Hierarchical convolutional models for automatic pneu-monia diagnosis based on X-ray images: new strategies in public health.

Conclusions: Despite some limits, our findings support the notion that deep learning methods can be used to simplify the diagnostic process and improve disease management. Background: In order to help physicians and radiologists in diagnosing pneumonia, deep learning and other artificial intelligence methods have been described in several researches to solve this task. The main objective of the present study is to build a stacked hierarchical model by combining several models in order to increase the procedure accuracy. Methods: Firstly, the best convolutional network in terms of accuracy were evaluated and described. Later, a stacked hierarchical model was built by using the most relevant features extracted by the selected two models. Finally, over the stacked model with the best accuracy, a hierarchically dependent second stage model for inner-classification was built in order to detect both inflammation of the pulmonary alveolar space (lobar pneumonia) and interstitial tissue involvement (interstitial pneumonia). Results: The study shows how the adopted staked model lead to a higher accuracy. Having a high accuracy on pneumonia detection and classification can be a paramount asset to treat patients in real health-care environments.

Severe Acute Respiratory Infections (SARI) surveillance in over-65-years-old patients: the experience of a University hospital (seasons 2017-2018 and 2018-2019).

Background: Influenza is a relevant public health problem, also due to the risk of complications. The most effective measure to prevent influenza is vaccination; therefore, at present, there is consensus among European countries, regarding the need for routine seasonal influenza vaccination of elderly and individuals at increased risk of severe influenza. At the same time, influenza surveillance is necessary to understand the viruses circulating and effectiveness of vaccination strategies. The present study reports the results of two seasons influenza surveillance (2017/2018 and 2018/2019) conduced in an University Hospital in Rome among hospitalized patients aged ≥65 years. Study design: A prospective cohort study. Methods: The study consisted of systematic daily screening of all admissions among patients aged ≥65 years meeting a syndromic SARI case definition during two consecutive influenza seasons: 2017/2018 and 2018/2019. Characteristics of patients and their risk factors were collected by a standardized questionnaire and nose-pharyngeal swabs were performed to each patient. Influenza vaccine effectiveness (IVE), rates of vaccinated subjects and case fatality rate were also evaluated. Results: Influenza was laboratory confirmed in 11 (9.9%) of the 111 and 11 (9.6%) of the 115 enrolled patients in seasons 2017/18 and 2018/19, respectively. Adjusted IVE against all influenza type, calculated for each season, was 88.5% (95% CI: 38.9 to 97.8) and 61.7% (95% CI: -59.9 to 90.9) for 2017/2018 and 2018/2019 seasons, respectively. Our analysis shows a Case Fatality Rate of 2.7% and 4.3% for the 2017/18 and 2018/19 seasons, respectively. Conclusions: The surveillance of SARI conduced in one hospital in Rome confirmed that influenza is an important cause of hospital admissions. Routine monitoring of infectious diseases and related aetiology associated with SARI, also at the local-level, is useful for targeting the right preventive measures.

Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma.

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.

PARP inhibitors enhance replication stress and cause mitotic catastrophe in MYCN-dependent neuroblastoma.

High-risk and MYCN-amplified neuroblastomas are among the most aggressive pediatric tumors. Despite intense multimodality therapies, about 50% of these patients succumb to their disease, making the search for effective therapies an absolute priority. Due to the important functions of poly (ADP-ribose) polymerases, PARP inhibitors have entered the clinical settings for cancer treatment and are being exploited in a variety of preclinical studies and clinical trials. PARP inhibitors based combination schemes have also been tested in neuroblastoma preclinical models with encouraging results. However, the expression of PARP enzymes in human neuroblastoma and the biological consequences of their inhibition remained largely unexplored. Here, we show that high PARP1 and PARP2 expression is significantly associated with high-risk neuroblastoma cases and poor survival, highlighting its previously unrecognized prognostic value for human neuroblastoma. In vitro, PARP1 and 2 are abundant in MYCN amplified and MYCN-overexpressing cells. In this context, PARP inhibitors with high 'PARP trapping' potency, such as olaparib or talazoparib, yield DNA damage and cell death preceded by intense signs of replication stress. Notwithstanding the activation of a CHK1-CDC25A replication stress response, PARP-inhibited MYCN amplified and overexpressing cells fail to sustain a prolonged checkpoint and progress through mitosis in the presence of damaged DNA, eventually undergoing mitotic catastrophe. CHK1-targeted inhibition of the replication stress checkpoint exacerbated this phenotype. These data highlight a novel route for cell death induction by PARP inhibitors and support their introduction, together with CHK1 inhibitors, in therapeutic approaches for neuroblastomas with high MYC(N) activity.

Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy.

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors.

Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a ß-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in most differentiated and less aggressive neuroblastic tumors, such as GN and ganglioneuroblastoma, as well as in a subset of NB cases. Gal-3 expression is associated with the INPC histopathological categorization (P<0.001) and Shimada favorable phenotype (P=0.001), but not with other prognostically relevant features. Importantly, Gal-3 expression was associated with a better 5-year overall survival (P=0.003), and with improved cumulative survival in patient subsets at worse prognosis, such as older age at diagnosis, advanced stages or NB histopathological classification. In vitro, Gal-3 expression and nuclear accumulation accompanied retinoic acid-induced cell differentiation in NB cell lines. Forced Gal-3 overexpression increased phenotypic differentiation and substrate adherence, while inhibiting proliferation. Altogether, these findings suggest that Gal-3 is a biologically relevant player for neuroblastic tumors, whose determination by conventional immunohistochemistry might be used for outcome assessment and patient's risk stratification in the clinical setting.

PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress.

The Hedgehog (Hh) signaling regulates tissue development, and its aberrant activation is a leading cause of malignancies, including medulloblastoma (Mb). Hh-dependent tumorigenesis often occurs in synergy with other mechanisms, such as loss of p53, the master regulator of the DNA damage response. To date, little is known about mechanisms connecting DNA-damaging events to morphogen-dependent processes. Here, we show that genotoxic stress triggers a cascade of signals, culminating with inhibition of the activity of Gli1, the final transcriptional effector of Hh signaling. This inhibition is dependent on the p53-mediated elevation of the acetyltransferase p300/CBP-associated factor (PCAF). Notably, we identify PCAF as a novel E3 ubiquitin ligase of Gli1. Indeed PCAF, but not a mutant with a deletion of its ubiquitination domain, represses Hh signaling in response to DNA damage by promoting Gli1 ubiquitination and its proteasome-dependent degradation. Restoring Gli1 levels rescues the growth arrest and apoptosis effect triggered by genotoxic drugs. Consistently, DNA-damaging agents fail to inhibit Gli1 activity in the absence of either p53 or PCAF. Finally, Mb samples from p53-null mice display low levels of PCAF and upregulation of Gli1 in vivo, suggesting PCAF as potential therapeutic target in Hh-dependent tumors. Together, our data define a mechanism of inactivation of a morphogenic signaling in response to genotoxic stress and unveil a p53/PCAF/Gli1 circuitry centered on PCAF that limits Gli1-enhanced mitogenic and prosurvival response.

BRCA1 and BRCA2 genetic testing in Italian breast and/or ovarian cancer families: mutation spectrum and prevalence and analysis of mutation prediction models.

BACKGROUND: Breast cancer is an extremely complex disease, characterized by a progressive multistep process caused by interactions of both genetic and non-genetic factors. A combination of BRCA1 and BRCA2 gene mutations appears responsible for about 20%-30% of the cases with breast cancer familial history. The prevalence of BRCA1/2 pathogenic mutations largely varies within different populations; in particular, the rate of mutations in Italian breast and/or ovarian cancer families is rather controversial and ranges from 8% to 37%. PATIENTS AND METHODS: Of the 152 breast/ovarian cancer families counseled in our centre, 99 were selected for BRCA1/2 mutation screening according to our minimal criteria. The entire coding sequences and each intron/exon boundary of BRCA1/2 genes were screened by direct sequencing (PTT limited to BRCA1 exon 11). For each proband, the a priori probability of carrying a pathogenic BRCA1/2 germline mutation was calculated by means of different mutation prediction models (BRCApro, IC and Myriad Table) in order to evaluate their performances. RESULTS: Our analysis resulted in the identification of 25 and 52 variants in the BRCA1 and BRCA2 genes, respectively. Seventeen of them represent novel variants, including four deleterious truncating mutations in the BRCA2 gene (472insA, E33X, C1630X and IVS6+1G>C). Twenty-seven of the 99 probands harbored BRCA1 (n = 15) and BRCA2 (n = 12) pathogenic germline mutations, indicating an overall detection rate of 27.3% and increasing by more than 15% the spectrum of mutations in the Italian population. Furthermore, we found the lowest detection rate (19.4%) in pure hereditary breast cancer family subset. All of the prediction models showed praises and faults, with the IC software being extremely sensitive but poorly specific, compared to BRCApro. In particular all models accumulated most false-negative prediction in the HBC subset. Interestingly preliminary results of a study addressing the presence of genomic rearrangements in HBC probands with BRCApro or IC prediction scores >/=95%, provided evidence for additional mutations undetectable with our conventional screening for point mutations. CONCLUSIONS: Altogether our results suggest that HBC families, the largest pool in our series, represent an heterogeneous group where the apparently faulty performances of the prediction models might be at least partially explained by the presence of additional kinds of BRCA1/2 alteration (such as genomic rearrangements) or by mutations on different breast cancer related genes.

A case of long surviving metastatic retroperitoneal epithelioid sarcoma in a 20 year old male.

This is the case of a 20 year-old male who came to our observation with a neoplastic lesion of the retroperitoneum. At diagnosis it had already spread to the lung, the liver and to the retroperitoneal para aortic lymph nodes. The patient was treated only with chemotherapy, first 4 cycles of PEI schedules and the second option were 3 cycles of EI schedule. After the first treatment the disease showed the enlargement of a liver lesion, in the VII segment and the vascular component of it was increased. This same lesion, after the EI administration, colliquated and didn't modify its size. Since the end of the therapy the patient has been followed up every 3 months for the first 3 years and every 6 months from the third year onward; he is now at 5 years from the last treatment with a stable disease.

Solitary splenic recurrence of epithelial ovarian cancer: a case report and review.

The metastatic involvement of the spleen in epithelial ovarian cancer is rare and usually reflects late disseminated disease. Isolated parenchymal metastasis in the spleen is an extremely unusual event, in fact in most cases in medical literature, the spleen was involved as part of diffuse peritoneal carcinomatosis. We report a rare case of epithelial ovarian carcinoma, which recurred in the splenic parenchyma 15 years after initial treatment. The patient underwent a splenectomy followed by six cycles of platinum-based poly-chemotherapy. Currently, 8 years after splenectomy, the patient has no evidence of relapsed disease. In the solitary splenic recurrence of epithelial ovarian cancer our case suggests that accurate surgical resection of the spleen, followed by platinum-based chemotherapy, is correlated with a prolonged survival.

Unique pineal gland metastasis of clear cell renal carcinoma: case report and review of the literature.

The metastatic involvement of the pineal gland is an extremely unusual event; it has a 4% incidence in patients with disseminated neoplasias. Most metastatic pineal lesions are asymptomatic. Only in a small number of cases the symptoms produced by metastatic involvement of this organ precede those of the primary tumor or those of another metastatic site. To our knowledge the herein reported case is the first in which the pineal gland was apparently the unique metastatic site of a primitive kidney carcinoma and where the symptoms produced by metastasis in the pineal region were the first sign of the disease.

Stability of personality traits in schizophrenia and schizoaffective disorder: a pilot project.

This study was performed in an effort to begin characterization of personality traits in schizophrenia. Specific concerns included personality profiles relative to normal adults, personality profile stability over time, and trait-state issues. The authors administered the NEO Personality Inventory as well as symptom ratings at two time points to 21 patients. Patients were all stabilized outpatients attending an adult continuing day treatment program and diagnosed with either schizophrenia or schizoaffective disorder. Personality profiles were determined for all patients. Compared with a normal adult sample, this sample's scores on three out of five of the personality domains assessed were not distinguishable from normal adults. Test-retest correlations were highly significant over an average 28.2-week time interval. In general, the presence of positive symptoms did not appear related to NEO-PI stability, while negative symptoms did show a relationship to the stability of personality profiles. These data suggest that personality profiles can be looked at in schizophrenia, that these profiles do appear stable over time, and that negative symptoms have a strong influence on profile stability and appear to be "trait-like."

A fenomenologia no pensamento de K.Jaspers. / Phenomenology in Karl Jasper's thought

A autora apresenta um relato historico da evolucao do pensamento fenomenologico, das origens husserlianas aos desdobramentos imprimidos por Karl Jaspers, cujo centenario de nascimento se comemorou em 1983.Sao revistos os principais conceitos da corrente fenomenologica, e uma enfase especial e dada as inter-relacoes entre a fenomenologia e a psiquiatria. Ressalta-se uma cuidadosa analise da obra de Karl Jaspers publicada apos o advento de sua "Psicopatologia Geral" em 1913, periodo que com frequencia e negligenciado na literatura psiquiatrica

Fenomenologia e psiquiatria. / Phenomenology and psychiatry

A autora pretende mostrar o emprego que Jaspers faz da fenomenologia de Husserl na descricao dos fenomenos psicopatologicos e como e possivel aproximar fenomenologia e psicanalise, abordando autores como Minkow-ski, Merleau-Ponty, Hesnard, De Waelhens e Ricoeur