The benefits of a longer course of cognitive behavioral therapy for some patients with social anxiety disorder.

Historically, cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) has been evaluated in randomized-controlled trials as a 12-16 session treatment and has demonstrated response rates ranging from 58% to 75%. Despite these promising results, some patients do not improve substantially after this short course of CBT. It is unclear whether non-responding patients would make substantial improvements in social anxiety with further treatment. In a university outpatient clinic specializing in CBT for SAD, we compared outcomes for patients who ended treatment after approximately 20 sessions of CBT (n = 38) to those who continued treatment for a variable number of additional sessions (n = 34). We found no between-group differences in demographic characteristics, number of comorbid diagnoses, comorbid generalized anxiety disorder or major depressive disorder, or severity of depression at baseline. Patients who ended treatment after 20 sessions experienced greater improvements in SAD over those 20 sessions compared to those who continued treatment. Both groups experienced changes in depression and quality of life over the first 20 sessions. Those who continued treatment showed additional decreases in social anxiety beyond session 20. For those who initially appear to be non-responsive to CBT for SAD, a longer course of treatment may elicit significant improvements.

The loss of a fellow service member: Complicated grief in post-9/11 service members and veterans with combat-related posttraumatic stress disorder.

Bereavement is a potent and highly prevalent stressor among service members and veterans. However, the psychological consequences of bereavement, including complicated grief (CG), have been minimally examined. Loss was assessed in 204 post-9/11, when service members and veterans with combat-related posttraumatic stress disorder (PTSD) took part in a multicenter treatment study. Those who reported the loss of an important person completed the inventory of complicated grief (ICG; n = 160). Over three quarters (79.41%) of the sample reported an important lifetime loss, with close to half (47.06%) reporting the loss of a fellow service member (FSM). The prevalence of CG was 24.75% overall, and nearly one third (31.25%) among the bereaved. CG was more prevalent among veterans who lost a fellow service member (FSM) (41.05%, n = 39) compared to those bereaved who did not (16.92%, n = 11; OR = 3.41, 95% CI: 1.59, 7.36). CG was associated with significantly greater PTSD severity, functional impairment, trauma-related guilt, and lifetime suicide attempts. Complicated grief was prevalent and associated with adverse psychosocial outcomes in veterans and service members with combat-related PTSD. Clinicians working with this population should inquire about bereavement, including loss of a FSM, and screen for CG. Additional research examining CG in this population is needed.

MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma.

BACKGROUND: MET gene amplification and Met protein overexpression may be associated with a poor prognosis. The MET/Met status is typically determined with fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Targeted proteomics uses mass spectrometry-based selected reaction monitoring (SRM) to accurately quantitate Met expression. FISH, IHC, and SRM analyses were compared to characterize the prognostic value of MET/Met in gastroesophageal adenocarcinoma (GEC). METHODS: Samples from 447 GEC patients were analyzed for MET gene amplification (FISH) and Met protein expression (IHC and SRM). Cox proportional hazards models and Kaplan-Meier estimates were applied to explore relations between Met, overall survival (OS), and clinical/pathological characteristics. Spearman's rank coefficient was used to assess the correlation between parameters. RESULTS: Patients with MET-amplified tumors had worse OS when: the MET/centromere enumeration probe for chromosome 7 FISH ratio was ≥ 2 (hazard ratio [HR], 3.13; 95% confidence interval [CI], 1.84-5.33), the MET gene copy number was ≥5 (HR, 2.51; 95% CI, 1.45-4.34), or ≥ 10% of the cells had ≥15 copies (HR, 4.28; 95% CI, 2.18-8.39). Similar observations were made with Met protein overexpression by IHC (≥1 + intensity in ≥ 25% of the tumor cell membrane: HR, 1.39; 95% CI, 1.04-1.86) or SRM (≥400 amol/µg: HR, 1.76; 95% CI, 1.06-2.90). A significant correlation was observed between MET FISH/Met IHC, MET FISH/Met SRM, and Met IHC/Met SRM; only MET FISH and Met SRM were independent negative prognostic biomarkers in multivariate analyses. CONCLUSIONS: MET amplification and overexpression, assessed by multiple methods, were associated with a worse prognosis in univariate analyses. However, only MET amplification by FISH and Met expression by SRM were independent prognostic biomarkers. Compared with IHC, SRM may provide an added benefit for informed decisions about Met-targeted therapy. Cancer 2017;123:1061-70. © 2016 American Cancer Society.

Outcomes From Pediatric Gastroenterology Maintenance of Certification Using Web-based Modules.

OBJECTIVES: Beginning in 2013, the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) sponsored and developed subspecialty field-specific quality improvement (QI) activities to provide Part 4 Maintenance of Certification (MOC) credit for ongoing certification of pediatric gastroenterologists by the American Board of Pediatrics. Each activity was a Web-based module that measured clinical practice data repeatedly over at least 3 months as participants implemented rapid cycle change. Here, we examine existing variations in clinical practice among participating pediatric gastroenterologists and determine whether completion of Web-based MOC activities improves patient care processes and outcomes. METHODS: We performed a cross-sectional and prospective analysis of physician and parent-reported clinical practice data abstracted from Web-based MOC modules on the topics of upper endoscopy, colonoscopy, and informed consent collected from pediatric gastroenterologists from North America from 2013 to 2016. RESULTS: Among 134 participating pediatric gastroenterologists, 56% practitioners practiced at an academic institution and most (94%) were NASPGHAN members. Participating physicians reported data from 6300 procedures. At baseline, notable practice variation across measured activities was demonstrated. Much of the rapid cycle changes implemented by participants involved individual behaviors, rather than system/team-based improvement activities. Participants demonstrated significant improvements on most targeted process and quality care outcomes. CONCLUSIONS: Pediatric gastroenterologists and parents reported baseline practice variation, and improvement in care processes and outcomes measured during NASPGHAN-sponsored Web-based MOC QI activities. Subspecialty-oriented Web-based MOC QI activities can reveal targets for reducing unwarranted variation in clinical pediatric practice, and can effectively improve care and patient outcomes.

Therapeutically Induced Changes in HER2, HER3, and EGFR Protein Expression for Treatment Guidance.

Protein-targeted therapies are expected to selectively kill tumor cells that express the targeted protein biomarker. Although a tumor mass may initially respond to targeted therapies based on expression of the targeted protein, all cells within a tumor may not express the targeted protein above a critical threshold level; therefore, those cells that do not express, or that downregulate expression of, the targeted protein may not be responsive to therapy. The ability to monitor the dynamic expression of these protein biomarkers throughout the course of therapy may allow for treatment to be personalized in real-time in response to the evolving nature of the tumor. This report demonstrates, by monitoring a single patient through multiple therapies, how targeted mass spectrometry is an effective, quantitative method that provides real-time analysis of multiple therapeutically associated targeted proteins that can be used to personalize a patient's treatment strategy throughout the course of care.

Mass-spectrometry-based quantitation of Her2 in gastroesophageal tumor tissue: comparison to IHC and FISH.

BACKGROUND: Trastuzumab has shown a survival benefit in cases of Her2-positive gastroesophageal cancer (GEC). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) currently determine eligibility for trastuzumab-based therapy. However, these low-throughput assays often produce discordant or equivocal results. METHODS: We developed a targeted proteomic assay based on selected reaction monitoring mass spectrometry (SRM-MS) and quantified levels (amol/µg) of Her2-SRM protein in cell lines (n = 27) and GEC tissues (n = 139). We compared Her2-SRM protein expression with IHC/FISH, seeking to determine optimal SRM protein expression cutoffs in order to identify HER2 gene amplification. RESULTS: After demonstrating assay development, precision, and stability, Her2-SRM protein measurement was observed to be highly concordant with the HER2/CEP17 ratio, particularly in a multivariate regression model adjusted for SRM expression of the covariates Met, Egfr, Her3, and HER2 heterogeneity, as well as their interactions (cell lines r (2) = 0.9842; FFPE r (2) = 0.7643). In GEC tissues, Her2-SRM protein was detected at any level in 71.2 % of cases. ROC curves demonstrated that Her2-SRM protein levels have a high specificity (100 %) at an upper-level cutoff of >750 amol/µg and sensitivity of 75 % at a lower-level cutoff of <450 amol/µg for identifying HER2 FISH-amplified tumors. An "equivocal zone" of 450-750 amol/µg of Her2-SRM protein was analogous to IHC2+ but represented fewer cases (9-16 % of cases versus 36-41 %). CONCLUSIONS: Compared to IHC, targeted SRM-Her2 proteomics provided more objective and quantitative Her2 expression with excellent HER2/CEP17 FISH correlation and fewer equivocal cases. Along with its multiplex capability for other relevant oncoproteins, these results demonstrate a refined HER2 protein expression assay for clinical application.

Cognitive Behavioral Therapy for Social Anxiety Disorder: Predictors of Treatment Outcome in a Quasi-Naturalistic Setting.

We examined the outcomes of individual cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) in a sample of 93 adults seeking treatment in a university outpatient clinic specializing in CBT for SAD. Treatment followed the structure of a manual, but number of sessions varied according to client needs. After approximately 20 weeks of therapy, patients' social anxiety had decreased and their quality of life had increased. Patients with more severe SAD or comorbid major depressive disorder (MDD) at pretreatment demonstrated higher levels of social anxiety averaged across pre- and posttreatment. However, clinician-rated severity of SAD, comorbid MDD, or comorbid generalized anxiety disorder did not predict treatment outcome. Higher pretreatment scores on measures of safety behaviors and cognitive distortions were associated with higher social anxiety averaged across pre- and posttreatment and predicted greater decreases from pre- to posttreatment on multiple social anxiety outcome measures. We found no predictors of change in quality of life. Those with high levels of safety behaviors and distorted cognitions may benefit more from CBT, perhaps due to its emphasis on targeting avoidance through exposure and changing distorted thinking patterns through cognitive restructuring methods. Our study lends support to the body of research suggesting that manualized CBT interventions can be applied flexibly in clinical settings with promising outcomes for patients over a relatively short course of therapy.

Reductions in social anxiety during treatment predict lower levels of loneliness during follow-up among individuals with social anxiety disorder.

INTRODUCTION: Individuals with social anxiety disorder (SAD) are at elevated risk of loneliness, yet little research has examined loneliness in this population. Cognitive-behavioral group therapy (CBGT) and mindfulness-based stress reduction (MBSR) have demonstrated efficacy in treating SAD, yet research has not examined whether they lead to reductions in loneliness. METHODS: This sample comprised 108 individuals with SAD who were randomized to CBGT, MBSR, or a waitlist control (WL); WL participants were re-randomized to CBGT or MBSR following WL. Assessments were completed pre- and post-treatment, and 3-, 6-, 9-, and 12-month follow-up assessments. RESULTS: Compared to WL, individuals in CBGT and MBSR were less lonely at post-treatment; there was no difference between treatments after treatment or during follow-up. Greater reductions in social anxiety from pre- to post-treatment predicted lower levels of loneliness during follow-up. Greater reductions in loneliness from pre- to post-treatment also predicted lower levels of social anxiety during follow-up. DISCUSSION: Individuals who experience reductions in their social anxiety during treatment may also feel less lonely following treatment. Reductions in loneliness also lead to improvements in social anxiety. Future research should continue to examine the relationship between social anxiety and loneliness and how interventions for SAD may help reduce loneliness.

Shame, guilt, and pride after loss: Exploring the relationship between moral emotions and psychopathology in bereaved adults.

BACKGROUND: Self-blame following bereavement has been implicated in the development of post-loss psychopathology. However, prior studies have not distinguished between the emotions of shame versus guilt. This study examined the cross-sectional associations among bereavement-related shame, bereavement-related guilt, and two mental disorders that commonly arise after bereavement: complicated grief and depression. In addition, exploratory analyses examined the associations between bereavement-related pride and post-loss psychopathology. METHODS: Participants included 92 bereaved adults who experienced the death of a family member at least one year prior to the study. Participants completed self-report measures of complicated grief symptoms, depression symptoms, shame, guilt, and pride. RESULTS: Shame and guilt were positively correlated with complicated grief and depression symptoms. When controlling for their shared variance, only shame remained a significant predictor of post-loss psychopathology. Follow-up analyses indicated that the effect of guilt on psychopathology depended on the level of shame, and vice versa. At low shame, guilt predicted psychopathology; however guilt did not predict psychopathology at moderate to high shame. At low to moderate guilt, shame predicted psychopathology; however shame did not predict psychopathology at high guilt. Pride negatively predicted depression symptoms, but not complicated grief symptoms, when we controlled for shame and guilt. LIMITATIONS: Limitations include the cross-sectional design and modest sample size. CONCLUSIONS: Our analyses identify shame as the more pathogenic moral emotion for bereaved adults. However, whereas guilt in the absence of shame is often considered adaptive, we found that guilt predicted greater psychological distress at low levels of shame in this sample.

Circulating PACAP peptide and PAC1R genotype as possible transdiagnostic biomarkers for anxiety disorders in women: a preliminary study.

Pituitary adenylate cyclase activating polypeptide (PACAP, gene Adcyap1) is a neuropeptide and hormone thought to play a critical role in stress response (Stroth et al., Ann NY Acad Sci 1220:49-59, 2011; Hashimoto et al., Curr Pharm Des 17:985-989, 2011). Research in humans implicates PACAP as a useful biomarker for the severity of psychiatric symptoms in response to psychological stressors, and work in rodent models suggests that PACAP manipulation exerts downstream effects on peripheral hormones and behaviors linked to the stress response, providing a potential therapeutic target. Prior work has also suggested a potential sex difference in PACAP effects due to differential estrogen regulation of this pathway. Therefore, we examined serum PACAP and associated PAC1R genotype in a cohort of males and females with a primary diagnosis of generalized anxiety disorder (GAD) and nonpsychiatric controls. We found that, while circulating hormone levels were not associated with a GAD diagnosis overall (p = 0.19, g = 0.25), PACAP may be associated with GAD in females (p = 0.04, g = 0.33). Additionally, among patients with GAD, the risk genotype identified in the PTSD literature (rs2267735, CC genotype) was associated with higher somatic anxiety symptom severity in females but lower somatic anxiety symptom severity in males (-3.27, 95%CI [-5.76, -0.77], adjusted p = 0.03). Taken together, the associations between the risk genotype, circulating PACAP, and somatic anxiety severity were stronger among females than males. These results indicate a potential underlying biological etiology for sex differences in stress-related anxiety disorders that warrants further study.

Targeting separate specific learning parameters underlying cognitive behavioral therapy can improve perceptual judgments of anger.

BACKGROUND AND OBJECTIVES: Anxiety disorders are characterized by biased perceptual judgment. An experimental model using simple verbal instruction to target specific decision parameters that influence perceptual judgment was developed to test if it could influence anger perception, and to examine differences between individuals with social anxiety disorder (SAD) relative to generalized anxiety disorder (GAD) or non-psychiatric controls. METHODS: Anger perception was decomposed into three decision parameters (perceptual similarity of angry vs. not-angry facial expressions, base rate of encountering angry vs. not-angry expressions, payoff for correct vs. incorrect categorization of face stimuli) using a signal detection framework. Participants with SAD (n = 97), GAD (n = 90), and controls (n = 98) were assigned an instruction condition emphasizing one of the three decision parameters. Anger perception pre-vs. post-instruction and its interaction with diagnosis were examined. RESULTS: For all participants, base rate instructions impacted response bias over and above practice effects, supporting the validity of this instructional task-based approach to altering response bias. We failed to find a similarity or payoff instruction effect, nor a diagnosis interaction. LIMITATIONS: Future instructional tasks may need to more closely target core cognitive and perceptual biases in anxiety disorders to identify specific deficits and how to optimally influence them. CONCLUSIONS: This study demonstrates that specific decision parameters underlying perceptual judgment can be experimentally manipulated. Although our study failed to show diagnosis specific effects, it suggests that individual parameter "estimation" deficits may be experimentally isolated and potentially targeted, with the ultimate goal of developing an objective approach to personalized intervention targeting biased perceptual judgments in anxiety disorders.

Do sudden gains predict treatment outcome in social anxiety disorder? Findings from two randomized controlled trials.

OBJECTIVE: Sudden gains (SGs) have been found to occur during randomized controlled trials (RCTs) for social anxiety disorder (SAD). Evidence is mixed whether SGs relate to treatment outcome in SAD. We examined SGs in two RCTs for SAD. METHOD: Study 1 (N = 68) examined SGs in individual cognitive-behavioral therapy (CBT), and Study 2 (N = 100) compared SGs in group CBT and Mindfulness-Based Stress Reduction (MBSR). Weekly ratings of social anxiety were used to calculate SGs. The Liebowitz Social Anxiety Scale-Self-Report and the Social Interaction Anxiety Scale were completed at pretreatment, posttreatment, and follow-up to assess outcome. RESULTS: In Study 1, 17.6% of participants experienced a SG. Participants with SGs started and ended treatment with lower social anxiety. SGs were not associated with greater decreases in social anxiety from pre-to posttreatment or 12-month follow-up. In Study 2, SGs occurred in 27% of participants and at comparable rates in MBSR and group CBT. SGs were not associated with changes in social anxiety during treatment in either condition. CONCLUSION: SGs occurred during treatment for SAD. In both RCTs, participants improved regardless of experiencing a SG, suggesting that SGs are not predictive of greater improvement during treatment for SAD.

Associations between feelings of social anxiety and emotion perception.

BACKGROUND: Abnormally biased perceptual judgment is a feature of many psychiatric disorders. Thus, individuals with social anxiety disorder are biased to recall or interpret social events negatively. Cognitive behavioral therapy addresses such bias by teaching patients, via verbal instruction, to become aware of and change pathological misjudgment. The present study examined whether targeting verbal instruction to specific decision parameters that influence perceptual judgment may affect changes in anger perception. METHOD: We used a signal detection framework to decompose anger perception into three decision parameters (base rate of encountering anger vs. no-anger, payoff for correct vs. incorrect categorization of face stimuli, and perceptual similarity of angry vs. not-angry facial expressions). We created brief verbal instructions that emphasized each parameter separately. Participants with social anxiety disorder, generalized anxiety disorder, and healthy controls, were assigned to one of the three instruction conditions. We compared anger perception pre-vs. post-instruction. RESULTS: Base rate and payoff instructions affected response bias over and above practice effects, across the three groups. There was no interaction with diagnosis. DISCUSSION: The ability to target specific decision parameters that underlie perceptual judgment suggests that cognitive behavioral therapy might be improved by tailoring it to patients' individual parameter "estimation" deficits.

Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma.

Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ≥1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.Significance: This paper highlights the role of EGFR inhibitors in EGFR-amplified GEA-despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. Cancer Discov; 8(6); 696-713. ©2018 AACR.See related commentary by Strickler, p. 679This article is highlighted in the In This Issue feature, p. 663.

Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.

In the Supplementary Information originally published with this article, a lane was missing in the ß-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article.

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma.

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37-48. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Janjigian et al., p. 49This article is highlighted in the In This Issue feature, p. 1.

Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.

The role of KRAS, when activated through canonical mutations, has been well established in cancer1. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2-4. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.