Median Survival Time Of Patients Research Articles

A fresh perspective on advances in pancreatic cancer treatment over the past two decades

In the past two decades, significant advances have been made in the treatment of pancreatic cancer.Numerous first-line treatments, such as gemcitabine combined with erlotinib, gemcitabine combined with albumin-bound paclitaxel, FOLFIRINOX, and NALIRIFOX, have emerged;surgery-centered treatment has gradually become the mains clinical strategy.However, behind these achievements, the new drugs developed with substantial funding have not extended the median survival time of patients with advanced pancreatic cancer to more than one year; the 5-year survival rate for postoperative patients remains below 30%. While harboring hope and being proactive, researchers must also soberly reflect and continually reassess our direction, in anticipation of bringing tangible clinical benefits to pancreatic cancer patients at an early date.

High expression of BTN3A1 is associated with clinical and immunological characteristics and predicts a poor prognosis in advanced human gliomas

IntroductionGliomas represent the most prevalent and aggressive tumors within the central nervous system. Despite the current standard treatments, the median survival time for glioblastoma patients remains dismal, hovering around 14 months. While attempts have been made to inhibit the PD-1/PD-L1 and CTLA-4/CD80-CD86 axes through immunotherapy, the outcomes have yet to demonstrate significant efficacy. The immune checkpoint Butyrophilin 3A1 (BTN3A1) can either be involved in advantageous or detrimental function depending on the cancer type.MethodsIn our study, we utilized a Moroccan cohort to delve into the role of BTN3A1 in gliomas. A transcriptomic analysis was conducted on 34 patients, which was then corroborated through a protein analysis in 27 patients and validated using the TCGA database (n = 667).ResultsOur results revealed an elevated expression of BTN3A1 in glioblastoma (grade 4), as evidenced in both the TCGA database and our cohort of Moroccan glioma patients. Within the TCGA cohort, BTN3A1 expression was notably higher in patients with wild-type IDH. We observed a positive correlation between BTN3A1 expression and immune infiltration of B cells, CD8+ T cells, naive CD4+ T cells, and M2 macrophages. Patients exhibiting increased BTN3A1 expression also presented elevated levels of TGF‐β, IL‐10, and TIM‐3 compared to those with reduced BTN3A1 expression. Notably, patients with high BTN3A1 expression were associated with a poorer prognosis than their counterparts with lower expression.ConclussionOur findings suggest that BTN3A1 might promote the establishment of an immunosuppressive microenvironment. Consequently, targeting BTN3A1 could offer novel therapeutic avenues for the management of advanced gliomas.

Abstract PO1-15-07: Subtyping-directed precision treatment refines traditional one-size-fits-all therapy in HR+/HER2- breast cancer: a sub-study of the MULAN umbrella trial

Abstract Background: The standard approach of using one-size-fits-all endocrine therapy for hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancers has faced significant challenges due to variations in treatment response among individuals. Consequently, there is still an urgent need to understand the molecular biology of HR+/HER2- breast cancer and explore precision treatment strategy. Methods: We established a multiomics cohort (n = 351), multicenter real-world clinical cohorts (n = 643), a prospective clinical cohort (MULAN trial), and a drug-testing platform containing patient-derived organoids (n = 126) and patient-derived tumor fragments (n = 49) of HR+/HER2- breast cancers. Integrating "bench" and “bedside” data, we conducted comprehensive preclinical and clinical translational research on precision strategies in HR+/HER2- breast cancer. Results: We implemented a comprehensive classification system for HR+/HER2- breast cancer, comprising four distinct subtypes. We further demonstrated the efficacy and mechanisms of subtyping-directed precision treatment strategies through clinical cohort studies, omics analysis and functional assays: endocrine therapy alone for the canonical luminal subtype; the addition of CDK4/6 inhibitor and PARP inhibitor for the proliferative subtype; the immunotherapy for the immunogenic subtype; and tyrosine kinase inhibitors for the receptor tyrosine kinase-driven subtype. Using clinically applicable subtyping methods, we validated that matched precision treatment strategies outperformed unmatched approaches in a real-world cohort, almost doubling the median progression-free survival time for patients with refractory advanced HR+/HER2- breast cancer (9.83 months [95% CI, 5.74-13.93] vs 4.77 months [95% CI, 3.35-6.18]; hazard ratio 0.64 [95% CI, 0.41-0.99]). Importantly, the first-stage analysis of the MULAN phase II umbrella clinical trial (NCT04355858) verified the higher objective response rate (88.9%, 95%CI: 51.7%-99.7%) of the subtyping-directed precision treatment. Conclusion: Our study emphasizes the superiority of subtyping-directed precision treatment strategies for HR+/HER2- breast cancer, refines traditional “one-size-fits-all” therapy, and facilitates the translation of precision treatment strategies from bench to bedside. Overall study design Part 1 Subtype Molecular Characteristics: Molecular features of the four subtypes of HR+/HER2- breast cancer. Part 2 Multidimensional Efficacy Validation: Integrating data from a multiomics cohort, real-world study, drug testing platform and prospective clinical research to validate the subtyping-directed precision treatment strategy in HR+/HER2- breast cancer. Part 3 Subtyping-directed Precision Treatment Strategy: Integrating clinical cohort studies, omics analysis and functional assays revealed the heterogeneity of treatment response in HR+/HER2- breast cancer, and proposed a subtyping-directed precision treatment strategy. CIN, chromosomal instability; RTK, receptor tyrosine kinase; CNA, copy-number alteration; ER, estrogen receptor; HR, hormone receptor; HER2, human epidermal growth factor receptor 2. Citation Format: Xiu-Zhi Zhu, Xi Jin, Hu-Yun-Long Zhang, Xiyu Liu, Yi-Fan Zhou, Yi-Yu Chen, Tong Fu, Ming-Liang Jin, Ya-Xin Zhao, Yi-Fan Xie, Ruo-Xi Wang, Zhong-Hua Wang, Lei Fan, Yi-Zhou Jiang, Zhi-Ming Shao. Subtyping-directed precision treatment refines traditional one-size-fits-all therapy in HR+/HER2- breast cancer: a sub-study of the MULAN umbrella trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-15-07.

Quantitative proteomics revealed protein biomarkers to distinguish malignant pleural effusion from benign pleural effusion

To identify protein biomarkers capable of early prediction regarding the distinguishing malignant pleural effusion (MPE) from benign pleural effusion (BPE) in patients with lung disease. A four-dimensional data independent acquisition (4D-DIA) proteomic was performed to determine the differentially expressed proteins in samples from 20 lung adenocarcinoma MPE and 30 BPE. The significantly differential expressed proteins were selected for Gene Ontology (GO) enrichment and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis. Protein biomarkers with high capability to discriminate MPE from BPE patients were identified by Random Forest (RF) algorithm prediction model, whose diagnostic and prognostic efficacy in primary tumors were further explored in public datasets, and were validated by ELISA experiment. 50 important proteins (30 up-regulated and 20 down-regulated) were selected out as potential markers to distinguish the MPE from BPE group. GO analysis revealed that those proteins involving the most important cell component is extracellular space. KEGG analysis identified the involvement of cellular adhesion molecules pathway. Furthermore, the Area Under Curve (AUC) of these proteins were ranged from 0.717 to 1.000，with excellent diagnostic properties to distinguish the MPE. Finally, significant survival and gene and protein expression analysis demonstrated BPIFB1, DPP4, HPRT1 and ABI3BP had high discriminating values. SignificanceWe performed a 4D-DIA proteomics to determine the differentially expressed proteins in pleural effusion samples from MPE and BPE. Some potential protein biomarkers were identified to distinguish the MPE from BPE patients., which may provide helpful diagnostic and therapeutic insights for lung cancer. This is significant because the median survival time of patients with MPE is usually 4–12 months, thus, it is particularly important to diagnose MPE early to start treatments promptly. The most common causes of MPE are lung cancers, while pneumonia and tuberculosis are the main causes of BPE. If more diagnostic markers could be identified periodically, there would be an important significance to clinical diagnose and treatment with drugs in lung cancer patients.

Identification of Novel Molecular and Clinical Biomarkers of Survival in Glioblastoma Multiforme Patients: A Study Based on The Cancer Genome Atlas Data.

Glioblastoma multiforme (GBM) is the most prevalent type of brain tumour; although advancements in treatment have been made, the median survival time for GBM patients has persisted at 15 months. This study is aimed at investigating the genetic alterations and clinical features of GBM patients to find predictors of survival. GBM patients' methylation and gene expression data along with clinical information from TCGA were retrieved. The most overrepresented pathways were identified independently for each omics dataset. From the genes found in at least 30% of these pathways, one gene that was identified in both sets was further examined using the Kaplan-Meier method for survival analysis. Additionally, three groups of patients who started radio and chemotherapy at different times were identified, and the influence of these variations in treatment modality on patient survival was evaluated. Four pathways that seemed to negatively impact survival and two with the opposite effect were identified. The methylation status of PRKCB was highlighted as a potential novel biomarker for patient survival. The study also found that treatment with chemotherapy prior to radiotherapy can have a significant impact on patient survival, which could lead to improvements in clinical management and therapeutic approaches for GBM patients.

The impact of modified T3 sub-staging on the prognosis of gallbladder cancer patients

Objective: To explore the value of a new modified T3 sub-staging for the prognosis evaluation in gallbladder cancer patients. Methods: This is a retrospective case-series study. The clinical data of patients with pathologically confirmed stage T3 gallbladder cancer who were admitted to the Department of Hepatobiliary Surgery,the First Affiliated Hospital of Xi'an Jiaotong University from January 2011 to December 2021 were retrospectively analyzed. A total of 190 patients were enrolled in this study, 67 males and 123 females, with an age (M(IQR)) of 63(14) years (range:17 to 88 years). The stage T3 was divided into four sub-stages according to the site of tumor invasion: (1) T3a:tumor perforates the serosa,but not invading the liver and one other adjacent structure; (2) T3b:tumor perforates the serosa and invades one other adjacent structure,but not the liver; (3) T3c:tumor perforates the serosa and invades the liver,but not one other adjacent structure; (4) T3d:tumor perforates the serosa,invades the liver and one other adjacent structure. To evaluate the application value of this modified sub-staging,the Kaplan-Meier method was used to draw the survival curve,univariate analysis and multivariate analysis were done using the Log-rank test and Cox proportional hazard model respectively. Results: According to the modified T3 sub-staging method,34 patients (17.9%) were in stage T3a,24 cases(12.6%) were in stage T3b, 97 cases (51.1%) were in stage T3c, and 35 cases (18.4%) were in stage T3d. The median survival time of patients in stages T3a,T3b,T3c and T3d after radical resection was 72.0 months, 32.0 months, 12.0 months and 10.0 months, respectively. The 1-, 3-, and 5-year survival rates of patients in stage T3a, T3b, T3c and T3d were 79.4%, 53.3%, and 53.3%; 79.2%, 44.6%, and 26.0%;49.5%,27.5%,and 18.1%;42.9%,15.9%, and 15.9% (χ2=18.349,P<0.01),respectively. Univariate analysis showed that gallbladder stones,pathological differentiation,perineural invasion, N stage,postoperative adjuvant therapy and modified T3 substage were factors affecting patient prognosis(all P<0.05). Cox multivariate analysis showed that modified sub-stages with T3c (HR=2.043, 95%CI:1.176 to 3.549) and T3d(HR=2.419, 95%CI:1.284 to 4.555), accompanied by gallbladder stones (HR=1.661,95%CI:1.150 to 2.398),pathological differentiation with poorly differentiated(HR=1.709,95%CI:1.198 to 2.438), and the N stage with N1 and N2(HR=1.602, 95%CI:1.090 to 2.355, 2.714, 95%CI: 1.621 to 4.544) were independent prognostic risk factors for patients in stage T3,while postoperative adjuvant chemotherapy(HR=0.351) was a protective factor for prognosis. There was no statistically significant difference in survival between patients with stage T3a and T3b who underwent hepatic wedge resection and liver segment or major resection (P=0.402). For patients with stage T3c and T3d with liver invasion,the survival difference after hepatic wedge resection and segmental or major resection was statistically significant (P=0.008). Conclusion: The modified T3 sub-staging system based on the depth and direction of tumor invasion maybe helpful to further stratify the prognosis of patients with gallbladder cancer.

Analysis of Time to Relapse among Schizophrenia Patients in St. Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia

Objective: To investigate the associated factors that affect time to relapse in patients with schizophrenia at St. Amanuel Mental Specialized Hospital, with recurrent events model.Material and Methods: A hospital-based retrospective review of the medical records of 332 patient with schizophrenia, covering a two-year period, were examined. Parametric frailty models were used to determine the correlation between discharge times and relapse, and to identify risk factors using R-software. Results: The distribution number of relapses was 162, and the median survival time of patients with schizophrenia was 665 days. The unobserved heterogeneity in patients and correlation between relapses, as estimated by the Weibull-gamma frailty model, was p-value≤0.001 and Kendall’s Tau (Γ)=0.498. This indicated that there was heterogeneity among participants and a correlation between relapses. The final model showed that the effect of psychiatric comorbidity (hazard ratio (HR)=6.522, p-value≤0.001), employment status (HR=5.334, p-value=0.001), history of suicide attempt (HR=2.167, p-value=0.003) and history of traditional treatment (HR=1.973262, p-value=0.021) had a significant effect on the hazard time to relapse. Onset Age of schizophrenia and drug adherence were not predictive. Subsequent relapses are likely dependent on both the first and previous relapses.Conclusion: Comorbidity, employment status, history of suicide attempt and history of traditional treatment are imperative risk factors influencing the hazard of time to relapse, which increases the risk of relapse.

Dynamic Treatment Strategy of Chinese Medicine for Metastatic Colorectal Cancer Based on Machine Learning Algorithm.

To establish the dynamic treatment strategy of Chinese medicine (CM) for metastatic colorectal cancer (mCRC) by machine learning algorithm, in order to provide a reference for the selection of CM treatment strategies for mCRC. From the outpatient cases of mCRC in the Department of Oncology at Xiyuan Hospital, China Academy of Chinese Medical Sciences, 197 cases that met the inclusion criteria were screened. According to different CM intervention strategies, the patients were divided into 3 groups: CM treatment alone, equal emphasis on Chinese and Western medicine treatment (CM combined with local treatment of tumors, oral chemotherapy, or targeted drugs), and CM assisted Western medicine treatment (CM combined with intravenous regimen of Western medicine). The survival time of patients undergoing CM intervention was taken as the final evaluation index. Factors affecting the choice of CM intervention scheme were screened as decision variables. The dynamic CM intervention and treatment strategy for mCRC was explored based on the cost-sensitive classification learning algorithm for survival (CSCLSurv). Patients' survival was estimated using the Kaplan-Meier method, and the survival time of patients who received the model-recommended treatment plan were compared with those who received actual treatment plan. Using the survival time of patients undergoing CM intervention as the evaluation index, a dynamic CM intervention therapy strategy for mCRC was established based on CSCLSurv. Different CM intervention strategies for mCRC can be selected according to dynamic decision variables, such as gender, age, Eastern Cooperative Oncology Group score, tumor site, metastatic site, genotyping, and the stage of Western medicine treatment at the patient's first visit. The median survival time of patients who received the model-recommended treatment plan was 35 months, while those who receive the actual treatment plan was 26.0 months (P=0.06). The dynamic treatment strategy of CM, based on CSCLSurv for mCRC, plays a certain role in providing clinical hints in CM. It can be further improved in future prospective studies with larger sample sizes.

Safety and efficacy of large-bore uncovered stents for treating malignant superior vena cava syndrome

PurposeTo investigate the safety and efficacy of large-bore uncovered stents for treating malignant superior vena cava syndrome. MethodsThis retrospective study included 115 patients (89 men, 26 women; mean age 63.2 years; range 21–83 years) who underwent endovascular large-bore (≥18 mm in diameter) uncovered stent placement between August 2015 and July 2022. One patient was lost to follow-up. Therefore, 114 patients were available for follow-up. ResultsStent placement was technically successful in all 115 patients. Minor procedure-related complications occurred in nine (7.8 %) patients. One hundred eight (93.9 %) patients experienced complete or marked symptomatic relief (Kishi score ≤ 2) at a mean of 3 days after procedure. The cumulative stent patency rates were 98.2 %, 95 %, 93.7 %, 91.5 %, 83.5 %, and 83.5 % at 1, 3, 6, 12, 18, and 24 months, respectively. Stent occlusion occurred in ten (8.8 %) of 114 patients at a mean of 215 days (range 1–732 days) due to thrombosis (n = 7) and tumor ingrowth (n = 3). Stent occlusion did not occur in 21 patients who underwent subsequent central venous catheter insertion. The median patient survival time was 159 days (95 % confidence interval 102–216 days). Univariate and multivariate Cox regression analysis revealed adjuvant anticancer treatment (p = 0.001) and tumor response (p < 0.001) as independent predictors of patient survival. ConclusionsEndovascular placement of large-bore uncovered stents was a safe and effective treatment for malignant superior vena cava syndrome. Large-bore stent placement can effectively prevent stent occlusion by tumor ingrowth in most cases, and it can provide a sufficient diameter for subsequent insertion of central venous catheters.

Abstract 3161: PCTK1 driven glutamine metabolic adaptation in brain metastasis

Abstract Brain metastasis (BrM) is the most common malignancy of the central nervous system and the median survival time of patients with BrM is less than 1 year. Although recent impressive advances in targeted therapy and immunotherapy enable more effective control of the systemic diseases, the incidence of BrM upon disease recurrence is steadily increasing. Unfortunately, there is no effective treatments for BrM. To surmount this challenge, we have performed an in vivo human kinome screening to uncover novel kinases that promote breast cancer (BC) BrMs in mice and may serve as therapeutic targets. We identified &amp;gt;20 different kinases enriched in BrM lesions of our mouse models and PCTK1 is one of the top “hits”. We transduced PCTK1 expression vector and the control vector into MDA-MB-231 human BC cells to generate 231.PCTK1 and 231.vector cells, respectively. Intra-carotid injection of the 231.PCTK1 cells into mice induced BrM significantly faster with shortened mouse survival than that of the control 231.vector cells, confirming PCTK1 as a BrM-promoting kinase. However, when 231.vector or 231.PCTK1 cells were injected into the mouse’ mammary glands, PCTK1 overexpression did not lead to enhanced primary tumor growth, suggesting that its pro-tumoral functions are BrM-specific. To uncover how PCTK1 promotes BrM but not primary tumor, we examined whether PCTK1 may confer growth advantage in BrM by utilizing the unique metabolic microenvironment of the brain. We analyzed the relationship between PCTK1 gene expression and gene expression of members of the glutamine metabolism pathway in TCGA database. We found that in the brain tumors, such as low-grade glioma, PCTK1 positively correlated with the expression of glutamine metabolizing genes, including glutaminase 1 and 2 (GLS and GLS2). To evaluate whether PCTK1-overexpressing cells can uptake glutamine from the media directly, we cultured 231.PCTK1 and 231.vector cells in low-nutrient BME media plus 5% d.FBS, with addition of different concentrations of glutamine. The PCTK1-overexpressing cells showed a clear growth advantage at glutamine concentrations ranging from 400 μM to 2 mM. Then, we knocked down PCTK1 in MDA-MB-231 cells by shRNAs and found that PCTK1 knocking down reduced the cell proliferation in 5% d.FBS.BME with 500 µM glutamine, a physiological glutamine level in the brain. We measured the expression of GLS, an enzyme that converts glutamine to glutamate, one of the key steps in the glutamine metabolism, and found that knockdown PCTK1 in MDA-MB-231 cells dramatically reduced the GLS expression, which indicates that PCTK1 can modulate glutamine metabolism in cancer cells. In summary, our data suggest that PCTK1 promotes BC BrM, at least partly, through increasing glutamine metabolism. Currently, we are exploring whether targeting PCTK1 or inhibiting glutamine metabolism can deter BrM progression. Our studies may reveal novel therapeutic targets for BrM inhibition. Citation Format: Lin Zhang, Frank Lowery, Chenyu Zhang, Yu-Wen Huang, Ya-Jing Jiang, Yimin Duan, Dihua Yu. PCTK1 driven glutamine metabolic adaptation in brain metastasis [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 3161.

Abstract 3763: Comparative spatial analyses of the tumor immune landscape in different mouse models of glioblastoma

Abstract Background: Despite advances in treatment, glioblastoma (GBM) remains one of the most difficult types of cancer to treat, and the prognosis is poor. The current median survival time for patients with GBM is about 12-15 months, and the five-year survival rate is less than 10%. There is an unmet need for better GBM treatment options, leveraged from relevant experimental models. To develop new therapies, preclinical animal models are important for analyzing the biology of GBM and evaluating the efficacy of novel therapeutic strategies. While a variety of experimental models are used to study GBM, most preclinical investigations involve mice. In this study we utilize a spatial phenotyping application that permits comprehensive characterization and comparison of key proteins in the brain tumor immune microenvironment (TiME), and detailed comparison the TiME between different immune-competent GBM mouse models. Methods: The Phenocycler-Fusion is a fast spatial biology solution that affords ultrahigh-plex single-cell spatial readouts. We used this solution for the whole slide imaging of mouse FFPE tissues and deep immune phenotyping of &amp;gt;40 proteins, comprising immune cell lineages, activation states and checkpoints, as well as biomarkers for tumor, vascular and neural landscapes of various GBM mouse models. Results: Via single cell spatial phenotyping, we isolated spatial signatures within the mouse GBM tissue immune microenvironment. We focused on multiple immune biomarkers, including microglia/myeloid cells that were identified via the combinatorial expression of the key markers CD68, Iba-1, F4/80, Tmem119 and CD11b. The macrophages and their biomarker expression profiles exhibited significant inter- and intra-tumoral heterogeneity within different mouse GBM models, indicative of the heterogeneous and complex biology of GBM. Conclusions: Our work encompasses the development of a custom antibody panel, an imaging workflow, as well as a novel bioinformatic analysis method. Deployment of this workflow on different mouse GBM models allowed us to study cell populations, according to biomarker profiles and spatial distribution. This study provides a deeper characterization of the diverse mouse GBM models to determine the optimal model that most accurately recapitulates the complex TiME of human GBM, including key features such as invasive tumor margins, high vascularity, blood-brain barrier, etc. We anticipate that this approach has enormous potential for a broad range of applications for which biomolecules’ spatial information is important and will deepen our understanding of the GBM TiME. Citation Format: Dmytro Klymyshyn, Niyati Jhaveri, Aditya Pratapa, Nadezhda Nikulina, Tsz H. Tam, Nadine Nelson, Riccardo Dolcetti, Davide Moi, Roberta Mazzieri, Theo Mantamadiotis. Comparative spatial analyses of the tumor immune landscape in different mouse models of glioblastoma [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 3763.

Abstract 4638: Integrated proteogenomic characterization of longitudinal glioblastoma

Abstract Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor, with no curative treatment options and median patient survival time of almost one year. Despite multi-modal therapy including surgery, irradiation and chemotherapy, all patients experience tumor progression and recurrence. Our group proposed and validated the first single cell guided functional classification of primary GBM in four tumor-intrinsic cell states which informed clinical outcome and delivered therapeutic options. However, recurrent GBM remains therapeutically unresolved due in part to the diffusely invasive nature and in part to marked cellular heterogeneity of the tumor.The evolutionary trajectory of glioblastoma after therapy is a multifaceted biological process that extends beyond discrete genetic alterations alone. Here, we profiled by multi-omics platforms the largest dataset of matched primary and recurrent GBM including 123 longitudinal glioblastoma pairs, temporally separated by standard-of-care treatment. Genomics, proteomics, and phosphoproteomics all independently captured the loss of proliferative-progenitor characteristics and a significant upregulation of specialized neuronal and synaptic signaling programs in recurrent GBM. Proteomic and phosphoproteomic analyses revealed that the molecular transition from proliferative to neuronal state at recurrence is marked by coherent post-translational activation of the WNT/PCP signaling pathway and the BRAF protein kinase. Multi-omic analysis of Patient-Derived Xenograft (PDX) models mimicked the patterns of evolutionary trajectory, consisting of marked activation of neuronal signaling programs in recurrent patients. Inhibition of the BRAF kinase with small molecule inhibitors impaired both neuronal transition and migration capability of recurrent glioblastoma cells, which are the phenotypic hallmarks of glioblastoma progression after therapy. Accordingly, combinatorial treatment of temozolomide with BRAF inhibitor, vemurafenib, significantly prolonged the survival of mouse PDX models. This work provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance and highlights new therapeutic opportunities to effectively counter them in the clinic. Citation Format: Simona Migliozzi, Kyung-Hee Kim, Harim Koo, Jun-Hee Hong, Seung Min Park, Hyung Joon Kwon, Luciano Garofano, Young Taek Oh, Fulvio D'Angelo, Chan Il Kim, Anna-Luisa Di Stefano, Franck Bielle, Jinlong Yin, Marc Sanson, Do-Hyun Nam, Jason K. Sa, Anna Lasorella, Jong Bae Park, Antonio Iavarone. Integrated proteogenomic characterization of longitudinal glioblastoma [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 4638.

Survival analysis of 37 cases of malignant mesothelioma

Objective: To explore the relationship between clinicopathological features, treatment and prognosis of patients with malignant mesothelioma, and provide theoretical basis for the prevention and treatment of malignant mesothelioma. Methods: In November 2022, the clinical data of 37 patients with malignant mesothelioma diagnosed in Qingdao Central Hospital from July 2014 to November 2022 were retrospectively analyzed, and the prognostic factors were analyzed by Kaplan-Meier and log-rank tests. Results: The median age of the 37 patients was 66 years old, all patients were confirmed by pathology. The median survival time of all patients was 30.00 months. The 1-year, 2-year, 3-year and 5-year cumulative survival rates were 70.27% (26/37), 48.65% (18/37), 16.22% (6/37) and 13.51% (5/37), respectively. Compared with different treatments, the median survival time of palliative care patients was 5.00 months, which was significantly lower than that of operation group (30.33 months), chemotherapy group (30.00 months), surgery combined with chemotherapy group (30.00 months) and chemotherapy combined with bevacizumab targeted therapy group (47.42 months) (P<0.05). Gender, age (≥60 years old or <60 years old), smoking history, occupational exposure history, disease site, and surgical history were not factors affecting the survival of malignant mesothelioma patients (P>0.05) . Conclusion: The clinical symptoms of malignant mesothelioma are not specific, but early initiation of treatment can still prolong survival, and chemotherapy combined with anti-vascular targeted therapy shows better therapeutic effect.

Comparative study between poorly differentiated thyroid cancer and anaplastic thyroid cancer: real-world pathological distribution, death attribution, and prognostic factor estimation.

The clinic-pathological boundary between poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) is unclear due to a wide spectrum of histopathological features and the rarity of the disease. In addition to that, with the highest mortality rate and non-standard treatment modality, the PDTC/ATC population has not been subjected to comprehensive description and comparison with the extent of histological characteristics, therapeutic response, prognostic factors, and death attribution analysis. A total of 4,947 PDTC/ATC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival curve estimation and Cox proportional hazard regression were applied. Overall, the 5- and 10-year DSS for PDTC were 71.9% and 68.0%, respectively, whereas the 5- and 10-year OS are 59.3% and 51.2%, respectively. The median survival time for ATC patients was 3 months with 1-year OS being 26.9% and 1-year DSS being 31.2%. During the follow-up period, 68.1% of the PDTC/ATC cohort were dead, 51.6% of which were attributed to thyroid malignancies and 16.5% to non-thyroid causes. The top three common non-thyroid causes of death were miscellaneous cancers, lower respiratory system disease, and heart disease. The histological feature of papillary thyroid cancer (PTC) was the leading pathological category for PDTC patients (51.7%), whereas 76.7% of ATC patients' pathological feature was characterized as unidentifiable. Sarcoma histological characteristics found in ATC cases suffer the highest overall mortality (vs. PTC, HR = 2.61, 95% CI 1.68-4.06, P < 0.001). Older age unidentifiable histology feature, more advanced AJCC N1b, AJCC M1, and SEER stage, tumor size larger than 5cm, and more invasive tumor extension were independent bad outcome predictors. The populational analysis of the PDTC/ATC cohort has provided reliable support for better understanding of the difference between PDTC and ATC cases and the guidance of clinical practice and further studies.

Correlation between prognostic nutritional index and pleural thickness with survival time of epithelial malignant pleural mesothelioma patients

Objective: To explore the role of prognostic nutritional index (PNI) and pleural thickness in the prognostic evaluation of patients with epithelial malignant pleural mesothelioma (MPM) . Methods: In April 2022, a retrospective analysis was conducted on the data and laboratory data of 41 patients with epithelial MPM admitted to the cardiothoracic surgery department of Chuxiong Yi Autonomous Prefecture People's Hospital from January 2018 to May 2021. Univariate and multivariate analysis were used to evaluate the relationships between total survival time, clinical characteristics, PNI and pleural thickness in patients. Results: The 41 patients were mostly male (26 cases, 63.4%) , with a median age of 55 years old. The main clinical manifestations were chest pain (53.7%) , bloody pleural effusion (75.6%) , and chest pain combined with bloody pleural effusion (36.6%) . The median survival time of patients with different TNM stage, efficacy after 4 cycles of chemotherapy, PNI, maximum pleural thickness after chemotherapy (post max) , sum of post max in 3 zones after chemotherapy (post sum) were statistically different (χ(2)=3.89, 14.51, 15.33, 4.33, 12.05, P<0.05) . Compared with patients with high PNI and post sum<32.26 mm, MPM patients with low PNI and post sum≥32.26 mm have higher risk of death, and the differences were statistically significant (HR=1.52, 95%CI: 1.75-11.93, P=0.002; HR=1.70, 95%CI: 1.84-16.23, P=0.002) . Conclusion: PNI and post sum can be used to predict the prognosis of patients with epithelial MPM.

Assessing the survival time of women with breast cancer in Northwestern Ethiopia: using the Bayesian approach

BackgroundDespite the significant weight of difficulty, Ethiopia's survival rate and mortality predictors have not yet been identified. Finding out what influences outpatient breast cancer patients' survival time was the major goal of this study.MethodsA retrospective study was conducted on outpatients with breast cancer. In order to accomplish the goal, 382 outpatients with breast cancer were included in the study using information obtained from the medical records of patients registered at the University of Gondar referral hospital in Gondar, Ethiopia, between May 15, 2016, and May 15, 2020. In order to compare survival functions, Kaplan-Meier plots and the log-rank test were used. The Cox-PH model and Bayesian parametric survival models were then used to examine the survival time of breast cancer outpatients. The use of integrated layered Laplace approximation techniques has been made.ResultsThe study included 382 outpatients with breast cancer in total, and 148 (38.7%) patients died. 42 months was the estimated median patient survival time. The Bayesian Weibull accelerated failure time model was determined to be suitable using model selection criteria. Stage, grade 2, 3, and 4, co-morbid, histological type, FIGO stage, chemotherapy, metastatic number 1, 2, and >=3, and tumour size all have a sizable impact on the survival time of outpatients with breast cancer, according to the results of this model. The breast cancer outpatient survival time was correctly predicted by the Bayesian Weibull accelerated failure time model.ConclusionsCompared to high- and middle-income countries, the overall survival rate was lower. Notable variables influencing the length of survival following a breast cancer diagnosis were weight loss, invasive medullar histology, comorbid disease, a large tumour size, an increase in metastases, an increase in the International Federation of Gynaecologists and Obstetricians stage, an increase in grade, lymphatic vascular space invasion, positive regional nodes, and late stages of cancer. The authors advise that it is preferable to increase the number of early screening programmes and treatment centres for breast cancer and to work with the public media to raise knowledge of the disease's prevention, screening, and treatment choices.

Clinical value of the expression levels of tumor protein D52 and miR-133a on prognosis assessment of pancreatic cancer surgery.

To investigate the clinical value of the expression levels of tumor protein D52 (TPD52) and miR-133a on the prognosis assessment of pancreatic cancer surgery. This was a retrospective study. Ninety-seven patients who underwent radical surgery for pancreatic cancer in Cangzhou Central Hospital from January 2018 to January 2022 were selected and divided into four groups: TPD52 high expression group, TPD52 low expression group, miR-133a high expression group and miR-133a low expression group. The relationship between the expression levels of TPD52 and miR-133a and the clinicopathological features of patients with pancreatic cancer was analyzed. The COX regression model was used to analyze the risk factors affecting the prognosis of patients with pancreatic cancer. The high expression rate of TPD52 and the low expression rate of miR-133a in pancreatic cancer tissues were higher than those in normal paracancerous tissues(P<0.05). Based on the comparison of prognosis and survival, the median survival time of patients with high expression of TPD52 and low expression of miR-133a was lower than that of patients with low expression of TPD52 and high expression of miR-133a, with a statistically significant difference(P<0.05). Moreover, multivariate Cox regression analysis showed that low differentiation of pancreatic cancer, III-IV stage of TNM, high expression of TPD52, as well as low expression of miR-133a were independent risk factors for postoperative survival of patients with pancreatic cancer(P<0.05). TPD52 is expressed at a high level whereas miR-133a at a low level in pancreatic cancer tissues, both of which together with low differentiation of pancreatic cancer and III-IV stage of TNM constitute independent risk factors affecting the surgical prognosis of patients with pancreatic cancer.

Pro-Fibrotic Effects of CCL18 on Human Lung Fibroblasts Are Mediated via CCR6.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities. We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines. We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression. Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis.

Surgery combined with adjuvant radiation and chemotherapy prolonged overall survival in stage IVC anaplastic thyroid cancer: a SEER-based analysis.

Anaplastic thyroid carcinoma (ATC) is a rare but aggressive malignancy, which accounts for only 1-2% of all thyroid cancers. The median overall survival (OS) time for all stages patients is at about 5 months. The benefit of surgery combined with adjuvant radiation and chemotherapy in stage IVC anaplastic thyroid cancer is still controversial. The aim of this study is to investigating surgery combined with adjuvant radiation and chemotherapy and survival outcomes in stage IVC ATC patients. Anaplastic thyroid carcinoma patients from the Surveillance, Epidemiology, and End Results database from 2004 to 2016 were used to conduct a cross-sectional study in the analysis. The endpoint of this study was overall survival. The median OS of the overall population was 2.0 months. Multivariate analysis showed that age (<67 vs. ≥67 years old, P = 0.017, HR = 1.355, 95% CI: 1.057-1.738), tumor size (<7 cm vs. ≥7 cm, P = 0.001, HR = 1.579, 95% CI: 1.202-2.073), Surgery (thyroidectomy vs. non-surgery, P < 0.001, HR = 0.554, 95% CI: 0.401-0.766), radiation therapy (P < 0.001, HR = 0.571, 95% CI: 0.445-0.733) and chemotherapy (P = 0.003, HR = 0.684, 95% CI: 0.531-0.881) were independent prognostic factor for worse OS in stage IVC ATC patients. Surgery combined with adjuvant radiation and chemotherapy exhibited the better overall survival time for 4 months. Surgery combined with adjuvant radiation and chemotherapy can improve overall survival in stage IVC ATC patients. We recommend surgical approach with fully evaluation combined with radiation therapy and chemotherapy for selected stage IVC ATC patients.

A Lactic Acid Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironmental Status in Patients with Hepatocellular Carcinoma

This study aims to build a prognostic model based on lactic acid metabolism-related genes (LMRGs) to predict survival outcomes and tumor microenvironment status of Hepatocellular carcinoma (HCC) patients. The model was used to calculate riskscores of clinical samples. Survival analysis and Cox regression analysis were conducted to verify the independence and reliability of the riskscore to determine its clinical significance in prognosis evaluation of HCC. Additionally, we conducted a comprehensive analysis of tumor mutation burden (TMB), immune cell infiltration, and gene set molecular function in the high- and low-risk groups. We obtained 134 LMRGs mainly involved in cellular calcium homeostasis and calcium signaling pathways. The LMRGs in the risk assessment model included PFKFB4, SLC16A3, ADRA2B, SLC22A1, QRFPR, and PROK1. This study discovered much shorter overall survival and median survival time of patients with higher riskscores when compared to those with lower riskscores. It was indicated that for independent prediction of patients’ prognosis, the riskscore had a significant clinical value. A remarkable difference was also found regarding TMB between the two groups. Finally, cell experiments demonstrated that the knockout of PFKFB4 and SLC16A3 genes suppressed lactate. Our research demonstrated that the riskscore, established based on LMRGs, is a promising biomarker.