Cancers最新文献

Lung cancer is the leading cause of cancer-related deaths worldwide, highlighting a major clinical challenge. Lung cancer is broadly classified into two histologically distinct subtypes, termed small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Identification of various oncogenic drivers of NSCLC has facilitated the development of targeted therapies that have dramatically improved patient outcomes. However, acquired resistance to these targeted therapies is common, which ultimately results in patient relapse. Several on-target and off-target resistance mechanisms have been described for targeted therapies in NSCLC. One common off-target mechanism of resistance to these therapies is histological transformation of the initial NSCLC into SCLC, a highly aggressive form of lung cancer that exhibits neuroendocrine histology. This mechanism of resistance presents a significant clinical challenge, since there are very few treatments available for these relapsed patients. Although the phenomenon of NSCLC-to-SCLC transformation was described almost 20 years ago, only recently have we begun to understand the mechanisms underlying this therapy-driven response. These recent discoveries will be key to identifying novel biomarkers and therapeutic strategies to improve outcomes of patients that undergo NSCLC-to-SCLC transformation. Here, we highlight these recent advances and discuss the potential therapeutic strategies that they have uncovered to target this mechanism of resistance.

Background: The phosphoinositide 3-kinase (PI3K) pathway is activated in multiple cancers. However, the significance of PIK3R1 encoding the PI3K regulatory subunit, an inhibitor of the PI3K catalytic subunit encoded by PIK3CA, in ovarian cancer development is largely unknown.

Methods: Here, we investigated PIK3R1 genomic alterations and gene expression by direct sequencing and qPCR methods in 197 ovarian cancers. The results were correlated with clinicopathological and molecular variables and patient outcomes.

Results: In addition to mutations (3.5%) and allelic losses (28.4%), we observed a very high frequency of decreased PIK3R1 mRNA levels in ovarian carcinomas (95.8%). Tumors with PIK3R1 mutations mostly represented low-stage cancers of endometrioid and clear-cell type. Tumors with PIK3R1 deletion and underexpression shared similar phenotypes of high-grade carcinomas (p = 0.003 and p = 0.025, respectively). Allelic loss was also associated with advanced stages (p = 0.003) and high-grade serous histotypes (p = 0.004). The PIK3R1 copy number correlated with mRNA levels (p = 0.009). PIK3R1 mutations coexisted with PTEN mutations (p = 0.041), whereas PIK3R1 deletion and underexpression were linked to PIK3CA amplification (p = 0.038 and p = 0.033, respectively). Low PIK3R1 expression diminished the probability of a complete response (OR 0.07, p = 0.03) in patients treated with platinum-based regimens.

Conclusions: PIK3R1 alterations may contribute to the development of ovarian cancers with different malignant potential and molecular changes. The high frequency of PIK3R1 aberrations suggests their importance in PI3K pathway deregulation, and they may potentially serve as an alternative to PIK3CA markers for therapy with these pathway inhibitors.

Background/objectives: Cirrhosis is the precursor to most cases of hepatocellular carcinoma (HCC). Understanding the mechanisms leading to the transition from cirrhosis to HCC and identifying key biomarkers is crucial to developing effective screening strategies and reducing HCC-related mortality. DNA methylation is associated with gene inactivation and plays an important role in physiological and pathological processes; however, its role in cirrhosis progression to HCC is unknown.

Methods: We performed genome-wide DNA methylation profiling using Illumina Infinium MethylationEPI BeadChip in pre-diagnostic samples from 22 cirrhosis patients who subsequently developed HCC and 22 cirrhosis patients who remained HCC-free during an average 4-year follow-up. In a secondary analysis, we examined a subset of patients without hepatitis C virus (HCV) infection.

Results: We identified three differentially methylated positions (DMPs) located in ADAM12 (cg13674437) and PSD3 (cg06758847 and cg24595678) that show a strong association with HCC risk (lower median vs. higher median hazards ratio (HR): HR _cg13674437 = 0.34, 95% CI = 0.14-0.83; HR _cg06758847 = 4.89, 95% CI = 1.79-13.33; HR _cg24595678 = 11.19, 95% CI = 3.27-38.35). After excluding all HCV-active patients from our analysis, the HR for the DMPs remained significant.

Conclusions: In conclusion, the findings in this study support the theory that buffy coat-derived DNA methylation markers could be used to identify biomarkers among cirrhosis patients at high risk for HCC before clinical symptoms appear. A further study with a large prospective cohort is required to validate these findings.

Tumors located at the tracheal bifurcation constitute a heterogeneous group of neoplasms whose treatment poses significant challenges due to their anatomical location, the requirement for radical resection, the need to restore local anatomy, and the necessity of maintaining adequate oxygenation throughout the entire procedure. Advances in airway reconstruction surgical techniques, anesthesia, and complementary therapies have progressively expanded indications for radical treatment of these neoplasms, resulting in significant improvements in both short- and long-term outcomes in recent years.

Background: Breast cancer patients who develop brain metastases have a high mortality rate and a massive decrease in quality of life. Approximately 10-15% of all patients with breast cancer (BC) and 5-40% of all patients with metastatic BC develop brain metastasis (BM) during the course of the disease. However, there is only limited knowledge about prognostic factors in the treatment of patients with brain metastases in breast cancer (BMBC). Therefore, we retrospectively analyzed data of BMBC patients from the University Hospital of Würzburg for treatment patterns to find characteristics associated with a better or worse prognosis. These findings should help to treat the ever-increasing collective of patients with BMBC better in the future. Methods: The clinical data of 337 patients with cerebral metastatic breast cancer (date of death between 2004 and 2021) treated at the Department of Gynecology and Obstetrics of the University Hospital Würzburg were retrospectively analyzed, with a focus on patients' survival. Results: The involvement of regional lymph nodes at initial diagnosis, the immunohistochemical subtype of TNBC at the onset of BMBC, and extracranial metastases at the time of BM diagnosis (bone, liver, lung metastases) were associated with a worse prognosis. In contrast, the immunohistochemical subtype of HER2/neu, the sole occurrence of a singular BM, the local surgical removal of BMs, and radiotherapy (especially stereotactic radiotherapy) were associated with prolonged survival. The number of therapies before the diagnosis of BMs also had a prognostic influence. Conclusions: Looking back at data is crucial for pinpointing risk elements affecting survival after a BM diagnosis. In our investigation, along with established factors like immunohistologic subtype, BM count, surgical excision, stereotactic irradiation, and type of extracranial metastasis, we also found that the number of therapies before BM diagnosis and the initial lymph node status were associated with patients' survival. Potentially, these factors could be included in prospective prognostic scores for evaluating brain metastasis survival rates, thereby aiding in making appropriate treatment suggestions for impacted patients.

Background/Objectives: This study aimed to construct a risk score (RS) based on necroptosis-associated genes to predict the prognosis of patients with advanced epithelial ovarian cancer (EOC). Methods: EOC data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) series 140082 (GSE140082) were used. Based on known necroptosis-associated genes, clustering was performed to identify molecular subtypes of EOC. A least absolute shrinkage and selection operator (LASSO)-Cox regression analysis identified key genes related to prognosis. The expression of one of them, RIPK3, was analyzed via immunohistochemistry in an EOC cohort. Results: An RS made from ten genes (IDH2, RIPK3, FASLG, BRAF, ITPK1, TNFSF10, ID1, PLK1, MLKL and HSPA4) was developed. Tumor samples were divided into a high-risk group (HRG) and low-risk group (LRG) using the RS. The model is able to predict the overall survival (OS) of EOC and distinguish the prognosis of different clinical subgroups. Immunohistochemical verification of the receptor-interacting serine/threonine-protein kinase (RIPK) 3 confirmed that high nuclear expression is correlated with a longer OS. In addition, the score can predict the response to a programmed death ligand 1 (PD-L1) blockade treatment in selected solid malignancies. Patients from the LRG seem to benefit more from it than patients from the HRG. Conclusions: Our RS based on necroptosis-associated genes might help to predict the prognosis of patients with advanced EOC and gives an idea on how the use of immunotherapy can potentially be guided.

Cholangiocarcinoma (CCA) represents approximately 3% of all gastrointestinal cancers and is a highly heterogeneous and aggressive malignancy originating from the epithelial cells of the biliary tree. CCA is classified by anatomical location into intrahepatic (iCCA), extrahepatic (eCCA), gallbladder cancer (GBC), and ampullary cancers. Although considered a rare tumor, CCA incidence has risen globally, particularly due to the increased diagnosis of iCCA. Genomic and immune profiling studies have revealed significant heterogeneity within CCA, leading to the identification of molecular subtypes and actionable genetic alterations in 40-60% of cases, particularly in iCCA. Among these, FGFR2 rearrangements or fusions (7-15%) and IDH1 mutations (10-20%) are common in iCCA, while HER2 amplifications/overexpression are more frequent in eCCA and GBC. The tumor-immune microenvironment (TIME) of CCAs plays an active role in the pathogenesis and progression of the disease, creating a complex and plastic environment dominated by immune-suppressive populations. Among these, cancer-associated fibroblasts (CAFs) are a key component of the TIME and are associated with worse survival due to their role in maintaining a poorly immunogenic landscape through the deposition of stiff extracellular matrix and release of pro-tumor soluble factors. Improved understanding of CCA tumor biology has driven the development of novel treatments. Combination therapies of cisplatin and gemcitabine with immune checkpoint inhibitors (ICIs) have replaced the decade-long standard doublet chemotherapy, becoming the new standard of care in patients with advanced CCA. However, the survival improvements remain modest prompting research into more effective ways to target the TIME of CCAs. As key mechanisms of immune evasion in CCA are uncovered, novel immune molecules emerge as potential therapeutic targets. Current studies are exploring strategies targeting multiple immune checkpoints, angiogenesis, and tumor-specific antigens that contribute to immune escape. Additionally, the success of ICIs in advanced CCA has led to interest in their application in earlier stages of the disease, such as in adjuvant and neoadjuvant settings. This review offers a comprehensive overview of the immune biology of CCAs and examines how this knowledge has guided clinical drug development, with a focus on both approved and emergent treatment strategies.

Background/Objectives: Bladder cancer is a significant clinical problem with approximately 500,000 new cases worldwide annually. In approximately 25% of cases, disease is diagnosed at a stage of invasion of the muscle layer of the bladder. The current standard approach in this disease is preoperative chemotherapy followed by radical cystectomy. Dose-dense MVAC (ddMVAC), a two-day chemotherapy regimen, is the reference treatment protocol in this setting. The presented study evaluated the effectiveness and safety of accelerated MVAC (aMVAC) chemotherapy-a one-day regimen given before the resection of the bladder due to muscle-invasive disease. Methods: A retrospective analysis included 119 consecutive patients diagnosed with urothelial muscle-invasive bladder cancer (MIBC) who underwent preoperative chemotherapy with the aMVAC regimen. The planned treatment included 4-6 cycles of preoperative chemotherapy. The analysis of the degree of histopathological response to treatment was based on the three-grade TRG (tumor regression grade) classification. Results: A complete pathological response (TRG1) was observed in 44 patients (36.7%), and a major pathologic response (p = 0.00118). Patients who received at least 4 cycles (compared to ≤3 cycles) of neoadjuvant chemotherapy had a significantly higher chance of achieving a pathological response (partial or complete) to treatment (78.1% vs. 52.2%, RR 0.68, p = 0.0374). Administration of at least five cycles of chemotherapy was associated (compared to four cycles) with a significantly higher likelihood of achieving a complete pathological response (63.2% vs. 33.8%, RR = 1.71, p = 0.0221). The vast majority of adverse events were in grades 1 and 2, according to CTCAE version 5.0. Only five patients experienced grade 3-4 toxicities. The most common adverse event was anemia, which occurred in 66.3% of patients. Conclusions: Our real-world data analysis confirms the activity, safety, and feasibility of the aMVAC regimen as neoadjuvant chemotherapy in patients with urothelial MIBC.

Background: Neoadjuvant systemic therapy is the preferred treatment approach for stage II-III HER2-positive breast cancer (BC). Real-life data comparing regimens with or without anthracyclines combined with two HER2 drugs is lacking. We compared the efficacy and toxicity of two commonly used regimens.

Methods: Retrospective data were collected on patients newly diagnosed with clinical stage II-III HER2-positive BC and treated at Sheba Medical Center, Israel, between September 2017 and June 2022 with either neoadjuvant DCbHP (docetaxel, carboplatin, trastuzumab, pertuzumab) or ACTHP (doxorubicin, cyclophosphamide, paclitaxel trastuzumab pertuzumab). PCR (pathological complete response) (ypT0/isN0) was evaluated in both cohorts and according to HER2 immunohistochemistry (IHC) staining (3+ or 2+ and fluorescence in situ hybridization [FISH] positive), estrogen receptor (ER), tumor size and nodal status. The toxicity indices evaluated were reductions in left ventricle ejection fraction (LVEF), dose reductions, hospitalizations and febrile neutropenia.

Results: Here, 106 received ACTHP and 73 received DCbHP. Median age at diagnosis, ER status, HER2 IHC (2+/FISH pos or 3+) and nodal status were balanced. PCR occurred in 63.1% of patients, 67.0% and 57.5% in the ACTHP and DCbHP groups, respectively (p = 0.129). In patients with HER2 3+ IHC, pCR rates were significantly better with the ACTHP regimen than with DCbHP (83% vs. 62.9%, p < 0.039). No difference was observed among patients with HER2 +2 IHC FISH pos. Symptomatic LVEF decrease was observed in seven patients (6.6%) receiving ACTHP vs. none (0%) receiving DCbHP (p < 0.001).

Conclusions: PCR rates were similar overall between ACTHP and DCbHP; however, in the HER2 3+ subgroup, ACTHP demonstrated increased efficacy. DCbHP was significantly less cardiotoxic.

Background: Mounting evidence exhibits circRNAs as critical regulators in the progression of many tumors. The regulatory function and potential mechanism by which circ_0008126 in gastric cancer (GC) is unknown.

Methods: To validate and analyze the expression levels and clinical values of circ_0008126 in GC patients, the biological phenotypes of circ_0008126 in GC were investigated in vitro and in vivo. The roles and effects of circ_0008126 on miR-502-5p, EIF4A3, and APC in GC cells were explored using rescue experiment, RNA stability assay, RNA pull-down, dual-luciferase reporter, RNA immunoprecipitation (RIP), RNA FISH, immunofluorescence (IF), and TOP/Flash and FOP/Flash assays.

Results: Circ_0008126 expression levels were prominently down-regulated in GC tissues and cells. Importantly, low expression of circ_0008126 was relevant to the more lymphatic metastasis, advanced TNM stage, and poor survival period in patients with GC. Functionally, circ_0008126 inhibited GC cell proliferative activity, metastatic ability, and epithelial-mesenchymal transition (EMT) in vitro and vivo. Mechanistically, we verified that EIF4A3 can mediate the formation of circ_0008126, and circ_0008126 could competitively bind miR-502-5p and alleviate its role and effect on APC, thus inactivating the β-catenin pathway in GC. Additionally, circ_0008126 was determined to increase the stability of APC mRNA by interacting with cytoplasmic EIF4A3 protein and then enhancing the APC expression.

Conclusions: These data demonstrate that EIF4A3-mediated circ_0008126 could regulate the APC expression and inactivate the β-catenin pathway partly by binding to miR-502-5p and EIF4A3, thus inhibiting the tumorigenesis and development of GC.