C-reactive protein and lactate dehydrogenase serum levels potentially predict the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer.

Background: Programmed cell death-ligand 1 (PD-L1) expression and other biomarkers are not completely reliable predictors of the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC). We investigated the value of peripheral serological inflammatory indicators and their combination in predicting the prognosis of patients with advanced NSCLC treated with checkpoint inhibitors. Methods: This study retrospectively analyzed 116 NSCLC patients treated with anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies. Clinical data of the patients were collected before treatment. X-tile plots determined the optimal cut-point for C-reactive protein (CRP) and lactate dehydrogenase (LDH). A survival analysis was performed using the Kaplan-Meier method. Multi-factor Cox regression analysis was used to evaluate the statistically significant factors identified in the univariate analysis. Results: The X-tile plots show the cut-points of CRP and LDH were 8 mg/L and 312 U/L, respectively. Univariate analyses showed high baseline serum LDH and low CRP levels were associated with adverse progression-free survival (PFS). Multivariate analyses indicated that CRP (HR, 0.214, 95% CI: 0.053-0.857, P=0.029) could be a predictive indicator for PFS. In addition, we evaluated the combination of CRP and LDH, and univariate analyses showed that patients with high CRP and low LDH exhibited significantly better PFS than those in the other groups. Conclusions: Baseline levels of serum CRP and LDH have the potential to become a convenient clinical tool to predict response to immunotherapy in advanced non-small cell lung cancer.

A multicenter-retrospective cohort study of chromosome instability in lung cancer: clinical characteristics and prognosis of patients harboring chromosomal instability detected by metagenomic next-generation sequencing.

Background: The usefulness of metagenomic next-generation sequencing (mNGS) in identifying the prognosis of lung cancer with chromosomal instability (CIN) remains unclear. We aimed to analyze clinical characteristics and prognosis of patients in patients harboring CIN. Methods: This retrospective cohort study included 668 patients diagnosed with suspected pulmonary infection or lung cancer whose samples underwent mNGS detection from January 2021 to January 2022. Difference between clinical characteristics were calculated by the Student's t-test and the chi-square test. The subjects were followed-up from registered to September 2022. Survival curves were analyzed by the Kaplan-Meier method. Results: Of 619 bronchoalveolar lavage fluid (BALF) samples collected by bronchoscopy, 30 CIN-positive samples were confirmed as malignant on histopathology, with a sensitivity of 61.22%, a specificity of 99.65%, and an 83.17% accuracy [cut-off values were established by the receiver operating characteristic (ROC) area under the curve (AUC) =0.804]. In 42 patients with lung cancer, mNGS detected 24 patients as CIN-positive and 18 as CIN-negative. There were no differences between two groups including ages, pathologic types, stage and metastases. In 25 cases, we detected 523 chromosomal copy number variants (CNVs) with forms including duplication (dup), deletion (del), mosaic (mos), and whole chromosome amplification or loss. A total of 243 duplication variants and 192 deletion variants occurred in all chromosomes. Duplications occurred in most chromosomes except for Chr9 and Chr13, in which CNV tended to delete. The median overall survival (OS) in patients with Chr5p15 duplication was 32.4 months [95% confidence interval (CI), 10.35-54.45 months]. The median OS differed significantly between the 5p15dup+ group and the combined group (32.4 vs. 8.63 months, P=0.049). In 29 patients with unresected lung cancer, the median OS of 18 cases in the CIN-positive group was 32.4 months (95% CI, 14.2-50.6 months) and the median OS of 11 cases in the CIN-negative group was 35.63 months (95% CI, 21.64-49.62 months; Wilcoxon, P=0.227). Conclusions: Various forms of CIN detected by mNGS may predict prognosis of patients with lung cancer differentially. CIN with duplication or deletion deserves further study to guide clinical treatment.

Cancer cell-derived exosomal LINC00313 induces M2 macrophage differentiation in non-small cell lung cancer

Purpose Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the leading cause of cancer death worldwide. Tumor-associated macrophages (TAMs) are one of the main non-tumor cells in the tumor microenvironment. Here, we investigated the effect of cancer cell-derived exosomal LINC00313 on the M2 macrophage differentiation in NSCLC and clarified its underlying mechanism. Methods Flow cytometry, Western blotting, ELISA and immunohistochemical staining were performed to identify the macrophage phenotype by detecting the expression of M2 markers. The expression levels of LINC00313 and miR-135a-3p were measured by qRT-PCR, and luciferase reporter assay was used to validate the binding of lncRNA to miRNA, and miRNA to the target gene STAT6. The mouse-xenograft models were established by subcutaneous injection of the NCl-H1299 cells with stable overexpression or knockdown of LINC00313. GW4869 was injected intra-tumorally after tumor implantation. Results It was found that the cancer cells promoted M2 macrophage differentiation by secreting exosomes. LINC00313 was overexpressed in H1299-derived exosomes, and its knockdown abolished the effect of H1299-induced M2 macrophage differentiation. LINC00313 sponged miR-135a-3p to increase the STAT6 expression, resulting in the M2 macrophage differentiation. LINC00313 promoted tumor progression and promoted the expression of M2 markers in isolated tumor macrophages. A novel regulatory mechanism of M2 macrophage differentiation in NSCLC was revealed. It was found that cancer cell-derived exosomal LINC00313 promoted M2 macrophage differentiation in NSCLC by up-regulating STAT6 as miR-135a-3p sponge. Conclusions This study provides a new mechanism and direction to prevent the M2 macrophage differentiation in NSCLC (AU)

Cancer cell-derived exosomal LINC00313 induces M2 macrophage differentiation in non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the leading cause of cancer death worldwide. Tumor-associated macrophages (TAMs) are one of the main non-tumor cells in the tumor microenvironment. Here, we investigated the effect of cancer cell-derived exosomal LINC00313 on the M2 macrophage differentiation in NSCLC and clarified its underlying mechanism. METHODS: Flow cytometry, Western blotting, ELISA and immunohistochemical staining were performed to identify the macrophage phenotype by detecting the expression of M2 markers. The expression levels of LINC00313 and miR-135a-3p were measured by qRT-PCR, and luciferase reporter assay was used to validate the binding of lncRNA to miRNA, and miRNA to the target gene STAT6. The mouse-xenograft models were established by subcutaneous injection of the NCl-H1299 cells with stable overexpression or knockdown of LINC00313. GW4869 was injected intra-tumorally after tumor implantation. RESULTS: It was found that the cancer cells promoted M2 macrophage differentiation by secreting exosomes. LINC00313 was overexpressed in H1299-derived exosomes, and its knockdown abolished the effect of H1299-induced M2 macrophage differentiation. LINC00313 sponged miR-135a-3p to increase the STAT6 expression, resulting in the M2 macrophage differentiation. LINC00313 promoted tumor progression and promoted the expression of M2 markers in isolated tumor macrophages. A novel regulatory mechanism of M2 macrophage differentiation in NSCLC was revealed. It was found that cancer cell-derived exosomal LINC00313 promoted M2 macrophage differentiation in NSCLC by up-regulating STAT6 as miR-135a-3p sponge. CONCLUSIONS: This study provides a new mechanism and direction to prevent the M2 macrophage differentiation in NSCLC.

Gene Mutation and Its Association with Clinicopathological Features in Young Patients with Non-Small-Cell Lung Cancer.

Background: We investigated the correlation between genetic mutations and clinical-pathological features in young patients with NSCLC. Methods: Clinicopathologic information of 102 young NSCLC patients was collected. Direct ctDNA sequencing of a portion of these patients was performed. The correlation between EGFR mutation and ALK fusions with clinicopathologic parameters was analyzed. Results: In young NSCLC patients, adenocarcinoma is the major histology (86.9%), and the misdiagnosis rate was as high as 45.7%. EGFR gene mutation was found in 13 patients (31.7%) and common mutations were with EGFR19del mutation (7 cases, 17.1%) and EGFR21L858R mutation (4 patients, 9.7%). EGFR mutation was constantly found in adenocarcinoma and male gender, and ever smokers (100%, P < 0.05). Furthermore, ALK fusions were found in 7 patients (31.8%), which include EML-4-ALK fusions; there was a trend that ALK fusions were associated with adenocarcinoma and female gender. However, there was no significant difference in overall survival between patients with or without gene mutations. Conclusions: EGFR mutation and ALK fusions are related to histology, gender, and smoke exposure in young NSCLC patients, and may be effective predictive factors.

A multicenter-retrospective study of non-small-cell lung carcinoma harboring uncommon epidermal growth factor receptor (EGFR) mutations: different subtypes of EGFR exon 19 deletion-insertions exhibit the clinical characteristics and prognosis of non-small cell lung carcinoma.

Background: The aim of this study was to investigate the clinical features, immunohistochemistry (IHC), compound mutation, and prognosis of patients with non-small cell lung cancer (NSCLC) harboring exon 19 deletion-insertion mutations. Methods: This retrospective analysis included 4,666 NSCLC patients harboring epidermal growth factor receptor (EGFR) mutations in a multi-center study from January 2017 to December 2020, and 69 patients with EGFR exon 19 deletion-insertions were taken to account. Next-generation sequencing (NGS) was used to detect the subtype of EGFR exon 19 deletion-insertions. These mutations were correlated with clinical features, immunophenotype and molecular characteristics of tumors and outcomes of patients. Results: Sixty-nine patients with EGFR exon 19 deletion-insertions were analyzed in this study, comprising 24 cases (34.8%) with L747_P753delinsS, 9 cases (13.1%) with L747_A750delinsP, both 5 cases (7.2%) in E746_A750delinsQP, E746_S752delinsV and both 4 cases (5.8%) in E746_T751delinsA and L747_T751delinsP. Twenty-nine males (42%) and 40 females (58%), with a median age of 59.7 years; 12 (21.7%) participants were smokers and 54 (78.3%) were nonsmokers. The compound mutations were tumor protein 53 (TP53) (45.83%), phosphoinositide-3-kinase (PIK3CA) (11.59%), and almost 16.67% in retinoblastoma 1 (RB1), melanocyte stimulating hormone (MSH), and myelocytomatosis (MYC). The best overall response was complete response (CR) in 47.8% of patients, partial response (PR) in 33.3% and stable disease (SD) in 13.1% of patients. Correlation between immunoreactivity of Napsin A, thyroid transcription factor (TTF), cytokeratin (CK7), surfactant proteins B (SPB), and the subtypes of EGFR exon 19 deletion-insertion was significantly statistically different (P<0.05). The disease control rate (DCR) was 29%. The median progression-free survival (mPFS) and 95% confidence interval (CI) of exon 19 deletion-insertion subtypes were 14.821 (9.917 to 19.726) months for L747_P753delinsS, 23.500 (15.877 to 31.123) months for L747_A750delinsP, 26.667 (11.731 to 41.603) months for L747_T751delinsP, and 11.713 (7.786 to 15.639) months for the others. Patients receiving treatment with 3rd generation tyrosine kinase inhibitors (TKI) had the shortest progression-free survival (PFS) (median: 7.179, 95% CI: 3.969-10.388). Conclusions: The subtypes of exon 19 deletion-insertion exhibited different clinical characteristics compared with other common mutations. Our finding argued in favor of analyzing the correlation between immunoreactivity and the subtypes of EGFR exon 19 deletion-insertion. The EGFR exon 19 deletion-insertion mutations exhibited limited sensitivity to 3rd generation TKI. Moreover, in light of therapeutic effect for the subtype, L747_T751delinsP achieved longer PFS.

Genetic alteration and PD-L1 expression profiles of Chinese patients with lung squamous cell carcinoma.

BACKGROUNDS: Despite the achievements made in treating lung cancer during the past decades, lung cancer still leads in cancer incidence and mortality worldwide. Compared to lung adenocarcinoma, the gene mutation profiles of Chinese lung squamous cell carcinoma (SQCC) have not been well established yet. METHODS: 488 Chinese SQCC patients were enrolled from 2017 to 2020, and 289 of them provided archived tumor specimens for genetic testing, 199 provided plasma instead. All samples were subjected to next-generation sequencing assay (295 took testing of 14 lung cancer-related genes, and the rest took the expanded panel). 120 patients provided blood samples applying for germline mutation testing using expanded panel. Moreover, 144 cases with enough tissue samples underwent PD-L1 immunohistochemical assay. RESULTS: Of the 488 patients with SQCC, 444 (90.98%) were proved to have at least one alteration in the 14 lung cancer-related genes. Compared with SQCC patients in The Cancer Genome Atlas (TCGA) database, a significant higher mutated frequency of EGFR (16.03% vs. 3.35%), ERBB2 (9.06% vs. 1.68%), KRAS (7.76% vs. 1.22%), and ALK (5.92% vs. 2.23%) was found in our cohort. Totally, 37.50% of patients were identified with actionable alterations, and most of them were detected in the testing using expanded panel than only the driver gene panel (49.22% vs. 29.83%, p < 0.01). Meanwhile, TP53, PIK3CA and actionable alterations were more identified in the genotyping on the tissue samples than the blood circulating tumor DNA (ctDNA). However, genes associated with clonal hematopoiesis, including KMT2D and RB1, were more prevalent in the plasma ctDNA samples. Of 120 patients undertook germline genetic testing, 5 (4.17%) patients were identified with six pathogenic/ likely pathogenic (P/LP) germline variants in DNA damage repair genes. Positive PD-L1 expression was identified in 61.27% of patients, presenting with a significantly positive correlation with KRAS alterations (58.33% vs. 16.67%). CONCLUSION: Our study identified unique genomic profiles of Chinese SQCC patients and provided novel insights into the detection of additional actionable genes and ctDNA in further genotyping. Genetic testing on expanded panel merits further study to comprehensive understanding the therapeutic value of targetable alterations in Chinses SQCC patients.

EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway.

DNA methylation is important for lung cancer prognosis. In this work, it is aimed to seek novel biomarkers with DNA methylation-expression-pathway pattern and explore its underlying mechanism. Prognostic DNA methylation sites and mRNAs were screened in NSCLC data set from TCGA, and further validated using the samples retrospectively collected, and EXT1 was identified as a potential target. Gene body methylation of three CpG sites (cg03276982, cg11592677, cg16286281) on EXT1 was significantly associated with clinical outcome, and the EXT1 gene expression also predicted prognosis. The expression level of EXT1 was also correlated with its DNA methylation level. This observation was further validated in a new data set consist of 170 samples. Knocking down of EXT1 resulted in decreased proliferation and migration. EXT1 targets were analysed using GSEA. It is found that the WNT signalling is the potential downstream target of EXT1. Further analyses revealed that the EXT1 targets the beta-catenin and effect migration rate of NSCLC cell lines. The WNT signalling inhibitor, XAV-939, effectively disrupted the migration promotion effect induced by EXT1. In summary, EXT1 methylation regulates the gene expression, effects the proliferation and migration via WNT pathway and predicted a poor prognosis for NSCLC.

Outcomes in Patients With Lung Adenocarcinoma With Transformation to Small Cell Lung Cancer After EGFR Tyrosine Kinase Inhibitors Resistance: A Systematic Review and Pooled Analysis.

BACKGROUND: Lung adenocarcinoma can transform into small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. Approximately 3% to 10% of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) could transform to SCLC. This phenomenon has been described in several case reports and small patient series. However, the characteristics and treatment outcomes of this population have not been comprehensively reported, and their clinical course is poorly characterized. METHODS: We performed a systematic review of the published literature to summarize the clinical and pathological features and prognosis of the reported cases and analyzed the demographics, disease features, and outcomes. RESULTS: A total of 72 patients (50 females and 22 males) initially diagnosed with lung adenocarcinoma were included. EGFR mutations included 19-deletion (75%), L858R (22%), and G719X (3%). All patients received EGFR-TKIs before SCLC transformation. The median time from diagnosis to transformation was 20.5 months (95% CI, 15.45 to 26.55 months). Of the 67 patients with post-translational gene test results, 58 maintained their EGFR mutation, and only 1 of 18 with prior T790M positivity retained T790M mutation. After the pathological transformation, both conventional chemotherapy regimen and chemotherapy combined targeted therapy yielded high response rates. The disease control rate of first-line therapy after transformation was 76%, while the objective response rate was 48%. The median overall survival (OS) since diagnosis was 27 months (95% CI, 22.90 to 31.10 months), whereas median OS since SCLC transformation was 8.5 months (95% CI, 5.50 to 11.60 months). CONCLUSION: The prognosis of transformed SCLC is worse than primary SCLC. The response rate to conventional chemotherapy was high. However, the progression-free survival and OS after transformation were short and the prognosis was poor with first-line therapies. New therapies are needed in the management of transformed SCLC.

Apatinib plus Chemotherapy as a Second-Line Treatment in Unresectable Non-Small Cell Lung Carcinoma: A Randomized, Controlled, Multicenter Clinical Trial.

LESSONS LEARNED: The efficacy of second-line treatment for advanced non-small cell lung carcinoma (NSCLC) without a sensitizing driver gene mutation is still unsatisfactory. The combination of apatinib and chemotherapy improved progression-free survival in the second-line therapy of advanced NSCLC without a sensitizing mutation. This study offers a new treatment strategy for second-line treatment of such patients but requires confirmation in a larger multi-institutional trial. BACKGROUND: This study explored the efficacy and safety of apatinib combined with single-agent chemotherapy versus single-agent chemotherapy in the second-line treatment of advanced non-small-cell lung carcinoma (NSCLC) without driver mutations. METHODS: In this double-arm, open label, exploratory clinical study, we enrolled patients with unresectable locally advanced or advanced NSCLC without driver mutations that had progressed following first-line chemotherapy. The subjects were allocated into an experimental group and a control group by 2:1. The experimental group received apatinib combined with four cycles of docetaxel or pemetrexed until disease progression, intolerable toxicity, or discontinuation at the patient' request. The control group only received four cycles of docetaxel or pemetrexed. The primary endpoints were progression-free survival (PFS), and the secondary endpoints were overall survival (OS), disease control rate (DCR), and safety. RESULTS: Thirty-seven patients were enrolled. The efficacy of 33 patients was evaluated. The median PFS was 5.47 versus 2.97 months, the DCR was 95% versus 73%, and the objective response rate (ORR) was 27% versus 9% in the experimental versus control group. The OS was still under follow-up. The most common adverse effects included hypertension, hand-foot skin reaction (HFSR), and fatigue. CONCLUSION: Apatinib combined with single-agent chemotherapy may be a novel option for second-line treatment of advanced NSCLC.

Hesperetin reverses P­glycoprotein­mediated cisplatin resistance in DDP­resistant human lung cancer cells via modulation of the nuclear factor­κB signaling pathway.

Lung cancer is the leading cause of cancer­associated mortality worldwide. Cisplatin (DDP) is a first­line chemotherapeutic drug for the treatment of lung cancer; however, the majority of patients develop resistance to DDP. P­glycoprotein (P­gp), also referred to as multidrug resistance (MDR) protein 1, is associated with an MDR phenotype, which results in failure of cancer chemotherapy; thus, identifying effective MDR pump inhibitors may improve the outcomes of patients who develop resistance to treatment. Hesperetin is a derivative of hesperidin, which is extracted from tangerine peel and exhibits multiple antitumor properties. In the present study, human lung adenocarcinoma A549 and A549/DDP cells were treated with different concentrations of hesperetin and DDP, respectively. Furthermore, rhodamine 123 efflux assays, Cell Counting Kit­8 assays, immunofluorescence, reverse transcription­quantitative PCR and western blot analysis were used to elucidate the mechanisms underlying the effects of hesperetin On A549/DDP cells. Additionally, a xenograft model of lung cancer in nude mice was established to explore the effects of hesperetin on A549/DDP cell growth in vivo. The results demonstrated that hesperetin sensitized A549/DDP cells to DDP. In vivo, hesperetin pretreatment significantly inhibited tumor growth. Mechanistically, hesperetin markedly decreased the expression of P­gp and increased the intracellular accumulation of the P­gp substrate, rhodamine 123, in A549/DDP cells. In addition, pretreatment of A549/DDP cells with hesperetin significantly inhibited nuclear factor (NF)­κB (p65) activity and its nuclear translocation. Taken together, the results of the present study suggest that hesperetin reversed P­gp­mediated MDR by decreasing P­gp expression in A549/DDP cells, which was associated with inhibition of the NF­κB signaling pathway. These findings may provide the basis for the use of hesperetin clinically to reverse MDR.

Amyloid precursor protein regulates 5-fluorouracil resistance in human hepatocellular carcinoma cells by inhibiting the mitochondrial apoptotic pathway.

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality globally. It accounts for the majority of primary liver cancer cases. Amyloid precursor protein (APP), a cell membrane protein, plays a vital role in the pathogenesis of Alzheimer's disease, and has been found to be implicated in tumor growth and metastasis. Therefore, to understand the relationship between APP and 5-fluorouracil (5-FU) resistance in liver cancer, Cell Counting Kit-8, apoptosis and cell cycle assays, western blotting, and reverse transcription-quantitative polymerase chain reaction (qPCR) analysis were performed. The results demonstrated that APP expression in Bel7402-5-FU cells was significantly up-regulated, as compared with that in Bel7402 cells. Through successful construction of APP-silenced (siAPP) and overexpressed (OE) Bel7402 cell lines, data revealed that the Bel7402-APP751-OE cell line was insensitive, while the Bel7402-siAPP cell line was sensitive to 5-FU in comparison to the matched control group. Furthermore, APP overexpression decreased, while APP silencing increased 5-FU-induced apoptosis in Bel7402 cells. Mechanistically, APP overexpression and silencing can regulate the mitochondrial apoptotic pathway and the expression of apoptotic suppressor genes (B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl)). Taken together, these results preliminarily revealed that APP overexpression contributes to the resistance of liver cancer cells to 5-FU, providing a new perspective for drug resistance.

CXCL1 Regulated by miR-302e Is Involved in Cell Viability and Motility of Colorectal Cancer via Inhibiting JAK-STAT Signaling Pathway.

PURPOSE: This study made a systemic description for the CXCL1-dependent regulatory mechanism in colorectal cancer (CRC). METHODS: Bioinformatics methods were applied to obtain target mRNA CXCL1 and corresponding upstream miRNA. qRT-PCR and Western blot were performed to measure the levels of CXCL1 and miR-302e in CRC tissue and cells. Experiments including CCK-8, wound healing assay, Transwell invasion assay, and flow cytometry were conducted to assess cell biological behaviors. Dual-luciferase reporter assay was carried out for verification of the targeting relationship between CXCL1 and miR-302e. The inhibitor AG490 of JAK-STAT signaling pathway was used to identify the functional mechanism of CXCL1/JAK-STAT underlying progression of CRC, and tumor xenograft experiments were performed for further validation. RESULTS: CXCL1 was highly expressed in CRC tissue and cells, while miR-302e was poorly expressed. Silencing CXCL1 or overexpressing miR-302e could lead to inhibition of cell proliferation, migration, invasion but promotion of cell apoptosis of CRC. Besides, CXCL1 was identified as a direct target of miR-302e, and CXCL1 could reverse the effect of miR-302e on cell proliferation, migration, invasion, and apoptosis. Furthermore, CXCL1 functioned on CRC cell biological behaviors via activation of JAK-STAT signaling pathway. CONCLUSION: CXCL1 could be regulated by miR-302e to inactivate JAK-STAT signaling pathway, in turn affecting cell proliferation, migration, invasion, and apoptosis of CRC. Our result provides a potential therapeutic target for CRC treatment.

Response of Metastatic Chordoma to the Immune Checkpoint Inhibitor Pembrolizumab: A Case Report.

Chordoma is a rare primary bone tumor that exhibits insensitivity to radiotherapy and chemotherapy and has a poor prognosis. Currently, resection is the primary treatment for affected patients, but the subsequent rate of recurrence is high, and both overall survival (OS) and progression-free survival (PFS) are consequentially relatively short. This case report describes a patient who was diagnosed with metastatic chordoma that was found to possess the A1209fs mutation of the PBRM1 gene, which may be associated with beneficial responses to immunotherapies. The patient received pembrolizumab, an immune checkpoint inhibitor (ICI) that targets the PD-1 receptor of lymphocytes, as second-line therapy, which he tolerated well (the most frequent adverse events were abnormal liver function and hyperglycemia, both of which were only grades 1-2), and achieved a PFS duration of 9.3 months. We hope these results will promote further research that will clarify the mechanisms underlying this beneficial response and that will further explore the use of immunotherapies in this population.

Pazopanib as salvage therapy in metastatic renal cell carcinoma with hypercalcemic crisis and renal insufficiency: a case report and literature review.

A hypercalcemic crisis in renal cell carcinoma (RCC) is an extremely rare and life-threatening condition for advanced RCC patients. It is considered nearly intractable for treatment and a poor-risk category by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. In our case, best supportive care was regularly administered according to the related guidelines and consensuses but with little high-quality, prospective clinical trial data to support the therapeutic strategy. Indeed, determining the individual etiological treatment for a given patient can be challenging. Here, we present a typical case with hypercalcemic crisis, reduced renal function (chronic kidney disease, CKD4), and poor performance status. The patient, who was treated with pazopanib of an individual lower dose of 200 mg daily as salvage therapy, had significantly improved quality of life (QOL) and prolonged progression-free survival (PFS) and overall survival (OS). These are the first results of their kind to be reported of a clinical benefit being generally observed with single doses of 800 mg. How to individually control the primary disease and concurrently relieve the symptoms in clinic to improve QOL and prolong the patient's PFS and OS is worthy of exploration.

Icariin induces apoptosis of human lung adenocarcinoma cells by activating the mitochondrial apoptotic pathway.

Lung cancer is the largest cause of morbidity and mortality among tumor diseases. Traditional first-line chemotherapeutic drugs are frequently accompanied by serious side effects when used to treat tumors, thus, novel drugs with reduced toxic effects may improve a patients' quality of life. Icariin, an extract of herba epimedii, has been demonstrated to exhibit multiple antitumor effects with low toxicity. In the present study, cell cycle analysis, apoptosis assays, DAPI staining, CCK8 assays, xenograft tumor models, mitochondrial membrane potential analysis, western blotting and reverse transcription-quantitative PCR were performed to determine the molecular mechanism underlying icariin activity in the human lung adenocarcinoma cell lines, A549 and H1975. The results showed that icariin reduced proliferation of A549 and H1975 cells in a time- and dose-dependent manner in vitro to a greater degree than the control BEAS-2B cells, and this was associated with increased apoptosis, but not with cell cycle progression. In vivo experiments showed that icariin treatment significantly decreased proliferation of H1975 cells in a xenograft mouse model. Mechanistically, icariin activated the mitochondrial pathway by inhibiting the activation of the PI3K-Akt pathway-associated kinase, Akt, resulting in the activation of members of the caspase family of proteins, and thus inducing apoptosis of A549 cells. Taken together, the results revealed that icariin has anti-cancer properties in lung cancer in vitro and in vivo without any noticeable toxic effects on normal lung epithelial cells. Icariin in combination with conventional anti-cancer agents may be an effective therapeutic strategy for treatment of lung carcinoma.

Expression and clinical significance of placenta-specific 1 in pancreatic ductal adenocarcinoma.

The limited efficacy of conventional therapies for pancreatic ductal adenocarcinoma has led to the growing interest for identifying potential antigenic targets for immunotherapy. Placenta-specific 1 (PLAC1) is a new member of cancer-testis antigens with restricted expression in normal tissues. Ectopic activation of PLAC1 has been found in different types of cancers, but its role in pancreatic ductal adenocarcinoma remains unknown. This study evaluated the protein expression of PLAC1 and its clinical significance in pancreatic ductal adenocarcinoma. We examined PLAC1 expression in 93 pancreatic ductal adenocarcinoma samples by immunohistochemistry. The expression of PLAC1 was detected in 41 (44.1%) patients. Among patients' clinicopathological characteristics, PLAC1 expression was only significantly correlated with tumor differentiation (p = 0.028). Univariate analysis revealed that PLAC1 expression (p = 0.016) and tumor differentiation (p = 0.003) were significantly correlated with poor survival in the whole cohort. Subgroup analysis showed that PLAC1 expression was an independent prognostic biomarker in the perineural invasion positive subgroup (p < 0.05). This study demonstrated that the protein expression of PLAC1 was significantly associated with decreased overall survival in patients with pancreatic ductal adenocarcinoma, indicating that it was a valuable prognostic marker for pancreatic ductal adenocarcinoma and might be a potential target for immunotherapy.

Clinicopathologic features and prognostic implications of MYBL2 protein expression in pancreatic ductal adenocarcinoma.

MYBL2 (B-MYB), a member of the MYB family of transcription factor genes, regulates the expression of genes in the process of tumorigenesis. Many studies have shown that MYBL2 is high expresssion in several human malignancies including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC is still unclear. The present study is designed to investigate MYBL2 expression levels and prognostic significance in PDAC patients. We assessed MYBL2 expression level by immunohistochemistry in tumor tissues from 93 PDAC patients undergoing curative resection. The association of MYBL2 expression with clinicopathological parameters was evaluated by Pearson's chi-square (χ2) test, Fisher's exact test, and Spearman's rank. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of MYBL2 expression on survival. The expression of MYBL2 was significantly higher in PDAC cells compared with adjacent non-cancerous tissues (P=0.000). The overexpression of MYBL2 in the tumor tissues was significantly correlated with a higher T classification (p=0.002), peri-neural invasion (PNI) (p=0.013) and vital status (p=0.045). Kaplan-Meier analysis indicated that high MYBL2 expression was significantly associated with shorter overall survival times in PDAC patients. Moreover, univariate and multivariate analysis confirmed MYBL2 expression (P=0.010), histological grade (P=0.001) as independent prognostic factors in PDAC. These results suggested that overexpression of MYBL2 might serve as a novel prognostic biomarker in PDAC patients.

Expression and prognosis value of SHP2 in patients with pancreatic ductal adenocarcinoma.

SHP2 is an src homology (SH) 2 domain-containing protein tyrosine phosphatase (PTP). SHP2 implicitly contributes to tumorigenesis, but the role of SHP2 in pancreatic ductal adenocarcinoma is still unknown. The purpose of this study was to evaluate the prognostic significance and associated expression of SHP2 in pancreatic ductal adenocarcinoma (PDAC) patients. We used immunohistochemistry to assess the protein expression levels of SHP2 in 79 PDAC specimens. The correlations between SHP2 expression and various clinicopathological features were evaluated by Pearson's chi-square (χ (2)) test, Fisher's exact test, and Spearman's rank. Univariate and multivariate Cox regression analyses were used to identify correlations between the immunohistochemical data for SHP2 expression and the clinicopathologic characteristics in PDAC. Kaplan-Meier survival analysis was used to demonstrate the relation between overall survival and the expression of SHP2. Immunohistochemistry revealed significantly higher rates of high SHP2 expression in PDAC tissues (55.7 %) versus adjacent non-cancer tissues (10.1 %) (P < 0.05). Expression of SHP2 was only significantly correlated with histological differentiation (P = 0.033) and vital status (P = 0.025). Patients with high SHP2 expression had shorter overall survival times compared to those with low SHP2 expression (P = 0.000). Multivariate Cox regression analysis revealed that SHP2 overexpression was an independent prognostic factor in PDAC (P = 0.012). Our study demonstrated for the first time that higher expression of SHP2 might be involved in the progression of pancreatic ductal adenocarcinoma, suggesting that SHP2 may be a potential prognostic marker and target for therapy.