A detrimental mutation on USP40 unlocks the tumorigenesis in a rare case of lung cancer.

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Previous research has shown heterogeneity in lung cancer, with the parallel existence of multiple subclones characterized by their own specific mutational landscape. The aim of our study was to gain insight into the evolutionary pattern of lung cancer by investigating the genomic heterogeneity between a nodule and its distant tumor. Luckily, we obtained nodule and tumor samples derived from surgery and a blood sample from a single patient. The samples are very unique, for tissues with the same genetic background from nodules to malignant tumors are rarely available and require precise micro-cutting. In this study, we performed whole-genome sequencing of these two samples, to identify novel candidate driver genes associated with LUAD. The nodule and tumor were found to have common significant ubiquitin-specific protease 40 (USP40) mutations, indicating an important driver role for the gene. Moreover, we also observed the two novel candidate driver genes ASCL5 and CAPNS1 in the LUAD sample. In summary, we pinpoint the predominant mutations in LUAD by WES, highlighting the substantial genetic alterations contributing to LUAD tumorigenesis. This may provide a better understanding of the clonal evolution during tumor development.

Significance of NLDA, the commixed index of inflammation, immune responses, hemostasis, and nutrition, for predicting metastatic non-small cell lung cancer prognosis and metastases.

PURPOSE: This study aimed to take a comprehensive review of the hematological indexes and discover a novel, comprehensive, and economical index for prognostic prediction. RESULTS: The predictive prognostic model revealed that an elevated value of NLDA (NLDA = neutrophil count/lymphocyte count × D-dimer count/albumin) was an independent risk factor for one-year adverse prognosis (hazard ratio = 3.038; 95% confidence interval [CI], 1.959-4.712; P < 0.001). The C-indexes of internal and external validation in nomogram were 0.738 (95% CI, 0.686-0.79) and 0.731 (95% CI, 0.631-0.831), respectively. The areas under the curves of the NLDA values in retrospective and prospective studies were 0.700 (95% CI, 0.631-0.769; P < 0.001) and 0.692 (95% CI, 0.535-0.822; P = 0.005), respectively. The cut-off value of NLDA was 0.15. NLDA was positively associated with M stage (P = 0.032), organ metastasis counts (P = 0.006), liver metastases (P = 0.019), and vertebrae metastases (P = 0.013). MATERIALS AND METHODS: This was a retrospective and prospective study. The clinicopathological characteristics and hematological parameters of stage IV non-small cell lung cancer patients were analyzed retrospectively and prospectively to establish a valid predictive prognostic model. The primary endpoint was the 1-year overall survival. The predictive prognostic model was established and validated by Cox Regression and nomogram. The cut-off and predictive prognostic values of the novel indexes were calculated through the receiver operating characteristic curves. The chi-square test was used to explore the correlation between the new prognostic hematological index and metastatic characteristics. CONCLUSIONS: In this study, NLDA, a new, comprehensive and economic parameter, was found to be an independent adverse prognostic factor for stage IV non-small cell lung cancer patients, and was positively associated with organ metastases.

Rituximab effectively reverses Tyrosine kinase inhibitors (TKIs) resistance through inhibiting the accumulation of rictor on mitochondria-associated ER-membrane (MAM).

Tyrosine kinase inhibitors (TKIs), a novel group of target-specific anti lung cancer drugs, have recently been found to resistant to some NSCLC cells which have the T790M EGFR mutation. However, recent investigations on the therapies of resistance to EGFR-TKIs are very limited. Therefore, it is important to develop more effective therapies to reverse EGFR-TKIs resistance. In our present study, erlotinib was used as the TKIs drug and the effects of the erlotinib on cell growth were evaluated. Cell viability and concentration dependent studies were performed using HCI-H1975 and HCI-H1299 cells alone with erlotinib, respectively. Further combined with rituximab, the results showed that erlotinib and rituximab were significantly inhibited the cell growth. Furthermore, the combination of erlotinib and rituximab greatly decreased the expression of p-mTOR and p-EGFR. Additional results from western blotting and immunofluorescence assays demonstrated that the accumulation of rictor was also decreased on MAM. Thus, all these results suggested that EGFR-TKIs combined with CD20 mono-antibody significantly decrease the cell growth of H1975 cells and H1299, with T790M EGFR mutation, and inhibit the localization of the key mTOR pathway proteins to MAM. So, it may be a promising strategy for overcoming EGFR TKI resistance in NSCLC patients.

Pulmonary enteric adenocarcinoma with pancreatic metastasis: A case report.

Pulmonary enteric adenocarcinoma is a markedly rare pathological type of lung adenocarcinoma. As the pancreas is a relatively uncommon site for metastasis, the present case is even more unusual. A 62-year-old male was admitted to hospital following the identification of masses in the left chest wall, right abdominal wall and right upper limb, but with no respiratory symptoms. Computed tomography (CT) of the chest revealed a lump in the lung and a mass in the left chest wall, and 18F-fluorodeoxyglucose (18F-FDG) uptake by the lumps was increased. An enhanced abdominal CT revealed a hypodense and homogeneous mass on the head of the pancreas, which was slightly enhanced compared with normal pancreatic tissue. In addition, the 18F-FDG uptake of the lesion was increased and the standardized uptake value (SUV) delayed was not evidently decreased compared with SUVearly. A number of other abnormal metabolic lesions were also identified using positron emission tomography/CT, whereas no abnormal 18F-FDG uptake was identified in the gastrointestinal organ. Furthermore, rectocolonoscopy was performed to exclude diagnosis of metastatic colorectal adenocarcinoma. The hematoxylin- and eosin-stained smears of the masses in the right lung and left chest demonstrated an enteric pattern, which shared morphological and immunohistochemical (IHC) features with those of colorectal adenocarcinoma. The IHC detection revealed that the lesions in the right lung were positive for cytokeratin 7 (CK7), and negative for CK20 and thyroid transcription factor 1 (TTF-1), and the expression of caudal type homeobox 2 (CDX2) was weakly positive; the masses in the left chest wall were positive for CK7, negative for TTF-1, and CK20 and CDX2 were weakly expressed.

Characteristics of circulating tumor cells in organ metastases, prognosis, and T lymphocyte mediated immune response.

Circulating tumor cells (CTCs) possess profound influence on tumor metastases and disease progression. This study aimed to investigate the correlation of CTCs with clinical characteristics and T-cell immunity, and to explore whether CTCs and the subpopulations can serve as an independent prognostic factor in advanced non-small cell lung cancer (NSCLC). A prospective study was conducted in late stages of NSCLC patients. The levels of overall CTCs and the three subpopulation CTCs were enumerated using the CanPatrol™ CTC enrichment system. The information about the patients which included the clinical characteristics, survival status at the 200th day postdiagnosis, and the levels of T cells was collected. Mann-Whitney U test, Kruskal-Wallis H test, Cox regression, and Spearman's rank correlation coefficient were the statistical methods used in this study. We detected CTCs in 27 of the 31 eligible patients; the level of epithelial-mesenchymal circulating tumor cells (EMCTCs) was higher than that of epithelial circulating tumor cells and that of mesenchymal circulating tumor cells (MCTCs) in the majority of NSCLC patients. Organ metastases were positively associated with the levels of overall CTCs, EMCTCs, and MCTCs (P<0.05). EMCTCs and MCTCs were associated with worse clinical outcomes. Additionally, the levels of EMCTCs were negatively associated with the levels of CD3+ T cells (P=0.01) and CD8+ T cells (P=0.04). In conclusion, the levels of CTCs were positively associated with organ metastases, particularly bone metastases, but were negatively associated with T-cell levels. The levels of EMCTCs and MCTCs had negative prognostic value.

Clinical Features of Pulmonary Sparganosis.

BACKGROUND: Sparganosis is an infectious disease caused by the sparganum of Spirometra species, which seldom invades the respiratory system. The aim was to describe the clinical features and outcomes of pulmonary sparganosis. METHODS: A total of 40 patients with pulmonary sparganosis were reviewed, including 12 cases known from this experience and 28 cases reported in the literature. RESULTS: Among these 40 patients at an average age of 45.4 ± 11.1 years (men 29), 34 (85%) had a history of ingesting raw or undercooked meat (mainly frogs or snakes). The top 3 symptoms were coughing (60.0%), fever (57.5%) and chest pain (42.5%). Peripheral blood eosinophilia was found in 30 cases (75%). Lesions were located in lung parenchyma, airway, pleura and pulmonary vessels of the patients. Thirty-one patients (77.5%) had pleural effusion. The diagnosis was established by antisparganum antibody test in 30 cases (75%) and by pathology in 9 cases (22.5%); 1 case was not mentioned. Among the 35 cases with follow-up information, 2 treated with complete surgical removal and 31 with oral administration of praziquantel had no recurrence; the remaining 2 died without effective treatments. CONCLUSIONS: As an extremely rare and life-threatening parasitic zoonosis, pulmonary sparganosis should be diagnosed by combining the epidemiology, patient history, eosinophilia and the positive antisparganum antibody test result together if no worm was detected. Oral praziquantel is considered to be an effective treatment.

Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for non-small cell lung cancer cells.

Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are effective clinical therapies for advanced non-small cell lung cancer (NSCLC) patients, while resistance to TKIs remains a serious problem in clinical practice. Recently, it has been proposed that targeting mTOR could overcome TKI resistance in NSCLC cells. Forkhead box class O1 (FOXO1) has emerged as an important rheostat that modulates the activity of Akt and mTOR signaling pathway. However, the role of FOXO1 and related regulatory mechanism in TKI resistance in NSCLC remain largely unknown. Here, we find that mTOR-AKT-FOXO1 signaling cascade is deregulated in TKI-resistant NSCLC cells and that FOXO1 was highly phosphorylated and lowly acetylated upon erlotinib treatment. Combination of mTOR or PI3K inhibitor and erlotinib overcomes TKI resistance to inhibit cell growth and induce apoptosis in TKI-resistant NSCLC cells. Furthermore, the phosphorylation and acetylation of FOXO1 are reversely modulated by mTORC2-AKT signaling pathway. FOXO1 mutation analyses reveal that FOXO1 acetylation inhibits cell proliferation and promotes NSCLC cell apoptosis, while the phosphorylation of FOXO1 plays opposite roles in NSCLC cells. Importantly, increasing FOXO1 acetylation by a HDAC inhibitor, depsipeptide, overcomes TKI resistance to effectively induce TKI-resistant NSCLC cell apoptosis. Together, FOXO1 plays dual roles in TKI resistance through posttranslational modifications in NSCLC and this study provides a possible strategy for treatment of TKI-resistant NSCLC patients.

A meta-analysis of olanzapine for the prevention of chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life and is one of the reasons for the discontinuation of treatment. Olanzapine is known as an atypical antipsychotic agent, but it has been reported to be effective in treating refractory CINV due to its broad and potent inhibitory activity at multiple receptors involved in the nausea and vomiting pathways. This study was conducted to assess the efficacy of olanzapine for the prevention of CINV after moderately or highly emetogenic chemotherapy. After a search of Medline (Ovid), PubMed, CNKI, Wanfang and Weipu from 1990 to October 2013, all randomised controlled trials of olanzapine for the prevention of CINV were included in this study. The meta-analysis was performed using RevMan 5.0.19 software. 6 studies involving 726 total patients were included, of which 441 were Chinese oncology patients. We found that for both general populations and Chinese populations, antiemetic regimens including olanzapine are more effective at reducing CINV than regimens that do not include olanzapine, especially in the delayed phase of CINV.

RAF1-MEK1-ERK/AKT axis may confer NSCLC cell lines resistance to erlotinib.

The fact that advanced NSCLC patients with wild type (wt) EGFR can benefit from erlotinib therapy makes it critical to find out biomarkers for effective selection of patients and improving the therapy effects. In present study, 3 NSCLC cell lines (U1752, Calu-6 and NCI-H292) with wt EGFR and different sensitivities to erlotinib were used for microarray analysis. The differential basal gene expression between 2 NSCLC cell lines was analyzed, about 353 genes were expression-altered with higher than 2-fold changes between Calu-6 and U1752. And Ingenuity Pathway Analysis (IPA) showed that these genes were mainly enriched in regulation of epithelial-mesenchymal transition (EMT) pathway, Wnt-ß catenin signaling, Tec kinase signaling and some types of cancer-related signaling. More interestingly, RAF1 (c-raf), MAP2K1 (MEK1), SNAI and downstream signaling molecules ERK and AKT were predicted to be activated in erlotinib-resistant cell line by IPA. Subsequent immunoblotting experiments showed that the phosphorylation of ERK and AKT were exactly increased stepwise from erlotinib sensitive cell line to erlotinib resistant cell lines. Collectively, activation of RAF1-MEK1-ERK/AKT axis may determine the resistance of NSCLC cell lines bearing wt EGFR to erlotinib. Our work provides potential biomarkers and therapeutic targets for NSCLC patients harboring wt EGFR.

Genetic polymorphisms of XPD and CDA and lung cancer risk.

To determine the susceptibility genes of lung cancer, we investigated the frequency distributions of the xeroderma pigmentosum complementary group D (XPD) and cytidine deaminase (CDA) genes in patients. A case-control study was conducted involving lung cancer patients and healthy controls. The genotypic distributions of XPD exon 10 G→A (Asp312Asn) and 23 T→G (Lys751Gln), and CDA 79 A→C (Lys27Gln) and 208 G→A (Ala70Thr), were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results demonstrated that the XPD Asp312Asn genotype distribution was G/G (82.52%) and A/G (17.48%) in the lung cancer patients, and G/G (82.52%), A/G (16.50%) and A/A (10.98%) in the controls. The genotypes of Lys751Gln were T/T (83.49%) and T/G (16.50%) in the lung cancer patients, and T/T (84.47%) and T/G (15.53%) in the controls. Mutations in the XPD single nucleotide polymorphism loci did not demonstrate a significant difference between the two groups (P>0.05). The risk of lung cancer in individuals with mutations at positions 312 and 751 increased 6.13-fold (P=0.047). The CDA Lys27Gln genotype distribution was A/A (78.65%), A/C (20.39%) and C/C (0.98%) in the lung cancer patients, and A/A (79.61%), A/C (19.42%) and C/C (0.98%) in the controls (P=0.985). The CDA Ala70Thr genotype distribution was G/G (98.06%) and A/G (1.94%) in the controls, while all the genotypes were wild-type in the lung cancer patients. The difference between the lung cancer patients and the controls was not statistically significant (P=0.155). There was also no significant difference in the frequency distribution of XPD or CDA between the different pathological types (P>0.05). Our findings demonstrate that the mutation of XPD codons 312 and 751 increases the risk of lung cancer. By contrast, polymorphisms of CDA appear to have little association with lung cancer.

[Pulmonary sclerosing hemangioma: report of 15 cases and review of the literature].

OBJECTIVE: To improve the understanding of pulmonary sclerosing hemangioma (PSH). METHODS: The clinical data of 15 cases of PSH were analyzed, and the literature was reviewed. The etiology, clinical manifestations, differential diagnosis, treatment and outcome of PSH were described. RESULTS: The etiology and histological origin of PSH were unclear. Most cases were asymptomatic or only with mild symptoms. The radiology of PSH often showed isolated nodule with distinct margin in the lung field. The characteristics of its pathological manifestation were as follows: (1) background of cell gathering or mucin matrix with scattered white blood cells; (2) proliferation of hemangioma with sclerosis of vessel wall; (3) papillary proliferation of small vessels intruding into the air space; (4) existence of hemorrhage or sclerosis zone. Immunohistological studies had not defined the correct histological origin of PSH. A pre-operation diagnosis of PSH was difficult. Thirteen cases had been misdiagnosed as malignancy. The outcome of the disease was good when early surgical resection was performed. CONCLUSIONS: PSH is an uncommon disease, and can be easily misdiagnosed. More attention should be paid to its clinical features and management.