Search

We demonstrated previously that the splicing of the actin regulator, hMENA, generates two alternatively expressed isoforms, hMENA11a and hMENAΔv6, which have opposite functions in cell invasiveness. Their mechanisms of action have remained unclear. Here we report two major findings: (i) hMENA regulates β1 integrin expression. This was shown by depleting total hMENA, which led to loss of nuclear expression of serum response factor (SRF)-coactivator myocardin-related transcription factor 1 (MRTF-A), leading to an increase in the G-actin/F-actin ratio crucial for MRTF-A localization. This in turn inhibited SRF activity and the expression of its target gene β1 integrin. (ii) hMENA11a reduces and hMENAΔv6 increases β1 integrin activation and signaling. Moreover, exogenous expression of hMENA11a in hMENAΔv6-positive cancer cells dramatically reduces secretion of extracellular matrix (ECM) components, including β1 integrin ligands and metalloproteinases. On the other hand, overexpression of the pro-invasive hMENAΔv6 increases fibronectin production. In primary tumors high hMENA11a correlates with low stromal fibronectin and a favorable clinical outcome of early node-negative non-small-cell lung cancer patients. These data provide new insights into the roles of hMENA11a and hMENAΔv6 in the druggable β1 integrin-ECM signaling axis and allow stratification of patient risk, guiding their clinical management.

OBJECTIVES Open in new tab Download slide Open in new tab Download slide Overlapping survival curves for N1b (multiple N1 stations), N2a2 (single N2 station + N1 involvement) and N2a1 (skip N2 metastasis) limit the current tumour–node–metastasis (TNM) node (N) subclassification for node involvement. We validated externally the proposed subclassification. METHODS Clinical records from a multicentric database comprising 1036 patients with pulmonary adenocarcinoma (ADC) or squamous cell carcinoma with N1/N2 involvement who underwent, from January 2002 to December 2014, complete lung resections were retrospectively reviewed. Patients were categorized according to the 8th TNM N subclassification proposal. Histological type, number of resected nodes (#RN) and adjuvant therapy (ADJ) were considered limiting factors. RESULTS No difference in the 5-year overall survival (-OS) was noted between N1b and N2a1 (49.6% vs 44.8%, P  = 0.72); instead, the 5-year-OS was significantly improved in patients with squamous cell carcinoma (63% in N1b vs 30.7% in N2a1, P  = 0.04). In patients with ADC, the 5-year-OS was better in those with N2a1 than with N1b (50.6% vs 37.5%, P  = 0.09). When we compared N1b with N2a2, the 5-year-OS was statistically significant (49.6% vs 32.8%, P  = 0.02); considering only patients with squamous cell carcinoma (63% vs 25.8%, P  = 0.003), #RN >10 (63.2% vs 35.3%, P  = 0.05) and without ADJ (56.4% vs 24.5%, P  = 0.02), the 5-year-OS was significantly different. Differences were not significant for ADC, #RN <10 and ADJ. Finally, the 5-year-OS was statistically significant when we compared N2a1 with N2a2 of the total cohort (44.8% vs 32.8%, P  = 0.04), in ADC (5-year-OS 50.6% vs 36.5%, P  = 0.04) and #RN >10 (5-year-OS 49.8% vs 32.1%, P  = 0.03) without ADJ. CONCLUSIONS Histological type, ADJ and #RN are relevant prognostic factors in N + non-small-cell lung cancer. Considering these results, we may better interpret the prognosis prediction limits of the proposed 8th TNM subclassification for the N descriptor. [ABSTRACT FROM AUTHOR]

The dynamic interplay between cancer cells and cancer‐associated fibroblasts (CAFs) is regulated by multiple signaling pathways, which can lead to cancer progression and therapy resistance. We have previously demonstrated that hMENA, a member of the actin regulatory protein of Ena/VASP family, and its tissue‐specific isoforms influence a number of intracellular signaling pathways related to cancer progression. Here, we report a novel function of hMENA/hMENAΔv6 isoforms in tumor‐promoting CAFs and in the modulation of pro‐tumoral cancer cell/CAF crosstalk via GAS6/AXL axis regulation. LC‐MS/MS proteomic analysis reveals that CAFs that overexpress hMENAΔv6 secrete the AXL ligand GAS6, favoring the invasiveness of AXL‐expressing pancreatic ductal adenocarcinoma (PDAC) and non‐small cell lung cancer (NSCLC) cells. Reciprocally, hMENA/hMENAΔv6 regulates AXL expression in tumor cells, thus sustaining GAS6‐AXL axis, reported as crucial in EMT, immune evasion, and drug resistance. Clinically, we found that a high hMENA/GAS6/AXL gene expression signature is associated with a poor prognosis in PDAC and NSCLC. We propose that hMENA contributes to cancer progression through paracrine tumor–stroma crosstalk, with far‐reaching prognostic and therapeutic implications for NSCLC and PDAC. Synopsis: This study reveals that inhibition of hMENA/hMENADv6 expression reduces pro‐tumor CAF‐cancer cell crosstalk and inhibits cancer cell invasiveness. CAFs with a pro‐tumor activated state express higher levels of hMENA/hMENADv6 compared to normal fibroblasts.CAFs over‐expressing hMENADv6 secrete GAS6 and favor the invasiveness of AXL‐ expressing PDAC and NSCLC cells.Reciprocally in tumor cells hMENA/hMENADv6 regulate AXL expression, and sustain GAS6‐AXL paracrine axis.A high hMENA/GAS6/AXL gene expression signature identifies PDAC and NSCLC patients with a poor prognosis. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are a subpopulation with the properties of extensive self‐renewal, capability to generate differentiated cancer cells and resistance to therapies. We have previously shown that malignant pleural effusions (MPEs) from patients with non‐small‐cell lung cancer (NSCLC) represent a valuable source of cancer cells that can be grown as three‐dimensional (3D) spheroids enriched for stem‐like features, which depend on the activation of the Yes‐associated protein‐transcriptional coactivator with PDZ‐binding motif (YAP‐TAZ)/Wnt‐βcatenin/stearoyl‐CoA desaturase 1 (SCD1) axis. Here, we describe a novel support, called CytoMatrix, for the characterization of limited amounts of cancer cells isolated from MPEs of patients with NSCLC. Our results show that this synthetic matrix allows an easy and fast characterization of several epithelial cellular markers. The use of CytoMatrix to study CSCs subpopulation confirms that SCD1 protein expression is enhanced in 3D spheroids when compared with 2D adherent cell cultures. YAP/TAZ nuclear‐cytoplasmic distribution analysed by CytoMatrix in 3D spheroids is highly heterogeneous and faithfully reproduces what is observed in tumour biopsies. Our results confirm and extend the robustness of our workflow for the isolation and phenotypic characterization of primary cancer cells derived from the lung MPEs and underscore the role of SCD1. [ABSTRACT FROM AUTHOR]

Objective: Although surgery in selected small-cell lung cancer (SCLC) patients has been proposed as a part of multimodality therapy, so far, the prognostic impact of node-spreading pattern has not been fully elucidated. To investigate this issue, a retrospective analysis was performed. Methods: From 01/1996 to 12/2012, clinico-pathological, surgical, and oncological features were retrospectively reviewed in a multicentric cohort of 154 surgically treated SCLC patients. A multivariate Cox proportional hazard model was developed using stepwise regression, in order to identify independent outcome predictors. Overall (OS), cancer-specific (CSS), and Relapse-free survival (RFS) were calculated by Kaplan-Meier method. Results: Overall, median OS, CSS, and RFS were 29 (95 % CI 18-39), 48 (95 % CI 19-78), and 22 (95 % CI 17-27) months, respectively. Lymphadenectomy was performed in 140 (90.9 %) patients (median number of harvested nodes: 11.5). Sixty-seven (47.9 %) pN0-cases experienced the best long-term survival (CSS: 71, RFS: 62 months; p < 0.0001). Among node-positive patients, no prognostic differences were found between pN1 and pN2 involvement (CSS: 22 vs. 15, and RFS: 14 vs. 10 months, respectively; p = 0.99). By splitting node-positive SCLC according to concurrent N1-invasion, N0N2-patients showed a worse CSS compared to those cases with combined N1N2-involvement (N0N2: 8 months vs. N1N2: 22 months; p = 0.04). On the other hand, the number of metastatic stations ( p = 0.80) and the specific node-level ( p = 0.85) did not affect CSS. At multivariate analysis, pN+ (HR: 3.05, 95 % CI 1.21-7.67, p = 0.02) and ratio between metastatic and resected lymph-nodes (RL, HR: 1.02, 95 % CI 1.00-1.04, p = 0.03) were independent predictors of CSS. Moreover, node-positive patients (HR: 3.60, 95 % CI 1.95-6.63, p < 0.0001) with tumor size ≥5 cm (HR: 1.85, 95 % CI 0.88-3.88, p = 0.10) experienced a worse RFS. Conclusions: In selected surgically treated SCLC, the long-term survival may be stratified according to the node-spreading pattern. [ABSTRACT FROM AUTHOR]

Background: Mutations in the TP53 (Tumour Protein 53) gene can lead to expression of mutant p53 proteins that accumulate in cancer cells and can induce circulating p53 antibodies in cancer patients. Our aim was to evaluate the presence and prognostic role of these antibodies in lung cancer patients and to investigate whether they were related to p53 expression or TP53 mutations in tumour tissues. Methods: A total of 201 lung cancer patients were evaluated for p53 antibodies by ELISA (Enzyme-Linked Immunosorbent Assay) and control was obtained from 54 patients with non-malignant disorders; p53 expression was evaluated in 131 of the lung cancer patients by immunohistochemistry and TP53 mutations were then investigated in 53 tumours positively staining for p53 and in 12 tumours without p53 overexpression, whose DNA was available for direct sequencing. Results: Our results show that 20.4% of cancer patients have positive levels of p53 antibodies, while none of the controls resulted positive. High levels of p53 expression are detected in 57.3% of cases and a significant correlation between serum p53 antibodies and high levels of p53 expression in the corresponding tumours is observed. In non-small cell lung cancer, p53 antibodies are significantly associated with poorly differentiated tumours; furthermore, high levels of p53 expression significantly correlated with squamous cell carcinoma and tumours with highest grade. Survival time of non-small cell lung cancer patients low/negative for serum p53 antibodies was significantly longer compared to patients with positive levels (p = 0.049); in particular, patients with squamous cell carcinoma, but not adenocarcinoma, low/negative for these antibodies show a significant better survival compared to serum-positive patients (p = 0.044). Conclusions: In our study, detection of serum p53 antibodies in non-small cell lung cancer patients has been shown to be useful in identifying subsets of patients with poor prognosis. A significant correlation between the presence of serum p53 antibodies in lung cancer patients and p53 overexpression in the corresponding tumours was also observed. We did not find a significant correlation between levels of serum p53 antibodies and TP53 mutations in the corresponding tumours. [ABSTRACT FROM AUTHOR]

Insulin has been known for a long time to influence the growth and differentiation of normal and transformed cells. In order to delineate the role of insulin specifically in non-small cell lung cancer (NSCLC), we have now searched by immunohistochemistry (IHC) for the presence of insulin in NSCLC samples. Among the 112 samples we studied, 30 were found to contain insulin, which was detected in the form of intracytoplasmic granula. Moreover, its expression significantly correlated with (a) the morphological/histopathological subtype of NSCLC, being more frequent in adenocarcinomas; (b) the grade of tumor differentiation, displaying an increase in low-grade carcinomas; (c) tumor size, occurring predominantly in smaller tumors; (d) the presence of phosphorylated, activated insulin receptor; (e) the median patient age, being present in relatively younger individuals. Furthermore and interestingly, surrounding atypical adenomatous hyperplastic areas and normal alveolar pneumocytes scored insulin-positive in some of the insulin-negative tumors. In addition, PCR exploration for insulin transcripts in some samples positive for immunoreactive insulin was negative, indicating a possibly exogenous origin for the intracellular insulin in our NSCLC cohort. Taken together, our data suggest that an intracellular insulin activity is important for the progression of low-grade human lung adenocarcinomas. J. Cell. Physiol. 221: 766–770, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Summary: Background: Docetaxel has to be considered as the reference control arm for second line chemotherapy for advanced NSCLC. Weekly docetaxel has been compared to standard 3-weekly schedule in a randomized fashion to determine if such schedule improves survival and quality of life. We performed a literature-based meta-analysis of all randomized clinical trials (RCTs) comparing weekly over 3-weekly docetaxel in advanced NSCLC. Methods: All randomized trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenszel method were applied. Heterogeneity test was applied as well. Results: We found six RCTs (three phase III, two phase II, 1018 patients), in which data for overall survival (OS), overall response rate (ORR) and grade 3–4 (G3-4) WHO neutropenia were available. When considering only phase III RCTs, OS did not significantly differ between the two arms (RR 1.01, 95% CI 0.76, 1.42, p =0.785) with no significant heterogeneity (p =0.42). Regarding activity, no significant differences in favour of weekly docetaxel were found, although a trend for 3-weekly schedule was observed (RR 0.81, 95% CI 0.47, 1.40, p =0.485), with no significant heterogeneity (p =0.27). No differences were found in the overall population also considering the phase II trials. Regarding G3-4 neutropenia, a significant homogenous advantage in favour of weekly docetaxel was found, with an absolute benefit of 15–19%. Conclusions: Although considering all drawbacks related to literature-based meta-analyses, weekly docetaxel seems not to improve survival when compared to 3-weekly docetaxel. The significant benefit in grade 3–4 neutropenia seems to suggest this approach in patients with NSCLC pretreated for advanced disease. The quality of life of both schedules needs to be evaluated in an individual patient data meta-analysis. [Copyright &y& Elsevier]

Simple Summary: Lung adenocarcinoma is the most common histology in non-small cell lung cancer that has a large variety of histological and also pathological presentations. However, mediastinal lymph node involvement remains one of the most important prognosticators in these patients, and treatment can vary from upfront surgery to induction therapy or definitive radio-chemotherapy. One of the most intriguing issues regards the identification of the most appropriate treatment for a patient and one of the parameters that may indicate upfront surgical resection is the presence of single mediastinal station involvement. Moreover, another interesting argument regards the adjuvant therapy indication for these patients. For these reasons, we investigated the survival outcome of patients who underwent surgical resection for lung adenocarcinoma and single mediastinal station involvement, with the aim to investigate the prognostic factors in this class of patients. Background: Prognostic factors in patients with single mediastinal station (sN2) involvement continues to be a debated issue. Methods: Data on 213 adenocarcinoma patients with sN2 involvement and who had undergone complete anatomical lung resection and lymphadenectomy, were retrospectively reviewed. Clinical and pathological characteristics together with adjuvant therapy (AD) and node (N) status classifications (number of resected nodes (#RN), number of metastatic nodes (#MN), and node ratio (#MN/#RN = NR) were analyzed. Results: Univariable analysis confirmed that age (0.009), #MN (0.009), NR (0.003), #N1 involved stations (p = 0.003), and skip metastases (p = 0.005) were related to overall survival (OS). Multivariable analysis confirmed, as independent prognostic factors, age <66 years and NR with a three-year OS (3YOS) of 78.7% in NR < 10% vs. 46.6% in NR > 10%. In skip metastases, NR (HR 2.734, 95% CI 1.417–5.277, p = 0.003) and pT stage (HR2.136, 95% CI 1.001–4.557, p = 0.050) were confirmed as independent prognostic factors. AD did not influence the OS of patients with singular positive lymph nodes (p = 0.41), while in patients with multiple lymph nodes and AD, a significantly better 3YOS was demonstrated, i.e., 49.1% vs. 30% (p = 0.004). In patients with N2 + N1 involvement, age (p = 0.002) and AD (p = 0.022) were favorable prognostic factors. Conclusions: Adenocarcinoma patients with single N2 station involvement had a favorable outcome in the case of skip metastases and low NR. Adjuvant therapy improves survival with multiple nodal involvement, while its role in single node involvement should be clarified. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about determining parameters during cardiopulmonary exercise testing that could predict complications after thoracic surgery in patients affected by moderate-severe chronic obstructive pulmonary disease.

• Oligometastatic NSCLC represents a category without a standard therapeutic approach. • In selected oligometastatic NSCLC, radical surgery seems to offer a good prognosis. • Treatment of selected synchronous oligometastatic NSCLC could be conducted safely. Oligometastatic Non-Small Cell Lung Cancer (NSCLC) patients represent a category without a standard therapeutic approach. However, in selected oligometastatic NSCLC, radical surgery seems to offer a good prognosis. This retrospective study aimed to analyse the long-term outcomes of synchronous oligometastatic patients treated with curative intent and identify the factors associated with better results and the proposal of a risk stratification system for classifying the synchronous oligometastatic NSCLC. The medical records of patients from 18 centres with pathologically diagnosed synchronous oligometastatic NSCLC were retrospectively reviewed. The inclusion criteria were synchronous oligometastatic NSCLC, radical surgical treatment of the primary tumour with or without neoadjuvant/adjuvant therapy and radical treatment of all metastatic sites. The Kaplan – Meier method estimated survivals. A stratified backward stepwise Cox regression model was assessed for multivariable survival analyses. 281 patients were included. The most common site of metastasis was the brain, in 50.89 % patients. Median overall survival was 40 months (95 % CI: 29–53). Age ≤65 years (HR = 1.02, 95 % CI: 1.00–1.05; p = 0.019), single metastasis (HR = 0.71, 95 % CI: 0.45–1.13; p = 0.15) and presence of contralateral lung metastases (HR = 0.30, 95 % CI: 0.15 – 0.62; p = 0.001) were associated with a good prognosis. The presence of pathological N2 metastases negatively affected survival (HR = 2.00, 95 % CI: 1.21–3.32; p = 0.0065). These prognostic factors were used to build a simple risk classification scheme. Treatment of selected synchronous oligometastatic NSCLC with curative purpose could be conducted safely and at acceptable 5-year survival levels, especially in younger patients with pN0 disease. [ABSTRACT FROM AUTHOR]

IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen- or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC). Interestingly, the analysis of tumor-infiltrating CD8+T cell populations showed that (i) the relative IL-18 receptor (IL-18R) is significantly more expressed by the minority of cells with a functional phenotype (T-bet+Eomes+), than by the majority of those with the dysfunctional phenotype T-bet−Eomes+generally resident within tumors; (ii) as a consequence, the former are significantly more responsive than the latter to IL-18 stimulus in terms of IFNγ productionex vivo; (iii) PD-1 expression does not discriminate these two populations. These data indicate that IL-18R may represent a biomarker of the minority of functional tumor-infiltrating CD8+T cells in adenocarcinoma NSCLC patients. In addition, our results lead to envisage the possible therapeutic usage of IL-18 in NSCLC, even in combination with other checkpoint inhibitor approaches. [ABSTRACT FROM PUBLISHER]

Summary: Objective: Large cell neuroendocrine carcinoma of the lung are considered aggressive. However, reported prognoses are heterogeneous and the optimum treatment remains undefined. We retrospectively evaluated outcomes in a series of patients with a pathological diagnosis of large cell neuroendocrine lung carcinoma, who underwent lung resection. We also assessed the utility of chemotherapy in a small subgroup. Patients and methods: The clinical records of 144 consecutive patients were reviewed in a multicenter study. Survival times, assessed from the day of surgery until death or most recent follow-up, were estimated by the Kaplan–Meier method, and compared by the log rank test. Results: There were 117 men and 27 women of median age 63 years. Twelve wedge resections, 3 segmentectomies, 95 lobectomies, 7 bilobectomies and 24 pneumonectomies were performed. Induction chemotherapy was given in 21 and postoperative chemotherapy in 24. Pathologically, 73 (50%) were stage I, 29 (20%) stage II, 40 (28%) stage III and 2 stage IV. Postoperative mortality was 2.8% and morbidity 26%. Overall 5-year survival was 42.5%: 52% for stage I, 59% for stage II and 20% for stage III (p =0.001 log-rank test on Kaplan–Meier curves). A trend to better outcome was associated with preoperative or postoperative chemotherapy in stage I disease (p =0.077) compared to no chemotherapy. The response rate to induction chemotherapy was 80% in the 15 patients with data available. Conclusion: large cell neuroendocrine carcinoma of the lung are confirmed as aggressive but are also chemosensitive. Our experience suggests that chemotherapy may improve prognosis in stage I disease. [Copyright &y& Elsevier]