Publications by authors named "Claudia Cippitelli"

12 Publications

  • Page 1 of 1

Low endometrial beta-catenin and cadherins expression patterns are predictive for primary infertility and recurrent pregnancy loss.

Gynecol Endocrinol 2019 Aug 26;35(8):727-731. Epub 2019 Feb 26.

a Department of Surgical and Medical Sciences and Translational Medicine , Sapienza University of Rome, Sant'Andrea University Hospital , Rome , Italy.

Inadequate uterine receptivity is responsible for two-third of implanting failures. Aim of the study was to investigate the role of epithelial adherence and tight-junction molecules expressed by human endometrium in predicting womens' fertility outcome. A total of 76 consecutive women, including 24 fertile (G1), 40 primary infertile (G2), and 12 recurrent pregnancy loss (RPL, G3) women, who underwent diagnostic hysteroscopy plus endometrial biopsy between 2005 and 2016 at the Gynecology Division of Sant'Andrea Hospital, Sapienza University of Rome, in Italy, were retrospectively identified and included into the study. Endometrial biopsies were assessed for the immunohistochemical expression of beta-catenin (β-catenin), E-cadherin and K-cadherin biomarkers. Expression profiles were compared between the three groups of patients and were correlated with patients' fertility outcome. In infertile patients there was a significant lower endometrial expression of β-catenin ( = .001), E-cadherin ( = .001) and K-cadherin ( = .002), compared to the fertile ones. Furthermore, β-catenin and E-cadherin intensity gradients of expression at glandular level were found totally reversed in infertile patients. Significant lower expression levels of K-catenin ( = .016) and E-cadherin ( < .0001) at glandular level were found in RPL patients. Results showed that the low endometrial expression of β-catenin, E-cadherin and K-cadherin were associated to fertility-related problems, such as primary intertility and RPL.
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http://dx.doi.org/10.1080/09513590.2019.1579790DOI Listing
August 2019

Raman spectroscopy discriminates malignant follicular lymphoma from benign follicular hyperplasia and from tumour metastasis.

Talanta 2019 Mar 28;194:763-770. Epub 2018 Oct 28.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy.

Raman spectroscopy is a non-destructive label-free technique providing biochemical tissue fingerprint. The objective of the present work was to test if Raman spectroscopy is a suitable tool to differentiate lymph nodes affected by different conditions, such as reactive follicular hyperplasia (benign), follicular lymphoma (low grade primary tumour), diffuse large B cell lymphoma (high grade primary tumour) and tumour metastasis (secondary tumours). Moreover, we tested its ability to discriminate follicular lymphomas by the tumour grade and the BCL2 protein expression. Lymph nodes collected from 20 patients, who underwent surgery for suspected malignancy, were investigated. Imaging of tissue areas from about 400 µm up to 2 mm was performed collecting Raman maps containing thousands of spectra. Partial least squares discriminant analysis (PLS-DA) - a bilinear classification method - was used to calculate lymph node classification models, in order to discriminate at first between benign and malignant tissues and successively among cancer types, grades and the BCL2 protein expression. This proof-of-concept study paves the way for the development of clinical optical biopsy tools for lymph node cancer diagnosis, complementary to histopathological assessment.
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http://dx.doi.org/10.1016/j.talanta.2018.10.086DOI Listing
March 2019

Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma.

J Exp Clin Cancer Res 2018 Dec 17;37(1):318. Epub 2018 Dec 17.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy.

Background: Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs.

Methods: SCD1 gene expression data of melanoma patients were downloaded from TCGA and correlated with disease progression by bioinformatics analysis and confirmed on patient's tissues by qRT-PCR and IHC analyses. The effects of combination of BRAF/MEKi and the SCD1 inhibitor MF-438 were monitored by spheroid-forming and proliferation assays on a panel of BRAF-mutated melanoma cell lines grown in 3D and 2D conditions, respectively. SCD1, YAP/TAZ and stemness markers were evaluated in melanoma cells and tissues by qRT-PCR, WB and Immunofluorescence.

Results: We first observed that SCD1 expression increases during melanoma progression. BRAF-mutated melanoma 3D cultures enriched for CSCs overexpressed SCD1 and were more resistant than 2D differentiated cultures to BRAF and MEK inhibitors. We next showed that exposure of BRAF-mutated melanoma cells to MAPK pathway inhibitors enhanced stemness features by upregulating the expression of YAP/TAZ and downstream genes but surprisingly not SCD1. However, SCD1 pharmacological inhibition was able to downregulate YAP/TAZ and to revert at the same time CSC enrichment and resistance to MAPK inhibitors.

Conclusions: Our data underscore the role of SCD1 as prognostic marker in melanoma and promote the use of SCD1 inhibitors in combination with MAPK inhibitors for the control of drug resistance.
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http://dx.doi.org/10.1186/s13046-018-0989-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298024PMC
December 2018

Burkitt lymphoma in Iraqi children: A distinctive form of sporadic disease with high incidence of EBV cases and more frequent expression of MUM1/IRF4 protein in cases with head and neck presentation.

Pediatr Blood Cancer 2018 12 11;65(12):e27399. Epub 2018 Sep 11.

Department of Clinical and Molecular Medicine, Pathology Unit, Sapienza University, Sant'Andrea Hospital, Rome, Italy.

Epstein-Barr virus (EBV)-related lymphoproliferative disorders are relatively common in Iraqi children. Burkitt lymphoma (BL) accounted for 40% of lymphoma cases. The mean age of 125 BL cases was 5.9 ± 3.1 years, and the male-to-female ratio was 3.6:1. Clinical presentation was abdominal in 66% and head and neck in 34%. Bone marrow involvement was higher (P < 0.001) in children with head and neck disease. Tumor cells had MYC translocation (96%) and were CD20 /CD10 /MYC /BCL2 . MUM1/IRF4 staining was expressed by a fraction of tumor cells in 19 of 125 cases (15%) and was more frequent (P < 0.007) in head and neck disease (12/42; 29%). EBV-encoded RNA was positive in 100 of 125 (80%) BL cases.
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http://dx.doi.org/10.1002/pbc.27399DOI Listing
December 2018

Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas.

Mod Pathol 2019 02 11;32(2):216-230. Epub 2018 Sep 11.

Department of Pathology and Cell Biology, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA.

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.
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http://dx.doi.org/10.1038/s41379-018-0130-7DOI Listing
February 2019

Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas.

Leukemia 2019 01 26;33(1):132-147. Epub 2018 Jun 26.

Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Some Epstein-Barr virus (EBV)-associated tumors have higher Programmed Cell Death Ligand, PD-L1 expression. However, it is not known how EBV alters ICs in the context of its preferred host, the B lymphocyte and in derived lymphomas. Here, we found that latency III-expressing Burkitt lymphoma (BL), diffuse large B-cell lymphomas (DLBCL) or their EBNA2-transfected derivatives express high PD-L1. In a DLBCL model, EBNA2 but not LMP1 is sufficient to induce PD-L1. Latency III-expressing DLBCL biopsies showed high levels of PD-L1. The PD-L1 targeting oncosuppressor microRNA miR-34a was downregulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR-34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-L1. MiR-34a reconstitution in EBNA2-transfected DLBCL reduced PD-L1 expression and increased its immunogenicity in mixed lymphocyte reactions (MLR) and in three-dimensional biomimetic microfluidic chips. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for combinatorial immunotherapy, which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.
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http://dx.doi.org/10.1038/s41375-018-0178-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327052PMC
January 2019

Reduced lymphotoxin-beta production by tumour cells is associated with loss of follicular dendritic cell phenotype and diffuse growth in follicular lymphoma.

J Pathol Clin Res 2018 04 6;4(2):124-134. Epub 2018 Mar 6.

Pathology Unit, Department of Clinical and Molecular Medicine, Sapienza University, Sant'Andrea Hospital, Rome, Italy.

Cytokine production is essential for follicular dendritic cell (FDC) maintenance and organization of germinal centres. In follicular lymphoma, FDCs are often disarrayed and may lack antigens indicative of terminal differentiation. We investigated the in situ distribution of cells producing lymphotoxin-beta (LTB), lymphotoxin-alpha (LTA), and tumour necrosis factor-alpha (TNFA) transcripts in human reactive lymph nodes and in follicular lymphomas with follicular or diffuse growth pattern. LTB was the cytokine most abundantly produced in germinal centres. LTB was present in nearly 90% of germinal centre cells whereas LTA and TNFA were detected in 30 and 50%, respectively. Moreover, the amount of LTB expressed in reactive germinal centre cells was 80-fold higher than that of LTA and 20-fold higher than that of TNFA. LTB-positive cells were more numerous in the germinal centre dark zone, whereas expression of the FDC proteins CD21, CD23, VCAM, and CXCL13 was more intense in the light zone. Tumour cells of follicular lymphomas produced less LTB than reactive germinal centre cells. The results of the in situ study were confirmed by RT-PCR; LTB was significantly more abundant in reactive lymph nodes than in follicular lymphoma, with the lowest values detected in predominantly diffuse follicular lymphoma. In neoplastic follicles, low production of LTB by tumour B cells was associated with weaker expression of CD21+/CD23+ by FDCs. Our findings detail for the first time the distribution of LTA-, LTB-, and TNFA-producing cells in human reactive germinal centres and in follicular lymphoma. They suggest the possibility that impaired tumour-cell LTB production may represent a determinant of FDC phenotype loss and for defective follicular organization in follicular lymphoma.
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http://dx.doi.org/10.1002/cjp2.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903694PMC
April 2018

Cytological diagnostic features of late breast implant seromas: From reactive to anaplastic large cell lymphoma.

PLoS One 2017 17;12(7):e0181097. Epub 2017 Jul 17.

Department of Clinical and Molecular Medicine, Sapienza University, Cytology Unit, Sant'Andrea Hospital, Roma, Italy.

Late breast implant seroma may be the presentation of a breast implant-associated anaplastic large cell lymphoma (BI-ALCL), which claims for a prompt recognition. However, BI-ALCL diagnosis on fine-needle aspiration (FNA) might be challenging for pathologists lacking experience with peri-implant breast effusions. Sixty-seven late breast implant seromas collected by FNA from 50 patients were evaluated by Papanicolaou smear stain and immunocytochemistry on cell blocks. A diagnostic algorithm based on the cellular composition, cell morphology and percentage of CD30+ cells was developed. Histological evaluation of the corresponding peri-prosthetic capsules was also performed. Most of the effusions (91% of the samples) were classified as reactive and 9% as BI-ALCL. In the BI-ALCL cases, medium-to-large atypical cells expressing CD30 represented more than 70% of the cellularity, whereas in in the reactive effusions CD30+ elements were extremely rare (<5%) and consisted of non-atypical elements. The reactive effusions were categorized into three patterns: i) acute infiltrate with prominent neutrophilic component (33% of the samples); ii) mixed infiltrate characterized by a variable number of neutrophils, lymphocytes and macrophages (30% of the samples); iii) chronic infiltrate composed predominantly of T lymphocytes or macrophages with only sporadic granulocytes (37% of the samples). The inflammatory cytological patterns were consistent with the histology of the corresponding capsules. Our results indicate that cytological analysis of late breast implant effusions, supported by the knowledge of the heterogeneous cytomorphological spectrum of late seromas, is a valuable approach for the early recognition of BI-ALCL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181097PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513491PMC
September 2017

Optimized immunohistochemistry using the D5F3 antibody provides a reliable test for identification of ALK-positive lung adenocarcinomas.

Virchows Arch 2017 Jul 17;471(1):123-127. Epub 2017 May 17.

Pathology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy.

We used optimized immunohistochemistry (IHC) with the D5F3 antibody for detection of tumours in a prospective study of 307 pulmonary adenocarcinomas. Cases positive by IHC (1+, 2+, 3+) were further investigated by fluorescent in situ hybridization (FISH). Of 307 cases, 22 (7.2%) were moderately intensely positive (2+/3+); 18 of these (82%) were also positive by FISH. Of the four IHC-positive/FISH-negative cases, one was unsuitable for FISH and three had abnormalities of the ALK gene. All cases with weak reactivity with D5F3 (1+) were FISH-negative. The FISH positive/IHC-positive cases with moderately intense reactivity had the typical clinicopathologic features of ALK-positive patients (younger age, p < 0.01; higher frequency in metastatic sites, p < 0.01; cribriform/mucinous/signet histology, p < 0.01; stage IV disease, p < 0.01). In conclusion, our findings indicate that optimized IHC using the D5F3 antibody provides a reliable and inexpensive test for identification of ALK-positive adenocarcinomas. Inclusion of this information in the pathology report at the time of the histological diagnosis might significantly shorten time to treatment.
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http://dx.doi.org/10.1007/s00428-017-2145-8DOI Listing
July 2017

Down-regulated miRs specifically correlate with non-cardial gastric cancers and Lauren's classification system.

J Surg Oncol 2017 Aug 5;116(2):184-194. Epub 2017 May 5.

Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy.

Background And Objectives: Gastric cancers are usually characterized using Lauren's classification into intestinal and diffuse types. We previously documented the down-modulation of miR31, miR148a, miR204, and miR375 in gastric cancers. We aimed this manuscript to investigate these miRs with the end-points of diagnosis, Lauren's classification and prognosis.

Methods: A total of 117 resected non-cardial adenocarcinomas were evaluated for miRs' expressions. The performance of miRs' expressions for cancer diagnosis was tested using ROC curves. Logistic regression was conducted with the end-point of Lauren's classification. Kaplan-Meier and Cox analyses were performed for OS, DFS, and DSS. miRs' targets were reviewed using PRISMA method and BCL-2 was further investigated in cell lines.

Results: ROC curves documented that miRs' down-modulation was significant in differentiating cancer versus normal tissues. Diffuse type cancers were associated with female sex, young age, and miR375 higher expression. We confirmed BCL-2 as a miR204 target. However, survival analyses confirmed the pathologic criteria (advanced stages, LNR, and low LNH) as the significant variables correlated to worse prognosis.

Conclusions: The down-modulation of miR31, miR148a, miR204, and miR375 is significantly associated with non-cardial gastric cancers and miR375 is specifically linked to Lauren's classification. Nevertheless, standard pathological features display as the independent variables associated with worse prognosis.
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http://dx.doi.org/10.1002/jso.24648DOI Listing
August 2017

Oncocytic Variant of Medullary Thyroid Carcinoma: A Rare Case of Sporadic Multifocal and Bilateral Wild-Type Neoplasm with Revision of the Literature.

Rare Tumors 2016 Nov 20;8(4):6537. Epub 2016 Dec 20.

Department of Pathology, Sant'Andrea Hospital, University Sapienza of Rome , Gemelli Hospital, Rome Italy.

Oncocytic variant of medullary thyroid carcinoma (OV-MTC) is a very unusual entity, up to date only 17 cases have been reported in the literature. MTC is a neuro-endocrine malignancy arising from the para-follicular C cells of the thyroid gland. It generally has a slight female predominance and appears as a single lesion. However in the Multiple Endocrine Neoplasia Syndrome 2, linked to the point mutation of oncogene, multifocal MTCs may also occur. Herein, we report the case of a 75 years old man with a rare form of sporadic multifocal and bilateral OV-MTC expressing wild-type gene. The histological and molecular features of this rare entity are presented and discussed with revision of the pertinent literature.
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http://dx.doi.org/10.4081/rt.2016.6537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226050PMC
November 2016

Nodular Lymphocyte-Predominant Hodgkin Lymphoma in a Warthin Tumor of the Parotid Gland: A Case Report and Literature Review.

Int J Surg Pathol 2015 Aug;23(5):419-23

Sant'Andrea Hospital, Sapienza University, Rome, Italy.

Hodgkin lymphoma (HL) associated with Warthin tumor (WT) is extremely rare, accounting for only 3 cases of classical HLs. Here, we report for the first time the occurrence of a nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) involving the lymphoid stroma of a WT of the parotid gland. Pathogenesis of WT is controversial, with both a nodal and a parenchymal possible origin. On the other hand, extranodal involvement by HLs is uncommon. In our case, the coexistence of a WT and of a NLPHL within its stroma and in cervical lymph node emphasizes the importance of a careful evaluation of the lymphoid tissue in WT in order to exclude the possibility of an associated lymphoid malignancy.
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http://dx.doi.org/10.1177/1066896915582263DOI Listing
August 2015