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Objective To estimate the cumulative radiation exposure and lifetime attributable risk of cancer incidence associated with lung cancer screening using annual low dose computed tomography (CT).Design Secondary analysis of data from a lung cancer screening trial and risk-benefit analysis.Setting 10 year, non-randomised, single centre, low dose CT, lung cancer screening trial (COSMOS study) which took place in Milan, Italy in 2004-15 (enrolment in 2004-05). Secondary analysis took place in 2015-16.Participants High risk asymptomatic smokers aged 50 and older, who were current or former smokers (≥20 pack years), and had no history of cancer in the previous five years.Main outcome measures Cumulative radiation exposure from low dose CT and positron emission tomography (PET) CT scans, calculated by dosimetry software; and lifetime attributable risk of cancer incidence, calculated from the Biological Effects of Ionizing Radiation VII (BEIR VII) report.Results Over 10 years, 5203 participants (3439 men, 1764 women) underwent 42 228 low dose CT and 635 PET CT scans. The median cumulative effective dose at the 10th year of screening was 9.3 mSv for men and 13.0 mSv for women. According to participants’ age and sex, the lifetime attributable risk of lung cancer and major cancers after 10 years of CT screening ranged from 5.5 to 1.4 per 10 000 people screened, and from 8.1 to 2.6 per 10 000 people screened, respectively. In women aged 50-54, the lifetime attributable risk of lung cancer and major cancers was about fourfold and threefold higher than for men aged 65 and older, respectively. The numbers of lung cancer and major cancer cases induced by 10 years of screening in our cohort were 1.5 and 2.4, respectively, which corresponded to an additional risk of induced major cancers of 0.05% (2.4/5203). 259 lung cancers were diagnosed in 10 years of screening; one radiation induced major cancer would be expected for every 108 (259/2.4) lung cancers detected through screening.Conclusion Radiation exposure and cancer risk from low dose CT screening for lung cancer, even if non-negligible, can be considered acceptable in light of the substantial mortality reduction associated with screening.

Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease.

Cutaneous melanoma is one of the most lethal forms of skin cancer, and its incidence is increasing globally. Its diagnosis typically relies on manual histopathological examination, a process that is both complex and time consuming. In this study, we propose an automated diagnostic tool, capable of generating interpretable results to aid clinical decision-making. A total of 146 whole slide images are included in the study, encompassing various lesion types: congenital nevi, dysplastic nevi, melanomas, and melanomas on nevi. The images were first processed using a multi-resolution image processing pipeline with the aim of segmenting nuclei, evaluating their geometrical and morphological features, as well as their spatial organization. To characterize each slide, these features were synthesized into 44 variables, which were then subjected to Linear Discriminant Analysis. Through this procedure, 18 relevant variables were identified demonstrating good performance in melanoma detection, as validated through Monte Carlo Cross-Validation. These variables were also interpreted within the framework of established histopathological diagnostic insights. By refining the analysis to the cellular level, we emulated standard clinical evaluation practices, ensuring that every aspect of the diagnostic process was accessible and verifiable by medical professionals. The proposed tool can offers significant potential to support clinicians in various tasks, such as prioritizing the analysis of critical samples and providing a secondary diagnostic opinion in complex cases.

The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non-small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4- counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type.

BackgroundThis study aimed to identify the results of the quality assessment and the learning curve of robot-assisted minimally invasive McKeown esophagectomy (RAMIE-MK).MethodsThe study retrospectively reviewed the data of 400 consecutive patients with esophageal cancer who underwent RAMIE-MK by a single surgeon from November 2015 to March 2019. Cumulative summation analysis of the learning curve was performed. The patients were divided into decile cohorts of 40 cases to minimize demographic deviations and to maximize the power of detecting statistically significant changes in performance.ResultsThe 90-day mortality rate for all the patients was 0.5% (2 cases). The authors’ experience was divided into the ascending phase (40 cases), the plateau phase (175 cases), and the descending phase (185 cases). After 40 cases, significant improvements in operative time (328 vs. 251 min; P = 0.019), estimated blood loss (350 vs. 200 ml; P = 0.031), and conversion rates (12.5% vs. 2.5%; P < 0.001) were observed. After 80 cases, a decrease in the rates of anastomotic leakage (22.5% vs. 8.1%; P = 0.001) and vocal cord palsy (31.3% vs. 18.4%; P = 0.024) was observed. The number of harvested lymph nodes increased after 40 cases (13 vs. 23; P < 0.001), especially for lymph nodes along the recurrent laryngeal nerve (3.0 vs. 6.0; P < 0.001).ConclusionsThe learning phase of RAMIE-MK consists of 40 cases, and quality outcomes can be improved after 80 procedures. Several turning points related to the optimization of surgical outcomes can be used as benchmarks for surgeons performing RAMIE-MK.

Background TiO 2 particles are commonly used as dietary supplements and may contain up to 36% of nano-sized particles (TiO 2 -NPs). Still impact and translocation of NPs through the gut epithelium is poorly documented. Results We show that, in vivo and ex vivo, agglomerates of TiO 2 -NPs cross both the regular ileum epithelium and the follicle-associated epithelium (FAE) and alter the paracellular permeability of the ileum and colon epithelia. In vitro, they accumulate in M-cells and mucus-secreting cells, much less in enterocytes. They do not cause overt cytotoxicity or apoptosis. They translocate through a model of FAE only, but induce tight junctions remodeling in the regular ileum epithelium, which is a sign of integrity alteration and suggests paracellular passage of NPs. Finally we prove that TiO 2 -NPs do not dissolve when sequestered up to 24 h in gut cells. Conclusions Taken together these data prove that TiO 2 -NPs would possibly translocate through both the regular epithelium lining the ileum and through Peyer’s patches, would induce epithelium impairment, and would persist in gut cells where they would possibly induce chronic damage.

Regulatory T (T reg ) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4 + T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3 + T reg and eomesodermin homolog (EOMES) + type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES + Tr1-like cells, but not T reg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES + Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of T reg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy. Human primary and metastatic tumors harbor CD4 + T reg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 T reg -like CD4 + T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES + T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.

Lung adenocarcinoma (LUAD) is the main non-small-cell lung cancer diagnosed in ~40–50% of all lung cancer cases. Despite the improvements in early detection and personalized medicine, even a sizable fraction of patients with early-stage LUAD would experience disease relapses and adverse prognosis. Previous reports indicated the existence of LUAD molecular subtypes characterized by specific gene expression and mutational profiles, and correlating with prognosis. However, the biological and molecular features of such subtypes have not been further explored. Consequently, the mechanisms driving the emergence of aggressive LUAD remained unclear. Here, we adopted a multi-tiered approach ranging from molecular to functional characterization of LUAD and used it on multiple cohorts of patients (for a total of 1227 patients) and LUAD cell lines. We investigated the tumor transcriptome and the mutational and immune gene expression profiles, and we used LUAD cell lines for cancer cell phenotypic screening. We found that loss of lung cell lineage and gain of stem cell-like characteristics, along with mutator and immune evasion phenotypes, explain the aggressive behavior of a specific subset of lung adenocarcinoma that we called C1-LUAD, including early-stage disease. This subset can be identified using a 10-gene prognostic signature. Poor prognosis patients appear to have this specific molecular lung adenocarcinoma subtype which is characterized by peculiar molecular and biological features. Our data support the hypothesis that transformed lung stem/progenitor cells and/or reprogrammed epithelial cells with CSC characteristics are hallmarks of this aggressive disease. Such discoveries suggest alternative, more aggressive, therapeutic strategies for early-stage C1-LUAD.

Attentional bias has been defined as the propensity of a person to allocate selective attention automatically to salient cues (Field and Powell, 2007). In the case of smoking, this bias implies that smokers are implicitly attracted by smoking-related stimuli, which produce behavioral, memory, and emotional effects (Volkow et al., 2006; Giardini et al., 2009). In more detail, scientific evidence pointed out that smoking is strongly supported by attentional bias that activates craving and urgency to smoke a cigarette. However, poor and conflicting data are available regarding the role of this cognitive bias on former smokers. The main aim of this study is to explore the occurrence of the attentional bias on of both current and former smokers, also with the aim to identify associations with behavioral, psychological and cognitive characteristic of participants. We collected data on 245 current, volunteers (male 50.6%; female 49.4%) aged 54.81 (SD = 14.352, range = 18-63), divided in current smokers (98), former smokers (102) and non-smokers (45). A combination of neuropsychology tests (Emotional Smoke Stroop Task and Go/no-Go task), and standardized questionnaires [Behavioral Inhibition System-Behavioral Approach System (BIS-BAS), Fagerström Test for Nicotine Dependence (FTND), Barratt Impulsiveness Scale, Motivational questionnaire] were used to assess the attentional bias, psychological variables, and smoking-related characteristics. Responses at the Emotional Smoke Stroop task revealed that current and former smokers are actually slower than non-smokers are when facing smoking cues, while performances at other Stroop conditions and at the Go/no-Go task are not statistically different. These results confirmed the occurrence of the attentional bias in current smokers, and above all points out that the same effect is present in former smokers. We found only small and selective correlations between attentional bias and psychological variables (e.g., impulsiveness and inhibition). In particular, impulsivity is not directly associated with the AB intensity. Also, smoking characteristics (e.g., years of smoking and dependence level) and the length of the period of abstinence do not seem to modulate implicit cognition of smoking cue. Our data support the idea that the attentional bias may be considered relevant in sustaining smoking and favoring relapse.

The identification of circulating microRNAs (miRNAs) in the blood has been recently exploited for the development of minimally invasive tests for the early detection of cancer. Nevertheless, the clinical transferability of such tests is uncertain due to still-insufficient standardization and optimization of methods to detect circulating miRNAs in the clinical setting. We performed a series of tests to optimize the quantification of serum miRNAs that compose the miR-Test, a signature for lung cancer early detection, and systematically analyzed variables that could affect the performance of the test. We took advantage of a large-scale (>1000 samples) validation study of the miR-Test that we recently published, to evaluate, in clinical samples, the effects of analytical and preanalytical variables on the quantification of circulating miRNAs and the clinical output of the signature (risk score). We developed a streamlined and standardized pipeline for the processing of clinical serum samples that allows the isolation and analysis of circulating miRNAs by quantitative reverse-transcription PCR, with a throughput compatible with screening trials. The major source of analytical variation came from RNA isolation from serum, which could be corrected by use of external (spike-in) or endogenous miRNAs as a reference for normalization. We also introduced standard operating procedures and QC steps to check for unspecific fluctuations that arise from the lack of standardized criteria in the collection or handling of the samples (preanalytical factors). We propose our methodology as a reference for the development of clinical-grade blood tests on the basis of miRNA detection.