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.

The impact of COVID-19 on rare metabolic patients and healthcare providers: results from two MetabERN surveys.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused disruption in all aspects of daily life, including the management and treatment of rare inherited metabolic disorders (IMDs). To perform a preliminary assessment of the incidence of COVID-19 in IMD patients and the impact of the coronavirus emergency on the rare metabolic community between March and April 2020, the European Reference Network for Hereditary Metabolic Diseases (MetabERN) has performed two surveys: one directed to patients' organizations (PO) and one directed to healthcare providers (HCPs). The COVID-19 incidence in the population of rare metabolic patients was lower than that of the general European population (72.9 × 100,000 vs. 117 × 100,000). However, patients experienced extensive disruption of care, with the majority of appointments and treatments cancelled, reduced, or postponed. Almost all HCPs (90%) were able to substitute face-to-face visits with telemedicine, about half of patients facing treatment changes switched from hospital to home therapy, and a quarter reported difficulties in getting their medicines. During the first weeks of emergency, when patients and families lacked relevant information, most HCPs contacted their patients to provide them with support and information. Since IMD patients require constant follow-up and treatment adjustments to control their disease and avoid degradation of their condition, the results of our surveys are relevant for national health systems in order to ensure appropriate care for IMD patients. They highlight strong links in an interconnected community of HCPs and PO, who are able to work quickly and effectively together to support and protect fragile persons during crisis. However, additional studies are needed to better appreciate the actual impact of COVID-19 on IMD patients' health and the mid- and long-term effects of the pandemic on their wellbeing.

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.

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.

T regulatory cells mediate immunosuppresion by adenosine in peripheral blood, sentinel lymph node and TILs from melanoma patients.

T regulatory cells (Tregs), involved in tumour tolerance, can generate Adenosine by CD39/CD73 surface enzymes, which identify four Tregs subsets: CD39+CD73- nTregs, CD39+CD73+ iTregs, CD39-CD73+ oTregs and CD39-CD73- xTregs. In melanoma patients, increased Tregs levels are detected in peripheral blood (PB), sentinel lymph node (SLN) and tumour infiltrating lymphocytes (TILs), but Adenosine role was not investigated yet. We examined total Tregs and Adenosine subsets in PB, SLN and TILs from melanoma patients (n = 32) and PB from healthy donors (HD; n = 10) by flow cytometry. Total Tregs significantly increased in stage III-IV patients PB, in SLN and TILs, as compared to HD/stage I-II patients. Tregs subsets analyses showed that: 1) PB nTregs significantly increased in SLN and decreased in TILs; 2) iTregs significantly increased in stage III-IV patients PB and further significantly increased in SLN and TILs; 3) PB oTregs and xTregs significantly decreased in SLN and TILs. Patients clinical features did not significantly influence total Tregs, except SLN excision order. Results confirmed Tregs role in melanoma progression and indicate Adenosine generation as a novel escape mechanism, being nTregs and iTregs increased in PB/SLN/TILs.

CD4+FOXP3+ T regulatory cells decrease and CD3+CD8+ T cells recruitment in TILs from melanoma metastases after electrochemotherapy.

Electrochemotherapy (ECT) represents an effective local treatment for skin unresectable melanoma metastases with high overall objective response rate. ECT is based on the combination of anti-neoplastic drugs administration and cancer cells electroporation. Whether ECT can also activate the immune system is a matter of debate, however a significant recruitment of dendritic cells in melanoma treated metastases has been described. Herein we investigated immediate and late effects of ECT treatment on T cell subsets in ECT-treated lesions by fluorescent immunohistochemistry. Biopsies from melanoma patients (n = 10) were taken before ECT (t0), at d1 and d14 from treatment. At t0, CD3+CD4+ T cells were the most represented T cells, well detected in the perilesional dermis, particularly at tumour margin, while CD3+CD8+ T cells were less represented. CD4+FOXP3+ T regulatory (Treg) cells were present in the perilesional dermis and within the lesion. ECT induced a significant decrease of CD4+FOXP3+ Treg cells percentage in the perilesional dermis, observed at d1 and at d14 (p < 0.001). CD3+CD8+ T cells frequency significantly increased at d14 from treatment in the perilesional dermis (p < 0.001). Furthermore calreticulin translocation to the plasma membrane, a hallmark of immunogenic cell death, was observed in metastatic cells after ECT. The data reported here confirm that ECT induces a local response, with a lymphoid infiltrate characterized by CD4+FOXP3+ Treg cells decrease and CD3+CD8+ T cells recruitment in the treated lesions. These results might contribute to design novel combinational therapeutic approaches with ECT and immunotherapy in order to generate a systemic long-lasting anti-melanoma immunity.

Presenting symptoms of giant fibrovascular polyp of the oesophagus: case report and literature review.

INTRODUCTION: Lipomas of the gastrointestinal tract are rare, slow-growing lesions that comprise 0.4% of all gastrointestinal neoplasms. They can cause dysphagia, dyspnoea or sudden choking. CASE HISTORY: Due to rarity of this condition and its uncommon presentation, a literature review was carried out (PubMed). This search revealed 290 articles, of which 74 were considered pertinent and were evaluated. We report a case of a 13cm pedunculated oesophageal lipoma that presented with increasing dysphagia and two episodes of suffocation. The patient underwent curative resection through a cervical approach. CONCLUSIONS: Resection is recommended for large (>5 cm) or symptomatic polyps. Outcomes are excellent given that lesions are universally benign and oesophageal resection is not required.

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.

New positron emission tomography derived parameters as predictive factors for recurrence in resected stage I non-small cell lung cancer.

BACKGROUND: The recurrence rate for stage I non-small cell lung cancer is high, with 20-40% of patients that relapse after surgery. The aim of this study was to evaluate new F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) derived parameters, such as standardized uptake value index (SUVindex), metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as predictive factors for recurrence in resected stage I non-small cell lung cancer. METHODS: We retrospectively reviewed 99 resected stage I non-small cell lung cancer patients that were grouped by SUVindex, TLG and MTV above or below their median value. Disease free survival was evaluated as primary end point. RESULTS: The 5-year overall survival and the 5-year disease free survival rates were 62% and 73%, respectively. The median SUVindex, MTL and TLG were 2.73, 2.95 and 9.61, respectively. Patients with low SUVindex, MTV and TLG were more likely to have smaller tumors (p ≤ 0.001). Univariate analysis demonstrated that SUVindex (p = 0.027), MTV (p = 0.014) and TLG (p = 0.006) were significantly related to recurrence showing a better predictive performance than SUVmax (p = 0.031). The 5-year disease free survival rates in patients with low and high SUVindex, MTV and TLG were 84% and 59%, 86% and 62% and 88% and 60%, respectively. The multivariate analysis showed that only TLG was an independent prognostic factor (p = 0.014) with a hazard ratio of 4.782. CONCLUSION: Of the three PET-derived parameters evaluated, TLG seems to be the most accurate in stratifying surgically treated stage I non-small cell lung cancer patients according to their risk of recurrence.

The surgical treatment of lung cancer in patients with previous lymphoproliferative disorders: a historical cohort study.

OBJECTIVES: We undertook a historical cohort study to compare, in terms of morbidity, mortality and long-term survival associated with lung cancer resection, a group of patients with previous lymphoproliferative disorders and a group without a hematological history. METHODS: We identified 29 patients with a previous lymphoproliferative disorder who underwent lung cancer resection. These subjects (Group-A) were matched with 87 patients without a hematological history who underwent pulmonary resection during the same period (Group-B). RESULTS: We found no significant difference between the two groups in length of hospitalization, comorbidities, spirometric parameters, type of surgery, histology, neoadjuvant chemotherapy, morbidity, mortality, median survival (Group-A = 37 months; Group-B = 52 months) and 5-year survival (Group-A = 37%; Group-B = 42%). The mean age of Group-A patients was significantly lower than that of Group-B patients (62 vs 66 years; p = 0.024). Group-A patients had a well differentiated lung cancer more frequently than Group-B patients (p = 0.001). Group-A patients had transitory bacteraemies more frequently than Group-B patients (p = 0.005). Multivariate Cox regression analysis showed that age (p = 0.01) and lung cancer stage (p = 0.04) were significantly associated with survival. CONCLUSIONS: Patients with lymphoproliferative disorders had a lower age and more differentiated lung cancers than those without lymphoproliferative disorders. Patients with lymphoproliferative disorders and those without a hematological history had similar morbidity, mortality and long-term survival after pulmonary resection. Distinguishing patients with and without a lymphoproliferative disorder seems to be of limited value in the decision-making process of evaluating the indications for surgical treatment of lung cancer.

'Animal-type' melanoma of the scalp with satellitosis and positive sentinel nodes in a 4-year-old child: case report and review of the literature.

BACKGROUND: Although showing a rapidly rising incidence, paediatric melanoma is relatively rare, accounting for 1-4% of all cases of melanoma and for 1-3% of all paediatric malignancies. The overall survival rate in paediatric patients seems to be similar to that recorded in adults. 'Animal-type' melanoma (ATM) is a rare melanoma subtype, occurring both in childhood and in adults, that shows a close histological resemblance to the heavily pigmented melanocytic tumours observed in grey and white horses. CASE PRESENTATION: We present a case of ATM of the scalp with satellitosis and two positive sentinel nodes in a 4-year-old male child. No other tumour deposits were found in the subsequent regional lymphadenectomy; the patient has been tumour free for 30 months. CONCLUSIONS: We treated our case of ATM in a child as the other types of paediatric melanoma, therefore as an adult melanoma. ATM is generally considered a neoplasm with an indolent course, that occasionally shows an aggressive behaviour, and patient deaths of ATM have been reported. Due to the rarity of ATM, further studies are needed to better define the biological behaviour of this particular melanoma subtype and the therapeutic and follow-up strategies.

PARP activity and NAD concentration in PMC from patients affected by systemic sclerosis and lupus erythematosus.

The enzyme poly(ADP-ribose) polymerase (PARP-1, EC 2.4.2.30) is activated by DNA strand breaks caused by several agents and utilizes NAD to form polyADPR, bound to acceptor proteins. The involvement of PARP-1 in autoimmune diseases has been suggested: antiPARP autoantibodies are described in systemic lupus erythematosus (SLE), DNA strand breaks have been evidenced in systemic sclerosis (SSc). We tested poly(ADP-ribosyl)ation activity and NAD concentration in PMC from patients affected by SLE or SSc and from controls. Lower PARP-1 activity and higher NAD concentration were observed in pathological conditions than controls, supporting the role of PARP-1 activation in modulating NAD concentration.

Prevalence and distribution of melanocytic naevi on the scalp: a prospective study.

BACKGROUND: Few studies have examined the incidence and characteristics of naevi on the scalp. Most studies of scalp naevi have been performed in children, whose incidence of scalp naevi is relatively high, at about 0.5-11.7% of the total body count of common naevi. OBJECTIVES: To investigate the prevalence and distribution of scalp melanocytic naevi in patients of all ages. To our knowledge, ours is the first study to analyse in detail the relationships between melanocytic naevi on the scalp and total body naevi and total body atypical naevi. METHODS: We conducted a prospective study of patients visiting the dermatology outpatient clinic at the University of Florence, for examinations unrelated to the presence of naevi or melanoma. The study enrolled 795 subjects (417 females; 52.4%), with a median age of 35 years (range 4-80). RESULTS: The number of melanocytic naevi on the scalp increased significantly (r = 0.2057, P = 0.0008) as the number of total body melanocytic naevi increased and a correlation was found between the number of clinically atypical total body naevi and the number of scalp naevi. Relatively few naevi (15.5%) were located at the frontal region compared with other regions of the scalp, although the frontal region is more exposed to ultraviolet (UV) rays. Compared with subjects without alopecia, whose hair shields the scalp from UV rays, subjects with androgenetic alopecia showed no significant increase in number of scalp naevi. CONCLUSIONS: Despite practical difficulties, early diagnostic screening for melanoma or screening during follow-up examination for previous melanoma should involve examination of the entire skin surface, scalp included.

The use of silicone gel in the treatment of fresh surgical scars: a randomized study.

AIM: To evaluate the effectiveness of a silicone gel in treating surgical wounds compared with a control group of the same phenotype and same scar site for which a placebo was advised. METHODS: This was a randomized controlled trial, carried out in a dermatology department of a university hospital. In total, we studied 110 patients (55 men, 55 women) who had undergone outpatient surgery at the Department of Dermatology, University of Florence, between May and July 2005. The patients were divided into two groups: a treatment group (group A) and a control group (group B). Subjects (n = 65) in group A were prescribed silicone gel to be applied to the wound twice a day for 60 days after the removal of stitches. Subjects (n = 45) in group B were prescribed the use of zinc oxide cream. All subjects, in both study and control groups, were examined by the same dermatologists every month for 3 months after surgery, then every 2 months for a total follow-up of 8 months from the date of surgery. RESULTS: In the treatment group, only 18 patients (27%) had formation of a nonphysiological scar: diastasic scar in 10 patients (15%), hypertrophic scar in 6 (9%) and atrophic scar in 2 (3%). No keloid scars were recorded. In the control group, 25 (55%) had an altered scar: keloid scars in 5 patients (11%), hypertrophic scar in 10 (22%), diastasic scar in 8 (18%) and atrophic scar in 2 (4%). CONCLUSIONS: The results of this study indicate that silicone gel is able to reduce the formation of keloid and hypertrophic scars and the signs/symptoms associated with the healing process (paraesthesia, pulling sensation, alterations in colour).

Prevalence and distribution of solitary oral pigmented lesions: a prospective study.

Solitary pigmented lesions are uncommon in the oral mucosa. A review of the literature reveals no information regarding the relative frequency of these lesions. The purpose of this study is to determine the relative prevalence of solitary oral pigmented lesions in a selected population of patients. This study includes 265 consecutive patients who accessed the dermatology out-patients' surgery of the Department of Dermatology, University of Florence between March 2006 and July 2007. The sample we studied presented 5.7% of oral pigmented lesions; the most frequent being vascular lesions. Despite the various methods used, the differential diagnosis for these particular lesions is not always easy. There is some difficulty in distinguishing between a benign pigmented lesion and a growing melanoma which, though rare (1% of all oral malignancies), is a serious and often fatal disease. Therefore, biopsy with histological exam represents the diagnostic gold standard.

Combined non-linear laser imaging (two-photon excitation fluorescence microscopy, fluorescence lifetime imaging microscopy, multispectral multiphoton microscopy) in cutaneous tumours: first experiences.

BACKGROUND: Two-photon excitation (TPE) fluorescence microscopy is a high-resolution laser-scanning imaging technique enabling deep imaging inside biological tissues. TPE microscopy has the triple advantage of offering high spatial resolution (250 nm radially, 800 nm axially), high penetration depth inside skin (200 mm ), and low photodamage effects. Further, cells and extracellular matrix intrinsically contain a variety of fluorescent molecules (NADH, tryptophan, keratins, melanin, elastin, cholecalciferol and others), so that biological tissues can be imaged by TPE microscopy without any exogenous probe. The time-resolved analysis of the fluorescence signal, known as fluorescence lifetime imaging microscopy (FLIM), is an additional non-invasive microscopy technique useful to characterize endogenous fluorescence species and their surrounding medium by measuring the mean lifetime of fluorescent emission. Finally, multispectral (MTPE) tissue imaging can also be used to identify different endogenous fluorescent species by measuring their two photon emission spectra. Those techniques offer functional information about the relative quantities of fluorescent molecules, which are correlated with tissue structure in physiological and pathological states. OBJECTIVE: We have decided to apply these three methods at the same time for cutaneous tumors in order to evaluate their possible future use. METHOD: We have analyzed a melanoma and a basal cell carcinoma, with their surrounding healthy skin, to evaluate any difference in healthy skin and neoplasia. The samples were excised during dermatological surgery, then cut, saving some healthy skin in both, to obtain a regular shape, allowing its positioning either with the skin surface parallel to the optical axis (horizontal optical sectioning), or perpendicular (vertical optical sectioning). CONCLUSION: This first result demonstrates that FLIM is effective in discriminating healthy skin from MM, while MTPE is effective in discriminating healthy skin from BCC.

Atypical Spitz tumour: a 'chameleon' lesion.

It is a common experience that many Spitz naevi deviate from the idealized or stereotypical representation found in the literature, often causing considerable difficulties in distinguishing them from melanoma. The diagnostic term 'atypical Spitz naevus' is used to describe lesions that deviate from the typical appearance of Spitz naevi and which have an uncertain biological significance and prognosis. The term 'Spitz tumour' has been proposed for these lesions, as the term 'naevus' indicates a lesion that is completely benign and presents no risk to the patient. We present a case of atypical Spitz tumour with peculiar atypical clinical and dermatoscopic features. The difficulty in managing this Spitz tumour was aggravated by the clinical diagnosis. In fact, the lesion appeared as a benign and nonmelanocytic lesion, a pigmented dermatofibroma. Our case underlines the difficulties present in the controversial chapter of spitzoid melanocytic lesions. The atypical Spitz tumour is a 'chameleon' lesion that can mimic not only melanocytic, but also nonmelanocytic lesions.