Baseline computed tomography screening and blood microRNA predict lung cancer risk and define adequate intervals in the BioMILD trial.

BACKGROUND: Large randomized trials have demonstrated that lung cancer (LC) screening with low-dose computed tomography (LDCT) reduces LC mortality in heavy smokers. We previously showed in the MILD screening trial that the combination of a prespecified circulating microRNA (miRNA) signature classifier (MSC) and LDCT improves the accuracy of LDCT alone. The primary aim of the prospective BioMILD study was to assess the additional value of the blood MSC assay at the time of baseline LDCT with the goal of personalizing LC screening intervals. PATIENTS AND METHODS: The study enrolled 4119 volunteers from January 2013 to March 2016, with a median follow-up of 5.3 years. Baseline LDCT and miRNAs stratified participants into four groups: CT-/MSC- (n = 2664; 64.7%); CT-/MSC+ (n = 800; 19.4%); CT+/MSC- (n = 446; 10.8%); and CT+/MSC+ (n = 209; 5.1%). As per the protocol, those in the CT-/MSC- and CT-/MSC+ groups were allocated to LDCT repeat at 3-year and 1-year intervals; CT+ participants were allocated for 1-year or earlier intervals on the basis of LDCT features independent of MSC results. RESULTS: CT+ participants had a 15.8-fold higher 4-year LC incidence than CT- participants (95% confidence interval 10.34-24.05), and MSC+ participants had a 2.0-fold higher 4-year LC incidence than MSC- participants (95% confidence interval 1.40-2.90); there was no evidence that the MSC effect differed between CT+ and CT- participants. LC incidence at 4 years was 0.8% in CT-/MSC-, 1.1% in CT-/MSC+, 10.8% in CT+/MSC-, and 20.1% in CT+/MSC+ participants. LC mortality rates at 5 years in the four risk groups were 0.5 in CT-/MSC-, 1.5 in CT-/MSC+, 4.2 in CT+/MSC-, and 10.1 in CT+/MSC+. CONCLUSION: The combined use of LDCT and blood miRNAs at baseline predicts individual LC incidence and mortality, with a major effect of MSC for LDCT-positive individuals. These findings may have important implications in personalizing screening intervals.

Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.

BACKGROUND: The National Lung Screening Trial showed that lung cancer (LC) screening by three annual rounds of low-dose computed tomography (LDCT) reduces LC mortality. We evaluated the benefit of prolonged LDCT screening beyond 5 years, and its impact on overall and LC specific mortality at 10 years. DESIGN: The Multicentric Italian Lung Detection (MILD) trial prospectively randomized 4099 participants, to a screening arm (n = 2376), with further randomization to annual (n = 1190) or biennial (n = 1186) LDCT for a median period of 6 years, or control arm (n = 1723) without intervention. Between 2005 and 2018, 39 293 person-years of follow-up were accumulated. The primary outcomes were 10-year overall and LC specific mortality. Landmark analysis was used to test the long-term effect of LC screening, beyond 5 years by exclusion of LCs and deaths that occurred in the first 5 years. RESULTS: The LDCT arm showed a 39% reduced risk of LC mortality at 10 years [hazard ratio (HR) 0.61; 95% confidence interval (CI) 0.39-0.95], compared with control arm, and a 20% reduction of overall mortality (HR 0.80; 95% CI 0.62-1.03). LDCT benefit improved beyond the 5th year of screening, with a 58% reduced risk of LC mortality (HR 0.42; 95% CI 0.22-0.79), and 32% reduction of overall mortality (HR 0.68; 95% CI 0.49-0.94). CONCLUSIONS: The MILD trial provides additional evidence that prolonged screening beyond 5 years can enhance the benefit of early detection and achieve a greater overall and LC mortality reduction compared with NLST trial. CLINICALTRIALS.GOV IDENTIFIER: NCT02837809.

RET fusions in a small subset of advanced colorectal cancers at risk of being neglected.

Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen.

OBJECTIVES: To compare the performance metrics of two different strategies of lung cancer screening by low-dose computed tomography (LDCT), namely, annual (LDCT1) or biennial (LDCT2) screen. METHODS: Recall rate, detection rate, interval cancers, sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) were compared between LDCT1 and LDCT2 arms of the MILD trial over the first seven (T0-T6; median follow-up 7.3 years) and four rounds (T0-T3; median follow-up 7.3 years), respectively. RESULTS: 1152 LDCT1 and 1151 LDCT2 participants underwent a total of 6893 and 4715 LDCT scans, respectively. The overall recall rate was higher in LDCT2 arm (6.97 %) than in LDCT1 arm (5.81 %) (p = 0.01), which was counterbalanced by the overall lower number of LDCT scans. No difference was observed for the overall detection rate (0.56 % in both arms). The two LDCT arms had similar specificity (99.2 % in both arms), sensitivity (73.5 %, in LDCT2 vs. 68.5 % in LDCT1, p = 0.62), PPV (42.4 %, in LDCT2, vs. 40.6 %, in LDCT1, p = 0.83) and NPV (99.8 %, in LDCT2 vs. 99.7 %, in LDCT1, p = 0.71). CONCLUSION: Biennial screen may save about one third of LDCT scans with similar performance indicators as compared to annual screening. KEY POINTS: • Biennial LDCT screening may be as efficient as the annual screening. • Annual and biennial LDCT screening have similar frequency of interval lung cancers. • Biennial screening may save about one third of LDCT scans.

Molecular profiling of pediatric and young adult colorectal cancer reveals a distinct genomic landscapes and potential therapeutic avenues.

Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a 'control group' consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor.

Adipose tissue displays trophic properties on normal lung cellular components without promoting cancer cells growth.

Surgical removal is the mainstay for early lung cancer treatment and persistent air leaks represent one of the most common clinical complications after lung surgery. Adipose tissue transplantation has been proposed as a new strategy for regenerative therapy after breast cancer surgery; however its efficacy and safety of lung tissue healing after lung resections are unknown. The purpose of this study was to test the biological activity of adipose tissue to facilitate lung tissue healing and evaluate its effect on cancer cells growth, thus providing insight for a possible clinical application. Different in vitro cellular models were used to prove the potential biologic effect of autologous fat tissue (AFT) in repairing injured lung tissue, and in vivo xenograft models were used to evaluate tumor promoting potential of AFT on putative residual cancer cells. Treatment of both embryonic (WI-38) and adult lung fibroblasts and of normal bronchial epithelial cells (HBEC-KT) with AFT samples, harvested from subcutaneous tissue layer of 20 patients undergoing pulmonary metastasectomy, improved wound healing and cell proliferation indicating a trophic effect on both mesenchymal and epithelial cell types. Conversely AFT-conditioned medium was unable to stimulate in vitro proliferation of a lung adenocarcinoma reporter cellular system (A549). Moreover, co-injection of AFT and A549 cells in nude mice did not promote engraftment and progression of A549 cells. These preclinical findings provide preliminary evidence on the potential efficacy of AFT to accelerate lung tissue repair without undesired tumor promoting effects on putative residual cancer cells.

Molecular sputum analysis for the diagnosis of lung cancer.

Lung cancer is the leading cause of cancer mortality rate worldwide, mainly because of the presence of metastatic disease at the time of diagnosis. Early detection of lung cancer improves prognosis, and towards this end, large screening trials in high-risk individuals have been conducted since the past century. Despite all efforts, the need for novel (complementary) lung cancer diagnostic and screening methods still exists. In this review, we focus on the assessment of lung cancer-related biomarkers in sputum in the past decennium. Besides cytology, mutation and microRNA analysis, special attention has been paid to DNA promoter hypermethylation, of which all available literature is summarised without time restriction. A model is proposed to aid in the distinction between diagnostic and risk markers. Research on the use of sputum for non-invasive detection of early-stage lung cancer has brought new insights and advanced molecular techniques. The sputum shows a promising potential for routine diagnostic and possibly screening purposes.

Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.

Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy, presents specific features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from the t(17;22). In this report, the breakpoints from translocations and rings in DP and its juvenile form, giant cell fibroblastoma (GCF), were characterised on the genomic and RNA level. These rearrangements fuse the platelet-derived growth factor B-chain (PDGFB, c-sis proto-oncogene) and the collagen type I alpha 1 (COL1A1) genes. PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes is not fully understood. COL1A1 is a major constituent of the connective tissue matrix. Neither PDGFB nor COL1A1 have so far been implicated in any tumour translocations. These gene fusions delete exon 1 of PDGFB, and release this growth factor from its normal regulation.

COVID-19 epidemic strongly affected cancer research in Italy: a survey of the Italian Cancer Society (SIC).

BACKGROUND: Italy was among the first countries hit by the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The application of strict lockdown measures disproportionately affected both cancer patient care as well as basic and translational cancer research. MATERIALS AND METHODS: The Italian Cancer Society (SIC) conducted a survey on the effect of lockdown on laboratories involved in cancer research in Italy. The survey was completed by 570 researchers at different stages of their career, working in cancer centers, research institutes and universities from 19 Italian regions. RESULTS: During the lockdown period, the impact of the COVID-19 pandemic emergency on face-to-face research activities was high, with a complete (47.7%) or partial (36.1%) shutdown of the laboratories. In the post-lockdown period, research activities were resumed in most of the respondents' institutions (80.4%), though with some restrictions (77.2%). COVID-19 testing was offered to research personnel only in ~50% of research institutions. Overall, the response to the pandemic was fragmented as in many cases institutions adopted different strategies often aimed at limiting possible infections without a clearly defined contingency plan. Nevertheless, research was able to provide the first answers and possible ways out of the pandemic, also with the contribution of many cancer researchers that sacrificed their research programs to help overcome the pandemic by offering their knowledge and technologies. CONCLUSIONS: Given the current persistence of an emergency situation in many European countries, a more adequate organization of research centers will be urgent and necessary to ensure the continuity of laboratory activities in a safe environment.

EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration.

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.

Adnexal Torsion in Pediatric Age: Does Bolli's Score Work? Report of Two Cases.

Adnexal torsion is a surgical emergency requiring early diagnosis in order to avoid demolitive surgery. Adnexal torsion's diagnosis could be very difficult in pediatric patients because children cannot explain symptoms accurately. Furthermore reproductive organs lie high in abdomen, causing unclear examinations findings. For reducing diagnostic mistakes or delay clinical and hematological criteria could be useful. No radiological criteria (CT or MRI) should be taken in count because of the costs and the required time. By combining clinical presentation in patients with OT three useful diagnostic variables have been identified: age, duration of pain, vomiting. Presence of vomiting, short duration of abdominal pain and high CRP levels have great predictive value for the diagnosis of adnexal torsion. In those patients an exploratory laparoscopy should be performed without any doubt and/or delay. These data may aid physicians in the evaluation of abdominal pain in premenarchal girls.

Ten-year results of the Multicentric Italian Lung Detection trial demonstrate the safety and efficacy of biennial lung cancer screening.

BACKGROUND: The Multicentric Italian Lung Detection (MILD) trial demonstrated that prolonged low-dose computed tomography (LDCT) screening could achieve a 39% reduction in lung cancer (LC) mortality. We have here evaluated the long-term results of annual vs. biennial LDCT and the impact of screening intensity on overall and LC-specific mortality at 10 years. PATIENTS AND METHODS: Between 2005 and 2018, the MILD trial prospectively randomised the 2376 screening arm participants to annual (n = 1190) or biennial (n = 1186) LDCT, for a median screening period of 6.2 years and 23,083 person-years of follow-up. The primary outcomes were 10-year overall and LC-specific mortality, and the secondary end-points were the frequency of advanced-stage and interval LCs. RESULTS: The biennial LDCT arm showed a similar overall mortality (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.57-1.12) and LC-specific mortality at 10 years (HR 1.10, 95% CI 0.59-2.05), as compared with the annual LDCT arm. Biennial screening saved 44% of follow-up LDCTs in subjects with negative baseline LDCT, and 38% of LDCTs in all participants, with no increase in the occurrence of stage II-IV or interval LCs. CONCLUSIONS: The MILD trial provides original evidence that prolonged screening beyond five years with biennial LDCT can achieve an LC mortality reduction comparable to annual LDCT, in subjects with a negative baseline examination.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Quantitative and qualitative characterization of plasma DNA identifies primary and recurrent colorectal cancer.

Because plasma DNA may be a useful tool for cancer detection, we screened primary tumors and related multiple plasma samples at the time of surgery and during the follow-up period for plasma DNA level as well as for K-Ras mutations and p16INK4a promoter hypermethylation in colorectal cancer patients. At the time of surgery, DNA levels were higher in tumor patients than in healthy donors, and K-Ras and p16INK4a alterations were detected in 7 and 11 cancers respectively, and in all related plasma samples. During the follow-up, plasma DNA levels decrease progressively but rapidly increased when a relapse occurred, whereas K-Ras and p16INK4a alterations were detected only in relapsed patients. Therefore, combined quantitative and qualitative analyses of plasma DNA confirm the presence of colorectal cancer, define disease-free status and indicate the presence of relapse.

Effect of inducible FHIT and p53 expression in the Calu-1 lung cancer cell line.

Loss of FHIT expression and p53 mutations are critical events in the early stages of lung carcinogenesis. The restoration of Fhit function in FHIT-negative cancer cells has been reported to cause tumour suppression by inhibition of cell proliferation and/or activation of apoptotic pathways. However, the studies designed to elucidate the biological role of Fhit and its potential interaction with p53 have produced conflicting results. We investigated here the effects of the simultaneous restoration of FHIT and p53 in Calu-1 cells by using a hormone-inducible gene expression system. We demonstrate that the restoration of FHIT expression reinforces the anti-proliferative effect associated with the simultaneous replacement of p53. Indeed, a more pronounced inhibition of cell proliferation associated with an earlier and higher induction of p21(waf1) mRNA and protein expression was observed in Fhit/p53-expressing cells compared with cells expressing p53 alone. This effect was not due to Fhit-mediated up-regulation of p53 expression; in fact p53 protein was expressed at the same level in both FHIT-positive and FHIT-negative cell clones. Consistent with this result, Fhit did not affect the expression of MDM2, a protein known to interact directly with p53 and target p53 for proteolytic degradation, thus down-regulating its activity.

Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: implications for lung cancer development.

BACKGROUND: Retinoids, analogues of vitamin A, are required for the normal growth and differentiation of human bronchial epithelium. They are also able to reverse premalignant lesions and prevent second primary tumors in some patients with non-small-cell lung cancer (NSCLC). These effects are thought to result from modulation of cell growth, differentiation, or apoptosis (programmed cell death). When certain retinoid receptors in the cell nucleus (i.e., retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which mediate most retinoid actions, are suppressed, abnormal activity may result that could enhance cancer development. PURPOSE: This study was designed to determine whether there are abnormalities in the expression of retinoid receptors in surgical specimens from patients with NSCLC. METHODS: Transcripts of nuclear retinoid receptors were detected in formalin-fixed, paraffin-embedded specimens by use of digoxigenin-labeled riboprobes specific for RAR alpha, RAR beta, RAR gamma, RXR alpha, RXR beta, and RXR gamma for in situ hybridization to histologic specimens from 79 patients with NSCLC and as control from 17 patients with non-lung cancer. The quality and specificity of the digoxigenin-labeled probes were determined by northern blotting, and the specificity of the binding of antisense riboprobes was verified by use of sense probes as controls. RESULTS: All receptors were expressed in at least 89% of control normal bronchial tissue specimens from 17 patients without a primary lung cancer and in distant normal bronchus specimens from patients with NSCLC. RAR alpha, RXR alpha, and RXR gamma were expressed in more than 95% of the NSCLC specimens. In contrast, RAR beta, RAR gamma, and RXR beta expression was detected in only 42%, 72%, and 76% of NSCLC, respectively. CONCLUSIONS: These data suggest that the expression of RAR alpha, RXR alpha, and RXR gamma is not altered in NSCLC; however, expression of RAR beta and possibly also of RAR gamma and RXR beta is suppressed in a large percentage of patients with lung cancer. IMPLICATIONS: The loss of expression of one or more of these nuclear retinoid receptors may be associated with lung carcinogenesis.

Ring 22 chromosomes in dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences.

Ring chromosomes have been found with some regularity as solid tumors have come increasingly under cytogenetic study. The full genetic content and significance of these rings remain unclear. Dermatofibrosarcoma protuberans, a tumor of the deep dermis, consistently has supernumerary ring chromosomes, sometimes as the sole detectable cytogenetic change. Using a modified method for comparative genomic hybridization and fluorescent in situ hybridization with a panel of various probes, we found that these ring chromosomes consistently contain the chromosome 22 centromere along with interstitial sequences from chromosomes 17 and 22, specifically from regions 17q23-24 and 22q11-12. The ring chromosomes in dermatofibrosarcoma protuberans are vehicles for a particular pattern of relatively low-level genomic amplification of selected sequences.

Microsatellite alterations in bronchial and sputum specimens of lung cancer patients.

Early diagnosis of lung cancer based on conventional screening procedures has been unable thus far to decrease lung cancer mortality. We explored the possibility of using microsatellite instability in the detection and screening of early phases of lung carcinogenesis. We studied tumor, histopathologically normal bronchial mucosa, and cytological specimens of 51 lung cancer patients for the presence of clonal variations at microsatellite polymorphisms. Microsatellite alterations were found in tumor, normal bronchial mucosa and cytological specimens of 25 of 51 (49%) of the patients. The detection of microsatellite alterations in histopathologically normal bronchial specimens and cytological clinical samples with minimal atypia suggests a possible application of this genetic marker in early diagnosis of precancerous lesions and lung cancer.