Reduced Response Rates Research Articles

Abstract 6274: Prognostic impact of Sarcopenia on clinical outcomes in advanced hepatocellular carcinoma (HCC) treated with systemic therapy

Abstract Background: Sarcopenia is one of the early pathological features of cancer cachexia, yet the effect of sarcopenia on clinical outcomes in patients with advanced HCC is unclear. Our objective was to determine the effect of Sarcopenia on response to systemic therapy with advanced HCC. Methods: Patients with unresectable and advanced liver cancer were retrospectively evaluated between 2010 to 2019. Skeletal muscle area (SMA) was computed with a previously validated computed tomography (CT) body composition AI algorithm. The skeletal muscle index (SMI) was derived from the skeletal muscle area (SMA) (cm2) divided by patient height (m2) calculated from images at the level of L3 on pretreatment CT. Sarcopenia cutoffs for females was less than 39 cm2/m2 SMI or less than 50 cm2/m2 SMI for males. Patients’ demographics, systemic treatment response, toxicity, progression-free survival (PFS) and overall survival (OS) were compared between first-line therapy groups. Kaplan-Meier and Cox proportional hazards regression were used for survival analysis comparisons. Results: A total of 146 patients with advanced HCC were assessed from Mayo Clinic Arizona and Emory University. Seventy-six patients received immunotherapy as first-line treatment and seventy patients received TKI as first-line therapy. Sarcopenia at baseline was assessed in a total of 91 patients at first-line systemic treatment: n=48 with immunotherapy (IO) and n=43 with tyrosine kinase inhibitor (TKI). Sarcopenia was more prevalent in male patients (p=0.009), and in patients with low BMI (p=0.02). When comparing those with sarcopenia at baseline, higher response rate was observed in patients treated with IO without sarcopenia (47% versus 15%, p=0.019), this was not observed in TKI group. Interestingly, median PFS and OS was not significantly changed in patients with or without sarcopenia treated with IO or TKI on first-line therapy. Conclusions: Sarcopenia was associated with reduced response rate (RR) in patients treated with IO, but not in TKI groups. Both didn’t translate into deleterious effect in PFS and or OS. Further research with sufficient adjustments for confounding factors is warranted to better elucidate the prognostic value of sarcopenia in these patients. Citation Format: Gehan Botrus, Pedro Luiz Serrano Uson Junior, Heidi Kosiorek, Mehmet Akce, Isabela Chang, Zhubene Mesbah, Eric Yancey, Daniel Blezek, Jason Klug, Lana Khalil, Puneet Raman, Mohamad Sonbol, Mitesh Borad, Daniel Ahn, Tanios Bekaii-Saab. Prognostic impact of Sarcopenia on clinical outcomes in advanced hepatocellular carcinoma (HCC) treated with systemic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6274.

High atezolizumab antidrug antibody levels are associated with unfavorable clinical outcomes and diminished T cell responses following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

4105 Background: Systemic administration of humanized monoclonal antibodies can be immunogenic and trigger unwanted anti-drug antibody (ADA) responses. In the IMbrave 150 study, 29.6% of advanced hepatocellular carcinoma (HCC) patients developed atezolizumab ADAs after atezolizumab and bevacizumab (atezo/bev) treatment. ADAs could impair the action of the therapeutic antibody by reduction of serum concentration or neutralization. We determined the clinical and immunological implications of high ADA levels in advanced HCC patients after atezo/bev treatment. Methods: Advanced HCC patients (n = 132) treated with first-line atezo/bev were prospectively enrolled (discovery cohort: 50 from an institute; validation cohort: 82 from four institutes). Serum levels of atezolizumab ADA at baseline and three weeks (C2D1) and atezolizumab concentrations at C2D1 were measured by competitive ELISA. The effects of ADA on T cell immunity were examined by multiplex flow cytometry. Results: Strong ADA (≥ 1000 ng/ml) responses at C2D1 were observed in 17.4% of advanced HCC patients. ADA elevation after atezo/bev at C2D1 was evident in non-responders but not significant in responders. In the discovery cohort, patients with high ADA at C2D1 showed a decreased response rate (ADA-high: 11% and ADA-low: 34%) and shorter progression-free survival (PFS) and overall survival (OS) with atezo/bev compared to those with low ADA levels ( P = 0.004 for PFS; P = 0.009 for OS). In the validation cohort, patients with high ADA at C2D1 showed reduced response rate than those with low ADA (ADA-high: 7% and ADA-low: 29%). PFS and OS were worse in ADA-high group than in ADA-low group ( P = 0.001 for PFS; P < 0.001 for OS). In multivariate Cox regression analysis, the clinical significance of high ADA levels was independently associated with shorter PFS and OS after adjustment for age, sex, ECOG performance status, Child-Pugh score, AFP, macroscopic vascular invasion, extrahepatic spread, and neutrophil-to-lymphocyte ratio (PFS: HR 2.27, P = 0.006; OS: HR 3.04, P = 0.006). The atezolizumab serum concentrations were 29.8% lower in patients with high ADA levels than in ADA-negative patients. Atezolizumab concentration at C2D1 was inversely correlated with ADA levels. Moreover, patients with high ADA lacked CD8+ T cell proliferative responses to atezo/bev treatment. Furthermore, patients with high ADA had decreased secretion of effector cytokines such as IFN-γ and TNF-α from CD8+ T cells compared to those with low ADA. Conclusions: Highly elevated ADA at C2D1 is associated with unfavorable clinical outcomes in advanced HCC patients treated with atezo/bev. High ADA levels were associated with reduced atezolizumab exposure and could limit the drug’s anti-cancer efficacy.

0765 Enhanced Response to Targeted Hypoglossal Nerve Stimulation in Patients with Normal Sleep Efficiency: A THN3 Post-Hoc Analysis

Abstract Introduction THN3 was the first reported parallel-arm, randomized controlled trial of hypoglossal nerve stimulation (HGNS), wherein targeted HGNS (THN) was shown to be safe and efficacious at ameliorating sleep disordered breathing in selected patients with moderate to severe OSA and BMI≤35kg/m2 without screening with drug-induced sleep endoscopy. A secondary THN3 objective was to identify baseline characteristics which enhance therapeutic response. Methods Predictors of long-term (Month 12/15) apnea-hypopnea index (AHI) response (reduction ≥50% to ≤20/hr) were identified in stages. Baseline characteristics, including polysomnography parameters, were screened one at a time using univariate logistic regression. Variables significant at α=0.25 were further selected using stepwise multivariate logistic regression. Candidate predictors were then optimized by manual, incremental threshold adjustment to maximize AHI response rate (RR). Optimized predictors were ranked according to the AHI RR and size of the corresponding subpopulation, with a goal of capturing at least 40% of the overall THN3 cohort. Results Baseline sleep efficiency (SE) in the normal range (>85%) achieved the highest AHI RR while retaining 42% (58/138) of the THN3 cohort. Similar to the overall study population, subgroup subjects were predominantly middle-aged (age 54±7 years), male (83%), Caucasian (86%) and overweight/obese (BMI 30±3 kg/m2). Short-term (Month 4) AHI RRs in the Treatment and Control groups were 59.5% and 20.0%, respectively, with long-term AHI RR at 50.9%. Median AHI was reduced from 35.1 to 16.0, as compared to 29.3 to 9.0 in the STAR trial of distal HGNS. ODI RRs (reduction ≥25%) for Treatment and Control were respectively 73.0% and 30.0% at Month 4 and 64.9% at Month12/15. Enhanced response carried through to larger point estimates for improvement in secondary variables, including the Epworth Sleepiness Scale and the Functional Outcomes of Sleep Questionnaire, exceeding minimum clinically important differences thresholds of 2-3 and 1.7-2.0, respectively. Conclusion Normal SE at Baseline was associated with enhanced AHI and ODI RR as well as patient-reported outcome measures for patients receiving THN therapy, providing results similar to those obtained with distal HGNS. Future studies, including the ongoing OSPREY trial, will be needed to prospectively validate these findings. Support (If Any) LivaNova

Does clozapine affect the discriminative stimulus effects of food deprivation in rats trained to discriminate between 2 and 22 hours food deprivation?

In humans, weight gain is a side effect of several atypical antipsychotics. Previous research with rodents indicates clozapine may increase food consumption for the first 2‐4 hours after injection (Antelman et al. 1977; Benvenga & Leander 1997; Lee & Clifton 2002) as well as increase motivation to acquire food under a progressive ratio schedule (Abela et al. 2020; Loh et al. 1992; Mobini et al. 2000). In other studies, however, clozapine has been shown to reduce response rates in lever pressing operant procedures (Ford et al., 1997; Kaempf & Porter, 1997; Varvel et al., 2002; Wiley et al., 1994; Abela 2020) and decrease food intake in rodents (Baptista et al., 1993). The current study investigated if clozapine would affect the discriminative stimulus effects of food deprivation. Male, Sprague‐Dawley rats (n = 11) were trained to discriminate 22 hrs of food deprivation from 2 hrs of food deprivation in a two‐lever, operant choice task. Rats were trained to respond on the right lever after 2 hrs of food deprivation to earn a 45 mg food pellet under an FR 15 schedule. Left lever presses were punished with 8 seconds of darkness. Under 22 hr deprivation conditions, the contingencies were reversed (left lever presses were reinforced with food delivery and right lever presses resulted in 8 seconds of darkness). Training sessions lasted until subjects earned 10 reinforcers or 15 minutes elapsed. Acquisition of discrimination was defined as 80% or greater condition appropriate responding both before the first reinforcer was earned and for the entire session for 8 out of 10 consecutive days. After acquiring the discrimination, subjects were food deprived for 2 or 22 hrs and administered clozapine (1.0 ‐ 5.6 mg/kg, s.c.). or vehicle (30% DMSO; 1.0 ml/kg, s.c.). During test sessions, responses toward either lever were reinforced under the FR 15. The session lasted until subjects earned 5 reinforcers or 5 minutes elapsed, whichever occurred first. The discriminative stimulus effects of food deprivation and response rates were assessed every 15 min for the succeeding 2 hrs. After test sessions, each subjects’ food intake was recorded for 1 hour. Clozapine had no effect on the discriminative stimulus effects of 2 hr deprivation, however, clozapine (1.0 ‐ 5.6 mg/kg) significantly decreased response rates. After 22 hrs food deprivation, clozapine (1.0 ‐ 5.6 mg/kg) significantly decreased % 22 hr deprivation‐appropriate responding. Response rates were significantly increased by 1.0 mg/kg clozapine, whereas response rates were decreased by 5.6 mg/kg clozapine compared to rates of responding following 30% DMSO. Clozapine (3.2 ‐ 5.6 mg/kg) decreased food intake in rats under both food deprivation conditions. These data provide further support for the notion that clozapine decreases feeding‐related behaviors in rats.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

COVID-19 infection in hypereosinophilic syndrome: A survey-based analysis

COVID-19 infection in hypereosinophilic syndrome: A survey-based analysis

Mutation in the kras gene as a predictor of the effectiveness of immunotherapy for non-small cell lung cancer

The purpose of the study: to conduct a systematic literature review on the effectiveness and feasibility of using information on the presence of KRAS gene mutations (in different codons), TP 53 (KP), ST K11/LKB1 (KL), and KEAP mutations and the association of KRAS m with PD -L1 status in patients with non-small cell lung cancer (NSCLC ) as a predictor of the effectiveness of immunotherapy with immune checkpoint inhibitors.Material and Methods. The review includes data from randomized clinical trials and meta-analyses on the predictive value of KRAS mutation status for response to immunotherapy in patients with NSCLC over the past 10 years.Results. The presence of KRAS mutations in NSCLC patients could be a predictive factor for their response to immunotherapy, as several studies have demonstrated benefit from immunotherapy in these patients. The combination of KRAS mutation with TP 53 (KP) co-mutation predicts a better response to immunotherapy, while a combination with ST K11/LKB1 (KL) and KEAP 1 predicts a worse response (reduced response rate and overall and disease-free survival). In PD -L1-positive patients, the presence of KRAS mutation is associated with a better prognosis after treatment with immunotherapy. Moreover, the presence of KRAS mutation is associated with a worse response to first-line and subsequent-line chemotherapy, thus indicating a more promising use of immunotherapy in these patients.Conclusion. Identification of TP 53 (KP), ST K11/LKB1 (KL), and KEAP 1 co-mutations and the presence of KRAS mutation in addition to determination PD -L expression enable selection of patients who will obtain the greatest benefit from immunotherapy. In addition, the ability to determine KRAS mutation and co-mutation status using a liquid biopsy (with acceptable specificity and sensitivity) makes it possible to use this method for determining sensitivity to immunotherapy when it is not possible to obtain tumor sample (to determine PD 1-L1 expression).

Review Article: vaccination for patients with inflammatory bowel disease during the COVID-19 pandemic.

SummaryBackgroundPoor immune responses are frequently observed in patients with inflammatory bowel disease (IBD) receiving established vaccines; risk factors include immunosuppressants and active disease.AimsTo summarise available information regarding immune responses achieved in patients with IBD receiving established vaccines. Using this information, to identify risk factors in the IBD population related to poor vaccine‐induced immunity that may be applicable to vaccines against COVID‐19.MethodsWe undertook a literature review on immunity to currently recommended vaccines for patients with IBD and to COVID‐19 vaccines and summarised the relevant literature.ResultsPatients with IBD have reduced immune responses following vaccination compared to the general population. Factors including the use of immunomodulators and anti‐TNF agents reduce response rates. Patients with IBD should be vaccinated against COVID‐19 at the earliest opportunity as recommended by International Advisory Committees, and vaccination should not be deferred because a patient is receiving immune‐modifying therapies. Antibody titres to COVID‐19 vaccines appear to be reduced in patients receiving anti‐TNF therapy, especially in combination with immunomodulators after one vaccination. Therefore, we should optimise any established risk factors that could impact response to vaccination in patients with IBD before vaccination.ConclusionsIdeally, patients with IBD should be vaccinated at the earliest opportunity against COVID‐19. Patients should be in remission and, if possible, have their corticosteroid dose minimised before vaccination. Further research is required to determine the impact of different biologics on vaccine response to COVID‐19 and the potential for booster vaccines or heterologous prime‐boost vaccinations in the IBD population.

Reconsidering the role of selective sodium channel blockers in genetic generalized epilepsy.

Selective sodium channel blockers (SSCBs) have a limited use in genetic generalized epilepsy (GGE), due to their well-known risk of seizure worsening. Although their therapeutic potential in GGE has been suggested by recent evidence, electro-clinical data supporting their prescription are lacking. We aimed to investigate SSCB safety and effectiveness in a GGE cohort. Subjects who received SSCBs and had ≥5-year follow-up were enrolled. Lamotrigine was excluded from analysis due to its broader pharmacodynamic spectrum and its better-documented efficacy in GGE. Fifty-six patients (median follow-up 28.5years) were included. The most used SSCB was carbamazepine in 40subjects. At the last medical observation, only 9subjects were still receiving SSCBs. The occurrence of generalized polyspike-wave discharges (GPSWDs) predicted reduced SSCB retention in Cox multivariate analysis. A seizure reduction ≥50% occurred in 53.5% (30/56) of subjects when considering all seizure types; however, the proportion of responders increased to 67.9% when considering only generalized tonic-clonic seizures (GTCS). GPSWDs were significantly associated with a reduced response rate, whereas GGE with GTCS only syndrome with a better outcome. The switch from SSCBs to antiseizure medications licensed for GGE improved seizure control in 65% of patients. Seizure worsening was reported in 5/56 patients; juvenile myoclonic epilepsy and a family history of epilepsy were significantly associated with seizure aggravation. SSCBs appeared effective on GTCS, but epilepsy aggravation and unsatisfactory control of other seizure types were not uncommon. Our study contributes to identifying new clinical and EEG variables associated with SSCB effectiveness and safety which may help neurologists in patients' management.

Abstract 2762: Spatial distribution and immune cell infiltration at different sites of melanoma metastases (mets)

Abstract Purpose: The site of metastasis in advanced melanoma patients (pts) influences pt response to immunotherapy and overall prognosis. Liver mets are particularly resistant to immunotherapy and their presence often confers shorter survival and reduced response rates. This study characterised and compared the tumor immune microenvironment of melanoma mets at different anatomical sites. Methods: T-cell and myeloid cell markers were stained using multiplex IHC on FFPE samples from 136 untreated metastatic melanoma pts, from 5 anatomical sites (liver, lung, brain, subcutaneous, and lymph node (LN)). Cell densities, subpopulations and the spatial distribution of cells were compared between sites. Results: CD3+ T cell infiltration was less dense in the liver (med = 154.3 cells/mm2) and brain mets (med = 180.7 cells/mm2) v's lung (med = 434.7 cells/mm2) and LN mets (med = 504.8 cells/mm2) (p<0.05), and T-cells were further away from melanoma cells in liver v's lung mets (med distance = 83µm v's 57µm respectively; P<0.05). The liver displayed a unique T-cell profile, with a significantly lower proportion of CD3+ T cells expressing PD-1 (med = 0.7%) compared to all other sites (P<0.05) while brain mets expressed the highest proportion of PD-1+ T cells (med = 8.9%). There were higher proportions of Tim3+ T cells in liver (10.7%) and lung mets (12.9%) v's brain, subcut and LN mets (P<0.05). Specifically, in liver mets CD3+ T cells within 20um of a melanoma cell had a significantly higher expression of Tim3 (med = 18.57%) v's PD-1 (med = 2%). Brain mets had the lowest density of CD68+ macrophages (med = 33 cells/mm2) v's lung (med = 372 cells/mm2), liver (med = 290 cells/mm2) and Subcut mets (med = 154 cells/mm2). Lung mets also had the highest proportion of PD-L1+ macrophages (med = 18.73%) compared to liver (med = 5.2%) and brain mets (med = 0.65%). While the most highly expressed T cell population varied between sites, CD16+ macrophages were consistently the highest expressed macrophage subpopulation regardless of metastatic site. Conclusion: These data suggest that liver mets are less immunogenic, with fewer T cells and greater distances between CD3+ T cells and melanoma cells, and may account for the poor prognosis of melanoma patients with liver metastases and their reduced response rate to immunotherapy compared to other mets. While liver mets have reduced PD-1 expression, higher Tim3 expression in the liver may provide a therapeutic opportunity to improve outcomes for pts with liver mets by using anti-TIM3 immunotherapy. Overall, these data provide novel insights into the site-specific biology of melanoma mets, heterogeneity in the tumor immune microenvironment, and the need for site specific biomarkers to be considered when selecting treatment targets. Citation Format: Jordan W. Conway, Robert V. Rawson, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Inês Pires Da Silva. Spatial distribution and immune cell infiltration at different sites of melanoma metastases (mets) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2762.

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia

Patients with chronic lymphocytic leukemia (CLL) have an increased risk for severe COVID-19 disease and mortality. The goal of this study was to determine the efficacy of COVID-19 vaccine in patients with CLL. We evaluated humoral immune responses to the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine in patients with CLL and compared responses with those obtained in age-matched healthy control subjects. Patients received 2 vaccine doses, 21 days apart, and antibody titers were measured by using the Elecsys Anti-SARS-CoV-2 S assay after administration of the second dose. In a total of 167 patients with CLL, the antibody response rate was 39.5%. A comparison between 52 patients with CLL and 52 sex- and aged-matched healthy control subjects revealed a significantly reduced response rate among patients (52% vs 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). The response rate was highest in patients who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients and 16.0% in patients under treatment at the time of vaccination. In patients treated with either Bruton's tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody, response rates were considerably low (16.0% and 13.6%). None of the patients exposed to anti-CD20 antibodies <12 months before vaccination responded. In a multivariate analysis, the independent predictors of response were younger age, female sex, lack of currently active treatment, immunoglobulin G levels ≥550 mg/dL, and immunoglobulin M levels ≥40 mg/dL. In conclusion, antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in patients with CLL is markedly impaired and affected by disease activity and treatment. This trial was registered at www.clinicaltrials.gov as #NCT04746092.

The effort-doors task: Examining the temporal dynamics of effort-based reward processing using ERPs

Aberrant reward processing is a cardinal feature of various forms of psychopathology. However, recent research indicates that aberrant reward processing may manifest at temporally distinct substages and involve interdependent subcomponents of reward processing. To improve our understanding of both the temporal dynamics and distinct subcomponents of reward processing, we added an effort manipulation to the "doors" reward-task paradigm, to derive behavioral and event-related potential (ERP) measures of effort-based reward processing. Behavioral measures consisting of reaction time, response rate, and response rate change were used to index effort expenditure, and ERP measures were used to index attention allocated toward effort-completion cues, anticipation of reward, valuation of reward, and attention toward monetary feedback. Reduced response rate and slowing of response were evident during the high effort versus the low effort condition. ERP findings indicated increased attention to signals of high- compared to low-effort completion cues-as well as reduced anticipation of rewards, and reduced attention toward feedback information following high effort expenditure. Participants showing the most response-rate slowing evidenced the greatest reward devaluation following high versus low effort. Findings demonstrate that the addition of an effort expenditure manipulation to the doors reward paradigm produced reliable ERP and behavioral measures of effort-based reward processing, providing opportunities for future researchers to utilize the effort-doors task to parse the temporal dynamics of both anticipatory and consummatory reward processing components.

The A150V Polymorphism of Genotype 3 Hepatitis C Virus Polymerase Inhibits Interferon Alfa by Suppressing Protein Kinase R Activation.

Background & AimsDespite recent advances in antiviral therapy for hepatitis C virus (HCV), a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals. We previously reported that amino the acid polymorphism, A150V, in the polymerase (NS5B) of G3 HCV reduces response to sofosbuvir. We now demonstrate that this polymorphism alters the response to interferon alpha.MethodsQuantitative polymerase chain reaction, immunofluorescence, luciferase activity assay, immunoblotting, and flow cytometry were used to study the antiviral effect of interferon (IFN) on DBN G3 HCV-infected cells and G3 HCV replicons.ResultsWe show the presence of the A150V polymorphism markedly reduces the response to IFN alpha (IC50 of S52_WT = 1.162 IU/mL and IC50 of S52_A150V = 14.45 IU/mL, 12.4-fold difference). The induction of IFN-stimulated genes in A150V replicon cells is unaffected, but nuclear localization of active protein kinase R (PKR) is reduced. Blockade of PKR activity reduced the antiviral effect of IFN on wild-type replicons, whereas augmented PKR activation promoted the antiviral effect of IFN on A150V replicons. Furthermore, we show that impaired activation of PKR in A150V replicon cells diminishes cellular apoptosis.ConclusionsThese results demonstrate that polymorphisms reducing response rates to direct-acting antivirals may function beyond conferring drug resistance by modulating the intrinsic cellular antiviral response.

Role of Circulating Myeloid-Derived Suppressor Cell (MDSC) in Hodgkin Lymphoma (HL) Progression: Updated Prospective Study

Introduction.Patients with HL normally undergo a risk-adapted treatment based on PET scans. Regardless of HL treatment high efficiency, (80-90% remission), the search of new prognostic markers has been a continued process in recent years. This is related to the disease recurrence in 25-35% of patients in the first 5 years. The studies show that MDSC expands dramatically with tumor growth and causes a tumor immunosuppressed environment. The aim of this study is to investigate the number of MDSC in HL patients' peripheral blood and its correlation with clinical variables when the diagnosis and outcome first set. Methods .43 primary HL patients, (median age: 30, range: 19-78 years; male: 18, female: 25), were included in the study since April, 2018. 58.2% and 41.8% of patients have been diagnosed with early and advanced stages of HL, respectively, and received the ABVD or BEACOPP (14/esc) as a 1st-line treatment regimen. Peripheral blood mononuclear cells (PBMC) were isolated by ficoll density gradient centrifugation treatment, after 2-3 chemotherapy cycles (interim), and at the end of treatment (EOT). We assessed the E-MDSC count (CD33+CD11b+CD14-HLA-DR-) using the anti-human antibodies purchased from Beckman Coulter (Brea, CA, USA). We have also used a routine protocol of metabolic PET assessed according to Deauville criteria of response. Results.83.7% of patients achieved remission (CR/PR) during the follow-up period (median timeline: 18.9 months). We recorded a disease progression in 5 (11.6%) patients during and after the 1st line therapy, (time to relapse - 8 months). In addition, those patients had a high level of MDSC before treatment, which also remained high after interim and EOT-PET. Median of EFS has not been reached and we continue monitoring all patients. The HL patients who achieved remission had an increased E-MDSC percent (median 12.5%) compared to the age and gender control group, (median 2.03%), and the non-responders' one (median 20%). The number of NK-T (CD3+CD16+CD56+) cells increased by 15 % after EOT compared to pretreatment number, 9.2%, p=0.05. PBMC Evaluation at baseline.The E-MSDC count increases significantly with age: 3.1% vs 12.9% in HL patients under 25 years of age vs over 40, respectively p=0.014. Pretreatment MDSC levels were potentially associated with the disease stage: early stages (1A-2A and 2B) vs advanced stages (12% vs 3.9% vs 15%, respectively p=0.07). Our PET imaging tentatively correlated to the above levels. With that, patients with PET 5DS had a higher number of E-MDSC compared to a healthy control group, while the count is reduced in responders during and after treatment (p=0.06). Theoretically, this means that immunosuppression would be reduced and the antitumor immune response of the body would improve. PBMC Evaluation at interim response assessment.At this step, the age was also confirmed as an independent predicting factor in patients under 25 vs &amp;gt; 40, according to the MDSC level (6% vs 11.5%, respectively p=0.008). The level of E-MDSC was higher in patients who failed to achieve CR/PR (p=0.08). PBMC Evaluation at the EOT:90.6% (39/43) and 9.4% (4/43) of patients had a PET-negative and PET-positivestatus at the EOT, respectively (p &amp;lt; 0.05). We found a strong correlation between the EOT-PET and E-MDSC level. With this, patients with EOT-PET-ve had a lower E-MDSC expression vs EOT-PET+ve (12% vs 42% respectively, p=0.0007), which may potentially become a prognostic factor of response prediction. IPS is an important independent prognostic factor positively correlated to the MDSC count at EOT. In our study, patients in the high-risk group (3-4 IPS) had a significantly higher level of MDSC number than the low-risk group (1-2 IPS) and are more likely not to achieve a positive response to treatment (25% vs 18%, respectively p=0.02). Conclusion.The obtained results suggest that the higher level of MDSC number is associated with unfavorable prognosis of HL, reduce response rate. The challenge of strictly prognostic factor application leads to the research of biomarkers in the HL field. The discovery of new prognostic factors will improve an individualized approach to patient treatment and decrease the disease relapse risk. Disclosures No relevant conflicts of interest to declare.

Does DRO type matter?: Cycle versus resetting contingencies in eliminating responding

Following lever-press training on variable-interval 30-s schedules, rats were exposed to three types of schedules designed to eliminate lever pressing. The first two were variations on what is called a differential-reinforcement-of-other-behavior (DRO, “zero rate”, or [target response] omission schedule) schedule. Under both variations, reinforcers were scheduled to occur in different conditions after either fixed or variable inter-reinforcer intervals (IRIs). Under one variation each lever press reset the time interval (i.e., “resetting DRO”) and under the other a reinforcer delivery scheduled at the end of an IRI was cancelled by the first response during the IRI (i.e., “cycle DRO”). In another condition reinforcers were delivered independently of responding after fixed or variable time periods. Each of the DRO procedures reduced response rates quickly and to near zero across ten sessions. The time schedules also reduced responding, albeit at a slower rate. The results extend the analogy of omission training to freeoperant avoidance to shock-deletion avoidance schedules.

Abstract 5086: The aged tumor microenvironment promotes melanoma metabolic plasticity and therapy

Abstract “Aged” melanoma patients (&amp;gt;55 years old) have poorer prognosis and reduced response rates to targeted therapy relative to “young” patients (&amp;lt;40 years old). Here, we report an altered metabolic landscape in the aged tumor microenvironment (TME) as critical for melanoma aggressiveness. Aged fibroblasts uptake high levels of glucose compared to their young counterparts, which fuels lipid production. Melanoma cells cultured in an aged TME in vitro or in vivo display elevated intracellular lipid levels and increased metastatic potential relative to melanoma cells in a young TME. Further, lipidomics reveal an elevated lipid profile (i.e., triglycerides, ceramides, and cholesterol) preferentially secreted by aged fibroblasts relative to young. In turn, we show that melanoma cells adaptively increase extracellular fatty acid scavenging via the lipid transporter FATP2 in the lipid rich aged TME. Melanoma cells cultured in the aged TME also display an increased oxygen consumption rate (OCR) relative to those grown in young TME, which could be ablated when fatty acid transport into the mitochondria is blocked with etomixir. Notably, melanoma cells in the aged TME treated with BRAFi/MEKi in combination with a FATP2 inhibitor display decreased OCR relative to BRAFi/MEKi inhibitor alone, which paralleled the increased overall survival of aged mice treated with BRAFi/MEKi/FATP2i relative to either agent alone. To rule out off-target effects of the FATP2 inhibitor, we used a doxycycline inducible system for FATP2 knockdown in melanoma cells and reproduced the abrogation of tumor growth and extension of survival in aged immune-competent mice when combined with BRAFi/MEK therapy. Additionally, elevated FATP2 levels correlate with worse response in human patients. We hypothesize the aged TME triggers adaptive metabolic plasticity of melanoma cells critical for therapy escape. Citation Format: Gretchen Marie Alicea, Vito W. Rebecca, Aaron Goldman, Mitchell Fane, Reeti Behera, Marie Webster, Brett Ecker, Ian Blair, David Speicher, Zachary Schug, Ashani Weeraratna. The aged tumor microenvironment promotes melanoma metabolic plasticity and therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5086.

Sustainability survey to assess student perspectives

Purpose The purpose of this study is to assess environmental concern at a Midwest university, analyze trends in concern over time and determine the effect of the development of a campus sustainability office. Design/methodology/approach A multi-question survey was administered through peer-to-peer recruitment from an undergraduate environmental science class each fall from 2010–2017. This exercise was originally developed as a pedagogical exercise on the scientific method. Findings Over eight years, incoming freshmen have expressed more concern that humans are harming the environment and students also express greater concern as they progress through college. Research limitations/implications The first year of the survey (2010) and the year that the lead PI was on sabbatical (2014) saw reduced response rates (∼1%–3% of the student population) compared to 6%–9% of the student population in other years. Practical implications Responses to all of the questions in the survey provide guidance for university administrations and sustainability offices about the concerns of the campus community, awareness about campus efforts and support for sustainability activities on campus. Originality/value Few studies have been published on students’ perspectives on environmental concern and sustainability activities on university campuses. These data provide an overview of environmental concern, perceived government action and empowerment to action over an eight-year period. This approach is recommended as a technique to teach the scientific method in introductory classes and as a means to collect data about student perspectives on sustainability.

Parkinsonism and subthalamic deep brain stimulation dysregulate behavioral motivation in a rodent model

BackgroundApathy and impulsivity constitute opposite poles of a behavioral motivation spectrum often disrupted by both the symptoms and therapies for Parkinson’s Disease (PD). Upwards of 70% of PD patients experience symptoms of apathy, frequently unresolved or worsened by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Worse, more than half of patients receiving DBS for PD experience new-onset impulse control disorders of varying severity following therapy initiation. While these symptoms and side-effects have been widely reported in clinical studies, they are largely unexplored in animal models. MethodsWe applied high-frequency DBS in a 6-OHDA hemiparkinsonian rat model. We trained rats on a series of go/stop and go/no-go behavioral paradigms and examined how parkinsonism and DBS modulated task responses. ResultsSTN DBS in healthy rodents drove impulsive behavior in the form of stop and no-go task failure, impulsive reward seeking, and noninstructed task attempts. While trained rats without DBS only tended to fail stop and no-go cues very shortly after the cue, DBS led to failures at significantly later time points. Hemiparkinsonism slowed response times and reduced response rates, not alleviated by effective DBS. InterpretationsPD interrupts neural signaling responsible for healthy action selection, not restored by DBS. PD may be associated with a dearth of action commands, manifesting as apathy. Conversely, effective DBS may bias the system toward the impulsive end of the behavioral motivation spectrum without restoring behaviorally reasonable actions, mis-weighting reward-based action selection and manifesting as impulsivity, aided by DBS interfering with stop signaling.

First-line treatment of metastatic renal cell carcinoma: current standard of care

The introduction of immune checkpoint inhibitors has further improved response and survival rates in patients with metastatic renal cell carcinoma. In this context, the most promising trial results in the past 12 months include KEYNOTE 426 and the 30-month update of CheckMate 214. Both trials, similar to IMmotion 151 and JAVELIN Renal 101, reported improved survival and response data. CheckMate 214 reported an overall survival benefit in intermediate and poor risk patients, however, such benefit was observed irrespective of conventional risk groups in KEYNOTE 426. These results prompted the European Association of Urology (EAU) to update their guidelines on the treatment of metastatic renal cell carcinoma and to recommend the combinations pembrolizumab/axitinib and nivolumab/ipilimumab as standard of care in previously untreated intermediate and poor risk patients and the combination pembrolizumab/axitinib as standard of care in previously untreated favorable risk patients. Inflammatory and angiogenic markers profiles may have the potential to become a tool aiding to better individualize treatment regimens in the future. Exploratory analyses of the IMmotion 151 trial present first results supporting such approach. Sarcomatoid variant histology remains an unfavorable prognostic parameter. Subgroup analyses of CheckMate 214 revealed exceptional response in patients with sarcomatoid histology. Whereas conventional therapy was inferior in such patients, more than 50% of patients responded to combined checkpoint inhibitor therapy. Increasing evidence points towards a crucial role of the gut microbiome in the response of patients to modern immune therapies. Any antibiotic treatment prior to the inition of immune checkpoint therapy can have detrimental impact on the intestinal microbiome, thereby dramatically reducing response rate to checkpoint inhibitors.

Regulation of PD-1/PD-L1 Pathway in Cancer by Noncoding RNAs.

Immune checkpoint blockade has demonstrated significant anti-tumor immunity in an array of cancer types, yet the underlying regulatory mechanism of it is still obscure, and many problems remain to be solved. As an inhibitory costimulatory signal of T-cells, the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway can paralyze T-cells at the tumor site, enabling the immune escape of tumor cells. Although many antibodies targeting PD-1/PD-L1 have been developed to block their interaction for the treatment of cancer, the reduced response rate and resistance to the therapies call for further comprehension of this pathway in the tumor microenvironment. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are two main types of noncoding RNAs that play critical parts in the regulation of immune response in tumorigenesis, including the PD-1/PD-L1 pathway. Here we summarize the most recent studies on the control of this pathway by noncoding RNAs in cancer and hopefully will offer new insights into immune checkpoint blockade therapies.