Rapid and durable response to fifth-line lorlatinib plus olaparib in an ALK -rearranged, BRCA2-mutated metastatic lung adenocarcinoma patient with critical tracheal stenosis: a case report.

Treatment options for heavily treated anaplastic lymphona kinase (ALK )-positive nonsmall cell lung cancer (NSCLC) patients, who typically bear-resistant mechanisms to ALK tyrosine kinase inhibitors (TKIs), are usually limited to chemotherapy, which elicits limited clinical benefit and may incur severe toxicity. It is clinically relevant to explore other revenues for these patients. poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib are currently approved to treat BReast CAncer gene 1/2 ( BRCA1/2 )-mutated patients in a few tumor types. There have been a trial and two case reports of an olaparib-containing regimen in treating epidermal growth factor receptor (EGFR)-positive or driver-negative NSCLC. We report a case of a 27-year-old female nonsmoker diagnosed with ALK -rearranged metastatic lung adenocarcinoma. She was treated with alectinib and acquired ALK p.I1171N and p.V1180L mutations. Germline BRCA2 p.F2801fs was also identified. After sequential lines of ceritinib and chemotherapy, lorlatinib was chosen as the fourth-line therapy and maintained control for 6 months. Shortly after progression, the patient was admitted to the ICU due to critically severe stenosis caused by a tracheal mass and soon relieved by embolization and stenting. Afterward lorlatinib plus olaparib was started and elicited a rapid response within 1 month. The progression-free survival was 6 months as of the latest follow-up, with the best response of partial response. To the best of our knowledge, this case is the first to provide clinical evidence of antitumor activity of olaparib plus ALK TKI in ALK -positive, g BRCA -mutated metastatic NSCLC. Together with previous reports in EGFR -positive or driver-negative patients, our finding warrants further studies on PARP inhibition in BRCA1/2 -mutated NSCLC.

Circ_0058058 Drives the Malignant Phenotypes and Immune Evasion of Pancreatic Cancer by the MicroRNA-557-Dependent Regulation of PDL1.

OBJECTIVES: Pancreatic cancer (PC) is one of the most deadly malignancies in the world. Recently, circular RNAs play crucial roles in PC progression. However, the functions of circ_0058058 in PC are barely known. METHODS: The expression of circ_0058058, microRNA-557-5p (miR-557), and programmed cell death receptor ligand 1 (PDL1) was detected by quantitative real-time polymerase chain reaction. Functional experiments were implemented to disclose the effect of circ_0058058 deficiency on PC cell proliferation, apoptosis, invasion, angiogenesis, and immune escape. The binding relationship between miR-557 and circ_0058058 or PDL1 was identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. In vivo assay was used to disclose the impact of circ_0058058 silencing on tumor formation in vivo. RESULTS: Circ_0058058 was highly expressed in PC tissues and cell lines. Knockdown of circ_0058058 repressed cell proliferation, invasion, angiogenesis, and immune escape while contributed to apoptosis in PC cells. Mechanically, circ_0058058 worked as a molecular sponge of miR-557 to regulate PDL1 expression. Moreover, circ_0058058 showed a promotional effect on tumor growth in vivo. CONCLUSIONS: Our findings suggested that circ_0058058 served as miR-557 sponge to upregulate PDL1, thereby triggering PC proliferation, invasion, angiogenesis, and immune escape.

The landscape of kinase domain duplication in Chinese lung cancer patients.

BACKGROUND: Kinase domain duplication (KDD) is a special type of large genomic rearrangement (LGR), occurring in the kinase domain of protein kinase genes. KDD of some lung cancer driver genes, such as. EGFR: KDD, has been identified and implicated to be oncogenic in non-small cell lung cancer (NSCLC). The present study aims to interrogate the spectrum of KDD occurring on classic driver genes in Chinese lung cancer patients without the presence of classic lung cancer driver mutations. METHODS: We retrospectively enrolled 10,525 Chinese lung cancer patients who met the following inclusion criteria; (I) do not carry classic lung cancer driver mutations in any of the 8 driver genes and (II) tyrosine kinase inhibitor (TKI)-naïve. Capture-based targeted sequencing was performed on tissue or plasma samples. LGR and KDD were identified by using in-house analysis scripts. The prevalence and distribution of LGR and KDD in our cohort were analyzed. RESULTS: The median age of the cohort was 64 years with 68.7% being male. Among all patients, 23.2% and 51.8% were diagnosed with stage III and IV disease respectively. We identified 43 cases (0.41%) harboring LGR in one of the driver genes (EGFR/ERBB2/ALK/RET/ROS1/MET/BRAF), with 24 (0.23%) patients harboring KDD. Of the patients harboring KDD, a majority (n=19) harbored canonical EGFR-KDD involving exons 18-25, whilst one patient harbored duplications of EGFR exons 18-26. There were three MET-KDD patients; in two, the alteration occurred in exons 15-21 and in one, the alteration occurred in exons 3-21. One patient harbored RET-KDD involving exons 12-18. KDD showed a comparable prevalence in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (0.33% vs. 0.11%, P=0.118). Nineteen non-KDD LGRs, spanning six genes including EGFR (n=6), MET (n=3), ALK (n=4), ROS1 (n=2), ERBB2 (n=2) and BRAF (n=2), were found, each occurring in one patient. The prevalence of LGR in LUADs and LUSCs was comparable (0.55% vs. 0.38%, P=0.452). CONCLUSIONS: We observed a prevalence of 0.41% and 0.23% for LGR and KDD, respectively. Twenty-four different LGR alterations, including 5 KDDs and 19 non-KDD LGRs, were observed. KDDs mainly occurred in EGFR involving exons 18-25 and non-KDD LGRs were distributed more randomly. The prevalence of LGR/KDD in LUSCs and LUADs was comparable.

MiR-142-3p suppresses the proliferation, migration and invasion through inhibition of NR2F6 in lung adenocarcinoma.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and lung adenocarcinoma is its main type. MicroRNAs are small, non-coding and single-strand RNAs that regulate gene expression in human cancers. The aim of our study is to investigate the underlying molecular mechanism of miR-142-3p in NSCLC. The expression of miR-142-3p in lung adenocarcinoma tissues and cells was detected by RT-qPCR. Next, cell proliferation, migration, invasion and apoptosis were examined by CCK-8, scratch assay, transwell assay and flow cytometry in A549 and HCC827 cells, respectively. Then, the target of miR-142-3p was predicted by targetscanHuman 7.2 and confirmed using dual-luciferase reporter assay. Additionally, RT-qPCR and western blot were used to detect the expression of NR2F6, MMP2, MMP9 and caspase-3. The results showed that miR-142-3p expression was significantly decreased in tumor tissues and cells. Overexpression of miR-142-3p inhibited the proliferation, migration, invasion and promoted cell apoptosis in vitro, while knockdown of miR-142-3p had reversed function. Furthermore, NR2F6 was identified as a direct target of miR-142-3p, which was negatively correlated with miR-142-3p expression. Finally, miR-142-3p overexpression suppressed the expression of NR2F6, MMP2 and MMP9, but improved caspase-3 expression, while miR-142-3p knockdown got the opposite expression results. Suppressing MMP2 and MMP9 activities inhibited cell invasion. In summary, these findings indicated that miR-142-3p inhibits lung adenocarcinoma cell proliferation, migration and invasion, and enhances cell apoptosis by targeting NR2F6, suggesting that miR-142-3p may be a novel therapeutic target for lung adenocarcinoma treatment.

XB130 enhances invasion and migration of human colorectal cancer cells by promoting epithelial­mesenchymal transition.

The expression of XB130 is associated with invasion and migration of many tumor cells, but its roles in human colorectal cancer (CRC) remains unknown. To investigate this, protein expression levels of XB130 in numerous human CRC cell lines were compared with a normal colorectal mucosa cell line by western blotting. Knockdown of XB130 using small interfering (si)RNA was performed to assess the effects on cell invasion and migration in a Transwell assay and a scratch test. Western blotting was also used to quantify the levels of proteins associated with epithelial­mesenchymal transition (EMT), including E­cadherin, vimentin, phosphorylated (p)­protein kinase B (AKT), p­forkhead homeobox type O 3a (FOXO3a) and zinc finger E­box­binding homeobox 1 (ZEB­1). The relative expression of XB130 protein was significantly higher in CRC cells compared with control cells (P<0.01). Knockdown of XB130 using siRNA significantly decreased the invasive and migratory responses of CRC cells (P<0.01). In addition, levels of E­cadherin were increased, while vimentin, p­AKT, p­FOXO3a and ZEB­1 were decreased (P<0.01). In conclusion, the present study demonstrated that the expression of XB130 is elevated in CRC cells. Loss of XB130 was associated with decreased invasion and migration of CRC cells, possibly as a result of EMT inhibition. Thus, upregulation of XB130 may underlie some of the tumorigenic events observed in human CRCs. XB130 may be a promising target for CRC therapy in humans; further mechanistic studies exploring the function of XB130 in CRC cells are warranted.

Involvement of the Toll-Like Receptor/Nitric Oxide Signaling Pathway in the Pathogenesis of Cervical Cancer Caused by High-Risk Human Papillomavirus Infection.

Human papillomavirus (HPV) can activate Toll-like receptor (TLR)/nitric oxide (NO) signaling pathways; however, whether the TLR/NO pathway is involved in cervical cancer caused by high-risk HPV (HR-HPV) remains unclear. In this study, 43 HR-HPV-positive patients with cervical cancer (CC group), 39 HR-HPV-positive patients with a healthy cervix (HR-HPV group), and 33 HR-HPV-negative controls were recruited. NO concentration in cervical canal and expression of inducible NO synthase (iNOS) in cervical tissues were detected. Expressions of key TLR/NO pathway genes (TLR3/4/7/8, NF-κB p65, and iNOS) in cervical epithelial cells were detected by quantitative reverse transcription PCR. Expressions of TLR4, NF-κB p65, and iNOS in CaSki, HeLa, and C33a cells were determined by Western blot. NO concentration in cervical canal of CC group was significantly higher than in other groups (P < 0.05). Positive rates of iNOS in cervical tissues were 72.1%, 28.2%, and 3.1% in the CC group, HR-HPV group, and controls, respectively (P < 0.05). Levels of TLR3, TLR4, TLR7, TLR8, NF-κB p65, and iNOS in cervical epithelial cells were higher in CC group than in other groups (P < 0.05). Both mRNA and protein levels of TLR4, NF-κB p65, and iNOS were higher in HPV-positive HeLa and CaSki cells than in HPV-negative C33a cells (P < 0.05). Together, these results suggest that TLR/NO signaling pathway may be involved in pathogenesis of cervical cancer caused by HR-HPV.

Efficacy of vasopressin/terlipressin and somatostatin/octreotide for the prevention of early variceal rebleeding after the initial control of bleeding: a systematic review and meta-analysis.

PURPOSE: Our purpose was to conduct a meta-analysis to compare the effectiveness of vasopressin/terlipressin and somatostatin/octreotide on variceal re-bleeding within and after 5 days of initial control bleeding. METHODS: A search was conducted of PubMed, the Cochrane database, and Google Scholar until June 31, 2014 using combinations of the search terms: esophageal varices, variceal re-bleeding, recurrent variceal hemorrhage, early re-bleeding, vasopressin, somatostatin, terlipressin, octreotide. Inclusion criteria were: (1) randomized controlled trials, (2) patients with esophageal or esophageal and gastric varices confirmed by endoscopy, (3) re-bleeding control was evaluated, (4) treatment with somatostatin/vasopressin. Outcome measures were the re-bleeding rates within 5 days (≤ 5 days) or after 5 days (>5 days) after initial treatment. RESULTS: Six studies were included in the analysis. Five studies had complete data of re-bleeding rate within 5 days after initial treatment, and the combined odds ratio (OR) of 0.87 [95% confidence interval (CI) 0.51, 1.50] indicated that there was no difference in the re-bleeding rate between patients treated with vasopressin/terlipressin or somatostatin/octreotide. Two studies had complete data of the re-bleeding rate 5 days after initial treatment, and the combined OR of 1.12 (95% CI 0.64, 1.95) indicated there was no difference in the re-bleeding rate between patients who were treated with vasopressin/terlipressin or somatostatin/octreotide. CONCLUSION: There is no difference between vasopressin/terlipressin and somatostatin/octreotide in prevention of re-bleeding after the initial treatment of bleeding esophageal varices.

A prospective randomized trial of selective versus nonselective esophagogastric devascularization for portal hypertension.

Cirrhosis with portal hypertension is a common disease which has a significant impact on the quality of patients' life. Esophagogastric devascularization (EGDV) has been demonstrated to be an effective method to treat portal hypertension, however certain complications are associated with it. The purpose of this study was to evaluate the effectiveness and clinical outcome of the selective EGDV (sEGDV) for the treatment of portal hypertension. The study was conducted prospectively from Jan. 1 2011 to Dec. 31, 2012, and 180 patients were randomized to the sEGDV group (n=90) or the non-sEGDV (n-sEGDV) group (n=90). Patients' demographics, preoperative lab test results and operative details were comparable between the two groups. Postoperative and short-term complications were analyzed in two groups. There was statistically significant difference (P<0.01) in the PVF reduction between the two groups. Post-operative complications showed no statistically significant difference between the two groups in the incidence of bleeding, ascites, acute portal vein thrombosis, fever and hepatic encephalopathy. Mortality between two groups was comparable. The incidence of splenic fossa effusion after the surgery was lower in sEGDV group than in n-sEGDV group. There were no significant differences in the short-term follow-up data such as esophageal varices and portal hypertensive gastropathy (P>0.05). It is suggested that sEGDV is a safe, simple and effective surgical procedure. It has both the advantages of the shunt and devascularization because it preserves body's voluntary diversion. With the advantage of low incidence of postoperative complications, it is an ideal surgical approach for the treatment of portal hypertension.

Role of hydrogen sulfide in portal hypertension and esophagogastric junction vascular disease.

AIM: To investigate the association between endogenous hydrogen sulfide (H2S) and portal hypertension as well as its effect on vascular smooth muscle cells. METHODS: Portal hypertension patients were categorized by Child-Pugh score based on bilirubin and albumin levels, prothrombin time, ascites and hepatic encephalopathy. Plasma H2S concentrations and portal vein diameters (PVDs) were compared between portal hypertension patients and control participants, as well as between portal hypertension patients with varying degrees of severity. In addition, we established a rabbit hepatic schistosomiasis portal hypertension (SPH) model and analyzed liver morphology, fibrosis grade, plasma and liver tissue H2S concentrations, as well as cystathionine γ-lyase (CSE) activity and phosphorylated extracellular signal-regulated kinase (pERK)1/2, B cell lymphoma (Bcl)-2 and Bcl-XL expression in portal vein smooth muscle cells, in addition to their H2S-induced apoptosis rates. RESULTS: In portal hypertension patients, endogenous H2S levels were significantly lower than those in healthy controls. The more severe the disease was, the lower were the H2S plasma levels, which were inversely correlated with PVD and Child-Pugh score. Liver tissue H2S concentrations and CSE expression were significantly lower in the SPH rabbit livers compared with the control animals, starting at 3 wk, whereas pERK 1/2 expressions gradually increased 12-20 wk after SPH model establishment. In portal vein smooth muscle cells, increasing H2S levels led to increased apoptosis, while Bcl-2 and Bcl-XL expression decreased. CONCLUSION: H2S prevents vascular restructuring caused by excessive proliferation of smooth muscle cells via apoptosis induction, which helps to maintain normal vascular structures.

Intelectin is required for IL-13-induced monocyte chemotactic protein-1 and -3 expression in lung epithelial cells and promotes allergic airway inflammation.

Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.