Predictors Of Response Research Articles

Abstract LB096: Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma

Abstract Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in epithelial ovarian carcinoma (OvC) onset. TL in either target or surrogate tissue (blood) is currently being investigated as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is presently an urgent need for an appropriate approach to chemotherapy response prediction. We performed a monochrome multiplex qPCR measurement of TL in peripheral blood and tumor tissues of 209 OvC patients. Methylation status and gene expression of shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n=46) had shorter telomeres in peripheral blood cells compared to those treatment-resistant (n=93; P=0.037). Cancer tissue TL lower than the median predisposed to better overall survival (P=0.002). Gene expression of TPP1, which recruits telomerase to telomeres, was positively associated with TL in tumor tissue (P=0.026). TL measured in peripheral blood cells could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' overall survival. The study was financed by the project NPO (LX22NPO05102), the Czech Health Research Council (NU21-03-00145), and the Czech Science Foundation (21-27902S). Citation Format: Kristyna Tomasova, Karolina Seborova, Michal Kroupa, Josef Horak, Ludmila Vodickova, Lukas Rob, Martin Hruda, Marcela Mrhalova, Alena Bartakova, Jiri Bouda, Thomas Fleischer, Vessela Kristensen, Pavel Vodicka, Radka Vaclavikova. Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB096.

Abstract LB104: Tumor fraction as a predictive factor of outcome in patients referred for oncology early phase clinical trials: Analyses of two precision medicine studies

Abstract Modern phase I trials have shown considerable advancement, demonstrating encouraging response rates and subsequently raising the demand for participant enrollment. Despite these advances, there remains a significant challenge: approximately 15% of patients enrolled in these trials pass away within the first 90 days, and nearly half of them do not experience any therapeutic benefit. These statistics underscore the critical need for more effective strategies in selecting suitable patients for trial participation. One promising avenue is the use of circulating tumor DNA (ctDNA) measurements to estimate tumor fraction (TF), a method that has shown potential in prognosticating outcomes for patients with solid tumors. Nevertheless, the effectiveness of TF as an indicator for predicting the clinical benefits of systemic treatments in patients referred for early phase studies is yet to be conclusively determined Methods: We analyzed adult patients with advanced solid tumors included from December 2020 to December 2021 in two precision medicine studies: BIP (NCT02534649) and STING (NCT04932525). Comprehensive genomic profiling was conducted using the FDA approved 324-gene FoundationOne Liquid Cdx assay. TF was categorized as ≥10% or <10%. Multivariate analysis incorporated established prognostic scores (Royal Marsden Hospital: RMH, Garrido-Laguna et al. 2012; and GRIm, Bigot et al., 2017) and their individual components (RMH: albumin, lactate dehydrogenase, number of metastatic sites; GRIm: neutrophil/lymphocyte ratio, lactate dehydrogenase, albumin). Results: A total of 1305 patients referred for early phase trials were evaluated: 871 in BIP and 434 in STING.The treatment regimens patients received post-TF assessment included: cytotoxic agents (BIP: 278 patients, 28.8%; STING: 106 patients, 24.4%), immunotherapy (BIP: 152 patients, 15.8%; STING: 76 patients, 17.5%), tyrosine kinase inhibitors (BIP: 126 patients, 13.1%; STING: 35 patients, 8.1%), hormonal therapy (BIP: 131 patients, 13.6%; STING: 9 patients, 2.1%), and various other therapies or combinations. High TF was significantly correlated with poorer objective response/stable disease rate, shorter progression-free survival (PFS), and lower overall survival (OS) in both studies. Multivariate analysis confirmed TF as an independent predictor of objective response, PFS, and OS, beyond the RMH and GRIm scores and their components. Conclusions: This is the first prospective analysis confirming that TF is a significant predictive marker of treatment efficacy in patients referred for early phase studies. Our findings suggest that TF could be a valuable tool in decision-making for phase I trial participation. Additionally, this research lays the groundwork for future exploration of TF in risk stratification of cancer patients in various clinical contexts. Citation Format: Laila Belcaid, Sophie Cousin, Arnaud Bayle, Melissa Alame, Etienne Rouleau, Laura Blouin, Ludovic Lacroix, Damien Vasseur, Maxime Brunet, Sofiane Taleb, Isabelle Soubeyran, Veronique Debien, Eurydice Angeli, Christophe Massard, Antoine Italiano. Tumor fraction as a predictive factor of outcome in patients referred for oncology early phase clinical trials: Analyses of two precision medicine studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB104.

Abstract LB422: Specific activation of the Epstein-Barr Virus BGLF4 locus via lowered DNA methylation in EBV-associated CNS lymphoproliferative disease

Abstract Introduction: Epstein-Barr virus positive (EBV+) central nervous system lymphoproliferative diseases (CNS-LPD) are aggressive clinical conditions with poor prognosis. We have previously reported use of a ganciclovir (GCV), zidovudine (AZT), rituximab and dexamethasone regimen (GARD) that induced complete and durable responses in patients with primary CNS post-transplant lymphoproliferative disease (PTLD). Responses were associated with detection of two GCV/AZT viral drug targets, the EBV protein kinases BGLF4 and BXLF1. These viral proteins are normally expressed in lytic phase EBV, and the molecular basis for expression in latently infected EBV+ CNS-LPD is unknown. Methods: RNA expression of EBV genes LMP1, BZLF1, BXLF1, and BGLF4 was measured in 12 CNS-LPD biopsies (n=8/12 DLBCL-type) via qRT-PCR. Mass spectrometry-based EpiTYPER assay was used to quantify DNA methylation in EBV gene promoters. Biopsies from 25 patients with systemic PTLD were used for comparison. The BGLF4 locus was investigated in detail using luciferase reporters and 5’RACE mapping of transcription start sites in 3 EBV-infected cell lines and 4 CNS-LPD biopsy samples. Overall EBV methylation was assessed in a screening assay covering 31 EBV loci. Mechanistic involvement of active demethylation via TET2 was studied in a HEK293 CRISPR-Cas9 gene knockout model under EBV (strain M81) infection. Results: Gene expression analysis of biopsy specimens showed expression of LMP1, BXLF1, and BGLF4, but not BZLF1. Expression of BXLF1 and BGLF4 was significantly higher in CNS-LPD when compared to systemic EBV+ PTLD (p=0.043 and p=0.00022, respectively). EpiTYPER data showed significantly decreased promoter methylation at BGLF4 (p=0.00013). Luciferase reporter analysis of the BGLF4 upstream sequence revealed 3 regions of promoter activity which were silenced by in vitro methylation of reporters. 5’RACE identified transcription start sites at all 3 BGLF4 promoters and detected their activity in EBV+ cell lines and CNS-LPD biopsies. By overlaying transcriptional activity, 5’RACE and DNA methylation data, we identified DNA methylation loss at single CpG dinucleotides correlated with BGLF4 expression (r2=0.73). These sites were specifically demethylated in CNS-LPD, while surrounding EBV methylation remained high. Knockout of TET2 followed by EBV infection revealed that active demethylation is required for demethylation at BGLF4 promoters. Conclusions: The molecular determinant for success of the GARD regimen in CNS-LPD has remained poorly understood, with immunohistochemical detection of BGLF4/BXLF1 as the only predictor of treatment response. Our results provide the molecular basis for expression of BGLF4 in CNS-LPD by showing decreased promotor DNA methylation. We identified specific BGLF4 methylation sites that hold promise as potential DNA biomarkers for EBV+ CNS-LPD. Citation Format: Christoph Weigel, Haley L. Klimaszewski, Selamawit Addissie, Sarah Schlotter, Fode Tounkara, James P. Dugan, Bradley M. Haverkos, Lynda Villagomez, Mark Lustberg, Pierluigi Porcu, Timothy Voorhees, Michael A. Caligiuri, Ginny Bumgardner, Christopher C. Oakes, Robert Baiocchi. Specific activation of the Epstein-Barr Virus BGLF4 locus via lowered DNA methylation in EBV-associated CNS lymphoproliferative disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB422.

Influence of barrens restoration treatments on soil carbon, nitrogen, and mercury pools and emissions

AbstractCurrently barrens communities only represent about 1% of their original area in the Great Lakes region. To maintain or restore barrens vegetation, prescribed fire is often applied to limit the regeneration of undesirable species and shrubs. Vegetation community response is a combination of direct fire effects on the vegetation vitality and the indirect effect of soil nitrogen (N) loss that favors nutrient‐poor adapted barren communities. In this study, we assessed forest floor and upper mineral soil (0–5 cm) pools of carbon (C), N, and mercury (Hg) before and after prescribed fire of the Moquah Barrens in northwest Wisconsin. Although we took measurements in four distinct cover types, we found no relationship between cover type and soil pools. Across all cover types, prescribed fire led to considerable emissions of C, N, and Hg in the forest floor but only Hg in the upper mineral soils (0–5 cm), presumably because maximum fire temperatures were met for Hg volatilization. We classified fire severity and soil surface temperatures at the quadrat scale, but no discernable relationships with emissions were observed. The lack of detectable relationships is likely the result of a mismatch between the scales of response variables and predictors. As a result, we calculated ecosystem‐scale fire emissions based on the total area burned because we could not discern other smaller scale predictors. Overall emissions from dormant, spring season prescribed fires at the Moquah Barrens were approximately 11,000 Mg (5.5 Mg ha−1) for C, 350 Mg for N (0.17 Mg ha−1), and 4,500 g for Hg (2.3 g ha−1).

Tumor lymphangiogenesis index reveals the immune landscape and immunotherapy response in lung adenocarcinoma.

Lymphangiogenesis (LYM) has an important role in tumor progression and is strongly associated with tumor metastasis. However, the clinical application of LYM has not progressed as expected. The potential value of LYM needs to be further developed in lung adenocarcinoma (LUAD) patients. The Sequencing data and clinical characteristics of LUAD patients were downloaded from The Cancer Genome Atlas and GEO databases. Multiple machine learning algorithms were used to screen feature genes and develop the LYM index. Immune cell infiltration, immune checkpoint expression, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and drug sensitivity analysis were used to explore the correlation of LYM index with immune profile and anti-tumor therapy. We screened four lymphangiogenic feature genes (PECAM1, TIMP1, CXCL5 and PDGFB) to construct LYM index based on multiple machine learning algorithms. We divided LUAD patients into the high LYM index group and the low LYM index group based on the median LYM index. LYM index is a risk factor for the prognosis of LUAD patients. In addition, there was a significant difference in immune profile between high LYM index and low LYM index groups. LUAD patients in the low LYM index group seemed to benefit more from immunotherapy based on the results of TIDE algorithm. Overall, we confirmed that the LYM index is a prognostic risk factor and a valuable predictor of immunotherapy response in LUAD patients, which provides new evidence for the potential application of LYM.

New knowledge on anti-IgLON5 disease.

Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported. Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects. Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.

Determinants of health as predictors for differential antibody responses following SARS-CoV-2 primary and booster vaccination in an at-risk, longitudinal cohort.

Post vaccine immunity following COVID-19 mRNA vaccination may be driven by extrinsic, or controllable and intrinsic, or inherent health factors. Thus, we investigated the effects of extrinsic and intrinsic on the peak antibody response following COVID-19 primary vaccination and on the trajectory of peak antibody magnitude and durability over time. Participants in a longitudinal cohort attended visits every 3 months for up to 2 years following enrollment. At baseline, participants provided information on their demographics, recreational behaviors, and comorbid health conditions which guided our model selection process. Blood samples were collected for serum processing and spike antibody testing at each visit. Cross-sectional and longitudinal models (linear-mixed effects models) were generated to assess the relationship between selected intrinsic and extrinsic health factors on peak antibody following vaccination and to determine the influence of these predictors on antibody over time. Following cross-sectional analysis, we observed higher peak antibody titers after primary vaccination in females, those who reported recreational drug use, younger age, and prior COVID-19 history. Following booster vaccination, females and Hispanics had higher peak titers after the 3rd and 4th doses, respectively. Longitudinal models demonstrated that Moderna mRNA-1273 recipients, females, and those previously vaccinated had increased peak titers over time. Moreover, drug users and half-dose Moderna mRNA-1273 recipients had higher peak antibody titers over time following the first booster, while no predictive factors significantly affected post-second booster antibody responses. Overall, both intrinsic and extrinsic health factors play a significant role in shaping humoral immunogenicity after initial vaccination and the first booster. The absence of predictive factors for second booster immunogenicity suggests a more robust and consistent immune response after the second booster vaccine administration.

Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Predictors of Quality of Life, Anxiety and Acceptance in Patients with Implantable Cardioverter-Defibrillator.

An implantable cardioverter-defibrillator (ICD) can cause high levels of anxiety and depression, resulting in negative effects on quality of life. To evaluate the quality of life, anxiety, and acceptance of the ICD using standardized measurement instruments and identify predictors of better responses for each of the outcomes studied. This is a prospective cohort study with patients undergoing initial ICD implantation or reoperation to maintain the device. The study outcomes included quality of life, anxiety, and acceptance of the ICD. The change in scores (30 and 180 days) was assessed using the minimal important difference (MID). Univariate analysis and the multivariate logistic regression model were used to identify predictors of better responses, adopting a significance level of 5%. A total of 147 patients were included between January/2020 to June/2021, with a mean age of 55.3 ± 13.4 years and a predominance of males (72.1%). The MID for quality of life, anxiety, and ICD acceptance were observed in 33 (22.4%), 36 (24.5%) and 43 (29.3%) patients, respectively. Age equal to or greater than 60 years (OR=2.5; 95%CI=1.14-5.53; p=0.022), absence of atrial fibrillation (OR=3.8; 95%CI=1.26-11.63; p=0.017) and female gender (OR=2.2; 95%CI=1.02-4.97; p=0.045) were independent predictors of better responses to quality of life, anxiety and acceptance of the ICD, respectively. The identification of predictors for better quality of life scores, anxiety, and acceptance of the device can support the implementation of specific care for patients with a greater chance of presenting unfavorable results.

Predictors of Inadequate Serum Urate Response to Low-Dose Febuxostat in Male Patients with Gout.

This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables. We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA<6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set. Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR. Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.

Predicting symptom response and quality of life to the low FODMAP diet in irritable bowel syndrome: a 6-month longitudinal study

The low fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) diet is recommended as a first line therapeutic management strategy for irritable bowel syndrome (IBS)(1). The low FODMAP diet is supported by meta-analytical evidence(2), and demonstrates acceptability and effectiveness for improving symptoms and quality of life (QoL) in 50-75% of individuals with IBS. However, a subset of individuals (25-50%) do not respond to the diet(3). The identification of individual-level predictors of treatment response across all three phases of the low FODMAP diet is currently lacking. The study aims were to assess psychological predictors of symptom and QoL response to the low FODMAP diet in patients with IBS. Adults with IBS underwent a three-phase low FODMAP diet, guided by individualised dietetic education. Predictor variables included levels of depressive, anxiety, and extraintestinal somatic symptoms, stress, treatment beliefs and expectations, behavioural avoidance, and illness perceptions. Symptom severity and QoL were the main outcomes. Questionnaires assessing psychological predictors, symptoms and QoL were administered at five points: pre-dietitian (week 0), post-dietitian, end of elimination (week 5), end of reintroduction (week 13), and end of personalisation (week 25) phases. Latent class growth analysis was used to identify classes of response trajectories for symptoms. Linear mixed models were used to test the effect of baseline psychological scores on symptoms and QoL over time. Cross lagged panel models determined the directional predictive relationship between psychological predictors and symptom severity. 112 participants (89% F) median age 30 ± 17 years were included. There were three classes of symptom response trajectories, including ‘non-improvers’ (21.3% of participants) with high initial symptom severity and minimal improvement, ‘improvers’ (22.5% of participants) with low initial symptom severity and significant improvement, and an ‘intermediate’ group (56.2% of participants) with moderate initial symptom severity and significant improvement. Higher treatment beliefs predicted a stronger initial symptom response (effect on linear slope p = 0.036). Lower gut-specific anxiety, as well as higher levels of personal and treatment control at baseline predicted a stronger reduction in IBS symptom severity and improved QoL from week 0 to week 25. Participants with higher levels of baseline psychological symptoms and negative illness perceptions (i.e., lower emotional representations) predicted a stronger initial and later QoL response (effect on linear (p = 0.006) and quadratic (p = 0.049) slopes). Increased cyclical time beliefs predicted poorer initial and later QoL response (effect on linear (p = 0.015) and quadratic (p = 0.029) slopes). Individuals experiencing lower to mid-range symptom severity at baseline had greater improvement with the low FODMAP diet. Lower anxiety, positive illness views and higher treatment beliefs predict better QoL and symptom response. Personalised strategies are crucial for optimising low FODMAP diet effectiveness in IBS.

CandeSpartan Study: Candesartan Spanish Response-prediction and Tolerability study in migraine.

Effectiveness of candesartan in migraine prevention is supported by two randomized controlled trials. We aimed to assess the effectiveness, tolerability, and response predictors of candesartan in the preventive treatment of migraine. Observational, multicenter, prospective cohort study. The 50%, 75% and 30% responder rates, between weeks 8-12 and 20-24, were compared with the baseline. Treatment emergent adverse effects were systematically evaluated. Response predictors were estimated by multivariate regression models. Eighty-six patients were included, 79.1% females, aged 39.5 (inter-quartile range [IQR] 26.3-50.3), with chronic migraine (43.0%), medication overuse headache (55.8%) and a median of two (inter-quartile range: 0.75-3) prior preventive treatments. At baseline patients had 14 (10-24) headache and 8 (5-11) migraine days per month. The 30%, 50% and 75% responder rates were 40%, 34.9% and 15.1% between weeks 8-12, and 48.8%, 36%, and 18.6% between weeks 20-24. Adverse effects were reported by 30 (34.9%) and 13 (15.1%) patients between weeks 0-12 and 12-24, leading to discontinuation in 15 (17.4%) patients. Chronic migraine, depression, headache days per month, medication overuse headache, and daily headache at baseline predicted the response between weeks 20-24. Candesartan effectiveness and tolerability in migraine prevention was in line with the clinical trials' efficacy.Trial registration: The study protocol is registered in ClinicalTrials.gov (NCT04138316).

Pretreatment Thyroid Profile and its Relationship with Response to Treatment with Lithium in Bipolar Mood Disorder: A Longitudinal Study from Northeast India

Abstract Background: The thyroid hormone’s significant impact on the treatment of depressive and other mood disorders is well documented. Even minor hypothyroidism can modify the progression and treatment results of major depressive disorder. This research aims to explore the correlation between initial thyroid levels and the treatment outcome in bipolar mood disorder using lithium, a well-established treatment method. Methodology: The study involved 45 bipolar mood disorder patients diagnosed according to the Diagnostic and Statistical Manual 5 criteria and admitted to a tertiary care teaching institute in Northeast India. The patients received lithium treatment, with injectable lorazepam used for immediate agitation control when necessary. On the 1st day, a semi-structured questionnaire and Brief Psychiatric Rating Scale (BPRS) 24-item scale were used to evaluate symptoms, and samples were collected for a thyroid profile, including T3, T4, FT3, FT4, and thyroid-stimulating hormone (TSH). The BPRS scale was used again on the 30th day to assess treatment response. Results: The BPRS subscale showed the highest treatment response for grandiosity and the lowest for depression. Factors such as age, illness duration, substance use, and family history of mood disorder were inversely correlated with the BPRS score’s decrease. Initial thyroid levels were identified as a predictor of treatment response, with baseline T4 levels showing a significant positive correlation with treatment response, while baseline TSH levels showed a negative correlation. Conclusion: Lithium proved to be an effective treatment for bipolar mood disorder, particularly for the manic subtype. Initial T4 and TSH levels were found to significantly predict treatment response, with T4 showing a positive correlation and TSH showing a negative correlation.

383 Epigenetic Potentiation of Anti-tumor Immune Responses Using Viral Mimicry for Gliomas

INTRODUCTION: Human endogenous retroviruses (HERVs) account for approximately 8% of our genome and are evolutionary relics of a germline retroviral infection. Although normally silenced by a master epigenetic regulator, np220, HERVs may be re-expressed in cellular states with marked epigenetic dysregulation and induce innate anti-viral inflammatory responses. This viral mimicry immune response sensitizes tumors to immunotherapy by eliciting double-stranded RNAs (dsRNA)-mediated interferon signaling cascades. Hence, viral mimicry could serve as a predictor of clinical responses to immunotherapy. METHODS: We conducted a preclinical study on the role of np220 in GBM and mediating viral mimicry responses. RESULTS: Using a tailored bulk transcriptional dataset from 71 newly diagnosed high-grade GBMs, we demonstrated significantly negative correlations between np220 expression and 48 HERV superfamilies. Additionally, using a transcriptional deconvolution pipeline of low-and high-grade gliomas, we demonstrated that np220 is negatively correlated with innate antiviral immune response signatures (TLR3) (RTLR3 = -0.300, pTLR3 = 0.00006). Our in vitro studies have shown that NP220 knockdown induces intracellular HERV-mediated dsRNA-signaling cascades via RIG-1 and TLR3. NP220 knockdown exponentially increases PD-L1 expression (p-value: &lt;0.001), and, increases cytoplasmic accumulation of cellular endogenous dsRNA in established human and mouse glioma cell lines which may induce the interferon-mediated response. This response was recapitulated in recurrent GBM samples with radiographic responses to checkpoint inhibition (anti-PD1) with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Furthermore, we showed np220 is linked to reduced immune cell infiltration (CD8, Dendritic Cells) in the glioma microenvironment through deconvolution of RNA-seq data from TCGA (RCD8 = -.202, RDC = -0.198) (pCD8 = 8.79E-06, pDC = 1.34E-05). CONCLUSIONS: Our findings suggest that np220 could serve as a target to potentiate glioma ICI for immune response.

Dynamic bTMB combined with residual ctDNA improves survival prediction in locally advanced NSCLC patients with chemoradiotherapy and consolidation immunotherapy

BackgroundLiquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB), are recognized as promising predictors of prognoses and responses to immune checkpoint inhibitor (ICI), despite insufficient sensitivity of single biomarker detection. This research aims to determine whether the combinatorial utility of longitudinal ctDNA with bTMB analysis could improve the prognostic and predictive effects. MethodsThis prospective two-center cohort trial, consisting of discovery and validation datasets, enrolled unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) patients and assigned them to chemoradiotherapy (CRT) or CRT + consolidation ICI cohorts from 2018 to 2022. Blood specimens were collected pretreatment, 4 weeks post-CRT, and at progression to assess bTMB and ctDNA using 486-gene next-generation sequencing. Dynamic ∆bTMB was calculated as post-CRT bTMB minus baseline bTMB levels. Decision curve analyses were performed to calculate C-index. ResultsOne hundred twenty-eight patients were enrolled. In the discovery dataset (n = 73), patients treated with CRT and consolidation ICI had significantly longer overall survival (OS; median not reached [NR] vs 20.2 months; P < 0.001) and progression-free survival (PFS; median 25.2 vs 11.4 months; P = 0.011) than those without ICI. Longitudinal analysis demonstrated a significant decrease in ctDNA abundance post-CRT (P < 0.001) but a relative increase with disease progression. Post-CRT detectable residual ctDNA correlated with significantly shorter OS (median 18.3 months vs NR; P = 0.001) and PFS (median 7.3 vs 25.2 months; P < 0.001). For patients with residual ctDNA, consolidation ICI brought significantly greater OS (median NR vs 14.8 months; P = 0.005) and PFS (median 13.8 vs 6.2 months; P = 0.028) benefit, but no significant difference for patients with ctDNA clearance. Dynamic ∆bTMB was predictive of prognosis. Patients with residual ctDNA and increased ∆bTMB (∆bTMB > 0) had significantly worse OS (median 9.0 vs 23.0 months vs NR; P < 0.001) and PFS (median 3.4 vs 7.3 vs 25.2 months; P < 0.001). The combinatorial model integrating post-CRT ctDNA with ∆bTMB had optimal predictive effects on OS (C-index = 0.723) and PFS (C-index = 0.693), outperforming individual features. In the independent validation set, we confirmed residual ctDNA predicted poorer PFS (median 50.8 vs 14.3 months; P = 0.026) but identified more consolidation ICI benefit (median NR vs 8.3 months; P = 0.039). The combined model exhibited a stable predictive advantage (C-index = 0.742 for PFS). ConclusionsThe multiparameter assay integrating qualitative residual ctDNA testing with quantitative ∆bTMB dynamics improves patient prognostic risk stratification and efficacy predictions, allowing for personalized consolidation therapy for LA-NSCLC.

Real-World Data on Pathological Response and Survival Outcomes After Neoadjuvant Chemotherapy in HER2-Low Breast Cancer Patients

BackgroundData on the pathological responses and survival outcomes after neoadjuvant chemotherapy (NACT) in human epidermal growth factor receptor-2 (HER2)-low breast cancer (BC) are lacking. This study aims to investigate this topic in the real world. MethodsClinicopathological data from 819 HER2-negative BC patients who underwent NACT between 2010 and 2020 were retrospectively retrieved from the Shanghai Jiaotong University Breast Cancer Database. These patients were categorized into HER2-low and HER2-0 groups. Logistic analyses were conducted to identify predictors of complete pathological response (pCR) and breast pCR. Cox regression analyses were conducted to assess the factors associated with disease-free survival (DFS) and overall survival (OS). Kaplan-Meier (K-M) curves were generated to compare DFS and OS between HER2-low BC and HER2-0 BC. ResultsOf the 819 BC patients, 669 (81.7%) had HER2-low tumors, and 150 (18.3%) had HER2-0 tumors. HER2-low BC had a significantly higher ratio of ER ≥ 10%, PR ≥ 20%, and Ki67 ≥ 15% than HER2-0 BC. A significantly higher breast pCR rate was observed in HER2-low BC than in HER2-0 BC (13.6% and 7.3%, respectively, P = .036). Age, HER2 status (low or 0), Ki67, and surgery options were associated with breast pCR in HER2-negative BC. In HER2-low BC, the pCR rate of ER ≥ 10% BC was significantly lower than that of ER < 10% BC. The K-M curve showed no significant differences in DFS or OS between HER2-low and HER2-0 BC. Cox regression revealed that ER expression and histological grade (III vs. I∼II) were significantly associated with survival in HER2-low BC. ConclusionsIn this real-world data (RWD) study, a significantly higher breast pCR rate was found in HER2-low BC than in HER2-0 BC, although there was no significant difference in survival. Moreover, ER expression had a significant prognostic impact on HER2-low BC.

Targeted DNA Sequencing Reveals Molecular Factors Associated with Clinical Outcomes in Recurrent Glioblastoma

INTRODUCTION: The prognostic significance of molecular alterations in recurrent glioblastoma (rGBM) remains unclear. METHODS: 121 consecutive glioblastoma (GBM) patients who underwent re-resection at a single institution from 2016-2021 were retrospectively reviewed. All patients underwent maximal safe resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ) at time of initial diagnosis. DNA mutations from re-resection samples were assessed with a CLIA certified next-generation targeted DNA sequencing assay. Overall (OS) and progression-free survival (PFS) from re-resection were analyzed with the Kaplan-Meier method and Cox regression analyses. RESULTS: Median age at first recurrence was 57 years (range, 27-78), and median follow up from re-resection was 11 months. Salvage therapy comprised re-irradiation (n = 52, 43%), temozolomide (TMZ) (n = 39, 32%), lomustine (n = 47, 39%), and/or bevacizumab (n = 22, 18%). Median OS and PFS times were 12.1 and 4.4 months, respectively. Median tumor mutation burden (TMB) was 4 mut/Mb (range, 1-650), microsatellite instability (MSI) was 1.16% (range, 0-20), and MGMT methylation was present in 71 (59%) patients. Longer OS was found after postoperative TMZ (19.1 vs. 9.1), KPS &gt;70 (13.6 vs. 11.1), and/or re-irradiation (12.6 vs. 8.4) (p &lt; .05 for each). On multivariate analysis, TMZ (HR 0.2, 0.079-0.48), re-irradiation (HR 0.27, 0.12-0.58), and mutations in the PDGFRA (HR 0.24, 0.067-0.83) or PTEN (HR 2.3, 1.1-4.8) genes on targeted sequencing were associated with longer OS after re-resection (p &lt; .05). Multivariate predictors of re-irradiation response included MSI &gt; 1.16 (HR 0.25, 0.084-0.75), and mutations in PDGFRA (HR 0.04, 0.005-0.33), TERT (HR 0.16, 0.033-0.78), or PIK3R1 (HR 0.18, 0.041-0.8) genes. In the 46 matched primary/recurrent tumors, 40 (46%) had a longitudinal change in a mutation and 9 (24%) demonstrated hypermutation, of which 4 (57%) had simultaneous mismatch repair deficiencies. CONCLUSIONS: Our study identifies molecular factors associated with survival and response to re-irradiation in rGBM.

Mitochondrial ribosomal protein S24 is associated with immunosuppressive microenvironment and cold tumor in lung adenocarcinoma

ObjectiveMRPS24 (Mitochondrial Ribosomal Protein S24) belongs to the mitochondrial ribosomal protein family, which participates in the protein synthesis of the mitochondrion. However, the relationship of MRPS24 with lung adenocarcinoma (LUAD) remained unknown. We aimed to identify its immunological and functional mechanisms in LUAD. MethodsThe analysis of MRPS24 expression, clinical features, diagnosis, prognosis, function analysis, genetic alteration, copy number variations, methylation, and tumor microenvironment was investigated by the TCGA, UCSC Xena, GEO, HPA, GEPIA, cBioPortal, MethSurv, TIMER, TIMER2.0, and TISIDB databases. ResultsMRPS24 was found to be more abundant in LUAD tumor tissue than in normal tissue. High levels of MRPS24 expression were found to be an independent prognostic factor by multivariate analysis. Functional analysis revealed that MRPS24 expression was associated with the immune, cell cycle and methylation. MRPS24 methylation level was inversely linked with its expression (p < 0.001). Patients with low MRPS24 methylation had a worse prognosis than those with high methylation (p < 0.05). In addition, the result revealed that the MRPS24 expression was inversely linked to the immune cell infiltration in LUAD. Finally, the validations of the expression level, prognosis, and immune cell infiltration of MRPS24 were in accordance with our previous results. ConclusionsThis study systematically explored that MRPS24 expression was significantly correlated with prognosis, tumorigenesis, genetic alteration, copy number variations, methylation, and immune cell infiltration in LUAD. MRPS24 might be a potential immune-related biomarker in the development and treatment of LUAD, thereby acting as a promising predictor of immunotherapy response in LUAD.

486 Responsive Neurostimulation of the Centromedian Nucleus of the Thalamus in Adult Epilepsy: Multi-center Case Series

INTRODUCTION: Responsive neurostimulation (RNS) is an FDA-approved therapy for focal drug-resistant epilepsy (DRE). Emerging evidence supports a role for RNS in DRE with regional, multifocal, or non-resectable seizure onset zones. The centromedian nucleus of the thalamus (CMT) is a promising target, although descriptions of predictors of longer-term response are lacking. METHODS: We retrospectively reviewed patients who underwent RNS implantation with at least one CMT electrode at Baylor College of Medicine (BCM) and the University of Utah (UoU) from 2019-2023. Patients with = 6 months of follow-up were assessed for changes in clinical seizure frequency following surgery, as well as changes in seizure severity and subjective quality-of-life (QoL). RESULTS: Sixteen patients underwent CMT RNS (n = 12 BCM, n = 4 UoU) at a median age of 30 years [range 20-51] with a median 19-year history of epilepsy. All patients were evaluated by a multidisciplinary team that recommended thalamic RNS. Thirteen underwent bilateral CMT implantation and 7 had a documented lesional effect (&gt;50% reduction in seizures in the months following implantation). Thirteen patients had = 6-month follow-up with which to do subsequent seizure outcome analysis. In these patients, with a median follow-up of 18 months [6-40], median clinical seizure reduction was 80% [0-100%], 2 patients were seizure free for 6 months, and 1 was seizure free for 40 months. Patients with a lesional effect had a median 87% seizure reduction at last follow-up while those without a lesional effect had a 51% seizure reduction (two-tailed, two-sample t-test, p = 0.04). Subjective reduced seizure severity and increased QoL was documented in 92% of patients. CONCLUSIONS: RNS of the CMT can result in robust seizure frequency, severity, and QoL improvements in patients with DRE. Post-implantation lesional effect may be associated with longer-term improved response.

Predictors of Immunotherapy Efficacy in Metastatic Non-Small Cell Lung Cancer: Lung Immune Prognostic Index and Immune-Related Toxicity.

Immune checkpoint inhibitors (ICIs) have been proposed as the standard first-line and subsequent treatment for metastatic non-small cell lung cancer (NSCLC). This study analyzed whether patients with good lung immune prognostic index (LIPI) have a better response to ICIs and the relationship between immune-related adverse events (irAEs) and response in clinical practice. This was an observational, retrospective, single-center study. Patients with stage IV NSCLC between 2016 and 2021 were included in the study. Toxicity was assessed according to The Common Terminology Criteria for Adverse Events. Response assessment was performed according to RECIST 2.0 and immuno-related criteria. Descriptive and survival analyses were conducted. Degree of toxicity and response to treatment (based on treatment and histology) were assessed. LIPI and response were assessed. LIPI included dNLR (absolute neutrophil count/(white blood cell count - absolute neutrophil count)) ≥ 3 and lactate dehydrogenase (LDH) greater than the upper limit of normal. Patients were stratified into good (G), intermediate (I), and poor (P) prognostic groups. A total of 168 patients were included (130 men and 38 women, mean age 64.3 years). ICI use in the first- or second-line treatment was 65% and 35%, respectively. Fifteen (9%) patients showed complete response (CR), 50 (30%) showed partial response (PR), 39 (22%) had stable disease (SD), 45 (28%) had progressive disease (PD), and 19 (11%) were not evaluated (NE). Patients with good prognostic LIPI (dNLR < 3 and normal LDH levels) showed a better response. Progression-free survival (PFS) was 19 months in G, 6 months in I, and 2 months in P. Overall survival (OS) was 27 months in G, 8 months in I, and 3 months in P. One hundred fourteen patients died (56% G, 76% I, 93% P). Patients with adenocarcinoma were 116 (77 with irAEs G1-4 (13 CR, 31 PR, 21 SD, eight PD, and four NE)), and without were 39 (three PR, six SD, 21 PD, and nine NE). Fifty-two patients had squamous carcinoma (27 with irAEs G1-4 (two CR, 12 PR, nine SD, and four PD)), and 25 did not (four PR, three SD, 12 PD, and six NE)). IrAEs appearance was observed in longer PFS (19 vs. 2 months) and OS (27 vs. 4 months; P < 0.0001). LIPI was a positive predictor of response to ICI. The presence of irAEs is associated with a better immune response. In contrast, the absence of toxicity predicted a worse prognosis.