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ABSTRACT: Abstract Bortezomib is a proteasome inhibitor active in classical Hodgkin lymphoma (cHL) cell lines, but poorly active in clinic when used as single agent, suggesting that the microenvironment could protect from drug efficacy. Therefore, we investigated the effects of bortezomib activity in the presence of HL-associated fibroblasts (HL-AFs) and sCD40L. We found that co-cultivation with human HL-AFs or addition of sCD40L during bortezomib treatment protected cHL-cells from apoptosis and cytotoxicity and rescued the down-regulation of the survival factor Interferon Regulatory Factor 4 (IRF4). On the contrary, bortezomib treatment before co-cultivation with HL-AFs, inhibited in a dose dependent manner cHL cells adhesion to HL-AFs and completely overcame HL-AFs protection against drug activity. Consistently, we found that bortezomib treatment down-regulated the surface expression of CD49d and CD44 that mediate the adhesion of cHL cells to HL-AFs, and of CD54 and CD40 that mediate the adhesion to CD40L+ rosetting T-cells. These pre-clinical findings suggest that the low in vivo activity of bortezomib, as single agent, may be due to a protective influence of the microenvironment. However, the inclusion of bortezomib in cHL drug regimen, by reducing IRF4 expression and the interactions with the microenvironment, could increase the efficacy of current chemotherapeutic treatment of relapsed/refractory cHL.
Leukemia & lymphoma 05/2013; · 2.40 Impact Factor
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ABSTRACT: PURPOSE: To assess the toxicity and cosmetic results in breast cancer patients undergoing adjuvant partial breast irradiation (PBI) to a total dose of 40 Gy in 10 daily fractions (4 Gy/fraction). METHODS AND MATERIALS: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old and treated with breast conservative surgery for early stage (pT1-T2 pN0-N1a) invasive ductal carcinoma. RESULTS: 77 patients were enrolled. Median follow-up was 18 months. The proposed schedule was well tolerated. One patient reported Grade 3 pain at the site of irradiation. Four (5%) patients experience Grade 2 erythema. Late Grade 2 and 1 fibrosis was observed in 3 (4%) and 14 (18%) patients, respectively. Cosmesis was judged "good/excellent" and "poor" in 75 (97%) and in 2 (3%) patients, respectively. CONCLUSIONS: 40 Gy in 10 daily fractions, 4 Gy/fraction, is a well tolerated regimen to deliver PBI.
Breast (Edinburgh, Scotland) 01/2013; · 2.09 Impact Factor
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ABSTRACT: Viral infections are important risk factors for tumor development in humans. Selected types of cancers, either lymphomas or carcinomas, for which there is sufficient evidence in humans of a causal association with specific viruses, have been identified. Experimental and clinical data on the possible association of other tumor types and carcinogenic viruses are presently controversial. In this article, we review the current evidence on the relationship between breast, colorectal and lung cancers and carcinogenic viruses. The majority of the publications reviewed do not provide definitive evidence that the viruses studied are associated with breast, colon, and lung cancers. However, since this association may be clinically relevant for some tumor subtypes (i.e. lung cancer and papillomaviruses), there is an urgent need for further investigation on this topic. By using innovative laboratory techniques for viral detection on well-defined tumor types, National and International networks against cancer should encourage and organise concerted research programs on viruses and solid cancer association. © 2012 Wiley Periodicals, Inc.
International Journal of Cancer 12/2012; · 5.44 Impact Factor
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American Journal of Hematology 10/2012; · 4.67 Impact Factor
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ABSTRACT: We report a case of left atrial cardiac myxoma harbouring an incidental atypical B-cell lymphoid proliferation. Histology disclosed classic myxoma cells embedded in a mucopolysaccharide-rich matrix and a micronodular lymphomatous proliferation under the surface of the mass. Myxoma cells were immunoreactive for calretinin, while lymphomatous cells expressed B lineage markers (CD 20+, CD79a), without evidence of clonality. Moreover, they were LMP1 positive; EBNA2 negative; KSHV/HHV8 negative; and, by in situ hybridization, EBER/Epstein-Barr virus (EBV) positive and Kappa and Lambda negative. According to the 2008 WHO schemes, the present case shares close similarities either with diffuse large B-cell lymphomas growing in the context of long-standing chronic inflammation or with primary effusion lymphomas, solid variant, both associated with EBV infection. This is the sixth case of incidental atypical lymphoid proliferation discovered in a cardiac myxoma reported so far. The optimal treatment of such lesions remains undefined, but their clinical course is indolent. After an accurate staging workup, without any postsurgical treatment, the patient we observed has been well with no recurrence of the disease at 6 years of follow-up.
Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 09/2012; · 1.63 Impact Factor
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Journal of clinical pathology 06/2012; 65(10):955-8. · 2.43 Impact Factor
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Debora Martorelli,
Massimo Guidoboni,
Valli De Re,
Elena Muraro,
Riccardo Turrini,
Anna Merlo,
Elisa Pasini,
Laura Caggiari,
Luca Romagnoli,
Michele Spina,
Roberta Mortarini,
Daniela Gasparotto,
Mario Mazzucato, Antonino Carbone,
Antonio Rosato,
Andrea Anichini,
Riccardo Dolcetti
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ABSTRACT: An increasing set of B-cell non-Hodgkin lymphomas (B-NHL) show a biased usage of IGKV3-20 and IGKV3-15 immunoglobulin genes, a feature that could be exploited for the development of ready-to-use, broadly applicable cancer vaccines.
The immunogenic properties of clonal IGKV3-20 and IGKV3-15 proteins were analyzed with particular focus on their ability to elicit cross-reactive responses against molecularly related IGKV proteins expressed by different B-cell lymphoproliferative disorders.
IGK+ lymphoma patients show humoral and T-cell responses to IGKV3-20 and IGKV3-15 proteins and IGKV3-specific cytotoxic T lymphocytes (CTL) can be easily induced ex vivo. IGKV3-20-specific CTLs cross-react against different IGKV3 proteins, an effect mediated by the presence of 21 shared, sometimes promiscuous, T-cell epitopes, presented by common HLA class I allele products, thus assuring a broad HLA coverage of IGKV3-based vaccines. Many natural epitope variants are carried by IGK light chains expressed by a broad spectrum of B-NHLs and we show that IGKV3-20-specific CTLs cross-react also against several of these variant epitopes. Both humoral and CTL-specific responses were induced by KLH-conjugated IGKV3-20 protein in HLA-A2-transgenic mice and coinjection of IGKV3-20-specific CTLs with IGKV3-20+ or IGKV3-15+ lymphoma cells into SCID mice totally prevented tumor growth, thus confirming the ability of these effectors to mediate efficient and cross-reactive cytotoxic responses also in vivo.
These results provide the rationale to exploit IGKV3 proteins as "off-the-shelf" vaccines for a large fraction of lymphoma patients.
Clinical Cancer Research 06/2012; 18(15):4080-91. · 7.74 Impact Factor
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Vincenzo Canzonieri,
Cristina Colarossi,
Laura Del Col,
Tiziana Perin,
Renato Talamini,
Roberto Sigon,
Renato Cannizzaro,
Eleonora Aiello,
Angela Buonadonna,
Fabrizio Italia,
Daniela Massi, Antonino Carbone,
Lorenzo Memeo
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ABSTRACT: Diagnostic and prognostic implications of endocrine differentiation were evaluated in 103 common gastric adenocarcinomas and undifferentiated carcinomas. Maturely differentiated exocrine and endocrine phenotypes were evaluated by using gastric exocrine and endocrine markers along with intestinal exocrine and endocrine markers. Immunohistochemical analysis revealed that 66 tumors (64%) were positive for generic endocrine markers such as chromogranin A and/or synaptophysin. The 14 patients with more than 20% tumor cells positive for at least 1 endocrine marker experienced a poorer prognosis than patients with no (n = 37) or 1% to 20% (n = 52) positivity. The 16 carcinomas expressing the maturely differentiated exocrine gastric phenotype significantly correlated with poorer outcome compared with carcinomas with mature exocrine intestinal (n = 22) or mixed/gastrointestinal (n = 64) phenotypes. Among tumors expressing chromogranin A and/or synaptophysin, the maturely differentiated endocrine gastric phenotype (n = 26) was a negative prognostic factor compared with mature endocrine intestinal (n = 21) and mixed/gastrointestinal (n = 5) phenotypes. Endocrine differentiation and maturely exocrine/endocrine gastric phenotypes are associated with an unfavorable prognosis and may identify subsets of patients for tailored therapy.
American Journal of Clinical Pathology 05/2012; 137(5):712-21. · 2.60 Impact Factor
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ABSTRACT: The International Agency for Research on Cancer has recently reassessed the carcinogenicity of the biological agents classified as 'carcinogenic to humans'. Among the biological agents having a direct role in carcinogenesis, Epstein-Barr virus, Kaposi's sarcoma-associated herpes virus and human papillomavirus contribute to a variety of malignancies worldwide in humans including nasopharyngeal carcinoma, several types of lymphomas, genital tract carcinomas and Kaposi's sarcoma. The authors review the current knowledge on cancers that have been attributed to Epstein-Barr virus, Kaposi's sarcoma-associated herpes virus and human papillomavirus looking at the pathological classification of these cancers and description of the implicated viruses, highlighting a wide range of pathological and virological diagnostic techniques. This review also focuses on the new oncological scenario ahead, once strategies against carcinogenic infectious agents are found to be effective.
Journal of clinical pathology 04/2012; 65(8):680-6. · 2.43 Impact Factor
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Daniela Capello,
Annunziata Gloghini,
Gianluca Baldanzi,
Maurizio Martini,
Clara Deambrogi,
Marco Lucioni,
Daniela Piranda,
Rosella Famà,
Andrea Graziani,
Michele Spina,
Umberto Tirelli,
Marco Paulli,
Luigi Maria Larocca,
Gianluca Gaidano, Antonino Carbone,
Fabiola Sinigaglia
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ABSTRACT: We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity. Copyright © 2012 John Wiley & Sons, Ltd.
Hematological Oncology 04/2012; · 2.47 Impact Factor
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Marco Trovo,
Elena Durofil,
Jerry Polesel,
Mario Roncadin,
Tiziana Perin,
Mario Mileto,
Erica Piccoli,
Daniela Quitadamo,
Samuele Massarut, Antonino Carbone,
Mauro G Trovo
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ABSTRACT: To assess the locoregional failure in patients with Stage I-II breast cancer treated with radical mastectomy and to evaluate whether a subset of these patients might be at sufficiently high risk of locoregional recurrence (LRR) to benefit from postmastectomy irradiation (PMRT).
Stage I-II breast cancer patients (n = 150) treated with radical mastectomy without adjuvant irradiation between 1999 and 2005 were analyzed. The pattern of LRR was reported. Kaplan-Meier analysis was used to calculate rates of LRR, and Cox proportional hazards methods were used to evaluate potential risk factors.
Median follow-up was 75 months. Mean patient age was 56 years. One-hundred forty-three (95%) patients received adjuvant systemic therapy: 85 (57%) hormonal therapy alone, 14 (9%) chemotherapy alone, and 44 (29%) both chemotherapy and hormonal therapy. Statistically significant factors associated with increased risk of LRR were premenopausal status (p = 0.004), estrogen receptor negative cancer (p = 0.02), pathologic grade 3 (p = 0.02), and lymphovascular invasion (p = 0.001). T and N stage were not associated with increased risk of regional recurrence. The 5-year LRR rate for patients with zero or one, two, three, and four risk factors was 1%, 10.3%, 24.2%, and 75%, respectively.
A subset of patients with early-stage breast cancer is at high risk of LRR, and therefore PMRT might be beneficial.
International journal of radiation oncology, biology, physics 03/2012; 83(2):e153-7. · 4.59 Impact Factor
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ABSTRACT: A 23-year-old male presented with severe rest dyspnoea, engorged jugular veins, ankle oedema and heart rate 140 bpm. Computed tomography (CT) scan showed a large mediastinal mass with pericardial and atrial infiltration, pulmonary artery and superior vena cava compression. HIV infection was detected. Echocardiography showed 5 × 4 cm masses both in the right and the left atria, pericardial effusion, thickening of the right and left ventricular walls and hypokinesis; after intravenous contrast medium (SonoVue), the ventricular myocardium showed an increased, granular echogenicity, as did the mediastinal mass and pericardium. Nadroparin, bisoprolol, amiodarone and (suspecting non-Hodgkin lymphoma) steroids were started. After 3 days, at echocardiogram, the thickness of the ventricular walls was reduced and ejection fraction was improved. Mediastinal biopsy disclosed a large B-cell lymphoma. After starting systemic chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin) and highly active antiretroviral therapy (HAART), 11 days after admission the patient was in New York Heart Association (NYHA) class 1-2, with normal jugular veins and no oedema. The echocardiogram showed no more pericardial effusion, atrial masses reduced by 50%, normal interventricular septum thickness and ejection fraction. In August 2010, after six cycles of chemotherapy followed by radiotherapy, the patient was in complete remission. This case shows both the echocardiographic findings typical of neoplastic infiltration of the myocardium and the rapid improvement observed within a few days after chemotherapy. In the HAART era patients with HIV-related lymphoma and even massive involvement of the heart may receive aggressive treatment with curative intent. Echocardiography is useful in early assessment of the response to therapy.
Journal of Cardiovascular Medicine 02/2012; · 1.51 Impact Factor
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ABSTRACT: The 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues has addressed the problem of intrafollicular neoplasia/"in situ" lesion for follicular lymphoma. The concept of intrafollicular neoplasia has also been proposed for other lymphomas in which the putative normal counterpart of the tumor cell is located in the germinal center or the mantle zone or the marginal zone of the follicle. However, unlike in situ follicular lymphoma, the precise histologic definition of this early lesion for other lymphomas is still lacking. When applied to nodular lymphocyte predominant Hodgkin lymphoma, another germinal center-derived lymphoma, "intrafollicular neoplasia" may be regarded as a neoplasia at an early stage of development, such as in situ follicular lymphoma. Interestingly, this early lesion can be observed in lymph nodes that otherwise show the most common nodular involvement by nodular lymphocyte predominant Hodgkin lymphoma. The recognition of intrafollicular neoplasia is based on the identification of typical, strongly stained BCL6+, lymphocyte predominant tumor cells located within altered follicles with a recognizable germinal center. Lymphocyte predominant tumor cells, surrounded by rosetting PD1+ T cells, reside in an environment reminiscent of a secondary follicle. Intrafollicular neoplasia in nodular lymphocyte predominant Hodgkin lymphoma is correctly identifiable based on immunohistochemical recognition of the CD23+ meshwork of follicular dendritic cells surrounded by an outer zone containing immunoglobulin D+ B cells. This immunoarchitectural pattern, highlighting the intrafollicular involvement by the neoplasia, is of great utility for diagnosis. An appropriate immunohistochemical characterization for diagnosis should include lymphocyte predominant (BCL6 and CD20) and microenvironmental (CD23, immunoglobulin D, and PD1) cell markers.
Human pathology 12/2011; 43(5):619-28. · 3.03 Impact Factor
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Elena Muraro,
Debora Martorelli,
Elisa Turchet,
Gianmaria Miolo,
Simona Scalone,
Elisa Comaro,
Renato Talamini,
Katy Mastorci,
Davide Lombardi,
Tiziana Perin, Antonino Carbone,
Andrea Veronesi,
Diana Crivellari,
Riccardo Dolcetti
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ABSTRACT: The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy.
Blood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Student's t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data.
The proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10).
Compared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects.
Breast cancer research: BCR 11/2011; 13(6):R117. · 5.24 Impact Factor
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ABSTRACT: In situ follicular lymphoma (FL) is usually an incidental finding in otherwise reactive lymph node. This report describes two cases of lymph nodal in situ FL complicated by the association with nonlymphoid neoplasms. In case 1, in situ FL was discovered incidentally on a biopsy performed for an unexplained cervical lymphadenopathy 6 months after the resection of a carotid body paraganglioma. In case 2, in situ FL was detected incidentally during surgery for radical resection of prostatic carcinoma. In the lymph nodes, the in situ FL foci were characterized immunohistologically by strong coexpression of BCL2 and CD10 in the involved GCs. FISH study demonstrated BCL2 rearrangement in one of the two tested cases. These data extend the spectrum of the clinical situations that may be associated with in situ FL, but the biological and clinical significance of the association of in situ FL with nonlymphoid neoplasms deserves further investigation. Important fields of investigation should include: (1) how to approach these patients who have a risk of progression to overt lymphoma; (2) is the association of in situ FL with concurrent nonlymphoid neoplasia incidental, related to immunosuppression or to previous treatment?
Leukemia & lymphoma 09/2011; 53(4):603-8. · 2.40 Impact Factor
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American Journal of Clinical Pathology 09/2011; 136(3):481-3. · 2.60 Impact Factor
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ABSTRACT: Inflammation and cancer are two independent biological events that can play an interdependent role. The model of such interaction is represented by Hodgkin lymphoma (HL), where the microenvironment is dominated by an extensive mixed, potentially cellular inflammatory infiltrate that plays a decisive role in the pathobiology of HL. In this review we summarize updated information on the complex interactions between Hodgkin Reed-Sternberg (HRS) cells and their tissue microenvironment, highlighting the functional role of CD40/CD40L and interferon regulatory factor 4 (IRF4).
Leukemia & lymphoma 08/2011; 53(2):195-201. · 2.40 Impact Factor
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ABSTRACT: In situ follicular lymphoma (FL) is usually an incidental finding in otherwise reactive lymph node [1–3]. However, it may be associated with overt FL, or with lymphomas other than FL or with other malignancies,in other sites or, less commonly, in the same lymph node [2,4–8]. Here we describe two cases of in situ FL, one with concurrent overt FL(Case 1), and one with concurrent peripheral T-cell lymphoma (PTCL),NOS (Case 2) in the same lymph node. Immunohistochemistry, polymerase chain reaction for B and T-cell clonality, and double-staining chromogenic in situ hybridization for BCL2 translocation were performed.In both cases, the in situ FL foci were characterized by strong expression of BCL2 and CD10 in the germinal center B cells of the affected follicles. Case 1 showed the concurrence of an overt B-cell FL with IgH@ rearrangement and expression of B-cell markers, but not BCL2. Case 2 demonstrated the concurrence of a PTCL, NOS with TCRG@ rearrangement and expression of T-cell markers. In conclusion,the association of in situ FL with PTCL expands the spectrum of lymphoproliferations that may coexist with in situ FL and suggests that in situ FL may not behave like a simple precursor for overt FL.
American Journal of Hematology 08/2011; 86(12):E66-70. · 4.67 Impact Factor
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Ivo Kwee,
Daniela Capello,
Andrea Rinaldi,
Paola M V Rancoita,
Govind Bhagat,
Tim C Greiner,
Michele Spina,
Annunziata Gloghini,
Wing C Chan,
Marco Paulli,
Emanuele Zucca,
Umberto Tirelli, Antonino Carbone,
Gianluca Gaidano,
Francesco Bertoni
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ABSTRACT: The objective of this study was to evaluate the prognostic impact of genomic regions in a series of human immunodeficiency virus (HIV)-related diffuse large B-cell lymphomas (HIV-DLBCLs) and post-transplant DLBCLs (PT-DLBCLs) analyzed by genome-wide DNA profiling. Minimal common regions (MCRs) were estimated on genomic profiles obtained using Affymetrix Human Mapping 250k Nsp I arrays and tested for their impact on clinical outcome by univariate analysis on 36 PT-DLBCLs, 19 HIV-DLBCLs and, as a control group, 149 DLBCLs arising in immunocompetent individuals (IC-DLBCLs). PT-DLBCL and HIV-DLBCL presented a similar outcome. Immunodeficiency-related DLBCL (ID-DLBCL) had a worse overall survival (OS) than IC-DLBCL. Seven MCRs showed a statistical impact on OS in PT-DLBCL and four in HIV-DLBCL. Among these, the presence of gains at 1q or at 18q defined a group of patients with PT-DLBCL with a very poor outcome (p < 0.0001). The presence of del(3p14.2) or of + 2p23.1 identified a group of HIV-DLBCLs with a very poor outcome (p = 0.0072). It was concluded that genomic aberrations affecting outcome differ between ID-DLBCL and IC-DLBCL and are also dependent on the type of acquired immunodeficiency.
Leukemia & lymphoma 07/2011; 53(1):71-6. · 2.40 Impact Factor
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Antonino Carbone
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ABSTRACT: The concept of in situ neoplasia, already well acknowledged in epithelial tumors, has now been extended to lymphoid neoplasms. Among germinal center (GC)-derived lymphomas, a type of "in situ follicular lymphoma (FL)" has been described in which cells that strongly express BCL2 are observed in histologically abnormal follicles. In this commentary, the author suggests that another GC-derived lymphoma, ie, nodular lymphocyte-predominant Hodgkin lymphoma with a micronodular pattern in which small GCs or broken-up GCs are present within nodules, may be regarded as an early lesion limited to GC. Like "in situ FL," this is likely to be an in situ step that potentially leads to overt lymphoma.
Cancer 07/2011; 118(1):15-6. · 4.77 Impact Factor
