31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Sleepiness, fatigue, and risk of obstructive sleep apnea using the STOP-BANG questionnaire in multiple sclerosis: a pilot study

Abstract Purpose This study aims: (1) to identify patients with multiple sclerosis (MS) who are at high risk for obstructive sleep apnea (OSA) by utilizing the STOP-BANG questionnaire and (2) to evaluate the relationship between OSA risk as determined by the STOP-BANG questionnaire and selfreported sleepiness and fatigue using the Epworth Sleepiness Scale (ESS) and the Fatigue Severity Scale (FSS), respectively. Methods A total of 120 consecutive patients presenting to the UC Davis Neurology MS Clinic were invited to participate in an anonymous survey. The exclusion criteria were: age &lt;18 years, indefinite MS diagnosis, or incomplete survey. Results There were 103 subjects included in our study: 42% of subjects (n043) met the criteria for high-risk OSA, 69% of subjects (n071) screened high for fatigue (FSS≥4), but only 24 subjects (23%) screened high for excessive daytime sleepiness (ESS&gt;10). In males, 44% of the variation in ESS scores and 63% in FSS scores were explained by the STOP-BANG components. However, only 17% of the variation in ESS scores and 15% of the variation in FSS scores was explained by the STOP-BANG components in females. Conclusions Over 40% of MS patients were identified as high risk for OSA based on the STOP-BANG questionnaire. The STOP-BANG questionnaire offers clinicians an efficient and objective tool for improving detection of OSA risk in MS patients

Long Non-Coding RNA MALAT1 Expression in Thyroid Tissues and Tumors

Background: Long non-coding RNAs (lncRNAs) participate in transcription and in epigenetic or post-transcriptional regulation of gene expression, and may contribute to carcinogenesis. MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1), a lncRNA that participates in the regulation of cell cycle and migration, is known to be deregulated in multiple cancers. Some studies suggest MALAT1 may function as both an oncogene and a tumor suppressor. We analyzed the expression of the MALAT1in thyroid tumors and compared its expression to miR-146b-5p, a microRNA known to be deregulated in papillary thyroid cancer. Design: Tissue microarrays (TMAs) were constructed with formalin-fixed paraffin-embedded (FFPE) tissues of normal thyroid ( NT, n=10), nodular goiters (NG, n=10), follicular adenoma (FA, n=32), follicular carcinoma (FCA, n=28), papillary thyroid carcinoma ( PTC n=28), follicular variant of papillary thyroid carcinoma( FVPTC, n=29), poorly differentiated thyroid carcinomas (PDC, n=21) and anaplastic thyroid carcinoma (ATC, n=35). TMA sections were analyzed by in situ hybridization (ISH) using RNAscope technology with a MALAT1 probe (Advanced Cell Diagnostics). ISH for miR-146b-5p was also performed on the same set of TMAs (Exiqon). qRT-PCR was performed on a subset of the TMA cases (n=16). The results of the MALAT1 TMA ISH were analyzed with Vectra imaging technology, Nuance\uae and inForm \uae software. Results: MALAT1 was highly expressed in NT, NG and in benign and malignant thyroid tumors predominantly in the nucleus, but also in the cytoplasm. The highest levels of MALAT1 wwere observed in PTCs which was significantly higher than in NT (p=0.014) and FVPTC (p=0.016). In contrast NT expressed higher levels of MALAT1 than PDC (p=0.015) or ATC (p<0.001). qRT-PCR analyses supported the ISH findings. Expression of miR-146b-5p was highest in PTC (89%) followed by FVPTC (41%) and was lowest in ATC (8%). Conclusions: MALAT1 is highly expressed in NT tissues and thyroid tumors with increased expression during progression from NT to PTCs. However both MALAT1 and miR-146b-5p are downregulated in ATC compared to PTCs, suggesting that MALAT1 may function both as an oncogene and as a tumor suppressor in different thyroid tumors and that non-coding RNAs may regulate the development of PTCs and ATCs. Category: Endocrine Patholog

Dioxin Causes Ventral Prostate Agenesis by Disrupting Dorsoventral Patterning in Developing Mouse Prostate

Prostate ductal development is initiated by androgen-dependent signals in fetal urogenital sinus (UGS) mesenchyme that stimulate prostatic bud formation in UGS epithelium. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, 5 μg/kg maternal dose) inhibited ventral and dorsolateral but not anterior prostatic budding. We sought to determine which stage of budding, specification or initiation, was inhibited. Ventral prostatic bud formation was maximally inhibited when TCDD exposure spanned E15.5–16.5 and dorsolateral prostatic bud formation when it spanned E14.5–15.5. Because ventral and dorsolateral buds are specified at these times, TCDD impaired bud specification. We hypothesized that TCDD inhibited ventral bud specification by forming a continuous smooth muscle barrier between UGS mesenchyme and epithelium in the ventral prostatic UGS region, blocking mesenchymal-epithelial signaling, but no such barrier was found. We hypothesized that increased aryl hydrocarbon receptor (AHR) signaling in ventral and dorsolateral UGS increased their sensitivity to TCDD, but levels of AHR nuclear translocator (ARNT) protein, Ahr mRNA, and AHR-dependent gene expression were not higher than in anterior UGS where budding was unaffected. However, we identified overlapping expression of Ahr, ARNT, and AHR-induced transcripts in the periprostatic mesenchyme which intimately contacts UGS epithelium where buds are specified. This was considered the putative TCDD site of action in the UGS for inhibition of ventral and dorsolateral prostatic bud specification. Thus, hyperactivation of AHR signaling appears to disrupt dorsoventral patterning of the UGS, reprogramming where prostatic buds are specified, and prostate lobes are formed. Disrupted axial patterning provides a new paradigm for understanding how in utero TCDD exposure causes ventral prostate agenesis and may shed light on how TCDD impairs development of other organs

Vitamin D Supplementation Does Not Affect Metabolic Changes Seen With ART Initiation

Abstract Background: Insulin resistance and lipid changes are common after antiretroviral therapy (ART) initiation. Observational studies suggest that vitamin D supplementation reduces the risk of developing diabetes and improves lipid profiles. Methods: This 48-week prospective, randomized, double-blind, placebo-controlled study evaluated high-dose vitamin D3 (4000 IU daily) plus calcium supplementation (1000 mg calcium carbonate daily) in HIV-infected participants initiating ART with efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Changes in insulin resistance (as estimated by homeostatic model assessment), fasting lipid profile, and components of the metabolic syndrome were assessed at baseline, 24 weeks, and 48 weeks. Stratified Wilcoxon rank sum tests and stratified normal score tests were used to evaluate differences between treatment arms, stratified by screening 25-OH vitamin D stratum (≤/>20 ng/mL). Results: A total of 165 participants enrolled: 79 in the vitamin D/calcium (Vit D/Cal) arm and 86 in the placebo arm. Only the placebo arm experienced a modest increase in insulin resistance at week 24 (P < .001). While increases in total and high-density lipoprotein cholesterol were significant in both arms at weeks 24 and 48, increases in low-density lipoprotein cholesterol at week 24 were only identified in the placebo arm (P = .011). Body mass index remained stable, whereas modest increases in waist circumference were observed in the placebo arm. Metabolic syndrome was present in 19 participants (12%) at baseline and 20 participants (14%) at week 48, without differences between arms. Conclusions: Vit D/Cal supplementation over 48 weeks did not alter the lipid profile or glucose metabolism experienced with initiation of EFV/FTC/TDF in ART-naïve persons. Vitamin D supplementation is unlikely to be an effective strategy to attenuate metabolic dysregulations with ART initiation

The dose of behavioral interventions to prevent and treat childhood obesity: a systematic review and meta-regression

Abstract Background A better understanding of the optimal “dose” of behavioral interventions to affect change in weight-related outcomes is a critical topic for childhood obesity intervention research. The objective of this review was to quantify the relationship between dose and outcome in behavioral trials targeting childhood obesity to guide future intervention development. Methods A systematic review and meta-regression included randomized controlled trials published between 1990 and June 2017 that tested a behavioral intervention for obesity among children 2–18 years old. Searches were conducted among PubMed (Web-based), Cumulative Index to Nursing and Allied Health Literature (EBSCO platform), PsycINFO (Ovid platform) and EMBASE (Ovid Platform). Two coders independently reviewed and abstracted each included study. Dose was extracted as intended intervention duration, number of sessions, and length of sessions. Standardized effect sizes were calculated from change in weight-related outcome (e.g., BMI-Z score). Results Of the 258 studies identified, 133 had sufficient data to be included in the meta-regression. Average intended total contact (# sessions x length of sessions) was 27.7 (SD 32.2) hours and average duration was 26.0 (SD 23.4) weeks. When controlling for study covariates, a random-effects meta-regression revealed no significant association between contact hours, intended duration or their interaction and effect size. Conclusions This systematic review identified wide variation in the dose of behavioral interventions to prevent and treat pediatric obesity, but was unable to detect a clear relationship between dose and weight-related outcomes. There is insufficient evidence to provide quantitative guidance for future intervention development. One limitation of this review was the ability to uniformly quantify dose due to a wide range of reporting strategies. Future trials should report dose intended, delivered, and received to facilitate quantitative evaluation of optimal dose. Trial registrations The protocol was registered on PROSPERO (Registration # CRD42016036124 )