Serial cytoreductive surgery and survival outcomes in recurrent adult-type ovarian granulosa cell tumors.

BACKGROUND: Few studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared with systemic therapy alone following the first recurrence and subsequent disease progressions. OBJECTIVE: This study aimed to determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. STUDY DESIGN: This is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumors of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least 1 documented recurrence, and treatment/treatment planning at the MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery, and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier, and were modeled via Cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. RESULTS: Among the 369 patients with adult granulosa cell tumors of the ovary in the registry, 149 patients met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (hazard ratio, 0.37; 95% confidence interval, 0.17-0.81, P=.01) and multivariable analyses (hazard ratio, 0.42; 95% confidence interval, 0.19-0.92; P=.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared with those who did not undergo cytoreductive surgery (181.92 vs 61.56 months, respectively; P=.002). Overall survival benefit remained statistically significant on multivariable analysis (hazard ratio, 0.28; 95% confidence interval, 0.11-0.67; P=.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (hazard ratio, 0.43; 95% confidence interval, 0.26-0.70; P=.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (hazard ratio, 0.74; 95% confidence interval, 0.42-1.26; P=.27). CONCLUSION: Among those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may have a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumors of the ovary.

Person-specific dynamics between negative emotions and suicidal thoughts.

INTRODUCTION: Recent technology has enabled researchers to collect ecological momentary assessments (EMA) to examine within-person correlates of suicidal thoughts. Prior studies examined generalized temporal dynamics of emotions and suicidal thinking over brief periods, but it is not yet known how variable these processes are across people. METHOD: We use data EMA data delivered over two weeks with youth/young adults (N = 60) who reported past year self-injurious thoughts/behaviors. We used group iterative multiple model estimation (GIMME) to model group- and person-specific associations of negative emotions (i.e., fear, sadness, shame, guilt, and anger) and suicidal thoughts. RESULTS: 29 participants (48.33%) reported at least one instance of a suicidal thought and were included in GIMME models. In group level models, we consistently observed autoregressive effects for suicidal thoughts (e.g., earlier thoughts predicting later thoughts), although the magnitude and direction of this link varied from person-to-person. Among emotions, sadness was most frequently associated with contemporaneous suicidal thoughts, but this was evident for less than half of the sample, while other emotional correlates of suicidal thoughts broadly differed across people. No emotion variable was linked to future suicidal thoughts in >14% of the sample, CONCLUSIONS: Emotion-based correlates of suicidal thoughts are heterogeneous across people. Better understanding of the individual-level pathways maintaining suicidal thoughts/behaviors may lead to more effective, personalized interventions.

EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer.

Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.

Using the experience sampling method to support clinical practice: An illustration with problematic cannabis use.

The experience sampling method (ESM) has been frequently used in clinical research; however, there is low translational uptake in clinical practice. This may be due to challenges with interpreting individual-level data at granular intervals. We provide an illustrative example of how ESM can be leveraged to generate personalized cognitive-behavioral strategies for problematic cannabis use.We conducted a descriptive case series analysis using ESM data from 30 individuals reporting on problematic cannabis use, craving, affect, and coping four times daily for 16-days (t = 64, T = 1,920).Analyzing ESM data using descriptive statistics and visualizations from individuals with similar clinical and demographic profiles supported a diverse array of personalized clinical insights and recommendations for each case. These recommendations included psychoeducation regarding affect- and boredom-regulation strategies, functional analyses of occasions during which cannabis was not used, and discussions on how cannabis use intersects with one's personal values.While many clinicians utilize measurement-based care, barriers have limited the incorporation of ESM towards personalized, data-informed approaches to treatment. We provide an illustrative example of how ESM data can be used to generate actionable treatment strategies for problematic cannabis use and highlight continued challenges with interpreting time-series data.

Clinical implications of tumor-based next-generation sequencing in high-grade epithelial ovarian cancer.

BACKGROUND: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer. METHODS: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox regression and clustering analyses were used to identify patterns of genetic alterations associated with survival. RESULTS: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results. Nearly all (96.1% [393/409]) had one or more genetic alterations. In 25.9% (106/409) of patients, an alteration that aligned with a targeted treatment was identified, and in an additional 48.7% (199/409), tbNGS results suggested eligibility for an investigational agent or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations, and CCNE1 amplification. Together, BRCA1 and BRCA2 mutations were associated with longer PFS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.42-0.92; p = .02), whereas AKT2 amplification was associated with shorter PFS (HR, 3.86; 95% CI, 1.002-14.88; p < .05). Multivariate Cox regression and clustering analyses identified several combinations of genetic alterations that corresponded to outcomes in patients with high-grade serous carcinoma. CONCLUSIONS: tbNGS often yields clinically relevant information. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools. PLAIN LANGUAGE SUMMARY: Although more and more patients with ovarian cancer are undergoing tumor-based next-generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established. In a group of over 400 patients with ovarian cancer who underwent tumor-based next-generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option.

Clinical outcomes of leuprolide acetate in the treatment of recurrent ovarian granulosa cell tumors.

BACKGROUND: The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Preclinical studies and small case series have suggested direct antitumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach. OBJECTIVE: This study aimed to describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors. STUDY DESIGN: This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting inclusion criteria had a diagnosis of recurrent granulosa cell tumor and received either leuprolide acetate or traditional chemotherapy as cancer treatment. Outcomes were separately examined for leuprolide acetate used as adjuvant treatment, maintenance therapy, and the treatment of gross disease. Demographic and clinical data were summarized using descriptive statistics. Progression-free survival was calculated from the initiation of treatment to the date of disease progression or death, and compared between groups with the log-rank test. The 6-month clinical benefit rate was defined as the percentage of patients without disease progression 6 months after starting therapy. RESULTS: Sixty-two patients received a total of 78 leuprolide acetate-containing therapy courses, owing to 16 instances of retreatment. Of these 78 courses, 57 (73%) were for treatment of gross disease, 10 (13%) were adjuvant to tumor reductive surgery, and 11 (14%) were for maintenance therapy. Patients had received a median of 2 (interquartile range, 1-3) systemic therapy regimens before their first leuprolide acetate treatment. Tumor reductive surgery (100% [62/62]) and platinum-based chemotherapy (81% [50/62]) were common before first leuprolide acetate exposure. The median duration of leuprolide acetate therapy was 9.6 months (interquartile range, 4.8-16.5). Nearly half of the therapy courses were single-agent leuprolide acetate (49% [38/78]). Combination regimens most often included an aromatase inhibitor (23% [18/78]). Disease progression was the most common cause of discontinuation (77% [60/78]); only 1 patient (1%) discontinued leuprolide acetate because of adverse events. In the treatment of gross disease, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% (95% confidence interval, 54-82). Median progression-free survival was not statistically different compared with that which followed chemotherapy (10.3 months [95% confidence interval, 8.0-16.0] vs 8.0 months [95% confidence interval, 5.0-15.3]; P=.3). CONCLUSION: In a large cohort of patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate of first-time leuprolide acetate treatment of gross disease was 66% and progression-free survival was comparable to patients treated with chemotherapy. Leuprolide acetate regimens were heterogeneous, but significant toxicity was rare. These results support leuprolide acetate as safe and effective for the treatment of relapsed adult granulosa cell tumors in the second line and beyond.

Characterizing morphologic subtypes of high-grade serous ovarian cancer by CT: a retrospective cohort study.

OBJECTIVE: A novel classification system of high-grade serous ovarian carcinoma based on gross morphology observed at pre-treatment laparoscopy was recently defined. The purpose of this study was to identify radiographic features unique to each morphologic subtype. METHODS: This retrospective study included 109 patients with high-grade serous ovarian cancer who underwent pre-operative computed tomography (CT) scanning and laparoscopic assessment of disease burden between 1 April 2013 and 5 August 2015. Gross morphologic subtype had been previously assigned by laparoscopy. Two radiologists independently reviewed CT images for each patient, categorized disease at eight anatomic sites, and assessed for radiographic characteristics of interest: large infiltrative plaques, mass-like metastases, enhancing peritoneal lining, architectural distortion, fat stranding, calcifications, and lymph node involvement. Demographic and clinical information was summarized with descriptive statistics and compared using Student's t-tests, χ² tests, or Fisher exact tests as appropriate; kappa statistics were used to assess inter-reader agreement. RESULTS: Certain radiographic features were found to be associated with gross morphologic subtype. Large infiltrative plaques were more common in type 1 disease (88.7% (47/53) vs 71.4% (25/35), p=0.04), while mass-like metastases were more often present in type 2 disease (48.6% (17/35) vs 22.6% (12/53), p=0.01). Additionally, radiographic presence of disease at the falciform ligament was more common in type 1 morphology (33.9% (19/56) vs 13.2% (5/38), p=0.02). CONCLUSION: Morphologic subtypes of high-grade serous ovarian cancer were associated with specific CT findings, including the presence of large infiltrative plaques, mass-like metastases, and falciform ligament involvement.

Sexual Offense Disclosure Assessment in Youth Referred to Community Treatment: A Latent Class Analysis.

This study seeks to extend research evaluating tools to assess the disclosure of sexually abusive behavior. The subjects were 239 male youth (ages 10-20 years) who were court-ordered to participate in a community-based collaborative intervention for sexual offending that includes outpatient and probationary services. All youth participated in an interview to capture referral incident details about admission, responsibility, empathy, and remorse at intake, during intervention, and at discharge. Intake, treatment, discharge, and recidivism measures were also collected from multiple sources. Latent class analysis identified three classes based on the intake interview: Empathetic Admitters (22%), Unempathetic Admitters (38%), and Unempathetic Deniers (40%). Significant class differences were found on intake (e.g., use of physical force, caregiver denial of youth responsibility), treatment (e.g., any sanctions/violations), and discharge measures (e.g., successful treatment, probation officer ratings), but not in recidivism rates. The findings extend efforts to identify and target different disclosure patterns whose clinical monitoring may support a comprehensive intervention.

Personalized models of personality disorders: using a temporal network method to understand symptomatology and daily functioning in a clinical sample.

BACKGROUND: An ongoing challenge in understanding and treating personality disorders (PDs) is a significant heterogeneity in disorder expression, stemming from variability in underlying dynamic processes. These processes are commonly discussed in clinical settings, but are rarely empirically studied due to their personalized, temporal nature. The goal of the current study was to combine intensive longitudinal data collection with person-specific temporal network models to produce individualized symptom-level structures of personality pathology. These structures were then linked to traditional PD diagnoses and stress (to index daily functioning). METHODS: Using about 100 daily assessments of internalizing and externalizing domains underlying PDs (i.e. negative affect, detachment, impulsivity, hostility), a temporal network mapping approach (i.e. group iterative multiple model estimation) was used to create person-specific networks of the temporal relations among domains for 91 individuals (62.6% female) with a PD. Network characteristics were then associated with traditional PD symptomatology (controlling for mean domain levels) and with daily variation in clinically-relevant phenomena (i.e. stress). RESULTS: Features of the person-specific networks predicted paranoid, borderline, narcissistic, and obsessive-PD symptom counts above average levels of the domains, in ways that align with clinical conceptualizations. They also predicted between-person variation in stress across days. CONCLUSIONS: Relations among behavioral domains thought to underlie heterogeneity in PDs were indeed associated with traditional diagnostic constructs and with daily functioning (i.e. stress) in person-specific networks. Findings highlight the importance of leveraging data and models that capture person-specific, dynamic processes, and suggest that person-specific networks may have implications for precision medicine.

Sex Differences in Subjective and Behavioral Responses to Stressful and Smoking Cues Presented in the Natural Environment of Smokers.

INTRODUCTION: Some evidence suggests that female smokers may show more context-dependent smoking and that males may show more stereotyped smoking (regardless of stress or cue exposure). The goal of this study was to characterize sex differences in response to stressful and smoking cues ecologically presented in daily life and variability in day-to-day smoking behavior. METHODS: Adult smokers (N = 177) provided ratings of mood and cigarette craving before and after stress and smoking cues were presented four times daily for 14 days via a mobile device. Linear mixed models tested whether (1) female smokers exhibited greater reactivity to stressful cues than male smokers; (2) pre-cue negative affect increased reactivity to smoking cues more in female smokers than male smokers; (3) across both sexes, greater reactivity to stressful and smoking cues correlated with greater quantity of smoking within a day; and (4) female smokers exhibited greater variability in cigarettes per day (CPD) relative to males. RESULTS: Relative to male smokers, female smokers reported greater negative affect, stress, and craving in response to stressful cues, but not smoking cues, after accounting for time since last cigarette and pre-cue responding. No sex differences in CPD or variability in CPD were detected. Days with higher subjective reactivity to cues were not associated with increased smoking, in either males or females. CONCLUSIONS: Sex differences were observed in response to stress but not smoking cues in the natural environment of regular cigarette smokers. Further research is necessary to evaluate whether stress reactivity in female smokers is associated with reduced latency to smoke following stress exposure in daily life. IMPLICATIONS: This study provides naturalistic evidence that female smokers may not be more reactive to smoking cues than males, but experience heightened stress and craving following stress exposure. There was no evidence to support the hypothesis that amount smoked per day varied more for females, relative to males, as a result of more context-driven smoking for females.

Psychosocial functioning among regular cannabis users with and without cannabis use disorder.

BACKGROUND: In the United States, cannabis accessibility has continued to rise as the perception of its harmfulness has decreased. Only about 30% of regular cannabis users develop cannabis use disorder (CUD), but it is unclear if individuals who use cannabis regularly without ever developing CUD experience notable psychosocial impairment across the lifespan. Therefore, psychosocial functioning was compared across regular cannabis users with or without CUD and a non-user control group during adolescence (age 17; early risk) and young adulthood (ages 18-25; peak CUD prevalence). METHOD: Weekly cannabis users with CUD (n = 311), weekly users without CUD (n = 111), and non-users (n = 996) were identified in the Minnesota Twin Family Study. Groups were compared on alcohol and illicit drug use, psychiatric problems, personality, and social functioning at age 17 and from ages 18 to 25. Self-reported cannabis use and problem use were independently verified using co-twin informant report. RESULTS: In both adolescence and young adulthood, non-CUD users reported significantly higher levels of substance use problems and externalizing behaviors than non-users, but lower levels than CUD users. High agreement between self- and co-twin informant reports confirmed the validity of self-reported cannabis use problems. CONCLUSIONS: Even in the absence of CUD, regular cannabis use was associated with psychosocial impairment in adolescence and young adulthood. However, regular users with CUD endorsed especially high psychiatric comorbidity and psychosocial impairment. The need for early prevention and intervention - regardless of CUD status - was highlighted by the presence of these patterns in adolescence.

Cutaneous manifestations of metastatic Crohn's disease.

Metastatic Crohn's disease is a rare cutaneous complication of primary Crohn's disease. It is a granulomatous inflammatory process, similar to the pathogenic mechanism of Crohn's disease, that occurs in sites discontiguous from the gastrointestinal tract. Metastatic Crohn's disease can precede the development of Crohn's disease by months to years, and children are more likely to present with metastatic Crohn's disease in the absence of gastrointestinal symptoms. Given that approximately 30% of individuals with Crohn's disease present in childhood, early recognition of extraintestinal manifestations of Crohn's disease such as metastatic Crohn's disease can aid in timely diagnosis and management of bowel disease. We present data from two pediatric cases of metastatic Crohn's disease recently seen at our institution in addition to the 61 reported cases of pediatric metastatic Crohn's disease in the literature. This review article will focus on the epidemiology, pathogenesis, clinical features, and histology of and treatment options for pediatric metastatic Crohn's disease.

Incidence of Primary Mitochondrial Disease in Children Younger Than 2 Years Presenting With Acute Liver Failure.

BACKGROUND: Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an important cause of acute liver failure (ALF) in infancy. Early and accurate diagnosis is important because liver transplantation (LT) is often contraindicated. It is unclear which methods are the best to diagnose MLD in the setting of ALF. OBJECTIVE: The aim of the study was to determine the incidence of MLD in children younger than 2 years with ALF and the utility of routine investigations to detect MLD. METHODS: Thirty-nine consecutive infants with ALF were admitted to a single unit from 2009 to 2011. All were extensively investigated using an established protocol. Genes implicated in mitochondrial DNA depletion syndrome were sequenced in all cases and tissue mtDNA copy number measured where available. RESULTS: Five infants (17%) had genetically proven MLD: DGUOK (n = 2), POLG (n = 2), and MPV17 (1). Four of these died, whereas 1 recovered. Two had normal muscle mtDNA copy number and 3 had normal muscle respiratory chain enzymes. An additional 8 children had low hepatic mtDNA copy number but pathogenic mutations were not detected. One of these developed fatal multisystemic disease after LT, whereas 5 who survived remain well without evidence of multisystemic disease up to 6 years later. Magnetic resonance spectroscopy did not distinguish between those with and without MLD. CONCLUSIONS: Low liver mtDNA copy number may be a secondary phenomenon in ALF.Screening for mtDNA maintenance gene mutations may be the most efficient way to confirm MLD in ALF in the first 2 years of life.

Examining time-varying dynamics of co-occurring depressed mood and anxiety.

BACKGROUND: Dimensional frameworks of psychopathology call for multivariate approaches to map co-occurring disorders to index what symptoms emerge when and for whom. Ecological momentary assessment (EMA) offers a method for assessing and differentiating the dynamics of co-occurring symptoms with greater temporal granularity and naturalistic context. The present study used multivariate mixed effects location-scale modeling to characterize the time-varying dynamics of depressed mood and anxiety for women diagnosed with social anxiety disorder (SAD) and major depression (MDD). METHODS: Women completed five daily EMA surveys over 30 days (150 EMA surveys/woman, T ≈ 5250 total observations) and two clinical diagnostic and retrospective self-report measures administered approximately two months apart. RESULTS: There was evidence of same-symptom lagged effects (bs = 0.08-0.09), but not cross-symptom lagged effects (bs < 0.01) during EMA. Symptoms co-varied such that momentary spikes from one's typical level of anxiety were associated with increases in momentary depressed mood (b = 0.19) and greater variability of depressed mood (b = 0.06). Similarly, spikes from one's typical levels of depressed mood were associated with increases in momentary anxiety (b = 0.19). Furthermore, the presence and magnitude of effects demonstrated person-specific heterogeneity. LIMITATIONS: Our findings are constrained to the dynamics of depressed and anxious mood among cisgender women with primary SAD and current or past MDD. CONCLUSIONS: Findings from this work help to characterize how daily experiences of co-occurring mood and anxiety fluctuate and offer insight to aid the development of momentary, person-specific interventions designed to regulate symptom fluctuations.

The link between daily affective complexity and anxiety is altered by oral contraceptive use.

Affective complexity - the unique ways in which individuals' emotions covary and differentiate - is an important aspect of internalizing problems. For instance, daily affective complexity has been linked to anxiety increases in women and to decreases in men. The mechanisms underlying this gender difference have not been widely investigated, but a role for ovarian hormones is likely. Research on oral contraceptives (OCs) provides promising insights into such mechanisms, as OCs suppress endogenous ovarian hormone production and vary in exogenous hormone formulations. Thus, the goal of this study was to examine links between daily affective complexity and internalizing problems in OC users (n = 84), focusing on dimensionally-assessed anxiety, and to investigate whether the links varied by pill formulation. Affective complexity was operationalized as number of factors for each person, as estimated by p-technique (i.e., person-specific factor analysis) of 75-day intensive longitudinal data. There was not a relation between affective complexity and anxiety in OC users, and this did not depend on OC pill formulation (i.e., estrogenic, progestational, or androgenic activities). Thus, OC use may blunt the relation between affective complexity and anxiety, as OC users had a relation in between the established positive relation for naturally cycling women and the inverse for men (despite a similar range of factors). Findings are consistent with a growing literature showing that OC use modulates stress and anxiety-linked processes, and suggest that gendered mechanisms underlying the relation between affective complexity and anxiety may be suppressed along with ovarian hormones in OC users.

Adapting a transdiagnostic digital mental health intervention for use among immigrant and refugee youth in Seattle: a human-centered design approach.

Digital mental health interventions show promise in addressing mental health needs, especially among youth and marginalized communities. This study adapted the World Health Organization -developed STARS (Sustainable Technology for Adolescents to Reduce Stress) digital mental health intervention for use among youth and young adults aged 14-25 from immigrant and refugee communities in Seattle, Washington. Human-centered design methods centered around qualitative semi-structured interviews were used to contextually and culturally adapt the intervention and prioritize the needs and preferences of the intended end user. Intervention prototypes were modified and then presented to the target groups in iterative cycles until saturation was achieved. Qualitative interviews occurred in three iterations of five participants each. Modifications were documented according to the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) implementation science framework. Modifications aligned with the FRAME process elements: (a) tailoring/refining, which included adapting language to less resemble digital phishing scams; (b) changes in packaging or materials, which included naming the chatbot and adopting a corresponding avatar; (c) adding/removing, which included changing existing emojis and adding additional media types including graphics interchange format images, pictures, and voice memos; (d) shortening/condensing, which included shortening the length of individual text sections as well as deleting redundant language; (e) lengthening/extending, which included allowing the user to choose to receive content catered to teenagers or to adults; and (f) loosening structure, including giving users options to skip parts of modules or to engage with additional material. The modified STARS intervention shows promise for engagement with immigrant and refugee youth in Seattle and can be examined for clinical effectiveness. Adaptations increased the relevance of content to the intended end user, expanded options for personalization and customization of the user experience, and utilized language that was age appropriate, engaging, and did not invoke feelings of stigma or distrust. Adaptations of digital mental health interventions should focus on modifications that maximize acceptability and appropriateness to intended audiences.

Digital mental health interventions like apps and online mental health tools show promise in addressing mental health needs. This study adapted the STARS (Sustainable Technology for Adolescents to Reduce Stress) digital mental health intervention for use among youth and young adults from immigrant and refugee communities in Seattle, Washington. In our study, we adapted the intervention in a way that prioritizes the preferences of the intended end user. Modifications occurred in cycles: each time modifications resulted in a new version, the version was presented to a group of participants for their feedback and further modifications. Modifications in the final version included adapting language to less resemble digital phishing scams; naming the chatbot and adopting a corresponding avatar; changing existing emojis and adding additional media types; shortening the length of individual text sections as well as deleting redundant language; allowing the user to choose content catered to teenagers or to adults; and giving users options to skip parts of modules or to engage with additional material. The modified STARS intervention shows promise for engagement with immigrant and refugee youth in Seattle and can be examined for clinical effectiveness.

Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer.

Despite modest clinical improvement with anti-vascular endothelial growth factor antibody (AVA) therapy in ovarian cancer, adaptive resistance is ubiquitous and additional options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance and we aimed to investigate the utility of a GLS inhibitor (GLSi). Our in vitro findings demonstrated increased glutamine abundance and a significant cytotoxic effect in AVA-resistant tumors when GLSi was administered in combination with bevacizumab. In vivo, GLSi led to a reduction in tumor growth as monotherapy and when combined with AVA. Furthermore, GLSi initiated after the emergence of resistance to AVA therapy resulted in a decreased metabolic conversion of pyruvate to lactate as assessed by hyperpolarized magnetic resonance spectroscopy and demonstrated robust antitumor effects with a survival advantage. Given the increasing population of patients receiving AVA therapy, these findings justify further development of GLSi in AVA resistance.

In situ profiling reveals metabolic alterations in the tumor microenvironment of ovarian cancer after chemotherapy.

In this study, we investigated the metabolic alterations associated with clinical response to chemotherapy in patients with ovarian cancer. Pre- and post-neoadjuvant chemotherapy (NACT) tissues from patients with high-grade serous ovarian cancer (HGSC) who had poor response (PR) or excellent response (ER) to NACT were examined. Desorption electrospray ionization mass spectrometry (DESI-MS) was performed on sections of HGSC tissues collected according to a rigorous laparoscopic triage algorithm. Quantitative MS-based proteomics and phosphoproteomics were performed on a subgroup of pre-NACT samples. Highly abundant metabolites in the pre-NACT PR tumors were related to pyrimidine metabolism in the epithelial regions and oxygen-dependent proline hydroxylation of hypoxia-inducible factor alpha in the stromal regions. Metabolites more abundant in the epithelial regions of post-NACT PR tumors were involved in the metabolism of nucleotides, and metabolites more abundant in the stromal regions of post-NACT PR tumors were related to aspartate and asparagine metabolism, phenylalanine and tyrosine metabolism, nucleotide biosynthesis, and the urea cycle. A predictive model built on ions with differential abundances allowed the classification of patients' tumor responses as ER or PR with 75% accuracy (10-fold cross-validation ridge regression model). These findings offer new insights related to differential responses to chemotherapy and could lead to novel actionable targets.