Median Survival Rate Research Articles

Генетические предикторы выживаемости и развития MACE в остром периоде инфекции, вызванной SARS-COV-2, у пациентов высокого кардиоваскулярного риска

Introduction. Despite the fact that the SARS-CoV-2 virus is highly contagious, the clinical manifestations of the disease caused by it can have significant differences: from a low-symptom course to extremely severe forms with the development of a fatal outcome. It is obvious that the observed polymorphism of the development of infection caused by SARS-CoV-2 is due, among other things, to genetic factors. These include single-nucleotide polymorphisms of genes involved in the stages of the pathogenesis of infection: from the penetration of the virus into target cells, the expression of its RNA to the response of the host organism. The study of genetic predictors that cause changes in susceptibility to the SARS-CoV-2 virus and differences in the severity of infection will help to better understand the pathogenesis of this disease and give an idea of promising areas of therapy and prevention. Aim. To study the relationship of genetic biomarkers with the severity of infection caused by SARS-CoV-2, cardiovascular complications and the risk of death in the early period of the disease. Design. A single-center retrospective study. Materials and methods. The study included 164 patients (90 men, 74 women) with infection caused by SARS-CoV-2. All patients were classified as high and very high cardiovascular risk. Concomitant somatic pathology: arterial hypertension in 164 (100%), coronary heart disease in 80 (48.9%), alimentary obesity in 100 (61%), prediabetes in 52 (31.74%), chronic kidney disease in 34 (20.7%) patients. At the first stage of the study, the relationship of genetic biomarkers with the severity of the disease was evaluated, at the second — with cardiovascular complications, and at the third — with the onset of death. Results. In the group of patients with severe disease, variant DD of ACE Alu I/D gene polymorphism, rs4646994 (p = 0.004), variant GG of IL-10 polymorphism 1082 G/A, rs1800896 (p = 0.043), allele *11 HLA-DRB1 (p = 0.015) were significantly more common. The genetic predictors of the development of cardiovascular complications were the genotype DD of the ACE gene (rs4646994) (p = 0.038), the allele *3 HLA-DRB1 (p = 0.041), the allele *13 HLA-DRB1 (p = 0.047) was less common. When searching for a correlation between the selected genetic biomarkers and mortality, only a negative contribution of the ACE Alu I/D polymorphism variant DD, rs4646994 (p = 0.015) was revealed. The survival analysis showed that in the DD variant of the ACE Alu polymorphism I/D, rs4646994, the median survival rate is lower than in the II variant (13 (9–15) days and 21 (12–n/o) days, respectively (p = 0.03)), and lower than in the ID (31 variant (14–n/ o) day (p < 0.0001)). The survival rate of patients with the heterozygous variant of the polymorphism MTRR –66 A/G, rs1801394 was 11.5 (9–16) days, with variant AA — 7 (3–n/o), and with variant GG — 6 (4–14), p = 0.013. With the *16 HLA DRB1 allele, survival was only 5.5 (2–n/o) days versus 22 (17–n/o) days in patients without it, p = 0.04. Conclusion. Predictors of an increased risk of severe infection caused by SARS-CoV-2 include the DD variant of the ACE Alu I/D gene polymorphism, rs4646994, the GG variant of the IL-10 1082 G/A gene polymorphism, rs1800896 and the *11 HLA-DRB1 allele. The negative effect of the DD variant of the polymorphism of the ACE Alu I/D gene, rs4646994, the *3 HLA-DRB1 allele and the protective effect of the *13 HLA-DRB1 allele have been proven in relation to the overall risk of major cardiovascular complications. The carriage of the *16 HLA-DRB1 allele and the DD variant of the ACE Alu I/D gene polymorphism, rs4646994, correlate with an increased risk of early hospital mortality in patients. At the same time, the heterozygous variant of the MTRR –66 A/G polymorphism, rs1801394, is a protective biomarker and is associated with better survival. Key words: COVID-19, SARS-CoV-2 virus, mortality, cardiovascular complications, cardiovascular risk, genetic biomarkers

Enhancing safety and therapeutic efficacy: PD-1 inhibitor and recombinant human endostatin combination in advanced non-small cell lung cancer patients.

To assess the therapeutic efficacy of combining a programmed death-1 (PD-1) inhibitor with recombinant human endostatin in patients diagnosed with advanced non-small cell lung cancer (NSCLC). We retrospectively collected data from 83 patients with advanced NSCLC who received treatment at Xi'an Daxing Hospital between May 2020 and July 2022. Among them, 42 patients were treated with a PD-1 inhibitor combined with recombinant human endostatin (observation group), while 41 patients received PD-1 inhibitor monotherapy (control group). We evaluated the objective response rate, changes in serum tumor markers pre- and post-treatment, occurrence of adverse reactions, progression-free survival (PFS), 1-year survival rate, and identified independent risk factors affecting prognosis in both groups. The treatment efficacy in the observation group significantly surpassed that in the control group. Following treatment, the levels of cytokeratin 19 fragment antigen 21-1, carcinoembryonic antigen, and carbohydrate antigen 125 decreased significantly in the observation group compared to the control group (P < 0.001). There was no notable difference in the incidence of adverse reactions between the two groups (P < 0.001). The median PFS and 1-year survival rate were notably higher in the observation group (P < 0.001). Age, liver metastasis, and treatment regimen emerged as independent risk factors affecting poor prognosis in patients (P < 0.001). Combining a PD-1 inhibitor with recombinant human endostatin in patients with advanced NSCLC not only enhances clinical efficacy but also increases PFS and the 1-year survival rate while ensuring treatment safety. This combination therapy shows promise for clinical application.

A review on potential heterocycles for the treatment of glioblastoma targeting receptor tyrosine kinases.

Glioblastoma, the most aggressive form of brain tumor, poses significant challenges in terms of treatment success and patient survival. Current treatment modalities for glioblastoma include radiation therapy, surgical intervention, and chemotherapy. Unfortunately, the median survival rate remains dishearteningly low at 12-15 months. One of the major obstacles in treating glioblastoma is the recurrence of tumors, making chemotherapy the primary approach for secondary glioma patients. However, the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms. Consequently, considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs. To tackle glioma, numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEK-ERK-MPAK. By targeting specific signaling pathways, heterocyclic compounds have demonstrated efficacy in glioma therapeutics. Additionally, key kinases including phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase, cytoplasmic tyrosine kinase (CTK), receptor tyrosine kinase (RTK) and lipid kinase (LK) have been considered for investigation. These pathways play crucial roles in drug effectiveness in glioma treatment. Heterocyclic compounds, encompassing pyrimidine, thiazole, quinazoline, imidazole, indole, acridone, triazine, and other derivatives, have shown promising results in targeting these pathways. As part of this review, we propose exploring novel structures with low toxicity and high potency for glioma treatment. The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier. By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics, we can maximize their therapeutic value and minimize adverse effects. Considering the complex nature of glioblastoma, these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.

Biophysical and Biological Mechanisms of Tumor Treating Fields in Glioblastoma.

Glioblastoma (GBM) is one of the most aggressive forms of brain cancer that presents with a median survival rate of 14-30 months and along with a discouraging five-year survival rate of 4-5%. Standard treatment of newly diagnosed GBM, also known as the Stupp protocol, includes a maximally safe surgical resection followed by radiation and chemotherapy. Despite these treatment regimens, recurrence is almost inevitable, emphasizing the need for new therapies to combat the aggressive nature of GBMs. Tumor Treating Fields (TTFs) are a relatively new application to the treatment of GBMs, and results have been promising with both progression-free survival and overall survival when TTFs have been used in combination with temozolomide. This article critically reviews the biophysical and biological mechanisms of TTFs, their clinical efficacy, and discusses the results in clinical trials, including EF-11 and EF-14. Both trials have demonstrated that TTFs can enhance progression free survival and overall survival without compromising quality of life or causing severe adverse effects. Despite the high cost associated with TTFs and the need for further analysis to determine the most effective ways to integrate TTFs into GBM treatments, TTFs represent a significant advancement in GBM therapy and offer hope for improved patient prognosis.

Interval-specific censoring set adjusted Kaplan–Meier estimator

We propose a non-parametric approach to reduce the overestimation of the Kaplan-Meier (KM) estimator when the event and censoring times are independent. We adjust the KM estimator based on the interval-specific censoring set, a collection of intervals where censored data are observed between two adjacent event times. The proposed interval-specific censoring set adjusted KM estimator reduces to the KM estimator if there are no censored observations or the sample size tends to infinity and the proposed estimator is consistent, as is the case for the KM estimator. We prove theoretically that the proposed estimator reduces the overestimation compared to the KM estimator and provide a mathematical formula to estimate the variance of the proposed estimator based on Greenwood's approach. We also provide a modified log-rank test based on the proposed estimator. We perform four simulation studies to compare the proposed estimator with the KM estimator when the failure rate is constant, decreasing, increasing, and based on the flexible hazard method. The bias reduction in median survival time and survival rate using the proposed estimator is considerably large, especially when the censoring rate is high. The standard deviations are comparable between the two estimators. We implement the proposed and KM estimator for the Nonalcoholic Fatty Liver Disease patients from a population study. The results show the proposed estimator substantially reduce the overestimation in the presence of high observed censoring rate.

The Effect of Histopathological Subtype on 5 Year and 10 Year Overall Survival in Primary Malign Tumors of the Chest Wall

Primary tumors of the chest wall are rare tumors comprising 5% of thoracic neoplasms. The current study was designed to evaluate the effect of histopathological subtype on the 5-year and 10-year overall survival and regional recurrence in primary malignant tumors of the chest wall. From December 2007 to December 2019, the data of 20 patients were analyzed. Overall survival rates, median overall survival, regional tumor recurrence and median disease-free survival rates were compared retrospectively between histopathological subtypes. Chondrosarcoma (n=7), desmoid tumor (n=6), undifferentiated pleomorphic sarcoma [(UPS), (n=4)], Ewing's sarcoma (n=1), malignant peripheral nerve sheath tumor (n=1), and liposarcoma (n=1) were the subtypes identified. A lower median overall survival was detected in the UPS histopathological subtype (p = 0.004). The 5 and 10-year overall survival rates in the chondrosarcoma group were 71% and 37%, respectively; desmoid tumors were found in 83% and 42%, respectively. There was no patient with 5-year survival in UPS. A shorter median overall survival was found in lateral wall masses compared to anterior and posterior wall masses (p = 0.001). During the follow-up, 10 patients (50%) died. It was observed that the median disease-free survival in the UPS subtype was shorter compared to the other subtypes (p = 0.002). The regional recurrence rate was 57%, 17% and 75% in chondrosarcoma, desmoid tumor and UPS, respectively. In UPS, a primary malignant tumor of the chest wall, 5-year and 10-year overall survival rates and median overall survival; it was found to be significantly shorter than the chondrosarcoma and desmoid tumor groups.

Assessing patient burden and benefit: A decade of cabozantinib clinical trials.

Drug development is complex and costly. Clinical trial participants take on risks, making it essential to maximize trial efficiency and maintain participant safety. Identifying periods of excessive burden during drug development can inform trial design, ensure patient benefit and prevent harm. This study aims to examine all published clinical trials for cabozantinib to assess patient benefit and burden over time. We conducted a retrospective cross-sectional review of interventional clinical trials of cabozantinib for solid cancer treatment. We searched PubMed/MEDLINE, Embase, Cochrane (CENTRAL) and ClinicalTrials.gov. We extracted adverse event rates, median progression-free survival (PFS), median overall survival and objective response rate (ORR) for each included trial. We calculated frequencies of trial characteristics, cumulative grade 3-5 adverse event rates and cumulative ORRs. Out of 1735 studies, 54 publications were included that involved 6372 participants and 21 cancers. Of the 54 studies in our sample, 31 (57.41%) were single-arm trials and 23 (42.60%) had negative results. Trials among and within various indications had conflicting results over time. Cumulative risk to participants increased over time, and clinical benefit decreased. The findings suggest that the risk profile of cabozantinib increased from 2011 to 2016 and has remained elevated but stable while benefit has decreased over time. The use of non-randomized and single-arm trials is concerning, and more methodologically rigorous trials are needed. The results of trials for different indications are inconsistent, and empirical administration may reduce the drug's efficacy.

The Prospect of Harnessing the Microbiome to Improve Immunotherapeutic Response in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma cancer (PDAC) is projected to become the second leading cause of cancer-related death in the United States by 2030. Patients are often diagnosed with advanced disease, which explains the dismal 5-year median overall survival rate of ~12%. Immunotherapy has been successful in improving outcomes in the past decade for a variety of malignancies, including gastrointestinal cancers. However, PDAC is historically an immunologically "cold" tumor, one with an immunosuppressive environment and with restricted entry of immune cells that have limited the success of immunotherapy in these tumors. The microbiome, the intricate community of microorganisms present on and within humans, has been shown to contribute to many cancers, including PDAC. Recently, its role in tumor immunology and response to immunotherapy has generated much interest. Herein, the current state of the interaction of the microbiome and immunotherapy in PDAC is discussed with a focus on needed areas of study in order to harness the immune system to combat pancreatic cancer.

Optimization of the Treatment Flow of Neurosurgical Patients with a Glioblastoma using the Enhanced Recovery After Surgery Methodology: A Literature Review

Purpose: This study aims to create an elaborated version of the Enhanced Recovery After Surgery methodology, specifically applied to neurosurgical patients with a glioblastoma. Introduction: Being diagnosed with a glioblastoma is a terminal diagnosis with a median survival rate of 14,6 months. The introduction of an Enhanced Recovery After Surgery can provide a solution for current challenges such as the under-pressure health care system because of a lack of nurses and welltrained nurses in neurosurgical problems. Enhanced Recovery After Surgery benefits the patient, healthcare teams and society. Methods: A literature review with two different search strategies was conducted. First, the needs and expectations of patients with a glioblastoma were identified. Seventy-five papers from four databases, PubMed, Embase, CINAHL and Cochrane Library, were eligible. Fourteen papers were included in this study. Second, the existing Enhanced Recovery After Surgery protocols were examined. A total of 3,521 papers were screened by two independent researchers, of which 82 met the inclusion criteria and 50 were determined relevant for this study. In this way, an elaborated version of the Enhanced Recovery After Surgery methodology based on the needs of patients with a glioblastoma is created. Results: Patients with a glioblastoma may face numerous needs. Due to a poor diagnosis and uncertain future, they could feel distressed and anxious. Patients expect more information, support and availability from health professionals. Therefore, it is important for healthcare professionals to make sure that patients do not lose all hope after the diagnosis because losing hope is associated with depression and a poorer quality of life. All these needs were integrated in the Enhanced Recovery After Surgery protocol and combined with new insights from the literature. The first bundle of recommendations in the Enhanced Recovery After Surgery for patients with a glioblastoma belongs to the preoperative phase and includes: information and education, prehabilitation, nutrition support and fasting time, alcohol and smoking, comorbidities and medication. The intraoperative phase includes advice about antibiotics, body temperature, craniotomy, stitches and extubating. Finally, the postoperative phase includes recommendations regarding thromboembolism, nausea and vomiting, analgesics, oral nutrition, fluids, invasive lines, mobilization, urinary catheter, drains, discharge, telephone follow-up and social and emotional support. Conclusion: The established protocol needs to be constantly adapted to new evidence. Only with an appropriate multidisciplinary collaboration and thoughtful introduction of the Enhanced Recovery After Surgery, the implementation and sustainability of the new Enhanced Recovery After Surgery protocol will succeed in daily practice.

Revisiting Ratify: Daunorubicin 60 Mg/m2 Vs 90 Mg/m2 in Previously Untreated FLT3mut Acute Myeloid Leukemia

1. Introduction Patients with FLT3mut acute myeloid leukemia (AML) have higher rates of relapse and a poor prognosis. FLT3 inhibitors and allogeneic stem cell transplant have resulted in improved survival, however, outcomes remain dismal - particularly for FLT3-ITD. Attempts to intensify established regimens are ongoing. The daunorubicin dose in the RATIFY trial was 60 mg/m 2; one common intensification approach in clinical practice is increasing the daunorubicin dose to 90 mg/m 2 in selected patient populations. The aim of this study was to define the baseline characteristics of these patient populations and analyze outcomes stratified by receipt of daunorubicin intensity in FLT3mut AML. 2. Methods We analyzed 40 patients from the Project ERIS database with newly diagnosed AML treated with 7+3 (daunorubicin and cytarabine) and midostaurin from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. All patients had FLT3-ITD or FLT3-TKD. We divided patients into two groups: receipt of daunorubicin 60 mg/m 2 and daunorubicin 90 mg/m 2. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino &amp; Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results In the overall cohort of 40 patients treated with 7+3 and midostaurin, 25 (62.5%) were treated with daunorubicin 60 mg/m 2 and 15 (37.5%) received daunorubicin 90 mg/m 2. Patients in the 60 mg/m 2 cohort were significantly older compared with the 90 mg/m 2 cohort (62 y. vs 47 y., p &amp;lt; 0.0001, Table A). Patients that received 60 mg/m 2 had worse CCI scores indicating more numerous comorbidities compared with those that received 90 mg/m 2 (4 vs 2, p &amp;lt; 0.0001). While the median ECOG score was 1 in both cohorts, the ECOG scores were significantly worse in the 60 mg/m 2 cohort - however, the significance disappeared after applying the Bonferroni correction (p = 0.029). All but one patient received next-generation testing at diagnosis. Significantly fewer patients in the 60 mg/m 2 cohort had FLT3-ITD (45.8% vs 93.3%, p = 0.0049); the remainder harbored FLT3-TKD. There was no difference in the proportion of ELN 2022 adverse-risk disease between the two cohorts (34.0% vs 26.7%, p &amp;gt; 0.999). The composite complete response rate (CRc; CR + CRi + CRh) was not significantly different between the two groups: 47.8% (95% CI, 29.2-67.0) for 60 mg/m 2 and 66.7% (95% CI, 41.7-84.8, p = 0.254) for 90 mg/m 2. There was no difference in the rates of MRD negativity between the lower and higher dose groups (18.2%, 95% CI, 3.2-47.7 vs 40.0%, 95% CI, 16.8-68.7, p = 0.254). Significantly more patients in the 90 mg/m 2 cohort proceeded to allogeneic stem cell transplant (53.3% vs 20.0%, p = 0.041). Despite this, we observed no difference in the median overall survival between the 60 mg/m 2 cohort at 20.7 m. and the 90 mg/m 2 cohort at 15.6 m. (p = 0.520, Figure B). 4. Discussion Individuals in the daunorubicin 60 mg/m 2 cohort were significantly older with worse comorbidities, resulting in significantly fewer patients proceeding to stem cell transplant. Despite this, there was no difference in the rates of response, MRD negativity, or median overall survival when stratified by receipt of daunorubicin intensity. A significantly higher proportion of FLT3-ITD relative to FLT3-TKD in the 90 mg/m 2 cohort may partially explain these findings. These results suggest a dose of daunorubicin 60 mg/m 2 in combination with cytarabine and midostaurin in patients fit for intensive chemotherapy.

Attrition after Referral for Chimeric Antigen Receptor T-Cell (CAR-T) Products in Multiple Myeloma (MM)

Introduction: Chimeric antigen receptor T-cell (CAR-T) products have shown an impressive response in relapsed/refractory MM patients (pts). The pivotal KarMMa-3 (Otero-Rodriguez P et al, NEJM, 2023) and CARTITUDE-4 (San Miguel J, et al, NEJM, 2023) studies showed that infusion of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) was superior to other standard of care therapies. However, some pts in these studies were unable to receive CAR-T even after being deemed eligible for apheresis. In KarMMa-3, 12/140 pts who completed apheresis did not receive their cells, 3 due to disease progression/death and 1 due to a true manufacturing failure. In CARTITUDE-4, 16/113 pts who completed apheresis did not receive their cells, with 9 dying prior to infusion and 0 having true manufacturing failures. Other studies have shown that factors like peripheral CD3 count (PCD3) affected the probability of a successful apheresis (Rytlewski et al, ASCO 2022). Known reasons for CAR-T attrition include lack of available spots, true manufacturing failures, death post-apheresis but prior to infusion (PAD; due to infection and/or disease progression), and cell product issues necessitating an expanded access program (EAP). This study aimed to find patient- and disease-specific variables associated with increased rates of CAR-T attrition. Methods: We retrospectively reviewed the medical records of all pts who were approved for either ide-cel or cilta-cel as standard of care (SOC) treatment for MM at MD Anderson between August 2021 and June 2023. The study was approved by the Institutional Review Board at MD Anderson. Pts were classified by CAR-T product received, and the number of apheresis procedures required to produce viable product. They were then classified based on need for EAP. Descriptive statistics including mean, standard deviation, median, and range for continuous variables such as age and lab measurements, and frequency counts and percentages for categorical variables such as stage, gender, comorbidity, treatment, and response were obtained. Fisher's exact test or Chi-square test was used to evaluate the association between two categorical variables. Wilcoxon rank sum test or Kruskal-Wallis test was used to evaluate the difference in a continuous variable between or among patient groups. Kaplan-Meier method was used to estimate overall survival and progression free survival for the pts who received CAR-T infusion. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for all the analyses. Results: Data from 153 pts were included. High-risk features, defined as the presence of high-risk cytogenetics, extramedullary disease, or R-ISS stage III, were present in 125 (81.7%), and 84 (54.9%) were penta-refractory. CAR-T cells were infused successfully in 86 (56.2%) pts, including 5 who were infused via EAP. Of the 67 pts who did not get infused, 26 (38.2%) died prior to apheresis, 8 (11.9%) were PAD, 10 (14.9%) were treated with a bispecific agent due to lack of available manufacturing slots, and 3 (4.5%) had true manufacturing failures. Of the 8 patients that were PAD, 2 died due to progression of disease, 4 died from complications of inpatient bridging chemo, and 2 died from complications from lymphodepleting chemo. For all pts with manufacturing failures, their apheresis had a low dose, with 2 out of 3 having PCD3 &amp;lt; 5%. The mean absolute lymphocyte count (ALC) at apheresis was significantly higher in the EAP group (n=5) compared with the non-EAP group, but significantly lower in the manufacturing failures group (n=3) compared with the successful CAR-T manufacturing (n=86) group (Table 1). For the overall cohort of pts receiving CAR-T (n=86), the median progression-free (PFS) and overall survival (OS) rates were 11.7 and 18.8 months, respectively (Figure 1). Conclusion: The PFS and OS for all pts, including those who received their CAR-T through EAP, were excellent. ALC at the time of apheresis was a predictor of true manufacturing failure. Surprisingly, pts successfully treated on EAP had an increased ALC compared with those receiving SOC. Further comparative studies of pts with barriers to CAR-T are needed to identify other variables that increase adverse outcomes so that these can be addressed. Hopefully, with a better understanding of the barriers patients have, we can ensure that more pts get access to this efficacious treatment.

NAMPT Haploinsufficiency Is a Therapeutic Vulnerability in High-Risk Myeloid Malignancies

Monosomy 7 (−7) and del7q are the most common high-risk cytogenetic abnormalities and occur across the spectrum of myeloid disorders. -7/del(7q) also co-occur with other high-risk factors such as mutations or deletion of TP53. Standard, non-specific chemotherapy drugs are less effective in these high-risk patients, resulting in a median survival rate of approximately one year. To identify novel, targeted agents for these neoplasms, we sought “collateral lethal” genes, i.e. essential, druggable genes encoded on chromosome 7 that are haploinsufficient upon their loss of heterozygosity. To this end, we first identified essential genes located on chromosome 7. We mined genome-wide CRISPR/Cas9 screen data from 27 human acute myeloid leukemia (AML) cell lines within the DepMap database and identified 65 chromosome 7-encoded, candidate essential genes in AML. To determine those essential genes with known inhibitors, we intersected these 65 candidates with the Drug-Gene Interaction and canSAR.ai databases. We found that nicotinamide phosphoribosyltransferase ( NAMPT), the rate-limiting enzyme that catalyzes the first step of NAD + biosynthesis from nicotinamide, was one of four essential and druggable targets on chromosome 7. Notably, NAMPT was the only essential gene on chromosome 7 with a first-in-class orally bioavailable inhibitor, KPT 9274, currently in clinical trials (NCT04914845). Moreover, NAMPT DNA copy number, mRNA, and protein levels all negatively correlated with cell line sensitivity to NAMPT loss, implicating NAMPT as a collateral lethal candidate gene. We confirmed that isogenic human AML cell lines CRISPR-engineered to partially reduce NAMPT DNA copy led to reduced NAMPT protein levels, indicating NAMPT is a haploinsufficient gene. Cells with ~50% NAMPT levels were significantly more sensitive to the KPT 9274 treatment, and became less viable and more apoptotic, compared to control locus edited cells. To determine whether TP53 status could alter this vulnerability, we generated cell lines with both TP53 loss and 50% NAMPT loss. We found TP53 mutational status did not attenuate the observed effects of NAMPT inhibition on cell survival. Viability assays with primary patient AML samples confirmed that -7/del(7q) status imparts significantly elevated sensitivity to KPT 9274 treatment than samples with diploid chromosome 7 alleles. In summary, our findings reveal NAMPT heterozygosity as a therapeutic vulnerability in high-risk myeloid neoplasms that warrants clinical follow-up. Further, we provide a framework centered on data-mining for uncovering collateral lethal genes in other cancers with recurrent chromosomal arm level deletions.

Comparison of the CXCR5-Antibody Drug Conjugate (ADC; VIP924) to a CD19-ADC and a CD79b-ADC in a Humanized Rec-1 Mantle Cell Lymphoma (MCL) Mouse Model

Introduction The chemokine receptor CXCR5 is highly expressed in MCL, which is a rare subtype of non-Hodgkin lymphoma. VIP924 is a first-in-class CXCR5-targeting ADC composed of a legumain-cleavable linker and a kinesin spindle protein inhibitor (KSPi) payload. We compared VIP924 with a CD19- and a CD79b- targeting ADC in a humanized mouse model of MCL. Methods Expression of CXCR5 and the B-cell targets CD19 and CD79b were analyzed on tumor samples from patients with MCL using immunohistochemistry. Slides were examined by a pathologist and scored for expression. NSG-SGM3 mice were transplanted with human hematopoietic stem cells from 4 different donors and after engraftment transplanted subcutaneously with REC-1 MCL cells into their flanks. When subcutaneous tumors reached a size of 100 mm 3, mice were randomized into 5 groups and treated with 10 mg/kg of an isotype control ADC, 3 mg/kg polatuzumab vedotin, 0.66 mg/kg loncastuximab teserine, 3 mg/kg VIP924, or 10 mg/kg VIP924 every 5 days for 4 doses. Immunophenotyping of peripheral blood was performed by flow cytometry before starting treatment (Day 0) and on Day 5 and Day 18 during the treatment. At the end of the experiment, immunophenotyping was also done on tumors, spleen, and bone marrow. Complete blood count was analyzed based on single cell evaluation (Drew Scientific HemaVet 950FS Auto Blood Analyzer). Results By immunohistochemistry CXCR5 and CD19 showed comparable high expression on patient samples, whereas CD79b expression was moderate. Treatment of humanized mice bearing REC-1 tumors with VIP924 at 10 mg/kg reduced tumor growth effectively (p&amp;lt;0.0001 vs. isotype control on Day 10), while treatment with polatuzumab vedotin and loncastuximab teserine showed no effects on tumor growth. This outcome was also reflected in the median survival rates for the different groups with 17 days for isotype control and polatuzumab vedotin, 14 days for loncastuximab teserine and not reached for the 10-mg/kg VIP924 group. However, polatuzumab vedotin treatment significantly reduced hCD45+ cells in peripheral blood and spleen, while loncastuximab teserine treatment showed a clear trend for reduction. VIP924 treatment in both arms had no effect on peripheral or splenic hCD45+ cells. All tested ADCs reduced the CD19+ and more mature CD19+/CXCR5+ B-cells in peripheral blood and spleen, with polatuzumab vedotin and loncastuximab teserine showing significant (p&amp;lt;0.0001 vs. isotype control on Day 18) effects on CD19+ cell reductions, while VIP924 treatment showed a milder reduction in CD19+ cells (p= 0.0051 for 3 mg/kg and p= 0.0407 for 10 mg/kg VIP924). Loncastuximab teserine treatment increased the amount of myeloid derived suppressor cells in the peripheral blood significantly (p= 0.0467). In contrast, VIP924 led to a significant (p&amp;lt; 0.0001) increase in peripheral regulatory T-cells compared with isotype control. Complete blood counts from treated mice showed a reduction of white blood cells (WBC), absolute lymphocyte count, and absolute monocyte count in loncastuximab teserine-treated animals. Loncastuximab teserine treatment also reduced red blood cell count and hemoglobin values. In VIP924-treated animals, no effects on WBC, red blood cell count, or hemoglobin values were observed. All treatments showed no detrimental effects on body weights of the mice. Conclusion CXCR5 is a highly attractive target in B-cell malignancies such as diffuse large B-cell lymphoma and MCL due to high CXCR5 surface expression. VIP924, a CXCR5-targeting ADC, showed high potency and superiority to other B-cell-targeted ADCs in a humanized mouse model of MCL. In this MCL model in humanized mice, VIP924 at 10 mg/kg treatment showed a significant reduction in tumor growth and improvement in survival, while polatuzumab vedotin and loncastuximab teserine had no effect on tumor growth or survival. Interestingly, VIP924 was the only ADC to cause a significant increase in peripheral T regulatory cells, which may enhance tumor growth inhibition. Loncastuximab teserine had a deleterious effect on several hematologic parameters, which was not observed with VIP924 or polatuzumab vedotin. The efficacy and tolerability observed in this study with VIP924 suggests further testing in human clinical trials is warranted.

An Optimized Method to Culture Human Primary Lung Tumor Cell Spheroids

Lung cancer is the leading cause of cancer mortality worldwide, with a median survival rate at 5 years of less than 20%. While molecular mapping aids in selecting appropriate therapies, it cannot predict personalized treatment response and long-term efficacy. For addressing these challenges, there is a great need for functional tests. Within this context, we developed patient-derived spheroids (PDS) from tumor and adjacent normal tissue to biomimic the respective tissue for assessing the personalized drug treatment response in vitro. Surgically resected lung specimens were used to generate spheroids using a two-step culture procedure. Flow cytometry and immune staining enabled the characterization of different cell populations resulting from the lung samples. PDS phenotype, cell proliferation and apoptosis were evaluated. Differential gene expression between tumor and adjacent normal tissue was analyzed via RT-qPCR. PDS drug sensitivity was assessed using a cell metabolic assay in response to two chemotherapeutic drug combinations. Cellular and molecular analysis revealed the proportion of epithelial cells, fibroblasts, and immune cells in the patients’ tissue samples. Subsequently, PDS models from tumor and normal lung were successfully established using the expanded epithelial cells. As a proof of concept, an analysis of the drug treatment using PDS of lung adenoid cystic carcinoma exhibited a dose-dependent effect in response to cisplatin/etoposide and cisplatin/paclitaxel. Our spheroid model of both tumor and non-tumor lung cells holds great promise for enhancing the treatment efficacy in the cancer patients.

A Novel Port to Facilitate Magnetic Hyperthermia Therapy for Glioma.

High-grade gliomas (HGG) are the most common primary brain malignancy and continue to be associated with a dismal prognosis (median survival rate of 15-18 months) with standard of care therapy. Magnetic hyperthermia therapy (MHT) is an emerging intervention that leverages the ferromagnetic properties of magnetic iron-oxide nanoparticles (MIONPs) to target cancer cells that are otherwise left behind after resection. We report a novel port device to facilitate localization, delivery, and temperature measurement of MIONPs within a target lesion for MHT therapy. We conducted an in-depth literature and intellectual property review to define specifications of the conceived port device. After setting the design parameters, a thorough collaboration with neurological surgeons guided the iterative modeling process. A prototype was developed using Fusion 360 (Autodesk, San Rafael, CA) and printed on a Form 3 printer (Formlabs, Medford, MA) in Durable resin. The prototype was then tested in a phantom skull printed on a Pro-Jet 660Pro 3D printer (3D Systems, Rock Hill, SC) and a brain model based on mechanical and electrochemical properties of native brain tissue. This phantom underwent MHT heating tests using an alternating magnetic field (AMF) sequence based on current MHT workflow. Successful localization, delivery, and temperature measurement were demonstrated. The purpose of this study was twofold: first, to create and validate the procedural framework for a novel device, providing the groundwork for an upcoming comprehensive animal trial and second, to elucidate a cooperative approach between engineers and clinicians that propels advancements in medical innovation.

Emphasis on targeted and immunotherapy for liver injury in hepatocellular carcinoma

Treatment with molecular targeted drugs and immune checkpoint inhibitors (ICIs) has become the first-line treatment options for unresectable HCC (hepatocellular carcinoma) and is also one of the anti-recurrence therapies of choice for patients at high risk of recurrence following radical treatment. First-line molecular targeted drugs combined with ICIs or dual-immune therapy significantly increase the median overall survival and objective response rate compared to single-targeted drugs. Targeted therapy and immunotherapy are suitable for HCC patients with Child-Pugh classes A~B. Liver damage caused by targeted drugs includes abnormal transaminases and bilirubin and, in severe cases, hypoproteinemia, ascites, and other occurrences. ICIs-associated immune-mediated hepatitis (IMH) mostly occurs within one to three sessions of treatment (4~12 weeks) and can be treated with glucocorticoids. However, immunosuppressants such as mycophenolate mofetil may be used as necessary.Targeted drugs and ICIs with different mechanisms of action can be selected based on the systemic condition and tumor treatment needs following the restoration of normal liver function.

DISP-08. UNMET NEEDS: WHAT PEOPLE LIVING WITH GLIOBLASTOMA LACK TODAY, INCLUDING ACCESS TO CRITICAL GENOMIC TUMOR TESTING

Abstract PURPOSE In 2022 and 2023, the non-profit OurBrainBank asked its community of people living with glioblastoma and care partners about the current state of GBM treatment in the USA including whether the patient received genomic tumor analysis. METHOD: OurBrainBank conducted an online survey in which we posted queries through two Facebook groups: “Glioblastoma — GBM SURVIVORS TO THRIVERS!” and “OurBrainBank GBM Patient &amp; Caregiver Community.” RESULTS More than 100 people responded to the Facebook posts stating the priorities they felt they most needed. Top of the list were faster FDA approval for promising therapies, better treatment for veterans, speedier approval for disability benefits as well as common-sense improvements to Medicare/Medicaid, a stop to unreasonable insurance practices, and more flexibility regarding clinical trials. For the survey, 133 people responded. Of the sample group, 50% reported that they had not been informed about tumor testing and 70% said they were unsure or not informed about storing tumor tissue. For the 30% who knew about storing tissue, only half actually had done so. More than 50% did not know about tumor types or mutations. Only half felt that they received enough information to make educated decisions. Those living in urban areas or able to travel received care at hospitals that specialized in brain tumors, but by contrast people living in rural areas or far from a center of excellence did not. Half of respondents felt that they did not enjoy an equal and collaborative relationship with their medical team. CONCLUSION GBM patients and their caregivers are not treated consistently, particularly in regard to genomic tumor testing, a vital first step toward personalized treatment. Many do not receive optimal care and may not even see a specialist. With a median survival rate of 12-18 months, there is much improvement needed.

BIOM-60. CONCATEMERIC CONSENSUS ERROR CORRECTED SEQUENCING (CCEC-SEQ) APPROACH FOR PLASMA CELL-FREE TUMOR DNA-BASED TREATMENT RESPONSE MONITORING IN PATIENTS WITH BRAIN TUMORS

Abstract BACKGROUND Diffuse midline gliomas (DMG) are aggressive and universally fatal with a median survival rate of only 9-12 months. MRIs can be difficult to interpret due to diffuse disease and radiation-induced swelling. Recent work has shown that liquid biopsy of cell-free tumor DNA (cf-tDNA) in patient plasma using digital droplet PCR (ddPCR) might help supplement radiographic monitoring, and enable more quantitative, low-cost, rapid tests. Nanopore sequencing has been employed to quickly and affordably measure and track treatment response in DMG patient cerebrospinal fluid (CSF) where cf-tDNA variant allele fractions are high ( &amp;gt;1%). However, plasma cf-tDNA signal is much lower than CSF (typically &amp;lt; 0.5%), and no platforms have demonstrated the feasibility of quickly (&amp;lt; 1day) sequencing brain tumor cf-tDNA in plasma samples to our knowledge. METHODS To solve these problems, we have developed a same-day, multiplexed, concatemeric consensus error corrected (CCEC-Seq) assay approach for Nanopore sequencing. We combine multiplex PCR and loop-mediated isothermal amplification (LAMP) to capture short cf-tDNA fragments and concatemerize them. Sequenced concatemer segments should agree, and allow informatic consensus error correction, reducing Nanopore error rates. RESULTS We generated a multiplex (n = 8) DMG hotspot loci panel, which was able to reduce sequencing false positive call rates by 3.1x-10.8x. We were able to employ the CCEC-Seq technique on serial plasma samples from a patient with DMG with H3.3K27M mutation undergoing treatment with ONC201 with results comparable to a previously validated ddPCR assay. Ongoing work will apply this multiplex CCEC-Seq panel to a larger cohort of serial DMG plasma samples. CONCLUSION To our knowledge, this is the first demonstration of same-day, sequencing-based, liquid biopsy protocol for a plasma sample from a brain tumor patient. This approach has the potential to greatly reduce resource requirements, and ease of operation for liquid biopsy for DMG and other brain tumor disease monitoring.

Nerve Growth Factor, Antimicrobial Peptides and Chemotherapy: Glioblastoma Combination Therapy to Improve Their Efficacy.

Glioblastoma (GBM) is an aggressive and lethal malignancy of the central nervous system with a median survival rate of 15 months. We investigated the combined anticancer effects of nerve growth factor (NGF), cathelicidin (LL-37), and protegrin-1 (PG-1) with chemotherapy (temozolomide, doxorubicin, carboplatin, cisplatin, and etoposide) in the glioblastoma U251 cell line to overcome the limitations of conventional chemotherapy and to guarantee specific treatments to succeed. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to study cell viability and to determine the cytotoxic effects of NGF, LL-37, and PG-1 and their combination with chemotherapy in U251 cells. Synergism or antagonism was determined using the combination index (CI) method. Caspase-3 activity was evaluated spectrophotometrically using a caspase-3 activity assay kit. Apoptosis was analyzed with flow cytometry using propidium iodide (PI) and YO-PRO-1. NGF and the peptides showed a strong cytotoxic effect on U251 glioma cells in the MTT test (IC50 0.0214, 3.1, and 26.1 μM, respectively) compared to chemotherapy. The combination of PG-1 + etoposide had a synergistic effect on apoptosis of U251 glioma cells. It should be noted that the cells were in the early and late stages of apoptosis, respectively, compared with the control cells. The caspase-3 activation analysis revealed that the caspase-3 level was not significantly (p > 0.05) increased in U251 cells following PG-1 with etoposide treatment compared with that in the untreated cells, suggesting that the combination of PG-1 and etoposide may induce caspase-independent apoptosis in U251 cells. NGF, LL-37, and PG-1 represent promising drug candidates as the treatment regimen for GBM. Furthermore, the synergistic efficacy of the combined protocol using PG-1 and etoposide may overcome some of the typical limitations of the conventional therapeutic protocols, thus representing a promising approach for GBM therapy.

Hepatocellular Carcinoma: Risk Factors and Diagnosis

Hepatocellular carcinoma, also known as hepatocarcinoma, is the most frequent type of primary liver cancer and the world's second leading cause of death, with a mortality rate of 700.000 per year. Due to the difficulty in diagnosing hepatocarcinoma because there are no obvious symptoms, the survival rate of hepatocarcinoma patients is still very low, particularly in Southeast Asian countries. Hepatocarcinoma is still a major health issue in Indonesia, with a very low median survival rate. The number of risk factors that cause hepatocarcinoma is what causes differences in hepatocarcinoma incidence across countries. This literature review aims to determine risk factors and to confirm the diagnosis of hepatocarcinoma. This literature review was conducted using the keywords “Hepatocellular Carcinoma AND risk factors AND diagnosis” from PubMed, Google Scholar, and non-peer-reviewed literature. This article uses 16 articles that were used as references in its preparation. In conclusion, hepatitis B and C virus, liver cirrhosis, fatty liver disease, diabetes, alcohol use, aflatoxin exposure, aristolochic acid exposure, smoking, and HIV are risk factors for hepatocarcinoma. On all individuals with hepatocarcinoma risk factors, screening procedures with US and AFP were carried out. An abdominal CT scan or an MRI with contrast can both be used to provide a firm diagnosis of hepatocarcinoma. A liver biopsy is used to confirm the diagnosis of space-occupying lesions that lack typical imaging characteristics.