Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities.

BACKGROUND: Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC. MATERIALS AND METHODS: Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20 815 genes. RESULTS: All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern. CONCLUSIONS: These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE).

Clinical characterization of status epilepticus in childhood: a retrospective study in 124 patients.

PURPOSE: The aim of this study is to describe demographic data, semiology and etiology in a pediatric population with status epilepticus (SE) and refractory SE (RSE). METHOD: We retrospectively reviewed patients with the following inclusion criteria: i) age between two months and eighteen years; ii) SE diagnosis; iii) admission from January 2001 to December 2016; iv) available clinical data. RESULTS: We enrolled 124 patients. Mean and median age was 4.6 ± 4.2 years and 3.3 [1.2-7.5] years respectively. SE had a "de novo" onset in 66.9%. Focal convulsive-SE was the most common semiology (50.8%) whilst generalised (32.3%) and nonconvulsive-SE (NCSE) (16.9%) were less represented. Some etiologies showed a different age distribution: febrile in youngest age (p = 0.002, phi 0.3) and idiopathic-cryptogenic in older children (p = 0.016, phi 0.2). A statistical significance correlation was detected between semiology and etiology (p < 0.001, Cramer's V 0.4), chemotherapy and NCSE (n = 6/21 vs 3/103, p < 0.001) as well as PRES and NCSE (n = 7/21 vs 5/103, p < 0.001). Only 17.7% had a RSE. No correlation was found in demographic and clinical data, but NCSE, acute and idiopathic-cryptogenic etiologies were more frequently associated to RSE. Encephalitis was the most common diagnosis in acute etiologies whereas unknown epilepsy in idiopathic-cryptogenic group. CONCLUSION: Most of our findings were previously described however we found a significant role of non-antiepileptic treatments (chemotherapy-dialysis) and comorbidity (PRES) determining acute etiology and NCSE. Acute (mostly encephalitis), idiopathic-cryptogenic (mainly unknown-epilepsy) and NCSE were frequently detected in RSE. In the above mentioned conditions a high level of suspicion was recommended.

Prevalence of sexually transmitted infections and enteric protozoa among homosexual men in western Sicily (south Italy).

INTRODUCTION: In recent years an increase in the number of sexually transmitted infections (STIs) in men who have sex with men (MSM) has been reported in different industrialised countries. Because few epidemiological data on the STls/MSM population in Sicily are available, a survey was conducted to assess the prevalence of STls/enteric protozoa and risky sexual behaviours among MSM in western Sicily. METHODS: In 2010, 74 MSM with median age of 30 years old, were recruited via networks. All participants to the study were interviewed by anonymous self-administered questionnaire in order to collect social/demographic information, clinic data and STI-related risky sexual behaviours. After completing the questionnaire, blood samples were collected to determine HIV, HCV, HHV8 and Treponema pallidum antibodies; presence of Giardia duodenalis and Cryptosporidium parvum was also investigated in faecal samples by immunofluorescence assay. RESULTS: HIV, HHV8, T. pallidum and Giardia prevalence were 8.1%, 16.2%, 21.6% and 16.4% respectively; all patients were negative for HCV and Cryptosporidium infections. The median values of sexual anal intercourse and oral sex per week were 2 and 1, respectively. 7% of participants always had unprotected anal sex, 50.7% sometimes used condom during sexual anal intercourse and 42.3% always had protected anal sex. All MSM-HIV+ and 7 (43.7%) syphilis seropositives were unaware of their own infection. DISCUSSION: MSM in western Sicily are a high risk group for important STIs. It seems necessary that continuous interventions for preventing HIV/AIDS and other STls and for improving the level of knowledge of symptoms are needed.

Medial temporal N-acetyl-aspartate in pediatric major depression.

The medial temporal cortex (MTC) has been implicated in the pathogenesis of pediatric major depressive disorder (MDD). Eleven MDD case-control pairs underwent proton magnetic resonance spectroscopic imaging. N-acetyl-aspartate was lower in the left MTC (27%) in MDD patients versus controls. Lower N-acetyl-aspartate concentrations in MDD patients may reflect reduced neuronal viability.

Gray matter structural alterations in psychotropic drug-naive pediatric obsessive-compulsive disorder: an optimized voxel-based morphometry study.

OBJECTIVE: Although several magnetic resonance imaging (MRI) studies have been conducted in adults with obsessive-compulsive disorder (OCD), few studies have used voxel-based morphometry to examine brain structure, especially in psychotropic drug-naive pediatric patients. METHOD: MRI examinations of 37 psychotropic drug-naive pediatric OCD patients and 26 age- and sex-matched healthy volunteers were acquired on a 1.5 T MRI system, normalized to a customized template, and segmented with optimized voxel-based morphometry. RESULTS: Pediatric OCD patients had significantly more gray matter in regions predicted to differ a priori between groups, including the right and left putamen and orbital frontal cortex. Among patients, more gray matter in the left putamen and right lateral orbital frontal cortex correlated significantly with greater OCD symptom severity, but not with anxiety or depression. Manual region-of-interest measurements confirmed more gray matter in the orbital frontal cortex and putamen in patients compared to healthy volunteers. More anterior cingulate gray matter was evident among patients compared to healthy volunteers with regional volumetry but not with voxel-based morphometry. Regions of significantly less gray matter in OCD were confined to the occipital cortex and were not predicted a priori. CONCLUSIONS: Our results suggest that OCD is characterized by more gray matter in brain regions comprising cortical-striatal-thalamic-cortical circuits. These findings are consistent with functional neuroimaging studies reporting hypermetabolism and increased regional cerebral blood flow in striatal, anterior cingulate, and orbital frontal regions among OCD patients while in a resting state.

Amygdala and hippocampal volumes in familial early onset major depressive disorder.

BACKGROUND: Abnormalities in the amygdala and hippocampus have been implicated in the pathogenesis of major depressive disorder (MDD). To our knowledge, no prior study has examined amygdala-hippocampus anatomy in pediatric patients with familial MDD (at least one first degree relative with MDD). METHODS: Thirty-two psychotropic-naive patients with familial MDD, aged 8-21 years (12 males and 20 females), and 35 group-matched healthy participants (13 males and 22 females) underwent volumetric magnetic resonance imaging in order to evaluate hippocampal and amygdala volumes. RESULTS: Patients with familial MDD had significantly smaller left hippocampal (p = .007, effect size [d] = .44) and right hippocampal volumes (p = .025, d = .33) than controls. No differences were noted in amygdala volumes between groups (right: p > .05, left: p > .05). No correlations between hippocampal or amygdala volumes and demographic or clinical variables were noted. CONCLUSIONS: Reduced hippocampal volume may be suggestive of a risk factor for developing MDD.

Development and sexual dimorphism of the pituitary gland.

The pituitary gland plays a central role in sexual development and brain function. Therefore, we examined the effect of age and gender on pituitary volume in a large sample of healthy children and adults. Volumetric magnetic resonance imaging (MRI) was conducted in one hundred and fifty four (77 males and 77 females) healthy participants. Males were between the ages of 7 to 35 years (16.91+/-5.89 years) and females were 7 to 35 years of age (16.75+/-5.75 years). Subjects were divided into subgroups of age (7 to 9, 10 to 13, 14 to 17, 18 to 21, 22 and older) and sex (male/female). Pituitary gland volume differed between sexes when comparing the age groups (F=3.55, df=2, 143, p=0.03). Females demonstrated larger pituitary glands than males in the age 14 to 17 year old groups (p=0.04). Young (19 years and under) and old (20 years and older) females demonstrated a correlation between pituitary volume and age. Males did not show this relationship. These findings provide additional evidence for gender differences in the normative anatomy of the pituitary and may have relevance for the study of various childhood onset neuropsychiatric disorders in which pituitary dysfunction has been implicated.

Pituitary volume in treatment-naïve pediatric major depressive disorder.

BACKGROUND: Prior pilot investigation identified a larger pituitary gland volume (PGV) in pediatric patients with major depressive disorder (MDD) compared with healthy pediatric control subjects that was most prominent in boys with MDD. In this independent sample, we focus on gender differences in pituitary volume in a larger sample of pediatric patients with MDD. METHODS: Volumetric magnetic resonance imaging studies were conducted in 35 psychotropic drug-naïve children (15 boys, 20 girls), ages 8-17 years, and 35 case-matched healthy control subjects. RESULTS: The MDD boys had larger PGV (19%) compared with male control subjects. No significant diagnostic group differences in pituitary volume were observed in girls. Healthy boys had significantly smaller PGV (27%) than healthy girls, whereas MDD boys did not differ from girls with MDD. Nonfamilial (without a family history of mood disorder) boys with MDD had significantly larger PGV (35%) than male healthy control subjects and tended to have a larger PGV (27%) than familial (at least one first-degree relative with MDD) boys with MDD. Boys with familial MDD did not differ from control subjects. CONCLUSIONS: These findings provide new evidence of increased pituitary volume in psychotropic-naïve pediatric patients with MDD that seems to be more prominent in male patients with nonfamilial MDD.

Analogous IgG subclass response to pertussis toxin in vaccinated children, healthy or affected by whooping cough.

The study of antigen specific IgG subclass distribution during disease, or during any other natural or artificial immunisation, can provide useful information on the kind of the immune response and the expected levels of protection. This is particularly true for diseases, such as pertussis in which the mechanisms underlying specific defence are still not completely understood. An investigation was therefore performed to evaluate the IgG subclass response to pertussis toxin (PT) in sera from 89 healthy vaccinated children and 131 vaccinated or unvaccinated children convalescent after a confirmed B. pertussis symptomatic infection. Antibody titres were expressed in arbitrary ELISA units/ml, and statistical analyses were performed. In unvaccinated convalescent children IgG1 and IgG3 were prevalent whereas in children immunised with two different acellular pertussis (aP) vaccines, both healthy and convalescent, IgG1, IgG2 and IgG4 antibodies were mainly produced. Maintenance of the same anti-PT antibody response pattern in healthy acellular pertussis vaccine recipients and in vaccinated children who later acquire the disease is an interesting result indicative of the priming effect induced by these vaccines in the direction of a relatively higher Th2 cell-polarisation of the immune response.

Immunity to tetanus in the 3-20 year age group in Italy.

In Italy, systematic mandatory tetanus immunization of children started in 1968. In 1989, immunity against tetanus was assessed in a random sample of 758 healthy subjects aged 3-20 y, from four Italian cities. There were 257 subjects 3-5 y old all residing in Southern Italy and 501 subjects 11-20 y old from both the South and North. The overall prevalence of non-immune subjects was 19.1%, without difference by sex. The rates of subjects lacking protective antibody titres was 25.3% in children 3-5 y old (all coming from South and the islands), 11.5% in those 11 y old, and 18.9% in the 18-20 y age-group, respectively. Subjects 11-20 y old residing in the South and the islands were more likely to be non-immune that those residing in the North (20.2% vs 6.0%; P < 0.01). Socio-demographic indicators such as lowest paternal education and largest family size were both unassociated with lack of protective antibodies. These findings indicate that an high rate of children in South of Italy do not have protective antibody levels, probably as consequence of lack of compliance with the vaccination programme. More efforts should be addressed to decrease geographical inequalities in the delivery of health care.

Serological responses to infection with B. pertussis.

The results of serological assays performed during the Italian controlled efficacy trial of two acellular vaccines and one whole-cell vaccine against pertussis are described and discussed. We examined 312 episodes of suspected pertussis disease confirmed by B. pertussis isolation, and 2862 episodes without any evidence of B. pertussis or B. parapertussis infection. Higher mean log ELISA titres for IgG to pertussis toxin (PT) were found in the acute-phase serum specimens of those children vaccinated with the acellular pertussis vaccines and particularly in the SmithKline Beecham DTaP vaccine group. These apparently anamnestic responses were responsible for the observed differences in ELISA diagnostic sensitivity exhibited by IgG to PT and by IgG to filamentous haemagglutinin (FHA). We observed minimal IgA responses to PT but vigorous IgA responses to FHA in the convalescent-phase serum specimens for the acellular pertussis vaccine groups, which contributed to the sensitivity of the serological series of assays for diagnostic purposes.

Prevalence of cytomegalovirus seropositivity in an urban childhood population in Cameroon.

In 1989, the prevalence of antibody to cytomegalovirus (CMV) was determined by the ELISA method in serum samples from 198 apparently healthy children 4-14 years old in Kumba City (Cameroon). Children were randomly recruited from six primary schools located in different districts of the city. The overall prevalence was 94.0%, increasing from 88.5% in 4-6 years old to 98% in subjects 11-14 years old. A slight male predominance was observed (96.2% versus 92.4%), which was not statistically significant. Family size and father's occupation were not associated with anti-CMV prevalence. These findings demonstrate a virtually total exposure to CMV infection by late childhood in Cameroon. However, the undesirable consequences of congenitally acquired CMV infection are rare, because nearly 100% of the women are seropositive by the time they reach childbearing age.

Seroepidemiology of pertussis in Italy.

During 1988 and 1989 the prevalence of serum IgG antibodies to pertussis toxin in a sample of 3,875 unvaccinated, apparently healthy persons between the ages of 1 year to 19 years was estimated by enzyme-linked immunosorbent assay. The participants were recruited by means of systematic cluster sampling from public and private schools in five geographic areas of Italy. The overall prevalence of IgG antibodies was 80.8%, with a steady increase from 33.5% among 1- to 3-year-old children to 95% among 17- to 19-year-old individuals. The prevalence of natural immunity was 50% and 75% at the ages of 4 and 6 years, respectively. No gender-related difference in immunity was observed. For children greater than 10 years of age, the seroprevalence of pertussis antibodies was significantly higher in northern regions than in southern regions until the age of 17-19 years, when the pattern reversed. There was no association of a child's immune status with the father's number of years of schooling or with family size. For children aged 1-3 years, serologic studies showed that the history of pertussis reported by parents in questionnaires was highly specific (97.6%) in predicting antibody status, with positive and negative predictive values of 90.5% and 79.2%, respectively. However, 20.8% of children had antibodies to pertussis toxin even though they had no history of whooping cough.

Immunity to diphtheria in the 3-19 year age group in Italy.

In Italy, immunization with diphtheria toxoid has been compulsory for all newborns since 1939. The last two clinical cases of diphtheria were reported in 1987. During the period 1987-1989, immunity against diphtheria was assessed by neutralization test in a random sample of 1740 healthy subjects 3-19 years old, from five geographical areas of Italy. Of the total population, 76.5% showed antibody levels considered to be protective (greater than or equal to 0.1 IU ml-1), 17.2% had a relative degree of protection (0.01-0.09 IU ml-1), and 6.3% lacked immunity (less than 0.01 IU ml-1). The percentage of unprotected subjects increased from 6.1% in the age group of 3-5 years to 11.4% in the age group of 18-19 years (p less than 0.01). A smaller proportion of males (5.3%) than of females (7.2%) was unprotected, but this difference was not statistically significant. Subjects residing in the south and the islands were more likely to be unprotected than those residing in the north (7.4 versus 4.1%, p less than 0.01). No association was found between lack of protective antibodies and family size (odds ratio 1.35, confidence interval 95% = 0.77-2.36). However, paternal education of less than 12 years was associated with a higher prevalence of non-responders. In order to maintain a high degree of immunity in the adult population, a routine adult booster dose of diphtheria toxoid is advisable.

Seroepidemiology of pertussis infection in an urban childhood population in Cameroon.

In 1989, the prevalence of IgG antibodies to pertussis toxin (PT) in a sample of 367 unvaccinated apparently healthy children 5-14 years old was estimated by ELISA in Kumba City (Cameroon). Children were recruited using a systematic random sampling from six primary schools located in different districts of the city. The sample was representative of the various socioeconomic classes. The overall prevalence was 75%; it increased from 62% in 5 year old children to 81% in children 12-14 years old (P less than 0.01). IgG antibody prevalence was positively related to the family size. Children belonging to households of nine or more members had a 2.2-fold risk (C.I. 95 per cent = 1.1-4.6) of previous exposure to B. pertussis infection. No association was found with the father's occupation (O.R. = 1). These findings demonstrate a great impact of pertussis infection in Cameroon, with a nearly total exposure by late childhood.

Prevalence of pertussis IgG antibodies in children in Palermo, Italy.

The prevalence of IgG antibodies to Bordetella pertussis in a sample of 615 1-12-year-old unvaccinated children in Palermo was estimated by ELISA. The overall prevalence was 56%; it increased from 24% in one to three-year-old children to 67% in 11-12-year-old children (p less than 0.01). IgG antibody prevalence was not associated with the father's years of schooling (OR 1), nor with the family size (OR 1.3; C.I. 95% = 0.8-2.2). For children aged one the three years, serological results showed that the history of pertussis reported by parents in questionnaires gave high specificity (93.2%) and negative predictive value (85.4%). Our seroepidemiological study evidences a great exposure of children to B. pertussis in Palermo, with a high proportion of infections occurring after three years of age.