Publications by authors named "Rachele Del Sordo"

53 Publications

Update on ozanimod for ulcerative colitis.

Drugs Today (Barc) 2022 Jul;58(7):351-367

Gastroenterology & Hepatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

Treating moderate to severe ulcerative colitis (UC) has been enriched by the increasing number of drugs available for this disease. However, failure of conventional therapies, an incomplete response, or loss of response to biologics is experienced in many UC patients. Thus, there is still a growing need for new drugs in the therapeutic arsenal for UC. Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator which has been recently approved for UC therapy. In this review, we focus on the mechanism of action of ozanimod hydrochloride in preclinical studies of intestinal inflammation as well as its clinical effectiveness and safety in moderate to severe UC patients. In this population, ozanimod was shown to be significantly more effective than placebo to induce clinical remission. Additionally, in terms of clinical response, corticosteroid-free remission, endoscopic improvement and mucosal healing, ozanimod performed significantly better than placebo in this population. No significant safety concerns about ozanimod emerged from clinical trials in UC.
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http://dx.doi.org/10.1358/dot.2022.58.7.3408818DOI Listing
July 2022

Fertility Preservation and Restoration Options for Pre-Pubertal Male Cancer Patients: Current Approaches.

Front Endocrinol (Lausanne) 2022 16;13:877537. Epub 2022 Jun 16.

Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

Fertility preservation for prepubertal male patients undergoing gonadotoxic therapies, potentially depleting spermatogonial cells, is an expanding necessity, yet most of the feasible options are still in the experimental phase. We present our experience and a summary of current and novel possibilities regarding the different strategies to protect or restore fertility in young male patients, before proceeding with chemotherapy or radiotherapy for malignances or other diseases. Adult oncological patients should always be counselled to cryopreserve the semen before starting treatment, however this approach is not suitable for prepubertal boys, who aren't capable to produce sperm yet. Fortunately, since the survival rate of pediatric cancer patients has skyrocketed in the last decade and it's over 84%, safeguarding their future fertility is becoming a major concern for reproductive medicine. Surgical and medical approaches to personalize treatment or protect the gonads could be a valid first step to take. Testicular tissue autologous grafting or xenografting, and spermatogonial stem cells (SSCs) transplantation, are the main experimental options available, but spermatogenesis is becoming an intriguing alternative. All of these methods feature both strong and weak prospects. There is also relevant controversy regarding the type of testicular material to preserve and the cryopreservation methods. Since transplanted cells are bound to survive based on SSCs number, many ways to enrich their population in cultures have been proposed, as well as different sites of injection inside the testis. Testicular tissue graft has been experimented on mice, rabbits, rhesus macaques and porcine, allowing the birth of live offspring after performing intracytoplasmic sperm injection (ICSI), however it has never been performed on human males yet. spermatogenesis remains a mirage, although many steps in the right direction have been performed. The manufacturing of 3D scaffolds and artificial spermatogenetic niche, providing support to stem cells in cultures, seems like the best way to further advance in this field.
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http://dx.doi.org/10.3389/fendo.2022.877537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244702PMC
June 2022

A giant polyp in a filiform polyposis hides Crohn's disease.

Dig Liver Dis 2022 Jun 24. Epub 2022 Jun 24.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

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http://dx.doi.org/10.1016/j.dld.2022.06.006DOI Listing
June 2022

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Nutrients 2022 Jun 15;14(12). Epub 2022 Jun 15.

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN 55907, USA.

Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. The median VH in NCGS was significantly shorter (600, IQR: 400-705) than controls (900, IQR: 667-1112) ( < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390-620) vs. 427 µm (IQR: 348-569, = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls ( < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. : NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.
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http://dx.doi.org/10.3390/nu14122487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230100PMC
June 2022

Case Report: Optic Atrophy and Nephropathy With m.13513G>A/MT-ND5 mtDNA Pathogenic Variant.

Front Genet 2022 3;13:887696. Epub 2022 Jun 3.

Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum-University of Bologna, Bologna, Italy.

Isolated complex I deficiency represents the most common mitochondrial respiratory chain defect involved in mitochondrial disorders. Among these, the mitochondrial DNA (mtDNA) m.13513G>A pathogenic variant in the NADH dehydrogenase 5 subunit gene (MT-ND5) has been associated with heterogenous manifestations, including phenotypic overlaps of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, Leigh syndrome, and Leber's hereditary optic neuropathy (LHON). Interestingly, this specific mutation has been recently described in patients with adult-onset nephropathy. We, here, report the unique combination of LHON, nephropathy, sensorineural deafness, and subcortical and cerebellar atrophy in association with the m.13513G>A variant.
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http://dx.doi.org/10.3389/fgene.2022.887696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204033PMC
June 2022

Histological Features of Celiac-Disease-like Conditions Related to Immune Checkpoint Inhibitors Therapy: A Signal to Keep in Mind for Pathologists.

Diagnostics (Basel) 2022 Feb 3;12(2). Epub 2022 Feb 3.

Institute of Pathology, ASST-Spedali Civili Brescia, 25123 Brescia, Italy.

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1), and its ligand PDL-1, are finding increasing application in the treatment of malignant neoplasms. The widespread clinical use of these drugs, however, resulted in the discovery of side effects. The occurrence of celiac disease (CD) after ICIs therapy has been reported in the literature, but its incidence remains unknown and the role of ICIs in its onset is not yet clear. In this review, we examine the published data on this topic in order to better understand and define this entity from a histological point of view. We performed an electronic literature search to identify original reports in which CD or pathological CD-like conditions were documented histologically in patients treated with ICIs. We identified ten papers. A total of twenty-five patients were included in these publications, eleven of them receiving a serologic and histological diagnosis of CD, and four a histological diagnosis of CD-like conditions, in which pathogenesis appears to be multifactorial. ICIs can cause a CD-like enteropathy and biopsies with clinical integration are crucial to diagnose this condition. CD rarely has been observed during treatment with ICIs and its morphological aspects are similar to ICIs-CD enteropathy. Moreover, the onset of ICIs-CD may have a distinct immune mechanism compared to classical CD. Thus, the pathologists must make a histological diagnosis of CD with caution and only in adequate clinical and serological context.
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http://dx.doi.org/10.3390/diagnostics12020395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871268PMC
February 2022

Therapeutic agents affecting the immune system and drug-induced inflammatory bowel disease (IBD): A review on etiological and pathogenetic aspects.

Clin Immunol 2022 01 29;234:108916. Epub 2021 Dec 29.

Institute of Pathology ASST-Spedali Civili Brescia, Brescia, Italy.

In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.
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http://dx.doi.org/10.1016/j.clim.2021.108916DOI Listing
January 2022

IgA deposits in celiac disease. Their immunohistochemistry value in early diagnosis.

Dig Liver Dis 2022 02 29;54(2):198-199. Epub 2021 Nov 29.

Institute of Pathology ASST Spedali Civili Brescia, Brescia, Italy.

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http://dx.doi.org/10.1016/j.dld.2021.11.007DOI Listing
February 2022

A rare finding of Actinomyces odontolyticus abdominal actinomycosis presenting as abdominal wall and pericolic pseudotumoral mass.

Ann Ital Chir 2021 Sep 27;10. Epub 2021 Sep 27.

Abdominal actinomycosis refers to a rare chronic suppurative infectious occurrence, caused by filamentous Gram-positive microaerophilic and anaerobic bacteria Actinomyces, that may appear as an abdominal mass and/or abscess, feasibly mimicking a malignancy 1,2. Due to its rarity and unspecific clinical evidence, the majority of cases are diagnosed after tissue specimen. We hereby report a case of a 69-year-old patient with a one week worsening abdominal pain and swelling. A large tender palpable mass in the epigastric region was noted on physical exam. An ultrasound-guided drainage followed by a surgical excision approach became both a way to confirm the diagnosis and a therapeutic tool. Diagnosis of actinomycosis was made on histopathology and microbiology. Even though the incidence of actinomycosis has decreased, the abdominal presentation has been observed with increasing frequency 3. KEY WORDS: Actinomycosis, Abdominal wall, Abdominal abscess, foreign-body reaction, Colonic neoplasms.
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September 2021

Imatinib and Dasatinib-induced Ulcerative Colitis: Case Report.

Inflamm Bowel Dis 2022 Jan;28(1):e1-e2

Institute of Pathology ASST-Spedali Civili Brescia, Brescia, Italy.

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http://dx.doi.org/10.1093/ibd/izab196DOI Listing
January 2022

Collagenous Sprue and Olmesartan: another pathological condition related to this drug.

Dig Liver Dis 2021 Nov 1;53(11):1524-1526. Epub 2021 Jul 1.

Division of Gastroenterology, 'Brotzu' Hospital, Cagliari,, Italy.

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http://dx.doi.org/10.1016/j.dld.2021.06.010DOI Listing
November 2021

[Relevance of an accurate microscopic examination of urinary sediment in a patient after mitral valve surgery].

G Ital Nefrol 2021 Jun 24;38(3). Epub 2021 Jun 24.

S.C. di Anatomia e Istologia Patologica, Ospedale S. Maria della Misericordia, Perugia, Italy.

Hemoglobinuria, clinically revealing as gross hematuria associated with anemia, increased hemolysis indices, acute kidney injury (AKI), can all be caused by mechanical intravascular hemolysis following mitral valve surgery. It can result from factors related to the surgical procedure or acquired later, such as paravalvular leak (PL), whose definite diagnosis is based on transesophageal echocardiography. We report the case of a patient who experienced macrohematuria and AKI, initially attributed to acute glomerulonephritis, two months after mitral valve surgery. Careful microscopic examination of the urinary sediment was a diriment diagnostic tool to differentiate acute renal failure caused by hemoglobinuria from hematuria in the course of acute glomerulonephritis, directing clinicians to investigate post-operative valvular dysfunction. From the literature review we can deduce that, notwithstanding new technologies in cardiac surgery, this rare form of AKI from intravascular hemolysis requires immediate nephrological attention and that the use of microscopic urinary sediment is decisive.
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June 2021

Olmesartan associated enteropathy. A multiface clinical and histological entity.

Dig Liver Dis 2021 05 17;53(5):666-668. Epub 2021 Mar 17.

Institute of Pathology, ASST-Spedali Civili Brescia, Italy.

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http://dx.doi.org/10.1016/j.dld.2021.02.024DOI Listing
May 2021

The implementation of a commercially available multi-gene profile test for breast cancer characterization in a department of pathology: what have we learned from the first 100 cases?

Virchows Arch 2021 Jun 6;478(6):1079-1087. Epub 2021 Jan 6.

Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, P.le Menghini 1, Perugia, 06129, Italy.

Analysis of breast cancer prognostic and predictive factors is still nowadays poorly accurate and standardized. The advent of multi-gene expression profiles (MGEPs) has improved the prediction of breast cancer outcome, particularly regarding early luminal breast cancers (LBCs). The availability in our Institute of EndoPredict® (EP), a last-generation prognostic gene signature assay, has prompted us to study a series of LBCs, firstly verifying its reproducibility on six routine representative cases, either presenting non-optimal preanalytical conditions or different tumor samples from the same patient; secondly, correlating EP results on 8 retrospectively recruited samples with patients' follow-up; thirdly, applying prospectively EP on 100 routinely diagnosed cases, assessing the oncologists' and pathologists' attitude toward it. The complete reproducibility of EP on all the samples investigated in the first phase allowed to state that EP overcomes the detrimental effects of an inaccurate pre-analytic phase, determining the most appropriate prognostic and predictive parameters of breast cancer. The second phase confirmed EP as a fundamental tool in guiding therapeutic decision, improving the classical bio-pathological characterization and recovering 38% patients' inadequately managed. Finally, the study disclosed how oncologists sometimes inadequately requested EP, but also how it allows a better stratification of breast cancer otherwise considered poorly aggressive and not requiring an EP test, such as G1 neoplasms or tubular histotype. In conclusion, the introduction of EP test in an Anatomic Pathology Department emerges as a useful tool in routine breast cancer diagnosis, both for the characterization of individual cases and, as a result, for more appropriate therapeutic choices.
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http://dx.doi.org/10.1007/s00428-020-02994-3DOI Listing
June 2021

PLA2R Immunohistochemistry Staining in Membranous Glomerulopathy: A Challenging Stain to Interpret But a Potentially Useful Diagnostic Tool.

Appl Immunohistochem Mol Morphol 2021 07;29(6):414-421

Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia.

Circulating autoantibodies to phospholipase A2 receptor (PLA2R-Ab) are detected in >70% of patients with primary membranous glomerulonephritis (MGN). Detection of PLA2R antigen in renal tissue, with immunohistochemistry (PLA2R IHC), strongly correlates with serum PLA2R-Ab, although it is more sensitive. As PLA2R IHC in literature has no univocal interpretation, we suggest reliable criteria for a standard approach for the assessment of immunostaining for differential diagnosis between primary and secondary MGN. We analyzed PLA2R IHC expression in 40 biopsies of patients with MGN and serum PLA2R-Ab titer at the time of biopsy. We carefully evaluated, at high magnification, the immunostaining pattern and distribution, regardless of intensity, in capillary loops, mesangium, and podocytes of all glomeruli.We defined, adopting this approach, positive stain when a granular pattern, coarse and/or fine, diffuse or focal, and global or segmental were observed. Negative stain was defined by mesangial staining, when there was a dirty pattern, or a peripheral staining of capillary loops with a smoky linear pattern. Podocytes showed homogenous cytoplasmatic stain both in positive and negative cases and in external negative controls. We found PLA2R IHC and serum PLA2R-Ab positivity in early-middle stage MGN compared with advanced stage more frequently. Correct stratification of patients with MGN needs PLA2R-Ab detection in serum and renal tissue. PLA2R IHC test, although a challenging stain, can be an easy diagnostic tool but requires reliable interpretation keys for a standard approach to the assessment of immunostaining.
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http://dx.doi.org/10.1097/PAI.0000000000000892DOI Listing
July 2021

Assessment of TILs, IDO-1, and PD-L1 in resected non-small cell lung cancer: an immunohistochemical study with clinicopathological and prognostic implications.

Virchows Arch 2019 Feb 17;474(2):159-168. Epub 2018 Nov 17.

Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy.

Several cancers, especially non-small cell lung cancer (NSCLC), are able to escape the immunosurveillance of tumor-infiltrating lymphocytes (TILs); among the molecules involved, the indoleamine 2,3-dioxygenase 1 (IDO-1) and the programmed cell death ligand-1 (PD-L1) play a crucial role. These aspects are of great interest in the current immunotherapeutic era, therefore the current study analyses the TILs, IDO-1, and PD-L1 interactions and their correlations with clinicopathological parameters and prognosis in NSCLC. One hundred ninety-three NSCLC surgical specimens, formalin-fixed, and paraffin-embedded were assessed for TILs density, TILs localization, IDO-1 (clone 4.16H1), and PD-L1 (clone E1L3N) immunohistochemical expressions. This data was correlated with clinicopathological parameters, disease free, and overall survivals. IDO-1 and PD-L1 high expressions were related to the solid pattern of adenocarcinomas (respectively p = 0.036 and p = 0.026); high PD-L1 expression was correlated with squamous histotype (p = 0.048). IDO-1 overexpression correlated with former smokers (p = 0.041), higher adenocarcinoma stages (p = 0.039), and with both higher TILs density and PD-L1 expression (respectively p = 0.025 and p = 0.0003). A better prognosis was associated with TILs intratumoral or mixed localizations (p = 0.029). TILs localization affects NSCLC prognosis; the higher expression of IDO-1 and PD-L1 in poorly differentiated and more aggressive lung adenocarcinomas, as well as the correlation between high PD-L1 expression and squamous cell histotype, confirm the more efficient immunoescaping of these NSCLC subgroups.
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http://dx.doi.org/10.1007/s00428-018-2483-1DOI Listing
February 2019

Intravascular NK/T-cell lymphoma, Epstein-Barr virus positive with multiorgan involvement: a clinical dilemma.

BMC Cancer 2018 Nov 15;18(1):1115. Epub 2018 Nov 15.

Pathology Unit, Ospedale di Terni, University of Perugia, Perugia, Italy.

Background: Intravascular lymphoma is a rare type of non-Hodgkin lymphoma mostly of B-cell lineage. A few cases of intravascular lymphoma have been found to be of NK/T-cell origin, mainly affecting the skin and central nervous system.

Case Presentation: A 54-year-old Caucasian man sought care because of a 2 weeks history of jaundice and intermittent fever, not responsive to antibiotics and antipyretics. Laboratory tests showed low blood oxygen concentration and pancytopenia. Serum microbiological tests were negative. Computerized tomography (CT) scan revealed hepatosplenomegaly and diffuse ground-glass opacities in both lungs without interlobular septal thickening. Despite oxygen therapy, the clinical conditions rapidly deteriorated leading to death 3 days after admission. Autopsy revealed a multiorgan involvement by an Epstein-Barr virus positive NK/T-cell lymphoma, strikingly growing within the blood vessel lumina, in absence of skin lesions.

Conclusions: The current case highlights the pathological features of this rare entity, the protean clinical presentation of which is often misleading, resulting in delayed diagnosis and treatment.
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http://dx.doi.org/10.1186/s12885-018-5001-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238309PMC
November 2018

IL-9 and Mast Cells Are Key Players of Candida albicans Commensalism and Pathogenesis in the Gut.

Cell Rep 2018 05;23(6):1767-1778

Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. Electronic address:

Candida albicans is implicated in intestinal diseases. Identifying host signatures that discriminate between the pathogenic versus commensal nature of this human commensal is clinically relevant. In the present study, we identify IL-9 and mast cells (MCs) as key players of Candida commensalism and pathogenicity. By inducing TGF-β in stromal MCs, IL-9 pivotally contributes to mucosal immune tolerance via the indoleamine 2,3-dioxygenase enzyme. However, Candida-driven IL-9 and mucosal MCs also contribute to barrier function loss, dissemination, and inflammation in experimental leaky gut models and are upregulated in patients with celiac disease. Inflammatory dysbiosis occurs with IL-9 and MC deficiency, indicating that the activity of IL-9 and MCs may go beyond host immunity to include regulation of the microbiota. Thus, the output of the IL-9/MC axis is highly contextual during Candida colonization and reveals how host immunity and the microbiota finely tune Candida behavior in the gut.
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http://dx.doi.org/10.1016/j.celrep.2018.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976578PMC
May 2018

Nephrotic syndrome in primary myelofibrosis with renal extramedullary hematopoiesis and glomerulopathy in the JAK inhibitor era.

Clin Nephrol Case Stud 2017 24;5:70-77. Epub 2017 Jul 24.

Department of Experimental Medicine-Section of Pathological Anatomy and Histology, Medical School, University of Perugia.

Primary myelofibrosis (PMF) is an uncommon form of myeloproliferative neoplasm (MPN) characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow that, in fully-developed disease, is associated with reactive deposition of fibrous connective tissue, extramedullary hematopoiesis (EMH), and splenomegaly. Kidney involvement is rare and clinically presents with proteinuria, nephrotic syndrome, and renal insufficiency. Renal damage can be due to EMH and glomerulopathy. Renal EMH presents three patterns: infiltration of the interstitium with possible renal failure caused by functional damage of parenchyma and vessels, infiltration of capsule and pericapsular adipose tissue, and sclerosing mass-like lesions that can cause hydronephrosis and hydroureter with obstructive uropathy and renal failure. Glomerulopathy associated with PMF is rarely described, ranging from 1 month to 18 years from diagnosis of the neoplasm to renal biopsy. It is characterized by expansion and hypercellularity mesangial, segmental sclerosis, features of chronic thrombotic microangiopathy (TMA), and intracapillary hematopoietic cells infiltrating in absence of immune-mediated glomerulonephritis. We present a nephrotic syndrome in PMF-related glomerulopathy, associated with EMH, without renal failure, in a patient under treatment for 2 years with JAK2 inhibitor ruxolitinib. Despite treatment, the patient died 7 months after renal biopsy. Nephrologists still know very little about this topic and there is no homogeneous data about incidence, pathogenesis, and optimal treatment of this poor prognostic PMF-associated nephrotic syndrome. We focus on data in the literature in the hope of stimulating hematologists, nephrologists, pathologists to future studies about the natural history of renal involvement, useful for optimal management of this rare pathology.
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http://dx.doi.org/10.5414/CNCS109100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715205PMC
July 2017

Prognostic implication of aquaporin 1 overexpression in resected lung adenocarcinoma.

Interact Cardiovasc Thorac Surg 2017 12;25(6):856-861

Department of Thoracic Surgery, University of Perugia Medical School, Perugia, Italy.

Objectives: Aquaporins (AQPs) are a group of transmembrane water-selective channel proteins thought to play a role in the regulation of water permeability for plasma membranes. Indeed, high AQP levels have been suggested to promote the progression, invasion and metastasis of tumours. Specifically, AQP1 and AQP5 overexpression in lung adenocarcinoma (AC) have been suggested to be involved in molecular mechanisms in lung cancer. The aim of this retrospective cohort single-centre study was to assess both the levels of expression and therein the prognostic significance, regarding outcome of AQP1 and AQP5 in resected AC patients.

Methods: Patients with histological diagnoses of lung AC submitted to pulmonary resection were included in this cohort study. Tissue microarrays containing cores from 185 ACs were prepared. AQP1 and AQP5 expressions were assessed by immunohistochemistry. Results were scored as either low (Score 0-2) or high (Score 3-9). Clinical data, pathological tumour-node-metastasis staging and follow-up were recorded. Multivariate Cox survival analysis and Fisher's t-test were performed.

Results: AQP1 overexpression was detected in 85 (46%) patients, while AQP5 overexpression was observed in 45 (24%) patients. AQP1 did not result being significantly correlated with clinical and pathological parameters, while AQP5 resulted more expressed in AC with mucinous and papillary predominant patterns. Patients with AQP1 overexpression had shorter disease-free survival (P = 0.001) compared with patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter disease-free survival (P = 0.001).

Conclusions: Our results evidenced that AQP1 overexpression resulted in a shorter disease-free survival in lung AC patients. Being so, AQP1 overexpression might be an important prognostic marker in lung AC.
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http://dx.doi.org/10.1093/icvts/ivx202DOI Listing
December 2017

WITHDRAWN: Nephrotic syndrome in primary myelofibrosis with renal extramedullary hematopoiesis and glomerulopathy in the JAK inhibitor era.

Clin Nephrol 2017 07 24. Epub 2017 Jul 24.

Ahead of Print article withdrawn by publisher. The publisher apologizes for any inconvenience this has caused. The article was scheduled for the journal "Clinical Nephrology. Case Studies" (issn 2196-5293). The article is available in PubmedCentral: https://www.ncbi.nlm.nih.gov/pubmed/29350220 
.
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http://dx.doi.org/10.5414/CNCS109100DOI Listing
July 2017

Mitotic index matter: how to improve the assessment of mitosis in order to better classify G2 breast cancer and luminal A category.

Histol Histopathol 2018 Jan 23;33(1):81-88. Epub 2017 Mar 23.

Department of Experimental Medicine-Section of Pathological Anatomy and Histology, Medical School, University of Perugia, Italy.

G2 ductal infiltrating carcinomas are a heterogeneous group of tumours with ambiguous clinical significance. This is because G2 carcinomas are almost always the largest category and poorly reproducible. Mitotic count (MC) is one of the causes of poor histological grading reproducibility. The phosphoistone H3 (PPH3) antibody improves identification of mitotic figures. The aim of our study is to demonstrate whether using a new histological grading system based on PPH3 immunostaining to assess MC can re-stratify G2 category. We selected 100 cases of G2 invasive carcinoma. The mitotic score was accurately re-evaluated performing MC on PPH3 immunostained sections. 21/100 G2 cases (21%) showed the same mitotic score both with hematoxilin and eosin (H&E) and PPH3 while 79 cases (79%) with PPH3 shifted to a higher mitotic score. After re-grading the 100 G2 cases based on the assessment of mitotic score with PPH3 only 53 cases (53%) were confirmed as G2, while 47 cases (47%) had shifted to G3. Finally we reclassified early tumours in the surrogate molecular subtype according to the 2013 St. Gallen Conference criteria and found that 13/40 cases (33%) classified as luminal A were G3 with the PPH3 mitotic score and could benefit from chemotherapy. In conclusion, PPH3 improving MC gives a better categorization by halving the G2 group. In particular, applied to the surrogate subtype luminal A breast cancer it identified cases that could benefit from adjuvant cytotoxic chemotherapy.
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http://dx.doi.org/10.14670/HH-11-891DOI Listing
January 2018

Malignant giant solitary fibrous tumor of the pleura metastatic to the thyroid gland.

Tumori 2016 Nov 11;102(Suppl. 2). Epub 2016 Nov 11.

Department of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia - Italy.

Purpose: Solitary fibrous tumor (SFT) of the pleura is a rare mesenchymal neoplasm arising from mesenchymal cells in the areolar tissue subjacent to the mesothelial-lined pleura and accounting for less than 5% of primary pleural tumors. SFTs are generally benign and asymptomatic, with 10-year survival rates of up to 98%. Unfortunately, approximately 10% have malignant potential, leading to local recurrence after radical surgery and/or metastatic spread. Of note, giant pleural SFT, which consists of a tumor occupying at least 40% of the affected hemithorax, is even less common with only anecdotal cases reported in the medical literature.

Methods: We describe a unique case of giant SFT of the pleura that metastasized to the thyroid gland 1 year after complete resection, focusing on its clinical and pathological features of presentation.

Results: En bloc resection remains the mainstay of therapy with curative intent. Patients with large tumors may undergo preoperative angiography with percutaneous embolization of the tumor, which allows to reduce perioperative bleeding. In case of local recurrence, surgery still remains the best treatment option. However, surgery can also be considered in patients with isolated metastatic spread.

Conclusions: Every suspected and proven SFT of the pleura should undergo surgical resection, as clinical and radiological criteria cannot accurately distinguish benign from malignant forms. Moreover, the peculiar histological features of SFT should not be neglected when planning clinicoradiological follow-up. Additionally, suspicious clinical findings during follow-up should always be thoroughly investigated in order to exclude or confirm the diagnosis of recurrent disease.
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http://dx.doi.org/10.5301/tj.5000514DOI Listing
November 2016

The enteric nervous system in patients with calculous and acalculous gallbladder.

Dig Liver Dis 2016 Jul 26;48(7):792-5. Epub 2016 Mar 26.

Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia School of Medicine, Perugia, Italy. Electronic address:

Background: It is generally thought that gallbladder motility plays a more or less important role in the pathogenesis of gallstones. Some studies have shown that some abnormalities of its intrinsic innervations, but these studies were usually limited to one cell component.

Aims: We investigated the main cell components of gallbladder intrinsic innervation in patients with and without gallstones.

Methods: Archival gallbladder specimens from 39 patients, 27 with gallstones (age range 45-69 yrs) and 12 patients without gallstones (age range 39-71 yrs) were obtained. Full thickness sections were obtained from the gallbladder neck and immunohistochemistry was carried out for enteric neurons (neuron-specific enolase and calretinin), enteric glia (S100) and interstitial cells of Cajal (CD117 and CD34); tryptase staining was also done to distinguish the latter from mast cells.

Results: Apart from calretinin-positive neurons, patients with gallstones featured a significant decrease of neurons, enteric glial cells (EGC) and mast cells compared to those without gallstones; interstitial cells of Cajal were extremely few and only found in two patients, one for each group.

Conclusions: The intrinsic innervations of the gallbladder is abnormal in gallstone patients, and this may contribute to gallstone formation in these subjects.
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http://dx.doi.org/10.1016/j.dld.2016.03.014DOI Listing
July 2016

Axillary Lymph Node Metastases of Melanoma: Management of Third-level Nodes.

In Vivo 2016 Mar-Apr;30(2):141-5

Department of Surgery, St. Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.

Aim: To state the limits of axillary lymphadenectomy in patients with metastatic melanoma.

Patients And Methods: We performed a prospective study on patients submitted to axillary dissection for stage III melanoma. At surgery, the third-level nodes were separately dissected to be examined by the pathologist.

Results: We analyzed 86 patients. In 93%, the third-level nodes were disease-free; none of the patients with previous positive sentinel nodes (SN) showed nodal metastases at level III. Patients (7%) found to have positive level III nodes had undergone therapeutic lymphadenectomy for bulky nodal disease.

Conclusion: Our data show that axillary non-sentinel nodes of level III are usually disease-free in cases of previously positive SN, while they can be involved in the presence of bulky disease. A prerequisite allowing sparing of level III nodes after a positive SN biopsy is the meticulous research of all level I and II lymph nodes.
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December 2016

Myenteric plexitis: A frequent feature in patients undergoing surgery for colonic diverticular disease.

United European Gastroenterol J 2015 Dec;3(6):523-8

Hospital of Baselland, University of Basel, Liestal, Switzerland.

Background: Diverticular disease of the colon is frequent in clinical practice, and a large number of patients each year undergo surgical procedures worldwide for their symptoms. Thus, there is a need for better knowledge of the basic pathophysiologic mechanisms of this disease entity.

Objectives: Because patients with colonic diverticular disease have been shown to display abnormalities of the enteric nervous system, we assessed the frequency of myenteric plexitis (i.e. the infiltration of myenteric ganglions by inflammatory cells) in patients undergoing surgery for this condition.

Methods: We analyzed archival resection samples from the proximal resection margins of 165 patients undergoing left hemicolectomy (60 emergency and 105 elective surgeries) for colonic diverticulitis, by histology and immunochemistry.

Results: Overall, plexitis was present in almost 40% of patients. It was subdivided into an eosinophilic (48%) and a lymphocytic (52%) subtype. Plexitis was more frequent in younger patients; and it was more frequent in those undergoing emergency surgery (50%), compared to elective (28%) surgery (p = 0.007). All the severe cases of plexitis displayed the lymphocytic subtype.

Conclusions: In conclusion, myenteric plexitis is frequent in patients with colonic diverticular disease needing surgery, and it might be implicated in the pathogenesis of the disease.
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http://dx.doi.org/10.1177/2050640614563822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669510PMC
December 2015

The Tm7sf2 Gene Deficiency Protects Mice against Endotoxin-Induced Acute Kidney Injury.

PLoS One 2015 5;10(11):e0141885. Epub 2015 Nov 5.

Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.

Cholesterol is essential for diverse cellular functions and cellular and whole-body cholesterol homeostasis is highly controlled. Cholesterol can also influence cellular susceptibility to injury. The connection between cholesterol metabolism and inflammation is exemplified by the Tm7sf2 gene, the absence of which reveals an essential role in cholesterol biosynthesis under stress conditions but also results in an inflammatory phenotype, i.e. NF-κB activation and TNFα up-regulation. Here, by using Tm7sf2+/+and Tm7sf2-/- mice, we investigated whether the Tm7sf2 gene, through its role in cholesterol biosynthesis under stress conditions, is involved in the renal failure induced by the administration of LPS. We found that the loss of Tm7sf2 gene results in significantly reduced blood urea nitrogen levels accompanied by decreased renal inflammatory response and neutral lipid accumulation. The increased expression of fatty acids catabolic enzymes reduces the need of the renal autophagy, a known crucial nutrient-sensing pathway in lipid metabolism. Moreover, we observed that the Tm7sf2 insufficiency is responsible for the inhibition of the NF-κB signalling thus dampening the inflammatory response and leading to a reduced renal damage. These results suggest a pivotal role for Tm7sf2 in renal inflammatory and lipotoxic response under endotoxemic conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141885PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635018PMC
June 2016

The HIV matrix protein p17 induces hepatic lipid accumulation via modulation of nuclear receptor transcriptoma.

Sci Rep 2015 Oct 15;5:15403. Epub 2015 Oct 15.

Department of Surgical and Biomedical Sciences, Section of gastroenterology, University of Perugia, Perugia, Italy.

Liver disease is the second most common cause of mortality in HIV-infected persons. Exactly how HIV infection per se affects liver disease progression is unknown. Here we have investigated mRNA expression of 49 nuclear hormone receptors (NRs) and 35 transcriptional coregulators in HepG2 cells upon stimulation with the HIV matrix protein p17. This viral protein regulated mRNA expression of some NRs among which LXRα and its transcriptional co-activator MED1 were highly induced at mRNA level. Dissection of p17 downstream intracellular pathway demonstrated that p17 mediated activation of Jak/STAT signaling is responsible for the promoter dependent activation of LXR. The treatment of both HepG2 as well as primary hepatocytes with HIV p17 results in the transcriptional activation of LXR target genes (SREBP1c and FAS) and lipid accumulation. These effects are lost in HepG2 cells pre-incubated with a serum from HIV positive person who underwent a vaccination with a p17 peptide as well as in HepG2 cells pre-incubated with the natural LXR antagonist gymnestrogenin. These results suggest that HIV p17 affects NRs and their related signal transduction thus contributing to the progression of liver disease in HIV infected patients.
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http://dx.doi.org/10.1038/srep15403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606811PMC
October 2015

IMP3 Is Strongly Expressed in Malignant Phyllodes Tumors of the Breast: An Immunohistochemical Study.

Int J Surg Pathol 2016 Feb 9;24(1):37-42. Epub 2015 Sep 9.

Department of Experimental Medicine - Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Italy.

Background: Phyllodes tumors (PTs) of the breast are rare biphasic neoplasms and are classified as benign, borderline, or malignant. Many biological markers have been studied to discriminate between different grades of PTs. IMP3 is a member of the insulin-like growth factor II mRNA binding protein (IMP) family and is expressed in developing tissues during embryogenesis, whereas in adult tissues it is found only at low or undetectable levels. IMP3 is considered a marker of biological aggressiveness in many cancers, including breast and lung. The aim of this study was to evaluate the immunohistochemical expression of IMP3 in a series of PTs and to determine its association with histological grade and clinical outcome.

Materials And Methods: We reviewed retrospectively 62 cases of PTs including their recurrences and 20 cases of fibroadenoma. PTs have been classified as benign in 40 cases, borderline in 13 cases, and malignant in 9 cases.

Results: There were significant differences in IMP3 expression: in malignant PTs IMP3 expression was higher (56% of cases) than in borderline (15%) and benign cases (5%), (P = .001). Fibroadenoma showed no expression for IMP3. IMP3 expression was different in cases with recurrence than cases without recurrence. Furthermore, 3 of the recurrences had a higher histological grade with a positive IMP3 expression compared with the primary tumor.

Conclusions: This is the first study evaluating the IMP3 immunohistochemical expression in PTs. Its expression correlates with histological grade and could be used in the differential diagnosis of fibroepithelial tumors and in predicting a more aggressive behavior.
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http://dx.doi.org/10.1177/1066896915603119DOI Listing
February 2016

Inflammatory nodule mimicking a phrenic neoplasm.

Clin Respir J 2016 May 4;10(3):400-3. Epub 2014 Sep 4.

Thoracic Surgery Unit, University of Perugia Medical School, Perugia, Italy.

Background And Aims: Isolated phrenic nerve nodule is usually a primitive tumour. Surgery is diagnostic and therapeutic at the same time. We report the case of a completely serum-negative Caucasian male with a right diaphragmatic relaxation associated to an isolated small nodule of the phrenic nerve.

Methods: The patient was referred to our unit complaining shortness of breath and progressive fatigue. A standard chest X-ray showed right diaphragmatic palsy; chest scanning revealed a nodular lesion belonging to the right phrenic nerve. Positron emission tomography was negative for glucose uptake. The preoperative diagnosis of primitive neurogenic tumour was thus supposed, and the patient treated by the lesion's surgical resection along with diaphragmatic plication.

Result: Histopathological examination revealed an idiopathic inflammatory nodule of the phrenic nerve.

Conclusion: Such condition has not previously been reported in the literature among the possible aetiology of a diaphragmatic relaxation.
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http://dx.doi.org/10.1111/crj.12195DOI Listing
May 2016
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