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PurposeNo consensus exists on the resection extent needed to ensure oncological safety in gastrectomy for gastric adenocarcinoma (GAC). This study aims to assess the impact of margin adequacy according to Japanese Gastric Cancer Association (JGCA) guidelines on overall survival (OS).Patients and MethodsPatients who underwent surgery for stage I–III GAC at our institution between 2010 and 2017 were included. Margin adequacy according to JGCA, National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) guidelines was assessed, and their predictive value on OS was evaluated with Harrell’s C-index. Patients were analyzed according to their margins’ adherence to JGCA guidelines, and a propensity score matching (PSM) was run. Indication to either total gastrectomy (TG) or distal gastrectomy (DG) according to each guideline was also assessed.ResultsA total of 279 patients were included, of whom 220 (79%) underwent DG. Adequate margins according to JGCA were obtained in 209 patients (75%). On multivariate analysis, JGCA margin adequacy was independently associated with OS, together with American Society of Anesthesiologist class, neoadjuvant chemotherapy, lymphadenectomy extent, R0 resection, and postoperative N stage. After PSM, patients with JGCA adequate margins showed better OS, recurrence-free survival (RFS), and local RFS than patients with JGCA inadequate margins. For 220 DG, JGCA guidelines would have recommended TG in 25 patients (11%), NCCN in 30 (14%), and ESMO in 90 (41%) (p < 0.001).ConclusionAdequacy of surgical resection margins to JGCA guidelines leads to improved survival outcomes and allows for a more organ-preserving approach than Western guidelines.

BackgroundControversies still persist regarding the terminology and pathologic classification of appendiceal mucinous neoplasms and associated pseudomyxoma peritonei (PMP). We assessed reproducibility and prognostic significance of the classification recently proposed by the Peritoneal Surface Oncology Group International (PSOGI).MethodsA prospective database of 265 PMP patients uniformly treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) from 1995 to 2017 was reviewed. According to the PSOGI, peritoneal disease was retrospectively classified into three categories: low-grade (LG-PMP), high-grade (HG-PMP), and signet-ring cells (SRC-PMP). Acellular mucin (AC) was classified separately. The extent of peritoneal involvement was quantified by the peritoneal cancer index (PCI).ResultsTwenty-six patients were diagnosed with AC (9.8%), 197 with LG-PMP (74.4%), 38 with HG-PMP (14.3%), and 4 with SRC-PMP (1.5%). In the overall series, median follow-up was 65.5 months (95% confidence interval 53.7–78.8) and 10-year overall survival was 62.9% (median 148.7 months). Operative death occurred in 10 patients (3.8%) and major complications occurred in 89 patients (33.6%). Ten-year survival was 89.6% for AC, 63.2% for LG-PMP, 40.1% for HG-PMP, and 0 for SRC-PMP. In a multivariate model, the World Health Organization (WHO) pathological classification independently correlated with survival (p = 0.028). In a separate model, the PSOGI classification did not reach statistical significance (p = 0.149). Completeness of cytoreduction and PCI > 22 correlated with prognosis in both models.ConclusionsAC and SRC-PMP pathological categories of the PSOGI classification identified two subsets of patients with favorable and exceedingly dismal prognosis, respectively. It remains unclear whether the PSOGI classification might provide better prognostic stratification than the current WHO classification. Further studies in larger prospective series are needed.

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80 hi CD115 hi C3aR hi CD88 hi ), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80 + HO-1 + bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1–CSF1R–C3aR axis. Inhibition of F4/80 + HO-1 + TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1 + myeloid subgroup as a new antimetastatic target and prognostic blood marker. Tumor-associated macrophages (TAMs) play multifaceted roles in establishing an immunosuppressive tumor microenvironment. Sica and colleagues find that macrophage-intrinsic complement signaling initiates a pathway leading to the induction of highly tumorigenic TAMs.

BackgroundSelecting patients with colorectal cancer peritoneal metastases (CRC-PMs) for surgery is still a concern. Biological features have the potential to improve prognostic stratification, but their significance in this clinical setting is still unclear. We assessed the prognostic impact of primary side and KRAS/NRAS/BRAF/PIK3CA mutations in patients treated with either cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) or CRS alone.MethodsWe reviewed a prospective database of 152 CRC-PM patients selected to undergo perioperative systemic chemotherapy and CRS with or without HIPEC. Extensive mutational analysis of KRAS, NRAS, BRAF, and PIK3CA was performed by polymerase chain reaction (PCR). In 68 patients, Ion Torrent next-generation sequencing technology was used to characterize the hotspot regions of 50 genes.ResultsThe primary tumor was right-sided in 61 patients (40.1%) and left-sided in 91 patients (59.9%). Right-sided primaries were associated with mutated KRAS (p = 0.01) and normal carcinoembryonic antigen (CEA; p = 0.03). KRAS was mutated in 71/152 patients (46.7%), NRAS in 7/152 patients (4.6%), BRAF in 10/152 patients (6.6%), PIK3CA in 17/78 patients (25.0%), TP53 in 37/68 patients (54.4%), APC in 25/68 patients (36.7%), SMAD4 in 13/68 patients (19.1%), and FBXW7 in 5/68 patients (7.4%). Median follow-up was 54.9 months and median survival from PM diagnosis was 45.1 months. The right-sided primary (hazard ratio [HR] 1.62, 95% confidence interval [CI] 0.43–0.89; p = 0.011), BRAF mutations (HR 2.21, 95% CI 1.05–4.63; p = 0.038), and Peritoneal Cancer Index (HR 1.47, 95% CI 1.03–2.10; p = 0.036) independently correlated with poorer survival, while APC mutations univariately correlated with better survival (p = 0.03).ConclusionsBRAF mutations and right-sided primary are adverse prognostic factors that may be used to optimize therapeutic strategies. APC may be involved in CRC-PM development and progression.

Genome-wide gene expression analyses of tumors are a powerful tool to identify gene signatures associated with biologically and clinically relevant characteristics and for several tumor types are under clinical validation by prospective trials. However, handling and processing of clinical specimens may significantly affect the molecular data obtained from their analysis. We studied the effects of tissue handling time on gene expression in human normal and tumor colon tissues undergoing routine surgical procedures. RNA extracted from specimens of 15 patients at four time points (for a total of 180 samples) after surgery was analyzed for gene expression on high-density oligonucleotide microarrays. A mixed-effects model was used to identify probes with different expression means across the four different time points. The p-values of the model were adjusted with the Bonferroni method. Thirty-two probe sets associated with tissue handling time in the tumor specimens, and thirty-one in the normal tissues, were identified. Most genes exhibited moderate changes in expression over the time points analyzed; however four of them were oncogenes, and two confirmed the effect of tissue handling by independent validation. Our results suggest that a critical time point for tissue handling in colon seems to be 60 minutes at room temperature. Although the number of time-dependent genes we identified was low, the three genes that already showed changes at this time point in tumor samples were all oncogenes, hence recommending standardization of tissue-handling protocols and effort to reduce the time from specimen removal to snap freezing accounting for warm ischemia in this tumor type.

Cancer cells within a tumor are functionally heterogeneous and specific subpopulations, defined as cancer initiating cells (CICs), are endowed with higher tumor forming potential. The CIC state, however, is not hierarchically stable and conversion of non-CICs to CICs under microenvironment signals might represent a determinant of tumor aggressiveness. How plasticity is regulated at the cellular level is however poorly understood. To identify determinants of plasticity in lung cancer we exposed eight different cell lines to TGFβ1 to induce EMT and stimulate modulation of CD133+ CICs. We show that response to TGFβ1 treatment is heterogeneous with some cells readily switching to stem cell state (1.5–2 fold CICs increase) and others being unresponsive to stimulation. This response is unrelated to original CICs content or extent of EMT engagement but is tightly dependent on balance between epithelial and mesenchymal features as measured by the ratio of expression of CDH1 (E-cadherin) to SNAI2. Epigenetic modulation of this balance can restore sensitivity of unresponsive models to microenvironmental stimuli, including those elicited by cancer-associated fibroblasts both in vitro and in vivo. In particular, tumors with increased prevalence of cells with features of partial EMT (hybrid epithelial/mesenchymal phenotype) are endowed with the highest plasticity and specific patterns of expression of SNAI2 and CDH1 markers identify a subset of tumors with worse prognosis. In conclusion, here we describe a connection between a hybrid epithelial/mesenchymal phenotype and conversion to stem-cell state in response to external stimuli. These findings have implications for current endeavors to identify tumors with increased plasticity. •Signals from the microenvironment are involved in modulation of cancer initiating cells (CICs) in lung cancer.•Balance between epithelial/mesenchymal features is a crucial determinant of proclivity to stemness phenotype acquisition.•Epigenetic modification of epithelial/mesenchymal balance can regulate response to microenvironmental stimuli.•A specific pattern of expression of E-cadherin and SNAI2 is associated with worst prognosis in NSCLC.

Statins can decrease hepatocellular carcinoma (HCC) occurrence, but the magnitude and the predictors of these effects remain unclear. This meta-analysis provides a pooled estimate of the impact of statin use on HCC occurrence. Pooled effects were calculated using a random-effects model by means of the DerSimonian and Laird test. Primary endpoint was the time-dependent correlation between statin use and HCC incidence expressed as hazard ratio (HR), both crude and adjusted. The crude and adjusted odds ratios (OR) for HCC occurrence between statin users and non-users were analyzed. Twenty-five studies with 1,925,964 patients were included. Crude OR for HCC incidence was 0.59 (95% CI: 0.47–0.74), confirmed in adjusted analysis (OR: 0.74, 95% CI: 0.70–0.78). Adjusted HR was 0.73 (95% CI: 0.69–0.76). This effect was more pronounced in HBV patients (HR: 0.46, 95% CI: 0.36–0.60) and with a cumulative daily dose beyond 365 (HR: 0.27, 95% CI: 0.11–0.67). Lipophilic statins were associated with reduced HCC incidence (HR: 0.49, 95% CI: 0.39–0.62). Atorvastatin determined the greater magnitude of effect (HR: 0.43, 95% CI: 0.28–0.65). This meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins.

Lung cancer is the leading cause of cancer‐related death worldwide. Late diagnosis and metastatic dissemination contribute to its low survival rate. Since microRNA (miRNA) deregulation triggers lung carcinogenesis, miRNAs might represent an interesting therapeutic tool for lung cancer management. We identified seven miRNAs, including miR‐126‐3p and miR‐221‐3p, that are deregulated in tumours compared with normal tissues in a series of 38 non‐small‐cell lung cancer patients. A negative correlation between these two miRNAs was associated with poor patient survival. Concomitant miR‐126‐3p replacement and miR‐221‐3p inhibition, but not modulation of either miRNA alone, reduced lung cancer cell viability by inhibiting AKT signalling. PIK3R2 and PTEN were validated as direct targets of miR‐126‐3p and miR‐221‐3p, respectively. Simultaneous miRNA modulation reduced metastatic dissemination of lung cancer cells both in vitro and in vivo through CXCR4 inhibition. Systemic delivery of a combination of miR‐126‐3p mimic and miR‐221‐3p inhibitor encapsulated in lipid nanoparticles reduced lung cancer patient‐derived xenograft growth through blockade of the PIK3R2–AKT pathway. Our findings reveal that cotargeting miR‐126‐3p and miR‐221‐3p to hamper both tumour growth and metastasis could be a new therapeutic approach for lung cancer. Lung cancer is the first cause of cancer‐related deaths in the world. MicroRNAs are deregulated during lung carcinogenesis, and their modulation could represent an interesting therapeutic approach. We demonstrated that concomitant miR‐126 replacement and miR‐221 inhibition reduced lung cancer growth and metastasis both in vitro and in vivo. This study provides evidence for the use of miRNAs as therapy in lung cancer.

Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29–0.85; P  = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33–0.98; P  = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.