Prognostic Impact of MCPyV and TIL Subtyping in Merkel Cell Carcinoma: Evidence from a Large European Cohort of 95 Patients.

Merkel cell carcinoma is a rare (∼ 2000 cases/year in the USA) but aggressive neuroendocrine neoplasm of the skin. In 2008, the Merkel cell polyomavirus (MCPyV) was found to be clonally integrated in approximately 80% of Merkel cell carcinomas. The remaining 20% have large numbers of UV-associated mutations. Importantly, both the UV-induced neoantigens in virus-negative Merkel cell carcinoma and the Merkel cell polyomavirus oncogenes that are required for virus-positive tumor growth are highly immunogenic. Indeed, antigen-specific T cells detected in patients are frequently "dysfunctional/exhausted," and the inhibitory ligand PD-L1 is often expressed by Merkel cell carcinoma cells. These data led to point our attention on the quantity and the quality of the immune response in Merkel cell carcinoma. Here, we found CD8+ lymphocytes are the only singly evaluated lymphocyte subclass that strongly influenced overall survival and disease-specific survival in Merkel cell carcinoma. In addition, we highlighted as Merkel cell polyomavirus is a strong prognostic factor and as it prompts a host immune response involving various lymphocyte subclasses (CD3, CD8, FoxP3, and PD-L1 positive) in MCC. For this reason, we proposed a novel eye-based "immunoscore" model, obtained by tumor infiltrating lymphocytes subtyping (CD3, CD8, FoxP3, and PD-L1) that could provide additional prognostic information in Merkel cell carcinoma.

Neuroendocrine neoplasms of the head and neck and olfactory neuroblastoma. Diagnosis and classification.

Neuroendocrine neoplasms (NENs) of the head and neck are a rare group of heterogeneous epithelial neoplastic proliferations arising in virtually all of the different organs of this region, particularly in the nasal cavity, the paranasal sinuses, the nasopharynx, the larynx, the salivary glands, and the middle ear. They encompass a wide spectrum of entities ranging from very indolent neuroendocrine tumors to highly aggressive neuroendocrine carcinomas. They may represent a challenge for radiologists, oncologists, and pathologists and a correct diagnosis is crucial for the management of patients. The nomenclature and classification of cervicocephalic NENs is currently under debate and for this reason a different diagnostic terminology has been used over the years, creating confusions among clinicians and pathologists. Olfactory neuroblastoma is a rare neuroectodermal neoplasm arising in the nasal cavity showing some challenging diagnostic aspects. In this review we give an update of the more relevant criteria for diagnosing head and neck NENs and olfactory neuroblastomas focusing on the critical use of morphological parameters and immunohistochemical staining.

[Neonatal sepsis: new preventive strategies]. / Sepsi neonatali: nuove strategie preventive.

More than one million neonatal deaths every year in the world are attributable to infection. In nurseries, infections occur with a reported incidence of 0.3-3%; in Neonatal Intensive Care Units (NICUs) the reported incidence is 7-24.5%, and up to 40% in newborns with birth weight less than 1000 g or gestational age at birth <28 weeks. Sepsis is the most severe and frequent infection, accounting for 45-55% of all infections. Several practices have been demonstrated to be effective in reducing the incidence of infection in NICUs, including hand hygiene practices, correct management of central venous catheters (CVC), accurate diagnostic strategies and correct use of antimicrobial drugs. Despite the reduction in the incidence of infection after implementation of these practices, nosocomial infections are still a relevant problem, with high mortality and morbidity rates in hospitalized newborns, especially preterm newborns. Searching for new strategies to further reduce the incidence of nosocomial sepsis in NICUs is a priority of clinical research. New and promising strategies for the prevention of nosocomial infection in NICU include: lactoferrin administration, early identification of infants at risk of infection by means of specific markers (e.g. mannose binding lectin), heparin use for the prevention of CVC-related infections, judicious use of antibiotics, and prevention of fungal sepsis with antifungal agents. On the contrary, recent studies demonstrated that the use of specific immunoglobulins directed against different staphylococcal antigens is not effective in preventing neonatal sepsis.

Cerebral and somatic rSO2 in sick preterm infants.

Near infrared spectroscopy (NIRS) measures the regional tissue oxygen saturation (rSO2) of various organs and provides a reflection of the balance between tissue oxygen supply and demand. Oxymetry assessed via NIRS has been proposed as a 'standard of care' and today it is already widely used in the NICU. This approach allows detection of any acute change in cerebral haemodynamics and continuous monitoring of cerebral and somatic oxygenation. This work describes three clinical cases of preterm VLBW infants which showed special points of interest during both cerebral and somatic NIRS monitoring.

Fluconazole use and safety in the nursery.

Fluconazole is a triazole antifungal agent that is widely used in the nursery. It is available in both intravenous and oral formulation, and is active against most of the fungal pathogens that require treatment when retrieved from culture samples in neonatal intensive care units. Although clinical use has been wide for over 15 years, there have been small safety and efficacy studies completed in young infants. Randomised clinical trials assessing effectiveness of this agent in prevention of systemic fungal infections in neonates have been published in the last decade, and one large additional randomised study has been recently completed. Nevertheless, a certain degree of uncertainty still exists regarding the kinetics and appropriate dosing of this agent in premature and term infants, as well as regarding safety. Areas of poignant debate include the feasibility of loading dose strategies, appropriate dosages in the early days of life in the different subgroups of preterm infants, and long-term safety of fluconazole administered in prophylaxis during the first weeks of life in extremely premature infants. This paper reviews the most recent evidence on fluconazole and its role in the NICU settings.

Clinical characteristics and response to prophylactic fluconazole of preterm VLBW neonates with baseline and acquired fungal colonisation in NICU: data from a multicentre RCT.

BACKGROUND: Fungal colonisation by Candida spp. affects a high proportion of VLBW neonates in NICU. However, few data are available on the clinical characteristics of colonisation in preterm infants who are colonised at baseline via vertical transmission, compared to preterms who become colonised during their stay in NICU via horizontal transmission. MATERIAL AND METHODS: We reviewed the database of a multicentre, randomised trial of prophylactic fluconazole in VLBW neonates conducted in 8 Italian NICUs in the years 2004 and 2005 (Manzoni et al., NEJM 2007;356(24):2483-95). Per the protocol, all enrolled infants underwent weekly surveillance cultures from birth till discharge. We investigated the frequency of the two different modalities of Candida colonisation in this population, as well as the clinical and outcome characteristics possibly related to them. RESULTS: Overall, Candida colonisation affected 54 of 336 infants (16.1%). Baseline (i.e., detected <3(rd) day of life) colonisation affected 16 (4.7%), and acquired 38 (11.4%), of the 54 colonised preterms. Infants with baseline colonisation had significantly higher birth weight (1229 ± 28 g vs. 1047 g ± 29, p = 0.01) and gestational age (30.2 wks ± 2.7 vs. 28.5 wks ± 2.6, p = 0.01), and were significantly more likely to limit progression from colonisation to invasive Candida infection when fluconazole prophylaxis was instituted (21.6% vs. 42.7%, p = 0.009). Isolation of C. parapsilosis was significantly more frequent in infants with acquired colonisation. CONCLUSIONS: Infants with baseline and acquired colonisation differ for demographics characteristics and for their response to fluconazole prophylaxis. This information may be useful for targeting more accurate management strategies for these two different groups of colonised preterms in NICU.

Correct choices for correct treatments: key issues in the management of Candida infections in preterm neonates.

Invasive Candida infections (ICI) have a high burden of morbidity and mortality in the neonatal setting. Although the identification of effective prophylactic strategies has recently led to the prevention of many episodes of systemic fungal disease, the identification of effective treatment strategies is still a priority. The correct choice of the most appropriate antifungal drug for treatment of such infections requires specific expertise, as well as careful consideration of a number of variables related both to the characteristics of the patient and to the peculiarities of these infections in neonates. The ideal antifungal drug for preterm neonates should have a good ability to target fungal biofilms, in order to prevent or improve the course of end-organ localisations. It should also be active against fluconazole-resistant species, as well as safe enough to be used with no or limited interference with other neonatal drugs. In this view, the echinocandin class of antifungal agents has recently proven to be a suitable option for treatment. However, further studies are warranted to better establish kinetics and appropriate dosing of these agents in premature and term infants, as well as their ability to improve late outcomes of ICI.