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Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts.

Background Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited. This study presents the quality indicators on morbidity after surgical treatment for non-metastatic skin melanoma in an Italian registry. Methods Data were extracted from the Central National Melanoma Registry (CNMR) promoted by the Italian Melanoma Intergroup (IMI). All surgical procedures (WE, SNLB or LFND) for non-metastatic skin melanoma between January 2011 and February 2017 were evaluated for inclusion in the study. Only centers with adequate completeness of information (> 80%) were included in the study. Short-term complications (wound infection, dehiscence, skin graft failure and seroma) were investigated. Results Wound infection rate was 1.1% (0.4 to 2.7%) in WE, 1.3% (0.7 to 2.5%) in SLNB and 4.1% (2.1 to 8.0%) in LFND. Wound dehiscence rate was 2.0% (0.8 to 5.1%) in WE, 0.9% (0.2 to 3.0%) in SLNB and 2.8% (0.9 to 8.6%) in LFND. Seroma rate was 4.2% (1.5 to 11.1%) in SLNB and 15.1% (4.6 to 39.9%) in LFND. Unreliable information was found on skin graft failure. Conclusions Our findings contribute to available literature in setting up the recommended standards for melanoma centers, thus improving the quality of surgery offered to patients. A consensus on the core issues around surgical morbidity is needed to provide practical guidance on morbidity prevention and management.

In the UK, women between 50-70 years are invited for 3-yearly mammography screening irrespective of their likelihood of developing breast cancer. The only risk adaption is for women with >30% lifetime risk who are offered annual magnetic resonance imaging (MRI) and mammography, and annual mammography for some moderate-risk women. Using questionnaires, breast density, and polygenic risk scores, it is possible to stratify the population into the lowest 20% risk, who will develop

The COVID-19 pandemic has severely hampered the functioning of any health system, absorbing a considerable amount of resources and with the threat of widespread infection in the health services. The present survey has been carried out in Italy to evaluate if and how COVID-19 also affected skin melanoma management. We enrolled 13 Italian centres highly qualified in the diagnosis and care of skin melanoma. We compared a set of information evaluating the amount of activity for melanoma performed during February-April 2020 with the same quarter in 2019. The number of new melanoma diagnosis, biopsies, wide local excisions, overall pathology reports decreased. However, the most severe cases seem promptly managed with sentinel lymph node biopsies, new systemic treatments (north) and the total number of (advanced) treated patients (centre-south). The COVID-19 experience has underlined the need to exploit the help which may come from telemedicine.

Background Identification of somatic mutations in key oncogenes in melanoma is important to lead the effective and efficient use of personalized anticancer treatment. Conventional methods focus on few genes per run and, therefore, are unable to screen for multiple genes simultaneously. The use of Next-Generation Sequencing (NGS) technologies enables sequencing of multiple cancer-driving genes in a single assay, with reduced costs and DNA quantity needed and increased mutation detection sensitivity. Methods We designed a customized IMI somatic gene panel for targeted sequencing of actionable melanoma mutations; this panel was tested on three different NGS platforms using 11 metastatic melanoma tissue samples in blinded manner between two EMQN quality certificated laboratory. Results The detection limit of our assay was set-up to a Variant Allele Frequency (VAF) of 10% with a coverage of at least 200x. All somatic variants detected by all NGS platforms with a VAF ≥ 10%, were also validated by an independent method. The IMI panel achieved a very good concordance among the three NGS platforms. Conclusion This study demonstrated that, using the main sequencing platforms currently available in the diagnostic setting, the IMI panel can be adopted among different centers providing comparable results.

Background Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. Limited information is available in the current scientific literature on the concordance of genetic alterations between primary and metastatic CMM. In the present study, we performed next-generation sequencing (NGS) analysis of the main genes participating in melanoma pathogenesis and progression, among paired primary and metastatic lesions of CMM patients, with the aim to evaluate levels of discrepancies in mutational patterns. Methods Paraffin-embedded tumor tissues of the paired lesions were retrieved from the archives of the institutions participating in the study. NGS was performed using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup (IMI) to explore the mutational status of selected regions (343 amplicons; amplicon range: 125–175 bp; coverage 100%) within the main 25 genes involved in CMM pathogenesis; sequencing was performed with the Ion Torrent PGM System. Results A discovery cohort encompassing 30 cases, and a validation cohort including eleven Sardinian patients with tissue availability from both the primary and metachronous metastatic lesions were identified; the global number of analyzed tissue specimens was 90. A total of 829 genetic non-synonymous variants were detected: 101 (12.2%) were pathogenic/likely pathogenic, 131 (15.8%) were benign/likely benign, and the remaining 597 (72%) were uncertain/unknown significance variants. Considering the global cohort, the consistency in pathogenic/pathogenic like mutations was 76%. Consistency for BRAF and NRAS mutations was 95.2% and 85.7% respectively, without statistically significant differences between the discovery and validation cohort. Conclusions Our study showed a high level of concordance in mutational patterns between primary and metastatic CMM, especially when pathogenic mutations in driver genes were considered.

Cutaneous malignant melanoma is a heterogeneous disease, being the consequence of specific genetic alterations along several molecular pathways. Despite the increased knowledge about the biology and pathogenesis of melanoma, the incidence has grown markedly worldwide, making it extremely important to develop preventive measures. The beneficial role of correct nutrition and of some natural dietary compounds in preventing malignant melanoma has been widely demonstrated. This led to numerous studies investigating the role of several dietary attitudes, patterns, and supplements in the prevention of melanoma, and ongoing research investigates their impact in the clinical management and outcomes of patients diagnosed with the disease. This article is an overview of recent scientific advances regarding specific dietary compounds and their impact on melanoma development and treatment.

Background: Our group previously demonstrated a high consistency of BRAF and NRAS mutations between primary tumors and lymph node metastases in melanoma patients (JCO 2012; 30: 2522-9). To further verify the level of homogeneity during clonal expansion to lymph node sites, we here performed a more detailed analysis on a subset of those paired samples using a NGS technology. Methods: Genomic DNA was isolated from tumor tissues of 12 melanoma patients, using standard methods. Specimens were analyzed for mutations in 50 most common cancer genes with the Ion Torrent AmpliSeq Cancer Panel HotSpot V2 (CHPv2) on the Ion Torrent platform. All variants detected by NGS were confirmed through PCR-based Sanger sequencing. Results: Genomic DNA was isolated from paired metastatic lymph nodes either asynchronously (n = 8) or synchronously (n = 4) excised from melanoma patients with clinically-evident nodal involvement. Data from the runs on the Ion Ampliseq Cancer Hotspot panel indicated an average of about 1500 reads (range, 500-2000) per amplicon. Overall, one (8%) out of the 12 analyzed patients presented discrepancies in mutation patterns during disease progression to lymph nodes and between the distinct lymph nodal metastases. In particular, the differences were represented by BRAF and CDKN2A mutations, suggesting that changes - when occur (though in a very limited fraction of cases) - may affect the main genes controlling cell proliferation and survival in melanoma. Mutations in BRAF, NRAS, CDKN2A, and TP53 genes were confirmed to play a predominant role in melanoma pathogenesis. Conclusions: Even with a more comprehensive mutation analysis, our findings indicated a very low genetic heterogeneity in metastatic lymph nodes during disease progression in melanoma patients, confirming previously published data on BRAF and NRAS mutational status only.

Previously reported results suggest that the analogue of the somatostatin des-AA1,2,5[D-Trp8,IAmp9]-somatostatin (CH-275) peptide bearing chelating agents able to coordinate radioactive metals could be used for scintigraphic imaging of tumor lesions overexpressing sstr1. An efficient synthetic procedure for the preparation of the somatostatin analogue CH-275 and its conjugate DTPAGlu-Gly-CH-275, bearing the chelating agent DTPAGlu (DTPAGlu = N,N-bis[2-[bis(carboxy-ethyl)amino]ethyl]-L-glutamic acid) on the N-terminus, by solid-phase peptide synthesis and 9-flourenymethyoxycarbonyl (Fmoc) chemistry, is here reported. Rapid and efficient labeling of DTPAGlu-Gly-CH-275 was achieved by addition of IIIIn(III) to the compound. Typical yields were greater than 97% as determined by reversed phase high performance liquid chromatography (HPLC) at specific activities in the range 4-9 GBq/μmol (100-250 Ci/mmol). A preliminary biological assay of the binding ability of IIIIn-DTPAGlu-Gly-CH-275 indicates, however, that the labeled compound does not display any specific interaction with somatostatin sstrl receptors in the tested cell lines. To confirm this unexpected negative result, competition binding experiments were carried out, in which fixed tracer amounts of the 125!-labeled somatostatin-14 were incubated with the receptor-expressing cells in the presence of DTPAGlu-Gly-CH-275 or CH-275 at concentrations ranging from 10-10 to 10-3 M. While CH-275 shows a IC50 of 80 nM similar to that already found in displacement experiments on CHO-Kl sstrl-transfected cells, DTPAGlu-Gly-CH-275 displays instead very low or negligible affinity towards this receptor. The NMR solution characterization indicates that the presence of DTPAGlu does not influence the conformational and chemical features of the peptide moiety, thus suggesting that the loss in binding activity should be due to steric hindrance of either the chelating agent DTPAGlu or its indium complex. © 2004 Wiley Periodicals, Inc.

The authors report a case of follicular thyroid cancer in "hot nodule" with micronodular synchronous lung metastases. The treatment consisted in TT associated with radioiodine therapy at the dose of 170 mCi with remission of cancer after six months of follow-up. Follicular variant is a prognostic unfavorable factor such as synchronous or metachronous pulmonary metastases. In those patients prognostic unfavorable variants are also age over 40 years, a poor radiofixation capacity, and a lesion of diameter up 1 cm. A strictly instrumental follow-up is mandatory to obtain diagnosis in a subclinical stage. In such cases the radiometabolic therapy agree to a remission of cancer with high survival after many years. TT yet represents a "minimal" surgical treatment for an accurate radioisotopic diagnosis. The authors report a case of follicular thyroid cancer in "hot nodule" with micronodular synchronous lung metastases. The treatment consisted in TT associated with radioiodine therapy at the dose of 170 mCi with remission of cancer after six months of follow-up. Follicular variant is a prognostic unfavorable factor such as synchronous or metachronous pulmonary metastases. In those patients prognostic unfavorable variants are also age over 40 years, a poor radiofixation capacity, and a lesion of diameter up 1 cm. A strictly instrumental follow-up is mandatory to obtain diagnosis in a subclinical stage. In such cases the radiometabolic therapy agree to a remission of cancer with high survival after many years. TT yet represents a "minimal" surgical treatment for an accurate radioisotopic diagnosis.

The Authors analyze 152 consecutive patients who underwent thyroidectomy for differentiated thyroid cancer, observed from 1978 to 1996, evaluating specifically prognostic factors. In accord with literature, total thyroidectomy represents the "gold standard" surgical treatment that allows diagnostic-therapeutic use of 131I and results. The Authors in case of N+ as routine perform a node picking with MRND (modified radical neck dissection) reserved to high risk patients. Age represents only independent prognostic factor that in association with M+ and follicular histotype classifies high risk patients in whom a more aggressive therapeutic approach is necessary. The Authors analyze 152 consecutive patients who underwent thyroidectomy for differentiated thyroid cancer, observed from 1978 to 1996, evaluating specifically prognostic factors. In accord with literature, total thyroidectomy represents the "gold standard" surgical treatment that allows diagnostic-therapeutic use of 131I and results. The Authors in case of N+ as routine perform a node picking with MRND (modified radical neck dissection) reserved to high risk patients. Age represents only independent prognostic factor that in association with M+ and follicular histotype classifies high risk patients in whom a more aggressive therapeutic approach is necessary.

Background Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease. Methods A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16 CDKN2A , BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16 CDKN2A genes. Results For melanoma susceptibility, investigations at germline level indicated that p16 CDKN2A was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16 CDKN2A gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16 CDKN2A silencing). Conclusion Our findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis.

Follicular carcinoma, in association with other prognostic factors, identifies a class of "high-risk" patients in which a more aggressive treatment is indicated. In fact, in patients operated on for follicular carcinoma bone metastases, also many years after primary surgery, are reported. A case of skull metastases in a young women occurred 3 years after a near total lobectomy for follicular thyroid carcinoma is described. After six years the patient underwent total thyroidectomy, resection of skull metastases, radiometabolic therapy with I131 180 m Ci; now she is disease free at three years of follow-up. The biology of metastases in thyroid follicular carcinoma, risk factors and diagnostic and therapeutic controversies are analyzed. Good prognostic factors are considered age < 45 years, good degree of differentiation of primary tumor, small size of bone metastases and early appearance after primary diagnosis. The conclusions is drawn that bone metastases are the worst prognostic factors. In case of single lesion, surgical treatment allows good results. Follicular carcinoma, in association with other prognostic factors, identifies a class of 'high risk' patients in which a more aggressive treatment is indicated. In fact, in patients operated on for follicular carcinoma bone metastases, also many years after primary surgery, are reported. A case of skull metastases in a young women occurred 3 years after a near total lobectomy for follicular thyroid carcinoma is described. After six years the patient underwent total thyroidectomy, resection of skull metastases, radiometabolic therapy with I131 180 m Ci; now she is disease free at three years of follow-up. The biology of metastases in thyroid follicular carcinoma, risk factors and diagnostic and therapeutic controversies are analyzed. Good prognostic factors are considered age < 45 years, good degree of differentiation of primary tumor, small size of bone metastases and early appearance after primary diagnosis. The conclusions is drawn that bone metastases are the worst prognostic factors. In case of single lesion, surgical treatment allows good results.

Paraesophageal hernia incidence is around 5-8%. The Authors analyze their experience of 5 patients operated on for paraesophageal hernia after preoperative manometric and pHmetric studies. Despite only in 3 patients a gastro-esophageal reflux was present, in all cases a suture of the diaphragmatic defect together with a modified Lortart-Jacob antireflux operation was performed. The results were considered satisfactory in all cases and there was no relapse after a 2 year follow-up. Following an accurate analysis of the literature the Authors conclude that in paraesophageal hernia a surgical treatment is mandatory. However, diagnostic instrumental preoperative data influence the choice of the appropriate surgical treatment for each patient. Paraesophageal hernia incidence is around 5-8%. The Authors analyze their experience of 5 patients operated on for paraesophageal hernia after preoperative manometric and pHmetric studies. Despite only in 3 patients a gastro-esophageal reflux was present, in all cases a suture of the diaphragmatic defect together with a modified Lortart-Jacob antireflux operation was performed. The results were considered satisfactory in all cases and there was no relapse after a 2 year follow-up. Following an accurate analysis of the literature the Authors conclude that in paraesophageal hernia a surgical treatment is mandatory. However, diagnostic instrumental preoperative data influence the choice of the appropriate surgical treatment for each patient.

The authors described a case of hernia of Morgagni-Larrey in aged patients with an acute sub-occlusive symptomatology. This type of diaphragmatic hernia is uncommon and caracterized by an aspecific symptomatology which realize different problems in children and adult patients, in whom diagnosis can be made incidentally, executing analysis for other pathologies. Using Marlex mesh to repare hernia represents an improvement of surgery, because it enables to repaire a great hernia with a better result, and no recurrence.