IBD change their rating of health over time because of response shift (RS). METHODS: This is a reanalysis of a population-based longitudinal study of IBD in Manitoba, Canada (n = 388). RS was examined using trajectories of the difference between observed and predicted health. Logistic regression and dual trajectories were used to identify predictors of RS. RESULTS: Disease activity, vitality, pain, somatization, and physical and social function explained 51% of the variation in general health over two years with no evidence of RS in 82% of the sample. Negative RS was found for 8%, who initially rated health better than predicted; positive RS was found for 6%. The positive RS group was younger and had better baseline scores on measures of general health, hostility, pain, mental health and social and role function; less pain and better social function scores at baseline were predictors of negative RS. CONCLUSIONS: In conclusion, the majority of people with IBD did not demonstrate a RS indicating that the health rating over time was stable in relation to that predicted by known time varying clinical variables. This adds to the evidence that the single question on self-rated health is useful for monitoring individuals over time.

Modeling health-related quality of life in people recovering from stroke.

BACKGROUND: The Wilson-Cleary (W-C) model of health-related quality of life (HRQL) has not been tested in stroke, and a better understanding of the components of HRQL during recovery would lead to a more integrated and person-centered approach to health management and outcome optimization for this vulnerable population. OBJECTIVE: To enhance our understanding for how QOL emerges from the sequelae of stroke during the recovery period, the aim was to empirically test a biopsychosocial conceptual model of HRQL for people recovering from stroke. METHODS: We present a multi-site longitudinal study of an inception cohort of 678 persons recruited at stroke onset and studied at key intervals over the first post-stroke year. As the most pronounced recovery after stroke occurs in the first 3 months, this time frame was chosen as the focus of this analysis. The measures for this study were chosen for their relevance to key constructs of stroke impact and for their optimal psychometric properties. Multiple measures for each of the W-C rubrics were available from instruments such as the Stroke Impact Scale, RAND-36, HUI, and EQ-5D, among others. A structural equation model (SEM) was fit using MPlus. To minimize potential bias arising from the missing data, multiple imputation was performed on the longitudinal data using SAS proc MI. RESULTS: Of the 678 subjects who entered the cohort, 618 were interviewed at 1 month post-stroke and 533 at 3 months (486 and 454 had data at 6 and 12 months, respectively). A 3-month model with paths from biological factors to symptoms and symptoms to function fits well (CFI:0.966, RMSEA:0.044), though one model with paths from function to health perception did not (CFI:0.934, RMSEA:0.058). Allowing additional paths across non-adjacent rubrics improved fit considerably (CFI:0.962, RMSEA:0.044). A final model included emotional well-being under the symptom rubric (CFI:0.955, RMSEA:0.047). Including social support as an environmental factor had little impact on the model. Total variance in health perception explained was 76.3 %. CONCLUSION: These results emphasize that to optimize overall HRQL during the crucial first 3 months of recovery, interventions need to continue to focus on comorbid health conditions and on reducing stroke impairments. A function-only focus too soon in the recovery process may not produce the desired impact to optimize HRQL.

Getting on with the rest of your life following stroke: a randomized trial of a complex intervention aimed at enhancing life participation post stroke.

OBJECTIVE: To enhance participation post stroke through a structured, community-based program. DESIGN: A controlled trial with random allocation to immediate or four-month delayed entry. SETTING: Eleven community sites in seven Canadian cities. SUBJECTS: Community dwelling persons within five years of stroke onset, cognitively intact, able to toilet independently. INTERVENTIONS: Evidence-based program delivered in three 12-week sessions including exercise and project-based activities, done as individuals and in groups. MAIN MEASURES: Hours spent per week in meaningful activities outside of the home and Reintegration to Normal Living Index; Stroke-Specific Geriatric Depression Scale, Apathy Scale, gait speed, EuroQuol EQ-5D, and Preference-Based Stroke Index. All measures were transformed to a scale from 0 to 100. Assessments prior to randomization, after the first session at three months, six months, 12 months, and 15 months. RESULTS: A total of 186 persons were randomized. The between-group analysis showed no disadvantage to waiting and so groups were combined and a within-person analysis was carried out at three time points. There were statistically significant increases in all study outcomes on average over all persons. Over 45% of people met or exceeded the pre-specified target of a three hour per week increase in meaningful activity and this most often took a full year of intervention to achieve. Greatest gains were in satisfaction with community integration (mean 4.78; 95% CI: 2.01 to 7.55) and stroke-specific health-related quality of life (mean 4.14; 95% CI: 2.31 to 5.97). CONCLUSIONS: Community-based programs targeting participation are feasible and effective, but stroke survivors require time to achieve meaningful gains.

Patterns of care at end of life for people with primary intracranial tumors: lessons learned.

To determine the variability in processes of care in the last 6 months of life experienced by patients dying of primary intracranial tumors and potential predictors of place of death, a death-backwards cohort was assembled using historical data and 1,623 decedents were identified. 90 % of people had ≥ 1 admission to an acute care hospital and 23 % spent ≥ 3 months of their last 6 months of life in acute care. 44 % had ≥ 1 ER visits and 30 % were admitted ≥ 1 times to ICU. Only 18 % had a home visit by a physician. 10 % died at home but 49 % died in hospital, while 40 % died in a palliative care facility. Age, comorbidities, and being diagnosed with grade 4 astrocytoma were associated with greater burden of care. Level of care burden and age were associated with higher odds of dying in a treatment intensive place of death, being diagnosed with grade 4 astrocytoma had opposite effect. Despite valuable research efforts to improve the treatment of primary intracranial tumors that focus on biology, refinements to surgery, radiation, and chemotherapy, there is also room to improve aspects of care at the end of life situation. An integrative approach for this patients' population, from diagnosis to death, could potentially reduce the care burden in the final period on the health care system, patient's family and improve access to a better place of death.

Necessary and sufficient causes of participation post-stroke: practical and philosophical perspectives.

INTRODUCTION: Participation, a construct within the disability/functioning framework, is evaluated on a person's involvement in life situations including family, community, work, social, and civic life. In the context of recovering from a major health event, participation is a treatment goal and it is known to correlate with the quality of life. OBJECTIVE: The purpose of this study is to track the dynamics of participation post-stroke in relationship to the dynamics of walking capacity, social support, and mood. METHODS: An inception cohort was followed over the first post-stroke year. Group-based trajectory analysis, a form of latent class analysis, was used to identify distinctive groups of individuals with similar trajectories. Dual trajectories were used to estimate concordance between participation trajectory and trajectories for each of the three constructs under study. RESULTS: From the sample of 102 persons (mean age 70), four trajectories of participation were identified, two of which were qualified as excellent and very good, and two qualified as fair and poor. All those with excellent walking showed excellent participation. However, people with excellent (and very good) community participation had a range of walking capacities. Most (82%) people with normal mood showed excellent participation. People with good mood but not meeting norms for age showed the complete range of participation trajectories from excellent to poor. The higher proportion of people with excellent or good social support (57%) showed excellent participation. CONCLUSION: Two treatable component causes of participation, walking capacity and mood, were identified; of these, only excellent walking capacity could be considered a sufficient cause.

Pedometer-facilitated walking intervention shows promising effectiveness for reducing cancer fatigue: a pilot randomized trial.

OBJECTIVE: Mechanisms for cancer related fatigue suggest that exercise but "not too much and not too little" could be effective. This study aimed to investigate feasibility and estimate the potential effects of a walking exercise program in people with advanced cancer and fatigue. DESIGN: A pilot randomized trial. SETTING: McGill University Health Centre (MUHC), Montreal, Canada. SUBJECTS: People with advanced cancer undergoing interdisciplinary assessment and rehabilitation with a fatigue level of 4 to 10 on a visual analogue scale. INTERVENTIONS: An 8-week fatigue-adapted, walking intervention, facilitated using a pedometer (STEPS), and offered at the same time as or after rehabilitation. MEASURES: Measures of fatigue, physical function and well-being were administered at entry, and 8, 16 and 24 weeks. Generalized estimating equations (GEE) estimated the odds of response for people receiving the STEPS program in comparison to the odds of response in the controls (odds ratio, OR). RESULTS: Twenty-six persons were randomized to three groups: during rehabilitation, after rehabilitation, and usual care. For the fatigue measures the OR for STEPS offered at any time using an intention-to-treat approach was 3.68 (95%CI: 1.05-12.88); for the physical function measures, the OR was 1.40 (95%CI: 0.41- 4.79) and 2.36 (95%CI: 0.66-8.51) for the well-being measures. CONCLUSION: Fifty percent of eligible people were able to participate. This small trial suggests that a personalized exercise program reduces fatigue and that 100 people are needed in a full strength trial.

First-line Osimertinib for Lung Cancer With Uncommon EGFR Exon 19 Mutations and EGFR Compound Mutations.

Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10-15), 22 months (95% CI: 17-32) and 36 months (95% CI, 29-48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10-15), median TTD was 19 months (95% CI: 17-38), and median OS was 48 months (95% CI: 25-not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5-22), median TTD of 26 months (95% CI: 5-36), and median OS of 36 months (95% CI: 20-46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.

Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

A randomized trial of two home-based exercise programmes to improve functional walking post-stroke.

OBJECTIVE: To estimate the relative effectiveness in improving walking ability and other mobility and health outcomes post-stroke of two home-based exercise programmes - stationary cycling and an exercise and walking programme. DESIGN: An observer-blinded, randomized, pragmatic, trial with repeated measures. SETTING: Hospital centers in two Canadian cities. SUBJECTS: People within 12 months of acute stroke who were able to walk >10 meters independently and healthy enough to engage in exercise. INTERVENTIONS: Two dose-equivalent interventions, one involving stationary cycling and the other disability-targeted interventions were tested. Both protocols required daily moderate intensity exercise at home building up to 30 minutes per day. One group exercised on a stationary bicycle, the second group carried out mobility exercises and brisk walking. MAIN MEASURES: The primary outcome was walking capacity as measured by the six-minute walk test (6MWT). Secondary outcomes were physical function, role participation, health-related quality of life exercise adherence, and adverse events. RESULTS: The study failed to meet recruitment targets: 87 participants (cycle group, n = 43; exercise group, n = 44) participated. No significant effects of group or time were revealed for the 6MWT, which was approximately 320 m at randomization. A significant effect for role participation was found in favor of the exercise group (global odds ratio (OR) for cycling vs. exercise was 0.51; 95% confidence interval (CI), 0.27-0.95). Change in the 6MWT between highest and lowest adherence categories was statistically significant (p = 0.022). CONCLUSIONS: Both programmes were equally effective in maintaining walking capacity after discharge from stroke rehabilitation; or were equally ineffective in improving walking capacity. Clinical Trials Gov number: NCT00786045.

Development of a Frailty Ladder Using Rasch Analysis: If the Shoe Fits.

Background: The current measurement approach to frailty is to create an index of frailty status, rather than measure it. The purpose of this study is to test the extent to which a set of items identified within the frailty concept fit a hierarchical linear model (e.g., Rasch model) and form a true measure reflective of the frailty construct. Methods: A sample was assembled from three sources: community organization for at-risk seniors (n=141); colorectal surgery group assessed post-surgery (n=47); and hip fracture assessed post-rehabilitation (n=46). The 234 individuals (age 57 to 97) contributed 348 measurements. The frailty construct was defined according to the named domains within commonly used frailty indices, and items drawn to reflect the frailty came from self-report measures. Performance tests were tested for the extent to which they fit the Rasch model. Results: Of the 68 items, 29 fit the Rasch model: 19 self-report items on physical function and 10 performance tests, including one for cognition; patient reports of pain, fatigue, mood, and health did not fit; nor did body mass index (BMI) nor any item representing participation. Conclusion: Items that are typically identified as reflecting the frailty concept fit the Rasch model. The Frailty Ladder would be an efficient and statistically robust way of combining results of different tests into one outcome measure. It would also be a way of identifying which outcomes to target in a personalized intervention. The rungs of the ladder, the hierarchy, could be used to guide treatment goals.

Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer.

PURPOSE: Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response. EXPERIMENTAL DESIGN: We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy. RESULTS: Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging. CONCLUSIONS: ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring. See related commentary by Pellini and Chaudhuri, p. 2176.

Improved lung cancer clinical outcomes in patients with autoimmune rheumatic diseases.

PURPOSE: Concomitant autoimmune rheumatic diseases (ARD) can add morbidity and complicate treatment decisions for patients with lung cancer. We evaluated the tumour characteristics at diagnosis and clinical outcomes in lung cancer patients with or without ARD. METHODS: This retrospective cohort study included 10 963 patients with lung cancer, treated at Johns Hopkins. Clinical data including tumour characteristics and outcomes were extracted from the cancer registry. Data on patients' history of 20 ARD were extracted from the electronic medical record. Logistic regression was used to compare tumour characteristics between those with and without ARD; Kaplan-Meier curves and Cox proportional hazards models were performed to compare survival outcomes. RESULTS: ARD was present in 3.6% of patients (n=454). The mean age at diagnosis was 69 (SD 10) and 68 (SD 12) in patients with and without ARD (p=0.02). Female sex and smoking history were significantly associated with a history of ARD (OR: 1.75, OR: 1.46, p<0.05). Patients with ARD were more likely to be diagnosed with stage 1 lung cancer (36.8% vs 26.9%, p<0.001) and with smaller tumour size (OR: 0.76, p=0.01), controlling for sex, race and histology. Notably, lung cancer patients with ARD had a significantly prolonged median overall survival (OS) (7.11 years vs 1.7 years, p<0.001), independent of stage. CONCLUSION: Patients with ARD and lung cancer had better OS compared with their counterparts, independent of cancer stage and treatments and were less likely to have advanced stage lung cancer at diagnosis. Additional studies are needed to investigate the differential immunological anti-tumour immune activity and genomic variations in patients with and without ARD.