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The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and its resistance to immunotherapies (Immuno-Oncology Therapy, IOT), by generating extracellular adenosine (eAdo).Using genetically engineered allograft models of PDAC in syngeneic mice with differential immune infiltration and response to IOT, we showed enrichment of the adenosine pathway in tumour-infiltrating immune cells (in particular, myeloid populations). Using MS-Imaging, we showed that extracellular adenosine distribution is heterogeneous in tumours, with high concentrations in hypoxic margins that surround necrotic areas, associated with a rich myeloid infiltration, demonstrated using Imaging Mass Cytometry (IMC). Pro-tumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking thein vivoformation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumour growth and reduced metastatic burden. In addition, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Finally, Adoi remodelled the tumour microenvironment (TME), as evidenced by reduced infiltration of M2 macrophages and Tregs. RNAseq analysis showed that genes related to immune modulation, hypoxia and tumour stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC.The formation of eAdo appears to promote the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the stroma and improve therapy response in patients with PDAC.

The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan–Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65–10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25–15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

Background:Genetic research has become an indispensable instrument for medical research, and the subjects involved have both divergent and convergent interests.Objective:The possibility of having more detailed genetic information undoubtedly offers benefits for the health of the subject, but could also pose risks and make the subject vulnerable to discrimination.The scientific community has viewed very favorably the public health utility of family history, in which data from a family whose members suffer from chronic pathologies is collected and filed, in order to develop a sort of "stratification of family risk."Even though in the last decade the scientific and juridical literature has contributed greatly to the topic of biobanks, the perplexities that continue to surround this theme give the idea that current ethical protocols on research are inadequate.Conclusion:Genetic data must be used not to exploit, but to serve the person. Freedom and responsibility must be the twin guiding lights for establishing parameters for the use of biological samples. An evaluation of how this technology impacts the various aspects of the future of society is urgently needed.

The prognosis for patients with pancreatic adenocarcinoma (PDAC) remains extremely poor. PDAC is resistant to both conventional therapies and emerging immunotherapies (IOT), apart from tumors with mismatch repair deficiency. This may be explained in part by its low tumor mutational burden (TMB) but also by its immunosuppressive tumor microenvironment (TME). It has been suggested that CD73, a member of the adenosine pathway, expressed on cancer cells contributes to immune escape and resistance to cytotoxic/radiotherapy treatment. The adenosine pathway converts the immune activator ATP, released by dying cells during cell turnover or after treatment, to extracellular Adenosine (eAdo), which is immunosuppressive. Using syngeneic, in vivo models by s.c. implantation of KPC-derived cell lines (courtesy of Ben Stanger, UPenn) with differential immune infiltration and response to IOT [resistant (IOTResi) or responsive (IOTResp)], we showed by flow cytometry that the adenosine pathway is enriched in the tumor-infiltrating immune cells (in particular myeloid populations) which co-express CD39 and CD73, enabling the formation of eAdo. Mass Spec Imaging (MSI) revealed that adenosine distribution is heterogeneous in the tumors with high concentrations in the hypoxic margins that surround necrotic areas. Subpopulations of myeloid cells infiltrating the lesions are a target for eAdo, expressing high levels of adenosine receptor Adora2a. We discovered that pro-tumorigenic M2 macrophages have the highest expression of the receptor and significantly higher in the IOTResi model. Blocking the in vivo formation and function of eAdo in IOTResi tumors, using a combination of anti-CD73 antibody (2C5, murine IgG1-Fc) and an inhibitor of Adora2a (AZD4635) reduced the presence of eAdo, slowed tumor growth and reduced the lung metastatic burden. The combination remodeled the TME, reducing the infiltration by M2 macrophages, particularly those that are PD-L1 positive and diminished the frequency of infiltrating Tregs. Bulk RNAseq analysis demonstrated a profound dependency of the TME on the presence of eAdo. Genes related to cytokine/chemokine signaling, immunosuppression/inflammation, hypoxia, metastasis and collagen production are strongly downregulated following administration of anti-CD73Ab/Adora2ai. In addition, blocking the adenosine pathway improved the efficacy of combinations of cytotoxics (gemcitabine/ATR inhibitor) and immunotherapy (aCD40/anti-PDL1Ab). The formation of eAdo appears to be a factor in the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway using a CD73Ab and an Adora2ai may represent a strategy to modulate the PDAC stroma and improve therapy response in patients with PDAC. Citation Format: Vincenzo Graziano, Andreas Dannhorn, Kate Williamson, Heather Hulme, Hannah Buckley, Sheng Y. Lee, Sabita Islam, James E. Thaventhiran, Richard Goodwin, Rebecca Brais, Simon J. Dovedi, Alwin Schuller, Jim Eyles, Duncan I. Jodrell. Reshaping the myeloid-dependent pro-tumorigenic microenvironment in PDAC by targeting the extracellular adenosine pathway: A therapeutic opportunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6103.

The 90K protein, also known as Mac-2 BP or LGALS3BP, can activate the immune response in part by increasing major histocompatibility (MHC) class I levels. In studies on a non-immune cell model, the rat FRTL-5 cell line, we observed that transforming growth factor (TGF)-β1, like γ-interferon (IFN), increased 90K levels, despite its immunosuppressive functions and the ability to decrease MHC class I. To explain this paradoxical result, we investigated the mechanisms involved in the TGF-β1 regulation of 90K expression with the aim to demonstrate that TGF-β1 utilizes different molecular pathways to regulate the two genes. We found that TGF-β1 was able to increase the binding of Upstream Stimulatory Factors, USF1 and USF2, to an E-box element, CANNTG, at −1926 to −1921 bp, upstream of the interferon response element (IRE) in the 90K promoter. Thyrotropin (TSH) suppressed constitutive and γ-IFN-induced 90K expression by decreasing USF binding to the E-box. TGF-β1 was able to overcome TSH suppression at the transcriptional level by increasing USF binding to the E-box. We suggest that the ability of TGF-β1 to increase 90K did not result in an increase in MHC class I because of a separate suppressive action of TGF-β1 directly on the MHC class I gene. We propose that the increased levels of 90K may play a role, rather than in immune response, in the context of the TGF-β1-induced changing of the cellular microenvironment that predisposes to cell motility and cancer progression. Consistently, analyzing the publicly available cancer patient data sets cBioPortal, we found that 90K expression directly correlated with TGF-β1 and USFs and that high levels of 90K were significantly associated with increased mortality in patients affected by different types of cancer.

Objectives: To evaluate autoptic histopathological findings of arrhythmogenic ventricular cardiomyopathy (AVC) as major cause of sudden cardiac death (SCD) in young adults. Background: According to Heart Rhythm Society (HRS)’s international consensus, histological criteria for AVC diagnosis include a progressive myocardial atrophy of the right ventricle characterized by a transmural fatty or fibrofatty replacement in a segmental or diffuse pattern (residual myocytes

Cerebral tissues in human remains are rare archaeological discoveries. These tissues are typically saponified, meaning that their triglycerides have been converted to glycerol and fatty acid salts, or soap. In c.e. 79, a volcanic hot ash avalanche rapidly killed the inhabitants of Pompeii and Herculaneum. In the 1960s, at the Collegium Augustalium in Herculaneum, a human victim of the avalanche was found lying on a wooden bed, buried by volcanic ash. In this victim’s skull, we discovered apparent brain remains that were vitrified instead of saponified.

Detecting the ultrastructure of brain tissue in human archaeological remains is a rare event that can offer unique insights into the structure of the ancient central nervous system (CNS). Yet ancient brains reported in the literature show only poor preservation of neuronal structures. Using scanning electron microscopy (SEM) and advanced image processing tools, we describe the direct visualization of neuronal tissue in vitrified brain and spinal cord remains which we discovered in a male victim of the AD 79 eruption in Herculaneum. We show exceptionally well preserved ancient neurons from different regions of the human CNS at unprecedented resolution. This tissue typically consists of organic matter, as detected using energy-dispersive X-ray spectroscopy. By means of a self-developed neural image processing network, we also show specific details of the neuronal nanomorphology, like the typical myelin periodicity evidenced in the brain axons. The perfect state of preservation of these structures is due to the unique process of vitrification which occurred at Herculaneum. The discovery of proteins whose genes are expressed in the different region of the human adult brain further agree with the neuronal origin of the unusual archaeological find. The conversion of human tissue into glass is the result of sudden exposure to scorching volcanic ash and the concomitant rapid drop in temperature. The eruptive-induced process of natural vitrification, locking the cellular structure of the CNS, allowed us to study possibly the best known example in archaeology of extraordinarily well-preserved human neuronal tissue from the brain and spinal cord.

Cesarean is defined as the delivery of a fetus through surgical incisions made through the uterine wall. Primary cesarean sections often lead to repeat cesareans, which may lead to placenta accreta spectrum disorders. The ethic of exposing mothers to these risks, as well as performing surgery on what is otherwise a healthy patient, become entangled with the demand for patient choice, as well as the increasing financial strain on our healthcare system. The main question to be examined is whether it is ethical to allow women to opt for cesarean delivery in the absence of obstetric indication (i.e. cesarean delivery on maternal request), taking into account the increased risk to the mother and her future offspring.

We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p

Background Despite vaccinations are scientifically proven to be safe and effective public controversies limit their application in many countries. Aims Aim of this review is to provide an overview of biological effects of vaccination and a picture of the ethical dilemmas about compulsory vaccination. Methods We conducted a review on the literature about the subject. Recent news were also included. Results Vaccines are the best weapon against many infectious diseases. The spread of false beliefs among people have led the government authorities to increase compulsory vaccination in order to embank new outbreaks of preventable infectious diseases. Conclusion Even if compulsory is quite drastic approach it could be the on only way to reach an adequate coverage and protect immunoexpressed subjects.

The aim of this article is to provide an analysis of the main issues related to the application of predictive medicine by analysing the most significant ethical implications. Genetic medicine is indeed a multidisciplinary matter that covers broad contexts, sometimes transversely. Its extreme complexity, coupled with possible perceived repercussions on an individual’s life, involves important issues in the ethical, deontological and legal medical field. The aspects related to the execution of genetic testing have to be addressed at different levels, starting with the correct information about the “cognitive” meaning they intend (by forcefully disassociating it from the strange “preventive aspect”) to the legal medical issues that can be aroused in the field of forensic pathology, medical responsibility and insurance. There is no doubt that in recent years, from the decoding of the human genome, genetic research has exponentially expanded with an equally exponential increase in its use in clinical practice and the ethical and social evolution of it.

Background:ATRiUM is a phase 1 trial to assess the safety, tolerability, pharmacokinetics and preliminary antitumour activity of ascending doses of combined therapy with the ATR inhibitor ceralasertib AZD6738 and gemcitabine, Using a Model based design NCT03669601. The combination was shown to act synergistically in laboratory models of pancreatic cancer. Based on these data, ATRiUM is now open to recruitment in Cambridge and Glasgow, UK. Methods:ATRiUM utilises a novel Bayesian model-based design for dual-agent dose escalation, that handles three levels of toxicity the highest of which is a dose limiting toxicity and two dosing schedules. The model assumes that the toxicity levels come from a multinomial distribution and toxicity increases monotonically as doses increase. Different schedules and doses 40-120 mg of ceralasertib; intermittent days 1-4, 8-11, 15-18 and continuous days 1-21 with gemcitabine 625-1000 mg/m2 administered on days 3, 10 and 17 of a 28-day cycle, will be assessed using the Bayesian framework. The aim is to recruit up to 55 patients, including up to 40 in the dose escalation phase across 3 gemcitabine doses and 6 ceralasertib dose/schedules. An expansion cohort (10-15 patients) is planned in patients with pancreatic cancer, based on our pre-clinical findings. Tumour monitoring will be undertaken by CT imaging RECIST 1.1, liquid biopsies circulating free DNA and advanced imaging radiomics. Baseline tissue biopsies will be analysed to identify potential predictive biomarkers e.g. ATM loss, as described pre-clinically. Imaging MSI will be used to characterise the intra-tumoural distribution of gemcitabine, its metabolites and ceralasertib and compared to plasma PK. Detailed studies of sequential tumour biopsies will include immunohistochemistry, RNAseq and Imaging Mass Cytometry IMC and be used to evaluate early pharmacodynamic responses to the combination. To investigate whether the combination increases tumour immunogenicity, the immune effects of the combination will be evaluated in both tumour by IMC and RNAseq and peripherally, by the serial collection and analysis of PBMCs and plasma for cytokine analysis. Adults with solid tumours are eligible for the dose escalation, if fulfilling standard Phase I eligibility criteria with measurable tumour lesions amenable to biopsy. Two out of six planned cohorts have been completed with no DLTs identified and cohort 3 will open in January 2021. ATRiUM is supported by the Integrative Cancer Medicine theme of the CRUK Cambridge Centre, the NIHR Cambridge Biomedical Centre, the Cambridge ECMC and a grant from AstraZeneca. Citation Format: Bruno Henrique de Paula, Bristi Basu, Adrian Mander, Josephine Khan, Purity Bundi, Richard Goodwin, James Thaventhiran, Gonzalez-Lopes Alberto, Godfrey Edmund, Sabita Islam, Subha Anand, Jeff Evans, Vincenzo Graziano, Eva Serrao, Maria Pawula, Tatiana Hernandez, Emma Dean, Simon Smith, Duncan Jodrell. ATRiUM: A first-in-human dose escalation phase I trial of ceralasertib (AZD6738) and gemcitabine as combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT214.

Common variable immunodeficiency disorders (CVID) represent a collection of diseases leading to an absent or strongly impaired antibody production. CVID presents a wide range of immunological abnormalities and clinical manifestations, including infections, inflammatory and autoimmune diseases, and malignancies. The aim of this observational study was to analyze the epidemiological and clinical features of a cohort of 75 Italian CVID patients, and evaluate the correlation with comorbidity and mortality. Clinical data were retrospectively collected: the cohort was followed-up for a maximum of 30 years (mean time of 10.24 years, median of 9 years). An higher age at the diagnosis of CVID and an higher age at onset of symptoms were significantly associated with a reduction of patients survival if stratified per median of IgA (less than or > 8.00 mg/dl). Thus IgA levels at diagnosis are correlated with patients survival contributing to identify a subset with a worse prognostic outcome.

Purpose To evaluate factors influencing the long-term outcome of patients presenting with 10 or more metastatic axillary lymph nodes (pN3a) after surgery for primary breast cancer. Method Between January 1990 and December 2015, a total of 130 patients with pN3a breast cancer at surgery were identified in our Institutions and included in the study. Twenty-nine of them (22.3%) received neoadjuvant chemotherapy. The Multivariate Cox proportional hazards model was used to determine independent prognostic factors associated with DFS and OS. Results After a median follow-up of 6.4 years (range 0.87–25 years), 2 patients had a local relapse, 59 distant metastases (1 with local relapse) and 52 patients died. The 5-year DFS and OS rates were 61.8% and 71.5%, respectively. At multivariate analysis, pN3a stage after neoadjuvant chemotherapy (ypN3a) was significantly associated with increased risk of recurrence (HR 1.92, p = 0.02) and death (HR 2.05, p = 0.029). Absence of progesterone receptor (PR) expression was the most important tumor characteristic associated with poor prognosis, both in terms of recurrence (HR 2.55, p Conclusions The results of this study indicate that ypN3a stage, lack of expression of PR, and Ki-67 ≥ 20% negatively affect long-term outcome of patients with pN3a breast cancer.

SummarySome studies suggest that patients with cirrhosis have an increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE). Unfortunately, available data on this association are contrasting. It was the objective of this study to perform a systematic review and meta-analysis of literature to evaluate the risk of venous thromboembolism (VTE) associated with cirrhosis. Studies reporting on VTE risk associated with cirrhosis were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. Eleven studies (15 data-sets) showed a significantly increased VTE risk in 695,012 cirrhotic patients as compared with 1,494,660 non-cirrhotic controls (OR: 1.703; 95 %CI: 1.333, 2.175; PSupplementary Material to this article is available online at www.thrombosis-online.com.

The recent introduction of the “precision medicine” concept in oncology pushed cancer research to focus on dynamic measurable biomarkers able to predict responses to novel anticancer therapies in order to improve clinical outcomes. Recently, the involvement of extracellular vesicles (EVs) in cancer pathophysiology has been described, and given their release from all cell types under specific stimuli, EVs have also been proposed as potential biomarkers in cancer. Among the techniques used to study EVs, flow cytometry has a high clinical potential. Here, we have applied a recently developed and simplified flow cytometry method for circulating EV enumeration, subtyping, and isolation from a large cohort of metastatic and locally advanced nonhaematological cancer patients (N = 106); samples from gender- and age-matched healthy volunteers were also analysed. A large spectrum of cancer-related markers was used to analyse differences in terms of peripheral blood circulating EV phenotypes between patients and healthy volunteers, as well as their correlation to clinical outcomes. Finally, EVs from patients and controls were isolated by fluorescence-activated cell sorting, and their protein cargoes were analysed by proteomics. Results demonstrated that EV counts were significantly higher in cancer patients than in healthy volunteers, as previously reported. More interestingly, results also demonstrated that cancer patients presented higher concentrations of circulating CD31+ endothelial-derived and tumour cancer stem cell-derived CD133 + CD326- EVs, when compared to healthy volunteers. Furthermore, higher levels of CD133 + CD326− EVs showed a significant correlation with a poor overall survival. Additionally, proteomics analysis of EV cargoes demonstrated disparities in terms of protein content and function between circulating EVs in cancer patients and healthy controls. Overall, our data strongly suggest that blood circulating cancer stem cell-derived EVs may have a role as a diagnostic and prognostic biomarker in cancer.

Hair, larvae and cardiac muscle, the only biological samples present on a skeletonized human body found in a rural area, were used for forensic toxicological analyses in order to determine possible causes of death. Since no information about the victim or the circumstances of death was available (except for the place where the corpse was found, known to be a gathering place for drug addicts), the first approach for the analysis of non-conventional matrices involved the screening of different classes of active principles, using a chemiluminescence-based screening assay designed for whole blood. The immunoassay test results showed positivity to amphetamines, cocaine and opiates on water/methanol extract from cardiac tissue, larvae and hair samples. Gas chromatography-mass spectrometry (GC/MS) analyses confirmed the immunoassay results, except for amphetamines. The minimal sample preparation (hydration and extraction in an ultrasonic bath), the reduced sample volume required for the analyses, together with the correctness of results as confirmed by GC/MS, showed the suitability of the screening test for forensic applications on non-conventional matrices. Quantitative analyses in GC/MS allowed the cause of death to be ascertained on the basis of the ratio between parent drugs and metabolites.

Background: Hardness is considered an important parameter for evaluating the clinical performance of dental implant bone drills. It is connected to the chemical composition, microstructure conformation and manufacture of the surgical drills. Methods: Microstructure of five dental implant drills using scanning electronic microscopy (SEM) integrated with energy dispersive X-ray spectrometry. Vickers microhardness was measured using a CV 2000 microhardness tester with an indentation force of 500 g. Results: Composition of the implant drills was typical of martensitic stainless steel (MSS). The drills contained 13%&ndash, 17% of Cr, Mo, Si and Mn were present as minor ligands. The examined bone drills showed different external surface conformation and hardness in relation to the different industrial production processes. A rougher external surface and a higher hardness value are characteristics of the surgical bone drills produced by hot forming, the implant drills produced by machining showed mailing lines on their external surface and a lower hardness. Conclusions: Different compositions and treatments were used by the manufacturers to improve the hardness of the external layer of the dental implant drills making them prone to a diverse heat generation during the implant site preparation.

Background: Endemic fluorosis induced by high concentrations of fluoride in groundwater and soils is a major health problem in several countries, particularly in volcanic areas.Aim: To evaluate the occurrence of dental fluorosis resulting from exposure to high levels of environmental fluoride in 79 AD Herculaneum and close Vesuvius towns.Subjects and methods: The occurrence of dental fluorosis from teeth of the Herculaneum victims of the 79 AD eruption and some individuals from Pompeii (14-37 AD) and Nocera Inferiore (Salerno, IV sec. AD) was detected by means of Particle Induced Gamma-ray Emission technique (PIGE).Results: A clinical and analytical scenario of dental fluorosis resulted from the extreme high fluorine tooth content detected in teeth from Herculaneum and the Vesuvius area inhabitants. The adoption of PIGE technique has proved to be particularly effective in showing moderate as well as milder forms of dental fluorosis, otherwise not clearly detectable by clinical and histological analysis.Conclusions: Morphological, histological and elemental analysis of teeth of the 79 AD Herculaneum population show that in this area fluorosis occurred since Roman times.

Background:Genetic research has become an indispensable instrument for medical research, and the subjects involved have both divergent and convergent interests.Objective:The possibility of having more detailed genetic information undoubtedly offers benefits for the health of the subject, but could also pose risks and make the subject vulnerable to discrimination.Methods:The scientific community has viewed very favorably the public health utility of family history, in which data from a family whose members suffer from chronic pathologies is collected and filed, in order to develop a sort of “stratification of family risk.”Even though in the last decade the scientific and juridical literature has contributed greatly to the topic of biobanks, the perplexities that continue to surround this theme give the idea that current ethical protocols on research are inadequate.Results:Researchers, citizens, International stakeholders, mass media, Public Health and Governments play a key role in genetic research. It is obvious that the methods used for genetic research do not present intrinsic risks; they are much less dangerous than other activities of diagnosis and research. Before authorizing a research project, it is important to reflect on the responsibility and transparency of the studies to be conducted, and on the impact they may have on the interests of public health.Conclusion:We believe that the highest priority need is to develop a common language on the theme, as is the case in the sphere of clinical experimentation where rules of good clinical practice, albeit at times conflicting, have led to uniform convergences in the scientific world on the points to be actuated.

Peripartum cardiomyopathy (PPCM), a rare and potentially fatal disease, occurs in young, previously healthy pregnant women in the last stages of pregnancy and up to 5-6 months after delivery. Since its etiology is multifactorial, diagnosis is generally made via exclusion of all other causes. We here describe three cases of three young women who died suddenly and unexpectedly after giving birth by Cesarean section (C-section). These cases were brought to our attention after malpractice claims had been brought against the hospitals’ health professionals. In all three reported cases, the cardiac function suddenly and unexpectedly worsened within a few hours after C-section. Strikingly, all three women had unremarkable clinical histories. Prior to postpartum complications, they had experienced uncomplicated gestation and had given birth to healthy full-term newborns. Therefore, since in none of these cases could the women’s uneventful clinical history have foreshadowed exitus, the hospital physicians attributed their deaths to sudden cardiac arrest. The macroscopic and microscopic histological findings ruled out any other condition that might have led to the women’s sudden and unexpected deaths; the toxicological test results were all negative and no surgical anomalies were found. After painstakingly analyzing the medical and clinical data reported in the women’s medical charts, together with the histological data emerging after autopsy, in agreement with the literature, we concluded that all three women had died of peripartum cardiomyopathy. Lastly, our three cases suggest that among the various forensic methods used to determine the causes of death, the histological approach remains the gold standard for identifying the causes of death especially in previously healthy individuals who die suddenly and unexpectedly.

Especially in oncology and in critical care, the provision of medical care can require therapeutic choices that could go beyond the patient’s will or intentions of the protection of his health, with the possible adoption of medical behaviors interpreted as unreasonable obstinacy or, at the opposite extreme, as euthanasia. In some cases, the demand for obstinate therapeutic services could come from the patient or from his relatives, in which case the dilemma arises for the health professional between rejecting such a request, in respect of their professional autonomy, or abiding by it for fear of a professional care responsibility for therapeutic abandonment. We analyzed and commented on emblematic clinical cases brought to court for alleged wrong medical conduct due to breach of the prohibition of unreasonable obstinacy. In healthcare it is impossible to fix a general rule defining any therapeutic act as appropriate, because on one hand there are technical assessments of medical competence, and on the other the perception of the patient and of his family members of the usefulness of the health care provided, which may be in contrast. The medical act cannot make treatments that are inappropriate for the needs of care or even be unreasonable; conversely, before the request by the patient or by his family members for disproportionate health services in relation to the results they may give in practice, in compliance with the legislative and deontological provisions, the doctor can refuse them, thus safeguarding both his decision-making autonomy and, therefore, his professional dignity. Significance for public healthThe aim of our research is to contribute to identify the technical parameters and the ethical and deontological aspects useful to qualify a treatment as obstinate, to ensure on the one hand a treatment process that does not exceed the patient's requests or expectations (especially if unexpressed), and on the other hand to protect health workers from charges of professional liability for overtreatment damages, while avoiding attitudes of defensive medicine. Reference to the current code of Italian medical deontology is helpful in making therapeutic choices. It recommends the physician not to undertake diagnostic procedures and therapeutic interventions that are clinically inappropriate and ethically disproportionate and against the current laws, according to which the patient cannot demand healthcare treatments contrary to the law, deontology and good clinical-care practices.

Background The use of electroconvulsive therapy (ECT) is still very limited in Italy for ideological rather than scientific reasons. Objectives To describe the public controversies surrounding ECT in Italy and to propose a plan of action to resolve the dispute. Methods We describe the historical background and the current public controversies about ECT by reviewing the official documents issued by the entities involved in the debate and by reporting our personal experiences of ECT practice. Results According to the highest legal and health authorities, there are no ethical reasons for doubting the licit nature of ECT. However, because of politically and ideologically based conflicts, public ECT centers are still lacking. The situation could further deteriorate because local initiatives are endeavoring to criminalize and ban the treatment. Conclusions The enactment of specific regulations and guidelines concerning the use of ECT by the Italian government is highly warranted to increase the availability of the treatment. Education and information campaigns must strive to increase the knowledge of health professionals and the lay public regarding the safe and beneficial use of ECT.

Introduction In Italy there has been an increase in claims for damages for alleged medical malpractice. A study was therefore conducted that aimed at assessing the content of the coverage of insurance policy contracts offered to oral health professionals by the insurance market. Material and methods The sample analysed composed of 11 insurance policy contracts for professional dental liability offered from 2010 to 2015 by leading insurance companies operating in the Italian market. Results The insurance products analysed are structured on the “claims made” clause. No policy contract examined covers the damage due to the failure to acquire consent for dental treatment and, in most cases, damage due to unsatisfactory outcomes of treatment of an aesthetic nature and the failure to respect regulatory obligations on privacy. Discussion On entering into a professional liability insurance policy contract, the dentist should pay particular attention to the period covered by the guarantee, the risks both covered and excluded, as well as the extent of the limit of liability and any possible fixed/percentage excess. Conclusions When choosing a professional liability contract, a dentist should examine the risks in relation to the professional activity carried out before signing.

Introduction Iatrogenic splenic injury is a recognized complication in abdominal surgery. The aim of this paper is to understand the medico-legal issues of iatrogenic splenic injuries. We performed a literature review on PubMed and Scopus using iatrogenic splenic or spleen injury and iatrogenic splenic rupture as keywords. Iatrogenic splenic injury cases were identified. Most cases were related to colonoscopy, but we also identified cases related to upper gastrointestinal procedures, colonic surgery, ERCP, left nephrectomy and/or adrenalectomy, percutaneous nephrolithotomy, vascular operations involving the abdominal aorta, gynecological operation, left lung biopsy, chest drain, very rarely spinal surgery and even cardiopulmonary resuscitation. There are several surgical procedures that can lead to a splenic injury. However, from a medico-legal point of view, it is important to assess whether the cause can be attributed to a technical error of the operator rather than being an unpredictable and unpreventable complication. It is important for the medico-legal expert to have great knowledge on iatrogenic splenic injuries because it is important to evaluate every step of the first procedure performed, how a splenic injury is produced, and whether the correct treatment for the splenic injury was administered in a judgment.

[This corrects the article DOI: 10.1155/2019/5879616.].

The immune system seems to play a fundamental role in breast cancer responsiveness to chemotherapy. We investigated two peripheral indicators of immunity/inflammation, i.e. neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in order to reveal a possible relationship with pathological complete response (pCR) in patients with early or locally advanced breast cancer treated with neoadjuvant chemotherapy (NACT). We retrospectively analyzed 373 consecutive patients affected by breast cancer and candidates to NACT. The complete blood cell count before starting NACT was evaluated to calculate NLR and PLR. ROC curve analysis determined threshold values of 2.42 and 104.47 as best cut-off values for NLR and PLR, respectively. The relationships between NLR/PLR and pCR, along with other clinical-pathological characteristics, were evaluated by Pearson's χ 2 or Fisher's exact test as appropriate. Univariate and multivariate analyses were performed using a logistic regression model. NLR and PLR were not significantly associated with pCR if analyzed separately. However, when combining NLR and PLR, patients with a NLRlow/PLRlow profile achieved a significantly higher rate of pCR compared to those with NLRhigh and/or PLRhigh (OR 2.29, 95% CI 1.22-4.27, p 0.009). Importantly, the predictive value of NLRlow/PLRlow was independent from common prognostic factors such as grading, Ki67, and molecular subtypes. The combination of NLR and PLR may reflect patients' immunogenic phenotype. Low levels of both NLR and PLR may thus indicate a status of immune system activation that may predict pCR in breast cancer patients treated with NACT.

Finding traumatic lesions on ancient skeletal remains offers a unique opportunity to investigate the circumstances surrounding the time of death. Here we present the unique find of a late 17

Background Despite vaccinations are scientifically proven to be safe and effective public controversies limit their application in many countries. Aims Aim of this review is to provide an overview of biological effects of vaccination and a picture of the ethical dilemmas about compulsory vaccination. Methods We conducted a review on the literature about the subject. Recent news were also included. Results Vaccines are the best weapon against many infectious diseases. The spread of false beliefs among people have led the government authorities to increase compulsory vaccination in order to embank new outbreaks of preventable infectious diseases. Conclusion Even if compulsory is quite drastic approach it could be the on only way to reach an adequate coverage and protect immunoexpressed subjects.

Otorhinolaryngologic manifestations are common in 22q11.2 deletion syndrome (22q11.2DS), but poorly described. This study aimed to better define the ear-nose-throat (ENT) phenotype of 22q11.2DS patients, in the attempt to best detect subjects requiring subspecialist intervention. We enrolled 25 patients affected with 22q11.2DS. Anatomic and functional ENT findings were investigated using clinical, laboratory and instrumental data. Immunophenotype and frequency of infections were evaluated. Univariate and multivariate analyses were performed. ENT anomalies were found in 88% of patients, and in 20% congenital palate defects required surgery. Adenoids hypertrophy or palatine tonsils hypertrophy were noted in 80 and 48%. Fourty-eight percent of subjects had rhinolalia/phonia, severe in half of these. We also found nasal regurgitation or laryngeal penetration/aspiration in 20 and 16%, respectively. Instrumental exams revealed a mild conductive hypoacusia in 32% (bilateral in most cases), tympanometric anomalies in 28%, and swallowing abnormalities in 16%. Statistical univariate analysis showed a direct association between rhinolalia/phonia and episodes of laryngeal aspiration (P=0.016) and between tympanometric anomalies and increased adenoid volume (P=0.044). No association between episodes of food aspiration and palatal anomalies was found. Moreover, no statistically significant association was observed between the number of airway infections and the ENT findings. This study contributes to better define the ENT phenotype in patients with 22q11.2DS, helpful to prevent potential complications. Furthermore, the identification of a subcategory of patients may allow the early adoption of specific speech therapy programs to improve the clinical outcome of 22q11.2DS patients.

Finding traumatic lesions on ancient skeletal remains offers a unique opportunity to investigate the circumstances surrounding the time of death. Here we present the unique find of a late 17th, early 18th century young male from Southern Italy with eight traumatic skull lesions. A detailed anthropological examination using X-ray and 3D CT scanning techniques was conducted in order to evaluate traumatic extent, direction and degree of severity of each skull injury. The nature, number and timing of repair of the traumata suggest that they were intentional blows inflicted in battle. Gross and radiographic evidence shows that the individual survived long after one of these traumata, most likely suffered in a previous battle. Shape, size and location, as well as different orientation and implied trajectory of the multiple wounds, suggest that they were produced by a heavy, sharp cutting weapon. The perimortem aspect of most of the traumata revealed them to be contemporary injuries, suffered in a final assault by a heavy sword during a face-to-face combat. The largest and deepest fracture penetrating the skull cavity possibly resulting in traumatic brain injury was here suggested as the fatal one, even if the victim may have survived for several days prior to death.

Minimally invasive surgical procedures have revolutionized the world of surgery in the past decades. While laparoscopy, the first minimally invasive surgical technique to be developed, is widely used and has been addressed by several guidelines and recommendations, the implementation of robotic-assisted surgery is still hindered by the lack of consensus documents that support healthcare professionals in the management of this novel surgical procedure. Here we summarize the available evidence and provide expert opinion aimed at improving the implementation and resolution of issues derived from robotic abdominal surgery procedures. A joint task force of Italian surgeons, anesthesiologists and clinical epidemiologists reviewed the available evidence on robotic abdominal surgery. Recommendations were graded according to the strength of evidence. Statements and recommendations are provided for general issues regarding robotic abdominal surgery, operating theatre organization, preoperative patient assessment and preparation, intraoperative management, and postoperative procedures and discharge. The consensus document provides evidence-based recommendations and expert statements aimed at improving the implementation and management of robotic abdominal surgery.

In AD 79 the town of Herculaneum was suddenly hit and overwhelmed by volcanic ash-avalanches that killed all its remaining residents, as also occurred in Pompeii and other settlements as far as 20 kilometers from Vesuvius. New investigations on the victims' skeletons unearthed from the ash deposit filling 12 waterfront chambers have now revealed widespread preservation of atypical red and black mineral residues encrusting the bones, which also impregnate the ash filling the intracranial cavity and the ash-bed encasing the skeletons. Here we show the unique detection of large amounts of iron and iron oxides from such residues, as revealed by inductively coupled plasma mass spectrometry and Raman microspectroscopy, thought to be the final products of heme iron upon thermal decomposition. The extraordinarily rare preservation of significant putative evidence of hemoprotein thermal degradation from the eruption victims strongly suggests the rapid vaporization of body fluids and soft tissues of people at death due to exposure to extreme heat.

Background. Considerations about heat generation, wear, and corrosion due to some macrostructural bur components (e.g., cutting lips, rake angle, flute, and helix angle) have been widely reported. However, little is known about how the microstructural components of the implant drill surface can influence the implant drill lifetime and clinical performance. Aim. To investigate accurately the surface morphology of surgical bone drill, by means of multivariate and multidimensional statistical analysis, in order to assess roughness parameters able to predict the evolution of tribological phenomena linked to heat development, wear, and corrosion occurring in clinical use. Materials and Methods. The surfaces of implant drills approximately 2.0mm in diameter made by five manufacturers were examined by means of confocal microscope with white light laser interferometry, obtaining several surface roughness parameters. Statistical multivariate analysis based on discriminant analysis showed, for each cut-off, the parameters which discriminate the manufacturers. Results. The microstructural parameters used by discriminant analysis evidenced several differences in terms of drill surface roughness between the five manufacturers. Conclusions. The observed surface roughness difference of drills is able to predict a different durability and clinical performance especially in heat generation and wear onset.

The occurrence of skin metastases is a common event in patients affected by advanced breast cancer, usually associated with systemic disease progression. Here we describe 2 cases of diffuse cutaneous metastases from HER2-overexpressing breast cancer occurring despite a dramatic response in liver and bone, respectively, during treatment with anti-HER2 antibodies Trastuzumab and Pertuzumab. We discuss the reasons for this discrepancy and suggest a possible implication of impaired immune response in the skin. Future research should provide strategies to overcome the induction of immune privilege in the skin in order to avoid discontinuation of effective treatments.

n thermally damaged archaeological bones the quantity, quality, and amplifiability of DNA are very much reliant on both the extent of heating and the environmental conditions of the burial context. In this study we tested the possibility of extracting and amplifying ancient DNA from human bone remains of Herculaneum victims of the 79 AD eruption of Vesuvius using a combination of histochemical and molecular methods. Long bone samples with variable degrees of chromatic and morphological alterations consistent with exposure to temperatures of about 300 °C were taken from four specimens. Using histochemical stains, bone cryostat sections from three individuals revealed DNA within osteocyte lacunae but only for one sample the DNA was suitable for PCR amplification obtained, namely from reactions with the primer pair for X and Y amelogenin (AMEL) loci. The relative sequence differed from the homologous trait of AMELX deposited in GenBank for six bases, probably due to degradation processes following death. Our data are indicative that archaeological bones exposed to high temperatures of about 300 °C should be considered for DNA analysis, given the favorable conditions of corpse burial and skeleton preservation, such as those that occurred for the 79 AD victims in Herculaneum and Pompeii.