Histological sarcomatoid transformation in a lung adenocarcinoma patient following immune checkpoint blockade.

Histological transformation is a phenomenon that is well described as one of the causes of tyrosine kinase inhibitor resistance in oncogene-driven non-small-cell lung cancer (NSCLC). The use of immune checkpoint inhibitors (ICIs) as a potential mechanism of acquired resistance to immunotherapy in NSCLC to small-cell lung cancer was also recently found. Here, we report the histological transformation of sarcomatoid carcinoma and metastasis in a lung adenocarcinoma patient without targetable genetic alterations who experienced long-term disease remission after nivolumab therapy. The patient subsequently developed rapid progression in the mediastinal and retroperitoneal lymph nodes, bones, and small intestine. Surgical resection of the small intestine lesion due to acute small intestine bleeding revealed the transformation of NSCLC to sarcomatoid carcinoma. The patient died 3 months after sarcomatoid carcinoma transformation and extensive disease progression, although he was rechallenged with immunotherapy. Genomic and immunohistochemical analyses revealed a comparable abundance of gene mutations and a limited number of immune cells in the tumor microenvironment, with low infiltration of CD8+ T cells, CD4+ T cells, regulatory T cells, and PD-L1+ macrophages in metastatic tumors, revealing a noninflamed immune microenvironment for ICI-resistant tumors.

Hsa_circ_0097922 promotes tamoxifen resistance and cell malignant behaviour of breast cancer cells by regulating ACTN4 expression via miR-876-3p.

An increasing number of findings have verified the critical roles of circular RNAs (circRNAs) in human cancers, and chemotherapy resistance is a poor prognostic factor for breast cancer (BC). This study is designed to explore the function of hsa_circ_0097922 in the tamoxifen resistance of breast cancer. Hsa_circ_0097922, microRNA-876-3p (miR-876-3p), and alpha-actinin 4 (ACTN4) level were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell survival, proliferation, apoptosis, migration and invasion were detected by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry, wound healing and Transwell assays. Protein levels of proliferating cell nuclear antigen (PCNA), B-cell lymphoma-2 (Bcl-2), cleaved caspase 3, matrix metalloproteinase 9 (MMP9), and ACTN4 were determined using western blot assay. Using bioinformatics software, the binding between miR-876-3p and hsa_circ_0097922 or ACTN4 was predicted, followed by confirmation by RNA immunoprecipitation (RIP) and RNA pull-down assays. A xenograft tumour model in vivo analysed the biological role of hsa_circ_0097922 on BC tumour growth and drug resistance. Hsa_circ_0097922 and ACTN4 were increased, and miR-876-3p was decreased in tamoxifen resistance BC cells. Moreover, hsa_circ_0097922 knockdown can block BC cell malignant behaviour and tamoxifen resistance in vitro. Mechanically, hsa_circ_0097922 acted as a sponge of miR-876-3p to regulate ACTN4 expression. Hsa_circ_0097922 silencing increased the drug sensitivity of BC in vivo. Hsa_circ_0097922 might regulate BC cell malignant behaviour and tamoxifen resistance partly by regulating the miR-876-3p/ACTN4 axis, hinting at a promising therapeutic target for the BC treatment.

Detection of ATP in cancer cells with a label-free fluorescent aptasensor.

Aim: To develop a new detection technique for ATP in cancer cells using fluorescent biosensing. Materials & methods: This research presents a new label-free fluorescent aptasensor for ATP measurement that incorporates a DNA aptamer, SYBR Gold and single-walled carbon nanohorns. Results: The aptasensor showed selectivity toward ATP and a low limit of detection (37.6 nM). The linear detection range was 100-50,000 nM, and the fluorescence intensity and ATP concentration logarithm showed an excellent linear correlation (R2 = 0.9924). Conclusion: The developed aptasensor may be used to detect cellular ATP in cancer cells and could be employed for biological sample analysis. The benefits of the aptasensor, such as its simplicity, speed, cost-effectiveness, specificity and sensitivity, give it promising implications as a potentially adaptable sensing platform.

Immune Thrombocytopenia Induced by Immune Checkpoint Inhibitors in Solid Cancer: Case Report and Literature Review.

Immune checkpoint inhibitors, including antibodies targeting programmed cell death protein-1 (PD-1) and its receptor programmed cell death ligand-1 (PD-L1), represent promising therapeutic strategies for advanced human malignancies. However, a subgroup of patients experiences various autoimmune toxicities, termed immune-related adverse events (irAEs), that occur as a result of on-target and off-tumor autoimmune responses. Although irAEs are generally confirmed to be less severe than toxicities caused by conventional chemotherapy and targeted therapy, uncommon irAEs, such as immune thrombocytopenia, may occur with a very low incidence and sometimes be severe or fatal. This review focuses on the epidemiology, clinical presentation, and prognosis of immune thrombocytopenia occurring in advanced cancer patients induced by immune checkpoint inhibitors, especially in those with PD-1 or PD-L1 inhibitor treatment. We also first present one patient with non-small cell lung cancer who received the PD-L1 inhibitor durvalumab and developed severe thrombocytopenia.

Severe Immune-Related Pneumonitis With PD-1 Inhibitor After Progression on Previous PD-L1 Inhibitor in Small Cell Lung Cancer: A Case Report and Review of the Literature.

Objective: Combination therapy with programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors might be viewed as a promising therapeutic strategy for resistant lung cancer, and it is becoming common that a second PD-1/PD-L1 inhibitor might be used following progression on previous PD-1/PD-L1 inhibitor. However, a subgroup of patients will experience various autoimmune toxicities, termed as immune-related adverse events (irAEs), that occur as a result of on-target and off-tumor inflammation. Materials and Methods: In this report, we presented a patient with small cell lung cancer who received different PD-1/PD-L1 inhibitors during the course of disease progression. This patient experienced radiation-related pneumonitis, immune-related pneumonitis, as well as concomitant bacterial pneumonia. Results: In particular, this patient developed immune-related pneumonitis with a second PD-1 inhibitor when she had a progressive disease on previous PD-L1 inhibitor. This patient was initially responsive to steroid treatment, but rapidly develop more severe pneumonitis and concomitant bacterial pneumonia with no response to antibiotics and steroid treatment. Finally, this patient got a good clinical response when receiving additional immunosuppressive medications infliximab and mycophenolate mofetil. Conclusions: Patients with a history of radiation-induced pneumonitis and treated with sequential different PD-1/PD-L1 inhibitors have a relative high risk to develop high-grade or steroid-resistant pneumonitis, and additional immunosuppressive medications should be used earlier when severe pulmonary toxicity occurs.

Direct sequencing and amplification refractory mutation system for epidermal growth factor receptor mutations in patients with non-small cell lung cancer.

Treatment with epidermal growth factor receptor (EGFR) tyrosine inhibitors (EGFR-TKIs) provides encouraging outcomes for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. Pleural effusion is a common complication of NSCLC. We compared direct DNA sequencing and ADx Amplification Refractory Mutation System (ADx-ARMS) to detect EGFR mutations in malignant pleural effusion samples. We obtained 24 samples from pleural effusion fluid of NSCLC patients. Three common types of EGFR mutations were examined by direct sequencing and ADx-ARMS analysis. The sensitivity of the methods was compared and the relationship between EGFR mutations and response rates of the patients determined. In 14/24 patients, we detected EGFR mutations (58.3%) by ADx-ARMS, and in 10 samples (41.7%) by direct sequencing. In 6 samples, EGFR mutations were on exon 19, and in 8 samples, mutations were on exon 21 by ADx-ARMS. By contrast, we found EGFR mutations in 4 samples on exon 19, and in 6 samples on exon 21 by direct sequencing. Neither method showed mutations on exon 20. Among the 24 patients, there was 83.3% concordance for the methods. In 18/24 patients, gefitinib treatment was administered, including 10 patients with mutations who showed improved response compared to 8 of the wild-type patients (P<0.05). In conclusion, EGFR mutation analysis by ADx-ARMS was the most sensitive compared to direct sequencing, and provided more reliable EGFR mutation assessments. ADx-ARMS could be introduced into the clinical practice to identify NSCLC patients likely to benefit from TKI treatment, especially those with malignant pleural effusion.

Cytoplasmic HuR expression correlates with P-gp, HER-2 positivity, and poor outcome in breast cancer.

HuR is an ubiquitously expressed RNA-binding protein that stabilizes messenger RNA and regulates translation. This protein has been shown to play an important role in carcinogenesis and cancer progression. P-glycoprotein (P-gp) is the product of the multidrug resistance 1 gene, and the overexpression of P-gp induces multidrug resistance and represents a major obstacle in cancer chemotherapy. The purpose of this study was to determine the expression of HuR and P-gp in human breast cancer tissues and analyze the relationship between HuR or P-gp expression and the clinical-pathological variables and patient outcomes. Immunohistochemistry was used to determine HuR and P-gp expression in 82 human breast cancer tissues and 20 matched adjacent noncancerous tissues. Additionally, 16 benign breast tumor samples were used as controls. The overexpression of cytoplasmic HuR was found in breast cancer but not in the matched adjacent noncancerous tissues or benign breast tumors. The expression levels of cytoplasmic HuR were significantly associated with increased age, high nuclear grade, and the positive expression of the ER, PR, and HER-2/neu. HuR was also associated with the expression of P-gp protein. Furthermore, univariate analysis indicates that patients with high expression levels of cytoplasmic HuR or P-gp had significantly reduced survival compared to patients with low expression levels. A multivariate analysis showed that age at diagnosis, nuclear grade, and cytoplasmic HuR positivity were independent indicators for disease-free survival and overall survival in patients with breast cancer. In conclusion, cytoplasmic HuR expression detected by immunohistochemical staining is a negative prognostic indicator for survival in patients with breast cancer.

Relationship between expression of EGFR in gastric cancer tissue and clinicopathological features.

OBJECTIVE: To investigate the relationship between the expression of epidermal growth factor receptor (EGFR) in gastric cancer and the clinicopathological features and prognosis. METHODS: A total of 78 paraffin specimens of gastric cancer operation were collected. The immunohistochemical method was used to detect the expression of EGFR in 78 cases of gastric cancer and 20 cases of adjacent normal tissue. The relationship between the high expression of EGFR and clinicopathological features was analyzed. RESULTS: EGFR positive expression rate in the 78 cases of gastric cancer tissue was 57.7 % (45/78), while EGFR was not expressed in 20 cases of adjacent normal tissue. The high EGFR expression was positively correlated with the position of gastric cancer, tumor size, cell differentiation, invasive depth, lymph node metastasis and TNM staging, yet having no obvious relation with gender or age. CONCLUSIONS: EGFR expression level in gastric cancer is closely related to the incidence and development of gastric cancer, which can provide a theoretical basis for the targeted therapy for gastric cancer with EGFR as the target.

Lymphatic microvessel density and vascular endothelial growth factor-C and -D as prognostic factors in breast cancer: a systematic review and meta-analysis of the literature.

The use of lymphatic microvessel density (LVD) and pro-lymphangiogenic mediators as prognostic factors for survival in breast cancer remains controversial. We searched the electronic databases PubMed and EMBASE without language restrictions for relevant literature to aggregate the survival results. To be eligible, every study had to include the assessment of the LVD or the expression of vascular endothelial growth factor (VEGF)-C or -D in patients with breast cancer and provide a survival comparison, including disease-free survival (DFS) or overall survival (OS), according to the LVD, VEGF-C or VEGF-D status. Across all studies, 56.64 % of patients were considered to have a VEGF-C-positive tumor, and 65.54 % of patients had VEGF-D-positive tumors. High LVD had an unfavorable impact on DFS, with a pooled hazard ratio (HR) of 2.222 (95 % CI 1.579-3.126) and an OS with a HR of 2.493 (95 % CI 1.183-5.25). According to the different lymphatic makers, the subgroup HR in the D2-40 studies was 2.431 (95 % CI 1.622-3.644) for DFS and 4.085 (95 % CI 1.896-8.799) for OS. VEGF-C overexpression, as assessed by immunochemistry, was a prognostic factor for decreased DFS (HR 2.164; 95 % CI 1.256-3.729) and for decreased OS (HR 2.613; 95 % CI 1.637-4.170). VEGF-D overexpression was a significant although weak prognostic factor for DFS only when assessed by immunochemistry, with a HR of 2.108 (95 % CI 1.014-4.384). Our meta-analysis demonstrated that LVD, VEGF-C and VEGF-D could predict poor prognosis in patients with breast cancer. However, standardization of the assessment of LVD and for the expression of lymphangiogenesis factors is needed.

Clinical significance and role of lymphatic vessel invasion as a major prognostic implication in non-small cell lung cancer: a meta-analysis.

BACKGROUND: Lymphatic vessel invasion (LVI) exerts an important process in the progression and local spread of cancer cells. However, LVI as a prognostic factor for survival in non-small cell lung cancer (NSCLC) remains controversial. METHODOLOGY/PRINCIPAL FINDINGS: A meta-analysis of published studies from PubMed and EMBASE electronic databases was performed to quantity the effects of LVI on both relapse-free survival and overall survival for patients with NSCLC. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the strength of these effects. This meta-analysis included 18,442 NSCLC patients from 53 eligible studies. LVI appeared in 32.1% (median; range, 2.8% to 70.9%) of tumor samples. In all, patients with LVI were 2.48 times more likely to relapse by univariate analysis (95% CI: 1.92-3.22) and 1.73 times by multivariate analysis (95% CI: 1.24-2.41) compared with those without LVI. For the analyses of LVI and overall survival, the pooled HR estimate was 1.97 (95% CI: 1.75-2.21) by univariate analysis and 1.59 (95% CI: 1.41-1.79) by multivariate analysis. Multivariate analysis showed a risk was 91% higher for recurrence (HR =1.91, 95% CI: 1.14-2.91) and 70% higher for mortality (HR=1.70, 95% CI: 1.38-2.10) in LVI-positive I stage patients compared with LVI-negative I stage patients. Subgroup analyses showed similar significant adjusted risks for recurrence and death in adenocarcinomas, and a significant adjusted risk for death in studies that utilized elastic staining with or without immunohistochemistry in defining LVI. CONCLUSIONS/SIGNIFICANCE: The present study indicates that LVI appears to be an independent poor prognosticator in surgically managed NSCLC. NSCLC patients with LVI would require a more aggressive treatment strategy after surgery. However, large, well-designed prospective studies with clinically relevant modeling and standard methodology to assess LVI are required to address some of these important issues.