Antigen Levels Research Articles

Automated manufacturing and characterization of clinical grade autologous CD20 CAR T cells for the treatment of patients with stage III/IV melanoma.

Point-of-care (POC) manufacturing of chimeric antigen receptor (CAR) modified T cell has expanded rapidly over the last decade. In addition to the use of CD19 CAR T cells for hematological diseases, there is a growing interest in targeting a variety of tumor-associated epitopes. Here, we report the manufacturing and characterization of autologous anti-CD20 CAR T cells from melanoma patients within phase I clinical trial (NCT03893019). Using a second-generation lentiviral vector for the production of the CD20 CAR T cells on the CliniMACS Prodigy®. We demonstrated consistency in cell composition and functionality of the products manufactured at two different production sites. The T cell purity was >98.5%, a CD4/CD8 ratio between 2.5 and 5.5 and transduction rate between 34% and 61% on day 12 (harvest). Median expansion rate was 53-fold (range, 42-65-fold) with 1.7-3.8×109 CAR T cells at harvest, a sufficient number for the planned dose escalation steps (1×105/kg, 1×106/kg, 1×107/kg BW). Complementary research of some of the products pointed out that the CAR+ cells expressed mainly central memory T-cell phenotype. All tested CAR T cell products were capable to translate into T cell activation upon engagement of CAR target cells, indicated by the increase in pro-inflammatory cytokine release and by the increase in CAR T cell amplification. Notably, there were some interindividual, cell-intrinsic differences at the level of cytokine release and amplification. CAR-mediated T cell activation depended on the level of CAR cognate antigen. In conclusion, the CliniMACS Prodigy® platform is well suited for decentralized POC manufacturing of anti-CD20 CAR T cells and may be likewise applicable for the rapid and automated manufacturing of CAR T cells directed against other targets. https://clinicaltrials.gov/study/NCT03893019?cond=Melanoma&term=NCT03893019&rank=1, identifier NCT03893019.

Unraveling molecular and clinical aspects of ALKBH5 as dual role in colorectal cancer.

This study investigates the dual role of ALKBH5, an eraser enzyme, in colorectal cancer (CRC), focusing on how N6-methyladenosine (m6A) mutations influence CRC development and progression. We reviewed various studies that highlighted the role of ALKBH5 in colorectal cancer (CRC). This includes the impact of ALKBH5 on tumor cell behavior including immune system interactions, invasion, and proliferation in CRC. We also looked into how ALKBH5 acts as a tumor suppressor under different conditions analyzed clinical data to assess the impact of ALKBH5 expression on outcomes in colorectal cancer patients. In CRC, ALKBH5 plays a dual role. In certain situations, it inhibits the progression of the tumor, but in other circumstances, it promotes tumor growth and immunosuppression. The interaction with RABA5 plays a role in the development of CRC. Having elevated levels of ALKBH5 has been associated with unfavorable patient outcomes, such as reduced survival rates and more advanced cancer stages. Various factors, including tumor differentiation, TNM stages, and carcinoembryonic antigen (CEA) levels, be linked to ALKBH5 expression. ALKBH5 plays a complicated and situation-specific role in colorectal cancer (CRC). Targeting ALKBH5 could result in novel therapy options that balance its tumor-promoting and tumor-fighting properties in CRC. Further research into m6A alterations and ALKBH5 could enhance CRC treatment approaches and patient outcomes.

Lifestyle and risk factors associated with elevated prostate-specific antigen levels in rural men: implications for health counseling.

The use of prostate-specific antigen (PSA) for early detection of prostate cancer (PCa) is common but controversial. In rural areas, PSA is widely used for screening because it is convenient and early-stage PCa often shows no symptoms. Studies suggest that PSA levels are linked to factors like unhealthy lifestyles, obesity, lack of exercise, inflammation, and aging. Proper use and interpretation of PSA are crucial for healthcare providers, especially in primary care settings. This study aims to explore the prevalence and factors linked to higher PSA levels in rural men. We conducted a community-based cross-sectional study from March to December 2023 in the western coastal region of Taiwan. Men aged 40-75 years participated, completing a lifestyle questionnaire and providing blood samples for cardiometabolic biomarkers and PSA levels. PSA levels of ≥ 4.0 ng/mL were considered elevated. We used propensity score matching (PSM) and genetic matching (GM) for analysis, followed by regression analysis. In total, 3347 male adults with a mean age of 56.3 years (SD=11.8, range 40-75), and without cancer-related diseases, were enrolled. Findings indicated that 3.9% (n=130) of men aged 40-75 years had a PSA ≥ 4 ng/mL. and many of them did not adopt health-related behaviors, including inadequate servings of vegetables, water intake, and engaging in regular exercise. Furthermore, more than half of the participants had high blood pressure, and over one-quarter exhibited a higher waist-hip ratio and cardiometabolic diseases. After employing propensity score matching (PSM) and genetic matching (GM) with respect to age and education, the multivariate logistic regression model indicated that less water intake (p<0.01), higher waist-hip ratio (> 0.95) (p<0.05), and being diagnosed with cardiometabolic diseases (p<0.05) were significantly associated with a higher serum PSA level. This study revealed that inadequate water intake and obesity related diseases are significant risk factors associated with elevated PSA levels among male adults living in rural areas. It is important for frontline healthcare providers to carefully interpret the meaning of a high PSA level. Additionally, launching a longitudinal study is necessary to further investigate its relation to PCa.

Abstract C060: Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors

Abstract Background: Disparities in prostate cancer (PCa) incidence and mortality persist among African Americans. Functional well-being plays a crucial role in the prognosis and survival of PCa patients. Prior studies show the association between African American race and health-related quality of life among PCa patients. However, no studies have examined possible mediational processes linking race to functional well-being in this population. Objective: To assess the association between race and functional well-being and the mediating pathways of clinical, social determinants, and psychological factors in PCa patients. Methods: We used clinic-based cohort data of PCa patients treated with radical prostatectomy from April 2017 through September 2021. We measured functional well-being, socioeconomic factors, social stressors, perceived stress, and primary and secondary appraisal by self-report. We obtained clinical variables such as disease stage, prostate-specific antigen (PSA) levels, and comorbidities through electronic medical records. We first conducted a path analysis based on linear regression to test the direct association between race and functional well-being, adjusting for age, marital status, education level, employment status, and income. We concurrently examined the mediational pathways linking race to functional well-being via mediators, including stage, PSA, primary appraisal, secondary appraisal, perceived stress, and social isolation. Results: A total of 163 participants (48 African American, 115 White) with a mean age of 66.7 years (SD=6.31) were included in the study. Participants' mean score of functional well-being was 20.32 (SD=6.70; Range=0-28). Compared to White individuals, African American participants exhibited significantly lower levels of functional well-being (b [95% CI] = -3.09 [-5.48, -0.72]). Mediation analyses linking race to functional well-being revealed that, compared to Whites, African Americans displayed significantly lower levels of secondary appraisal (b [95% CI] = -1.45 [-2.85, -0.05]), which, in turn, were associated with higher levels of functional well-being (b [95% CI] = 0.27 [0.01, 0.53]). In addition, African Americans also displayed higher levels of social isolation (b [95% CI] = 0.55 [0.14, 0.97]), which were significantly associated with lower levels of functional well-being (b [95% CI] = -0.91 [-1.64, -0.17]). Both indirect effects of race → secondary appraisal → functional well-being (b [95% CI] = -0.39 [-0.88, -0.01]) and race → social isolation → functional well-being (b [95% CI] = -0.50 [-1.06, -0.02]) were significant and explained 12.6% and 16.2%, respectively, of the total relationship between race and functional well-being. Conclusion: Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors. There is a need to understand the lived experiences of Black men and develop interventions that mitigate the impact of social barriers and psychological stressors on functional well-being to advance health equity. Citation Format: Fatimata Sanogo, Junhan Cho, Trista Beard, Chanita Hughes Halbert. Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C060.

Clinical Value of Dual Tracer PET Imaging With 68Ga-PSMA and 18F-FDG in Patients With Metastatic Prostate Cancer

In this study, we retrospectively analyzed the imaging characteristics of dual-tracer 68Ga-prostate specific membrane antigen (PSMA) and 18F-flurodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in metastatic prostate cancer (mPCa) patients. We analyzed the uptake modes of the dual tracers, explored clinical pathological parameters affecting the 18F-FDG uptake in the lesions, and evaluated their prognostic implications for prostate specific antigen progression-free survival (PSA-PFS). A total of 41 mPCa patients who underwent dual-tracer PET/CT (68Ga-PSMA and 18F-FDG) scans between September 2021 and January 2024 were retrospectively enrolled. One patient had negative uptake of both PSMA and FDG. According to the uptake patterns of the 2 tracers, the other patients, 40 in total, were categorized in 2 groups, including group A consisting of 33 cases who showed PSMA and FDG dual and those who showed FDG only avidity, and group B consisting of 7 cases who showed PSMA avidity only. Comparative analyses of clinical pathological characteristics between group A and group B were conducted. The relationship between various parameters and PSA-PFS was analyzed by the Kaplan-Meier method. A total of 26 patients (63.4%) were diagnosed with metastatic castration-resistant prostate cancer (mCRPC), and 38 cases (92.7%) had a Gleason score of 8-9. Bone metastasis, the predominant type of distant metastasis, occurred in 36 cases (87.8%). The skeletal and distant lymph node metastases mostly showed a dual positive uptake pattern for both PSMA and FDG (85.7% [24/28] and 81.8% [9/11]). 37.5% (3/8) of the metastases to organs showed FDG only positive uptake pattern. The serum levels of prostate specific antigen (PSA) in group A were significantly higher than those in group B (P=0.013). A total of 13 patients of special pathological classification (intraductal carcinoma and neuroendocrine differentiation) were all found to be in group A. Among the 41 cases, 16 were lost to follow-up. Of the 25 patients who completed follow-up, 9 patients, with a median PSA value of 104 ng/mL, experienced PSA progression, while the 16 other patients, with a median PSA of 0.34 ng/mL, did not incur any PSA progression. There was significant difference in the median PSA between patients showing PSA progression and those who did not show PSA progression (P<0.001). Kaplan-Meier survival analysis revealed that the median PSA-PFS of patients of specific pathological classifications was 7 months, which was shorter than the 16 months of the patients with typical prostate cancer, with the difference between the two groups being statistically meaningful (P=0.043). The median PSA-PFS for group A was 30 months. With more than half of the patients in the group not experiencing any PSA progression, group B did not reach the median PSA-PFS (P=0.645). Dual-tracer PET/CT imaging with 68Ga-PSMA and 18F-FDG commonly exhibits avidity for both tracers in mPCa. Serum PSA level is a reliable biomarker for predicting FDG-positive lesions. mPCa presented with intraductal carcinoma and neuroendocrine differentiation tends to exhibit FDG avidity and is more susceptible to PSA progression.

Evaluation of a semi-automated test for quantification of von Willebrand multimers

The assessment of von Willebrand factor (VWF) multimer distribution, particularly following the implantation of circulatory support devices, is a crucial parameter in hemostasis. Our study aimed to evaluate the semi-automated quantification of VWF multimers using the Sebia Hydrasys analyzer. Our analysis focused on quantifying high molecular weight, intermediate weight, and low molecular weight VWF multimers. Electrophoretic migration was performed using the Hydrasys 2 scan, and interpretation was carried out using densitometric analysis with the Phoresis software. The Hydrasys scan 2 successfully separated all the expected VWF multimer profiles based on the type of von Willebrand disease. The analysis revealed that in patients with circulatory support devices, elevated levels of plasma VWF rendered multimer migration unanalyzable using the methodology recommended by the manufacturer. Therefore, adjustment to a 100% VWF antigenic level improved gel precision. We also suggest using as a standardized control the Cryocheck™ plasma, and have established reference values. Overall, this semi-automated, standardized, and optimized VWF multimer analysis system allows for an effective assessment of the VWF multimeric profile.

Adult Uterine Wilm’s Tumor Miss-interpreted as Carcinosarcoma: A Case Report

Introduction: Wilm’s tumor (WT) is a common renal malignancy in children. Adult extrarenal WT involving the uterus is extremely rare. Herein, we reported a case of uterine WT in an old woman who was primarily diagnosed with carcinosarcoma. Case Presentation: A 63-year-old woman presented with abdominal pain and radiologic evidence of pelvic mass originating from the uterus, which was suggestive of sarcoma. Her Serum levels of Cancer Antigen 125 (CA125), Human Epididymis protein 4 (HE4), Cancer Antigen 19-9 (CA19-9), and Alpha Fetoprotein (AFP) were found to be elevated. She underwent total hysterectomy, bilateral salpingo-oophrectomy, and omentectomy. Pathologic examination of the specimens revealed a large uterine mass with serosal surface and omental invasion. The initial diagnosis was carcinosarcoma based on the mixed epithelial and mesenchymal components observed on microscopic examination. Triphasic components of papillary, primitive tubules, and glomeruloid structures, along with mesenchymal and blastemal elements were identified upon second opinion. An immunohistochemistry (IHC) study revealed positive reactions for WT1, CKAE1 /AE3, EMA, Glypican-3, and CD56 in all components of the tumor cells. P53 expression was normal. GATA3, ER, PR, and CD10 were negative. The final diagnosis was changed to WT. Conclusions: Uterine WT is an extremely rare malignancy, which could be associated with elevated serum AFP. Diagnosis and treatment of these rare tumors pose challenges for both pathologists and clinicians.

A single-center retrospective review of metastatic prostate cancer on PSMA position emission tomography/computed tomography: Beyond lymph nodes and bones.

Prostate-specific membrane antigen (PSMA) Positron emission tomography/computed tomography (PET/CT) has become a crucial imaging modality for the staging of patients with prostate cancer. The purpose of this study is to retrospectively determine the frequency, anatomical distribution, and clinical-pathologic correlates of extra-nodal and extra-osseous metastatic prostate cancer detected on PSMA PET/CT. All available 650 PSMA PET/CT performed in patients with biopsy-proved prostate cancer in our institution between September 2021 and December 2023 were reviewed for the presence of extra-nodal and extra-osseous metastatic disease (M1C disease). Thirty-four patients with M1C disease were identified. The most frequent sites of visceral/soft tissue metastases were the lungs (58.8%), liver (23.5%) and adrenal glands (20.6%). 75% of patients with lung metastases detected on PSMA PET/CT had concurrent intrathoracic lymph node involvement. A higher frequency of patients with M1C disease (55.9%) had a high Gleason score. The median prostate-specific antigen (PSA) level at the time of the PSMA scan was 20.16 ng/mL. There was a statistically significant association between PSA level and osseous disease (p = 0.004), as well as PSA level and nodal disease (p = 0.008). While a large number of patients had concurrent osseous and nodal disease (82.4% and 79.4%, respectively), no visceral/soft tissue sites demonstrated a significant association with the presence of osseous or nodal involvement. Given the increasing utilization of PSMA PET/CT, increased knowledge of the location and pattern of distribution of visceral/soft tissue metastatic sites is crucial not only for staging but also to better understand patterns of therapeutic response. We identified the lungs, liver and adrenal glands as the most common visceral/soft tissue metastatic sites from prostate cancer. We found that higher PSA levels at the time of PSMA PET/CT imaging were positively associated with concurrent osseous and nodal involvement.

High serum growth differentiation factor 15 is a risk factor for the occurrence of hepatocellular carcinoma in chronic hepatitisB patients treated with nucleos(t)ide analogs.

Patients with chronic hepatitisB (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitisB virus (HBV) RNA, hepatitis B core-related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitisC. We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15. Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB-4 index, alpha-fetoprotein and gamma-glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0ng/mL, gamma-glutamyl transpeptidase ≥22U/L, FIB-4 index≥1.93, and GDF-15≥1.17ng/mL groups. In patients with no or more than three of these five risk factors, the 10-year HCC cumulative incidence rates were 0% and 41.0%, respectively. High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs.

Autoantibodies to ADAMTS13 in human immunodeficiency virus-associated thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal thrombotic microangiopathic disorder that can result from human immunodeficiency virus (HIV) infection. The pathogenesis involves a deficiency of the von Willebrand factor (vWF) cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs member 13) and the presence of anti-ADAMTS13 autoantibodies. However, there is insufficient information regarding the epitope specificity and reactivity of these autoantibodies. This study aimed to perform epitope-mapping analysis to provide novel insights into the specific epitopes on ADAMTS13 domains affected by autoantibodies. The study analysed 59 frozen citrate plasma samples from HIV-associated TTP patients in South Africa, measuring ADAMTS13 activity using Technozyme® ADAMTS13 activity test, total immunoglobulin (Ig) M and IgA antibodies levels using ELISA kit and purifying IgG antibodies using NAb™ Protein G spin columns. A synthetic ADAMTS13 peptide library was used for epitope mapping. Overall, 90% of samples showed anti-ADAMTS13 IgG autoantibodies, with 64% of these antibodies being inhibitory, as revealed by mixing studies. Samples with ADAMTS13 antigen levels below 5% showed high anti-ADAMTS13 IgG autoantibody titres (≥50 IU/mL), whereas those with 5%-10% levels had low autoantibody titres (<50 IU/mL).The metalloprotease, cysteine-rich and spacer domains were 100% involved in binding anti-ADAMTS13 IgG antibodies, with 58% of samples containing antibodies binding to the C-terminal part of the ADAMTS13 disintegrin-like domain, indicating different pathogenic mechanisms. The metalloprotease, cysteine-rich and spacer domains are the primary targets for anti-ADAMTS13 IgG autoantibodies in patients with HIV-associated TTP. These findings suggest potential effects on the proteolytic activity of ADAMTS13, highlighting the complex nature of the pathogenic mechanisms involved.

Genetically defined causal effects of natural killer cells related traits in risk of infection: a Mendelian randomization study

BackgroundThe intricate interplay between genetics and immunology often dictates the host’s susceptibility to various diseases. This study explored the genetic causal relationship between natural killer (NK) cell-related traits and the risk of infection.MethodsSingle-nucleotide polymorphisms (SNPs) significantly associated with NK cell-related traits were selected as instrumental variables to estimate their genetic causal effects on infection. SNPs from a genome-wide association study (GWAS) on NK cell-related traits, including absolute cell counts, median fluorescence intensities reflecting surface antigen levels, and relative cell counts, were used as exposure instruments. Summary-level GWAS statistics of four phenotypes of infection were used as the outcome data. The exposure and outcome data were analyzed via the two-sample Mendelian randomization method.ResultsEach one standard deviation increase in the expression level of human leukocyte antigen (HLA)-DR on HLA-DR+ NK cells was associated with a lower risk of pneumonia (P < 0.05). An increased HLA-DR+ NK/CD3− lymphocyte ratio was related to a lower of risk of pneumonia (P < 0.05). Each one standard deviation increase in the absolute count of HLA-DR+ NK cells was associated with a lower risk of both bacterial pneumonia and pneumonia (P < 0.05). An increased HLA-DR+ NK/NK ratio was associated with a decreased risk of both pneumonia and bacterial pneumonia (P < 0.05). The results were robust under all sensitivity analyses. No evidence for heterogeneity, pleiotropy, or potential reverse causality was detected. Notably, our analysis did not reveal any significant associations between NK cell-related traits and other phenotypes of infection, including cellulitis, cystitis, and intestinal infection.ConclusionsHLA-DR+ NK cells could be a novel immune cell trait associated with a lower risk of bacterial pneumonia or pneumonia.

Leveraging cell death patterns to predict metastasis in prostate adenocarcinoma and targeting PTGDS for tumor suppression

Metastasis is the major cause of treatment failure in patients with prostate adenocarcinoma (PRAD). Diverse programmed cell death (PCD) patterns play an important role in tumor metastasis and hold promise as predictive indicators for PRAD metastasis. Using the LASSO Cox regression method, we developed PCD score (PCDS) based on differentially expressed genes (DEGs) associated with PCD. Clinical correlation, external validation, functional enrichment analysis, mutation landscape analysis, tumor immune environment analysis, and immunotherapy analysis were conducted. The role of Prostaglandin D2 Synthase (PTGDS) in PRAD was examined through in vitro experiments, single-cell, and Mendelian randomization (MR) analysis. PCDS is elevated in patients with higher Gleason scores, higher T stage, biochemical recurrence (BCR), and higher prostate-specific antigen (PSA) levels. Individuals with higher PCDS are prone to metastasis, metastasis after BCR, BCR, and castration resistance. Moreover, PRAD patients with low PCDS responded positively to immunotherapy. Random forest analysis and Mendelian randomization analysis identified PTGDS as the top gene associated with PRAD metastasis and in vitro experiments revealed that PTGDS was considerably downregulated in PRAD cells against normal prostate cells. Furthermore, the overexpression of PTGDS was found to suppress the migration, invasion, proliferationof DU145 and LNCaP cells. To sum up, PCDS may be a useful biomarker for forecasting the possibility of metastasis, recurrence, castration resistance, and the efficacy of immunotherapy in PRAD patients. Additionally, PTGDS was identified as a viable therapeutic target for the management of PRAD.

Combined KRAS and TP53 mutation in patients with colorectal cancer enhance chemoresistance to promote postoperative recurrence and metastasis

The response of patients with colorectal cancer to chemotherapy is tightly correlated with their genomic variation. Among these, APC, TP53, KRAS, PIK3CA are the most frequently mutated genes in advanced colorectal cancer patients. However, the precise correlation between these mutations and the therapeutic effects of chemotherapy remains elusive. Here, we conducted genome sequencing to identify commonly mutated genes in colorectal cancer patients and comprehensively assessed their sensitivity to chemotherapy drugs by monitoring computer tomography (CT) scans and carcinoembryonic antigen (CEA) levels. Surprisingly, we discovered that the objective response rate to the standard first-line chemotherapy among patients harboring combined KRAS and TP53 mutations is dismal, and these patients are predisposed to recurrence and metastasis. Furthermore, advanced-stage patients with concurrent KRAS and TP53 mutations are susceptible to developing cancer-associated cachexia due to chemotherapy resistance or forced cessation of treatment. Our findings underscore the urgent need for the development of innovative and novel chemotherapeutic strategies to effectively manage colorectal cancer patients harboring combined KRAS and TP53 mutations.

Ipilimumab with nivolumab in molecularly selected patients with castration-resistant prostate cancer: primary analysis of the phase II INSPIRE trial

Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC. This single-arm, phase II trial included 69 molecularly selected mCRPC patients with mismatch repair deficiency (dMMR), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST 1.1 (A1) and Prostate Cancer Working Group 3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR > 6), aiming to surpass a DCR > 6 of 22%. Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had dMMR (32%), 8 had hTMB (12%), 20 had BRCAm (31%), and 16 had CDK12i (25%). DCR > 6 was achieved in 38% of patients [95% confidence interval (CI) 27% to 51%], and was highest in dMMR (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective response rate in cohort A was 38% (95% CI 22% to 55%) and 47% (95% CI 34% to 60%) exhibited a 50% decline in prostate-specific antigen levels. Median progression-free survival (PFS) was 4.0 months (95% CI 3.5-12.0 months) in cohort A, and 32.7 months (95% CI 21.8 months-not reached) in dMMR patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity. This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR > 6 in 38% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm, and CDK12i subgroups, but demonstrated exceptional efficacy in dMMR.

Abstract B015: Duodenal aspiration biopsy in diagnosis of pancreatic neoplasms

Abstract Introduction Intraductal papillary mucinous neoplasms (IPMNs) are a subset of lesions with elevated malignant potential, warranting their inclusion in screening standards. Despite endoscopic ultrasound (EUS) with fine-needle aspiration biopsy (FNAB) serving as the standard for verification, the occurrence of erroneous conclusions remains significant. Consequently, analysis of pancreatic juice is considered as a potential adjunctive diagnostic method. However, the absence of methods for obtaining pancreatic juice in adequate volume and quality poses a barrier to the widespread adoption of this approach.Materials and MethodsA method of duodenal aspiration biopsy (DAB) was developed involving active aspiration from the lumen of duodenum, yielding large volume of the mix of pancreatic juice and bile uncontaminated by gastric juice. Patients diagnosed with pancreatic neoplasms utilizing EUS with FNAB, were enrolled and ALB was implemented as an adjunctive diagnostic procedure. Cytological analysis of the material obtained was performed along with measuring the level of carcinoembryonic antigen (CEA). The level &amp;gt;192 ng/mL was considered significant, according to the Fukuoka 2017 guidelines.ResultsIn patients with cystic neoplasms of the pancreas undergoing DAB, results of cytological examination were non-informative in certain cases. However, analysis of CEA levels in the pancreatic juice and bile mixture always demonstrated strong concordance with the degree of dysplasia. In some instances, elevated CEA values facilitated the adoption of a more aggressive treatment strategy, leading to the detection of carcinoma. Conversely, low CEA levels prompted the decision to opt for observation rather than radical surgery in other cases.ConclusionDiagnosing precancerous transformations of the pancreas remains a challenging task, characterized by a notable rate of false-positive or false-negative conclusions. The DAB method offers a promising solution, seamlessly integrating into routine clinical practice and offering supplementary data to enhance the verification of pancreatic cancer. Citation Format: Aleksei Kashintsev, Vitali Proutski. Duodenal aspiration biopsy in diagnosis of pancreatic neoplasms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B015.

Predicting prognosis for epithelial ovarian cancer patients receiving bevacizumab treatment with CT-based deep learning

Epithelial ovarian cancer (EOC) presents considerable difficulties in prognostication and treatment strategy development. Bevacizumab, an anti-angiogenic medication, has demonstrated potential in enhancing progression-free survival (PFS) in EOC patients. Nevertheless, the identification of individuals at elevated risk of disease progression following treatment remains a challenging task. This study was to develop and validate a deep learning (DL) model using retrospectively collected computed tomography (CT) plain scans of inoperable and recurrent EOC patients receiving bevacizumab treatment diagnosed between January 2013 and January 2024. A total of 525 patients from three different institutions were retrospectively included in the study and divided into training set (N = 400), internal test set (N = 97) and external test set (N = 28). The model’s performance was evaluated using Harrell’s C-index. Patients were categorized into high-risk and low-risk group based on a predetermined cutoff in the training set. Additionally, a multimodal model was evaluated, incorporating the risk score generated by the DL model and the pretreatment level of carbohydrate antigen 125 as input variables. The Net Reclassification Improvement (NRI) metric quantified the reclassification performance of our optimal model in comparison to the International Federation of Gynecology and Obstetrics (FIGO) staging model. The results indicated that DL model achieved a PFS predictive C-index of 0.73 in the internal test set and a C-index of 0.61 in the external test set, along with hazard ratios of 34.24 in the training set (95% CI: 21.7, 54.1; P < 0.001) and 8.16 in the internal test set (95% CI: 2.5, 26.8; P < 0.001). The multimodal model demonstrated a C-index of 0.76 in the internal test set and a C-index of 0.64 in the external test set. Comparative analysis against FIGO staging revealed an NRI of 0.06 (P < 0.001) for the multimodal model. The model presents opportunities for prognostic assessment, treatment strategizing, and ongoing patient monitoring.

Evaluating Prostate Cancer: The Diagnostic Impact of MRI and Its Relationship With Transrectal Ultrasound (TRUS)-Guided Biopsy.

Background Prostate disorders, including benign enlargement and malignancy, are commonly evaluated through imaging techniques. Historically, transrectal ultrasound (TRUS) has been used for prostate imaging and biopsy. However, multiparametric MRI (mpMRI), which integrates structural and functional imaging methods, offers enhanced diagnostic capabilities. This study evaluates the effectiveness of mpMRI, including its grading via Prostate Imaging - Reporting and Data System (PI-RADS) or Likert scoring, in distinguishing between benign and malignant prostatic conditionsand compares these findings with TRUS outcomes. Methodology This prospective study enrolled 30 male patients aged 45 to 75 years (mean age 60 years), selected based on prostatic abnormalities, elevated prostate-specific antigen (PSA) levels (>4 ng/dL), or palpable nodules detected via digital rectal examination. MRI, including PI-RADS or Likert scoring, was utilized to assess prostatic lesions, and results were compared with histopathological data obtained from TRUS-guided biopsies. Results Among the 30 patients, common symptoms included urinary retention (60%) and painful urination (53.3%). Malignant tumors were diagnosed in 12 patients (40%). MRI identified eight cases with enlarged transitional zones and irregular signals in peripheral zones (benign prostatic hyperplasia with tumor)and four cases with irregular signals in both zones (sarcoma). Concordance between MRI T2-weighted (T2W) observations and biopsy results showed 60% malignancy detection. Sensitivity assessments revealed MRI detected 15 true-positives (50%), TRUS detected six true positives (20%), and multivoxel spectroscopic analysis (MVS) identified 14 true-positives (46.7%). PI-RADS or Likert scoring of mpMRI was correlated with TRUS outcomes, highlighting its enhanced diagnostic accuracy compared to TRUS alone. Conclusion While TRUS remains a standard diagnostic tool, it is limited by significant sampling errors and complications. The integration of mpMRI, with its grading system, significantly improves diagnostic accuracy and treatment planning. Although mpMRI alone has limitations, its combination with contrast-enhanced MRI, diffusion-weighted imaging, and MR spectroscopy offers a comprehensive approach to enhanced prostate cancer detection.

Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation.

T cell receptor (TCR) sensitivity to peptide-major histocompatibility complex (MHC) dictates T cell fate. Canonical models of TCR sensitivity cannot be fully explained by transcriptional regulation. In this work, we identify a posttranscriptional regulatory mechanism of TCR sensitivity that guides alternative splicing of TCR signaling transcripts through an evolutionarily ultraconserved poison exon (PE) in the RNA-binding protein (RBP) TRA2β in mouse and human. TRA2β-PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. Tra2β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, Tra2β-PE reinclusion allowed T cell survival. Finally, we found that TRA2β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that TRA2β-PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.

HBcrAg values may predict virological and immunological responses to pegIFN-α in NUC-suppressed HBeAg-negative chronic hepatitis B

ObjectiveSelected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess...

Gut Dysbiosis in Patients With Fontan Circulation.

The process underlying Fontan pathophysiology is multifactorial and may include gut dysbiosis (GD). We investigated the presence of GD and elucidated its correlation with Fontan pathophysiology. Gut microbiomes of 155 consecutive patients with Fontan pathophysiology and 44 healthy individuals were analyzed using 16S rRNA sequencing of bacterial DNA extracted from fecal samples. GD was evaluated on the basis of α and ß diversities of the gut microbiome and was compared with natural log-transformed C-reactive protein, hemodynamics, von Willebrand factor antigen (a bacterial translocation marker), Mac-2 binding protein glycosylation isomer (a liver fibrosis indicator), peak oxygen uptake, and heart failure hospitalization. Patients with Fontan exhibited GD in terms of α and ß diversities as compared with controls (P<0.01). Reduced α diversity was associated with a failed hemodynamic phenotype, hypoxia, high natural log-transformed C-reactive protein levels, and elevated von Willebrand factor antigen and Mac-2 binding protein glycosylation isomer levels (P<0.05-0.01). In addition to elevated von Willebrand factor antigen and hypoxia, decreased α diversity was independently correlated with a high natural log-transformed C-reactive protein level (P<0.05), which was associated with liver imaging abnormalities and a heightened risk of heart failure hospitalization (P<0.01 for both). Patients with Fontan pathophysiology exhibited GD compared with healthy individuals, and GD was linked to failed hemodynamics and systemic inflammation with a poor prognosis. Therefore, GD may play a pivotal role in a failing Fontan status, including Fontan-associated liver disease, through GD-associated systemic inflammation.