Biopsies Of Patients Research Articles

Relationship between Body Mass Index and Prostate Specific Antigen among Community Men in Port Harcourt, Nigeria

Background: The prevalence of prostate cancer is increasing at a high rate in the Niger Delta region of Nigeria. The role of androgens, age and genetics are established worldwide. Among others, obesity, a consequence of Improvement in quality of life in the oil rich region, which has also been implicated in several conditions like diabetes, hypertension, depression, osteoarthritis and several other malignancies, could be a risk factor. Our aim in this study is to establish a relationship between BMI, an index of obesity and Prostate Specific Antigen (PSA), a marker for prostate cancer. Materials and Methods: We carried out a community-based observational study in Port Harcourt, Rivers State. The demographic, anthropometric and medical history of men, forty years and above who have lived in the Niger Delta area of Nigeria for over 15 years and who had no prior history of prostate cancer was taken. The BMI and the quantitative PSA of the participants were determined. The corelation of BMI and PSA was established. Results: A total of 583 respondents participated in the study. Mean age was 60.53 ±7.82. Mean BMI was 24.49 ±3.75. 18% of respondents were underweight, 53.3% were of normal weight, 35.3% were overweight and 7% were obese. The mean PSA was 4.12ng/ml, 84.5% had normal PSA, 15.5% had PSA greater than 4. There was a weak negative correlation between BMI and serum PSA with Pearson correlation of -0.010. Conclusion: This study shows a negative correlation between BMI and prostate cancer. In view of this inverse relationship between PSA and BMI it may be necessary to reduce the threshold for further evaluations like prostate biopsies in patients with high BMI. Additionally more specific diagnostic tools like ultrasound guidance during prostate biopsy may be helpful.

Endomyocardial biopsy in patients with myocarditis-still justified in the CMR era? A single-centre experience.

In the past decades, cardiovascular magnetic resonance (CMR) was established as a non-invasive tool supporting the diagnosis of myocarditis and there is often reluctance in performing EMB due to potentially severe complications. We sought to identify patient subgroups that could still benefit from EMB in the CMR era. Data of patients presenting with myocarditis between 01/2016 and 06/2023 were analysed according to patient risks. Prespecified risk factors were (i) left ventricular ejection fraction (LVEF) ≤ 30%; (ii) severe arrhythmias; or (iii) pre-existing autoimmune disease. Furthermore, the subgroup of recurrent myocarditis cases was analysed separately. A total of 137 patients (35.5 ± 14.8years, 80.3% male) were included. 26/137 patients had a documented LVEF ≤ 30%, 13/137 a LVEF > 30% with at least one other risk factor and 98/137 a LVEF > 30% without risk factors. EMB was performed in 21/26 patients with LVEF ≤ 30% (80.8%), in 7/13 patients with LVEF > 30% and risk factors (53.8%) and in 16/98 (16%) patients without risk factors. EMB led to the initiation of immunosuppressive therapy in 11/28 patients with risk factors (39.3%) and in none of the patients without risk factors (0/16, 0%, p = 0.003). With respect to the subgroup of patients presenting with recurrent myocarditis (n = 10), no specific therapy was initiated. Due to a high therapeutic yield for initiation of immunosuppressive therapy in non-infectious myocarditis, performing EMB should be considered in all high-risk patients. In patients without clinical risk factors including cases of recurrent or relapsing myocarditis no specific therapy was initiated.

Impact of post RFA treatment on neosquamous epithelium microstructure

Radiofrequency ablation (RFA) is effective treatment for Barrett’s esophagus (BE). Product of successful RFA is neosquamous epithelium (NSE), which resembles native squamous epithelium and has lower risk for neoplastic transformation. Dilated intercellular spaces (IS) are common microscopic feature of reflux induced injury of esophagus. The aim of this study was to analyze the ultrastructure of NSE by transmission electron microscopy (TEM), depending on the post RFA treatment modalities and to asses impact of these findings on BE recurrence. Prospective observational clinical study based on TEM analysis of biopsy of specimens obtained from patients in whom CE of BE was achieved minimum 6 months after the last RFA session. In each patient biopsies were taken from NSE and proximal esophagus. Two groups of patients were defined according to the post RFA treatment: proton pump inhibitors (PPI’s) or laparoscopic Nissen fundoplication (LNF). Comparative analysis of IS length was made between two groups. Endoscopic surveillance with biopsies was conducted for 5 years. Overall 22 patients with CE of BE after RFA underwent complete study protocol, out of whom in 10 LNF was performed, while 12 were treated with PPI’s. The mean values of IS length in the proximal esophagus and NSE in LNF group were 0.378 ± 0.116 µm and 0.878 ± 0.354, while in PPI’s group 0.724 ± 0.325 µm and 1.228 ± 0.226 µm, respectively. Mean lenghts of IS were statistically significantly higher in PPI’s group both in NSE (p = 0.032) and proximal esophagus (p = 0.009). There were 5 BE recurrences after 5 years surveillance, 4 in PPI group and 1 in LNF group, without statistical significance (p = 0.084). Dilated IS are commonly presented in NSE of patients with CE of BE with RFA who are treated with PPI’s. LNF provides may offer better reflux protection of NSE than PPI’s and may reduce the rates of recurrence after successful RFA treatment.

Nodular Regenerative Hyperplasia: Report of 82 Patients and Systematic Review of Literature.

Data about the clinical significance and outcome of patients with nodular regenerative hyperplasia are limited. The aim of this study was to describe the clinical and histopathological characteristics of patients with nodular regenerative hyperplasia and compare our findings with the literature. From January 2015 to March 2021, patients with a diagnosis of nodular regenerative hyperplasia were included. They were extracted from the database of the pathology department of Cliniques universitaires Saint-Luc. Clinical and histological data were retrospectively recorded and complications of portal hypertension and mortality were analyzed. We also performed a systematic review of the literature. Eighty-two histology-proven nodular regenerative hyperplasia were included. The mean age at diagnosis was 58±14years. At least one clinical sign of portal hypertension was present in 37 patients (45%), and liver tissue sampling was performed for 29 of them for evaluation of portal hypertension. Conversely, nodular regenerative hyperplasia was an incidental discovery in 27 patients (33%), mostly after liver resection for metastasis (n=15) or protocol biopsy in liver-transplanted patients (n=9). The 5-year liver-related mortality was 5%. The 5-year non-liver-related mortality was 20%. Patients diagnosed by clinical suspicion (n=55) were compared to patients diagnosed incidentally (n=27). Patients with an incidental diagnosis had more frequently a condition associated with nodular regenerative hyperplasia than patients diagnosed clinically (93% vs. 66%, p=0.008) and they developed significantly lower liver-related complications (4% vs. 27%, p=0.01). A systematic review allowed us to compare our patients with 10 case series in the literature. The clinical spectrum of patients with nodular regenerative hyperplasia is heterogeneous, including patients with clinical liver manifestations and patients diagnosed incidentally who could remain free of liver-related complications. This suggests that nodular regenerative hyperplasia could be a histological epiphenomenon as well as a clinical entity.

Advancing precision in CT-guided bone biopsies: exploring the potential of dual-energy CT imaging.

This study aimed to investigate the integration of dual-energy CT (DECT) into CT-guided bone biopsy procedures, comparing it with conventional CT techniques. The focus was on technical aspects, accuracy and radiation dose exposure. A total of 51 bone biopsies were conducted, with 36 using conventional CT and 15 utilizing DECT. Patient data, lesion characteristics and biopsy techniques were analyzed. Statistical analyses, including Fisher's exact test and independent samples t-test, were performed to compare accuracy and radiation doses between the two methods. DECT-guided biopsies demonstrated a significantly higher accuracy (93.33%) compared to conventional CT biopsies (86.11%). The radiation dose exposure for DECT was comparable to conventional CT. DECT's ability to differentiate tissues, especially in bone marrow edema detection, led to higher precision. Integrating DECT into CT-guided bone biopsies enhances tissue differentiation and accuracy without significantly increasing radiation exposure. This advancement holds promise for improving musculoskeletal interventional radiology, leading to more precise diagnoses, informed treatment decisions and improved patient outcomes.

FOSL2 activates TGF-β1-mediated GLUT1/mTOR signaling to promote diabetic kidney disease.

Diabetic kidney disease (DKD) is a major cause of kidney failure. FOS-like antigen 2 (FOSL2) has been revealed to be increased in kidney biopsies of patients with lupus nephritis, while its association with DKD remains unsolved. This study aimed to characterize the role of FOSL2 in DKD and its mechanism. The kidney tissues of DKD mice induced by STZ and a high-fat diet were subjected to PAS and Masson's staining. Glomerular mesangial cells (MCs) were treated with high glucose (HG) or normal glucose (NG). CCK-8 and EdU assays were performed to detect cell proliferation, and immunoblotting was conducted to analyze ECM deposition. ChIP-qPCR was performed on MCs to detect the binding of FOSL2 on the TGF-β1 promoter and a dual-luciferase assay to detect the impact of FOSL2 on the transcription of the TGF-β1 promoter. FOSL2 was elevated in the kidney tissues of DKD mice. Knockdown of FOSL2 reduced the mRNA expression of TGF-β1 to decrease the protein expression of GLUT1 and mTOR in the kidney tissues of DKD mice, and TGF-β1 reversed the effects caused by knockdown of FOSL2. The mTOR inhibitor Rapamycin alleviated kidney injury in the presence of FOSL2. Knockdown of FOSL2 inhibited the proliferation and improved ECM deposition of MCs, which were reversed by TGF-β1. Rapamycin and GLUT1 inhibitor BAY-876 reversed the promotion effect of FOSL2 on the proliferation of NG-MCs/HG-MCs and improved ECM deposition of MCs. Our data demonstrated that FOSL2 accentuates DKD in mice by increasing TGF-β1-induced GLUT1/mTOR signaling.

PH-Activatable Molecular Probe for COX-2 Imaging in Human Oral Squamous Carcinoma Cells and Patient-Derived Tissues.

For developing a successful cancer therapeutic modality, the early precise detection of cancer cells in patient biopsies in oral squamous cell carcinoma (OSCC) is crucial. This could help researchers create new diagnostic and therapeutic tools and assist clinicians in recommending more effective treatment plans and improving patient survival. We have developed an SMPD, cyclooxygenase-2 (COX-2) targeting pH-activable fluorophore named CNP, combining a potent COX-2 inhibitor, celecoxib, linked to a naphthalimide fluorophore with an acidic microenvironment-responsive piperazine moiety for specific optical imaging of OSCC in cells and patient tissues. Compared to reference probe RNP lacking celecoxib, CNP selectively enters the COX-2 overexpressing oral cancer cells. Its acidity-responsive imaging response enhances selectivity over cancers with lower COX-2 expression levels and normal cells. Further, CNP is demonstrated in imaging OSCC cells in patient-derived biopsies. Thus, multifunctional CNP shows potential in exploring more reagents for fluorescence-based detection of OSCC cells in patient tissues with translational applications.

Adjuvant Radiation Therapy in Desmoplastic Melanoma: A Scoping Review.

Desmoplastic melanoma (DM) is an uncommon subtype of cutaneous melanoma that presents distinct diagnostic and treatment challenges. This review aims to explore the role of adjuvant radiation therapy (RT) in managing DM. To evaluate this question, we reviewed relevant published reports on DM and its treatment and synthesized these findings. It was found that the clinical behavior of DM varies significantly based on its classification as either "pure" DM (pDM, ≥90% desmoplastic features) or mixed DM (mDM, ≤90% desmoplastic features). Patients with pDM have a uniquely high risk of local recurrence but a relatively lower likelihood of nodal disease. Recent studies question the necessity of sentinel lymph node biopsy for pDM patients while illustrating impressive response rates to immune checkpoint inhibition. Most data supporting adjuvant RT predate these changes in surgical management and systemic therapy, yet consistently demonstrate that adjuvant RT reduces the absolute risk of local recurrence by >50%, without significant long-term toxicity. Thus, the existing literature continues to support the conclusion that adjuvant RT effectively reduces the likelihood of local recurrence in pDM patients. Although evolving surgical and systemic therapies are reshaping treatment approaches, adjuvant RT should remain a standard of care.

Large B Cell Lymphoma as A Rare Cause of Gastrointestinal Bleeding and Melena in An Elderly Patient: A Case Report

Large B-cell lymphoma is a rare form of non-Hodgkin lymphoma that can affect the gastrointestinal (GI) tract and poses diagnostic challenges owing to its non-specific symptoms. This study reports the case of a 70-year-old male with a history of cardiovascular disease who presented with melena and vague abdominal pain, initially regarded as emerging from common GI disorders. Endoscopic findings revealed large gastric ulcers with suspicious features, and biopsy confirmed the diagnosis of large B-cell lymphoma. Imaging showed metastasis, complicating the patient’s condition. Managing this case required careful balancing of antiplatelet therapy for his cardiovascular disease with the pressing need to control GI bleeding. The patient benefited from a multidisciplinary approach involving gastroenterology, cardiology, and oncology teams. This case shows the importance of early endoscopic evaluation and biopsy in elderly patients with persistent GI symptoms, as early diagnosis of rare conditions like gastric lymphoma can significantly improve treatment outcomes.

Comparing Needle and Surgical Biopsy in Small Peripheral Non-Small Cell Lung Cancer With Suspected Pleural Invasion: A Propensity Score-Matched Study.

This study aimed to compare long-term clinical outcomes of percutaneous needle biopsy (PCNB) versus surgical biopsy in patients with peripheral, small-sized clinical stage 1 non-small cell lung cancer (NSCLC) with computed tomography (CT)-defined visceral pleural invasion (VPI). We retrospectively analyzed patients who underwent surgery for NSCLC with CT-defined VPI between 2010 and 2017. We excluded patients with non-peripheral NSCLC, or cancers > 3 cm. Propensity score matching was carried out to adjust for confounding variables. The primary endpoint was ipsilateral pleural recurrence-free survival, while secondary endpoints included overall survival and recurrence-free survival. Of the 1671 patients with peripheral, small-sized clinical stage 1 NSCLC with CT-defined VPI, 805 underwent PCNB, and 866 had a surgical biopsy. Propensity score matching assigned 562 patients to each group. Before matching, the PCNB group demonstrated worse baseline characteristics, including older age, higher smoking history, and more adverse pathological findings. After matching, the 5-year recurrence-free survival for ipsilateral pleural recurrence (98.6% vs. 96.0%, p = 0.002) and overall survival (93.8% vs. 90.2%, p = 0.003) were significantly higher in the surgical biopsy group compared with the PCNB group. Multivariable analysis revealed that PCNB significantly increased the risks of all-cause mortality and various recurrences before and after matching. Compared with surgery biopsy, PCNB was associated with higher risks of all-cause mortality and recurrences, including ipsilateral pleural recurrence. PCNB should be considered with caution in cases of peripheral stage 1 NSCLC where CT-defined VPI is suspected.

The Comparative Study on the Application Value of Transperineal Prostate Combined Biopsy and Transrectal Prostate Systematic Biopsy in Diagnosing Prostate Cancer in Patients with Different PSA Zones.

This study aimed to compare the effects of transperineal prostate combined biopsy (TP-CB) and transrectal prostate systematic biopsy (TR-SB) on the detection rate and safety of prostate cancer in patients with prostate-specific antigen (PSA) gray zone, PSA levels of 10~20 ng/mL, and 20~40 ng/mL, and explore the comparative value of their applications. We collected 243 samples from patients with PSA ≤ 40 ng/mL who underwent prostate biopsy. All patients were divided into two groups according to different patterns of prostate biopsy. The detection rates of prostate cancer and clinically significant prostate cancer (CsPCa) in patients with PSA levels of 4~10, 10~20, and 20~40 ng/mL were compared between two different biopsy methods, surgical conditions, and the incidence of complications. The rate of a positive prostate cancer biopsy was significantly higher in TP-CB than in TR-SB (P < 0.05). Further subgroup analyses revealed no statistical significance in the rate of positive prostate cancer biopsy in patients with PSA levels of 4~10 and 20~40 ng/mL between the two groups (P > 0.05). However, patients with PSA levels of 10~20 ng/mL in the TP-CB group exhibited a higher detection rate (P < 0.05), with CsPCa accounting for a higher proportion. The TP-CB and TR-SB groups did not exhibit a significant difference in surgical conditions or overall complication rates (P > 0.05). However, the TR-SB group exhibited a higher risk of postoperative febrile infection than the TP-CB group (P < 0.05). For patients with PSA in the 'sub-gray zone' (10~20 ng/mL), TP-CB has a better diagnostic and application value and is more suitable for clinical promotion.

The application of statistical techniques in assessing the impact of medical interventions: A case study of diabetes management

Abstract. Esophageal cancer (EC) ranks seventh among all cancers in terms of frequency and is the sixth leading cause of cancer-related deaths worldwide. The 5-year relative survival rate for esophageal cancer stands at a dismal 21%, which is nearly the lowest among all cancers. In China alone, over 477,900 individuals are diagnosed with EC annually. Advances in whole-genome sequencing technologies have enabled researchers to identify numerous gene mutations across the entire gene sequence in EC patients. This paper aims to consolidate current knowledge on several key genes implicated in EC, as revealed by whole-genome sequencing of patient biopsies. By examining research papers published within the last decade, this study captures the main findings and elucidates the influence of mutations in SOX2, TP53, NOTCH1, SMAD4, and CDKN2A on the formation, progression, and prognosis of both esophageal adenocarcinomas and squamous cell carcinomas. The insights gained are expected to contribute positively to the overall comprehension of esophageal cancer.

Safety outcomes and immunological correlates in a prospective clinical trial of immune checkpoint therapy plus debulking surgery for patients with metastatic renal cell carcinoma.

Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma (mccRCC). Based upon baseline evaluation and surgical eligibility after 6 weeks of ICT treatment, 43 patients on this trial proceeded with cytoreductive surgery, while 36 patients who had medical comorbidities preventing surgery or did not have a lesion amenable for surgical resection underwent post-ICT biopsy as specified in the clinical trial protocol, and 25 patients who discontinued study participation due to progressive disease or toxicities or withdrawal of consent did not receive either procedure (total N=104). Our data demonstrated that, in the subgroup of patients receiving the combination of ICT with cytoreductive surgery or biopsy, no additional ICT- or procedure-related toxicities were observed as compared to historical data. The median OS (overall survival) was 54.7 months for patients who received ICT-containing regimens plus cytoreductive surgery (n=43). Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing (sc-RNA-seq) data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

Diagnostic value and safety of transbronchial cryobiopsy in postoperative complications after lung transplantation

Objective: To compare the diagnostic rate and safety of postoperative complications between transbronchial cryobiopsy (TBCB) and transbronchial lung biopsy (TBLB) in patients with lung transplantation. Methods: A retrospective analysis of patients who underwent TBCB or TBLB in the Department of Lung Transplantation in China-Japan Friendship Hospital from June 2017 to June 2024 was conducted to determine the postoperative complications and analyze clinical characteristics, procedures, diagnostic rates and safety. Results: Thirty-five and 153 patients with lung transplantation received TBCB and TBLB, respectively. Patients who received TBCB had lower preoperative oxygenation index (t'=2.4, P<0.01). Meanwhile, the pathological diagnosis rate (85.7% vs. 45.7%, χ²=18.27, P<0.01) and clinical diagnosis rate (94.2% vs. 69.9%, χ²=8.80, P<0.01) of patients who received TBCB were significantly higher than those who received TBLB. There was no significant difference in the incidence of severe bleeding (2.9% vs. 0.7%, χ²=1.3, P=0.86) and pneumothorax (0 vs. 3.9%, χ²=0.43, P=0.24) between patients receiving TBCB and TBLB. The most common complications after lung transplantation in the group of TBCB were chronic lung allograft dysfunction (45.4%, 15/33), antibody mediated rejection (18.2%, 6/33) and organizing pneumonia (12.2%, 4/33). While antibody mediated rejection (29.9%, 32/107), chronic lung allograft dysfunction (16.8%, 18/107), and pneumonia (16.8%, 18/107) were more frequent in the patients who received TBLB. Conclusions: TBCB has a high diagnostic value for postoperative complications after lung transplantation, with an acceptable complication rate of bleeding and pneumothorax.

Abstract 4125893: Deciphering the Mechanism of Action of Drug Combinations by Boolean Modeling of Transcriptomes: a Case Study of Atorvastatin/Simvastatin and Ezetimibe

Introduction: Drug combinations offer increased therapeutic efficacy and reduced toxicity and plays a vital role in treating chronic complex diseases. Understanding a drug combination's mechanism of action (MoA) can provide important insights into its therapeutic efficacy. The MoA of many FDA-approved drugs, however, often remains unclear. Methods: In this study, we investigated the combination of a statin [atorvastatin (ATO) or simvastatin (SIM) plus ezetimibe (EZE)] and utilized drug-treated RNA-seq transcriptome data from SOAT2-only-HepG2 cells (treated with ATO 5 umol/L, EZE, 25 umol/L, their combination or vehicle) and from liver biopsies of patients with uncomplicated cholesterol gallstone disease in the Stockholm Study (a single-blind, randomized trial with SIM 80 mg daily, EZE 10 mg daily, their combination, or placebo) to decipher the underlying molecular mechanisms of the drug combination. We proposed a Boolean logical modeling framework to simulate the MoA of a drug combination. Specifically, fourteen two-variable Boolean models were used to describe the combinatory relationships of ATO/SIM and EZE. Thereafter, a pattern matching approach was applied to associate drug-induced differentially expressed genes with the idealized differential expression templates derived from Boolean models. Results: We found 1,560 and 594 genes differentially expressed in at least one treatment condition in SOAT2-only-HepG2 cells and liver biopsies, respectively. Our analysis revealed both expected and novel combinatorial modes of ATO/SIM and EZE. For example, ATO independently activates downstream genes (i.e. B 4 (ATO,EZE)=ATO), and ATO and EZE synergistically inhibits downstream genes (i.e. B 15 (ATO,EZE)=NOT (ATO AND EZE)) , as the two most prevalent MoAs in SOAT2-only-HepG2 cells (Figure 1). Similarly, the combination of SIM and EZE synergistically inhibiting downstream genes was also the most prevalent MoA in the liver biopsies. We mapped the downstream genes of each combinatorial mode to the human interactome and obtained underlying subnetworks, which are important for understanding the therapeutic effects of the drug combination. Functional enrichment and disease-association analyses of the downstream suggest the additional therapeutic indications of the drugs. Conclusion: Drug-induced transcriptomes are informative in deciphering the MoA of drug combinations using Boolean logical modeling. This framework can be easily extended to the combinations of three drugs.

Abstract 4134975: ROS-Traf6-Yap Promotes the Development of Cardiac Hypertrophy

Introduction: Heart failure (HF) is caused by structural and functional abnormalities of the heart and is associated with high morbidity and mortality. Pathological myocardial hypertrophy accounts for a significant portion heart failure. The Yap protein was found to be responsive to mechanotransduction signals and can limit organ size by inducing cell cycle arrest during development. In the heart, pathological activation of Yap has been shown to drive cardiac hypertrophy, but regenerative activation of Yap can promote myocardial cell-cycle re-entry. However, how Yap is pathologically activated in the beating cardiomyocyte remains elusive. Hypothesis: ROS-Traf6 promotes the development of cardiac hypertrophy by activating Yap in a non-canonical fashion. Methods: Traf6 protein levels in heart failure patients biopsies as well as in various murine failing hearts were examined by immunofluorescence. Molecular interrogation of ROS-Traf6-Yap signaling axis was performed in primary neonatal rat cardiomyocytes (NRCM) and human induced pluripotent stem cell derived cardiomyocytes. Yap protein stability and activation by Traf6 was examined by immunoprecipitation, CHX induction, and point mutation. Myocardial specific Traf6 knockout and Yap mutant animals were used to evaluate Traf6-Yap signaling in vivo . Results: We found that Traf6 expression was significantly elevated in multiple heart failure models. Using the transverse aortic constriction (TAC)-induced cardiac hypertrophy model, pressure overload increased ROS levels which activated Traf6. Traf6 overexpression induced myocardial hypertrophy while knockdown blocked myocardial hypertrophy in Ang II treated NRCMs. Mechanistically, Traf6 binds to and ubiquitinates Yap-K234 – this promotes Yap protein stability and nuclear translocation evidenced by increase in phosphorylated Yap. Myocardial Traf6 deficiency prevents TAC-induced cardiac hypertrophy. Moreover, overexpression of Yap-K237 mutant did not restore TAC-induced cardiac hypertrophy in myocardial Yap deficient mice. Conclusions: Our results demonstrate that non-canonical Yap activation is responsible for pressure overload induced cardiac hypertrophy. Targeting of the newly identified ROS-Traf6-Yap signaling axis may provide a new approach to prevent pathogenic cardiac hypertrophy.

TMET-30. ONCOLYTIC HSV REWIRES METABOLISM TO PROMOTE ANTITUMOR IMMUNITY THROUGH REDUCTIVE CARBOXYLATION AND FERROPTOSIS

Abstract Cancer cells autonomously rewire metabolism to meet increased bioenergetic demands. Oncolytic HSVs (oHSVs) are attenuated Herpes simplex type 1 derived viruses that lyse tumor cells releasing damage-associated molecules triggering antitumor immunity. Currently one oHSV-1 derived virus is approved for melanoma treatment in the USA and another for recurrent GBM in Japan. While several other viruses are being evaluated in clinical trials for safety and efficacy, an understanding of the impact of oHSV therapy on cancer cell metabolism is largely unexplored. A detailed understanding of how oHSV impact tumor cell metabolism and oxidative stress is important to understand the unique susceptibilities that can further be exploited to improve the therapeutic index. Here, we analyzed transcriptomic changes in tumor biopsies of recurrent high-grade glioma patients treated with oHSV. RNA-seq data obtained from pre- and post-G207 treated biopsies from phase-Ib study patients (NCT00028158) revealed enrichment in pathways related to citric acid cycle, oxidative phosphorylation, and glutamate metabolism. We confirmed these changes by RNA sequencing of oHSV-infected patient derived GBM cells. Mechanistically, oHSV hijacked cellular glucose metabolism to increase oxidative phosphorylation and modulated cellular glutamine metabolism towards reductive carboxylation and reduced free glutathione, collectively contributing to increased ROS generation. Kinome profiling revealed PKC activation upon treatment with oHSV. Increased ROS combined with reduced glutathione, and PKC activation promoted ferroptotic cell death characterized by increased lipid peroxidation and smaller, ruptured mitochondria, and contributed to immunotherapy by this treatment. IDH mutant tumors that block reductive carboxylation were resistant to oHSV-induced ferroptotic cell death and did not benefit from oHSV-induced antitumor benefit. Together, this study presents avenues to enhance antitumor immunity by oHSV therapy.

CTNI-52. EXPEDITED CHEMORADIATION AFTER LASER INTERSTITIAL THERMAL THERAPY (LITT) IS FEASIBLE AND SAFE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND High-grade gliomas (HGG) are incurable primary brain tumors. Laser Interstitial Thermal Therapy (LITT) has emerged as an alternative to surgery for select patients. Hyperthermia can improve the efficacy of radiation and chemotherapy. Shortening the time between LITT and chemoradiation may maximize their biological and clinical benefits. This clinical trial evaluated the safety and feasibility of expediting chemoradiation after biopsy and LITT in patients with newly-diagnosed HGG. METHODS Patients with suspected HGG were enrolled. Those with pathologic confirmation of HGG and deemed appropriate candidates for LITT and chemoradiation were considered evaluable. Participants underwent 6 weeks of adjuvant chemoradiation within seven days of LITT. Endpoints were assessed until the completion of radiation, and included the occurrence of wound dehiscence; new, treatment-refractory seizures; cerebral edema; and completion of planned radiotherapy. RESULTS Fifteen patients with suspected HGG were enrolled and ten were considered evaluable. All ten patients were diagnosed with glioblastoma (GBM, IDHwt). Five patients were deemed unevaluable: four patients with other CNS tumors and one GBM patient who developed grade 4 postoperative edema. Of ten evaluable patients, the median age was 60.2 years (IQR: 51.0, 69.4), and median preoperative KPS was 90 (IQR: 90, 80). The median time between LITT and the initiation of chemoradiation was seven days. There were no occurrences of significant protocol-related adverse events. CONCLUSIONS Accelerated initiation of chemoradiation after biopsy and LITT is safe and feasible for patients with newly diagnosed HGG. A larger study is needed to assess potential synergy of hyperthermia and chemoradiation to improve survival.

BIOM-40. BLOOD AND NASAL BIOMARKERS OF BRAIN MICROENVIRONMENT BLOOD–BRAIN BARRIER PERMEABILITY: CLINICAL AND APPLIED CONCEPTS

Abstract The limiting step to treating glioblastoma (GBM) patients is the close blood-brain barrier (BBB) which protects the brain making it an inaccessible compartment. Although multiple studies have highlighted the presence of circulating tumour cells (CTCs) in glioblastoma multiforme (GBM) patients their relationship with brain microenvironment and BBB permeability was not explored in depth. We studied the development of GBM by transferring tumour cells into the mouse brain and also in a subcutaneous location to verify how the different microenvironment affected the release of circulating tumour and endothelial cells. Glioblastoma U3T3MG IDHwt secondary cell line was transfected to track circulating tumour cells released. Moreover, both U3T3 cells and short-time-expanded CTCs1 from GBM patients were used for intracranial xenografts and patient-derived xenografts (PDX). The in vivo models demonstrated the correspondence between BBB permeability with the release of CTCs and the increment of endothelial progenitor cells in GBM HIFpos &amp;gt;20% compared to subcutaneous xenografts releasing CTCs in GBM HIFpos&amp;lt; 20%. These data were confirmed in HIFpos tissue biopsy of GBM-IDHwt patients with CTCs &amp;gt;30 cells/ml. Both in PDXs and in the GBM patient demonstrated that the release of CTCs was intermittent, related to BBB opening induced by HIF-dependent cytokines release (IL8, TNFa)2. In parallel, the analysis of structural Glial fibrillary acidic protein (GFAP)3, on nasal secretion and interstitial fluid, collected in surgical treated GBM patients, demonstrated that the recognition of the two GFAP isoforms (p150 and p50 kDa) were the result of inflammatory microenvironment enriched for proteases induced by IL8, TNFa. Overall data indicate at least two different ways of monitoring the BBB and the brain microenvironment, one distal (blood) and one proximal (nasal secretion) useful to perform precision treatments in patients with GBM. REFERENCES 1) Malara, N. et al. Mol Cancer 23, 32 (2024). doi.org/10.1186/s12943-024-01951-x2) Coluccio ML. et al Cancers (2020) doi: 10.3390/cancers12061362.3) Malara, N. et al Front. Oncol.(2021) doi.org/10.3389/fonc.2021.737730

BIOM-10. CLINICAL PERFORMANCE EVALUATION OF A BRAIN CANCER LIQUID BIOPSY

Abstract Diagnostic delays impact the quality of life and survival of patients with brain cancer. Currently, with no blood test to assist them, clinicians must make their referral decision based on symptoms. Existing symptom-based referral guidelines inadequately stratify patients for brain imaging based on suspicion of cancer. A simple, rapid liquid biopsy placed in a primary care setting would enable more efficient triage of patients with non-specific symptoms related to brain cancer. The Dxcover® Liquid Biopsy is a rapid multi-omic liquid biopsy that interrogates a blood sample with infrared radiation and produces a distinctive signature that represents the whole biomolecular profile of the sample, and is sensitive to the hallmarks of brain cancer. The nature of the technology also allows for the diagnostic models to be tailored towards higher sensitivity (or specificity) depending on clinical priorities and international healthcare markets. In initial feasibility studies, we recruited 988 patients prospectively with non-specific symptoms associated with a brain tumor, and the algorithm detected 96% of the patients with brain tumors and 100% of glioblastomas (GBM), when tuned for greater sensitivity. EMBRACE is a prospective, observational, multicenter study, currently recruiting patients across seven sites in the United Kingdom, Belgium, Sweden and Switzerland. The study duration is 24 months and will recruit a minimum of 2200 participants. The target population is comprised of patients presenting to primary care with non-specific symptoms that are associated with brain cancer, such as headache and new onset neurological defect. The primary objective is to determine the clinical performance of the liquid biopsy for patients with brain cancer, in terms of diagnostic sensitivity and specificity. The test performance will be determined by comparing the liquid biopsy result to diagnostic imaging. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain cancer. This simple, non-invasive liquid biopsy would facilitate the triage of brain tumor patients for rapid imaging.