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Lombardy is the Italian region most affected by COVID-19. We tested the presence of plasma anti-SARS-CoV-2 IgG antibodies in 3985 employees across 7 healthcare facilities in areas of Lombardy with different exposure to the SARS-CoV-2 epidemic. Subjects filled a questionnaire to self-report on COVID-19 symptoms, comorbidities, smoking, regular or remote working, and the exposure to COVID-infected individuals. We show that the number of individuals exposed to the virus depended on the geographical location of the facility, ranging between 3 and 43%, consistent with the spatial variation of COVID-19 incidence in Lombardy, and correlated with family interactions. We observed a higher prevalence of females than males positive for IgG, however the level of antibodies was similar, suggesting a comparable magnitude of the anti-spike antibody response. IgG positivity among smokers was lower (7.4% vs 13.5%) although without difference in IgG plasma levels. We observed 11.9% of IgG positive asymptomatic individuals and another 23.1% with one or two symptoms. Interestingly, among the IgG positive population, 81.2% of subjects with anosmia/dysgeusia and fever were SARS-CoV-2 infected, indicating that these symptoms are strongly associated to COVID-19. In conclusion, the frequency of IgG positivity and SARS-CoV-2 infection is dependent on the geographical exposure to the virus and primarily to family rather than hospital exposure.

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.

Diagnosis of Arrhythmogenic CardioMyopathy (ACM) is challenging and often late after disease onset. No circulating biomarkers are available to date. Given their involvement in several cardiovascular diseases, plasma microRNAs warranted investigation as potential non-invasive diagnostic tools in ACM. We sought to identify circulating microRNAs differentially expressed in ACM with respect to Healthy Controls (HC) and Idiopathic Ventricular Tachycardia patients (IVT), often in differential diagnosis. ACM and HC subjects were screened for plasmatic expression of 377 microRNAs and validation was performed in 36 ACM, 53 HC, 21 IVT. Variable importance in data partition was estimated through Random Forest analysis and accuracy by Receiver Operating Curves. Plasmatic miR-320a showed 0.53 ± 0.04 fold expression difference in ACM vs. HC (p < 0.01). A similar trend was observed when comparing ACM (n = 13) and HC (n = 17) with athletic lifestyle, a ACM precipitating factor. Importantly, ACM patients miR-320a showed 0.78 ± 0.05 fold expression change vs. IVT (p = 0.03). When compared to non-invasive ACM diagnostic parameters, miR-320a ranked highly in discriminating ACM vs. IVT and it increased their accuracy. Finally, miR-320a expression did not correlate with ACM severity. Our data suggest that miR-320a may be considered a novel potential biomarker of ACM, specifically useful in ACM vs. IVT differentiation.

Abstract Despite the strong prognostic stratification of circulating tumor cells (CTCs) enumeration in metastatic breast cancer (MBC), current clinical trials usually do not include a baseline CTCs in their design. This study aimed to generate a classifier for CTCs prognostic simulation in existing datasets for hypothesis generation in patients with MBC. A K-nearest neighbor machine learning algorithm was trained on a pooled dataset comprising 2436 individual MBC patients from the European Pooled Analysis Consortium and the MD Anderson Cancer Center to identify patients likely to have CTCs ≥ 5/7 mL blood (StageIVaggressive vs StageIVindolent). The model had a 65.1% accuracy and its prognostic impact resulted in a hazard ratio (HR) of 1.89 (Simulatedaggressive vs SimulatedindolentP < .001), similar to patients with actual CTCs enumeration (HR 2.76; P < .001). The classifier’s performance was then tested on an independent retrospective database comprising 446 consecutive hormone receptor (HR)-positive HER2-negative MBC patients. The model further stratified clinical subgroups usually considered prognostically homogeneous such as patients with bone-only or liver metastases. Bone-only disease classified as Simulatedaggressive had a significantly worse overall survival (OS; P < .0001), while patients with liver metastases classified as Simulatedindolent had a significantly better prognosis (P < .0001). Consistent results were observed for patients who had undergone CTCs enumeration in the pooled population. The differential prognostic impact of endocrine- (ET) and chemotherapy (CT) was explored across the simulated subgroups. No significant differences were observed between ET and CT in the overall population, both in terms of progression-free survival (PFS) and OS. In contrast, a statistically significant difference, favoring CT over ET was observed among Simulatedaggressive patients (HR: 0.62; P = .030 and HR: 0.60; P = .037, respectively, for PFS and OS). Current clinical trials usually do not include a baseline circulating tumor cells (CTCs) enumeration in the trial design. This article reports a classifier to simulate the prognostic stratification of CTCs in existing datasets for hypothesis generation in metastatic breast cancer scenarios. This classifier has the potential to inform and potentially drive future clinical trial design.

Background: HPV tests differ for technology, targets, and information on genotyping of high risk (HR) HPV. In this study, we evaluated the performance of 6 HPV DNA tests and one mRNA test in the detection of cervical intraepithelial lesions (CIN) and as a test-of-cure in the follow-up after surgical conservative treatment. Methods: One hundred seventy-two women referred to the European Institute of Oncology, Milan, for surgical treatment of pre-neoplastic cervical lesions, were enrolled in this study (IEO S544) from January 2011 to June 2015. For all women, a cervical sample was taken before treatment (baseline) and at the first follow-up visit (range 3 to 9 months): on these samples Qiagen Hybrid Capture 2 (HC2), Roche Linear Array HPV Test (Linear Array), Roche Cobas 4800 HPV test (Cobas), Abbott RealTime High Risk HPV test (RT), BD Onclarity HPV assay (Onclarity), Seegene Anyplex II HPV HR Detection (Anyplex), and Hologic Aptima HPV Assay (Aptima) histology and cytology were performed at baseline, and the same tests and cytology were performed at follow-up. Results: At baseline 158/172 (92%), histologies were CIN2+, and 150/172 (87%) women were recruited at follow-up. Assuming HC2 as a comparator, the concordance of HPV tests ranges from 91% to 95% at baseline and from 76% to 100% at follow-up (PABAK ranging from 0.81 to 0.90 at baseline and PABAK ranging from 0.53 to 1 at follow-up). All HPV showed a very good sensitivity in CIN2+ detection at baseline, more than 92%, and a very good specificity at follow-up, more than 89%. Conclusions: HPV tests showed a good concordance with HC2 and a very good and comparable sensitivity in CIN2+ detection. Hence, an HPV test represents a valid option as test-of-cure in order to monitor patients treated for CIN2+ lesions during follow-up.

Background Endogenous hormones and insulin-like growth factors (IGF) play a central role in breast cancer development. Mammographic density, an important breast cancer risk factor, has been associated with these biomarkers in premenopausal women. The aim of this study was to assess the relationships between circulating hormones, clinical features related to breast cancer risk and mammographic density in postmenopausal women. Subjects and methods The study included 226 postmenopausal women participating in a clinical prevention trial. We performed baseline measurements of mammographic percent density and circulating levels of estradiol, sex-hormone binding globulin (SHBG), follicle stimulating hormone (FSH), prolactin, C-terminal cross-link telopeptide, IGF-I, and IGF binding protein-3. Results Median age and time since last menses were 52 years and 15 months, respectively. Median body mass index was 24.1 kg/m 2 . After adjusting for age and body mass index, estradiol was the only biomarker significantly correlated with mammographic density ( r  = 0.17; P  = 0.04). Women with normal body mass index had higher mammographic density ( P  < 0.001), higher SHBG ( P  < 0.0001), higher FSH ( P  = 0.002) and lower estradiol levels ( P  = 0.01) than those who were overweight. Women who had previous biopsies for benign breast disease had a higher mammographic density ( P  = 0.006). Conclusions In these recently postmenopausal women, mammographic percent density is directly associated with circulating estradiol levels. Our results provide further support to the role of circulating hormones in breast cancer risk.

Pancreatic cancer patients underwent surgical resection often present distant metastases early after surgery. Detection of circulating tumor cells (CTCs) has been correlated to a worse oncological outcome in patients with advanced pancreatic cancer. The objective of this pilot study is to investigate the possible prognostic role of CTCs in patients undergoing surgery for pancreatic cancer. In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation (SC) and portal vein (PV). Blood sample was analyzed for CTCs with CellSearch® system. All patients underwent an oncologic follow-up for at least 3 years, quarterly. CTCs were detected in nine (45 %) patients: five patients had CTCs in PV only, three patients in both SC and PV, and one patient in SC only. CTC-positive and CTC-negative patients were similar for demographics and cancer stage pattern. No significant differences were found in both overall and disease-free survival between CTC-positive and CTC-negative patients. At 3-year follow-up, portal vein CTC-positive patients presented a higher rate of liver metastases than CTC-negative patients (53 vs. 8 %, p  = 0.038). CTCs were found in 45 % of the patients. No correlation between CTCs and survival was found. The presence of CTCs in portal vein has been associated to higher rate of liver metastases after surgery.

We aimed to assess the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with metastatic breast cancer by undertaking a pooled analysis of individual patient data. We contacted 51 European centres and asked them to provide reported and unreported anonymised data for individual patients with metastatic breast cancer who participated in studies between January, 2003, and July, 2012. Eligible studies had participants starting a new line of therapy, data for progression-free survival or overall survival, or both, and CTC quantification by the CellSearch method at baseline (before start of new treatment). We used Cox regression models, stratified by study, to establish the association between CTC count and progression-free survival and overall survival. We used the landmark method to assess the prognostic value of CTC and serum marker changes during treatment. We assessed the added value of CTCs or serum markers to prognostic clinicopathological models in a resampling procedure using likelihood ratio (LR) χ2 statistics. 17 centres provided data for 1944 eligible patients from 20 studies. 911 patients (46·9%) had a CTC count of 5 per 7·5 mL or higher at baseline, which was associated with decreased progression-free survival (hazard ratio [HR] 1·92, 95% CI 1·73–2·14, p<0·0001) and overall survival (HR 2·78, 95% CI 2·42–3·19, p<0·0001) compared with patients with a CTC count of less than 5 per 7·5 mL at baseline. Increased CTC counts 3–5 weeks after start of treatment, adjusted for CTC count at baseline, were associated with shortened progression-free survival (HR 1·85, 95% CI 1·48–2·32, p<0·0001) and overall survival (HR 2·26, 95% CI 1·68–3·03) as were increased CTC counts after 6–8 weeks (progression-free survival HR 2·20, 95% CI 1·66–2·90, p<0·0001; overall survival HR 2·91, 95% CI 2·01–4·23, p<0·0001). Survival prediction was significantly improved by addition of baseline CTC count to the clinicopathological models (progression-free survival LR 38·4, 95% CI 21·9–60·3, p<0·0001; overall survival LR 64·9, 95% CI 41·3–93·4, p<0·0001). This model was further improved by addition of CTC change at 3–5 weeks (progression-free survival LR 8·2, 95% CI 0·78–20·4, p=0·004; overall survival LR 11·5, 95% CI 2·6–25·1, p=0·0007) and at 6–8 weeks (progression-free survival LR 15·3, 95% CI 5·2–28·3; overall survival LR 14·6, 95% CI 4·0–30·6; both p<0·0001). Carcinoembryonic antigen and cancer antigen 15-3 concentrations at baseline and during therapy did not add significant information to the best baseline model. These data confirm the independent prognostic effect of CTC count on progression-free survival and overall survival. CTC count also improves the prognostication of metastatic breast cancer when added to full clinicopathological predictive models, whereas serum tumour markers do not. Janssen Diagnostics, the Nuovo-Soldati foundation for cancer research.

Background: α-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. Patients and Methods: In a randomized phase II trial to assess tolerability and safety, we assigned patients with advanced slow-growing solid tumours to 1 of 6 two- or three-drug combinations: α-interferon 0.5 million IU b.i.d., thalidomide (100 mg b.i.d. reduced to 100 mg daily), or celecoxib (400 mg daily reduced to 200 mg). Circulating endothelial cells and progenitors (CECs, CEPs) and vascular endothelial growth factor were also studied. Results: From January 2002 to September 2005, 62 patients were enrolled. Four months after initiating treatment, 3 (4%) had partial response, 40 (64%) had stable disease and 19 (30%) had disease progression. Median duration of clinical benefit (partial response/stable disease) was 11.3 months. Patients receiving a third drug had significantly less stable disease plus partial response (χ 2 test, p = 0.002) than those receiving two drugs. The treatments were generally well tolerated, but neurotoxicity (G3 lethargy) occurred in 6 patients. Baseline CEPs were lower (p = 0.004) in patients with clinical benefit at 6 months than those without benefit. After 2 months of treatment CECs were lower than at baseline (p = 0.018) in patients without clinical benefit, and CEPs were higher than at baseline (p = 0.003) in patients with benefit. Conclusions: In pretreated patients with advanced slow-growing solid tumours, long-term metronomic administration of two-drug combinations of α-interferon, thalidomide or celecoxib was well tolerated and had antitumour activity. Low baseline CEPs in patients with subsequent clinical benefit suggest that CEC count may identify patients likely to benefit from long-term metronomic anti-angiogenic treatment.

Prospective studies have shown an association between elevated plasma levels of insulin-like growth factor-I (IGF-I) and/or decreased levels of its major circulating carrier protein insulin-like growth factor binding protein-3 (IGFBP-3) and increased risk of major cancers. Identifying the factors which affect these biomarkers is of particular interest as subjects at increased risk could benefit from lifestyle changes, and/or chemoprevention intervention. We evaluated the association between constitutional, hormonal and clinical factors and IGF-I and IGFBP-3 in 740 women, including 376 unaffected women and 364 women with intraepithelial neoplasia (IEN) or early invasive breast cancer enrolled in breast cancer chemoprevention trials, conducted at a single institution. Age, body mass index (BMI), height, waist to hip girth ratio (WHR), parity, menopausal status, age at menarche, number of affected first degree relatives, number of biopsies and breast cancer status were considered in the analysis. Women with early breast cancer had 21% higher IGF-I levels (p = 0.033) and 19% higher IGF-I/IGFBP-3 molar ratio (p = 0.047) than unaffected women. In unaffected women, age was negatively associated with IGF-I (p = 0.002) and IGF-I/IGFBP-3 (p = 0.001), while age at menarche was negatively associated with IGFBP-3 levels (p = 0.043). In women with IEN or early breast cancer, IGF-I levels were negatively associated with age (p < 0.001), and positively associated with prior biopsies for benign disease (p = 0.013), while age, parity and menopausal status were significant predictors of IGF-I/IGFBP-3 molar ratio. We conclude that circulating IGF-I levels are higher in women with prior breast cancer compared to unaffected women, and that IGF-I and/or IGFBP-3 levels are influenced by age and by reproductive and hormonal factors. These findings support their putative role as breast cancer risk biomarker.