Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. We examined the utility of circulating tumor DNA (ctDNA) as a prognostic biomarker for EOC by assessing its relationship with patient outcome and CA-125, pre-surgically and during post-treatment surveillance. METHODS: Plasma samples were collected from patients with stage I-IV EOC. Cohort A included patients with pre-surgical samples (N = 44, median follow-up: 2.7 years), cohort B and C included: patients with serially collected post-surgically (N = 12) and, during surveillance (N = 13), respectively (median follow-up: 2 years). Plasma samples were analyzed using a tumor-informed, personalized multiplex-PCR NGS assay; ctDNA status and CA-125 levels were correlated with clinical features and outcomes. RESULTS: Genomic profiling was performed on the entire cohort and was consistent with that seen in TCGA. In cohort A, ctDNA-positivity was observed in 73% (32/44) of presurgical samples and was higher in high nuclear grade disease. In cohort B and C, ctDNA was only detected in patients who relapsed (100% sensitivity and specificity) and preceded radiological findings by an average of 10 months. The presence of ctDNA at a single timepoint after completion of surgery +/- adjuvant chemotherapy and serially during surveillance was a strong predictor of relapse (HR:17.6, p = 0.001 and p < 0.0001, respectively), while CA-125 positivity was not (p = 0.113 and p = 0.056). CONCLUSIONS: The presence of ctDNA post-surgically is highly prognostic of reduced recurrence-free survival. CtDNA outperformed CA-125 in identifying patients at highest risk of recurrence. These results suggest that monitoring ctDNA could be beneficial in clinical decision-making for EOC patients.

Modulating native GABAA receptors in medulloblastoma with positive allosteric benzodiazepine-derivatives induces cell death.

PURPOSE: Pediatric brain cancer medulloblastoma (MB) standard-of-care results in numerous comorbidities. MB is comprised of distinct molecular subgroups. Group 3 molecular subgroup patients have the highest relapse rates and after standard-of-care have a 20% survival. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABAAR). We are advancing a therapeutic approach for group 3 based on GABAAR modulation using benzodiazepine-derivatives. METHODS: We performed analysis of GABR and MYC expression in MB tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional 'druggable' GABAAR in group 3 cells. RESULTS: Analysis of expression of 763 MB tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABAAR subunits α5, ß3 and γ2 and 3. There are ~ 1000 functional α5-GABAARs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2 × 109 ions/s. Benzodiazepines, designed to prefer α5-GABAAR, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine ('KRM-II-08') binds to the α5-GABAAR (0.8 µM EC50) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter protein localization. CONCLUSION: GABRA5 expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABAAR is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis.

The role of erlotinib and the Optune device in a patient with an epidermal growth factor receptor viii amplified glioblastoma.

The standard treatment for patients diagnosed with glioblastoma is surgical resection of tumor followed by high dose radiation and chemotherapy with temozolomide. For patients who experience allergic reactions to temozolomide despite desensitization protocols, alternative therapies must be considered. In this report, we present such a patient who then received treatment with an epidermal growth factor receptor inhibitor, erlotinib, concurrent with a tumor-treating field device, Optune. Through this combination of a targeted molecular therapy and the Optune device, the patient has been able to achieve stable disease 9 months after completing radiation.

A prospective study comparing perioperative anxiety and posthospital behavior in children with autism spectrum disorder vs typically developing children undergoing outpatient surgery.

BACKGROUND: Research describing the experience of youth with autism spectrum disorders in the perioperative setting is limited. This study compared youth with autism spectrum disorder to typically developing children in the perioperative setting and examined group differences in: child anxiety, parent anxiety, premedication patterns, induction compliance, and changes in behavior postprocedure. METHODS: Participants were 60 youth (32 with autism spectrum disorder, 28 typically developing) of ages 2-19 years undergoing outpatient surgery and their parents. Parents and research assistants rated children's anxiety at 3 time points (waiting room, preoperative holding, separation), and parents rated their own anxiety in the waiting room and at separation. The anesthesiologist rated induction compliance. Postprocedure behavior change was assessed via phone survey 1 and 7 days postprocedure. Analyses examined group differences in anxiety, medication patterns, and behavior. RESULTS: Children with autism spectrum disorder had higher research assistant reported anxiety than typically developing youth in the holding room only. There were no group differences in parent report of their own anxiety or their child's anxiety across time points. Compared to typically developing youth, children with autism spectrum disorder were more likely to receive a premedication (including nonstandard premedication), and had poorer induction compliance. Groups did not differ on posthospital behavior change 1 or 7 days postsurgery. CONCLUSION: Findings revealed ratings of anxiety in youth with and without autism spectrum disorder facing surgery varied by reporter and setting, highlighting the importance of using multiple reporters in research of youth with autism spectrum disorder in the perioperative period. Furthermore, while results showed group differences in premedication patterns and induction compliance, groups did not differ in level of negative behavior change after surgery. Future research can examine how individual differences in youth with autism impact anxiety in the perioperative setting and degree of behavior change postprocedure.

Qualitative Exploration of a Smoking Cessation Trial for People Living With HIV in South Africa.

Introduction: In South Africa, people living with HIV have a high prevalence of smoking, which undermines the beneficial effects of antiretroviral therapy. However, little is known about barriers to smoking cessation and what interventions work for people living with HIV in this setting. Methods: A randomized trial comparing intensive anti-smoking counseling versus counseling and nicotine replacement therapy was recently concluded in Klerksdorp, South Africa. In a post-trial follow-up, 23 in-depth interviews with patients and one focus group discussion with counselors from the trial were conducted. A codebook was developed and codes were applied to the transcripts, which were analyzed using a thematic analysis. Results: Barriers at the economic, social/interpersonal, and individual levels induced stress, which hindered smoking cessation. Economic stressors included unemployment and poverty. Social or interpersonal stressors were lack of social support for quitting smoking and lack of social support due to having HIV. Individual stressors were traumatic life events. Alcohol was used to cope with stress and frequently co-occurred with smoking. Managing cravings was a barrier unrelated to stress. Participants proposed income and employment opportunities, group counseling, and more frequent counseling as solutions to address stressors at different levels. Nicotine replacement therapy was helpful to mitigate cravings. Conclusions: Future smoking cessation interventions need to target barriers at multiple levels. Increasing the supply and duration of nicotine replacement therapy may increase its effectiveness. Other behavioral approaches such as group counseling or peer counseling could hold promise in this setting but need to be tested for efficacy through randomized controlled trials. Implications: To our knowledge, this is the first qualitative study examining barriers to smoking cessation for people living with HIV in South Africa. Smoking is highly prevalent among people with HIV in South Africa and cessation interventions are urgently needed. A better understanding of barriers to smoking cessation that people with HIV face will lead to the development of contextually appropriate interventions. This study also provides feedback on interventions from a recently concluded smoking cessation randomized trial and will help guide the design of future smoking cessation trials.

Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab.

BACKGROUND: Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy. METHODS AND RESULTS: We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 ± 14.7 years) were younger than those receiving basiliximab (55.8 ± 11.2 years) or no induction therapy (54.9 ± 14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients). CONCLUSIONS: Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support.