Chest radiography predictor of COVID-19 adverse outcomes. A lesson learnt from the first wave.

AIM: To assess the role of a severity score based on chest radiography (CXR) in predicting the risk of adverse outcomes in coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: Of the patients who presented to L. Sacco Hospital (Milan, Italy) between 21 February and 31 March 2020, patients with a laboratory confirmation of COVID-19 who also underwent a CXR were included in the study. To quantify the extent of lung involvement, each CXR image was given a score (Milan score), ranging from 0 to 24, depending on the presence of reticular pattern and/or ground-glass opacities and/or extensive consolidations in each of the 12 areas in which the lungs were divided. The score was calculated by an expert radiologist, blinded to laboratory tests. The ability of the Milan score to predict hospital admission and mortality, after adjusting for some variables (age; gender; comorbidities; time between symptoms onset and admission), using univariate and multivariate statistical analysis was investigated retrospectively. RESULTS: Among the 554 patients, 115 of which (21%) had a negative CXR, the in-hospital mortality was 16% (90/554). At univariate analysis, age, gender, and comorbidities were significant predictors of mortality and hospital admission. At multivariate analysis, adjusting for age and gender, the Milan score was an independent predictor of mortality and hospitalisation. In particular, patients with a Milan score ≥ 9 had a mortality risk five-times higher than those with a lower score. Other independent predictors of mortality were gender and age. CONCLUSIONS: The CXR Milan score was an independent predictive factor of both in-hospital mortality and hospital admission.

18F-FDG-PET/CT Imaging in Advanced Glottic Cancer: A Tool for Clinical Decision in Comparison with Conventional Imaging.

This study assessed the role of 18F-FDG PET-CT (PET/CT) to detect the cartilage and paraglottic infiltration in advanced glottic cancer comparing the results with those of conventional imaging (CI) (contrast-enhanced computed tomography and/or magnetic resonance). In addition, we assessed the prognostic value of quantitative parameters, measured on baseline PET/CT, in terms of event-free survival (EFS) and overall survival (OS). We retrospectively analyzed 27 patients with glottic squamous cell carcinoma stage III and IVA, treated in our institute between 2010 and 2016, comparing PET/CT, performed for staging and radiotherapy planning, and CI findings. Cohen's K was used to compare concordance between PET/CT and CI. Imaging findings were correlated with endoscopic evaluation and histological reports (gold standard (GS)). All lesions shown by CI were also detected by PET/CT imaging, and in 5 cases, a better definition of local infiltration was achieved with PET/CT than CI (5 CT). Sensitivity, specificity, and accuracy of PET/CT and CT were 95%, 86%, and 93% and 70%, 86%, and 74% for, respectively. MRI showed sensitivity and specificity of 100%. One false-negative (FN) cases and 1 false-positive (FP) case were observed with PET/CT with no difference compared to MRI (10 cases). Six FN cases and 1 FP case were observed with CT. Cohen's K was 0.60 (PET vs. CI) and 0.80 (PET vs. GS). Patients were followed-up for at least 24 months to calculate EFS and OS. 13 local recurrence and 7 deaths were recorded. Among quantitative PET parameters, baseline MTV was the most powerful predictor of outcome. Our data suggest a reliable sensitivity and accuracy of PET/CT in the evaluation of local extension, proving a useful method for initial local staging in addition to the well-established role in lymph-node and distant sites assessment. Furthermore, pretreatment MTV provides better prognostic information than other PET/CT parameters.

Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.

PURPOSE: To evaluate acute and late skin/subcutaneous toxicities and radiation-induced lung fibrosis (RILF) in patients treated with adjuvant radiotherapy (RT) for synchronous bilateral breast cancers (SBBC), after conservative surgery. METHODS/PATIENTS: Twenty-five patients were treated with volumetric-modulated arc therapy (VMAT/RapidArc®) on both breasts, and checked clinically for detecting RT toxicities during and after treatment. A high-resolution computed tomography (HRCT) was performed, for detecting RILF during follow-up. RESULTS: We registered acute Grade-1 skin toxicity in 18 patients (72%), while six patients (24%) experienced Grade-2 toxicity. No breath symptoms were reported during and after RT. Late Grade-1 subcutaneous toxicity and late Grade-2 skin toxicity were registered in four patients (16%) and one patient (4%), respectively, at a mean follow-up of 36 months. Grade-1 RILF was detected in six patients (30%). The median volume of fibrosis area was 6.5 cc (range 1.3-21.5 cc). The partial volumes receiving a specified dose (V20, V30, V40, and V50) in patients who developed lung fibrosis were significantly bigger than who did not (p < 0.01). We showed that the mean volume of the tumour boost of patients who developed fibrosis (77.7 cc) was not significantly different from the other patients (90.8 cc) (p = 0.5). CONCLUSION: The clinical impact of this technique is favourable, and this is the first clinical study showing RILF by HRCT in a setting of SBBC. Further study with larger accrual is mandatory.

Dioxin-like Compounds in Lake Fish Species: Evaluation by DR-CALUX Bioassay.

Fish consumption is the principal source of intake of organochlorinated compounds in humans. Compared with other types of foods of animal origin, fish contain the highest levels of polychlorinated biphenyls (PCBs), polychlorinated dibenzo- p-dioxins, and polychlorinated dibenzofurans, all of which are classified as highly toxic organochlorine compounds. Currently, lakes and fish farms in northern Italy are not regularly monitored for PCBs and dioxins in areas contaminated by industrial sources, partially because of the high costs of traditional analytical methods that limit the number of samples to be analyzed. The DR-CALUX cell bioassay is based on the uptake of the cellular aryl hydrocarbon receptor (AhR) for dioxins and dioxin-like compounds. The aim of this study was to assess the levels of dioxins and dioxin-like PCB contamination in Lake Maggiore and Lake Como, two lakes in northwestern Italy, and in nearby areas. The levels were quantified using the cell bioassay DR-CALUX and reference controls in two wild fish species, perch ( Perca fluviatilis) and roach ( Rutilus rutilus), and in a farmed species, rainbow trout ( Oncorhynchus mykiss). Tissue samples collected from the farmed rainbow trout were also submitted to immunohistochemical analysis of CYP1A expression as a marker for environmental pollutant-induced liver damage. The levels of dioxins, furans, and dioxin-like PCBs were all below the maximum levels and action limits set by European Union Regulation, suggesting no risk for human health associated with the consumption of the fish species caught or farmed in these areas.

NAFLD/NASH in patients with type 2 diabetes and related treatment options.

Type 2 diabetes may reduce life expectancy and patients' quality of life due to its micro- and macro-vascular complications and to the higher risk of several types of cancer. An emerging important factor is represented by the hepatic involvement; it is recognized that excessive hepatic fat accumulation represents a typical feature of diabetic patients and that it also plays an important pathogenic role. It is now evident that non-alcoholic fatty liver disease (NAFLD), generally perceived as a benign condition, may have on the contrary an important deleterious impact for diabetic patients increasing the risk to develop cardiovascular complications but also serious hepatic diseases, in particular non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Lifestyle intervention, bariatric surgery and several drug therapies have now accumulated evidence of efficacy in treating NASH. On the other hand, their durability and safety in the long-term is yet to be proven and their use may be sometimes associated with side effects or higher risk of adverse events limiting the regular administration or contraindicating it. Professional health care providers, building awareness about the importance of these hepatic complications, should put more efforts in primary prevention using a behavioral therapy needing a multidisciplinary approach, in secondary prevention applying on a regular basis in the clinical setting available predictive algorithms to identify the patients at higher cardiovascular and hepatologic risk, and in tertiary prevention treating, when not contraindicated, the diabetic patients preferentially with drugs with proven benefit on NAFLD/NASH.

Stimulatory effect of SOM230 on human and rat adrenal corticosteroid secretion in vitro.

SOM230 (pasireotide, Signifor), a recently developed somatostatin analog, has been tested in ACTH-secreting pituitary tumors with promising results. No study has yet evaluated whether this analog also directly affects adrenal steroid production. The aim of the current study was to evaluate whether SOM230 modulates corticosteroid secretion by normal adrenals in vitro. Primary cultures from normal human and rat adrenals were incubated with 10-100 nM SOM230 with and without 10nM ACTH. Dose-response studies with 1 nM-1 µM SOM230 were performed on rat adrenals. Cortisol/corticosterone levels in medium were measured after 4 and 24h. SOM230 (10nM) significantly increased corticosteroid levels after 24h incubation in both human (36.4 ± 0.43 ng/well vs 27.7 ± 3.17 ng/well, p<0.05) and rat (16.2 ± 1.16 ng/well vs 11.6 ± 0.92 ng/well p<0.05) adrenals; lesser effects were observed with 100 nM SOM (33.4 ± 2.59 ng/well vs 27.7 ± 3.17 ng/well p<0.05; 13.4 ± 0.82 ng/well vs 11.6 ± 0.92 ng/well, N.S. vs baseline secretion for human and rat adrenals, respectively). Dose-response curves confirmed maximal effect at 10nM SOM230. The corticosteroid secretory response to ACTH was unaffected by SOM230 co-incubation. In conclusion, SOM230 exerts a moderate stimulatory effect on adrenal corticosteroid secretion in vitro. This argues against a direct adrenal involvement in the clinical efficacy of SOM230 in patients with ACTH-secreting pituitary tumors and widens the known range of action of SOM230.

Familial isolated pituitary adenomas: an emerging clinical entity.

Familial pituitary tumors are increasingly recognized. While some of these cases are related to wellknown syndromic conditions such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex, others belong to the familial isolated pituitary adenoma (FIPA) patient group. The discovery of heterozygous, loss-of-function germline mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in 2006 has subsequently enabled the identification of a mutation in this gene in 20% of FIPA families and 20% of childhood-onset simplex soma- totroph adenomas. The exact mechanism by which the lack of AIP leads to pituitary adenomas is not clear. AIP mutations cause a low penetrance autosomal dominant disease with often a distinct phenotype characterized by young-onset, aggressive, large GH, mixed GH and PRL or PRL-secreting adenomas. This review aims to summarize currently available clinical data on AIP mutation-positive and negative FIPA patients.

Weekly and 3-weekly cisplatin concurrent with intensity-modulated radiotherapy in locally advanced head and neck squamous cell cancer.

In loco-regionally advanced head and neck squamous cell cancer (HNSCC), concurrent 3-weekly cisplatin improves overall survival (OS) compared to radiotherapy alone, but is often associated with renal toxicity. The use of radiotherapy with accelerated fractionation schedules has been reported to improve survival but its optimal combination with chemotherapy is unclear. Retrospective analysis of treatment outcome and nephrotoxicity of radiotherapy given with an intensity-modulated approach (IMRT) concurrent with either 3-weekly or weekly cisplatin in 94 patients with stage III/IV HNSCC. Patients treated with weekly cisplatin were significantly older (p=0.0014) and received a significantly lower total cisplatin dose (p=0.0002). With a median follow-up of 2.8 years, at univariate analysis, 3-weekly cisplatin shows a longer OS (p=0.041) but progression-free survival (PFS) is similar for both schedules (p=0.47). Cisplatin doses >240 mg/m(2) were associated with better OS but not PFS. Chronic renal failure rate was significantly higher with 3-weekly cisplatin (p=0.04). Multivariate analysis (Cox regression controlling for age) confirmed the significant and independent impact of alcohol and smoking habits on both PFS (HR, 2.2) and OS (HR, 2.3), while the treatment schedule affected only OS (HR, 2.2). Weekly cisplatin is less nephrotoxic. Both schedules can be combined to curative IMRT. PFS was not significantly different even if patients treated with the weekly schedule were significantly older and received reduced cisplatin doses. The study suggests that the different cisplatin dose doesn't affect the PFS results if concomitant to IMRT. Controlled prospective studies are needed.

Lack of association between IgA deficiency and respiratory atopy in young male adults.

BACKGROUND: The issue of atopy and increased serum IgE in IgA deficiency is still a matter of debate. The aim of this study was to evaluate the prevalence of IgA deficiency and its relationship with respiratory atopy. MATERIALS AND METHODS: A retrospective study on 4700 consecutive young males (age range 18-23), who underwent a health screen for admission to the Italian Airforce Academy between 1993 and 1995 was conducted. Serum IgA was measured by immunoturbidimetry and total and specific IgE by fluorescent enzyme immunoassay (Phadiatop FEIA, Pharmacia Cap System). Airway responsiveness was assessed by methacholine challenge. RESULTS: IgA deficiency was detected in 0.34% (16/4700) subjects and atopy was detected in 8.6% (406/4700). The mean IgA was 243 mg/dl (95% CI 107, 442) in the 406 atopic subjects and 238 mg/dl (95% CI 100, 441) in 1544 controls. Only 6 (37.5%) of the IgA deficient subjects had subnormal IgE levels and 6 were positive in the fluorescent EIA. None of the IgA deficient patients presented with respiratory hyper-reactivity. CONCLUSION: Atopy is not more prevalent in young male adult IgA deficient subjects, who rather display a high frequency of recurrent sinusitis.

Co-existence of classical scrapie and Nor98 in a sheep from an Italian outbreak.

Nor98 is an atypical scrapie strain characterized by a molecular pattern and brain distribution of the pathological prion protein (PrP(Sc)) different from classical scrapie. In Italy, 69 atypical cases have been identified so far and all were characterized as Nor98 strain. In this paper we report an unusual case in a sheep which showed immunohistochemical and molecular features of PrP(Sc) different from the other atypical cases. The sheep was from an outbreak where the index and the other four cases were affected by classical scrapie. Histopathological, immunohistochemical and Western blot analyses on the brain of the unusual case revealed the simultaneous presence of pathological features characteristic of Nor98 and classical scrapie. Interestingly, the prevalent disease phenotype in the brainstem was classical scrapie-like, while in the cerebral cortex and cerebellum the Nor98 phenotype was dominant. The sub-mandibular lymph node was positive and showed a PrP(Sc) molecular pattern referable to classical scrapie. The PrP genotype was AL(141)RQ/AF(141)RQ. Taken together, the occurrence of classical scrapie in the outbreak, the PrP genotype, the involvement of different cellular targets in the brain and the pathological and molecular PrP(Sc) features observed suggest that this unusual case may result from the co-existence of Nor98 and classical scrapie.

A case of scrapie in a sheep carrying the lysine-171 allele of the prion protein gene.

Susceptibility to scrapie in sheep depends on the host PrP genotype. No data about the linkage of the rare ARK allele to differential scrapie susceptibility are currently available. Several tissues isolated from sheep from an Italian scrapie outbreak and carrying the ARK allele were examined for the presence of the pathological prion protein. A weak positivity was detected only by Western blot in the brainstem of one ARK/ARH sheep. This result shows that the ARK allele does not confer full resistance against scrapie and that the allele needs to be studied further before it can be considered for breeding purposes.

Evaluation of rapid tests for the diagnosis of transmissible spongiform encephalopathies in sheep and goats.

In accordance with EU Regulation 999/2001, rapid tests already adopted for bovine spongiform encephalopathy (BSE; Prionics Check Western, Platelia-BSE and Enfer TSE) are to be applied in all European countries to a sub-population of over 18-month-old slaughtered or dead sheep and goats to improve Scrapie surveillance and to determine the possible presence of BSE in sheep; however, the three tests have thus far been evaluated only for BSE and no official data are available about their performances on Scrapie. We evaluated the accuracy of these methods for TSE diagnosis in Italian sheep and goats, using a pre-homogenisation protocol on brain-stem samples to obtain comparable data from the three tests. Our results show that the tests can be considered reliable tools for active surveillance in the small ruminants population.

Angiotensin II inhibition with captopril on plasma ADH, PG synthesis, and renal function in humans.

Using captopril (C), an angiotensin (ANG) I converting-enzyme inhibitor, to increase endogenous prostaglandins (PGs) and to decrease endogenous ANG II synthesis, we studied the relationship between endogenous ANG II, PG, and antidiuretic hormone (ADH) release in seven normal volunteers before (control study) and after inhibition of PG synthesis by a single dose of aspirin (ASA study). In the control study, following the administration of 100 mg of C, there was a significant increase of plasma PGE2, plasma-renin activity (PRA), and urinary PGE2 and 6-keto-PGF1 alpha and a decrease of plasma ADH. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were unaffected by C; urine output, fractional sodium excretion (FENa), and osmolal clearance (Cosmol) increased; and urinary osmolality (Uosmol) decreased significantly after C. In the ASA study PG were undetectable in plasma and significantly reduced in urine 1 h after aspirin and did not increase when C was added. Plasma ADH decreased and PRA increased, as in the control study, after C, whereas GFR, RPF, urine output, FENa, Cosmol, and Uosmol were unchanged. These results suggest that the effect of C on ADH release may be mediated, to a large extent, by a fall in endogenous circulating ANG II, since ADH decreased in the presence of both high or undetectable levels of PGE2. The results also suggest that the increase in PGE2 induced by C may precipitate the diuretic and natriuretic effects of acute C administration.