Up-regulated tumor intrinsic growth potential and decreased immune function orchestrate the evolution of lung adenocarcinoma

Introduction Lung adenocarcinoma is the most common pathological subtype of lung cancer. Precursors of lung adenocarcinoma, namely adenocarcinoma in situ and minimally invasive adenocarcinoma, have a superb 5-year survival rate after surgical resection. A deeper understanding of the key genetic changes driving the progression of lung adenocarcinoma is needed. Methods In this study, we performed whole-exome sequencing and RNA-sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens and their adjacent paired normal tissues. Radiological, clinical, and pathological characteristics were recorded. Gene expression patterns were identified to find key pathways driving the progression of lung adenocarcinoma. Furthermore, genomic alterations and differential expression analyses were performed to compare tumors with different radiological manifestations. Finally, a progressive index was developed to quantitatively measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment. Results 12 patterns of gene expression were identified. Pathways associated with tumor growth and metastasis were found to be up-regulated as tumors progressed, while pathways associated with immune function were found to be down-regulated. Deconvolution of RNA-seq data also showed a decrease of CD8+ T cells and an increase of Tregs as the tumors progressed. Furthermore, tumors with more solid components on CT scan had a higher mutation frequency of tumor suppressor genes, higher tumor mutation burden and higher frequency of somatic copy number alterations. Finally, tumor progressive index demonstrated an increasing trend with the progression of lung adenocarcinoma. Discussion Imbalance of tumor intrinsic growth potential and immune function orchestrate the evolution of lung adenocarcinoma.

The treatment of advanced pulmonary sarcomatoid carcinoma

Pulmonary sarcomatoid carcinoma (PSC) is a pathological subtype of non-small cell lung cancer. Although the incidence of PSC in lung cancer is very low, it is an aggressive cancer, leading to a poor prognosis. Currently, there is no standard treatment for advanced PSC. Targeted therapy can be used for patients with MET exon 14 mutations and patients with other driver gene mutations may also benefit from treatment. The emergence of immune checkpoint inhibitors also provides potential options for advanced PSC treatment, but more clinical data is needed. Additionally, more research may be warranted to explore the effects of chemotherapy, radiotherapy and antiangiogenic therapy. In this review, the authors summarize the research regarding the treatment of advanced PSC.

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention.

Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

Pancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting.

Automated Classification of Papillary Renal Cell Carcinoma and Chromophobe Renal Cell Carcinoma Based on a Small Computed Tomography Imaging Dataset Using Deep Learning

ObjectivesThis study was conducted in order to design and develop a framework utilizing deep learning (DL) to differentiate papillary renal cell carcinoma (PRCC) from chromophobe renal cell carcinoma (ChRCC) using convolutional neural networks (CNNs) on a small set of computed tomography (CT) images and provide a feasible method that can be applied to light devices.MethodsTraining and validation datasets were established based on radiological, clinical, and pathological data exported from the radiology, urology, and pathology departments. As the gold standard, reports were reviewed to determine the pathological subtype. Six CNN-based models were trained and validated to differentiate the two subtypes. A special test dataset generated with six new cases and four cases from The Cancer Imaging Archive (TCIA) was applied to validate the efficiency of the best model and of the manual processing by abdominal radiologists. Objective evaluation indexes [accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curve, and area under the curve (AUC)] were calculated to assess model performance.ResultsThe CT image sequences of 70 patients were segmented and validated by two experienced abdominal radiologists. The best model achieved 96.8640% accuracy (99.3794% sensitivity and 94.0271% specificity) in the validation set and 100% (case accuracy) and 93.3333% (image accuracy) in the test set. The manual classification achieved 85% accuracy (100% sensitivity and 70% specificity) in the test set.ConclusionsThis framework demonstrates that DL models could help reliably predict the subtypes of PRCC and ChRCC.

CircRUNX1 Drives Immune Evasion and anti-PD1 Immunotherapy Resistance in Lung Adenocarcinoma by the miR-4739/PCSK9/MHC I Axis

Background: Lung adenocarcinoma (LUAD) is the commonest pathological subtype of lung-derived malignant tumor. Blocking the immune checkpoints interaction between programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) via naturalizing PD-1 or PD-L1 monoclonal antibody is proved to be a effective therapeutic method for drive gene negative LUAD. Dysregulation of circular RNA (circRNA) is a hallmark of cancer and has a critical role in the progression of cancers, including LUAD. However, the exact role of circular RUNX family transcription factor 1 (circRUNX1, hsa_circ_0002360) in LUAD remains unknown. Methods: The expression levels of circRUNX1, miR-4739, and proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA were examined by quantitative real-time polymerase chain reaction (qRT-PCR). PCSK9, histocompatibility complex I (MHC I), CD8, and Foxp3 protein expression was examined by immunohistochemistry (IHC) or western blot analysis. In vivo assay was carried out to determine the biological function of circRUNX1 on LUAD immune evasion in vivo. The binding relationship between miR-4739 and circRUNX1 or PCSK9 was predicted and verified by Starbase V3.0 online databases, dual-luciferase reporter assay, and RNA-pull down assay. Results: CircRUNX1 expression was frequently increased in LUAD tissues, and forced circRUNX1 expression was associated with poor prognosis, big tumor size, advanced stage, and resistance to anti-PD1 immunotherapy in LUAD patients. Functionally, circRUNX1 overexpression promoted LUAD immune evasion in vivo. In addition, our results demonstrated that circRUNX1 could sponge miR-4739, subsequently, upregulating the PCSK9 expression and promoting to LUAD immune evasion. Conclusion: circRUNX1 promoted cancer immune evasion and resistance to anti-PD1 immunotherapy by regulate miR-4739/PCSK9/MHC I axis in LUAD. Taken together, our findings indicate that circRUNX1 may be a promising therapeutic target for improve the anti-PD1 therapy effect in LUAD patients.

Sudden Loss of Ovarian Function Exacerbate Cancer-related Fatigue in Patients with Ovarian Carcinoma

Objective: We aimed to investigate whether ovarian cancer and cancer-related fatigue are associated with a sudden loss of ovarian dysfunction.Methods: In total, we retrospectively analyzed 211 survivors of ovarian carcinoma from the First Affiliated Hospital of Soochow University between January 2015 and January 2020. Fatigue was measured with the Cancer Fatigue Scale (CFS). Single and multiple linear regression were used to determine statistical differences.Results: Fatigue was reported in 206 of all completed questionnaires. Patients who had a menstrual period prior to treatment had a higher fatigue score. The CRF score was highest during the first two years after treatment and gradually decreased over time. Patients with sleep disorders became fatigued more easily. We identified a negative correlation between hemoglobin and CRF. There were no significant correlations between CRF, the number of chemotherapy cycles, the type of chemotherapy regimen, or the pathological subtype of ovarian cancer.Conclusion: CRF is common in ovarian cancer patients and improve CRF are important for improving the quality of life. The fatigue experienced by patients with ovarian cancer may be related to the deprivation of sex hormones. It may be prudent to add such hormones to the treatment regimen in order to improve CRF.

An Unusual Breast Mass in a 13-year-old Girl: a Case Report

BackgroundIn puberty breast intraductal papilloma was rare, but the pathological changes of intraductal papilloma combined with intraductal fibroadenoma in the duct lumen were even less reported. Herein we reported a case of adolescent benign breast disease that contained the two features of neoplasm in the same duct and discussed its clinical course.Case presentationA 13-year-old adolescent female presented to our hospital with spontaneous bloody discharge of the left nipple. On clinical examination, a 2.5cmx1.5cm mass could be palpable under the left nipple, and a single-hole bloody discharge could be seen by squeezing the mass. Surgical resection of the mass and part of the breast duct was confirmed by postoperative pathology as intraductal papilloma and intracanalicular type fibroadenoma, with cystic changes of ductal epithelium hyperplasia. After 15 months of follow-up, there was no evidence of recurrence.ConclusionsIntraductal fibroadenomatosis may be a new pathological subtype in which multiple histologic characteristics can be seen in the same duct. Surgical resection is the only effective treatment. Its etiology is still unknown, and it remains to be accumulated more cases for further exploration.

Clinical value of tumor-associated antigens and autoantibody panel combination detection in the early diagnostic of lung cancer

BACKGROUND: This study aimed to investigate the efficiency of combining tumor-associated antigens (TAAs) and autoantibodies in the diagnosis of lung cancer. METHODS: The serum levels of TAAs and seven autoantibodies (7-AABs) were detected from patients with lung cancer, benign lung disease and healthy controls. The performance of a new panel by combing TAAs and 7-AABs was evaluated for the early diagnosis of lung cancer. RESULTS: The positive rate of 7-AABs was higher than the single detection of antibody. The positive rate of the combined detection of 7-AABs in lung cancer group (30.2%) was significantly higher than that of healthy controls (16.8%), but had no statistical difference compared with that of benign lung disease group (20.8%). The positive rate of 7-AABs showed a tendency to increase in lung cancer patients with higher tumor-node-metastasis (TNM) stages. For the pathological subtype analysis, the positive rate of 7-AABs was higher in patients with squamous cell carcinoma and small cell lung cancer than that of adenocarcinoma. The levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 211 (CYFRA 211) were significantly higher than that of benign lung disease and healthy control groups. An optimal model was established (including 7-AABs, CEA and CYFRA21-1) to distinguish lung cancer from control groups. The performance of this model was superior than that of single markers, with a sensitivity of 52.26% and specificity of 77.46% in the training group. Further assessment was studied in another validation group, with a sensitivity of 44.02% and specificity of 83%. CONCLUSIONS: The diagnostic performance was enhanced by combining 7-AABs, CEA and CYFRA21-1, which has critical value for the screening and early detection of lung cancer.

Identification and Validation of Immune-Related Gene Signature for Predicting Lymph Node Metastasis and Prognosis in Lung Adenocarcinoma

Lung cancer is a serious malignancy, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Immune-related factors play an important role in lymph node metastasis. In this study, we obtained gene expression profile data for LUAD and normal tissues from the TCGA database and analyzed their immune-related genes (IRGs), and observed that 459 IRGs were differentially expressed. Further analysis of the correlation between differentially expressed IRGs and lymph node metastasis revealed 18 lymph node metastasis-associated IRGs. In addition, we analyzed the mutations status, function and pathway enrichment of these IRGs, and regulatory networks established through TF genes. We then identified eight IRGs (IKBKB, LTBR, MIF, PPARD, PPIA, PSME3, S100A6, SEMA4B) as the best predictors by LASSO Logistic analysis and used these IRGs to construct a model to predict lymph node metastasis in patients with LUAD (AUC 0.75; 95% CI: 0.7064–0.7978), and survival analysis showed that the risk score independently affected patient survival. We validated the predictive effect of risk scores on lymph node metastasis and survival using the GEO database as a validation cohort and the results showed good agreement. In addition, the risk score was highly correlated with infiltration of immune cells (mast cells activated, macrophages M2, macrophages M0 and B cells naïve), immune and stromal scores, and immune checkpoint genes (LTBR, CD40LG, EDA2R, and TNFRSF19). We identified key IRGs associated with lymph node metastasis in LUAD and constructed a reliable risk score model, which may provide valuable biomarkers for LUAD patients and further reveal the mechanism of its occurrence.