Pathology & Oncology Research最新文献

Background: Waldenström macroglobulinemia (WM) is a rare subtype of B-cell lymphoma. Rituximab-based combination therapy and Bruton's tyrosine kinase (BTK) inhibitors have greatly improved the prognosis of WM. Despite the high response rate and good tolerance of BTK inhibitors in treatment of WM, a proportion of patients still experience disease progression. Case presentation: We report a 55-year-old man with relapsed WM. The patient achieved partial remission after six courses of CHOP chemotherapy and multiple plasma exchanges in initial treatment. He was admitted to the hospital with abdominal distension, and was diagnosed with relapsed WM and subsequently started on zanubrutinib. Disease progression and histological transformation occurred during treatment. We performed liquid biopsies on transformed plasma, tumor tissue and ascites at the same time and found high consistency between ascites and tissues. Moreover, we detected resistance mutations of BTK inhibitors (BTK, PLCG2) in ascites that were not detected in plasma or tissue. Eventually, the patient died during the 15-month follow-up after relapse. Conclusion: We describe a rare case of WM transformation to DLCBCL treated with chemoimmunotherapy and BTK inhibition. We analyzed tumor DNA obtained at different anatomic sites and circulating tumor DNA (ctDNA) derived from plasma and ascites specimens, with apparent significant temporal and spatial heterogeneity. The case specifically highlights the clinical value of ctDNA of ascites supernatant from WM patients, which is a more convenient and relatively noninvasive method compared with traditional invasive tissue biopsy.

Tisagenlecleucel (tisa-cel) is a CD19^-specific CAR-T cell product approved for the treatment of relapsed/refractory (r/r) DLBCL or B-ALL. We have followed a group of patients diagnosed with childhood B-ALL (n = 5), adult B-ALL (n = 2), and DLBCL (n = 25) who were treated with tisa-cel under non-clinical trial conditions. The goal was to determine how the intensive pretreatment of patients affects the produced CAR-T cells, their in vivo expansion, and the outcome of the therapy. Multiparametric flow cytometry was used to analyze the material used for manufacturing CAR-T cells (apheresis), the CAR-T cell product itself, and blood samples obtained at three timepoints after administration. We present the analysis of memory phenotype of CD4/CD8 CAR-T lymphocytes (CD45RA, CD62L, CD27, CD28) and the expression of inhibitory receptors (PD-1, TIGIT). In addition, we show its relation to the patients' clinical characteristics, such as tumor burden and sensitivity to prior therapies. Patients who responded to therapy had a higher percentage of CD8⁺CD45RA⁺CD27⁺ T cells in the apheresis, although not in the produced CAR-Ts. Patients with primary refractory aggressive B-cell lymphomas had the poorest outcomes which was characterized by undetectable CAR-T cell expansion in vivo. No clear correlation of the outcome with the immunophenotypes of CAR-Ts was observed. Our results suggest that an important parameter predicting therapy efficacy is CAR-Ts' level of expansion in vivo but not the immunophenotype. After CAR-T cells' administration, measurements at several timepoints accurately detect their proliferation intensity in vivo. The outcome of CAR-T cell therapy largely depends on biological characteristics of the tumors rather than on the immunophenotype of produced CAR-Ts.

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The RET gene rearrangements CCDC6::RET and NCOA4::RET are the most common RET gene rearrangements in PTC patients. Different RET::PTC rearrangements are associated with different PTC phenotypes. Methods: Eighty-three formalin-fixed paraffin-embedded (FFPE) PTC samples were examined. The prevalence and expression levels of CCDC6::RET and NCOA4::RET were determined using semi-quantitative polymerase chain reaction (qRT-PCR). The association of these rearrangements with clinicopathological data was investigated. Results: The presence of CCDC6::RET rearrangement was significantly associated with the classic subtype and absence of angio/lymphatic invasion (p < 0.05). While NCOA4::RET was associated with the tall-cell subtype, and presence of angio/lymphatic invasion and lymph node metastasis (p < 0.05). Multivariate analysis demonstrated that an absence of extrathyroidal extension and extranodal extension were independent predictive factors for CCDC6::RET, whereas the tall-cell subtype, large tumor size, angioinvasion, lymphatic invasion and perineural invasion were independent predictive factors for NCOA4::RET (p < 0.05). However, the mRNA expression level of CCDC6::RET and of NCOA4::RET were not significantly associated with clinicopathological data. Conclusion: CCDC6::RET was correlated with an innocent PTC subtype and characteristics, but NCOA4::RET correlated with an aggressive phenotype of PTC. Therefore, these RET rearrangements strongly associated with clinicopathological phenotypes and can be used as predictive markers in PTC patients.

Background: Neutrophil Extracellular Traps (NETs) are fibrous networks made of DNA-histone complexes and proteins protruded from activated neutrophils. Accumulating evidences have highlighted the vital role of NETs in tumor progression and diffusion. However, limited systematic studies regarding the role of NETs in LUAD have been performed. Methods: Differentially expressed NETs-related genes and their mutation landscape were identified with TCGA database. Consensus clustering analysis was performed to determine the NETs-related subtypes of LUAD. LASSO algorithm was employed to construct a prognostic signature. Moreover, GSE30219 and GSE31210 were used as independent validation. We also constructed a lncRNA-miRNA-mRNA regulatory axis with several miRNA and lncRNA databases. Results: Consensus clustering identified two NETs-related clusters in LUAD. High NETs score was correlated with a favorable overall survival, abundant immune cell infiltration, and high activity of immune response signal pathways. Six NET-related genes (G0S2, KCNJ15, S100A12, AKT2, CTSG, and HMGB1) with significant prognostic value were screened to develop a prognostic signature. LUAD patients with low-risk had a significantly favorable overall survival both in the training set and validation set. Moreover, NETs-related risk score and clinical stage could act as an independent prognostic factor for LUAD patients. Significant correlation was obtained between risk score and tumor immune microenvironment. We also identified lncRNA BCYRN1/miR-3664-5p/CTSG regulatory axis that may be involved in the progression of LUAD. Conclusion: We developed two molecular subtypes and a prognostic signature for LUAD based on NETs-related genes. This stratification could provide more evidences for estimating the prognosis and immunotherapy of LAUD patients.

[This corrects the article DOI: 10.3389/pore.2022.1610383.].

Gastric cancer (GC) is one of the most common malignancies worldwide. Patients with advanced GC need palliative care to ensure survival. This includes the use of chemotherapy agents, such as cisplatin, 5-fluorouracil, oxaliplatin, paclitaxel, and pemetrexed, as well as targeted agents. However, the emergence of drug resistance evidence in poor patient outcomes and poor prognosis is a motivation to determine the specific mechanism of drug resistance. Interestingly, circular RNAs (circRNAs) play an important part in the carcinogenesis and progression of GC and are involved in GC drug resistance. This review systematically summarizes the functions and mechanisms of circRNAs underlying GC drug resistance, especially chemoresistance. It also emphasizes that circRNAs can serve as promising targets for improving drug resistance and therapeutic efficacy.

Background: Programmed cell death (PD)-1/PD-ligand 1 (PD-L1) inhibitors have made a breakthrough in the therapy of advanced urothelial bladder cancer (UBC). The impact of Fibroblast Growth Factor Receptor 3 (FGFR3) mutation on the effectiveness of PD-L1 treatment remains still unclear. Objective: Our study aimed to investigate the frequency of FGFR mutations at different tumor stages, and their relation to PD-L1 status and survival. Methods: 310 patients with urothelial bladder cancer and subsequent radical cystectomy were included in a retrospective study over a 10-year study period at the University of Szeged, Hungary. FGFR3 mutations from the most infiltrative areas of the tumor were analyzed by targeted next-generation sequencing and PD-L1 (28-8 DAKO) tests (tumor positive score -TPS and combined positives score-CPS). In T0 cases FGFR3 mutations were analyzed from the earlier resection samples. Survival and oncological treatment data were collected from the National Health Insurance Fund (NHIF). Neoadjuvant, adjuvant and palliative conventional chemotherapies were allowed; immunotherapies were not. The relationship between the covariates was tested using chi-square tests, and survival analysis was performed using the Kaplan-Meier model and Cox proportional hazards regression. Results: PD-L1 and FGFR could be tested successfully in 215 of the 310 UBC samples [pT0_cyst 19 (8.8%); St.0-I 43 (20%); St.II 41 (19%); St.III-IV 112 (52%)]. Significant pairwise dependency was found between tumor stage, FGFR3 mutation status and PD-L1 expression (p < 0.01). Samples with FGFR mutation were more common in less advanced stages and were also less likely to demonstrate PD-L1 expression. The effect of all investigated factors on survival was found to correlate with tumor stage. Conclusion: FGFR alteration frequency varied between the different stages of cancer. Higher positivity rates were observed at early stages, but lower levels of PD-L1 expression were detected in patients with FGFR mutations across at all stages of the disease.

Background: The association between pretreatment skeletal muscle index (SMI) and long-term survival of gastric cancer patients remains unclear up to now. The aim of this meta-analysis was to identify the prognostic value of pretreatment SMI in gastric cancer. Methods: The PubMed, EMBASE and Web of Science electronic databases were searched up to 5 June 2022 for relevant studies. The primary outcome was overall survival (OS) and the second outcomes were disease-free survival (DFS) and cancer-specific survival (CSS). The hazard ratios (HRs) and 95% confidence intervals (CIs) were combined to assess the relationship between pretreatment SMI and survival of gastric cancer patients. All statistical analyses were conducted by STATA 15.0 software. Results: A total of 31 retrospective studies involving 12,434 patients were enrolled in this meta-analysis. The pooled results demonstrated that lower pretreatment was significantly associated with poorer OS (HR = 1.53, p < 0.001). Besides, lower pretreatment SMI was also related with worse DFS (HR = 1.39, p < 0.001) and CSS (HR = 1.96, p < 0.001). Conclusion: Pretreatment SMI was significantly associated with prognosis of gastric cancer patients and lower SMI predicted worse survival. However, more prospective high-quality studies are still needed to verify our findings.

We aimed to characterize clinical and prognostical factors of primary head and neck squamous cell carcinoma (HNSCC) in 85 young patients (≤39 years, median age: 37 years; between 2000-2018) in comparison with 140 institutional general HNSCC patients (median age: 61.5 years). The patient's medical records were collected from the institutional database. The prevalence of smoking and alcohol consumption (65.8% and 48.1%) in the young group exceeded the regional population average but was below the institutional (86.4% and 55%) general HNSCC patient population. Primary tumor sites in the group of young patients were as follows: oral cavity (56.4%), oropharynx (17.6%), hypopharynx (11.7%), and larynx (14.1%). Cumulative five-year overall survival was 44.2% in the young group, but significantly better with early T (T1-2 vs. T3-4: 52.6% vs. 26.7%; p = 0.0058) and N0 status (N0 vs. N+: 65.2% vs. 32.3%; p = 0.0013). Young age, abstinence, earlier stage and laryngeal tumor site might predict a better prognosis. The age distribution and the high prevalence of traditional risk factors among the young patients as well as the predominance of oral cavity tumor localization suggest that the early onset of tumor development could be originated from the premature failure of the intrinsic protective mechanisms.

Introduction: Head and neck cancers represent a major health problem in Hungary. With their high incidence and mortality rates, Hungary is one of the world leaders in these indicators. The length of patient delay, defined as time from onset of symptoms to first medical consultation, is unknown in Hungarian patients with head and neck cancer. We aimed to use a representative sample of the Hungarian head and neck cancer patient population to determine patient delay according to disease localization and stage and to identify correlations with other clinical parameters. Methods: In our retrospective study, we reviewed patient documentation. For the inclusion, the patients had to be diagnosed with malignant tumors of the oral cavity, oropharynx, hypopharynx or larynx at the Department Head and Neck Surgery of Semmelweis University between 2012 and 2017. Results: We identified 236 patients who met the inclusion criteria. The median delay was 9.5 weeks (range 0-209 weeks) and the mean delay of patients was 17.57 weeks (SD 23.67). There was a significant difference in patient delay data by location. Among glottic cancers, the most common diagnosis was an early stage (67%), compared with other localizations, including most commonly the oropharynx (81%) and hypopharynx (80%), where a locoregionally advanced stage was more frequent. Discussion: Compared to data from different countries, the delay of Hungarian patients with head and neck cancer is significantly longer, which may contribute to the high mortality in Hungary. Screening and patient education in high-risk groups could contribute to earlier diagnosis and thus improve prognosis.