Publications by authors named "Alessandro Montanelli"

49 Publications

Coronavirus Disease 2019 (COVID-19) in Italy: Double Reading of Chest CT Examination.

Biology (Basel) 2021 Jan 25;10(2). Epub 2021 Jan 25.

Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80121 Naples, Italy.

To assess the performance of the second reading of chest compute tomography (CT) examinations by expert radiologists in patients with discordance between the reverse transcription real-time fluorescence polymerase chain reaction (RT-PCR) test for COVID-19 viral pneumonia and the CT report. Three hundred and seventy-eight patients were included in this retrospective study (121 women and 257 men; 71 years median age, with a range of 29-93 years) and subjected to RT-PCR tests for suspicious COVID-19 infection. All patients were subjected to CT examination in order to evaluate the pulmonary disease involvement by COVID-19. CT images were reviewed first by two radiologists who identified COVID-19 typical CT patterns and then reanalyzed by another two radiologists using a CT structured report for COVID-19 diagnosis. Weighted к values were used to evaluate the inter-reader agreement. The median temporal window between RT-PCRs execution and CT scan was zero days with a range of (-9,11) days. The RT-PCR test was positive in 328/378 (86.8%). Discordance between RT-PCR and CT findings for viral pneumonia was revealed in 60 cases. The second reading changed the CT diagnosis in 16/60 (26.7%) cases contributing to an increase the concordance with the RT-PCR. Among these 60 cases, eight were false negative with positive RT-PCR, and 36 were false positive with negative RT-PCR. Sensitivity, specificity, positive predictive value and negative predictive value of CT were respectively of 97.3%, 53.8%, 89.0%, and 88.4%. Double reading of CT scans and expert second readers could increase the diagnostic confidence of radiological interpretation in COVID-19 patients.
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http://dx.doi.org/10.3390/biology10020089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911408PMC
January 2021

Covid-19 Gastrointestinal symptoms are not a secondary clinical manifestation: the Italian experience.

Gastroenterol Hepatol Bed Bench 2020 ;13(4):415-416

Clinical Investigation Laboratory, Ospedale Bolognini Seriate, Bergamo, Italy.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682966PMC
January 2020

Modified Corona Score can easily identify Covid-19 patients with gastrointestinal symptoms: An Italian proposal.

Gastroenterol Hepatol Bed Bench 2020 ;13(4):393-395

Clinical Investigation Laboratory, Ospedale Bolognini Seriate, Bergamo, ASST-Seriate, Bergamo Italy.

Aim: We propose the Modified Corona Score (MCorona score), an alternative approach to identifying new likely Covid-19 patients without positive chest images, but with gastrointestinal onset.

Background: In April, 2020, a total of 104,291 laboratory-confirmed cases had been documented in Italy; Lombardy, the Northern Italian Region, recorded over 60,000 Covid-19 cases.

Method: The MCorona score is built by several laboratory parameters linked between age and gender, ranging from 0 to 10.

Results: Using the preliminary score cut-off of 4, we successfully identified likely Covid-19 patients with gastrointestinal onset. However, more caution is needed, and a larger sample size is required to verify the accuracy and specificity of the score.

Conclusion: We propose the complete validation of the MCorona score, an instrument able to diagnose likely Covid-19 patients with symptoms other than respiratory distress.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682955PMC
January 2020

COVID-19 pneumonia: computer-aided quantification of healthy lung parenchyma, emphysema, ground glass and consolidation on chest computed tomography (CT).

Radiol Med 2020 Nov 18. Epub 2020 Nov 18.

Division of Radiodiagnostic, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy.

Objective: To calculate by means of a computer-aided tool the volumes of healthy residual lung parenchyma, of emphysema, of ground glass opacity (GGO) and of consolidation on chest computed tomography (CT) in patients with suspected viral pneumonia by COVID-19.

Materials And Methods: This study included 116 patients that for suspected COVID-19 infection were subjected to the reverse transcription real-time fluorescence polymerase chain reaction (RT-PCR) test. A computer-aided tool was used to calculate on chest CT images healthy residual lung parenchyma, emphysema, GGO and consolidation volumes for both right and left lung. Expert radiologists, in consensus, assessed the CT images using a structured report and attributed a radiological severity score at the disease pulmonary involvement using a scale of five levels. Nonparametric test was performed to assess differences statistically significant among groups.

Results: GGO was the most represented feature in suspected CT by COVID-19 infection; it is present in 102/109 (93.6%) patients with a volume percentage value of 19.50% and a median value of 0.64 L, while the emphysema and consolidation volumes were low (0.01 L and 0.03 L, respectively). Among quantified volume, only GGO volume had a difference statistically significant between the group of patients with suspected versus non-suspected CT for COVID-19 (p < < 0.01). There were differences statistically significant among the groups based on radiological severity score in terms of healthy residual parenchyma volume, of GGO volume and of consolidations volume (p < < 0.001).

Conclusion: We demonstrated that, using a computer-aided tool, the COVID-19 pneumonia was mirrored with a percentage median value of GGO of 19.50% and that only GGO volume had a difference significant between the patients with suspected or non-suspected CT for COVID-19 infection.
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http://dx.doi.org/10.1007/s11547-020-01305-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673247PMC
November 2020

Coronavirus disease 2019 (COVID-19) in Italy: features on chest computed tomography using a structured report system.

Sci Rep 2020 10 14;10(1):17236. Epub 2020 Oct 14.

Division of Radiodiagnostic, "Università Degli Studi Della Campania Luigi Vanvitelli", Naples, Italy.

To assess the use of a structured report in the Chest Computed Tomography (CT) reporting of patients with suspicious viral pneumonia by COVID-19 and the evaluation of the main CT patterns. This study included 134 patients (43 women and 91 men; 68.8 years of mean age, range 29-93 years) with suspicious COVID-19 viral infection evaluated by reverse transcription real-time fluorescence polymerase chain reaction (RT-PCR) test. All patients underwent CT examinations at the time of admission. CT images were reviewed by two radiologists who identified COVID-19 CT patterns using a structured reports. Temporal difference mean value between RT-PCRs and CT scan was 0.18 days ± 2.0 days. CT findings were positive for viral pneumonia in 94.0% patients while COVID-19 was diagnosed at RT-PCR in 77.6% patients. Time mean value to complete the structured report by radiologist was 8.5 min ± 2.4 min. The disease on chest CT predominantly affected multiple lobes and the main CT feature was ground glass opacity (GGO) with or without consolidation (96.8%). GGO was predominantly bilateral (89.3%), peripheral (80.3%), multifocal/patching (70.5%). Consolidation disease was predominantly bilateral (83.9%) with prevalent peripheral (87.1%) and segmental (47.3%) distribution. Additional CT signs were the crazy-paving pattern in 75.4% of patients, the septal thickening in 37.3% of patients, the air bronchogram sign in 39.7% and the "reversed halo" sign in 23.8%. Less frequent characteristics at CT regard discrete pulmonary nodules, increased trunk diameter of the pulmonary artery, pleural effusion and pericardium effusion (7.9%, 6.3%, 14.3% and 16.7%, respectively). Barotrauma sign was absent in all the patients. High percentage (54.8%) of the patients had mediastinal lymphadenopathy. Using a Chest CT structured report, with a standardized language, we identified that the cardinal hallmarks of COVID-19 infection were bilateral, peripheral and multifocal/patching GGO and bilateral consolidation with peripheral and segmental distribution.
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http://dx.doi.org/10.1038/s41598-020-73788-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566610PMC
October 2020

Chest CT Computerized Aided Quantification of PNEUMONIA Lesions in COVID-19 Infection: A Comparison among Three Commercial Software.

Int J Environ Res Public Health 2020 09 22;17(18). Epub 2020 Sep 22.

Division of Radiodiagnostic, Azienda Ospedaliero-Universitaria Careggi, 50139 Firenze, Italy.

Purpose: To compare different commercial software in the quantification of Pneumonia Lesions in COVID-19 infection and to stratify the patients based on the disease severity using on chest computed tomography (CT) images.

Materials And Methods: We retrospectively examined 162 patients with confirmed COVID-19 infection by reverse transcriptase-polymerase chain reaction (RT-PCR) test. All cases were evaluated separately by radiologists (visually) and by using three computer software programs: (1) Thoracic VCAR software, GE Healthcare, United States; (2) Myrian, Intrasense, France; (3) InferRead, InferVision Europe, Wiesbaden, Germany. The degree of lesions was visually scored by the radiologist using a score on 5 levels (none, mild, moderate, severe, and critic). The parameters obtained using the computer tools included healthy residual lung parenchyma, ground-glass opacity area, and consolidation volume. Intraclass coefficient (ICC), Spearman correlation analysis, and non-parametric tests were performed.

Results: Thoracic VCAR software was not able to perform volumes segmentation in 26/162 (16.0%) cases, Myrian software in 12/162 (7.4%) patients while InferRead software in 61/162 (37.7%) patients. A great variability (ICC ranged for 0.17 to 0.51) was detected among the quantitative measurements of the residual healthy lung parenchyma volume, GGO, and consolidations volumes calculated by different computer tools. The overall radiological severity score was moderately correlated with the residual healthy lung parenchyma volume obtained by ThoracicVCAR or Myrian software, with the GGO area obtained by the ThoracicVCAR tool and with consolidation volume obtained by Myrian software. Quantified volumes by InferRead software had a low correlation with the overall radiological severity score.

Conclusions: Computer-aided pneumonia quantification could be an easy and feasible way to stratify COVID-19 cases according to severity; however, a great variability among quantitative measurements provided by computer tools should be considered.
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http://dx.doi.org/10.3390/ijerph17186914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558768PMC
September 2020

Laboratory markers included in the Corona Score can identify false negative results on COVID-19 RT-PCR in the emergency room.

Biochem Med (Zagreb) 2020 Oct 5;30(3):030402. Epub 2020 Aug 5.

Clinical Investigation Laboratory, ASST-Bergamo Est, Bolognini Hospital Seriate, Bergamo, Italy.

After December 2019 outbreak in China, the novel Coronavirus infection (COVID-19) has very quickly overflowed worldwide. Infection causes a clinical syndrome encompassing a wide range of clinical features, from asymptomatic or oligosymptomatic course to acute respiratory distress and death. In a very recent work we preliminarily observed that several laboratory tests have been shown as characteristically altered in COVID-19. We aimed to use the Corona score, a validated point-based algorithm to predict the likelihood of COVID-19 infection in patients presenting at the Emergency rooms. This approach combines chest images-relative score and several laboratory parameters to classify emergency room patients. Corona score accuracy was satisfactory, increasing the detection of positive patients' rate.
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http://dx.doi.org/10.11613/BM.2020.030402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394256PMC
October 2020

Considerations on COVID-19 pregnancy: a cases series during outbreak in Bergamo Province, North Italy.

J Matern Fetal Neonatal Med 2020 Jul 15:1-4. Epub 2020 Jul 15.

Department of Radiology, Bolognini Hospital, ASST-Bergamo Est, Seriate, Italy.

Background: COVID-19 has rapidly spread worldwide, with severe complications affecting particularly elderly and compromised subjects. Less information about COVID-19 in pregnancy has been reported so far in the literature.

Methods: Case series on pregnancies complicated by COVID-19. All cases were diagnosed at Bolognini Hospital, Seriate, Italy. These cases are presented to clarify the features of COVID-19 occurring in pregnancy.

Results: Four women had symptoms of COVID-19 during pregnancy or immediately after delivery. All cases were confirmed by oropharyngeal swab. All patients presented with fever and low saturation levels at the diagnosis. One case was transferred after diagnosis to a tertiary referral center and delivered the day after for worsening clinical conditions. In the other three cases, bilateral pneumonia was documented at the admission. Antithrombotic therapy was used in most cases. No cases of the infected neonate was reported. At 2 month follow-up, all patients were alive, three were asymptomatic while one presented neurological complication. One more case was described because suspicious for COVID-19, however, it was not confirmed by oropharyngeal swab.

Conclusions: In pregnant women, the peripheral nervous system could be affected. No case of trans-placental passage was reported. The swab could be helpful in diagnosis. The antithrombotic therapy could play a role in the positive course of COVID-19 also in pregnant women.
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http://dx.doi.org/10.1080/14767058.2020.1791817DOI Listing
July 2020

Laboratory Biomarkers Predicting COVID-19 Severity in the Emergency Room.

Arch Med Res 2020 08 21;51(6):598-599. Epub 2020 May 21.

Clinical Investigation Laboratory, Ospedale Bolognini Seriate, Bergamo, Italy.

Infection of novel Coronavirus has been declared pandemic by the WHO and now is a world public health crisis. Laboratory activity becames essential for the timely diagnosis. Few parameters, such Lymphocytes count, SaO2 and CRP serum level can be used to assess the severity of COVID-19 in emergency room.
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http://dx.doi.org/10.1016/j.arcmed.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241376PMC
August 2020

Diagnosis of gluten-related enteropathy in a newborn: how and when?

Gastroenterol Hepatol Bed Bench 2019 ;12(4):278-286

Department of Health Prevention Clinical Chemistry Laboratory, ATS Bergamo, Italy.

Aim: To analyze the development of gliadin-specific immune responses in children with a genetic risk for CD and to determine whether these could be detected before the clinical onset of the disease by using immunological tests.

Background: Clinical manifestations of celiac disease (CD) in the first year of life is uncommon, which is due to the suboptimal sensitivity of tissue transglutaminase IgA antibodies (tTG-IgA) at this age and other possible causes of malabsorption in infants. The development of Deamidate gliadin peptide-specific antibodies (in particular DGP-IgG) in young children was poorly considered in the CD diagnosis.

Methods: We conducted a retrospective cross-sectional study on children between one month and forty-eight months of life, which performed in our health center from 2016 to 2018. Three hundred and fifty children were selected according to strict inclusion criteria: positive for HLA-DQA1 and DQB1 alleles, positive anti tTG-IgA/IgG and/or positive DGP-IgG/IgA. Eighty-two children were selected and divided into two different groups of patients: Group one (forty newborns under twenty-four months of life) and Group two (children from twenty-five months to 48 months of life).

Results: Anti-DGP-IgG antibodies precede anti tTG-IgA seroconversion in children under two years in 80% of cases. Anti-DGP-IgG positive patients had milder symptomatic forms of CD than anti tTG-IgA positive children, characterized by gastrointestinal symptoms in the presence of normal growth, normal serum iron, and low MCH level. At tTG-IgA seroconversion, children present gastrointestinal clinical forms associated with impaired growth. The combined use of tTG-IgA and DGP-IgG antibodies upgrade the diagnostic sensitivity from 50% to 92%.

Conclusion: Anti-DGP-IgG antibodies precede tTG-IgA seroconversion in newborns and identified two distinct clinical phenotypes. At this point, if you wanted to test your newborn patients for CD serology, how would you proceed?
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820841PMC
January 2019

Pentraxin 3 and biopsy status in celiac patients.

Gastroenterol Hepatol Bed Bench 2018 ;11(3):225-232

Clinical Chemistry Laboratory, Spedali Civili di Brescia, Italy.

Aim: In our study we explored a possible relationship between PTX3 and CD.

Background: Gluten sensitivity is known as a hallmark of celiac disease (CD). The diagnosis of CD requires demonstration of a typical enteropathy, and positive serology supports the diagnosis. The CD immune response involves the adaptive, as well as the innate immunity and is characterized by the presence of anti-gliadin (AGA) and anti-transglutaminase 2 antibodies (tTGA), lymphocytic infiltration in the intestinal epithelial membrane and expression of multiple cytokines. The long pentraxin 3 (PTX3), an acute-phase inflammatory molecule, plays an important role in innate immunity.

Methods: 108 CD patients were divided according to Marsh Histological grade following Marsh criteria classification in three groups: Group 1: Marsh 0, patients with a known history of CD under gluten free diet, complete remission; Group 2: Marsh1 and Marsh 2; Group 3: Marsh 3. Healthy age-matched controls without a known history of CD or gastrointestinal symptoms (n=30) served as controls. PTX3 serum levels were measured by sandwich ELISA on an automated platform.

Results: PTX3 serum levels were significantly elevated in group 3 and group 2 compared with HC (mean 3.31± 1.27 ng/mL and 3.97 ± 0.54 ng/mL versus 1.06 ± 0.59 ng/mL; < 0.005), with group 1 (0.76±0.31 ng/mL). No statistically significant differences were found between group 1 and HC group. We found a strong linear correlation between PTX3 serum levels and AGA levels in group 2 (r=0.78, <0.0001), and group 3 (r =0.63, < 0.005) but no correlations were detected between PTX3 serum levels and tTGA levels (group 2, r= 0.04; group 3, r=0.24). Serological data revealed that PTX3 correlated with major gastrointestinal damage patients.

Conclusion: PTX3 is a component of the humoral arm of the innate immune system. Our data showed that PTX3 serum levels were high in active disease patients with pathological levels of AGA. We also demonstrated that patients with normal AGA IgA levels had PTX3 serum levels compared to healthy control. We hypothesized that PTX3 is able to modulate the innate response to gliadin in CD and it could regulate the adaptive immune response.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040031PMC
January 2018

Comparison of β2-microglobulin serum level between Alzheimer's patients, cognitive healthy and mild cognitive impaired individuals.

Biomarkers 2018 Sep 23;23(6):603-608. Epub 2018 May 23.

d Fondazione Golgi-Cenci Abbiategrasso (MI) , Milano , Italy.

Background: Several studies performed in the last years on the brain, showed that beta2-microglobulin (β2m) and MHC can act independently of their canonical immune function to regulate normal brain development, synaptic plasticity and behaviour. Increased systemic levels of soluble β2m have been implicated in cognitive impairments like that associated with chronic haemodialysis, or aortic valve replacement. Increased soluble β2m has also been detected in the cerebral spinal fluid (CSF) of patients with HIV-associated dementia and Alzheimer's disease (AD).

Objective: To compare plasma β2m levels in healthy subjects and subjects with dementia or cognitive impairment.

Methods: We measured the concentration of β2m in a cohort of 245 individuals and compared sex matched, cognitive healthy individuals.

Results: We found higher levels of β2m in AD patients compared to non-AD MCI and healthy controls (2063 ng/mL ±852 versus 1613 ± 503 and 1832 ± 382 ng/mL, p< 0.001 and <0.033, respectively), while there was no difference between mild cognitive impairment (MCI) and healthy controls (p > 0.05).

Conclusions: Our data confirm that β2m could play a role in AD. However, a replication study in an independent cohort would be necessary to confirm our preliminary results.
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http://dx.doi.org/10.1080/1354750X.2018.1468825DOI Listing
September 2018

Cryptococcal-related meningoencephalitis in a patient with sarcoidosis and CD4 lymphocytopenia: thorough immunological characterization of lymphocyte homeostasis.

J Neurosurg Sci 2018 Feb 23. Epub 2018 Feb 23.

Centro di Ricerca Emato-oncologica AIL (CREA), Clinical Chemistry Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy -

Cryptococcal meningoencephalitis is the most common infective complication observed in patients with CD4 lymphocytopenia, including sarcoidosis. T-cell immunity is well characterized in HIV-related infections and data regarding immunity in cryptococcosis animal models is now available; on the contrary, little is known about the immune status in non-HIV-related infections. We report on reduced production of new T cells observed in a patient with sarcoidosis, CD4 lymphocytopenia, and cryptococcal-related meningoencephalitis. Although T cells presented with an intact proliferative capacity, they were oligoclonally expanded showing an effector memory phenotype. However, the deleterious activity of effector memory cells could have been controlled by the expansion of the regulatory T cell subset with the highest suppressive capability. This information provide a better understanding of the immune response to cryptococcus occurring in non-HIV-associated cases, the predisposition to infection, and the role of different cell subtypes in controlling the disease in humans.
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http://dx.doi.org/10.23736/S0390-5616.18.04375-8DOI Listing
February 2018

Development of PBC/SSc overlap syndrome in chronic GVHD patient: immunological implications in the presence of mitochondrial, nucleolar and spindle midzone autoantigens.

Gastroenterol Hepatol Bed Bench 2017 ;10(4):323-331

Clinical Investigation Laboratory, Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy.

Chronic Graft versus Host Disease (cGVHD) is a complex disease resulting from donor T-cell recognition of a genetically disparate recipient that is unable to reject donor cells after allogeneic Stem Cell Transplantation (HSCT). cGVHD has some features resembling to autoimmune diseases (AD) such as Sjögren syndrome, primary biliary cirrhosis (PBC) and scleroderma (SSc). Also patients with cGVHD could develop extensive cGVHD with scleroderma-like skin manifestations and other clinical signs similar to those of patients with scleroderma. We take into consideration a patient with GVHD that developed PBC/SSc overlap syndrome with a complex and particular autoantibodies profile. Indirect immunofluorescence (IIF) with double coloration showed a cytoplasmic mitochondrial-like pattern, a clumpy nucleolar staining pattern, and a cell-cycle related staining pattern. Following anaphase onset, proteins regulator of cytokinesis localizes to the overlap zone on the ends of midzone microtubules and becomes compacted during furrow ingression to form the midbody. Second level tests confirmed the presence of anti-mitochondrial antibodies M2-subunit but no other autoantibodies were found. We performed a home-made immunoblot analysis that identified a 37 kDa fibrillarin band, and not identify 47 kDa, 31KDa and 18/20 kDa bands. After literature review of these possible cellular localizations, the proteins recognized by our patient's serum seem likely to be Aab to core midzone organizer components. However, due to the unavailability of the proper techniques in our laboratory, we were not able to further characterize them. The pathogenesis and morbidity of cGVHD after HSCT remains enigmatic, but the presence of specific autoantibodies are the hallmark of AD and represent a possibility of differential diagnosis. Standard techniques combined with the use of non-routinely laboratory techniques are a usefully and complementary method for studying difficult and particular cases. In fact, these autoantibodies will be considered as ''diagnostic'' and not as ''esoteric'' antibodies. In conclusion, a re-assessment of the diagnostic protocols in cGVHD together with a precise observation of the clinical and laboratory picture will ultimately help us clarify the disease and could provide a better understanding of the immune network deregulation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758742PMC
January 2017

Maternal T-cell engraftment impedes with diagnosis of a SCID-ADA patient.

Clin Immunol 2018 08 7;193:118-120. Epub 2018 May 7.

Pediatric Onco-Haematology and BMT Unit, Children's Hospital, ASST Spedali Civili of Brescia, Brescia, Italy.

We describe the case of a child affected by severe combined immunodeficiency (SCID) with adenosine deaminase (ADA) deficiency showing a maternal T-cell engraftment, a finding that has never been reported before. The presence of engrafted maternal T cells was misleading. Although ADA enzymatic levels were suggestive of ADA-SCID, the child did not present the classical signs of ADA deficiency; therefore, the initial diagnosis was of a conventional SCID. However, ADA toxic metabolites and molecular characterization confirmed this diagnosis. Polyethylene glycol-modified bovine (PEG) ADA therapy progressively decreased the number of maternal engrafted T cells. The child was grafted with full bone marrow from a matched unrelated donor, after a reduced conditioning regimen, and the result was the complete immunological reconstitution.
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http://dx.doi.org/10.1016/j.clim.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106042PMC
August 2018

Chronic Granulomatous Disease in children: a single center experience.

Clin Immunol 2018 03 7;188:12-19. Epub 2017 Dec 7.

Stem Cell Laboratory, Section of Hematology and Blood Coagulation, Clinical Chemistry Laboratory, Diagnostics Department, ASST Spedali Civili of Brescia, Brescia, Italy. Electronic address:

Chronic Granulomatous Disease (CGD) is caused by the failure of the phagocytes to kill pathogens. We carried out a retrospective analysis of cellular, molecular and clinical features of 14 young patients (mean age at the onset of symptoms and diagnosis: 10 and 25months, respectively), 7 with autosomal recessive and 7 X-linked form, referred to the Children's Hospital of Brescia between 1999 and 2016. Two new mutations were found, one localized in the CYBB and one in the NCF1 genes. Twelve patients were followed in our institution; the average length of their follow-up after diagnosis was 66months in X-linked patients and 126months in autosomal recessive inheritance. The overall survival was 67%, 40% in X-linked and 86% in autosomal recessive form. Eight patients were treated with HSCT. We did not find a clear correlation between the clinical symptoms and the type of mutation, but the fine characterization of the patients was mandatory for therapeutic option, genetic counseling and prenatal diagnosis.
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http://dx.doi.org/10.1016/j.clim.2017.11.016DOI Listing
March 2018

Bone Marrow Stroma and Vascular Contributions to Myeloma Bone Homing.

Curr Osteoporos Rep 2017 10;15(5):499-506

Clinical Research Development and Phase I Unit, ASST Spedali Civili di Brescia, P.le Spedali Civili, n.1, 25123, Brescia, Italy.

Purpose Of The Review: Herein we dissect mechanisms behind the dissemination of cancer cells from primary tumor site to the bone marrow, which are necessary for metastasis development, with a specific focus on multiple myeloma.

Recent Findings: The ability of tumor cells to invade vessels and reach the systemic circulation is a fundamental process for metastasis development; however, the interaction between clonal cells and the surrounding microenvironment is equally important for supporting colonization, survival, and growth in the secondary sites of dissemination. The intrinsic propensity of tumor cells to recognize a favorable milieu where to establish secondary growth is the basis of the "seed and soil" theory. This theory assumes that certain tumor cells (the "seeds") have a specific affinity for the milieu of certain organs (the "soil"). Recent literature has highlighted the important contributions of the vascular niche to the hospitable "soil" within the bone marrow. In this review, we discuss the crucial role of stromal cells and endothelial cells in supporting primary growth, homing, and metastasis to the bone marrow, in the context of multiple myeloma, a plasma cell malignancy with the unique propensity to primarily grow and metastasize to the bone marrow.
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http://dx.doi.org/10.1007/s11914-017-0399-3DOI Listing
October 2017

Clinical Laboratory Automation: A Case Study.

J Public Health Res 2017 Apr 16;6(1):881. Epub 2017 Jun 16.

Unique Laboratory, ASST Spedali Civili, Brescia.

Background: This paper presents a case study of an automated clinical laboratory in a large urban academic teaching hospital in the North of Italy, the Spedali Civili in Brescia, where four laboratories were merged in a unique laboratory through the introduction of laboratory automation.

Materials And Methods: The analysis compares the preautomation situation and the new setting from a cost perspective, by considering direct and indirect costs. It also presents an analysis of the turnaround time (TAT). The study considers equipment, staff and indirect costs.

Results: The introduction of automation led to a slight increase in equipment costs which is highly compensated by a remarkable decrease in staff costs. Consequently, total costs decreased by 12.55%. The analysis of the TAT shows an improvement of nonemergency exams while emergency exams are still validated within the maximum time imposed by the hospital.

Conclusions: The strategy adopted by the management, which was based on re-using the available equipment and staff when merging the pre-existing laboratories, has reached its goal: introducing automation while minimizing the costs.
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http://dx.doi.org/10.4081/jphr.2017.881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477477PMC
April 2017

Development of systemic sclerosis in patients with autoimmune hepatitis: an emerging overlap syndrome.

Gastroenterol Hepatol Bed Bench 2016 ;9(3):211-9

Clinical Laboratory, Diagnostics Department, Spedali Civili of Brescia, Piazzale Spedali Civili 1 - Brescia, Italy.

Aim: We described two case reports of AIH/SSc overlap syndrome and reviewed literatures regarding this issue.

Background: AIH is a chronic hepatitis of unknown aetiology characterized by continuing hepatocellular necrosis and inflammation. AIH overlap syndromes have been reported with other autoimmune diseases.

Patients And Methods: According to the classification criteria for SSc, we conducted a retrospective chart review of 35 cases with biopsy-proven AIH over the past 5 years at our institution. We reviewed the MEDLINE database using the appropriate key-words.

Results: A chart review of 35 cases (M/F ratio 1:2, mean age 47.6±10.3 years) revealed nine patients (9/35, 25.7%) with CTD (four males and three females with a mean age of 45.1±8.4 years). All patients had ANA. Four patients were SSA/Ro positive UCTD (1/35, 2.85%), and six patients developed SLE (6/35, 17.1%). Only two female patients (2/35, 5.7%) with specific SSc AAb developed a systemic sclerosis. We described a patient with AIH who was diagnosed with diffuse systemic sclerosis-sine scleroderma with positive anti-centromere B and SSA/Ro52 KDa antibodies. We also reported a patient with AIH who was diagnosed limited SSc with contemporary presence of anti-centromere A and anti-RNA polymerase III antibody.

Conclusion: We suggest that SSc may be considered to be one of the manifestations associated with AIH. Patients with AIH may have an increased risk to develop SSc and should be followed, especially when Raynaud phenomenon was found.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947136PMC
July 2016

Caveolin-1, Caveolin-2 and Cavin-1 are strong predictors of adipogenic differentiation in human tumors and cell lines of liposarcoma.

Eur J Cell Biol 2016 Aug 4;95(8):252-64. Epub 2016 May 4.

Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. Electronic address:

Caveolins (Cav-1, -2 and -3) and Cavins (Cavin-1, -2, -3 and -4) are two protein families controlling the biogenesis and function of caveolae, plasma membrane omega-like invaginations representing the primary site of important cellular processes like endocytosis, cholesterol homeostasis and signal transduction. Caveolae are especially abundant in fat tissue, playing a consistent role in a number of processes, such as the insulin-dependent glucose uptake and transmembrane transport of lipids underlying differentiation, maintenance and adaptive hypertrophy of adipocytes. Based on this premise, in this work we have investigated the expression of caveolar protein components in liposarcoma (LPS), an adipocytic soft tissue sarcoma affecting adults categorized in well-differentiated, dedifferentiated, myxoid and pleomorphic histotypes. By performing an extensive microarray data analysis followed by immunohistochemistry on human LPS tumors, we demonstrated that Cav-1, Cav-2 and Cavin-1 always cluster in all the histotypes, reaching the highest expression in well-differentiated LPS, the least aggressive of the malignant forms composed by tumor cells with a morphology resembling mature adipocytes. In vitro experiments carried out using two human LPS cell lines showed that the expression levels of Cav-1, Cav-2 and Cavin-1 proteins were faintly detectable during cell growth, becoming consistently increased during the accumulation of intracellular lipid droplets characterizing the adipogenic differentiation. Moreover, in differentiated LPS cells the three proteins were also found to co-localize and form molecular aggregates at the plasma membrane, as shown via immunofluorescence and immunoprecipitation analysis. Overall, these data indicate that Cav-1, Cav-2 and Cavin-1 may be considered as reliable markers for identification of LPS tumors characterized by consistent adipogenic differentiation.
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http://dx.doi.org/10.1016/j.ejcb.2016.04.005DOI Listing
August 2016

Pentraxin 3 Plasma Levels and Disease Activity in Systemic Lupus Erythematosus.

Autoimmune Dis 2015 3;2015:354014. Epub 2015 Nov 3.

Clinical Investigation Laboratory, Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy.

SLE is an autoimmune disorder that involves polyclonal autoimmunity against multiple autoantigens. PTX3, a marker of the acute-phase inflammatory response, plays an important role in innate immunity and in modulation of the adaptive immune response. Our study tried to resolve some rather controversial aspects of the use of PTX3 as a biomarker of disease activity in SLE patients. We demonstrated that plasma PTX3 concentration of the SLE patients was significantly higher than the healthy control groups and reflected disease activity. ROC curve analysis was used to determine best cut-off point (2.8 ng/mL) with a good sensitivity and specificity. In patients with SLE, PTX3 concentrations were correlated with SLEDAI. Trend to remission (TTR) curve was created by plotting PTX3 levels and SLEDAI and we applied the curve as a model for the analysis of two patients with different follow-up. PTX3 plasma levels declined significantly and this decline occurred parallel to the clinical improvement with a complete remission of disease. In patients who experienced a clinical relapse, an increase in PTX3 levels followed the lupus flare. The proposal of PTX3 cut-off associated with TTR and monitoring of PTX3 plasma levels could be an innovative approach to follow-up of SLE patients.
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http://dx.doi.org/10.1155/2015/354014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646995PMC
November 2015

Merging colloidal nanoplasmonics and surface plasmon resonance spectroscopy for enhanced profiling of multiple myeloma-derived exosomes.

Biosens Bioelectron 2016 Mar 3;77:518-24. Epub 2015 Oct 3.

Department of Molecular and Translational Medicine and INSTM, University of Brescia, Viale Europa, 11, 25132 Brescia, Italy. Electronic address:

A novel approach for sorting exosomes from multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and healthy individuals is presented. The method is based on the combination of colloidal gold nanoplasmonics and surface plasmon resonance (SPR) biosensing and probes distinctive colloidal properties of MM-derived exosomes, such as molar concentration and cell membrane binding preferences. It allowed to discover that MM patients produce about four folds more exosomes than MGUS and healthy individuals. In addition, it showed that among the analyzed exosomes, only the MM-derived ones bind heparin - a structural analog of heparan sulfate proteoglycans known to mediate exosome endocytosis - with an apparent dissociation constant (Kd) equal to about 1 nM, indicating a high affinity binding. This plasmonic method complements the classical biochemical profiling approach to exosomes, expanding the MM biomarker panel and adding biosensors to the toolbox to diagnose MM. It may find applications for other diseases and has wider interest for fundamental and translational research involving exosomes.
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http://dx.doi.org/10.1016/j.bios.2015.09.061DOI Listing
March 2016

Prognostic and diagnostic potential of local and circulating levels of pentraxin 3 in lung cancer patients.

Int J Cancer 2016 Feb 8;138(4):983-91. Epub 2015 Sep 8.

Thoracic Surgery Department, Humanitas Research Hospital, Rozzano, Milano, Italy.

There is a well-established link between inflammation and cancer of various organs, but little data are available on inflammation-associated markers of diagnostic and prognostic clinical utility in pulmonary malignancy. Blood samples were prospectively collected from 75 resectable lung cancer patients before surgery and in a cohort of 1,358 high-risk subjects. Serum levels of long pentraxin 3 (PTX3) were determined by high-sensitivity ELISA. PTX3 immunostaining was evaluated by immunohistochemistry in cancer tissue. Serum PTX3 levels in the high-risk population were not predictive of developing subsequent lung cancer or any other malignancy; however, serum PTX3 values in patients with lung cancer were significantly higher compared with cancer-free heavy smokers. With a cutoff of 4.5 ng/ml, specificity was 0.80, sensitivity 0.69, positive predictive value 0.15 and negative predictive value 0.98. The receiver operating curve (ROC) for serum PTX3 had an area under the curve (AUC) of 83.52%. Preoperative serum PTX3 levels in lung cancer patients did not correlate with patient outcome, but high interstitial expression of PTX3 in resected tumor specimens was a significant independent prognostic factor associated with shorter survival (p < 0.001). These results support the potential of serum PTX3 as a lung cancer biomarker in high-risk subjects. Furthermore, PTX3 immunohistochemistry findings support the role of local inflammatory mechanisms in determining clinical outcome and suggest that local expression of PTX3 may be of prognostic utility in lung cancer patients.
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http://dx.doi.org/10.1002/ijc.29822DOI Listing
February 2016

Elevations of inflammatory markers PTX3 and sST2 after resuscitation from cardiac arrest are associated with multiple organ dysfunction syndrome and early death.

Clin Chem Lab Med 2015 Oct;53(11):1847-57

Background: A systemic inflammatory response is observed after cardiopulmonary resuscitation. We investigated two novel inflammatory markers, pentraxin 3 (PTX3) and soluble suppression of tumorigenicity 2 (sST2), in comparison with the classic high-sensitivity C-reactive protein (hsCRP), for prediction of early multiple organ dysfunction syndrome (MODS), early death, and long-term outcome after out-of-hospital cardiac arrest.

Methods: PTX3, sST2, and hsCRP were assayed at ICU admission and 48 h later in 278 patients. MODS was defined as the 24 h non-neurological Sequential Organ Failure Assessment (SOFA) score ≥ 12. Intensive care unit (ICU) death and 12-month Cerebral Performance Category (CPC) were evaluated.

Results: In total, 82% of patients survived to ICU discharge and 48% had favorable neurological outcome at 1 year (CPC 1 or 2). At ICU admission, median plasma levels of hsCRP (2.8 mg/L) were normal, while levels of PTX3 (19.1 ng/mL) and sST2 (117 ng/mL) were markedly elevated. PTX3 and sST2 were higher in patients who developed MODS (p<0.0001). Admission levels of PTX3 and sST2 were also higher in patients who died in ICU and in those with an unfavorable 12-month neurological outcome (p<0.01). Admission levels of PTX3 and sST2 were independently associated with subsequent MODS [OR: 1.717 (1.221-2.414) and 1.340, (1.001-1.792), respectively] and with ICU death [OR: 1.536 (1.078-2.187) and 1.452 (1.064-1.981), respectively]. At 48 h, only sST2 and hsCRP were independently associated with ICU death.

Conclusions: Higher plasma levels of PTX3 and sST2, but not of hsCRP, at ICU admission were associated with higher risk of MODS and early death.
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http://dx.doi.org/10.1515/cclm-2014-1271DOI Listing
October 2015

Innate immune system: the no man's land where discover new biomarkers for gluten-related-disorders.

Gastroenterol Hepatol Bed Bench 2015 ;8(2):95-8

Humanitas Clinical and Research Center, Rozzano, Milan, Italy.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403021PMC
April 2015

Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis.

J Bone Miner Res 2015 Oct 21;30(10):1814-21. Epub 2015 May 21.

UOS/IRGB, Milan Unit, National Research Council (CNR), Milan, Italy.

Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease with genotypic and phenotypic heterogeneity, sometimes translating into delayed diagnosis and treatment. In particular, cases of intermediate severity often constitute a diagnostic challenge and represent good candidates for exome sequencing. Here, we describe the tortuous path to identification of the molecular defect in two siblings, in which osteopetrosis diagnosed in early childhood followed a milder course, allowing them to reach the adult age in relatively good conditions with no specific therapy. No clearly pathogenic mutation was identified either with standard amplification and resequencing protocols or with exome sequencing analysis. While evaluating the possible impact of a 3'UTR variant on the TCIRG1 expression, we found a novel single nucleotide change buried in the middle of intron 15 of the TCIRG1 gene, about 150 nucleotides away from the closest canonical splice site. By sequencing a number of independent cDNA clones covering exons 14 to 17, we demonstrated that this mutation reduced splicing efficiency but did not completely abrogate the production of the normal transcript. Prompted by this finding, we sequenced the same genomic region in 33 patients from our unresolved ARO cohort and found three additional novel single nucleotide changes in a similar location and with a predicted disruptive effect on splicing, further confirmed in one of them at the transcript level. Overall, we identified an intronic region in TCIRG1 that seems to be particularly prone to splicing mutations, allowing the production of a small amount of protein sufficient to reduce the severity of the phenotype usually associated with TCIRG1 defects. On this basis, we would recommend including TCIRG1 not only in the molecular work-up of severe infantile osteopetrosis but also in intermediate cases and carefully evaluating the possible effects of intronic changes.
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http://dx.doi.org/10.1002/jbmr.2517DOI Listing
October 2015

Pentraxin 3 serum levels in celiac patients: evidences and perspectives.

Recent Pat Food Nutr Agric 2014 ;6(2):82-92

Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano - Milano, Italy.

Celiac disease (CD) is now considered, more than a just gluten sensitivity enteropathy, a multiple and systemic immune-mediate disorder triggered by the ingestion of wheat gluten and related proteins. Following the discovery of a link between gluten and CD, it was demonstrated that gliadin, one of the two principal protein groups comprising gluten, plays a key role in CD. It has since become clear that the different and crucial roles of gliadin in CD result from its ability to activate multiple signaling pathways that modulate CD pathology. Most of these pathways involve the host innate and adaptive immune responses, but some pathways are activated when gliadin interacts with the intestinal cellular compartment. The long pentraxin (PTX3), a marker of the acute-phase inflammatory response, plays an important role in innate immunity and in modulation of the adaptive immune response. We investigated whether CD patients, considered as a model of gluten-sensitivity condition, have increased PTX3 levels. Our data showed that PTX3 serum levels were high in active CD patients and serum levels of PTX3 correlated with DGP IgA levels. We provide evidences that the bad compliance of GFD in patients 2 concurred with a pathological PTX3 concentration that could follow the improvement of both gastrointestinal and extraintestinal symptoms. We hypothesized that PTX3 is able to modulate the innate response to gliadin in CD and it could regulate the adaptive immune response. It is also evidenced that a common "wooden horse" of CD and Non Celiac Gluten Sensitivity (NCGS) is the ingestion of gluten and related toxic peptides. At the moment we don't have adequate elements to suggest the use of PTX3 in diagnosis of NCGS, but we are obliged to speculate about the possible role of PTX3 molecules in NCGS pathogenesis. The identified new strategies and uses of PTX3 could improve the management of gluten sensitivity conditions in the next future.
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http://dx.doi.org/10.2174/2212798407666141231115531DOI Listing
October 2015

Early activation of the kynurenine pathway predicts early death and long-term outcome in patients resuscitated from out-of-hospital cardiac arrest.

J Am Heart Assoc 2014 Aug 4;3(4). Epub 2014 Aug 4.

Department of Anesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland (J.V., T.V., V.P., M.B.S.).

Background: The kynurenine pathway (KP) is the major route of tryptophan (TRP) catabolism and is activated by inflammation and after cardiac arrest in animals. We hypothesized that the KP activation level correlates with severity of post-cardiac arrest shock, early death, and long-term outcome.

Methods And Results: Plasma was obtained from 245 patients enrolled in a prospective multicenter observational study in 21 intensive care units in Finland. Time to return of spontaneous circulation, lowest systolic arterial pressure, and bicarbonate during the first 24 hours were collected. A cerebral performance category of 3 to 5 defined 12-month poor outcome. Plasma TRP and KP metabolites, kynurenine (KYN), kynurenic acid, 3-hydroxyanthranilic acid, and the ratio of KYN to TRP were measured by liquid chromatography and mass spectrometry. All KP metabolites at intensive care unit admission were significantly higher in cardiac arrest patients with a nonshockable rhythm compared to those with a shockable rhythm, and kynurenic acid and 3-hydroxyanthranilic acid correlated with time to return of spontaneous circulation. Patients with higher levels of KYN, KYN to TRP, kynurenic acid, and 3-hydroxyanthranilic acid had lower 24-hour systolic arterial pressure and bicarbonate. All KP metabolites and the ratio of KYN to TRP, but not TRP, were significantly higher in patients who died in the intensive care unit in comparison to those who survived. Multivariable logistic regression showed that high kynurenic acid (odds ratio: 1.004; 95% confidence interval: 1.001 to 1.008; P=0.014), and 3-hydroxyanthranilic acid (odds ratio: 1.011; 95% confidence interval: 1.001 to 1.022; P=0.03) were independently associated with 12-month poor outcome and significantly improved risk reclassification.

Conclusions: KP is activated early after cardiac arrest and is associated with severity of post-cardiac arrest shock, early death, and poor long-term outcome.
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http://dx.doi.org/10.1161/JAHA.114.001094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310405PMC
August 2014