Involvement of the Superior Colliculus in SIDS Pathogenesis.

The aim of this study was to investigate the involvement of the mesencephalic superior colliculus (SC) in the pathogenetic mechanism of SIDS, a syndrome frequently ascribed to arousal failure from sleep. We analyzed the brains of 44 infants who died suddenly within the first 7 months of life, among which were 26 infants with SIDS and 18 controls. In-depth neuropathological investigations of serial sections of the midbrain showed the SC layered cytoarchitectural organization already well known in animals, as made up of seven distinct layers, but so far never highlighted in humans, albeit with some differences. In 69% of SIDS cases but never in the controls, we observed alterations of the laminar arrangement of the SC deep layers (precisely, an increased number of polygonal cells invading the superficial layers and an increased presence of intensely stained myelinated fibers). Since it has been demonstrated in experimental studies that the deep layers of the SC exert motor control including that of the head, their developmental disorder could lead to the failure of newborns who are in a prone position to resume regular breathing by moving their heads in the sleep-arousal phase. The SC anomalies highlighted here represent a new step in understanding the pathogenetic process that leads to SIDS.

The Histogenetic Model of Melanoma in the Modern Era of Personalized Medicine.

Malignant melanoma (M) can be defined, quite simply, as a malignant neoplasm derived from melanocytes; however, there is great histological and, consequently, clinical variability from case to case (1). In order to try to overcome this intrinsic difficulty, various classification systems have been proposed over the years; as part of this effort, the World Health Organization (WHO) introduced its famous classification about half a century ago (2). Currently, the International Classification of Diseases for Oncology (ICD-O), provided by the WHO International Agency for Research on Cancer (IARC), distinguishes the in situ forms from invasive ones, recognizing four main morphological subtypes: nodular M, superficial spreading M, lentigo maligna M, and acral lentiginous M (3). The ICD-O classification includes further morphological codes, such as: balloon cell M, regressing M, amelanotic M, M in junctional nevus, M in precancerous melanosis, desmoplastic M, neurotropic M, mucosal lentiginous M, M in giant pigmented nevus / congenital melanocytic nevus, mixed epithelioid and spindle cell M, epithelioid cell M, spindle cell M (not otherwise specified), spindle cell melanoma (type A), spindle cell M (type B), and malignant blue nevus (3). Alongside a strictly morphological classification, a histogenetic model, based on the concept of tumor progression, has been regaining ground (4,5). In fact, at the onset, M is characterized by a non-tumorigenic radial growth phase (RGP), inside the epidermis (intraepidermal) or within the papillary dermis (microinvasive), which is devoid of metastatic potential and which may be followed, early or late, by a tumorigenic vertical growth phase (VGP), with deeper extension in the dermis or beyond, nodular confluence, mitotic activity, and metastatic capacity (Table 1). The unique exception to this is nodular M, in which either RGP is rapidly overrun by VGP or the tumor arises directly from dermal melanocytes (6). Today, Breslow depth remains the single most important prognostic factor for clinically localized primary M: it allows us to distinguish M as ultra-thin (≤0.5 mm), thin (≤1 mm), thick (>1 mm), or ultra-thick (>6 mm) (7-10). The systematic application of the histogenetic model to Breslow depth allows us to explain the oft-debated question why some thin M behave aggressively: because they possess an early tumorigenic VGP inside them (11). Moreover, any diagnostic report should be also accompanied by further well-known microstaging attributes, such as Clark level, mitotic count, lymphovascular invasion, perineural infiltration, ulceration, satellitosis, tumor infiltrating lymphocytes, and, if available, sentinel lymph node status (12,13). In conclusion, we believe that a renewed histogenetic approach to M diagnosis deserves wide scientific dissemination in order to achieve better clinical management of individual cases in the era of personalized medicine.

Sudden intrauterine unexplained death: time to adopt uniform postmortem investigative guidelines?

BACKGROUND: Worldwide approximately 2.6 million are stillborn, mostly occurring in developing countries. In the great part these deaths are inexplicable. The evenness and standardisation of the diagnostic criteria are prerequisites to understand their pathogenesis. The core goal of this article is to propose new evidence based investigative post-mortem guidelines that should be adopted in all the Institutions especially when a fetal death, after a routine autopsy procedure, is diagnosed as "unexplained". The proposed protocol is mainly focused on the anatomopathological examination of the autonomic nervous system and in particular of the brainstem where the main centers that control vital functions are located. METHODS: Updated investigative guidelines for the examination of unexplained stillbirths, prevalently focused on the histological examination of the brainstem, where the main centers that are involved in monitoring the vital functions are located, are here presented. A section of this protocol concerns the Immunohistochemical evaluation of specific functional markers such as the neuronal nuclear antigen, nicotinic acetylcholine receptors, serotonin, orexin, apoptosis and gliosis. The important role of risk factors, having regard in particular to maternal smoking and air pollution is also contemplated in these guidelines. RESULTS: Specific morphological and/or functional alterations of vital brainstem structures have been found with high incidence in over 100 cases of unexplained fetal death sent to the "Lino Rossi Research Center" of the Milan University according to the Italian law. These alterations were rarely detected in a group of control cases. CONCLUSIONS: We hope this protocol can be adopted in all the Institutions notably for the examination of unexplained fetal deaths, in order to make uniform investigations. This will lead to identify a plausible explanation of the pathogenetic mechanism behind the unexplained fetal deaths and to design preventive strategies to decrease the incidence of these very distressing events for both parents and clinicians. TRIAL REGISTRATION: not applicable for this study.

Neuropathology of Early Sudden Infant Death Syndrome-Hypoplasia of the Pontine Kolliker-Fuse Nucleus: A Possible Marker of Unexpected Collapse during Skin-to-Skin Care.

OBJECTIVE: To find a possible pathogenetic mechanism of the early sudden infant death occurring in newborns during the skin-to-skin care (SSC), through the examination of neuronal centers regulating the vital activities. STUDY DESIGN: This is an in-depth examination of the brain stem in 22 healthy term newborns, suddenly died in the first hour of life without the identification of a cause at autopsy (early sudden infant death syndrome [eSIDS]), 12 of them concomitantly with SSC, and 10 with age-matched controls died of known pathology. RESULTS: Developmental alterations of neuronal structures of the brain stem were highlighted in 19 of the 22 eSIDS, but not in control. The hypoplasia of the pontine Kölliker-Fuse nucleus (KFN), an important respiratory center, was diagnosed at the histological examination, validated by morphometric quantifications, in 11 of the 12 eSIDS while they were placed on the mother's chest and in 2 of the 10 SSC unrelated neonatal deaths. CONCLUSION: The delayed development of the KFN could represent a specific finding of eSIDS occurring during SSC. Therefore, it is necessary to point out that the SSC represents a further risk factor that must be added to others already known for sudden infant death syndrome. Then this practice needs appropriate monitoring strategies of the infant's conditions.

In Vivo Uptake of Rare Earth Metals by Triple-Negative Breast Cancer Cells.

Rare earth metals (REM) are a group of 17 chemical elements in the periodic table, namely scandium (Sc), yttrium (Y) and the lanthanides. In relation to atomic volume and geological behavior, the lanthanides are further subdivided into light, medium and heavy REM. They find many applications in the technological field; however, their impact on the human health is still conflicting and, for many aspects, unknown. During a research program carried on 113 cases of female breast cancer, immunohistochemically categorized in Her2-positive (29 cases), Her2-negative (57 cases) and triple negative (27 cases), aimed to evaluate the role of environmental particulate in carcinogenesis by elemental microanalysis, for the first time in literature we have detected a REM uptake, in detail europium (Eu), dysprosium (Dy) and praseodymium (Pr), inside the neoplastic cells belonging to a single triple negative breast cancer. Curiously, the woman affected by this form of malignancy had worked in the ceramic industry, a well-known source of REM, during her life, and she was the one and only patient of our series to be dedicated to this activity. The medical repercussions of our findings are here discussed: in fact, a REM detection in only 1 of 113 examined cases seems to exclude active roles in breast carcinogenesis and discloses new possibilities for therapeutic developments in triple negative breast cancer.

Pathobiological expression of the brain-derived neurotrophic factor (BDNF) in cerebellar cortex of sudden fetal and infant death victims.

Brain-derived neurotrophic factor (BDNF), a neurotrophin of the central nervous system, is able to regulate neuronal differentiation and modulate synaptic plasticity, being particularly involved in the development of the cerebellar cortical structure. The main aim of this study was to delineate, by immunohistochemistry, the BDNF expression in human cerebellar cortex of victims of fetal and infant death. The study was performed on a total of 45 cases, aged between 25 gestational weeks and 6 postnatal months, including 29 victims of sudden fetal and infant death and 16 age-matched subjects who died of known causes (Controls). We observed, in sudden death groups compared with Controls, a significantly higher incidence of defective BDNF expression in granule layers of the cerebellar cortex, which was particularly evident in the posterior lobule, a region that participates in respiratory control. These results were related to maternal smoking, allowing to speculate that nicotine, in addition to the well-known damages, can exert adverse effects during cerebellar cortex development, in particular in hindering the BDNF expression in the posterior lobule. This implies modifications of synaptic transmission in the respiratory circuits, with obvious deleterious consequences on survival.

Sudden unexpected postnatal collapse at 20 hours from birth during skin-to-skin care related to brainstem developmental alterations - a case report.

This report describes a case of sudden collapse of a 20-hour-old newborn, while he was placed close to their mother according to skin-to-skin care, attributed to developmental alterations of brainstem nuclei involved in regulation of the vital functions. The infant, after a normal pregnancy, appeared well developed at birth, with no evidence of malformations or trauma, but showing severe asphyxia. The routine autopsy did not reveal a possible cause of death. Only the in-depth anatomopathological examination of the autonomic nervous system, according to the protocol developed by the "Lino Rossi" Research Center of Milan University, provided an explanation of the pathogenetic mechanism of this early death. The sudden death, a few hours after birth, was the unavoidable outcome of a complex of abnormalities of brainstem nuclei, particularly of the Kölliker-Fuse nucleus, an essential structure for eupneic breathing at birth, exacerbated by the prone position implied by the skin-to-skin contact.

Prognostic Predictors of Thin Melanoma in Clinico-Pathological Practice.

The latest reviews on thin melanoma (TM) continue to consider it a melanoma within 1 mm in thickness, but no consensus exists as to which patients with TM are at risk for lymph node metastases (1). Numerous studies have evaluated the impact of various predictors (Breslow thickness, Clark level, ulceration, regression, vascular invasion, mitotic activity, location, sex) for nodal disease in melanoma, but the conclusions have not been homogenous (2,3). For this reason, we read the paper by Homolak et al. with great interest, where the authors examine the sentinel lymph node biopsies (SLNB) of 184 patients affected by melanoma of thickness less than 1.5 mm, defined as thin (4). SLNB was positive in 22 patients (12%), and 30 patients (7.65%) developed metastatic disease. The group of thinnest tumors (<0.50 mm) had the highest proportion of positive nodes (33%); the group of thickest tumors (1.26-1.50 mm) had the highest proportion of patients with metastatic disease (23%). The authors divided TM into 5 groups: 1) <0.50 mm (15 patients, 5 with positive SLNB); 2) 0.50-0.75 mm (18 patients, 3 with positive SLNB); 3) 0.76-1.00 mm (67 patients, 7 with positive SLNB); 4) 1.01-1.25 mm (45 patients, 4 with positive SLNB); 5) 1.26-1.50 mm (36 patients, 3 with positive SLNB). The current staging system of the American Joint Committee on Cancer (AJCC) uses Breslow thickness as the primary attribute, and up to 1 mm thick melanoma is defined as 'thin' because it shows a good prognosis after surgical excision, with a 10-year survival rate of 85-90% in case of a tumor-free margin of at least 1 cm (5). Based on our experience, this limit should be maintained at 1 mm because TM includes four main histological subtypes, which reflect specific biological attitudes: the intra-epidermal (in situ) radial growth phase (RGP), the non-tumorigenic micro-invasive radial growth phase without regression, the micro-invasive radial growth phase with regression (>75%) of uncertain tumorigenic potential, and the tumorigenic early (≤1 mm) invasive vertical growth phase (VGP) (6-10). This proposed sub-typing fits better with the AJCC staging system, as elucidated below and in Table 1: intra-epidermal radial growth phase (pTis), micro-invasive radial growth phase without regression (pT1), micro-invasive radial growth phase with regression (pT1), early invasive vertical growth phase (pT1), invasive vertical growth phase >1 mm, ≤2 mm (pT2), invasive vertical growth phase >2 mm, ≤4 mm (pT3), invasive vertical growth phase >4 mm (pT4). The in situ RGP and micro-invasive RGP without regression are biologically indolent if completely removed, and SLNB is not necessary in these cases (6). In micro-invasive RGP with regression, performing SLNB is prudent, in particular if accompanied by high mitotic rates, while it is mandatory in early invasive VGP (7). Therefore, the prognostic predictors of nodal and distant metastases require further research in the four above-mentioned histological subtypes of thin melanoma.

Nicotinic Receptor Abnormalities in the Cerebellar Cortex of Sudden Unexplained Fetal and Infant Death Victims-Possible Correlation With Maternal Smoking.

Nicotinic acetylcholine receptors (nAChRs) are cationic channels of the neuronal cell membrane, differentially expressed in the central nervous system which, when activated by endogenous acetylcholine or exogenous nicotine, are able to enhance cholinergic transmission. The aim of this study was to investigate in human perinatal age the immunohistochemical expression of the α7-nAChR subtype, given its involvement in neuronal differentiation and its significant vulnerability to the toxic effects of nicotine. Thirty fetuses (with a gestational age between 25 and 40 weeks) and 35 infants (1-6 months old), suddenly died of known (controls) and unknown causes (unexplained deaths), with smoking and nonsmoking mothers, were included in this study. A negative or low immunoexpression of α7-nAChRs, indicative of their inactivation, was observed in the granular layers of the cerebellar cortex in 66% of the sudden unexplained perinatal deaths and 11% of the controls. A high correlation was also observed between these findings and maternal smoking. Apart from the well-known adverse effects of nicotine exposure during pregnancy, it may also cause significant alterations in cerebellar cholinergic transmission in areas of the brain involved in vital functions. These events may give us insights into the pathogenetic mechanisms leading to sudden unexplained fetal and infant death.

Neuropathological protocol for the study of unexplained stillbirth.

An updated neuropathological protocol for the examination of the nervous system in case of unexplained stillbirth has been elaborated and presented in this review. It is focused on the examination of the nervous centers located in the brainstem, which are involved in monitoring the vital functions. Only through a deep analysis of the brainstem it is possible to highlight developmental alterations of these essential centers, and then provide a plausible explanation of the pathogenetic mechanism behind the death. The guidelines, drawn up on the basis of numerous researches performed by the authors, include a histopathological protocol, with an indication of standardized samples, and an immunohistochemical protocol for the study of biological markers, frequently involved in these deaths. The main risk factors that can be related to the neuronal alterations are also reported, together with the indications for the toxicological examination, which should be possibly applied. The authors hope that this protocol will be soon adopted in all the institutions where a fetal death, after a routine autopsy procedure, is diagnosed as "unexplained", in order to make standardized investigations on stillbirth. Nowadays, preventive strategies to decrease the incidence of these very distressing events for both parents and clinicians are necessary. .