BMC Cancer最新文献

Background: Further research is still needed to fully understand the potential of prostate-specific membrane antigen (PSMA) in breast cancer (BC) and to develop and optimize targeted therapies and imaging modalities. The objective of this study was to present a comprehensive analysis of immunohistochemistry data on PSMA staining in BC and to discuss its potential value in a theranostic approach.

Methods: Fifty-eight male and female patients were randomly selected from a retrospective database of patients who underwent surgery for breast cancer between January 2012 and December 2017 and for whom a specimen is available in our tumour library. Immunodetection of PSMA and CD31 was performed on serial slides. The digitized slides were reviewed and analysed by an experienced pathologist. Additionally, the corresponding TIFF images were processed to calculate the percentage of positive neovessels.

Results: Eighteen patients (31.6%) had no expression, 29 (50.9%) had PSMA neovascular expression scored as "1", and 10 (17.5%) had neovascular expression scored as "2". Digital immunohistochemistry analysis for this last specific group of patients showed a median proportion of positive neovessels equal to 5% (range: 3-19). A multivariable logistic regression demonstrated that the odds of PSMA positivity were 4.55 times higher in non-luminal tumours and decreased by a factor of 0.12 in lobular subtypes. There was no association between sex or the presence of a germline BRCA1/2 mutation and PSMA expression in tumours.

Conclusions: Our study highlights generally low neovascular expression of PSMA in specific histopathological subtypes of breast cancer, which will likely hamper the development of an adequate theranostic strategy.

Trial registration: The procedure has been retrospectively registered to the French National Institute for Health Data (N° F20220615153900).

Background: Chemotherapy including cisplatin is recommended for the treatment of advanced bladder cancer, but its effectiveness is limited due to the acquisition of drug resistance. Although several mechanisms of cisplatin resistance have been reported, there are still many unknowns, and treatment of cisplatin-resistant bladder cancer remains difficult. Accordingly, in this study, we aimed to identify and characterize microRNAs involved in cisplatin resistance.

Methods: Small RNA sequencing analysis was performed to search for microRNAs related to cisplatin resistance. The identified microRNAs were then characterized using gain-of-function studies, sensitivity analysis, target gene analysis, and cellular assays.

Results: We identified miR-424-5p as a candidate microRNA that was downregulated in cisplatin-resistant strains compared with parental strains. Notably, in gain-of-function studies, miR-424-5p suppressed the proliferative ability of cisplatin-resistant bladder cancer (CDDP-R BC). Furthermore, miR-424-5p restored sensitivity to cisplatin. RNA sequence analysis revealed seven candidate genes targeted by this microRNA. Among them, cyclin E1 (CCNE1) was chosen for subsequent analyses because its expression was upregulated in cisplatin-resistant cells compared with parental cells and because recent studies have shown that CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Therefore, we performed functional analysis using the PKMYT1 inhibitor RP-6306 and demonstrated that RP-6306 inhibited cell growth through suppression of mitotic entry and restored cisplatin sensitivity in CDDP-R BC.

Conclusions: Overall, our findings provided insights into the development of novel therapeutic strategies for CDDP-R BC.

Background: The safety and efficacy of combination of gefitinib with chemotherapy and bevacizumab in treatment patients with epidermal growth factor receptor (EGFR) mutations are currently unknown. This study was designed to evaluate the safety and preliminary efficacy of a combination therapy consisting of gefitinib, bevacizumab, pemetrexed, and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations.

Methods: Eligible patients with EGFR-mutated advanced non-squamous NSCLC were recruited and received gefitinib combination with bevacizumab plus pemetrexed and carboplatin treatment. The primary endpoints were safety and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS).

Results: From June 2019 to June 2021, 20 patients were enrolled in this study. The median follow-up was 33.8 months (95% CI, 31.0-36.6). Grade ≥ 3 adverse events was 65%, including neutropenia (30%), thrombocytopenia (20%), nausea (20%), skin rash (20%), bleeding (10%), and increased ALT (10%). There was no death related to toxicity occurred. The median PFS was 28 months (95% CI, 20.4-35.6). the ORR was 95% (95% CI, 75.1-99.9%), the DCR was 100% (95% CI, 83.2-100%), and the median DOR was 26.4 months (95% CI, 18.9-33.9). The median OS has not been reached.

Conclusion: The results of this study demonstrate that the four-drug combination regimen, led by gefitinib, is manageable and tolerated and effective for patients with EGFR-mutated advanced non-squamous NSCLC.

Background: The aim of this study is to investigate the real-world efficacy and safety of nivolumab in combination with chemotherapy for patients with advanced human epidermal growth factor receptor 2 (HER2)-negative gastric cancer (GC).

Methods: We enrolled patients diagnosed with unresectable advanced or metastatic GC who received nivolumab plus chemotherapy as first-line systemic treatment. The combined positive score (CPS), indicating the number of programmed cell death-ligand 1 (PD-L1)-stained cells, was utilized. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Adverse events (AEs) were graded, and treatment was ceased upon disease progression or intolerance.

Results: A total of 27 patients were included in the study, comprising 15 patients with CPS ≥ 5 and 12 patients with CPS < 5. The objective response rate (ORR) was 55.6%, with a disease control rate (DCR) of 74.1%. Patients in the CPS ≥ 5 group exhibited higher ORR and DCR compared to those in the CPS < 5 group. Median PFS and OS were 6.1 months and 14.6 months, respectively; patients with CPS ≥ 5 showed a trend towards better PFS and OS than those with CPS < 5. Most AEs were grade 1-2, with a few instances of grade 3-4 toxicities reported, including neutropenia, thrombocytopenia, diarrhea, and anemia. There were no grade 5 AEs reported in our cohort. Furthermore, 64.7% of patients received subsequent anticancer treatment following disease progression on nivolumab plus chemotherapy.

Conclusions: The results of our study demonstrate the efficacy and safety of nivolumab plus chemotherapy in real-world practice support its adoption as a new standard first-line treatment for patients with advanced HER2-negative GC, particularly those with CPS ≥ 5.

Objective: To compare the diagnostic performance of pancreatic lesions using percutaneous ultrasound (US)-guided core needle biopsy (CNB) with and without contrast-enhanced ultrasound (CEUS).

Method: The patients were divided into two groups, US and CEUS group, based on whether CEUS was performed prior to biopsy. Before and after propensity score matching (PSM), the CNB-relevant characteristics of the two groups, including the first puncture success rate, the number of sampling, complication rate, type of complications, and degree of abdominal pain, were compared. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of percutaneous US-guided CNB were compared between the groups.

Results: This study included 277 patients (173 men and 104 women) with pancreatic lesions who underwent percutaneous CNB before PSM; 190 patients in the CEUS group, and 87 in the US group prior to CNB. After controlling for potential biases using PSM, no significant differences were observed in the complication rate, type of complications, or degree of abdominal pain between the CEUS and US groups (P > 0.05). However, significant differences were observed in the first puncture success rate and the number of sampling (P < 0.05). Importantly, before and after PSM, the CEUS group achieved a higher first-puncture success rate while obtaining a lower number of sampling (P < 0.05). Compared to the US group, the CEUS group demonstrated improved accuracy, sensitivity, specificity, PPV, and NPV of 13.1%, 14.9%, 13.4%, 2.5%, and 38.7%, respectively. Furthermore, the significant difference was observed in the AUC for diagnostic performance between the two groups when compared using DeLong's test (P = 0.043).

Conclusions: Performing CEUS before percutaneous CNB for pancreatic lesions can help achieve better biopsy results, reduce the number of punctures samples, increase the success rate of biopsies, and avoid the need for repeat biopsies.

Background: In patients undergoing breast-conserving therapy without surgical clip implantation, the accuracy of tumor bed identification and the consistency of clinical target volume (CTV) delineation under computed tomography (CT) simulation remain suboptimal. This study aimed to investigate the feasibility of implementing preoperative magnetic resonance (MR) simulation on delineations by assessing interobserver variability (IOV).

Methods: Preoperative MR and postoperative CT simulations were performed in patients who underwent breast-conserving surgery with no surgical clips implanted. Custom immobilization pads were used to ensure the same supine position. Three radiation oncologists independently delineated the CTV of tumor bed on the images acquired from MR and CT simulation registration and CT simulation alone. Cavity visualization score (CVS) was assigned to each patient based on the clarity of the tumor bed on CT simulation images. IOV was indicated by generalized conformity index (CI_gen), denoted as CI_gen-CT and CI_gen-MR/CT, and the distance between the centroid of mass (dCOM), denoted as dCOM_CT and dCOM_MR/CT. The variation of IOV in different CVS subgroups was analyzed.

Results: A total of 10 patients were enrolled in this study. The median and interquartile range (IQR) of maximum pathological diameter of the tumors in all patients were 1.55 (0.80-1.92) cm. No statistical significance was found between the volumes of CTVs on CT simulation and on MR/CT simulation registration images (p = 0.387). CI_gen-MR/CT was significantly larger than CI_gen-CT (p = 0.005). dCOM_MR/CT was significantly smaller than dCOM_CT (p = 0.037). The median and IQR of CVS in all patients were 2.34 (2.00-3.08). The difference of CI_gen between CI_gen-MR/CT and CI_gen-CT was larger in the low CVS group (p = 0.016). The difference of dCOM showed a decreasing trend when CVS was lower, although it did not reach statistical significance (p = 0.095).

Conclusions: For patients who underwent breast-conserving surgery without surgical clip implantation, the use of preoperative MR simulation in delineating the CTV of tumor bed decreased the IOV among observers. The consistency of tumor bed identification was improved especially in cases where the margins of tumor bed were challenging to visualize on CT simulation images. The study findings offer potential benefits in reducing local recurrence and minimizing tissue irritation in the surrounding areas. Future investigation in a larger patient cohort to validate our results is warranted.

Background: Cholangiocarcinoma is a highly heterogeneous tumor with bile acid metabolism involving in its development. The aim of this study was to characterize bile acid metabolism and identify specific subtypes to better stratify cholangiocarcinoma patients for individualized treatment and prognostic assessment.

Methods: A total of 30 bile acids were quantified using the ultra-performance liquid chromatography tandem mass spectrometry. Using Consensus clustering, the molecular subtypes related to bile acid metabolism were identified. The prognosis, clinicopathologic characteristics, immune landscape, and therapeutic response were compared between these subtypes. The single-cell RNA sequencing (scRNA-seq) analysis and preliminary cell experiment were also conducted to verify our findings.

Results: The altered bile acid profile and genetic variation of bile acid metabolism-related genes in cholangiocarcinoma were demonstrated. The cholangiocarcinoma was categorized into bile acid metabolism-active and -inactive subtypes with different prognoses, clinicopathologic characteristics, tumor microenvironments (TME) and therapeutic responses. This categorization was reproducible and predictable. Specifically, the bile acid metabolism-active subtype showed a poor prognosis with an immunosuppressive microenvironment and an inactive response to immunotherapy, while the bile acid metabolism-inactive subtype showed the opposite characteristics. Moreover, the scRNA-seq revealed that immunotherapy altered bile acid metabolism in TME of cholangiocarcinoma. Finally, a prognostic signature related to bile acid metabolism was developed, which exhibited strong power for prognostic assessment of cholangiocarcinoma. Consistently, these results were verified by immunohistochemistry, cell proliferation, migration, and apoptosis assays.

Conclusion: In conclusion, a novel cholangiocarcinoma classification based on bile acid metabolism was established. This classification was significant for the estimation of TME and prognosis.