Publications by authors named "Maria Pia Foschini"

65 Publications

Persistent lesions in oral cavity after SARS-CoV-2 infection.

Oral Dis 2021 Feb 18. Epub 2021 Feb 18.

Section of Oral Sciences, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1111/odi.13805DOI Listing
February 2021

Co-expression of Myoepithelial and Melanocytic Features in Carcinoma Ex Pleomorphic Adenoma.

Head Neck Pathol 2021 Feb 16. Epub 2021 Feb 16.

Section of Anatomic Pathology, Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, Bologna, Italy.

The presence of melanin pigment and melanocytic markers expression have been rarely reported in salivary gland tumors. Herein, two cases of carcinoma arising in pleomorphic adenoma of the parotid gland and showing diffuse expression of myoepithelial and melanocytic markers are described. The clinical-pathological clues useful in the differential diagnosis with melanoma are discussed. In addition, a review of the pertinent literature is also proposed, discussing the pathologic mechanisms potentially involved in this phenomenon.
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http://dx.doi.org/10.1007/s12105-021-01299-4DOI Listing
February 2021

Clinical validation of 13-gene DNA methylation analysis in oral brushing samples for detection of oral carcinoma: An Italian multicenter study.

Head Neck 2021 Jan 28. Epub 2021 Jan 28.

Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy.

Background: The aim of this Italian multicenter study was to evaluate the diagnostic performance of a minimally invasive method for the detection of oral squamous cell carcinoma (OSCC) based on 13-gene DNA methylation analysis in oral brushing samples.

Methods: Oral brushing specimens were collected in 11 oral medicine centers across Italy. Twenty brushing specimens were collected by each center, 10 from patients with OSCC, and 10 from healthy volunteers. DNA methylation analysis was performed in blindness, and each sample was determined as positive or negative based on a predefined cutoff value.

Results: DNA amplification failed in 4 of 220 (1.8%) samples. Of the specimens derived from patients with OSCC, 93.6% (103/110) were detected as positive, and 84.9% (90/106) of the samples from healthy volunteers were negative.

Conclusion: These data confirmed the diagnostic performance of our novel procedure in a large cohort of brushing specimens collected from 11 different centers and analyzed in blindness.
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http://dx.doi.org/10.1002/hed.26624DOI Listing
January 2021

HER2 Overexpression and Amplification in Feline Pulmonary Carcinoma.

Vet Pathol 2021 Jan 19:300985820988147. Epub 2021 Jan 19.

University of Bologna, Bologna, Italy.

HER2 is overexpressed, amplified, and mutated in a subset of human lung cancer. The aim of this study was to investigate HER2 protein overexpression and gene amplification in feline pulmonary carcinomas. Thirteen pulmonary carcinomas were selected and TTF-1 and HER2 expression was evaluated by immunohistochemistry. Fluorescence in situ hybridization (FISH) was performed with a probe and a BAC probe for the feline chromosome E1p1.12-p1.11 region. Twelve adenocarcinomas and 1 squamous cell carcinoma were diagnosed. TTF-1 was positive in 7 carcinomas (58%). HER2 was overexpressed in 2 (15%), equivocal in 5 (38%), and negative in 6 cases (46%). FISH analysis of was indeterminate in 2 cases. Three pulmonary carcinomas (27%) had amplification and 8 cases were not amplified (73%). The significant correlation between HER2 protein overexpression and gene amplification are promising preliminary data, but study of additional cases is needed to confirm HER2 as a target for possible innovative treatments.
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http://dx.doi.org/10.1177/0300985820988147DOI Listing
January 2021

Early stability and late random tumor progression of a HER2-positive primary breast cancer patient-derived xenograft.

Sci Rep 2021 Jan 15;11(1):1563. Epub 2021 Jan 15.

Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy.

We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.
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http://dx.doi.org/10.1038/s41598-021-81085-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810859PMC
January 2021

Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management.

Histopathology 2020 Oct 28. Epub 2020 Oct 28.

Department of Histopathology, The University of Nottingham and the Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.

Aims: Although rare, malignant sarcomatoid breast tumours without evidence of epithelial differentiation comprise a diagnostic challenge with management implications. Earlier studies have generally considered these to be primary breast sarcomas; however, supporting evidence is lacking and management remains variable. This study aimed to provide an evidence-based approach to improve the consistency of diagnosis and management for such cases.

Methods And Results: A large series (n = 140) of metaplastic breast carcinoma (MBC) diagnosed in Nottingham over 18 years was analysed. Only cases with available data on immunohistochemical expression of cytokeratins (CKs) were included. The prevalence and pattern of expression for various CKs were assessed and details of tumours negative for CKs were collected. A diagnostic approach based on our experience is provided. Forty-seven cases (34%) showed foci of conventional type invasive breast carcinoma or ductal carcinoma in situ (DCIS), while 93 cases (66%) were diagnosed as MBC based on morphology and/or CK expression. Ninety-seven cases (69%) were negative for one or more CKs, with 18 cases (13%) negative for five or more CKs. Eight cases (6%) lacked expression of all CKs tested. Further examination showed evidence of carcinomatous nature in five cases, and three were diagnosed as MBC following extensive diagnostic work-up and based on our experience.

Conclusion: This study suggests that MBC represents a spectrum of neoplasms, with some lacking CK expression. Sarcomatoid neoplasms of the breast lacking evidence of carcinomatous morphology and CK expression may represent an extreme end of differentiation that can be considered as carcinomas rather than sarcomas for management purposes (following extensive work-up).
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http://dx.doi.org/10.1111/his.14290DOI Listing
October 2020

Pathological post-mortem findings in lungs infected with SARS-CoV-2.

J Pathol 2021 01 4;253(1):31-40. Epub 2020 Nov 4.

Department of Pathology, Bellaria-Maggiore Hospital, University of Bologna School of Medicine, Bologna, Italy.

Italy was the first European nation to be massively infected by SARS-CoV-2. Up to the end of May 2020, more than 33,000 deaths had been recorded in Italy, with a large prevalence among males, those over 75 years of age, and in association with co-morbidities. We describe the lung pathological and immunohistochemical post-mortem findings at the autopsy of nine patients who died of SARS-CoV-2-associated disease. We found in the lung tissues of all patients histological changes consistent with diffuse alveolar damage in various evolution phases ranging from acute exudative to acute proliferative to fibrotic phase. Alveolar damage was associated with prominent involvement of the vascular component in both the interstitial capillaries and the mid-size vessels, with capillary fibrin micro-thrombi, as well as organized thrombi even in medium-sized arteries, in most cases not related to sources of embolism. Eosinophilic infiltrate was also seen, probably reactive to pharmacological treatment. Viral RNA of SARS-CoV-2 was detected from the lung tissues of all the nine patients. Immunohistochemistry for the receptor of the SARS-CoV-2, ACE2, and its priming activator TMPRSS2 revealed that both proteins co-localize in airway cells. In particular, the ACE2 protein was expressed in both endothelial cells and alveolar type I and II pneumocytes in the areas of histological diffuse alveolar damage (DAD). Pneumocytes, but not endothelial cells, also expressed TMPRSS2. There are no distinctive histological features of SARS-CoV-2 infection with respect to SARS-CoV-1 and other DAD with different aetiology. The identification of the cause of death in the course of SARS-CoV-2 infection is more likely multi-factorial. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5549DOI Listing
January 2021

Association of Clinicopathological Features With Outcome in Chondrosarcomas of the Head and Neck.

Otolaryngol Head Neck Surg 2020 Sep 15:194599820957271. Epub 2020 Sep 15.

Service of Anatomic Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Objective: The aim of this study is to assess the association between clinical and radiological features as well as of isocitrate dehydrogenase 1 and 2 ( 1,2) mutations with outcome in head and neck chondrosarcomas.

Study Design: Retrospective study.

Setting: Tertiary referral center.

Methods: Clinical, histological, and molecular data of patients with head and neck chondrosarcomas treated by surgery were collected.

Results: Forty-six patients were included. The mean age at diagnosis was 56 years (range, 17-78). The tumor originated from the skull base (52.2%), facial bones (28.2%), or laryngotracheal area (19.6%). At last follow-up (median 52.5 months), 38 patients were alive, 30 of which were disease free, whereas 8 had died, 4 of disease progression and 4 of other causes. Fourteen (30.4%) had local recurrence and 2 (4.3%) had lung metastasis. All cases were negative for cytokeratin AE1/AE3, brachyury, and IDH1 at immunohistochemistry, while Sanger sequencing identified IDH1/2 point mutations, typically IDH1 R132C, in 9 (37.5%) tumors arising from the skull base. Margin infiltration on the surgical specimen negatively affected the outcome, whereas no correlation was identified with mutation status.

Conclusions: An adequate margin positively affects survival. mutation status does not affect patient outcome.
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http://dx.doi.org/10.1177/0194599820957271DOI Listing
September 2020

Exploring the Prognostic Role of Ki67 Proliferative Index in Merkel Cell Carcinoma of the Skin: Clinico-Pathologic Analysis of 84 Cases and Review of the Literature.

Endocr Pathol 2020 Dec 22;31(4):392-400. Epub 2020 Jul 22.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

The exact prediction of outcome of patients with Merkel cell carcinoma (MCC) of the skin is difficult to determine, although several attempts have been made to identify clinico-pathologic prognostic factors. The Ki67 proliferative index is a well-known marker routinely used to define the prognosis of patients with neuroendocrine neoplasms. However, its prognostic value has been poorly investigated in MCC, and available published results are often contradictory mainly because restricted to small series in the absence of standardized methods for Ki67 evaluation. For this reason, we explored the potential prognostic role of Ki67 proliferative index in a large series of MCCs using the WHO standardized method of counting positive cells in at least 500 tumor cells in hot spot areas on camera-captured printed images. In addition, since MCC may be considered as the cutaneous counterpart of digestive neuroendocrine carcinomas (NECs), we decided to stratify MCCs using the available and efficient Ki67 threshold of 55%, which was found prognostic in digestive NECs. This choice was also supported by the Youden index analysis. In addition, we analyzed the prognostic value of other clinico-pathologic parameters using both univariate and multivariate analysis. Ki67 index appeared significantly associated with prognosis at univariate analysis together with stage IV, lack of MCPyV, and p63 expression, but not at the multivariate analysis, where survival resulted independently influenced by p63 expression and tumor stage, only.
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http://dx.doi.org/10.1007/s12022-020-09640-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666272PMC
December 2020

Headache and Dural Enhancement: Two Case Studies of Different Treatable Pathologies.

World Neurosurg 2020 09 25;141:306-310. Epub 2020 Jun 25.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Background: Hypertrophic pachymeningitis (HP) and spontaneous intracranial hypotension are different treatable diseases, which should promptly be recognized and treated to prevent neurologic sequelae. Headache and dural enhancement are the main features of both diseases, thus differentiating between these 2 conditions can be difficult.

Cases Description: We present 2 cases with headache and dural enhancement, in which the differential diagnosis was challenging at presentation because, in both cases, clear positional pain modification was not reported. Each patient was referred to us with the suspicion of a diagnosis actually affecting the other one. Based on further findings, which supported diagnosis of spontaneous intracranial hypotension in the first case and of HP in the second one, we briefly review clinical, radiologic, and laboratory features, which can help in the differential diagnosis.

Conclusions: An accurate diagnostic workup is mandatory to distinguish among HP and intracranial hypotension.
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http://dx.doi.org/10.1016/j.wneu.2020.06.126DOI Listing
September 2020

Liver metastasis from a non-recurrent atypical cranial meningioma: a case report.

Pathologica 2020 Mar;112(1):46-49

G.B. Morgagni-L. Pierantoni Hospital, Forlì, Italy.

Extracranial metastases from atypical meningioma are rare, and even more so in the liver. We report a case of a 68-years-old patient with atypical meningioma, treated with partial surgical resection in 2012, and gamma knife radiotherapy in 2014 in another hospital, exhibiting a liver metastasis 6 years after the initial surgical resection.
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http://dx.doi.org/10.32074/1591-951X-29-19DOI Listing
March 2020

Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial.

BMC Med 2019 11 21;17(1):207. Epub 2019 Nov 21.

Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.

Background: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial.

Methods: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death.

Results: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080).

Conclusions: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment.

Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.
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http://dx.doi.org/10.1186/s12916-019-1445-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868696PMC
November 2019

A 36-Year-Old Woman With Right Eye Ptosis.

Brain Pathol 2019 05;29(3):451-452

Department of Biomedical and Neuromotor Sciences, University of Bologna.

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http://dx.doi.org/10.1111/bpa.12722DOI Listing
May 2019

HER2 Amplification Status in Feline Mammary Carcinoma: A Tissue Microarray-Fluorescence In Situ Hydridization-Based Study.

Vet Pathol 2019 Mar 1;56(2):230-238. Epub 2018 Nov 1.

1 Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor overexpressed in a subset of breast cancer due to HER2 gene amplification. HER2 protein is expressed in feline mammary carcinomas, but little is known about its cytogenetic alterations. The aim of this study was to evaluate HER2 gene amplification status and its correlation with HER2 protein expression in feline mammary carcinomas. Feline mammary carcinomas were retrospectively selected and immunohistochemically (IHC) evaluated for HER2 protein expression. All the HER2 IHC-positive (3+) and equivocal (2+) cases and a subset of negative cases (0/1+) were selected for fluorescence in situ hybridization (FISH). Dual-core tissue microarrays were prepared for FISH. IHC and FISH were evaluated according to the 2013 American Society of Clinical Oncology/College of American Pathologists guidelines. The study included 107 feline mammary carcinomas from 88 queens. HER2 protein expression was positive (3+) in 7 cases (6.5%), equivocal (2+) in 48 cases (45%), and negative (0/1+) in 52 cases (48.5%). HER2 status was indeterminate in 8 feline mammary carcinomas (12%), amplified in 3 (4%), equivocal in 4 (6%), and nonamplified in 53 (78%). HER2 gene amplification and protein expression were significantly positively correlated ( R = 0.283; P < .0001). HER2 gene is amplified in a subset of feline mammary carcinomas despite the HER2 positive or equivocal protein expression, but it remains to be determined if the HER2 amplification is a gene alteration that drives mammary tumor carcinogenesis or only a bystander passenger mutation.
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http://dx.doi.org/10.1177/0300985818808531DOI Listing
March 2019

Intratumoral Heterogeneity in Recurrent Metastatic Squamous Cell Carcinoma of the Oral Cavity: New Perspectives Afforded by Multiregion DNA Sequencing and mtDNA Analysis.

J Oral Maxillofac Surg 2019 Feb 20;77(2):440-455. Epub 2018 Sep 20.

Research Laboratory Technical Director, Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology "M. Malpighi", Bellaria Hospital, Bologna, Italy. Electronic address:

Purpose: Improvements in sequencing technologies have shown that genetic differences among neoplastic cells can reflect clonal expansion. Intratumor heterogeneity (ITH) has been suggested to explain differences in prognosis and treatment response, indicating that personalized medicine is the goal of the future. This study evaluated ITH in 5 patients with recurrent metastatic oral squamous cell carcinoma (OSCC) and tracked the evolution from non-neoplastic tissue to neoplastic events developing after primary tumor formation.

Patients And Methods: Representative regions were macrodissected from specimens obtained from patients with OSCC of the tongue (n = 4) and floor of the mouth (n = 1). ITH and tumor evolution were explored by analyzing DNA mutations disclosed by next-generation sequencing of specific driver genes combined with changes in the mtDNA D-loop hypervariable region. Phylogenetic trees were generated employing MAFFT tool with UPGMA/Jukes-Cantor serving as the substitute model.

Results: High levels of heterogeneity were observed within and among tumors. ITH emerged as metastatic and recurrent events progressed, but the evolutionary patterns differed. In some patients, specific subclones persisted during tumor relapse. Neighboring tissue also was heterogeneous at the premalignant level.

Conclusions: A multiregion approach yielded more representative data than did single samples when tumors were subjected to molecular investigation. Persistent mutations that might be targeted by individualized medicine were thus exposed. Mitochondrial DNA is a useful adjunct tool when studying the phylogenetic evolution of subclones. The clinical implications of "field" heterogeneity should be studied in depth.
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http://dx.doi.org/10.1016/j.joms.2018.09.014DOI Listing
February 2019

The role of clinical and molecular factors in low-grade gliomas: what is their impact on survival?

Future Oncol 2018 Jul 25;14(16):1559-1567. Epub 2018 Jun 25.

Department of Medical Oncology, Bellaria-Maggiore Hospitals, Azienda USL, IRCCS Institute of Neurological Sciences, Bologna, Italy.

Aim: To evaluate relevance of clinical and molecular factors in adult low-grade gliomas (LGG) and to correlate with survival.

Methods: We reviewed records from adult LGG patients from 1991 to 2015 who received surgery and had sufficient tissue to molecular biomarkers characterization.

Results: 213 consecutive LGG patients were included: 17.4% were low-risk, according to Radiation Therapy Oncology Group (RTOG) risk assessment. IDH 1/2 mutation, 1p/19q co-deletion, MGMT methylation were found in 93, 50.8 and 65.3% of patients. Median follow-up was 98.3 months. In univariate analysis, overall survival was influenced by extent of resection (p = 0.011), IDH mutation (p < 0.001), 1p/19q co-deletion (p = 0.015) and MGMT methylation (p = 0.013). In multivariate analysis, RTOG clinical risk (p = 0.006), IDH mutation (p < 0.001) and 1p/19q co-deletion (p = 0.035) correlated with overall survival. RTOG clinical risk (p = 0.006), IDH mutation (p < 0.001) and 1p/19q co-deletion (p = 0.035) correlated with overall survival.

Conclusion: Both clinical and molecular factors are essential to determine prognosis and treatment strategies.
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http://dx.doi.org/10.2217/fon-2017-0634DOI Listing
July 2018

Histological Analysis of Term Placentas from Hyperimmune Globulin-Treated and Untreated Mothers with Primary Cytomegalovirus Infection.

Fetal Diagn Ther 2019 23;45(2):111-117. Epub 2018 Apr 23.

Department of Specialized, Experimental, and Diagnostic Medicine, Operative Unit of Clinical Microbiology, St Orsola-Malpighi University Hospital, Bologna, Italy.

Background: The Congenital Human Cytomegalovirus Infection Prevention (CHIP) study, a randomized, blinded, placebo-controlled trial, demonstrated that the efficacy of hyperimmune globulin (HIG) was not different from that of placebo regarding transmission of cytomegalovirus (CMV) from mothers to newborns. Our aim was to analyze histologically HIG effects on placentas collected for the CHIP study.

Materials And Methods: Virological and histological analyses were performed on 40 placentas from transmitter and nontransmitter HIG-treated and untreated mothers by assessing the number of CMV-positive cells, tissue viral load, tissue damage, and compensatory mechanisms.

Results: The HIG and placebo groups showed no significant differences in the number of CMV-positive cells (median number in 10 fields at 10 high-power fields: 2.5 vs. 2, p = 0.969) and viral load (median load: 5 copies/5 ng vs. 10.5 copies/5 ng, p = 0.874). Regarding histological examination, the scores of parameters related to tissue damage and hypoxic parenchymal compensation were higher in transmitters except for chorangiosis, with statistically significant differences observed for chronic villitis (p = 0.007), calcification (p = 0.011), and the total score of tissue damage (p < 0.001). The HIG and placebo groups showed no significant differences for all tissue damage and compensation parameters and overall scores.

Discussion: HIGs are not able to reduce placental viral load and histological damage, which was significantly associated only with infection.
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http://dx.doi.org/10.1159/000487302DOI Listing
September 2019

Immunotherapy in head and neck cancer: evidence and perspectives.

Immunotherapy 2017 12;9(16):1351-1358

Department of Medical Oncology, Bellaria-Maggiore Hospitals, Azienda AUSL, Bologna, Italy.

Head and neck squamous cell carcinomas evade immune response through multiple immunologic resistance mechanisms. Two of the most commonly involved checkpoint inhibitory mechanisms are CTLA-4 and PD-1/PD-L1, which act at earlier and later stages of immune response to tumors. Pembrolizumab and nivolumab are PD-1 antibodies that interrupt the immunosuppressive pathway of inhibitory checkpoints, which are used by tumor cells to prevent immune reaction. Both recently gained US FDA approval for the treatment of patients with recurrent or metastatic head and neck cancer with disease progression during or following platinum containing chemotherapy. No conclusions can be drawn on the role of PD-L1 in identifying patients responding to immunotherapy, given that similar studies lead to contrasting results. It will be crucial to identify predictive markers of immunotherapy response, and to evaluate them prospectively. A better understanding of the complex network between tumor, immune system and other oncologic treatments will help us to develop more efficient multimodality treatments.
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http://dx.doi.org/10.2217/imt-2017-0125DOI Listing
December 2017

Preferential expression of NY-BR-1 and GATA-3 in male breast cancer.

J Cancer Res Clin Oncol 2018 Feb 7;144(2):199-204. Epub 2017 Nov 7.

Department of Pathology and Molecular Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.

Background: Male breast cancer is an uncommon disease often discovered in advanced stage; thus, in the setting of metastatic adenocarcinoma, breast origin must be taken to account. Breast markers as NY-BR-1, GATA-3, mammaglobin, and BRST-2 are established tools for labelling primary and metastatic female breast cancer; however, none of them has been sufficiently studied in male breast cancer. The aim of this study was to analyze the expression of these markers in male breast cancer.

Materials And Methods: Thirty consecutive cases of male breast cancer and eight loco-regional metastases were re-revaluated, assembled in tissue micro array (TMA), and stained with immunohistochemistry (IHC) for NY-BR-1, GATA-3, mammaglobin, and BRST-2. The IHC stains were scored either positive or negative. In addition, concordant expression patterns of primary tumors and matched metastasis were noted.

Results: 30 of 30 (100%) primary tumors and 8 of 8 (100%) metastases were positive for NY-BR-1. 30 of 30 (100%) primary tumors and 6 of 8 (75%) metastases were positive for GATA-3. 22 of 30 (73.3%) primary tumors and 6 of 8 (75%) metastases were positive for Mammaglobin. 18 of 30 (60%) primary tumors and 5 of 8 (62.5%) metastases were positive for BRST-2. Differences in staining percentage were not significant with Fisher's exact test.

Conclusion: We found a high sensitivity for all the markers analyzed. Moreover, the expression of NY-BR-1 and GATA-3 seemed the most effective for labelling male breast cancer in primary and metastatic setting.
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http://dx.doi.org/10.1007/s00432-017-2542-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794829PMC
February 2018

The clinicopathological spectrum of olfactory neuroblastoma and sinonasal neuroendocrine neoplasms: Refinements in diagnostic criteria and impact of multimodal treatments on survival.

Oral Oncol 2017 11;74:21-29

Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland.

Objectives: To provide a comprehensive review of the clinical and histopathological features of olfactory neuroblastoma (ONB) and other sinonasal neuroendocrine neoplasms (NENs), in order to refine diagnostic criteria, analyze treatment outcomes, and identify prognostic factors.

Methods: Data from an Italian multi-institutional database were analyzed. Patients were treated surgically via a minimally-invasive endoscopic approach followed by adjuvant radiotherapy or radiochemotherapy. Neoadjuvant cisplatin/etoposide chemotherapy was administered in cases of poorly-differentiated tumors. A centralized pathology review was performed in all cases. Patients were prospectively observed for survival. Overall (OS) and Disease-free survival (DFS) estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Statistically significant variables were entered in a multivariate Cox regression model.

Results: 98 patients with a median follow-up of 53months were included. Morphology review and the incorporation of cytokeratin 8/18 in the immunohistochemical panel modified the final diagnosis in 8/98 (8.2%) cases. The neoplasms were ultimately classified into four groups with different immunohistochemical profiles and clinical behaviors: ONB in 67 cases (5-year-OS, 91.6%); NEC (poorly-differentiated neuroendocrine carcinoma) in 22 cases (5-year-OS, 42.6%); MiNEN (mixed neuroendocrine/non-neuroendocrine neoplasm) in five cases (5-year-OS, 0%,0/5 cases); and NET (well-differentiated neuroendocrine tumor) in four cases (5-year-OS, 50%, 2/4 cases). Hyams grade and Ki67 index were independent prognostic factors for ONB. Neoadjuvant chemotherapy appeared to be associated with improved OS and DFS for NEC, independent of other clinicopathological variables.

Conclusions: Induction chemotherapy improves survival outcomes in patients affected by poorly-differentiated tumors. Recent advances in histopathological diagnosis, including CK8/18 staining, allow to plan the most appropriate range of multimodal treatments.
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http://dx.doi.org/10.1016/j.oraloncology.2017.09.010DOI Listing
November 2017

CpG location and methylation level are crucial factors for the early detection of oral squamous cell carcinoma in brushing samples using bisulfite sequencing of a 13-gene panel.

Clin Epigenetics 2017 15;9:85. Epub 2017 Aug 15.

"M. Malpighi" Section of Anatomic Pathology, Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, via Altura n.3, 40137 Bologna, Italy.

Background: Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next-generation sequencing.

Methods: With minimally invasive oral brushing, 28 consecutive OSCC, one squamous cell carcinoma with sarcomatoid features, six high-grade squamous intraepithelial lesions (HGSIL), 30 normal contralateral mucosa from the same patients, and 65 healthy donors were evaluated for DNA methylation analyzing 18 target genes by quantitative bisulfite next-generation sequencing. We further evaluated an independent cohort (validation dataset) made of 20 normal donors, one oral fibroma, 14 oral lichen planus (OLP), three proliferative verrucous leukoplakia (PVL), and two OSCC.

Results: Comparing OSCC with normal healthy donors and contralateral mucosa in 355 CpGs, we identified the following epigenetically altered genes: , , , , , , , , , , , and showing hypermethylation and , , and showing hypomethylation The behavior of , , , , and fluctuated among different interrogated CpGs. The gap between normal and OSCC samples remained mostly the same (Kruskal-Wallis values < 0.05), but the absolute values changed conspicuously. ROC curve analysis identified the most informative CpGs, and we correctly stratified OSCC and HGSIL from normal donors using a multiclass linear discriminant analysis in a 13-gene panel (AUC 0.981). Only the OSCC with sarcomatoid features was negative. Three contralateral mucosa were positive, a sign of a possible field cancerization. Among imprinted genes, only showed loss of imprinting. , , and together with the global methylation of were unchanged. In the validation dataset, values over the threshold were detected in 2/2 OSCC, in 3/3 PVL, and in 2/14 OLP.

Conclusions: Our data highlight the importance of CpG location and correct estimation of DNA methylation level for highly accurate early diagnosis of OSCC.
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http://dx.doi.org/10.1186/s13148-017-0386-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558660PMC
May 2018

The Milan System for Reporting Salivary Gland Cytopathology: Analysis and suggestions of initial survey.

Cancer Cytopathol 2017 Oct 14;125(10):757-766. Epub 2017 Jul 14.

Department of Pathology and Laboratory Medicine, Wisconsin State Laboratory of Hygiene, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Background: An international panel of experts in the field of salivary gland cytology (SGC), supported by the American Society of Cytopathology (ASC) and the International Academy of Cytology, conducted a survey to seek evidence and practice patterns regarding SGC. Results were used to provide focus for the proposed Milan System for Reporting Salivary Gland Cytopathology.

Methods: The study group, formed during the 2015 European Congress of Cytology held in Milan, Italy, generated a survey that included 49 specific questions related to the taxonomies, practices, and diagnostic entities of salivary cytology. Qualtrics software was used as the study platform. Software and server support were provided by the division of information technology at the University of Wisconsin. The survey was available online from November 2015 until February 2016. Participants were invited through the Web sites of the ASC, the International Academy of Cytology, and the Papanicolaou Society of Cytopathology as well as by the ASC e-mail "ListServe"; responses were evaluated by the Milan System editors.

Results: Responses from a total of 515 participants were collected and reviewed. A total of 347 participants provided demographic data information. Responses revealed variations in diagnostic practice and subsequent management. Participants believed that the acceptable rate for nondiagnostic samples should not be higher than 10%. There were varied opinions regarding the approach to neoplastic lesions of uncertain malignant potential, those that may or may have not local invasion and distant spread.

Conclusions: Results of the survey demonstrated strong support for the development of a unified system for reporting SGC. Cancer Cytopathol 2017;125:757-66. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncy.21898DOI Listing
October 2017

Endoscopic Endonasal Surgery for Pituitary Apoplexy: Evidence On a 75-Case Series From a Tertiary Care Center.

World Neurosurg 2017 Oct 30;106:331-338. Epub 2017 Jun 30.

Center of Pituitary Tumors and Endoscopic Skull Base Surgery, Department of Neurosurgery, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Background: The optimal management of pituitary apoplexy (PA) remains debated. The aim of this study was to assess the outcome of the transsphenoidal approach for PA in a large surgical experience.

Materials: Each consecutive case of PA consecutively operated by endoscopic endonasal approach from our tertiary care center, from 1998 to 2015, was included in this series.

Results: Seventy-five patients (47 male; mean age 52.4 ± 16.2 years) were included. Mean follow-up was 69.3 ± 46.7 months. On admission, all patients presented with abrupt severe headache (100%), associated with anterior hypopituitarism in 51 patients (68%), visual disturbances in 55 (73.4%), ophthalmoplegia in 38 (50.7%), and a remarkable reduction of consciousness in 2 (2.6%). Apoplexy proved to be ischemic in 35 patients (46.7%) and hemorrhagic in 40 (53.3%). Patients with hemorrhagic necrosis presented more often with major suprasellar expansion (P = 0.012) Radical removal was achieved in 60 cases (80%). Surgical morbidity consisted in one case of postoperative cerebrospinal fluid leak (1.3%). Anterior hypopituitarism worsened in 15 cases (20%), and diabetes insipidus occurred in 4 cases (5.3%). Ophthalmoplegia improved/normalized in 71% and visual symptoms in 85.5% of the patients, with better results achieved in ischemic forms (P = 0.043). The 2 comatose patients regained normal consciousness.

Conclusions: The endoscopic endonasal approach represents a valid, effective, and safe technique in the management of PA. Favorable outcomes can be achieved by referring patients to dedicated pituitary centers with a multidisciplinary team. Further studies are still needed to define criteria for surgical indication and to identify outcome predictors.
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http://dx.doi.org/10.1016/j.wneu.2017.06.117DOI Listing
October 2017

p16 protein expression and correlation with clinical and pathological features in osteosarcoma of the jaws: Experience of 37 cases.

Head Neck 2017 09 31;39(9):1825-1831. Epub 2017 May 31.

Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology "M. Malpighi" at Bellaria Hospital, University of Bologna, Bologna, Italy.

Background: In literature, no markers have been reported as predictive and prognostic factors in osteosarcoma of the jaw.

Methods: A retrospective analysis of p16 expression was performed in 37 patients with high-grade osteosarcoma of the jaw to investigate its potential prognostic and predictive value.

Results: p16 positivity was found in 56.7% of cases. The absence of p16 expression was associated with an adverse disease-free survival (P = .003). At the multivariate Cox regression, positive margins were the only independent factor. In the subgroup of 17 patients who underwent neoadjuvant chemotherapy, a significant association was noted between p16 expression and pathological response to chemotherapy (P = .015) and the negativity of p16 increased the risk of negative outcome (P = .01).

Conclusion: Our data indicate that the wide surgical margin is the most important prognostic factor. The expression of p16 confers greater sensitivity to chemotherapy and its loss of expression is associated with a worse prognosis.
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http://dx.doi.org/10.1002/hed.24835DOI Listing
September 2017

Role of Methylation Status at Time of Diagnosis and Recurrence for Patients with Glioblastoma: Clinical Implications.

Oncologist 2017 04 8;22(4):432-437. Epub 2017 Mar 8.

Department of Neurosciences, Statistic and Informatic Unit, Azienda Ospedale-Università, Padova, Italy.

Background: methylation status represents a powerful prognostic factor in newly diagnosed glioblastoma (GBM). Recently, its role in recurrent tumors has also been suggested; however, few data investigating the stability of this biomarker during the clinical course of the disease are available. In this study, we evaluated the rate of change of methylation status between diagnosis and first recurrence in patients who received tumor resection for recurrent GBM.

Methods: We included patients who received temozolomide concurrent with and adjuvant to radiotherapy after diagnosis of GBM and had a second surgery performed at least 3 months after radiotherapy completion. Other eligibility criteria were age ≥18 years and Eastern Cooperative Oncology Group performance status 0-2. We evaluated the methylation status by methylation-specific polymerase chain reaction.

Results: From our institutional data warehouse, 295 patients with recurrent GBM who underwent second surgery were evaluated. methylation status at both first and second surgery was available for 108 patients. MGMT was methylated in both surgeries in 38 patients (35.2%), while it was unmethylated in 43 patients (39.8%). We found a significant concordance between the first and the second methylation assessments (K = 0.500,  < .001), methylation being stable in 75% of the cases.

Conclusion: methylation presents relative stability during the clinical course of GBM. 2017;22:432-437 IMPLICATIONS FOR PRACTICE: methylation is a prognostic factor in newly diagnosed glioblastoma. In this study, we evaluated the rate of change of methylation during the clinical course of the disease, and we found a significant concordance between the first and the second methylation assessments, with methylation being stable in 75% of the cases. Thus, re-testing this biomarker at recurrence does not provide further information for clinicians. methylation at first surgery, extent of resection at second surgery, and time between first and second surgery are significantly correlated with overall survival. Age and extent of resection are correlated with post-progression survival.
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http://dx.doi.org/10.1634/theoncologist.2016-0254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388380PMC
April 2017

Paraneoplastic cerebellar degeneration and lambert-eaton myasthenia in a patient with merkel cell carcinoma and voltage-gated calcium channel antibodies.

Muscle Nerve 2017 Nov 23;56(5):998-1000. Epub 2017 Mar 23.

Department of Biomedical and Neuromotor Sciences (DiBiNeM), University of Bologna, Via Altura 3, 40139, Bologna, Italy.

Introduction: Merkel cell carcinoma is a rare cutaneous, aggressive tumor. Although it shares many neuroendocrine features with small cell lung carcinoma, it has only occasionally been reported with paraneoplastic neurological syndromes.

Methods: A healthy 67-year-old man developed acute ataxia, vertigo, and nausea. Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia. He underwent a full diagnostic workup and was found to have a high titer of voltage-gated calcium channel antibodies in serum and cerebrospinal fluid, neurophysiological findings compatible with Lambert-Eaton myasthenia and neurological signs compatible with cerebellar degeneration.

Results: A positron emission tomography study revealed a hypermetabolic lesion in the axilla, subsequently biopsied and consistent with Merkel cell carcinoma.

Conclusions: In most previous reports, neurological symptoms preceded the Merkel cell carcinoma diagnosis, and the primary localization was in lymph nodes. This tumor should be considered in patients with paraneoplastic syndrome, and particularly Lambert-Eaton myasthenia after exclusion of small cell lung carcinoma. Muscle Nerve 56: 998-1000, 2017.
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http://dx.doi.org/10.1002/mus.25530DOI Listing
November 2017

Laminin-5 and insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression in preoperative biopsy specimens from oral cancer patients: Their role in neural spread risk and survival stratification.

J Craniomaxillofac Surg 2016 Dec 21;44(12):1896-1902. Epub 2016 Jul 21.

Department of Biomedical and Neuromotor Sciences, Section of Maxillofacial Surgery, University of Bologna, Policlinico S. Orsola, Bologna, Italy.

Perineural invasion (PNI) hinders the ability to establish local control of oral squamous cell carcinoma (OSCC). To date, PNI can be evaluated only in surgical specimens and not in preoperative biopsy material, rendering timely therapeutic planning impossible. Insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression appears to be of diagnostic and prognostic utility for many solid tumours, and laminin-5 expression in surgical specimens has been identified as a valid predictor of neural spread of head-and-neck neoplasms. The ability to use preoperative biopsy material to identify patients exhibiting PNI is fundamental for good management of OSCC. We examined a series of 64 consecutive patients treated (primarily via surgery) for OSCC between 2009 and 2014 at the Maxillofacial Surgery Unit, University of Bologna. We evaluated IMP3 and laminin-5 expression in preoperative biopsy material using immunohistochemistry and quantitative reverse transcription polymerase chain reaction. We sought to correlate expression of IMP3 and laminin-5 with PNI evident in surgical specimens. Expression of IMP3 and laminin-5 in preoperative biopsy material appeared to be predictive of PNI in patients with OSCC (P < 0.001). Additionally, the results of multivariate analyses showed that IMP3 status was an independent predictor of death of patients with OSCC (P = 0.001). The present study demonstrates that IMP3 and laminin-5 expression in preoperative biopsy material correlate well with PNI status and may allow accurate preoperative risk stratification of patients with OSCC.
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http://dx.doi.org/10.1016/j.jcms.2016.07.012DOI Listing
December 2016

The changing faces of corticotroph cell adenomas: the role of prohormone convertase 1/3.

Endocrine 2017 May 4;56(2):286-297. Epub 2016 Aug 4.

Department of Biomedical and Neuro-Muscular Sciences, Section of Anatomic Pathology 'M.Malpighi' at Bellaria Hospital, University of Bologna, Bologna, Italy.

The spectrum of corticotroph cell adenomas is very wide. Though rarely, silent corticotroph cell adenomas (SCA) may transform into corticotroph cell adenomas associated with Cushing's disease (CD). The aim of the study was to investigate the role of prohormone convertase 1/3 (PC1/3) in the transformation of SCA into CD. We reviewed the records of 1259 consecutive endoscopic endonasal procedures for pituitary adenomas from 1998 to 2013. Of these, 132 were CD and 44 were SCA. During the follow-up, three patients with SCA showed a clear transformation from SCA into CD and underwent surgery once again to remove the recurrent tumour. The PC1/3 expression was analysed by both immunohistochemistry and quantitative real time-polymerase chain reaction (qRT-PCR) in primary and recurrent tumours. The immunohistochemical PC1/3 expression was negative or weak in the three patients in the initial phase of SCA, while a strong expression was observed in the majority of neoplastic cells in tissue specimens obtained from the same three patients at the time of recurrence as CD. The immunohistochemical PC1/3 expression showed a strict correlation with the PC1/3 levels obtained by qRT-PCR. In 14 cases of SCA with no change of phenotype during the follow-up, the immunohistochemical PC1/3 expression was low and strictly associated with the level of PC1/3 obtained by qRT-PCR both in primary (14/14 cases) and in recurrent tumours (4/4 cases). Our study provides insight into the crucial role of the PC1/3 protein in the transformation of phenotype from SCA to CD.
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http://dx.doi.org/10.1007/s12020-016-1028-0DOI Listing
May 2017