Double-dose osimertinib combined with intrathecal injection of pemetrexed improves the efficacy of EGFR-mutant non-small cell lung cancer and leptomeningeal metastasis: case report and literature review.

Leptomeningeal metastasis (LM) is a complication of non-small cell lung cancer (NSCLC) characterized by poor prognosis and short survival. A variety of therapeutic approaches have been sought to improve the efficacy of LM. Here we present a clinical case and conduct a literature review to investigate the effectiveness and safety of double-dose osimertinib combined with a pemetrexed intrathecal injection. This is an older man who underwent thoracoscopic pneumonectomy and was diagnosed with stage IIA lung adenocarcinoma with EGFR21 L858R mutation. He experienced thoracic vertebral metastases 33 months postoperatively and received first-line treatment with gefitinib combined with radiotherapy for vertebral metastases. However, the patient developed a grade 3 rash with unacceptable toxicity and his CEA levels were significantly increased 22 months later, leading to a targeted treatment adjustment to 80 mg of osimertinib orally once daily. Four months later, the patient developed LM and osimertinib dosage was increased to 160 mg once daily; however, neurological symptoms did not improve, and cerebrospinal fluid (CSF) tumor cells remained detected. Accordingly, the patient received an intrathecal injection of pemetrexed (dose 30 mg) every 2-3 months, 2-3 times per course (4-6 days each time), and continued to receive a double dose of osimertinib. After three courses of intrathecal chemotherapy, CSF tumor cells were eliminated, and neurological symptoms significantly improved. During the treatment, he experienced a one-degree rash, leukopenia, thrombocytopenia, and fatigue. This patient has been alive and well with disease control for 28 months since the diagnosis of meningeal metastases. Combining double-dose osimertinib and an intrathecal injection of pemetrexed demonstrated therapeutic efficacy and manageable adverse effects in this patient with advanced NSCLC with EGFR-mutant and LM.

Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.

BACKGROUND: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated. METHODS: Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. RESULTS: Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7 months (95% CI, 8.7-not estimable) in pretreated patients and 12.7 months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events. CONCLUSION: Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC. CLINICAL TRIAL REGISTRATION: NCT03037385.

Oncogenic zinc finger protein ZNF687 accelerates lung adenocarcinoma cell proliferation and tumor progression by activating the PI3K/AKT signaling pathway.

BACKGROUND: Zinc finger protein 687 (ZNF687) has previously been discovered as a potential oncogene in individuals with giant cell tumors of the bone, acute myeloid leukemia, and hepatocellular carcinoma. However, its role and mechanism in lung adenocarcinoma (LUAD) remain unclear. METHODS: In LUAD cells, tumor, and matched adjacent tissue specimens, quantitative real-time RT- polymerase chain reaction (qRT-PCR), western blotting analyses, and immunohistochemistry staining (IHC) were conducted. Cell counting kit-8 (CCK8) assay, clonogenicity analysis, flow cytometry, and transwell assays were utilized to detect ZNF687 overexpression and knockdown impacts on cell growth, colony formation, cell cycle, migration, and invasion. Bioinformatic studies, qRT-PCR and western blotting studies were employed to validate the underlying mechanisms and signaling pathways implicated in the oncogenic effect of ZNF687. RESULTS: This study demonstrated that ZNF687 expression was elevated in LUAD cells and tissues. Individuals with upregulated ZNF687 had a poorer prognosis than those with downregulatedZNF687 (p < 0.001). ZNF687 overexpression enhanced LUAD growth, migration, invasion and colony formation, and the cell cycle G1-S transition; additionally, it promoted the epithelial-mesenchymal transition (EMT). In contrast, knocking down ZNF687 showed to have the opposite impact. Moreover, these effects were associated with the activity of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling mechanism. CONCLUSION: ZNF687 was upregulated in LUAD, and high ZNF687 expression levels are associated with poor prognoses. The activation of the PI3K/AKT signaling pathway by upregulated ZNF687 increased the proliferation of LUAD cells and tumor progression. ZNF687 may be a beneficial predictive marker and a therapeutic target in LUAD.

Effectiveness and safety of camrelizumab in inoperable or advanced non-small cell lung cancer patients: a multicenter real-world retrospective observational study (CTONG2004-ADV).

Background: Camrelizumab plus chemotherapy have been approved as standards for the treatment of advanced non-small cell lung cancer (NSCLC) patients based on two phase III trials. However, clinical trial results may not be representative of the general population, as clinical trials often have specific inclusion and exclusion criteria. Our research aims to investigate the real-world effectiveness and safety of camrelizumab in inoperable or advanced NSCLC patients. Methods: This multicenter retrospective observational study included inoperable or advanced pathologically confirmed NSCLC patients who received at least one dose of camrelizumab at 22 hospitals. Clinical and follow-up data of camrelizumab were collected retrospectively from the medical records. The primary outcome was the objective response rate (ORR) and secondary outcomes were disease control rate (DCR), 6-month progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Multivariate logistic and Cox regression analyses were applied to identify potential predictive factors of ORR and PFS, respectively. Results: Between July 2019 and March 2021, 336 patients were included. Adenocarcinoma was seen in 58.4% and stage IV disease in 69.3%. Twenty-nine (8.6%) had liver metastasis at baseline. Most patients received camrelizumab in the first-line setting (74.1%) and in combination with chemotherapy (60.7%). The ORR was 40.2% [95% confidence interval (CI): 34.9-45.6%] and DCR was 85.1% (95% CI: 81.3-88.9%), while the 6-month PFS and OS rates were 73.0% (95% CI: 67.1-78.0%) and 93.1% (95% CI: 89.8-95.4%), respectively. In multivariate analyses, liver metastasis [odds ratio (OR), 0.324; 95% CI: 0.115-0.915; P=0.033] and increasing lines of camrelizumab treatment (vs. first line, second line: OR, 0.347; 95% CI: 0.162-0.741; P=0.006; ≥ third line: OR, 0.126; 95% CI: 0.043-0.367; P<0.001) were negatively associated, while a longer duration of camrelizumab treatment was positively associated with ORR and PFS. TRAEs were recorded in 164 (48.8%) patients, without new safety signal. Conclusions: We conducted a comprehensive overview of the effectiveness and safety profile of camrelizumab in a broader NSCLC population in real world NSCLC patients, and subgroup analysis indicated the presence of liver metastasis was associated with worse outcomes.

Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma.

BACKGROUND: Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth. METHODS: In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts. RESULTS: A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor. CONCLUSIONS: These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.

The efficacy and safety of conventional transcatheter arterial chemoembolization combined with PD-1 inhibitor and anti-angiogenesis tyrosine kinase inhibitor treatment for patients with unresectable hepatocellular carcinoma: a real-world comparative study.

Aim: We sought to evaluate the efficacy and safety of conventional transcatheter arterial chemoembolization (cTACE) sequentially combined with systemic treatment by programmed cell death protein 1 (PD-1) inhibitor and anti-angiogenesis tyrosine kinase inhibitor (Anti-angiogenesis TKI) in patients with unresectable hepatocellular carcinoma (HCC). Materials and methods: One hundred and forty-seven advanced HCC patients who received PD-1 inhibitors and TKIs as first-line systemic treatment between August 2019 and April 2021 were collected retrospectively. Fifty-four patients were finally included and divided into cTACE and no-cTACE groups, according to whether cTACE treatment was performed within 8 weeks before systemic treatment. The tumor objective response ratio (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were compared between the groups. Significant factors affecting PFS and OS were determined by Cox regression. Results: Thirty-one patients received cTACE followed by systemic treatment and 23 patients received systemic treatment only. The ORRs of the cTACE group were 48.4% (after two cycles of systemic treatment) and 51.6% (after four cycles of systemic treatment), while those of the no-cTACE group were only 17.4% and 21.7%. cTACE patients also had a longer median PFS (11.70 vs. 4.00 months, P = 0.031) and median OS (19.80 vs. 11.6 months, P = 0.006) than no-cTACE patients. Regression analyses indicated that cTACE therapy and Eastern Cooperative Oncology Group performance status were independent risk factors for PFS and OS. AEs by type were similar between the cTACE and no-cTACE groups, except for liver function injury, which was more common among cTACE patients. Fourteen patients suffered with grade 1-2 of rash in 21 patients with objective response, while only 10 patients suffered with rash in 33 patients without objective response, the adjusted hazard ratio (HR) was 4.382 (1.297-14.803). Conclusions: The combination of cTACE and PD-1 inhibitors and anti-angiogenesis TKIs as therapy significantly improved markers of treatment efficacy, including ORR, PFS, and OS, in unresectable HCC patients, while no more serious AEs recorded in this population compared to those receiving systemic treatment alone. Skin rash might be a predict factor to the efficacy of PD-1 inhibitors and TKI treatment.

CircFBXW7 Inhibits Proliferation, Migration, and Invasion of Nonsmall Cell Lung Cancer Cells by Regulating miR-492.

Background: CircFBXW7 has been determined to be involved in various cancers; however, its role in nonsmall cell lung cancer (NSCLC) remains unclear. This study examined the function and potential mechanism of circFBXW7 in NSCLC. Methods: The structure of circFBXW7 was verified via RT-PCR and Sanger sequencing. The expression of circFBXW7 in NSCLC was determined by qRT-PCR. The effect of circFBXW7 overexpression on the proliferation, migration, and invasion of NSCLC cells was examined by CCK-8 and Transwell assays. Furthermore, a circFBXW7-miRNA network was established to explore their interaction. Predicted miRNA was determined by qRT-PCR. Moreover, the miRNA mimics were synthesized, wherein its effect on proliferation, migration, and invasion of NSCLC cells overexpressed circFBXW7 was assessed. Results: The circularity of circFBXW7 was verified. The expression of circFBXW7 was found to be downregulated in NSCLC cells compared with that in normal human lung epithelial BEAS-2B cells. Overexpression of circFBXW7 reduced cell proliferation, migration, and invasion. Furthermore, according to the circFBXW7-miRNA network prediction and qRT-PCR validation, miR-492 was identified to be the target of circFBXW7. The inhibitory effect of circFBXW7 overexpression on cell proliferation, migration, and invasion was reversed by miR-492 mimics. Conclusion: CircFBXW7 is downregulated in NSCLC. CircFBXW7 inhibits NSCLC cells proliferation, migration, and invasion by regulating miR-492.

Platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios are associated with the efficacy of immunotherapy in stage III/IV non-small cell lung cancer.

Peripheral serological indicators are novel markers associated with prognosis in multiple malignant tumors. In the present study, platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) were selected to construct a model that predicts long-term survival of patients with stage IIIB-IV non-small cell lung cancer (NSCLC) who received treatment with an anti-programmed cell death protein-1 (PD-1) monoclonal antibody. A total of 133 patients were eligible for the present retrospective study (January 2019-February 2021). The area under the receiver operating characteristic curve was used to compare the diagnostic value of PLR and NLR, and combined PLR and NLR. The objective response rate and disease control rate of each group were obtained and the differences were compared using the χ2 test. The prognostic value of these indicators was assessed using the Kaplan-Meier method. Cox regression analysis was used to evaluate risk factors associated with long-term survival. Statistically significant parameters were included in the nomogram. Based on the median PLR and NLR values, the patients were divided into high PLR (H-PLR) (PLR >200.00, 67 patients) and low PLR (L-PLR) (PLR ≤200.00, 66 patients), and high NLR (H-NLR) (NLR >3.56, 65 patients) and low NLR (L-NLR) (NLR ≤3.56, 68 patients) groups. Immune-related adverse events (irAEs) occurred in 22 patients (16.5%) during the observation period, including 18 grade 2-3 irAEs and 4 grade 4 cases. H-NLR and H-PLR were associated with poor progression-free (PFS) and overall survival (OS) in the present study. NLR was an independent prognostic factor for PFS [hazard ratio (HR): 0.201, 95% confidence interval (CI): 0.060-0.670; P=0.009) and OS (HR: 0.413, 95% CI: 0.226-0.754; P=0.004) in this patient group. Therefore, NLR may be used in the prognostication of patients with stage IIIB-IV NSCLC treated with PD-1 inhibitors. These serological markers may be used in combination with established immunomarkers to help predict outcomes.

Lactate: The Mediator of Metabolism and Immunosuppression.

The Warburg effect, one of the hallmarks of tumors, produces large amounts of lactate and generates an acidic tumor microenvironment via using glucose for glycolysis. As a metabolite, lactate not only serves as a substrate to provide energy for supporting cell growth and development but also acts as an important signal molecule to affect the biochemical functions of intracellular proteins and regulate the biological functions of different kinds of cells. Notably, histone lysine lactylation (Kla) is identified as a novel post-modification and carcinogenic signal, which provides the promising and potential therapeutic targets for tumors. Therefore, the metabolism and functional mechanism of lactate are becoming one of the hot fields in tumor research. Here, we review the production of lactate and its regulation on immunosuppressive cells, as well as the important role of Kla in hepatocellular carcinoma. Lactate and Kla supplement the knowledge gap in oncology and pave the way for exploring the mechanism of oncogenesis and therapeutic targets. Research is still needed in this field.

Successful treatment of EGFR T790M-mutant non-small cell lung cancer with almonertinib after osimertinib-induced interstitial lung disease: a case report and literature review.

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the standard treatment for EGFR T790M-positive non-small cell lung cancer (NSCLC). Osimertinib is one of the third-generation EGFR-TKIs and is currently the most advanced in clinical development. Interstitial lung disease (ILD) is a potentially fatal side effect of osimertinib use. Successful rechallenge with the second-generation TKI afatinib following osimertinib-induced ILD has been reported. However, few reports have discussed the safety and efficacy of third-generation TKI rechallenge in this patient population. In this paper, a case of lung adenocarcinoma is retrospectively analyzed, and the relevant literature is reviewed. The patient was initially diagnosed with early lung cancer, for which surgical treatment was performed. The postoperative diagnosis indicated stage IB (pT2N0M0) right lung adenocarcinoma. Genetic testing (amplification-refractory mutation system) revealed EGFR exon 19 deletion. More than 2 years after surgery, multiple metastases occurred in both lungs, so gefitinib (250 mg per day) was administered. However, 6 months after the start of gefitinib treatment, the tumor progressed. Lung tumor biopsy was performed for genetic testing (NGS) and an EGFR T790M mutation was observed. Subsequently, second-line treatment with osimertinib (80 mg per day) was given for 3 months. The evaluated response suggested a partial response (PR) with the occurrence of grade 3 ILD. Pemetrexed plus bevacizumab chemotherapy was subsequently administered, resulting in stable disease. However, following a severe drug reaction after six courses, the patient's chemotherapy was discontinued. Another third-generation TKI, almonertinib (110 mg per day), was rechallenged based on no ILD having been reported in a phase I/II study of this drug. After 4 months of almonertinib administration and 6 months without ILD recurrence, partial remission was attained. This is the first report of successful treatment with almonertinib after osimertinib-induced ILD. The results suggested that almonertinib had a significant effect in patients with EGFR T790M mutation, with fewer side effects and better survival benefits for patients with advanced lung cancer.

Elastic Net Models Based on DNA Copy Number Variations Predicts Clinical Features, Expression Signatures, and Mutations in Lung Adenocarcinoma.

In the precision medicine of lung adenocarcinoma, the identification and prediction of tumor phenotypes for specific biomolecular events are still not studied in depth. Various earlier researches sheds light on the close correlation between genetic expression signatures and DNA copy number variations (CNVs), for which analysis of CNVs provides valuable information about molecular and phenotypic changes in tumorigenesis. In this study, we propose a comprehensive analysis combining genome-wide association analysis and an Elastic Net Regression predictive model, focus on predicting the levels of many gene expression signatures in lung adenocarcinoma, based upon DNA copy number features alone. Additionally, we predicted many other key phenotypes, including clinical features (pathological stage), gene mutations, and protein expressions. These Elastic Net prediction methods can also be applied to other gene sets, thereby facilitating their use as biomarkers in monitoring therapy.

Peripheral blood inflammation indices are effective predictors of anastomotic leakage in elective esophageal surgery.

BACKGROUND: This study investigated the predictive value of peripheral inflammatory indices, including neutrophil count, lymphocyte count, platelet count, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), in anastomotic leakage during elective esophageal surgery. METHODS: This retrospective study included all patients who underwent esophagectomy for esophageal squamous cell carcinoma from 2016 to 2020 in our institution. The peripheral blood inflammatory indices were obtained on preoperative days 1-7 (PRD 1-7), and postoperative days 1-3 (POD 1-3) and 4-7 (POD 4-7). Univariate, multivariate logistic, and receiver operating characteristic curve analyses were conducted to evaluate the diagnostic value of these peripheral blood inflammatory indices. RESULTS: A total of 198 patients were included in the study, and 25 (13%) patients experienced anastomotic leakage. Multivariate analyses identified diet, neutrophil count, and PLR on POD 1-3, and NLR on POD 4-7 as independent factors associated with anastomotic leakage. Using the receiver operating characteristic curve, the variable with the best area under curve was a neutrophil cutoff count of 4.1 [0.737; 95% CI: 0.639-0.835], with a sensitivity and specificity of 60.0% and 66.5%, respectively. This was followed by an NLR cutoff value of 9.5 on POD 4-7 (0.628; 95% CI: 0.505-0.752) and a cutoff PLR value of 220.1 on POD 1-3 (0.643; 95% CI: 0.536-0.750). Diet showed a poor result on the receiver operating characteristic curve analysis. CONCLUSIONS: Neutrophil count and PLR on POD 1-3 and NLR on POD 4-7 were shown to have predictive value for anastomotic leakage in elective esophageal surgery.

Long Non-Coding RNA (LncRNA) UFC1/miR-34a Contributes to Proliferation and Migration in Breast Cancer.

BACKGROUND At present, a number of long non-coding RNAs (lncRNAs) have been realized as the critical regulators of breast cancers. Current evidence indicates that dysregulation of UFC1 contributes to the tumorigenesis and progression of various types of human cancer. However, the roles of UFC1 in breast cancer are still unclear. MATERIAL AND METHODS Firstly, we measured the expression of UFC1 in breast cancer tissues and cells lines compared with corresponding controls. Then, cell functional assays were performed to determine the roles of UFC1 in breast cancer progression in vitro. Moreover, the correlation between UFC1 and miR-34a was determined by luciferase reporter assays. Further, the role of miR-34a in regulating biological function of breast cancer and its downstream target CXCL10 was applied by a series of functional assays. RESULTS In present study, we found that UFC1 was highly expressed in breast tissue and cells lines compared with normal tissues and cell lines. Silenced UFC1 suppressed multiple biological activities of breast cancer cells, which also functioned as a miR-34a sponge in breast cancer. Furthermore, over-expressing miR-34a could prominently suppress cell growth, invasion, migration and inducing apoptosis in breast cancer cells. In addition, we verified that miR-34a was a target of CXCL10 by bioinformatics analysis and luciferase reporter assay. CONCLUSIONS LncRNA UFC1 regulated biological activity of breast cancer via miR-34a/CXCL10 axis, providing a novel diagnosis biomarker and potential therapeutic target for breast cancer.