Metabolomic adaptations and correlates of survival to immune checkpoint blockade.

Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors.

Urgent Complex Intraoperative Reintubation in a Known Difficult Airway After Endotracheal Tube Damage: A Case Report.

Treacher Collins syndrome is an inherited disorder resulting in maldevelopment of the first and second branchial arches. Patients have complex orofacial anatomy often requiring airway interventions from birth. A 17-year-old boy with Treacher Collins syndrome and history of difficult ventilation and intubation presented for elective maxillofacial reconstruction. After uneventful awake nasal fiberoptic intubation, the nasotracheal tube was damaged intraoperatively. Due to the patient's unique anatomy, a fiberoptic bronchoscope and ventilating exchange catheter were utilized together to facilitate a nasotracheal tube exchange. This case demonstrates the utilization of a combination of advanced airway techniques in an urgent perioperative setting.

A real-world, comparative study of FDA-approved diagnostic assays PD-L1 IHC 28-8 and 22C3 in lung cancer and other malignancies.

AIMS: At the time of analysis, two widely used, drug-specific, tumour-cell programmed death ligand 1 (PD-L1) assays were approved by the US Food and Drug Administration for anti-PD-1 therapies: the Dako PD-L1 immunohistochemistry (IHC) 28-8 pharmDx assay and the Dako PD-L1 IHC 22C3 pharmDx assay. Given that the majority of current PD-L1 testing in US clinical practice is performed at commercial reference laboratories, we aimed to evaluate the concordance of the 28-8 and 22C3 assays in a real-world setting. METHODS: Matched PD-L1 IHC 28-8 and 22C3 results from routine assessment were obtained from 1930 patients, including 412 confirmed to have lung cancer, submitted from hospitals in over 38 US states/territories. Biopsies were stained, reviewed and scored by trained/certified pathologists at a single cancer reference laboratory between 2015 and 2017. Rate of concordance between assay findings was assessed by Bland-Altman analysis; overall per cent agreement (OPA), positive per cent agreement and negative per cent agreement; and Cohen's kappa. RESULTS: PD-L1 IHC 28-8 and 22C3 displayed strong correlation across all samples and in samples with a confirmed lung cancer diagnosis irrespective of biopsy site. The OPA was 97%-98% for all samples, depending on the expression level defining PD-L1 positivity. In the Bland-Altman analysis, the mean difference in percentage of tumour cells positively stained for PD-L1 between the paired assay findings was -0.80% for all samples and -0.93% in samples with a confirmed lung cancer diagnosis. CONCLUSIONS: These data, in conjunction with recent findings, support the analytical concordance of the PD-L1 IHC 28-8 and 22C3 assays for assessing per cent tumour-cell membrane PD-L1 expression.

MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma.

Combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8+ and CD4+ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti-CTLA-4, anti-PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti-CTLA-4, but not anti-PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ-mediated gene signatures, and predicted response to anti-PD-1, but not anti-CTLA-4, therapy. We conclude that primary response to anti-CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti-PD-1 is associated with preexisting IFN-γ-mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.

Towards a comprehensive developmental model of pathological gambling.

AIMS: To develop a comprehensive etiological model of pathological gambling (PG) for men and women based on Kendler's development model for major depression, which groups 22 risk factors into five developmental tiers (childhood, early adolescence, late adolescence, adulthood, last year). We hypothesized that: (1) all risk factors would be associated significantly with PG; (2) the effect of risk factors in earlier developmental tiers would be accounted for by later tiers; and (3) there would be few gender differences. DESIGN: Separate models were built for life-time gambling and for 12-month PG among those with life-time gambling. SETTING: Data drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) in the United States. PARTICIPANTS: Respondents to NESARC wave 1 (n = 43 093). MEASUREMENTS: Odds ratios (OR) and adjusted OR (AOR) were used to determine the risk factors in multiple models. FINDINGS: After mutually adjusting for other risk factors, family history of substance use disorders (SUD) or depression, impulsivity, childhood-onset anxiety, number of Axis I and II disorders, history of SUD, nicotine dependence, social deviance in adulthood, and past-year history of SUD, nicotine dependence and independent stressful life events predicted life-time gambling. Past history of PG, number of personality disorders and past year nicotine dependence were associated significantly with 12-month PG (all P < 0.05). There were no significant gender interactions for 12-month PG. CONCLUSIONS: A modification of Kendler's model for major depression provides a foundation for the development of a comprehensive developmental model of pathological gambling. Life-time history of gambling and 12-month pathological gambling appear to be determined by risk factors in several developmental levels, with the effect of earlier development tiers accounted for by later ones.

The space of common psychiatric disorders in adolescents: comorbidity structure and individual latent liabilities.

OBJECTIVE: To construct a virtual space of common adolescent psychiatric disorders, spanned by factors reflecting major psychopathological dimensions; and to locate psychiatric disorders in that space, examine whether the major psychopathological dimensions can be hierarchically organized, and determine the distribution of the latent scores of individuals in the space spanned by those dimensions. METHOD: Exploratory factor analyses of data from the National Comorbidity Survey Adolescent Supplement (NCS-A) using the psychiatric diagnoses as indicators were used to identify the latent major psychopathological dimensions. The loadings of the disorders on those dimensions were used as coordinates to calculate the distance among disorders. The distribution of individuals in the space was based on the latent scores on the factors reflecting the major psychopathological conditions. RESULTS: A model with 3 correlated factors provided an excellent fit (Comparative Fit Index [CFI] = 0.97, Tucker-Lewis Index [TLI] = 0.95, the root mean squared error of approximation [RMSEA] = 0.008) for the structure of disorders and a 4-factor model could be hierarchically organized, ultimately yielding a general psychopathology factor. Distances between disorders ranged from 0.079 (between social phobia and generalized anxiety disorder [GAD]) and 1.173 (between specific phobia and conduct disorder [CD]). At the individual level, there were 546 distinct liabilities observed (22% of all 2,455 potential liabilities). CONCLUSION: A novel way of understanding psychiatric disorders in adolescents is as existing in a space with a limited number of dimensions with no disorder aligning along 1 single dimension. These dimensions are hierarchically organized, allowing analyses at different levels of organization. Furthermore, individuals with psychiatric disorders present with a broad range of liabilities, reflecting the diversity of their clinical presentations.

Probability and predictors of the cannabis gateway effect: a national study.

BACKGROUND: While several studies have shown a high association between cannabis use and use of other illicit drugs, the predictors of progression from cannabis to other illicit drugs remain largely unknown. This study aims to estimate the cumulative probability of progression to illicit drug use among individuals with lifetime history of cannabis use, and to identify predictors of progression from cannabis use to other illicit drugs use. METHODS: Analyses were conducted on the sub-sample of participants in Wave 1 of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) who started cannabis use before using any other drug (n=6624). Estimated projections of the cumulative probability of progression from cannabis use to use of any other illegal drug use in the general population were obtained by the standard actuarial method. Univariate and multivariable survival analyses with time-varying covariates were implemented to identify predictors of progression to any drug use. RESULTS: Lifetime cumulative probability estimates indicated that 44.7% of individuals with lifetime cannabis use progressed to other illicit drug use at some time in their lives. Several sociodemographic characteristics, internalizing and externalizing psychiatric disorders and indicators of substance use severity predicted progression from cannabis use to other illicit drugs use. CONCLUSION: A large proportion of individuals who use cannabis go on to use other illegal drugs. The increased risk of progression from cannabis use to other illicit drugs use among individuals with mental disorders underscores the importance of considering the benefits and adverse effects of changes in cannabis regulations and of developing prevention and treatment strategies directed at curtailing cannabis use in these populations.

Toward a comprehensive developmental model of smoking initiation and nicotine dependence.

BACKGROUND: This study aims to identify predictors of smoking initiation and nicotine dependence (ND) to develop a comprehensive risk-factor model based on Kendler's development model for major depression. METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), Wave 2 (n=34,653). Risk factors were divided into five developmental tiers according to Kendler's model (childhood, early adolescence, late adolescence, adulthood, past-year). Hierarchical logistic regression models were built to predict the risk of smoking initiation and the risk of ND, given initiation. The continuation ratio (CR) was tested by ordinal logistic regression to examine whether the impact of the predictors was the same on smoking initiation or ND. RESULTS: The final models highlighted the importance of different tiers for each outcome. The CR identified substantial differences in the predictors of smoking initiation versus ND. Childhood tier appears to be more determinant for smoking initiation while the effect of more distal tiers (i.e. childhood and early adolescence) was tempered by more proximal ones (i.e. late adolescence, adulthood and past-year) in ND, with few sex differences. CONCLUSIONS: The differential effect of some predictors on each outcome shows the complexity of pathways from smoking initiation to ND. While some risk factors may be shared, others impact only at one stage or have even an inverse effect. An adaptation of Kendler's developmental model for major depression showed high predictive power for smoking initiation and ND.

Predictors of quit attempts and successful quit attempts among individuals with alcohol use disorders in a nationally representative sample.

BACKGROUND: This study sought to identify predictors of attempting to quit and of successfully quitting alcohol abuse or dependence in the general population. METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). RESULTS: Approximately 10% of individuals with alcohol abuse and 18% of those with dependence attempted to quit over the three year follow-up period. Of those who tried, 38% of individuals with abuse and 30% of those with dependence successfully quit. Among individuals with alcohol abuse or dependence, being single, younger than 40 years old, having low income, a co-occurring psychiatric disorder and greater number of dependence symptoms increased the likelihood of attempting to quit. Among individuals with alcohol abuse, male gender and low educational attainment further increased the odds of quit attempts. However, greater severity of alcohol use disorder, having a co-occurring drug use disorder and greater number of psychiatric disorders decreased the odds of success among individuals with alcohol abuse, while female gender, being married and older than 40 years old increased the odds of success. Among individuals with alcohol dependence, having nicotine dependence, greater number of psychiatric disorders and personality disorders decreased the odds of success. CONCLUSIONS: Predictors of attempts to quit are different and sometimes opposite from those leading to successful quitting probably indicating that some factors that increase motivation may decrease ability to quit. These findings may help in the development of more targeted and effective interventions for alcohol use disorders.

Concordance between gambling disorder diagnoses in the DSM-IV and DSM-5: Results from the National Epidemiological Survey of Alcohol and Related Disorders.

The fifth edition of the Diagnostic and Statistic Manual for Mental Disorders (DSM-5) eliminates the committing illegal acts criterion and reduces the threshold for a diagnosis of gambling disorder to 4 of 9 criteria. This study compared the DSM-5 "4 of 9" classification system to the "5 of 10" DSM-IV system, as well as other permutations (i.e., just lowing the threshold to 4 criteria or just eliminating the illegal acts criterion) in 43,093 respondents to the National Epidemiological Survey of Alcohol and Related Conditions. Subgroups were analyzed to ascertain whether changes will impact differentially diagnoses based on gender, age, or race/ethnicity. In the full sample and each subpopulation, prevalence rates were higher when the DSM-5 classification system was employed relative to the DSM-IV system, but the hit rate between the two systems ranged from 99.80% to 99.96%. Across all gender, age, and racial/ethnic subgroups, specificity was greater than 99% when the DSM-5 system was employed relative to the DSM-IV system, and sensitivity was 100%. Results from this study suggest that eliminating the illegal acts criterion has little impact on diagnosis of gambling disorder, but lowering the threshold for diagnosis does increase the base rate in the general population and each subgroup, even though overall rates remain low and sensitivity and specificity are high.

The latent structure and predictors of non-medical prescription drug use and prescription drug use disorders: a national study.

BACKGROUND: Despite growing concerns about non-medical prescription drug use and prescription drug use disorders, whether vulnerability for these conditions is drug-specific or occurs through a shared liability and common risk factors is unknown. METHODS: Exploratory and confirmatory factor analysis of Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions were used to examine the latent structure of non-medical prescription drug use and prescription drug use disorders. Multiple Indicators Multiple Causes (MIMIC) analysis was used to examine whether the effect of sociodemographic and psychiatric covariates occurred through the latent factor, directly on each drug class or both. RESULTS: A one-factor model described well the structure of both non-medical prescription drug use and prescription drug use disorders. Younger age, being White, having more intense pain or one of several psychiatric disorders increased the risk of non-medical prescription drug use through the latent factor. The same covariates, except for anxiety disorders also significantly increased the risk of prescription drug use disorders through the latent factor. Older age directly increased the risk of non-medical use of sedatives, and alcohol use disorders decreased the risk of non-medical tranquilizer use. No covariates had direct effects on the risk of any prescription drug use disorders beyond their effect through the latent factor. CONCLUSION: The risk for non-medical prescription drug use and prescription drug use disorders occurs through a shared liability. Treatment, prevention and policy approaches directed at these drugs as a group maybe more effective than those focused on individual classes of drugs.

Persistence of chronic major depression: a national prospective study.

BACKGROUND: Chronic major depressive disorder (CMDD) is highly prevalent and associated with high personal and societal cost. Identifying risk factors for persistence and remission of CMDD may help in developing more effective treatment and prevention interventions. METHODS: Prospective cohort study of individuals participating in the National Epidemiologic Survey on Alcohol and Related Conditions (Wave 1; n=43,093) and its 3-year follow-up (Wave 2; n=34,653) who met a diagnosis of CMDD at the Wave 1 assessment. RESULTS: Among the 504 respondents who met criteria for present CMDD at Wave 1, only 63 (11.52%) of them continued to meet criteria of CMDD. A history of childhood sexual abuse, earlier onset of MDD, presence of comorbidity and a history of treatment-seeking for depression predicted persistence of CMDD three years after the baseline evaluation. LIMITATIONS: Our sample is limited to adults, our follow-up period was only three-years and the diagnosis of CMDD at baseline was retrospective. CONCLUSIONS: CMDD shows high rates of remission within three years of baseline assessment, although some specific risk factors predict a persistent course. Given the high personal and societal cost associated with CMDD, there is a need to develop and disseminate effective interventions for CMDD.