Publications by authors named "Paolo Fociani"

29 Publications

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The forensic application of the Glycophorin A on the Amussat's sign with a brief review of the literature.

J Forensic Leg Med 2021 Aug 10;82:102228. Epub 2021 Aug 10.

Laboratorio di Istopatologia Forense e Microbiologia Medico Legale, Sezione di Medicina Legale e delle Assicurazioni, Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano Via Luigi Mangiagalli, 37, 20133, Milano, Italy.

Even if the Amussat's sign is known since the mid-19th century, few studies have been made in order to assess its real occurrence. In particular, the histopathologic examination of the Amussat's sign lacks in the medicolegal literature. The review of the literature shows indeed a significant range of variability (from 1.1 % up to 25 %) regarding the macroscopic detection of the Amussat's sign. In this study, the authors report that the identification of a vital Amussat's sign is important and may require the immunohistochemical staining for the Glycophorin A (a marker of vital reaction). The victim was a 63-year-old man, who was found suspended from the staircase with a rope. Both the carotid arteries were opened in situ by using fine scissors with blunt tips. A horizontal lesion (length 4 mm) of the intima of the left common carotid artery was documented. A sample was obtained; then, a standard post-fixative histopathologic examination and immunohistochemical staining for the Glycophorin A were carried out. The standard histopathologic examination only revealed the intimal laceration with a poor hemorrhagic infiltration. However, the immunohistochemical staining for the Glycophorin A allowed the clear identification of the hemorrhagic infiltration, which was documented both in the intimal laceration and in the periadventitial soft tissues. The immunohistochemical staining for the Glycophorin A can identify the vitality of an Amussat's sign. When an Amussat's sign is documented, the Glycophorin A may therefore help the forensic pathologist to differentiate a hanging death from a postmortem suspension of the body.
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http://dx.doi.org/10.1016/j.jflm.2021.102228DOI Listing
August 2021

Noninvasive Monitoring After Azathioprine Withdrawal in Patients With Inflammatory Bowel Disease in Deep Remission.

Clin Gastroenterol Hepatol 2021 Jun 15. Epub 2021 Jun 15.

Gastroenterology Unit, "L. Sacco" University Hospital, ASST Fatebenefratelli Sacco, Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco," University of Milan, Milan, Italy.

Background & Aims: There is uncertainty regarding the optimal duration of treatment with azathioprine (AZA) in ulcerative colitis (UC) and Crohn's disease (CD). We analyzed the clinical course and predictors of relapse after AZA withdrawal in patients in sustained deep remission.

Methods: A prospective study was performed on patients who stopped their treatment with AZA while being in steroid-free, extended deep remission (normal clinical, endoscopic, and histologic indexes, C-reactive protein, and fecal calprotectin [FC]). Standard biochemical tests and FC were measured at 3 and 6 months, then every 6 months. Bowel ultrasounds and ileocolonoscopy were performed every 6 and 12 months, respectively. Multivariate analysis for predictors of relapse was performed using a Cox proportional hazards model and hazard ratios were calculated. Spearman nonparametric correlation test was also used. The accuracy of significant predictors was calculated.

Results: Fifty-seven patients with inflammatory bowel disease stopped AZA after median 7 years (range, 5-19) and were followed up for median 50 months (range, 25-85). Twenty-six patients (18/31 UC, 8/26 CD; P = .003) relapsed, within a median 15 months (range, 2-37). FC was the only variable significantly correlated with later relapse of both diseases (UC: hazard ratio, 3.3; 95% confidence interval, 1.2-10; CD: hazard ratio, 4.5; 95% confidence interval, 1.4-12.5). The sensitivity, specificity, and positive and negative predictive values of FC were 50%, 100%, 100%, and 59% in UC and 50%, 94%, 80%, and 81% in CD.

Conclusions: More than half patients with UC and one-third of patients with CD relapse after AZA withdrawal despite previous deep remission. FC positivity is associated with high risk of relapse, allowing early correction of the therapeutic strategy.
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http://dx.doi.org/10.1016/j.cgh.2021.06.014DOI Listing
June 2021

Limbic encephalitis in a COVID-19 patient?

J Neurovirol 2021 06 31;27(3):498-500. Epub 2021 Mar 31.

Neurology Departement, ASST Ovest Milanese, Via Papa Giovanni Paolo II 20025, Legnano, Italy.

We describe the case of a 79-year-old woman infected by SARS-CoV-2 and purely neurological confusional syndrome without clinically relevant respiratory disease and NMR alterations of the limbic system.
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http://dx.doi.org/10.1007/s13365-021-00971-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023772PMC
June 2021

Modified Kudo classification can improve accuracy of virtual chromoendoscopy with FICE in endoscopic surveillance of ulcerative colitis.

Endosc Int Open 2020 Oct 22;8(10):E1414-E1422. Epub 2020 Sep 22.

Gastroenterology Unit, ASST Fatebenefratelli Sacco, Milan, Italy.

 Virtual chromoendoscopy with Fuji Intelligent Color Enhancement (FICE) has never been studied in prospective trials of endoscopic surveillance for ulcerative colitis (UC). We compared FICE and white light endoscopy (WLE) in differentiation of visible lesions in UC.  In a prospective parallel study, we compared consecutive outpatients with UC submitted to surveillance colonoscopy with FICE or WLE. At least one visible polypoid or non-polypoid lesion for each patient was required. Random biopsies from normal mucosa, targeted biopsies or removal of suspected neoplastic lesions and targeted biopsies of unsuspected lesions were performed. In the FICE arm, neoplasia was suspected according to a modified Kudo classification (FICE-KUDO/inflammatory bowel disease [IBD]). Sensitivity (SE), specificity (SP), positive and negative likelihood ratios (LR) and negative predictive value (NPV) were analyzed.  One hundred patients were submitted to FICE (n = 46) or WLE (n = 54). Twenty-two patients (11 in WLE, 11 in FICE) had a least one neoplastic lesion. No neoplasia was found in random biopsies. Among 275 lesions, 17 of 136 by FICE and 27 of 139 by WLE were suspected neoplasia, but 28 (14 in each arm) were true neoplastic lesions. The accuracy of FICE-KUDO/IBD vs WLE (per lesion) was: SE 93 % vs 64 % (  = 0.065), SP 97 % vs 86 % (  = 0.002), positive-LR 28.3 vs 4.5 (  = 0.001), negative-LR 0.07 vs 0.42 (  = 0.092), NPV 99 % vs 96 % (  = 0.083). FICE-KUDO/IBD detected more non-polypoid lesions than WLE (  = 0.016).  Targeted biopsies of polypoid and non-polypoid lesions, using the modified Kudo classification with FICE are more accurate than WLE in UC surveillance.
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http://dx.doi.org/10.1055/a-1165-0169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508663PMC
October 2020

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

Ann Surg Oncol 2021 Feb 5;28(2):1167-1177. Epub 2020 Aug 5.

Unit of Pathology, Cervello Hospital, Palermo, Italy.

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer.

Patients And Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability.

Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status.

Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-08926-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801310PMC
February 2021

Lethal cardiac amyloidosis: Microscopic differential diagnosis with microfibrillar cardiomyopathy in a forensic case.

J Forensic Leg Med 2020 Apr 10;71:101939. Epub 2020 Mar 10.

Dipartimento di Scienze Biomediche per la Salute, Sezione di Medicina Legale e delle Assicurazioni, Università degli Studi di Milano, Via Luigi Mangiagalli, 37, 20133, Milano, Italy. Electronic address:

In a previous study, we presented a case of an elderly woman's sudden death, in which microscopic examinations showed intramyocardial eosinophilic material suspected for amyloid, but not definable as such to the classic Congo Red staining. To overcome the arisen interpretative and diagnostic difficulties, we experimentally modified the classic Congo Red staining, using a specific one for corpse. The finding of a low-intensity positivity allowed us to formulate a very likely diagnosis of occult lethal cardiac amyloidosis. However, this low-intensity positivity obtained after having applied this experimental method for the first time and in only one case, as well as the existence of the rare pathology known as microfibrillar cardiomyopathy, which may be related to the observed microscopic findings, have forced us to investigate the correctness of the diagnosis. For this purpose, we performed in-depth investigations with sodium sulphate-Alcian Blue (SAB) staining and immunohistochemistry. Thanks to them, the amyloid nature of the intramyocardial material was confirmed and has been proved not only the reliability of our experimentally modified technique, but also the appropriateness of the diagnosis previously formulated. Therefore, the supposed involvement of the microfibrillar cardiomyopathy was excluded.
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http://dx.doi.org/10.1016/j.jflm.2020.101939DOI Listing
April 2020

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Mod Pathol 2020 07 17;33(7):1398-1409. Epub 2020 Feb 17.

Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1 immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1 cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1 microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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http://dx.doi.org/10.1038/s41379-020-0497-0DOI Listing
July 2020

A Pilot Study on the Diagnosis of Fatal Electrocution by the Detection of Myocardial Microhemorrhages.

J Forensic Sci 2020 May 10;65(3):840-845. Epub 2019 Dec 10.

Sezione di Medicina Legale e delle Assicurazioni, Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, via Luigi Mangiagalli, 37, 20133, Milano, Italy.

In electrocutions, death may be caused by alterations in the heart conduction system provoking ventricular fibrillation. This study aims to identify histological cardiac markers of high- and low-voltage electrocution. Two groups of decedents were evaluated: group A included 14 fatalities caused by high- or low-voltage electrocution and group B (control) included 14 fatalities due to other traumatic or disease causes. Myocardial sampling with microscopic examination was performed on all the hearts using the hematoxylin and eosin and Masson's trichrome stains to investigate morphological characteristics that could indicate the damage caused by high- and low-voltage electrocutions. Interstitial myocardial hemorrhagic infiltration was the only differentiating finding, which was shown only in high-voltage electrocution. This pathological finding has not been previously reported, and it may be specific to high-voltage electrocution deaths. Further studies are warranted.
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http://dx.doi.org/10.1111/1556-4029.14255DOI Listing
May 2020

Separation of Low- Versus High-grade Crohn's Disease-associated Small Bowel Carcinomas is Improved by Invasive Front Prognostic Marker Analysis.

J Crohns Colitis 2020 Mar;14(3):295-302

IBD, San Filippo Neri Hospital, Rome, Italy.

Background And Aims: Crohn's disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn's disease-associated small bowel carcinoma prognosis.

Methods: As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn's disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium.

Results: Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn's disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months.

Conclusions: The improved distinction of lower- from higher-grade Crohn's disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.
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http://dx.doi.org/10.1093/ecco-jcc/jjz140DOI Listing
March 2020

5-ALA Fluorescence in Case of Brain Abscess by Aggregatibacter Mimicking Glioblastoma.

World Neurosurg 2019 05 8;125:175-178. Epub 2019 Feb 8.

Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Neurological Surgery, John Hopkins Medical School, Baltimore, Maryland, USA.

Background: At present, the differential diagnosis of magnetic resonance imaging enhancing lesions can still be challenging. Preoperative imaging is a valuable tool characterized by high informative value, even if false-positive and false-negative results are possible. In this context, 5-aminolevulenic acid (5-ALA) represents a significant adjunct in glioblastoma (GBM) surgery displaying an assumed specific accumulation only in tumor cells. However, it was anecdotally reported that in some cases it can also be detected in nonneoplastic lesions mimicking GBM, thus potentially leading to misdiagnosis. Moreover, precise identification of involved pathogens from intraoperative brain samples may remain difficult. We report the case of an abscess from Aggregatibacter mimicking a GBM both during preoperative imaging and intraoperatively, since showing 5-ALA fluorescence.

Case Description: A 54-year-old man presented with intense cephalalgia, vomiting, and scotomas in his left eye. Brain magnetic resonance imaging demonstrated a right temporo-occipital rim-enhancing mass, highly suggestive of a GBM, and for this reason the patient underwent 5-ALA-guided complete removal. Histopathologic analysis proved the lesion to be a bacterial abscess from Aggregatibacter as confirmed by polymerase chain reaction on bacterial deoxyribonucleic acid.

Conclusions: 5-ALA fluorescence may not be specifically involved only in malignant tumor cells, thus raising the suspect for alternative diagnoses to GBM and inviting caution into fluorescence-guided surgery.
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http://dx.doi.org/10.1016/j.wneu.2019.01.190DOI Listing
May 2019

Prion-related peripheral neuropathy in sporadic Creutzfeldt-Jakob disease.

J Neurol Neurosurg Psychiatry 2019 04 24;90(4):424-427. Epub 2018 Oct 24.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy

Objective: To assess whether the involvement of the peripheral nervous system (PNS) belongs to the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease (sCJD).

Methods: We examined medical records of 117 sCJDVV2 (ataxic type), 65 sCJDMV2K (kuru-plaque type) and 121 sCJDMM(V)1 (myoclonic type) subjects for clinical symptoms, objective signs and neurophysiological data. We reviewed two diagnostic nerve biopsies and looked for abnormal prion protein (PrP) by western blotting and real-time quaking-induced conversion (RT-QuIC) in postmortem PNS samples from 14 subjects.

Results: Seventy-five (41.2%) VV2-MV2K patients, but only 11 (9.1%) MM(V)1, had symptoms or signs suggestive of PNS involvement occurring at onset in 18 cases (17 VV2-MV2K, 9.3%; and 1 MM(V)1, 0.8%) and isolated in 6. Nerve biopsy showed a mixed predominantly axonal and demyelinating neuropathy in two sCJDMV2K. Electromyography showed signs of neuropathy in half of the examined VV2-MV2K patients. Prion RT-QuIC was positive in all CJD PNS samples, whereas western blotting detected PrP in the sciatic nerve in one VV2 and one MV2K.

Conclusions: Peripheral neuropathy, likely related to PrP deposition, belongs to the phenotypic spectrum of sCJDMV2K and VV2 and may mark the clinical onset. The significantly lower prevalence of PNS involvement in typical sCJDMM(V)1 suggests that the PNS tropism of sCJD prions is strain dependent.
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http://dx.doi.org/10.1136/jnnp-2018-319221DOI Listing
April 2019

Totally laparoscopic, multi-stage, restorative proctocolectomy for inflammatory bowel diseases. A prospective study on safety, efficacy and long-term results.

Dig Liver Dis 2018 12 21;50(12):1283-1291. Epub 2018 May 21.

Division of General Surgery, ASST Fatebenefratelli - Sacco, Milan, Italy.

Background: Laparoscopic ileo-pouch-anal anastomosis (IPAA) has been reported as having low morbidity and several advantages.

Aims: To evaluate safety, efficacy and long-term results of laparoscopic IPAA, performed in elective or emergency settings, in consecutive unselected IBD patients.

Methods: All the patients received totally laparoscopic 2-stage (proctocolectomy and IPAA - stoma closure) or 3-stage (colectomy - proctectomy and IPAA - stoma closure) procedure according to their presentation.

Results: From July 2007 to July 2016, 160 patients entered the study. 50.6% underwent a 3-stage procedure and 49.4% a 2-stage procedure. Mortality and morbidity were 0.6% and 24.6%. Conversion rate was 3.75%. 8.7% septic complications were associated with steroids and Infliximab treatment (p = 0.0001). 3-stage patients were younger (p = 0.0001), with shorter disease duration (p = 0.0001), minor ASA scores of 2 and 3 (p = 0.0007), lower inflammatory index and better nutritional status (p = 0.003 and 0.0001), fewer Clavien-Dindo's grade II complications (p = .0001), reduced rates of readmission and reoperation at 90 days (p = 0.03), and shorter hospitalization (p = .0001), but with similar pouch and IPAA leakage, compared to 2-stage patients. 8 years pouch failure and definitive ileostomy were 5.1% and 3.7%.

Conclusion: A totally laparoscopic approach is safe and feasible, with very low mortality and morbidity rates and very low conversion rate, even in multi-stage procedures and high-risk patients.
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http://dx.doi.org/10.1016/j.dld.2018.05.009DOI Listing
December 2018

Increase in chromogranin A- and serotonin-positive cells in pouch mucosa of patients with ulcerative colitis undergoing proctocolectomy.

Dig Liver Dis 2018 11 28;50(11):1205-1213. Epub 2018 Apr 28.

First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy. Electronic address:

Background: Inflammatory bowel disease (IBD) is associated with neuroendocrine cell hyperplasia.

Aims: We investigated neuroendocrine cells in J-pouches of patients with ulcerative colitis undergoing restorative proctocolectomy and ileal pouch-anal anastomosis.

Methods: Sections from pouch biopsies of 17 patients and ileal biopsies of 17 active IBD patients and 16 controls were processed by immunohistochemistry for chromogranin A (CgA) and serotonin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative RT-PCR. TpH-1 and SERT transcripts were detected in pouch biopsies cultured with infliximab or its isotype control, while interleukin (IL)-6 and IL-8 were measured in biopsy supernatants.

Results: A significant increase in CgA-positive cells and serotonin-positive cells was observed in both pouch and IBD ileum compared to control ileum. Significantly raised transcripts of TpH-1, but not SERT, were found in IBD ileum in comparison to control ileum, with no significant difference between pouch and IBD ileum. Infliximab had no influence on ex vivo pouch expression of TpH-1 and SERT, nor on the production of IL-6 and IL-8.

Conclusion: We here demonstrated neuroendocrine cell hyperplasia in pouch mucosa. Further studies are needed to clarify the pathophysiological implication of this finding.
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http://dx.doi.org/10.1016/j.dld.2018.04.021DOI Listing
November 2018

Virtual Chromoendoscopy With FICE for the Classification of Polypoid and Nonpolypoid Raised Lesions in Ulcerative Colitis.

J Clin Gastroenterol 2019 04;53(4):269-276

Gastroenterology Unit.

Goals: The aim of this study was to analyze the performance of Fuji Intelligent Color Enhancement (FICE) using the classification of Kudo in the differentiation of neoplastic and non-neoplastic raised lesions in ulcerative colitis (UC).

Background: The Kudo classification of mucosal pit patterns is an aid for the differential diagnosis of colorectal polyps in the general population, but no systematic studies are available for all forms of raised lesions in UC.

Study: All raised, polypoid and nonpolypoid, lesions found during consecutive surveillance colonoscopies with FICE for long-standing UC were included. In the primary prospective analysis, the Kudo classification was used to predict the histology by FICE. In a post hoc analysis, further endoscopic markers were also explored.

Results: Two hundred and five lesions (mean size, 8 mm; range, 2 to 30 mm) from 59 patients (mean age, 56 y; range, 21 to 79 y) were analyzed. Twenty-three neoplastic (11%), 18 hyperplastic (9%), and 164 inflammatory (80%) lesions were found. Thirty-one lesions (15%), none of which were neoplastic, were unclassifiable according to Kudo. After logistic regression, a strong negative association resulted between endoscopic activity and neoplasia, whereas the presence of a fibrin cap was significantly associated with endoscopic activity. Using FICE, the sensitivity, specificity, and positive and negative likelihood ratios of the Kudo classification were 91%, 76%, 3.8, and 0.12, respectively. The corresponding values by adding the fibrin cap as a marker of inflammation were 91%, 93%, 13, and 0.10, respectively.

Conclusions: FICE can help to predict the histology of raised lesions in UC. A new classification of pit patterns, based on inflammatory markers, should be developed in the setting of UC to improve the diagnostic performance.
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http://dx.doi.org/10.1097/MCG.0000000000000974DOI Listing
April 2019

Inhibition of Fibroblast Activation Protein Restores a Balanced Extracellular Matrix and Reduces Fibrosis in Crohn's Disease Strictures Ex Vivo.

Inflamm Bowel Dis 2018 01;24(2):332-345

Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy.

Background: Crohn's disease (CD) is a chronic bowel inflammation that ultimately leads to fibrosis, for which medical therapy is currently unavailable. Fibrotic strictures in CD are characterized by excessive extracellular matrix (ECM) deposition, altered balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), and overexpression of fibroblast activation protein (FAP), a marker of active fibroblasts. Here we investigated the role of FAP-targeted therapy in ECM remodeling in CD strictures ex vivo.

Methods: Bowel specimens were obtained from stenotic and nonstenotic ileal segments from 30 patients with fibrostenotic CD undergoing surgery. FAP expression was evaluated in isolated mucosal myofibroblasts by immunoblotting and flow cytometry. Bowel tissue cultures were treated with anti-FAP antibody, and soluble collagen, TIMP-1, and MMPs were measured in tissue culture supernatants by immunoblotting. Anti-FAP-treated myofibroblasts were analyzed for TIMP-1 expression by immunoblotting, for migratory potential by wound healing assay, and for apoptosis by Annexin V staining.

Results: Myofibroblasts from stenotic CD mucosa showed upregulation of FAP expression when compared with nonstenotic mucosa. Treatment of stenotic tissues with anti-FAP antibody induced a dose-dependent decrease in collagen production, particularly affecting type I collagen. The treatment also reduced TIMP-1 production in CD strictures, without altering MMP-3 and MMP-12 secretion. Accordingly, anti-FAP treatment inhibited TIMP-1 expression in stenotic CD myofibroblasts and enhanced myofibroblast migration without affecting survival.

Conclusions: FAP inhibition reduced type I collagen and TIMP-1 production by CD strictures ex vivo without compromising uninvolved bowel areas. These results suggest that targeting FAP could reconstitute ECM homeostasis in fibrostenotic CD.
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http://dx.doi.org/10.1093/ibd/izx008DOI Listing
January 2018

Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns.

Mod Pathol 2017 10 30;30(10):1453-1466. Epub 2017 Jun 30.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (β-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear β-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat β-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.
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http://dx.doi.org/10.1038/modpathol.2017.40DOI Listing
October 2017

Small Bowel Carcinomas in Coeliac or Crohn's Disease: Clinico-pathological, Molecular, and Prognostic Features. A Study From the Small Bowel Cancer Italian Consortium.

J Crohns Colitis 2017 Aug;11(8):942-953

Pathology Section, Spedali Civili Hospital, Brescia, Italy.

Background And Aims: An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC].

Methods: A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations.

Results: CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications.

Conclusions: In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.
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http://dx.doi.org/10.1093/ecco-jcc/jjx031DOI Listing
August 2017

Small bowel adenocarcinomas complicating Crohn's disease are associated with dysplasia: a pathological and molecular study.

Inflamm Bowel Dis 2014 Sep;20(9):1584-92

1Department of Pathology, Saint-Antoine Hospital, AP-HP, Hôpitaux Universitaires Est Parisien, Paris, France; 2University Pierre et Marie Curie-Paris 6, Paris, France; 3Intensive Care Unit, Besançon University, CHU of Besançon, Besançon, France; 4Department of Gastroenterology, Saint-Antoine Hospital, AP-HP, Hôpitaux Universitaires Est Parisien, Paris, France; Departments of 5Gastroenterology, and 6Pathology, University Hospitals Leuven, Leuven, Belgium; 7Department of Biochemistry and Oncogenetics, AP-HP, Hôpitaux Universitaires Paris Sud, University Paris Sud, Paul Brousse Hospital, Villlejuif, France; 8Department of Biochemistry, Saint-Antoine Hospital, AP-HP, Hôpitaux Universitaires Est Parisien, Paris, France; Departments of 9Gastroenterology, and 10Pathology, Luigi Sacco Hospital, Milan, Italy; Departments of 11Gastroenterology, and 12Pathology, Rouen University, CHU Charles Nicolle, Rouen, France; 13Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 14Department of Pathology, Medical University of Vienna, Vienna, Austria; Departments of 15Gastroenterology, and 16Pathology, Lille University, CHU of Lille, France; Departments of 17Gastroenterology, and 18Pathology, Beaujon Hospital, AP-HP, Université Paris Diderot, France; Departments of 19Gastroenterology, and 20Pathology, CHU of Reims, Université de Reims Champagne-Ardenne, Reims, France; Departments of 21Gastroenterology, and 22Pathology, Cliniques Universitaires UCL de Mont-Godinne, Louvain, Belgium; and 23Department of Gastroenterology, AP-HP, Hôpitaux Universitaires Paris Sud, Site de Bicêtre, University Paris Sud, Le Kremlin-Bicêtre, France.

Background: Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD.

Methods: Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, β-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations.

Results: All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for β-catenin and p16. No PIK3CA mutations were observed.

Conclusions: These results suggest that there is an inflammation-dysplasia-adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.
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http://dx.doi.org/10.1097/MIB.0000000000000112DOI Listing
September 2014

Propionyl-L-Carnitine is Efficacious in Ulcerative Colitis Through its Action on the Immune Function and Microvasculature.

Clin Transl Gastroenterol 2014 Mar 20;5:e55. Epub 2014 Mar 20.

Anatomic Pathology, Tor Vergata University, Rome, Italy.

Objectives: Microvascular endothelial dysfunction characterizes ulcerative colitis (UC), the most widespread form of inflammatory bowel disease. Intestinal mucosal microvessels in UC display aberrant expression of cell adhesion molecules (CAMs) and increased inflammatory cell recruitment. Propionyl-L-carnitine (PLC), an ester of L-carnitine required for the mitochondrial transport of fatty acids, ameliorates propionyl-CoA bioavailability and reduces oxidative stress in ischemic tissues. The present study aimed to document the efficacy of anti-oxidative stress properties of PLC in counteracting intestinal microvascular endothelial dysfunction and inflammation.

Methods: To evaluate the efficacy in vivo, we analyzed the effects in intestinal biopsies of patients with mild-to-moderate UC receiving oral PLC co-treatment and in rat TNBS-induced colitis; in addition, we investigated antioxidant PLC action in TNF-α-stimulated human intestinal microvascular endothelial cells (HIMECs) in vitro.

Results: Four-week PLC co-treatment reduced intestinal mucosal polymorph infiltration and CD4(+) lymphocytes, ICAM-1(+) and iNOS(+) microvessels compared with placebo-treated patients with UC. Oral and intrarectal administration of PLC but not L-carnitine or propionate reduced intestinal damage and microvascular dysfunction in rat TNBS-induced acute and reactivated colitis. In cultured TNF-α-stimulated HIMECs, PLC restored β-oxidation and counteracted NADPH oxidase 4-generated oxidative stress-induced CAM expression and leukocyte adhesion. Inhibition of β-oxidation by L-aminocarnitine increased reactive oxygen species production and PLC beneficial effects on endothelial dysfunction and leukocyte adhesion. Finally, PLC reduced iNOS activity and nitric oxide accumulation in rat TNBS-induced colitis and in HIMEC cultures.

Conclusions: Our results show that the beneficial antioxidant effect of PLC targeting intestinal microvasculature restores endothelial β-oxidation and function, and reduces mucosal inflammation in UC patients.
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http://dx.doi.org/10.1038/ctg.2014.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972692PMC
March 2014

Role of the advanced glycation end products receptor in Crohn's disease inflammation.

World J Gastroenterol 2013 Dec;19(45):8269-81

Rachele Ciccocioppo, Venerina Imbesi, Vincenzo Boccaccio, Elena Betti, Giuseppina Cristina Cangemi, Gino Roberto Corazza, Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy.

Aim: To investigate the level of mucosal expression and the involvement of the receptor for the advanced glycation end products (RAGE) in delayed apoptosis and tumor necrosis factor (TNF)-α production in Crohn's disease (CD).

Methods: Surgical and endoscopic specimens from both inflamed and non-inflamed areas of the ileum and/or colon were collected from 20 and 14 adult CD patients, respectively, and used for the assessment of RAGE expression by means of immunohistochemistry and western blotting analysis. Normal tissues from 21 control subjects were used for comparison. The same polyclonal anti-human RAGE antibody (R and D System) was used in all experimental conditions. RAGE staining was quantized by a score including both the amount of positive cells and intensity of immunoreactivity; cellular pattern was also described. The effects of RAGE blocking on apoptotic rate and TNF-α production were investigated on immune cells freshly isolated from CD mucosa and incubated both with and without the muramyl dipeptide used as antigenic stimulus. Statistical analysis was performed via the test for trend, with regression models to account for intra-patient correlations. A 2-sided P < 0.05 was considered significant.

Results: In inflamed areas, RAGE expression in both the epithelial and lamina propria compartments was higher than control tissues (P = 0.001 and 0.021, respectively), and a cluster of positive cells were usually found in proximity of ulcerative lesions. Similar results were obtained in the lamina propria compartment of non-inflamed areas (P = 0.025). The pattern of staining was membranous and granular cytosolic at the epithelial level, while in the lamina propria it was diffuse cytosolic. When evaluating the amount of protein expression by immunoblotting, a significant increase of both surface area and band intensity (P < 0.0001 for both) was observed in CD inflamed areas compared to control tissue, while in non-inflamed areas a significant increase was found only for band intensity (P < 0.005). Moreover, a significantly lower expression in non-inflamed areas in comparison with inflamed areas was found for both surface area and band intensity (P < 0.0006 for both). Finally, RAGE blocking largely affects both the apoptotic rate of mucosal cells (towards an increase in both non-inflamed and inflamed areas of P < 0.001 and < 0.0001, respectively) and TNF-α secretion (towards a decrease in both non-inflamed and inflamed areas of P < 0.05 and < 0.01, respectively), mainly in the presence of antigenic stimulation.

Conclusion: RAGE is up-regulated in CD, especially in inflamed areas, and it appears to play a role in the mechanisms involved in chronic inflammation.
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http://dx.doi.org/10.3748/wjg.v19.i45.8269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857450PMC
December 2013

Panencephalopathic Creutzfeldt-Jakob disease with distinct pattern of prion protein deposition in a patient with D178N mutation and homozygosity for valine at codon 129 of the prion protein Gene.

Brain Pathol 2014 Mar 27;24(2):148-51. Epub 2013 Nov 27.

Department of Biological and Medical Sciences (DSMB), University of Udine, Udine, Italy.

Prion diseases include sporadic, acquired and genetic forms linked to mutations of the prion protein (PrP) gene (PRNP). In subjects carrying the D178N PRNP mutation, distinct phenotypes can be observed, depending on the methionine/valine codon 129 polymorphism. We present here a 53-year-old woman with D178N mutation in the PRNP gene and homozygosity for valine at codon 129. The disease started at age 47 with memory deficits, progressive cognitive impairment and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years and the disease course was 6 years. The neuropathologic examination demonstrated severe diffuse cerebral atrophy with neuronal loss, spongiosis and marked myelin loss and tissue rarefaction in the hemispheric white matter, configuring panencephalopathic Creutzfeldt-Jakob disease. PrP deposition was present in the cerebral cortex, basal ganglia and cerebellum with diffuse synaptic-type pattern of immunoreactivity and clusters of countless, small PrP deposits, particularly evident in the lower cortical layers, in the striatum and in the molecular layer of the cerebellum. Western blot analysis showed the presence of type 1 PrP(Sc) (Parchi classification). These findings underline the clear-cut distinction between the neuropathological features of Creutzfeldt-Jakob disease associated with D178N PRNP mutation and those of fatal familial insomnia.
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http://dx.doi.org/10.1111/bpa.12095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029333PMC
March 2014

MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

Brain Pathol 2012 Sep 21;22(5):662-9. Epub 2012 Feb 21.

Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.
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http://dx.doi.org/10.1111/j.1750-3639.2012.00572.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057639PMC
September 2012

Immunomodulatory effects of unselected haematopoietic stem cells autotransplantation in refractory Crohn's disease.

Dig Liver Dis 2011 Dec 9;43(12):946-52. Epub 2011 Sep 9.

Chair of Immunology, Department of Biomedical Sciences and Technologies, University of Milano, Milano, Italy.

Background: Autologous haematopoietic stem cells transplantation (HSCT) has been shown to be effective in refractory Crohn's disease.

Aim: We analysed the effects of HSCT on the immune response of patients treated for moderate-severe Crohn's disease, refractory or intolerant to multiple drugs.

Methods: Unselected peripheral blood stem cells were collected after mobilisation with cyclophosphamide (CTX) and G-CSF. The conditioning regimen included CTX and rabbit antithymocyte globulin. Blood samples for immunological analyses were collected at baseline, after mobilisation, and 3, 6 and 12 months after transplantation. Immunological analyses evaluated: (1) CD4(+)/CD25(high+)/FoxP3(+) regulatory T cells (T-regs); (2) Toll-like receptor 2-(TLR2) and TRL4-expressing monocytes (CD14(+) cells); (3) IL-12, IL-10, TNF-alpha-production by mitogen-stimulated CD14(+) cells and IFN-gamma production by CD4(+) T cells. Immunological results were compared with healthy donors and associated with clinical and endoscopic response during 12 months of follow-up.

Results: Overall, T-regs increased, whilst TLR4-expressing cells, as well as TNF-alpha and IL-10, all higher than healthy donors at baseline, significantly decreased after transplantation. Full responders at T(3) had higher T-regs and lower IFN-gamma and IL12. T-regs decreased and IL12 and TLR2 increased in the only relapsed patient.

Conclusions: HSCT can induce and maintain clinical and endoscopic remission in refractory Crohn's disease, which is associated with immunomodulation.
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http://dx.doi.org/10.1016/j.dld.2011.07.021DOI Listing
December 2011

IBD care in Europe: A comparative audit of the inpatient management of Crohn's disease and ulcerative colitis using the national UK IBD audit tool.

J Crohns Colitis 2009 Dec 17;3(4):291-301. Epub 2009 Sep 17.

Department of Clinical Sciences, Gastroenterology Unit, L. Sacco University Hospital, Milan, Italy.

Background And Aims: The National UK IBD audit tool is an electronic database created to improve the quality and safety of care for IBD patients by auditing individual patient care, service resources and organisation against national standards. We used the National UK IBD audit tool to compare the organisation and process of IBD care between services in Oxford (UK) and Milan (Italy), as a pilot study to evaluate its application outside national boundaries.

Methods: Clinical and demographic data of patients with CD and UC, consecutively admitted during a 2month period, were collected and compared between the centres, to each other and to the UK IBD standards obtained by previous audit analyses performed in Oxford in 2006.

Results: 20 and 26 patients with UC were admitted in Oxford and Milan, as well as 21 and 20 patients with CD, respectively. Most admissions in Milan were planned admissions for moderately active treatment-refractory disease. No patient died. Oxford had a higher surgery rate. Endoscopy for UC consisted mainly of colonoscopy in Milan (92%) and flexible sigmoidoscopy in Oxford (64%). In CD, Oxford data revealed a higher use of immununomodulators and CT scan, compared with higher use of bowel ultrasound in Milan. CRP was the preferred biomarker of disease activity. The following areas did not reach the standards set for the 2006 UK IBD Audit: the lack in Milan of IBD specialist nurses and few dietitian visits, as well as little attention to heparin prophylaxis and abdominal radiography in UC. Both sites paid little attention to stool cultures and revealed a high rate of active smokers in CD and little attention to bone protection in steroids users. Since the 2006 audit in Oxford, improvements include IBD specialist nurse visits, dietitian visits, number of active smokers, stool samples, prophylactic heparin, bone protection and nutritional assessment.

Conclusions: Consistent procedural differences between Oxford and Milan identified by audits of both UC and CD could be resolved by organisational change, with an improvement in the service. The UK IBD audit tool is an easy instrument to assess the processes and outcomes of care delivery in IBD and can be applied also outside UK.
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http://dx.doi.org/10.1016/j.crohns.2009.08.002DOI Listing
December 2009

A novel phenotype of sporadic Creutzfeldt-Jakob disease.

BMJ Case Rep 2009 2;2009. Epub 2009 Feb 2.

Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, Milan, 20133, Italy.

An atypical case of sporadic Creutzfeldt-Jakob disease (CJD) is described in a 78-year-old woman homozygous for methionine at codon 129 of the prion protein (PrP) gene. The neuropathological signature was the presence of PrP immunoreactive plaque-like deposits in the cerebral cortex, striatum and thalamus. Western blot analysis showed a profile of the pathological form of PrP (PrP(Sc)) previously unrecognised in sporadic CJD, marked by the absence of diglycosylated protease resistant species. These features define a novel neuropathological and molecular CJD phenotype.
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http://dx.doi.org/10.1136/bcr.09.2008.0945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029211PMC
November 2011

Sporadic Creutzfeldt-Jakob disease: the extent of microglia activation is dependent on the biochemical type of PrPSc.

J Neuropathol Exp Neurol 2005 Oct;64(10):902-9

Istituto Nazionale Neurologico Carlo Besta, Milano, and Dipartimento di Scienze Neurologiche, Seconda Università di Napoli, Napoli, Italy.

In prion-related encephalopathies, microglial activation occurs early and is dependent on accumulation of disease-specific forms of the prion protein (PrPSc) and may play a role in nerve cell death. Previously, we found that different types of PrPSc (i.e. type 1 and type 2) coexisted in approximately 25% of patients with sporadic Creutzfeldt-Jakob disease (CJD); and a close relationship was detected between PrPSc type, the pattern of PrP immunoreactivity, and extent of spongiform degeneration. To investigate whether microglial reaction is related to the biochemical type and deposition pattern of PrPSc, we carried out a neuropathologic and biochemical study on 26 patients with sporadic CJD, including all possible genotypes at codon 129 of the prion protein gene. By quantitative analysis, we demonstrated that strong microglial activation was associated with type 1 PrPSc and diffuse PrP immunoreactivity, whereas type 2 PrPSc and focal PrP deposits were accompanied by mild microglia reaction. These findings support the view that the phenotypic heterogeneity of sporadic CJD is largely determined by the physicochemical properties of distinct PrPSc conformers.
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http://dx.doi.org/10.1097/01.jnen.0000183346.19447.55DOI Listing
October 2005

Flexible argon plasma coagulation treatment of obstructive tracheal metastatic melanoma.

Am J Otolaryngol 2002 Jul-Aug;23(4):253-5

IV Clinica Otorinolaringoiatrica - Università degli Studi di Milano, Polo Universitario, Ospedale L. Sacco, Milan, Italy.

Metastases to the tracheobronchial tree may be considered rare, and melanoma metastases to the trachea are very uncommon. We here report the case of a 61-year-old woman with metastatic melanoma to the trachea occurring 2 years after the excision of a right shoulder skin nodule. The patient underwent argon plasma coagulation (APC) recanalization of the malignant airway under flexible bronchoscopy, which led to the stable resolution of the respiratory symptoms. We also discuss the possible palliative therapeutic options for such metastases, including the APC technique.
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http://dx.doi.org/10.1053/ajot.2002.123455DOI Listing
September 2002
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