Marker Of Therapeutic Response Research Articles

PSA Levels and Mortality in Prostate Cancer Patients

IntroductionProstate cancer (PC)11Prostate cancer - PC is the second most common cancer among men around the world. Several smaller studies have explored the relationship between elevated PSA and mortality, but results have been conflicting. Additionally, studies have shown that Black men are more likely to be diagnosed with PC at late-stages and may have a twofold increase in mortality risk. This study aims to evaluate the relationship between PSA levels and mortality in patients with PC and differences between Black vs White patients. MethodsIn this retrospective study, the TriNetX database, was used to extract de-identified EMRs of 198,083 patients. Patients were included if they were diagnosed with PC and had obtained a PSA level (measured in ng/mL) within 6 months prior to diagnosis. Cohorts were separated into 7 groups based on intervals of PSA, ranging from <2 to ≥500 and compared to a control cohort with a PSA of 4-20 for differing 2-year mortality rates. A subgroup analysis was performed to compare mortality differences between Black and White patients. A post-hoc analysis evaluated 5- and 10-year mortality amongst all patients with PC. ResultsAfter propensity matching, mortality risk was significantly lower for patients with PSA <2 (5.9% vs 7.5%; RR 0.784; p<0.001) when compared to the control cohort. Mortality was significantly higher for all other subsequent PSA intervals >20, with the lowest risk ratios at PSA 20-100 (24.1% vs 10.0%; RR 2.419; p<0.001) and highest at PSA 200-500 (50.4% vs 10.8%; RR 4.673; p<0.001). The sub-group analysis showed that when compared to White patients, Black patients with PSA <20 had similar mortalities, but had significantly lower 2-year mortality rates at PSA levels ≥20. The post-hoc analysis of PSA levels and 5- and 10-year mortality of all patients with PC showed similar trends to the 2-year outcomes. ConclusionThis study found that prostate cancer patients with significantly elevated PSA levels have a greater mortality, and Black patients have lower 2-year mortality rates than their White counterparts when matched for PSA levels greater than 20. MicroabstractWithin the domain of genitourinary oncology, this study evaluates prostate specific antigen as a predictive marker for mortality in patients with established prostate cancer. A retrospective cohort study utilizing the TriNetX database was implemented, analyzing 198,083 patients from 01/2003 – 01/2021. We conclude that increased PSA concentration, drawn prior to time of diagnosis, is associated with increased mortality and that Black patients have a lower 2-year mortality rate compared to their White counterparts at elevated PSA concentrations. These results suggest that in addition as its usage as a marker of therapeutic response, PSA levels can also be used to help determine the prognosis of prostate cancer patients.

Antidepressant-related microstructural changes in the external capsule.

Several magnetic resonance imaging (MRI) studies have reported that antidepressant medications are strongly linked to brain microstructural alterations. Notably, external capsule alterations have been reported to be a biological marker for therapeutic response. However, prior studies did not investigate whether a change in the neurite density or directional coherence of white matter (WM) fibers underlies the observed microstructural alterations. This MRI-based case-control study examined the relationship between patients' current use of antidepressant medications and advanced measurements of external capsule WM microstructure derived from multishell diffusion imaging using neurite orientation dispersion and density imaging (NODDI). The study compared a group of thirty-five participants who were taking antidepressant medications comprising selective serotonin reuptake inhibitors (SSRIs) (n = 25) and serotonin and norepinephrine reuptake inhibitors (SNRIs) with a control group of thirty-five individuals matched in terms of age, sex, race, and atherosclerotic cardiovascular risk factors. All participants were selected from the Dallas Heart Study phase 2, a multi-ethnic, population-based cohort study. A series of multiple linear regression analyses were conducted to predict microstructural characteristics of the bilateral external capsule using age, sex, and antidepressant medications as predictor variables. There was significantly reduced neurite density in the bilateral external capsules of patients taking SSRIs. Increased orientation dispersion in the external capsule was predominantly seen in patients taking SNRIs. Our findings suggest an association between specific external capsule microstructural changes and antidepressant medications, including reduced neurite density for SSRIs and increased orientation dispersion for SNRIs.

Eosinophilic granulocytes as a potential prognostic marker for cancer progression and therapeutic response in malignant melanoma.

The importance of eosinophilic granulocytes in cancer has been widely discussed in recent years. The current study reviews the evidence on the role of eosinophilic granulocytes in melanoma as a prognostic marker for cancer progression and the efficacy of treatment with modern immune checkpoint inhibitors. A total of 33 human clinical studies were included in the review, with heterogeneous data due to differences in patients populations, study design and inclusion of small study groups. However, 28 of the 33 studies suggested that eosinophilic granulocytes could be used as a prognostic biomarker for outcome and/or potential response to systemic treatment and/or occurrence of adverse events in melanoma patients. Nevertheless, the exact role of eosinophils remains to be elucidated. Further prospective, larger and better controlled studies are warranted to clarify the significance of eosinophilic granulocytes in patients with melanoma, in more details.

Abstract PO1-18-10: ANNE: A phase II single-arm clinical trial to assess the feasibility and efficacy of neoadjuvant anastrozole in patients with luminal breast cancer and low proliferative index in TNM stages II and III

Abstract Background: Neoadjuvant endocrine therapy (NET) is recommended for the treatment of invasive breast cancer (BC), particularly luminal subtypes, in locally advanced stages. Previous randomized studies have demonstrated the benefits of aromatase inhibitors (AIs) in this context. However, in clinical practice, NET is typically reserved for elderly or frail patients who may not tolerate neoadjuvant chemotherapy. Ideally, after identifying suitable candidates for NET, patients undergo tumor re-biopsy after 2 to 4 weeks of treatment, and only those with Ki67 ≤ 10% proceed with NET. Limitations of this strategy include the standardization of re-biopsy and the reliability of Ki67 immunohistochemical analysis, as treatment decisions are based on these results. Objective: To evaluate the feasibility and efficacy of NET in postmenopausal patients with stage II and III luminal BC and to identify predictive biomarkers of therapeutic response. The efficacy will be measured by the rate of patients with Ki67 ≤ 10% after 4 weeks and Preoperative Endocrine Prognostic Index (PEPI) score 0 on the surgical specimen. The feasibility of the study will be assessed by the acceptance rate of participating in the study (recruitment rate ≥ 50%) and the inclusion rate of &amp;gt;2 patients per month. Methods: This non-randomized phase II clinical trial includes postmenopausal women with invasive breast carcinoma, Scarf-Bloom-Richardson histological grades 1 or 2, Estrogen Receptor positive (Allred ≥ 6), progesterone receptor positive (any value), HER2 negative, Ki-67 antigen &amp;lt; 50% on immunohistochemistry, stages TNM II-III, with palpable tumor ≥ 2 cm, and ECOG 0-2. All eligible patients will receive anastrozole (1 mg/day) continuously until the day before the surgical procedure or exclusion from the study (in case of disease progression during endocrine therapy). After 2 to 4 weeks, a re-biopsy of the breast tumor will be performed. If Ki67 &amp;gt; 10%, endocrine therapy will be suspended, and the patient will be excluded from the study and redirected to neoadjuvant chemotherapy (routine care) or immediate surgery (as per attending clinical oncologist and surgeon). If Ki67 ≤ 10%, the patient will continue to receive NET. Extended NET will be administered for up to 10 months, with monthly physical examinations (using calipers) and bimonthly breast ultrasound. The presence of stable disease on ultrasound at 4, 6, and 8 months indicates scheduling surgery within 2 months thereafter, and disease progression at any time indicates surgery within one month. Patients will complete the EORTC QLQ-C30 and its supplemental module BR45 questionnaires every 2 months. Toxicity will be assessed using CTCAE version 4.0, and patients will respond to 11 specific items extracted from the Brazilian version of PRO-CTCAE. The radiological response will be evaluated by RECIST 1.1. Blood samples for molecular analyses will be collected at baseline and during re-biopsy. MicroRNA profiles will be evaluated using Nanostring, and extracellular vesicles will be examined using ATR-FTIR to identify predictive markers of therapeutic response (Ki67 &amp;lt; 10%) in re-biopsy. All cases will be evaluated using PAM50 at the initial biopsy and at surgery to determine the molecular phenotype (luminal A, B, or other) and molecular response (ROR score difference). Pathologic therapeutic response will be assessed using the PEPI score in all operated cases. The sample size was calculated to be 59 patients. The study was initiated in July 2022, and since then, a total of 26 patients have been enrolled. This study is registered with The Brazilian Registry of Clinical Trials (ReBEC): RBR-5pygzhj. Citation Format: Carlos Paiva, Izabella Oliveira, Vitor Guimarães, Alinne Faria, Domício Lacerda, Anapaula Uema, Nilton Onari, Bianca Paiva, Augusto Antoniazzi, Karina Oikawa, Maria Fernanda Machado, Matheus Godinho, Cristiano Souza, Chrissie Amirati, Gustavo Teixeira, Idam de Oliveira Jr, Márcia Marques, Yara Maia. ANNE: A phase II single-arm clinical trial to assess the feasibility and efficacy of neoadjuvant anastrozole in patients with luminal breast cancer and low proliferative index in TNM stages II and III [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-10.

Cognitive impairment and therapeutic response in resistant depression

ObjectivesTherapeutic response in depression is a major challenge since more than one third of patients are not in remission after two attempts of antidepressant treatment and will present a treatment-resistant depression. In order to better adapt therapeutic strategies for treatment-resistant patients, predictive indicators and markers of therapeutic response still need to be identified. In parallel, patients with depression exhibit disturbances in cognitive functioning. This study aims to describe and compare cognitive performances collected at inclusion of patients presenting treatment-resistant depression who will be responders at 6 months to those of non-responders, and to evaluate the predictive value of cognitive indicators on clinical therapeutic response at 6 months after a therapeutic modification. MethodsObservational study. Patients were evaluated at the clinical (HDRS and BDI-II) and cognitive levels using standardized tools assessing memory, executive functions, attention, and social cognition, prior to a change in antidepressant treatment. Six months after inclusion, they were reassessed and classified into two groups based on the presence or absence of therapeutic response, defined by a 50% improvement on HDRS and BDI-II. The cognitive scores collected at inclusion were then compared. Additionally, univariate logistic regression models were used. ResultsThirty patients were included in this study. Only 13 could be evaluated at 6 months. Among these patients, four had responded to the new treatment while nine were non-responders. Both groups of patients presented deviant cognitive performances compared to norms on tests evaluating executive functions and attention. Statistical analyses did not reveal any difference between the cognitive performances of responders and non-responders at 6 months. Regression analyses showed no association between cognitive scores and therapeutic response at 6 months. ConclusionExecutive functioning plays a significant role in treatment-resistant depression. In order to improve the understanding and identification of subtypes of depression, cognitive indicators should be systematically integrated into future research.

Abstract 6646: Investigating the combination of radiation and subsequent immune checkpoint inhibitor treatment in head and neck squamous cell carcinoma models

Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) is often marked by an immunosuppressive tumor microenvironment, which contributes to the dismal 10-20% response rate to immune checkpoint inhibitor (ICI) therapy in HNSCC patients. Radiotherapy (RT) is a currently standard of care and frontline therapy for HNSCC, yet resistance is common. We sought to examine the combination therapy of RT followed by ICI therapy to test if RT induces an in situ vaccination which enhances the efficacy of subsequent ICI. Methods: We utilized SCC cell lines derived from K15.KrasG12D/Smad4−/− SCCs, which mimic the progression of HPV-unrelated HNSCC, and transplanted SCC cells into immune-competent C57BL/6J mouse recipients. Mice were subjected to RT followed by anti-PD-L1/anti-TGFb therapy. CD8+ splenic T cells of responder or non-responder mice were examined by paired single-cell VDJ sequencing and single cell RNA sequencing (TCR/sc-RNAseq) to look for adaptations of the cytotoxic T cell compartment following combination therapy. Responder and non-responder tumor lines or tumors were treated with RT alone in vitro and in vivo, respectively, to examine major histocompatibility complex I (MHC-I) levels on tumor cells. Results: Responders to this combination therapy exhibited complete tumor eradication while non-responders displayed rapid tumor progression. When re-challenged with same HNSCCs cells, responders rejected implanted tumor cells while naïve recipients rapidly developed HNSCCs. Single-cell TCR sequencing of splenic CD8+ T cells revealed that responders, but not naïve recipients exhibited multiclonal CD8+ T cell expansion specifically of memory cell populations. Responder tumor cells exhibited greater levels of MHC-I protein level presentation than non-responders when stimulated with RT. Conclusions: Our data suggest that 1) elevated MHC-I by SCC tumor cells presentation driven by RT and ICI combination therapy facilitate a systemic expansion of memory CD8+ T cell clonotypes which drive anti-tumor immunity and 2) MHC-I expression at baseline or when induced by RT may serve as a predictive marker for therapeutic response to RT and ICI combination therapy in HNSCCs. Citation Format: Hanne Lind, Alexander Strait, Spencer Hall, Jack B. Goon, John D. Aleman, Samantha Chen, Philip Owens, Jing H. Wang, Christian Young, Xiao-Jing Wang. Investigating the combination of radiation and subsequent immune checkpoint inhibitor treatment in head and neck squamous cell carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6646.

Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications.

Cancer is a major cause of death globally, and traditional treatments often have limited efficacy and adverse effects. Immunotherapy has shown promise in various malignancies but is less effective in tumors with low immunogenicity or immunosuppressive microenvironment, especially sarcomas. Tertiary lymphoid structures (TLSs) have been associated with a favorable response to immunotherapy and improved survival in cancer patients. However, the immunological mechanisms and clinical significance of TLS in malignant tumors are not fully understood. In this review, we elucidate the composition, neogenesis, and immune characteristics of TLS in tumors, as well as the inflammatory response in cancer development. An in-depth discussion of the unique immune characteristics of TLSs in lung cancer, breast cancer, melanoma, and soft tissue sarcomas will be presented. Additionally, the therapeutic implications of TLS, including its role as a marker of therapeutic response and prognosis, and strategies to promote TLS formation and maturation will be explored. Overall, we aim to provide a comprehensive understanding of the role of TLS in the tumor immune microenvironment and suggest potential interventions for cancer treatment.

P576 Fecal calprotectin could predict clinical and endoscopic response to ustekinumab therapy

Abstract Background Ustekinumab (UST) is one of the most used biologic drugs for the treatment of Crohn’s Disease (CD) and Ulcerative Colitis (UC). However, not all patients achieve clinical remission and even less mucosal healing. There is currently scarce knowledge about the early markers of therapeutic response in this setting, with particular regard to mucosal healing. The aim of this multicenter study was to evaluate the role of fecal calprotectin (FC) as early predictor of mucosal healing. Methods We enrolled consecutive patients with CD or UC treated with UST for at least 48 weeks at four referral centers in the last 5 years. Therapeutic response was evaluated in terms of clinical remission (defined as a Partial Mayo Score &amp;lt;2 for patients with UC and as Harvey Bradshaw Index &amp;lt;5 for patients with CD, without concomitant corticosteroid therapy) and mucosal healing (defined as a Mayo Endoscopic Score &amp;lt;2 for UC and as the disappearance of ulcers for CD). We collected clinical and demographic data, as well as fecal calprotectin (FC) and C-Reactive Protein (CRP) levels at baseline and at week 24. Results Among 196 patients enrolled (73 [37.2%] women), 167 were affected by CD, whereas 29 by UC. Globally, 128 (65.3%) patients achieved clinical remission and 83 (42.3%) endoscopic remission at 48 weeks of treatment. There were no group differences in age, sex, BMI, baseline clinical and endoscopic indexes, or baseline CRP levels between patients achieving or not either clinical or endoscopic remission. Baseline calprotectin levels were lower in patients who achieved endoscopic remission (median [interquartile range] 391 [103, 1050] versus 825 [317, 1800] µg/mL,p=0.002). At week 24, lower calprotectin levels were observed in both the groups who achieved clinical (160 [50, 426] versus 439 [146, 1000] µg/mL,p&amp;lt;0.0001) and endoscopic remission (114 [43, 265] versus 392 [139, 912] µg/mL,p&amp;lt;0.0001) compared with non-responders. The effects of week-24 calprotectin levels on clinical remission (β= -0.003,p&amp;lt;0.0001) and endoscopic remission (β= -0.004,p&amp;lt;0.0001) remained significant in multivariable models adjusted for age, sex, and BMI. A cut-point of 268 µg/mL was identified as the optimal threshold of week-24 calprotectin for predicting clinical remission (sensitivity 65%, specificity 67%, ROC AUC 0.689), while a cut-point of 309 µg/mL was identified to predict endoscopic remission (sensitivity 79%, specificity 59%, ROC AUC 0.712). Conclusion Our data suggest that FC assessment after 24 weeks of treatment with UST could represent a promising early marker of response, even in terms of mucosal healing, in both CD and UC.

Leveraging diverse cell-death patterns to predict the clinical outcome of immune checkpoint therapy in lung adenocarcinoma: Based on muti-omics analysis and vitro assay.

Advanced LUAD shows limited response to treatment including immune therapy. With the development of sequencing omics, it is urgent to combine high-throughput multi-omics data to identify new immune checkpoint therapeutic response markers. Using GSE72094 (n = 386) and GSE31210 (n = 226) gene expression profile data in the GEO database, we identified genes associated with lung adenocarcinoma (LUAD) death using tools such as "edgeR" and "maftools" and visualized the characteristics of these genes using the "circlize" R package. We constructed a prognostic model based on death-related genes and optimized the model using LASSO-Cox regression methods. By calculating the cell death index (CDI) of each individual, we divided LUAD patients into high and low CDI groups and examined the relationship between CDI and overall survival time by principal component analysis (PCA) and Kaplan-Meier analysis. We also used the "ConsensusClusterPlus" tool for unsupervised clustering of LUAD subtypes based on model genes. In addition, we collected data on the expression of immunomodulatory genes and model genes for each cohort and performed tumor microenvironment analyses. We also used the TIDE algorithm to predict immunotherapy responses in the CDI cohort. Finally, we studied the effect of PRKCD on the proliferation and migration of LUAD cells through cell culture experiments. The study utilized the TCGA-LUAD cohort (n = 493) and identified 2,901 genes that are differentially expressed in patients with LUAD. Through KEGG and GO enrichment analysis, these genes were found to be involved in a wide range of biological pathways. The study also used univariate Cox regression models and LASSO regression analyses to identify 17 candidate genes that were best associated with mortality prognostic risk scores. By comparing the overall survival (OS) outcomes of patients with different CDI values, it was found that increased CDI levels were significantly associated with lower OS rates. In addition, the study used unsupervised cluster analysis to divide 115 LUAD patients into two distinct clusters with significant differences in OS timing. Finally, a prognostic indicator called CDI was established and its feasibility as an independent prognostic indicator was evaluated by Cox proportional risk regression analysis. The immunotherapy efficacy was more sensitive in the group with high expression of programmed cell death models. Relationship between programmed cell death (PCD) signature models and drug reactivity. After evaluating the median inhibitory concentration (IC50) of various drugs in LUAD samples, statistically significant differences in IC50 values were found in cohorts with high and low CDI status. Specifically, Gefitinib and Lapatinib had higher IC50 values in the high-CDI cohort, while Olaparib, Oxaliplatin, SB216763, and Axitinib had lower values. These results suggest that individuals with high CDI levels are sensitive to tyrosine kinase inhibitors and may be resistant to conventional chemotherapy. Therefore, this study constructed a gene model that can evaluate patient immunotherapy by using programmed cell death-related genes based on muti-omics. The CDI index composed of these programmed cell death-related genes reveals the heterogeneity of lung adenocarcinoma tumors and serves as a prognostic indicator for patients.

Dementia is an auditory brain disorder

AbstractBackgroundWhile impaired hearing has emerged as a major potentiating factor for dementia, the basis for this relationship has not been defined. Most studies have emphasised the role of peripheral hearing loss. However, we hear with our brains: natural listening places immense computational demands on neural circuitry, and the neural networks pre‐eminently targeted by major dementias are essential for decoding and responding appropriately to the auditory environment. Auditory brain dysfunction is therefore predicted both to contribute importantly to hearing impairment in Alzheimer’s and other dementias and to be integral to the expression of neurodegenerative pathologies. Here I present an overview of evidence that speaks to this hypothesis.MethodsIn a series of linked experiments, we have assessed aspects of auditory cognition – the processes whereby the brain perceives, interprets and acts upon sounds ‐ in patient cohorts with Alzheimer’s disease and major syndromes of frontotemporal dementia, relative to healthy older individuals. We designed novel psychoacoustic tests to assess aspects of auditory scene analysis (the ‘cocktail party effect’ and localisation of sounds in space), comprehension of acoustically degraded speech and the processing of semantic and emotional information in sound in cognitively impaired people. Neuroanatomical mechanisms were assessed using voxel‐based morphometry and functional MRI.ResultsAcross experiments, after taking peripheral hearing function and general cognitive performance into account, patients with Alzheimer’s disease and frontotemporal dementias showed characteristic ‘auditory phenotypes’ or profiles of auditory cognitive impairment. Alzheimer’s disease is associated with impaired auditory scene analysis, linked to atrophy and dysfunction of temporo‐parietal cortical regions in the core ‘default mode network’ targeted by Alzheimer pathology. Frontotemporal dementia syndromes produce distinct impairments of auditory feature analysis, sound recognition and emotional valuation.ConclusionsAuditory brain dysfunction plays a key role in everyday hearing impairment and reflects core pathophysiology in major dementias. These findings raise the exciting prospect that auditory cognitive measures might be used in the early diagnosis of dementia, in guiding novel hearing interventions and as dynamic markers of therapeutic response in the dawning era of disease modification.

Dynamic blood flow imaging with 99mTc-hydroxymethylene diphosphonate as a therapeutic response marker in patients with Raynaud's phenomenon.

We evaluated the predictive value of dynamic blood flow scintigraphy with 99mTc-HDP (hydroxymethylene diphosphonate) for therapeutic response in patients with Raynaud's phenomenon (RP). Eighty patients who underwent dynamic blood flow scintigraphy using the one-hand chilling method were enrolled. We analyzed the quantitative variables as the ratio of chilled fingers to ambient fingers (CAfinger), that of the chilled hand to ambient hand (CAhand), and that of chilled fingers to ambient palm (FPR) (CAFPR) at 15 and 30s after 99mTc-HDP bolus injection. Total cumulative radioactivity counts for 180s were obtained. We evaluated the clinical utility of these quantitative parameters with other clinical variables, including RP severity, therapeutic compliance, types of RP, and scintigraphic interpretation of findings in patients with RP. Fifty-two patients showed poor therapeutic response. There were significant differences between good- and poor-therapeutic responder groups in RP intensity (p = 0.003), CAfinger15s (p = 0.008), CAfinger30s (p = 0.002), CAfinger180s (p = 0.011), CAhand15s (p = 0.008), CAhand30s (p = 0.007), CAhand180s (p = 0.017), CAFPR30s (p = 0.004), and CAFPR180s (p = 0.002). After multivariate logistic regression analysis, only CAfinger30s (p = 0.002) had an independent predictive value of the therapeutic response. 99mTc-HDP dynamic blood flow scintigraphy could be helpful in predicting the therapeutic response in patients with RP.

NCOG-37. BELZUTIFAN IN ADULTS WITH VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA: A SINGLE-CENTER EXPERIENCE

Abstract INTRODUCTION Belzutifan is a selective inhibitor of hypoxia-inducible factor 2-alpha that has been FDA approved for Von Hippel–Lindau (VHL) syndrome-associated tumors. There is limited real-world evidence in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan. METHODS We retrospectively reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2023. RESULTS 4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated. The most common adverse effect was anemia. No patients had treatment pauses or dose adjustments due to toxicity. No patients experienced hypoxia. DISCUSSION We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.

Longitudinal Analysis of Circulating Tumor DNA and Detection of Tumor Genomic Alterations Using Liquid Biopsy in Patients with Locally Advanced Esophagogastric Carcinoma

For locally advanced esophageal (E), esophagogastric junction (EGJ), and gastric (G) carcinoma, the standard treatment is neoadjuvant chemoradiotherapy followed by surgery. The curative goal is to control the tumor locally, prevent regional recurrence, and prevent or delay metastatic progression. Up to one-third of patients will achieve complete pathologic response rate (pCR) under this treatment. Yet disease recurrence can occur in one-third of patients after definitive treatment. Our study provides real-world longitudinal data of liquid biopsy to analyze circulating tumor deoxyribonucleotide acid (ctDNA) for minimal residual disease (MRD) as an informative marker for early therapeutic response, detectable disease, and risk for recurrence. Furthermore, the liquid biopsy reveals variable tumor-specific sequence alterations. A total of 8 patients with newly diagnosed locoregional esophagogastric cancers were evaluated with non-invasive plasma sample, collected at baseline, post-neoadjuvant chemoradiation, post-surgery, and serially as disease surveillance. Bespoke mPCR-NGS assay measured the ctDNA-based MRD levels and identified a comprehensive tumor-specific genomic profile. The primary outcome is assay recurrence compared to radiologic disease recurrence, defined as radiologic confirmed disease. Exploratory endpoints are used to examine the profile of tumor. Baseline ctDNA levels were detected in 8 newly diagnosed patients. Longitudinal testing showed a decrease in ctDNA in 4 patients and residual disease in 2 patients after the start of neoadjuvant therapy. 1 patient demonstrated pCR in conjunction with ctDNA clearance. Clearance of ctDNA may correlate to a favorable pCR and indicate a lower risk of relapse, guiding the strategy for adjuvant treatment. Personalized, tumor-informed sequence alterations of the 8 patients revealed a high frequency in TP53 alterations, which occurs early during development in esophagogastric cancer. This prospective study seeks to validate the application of ctDNA surveillance and tumor molecular alterations in a larger cohort after 5 years.

Diagnosis and prognosis of pancreatic cancer with immunoglobulin heavy constant delta blood marker.

Pancreatic cancer (PC) is highly malignant and difficult to detect, while few blood markers are currently available for diagnosing PC. We obtained differential expression genes (DEGs) from GEO (gene expression omnibus) database and assessed by quantitative real-time polymerase chain reaction (qRT-PCR), receiver operating characteristic (ROC), univariate and multifactorial regression analysis, and survival analysis in our clinic center. Through the TCGA (the cancer genome atlas) database, we analyzed functional enrichment, different risk groups with survival analysis, immunological features, and the risk score established by the Cox regression model and constructed a nomogram. Immunoglobulin heavy constant delta (IGHD) was remarkably upregulated in peripheral blood from PC patients, and IGHD was a potential independent biomarker for PC diagnosis (ROC sensitivity, 76.0%; specificity, 74.2%; area under the curve (AUC) = 0.817; univariate logistic regression analysis: odds ratio (OR) 1.488; 95% confidence interval (CI) 1.182-1.872; P < 0.001; multiple logistic: OR 2.097; 95% CI 1.276-3.389, P = 0.003). In addition, the IGHD expression was remarkably reduced after resectioning the primary tumor. High IGHD expression indicated higher lymphocyte infiltration and increased activities of immunological pathways in PC patients. KRAS and SMAD were observed with a prominent difference among top mutated genes between the two groups. The risk score predicted reliable clinical prognosis and drug responses. Furthermore, a nomogram with the risk score and clinical characteristics was constructed, showing a better predictive performance. IGHD is a valuable PC diagnosis, prognosis, and therapeutic response marker.

Belzutifan in adults with VHL-associated central nervous system hemangioblastoma: a single-center experience.

Belzutifan is a selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a) that has emerged as a targeted therapy option for Von Hippel-Lindau (VHL) syndrome-associated tumors with recent FDA approval. There is limited real-world evidence regarding safety and efficacy in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan in adult patients with VHL-associated CNS hemangioblastoma. We retrospectively reviewed our institutional experience of belzutifan in adult patients (> 18 years of age at time of therapy) with VHL and craniospinal CNS hemangioblastomas not amenable to surgical resection. The period for study review was October 2021 to March 2023. 4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated, with the most common adverse effect being anemia. No patients had treatment pauses or dose adjustments due to belzutifan-related toxicity. No patients experienced hypoxia. We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.

Factors leading to supranormal cardiac index in pediatric pulmonary hypertension patients treated with parenteral prostanoid therapy.

Parenteral prostanoid therapy (PPT) can result in supranormal cardiac index (SCI; >4 L/min/m2) in pediatric pulmonary hypertension (PPH) patients. We evaluated the incidence, hemodynamic factors, and outcomes associated with SCI in PPH. This retrospective cohort study included 22 PPH patients on PPT from 2005 to 2020. Hemodynamic profiles were compared between the baseline and 3-6 month follow-up catheterization in the SCI and non-SCI cohorts. Cox regression analysis examined time to composite adverse outcome (CAO; Potts shunt, lung transplant, or death) controlling for initial disease severity. SCI developed in 17 (77%) patients, of whom 11 (65%) developed SCI within 6 months. The SCI cohort was characterized by significant augmentation of cardiac index (CI) and stroke volume (SV) as well as reductions in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). Conversely, the non-SCI cohort had unchanged SV despite a modest rise in CI as well as persistent vasoconstriction. After median follow-up of 4.3 years (range 0.2-13 years), non-SCI patients were at significantly increased risk for the CAO (5/5: three deaths, two Potts shunts) compared withSCI patients (5/17: two deaths, three lung transplants; adjusted hazard ratio 14.0 [95% confidence interval: 2.1-91.3], p < 0.001). A majority of PPH patients developed SCI within 6-12 months of starting PPT and demonstrated lower risk of adverse outcomes compared withnon-SCI patients. These data suggest that change in SVR and SV after 3-6 months of PPT may be early markers of therapeutic response and prognosis.

Role of Circular RNAs in Prostate Cancer.

This study aims to summarize the current literature to demonstrate the importance of circular RNAs (circRNAs) in multiple aspects of prostate cancer (PCa) occurrence, progression, and treatment resistance and explore the potential role in therapeutic strategies aimed at targeting this molecule in PCa. The relevant literature from PubMed and Medline databases is reviewed in this article. Non-coding RNA has been proven to play a vital role in regulating tumor progression. Among them, circular RNA plays a more unique role due to its nonlinear structure. Lots of circRNAs were found to be differentially expressed in PCa and regulate cell signaling pathways by regulating particular gene expressions. Recent studies have demonstrated that circRNAs are associated with the chemoresistance of urinary tumors, suggesting that circRNAs might be a novel therapeutic target and a marker for therapeutic response and prognosis assessment. The potential crosstalk of circRNAs modifications in PCa development, therapy, and regulation of tumor metabolism is portrayed in this review. However, more preclinical and clinical trials of this targeted strategy are necessary for the treatment of urinary tumors.

Protein kinase C delta mediates Pasireotide effects in an ACTH-secreting pituitary tumor cell line

PurposeClinical control of corticotroph tumors is difficult to achieve since they usually persist or relapse after surgery. Pasireotide is approved to treat patients with Cushing’s disease for whom surgical therapy is not an option. However, Pasireotide seems to be effective only in a sub-set of patients, highlighting the importance to find a response marker to this approach. Recent studies demonstrated that the delta isoform of protein kinase C (PRKCD) controls viability and cell cycle progression of an in vitro model of ACTH-secreting pituitary tumor, the AtT-20/D16v-F2 cells. This study aims at exploring the possible PRKCD role in mediating Pasireotide effects.MethodsIt was assessed cell viability, POMC expression and ACTH secretion in AtT20/D16v-F2 cells over- or under-expressing PRKCD.ResultsWe found that Pasireotide significantly reduces AtT20/D16v-F2 cell viability, POMC expression and ACTH secretion. In addition, Pasireotide reduces miR-26a expression. PRKCD silencing decreases AtT20/D16v-F2 cell sensitivity to Pasireotide treatment; on the contrary, PRKCD overexpression increases the inhibitory effects of Pasireotide on cell viability and ACTH secretion.ConclusionOur results provide new insights into potential PRKCD contribution in Pasireotide mechanism of action and suggest that PRKCD might be a possible marker of therapeutic response in ACTH-secreting pituitary tumors.

Searching for biomarkers in the fluidity of mental ill-health.

Searching for biomarkers in the fluidity of mental ill-health.

The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer

The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes downregulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides upstream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of upregulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023), and its ability to downregulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302.