PC Patients Research Articles

Post-COVID-19 syndrome, who at risk and why: an insight from Qatar 2022

BackgroundDespite the recovery from the COVID-19 pandemic, many people experience post-COVID-19 syndrome, which negatively impacts their health and function. This condition has become a significant public health problem that requires immediate attention.ObjectiveTo study the prevalence, clinical characteristics, and predictors of post-COVID-19 Syndrome in Qatar during 2022.MethodsAn analytic cross-sectional study was conducted among COVID-19 confirmed cases from January 2022 to July 2022 in Qatar. A simple random sample was employed to include (n = 588) participants from the list of cases and invited to participate in a telephone survey. The World Health Organization’s standard case definition for PCS was adopted.ResultsOut of 368, the prevalence of post-COVID-19 syndrome was 43.2% (n = 159). Most PCS cases were females (67.9%; n = 108), married (73.6%; n = 117), and university and higher educational level (83.6%; n = 133). However, 78.7% (n = 125) reported poor to moderate levels of social support. Only 30.2% (n = 48) of PCS patients had a history of chronic diseases, and 5.7% (n = 9) required hospital admission during acute illness. Among PCS cases, the most commonly reported symptoms were fatigue (75.5%), followed by anxiety (49.1%), forgetfulness (46.5%), mood alteration (45.3%), and general weakness (39.6%). The logistic regression revealed that female gender (AOR: 2.58 95%CI: 1.58–4.225, p < 0.0001), university and high educational level (AOR: 2.2, 95%CI: 1.256–3.98, p < 0.006), poor level of social support (AOR: 2.45; 95%CI: 1.55–4.13; p < 0.002), were significant predictors for PCS.ConclusionPost-COVID-19 syndrome may go under-recognized. More efforts are needed to raise awareness and mobilize the resources to respond to this ongoing public health problem.

Estimating cost of prostate cancer management: an experience from Tanzania

BackgroundProstate cancer (PC) is a significant public health problem affecting men worldwide and ranks third in incidence and mortality in East Africa. Cost of prostate cancer management is high in low-income countries because majority of patients presents with advanced (metastatic) PC. The cost related to management of PC including castrate resistant cancer in Tanzania has remained unknown; hence, policy makers do not have enough information for planning and resource allocation. This study therefore aimed to document costs related to the management of patients with prostate cancer including castrate resistant prostate cancer (CRPC) at Muhimbili National Hospital in Tanzania.MethodsThis was a retrospective descriptive hospital-based study which was conducted at Muhimbili National Hospital (MNH). Case notes of patients who were treated for prostate cancer were retrieved from medical records for review. A structured checklist was used to extract information regarding age, clinical presentation, investigations, stage of disease, type of treatment, payment modality and reimbursement. We considered data on the direct costs of prostate cancer management (diagnosis, treatment and follow-up) based on hospital price list of different categories. Costs reported were based on payment category in total and unit cost but also source of funding. Descriptive statistics were prepared and summarized as tables and figures.ResultsA total of 292 case notes of patients with prostate cancer were reviewed of which 189 patients received androgen deprivation therapy. Ninety-six (50.8%) met the criteria for the diagnoses of CRPC, and their mean age was 71.23 ± 4.2. Most of the patients had a poorly differentiated histology with prostate-specific antigen (PSA) over 100 ng/l. Bilateral orchiectomy was the most common treatment modality offered for advanced prostate cancer. Total cost for all PC patients was $148,136.4, equivalent to a unit cost per patient of $507.3. However, patients were in different categories of payment, 53% were public patients with an average cost of $471.3 per patient; 36.6% were cost sharing patients with an average cost of $441.8 per patient; 8.2% were National Health Insurance (NHIF) patients with an average cost of $893.8 per patient; and only 2.2% were private patients with an average cost of $1060.9 per patient.ConclusionCosts related to prostate cancer management need harmonization to accommodate different categories of patients in need.

Abstract 3725: Exosomal Galactin-3 promotes pre-metastatic niche formation that accelerates peritoneal metastases of gastric adenocarcinoma

Abstract Peritoneal carcinomatosis (PC) in gastric adenocarcinoma (GAC) lead to a short median survival (≤6 months). Pre-metastatic niche (PMN) formation, in a distant organ to prepare for tumor seeding and colonization, has long been recognized. However, the precise molecular and mechanistic contributions of exosomes in PMN formation of PC remain unclear. We identify that exosomes promote PMN formation in the peritoneal cavity by patient-derived orthotopic mouse model. Using an in-depth proteomic profiling of paired ascites cells and ascites-derived exosomes from PC patients, we discover that Galectin-3 as the exosomal payload is responsible for PC by promoting PMN formation in both patient-derived orthotopic model and syngeneic mouse model. Inhibition of exosomal Galectin-3 reverses PC. Furthermore, exosomal Galectin-3 activates cancer-associated fibroblasts (CAFs), which further activate the CXCL12/CXCR4 axis to orchestrate the immunosuppressive PMN. Simultaneous inhibition of exosomal Galectin-3, CXCR4, and PD-1 leads to tumor regression and durable anti-tumor responses. Thus, this study provides a rationale for the novel clinical strategy for GAC patients with PC. Citation Format: Yibo Fan, Shumei Song, Melissa Pool Pizzi, Katsuhiro Yoshimura, Jody V. Vykoukal, Samir Hanash, Jaffer Ajani. Exosomal Galactin-3 promotes pre-metastatic niche formation that accelerates peritoneal metastases of gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3725.

Abstract 6265: FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors

Abstract Parathyroid carcinoma (PC) is rare, poses challenges in definitive diagnosis and treatment, and carries a high rate of recurrence and mortality. Atypical parathyroid tumors (APT) have histopathologic features of malignancy but lack unequivocal evidence of invasion and are of uncertain malignant potential. Analysis of genetic alterations that may play a role in PC development, particularly those that might serve as markers of malignant potential, is important for further understanding this disease. FLCN is a gene found on chromosome 17 that encodes folliculin, a ubiquitously expressed protein with roles in multiple cellular processes such as apoptosis and cell signaling. Inactivating FLCN mutations cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant condition characterized by benign fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, and increased risk of renal cancer. Benign parathyroid tumors had previously been reported in a few BHD patients and recently one study has reported a link between FLCN mutations and parathyroid carcinoma. Germline frameshift mutations in FLCN, accompanied by somatic loss of the normal allele, were reported in two unrelated PC patients, both with clinical features suggestive of BHD, but no established diagnosis of BHD. An identical somatic frameshift FLCN mutation was reported in one PC and one APT. Interestingly, the authors noted low coverage of FLCN on whole exome sequencing, resulting in the failure to detect variants identified by Sanger sequencing, thus raising the possibility that prior studies may have missed FLCN variants. To better understand the frequency of germline or somatic FLCN mutations in PC and APT, we performed Sanger sequence analysis of the entire coding region of the FLCN gene on available tumor DNA from 11 PCs and 15 APTs. We identified no inactivating FLCN mutations in any of the PC or APT samples examined. A germline missense variant, resulting in a p.Gly325Val change, predicted to be benign/tolerated by in silico analyses, was seen in one PC and a synonymous variant (c.1233G>A) was seen in one APT. The absence of pathogenic mutations in our series parathyroid carcinoma and atypical parathyroid tumors suggests that FLCN mutations are rare in these parathyroid tumors. Nevertheless, germline FLCN testing and/or additional screening for BHD-related lesions in parathyroid carcinoma patients merits further consideration and study. Citation Format: Callie Burke, Justin Bellizzi, Jessica Costa-Guda, Andrew Arnold. FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6265.

Abstract 4369: CYP3A5 promotes aggressive and therapeutically resistant prostate cancer by modulating AR and Wnt signaling: Implications for racially disparate clinical outcomes

Abstract Prostate cancer (PC) is the second leading cause of cancer-related death in American men, which disproportionately affects Black/African American (AA) men. The androgen receptor (AR) signaling plays a pivotal role in PC development and is a primary target for intervention in patients with advanced disease. Aberrant activation of AR is also suggested to play a significant role in castration-resistant prostate cancer (CRPC). Despite advancements in anti-androgen therapies with new targeting agents, such as enzalutamide, metastatic CRPC (mCRPC) remains incurable. CYP3A5, a monooxygenase expressed in the prostate, liver and intestine, is involved in drug metabolism and steroid biosynthesis. We earlier reported that intratumoral CYP3A5 activated AR signaling by facilitating its nuclear translocation of AR. More notably, we found a higher CYP3A5 expression in AAs, attributed to the *1 CYP3A5 variant, as compared to non-Hispanic White Americans (NHWA) possessing the *3 variant. Analysis of RNA-seq data using patient tumor samples revealed that elevated CYP3A5 in AA PC patients was associated with Wnt-β catenin signaling activation via TCF4 overexpression. Here, we investigated the role of CYP3A5 in enzalutamide resistance and Wnt signaling by generating enzalutamide-resistant PC cell lines of NHWA (low CYP3A5-LNCaP) and AA-origin (high CYP3A5-MDAPCa2b). RT-qPCR assay was used to examine the changes in AR and CYP3A5 expression between the parental and the enzalutamide-resistant cell lines. The data show heightened CYP3A5 expression in enzalutamide-resistant cells of AA origin (MDAPCa2b/EnzR) but not of NHWA origin (LNCaP/EnzR). Interestingly, MDAPCa2b/EnzR exhibited no change in AR levels whereas it was increased in LNCaP/EnzR cells relative to parental lines. A loss of function assay was performed for siRNA-mediated silencing of CYP3A5 to study its effect on Wnt signaling. RNA sequencing results show that CYP3A5 inhibition in MDAPCa2b downregulated Wnt pathway genes (Wnt5A, Wnt10B, Wnt11, Fzd2, and Dvl3). These observations align with our previous RNA seq results using patient samples where we observed upregulated Wnt-β catenin signaling in high CYP3A5 expressing patient tumor samples. Western analysis post-CYP3A5 inhibition in LNCaP and MDAPCa2b cells revealed upregulated Axin and downregulated LRP6 and Dvl-3, signifying CYP3A5's regulation of the canonical Wnt-β catenin pathway. Additionally, MDAPCa2b saw downregulated Wnt 5A and Wnt 10B, known to influence the Wnt non-canonical pathway. Altogether, our data suggest that *1 CYP3A5 variant in AAs likely contributes to aggressive behavior and therapeutic resistance of PC and serves as a molecular determinant of disparate clinical outcomes. Citation Format: Jake McLean, Ajay P. Singh, Edwin Oh, Ranjana Mitra. CYP3A5 promotes aggressive and therapeutically resistant prostate cancer by modulating AR and Wnt signaling: Implications for racially disparate clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4369.

Abstract 6205: Identify drugs for metastatic castration-resistance prostate cancer (mCRPC) patients with high glycolytic activity through in silico approach

Abstract Prostate cancer (PC) remains a prominent cause of cancer-related mortality among men in the United States. A significant factor contributing to the mortality of PC patients is the development of resistance to second-generation antiandrogen therapies, particularly androgen receptor-signaling inhibitors (ARSI), which is pronounced in patients with late-stage PC, metastatic castration-resistance prostate cancer (mCRPC). Therefore, there is an urgent need for novel therapeutics beyond AR signaling inhibition for patients with mCRPC. One of the key drivers of resistance to ARSI and a critical feature of CRPC is cancer metabolism reprogramming to elevated glycolysis. However, the current research on finding drugs to impede high-glycolytic tumor growth is hurdled by a resistance raised from metabolic plasticity. The aim of this research is to quickly repurpose existing drugs for inhibiting high-glycolytic mCRPC growth while proactively circumstancing resistance from metabolic plasticity through computational approaches. To do this, we imputed a large number of drug responses in patients with mCRPC using a computational algorithm (OncoPredict), identified drugs that were projected to show higher sensitivity in high-glycolytic tumors, and performed in vitro validation. Furthermore, to maximize drug efficacy, we identified biomarkers for drug candidates. By implementing this computational pipeline, we identified a number of drugs with various mechanisms of action that show higher efficacy in mCRPC with high glycolysis. Furthermore, we successfully validated the efficacy of these nominated drug candidates including an anti-parasitic agent, an HSP90 inhibitor, and a CDK inhibitor. These drug candidates exhibited superior tumor growth inhibition in in vitro models of high glycolysis-induced advanced PC. In conclusion, this study introduces an innovative in silico approach to unveil the existing drugs’ unknown potential for the treatment of patients with mCRPC. Our findings hold promise for development of effective therapeutics for combating this challenging disease. Citation Format: Mei-Chi Su, Adam M. Lee, R. Stephanie Huang. Identify drugs for metastatic castration-resistance prostate cancer (mCRPC) patients with high glycolytic activity through in silico approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6205.

Abstract 7202: Strategy of targeting PKCβΙ protein to overcoming the acquired gemcitabine resistant pancreatic cancer cells

Abstract Pancreatic cancer (PC) is one of the most malignant cancers with limitation of treatment options such as resection surgery, radiation therapy and gemcitabine-based chemotherapy. To treating PC patients, gemcitabine-based chemotherapy is common and effective for PC, acquired gemcitabine resistance is one of the major reasons for treatment failure. Therefore, there is a need to suggest effective strategies and novel therapeutic approach for gemcitabine-resistant PC. Protein Kinase C β1 (PKC β1) is known as involved in multiple signal transduction related to oncogenic functions in cancer. We suggested that PKC β as one of the novel biomarker of drug resistance and further investigated the molecular mechanism. Among the natural products as small molecule inhibitor, we found that evodiamine has potent antitumor activity and various biological activities. Based on various biological activities of evodiamine, the scaffold was synthesized and investigated for antiproliferative and antitumor activities against gemcitabine resistant PANC-1 (PANC-GR) cells. Also, target validation experiment was employed to elucidate the molecular mechanism and verifying the target to overcoming gemcitabine resistance. Mechanistically, evodiamine derivatives have shown that inhibition of PKC β1 can modulate the proliferation of PANC-GR cells and exhibited tumor growth inhibitory activity in xenograft mouse model. Keywords: Pancreatic cancer cell, Gemcitabine resistance, Protein Kinase C β1 (PKC β1), Molecular mechanism Acknowledgements: This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (RS-2023-00273240). Citation Format: EunSeo Bae, Yijae Lim, Junhwa Hong, Woong Sub Byun, Simin Chun, Suckchang Hong, Sang Kook Lee. Strategy of targeting PKCβΙ protein to overcoming the acquired gemcitabine resistant pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7202.

Abstract 5270: Androgen receptor blockade in macrophages primes NLRP3 inflammasome-mediated phagocytosis and tumor clearance in advanced prostate cancer

Abstract Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor-associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Our single-cell RNA sequencing analysis in human tumors revealed that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is differentially expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT), relative to other tumor types and untreated primary PC. Furthermore, bulk RNA sequencing analysis in human mCRPC samples revealed an inverse relationship between NLRP3 expression and AR activity, with high NLRP3 expression associated with an M1 signature and a favorable clinical response to ICI in mCRPC. Based on these findings, we hypothesized that androgen axis blockade could enhance NLRP3 expression and potentiate innate immune tumor control in advanced PC. Critically, we discovered that blockade of TAM-intrinsic androgen receptor (AR) activity enhanced NLRP3 expression, but not inflammasome activity in the immunosuppressive (M2) TAM. In contrast, anti-tumor (M1) TAM exhibited high de novo NLRP3 expression, regardless of AR activity. The combination of AR blockade and NLRP3 agonism significantly enhanced phagocytosis of cancer cells by M2 TAM, whereas NLRP3 agonist treatment alone was sufficient to induce phagocytosis in M1 TAM. Following AR blockade/NLRP3 agonist combination treatment, all TAM acquired a distinct phenotype with high PD-L1 and CD86 expression, indicative of phagocytic TAM. Critically, NLRP3 agonism in combination with ADT resulted in significant tumor control in an aggressive c-myc driven advanced PC model, with 55% of mice achieving complete tumor clearance, which was abrogated by concurrent clodronate treatment (which systemically depletes phagocytic macrophages), thus demonstrating TAM-mediated phagocytosis enhancement as a major driver of the observed anti-tumor response. Collectively, our results identify NLRP3 as an AR-regulated “macrophage phagocytic checkpoint” that can be inducibly expressed and activated in TAM following ADT and NLRP3 agonist treatment, respectively, the combination resulting in TAM-mediated phagocytosis and tumor control. Citation Format: Kiranj Chaudagar, Srikrishnan Rameshbabu, Shenglin Mei, Taghreed Hirz, Ya-Mei Hu, Anna Argulian, Brian Labadie, Kunal Desai, Sam Grimaldo, Doga Kahramangil, Rishikesh Nair, Sabina DSouza, Dylan Zhou, Raymond Chen, Jordan Shafran, Mayme Loyd, Zheng Xia, David Sykes, Amy Moran, Akash Patnaik. Androgen receptor blockade in macrophages primes NLRP3 inflammasome-mediated phagocytosis and tumor clearance in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5270.

Abstract 2272: Unlocking the potential of miRNA sequencing for early detection and monitoring of pancreatic cancer progression and recurrence

Abstract Pancreatic cancer (PC) is an elusive and deadly disease. Many patients with PC are diagnosed with metastatic or locally advanced tumors, limiting surgical resection, and increasing the risk of relapse after treatment. Relapse is recorded to be as high as 75% in the first 2 years after clinical intervention, resulting in a mean 5-year survival of 12% in the US, and as low as 2% worldwide. It is vital to develop diagnostic and monitoring techniques for PC. MicroRNAs (miRNAs) are robustly expressed in patient tumors and provide a rich source of biomarkers for disease detection and status. miRNA are short nucleic acid strands that bind to catalytic proteins to guide the regulation of large RNAs within the cellular space. This system is altered in tumors, leading to abhorrent expression of miRNA. Due to significant advancements in sequencing technology, miRNA-seq has become more accurate and affordable in detecting profile changes. To identify biomarkers for PC progression, we developed from the Gemcitabine-sensitive MIA-PaCa-2 (MP2) cell line the Gemcitabine and FOLFIRINOX resistant MP2-GR cell line. MiRNA-seq was conducted on the parental MP2 and resistant MP2-GR cells to identify those miRNAs that were differentially expressed between the cell lines. These miRNAs were analyzed via pathway analysis and gene ontology to find predicted functions followed by annotations from the miRNA Enrichment Analysis and Annotation tool (miEAA) to identify differentially expressed miRNAs associated with PC progression. This comparison indicated several miRNAs related to PC resistance. This dataset was then compared to The Cancer Genome Atlas (TCGA), which contains data from over 300 PC patients. The miRNA set was used to predict both PC progression after treatment, and recurrence. We are currently refining this data set to increase its predictive sensitivity and widen our patient data set comparison to further elucidate this approach in a clinical setting. Citation Format: Ryan N. Fuller, Ann Morcos, Desirae Escalera, Nathan R. Wall. Unlocking the potential of miRNA sequencing for early detection and monitoring of pancreatic cancer progression and recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2272.

PD-1 inhibitor combined with chemotherapy for first-line treatment of esophageal squamous cell carcinoma patients with distant metastasis: a real-world retrospective study.

The aim of this study was to evaluate whether the efficacy and safety of PD-1 inhibitors combined with chemotherapy in the treatment of patients with esophageal squamous cell carcinoma (ESCC) with distant metastasis in the real world are as effective and safe as in clinical trials. From July 2019 to July 2023, a total of 422 patients with distant metastasis of ESCC were included and divided into the PD-1 inhibitor combined chemotherapy group (PC group) and the chemotherapy alone group (C group) according to the treatment regimen. There were 278 patients in the PC group and 144 patients in the C group. The primary endpoint of this study was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The objective response rate (ORR) and disease control rate (DCR) of the PC group were 44.60% (124/278) and 91.00% (253/278), respectively, which were 18.9% and 3.5% higher than those of the C group. The median PFS and median OS of the PC group were significantly better than those of the C group (median PFS: 6.5 vs. 5.5 months, P < 0.001; median OS: 16.6 vs. 13.9 months, P = 0.002). Further univariate and multivariate Cox analysis showed that the Eastern Cooperative Oncology Group performance status (ECOG PS) score and the number of metastatic sites were potential predictors of PFS in PC patients. The combination of PD-1 inhibitors with cisplatin and paclitaxel (TP) was more beneficial for patients with PFS compared to the combination of cisplatin and fluorouracil (PF). Furthermore, the presence of bone metastasis, body mass index (BMI), and lymphocyte-to-monocyte ratio (LWR) before treatment may be potential predictive factors for patient OS. The adverse reactions that occurred in the PC group can be tolerated or alleviated after both prevention and active treatment. The combination of PD-1 inhibitors and chemotherapy as first-line treatment for ESCC patients with distant metastasis still has good efficacy and safety compared to clinical trials in the real world.

Clinical characteristics, Risk factors, and outcomes of Posterior circulation stroke: A retrospective study between younger and older adults in Saudi Arabia

IntroductionPosterior circulation stroke (PCS) may be less prevalent than its anterior counterpart but contributes to substantial morbidity and mortality. The aim was to characterize PCS's demographics, clinical presentation, management, and outcomes between younger and older adults in Saudi Arabia. MethodsThis retrospective cohort study was conducted at two tertiary medical centers in Saudi Arabia between March 2016 and December 2020. All patients who presented with symptoms of posterior circulation stroke and had positive brain imaging were included. ResultsThe study involved 160 posterior circulation stroke patients, stratified into two age groups: 71 patients aged 18-59 years and 89 patients aged 60 years and above. The mean age of the entire cohort was 60.9 years, and 77 % were males. Hypertension was more prevalent in the older age group (88 % vs. 69 %, p=0.005), and smoking was significantly higher among younger patients (38 % vs. 15 %; p=0.0009). Only 22.4 % received thrombolysis and/or thrombectomy. Most strokes involved the posterior cerebral artery (45.6 %). Large artery atherosclerosis was the most common subtype. At discharge, younger patients had higher NIHSS compared to older patients. ConclusionOur investigation of 160 PCS patients in Saudi Arabia uncovers notable trends: a mere 22.4 % received thrombolysis and/or thrombectomy and a significant prevalence of posterior cerebral artery involvement due to large artery atherosclerosis. The study further reveals younger patients disproportionately had severe outcomes. Highlighting the need for improved stroke care and heightened awareness, this research contributes vital data to an underexplored domain, urging further study to optimize care and understand PCS dynamics in Saudi Arabia.

Activation of the PI3K/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib

BackgroundPancreatic adenocarcinoma (PC) is an aggressive malignancy with limited treatment options. The poor prognosis primarily stems from late-stage diagnosis and when the disease has become therapeutically challenging. There is an urgent need to identify specific biomarkers for cancer subtyping and early detection to enhance both morbidity and mortality outcomes. The addition of the EGFR tyrosine kinase inhibitor (TKI), erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer slightly improved outcomes. However, restricted clinical benefits may be linked to the absence of well-characterized criteria for stratification and dependable biomarkers for the prediction of treatment effectiveness.Methods and resultsWe examined the levels of various cancer hallmarks and identified glycolysis as the primary risk factor for overall survival in PC. Subsequently, we developed a glycolysis-related score (GRS) model to accurately distinguish PC patients with high GRS. Through in silico screening of 4398 compounds, we discovered that erlotinib had the strongest therapeutic benefits for high-GRS PC patients. Furthermore, we identified ARNTL2 as a novel prognostic biomarker and a predictive factor for erlotinib treatment responsiveness in patients with PC. Inhibition of ARNTL2 expression reduced the therapeutic efficacy, whereas increased expression of ARNTL2 improved PC cell sensitivity to erlotinib. Validation in vivo using patient-derived xenografts (PDX-PC) with varying ARNTL2 expression levels demonstrated that erlotinib monotherapy effectively halted tumor progression in PDX-PC models with high ARNTL2 expression. In contrast, PDX-PC models lacking ARNTL2 did not respond favorably to erlotinib treatment. Mechanistically, we demonstrated that the ARNTL2/E2F1 axis-mediated cellular glycolysis sensitizes PC cells to erlotinib treatment by activating the PI3K/AKT signaling pathway.ConclusionsOur investigations have identified ARNTL2 as a novel prognostic biomarker and predictive indicator of sensitivity. These results will help to identify erlotinib-responsive cases of PC and improve treatment outcomes. These findings contribute to the advancement of precision oncology, enabling more accurate and targeted therapeutic interventions.

Maternal pheochromocytoma and childbirth in Sweden 1973-2015: a population-based study on short and long-term outcome.

Data guiding management of pheochromocytoma and paraganglioma (PPGL) in pregnant women is limited, and long-term effects on the child are unknown. The aim of this retrospective registry-based case-cohort study was to assess how maternal PPGL and treatment impacts maternal and fetal outcome, including long-term outcome for the child. The main outcomes were maternal and fetal mortality and morbidity at delivery and relative healthcare consumption in children born by mothers with PPGL during pregnancy. The National Birth Register identified 4,390,869 pregnancies between 1973-2015. Data was crosslinked with three Swedish national registers to identify women diagnosed with pheochromocytoma or paraganglioma within one year before or after childbirth. Hospital records were reviewed and register data was collected for five age-matched controls for each child until age 18. 21 women and 23 children were identified (incidence 4.8/1.000.000 births/year), all women with adrenal pheochromocytomas (Pc). The majority (71%) were diagnosed post-partum. Nine women (43%) were hypertensive during pregnancy. Preterm delivery was more common in Pc patients compared to controls (30% vs 6%, p < 0.001). There was no maternal or fetal mortality. Timing of tumor removal did not affect gestational weight or APGAR scores. There was no observed difference in hospital admissions between children affected by maternal Pc and controls. Pc was commonly diagnosed after delivery and raised the risk of pre-term delivery, suggesting a need for an increased awareness of this diagnosis. However, reassuringly, there was no fetal or maternal mortality or any observed long-term impact on the children.

Instrumental activities of daily living in older patients with metastatic prostate cancer: results from the meet-URO network ADHERE prospective study

Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients’ IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5—ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28–37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs.

Effects of androgen deprivation therapy on elderly men with high-risk prostate cancer: PROSARC observational study

IntroductionProstatic carcinoma (PC) is a frequent neoplasm in elderly patients. Although androgen deprivation is associated with survival benefits, it is also related to adverse effects such as osteoporosis, frailty, or sarcopenia, which can negatively affect the patient’s quality of life. This study aims to quantify and evaluate the prevalence of osteoporosis, frailty, or sarcopenia in elderly PC patients before and after androgen deprivation. We present data from an interim analysis. Materials and methodsPROSARC is a national (Spain) prospective observational study (May-2022–May-2025) still in progress in 2 hospitals. It includes patients with high-risk PC, aged ≥70 years, non-candidates for local treatment and scheduled to start androgen deprivation therapy. The following variables are analyzed: comorbidity, frailty (Fried frailty phenotype criteria), osteoporosis, sarcopenia (EWGSOP2), fat mass and muscle mass, before treatment and after 6 months of follow-up. ResultsA 6-month follow-up was completed by 12/25 included patients (mean age, 84 years), with a high baseline prevalence of pre-frailty/frailty (67.7%), sarcopenia (66.7%) and osteoporosis (25%). Treatment did not significantly alter these variables or comorbidity. We observed changes in body mass index (p = 0.666), decreased mean value of appendicular muscle mass (p = 0.01) and increased percentage of fat mass (p = 0.012). ConclusionIn patients with high-risk PC, advanced age and a considerable prevalence of osteoporosis, frailty and sarcopenia, androgen deprivation (ADT; 6 months) produces decreased muscle mass without impact on the incidence of the known adverse effects of androgen deprivation.

Сombined rehabilitation after COVID-19 coronavirus infection

Aim. To study the efficacy of personalized combined rehabilitation of PCS patients in the setting of a day hospital.Materials and methods. The study involved 68 patients with PCS (49 women and 19 men) aged from 36 to 76 years. Bronchial asthma (BA) was detected in 26 patients, chronic obstructive pulmonary disease (COPD)– in 9 patients, and stage II hypertension– in 12 patients. Depending on severity of PCS, the treatment program included drug therapy and physiotherapeutic treatment. The rehabilitation course lasted for 14 days. The efficacy of medical rehabilitation was assessed by the dynamics of clinical and functional indicators.Results. After the rehabilitation course, asthenic syndrome decreased in all patients. The majority of patients reported improvement in dyspnea according to the mMRC scale. In COPD patients, the CAT test score decreased by 26%. After rehabilitation, the asthma patients showed a decrease in the ACQ test score by 45%, with the peakflowmetry indicators having improved. Improvements in spirometry and peripheral oxygen saturation of capillary blood were recorded.Conclusion. Personalized medical rehabilitation of patients after coronavirus infection can reduce the severity of PCS signs. The rehabilitation methods used contributed to the restoration of external respiratory function, stabilization of the patients’ emotional state, reduction of shortness of breath, hypoxemia, and other impaired functions in patients after COVID-19.

Abstract C061: Therapeutic profiling, patient response prediction, and tumor evolution in pancreatic cancer organoids

Abstract Pancreatic cancer (PC) is characterized by an aggressive biology and high tumor heterogeneity causing considerable variations in therapy response. Patient-derived organoids (PDOs) reflect parental tumor features and represent a powerful preclinical tool to predict drug response and harness personalized treatment. We have derived &amp;gt;100 PDO lines from treatment-naïve and pretreated PC patient primary tumor and metastases with a reliable efficacy and previously developed a pharmacotyping-guided prediction model to prognosticate patient therapy response (Beutel, 2021). Following up our initial feasibility trial, we now validated the model accuracy in real-life in a higher number of PC patients (43 cases). Additionally, a limited set of 7 PDO pairs were derived from the same patients at two distinct timepoints, followed by pharmacotyping and whole exome sequencing (WES). Our model allowed overall a successful drug-response prediction in naïve patients with an accuracy of 85.7% for first and second-line regimens. Prediction power was nevertheless lower in pretreated patients with a precision of 57.1% for subsequent chemotherapy lines. Intriguingly, a trend was observed towards a better performance of our system in prognosticating chemoresponsiveness vs. unresponsiveness (89.5% vs. 68.8%). Retrospective analysis of patient clinical data finally showed that the administration of a regimen predicted to be efficient ultimately translated into a longer progression-free survival. Importantly, the implementation of an automated pipetting system and the subsequent miniaturization of drug screenings enhanced our process capacity, conferring the possibility to extend our panel to a second list of approved targeted substances and significantly reducing the time before pharmacotyping. The access to longitudinal biopsies allowed to conduct WES on 14 PDOs to capture a comprehensive genetic profiling over the time of treatment, notably revealing a CHEK2-mutated patient responding over time upon PARP inhibitor maintenance therapy, in line with our PDO-based prediction, further highlighting the robustness of our method and algorithm. WES revealed a lower mutational burden and amount of nonsynonymous mutations upon chemotherapy, while tracking clonal evolution also revealed therapy-linked changes. Finally, to decipher the molecular mechanisms driving PC chemoresistance with an unprecedented level of accuracy, we took advantage of our phenotypically and therapeutically-profiled PDO living biobank and employed a true single-nucleus multiome approach to fully capture the transcriptome, as well as the chromatin accessibility landscape, of chemotherapy responsive and non-responsive PC PDOs. Overall, we report a robust and clinically-relevant preclinical tool for drug-response prediction, paving the way towards a PDO therapeutic profiling-guided true precision medicine in clinical routine. The identification of gene-regulatory networks and expression signatures driving chemoresistance may dramatically improve patient stratification and thus, foster true precision oncology. Citation Format: Johann Gout, Yazid J. Resheq, Jessica Lindenmayer, Thomas Ettrich, Lukas Perkhofer, Thomas Seufferlein, Alexander Kleger. Therapeutic profiling, patient response prediction, and tumor evolution in pancreatic cancer organoids [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C061.

Abstract A053: The effects of chemotherapy on B cells and T cells in blood and tumor tissue in patients with pancreatic cancer – from diagnosis to terminal disease

Abstract Pancreatic cancer (PC) is a devastating disease and is almost always synonymous with a poor outcome. Chemotherapy is the standard treatment and is administered in either an adjuvant or palliative setting. However, nearly all patients, regardless of treatment intent, eventually develop chemoresistance. Little is known about the events causing chemoresistance, but increased knowledge is essential for improving patient outcomes. The aim of this study was to increase the knowledge of how the immune system, locally and systemically, is affected by chemotherapy and how this influences patient outcomes. Hence, immunohistochemical analysis of T and B cell prevalence in post-mortem tumor tissue was performed and combined with flow cytometric analysis of the dynamics of circulating T and B cell subsets during chemotherapy in nine PC patients enrolled in a clinical study. Despite the small number of patients included in this study, some interesting results were found. A high number of tertiary lymphoid-like structures (TLLSs) in the primary tumor was associated with shorter survival, which is contradictory to previous findings and possibly indicates a negative effect of chemotherapy on TLLSs. Certain subpopulations of T and B cells exhibited variations during treatment, possibly in response to chemotherapy. The frequency of T cells in blood also tended to correlate inversely with the frequency in primary tumor and liver metastases. Overall, this exploratory study provides insights into how the immune system in PC is affected by chemotherapy. Further study is warranted to shed more light on the intrinsic chemoresistance of PC and to identify new therapeutic strategies. Citation Format: Hedda Jacobsen. The effects of chemotherapy on B cells and T cells in blood and tumor tissue in patients with pancreatic cancer – from diagnosis to terminal disease [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A053.

FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation

FBXO31, a member of F-box family to comprise of SCF complex, contributes to a pivotal role in cancer progression. However, the possible involvements of FBXO31 in PC are unelucidated. Here, we reported that FBXO31 was overexpressed in PC patients, which was negatively associated with survival in PC patients. Furthermore, FBXO31 significantly enhanced growth, migration and invasion of PC cells in vitro. Consistently, FBXO31 overexpression promoted tumor growth in nude mice. Mechanistically, SIRT2 was a target of FBXO31 and interacted with FBXO31. Protein half-life and ubiquitination analysis demonstrated that FBXO31 promoted proteasome-dependent degradation of SIRT2. In addition, FBXO31 binds to sirtuin-type domain of SIRT2. Moreover, SIRT2 is required for the oncogenic role of FBXO31 in PC progression. Impressively, METTL3 induced m6A modification of FBXO31 and up-regulated FBXO31 expression, subsequently leading to SIRT2 down-regulation in PC cells. The results showed that METTL3 enhanced FBXO31 mRNA translation in YTHDF1-dependent manner. Taken together, we suggest that METTL3–FBXO31–SIRT2 axis was involved in PC tumorigenesis, which could identify new targets for PC treatment.

Long non-coding RNA MIR600HG as a ceRNA inhibits the pancreatic cancer progression through regulating the miR-1197/PITPNM3 axis

ObjectivePancreatic cancer (PC) is considered to be a highly malignant cancer with poor prognosis. Long non-coding RNAs (lncRNAs) is the potential factor to predict cancer prognosis. The effect of MIR600HG in PC needs to be further studied. Our work mainly focused on the importance of MIR600HG for PC prognosis and its underlying molecular mechanism of regulating PC progression. MethodsData set was acquired from TCGA database to find differentially expressed genes and prognostic significance of MIR600HG in PC, and to construct the MIR600HG competitive endogenous RNA (ceRNA). Clinical specimens were collected to prove the analysis results. Vector over-expressed MIR600HG was transfected to study the roles of MIR600HG in proliferation, apoptosis, invasion and migration. The methods of CCK-8, flow cytometry, Transwell and scratch assays were all used in order to explore the apoptosis, migration and invasion. We evaluated the proliferation-related genes (PCNA, CyclinD1 and P27), as well as invasion and migration-related genes such as MMP-9, MMP-7 and ICAM-1. The transcriptional regulation between MIR600HG and miR-1197/PITPNM3 axis was determined with luciferase reporter assays. ResultsIn present study, MIR600HG was dropped in both PC tissues and cells, and the down-regulated MIR600HG was closely related to the poor clinical outcomes in PC patients. MIR600HG could inhibit proliferation, migration and invasion in PC cells. We also investigated whether MIR600HG acting as a sponge of microRNA-1197 (miR-1197) and miR-1197 acting on PITPNM3. We found the positive association between MIR600HG and PITPNM3, as well as the negative association of miR-1197 and MIR600HG (or PITPNM3). Moreover, PITPNM3 mRNA and protein expression saw a simultaneous increase after the MIR600HG-overexpression (MIR600HG-OE), but this result partially diminished in MIR600HG-OE cells and miR-1197 mimics. ConclusionsOur study explored the anticancer action of MIR600HG in PC by regulating miR-1197 to increase the expression of PITPNM3, which might help the diagnosis and therapy of PC.