Search

Background: This pilot study aimed to evaluate the effectiveness of digitally crafted customized healing abutments in stabilizing peri-implant soft tissues following tooth extraction and assess the preservation of peri-implant soft tissue architecture over 5 years. Material and Methods: Forty patients (age ≥ 25 years) were divided into test (n = 20) and control (n = 20) groups. The test group received dental implants with immediate loading after tooth extraction, along with customized healing abutments fabricated using CAD/CAM technology. The control group received dental implants with immediate loading without customized healing abutments. The primary outcome was the change in distance between the peri-implant soft tissue margin and implant fixture surface from baseline to 5 years post implantation. Results: In the test group, there was a significant decrease in the distance between the peri-implant soft tissue margin and fixture surface from baseline to 5 years (p < 0.001), with pairwise comparisons showing significant differences between multiple time points (p < 0.05). The control group showed less pronounced changes over time. Conclusions: Within the limitations of this pilot study, digitally fabricated customized healing abutments appear effective in stabilizing peri-implant soft tissues and preserving soft tissue architecture around dental implants over 5 years following immediate implant placement. Randomized controlled trials are needed to confirm these findings.

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C as a key factor for B-ALL development and maintenance. While cyclin C is non-essential for normal hematopoiesis, CcncΔ/Δ BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ BCR::ABL1+ cells resulting in the incapability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.

Tertiary Lymphoid Structures (TLS) are lymphoid structures commonly associated with improved survival of cancer patients and response to immunotherapies. However, conflicting reports underscore the need to consider TLS heterogeneity and multiple features such as TLS size, composition, and maturation status, when assessing their functional impact. With the aim of gaining insights into TLS biology and evaluating the prognostic impact of TLS maturity in Non-Small Cell Lung Carcinoma (NSCLC), we developed a multiplex immunofluorescent (mIF) panel including T cell (CD3, CD8), B cell (CD20), Follicular Dendritic cell (FDC) (CD21, CD23) and mature dendritic cell (DC-LAMP) markers. We deployed this panel across a cohort of primary tumor resections from NSCLC patients (N=406) and established a mIF image analysis workstream to specifically detect TLS structures and evaluate the density of each cell phenotype. We assessed the prognostic significance of TLS size, number, and composition, to develop a TLS scoring system representative of TLS biology within a tumor. TLS relative area, (total TLS area divided by the total tumor area), was the most prognostic TLS feature (C-index: 0.54, p = 0.04). CD21 positivity was a marker driving the favorable prognostic impact, where CD21+ CD23- B cells (C-index: 0.57, p = 0.04) and CD21+ CD23- FDC (C-index: 0.58, p = 0.01) were the only prognostic cell phenotypes in TLS. Combining the three most robust prognostic TLS features: TLS relative area, the density of B cells, and FDC CD21+ CD23- we generated a TLS scoring system that demonstrated strong prognostic value in NSCLC when considering the effect of age, sex, histology, and smoking status. This TLS Score also demonstrated significant association with Immunoscore, EGFR mutational status and gene expression-based B-cell and TLS signature scores. It was not correlated with PD-L1 status in tumor cells or immune cells. In conclusion, we generated a prognostic TLS Score representative of the TLS heterogeneity and maturity undergoing within NSCLC tissues. This score could be used as a tool to explore how TLS presence and maturity impact the organization of the tumor microenvironment and support the discovery of spatial biomarker surrogates of TLS maturity, that could be used in the clinic.

BackgroundPostoperative seroma is most frequent after mastectomy (ME) in combination with axillary lymph node dissection (ALND), and its reported incidence varies from 15.5% up to 90%. Seromas can be responsible for discomfort, infections and can lead to reconstruction failure. Therefore, many ways of seroma prevention have been studied, although from a recent overview it has become clear that no single method is reliably successful. Mechanical closure of the dead space, however, was consistently found to be significantly effective. The aim of our study is to evaluate if quilting of the axilla, in patients undergoing ME, immediate prosthetic breast reconstruction and ALND reduces the duration of drain maintenance, the incidence of seromas that require aspiration (clinically significant seromas, CSS) and reconstruction failure rate.Materials and methodsIn our study population we analyzed a total of 81 patients divided into two groups: 27 consecutive patients undergoing mastectomy, axillary lymph node dissection (ALND), breast reconstruction and quilting of the axilla. We subsequently randomly picked up a double number of patients (54) undergoing the same oncological and reconstructive procedures without undergoing axillary quilting, matched for clinical characteristics in order to analyze efficacy of the procedure while reducing any bias. Our observational retrospective data was collected from October 2016 to July 2020 in one single high-volume center. Our median follow-up time was of 40.6 months.ResultsIn the case group we observed a reduced time of drain maintenance: 16 vs. 20 days observed in the non-quilted group (p

Abstract Objectives Autologous dentin grafts derived from extracted teeth have shown promise as bone graft materials for promoting bone regeneration. This retrospective case series aimed to evaluate clinical, radiographic, and histologic outcomes of using autologous dentin matrices in various bone regeneration procedures. Materials and Methods This case series included 26 eligible patients and encompassed 4 socket preservation cases, 5 cases of guided tissue regeneration, 5 cases of guided bone regeneration (GBR), 10 cases of sinus augmentation procedures, 2 immediate placement implants, and 2 socket shields. Dentin grafts were prepared from extracted teeth, cleaned, and processed. These grafts were combined with platelet‐rich fibrin (PRF) to create adhesive dentin matrices, then covered with collagen membranes for simultaneous guided bone augmentation cases. Cone beam computed tomography (CBCT) scans were conducted before surgery and 4 months postoperatively to assess ridge dimensions. Histologic evaluation was performed through bone core biopsies for socket preservation cases at the 4‐month mark. Results A total of 42 implants were placed in 26 patients, with an average follow‐up of 32 months. Notably, two implant failures occurred following lateral maxillary sinus augmentation. CBCT scans at the 4‐month interval revealed bone coverage over implant platforms in the majority of cases. Histologic analysis from two cases of socket preservation demonstrated dentin granules enveloped by newly formed bone undergoing continuous remodeling. The quantitative histomorphometric assessment revealed a bone area of 42.8 ± 3.56%, a remaining graft area of 19.05 ± 4.58%, and a viable bone of 38.15 ± 7.84%. Conclusions The utilization of autologous dentin particles mixed with PRF proved effective as an alternative to conventional bone graft materials in GBR and maxillary sinus augmentation procedures. Larger controlled clinical trials are recommended to further substantiate these findings.

Photobacterium damselae subsp. damselae (Pdd) is an increasingly common bacterium in post-mortem diagnostics of beached marine mammals, but little is known about its precise etiological responsibility. To estimate the prevalence of Pdd in stranded cetaceans from 2017 to 2022 on the Ligurian coast (Pelagos Sanctuary), we tested tissues from 53 stranded individuals belonging to four cetacean species. DNA extracts from cetacean tissue were screened using a polymerase chain reaction (PCR) assay targeting the Pdd ureC gene. Positive samples were screened by PCR for dly, hlyApl and hlyAch hemolysin genes, which were confirmed by sequencing. Twenty-two out of 53 (41.5%) cetaceans analyzed by PCR were confirmed for Pdd DNA in at least one tissue among those analyzed. Five of these cetaceans were positive for at least one of the hemolysin genes tested. In all Pdd-positive cetaceans, other pathogens that were considered responsible for the causa mortis of the animals were also found. The results provide new information on the spread of Pdd in cetaceans and support the thesis that Pdd might be an opportunistic agent that could contribute to worsening health conditions in subjects already compromised by other pathogens. However, further studies are needed to investigate and deepen this hypothesis.

Video assisted thoracic surgery (VATS) lobectomy is the treatment of choice for early-stage lung cancer. It is safe and effective compared to open surgery, as demonstrated by a large body of scientific evidence over the last few decades. VATS lobectomy’s evolution was driven by the need to decrease post-operative pain by reducing the extent of surgical accesses, maintaining the same oncological efficacy of open lobectomy with less invasiveness. VATS lobectomy just turned 30 years old, evolving and changing significantly from its origins. The aim of this mini review is to retrace the history, starting from a multiport approach to a single port approach. At the end of this mini review, we will discuss the advanced and the future challenges of the technique that has revolutionized thoracic surgery.

Abstract The Great Debate session at the 2022 Melanoma Bridge congress (December 1–3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate.

Background: This study evaluated the outcome, toxicity and predictive factors in patients unfit for concurrent chemo-radiotherapy (CT-RT) treated with hypofractionated sequential CT-RT or exclusive radiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: We included patients affected by LA-NSCLC (stage IIA-IVA) treated with a total dose of 50–60 Gy in 20 fractions. The primary outcomes were local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS). Univariate analysis was used to correlate outcomes with prognostic factors. Results: Between 2011 and 2019, 210 patients were treated, 113 (53.8%) with sequential CT-RT and 97 (46.2%) with exclusive RT. After a median follow-up of 15.3 months, 74 patients (35.2%) had a local progression and 133 (63.3%) had a distant progression. The one-, two- and five-year LC were 73.6%, 55.3% and 47.9%, respectively. At the time of analysis, 167 patients (79.5%) died. The one-, two- and five-year OS were 64.7%, 36% and 20%, respectively. PTV volume correlated with PFS (p = 0.001) and LC (p = 0.005). Acute and late toxicity occurred in 82% and 26% of patients. Conclusions: Albeit with the known limitations of a retrospective and heterogeneous study, our work shows that hypofractionated sequential CT-RT or exclusive RT offer a good local control and toxicity profile and a promising survival rate in LA-NSCLC patients unfit for the concurrent CT-RT scheme.

Summary: Interleukin (IL)-10 is a main player in peripheral immune tolerance, the physiological mechanism preventing immune reactions to self/harmless antigens. Here, we investigate IL-10-induced molecular mechanisms generating tolerogenic dendritic cells (tolDC) from monocytes. Using genomic studies, we show that IL-10 induces a pattern of accessible enhancers exploited by aryl hydrocarbon receptor (AHR) to promote expression of a set of core genes. We demonstrate that AHR activity occurs downstream of IL-10 signaling in myeloid cells and is required for the induction of tolerogenic activities in DC. Analyses of circulating DCs show that IL-10/AHR genomic signature is active in vivo in health. In multiple sclerosis patients, we instead observe significantly altered signature correlating with functional defects and reduced frequencies of IL-10-induced-tolDC in vitro and in vivo. Our studies identify molecular mechanisms controlling tolerogenic activities in human myeloid cells and may help in designing therapies to re-establish immune tolerance.

Abstract Humans are often shown to cooperate with one another. Most of the mechanisms that foster cooperation among humans rely on reputation, which itself relies on the acquisition of information about other people’s behaviors. Gossip has been proposed as a cheap yet efficient tool to acquire information, and it has largely been proved to be an effective means to foster and maintain cooperation. However, empirical studies supporting this claim have ignored two aspects: (1) they often compared gossip to treatments in which no reputation was available, impeding a direct assessment of whether it is gossip that promotes cooperation or rather the introduction of a reputation system; and (2) they focused on pro-social gossip (e.g., gossip aimed at helping the receiver), neglecting the impact of other types of gossip. We show here that, in contrast with the widespread notion that gossip promotes cooperation, gossip mostly depletes cooperation compared to first-hand information. If lying is fruitful for individuals or if a group’s behavior is largely uncooperative, gossip leads to negative reputational information and decreased cooperation.

Purpose. In modern breast cancer treatment, a growing role has been observed for breast reconstruction together with an increase in clinical indications for postmastectomy radiotherapy (PMRT). Choosing the optimum type of reconstructive technique is a clinical challenge. We therefore conducted a national multicenter study to analyze the impact of PMRT on breast reconstruction. Methods. We conducted a retrospective case-control multicenter study on women undergoing breast reconstruction. Data were collected from 18 Italian Breast Centres and stored in a cumulative database which included the following: autologous reconstruction, direct-to-implant (DTI), and tissue expander/immediate (TE/I). For all patients, we described complications and surgical endpoints to complications such as reconstruction failure, explant, change in type of reconstruction, and reintervention. Results. From 2001 to April 2020, 3116 patients were evaluated. The risk for any complication was significantly increased in patients receiving PMRT (aOR, 1.73; 95% CI, 1.33–2.24; p

Summary: Pleiotropic genetic factors (e.g., DNA polymorphisms) may be involved in the initiation of neuroblastoma (NB) and coronary artery disease (CAD) given their common origin from defects in neural crest development. To discover novel NB susceptibility genes, we conducted a three-stage survey including a meta-analysis of NB and CAD genome-wide association data, prioritization of NB causal variants, and validation in an independent cohort of affected individuals–control subjects. The lead SNP, rs13337397 at the 16q23.1 locus, associated with both diseases in the meta-analysis and with NB in the validation study. All the SNPs in linkage disequilibrium with rs13337397 were annotated using the H3K27ac epigenetic marker of neural crest cells (NCC) and NB cell lines. Indeed, we identified the functional SNP rs13337017, mapping within an enhancer of NCCs and NB cell lines and showing long-range interactions with CFDP1 by Hi-C analysis. Luciferase assays indicated that the risk allele of rs13337017 increased CFDP1 expression in NB cell lines. Of note, CFDP1 high expression associated with unfavorable prognostic markers in an analysis including 498 NB transcriptomes. Moreover, depletion of CFDP1 markedly decreased viability and migration and increased apoptotic rates in NB cell lines. Finally, transcriptome and qPCR analyses revealed that the depletion of CFDP1 may affect noradrenergic neuron differentiation by downregulating master regulators of sympathetic noradrenergic identity, including PHOX2B, HAND2, and GATA3. Our data strongly suggest that CFDP1 acts as oncogene in NB. In addition, we provide evidence that genetic predisposition to NB can be mediated by the alteration of noradrenergic lineage-specific gene expression.

Abstract Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation that arise in most organs of the body. Mediastinal NETs are very rare, and account for no more than 5% of all mediastinal tumors. R0 surgery represents the milestone of treatment. Here, we describe a case of a locally advanced primary atypical carcinoid of the mediastinum. This was initially considered inoperable due to infiltration of a great vessel and was successfully resected after neoadjuvant treatment as a result of very extensive surgery. Only through an accurate preoperative diagnosis and good radiological planning is it possible to obtain satisfactory oncological results.

Losurdo et al analyze breast cancer-infiltrating T cells by single-cell technologies . The find that the extent of infiltration of a small subset of tissue-resident memory CD8+ T cells identify patients with improved survival, highlighting the importance of the specific T cell immune microenvironment.

The use of extracorporeal lung support (ECLS) during thoracic surgery is a recent concept that has been gaining increasing approval. Firstly introduced for lung transplantation, this technique is now increasingly adopted also in oncological thoracic surgical procedures. In this review, we focus on the cutting-edge application of extracorporeal membrane oxygenation (ECMO) during oncological thoracic surgery. Therefore, we report the most common surgical procedures in oncological thoracic surgery that can benefit from the use of ECMO. They will be classified and discussed according to the aim of ECMO application. In particular, the use of ECMO is usually limited to certain lung surgery procedures that can be resumed such as in procedures in which an adequate ventilation is not possible such as in single lung patients, procedures where conventional ventilation can cause conflict with the surgical field such as tracheal or carinal surgery, and conventional procedures requiring both ventilators and hemodynamic support. So far, all available evidence comes from centers with large experience in ECMO and major thoracic surgery procedures.

Abstract Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis that accounts for 10% of all cases of clinical lung cancer. Due to its high growth fraction and rapid doubling time it is usually diagnosed as extensive local or metastatic disease in 60%–70% of cases. Combined small cell lung cancer (C‐SCLC) is a relatively rare subtype of SCLC and is defined as SCLC combined with any elements of non‐small cell lung cancer (NSCLC). Clinical presentation of SCLC as an isolated pedunculated endotracheal lesion is an especially rare occurrence. Here, we report for the first time the occurrence of a C‐SCLC as a polypoid tumor of the trachea diagnosed in an 80‐year‐old woman admitted to the emergency department with a principal complaint of cough and wheezing.

Abstract Background Percutaneous dilatational tracheotomy (PDT) has become an established procedure in intensive care units (ICU). However, the safety of this method has been under debate given the growing number of critically ill patients with high bleeding risk receiving anticoagulation, dual antiplatelet therapy (DAPT) or even a combination of both, i.e. triple therapy. Therefore, the purpose of this study, including such a high proportion of patients on antithrombotic therapy, was to investigate whether PDT in high-risk ICU patients is associated with elevated procedural complications and to analyse the risk factors for bleeding occurring during and after PDT. Methods PDT interventions conducted in ICUs at 12 European sites between January 2016 and October 2019 were retrospectively analysed for procedural complications. For subgroup analyses, patient stratification into clinically relevant risk groups based on anticoagulation and antiplatelet treatment regimens was performed and the predictors of bleeding occurrence were analysed. Results In total, 671 patients receiving PDT were included and stratified into four clinically relevant antithrombotic treatment groups: (1) intravenous unfractionated heparin (iUFH, prophylactic dosage) (n = 101); (2) iUFH (therapeutic dosage) (n = 131); (3) antiplatelet therapy (aspirin and/or P2Y12 receptor inhibitor) with iUFH (prophylactic or therapeutic dosage) except for triple therapy (n = 290) and (4) triple therapy (DAPT with iUFH in therapeutic dosage) (n = 149). Within the whole cohort, 74 (11%) bleedings were reported to be procedure-related. Bleeding occurrence during and after PDT was independently associated with low platelet count (OR 0.73, 95% CI [0.56, 0.92], p = 0.009), chronic kidney disease (OR 1.75, 95% CI [1.01, 3.03], p = 0.047) and previous stroke (OR 2.13, 95% CI [1.1, 3.97], p = 0.02). Conclusion In this international, multicenter study bronchoscopy-guided PDT was a safe and low-complication airway management option, even in a cohort of high risk for bleeding on cardiovascular ICUs. Low platelet count, chronic kidney disease and previous stroke were identified as independent risk factors of bleeding during and after PDT but not triple therapy.

Abstract Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd–5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.

BackgroundThe single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment.Patients and methodsForty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors.ResultsORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib.ConclusionNilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.Clinical trial registrationClinicalTrials.gov, NCT01028222.

BackgroundThe increased incidence of conservative mastectomy operations (nipple- and skin- sparing) has increased the frequency of immediate breast reconstructions (IBR). In order to guarantee patients the best possible aesthetic outcome, the least chance of complications and moreover, the least postoperative pain, the technique with prepectoral prosthetic pocket was recently reconsidered with the use of ADM. This is the first study using Fortiva® in prepectoral breast reconstruction, and it compares the outcomes of three different patient populations (undergoing retromuscular, prepectoral and prepectoral reconstruction with ADM). The authors suggest that prepectoral breast reconstruction with ADM may bring benefits compared to the current standard technique (retromuscular) as well as compared to the prepectoral reconstruction without ADM.MethodsRetrospective data analysis of patients who underwent mastectomy followed by immediate breast reconstruction with silicone implants (DTI), performed by a team of breast surgeons and plastic surgeons. Logistic factor regressions were performed in order to investigate the effects of the three different intervention techniques on the incidence of complications. Fisher's exact test was used to analyze the differences in the occurrence of each complication. Mann Whitney test was used to compare the averages of referred pain. A p value

Localization of small-sized pulmonary nodules is challenging during video-assisted thoracoscopic surgery. Several preoperative strategies have been developed to mark these targets. We describe our localization strategy using a preoperative computed tomography-guided near-infrared dye marking.

The implementation of preparedness strategies to prevent and mitigate the impact of global health threats poses several challenges. It should promptly identify cross-cutting drivers of pandemic threats, assess context-specific risks, engage multiple stakeholders, and translate complex data from multiple sources into accessible information for action. This requires a coordinated, multidisciplinary and multisectoral effort engaging systems that, most of the time, work in isolation.The One Health (OH) approach promotes the collaboration and communication among different disciplines and sectors, and could be applied across the preparedness phases at national and international level.We discuss here gaps and needs in preparedness strategies, which can benefit from the OH approach, and a set of actionable recommendations, as shared with the G20–2021 with a dedicated Policy Brief.The discussion adds to the current debate about OH operationalization and promotes a paradigm shift towards coordinated prevention and preparedness strategies for early assessment and management of global health threats.

Abstract Primary lung signet‐ring cell carcinomas are a rare entity and only a few cases of pure signet‐ring cell carcinomas of the lung are reported in the English literature. They usually have an aggressive behavior and a poor prognosis because in most cases they are identified at an advanced stage. We present a unique case of primary signet‐ring cell carcinoma of the lung because the patient was HIV positive, a heavy smoker, and also the tumor, discovered incidentally during chest x‐ray, was a pure type of signet‐ring cell carcinoma. Surgical therapy associated with chemoradiotherapy represents the gold standard in the care of these patients.

Complete animal welfare evaluation in intensive farming is challenging. With this study, we investigate new biomarkers for animal physical and mental health by comparing plasma expression of biochemical indicators in dairy cows reared in three different systems: (A) semi-intensive free-stall, (B) non-intensive tie-stall, and (C) intensive free-stall. Additionally, protein levels of mature brain-derived neurotrophic factor (mBDNF) and its precursor form (proBDNF) and indoleamine 2,3-dioxygenase (IDO1) specific activity were evaluated in brain samples collected from 12 cattle culled between 73 and 138 months of age. Alterations in plasma lipid composition and in the kynurenine pathway of tryptophan metabolism were observed in the tie-stall-reared animals. The total plasma BDNF concentration was higher in tie-stall group compared to the two free-housing groups. Brain analysis of the tie-stall animals revealed a different mBDNF/proBDNF ratio, with a higher level of proBDNF (p < 0.001). Our data are similar to previous studies on animal models of depression, which reported that inhibition of the conversion of proBDNF in its mature form and/or elevated peripheral kynurenine pathway activation may underlie cerebral biochemical changes and induce depressive-like state behavior in animals.

Abstract 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.

Lung cancer (LC) is the second most commonly diagnosed cancer and the primary cause of cancer death worldwide in 2020. LC treatment is associated with huge costs for patients and society; consequently, there is an increasing interest in the prevention, early detection with screening, and development of new treatments. Its surgical management accounts for at least 90% of the activity of thoracic surgery departments. Surgery is the treatment of choice for early-stage non-small cell LC. In this article, we discuss the state of the art of thoracic surgery for surgical management of LC. We start by describing the milestones of LC treatment, which are lobectomy and an adequate lymphadenectomy, and then we focus on the traditional and innovative minimally invasive surgical approaches available: video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS). A brief overview of the innovation and future perspective in thoracic surgery will close this mini-review.

Pulmonary metastasectomy is an established treatment that can provide improved long- term survival for patients with metastatic tumor(s) in the lung. In this mini-review, we discuss the state of the art of thoracic surgery in surgical management of lung metastases which actually occurs for a large part of surgical activity in thoracic surgery department. We describe the principles of surgical therapy that have been defined across the time, and that should remain the milestones of lung metastases treatment: a radical surgery and an adequate lymphadenectomy. We then focus on current surgical indications and report the oncological results according to the surgical approach (open vs. mini-invasive), the histological type and number of lung metastases, and in case of re-metastasectomy. Finally, we conclude with a brief overview about the future perspectives in thoracic surgery in treatment of lung metastases.

MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance Stefani Spranger, Thomas F. Gajewski K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma Yangyang Wang, Soldano Ferrone Combination therapies K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade Haidong Tang, Yang Wang, Yang-Xin Fu K7 Biomarkers for treatment decisions? Reinhard Dummer K8 Combining oncolytic therapies in the era of checkpoint inhibitors Igor Puzanov K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy? Michael A. Postow News in immunotherapy K10 An update on adjuvant and neoadjuvant therapy for melanom Ahmad Tarhini K11 Targeting multiple inhibitory receptors in melanoma Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour K12 Improving adoptive immune therapy using genetically engineered T cells David F. Stroncek Tumor microenvironment and biomarkers K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression? Veronica Huber, Licia Rivoltini K14 Update on the SITC biomarker taskforce: progress and challenges Magdalena Thurin World-wide immunoscore task force: an update K15 The immunoscore in colorectal cancer highlights the importance of digital scoring systems in surgical pathology Tilman Rau, Alessandro Lugli K16 The immunoscore: toward an integrated immunomonitoring from the diagnosis to the follow up of cancer’s patients Franck Pagès Economic sustainability of melanoma treatments: regulatory, health technology assessment and market access issues K17 Nivolumab, the regulatory experience in immunotherapy Jorge Camarero, Arantxa Sancho K18 Evidence to optimize access for immunotherapies Claudio Jommi ORAL PRESENTATIONS Molecular and immuno-advances O1 Ipilimumab treatment results in CD4 T cell activation that is concomitant with a reduction in Tregs and MDSCs Yago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf Kiessling O2 Evaluation of prognostic and therapeutic potential of COX-2 and PD-L1 in primary and metastatic melanoma Giosuè Scognamiglio, Francesco Sabbatino, Federica Zito Marino, Anna Maria Anniciello, Monica Cantile, Margherita Cerrone, Stefania Scala, Crescenzo D’alterio, Angela Ianaro, Giuseppe Cirino, Paolo Antonio Ascierto, Giuseppina Liguori, Gerardo Botti O3 Vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma: final overall survival results of the BRIM-3 study Paul B. Chapman, Caroline Robert, James Larkin, John B. Haanen, Antoni Ribas, David Hogg, Omid Hamid, Paolo Antonio Ascierto, Alessandro Testori, Paul Lorigan, Reinhard Dummer, Jeffrey A. Sosman, Keith T. Flaherty, Huibin Yue, Shelley Coleman, Ivor Caro, Axel Hauschild, Grant A. McArthur O4 Updated survival, response and safety data in a phase 1 dose-finding study (CA209-004) of concurrent nivolumab (NIVO) and ipilimumab (IPI) in advanced melanoma Mario Sznol, Margaret K. Callahan, Harriet Kluger, Michael A. Postow, RuthAnn Gordan, Neil H. Segal, Naiyer A. Rizvi, Alexander Lesokhin, Michael B. Atkins, John M. Kirkwood, Matthew M. Burke, Amanda Ralabate, Angel Rivera, Stephanie A. Kronenberg, Blessing Agunwamba, Mary Ruisi, Christine Horak, Joel Jiang, Jedd Wolchok Combination therapies O5 Efficacy and correlative biomarker analysis of the coBRIM study comparing cobimetinib (COBI) + vemurafenib (VEM) vs placebo (PBO) + VEM in advanced BRAF-mutated melanoma patients (pts) Paolo A. Ascierto, Grant A. McArthur, James Larkin, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Ilsung Chang, Daniel O. Koralek, Isabelle Rooney, Yibing Yan, Antoni Ribas, Brigitte Dréno O6 Preliminary clinical safety, tolerability and activity results from a Phase Ib study of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600-mutant metastatic melanoma Ryan Sullivan, Omid Hamid, Manish Patel, Stephen Hodi, Rodabe Amaria, Peter Boasberg, Jeffrey Wallin, Xian He, Edward Cha, Nicole Richie, Marcus Ballinger, Patrick Hwu O7 Preliminary safety and efficacy data from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with advanced/metastatic melanoma Thomas F. Gajewski, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Jason J. Luke, Ani S. Balmanoukian, David R. Kaufman, Yufan Zhao, Janet Maleski, Lance Leopold, Tara C. Gangadhar O8 Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma Reinhard Dummer, Georgina V. Long, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari VanderWalde, Robert H.I. Andtbacka, Jonathan Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J. Olszanski, Thomas F. Gajewski, John M. Kirkwood, Christine Gause, Lisa Chen, David R. Kaufman, Jeffrey Chou, F. Stephen Hodi News in immunotherapy O9 Two-year survival and safety update in patients (pts) with treatment-naïve advanced melanoma (MEL) receiving nivolumab (NIVO) or dacarbazine (DTIC) in CheckMate 066 Victoria Atkinson, Paolo A. Ascierto, Georgina V. Long, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Celeste Lebbé, Lars Ny, Matias Chacon, Paola Queirolo, Carmen Loquai, Parneet Cheema, Alfonso Berrocal, Karmele Mujika Eizmendi, Luis De La Cruz-Merino, Gil Bar-Sela, Christine Horak, Joel Jiang, Helene Hardy, Caroline Robert O10 Efficacy and safety of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL) who were treated beyond progression in CheckMate 066/067 Georgina V. Long, Jeffrey S. Weber, James Larkin, Victoria Atkinson, Jean-Jacques Grob, Reinhard Dummer, Caroline Robert, Ivan Marquez-Rodas, Catriona McNeil, Henrik Schmidt, Karen Briscoe, Jean-François Baurain, F. Stephen Hodi, Jedd D. Wolchok Tumor microenvironment and biomarkers O11 New biomarkers for response/resistance to BRAF inhibitor therapy in metastatic melanoma Rosamaria Pinto, Simona De Summa, Vito Michele Garrisi, Sabino Strippoli, Amalia Azzariti, Gabriella Guida, Michele Guida, Stefania Tommasi O12 Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma and response to ipilimumab Nicolas Jacquelot, David Enot, Caroline Flament, Jonathan M. Pitt, Nadège Vimond, Carolin Blattner, Takahiro Yamazaki, Maria-Paula Roberti, Marie Vetizou, Romain Daillere, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L Slingluff Jr, Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michaele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel O13 Serum levels of PD1- and CD28-positive exosomes before Ipilimumab correlate with therapeutic response in metastatic melanoma patients Passarelli Anna, Tucci Marco, Stucci Stefania, Mannavola Francesco, Capone Mariaelena, Madonna Gabriele, Ascierto Paolo Antonio, Silvestris Franco O14 Immunological prognostic factors in stage III melanomas María Paula Roberti, Nicolas Jacquelot, David P Enot, Sylvie Rusakiewicz, Michaela Semeraro, Sarah Jégou, Camila Flores, Lieping Chen, Byoung S. Kwon, Ana Carrizossa Anderson, Caroline Robert, Christophe Borg, Benjamin Weide, François Aubin, Stéphane Dalle, Michele Maio, Jedd D. Wolchok, Holbrook Kohrt, Maha Ayyoub, Guido Kroemer, Aurélien Marabelle, Andréa Cavalcanti, Alexander Eggermont, Laurence Zitvogel POSTER PRESENTATIONS Molecular and immuno-advances P1 Human melanoma cells resistant to B-RAF and MEK inhibition exhibit mesenchymal-like features Anna Lisa De Presbiteris, Fabiola Gilda Cordaro, Rosa Camerlingo, Federica Fratangelo, Nicola Mozzillo, Giuseppe Pirozzi, Eduardo J. Patriarca, Paolo A. Ascierto, Emilia Caputo P2 Anti-proliferative and pro-apoptotic effect of ABT888 on melanoma cell lines and its potential role in the treatment of melanoma resistant to B-RAF inhibitors Federica Fratangelo, Rosa Camerlingo, Emilia Caputo, Maria Letizia Motti, Rosaria Falcone, Roberta Miceli, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Maria Vincenza Carriero, Giuseppe Pirozzi and Paolo Antonio Ascierto P3 Involvement of the L-cysteine/CSE/H2S pathway in human melanoma progression Elisabetta Panza, Paola De Cicco, Chiara Armogida, Giuseppe Ercolano, Rosa Camerlingo, Giuseppe Pirozzi, Giosuè Scognamiglio, Gerardo Botti, Giuseppe Cirino, Angela Ianaro P4 Cancer stem cell antigen revealing pattern of antibody variable region genes were defined by immunoglobulin repertoire analysis in patients with malignant melanoma Beatrix Kotlan, Gabriella Liszkay, Miri Blank, Timea Balatoni, Judit Olasz, Emil Farkas, Andras Szollar, Akos Savolt, Maria Godeny, Orsolya Csuka, Szabolcs Horvath, Klara Eles, Yehuda Shoenfeld and Miklos Kasler P5 Upregulation of Neuregulin-1 expression is a hallmark of adaptive response to BRAF/MEK inhibitors in melanoma Debora Malpicci, Luigi Fattore, Susan Costantini, Francesca Capone, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto P6 HuR positively regulates migration of HTB63 melanoma cells Farnaz Moradi, Pontus Berglund, Karin Leandersson, Rickard Linnskog, Tommy Andersson, Chandra Prakash Prasad P7 Prolyl 4- (C-P4H) hydroxylases have opposing effects in malignant melanoma: implication in prognosis and therapy Cristiana Lo Nigro, Laura Lattanzio, Hexiao Wang, Charlotte Proby, Nelofer Syed, Marcella Occelli, Carolina Cauchi, Marco Merlano, Catherine Harwood, Alastair Thompson, Tim Crook P8 Urokinase receptor antagonists: novel agents for the treatment of melanoma Maria Letizia Motti, Katia Bifulco, Vincenzo Ingangi, Michele Minopoli, Concetta Ragone, Federica Fratangelo, Antonello Pessi, Gennaro Ciliberto, Paolo Antonio Ascierto, Maria Vincenza Carriero P9 Exosomes released by melanoma cell lines enhance chemotaxis of primary tumor cells Francesco Mannavola, Stella D’Oronzo, Claudia Felici, Marco Tucci, Antonio Doronzo, Franco Silvestris P10 New insights in mitochondrial metabolic reprogramming in melanoma Anna Ferretta, Gabriella Guida, Stefania Guida, Imma Maida, Tiziana Cocco, Sabino Strippoli, Stefania Tommasi, Amalia Azzariti, Michele Guida P11 Lenalidomide restrains the proliferation in melanoma cells through a negative regulation of their cell cycle Stella D’Oronzo, Anna Passarelli, Claudia Felici, Marco Tucci, Davide Quaresmini, Franco Silvestris Combination therapies P12 Chemoimmunotherapy elicits polyfunctional anti-tumor CD8 + T cells depending on the activation of an AKT pathway sustained by ICOS Ornella Franzese, Belinda Palermo, Cosmo Di Donna, Isabella Sperduti, MariaLaura Foddai, Helena Stabile, Angela Gismondi, Angela Santoni, Paola Nisticò P13 Favourable toxicity profile of combined BRAF and MEK inhibitors in metastatic melanoma patients Andrea P. Sponghini, Francesca Platini, Elena Marra, David Rondonotti, Oscar Alabiso, Maria T. Fierro, Paola Savoia, Florian Stratica, Pietro Quaglino P14 Electrothermal bipolar vessel sealing system dissection reduces seroma output or time to drain removal following axillary and ilio-inguinal node dissection in melanoma patients: a pilot study Di Monta Gianluca, Caracò Corrado, Di Marzo Massimiliano, Marone Ugo, Di Cecilia Maria Luisa, Mozzillo Nicola News in immunotherapy P15 Clinical and immunological response to ipilimumab in a metastatic melanoma patient with HIV infection Francesco Sabbatino, Celeste Fusciello1, Antonio Marra, Rosario Guarrasi, Carlo Baldi, Rosa Russo, Di Giulio Giovanni, Vincenzo Faiola, Pio Zeppa, Stefano Pepe P16 Immunotherapy and hypophysitis: a case report Elisabetta Gambale, Consiglia Carella, Alessandra Di Paolo, Michele De Tursi Tumor microenvironment and biomarkers P17 New immuno- histochemical markers for the differential diagnosis of atypical melanocytic lesions with uncertain malignant potential Laura Marra, Giosuè Scognamiglio, Monica Cantile, Margherita Cerrone, Fara De Murtas, Valeria Sorrentino, Anna Maria Anniciello, Gerardo Botti P18 Utility of simultaneous measurement of three serum tumor markers in melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P19 The significance of various cut-off levels of melanoma inhibitory activity in evaluation of cutaneous melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P20 The long noncoding RNA HOTAIR is associated to metastatic progression of melanoma and it can be identified in the blood of patients with advanced disease Chiara Botti, Giosuè Scognamiglio, Laura Marra, Gabriella Aquino, Rosaria Falcone, Annamaria Anniciello, Paolo Antonio Ascierto, Gerardo Botti, Monica Cantile Other P21 The effect of Sentinel Lymph Node Biopsy in melanoma mortality: timing of dissection Cristina Fortes, Simona Mastroeni, Alessio Caggiati, Francesca Passarelli, Alba Zappalà, Maria Capuano, Riccardo Bono, Maurizio Nudo, Claudia Marino, Paola Michelozzi P22 Epidemiological survey on related psychopathology in melanoma Valeria De Biasio, Vincenzo C. Battarra IMMUNOTHERAPY BRIDGE KEYNOTE SPEAKER PRESENTATIONS Immunotherapy beyond melanoma K19 Predictor of response to radiation and immunotherapy Silvia Formenti K20 Response and resistance to PD-1 pathway blockade: clues from the tumor microenvironment Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube and Suzanne L. Topalian K21 Combination immunotherapy with autologous stem cell transplantation, protein immunization, and PBMC reinfusion in myeloma patients Sacha Gnjatic, Sarah Nataraj, Naoko Imai, Adeeb Rahman, Achim A. Jungbluth, Linda Pan, Ralph Venhaus, Andrew Park, Frédéric F. Lehmann, Nikoletta Lendvai, Adam D. Cohen, and Hearn J. Cho K22 Anti-cancer immunity despite T cell “exhaustion” Speiser Daniel Immunotherapy in oncology (I-O): data from clinical trial K23 The Checkpoint Inhibitors for the Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC) Vera Hirsh

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.

Abstract The Great Debate session at the 2019 Melanoma Bridge congress (December 5-7, Naples, Italy) featured counterpoint views from experts on five topical issues in melanoma. These were whether to choose local intratumoral treatment or systemic treatment, whether patients with stage IIIA melanoma require adjuvant therapy or not, whether treatment is better changed at disease progression or during stable disease, whether adoptive cell transfer (ACT) therapy is more appropriate used before or in combination with checkpoint inhibition therapy, and whether treatment can be stopped while the patient is still on response. As was the case for previous meetings, the debates were assigned by meeting Chairs. As such, positions taken by each of the melanoma experts during the debates may not have reflected their respective personal approach.

Mucinous carcinoma (MC) is a rare breast cancer characterized by the presence of large extracellular mucin amount. Two main subtypes can be distinguished: pure (PMC) and mixed (MMC).We conducted a retrospective MC analysis in our prospective maintained database, calculating disease-free survival (DFS) and 5-year overall survival (OS). We found a global 92.1% OS (higher in MMC group and statistically significative) and a DFS of 95.3% (higher in MMC group but not statistically significative).

Objective: To provide a narrative review of the preprocedural mouth rinse protocols suggested for oral surgery in order to contrast the presence of SARS-CoV-2 in aerosol. Sources and Methods: Electronic searches were performed in medical databases PubMed, Medline, CINAHN and Scopus to identify relevant studies published up until the third week of April 2020. This research was supplemented by exploration through a web-based search engine as well as a manual search for international and national guidelines. Studies and protocols which suggested preoperative mouth rinsing as a recommended measure during the COVID-19 outbreak were included. Given the small number of studies, a narrative literature review was conducted. In total, 15 references (11 articles and 4 guidelines) were considered relevant and were critically analysed. Conclusion: The findings show a high heterogeneity in the protocols suggested. Further research is required to better understand the viral features and epidemiologic characteristics of this new virus and to test the efficacy of commonly used antiseptics against SARS-CoV-2 in future clinical trials. However, the use of chlorhexidine, hydrogen peroxide, PVP-I and cetylpyridinium chloride in contrasting the spread of Covid-19 is described as advisable and substantial in different publications.