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PubMed | Anatomia Patologica, IRCCS Instituto Giannina Gaslini, University of Genoa, Diagnostica Molecolare and 3 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Oncogene-targeted therapies based on mutated BRAF- and/or MEK-specific inhibitors have been developed for melanoma treatment. Although these drugs induce tumor regression in a high percentage of patients, clinical responses are frequently limited in time and tumors often recur. Recent studies suggested that the combination of BRAF/MEK inhibition with immunotherapy could represent a promising strategy for the cure of melanoma. NK cells are suitable effectors for tumor immunotherapy. Here we show that PLX4032 (a mutant BRAFV600 inhibitor) had no effect on the functional properties of NK cells cultured in the presence of IL-2 or IL-15. In contrast, PD0325901 (a MEK inhibitor) induced the down-regulation of the main activating NK receptors and inhibited NK cell function. Importantly, PD0325901 did not affect the anti-tumor activity of NK cells that had been exposed to a combination of IL-15 and IL-18. In addition, both PLX4032 and PD0325901 did not exert any inhibitory effect on in vitro IL-2 or IL-15 pre-activated NK cells.Our data may provide a rationale for future clinical protocols that combine IL-15/IL-18 cytokine administration with MEK inhibitors. In addition, they suggest that oncogene-targeting drugs are compatible with NK-based adoptive therapy.


Bertani H.,Endoscopia Digestiva | Frazzoni M.,Fisiopatologia Digestiva | Dabizzi E.,Endoscopia Digestiva | Pigo F.,Endoscopia Digestiva | And 5 more authors.
Digestive Diseases and Sciences | Year: 2013

Background: Probe-based confocal laser endomicroscopy (pCLE) is a new technique allowing in vivo detection of neoplastic tissue using a standard endoscope. Aims: Our aim was to compare the incident dysplasia detection rate of biopsies obtained by high-definition white light endoscopy (HD-WLE) or by pCLE in a cohort of patients with Barrett's esophagus (BE) participating in a surveillance program. Methods: Fifty of 100 patients underwent pCLE in addition to HD-WLE. Four-quadrant biopsy specimens according to the Seattle biopsy protocol were obtained in all patients to ensure standard-of-care. Diagnosis of dysplasia/neoplasia was made by a blinded gastrointestinal pathologist. Results: Incident high-grade dysplasia (HGD) and low-grade dysplasia (LGD) were diagnosed in 3/100 and in 16/100 cases. In the HD-WLE group, areas suspicious for neoplasia were not observed and dysplasia was diagnosed in 5/50 (10 %) patients (one with HGD). In the pCLE group, areas suspicious for neoplasia were observed by pCLE in 21/50 (42 %) patients; dysplasia was confirmed in 14 cases (28 %) (two with HGD). The dysplasia detection rate was significantly higher in the pCLE group than in the HD-WLE group (P = 0.04). The sensitivity, specificity, positive and negative predictive values of pCLE for dysplasia were 100, 83, 67, and 100 %, respectively. Conclusions: Incident dysplasia can be more frequently detected by pCLE than by HD-WLE in BE. The higher dysplasia detection rate provided by pCLE could improve the efficacy of BE surveillance programs. © 2012 Springer Science+Business Media, LLC.


PubMed | University of Catania, Anatomia Patologica and Thomas Jefferson University
Type: Journal Article | Journal: Pathology, research and practice | Year: 2016

We herein report the clinical, radiological, and pathological findings of a rare case of a solitary fibrous tumor (SFT) occurring in the breast parenchyma of a 62-year-old female. The tumor was incidentally detected at a mammographic screening, and, ultrasonographically, presented as a single, well-circumscribed nodule. On needle core biopsy, the diagnosis of SFT was suggested based on a proliferation of CD34-positive spindly cells set in a fibrous stroma containing medium-sized blood vessels with hyalinization of their walls and branching configuration. The diagnosis was confirmed in the excised specimen, which exhibited a tumor with an immunohistochemical profile consistent with SFT, including diffuse expression of CD34, CD99 and bcl2. As STAT6 nuclear immunoexpression is the result of the inv12(q13q13)-derived NAB2-STAT6 fusion, which characterizes SFT, we analyzed immunohistochemically our case with a commercially available anti-STAT6 antibody. We showed that mammary SFT exhibits a diffuse nuclear STAT6 immunoreactivty, suggesting its potential diagnostic role. The present case emphasizes that the diagnosis of SFT can be confidentially rendered on needle core biopsy. Although SFT is suspected on characteristic morphologic features, immunohistochemistry, revealing immunoreactivity for CD34, bcl-2, CD99 and STAT6, is crucial in the differential diagnosis of potential benign and malignant mimics.


Barbetti V.,University of Florence | Morandi A.,University of Florence | Tusa I.,University of Florence | Digiacomo G.,University of Florence | And 8 more authors.
Oncogene | Year: 2014

The colony-stimulating factor-1 (CSF-1) and its receptor CSF-1R physiologically regulate the monocyte/macrophage system, trophoblast implantation and breast development. An abnormal CSF-1R expression has been documented in several human epithelial tumors, including breast carcinomas. We recently demonstrated that CSF-1/CSF-1R signaling drives proliferation of breast cancer cells via 'classical' receptor tyrosine kinase signaling, including activation of the extracellular signal-regulated kinase 1/2. In this paper, we show that CSF-1R can also localize within the nucleus of breast cancer cells, either cell lines or tissue specimens, irrespectively of their intrinsic molecular subtype. We found that the majority of nuclear CSF-1R is located in the chromatin-bound subcellular compartment. Chromatin immunoprecipitation revealed that CSF-1R, once in the nucleus, binds to the promoters of the proliferation-related genes CCND1, c-JUN and c-MYC. CSF-1R also binds the promoter of its ligand CSF-1 and positively regulates CSF-1 expression. The existence of such a receptor/ligand regulatory loop is a novel aspect of CSF-1R signaling. Moreover, our results provided the first evidence of a novel localization site of CSF-1R in breast cancer cells, suggesting that CSF-1R could act as a transcriptional regulator on proliferation-related genes. © 2014 Macmillan Publishers Limited.


PubMed | Anatomia Patologica, Hospital Infanta Cristina and Fundacion Jimenez Diaz
Type: | Journal: Neuropathology : official journal of the Japanese Society of Neuropathology | Year: 2016

We describe an unusual presentation of primary effusion lymphoma in CSF of a 45-year-old HIV-positive man, with no evidence of involvement of pleural, peritoneal or pericardial cavities. Cytologic examination and flow cytometric analysis suggested the diagnosis, eventually made in an excised deep cervical lymph node, in which the neoplastic cells involved selectively the sinuses. This case represents the fifth reported example of CSF involvement by this type of lymphoma, and supports the alleged connection between CSF and cervical lymph nodes via lymphatic vessels. Interestingly, review of an adenoidectomy specimen obtained 9 months before presentation for nonspecific complaints showed rare clusters of neoplastic cells involving surface epithelium and chorium, a finding that might represent a homing mechanism and implies an asymptomatic, occult phase of lymphoma development.


Bellevicine C.,University of Naples Federico II | Vita G.D.,Anatomia Patologica | Malapelle U.,University of Naples Federico II | Troncone G.,University of Naples Federico II
Seminars in Diagnostic Pathology | Year: 2013

In an increased number of settings, cytology represents the only source of sampling and it often substitutes histology as an independent diagnostic modality. Thus, DNA molecular targets to stratify patients for targeted therapy are often evaluated on cytology. In addition, DNA mutational tests may refine indeterminate thyroid and pancreas cytology. This review discusses the applications and limitations of DNA mutational testing on cytology. With respect to histology, most cytological samples have the advantages of a purer population of tumor cells, with low stromal component, a better preserved DNA, and assessing at the same time of sample collection cellular adequacy for DNA testing. However, since in vitro diagnostic tests are licensed only for paraffin-tissue, all mutational assays on cytology are "home brew," requiring a rigorous validation process. This should take into account not only the performance characteristics of the molecular assay but also features inherent to any given cytological samples, such as its source, preparation type, fixation and staining modalities, and the most effective tumor cell enrichment methods. This calls for a change of cytotechnologists and cytopathologists mentality to collect and process the cytological samples not only for microscopy but also to assess clinically relevant molecular markers. © 2013 Elsevier Inc.


Dalla Palma P.,Anatomia Patologica | Moresco L.,Anatomia Patologica | Giorgi Rossi P.,Servizio Interaziendale di Epidemiologia
Acta Cytologica | Year: 2013

Objective: To assess the introduction of computer-assisted Pap test screening in cervical cancer screening. Various scenarios are considered: conventional and liquid-based cytology (LBC) slides, fully automatic instrumentation (Becton Dickinson FocalPoint™ Slide Profiler and Hologic ThinPrep® Imaging System), and semiautomatic scanner (Hologic Integrated Imager I-Squared). Methods: A working group was formed that included researchers from the largest centers already using instrumentation. A questionnaire on laboratory management and on socialethical issues and annual workload was proposed. Prices for the technology were obtained directly from the producers; costs were calculated from observed and literature data. The scope of the report and final draft were submitted to a consulting committee of stakeholders. Results: The break-even point was found to be 49,000 casesyear, if conventional slides were used, while it was near the theoretical maximum capacity, 70,000 casesyear, with LBC slides. Efficiency increased with the volume of slides. Screening time decreased by two thirds for conventional slides and by less than half for LBC slides. Acceptance of the instrumentation by the users was good. Conclusions: Computer-assisted screening may increase productivity even if in most situations it will mean additional costs. Furthermore, primary screening with human papillomavirus tests will drastically reduce the need for Pap test reading. Copyright © 2013 S. Karger AG, Basel.


Pisani V.,Pediatric Dermatology Bari | Caniglia A.,Anatomia Patologica | Bonifazi E.,Pediatric Dermatology Bari
European Journal of Pediatric Dermatology | Year: 2012

Like many other inherited skin disorders with autosomal dominant transmission also neurofibromatosis type 1 (NF1) can manifest itself in a segmental distribution, due to a not early post-zygotic mutation of the gene responsible for NF1. In this paper, we revised the clinical data of 11 cases of childhood segmental NF1. While in adult segmental NF1 prevail forms characterized by the exclusive presence of neurofibromas, in children prevail forms characterized only by café-au-lait macules (CALMs). Both in children and adults is rare to observe the simultaneous presence of café-au-lait macules and neurofibromas. This behavior is probably due to the fact that the CALMs and neurofibromas are due to different mutations, which affect different cell lines, particularly the fibroblast in CALMs and the Schwann cell in neurofibromas.


Canessa P.A.,Science Pneumologia | Ferro P.,Anatomia patologica | Manta C.,Science Pneumologia | Sivori M.,Science Pneumologia | And 3 more authors.
Medical Oncology | Year: 2013

The aim of this study based on the third phase of the architecture of diagnostic research was to assess the sensitivity and specificity of soluble mesothelin-related peptide (SMRP) in pleural exudative effusions (PE) compared to the histology obtained by medical thoracoscopy as the diagnostic gold standard examination. We assessed 104 consecutive thoracoscopies. SMRP concentrations were obtained using an ELISA test. We had 34 mesotheliomas (25 epithelioid and 9 sarcomatoid), 35 pleural metastases, and 35 benign diseases. PE-SMRP were significantly higher in patients with epitheliomorphic mesothelioma (mean ± SD 46.55 ± 44.29 nM) than in patients with sarcomatoid mesothelioma (16.11 ± 25.02 nM; p = 0.061), pleural metastasis (7.52 ± 10.77 nM; p < 0.0001), or benign diseases (5.82 ± 8.86 nM; p < 0.0001). Using ROC curve analysis, PE-SMRP offered an AUC of 0.767 in its ability to differentiate between patients with mesothelioma and all other diagnoses. The diagnostic sensitivity and specificity of PE-SMRP for distinguishing mesothelioma from all other causes of pleural effusion, at a cut-off value of 19.6 nM, were 58.8 and 97.1 %, respectively. PE-SMRP higher than the assumed cut-off of 19.6 nM were observed in 18/25 (72.0 %) epitheliomorphic mesotheliomas, 2/9 (22.2 %) sarcomatoid mesotheliomas, 5/35 (14.3 %) pleural metastases, and 1/35 (2.9 %) benign diseases. We conclude that PE-SMRP adds some clinical information in the work-up of patients with a PE of unknown origin: (1) thoracoscopy should always be done in patients with a positive mesothelin; (2) a negative mesothelin does not exclude a malignant disease. © Springer Science+Business Media New York 2013.


Sironi M.,Anatomia Patologica
Updates in Surgery | Year: 2011

Intra-abdominal metastases from breast carcinomas are rarely reported in the literature. Least are those originating from occult breast primary. We report, one case of pancreatic metastasis and one case of metastatic infiltration of the colonic wall, both by occult lobular breast carcinoma. The first patient underwent pancreaticoduodenectomy for obstructive jaundice, with unexpected histological finding of infiltration of distal bile duct, pancreatic gland, portal vein and retroperitoneal soft tissue by lobular carcinoma of the breast. The second patient complained of diffuse abdominal pain associated with constipation and rectal bleeding and underwent endoscopic biopsy of three intestinal strictures, revealing metastatic lobular carcinoma with signet-ring cell morphology. In both cases, a subsequent complete diagnostic work-up demonstrated asymptomatic multiple breast nodules, diagnosed as lobular carcinoma by fine needle aspiration cytology. © 2011 Springer-Verlag.

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