Shorter Patient Survival Research Articles

Prognostic impact of primary versus secondary resistance to sorafenib in patients with HCC

Background: Sorafenib is a first-line treatment option for patients with hepatocellular carcinoma (HCC). However, the impact of sorafenib resistance type on patient survival prediction and choice of second-line treatment regimen is unknown. Objectives: This study aims to explore the factors predicting resistance in patients with HCC receiving sorafenib, the impact of resistance on survival, and the optimal second-line treatment regimen. Design: This was a retrospective cohort study. Methods: We recruited all patients with advanced HCC who received first-line sorafenib from January 2019 to January 2023 in two medical centers in China. They were divided into primary and secondary resistance groups according to tumor progression within 3 months. Resistance was the primary outcome of this study. The secondary outcomes were progression-free survival (PFS) and overall survival (OS). Results: A total of 424 patients met the inclusion criteria, including 165 patients (38.9%) in the primary group and 259 patients (61.1%) in the secondary group. The independent risk factors for primary resistance were alpha-fetoprotein (AFP) > 400 ng/mL and alanine aminotransferase (ALT) > 40 U/L. Patients in the primary group had significantly shorter median OS than those in the secondary group (9.0 months vs 23.0 months, p < 0.001). Compared with tyrosine kinase inhibitor (TKI) monotherapy, the use of TKI plus PD-1 inhibitor combination therapy as second-line treatment conferred a longer median PFS (6.0 vs 10.0 months, p < 0.001) and OS (13.0 vs 22.0 months, p < 0.001). Conclusion: Sorafenib has a high incidence of primary resistance and short survival in patients who develop primary resistance. AFP and ALT are influential factors in primary resistance, and it is valuable to use these two metrics to guide the use of sorafenib. As second-line therapy, a TKI plus PD-1 inhibitor regimen should be preferentially recommended.

Risk factors of Hypersensitivity Reactions to Carboplatin: A Systematic Review and Meta-analysis.

The development of hypersensitivity reactions (HSRs) to carboplatin can interrupt anticancer treatment and may shorten patient survival. Several studies have evaluated the risk factors for carboplatin HSRs, but the results have been inconclusive. This systematic review and meta-analysis aim to establish a consensus on the risk factors of HSRs to carboplatin in cancer patients. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, relevant studies were searched across MEDLINE, EMBASE, and Korean Medical Database. Inclusion criteria focused on original articles of case-control or cohort studies that evaluated risk factors for carboplatin HSRs in cancer patients. Exclusion criteria targeted articles with incomplete or overlapping data. The latest search and quality assessment of the included studies, using the Newcastle-Ottawa scale, was performed on February 1, 2023. Among 1,182 articles identified, 19 studies were included in the final systematic review and meta-analysis. The identified risk factors for carboplatin hypersensitivity included a history of allergy to medicines, food, or environmental factors (OR of 1.76, 95% CI 1.46 - 2.12), BRCA mutation (OR of 4.03, 95% CI 2.00 - 8.13), carboplatin free interval of 12 months or more (OR of 4.93, 95% CI 2.89 - 8.40), increased cumulative dose (SMD of 0.58, 95% CI 0.41 - 0.75), relapse (OR of 2.26, 95% CI 1.58 - 3.25), and younger age (SMD of -0.15, 95% CI: -0.26 - -0.03). This meta-analysis provides the first comprehensive quantitative evaluation of risk factors for carboplatin HSRs in cancer patients. These findings can guide the development of personalized risk assessment tools and preventive strategies, potentially improving patient safety and treatment outcomes in carboplatin-based chemotherapy.

Impact of the Spinal Instability Neoplastic Score on Postoperative Prognosis in Patients with Metastatic Cancer of the Cervical Spine.

Background: Although the Spinal Instability Neoplastic Score (SINS) is widely utilized to evaluate spinal instability, its prognostic value for survival in patients with cervical spinal metastases remains unclear. This study investigated the association between the SINS and survival outcomes in patients with metastatic cervical spine cancer. Methods: This retrospective cohort study included 106 patients who underwent surgery for metastatic cervical spine cancer at a single institution between 1995 and 2023. Patients were divided into two groups: high SINS (≥13) and low-to-moderate SINS (0-12). Overall survival (OS) was the primary outcome and was analyzed using Kaplan-Meier estimates and Cox regression. Secondary outcomes included changes in Eastern Cooperative Oncology Group Performance Status (ECOG-PS), operation time, estimated blood loss, and postoperative complications. Results: The median OS was significantly shorter in the high SINS group compared to the low-to-moderate SINS group (5.3 months versus 8.6 months; p = 0.023). A high SINS was independently associated with increased mortality risk (hazard ratio [HR], 1.959; 95% CI, 1.221-3.143; p = 0.005). Lung cancer (HR, 4.004; 95% CI, 1.878-8.535; p < 0.001) and rectal cancer (HR, 3.293; 95% CI, 1.126-9.632; p = 0.029) were predictive of worse survival, whereas postoperative chemotherapy (HR, 0.591; 95% CI, 0.381-0.917; p = 0.019) and radiotherapy (HR, 0.531; 95% CI, 0.340-0.827; p = 0.005) were associated with improved survival. Changes in the ECOG-PS and postoperative complication rates were not significantly different between the groups. Conclusions: A high SINS was associated with significantly shorter survival in patients with metastatic cervical spine cancer, reflecting both mechanical instability and tumor aggressiveness.

Association between higher glucose levels and reduced survival in patients with non-small cell lung cancer treated with immune checkpoint inhibitors

BackgroundObesity and hypercholesterolemia have been associated with better responses to ICIs in NSCLC, while type 2 diabetes (T2D) has been associated with a worse response. However, the association between glucose levels and outcomes remains unknown. This study investigated the impact of mean baseline glucose levels, T2D, dyslipidemia, and obesity on overall survival (OS) in NSCLC patients undergoing ICI therapy. MethodsA multicenter retrospective cohort study was conducted using data from three medical centers, with locally advanced or metastatic NSCLC patients receiving ICI, regardless of treatment line or concurrent therapy. Random venous glucose levels within 4 weeks prior to ICI initiation, BMI, history of dyslipidemia, and T2D, along with OS, were assessed. Patients with BMI < 18.5 were excluded. ResultsAmong 438 patients, those with the highest quartile of baseline glucose levels had significantly shorter OS compared to those in the lowest quartile (HR, 1.53; 95 % CI, 1.08 – 2.15; p-value = 0.016). This association remind consistent after adjusting for steroid use, diabetes, performance status and glucose-lowering medication use. These effects were consistently observed in subsets of patients treated with ICI monotherapy and with PD-L1 TPS ≥ 1 %. ConclusionHigher mean baseline glucose levels correlated with shorter survival in patients with NSCLC treated with ICIs. The divergent effects of individual metabolic syndrome components on ICI response in patients with NSCLC underscore the complexity of metabolic influences on treatment outcomes.

Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity.

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in immune exhaustion. However, little is known about the mechanisms that regulate TIM-3 surface expression and turnover. Here, we report that human TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at residue cysteine 296 (Cys296). Palmitoylation stabilized TIM-3 by preventing binding to E3 ubiquitin ligase HRD1, thereby suppressing its polyubiquitination and degradation. DHHC9 knockdown attenuated chimeric antigen receptor T (CAR-T) cell exhaustion, and a peptidic inhibitor of TIM-3 palmitoylation accelerated TIM-3 degradation and enhanced antitumor immunity mediated by CAR-T cells and natural killer (NK) cells. In hepatocellular carcinoma, DHHC9 expression correlated with TIM-3 expression in CD8+ T cells and NK cells, and high DHHC9 expression was associated with shorter survival in patients with high TIM-3. These findings demonstrate that palmitoylation of TIM-3 catalyzed by DHHC9 promotes its stability, resulting in immune exhaustion and impaired antitumor immunity.

Abstract PR014: PVT1 fusion on extrachromosomal DNA (ecDNA) increases oncogene RNA stability and cancer cell growth

Abstract Extrachromosomal DNA (ecDNA), highly amplified circular DNA, is widespread in human cancers and serves as a primary location for oncogene amplification. Due to its dynamic structural rearrangement and asymmetric inheritance during cell division, ecDNA increases tumor genome complexity, contributing to drug resistance and shortened patient survival. Here, we show that ecDNA-mediated genomic amplification is highly associated with transcript fusion events, which are prevalent in cancer and often lead to tumor development. We discovered that transcripts with the highest fusion events originate from genes amplified on ecDNA across ecDNA(+) cell lines. Notably, PVT1 (Plasmacytoma Variant Translocation 1) long noncoding RNA, which is known to be a hotspot for chromosomal translocation, is the most frequently fused RNA species in MYC/PVT1-amplified ecDNA(+) cancer cells. Exon 1 of PVT1 is the predominant fusion partner and confers RNA stability, increasing the RNA abundance of the partner oncogene. Using a model cell line with PVT1-MYC fusion on ecDNA, we found that RNA expression of PVT1-MYC increases in vivo in an ecDNA-dependent manner, while canonical MYC does not show a prominent increase. Additionally, ectopic expression of PVT1- MYC in MYC-depleted cancer cells provides higher rescue efficiency than canonical MYC. In contrast, a PVT1-MYC mutant that is unable to enhance RNA stability fails to rescue, highlighting the functional significance of PVT1-mediated RNA stabilization in cancer. This study unveils the link between PVT1 fusion and ecDNA in cancer, providing insights for developing diagnostic and therapeutic approaches tailored to target ecDNA. Citation Format: Hyerim Yi, Shu Zhang, Matthew G Jones, Julia A Belk, Jason Swinderman, Quanming Shi, Ellis J Curtis, Vishnu P Kanakaveti, Paul S Mischel, Howard Y Chang. PVT1 fusion on extrachromosomal DNA (ecDNA) increases oncogene RNA stability and cancer cell growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR014.

Abstract B026: Glioblastoma multiforme disseminates outside the central nervous system

Abstract Introduction: The liquid biopsy (LB) concept has gained significant attention in the last decade and has the potential to revolutionize cancer care. However, more validation in clinical trials is required on the value of LB in medical settings. Here, we focus on glioblastoma multiforme (GBM), a highly invasive and fatal subtype of the central nervous system malignant tumors. Circulating tumor cells (CTCs) are primary tumor cells released into the peripheral blood and migrating to distant organs. CTC presence is related to tumor spread and recurrence. In GBM, factors like short patient survival, the blood-brain barrier (BBB), and lack of lymphatic drainage in brain tissue make systemic dissemination rare but possible. Thus, noninvasive CTC detection can hold potential for diagnostic, predictive, and prognostic applications. Material and Methods: For cell stability preservation before sample processing, the peripheral blood samples from curatively resected GBM patients were collected preoperatively in Cell-Free DNA BCT® tubes (Streck, Inc.). CTCs were identified using CytoTrack CT11TM (2/C), a semi-automated immunofluorescence microscopy using glial fibrillary acidic protein, vimentin, and CD45 immunostaining, and DAPI counterstaining. The preliminary Kaplan-Maier survival analysis based on CTC positivity was performed in 39 patients with a follow-up longer than two years. Results: We analyzed the CTC presence in 100 GBM patient peripheral blood samples. The CTCs or cancer cell clusters were found in 35% of GBM patients. The Kaplan-Maier survival analysis did not show a correlation between CTC presence and survival. This phenomenon may be associated with the generally short survival of these patients, which is expected to increase with advances in oncology and palliative care and/or a possible suppression of tumor cell growth outside the CNS. Conclusions: We have observed the CTCs in the peripheral blood of GBM patients. The patient enrollment and clinical data recording are still ongoing. Citation Format: Pavel Stejskal, Josef Srovnal, Alona Rehulkova, Ondrej Kalita, Marek Slachta, Marian Hajduch. Glioblastoma multiforme disseminates outside the central nervous system [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B026.

Associations Between Patient-Reported Nutritional Status, Toxicity, and Survival in Limited-Stage SCLC

IntroductionIn general, malnutrition is associated with more treatment toxicity and shorter survival in patients with cancer, but little is known about its impact on limited-stage (LS) SCLC. We investigated whether nutritional status and weight loss were associated with treatment outcomes in a randomized trial of thoracic radiotherapy (TRT) in LS SCLC (NCT02041845, n = 170). MethodsPatients received platinum/etoposide-chemotherapy and were randomized to receive TRT of 60 Gy/40 fractions or 45 Gy/30 fractions. They reported nutritional status on the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) and were categorized as having low (PG-SGA SF score 0–3), intermediate (score 4–8), or high (score ≥ 9) malnutrition risk. ResultsIn total, 113 patients who completed the PG-SGA SF at baseline and received one or more fractions of TRT were analyzed. Median PG-SGA SF score was 3.0; 52.2% had low, 29.2% intermediate, and 18.6% had high malnutrition risk; and 22.1% had 5% or more weight loss three months before enrolment. There were no significant differences in grade 3 to 4 toxicity (low: 88.1%, intermediate: 90.9%, high: 85.7%; p = 0.86), median progression-free survival (low: 15.8 months, intermediate: 11.8 months, high: 47.0 months; p = 0.25) or median OS (low: 35.5 months, intermediate: 26.8 months, high: 47.0 months; p = 0.24) across malnutrition categories. Weight loss was not significantly associated with grade 3 to 4 toxicity (≥5%: 92.0%, <5%: 87.0%; p = 0.73), median progression-free survival (≥5%: 24.0 months, <5%: 15.9 months; p = 0.51) or median OS (≥5%: 30.6 months, <5%: 35.5 months; p = 0.74). ConclusionPatient-reported nutritional status and weight loss before concurrent chemoradiotherapy were neither associated with toxicity nor survival.

PATH-27. MOLECULAR, IMAGING, AND SURVIVAL MANIFESTATIONS IN MOLECULAR GLIOBLASTOMAS: INSIGHTS FROM A MULTI-NATIONAL STUDY

Abstract Apart from the traditional definition of IDH-wildtype GBM based on histological characteristics, IDH-wildtype diffuse gliomas previously assigned to histological grade 2 or 3 are now defined as IDH-wildtype GBM in the presence of qualifying molecular markers (TERTp mutation, EGFR amplification, or chromosome +7/-10) (“molecular GBM”) in the 2021 WHO classification. However, the clinical significance of molecular GBM is unrevealed. This collaboration aims to comprehensively evaluate the clinical, molecular, imaging characteristics, and prognosis of molecular GBMs in a multi-national dataset and stratify survival. Retrospective chart and imaging review was performed in 258 molecular GBM patients from eight centers across three continents. Clinical, molecular, imaging, and survival characteristics were analyzed. The median age of molecular GBM patients was 58 years (range: 23-83) with 139 males, with TERTp mutation (83 of 214 [38.8%]), EGFR amplification (160 of 204 [78.4%]), and chromosome +7/-10 (82 of 143 patients [57.3%]). The majority of tumors were located at the frontal and temporal lobes (48.4%) and exhibited non-contrast-enhancing (CE) tumors (73.7%). Gliomatosis cerebri pattern was shown with 27 patients (12.4%). The median OS was 28.1 months (95% confidence interval 22.1-34.1). There was significantly shorter survival in patients with high Ki-67 index (&amp;gt; 20) compared to those with low Ki-67 index (median OS 19.3 vs. 31.5 months, log-rank test P = 0.002), while no survival differences were found according to histological grade or molecular diagnostics. Survival was significantly shorter in patients with infiltrative imaging appearance compared to those without (median OS 24.7 vs 41.0 months, log-rank test P = 0.014). In conclusion, survival within molecular GBM patients may be heterogeneous and associated with Ki-67 index and infiltrative imaging appearance.

STEM-06. DISTANT ORIGIN OF GLIOBLASTOMA RECURRENCE: NEURAL STEM CELLS IN THE SUBVENTRICULAR ZONE SERVE AS A SOURCE OF TUMOR RECONSTRUCTION AFTER PRIMARY RESECTION

Abstract The recurrence of glioblastoma (GBM) remains unavoidable. Neural stem cells (NSCs) in the subventricular zone (SVZ) are considered a treatment target due to their potential role as the cellular origin of GBM. However, it is not yet confirmed whether GBM recurrence also originates from these cells. We first conducted deep sequencing on paired patient samples, including primary tumors (pT), recurrent tumors (rT), and SVZ tissues. The sequencing results revealed that in 5 out of 9 patients, the rT evolved independently from the SVZ rather than directly from the pT. Based on this, we developed a mouse model to simulate the GBM recurrence process by transforming SVZ NSCs into GFP-labeled cells carrying cancer mutations via electroporation. Following the resection of the tdTomato-labeled pT, we observed that 57.1% of the rT consists of a mixture of GFP- and tdTomato-positive tumor cells. To study the behavior of NSCs, we improved the existing mouse model by removing cortical tissue to simulate the complete resection of the pT. Four weeks post-surgical resection, 64.7% of tumors reconstructed in the resection cavity (RC), driven by the migration of OPC lineage cells. Time-course RNA-seq results indicated that the CXCL12-CXCR4 pathway might be responsible for driving the migration of SVZ NSCs to the RC. Further deconvolution and fluorescence staining analysis confirmed that CXCL12 secreted by endothelial cells around the RC could drive CXCR4-positive NSCs to migrate to the area. Additionally, the CXCR4 antagonist AMD3100 significantly reduced tumor recurrence in mice and extended survival. RNA-seq results from both mouse and human paired tumor samples confirmed that the CXCL12-CXCR4 pathway was enriched in locally recurrent tumor specimens and was correlated with shorter patient survival. In summary, our study provides evidence that GBM recurrence originates from SVZ NSCs. Moreover, we identified the CXCL12-CXCR4 pathway as a potential therapeutic target for GBM recurrence.

PTPN11 Mutations Are Associated with Shorter Survival in Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents and Venetoclax

<i>PTPN11</i> Mutations Are Associated with Shorter Survival in Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents and Venetoclax

STEMI SHOCK outcomes with SCAI classification

Abstract Background Patients with ST-elevation myocardial infarction who develop cardiogenic shock (STEMI-SHOCK) face significantly increased risk compared to those without shock. Mechanical circulatory support (MCS) devices are commonly utilized in STEMI-SHOCK patients, but the benefits of MCS remain uncertain. This study aims to apply the Society for Cardiovascular Angiography and Interventions (SCAI) shock classification system to STEMI-SHOCK patients, examining outcomes and identifying subgroups that may benefit from MCS. Purpose Our study assessed SHOCK severity in STEMI-SHOCK patients using the updated 2021 SCAI-SHOCK classification system and determined survival at various endpoints (30 days, 1 year, and 3 years), along with other outcomes such as vascular access complications and major adverse cardiac events, based on the severity class. Methods Patients with angiograms and indications of STEMI-SHOCK between 2012 and 2021 admitted to Liverpool Hospital Australia, were included after adjudication they had STEMI-SHOCK. Angiograms were eligible for adjudication if they met criteria for both STEMI and SHOCK. Each patient underwent individual adjudication by three researchers to confirm STEMI-SHOCK status. Patients were followed from the time of the first SHOCK diagnosis until censoring at the last follow-up. Data were retrieved from electronic and paper-based patient records. The primary outcome was 30-day survival, and secondary outcomes were 1-year and 3-year survival. Results The SCAI stages of 160 (Estimated 220) STEMI-SHOCK patients were determined, with 17 in Stage A, 39 in Stage B, 53 in Stage C, 25 in Stage D, and 26 in Stage E. Worse SCAI stages were associated with significantly lower 30-day, 1-year, and 3-year survival. No difference in survival between the time periods 2013-2015 and 2018-2021 was found. An eGFR &amp;lt; 60 millilitres/minute/1.73 meters^2 (hazard ratio [HR] 3.41; 95% confidence interval [CI] 1.18 – 9.92, p=0.024) and lactate greater than 4.15 millimoles/liter (HR 6.48; 95% CI [2.84 – 51.64], p=0.001) at shock were associated with lower 30-day and 3-year survival. Patients in the SCAI C subgroup treated with an IABP had significantly higher 1-year (p=0.001) and 3-year (p=0.001) survival compared to those not treated with an IABP. Conclusion The SCAI classification system successfully predicted short and long-term survival in STEMI-CS patients, with worse stages having progressively worse outcomes. No improvement in survival outcomes was observed in the overall SCAI C-E group of patients treated with mechanical support. However, patients in the SCAI C subgroup of SHOCK treated with mechanical support showed a statistically significant improvement in survival outcomes compared to those treated without mechanical support. Further studies with adequate sample sizes are required to investigate sub-populations of SCAI classes that may benefit from MCS devices.

Short Survival of Patients with Chronic Obstructive Pulmonary Disease and a Do-Not-Resuscitate Order Despite the Noninvasive Positive Pressure Ventilatory Support: A Retrospective Cohort Study in Taiwan

Short Survival of Patients with Chronic Obstructive Pulmonary Disease and a Do-Not-Resuscitate Order Despite the Noninvasive Positive Pressure Ventilatory Support: A Retrospective Cohort Study in Taiwan

Brain Metastases from Esophageal Cancer: A Retrospective Review from a Single Institution

Patients with brain metastases (BrMs) from esophageal cancer have poor prognosis, the incidence of which is expected to rise due to improved survival from the primary tumor and increased neuroimaging. We aimed to identify patient and esophageal cancer characteristics associated with shorter survival in patients with BrMs and, secondly, to compare the prognosis of patients with HER2 overexpression. We retrospectively reviewed patients with BrMs from esophageal cancer at a single institution from 2008-2021. We collected patient demographics, primary tumor and BrM characteristics, and treatment. Our primary outcome was median survival from the time of BrM. The median age at primary diagnosis was 66.5 years and 86% were male. Of the 49 patients, 71% had adenocarcinoma, 20% squamous cell carcinoma and 8% other. In this group, 71% of patients presented with stage III or IV disease, including 16% with synchronous primary metastatis and BrM. The median time to BrM was 10.1 months (interquartile range 1.7-22.8) and the median survival from BrM was 8.4 months (95% CI 4.8-16.8 months). On multivariable analysis, treatment with stereotactic radiosurgery (hazard ratio [HR]=0.19; P= 0.04), surgical resection (HR 0.24; P= 0.03), and immunotherapy (HR 0.19; P= 0.04) were associated with increased survival while Karnofsky Performance Status (KPS) ≤70 (HR=13.2; P < 0.001) was associated with decreased survival. HER2 overexpression was found in 22% of patients, but we noted no survival difference (5.2 months HER2+ vs. 9.8 months HER2neg; P= 0.95). The median survival from esophageal-to-brain metastasis was 8.4 months. Patients with a single lesion, KPS score >70, and treatment with surgical resection was correlated with improved survival. Further, HER2+ patients had distinct patient and BrM characteristics.

Analysis of the implication of steroid 5 alpha-reductase 3 on prognosis and immune microenvironment in Liver Hepatocellular Carcinoma

Introduction This study combined the bioinformatics and in vitro experiment-related technologies to analyze the impact of steroid 5 alpha-reductase 3 (SRD5A3) on the prognosis and immune microenvironment of Liver Hepatocellular Carcinoma (LIHC). Method Gene expression and clinical data were obtained from public databases. The prognosis was evaluated using survival, multifactor Cox, enrichment, and mutation analyses. This was then verified through in vitro experiments. Results The expression level of SRD5A3 in LIHC tissues was significantly higher than that in the adjacent tissues. Kaplan–Meier survival analysis showed that high SRD5A3 expression was associated with poor overall survival (OS) and short progression-free survival in patients with LIHC. Multivariate Cox regression analysis revealed that positive SRD5A3 expression was an independent risk factor for OS in patients with LIHC. Expression of SRD5A3 was negatively correlated with immune cell infiltration of CD4+ T, CD8+ T, and B cells. GO and KEGG enrichment analyses showed that SRD5A3 was significantly enriched in signaling- and tumor metastasis-related pathways. Nomogram and calibration curve showed that the predicted performance of the model was consistent with the actual results. In vitro results confirmed that SRD5A3 knockdown inhibited the migration, invasion, and proliferation of LIHC cells. Conclusions SRD5A3 is actively expressed in LIHC, and positive expression of SRD5A3 is an independent risk factor for different prognoses in patients with LIHC. SRD5A3 can promote the proliferation, migration, and invasion of liver cancer cells and is related to short immune infiltration in patients with LIHC.

Facilitating cholangiocarcinoma inhibition by targeting CD47

Immune evasion is one of the mechanisms by which cancer cells acquire immunity during cancer development and progression. One of these is the increased expression of cluster of differentiation 47 (CD47), a transmembrane glycoprotein that protects cells from phagocytic elimination. The interaction between CD47 and signal regulatory protein alpha (SIRPα) on macrophages alleviates the phagocytic signal. The present group previously reported high CD47 expression in cholangiocarcinoma (CCA), a major health problem in Thailand and East Asia, and that blocking CD47 using anti-CD47 antibodies promoted the removal of CCA. However, the mechanism through which CD47 inhibition attenuates CCA growth remains unclear. This study explored the clinical significance of targeting CD47 in CCA. Expression levels of CD47 and the macrophage marker CD68 were determined in CCA tissues by immunohistochemistry and correlated with clinical parameters. The role of CD47 in CCA cells was established using CD47-deficient KKU-213A CCA clones in vitro and in vivo. The results showed that CD47 was highly expressed in CCA tissues and significantly correlated with lymph node metastasis (P = 0.038). Moderate-to-dense CD68-positive infiltrating cells in CCA tissues were significantly associated with shorter survival of patients (P = 0.019) and were an independent prognostic factor of CCA patients as determined by the Cox proportional hazard model (hazard ratio, 2.040; 95 % confidence interval, 1.109–3.752; P = 0.022). Three CD47-deficient KKU-213A clones (#19, #23, and #28) were generated. The elimination of CD47 did not affect cell proliferation but increased monocyte-derived macrophage-mediated phagocytosis in vitro. Decreased tumor weights and volumes were observed in mice injected with CD47-deficient CCA clones. This revealed a significant role for CD47 in CCA, with a focus on protecting cancer cells from macrophage phagocytosis.

TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis.

Metabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. Here, we identified that the tectonic family member TCTN1 promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo, and TCTN1 induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor EMT and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.

An elevated rate of whole-genome duplications in cancers from Black patients

In the United States, Black individuals have higher rates of cancer mortality than any other racial group. Here, we examine chromosome copy number changes in cancers from more than 1800 self-reported Black patients. We find that tumors from self-reported Black patients are significantly more likely to exhibit whole-genome duplications (WGDs), a genomic event that enhances metastasis and aggressive disease, compared to tumors from self-reported white patients. This increase in WGD frequency is observed across multiple cancer types, including breast, endometrial, and lung cancer, and is associated with shorter patient survival. We further demonstrate that combustion byproducts are capable of inducing WGDs in cell culture, and cancers from self-reported Black patients exhibit mutational signatures consistent with exposure to these carcinogens. In total, these findings identify a type of genomic alteration that is associated with environmental exposures and that may influence racial disparities in cancer outcomes.

Intratumoral microbiota of pancreatic ductal adenocarcinoma impact patient prognosis by influencing tumor microenvironment

BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by a highly metastatic potential and a heterogeneous tumor microenvironment. It exhibits limited sensitivity to conventional therapies, necessitating a deeper understanding of its pathogenesis. The role of the intratumoral microbiome in regulating cancer development in PDAC has been the subject of debate. Previous investigations into intra-tumor microbiomes have yielded uncertain results due to sample size limitations and insufficient decontamination procedures. Further research is imperative to elucidate the intricate relationship between intra-tumor microbiomes, the immune landscape of PDAC, and overall prognosis.ResultsOur findings revealed that the intratumor microbiota in PDAC tissue exhibited lower diversity and distinct communities compared to non-tumor tissues. The top microorganisms distinguishing between patients with long or short survival were used to construct the risk signature. We found that Stenotrophomonas is implicated in short survival of PDAC patients, while Neorickettia and Mediterraneibacter are correlated with long survival. This microbiome-based PDAC subtyping, grounded in prognosis-related signatures, exhibited significant correlations with distinct clinical prognoses and immune microenvironments. Microorganisms associated with negative prognoses were linked to pro-tumor immune activation, while those associated with positive prognoses were linked to anti-tumor immune response activation and a more favorable prognosis.ConclusionsOur PDAC subtyping approach, based on a microbiome-derived prognostic risk signature, unveiled compelling associations between the PDAC microbiota and disparities in both clinical prognosis and the tumor microenvironment. These findings suggest that microbiota may serve as a promising biomarker for predicting the prognosis of PDAC.

Prognostic and Clinical Significance of the Proliferation Marker MCM7 in Breast Cancer.

Minichromosome maintenance complex component 7 (MCM7) plays an essential role in proliferation and DNA replication of cancer cells. However, the expression and prognostic significance of MCM7 in breast cancer (BC) remain to be defined. In this study, we aimed to evaluate the role of MCM7 in BC. We conducted immunohistochemistry staining of MCM7 in 1,156 operable early-stage BC samples and assessed MCM7 at the transcriptomic levels using publicly available cohorts (n = 13,430). MCM7 expression was evaluated and correlated with clinicopathological parameters including Ki67 labelling index and patient outcome. At the transcriptomic level, there was a significant association between high MCM7 mRNA levels and shorter patient survival in the whole cohort and in luminal BC class but not in the basal-like molecular subtype. High MCM7 protein expression was detected in 43% of patients and was significantly associated with parameters characteristic of aggressive tumour behaviour. MCM7 was independently associated with shorter survival, particularly in oestrogen receptor-positive (luminal) BC. MCM7 stratified luminal tumours with aggressive clinicopathological features into distinct prognostic groups. In endocrine therapy-treated BC patients, high MCM7 was associated with poor outcome, but such association disappeared with administration of adjuvant chemotherapy. Patients with high expression of Ki67 and MCM7 showed worst survival, while patients with double low expression BC showed the best outcome compared with single expression groups. The current findings indicate that MCM7 expression has a prognostic value in BC and can be used to identify luminal BC patients who can benefit from adjuvant chemotherapy.