Treatment-related Changes Research Articles

Interpretation of Tumor Response Grade following Preoperative Therapy for Gastric Cancer: An Overview.

Gastric cancer is among the top five causes of cancer-related death worldwide. Preoperative chemotherapy has been established as an option in patients with locally advanced gastric cancer. However, chemotherapy yields variable results, owing to the cellular and molecular heterogeneity of this disease. Identifying patients who did or did not respond to preoperative therapy can allow clinicians to alter treatment modalities and provide important information related to prognostication. A pathologic response to preoperative therapies, called the Tumor Response Grade (TRG), has been evaluated to quantify treatment response. Multiple systems for TRG have been established. However, the literature has demonstrated inconsistent results for TRG systems and prognosis, possibly due to variability in interpretation of tumor response between systems and interobserver variability. Radiographic responses to preoperative therapies using RECIST 1.1 criteria and endoscopically assessed tumor response have demonstrated association with survival; however, their use in gastric cancer remains challenging given the inability to accurately and consistently identify and measure the tumor, especially in the setting of neoadjuvant therapy, where treatment-related changes can obscure the gastric wall layers. While the response to preoperative therapies with positron emission tomography (PET) has shown promising results in esophageal and esophagogastric junction (EGJ) malignancies, its role in gastric cancer is still under investigation. This review is focused on summarizing the available literature related to evaluating TRG in gastric cancer, as well as providing a brief overview of the use of radiographic and endoscopic methods to assess response to preoperative therapies. Lastly, we outline future directions regarding the use of a universal TRG system to guide care and assist with prognosis.

A Rapid Access Brief Psychotherapy Intervention to Respond to Healthcare Workers in Ontario Whose Mental Health was Negatively Impacted During the COVID-19 Pandemic.

Although the coronavirus disease 2019 (COVID-19) pandemic has had widespread negative impacts on the mental health of healthcare workers (HCWs), there has been little research on psychological interventions during the pandemic for this population. The current study examines whether a brief coping-focused treatment intervention delivered in a virtual individual format would be associated with positive changes in Canadian HCWs' mental health during the pandemic. Three hundred and thirty-three HCWs receiving the intervention at 3 large specialty tertiary care hospitals in Ontario, Canada, completed measures of anxiety, depression, perceived stress, work/social impairment, insomnia and fear of COVID-19. After completing treatment, HCWs rated their satisfaction with the treatment. The intervention was associated with large effect size improvements in anxiety, depression, perceived stress, insomnia and fear of COVID-19, and moderate effect size improvements in work/social impairment. At treatment session 1, prior mental health diagnosis and treatment were both significantly correlated with depression, anxiety, and work/social impairment scores. Secondary analyses of data from one of the sites revealed that treatment-related changes in anxiety, depression, perceived stress and work/social impairment were independent of age, gender, occupational setting, profession and the presence of a previous mental health diagnosis or treatment, with the exception that nurses improved at a slightly greater rate than other professions in terms of work/social impairment. HCWs were highly satisfied with the treatment. A large number of HCWs experiencing significant distress at baseline self-referred for assistance. Timely and flexible access to a brief virtual coping-focused intervention was associated with improvements in symptoms and impairment, and treatment response was largely unrelated to demographic or professional characteristics. Short-term psychological interventions for HCWs during a pandemic may have a highly positive impact given their association with improvement in various aspects of HCWs' mental health improvement.

Hybrid PET/MRI in Cerebral Glioma: Current Status and Perspectives.

Advanced MRI methods and PET using radiolabelled amino acids provide valuable information, in addition to conventional MR imaging, for brain tumour diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumour progression from treatment-related changes, and the early assessment of responses to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing, and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other, leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods, but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumours. PET is only required in equivocal situations, and the spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumours compared with a single modality. This review focuses on studies investigating the diagnostic value of combined amino acid PET and 'advanced' MRI in patients with cerebral gliomas. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterisation of newly diagnosed tumours. Few data are available concerning the delineation of tumour extent. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumour recurrence from treatment-related changes. Here, the PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of cerebral gliomas, for which hybrid PET/MRI offers optimal conditions.

Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis.

Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment.

Tumor Response Metrics in Neuro-Oncology: A Review

Despite the efforts spent in clinical trials in neuro-oncology during the last few decades, many challenges remain in the radiologic evaluation of brain tumors and metastases. This article aims to explain the current use of tumor metrics, especially in phase II clinical trials, to evaluate response to systemic therapy in neuro-oncology. We will discuss the imaging findings associated with progression and with partial, minor, or complete response to treatment, as well as the method of measurement, the distinction between disease-related and treatment-related changes, and inclusion of clinical symptoms to define treatment response and progression. The evaluation of response in brain tumors requires metrics that account for differences in response between high- and low-grade gliomas and specific tumor behaviors associated with radiation and immunotherapy, among other pitfalls. Advanced brain imaging techniques, such as perfusion and permeability imaging, should be incorporated into clinical trials to measure response to novel therapeutic agents more accurately.Learning Objectives: To understand the role of tumor metrics analysis and the main challenges and pitfalls of applying neuro-oncology imaging criteria

Toxicological Evaluation of Cod Liver Oil-Enriched Vernonia amygdalina Leaf-Based Diet in Wistar Rats

Cod Liver Oil-Enriched V.amygdalina Leaf-Based Diet in our previous study elicited wound-healing effect in Type 2 diabetic rats. As part of the safety evaluation of this nutraceutical formulation, it is important to evaluate it toxicity profile. Therefore the purpose of this study was to determine the toxicological effect of cod liver oil-enriched V. amygdalina leaf-based diet (CLVA) in Wistar rats. Acute oral toxicity (limit test) and sub-acute toxicity (repeated dose 28-days oral toxicity) tests were carried out using Organization of Economic Cooperation and Development guidelines. For acute toxicity experiment, 2000 mg/kg body weight (b.wt.) single dose administration was given to 5 overnight-fasted female rats. This was done sequentially in an interval of 48 hr. While for the sub-acute study, 30 male and 30 female rats were assigned randomly to 6 groups constituting 4 main and 2 reversal groups, each containing 10 rats (5 male and 5 females). CLVA at the following doses; 0, 250, 500 and 1000 mg/kg b.wt. were administered daily to Wistar rats for 28 days. Rats in the Main groups (G1, G2, G3 & G4) were sacrificed at day 29 while the reversal groups (G1R & G4R) were monitored for another 14 days without CLVA administration. Data were analysed using the 20th version of Statistical Package for Social Sciences. Results showed that the lethal dose of CLVA in Wistar rat was above 2000 mg/ kg b.wt. Water, feed intake, liver function indices (alanine aminotransferase, aspartate aminotransferase, albumin, total protein and total bilirubin), kidney function indices (alkaline phosphatase, blood urea nitrogen, urea, and electrolytes), lipid profile (total cholesterol, triglycerides), glucose concentration and haematological parameters were not altered significantly (p > 0.05) in CLVA-fed groups. Histopathological examination of kidneys and livers did not show any treatment-related changes as well. In conclusion, administration of CLVA at the studied doses is safe for consumption and can therefore be recommended for use by patients suffering from diabetes with delayed wound healing.

Development of a Patient-Reported Outcome (PRO) Measure to Assess Emotional Impact of Treatment for Type2 Diabetes.

Patients receiving treatment for type2 diabetes (T2D) may experience an emotional impact associated with treatment-related changes. A patient-reported outcome (PRO) measure assessing both positive and negative emotional impact of medication treatment for T2D is needed to better understand the patient experience of treatment. The purpose of this qualitative study was to explore the emotional impact of treatment for T2D and support the development of a questionnaire to assess the emotional impact of treatment for T2D. Exit interviews were conducted with patients with T2D participating in the SURPASS-2 and SURPASS-3 trials for tirzepatide. The exit interviews included a concept elicitation section focusing on the emotional impact of their study treatment. Results were used to develop two questionnaires that were evaluated in cognitive interviews with patients with T2D. The concept elicitation interviews included 28 patients (mean age 57.6years; 64.3% female). Most patients reported positive changes in emotions associated with tirzepatide, including increased confidence (n = 23; 82.1%), hope (n = 23; 82.1%), self-esteem (n = 23; 82.1%), relief (n = 22; 78.6%), optimism (n = 21; 75.0%), sense of control (n = 21; 75.0%), happiness (n = 15; 53.6%), and motivation (n = 15; 53.6%), as well as reduced worry/anxiety (n = 19; 67.9%). Negative emotional impact was less commonly reported but included frustration (n = 2; 7.1%), worry/anxiety (n = 1; 3.6%), fear (n = 1; 3.6%), and feeling depressed (n = 1; 3.6%). Two new PROs, the Emotional Impact of Diabetes Treatment Questionnaires (EIDTQ, status and comparison versions), were developed based on these finding. The status version assesses the emotional impact of current treatment, while the comparison version allows for comparison of the current treatment to a previous treatment. The questionnaires were refined on the basis of cognitive interviews with 20 additional patients (mean age 58.3years; 60.0% female), and results suggest that the final instruments were clear, comprehensible, and relevant to patients. The EIDTQ-Status and Comparison measures can be used as a supplement to clinical outcomes, such as hemoglobin A1c (HbA1c) and body weight, to provide a broader picture of the patient's emotional experience with medication treatment for T2D.

Effects of fixed functional orthodontic treatment in hypodivergent and hyperdivergent class II patients—a retrospective cephalometric investigation

ObjectiveTo compare skeletal and dentoalveolar changes after orthodontic treatment of class II malocclusion in patients with hypodivergent and hyperdivergent growth patterns through cast splint fixed functional appliances (FFA).Materials and methodsN = 42 out of n = 47 patients with mandibular plane angles < 34° or ≥ 34° were divided into a hypodivergent (n = 24) and a hyperdivergent (n = 18) group. All patients received a single-step mandibular advancement protocol through an FFA. Lateral cephalograms were analyzed after initial leveling and alignment (T1) and immediately after FFA removal (T2). The therapeutic effect was calculated through comparison with age-matched controls from a growth survey. Statistical significance was set at p < 0.05.ResultsHypodivergent and hyperdivergent patients showed different treatment outcomes, but significant differences existed only for overbite and interincisal angle. Nearly all measurements suggested similar treatment-related changes for both groups with exception for dentoalveolar parameters.ConclusionTreatment with FFA causes similar skeletal and dentoalveolar effects in hypodivergent and in hyperdivergent patients. The correction of overjet and molar relationship is mainly caused by dentoalveolar changes.Clinical relevanceHyperdivergent patients do not respond unfavorably to FFA treatment compared to hypodivergent patients. Lower incisor protrusion occurs more pronounced in hypodivergent patients. The growth pattern ought to be considered when choosing FFA for class II treatment.

With a little help from my friends: Changes in symptoms, cognitions and self-ambivalence after a group based cognitive-behavioral treatment for obsessive-compulsive disorder

Obsessive Compulsive Disorder (OCD) is a debilitating illness affecting 2% of the population. Psychological treatments consisting of exposure and response prevention (ERP) and cognitive behavioral based methods are efficacious for most individuals with OCD and have been found to yield long-term positive outcomes. Most research on such outcomes have focused on individual treatment and the outcomes associated with group-based treatments are less well established. Further, the mechanisms that account for outcomes of individual and group based treatments for OCD remain unclear. Cognitive theories suggest that changes in cognitive structures including self-related beliefs may account for treatment related changes, yet limited research has empirically examined such suggestions. This study examined the outcomes of a low-intensity 10-session group CBT program for OCD in real-world effectiveness. The final sample consisted of 78 participants (M = 34.9 years, 50% Males), who answered symptom and cognition measures following each session. Overall, using hierarchical linear modelling, it was found that the program was effective in reducing symptoms (modelled fall of 7.64 on the YBOCS). In addition, both OCD-relevant beliefs and self-ambivalence also reduced significantly, and both significantly related to symptom level. Implications are discussed.

Imaging of Skull Base Tumors.

The skull base provides a platform for supporting the brain while serving as a conduit for major neurovascular structures. In addition to malignant lesions originating in the skull base, there are many benign entities and developmental variants that may simulate disease. Therefore, a basic understanding of the relevant embryology is essential. Lesions centered in the skull base can extend to the adjacent intracranial and extracranial compartments; conversely, the skull base can be secondarily involved by primary extracranial and intracranial disease. CT and MRI are the mainstay imaging methods and are complementary in the evaluation of skull base lesions. Advances in cross-sectional imaging have been crucial in the management of patients with skull base pathology, as this represents a complex anatomical area that is hidden from direct clinical exam. Furthermore, the clinician must rely on imaging studies for therapy planning and to monitor treatment response. It is crucial to have a thorough understanding of skull base anatomy and its various pathologies, as well as to recognize the appearance of treatment-related changes. In this review, we aim to describe skull base tumors and tumor-like lesions in an anatomical compartmental approach and present imaging methods that aid in diagnosis, management, and follow-up.

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma

A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.

1709-P: Perceptions of Treatment Outcomes in People with Obesity and T2D—A Qualitative Study

Background: Treatments for obesity and T2D often combine lifestyle changes (diet, physical activity) and medication. Weight reduction is an expected outcome of obesity and some T2D treatments. Individuals’ perspectives on obesity treatments, attitudes towards reduced food intake via appetite changes, and treatment-related gastrointestinal adverse events (GI AEs) are not well characterized. The current study assessed individuals’ perceptions of obesity/T2D treatments that impact appetite, eating behaviors, and weight, and concerns about GI AEs. Methods: This cross-sectional study involved semi-structured interviews with 45 US adults (obesity, n=15; overweight, n=10; T2D, n=20). Two creative tasks explored participants’ perceptions of obesity/T2D treatment outcomes: 1) participants discussed perspectives on hypothetical obesity/T2D treatments that reduced appetite, hunger, and cravings; 2) participants indicated their choice from two hypothetical obesity/T2D treatments, which varied by degree of GI AEs, appetite changes, and weight reduction. Interviews were audio recorded and transcribed for analysis. Results: Most participants asked (28/35; 80%) perceived the hypothetical scenarios as a positive outcome of obesity/T2D treatment. Most (30/35; 86%) considered appetite reduction to be an important treatment benefit. Many also perceived fewer cravings (13/29; 45%) and lesser desire to eat (12/29; 41%) to be positive treatment outcomes. Participants associated treatment-related appetite changes with improvements in diet (10/33; 30%), emotional well-being (9/33; 27%), and daily activities (8/33; 24%). In the choice task, participants perceived appetite and weight reduction as positive treatment outcomes, irrespective of degree of GI AEs. Conclusions: Findings demonstrate that participants value appetite changes and/or weight reduction as treatment priorities, and are willing to accept potential GI AEs for these treatment outcomes. Disclosure J.Poon: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. L.O'hara: Other Relationship; Lilly. H.Kendal: Other Relationship; Eli Lilly and Company. K.Sully: None. M.Guy: Employee; Adelphi Values, Other Relationship; Eli Lilly and Company. H.Bradley: Other Relationship; Eli Lilly and Company. C.Tolley: None. B.Mason: None.

Abdominal Diffusion-Weighted MRI With Simultaneous Multi-Slice Acquisition: Agreement and Reproducibility of Apparent Diffusion Coefficients Measurements.

Simultaneous multi-slice diffusion-weighted imaging (SMS-DWI) can shorten acquisition time in abdominal imaging. To investigate the agreement and reproducibility of apparent diffusion coefficient (ADC) from abdominal SMS-DWI acquired with different vendors and different breathing schemes. Prospective. Twenty volunteers and 10 patients. 3.0 T, SMS-DWI with a diffusion-weighted echo-planar imaging sequence. SMS-DWI was acquired using breath-hold and free-breathing techniques in scanners from two vendors, yielding four scans in each participant. Average ADC values were measured in the liver, pancreas, spleen, and both kidneys. Non-normalized ADC and ADCs normalized to the spleen were compared between vendors and breathing schemes. Paired t-test or Wilcoxon signed rank test; intraclass correlation coefficient (ICC); Bland-Altman method; coefficient of variation (CV) analysis; significance level: P < 0.05. Non-normalized ADCs from the four SMS-DWI scans did not differ significantly in the spleen (P = 0.262, 0.330, 0.166, 0.122), right kidney (P = 0.167, 0.538, 0.957, 0.086), and left kidney (P = 0.182, 0.281, 0.504, 0.405), but there were significant differences in the liver and pancreas. For normalized ADCs, there were no significant differences in the liver (P = 0.315, 0.915, 0.198, 0.799), spleen (P = 0.815, 0.689, 0.347, 0.423), pancreas (P = 0.165, 0.336, 0.304, 0.584), right kidney (P = 0.165, 0.336, 0.304, 0.584), and left kidney (P = 0.496, 0.304, 0.443, 0.371). Inter-reader agreements of non-normalized ADCs were good to excellent (ICCs ranged from 0.861 to 0.983), and agreement and reproducibility were good to excellent depending on anatomic location (CVs ranged from 3.55% to 13.98%). Overall CVs for abdominal ADCs from the four scans were 6.25%, 7.62%, 7.08, and 7.60%. The normalized ADCs from abdominal SMS-DWI may be comparable between different vendors and breathing schemes, showing good agreement and reproducibility. ADC changes above approximately 8% may potentially be considered as a reliable quantitative biomarker to assess disease or treatment-related changes. 2 TECHNICAL EFFICACY: Stage 2.

Treatment-related changes in serum neutrophil gelatinase-associated lipocalin (NGAL) in psoriatic arthritis: results from the PIPA cohort study

Objectives Obesity and psoriatic arthritis (PsA) have a complicated relationship. While weight alone does not cause PsA, it is suspected to cause worse symptoms. Neutrophil gelatinase-associated lipocalin (NGAL) is secreted through various cell types. Our objective was to assess the changes and trajectories in serum NGAL and clinical outcomes in patients with PsA during 12 months of anti-inflammatory treatment. Method This exploratory prospective cohort study enrolled PsA patients initiating conventional synthetic or biological disease-modifying anti-rheumatic drugs (csDMARDs/bDMARDs). Clinical, biomarker, and patient-reported outcome measures were retrieved at baseline, and 4 and 12 months. Control groups at baseline were psoriasis (PsO) patients and apparently healthy controls. The serum NGAL concentration was quantified by a high-performance singleplex immunoassay. Results In total, 117 PsA patients started a csDMARD or bDMARD, and were compared indirectly at baseline with a cross-sectional sample of 20 PsO patients and 20 healthy controls. The trajectory in NGAL related to anti-inflammatory treatment for all included PsA patients showed an overall change of −11% from baseline to 12 months. Trajectories in NGAL for patients with PsA, divided into treatment groups, showed no clear trend in clinically significant decrease or increase following anti-inflammatory treatment. NGAL concentrations in the PsA group at baseline corresponded to the levels in the control groups. No correlation was found between changes in NGAL and changes in PsA outcomes. Conclusion Based on these results, serum NGAL does not add any value as a biomarker in patients with peripheral PsA, either for disease activity or for monitoring.

Triple network model of brain connectivity changes related to adverse mood effects in an oral contraceptive placebo-controlled trial

Combined oral contraceptives (COC) are among the most commonly used contraceptive methods worldwide, and mood side effects are the major reason for discontinuation of treatment. We here investigate the directed connectivity patterns associated with the mood side effects of an androgenic COC in a double-blind randomized, placebo-controlled trial in women with a history of affective COC side effects (n = 34). We used spectral dynamic causal modeling on a triple network model consisting of the default mode network (DMN), salience network (SN) and executive control network (ECN). Within this framework, we assessed the treatment-related changes in directed connectivity associated with adverse mood side effects. Overall, during COC use, we found a pattern of enhanced connectivity within the DMN and decreased connectivity within the ECN. The dorsal anterior cingulate cortex (SN) mediates an increased recruitment of the DMN by the ECN during treatment. Mood lability was the most prominent COC-induced symptom and also arose as the side effect most consistently related to connectivity changes. Connections that were related to increased mood lability showed increased connectivity during COC treatment, while connections that were related to decreased mood lability showed decreased connectivity during COC treatment. Among these, the connections with the highest effect size could also predict the participants’ treatment group above chance.

Toxicological safety assessment of AP-Bio®, a standardized extract of Andrographis paniculata in Sprague Dawley rats.

Andrographis paniculata, commonly known as green chiretta, is a traditionally used plant in India, China, and Southeast Asian countries for its varied health benefits including immune health. The objective of the present study was to assess the safety of AP-Bio®, a standardized A. paniculata extract in Sprague Dawley rats by following the Organisation for Economic Cooperation and Development (OECD) test guidelines of acute and 90-day repeated dose sub-chronic toxicity studies. AP-Bio® did not show any treatment-related clinical signs of toxicity or mortality during the 14-day observation period in animals tested in the single-dose acute oral toxicity study up to a dose of 5000 mg/kg body weight. In the 90-day repeated dose sub-chronic oral toxicity study, no treatment-related adverse clinical signs were observed in any of the treated groups (300, 600, and 900 mg/kg). All treated animals showed usual weight gain and comparable feed intake. The ophthalmoscope examination did not reveal any abnormalities. Also, no toxicologically significant changes were observed in urinalysis, hematology, and blood chemistry parameters. Absolute organ weights and relative organ weights of vital organs did not differ significantly compared to control. Gross and histopathological findings did not show any remarkable and treatment-related changes. Results of the safety evaluation showed the median lethal dose (LD50 ) of AP-Bio® was found to be more than 5000 mg/kg rat body weight and the no observed adverse effect level (NOAEL) of AP-Bio® was found to be 900 mg/kg rat body weight.

EE227 The Impact of Treatment-Related Changes in Lipids on the Cost-Effectiveness of Resmetirom and Obeticholic Acid for Treatment of Nonalcoholic Steatohepatitis

Lipid levels impact cardiovascular disease (CVD) risk, including stroke and myocardial infarction. This analysis assessed the impact of treatment-related changes in lipid levels resulting from two potential treatments for nonalcoholic steatohepatitis (NASH), resmetirom and obeticholic acid (OCA), on costs and health outcomes versus placebo from a U.S. healthcare payer perspective over a lifetime horizon.

The genomic and transcriptomic landscapes of chemotherapy naïve vs post-chemotherapy germ cell tumors.

5007 Background: Cisplatin resistance occurs in up to 30% of patients with advanced germ cell tumors (GCTs). Despite effective salvage treatment regimen, there is a 50% risk of cancer-specific death. Previously, we identified molecular features, including TP53 mutations and MDM2 amplification, associated with cisplatin resistance (Bagrodia, 2016). Herein, we evaluate the genomic and transcriptomic landscapes of chemotherapy naïve vs post-chemotherapy GCT’s to uncover genetic factors that might drive cisplatin resistance. Methods: GCTs (N = 138) were tested at Caris Life Sciences (Phoenix, AZ) with next-generation sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). Prevalence was calculated for pathogenic SNVs/indels and copy number amplifications (CNA≥6 copies). Primary (N = 65) and metastatic (N = 73) sites were defined based on the biopsy site. A specialized genitourinary pathologist blindly reviewed selected H&amp;E-stained slides and designated tumors as chemotherapy naïve (N = 66) or post-chemotherapy (N = 17) based on treatment related changes. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Transcriptomic signatures predictive of response to immunotherapy (T cell-inflamed) and platinum sensitivity (PSS, high score suggests increased platinum sensitivity) were applied. Mann-Whitney U and χ² tests were applied, with P-values adjusted for multiple comparisons. Results: Primary and metastatic GCT had slight differences between putative drivers of platinum therapy resistance: KIT (15% vs 1), TP53 (10% vs 17), KRAS (13% vs 9) mutations and MDM2 CNA (4% vs 3), all p &gt; 0.05. When comparing post-chemo vs chemo naïve GCTs, no significant differences in the genomic landscape were observed (p &gt; 0.05). Chemo naïve tumors were shown to be enriched for gene sets associated with KRAS signaling and epithelial-to-mesenchymal transition. Additionally, they trended towards a higher proportion of T cell-inflamed tumors as compared to post-chemo samples (32% vs 18, p = 0.36). The average PSS for chemo naïve was slightly higher than post-chemo (CN: 0.07 Arbitrary Units (AU), N = 62 vs PC: -1.82, N =16, p = .52). Chemo naïve tumors with TP53, KRAS, or KIT mutation or MDM2 CNA had a lower PSS (-4.16 AU, N= 18) than tumors with none of those alterations (2.17, N = 38), p = 0.05. Finally, chemo naïve tumors with MDM2 CNA (N=2, -16.26 AU) had the lowest PSS followed by tumors with mutations in TP53 (N=6, -2.04), KIT (N = 2, -1.77) and KRAS (N=9, -1.05) (mutations were mutually exclusive except for a concurrent KRAS and TP53 mutation). Conclusions: This study provides evidence that chemo naïve GCTs with mutations in TP53, KRAS, KIT or MDM2 CNA have higher expression of genes associated with resistance to platinum-based chemotherapy. These findings contribute to a better understanding of the molecular characteristics of GCTs and may inform prognosis and treatment.

Chronic toxicity and carcinogenicity study of dietary gardenia blue in Sprague Dawley rats.

In this combined chronic toxicity/carcinogenicity study of gardenia blue as a natural food color additive, Sprague Dawley rats were administered 0.5%, 2.5%, or 5.0% gardenia blue via the feed or carrier diet (0.0% gardenia blue) for 12 (chronic toxicity cohort) or 24 (carcinogenicity cohort) months. No abnormal clinical, ophthalmological, neurotoxicity or clinical pathology changes were attributed to treatment, and there was no increase in mortality due to gardenia blue exposure. The only treatment-related change was grossly observed blue discoloration of the stomach, intestines, and mesenteric lymph nodes as well as reversible dark discoloration of the kidneys all without associated histopathology. The no-observed-adverse-effect level (NOAEL) for gardenia blue exposure via the diet for one or two years was determined to be 5.0% (2175.3 mg/kg body weight/day in male rats and 3075.4 mg/kg body weight/day in female rats).

Commentary: Optimism and guidance for improving treatment effects among children with callous-unemotional traits - reflections on Perlstein et al. (2023).

Callous-unemotional (CU) traits have increasingly received attention as a potential predictor and outcome of treatment for children with conduct problems. The results of Perlstein etal. (2023) offer the first meta-analytic evidence against the long-held belief that CU traits confer treatment resistance. The results also suggest that children with conduct problems and CU traits require something more or different to achieve treatment outcomes commensurate with their conduct problems-only peers. In this commentary, I reflect on how treatment adaptations for children with conduct problems and CU traits have attempted to achieve this goal, emphasizing that more work is needed to maximize improvement in putative mechanisms and mediators of treatment-related change. In this way, I argue that Perlstein etal. (2023) offer both optimism and guidance for improving treatment effects among children with conduct problems and CU traits.