Publications by authors named "Laura Bonaldi"

32 Publications

The complex karyotype landscape in chronic lymphocytic leukemia allows to refine the risk of Richter syndrome transformation.

Haematologica 2021 Jun 3. Epub 2021 Jun 3.

Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy; Veneto Institute of Molecular Medicine, Padua.

Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with C5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter reallife retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q-/TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; while mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (p<0.0001). We herein demonstrated that CK landscape at CLL diagnosis allows to refine the risk of RS transformation and we recapitulated clinico-biological variables into a prognostic model.
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http://dx.doi.org/10.3324/haematol.2021.278304DOI Listing
June 2021

Uveal Melanoma Biopsy: A Review.

Cancers (Basel) 2019 Jul 30;11(8). Epub 2019 Jul 30.

Department of Ophthalmology, University of Padova, 35128 Padova, Italy.

Intraocular tumor diagnosis is based on clinical findings supported by additional imaging tools, such as ultrasound, optical coherence tomography and angiographic techniques, usually without the need for invasive procedures or tissue sampling. Despite improvements in the local treatment of uveal melanoma (UM), the prevention and treatment of the metastatic disease remain unsolved, and nearly 50% of patients develop liver metastasis. The current model suggests that tumor cells have already spread by the time of diagnosis, remaining dormant until there are favorable conditions. Tumor sampling procedures at the time of primary tumor diagnosis/treatment are therefore now commonly performed, usually not to confirm the diagnosis of UM, but to obtain a tissue sample for prognostication, to assess patient's specific metastatic risk. Moreover, several studies are ongoing to identify genes specific to UM tumorigenesis, leading to several potential targeted therapeutic strategies. Genetic information can also influence the surveillance timing and metastatic screening type of patients affected by UM. In spite of the widespread use of biopsies in general surgical practice, in ophthalmic oncology the indications and contraindications for tumor biopsy continue to be under debate. The purpose of this review paper is to critically evaluate the role of uveal melanoma biopsy in ophthalmic oncology.
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http://dx.doi.org/10.3390/cancers11081075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721328PMC
July 2019

The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia.

Br J Cancer 2019 07 18;121(2):150-156. Epub 2019 Jun 18.

Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy.

Background: Complex karyotype (CK) is a heterogeneous category with a negative impact in chronic lymphocytic leukaemia (CLL). Our group has recently reported that CK patients with major structural abnormalities (i.e. CK2) are characterised by a worse prognosis, as compared to other lesions within CK(CK1).

Methods: We performed a multicentre retrospective study to test whether the combination of CK subtypes with IGHV status could be a relevant prognostic and predictive tool.

Results: Among 522 patients 13% harboured CK2, 41% CK1 and/or U-IGHV (U-CK1) and 46% M-IGHV without any CK subtypes (M-noCK). After a median follow-up of 5.8 years, CK2 patients had the shortest TTFT (5-year TTFT 31%, 39 and 81%, p < 0.0001) and OS (5-year OS 67%, 85 and 93%, p < 0.0001) as compared to U-CK1 or M-noCK cases, regardless of TP53 abnormalities. CK2 patients also had the worst outcome after chemoimmunotherapy. In fact, the median TTNT after FCR or BR was 1.86 and 4.79 years for CK2 and U-CK1, but not reached for M-noCK patients (p < 0.0005).

Conclusions: We herein suggest that the combined assessment of the IGHV mutational status and CK subtypes refines the prognostication of CLL, allowing to identify M-IGHV patients without any CK subtypes who are characterised by an indolent disease and excellent outcome after chemoimmunotherapy.
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http://dx.doi.org/10.1038/s41416-019-0502-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738078PMC
July 2019

Chronic Myeloid Leukemia With Myelofibrosis-Like Features. Clues of Accelerated Phase?

Int J Surg Pathol 2019 Oct 27;27(7):771-772. Epub 2019 Feb 27.

3 Surgical Pathology and Cytopatology Unit, University of Padua, Padova, Italy.

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http://dx.doi.org/10.1177/1066896919833170DOI Listing
October 2019

Genetic, Epigenetic, and Immunologic Profiling of MMR-Deficient Relapsed Glioblastoma.

Clin Cancer Res 2019 03 4;25(6):1828-1837. Epub 2018 Dec 4.

Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV -IRCCS, Padova, Italy.

Purpose: In-depth characterization of recurrent glioblastoma (rGBM) might contribute to a better understanding of the mechanisms behind tumor progression and enable rGBM treatment with targeted drugs. In this study, GBM samples were collected at diagnosis and recurrence from adult patients treated with Stupp protocol. Expression of mismatch repair (MMR) proteins was evaluated by IHC, followed by whole exome sequencing (WES) of tumor samples showing loss of MSH6 reactivity. Established genetic, epigenetic, and immunologic markers were assessed by standard methods and correlated with loss of MMR proteins and patient survival.

Results: Expression of MMR proteins was partially or completely lost in 25.9% rGBM samples. Specifically, 12 samples showed partial or total MSH6 expression reduction. Conversely, 96.4% of GBM samples at diagnosis expressed MMR markers. WES disclosed lack of variants in MMR genes in primary samples, whereas two MSH6-negative rGBM samples shared a c.3438+1G>A* splicing variant with a potential loss of function effect. MSH6-negative rGBM specimens had high tumor mutational burden (TMB), but no microsatellite instability. In contrast, GBM samples with partial loss of MMR proteins disclosed low TMB. MMR-deficient rGBM showed significant telomere shortening and MGMT methylation and are characterized by highly heterogeneous MHC class I expression.

Conclusions: Multilevel profiling of MMR-deficient rGBM uncovered hypermutated genotype uncoupled from enriched expression of immune-related markers. Assessment of MHC class I expression and TMB should be included in protocols aiming to identify rGBM patients potentially eligible for treatment with drugs targeting immune-checkpoint inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1892DOI Listing
March 2019

Splenic marginal zone lymphoma with a de novo t(8;14)(q24;q32) and a prolymphocytoid evolution responsive to rituximab-bendamustine.

Ann Hematol 2018 Oct 4;97(10):2001-2003. Epub 2018 May 4.

Hematology Unit, Department of Medicine - DIMED, University of Padova, Via Giustiniani, 2, Padova, Italy.

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http://dx.doi.org/10.1007/s00277-018-3351-4DOI Listing
October 2018

In chronic lymphocytic leukaemia with complex karyotype, major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics.

Br J Haematol 2018 04 2;181(2):229-233. Epub 2018 Apr 2.

Haematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Ferrara, Italy.

Complex karyotype (CK) is a negative prognostic factor in chronic lymphocytic leukaemia (CLL). However, CK is a heterogeneous cytogenetic category. Unbalanced rearrangements were present in 73·3% of 90 CLL patients with CK (i.e. ≥3 chromosome aberrations in the same clone), and were associated with a shorter overall survival (P = 0·025) and a shorter time to first treatment (P = 0·043) by multivariate analysis. Patients with unbalanced rearrangements presented a distinct mRNA expression profile. In conclusion, CLL patients with unbalanced rearrangements might represent a subset of very high-risk CLL patients with distinct clinical and biological characteristics.
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http://dx.doi.org/10.1111/bjh.15174DOI Listing
April 2018

Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and β-catenin survival signaling pathways.

Oncotarget 2017 Feb;8(9):14604-14619

Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.

Recent evidence indicates that protein kinase CK1α may support the growth of multiple myeloma (MM) plasma cells. Here, by analyzing a large cohort of MM cases, we found that high CK1α mRNA levels are virtually associated with all MM patients. Moreover, we provided functional evidence that CK1α activity is essential for malignant plasma cell survival even in the protective niche generated by co-cultures with bone marrow stromal cells. We demonstrated that CK1α inactivation, while toxic for myeloma cells, is dispensable for the survival of healthy B lymphocytes and stromal cells. Disruption of CK1α function in myeloma cells resulted in decreased Mdm2, increased p53 and p21 and reduced expression of β-catenin and AKT. These effects were mediated partially by p53 and caspase activity. Finally, we discovered that CK1α inactivation enhanced the cytotoxic effect of both bortezomib and lenalidomide. Overall, our study supports a role for CK1α as a potential therapeutic target in MM in combination with proteasome inhibitors and/or immunomodulatory drugs.
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http://dx.doi.org/10.18632/oncotarget.14654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362429PMC
February 2017

Complex chromosomal rearrangements leading to MECOM overexpression are recurrent in myeloid malignancies with various 3q abnormalities.

Genes Chromosomes Cancer 2016 Apr 27;55(4):375-88. Epub 2016 Jan 27.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology and Medical Oncology "Seragnoli," Sant'Orsola-Malpighi Hospital-University, Bologna, Italy.

Chromosomal rearrangements involving 3q26 are recurrent findings in myeloid malignancies leading to MECOM overexpression, which has been associated with a very poor prognosis. Other 3q abnormalities have been reported and cryptic MECOM rearrangements have been identified in some cases. By fluorescence in situ hybridization (FISH) analysis, we investigated 97 acute myeloid leukemia/myelodysplastic syndrome patients with various 3q abnormalities to determine the role and the frequency of the involvement of MECOM. We identified MECOM rearrangements in 51 patients, most of them showed 3q26 involvement by chromosome banding analysis (CBA): inv(3)/t(3;3) (n = 26) and other balanced 3q26 translocations (t(3q26)) (n = 15); the remaining cases (n = 10) showed various 3q abnormalities: five with balanced translocations involving 3q21 or 3q25; two with homogenously staining region (hsr) on 3q; and three with other various 3q abnormalities. Complex rearrangements with multiple breakpoints on 3q, masking 3q26 involvement, were identified in cases with 3q21/3q25 translocations. Furthermore, multiple breaks were observed in two cases with t(3q26), suggesting that complex rearrangement may also occur in apparently simple t(3q26). Intrachromosomal gene amplification was another mechanism leading to MECOM overexpression in two cases with hsr on 3q. In the last three cases, FISH analysis revealed 3q26 involvement that was missed by CBA because of metaphases' suboptimal quality. All cases with MECOM rearrangements showed overexpression by real-time quantitative PCR. Finally, MECOM rearrangements can occur in patients with 3q abnormalities even in the absence of specific 3q26 involvement, underlining that their frequency is underestimated. As MECOM rearrangement has been associated with very poor prognosis, its screening should be performed in patients with any 3q abnormalities.
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http://dx.doi.org/10.1002/gcc.22341DOI Listing
April 2016

Non-Small Cell Lung Cancer in a Very Young Woman: A Case Report and Critical Review of the Literature.

Am J Case Rep 2015 Nov 3;16:782-9. Epub 2015 Nov 3.

Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.

Background: Lung cancer in young patients is quite uncommon; clinical presentation and outcome in this population compared to the older group are not yet well defined and data about this setting are mostly single-institutional retrospective analyses.

Case Report: We report here a case of a very young woman with diagnosis of early-stage lung adenocarcinoma harboring EML4-ALK rearrangement; she underwent radical surgery and adjuvant chemotherapy according to the pathologic stage. Potential risk factors for lung cancer in our patient are discussed and clinico-pathologic features and outcomes of lung cancer in the young population compared to the elderly are reviewed through discussing studies with sample sizes larger than 100 patients.

Conclusions: A wide clinical overview should be performed when lung cancer is diagnosed in a young patient. Large-population studies are required to define the molecular signature and clinical behavior of lung cancer in young patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642365PMC
http://dx.doi.org/10.12659/ajcr.894426DOI Listing
November 2015

Integrated CLL Scoring System, a New and Simple Index to Predict Time to Treatment and Overall Survival in Patients With Chronic Lymphocytic Leukemia.

Clin Lymphoma Myeloma Leuk 2015 Oct 20;15(10):612-20.e1-5. Epub 2015 Jun 20.

Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy; Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica Avanzata, Avanzata, Italy. Electronic address:

Introduction: Several prognostic factors have been identified to predict the outcome of patients with chronic lymphocytic leukemia (CLL), but only a few studies analyzed more markers together.

Patients And Methods: Taking advantage of a population of 608 patients, we identified the strongest prognostic markers of survival and, subsequently, in a cohort of 212 patients we integrated data of cytogenetic lesions, IGHV mutational status, and CD38 expression in a new and easy scoring system we called the integrated CLL scoring system (ICSS). ICSS defines 3 groups of risk: (1) low risk (patients with 13q(-) or normal fluorescence in-situ hybridization analysis results, mutated IGHV, and CD38) (2) high risk (all 11q(-) or 17p(-) patients and/or all unmutated IGHV and CD38(+) patients); and (3) intermediate risk (all remaining patients).

Results: Using only these 3 already available prognostic factors, we were able to properly redefine patients and better predict the clinical course of the disease.

Conclusion: ICSS could become a useful tool for CLL patients' management.
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http://dx.doi.org/10.1016/j.clml.2015.06.001DOI Listing
October 2015

Cytogenetic Impact on Lenalidomide Treatment in Relapsed/Refractory Multiple Myeloma: A Real-Life Evaluation.

Clin Lymphoma Myeloma Leuk 2015 Oct 6;15(10):592-8. Epub 2015 Jun 6.

Department of Medicine, Hematology and Clinical Immunology Branch, Padova University, Padova, Italy.

Introduction: In this retrospective real-life study in relapsed/refractory multiple myeloma patients, we analyzed clinical and biologic features distinguishing patients with rapidly progressing disease while receiving lenalidomide therapy from those without progression.

Patients And Methods: According to time of stopping lenalidomide, patients were subdivided into 3 groups: early stop (ES) (n = 23), when therapy was discontinued within 6 months; intermediate (INT) (n = 23), when therapy was stopped between 7 to 24 months; and long survival (LS) (n = 45), when therapy was maintained for more than 2 years. The median age of the whole cohort was 70 years (range, 42-85 years); 40% had an International Staging System score of 2 or 3.

Results: High-risk cytogenetic findings, including 1q gain, was reported in 65% ES, 43% INT, and 21% LS. Overall response rate was 63%, with median progression-free survival and overall survival of 33 and 56 months, respectively.

Conclusion: Although high-risk cytogenetic findings negatively affect progression-free survival and overall survival, 28% of cytogenetic high-risk patients experienced long survival, provided that lenalidomide therapy was not discontinued, thus pointing to the role of maintenance therapy in this subset of patients.
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http://dx.doi.org/10.1016/j.clml.2015.05.003DOI Listing
October 2015

Clinical significance of LAIR1 (CD305) as assessed by flow cytometry in a prospective series of patients with chronic lymphocytic leukemia.

Haematologica 2014 May 10;99(5):881-7. Epub 2014 Jan 10.

Most patients affected by chronic lymphocytic leukemia are diagnosed by flow cytometry. Several immunophenotypic markers have been identified as significant and independent prognostic variables, especially from retrospective cohorts. However, while attractive because their detection is inexpensive and feasible in most laboratories, only few have been validated by independent series. The expression of leukocyte-associated immunoglobulin-like receptor-1 (also known as LAIR1, LAIR-1 or CD305), an inhibitor of B-cell receptor-mediated signaling, has been reported to be lacking in high-risk chronic lymphocytic leukemia. However, its correlation with biological variables and its prognostic significance remain unknown. We investigated 311 consecutive patients, prospectively enrolled since 2007. Methods for studying patients were standardized and included clinical assessment, immunophenotype, fluorescence in situ hybridization, and status of immunoglobulin heavy chain variable region genes. Overall, 22.1% of patients had Binet stage B or C disease, 38.5% had unmutated immunoglobulin genes, 15.1% had high-risk cytogenetic abnormalities, 23.4% were CD38(+), 37.8% CD49d(+), and 59.8% LAIR1(+). Expression of LAIR1 was inversely related to that of CD38 (P=0.0005), but was not associated with CD49d expression (P=0.96). A significantly lower expression of LAIR1 was observed in patients with Binet stage B or C disease (P=0.023), and in the presence of high-risk cytogenetic abnormalities (P=0.048) or unmutated immunoglobulin heavy chain variable region genes (P<0.0001). At univariate analysis LAIR1(+) was significantly associated with longer time to first treatment (P=0.0002). This favorable effect of LAIR1(+) was confirmed by multivariate analysis (hazard ratio=2.1, P=0.03 for LAIR1). Our results indicate that LAIR1 expression is a reliable and inexpensive marker capable of independently predicting time to first treatment in newly diagnosed unselected patients with chronic lymphocytic leukemia.
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http://dx.doi.org/10.3324/haematol.2013.096362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008102PMC
May 2014

Survivin expression and prognostic significance in pediatric malignant peripheral nerve sheath tumors (MPNST).

PLoS One 2013 26;8(11):e80456. Epub 2013 Nov 26.

Department of Medicine, University of Padova, Padova, Italy.

Malignant peripheral nerve sheath tumors (MPNST) are very aggressive malignancies comprising approximately 5-10% of all soft tissue sarcomas. In this study, we focused on pediatric MPNST arising in the first 2 decades of life, as they represent one the most frequent non-rhabdomyosarcomatous soft tissue sarcomas in children. In MPNST, several genetic alterations affect the chromosomal region 17q encompassing the BIRC5/SURVIVIN gene. As cancer-specific expression of survivin has been found to be an effective marker for cancer detection and outcome prediction, we analyzed survivin expression in 35 tumor samples derived from young patients affected by sporadic and neurofibromatosis type 1-associated MPNST. Survivin mRNA and protein expression were assessed by Real-Time PCR and immunohistochemical staining, respectively, while gene amplification was analyzed by FISH. Data were correlated with the clinicopathological characteristics of patients. Survivin mRNA was overexpressed in pediatric MPNST and associated to a copy number gain of BIRC5; furthermore, increased levels of transcripts correlated with a higher FNCLCC tumor grade (grade 1 and 2 vs. 3, p = 0.0067), and with a lower survival probability (Log-rank test, p = 0.0038). Overall, these data support the concept that survivin can be regarded as a useful prognostic marker for pediatric MPNST and a promising target for therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080456PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841247PMC
October 2014

Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity.

J Hematol Oncol 2013 Oct 12;6:78. Epub 2013 Oct 12.

Background: The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications also in the resistance to conventional and unconventional therapies. Moreover, CK2 role in blood tumors is rapidly emerging and this kinase has been recognized as a potential therapeutic target. Phase I clinical trials with the oral small ATP-competitive CK2 inhibitor CX-4945 are currently ongoing in solid tumors and multiple myeloma.

Methods: We have analyzed the expression of CK2 in acute myeloid leukemia and its function in cell growth and in the response to the chemotherapeutic agent daunorubicin We employed acute myeloid leukemia cell lines and primary blasts from patients grouped according to the European LeukemiaNet risk classification. Cell survival, apoptosis and sensitivity to daunorubicin were assessed by different means. p53-dependent CK2-inhibition-induced apoptosis was investigated in p53 wild-type and mutant cells.

Results: CK2a was found highly expressed in the majority of samples across the different acute myeloid leukemia prognostic subgroups as compared to normal CD34+ hematopoietic and bone marrow cells. Inhibition of CK2 with CX-4945, K27 or siRNAs caused a p53-dependent acute myeloid leukemia cell apoptosis. CK2 inhibition was associated with a synergistic increase of the cytotoxic effects of daunorubicin. Baseline and daunorubicin-induced STAT3 activation was hampered upon CK2 blockade.

Conclusions: These results suggest that CK2 is over expressed across the different acute myeloid leukemia subsets and acts as an important regulator of acute myeloid leukemia cell survival. CK2 negative regulation of the protein levels of tumor suppressor p53 and activation of the STAT3 anti-apoptotic pathway might antagonize apoptosis and could be involved in acute myeloid leukemia cell resistance to daunorubicin.
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http://dx.doi.org/10.1186/1756-8722-6-78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852751PMC
October 2013

Survivin expression impacts prognostically on NSCLC but not SCLC.

Lung Cancer 2013 Feb 4;79(2):180-6. Epub 2012 Dec 4.

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

Survivin is expressed in lung cancer and in most cancer tissues and has a significant impact on prognosis. This work aimed to comparatively assess survivin expression and significance in Non-Small (NSCLC) and Small Cell Lung Cancers (SCLC). Sixty-five NSCLC and 35 SCLC samples were analyzed by semi-quantitative real-time RT-PCR. Survivin mRNA levels were significantly higher in tumors than in normal tissue, and in SCLC than in NSCLC samples. Immunohistochemistry and FISH analyses were performed in 59 and 26 tumor specimens, respectively. In SCLC survivin was only present in cytoplasm, while in some NSCLC cases it also showed nuclear or mixed patterns. FISH analysis did not disclose survivin gene amplification, except for one NSCLC case. Finally, 90 samples were genotyped for the -31G/C SNP of survivin promoter by direct sequencing; the -31G/C SNP genotype status showed a significant association only with nodal NSCLC metastasis, but not with survivin expression in any tumor group. A better prognosis was correlated to higher levels of survivin mRNA and to the presence of at least one G allele at -31 SNP in NSCLC, while these parameters did not correlate with overall survival in SCLC. Moreover, this SNP would appear to have no effect on the risk of lung cancer in our samples. The different prognostic role played by survivin in NSCLC and SCLC highlights the biological differences between these lung tumor histotypes and stresses the need to clarify the molecular pathways leading to their neoplastic transformation.
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http://dx.doi.org/10.1016/j.lungcan.2012.11.004DOI Listing
February 2013

Telomere length and telomerase levels delineate subgroups of B-cell chronic lymphocytic leukemia with different biological characteristics and clinical outcomes.

Haematologica 2012 Jan 20;97(1):56-63. Epub 2011 Sep 20.

Department of Oncology and Surgical Sciences, Oncology Section, University of Padova,Padova, Italy.

Background: B-cell chronic lymphocytic leukemia is a clinically heterogeneous disease; some patients rapidly progress and die within a few years of diagnosis, whereas others have a long life expectancy with minimal or no treatment. Telomere length and telomerase levels have been proposed as prognostic factors; however, very few cases have been characterized for both parameters and no study has analyzed the prognostic value of the telomere/telomerase profile.

Design And Methods: One hundred and seventy-three cases of chronic lymphocytic leukemia were characterized for telomere lengths and telomerase levels by real-time polymerase chain reaction. Data were correlated with established prognostic markers, IGVH mutational status and chromosomal aberrations, and clinical outcome.

Results: Telomere lengths were inversely correlated with telomerase levels (r(s) = -0.213; P = 0.012), and most of the cases of chronic lymphocytic leukemia with high levels (above median) of telomerase had short (below median) telomeres (P = 0.0001). Telomerase levels were higher and telomeres were shorter in unmutated IGVH cases than in mutated IGVH ones (P<0.0001). Chronic lymphocytic leukemias with 11q, 17p deletion or 12 trisomy had significantly higher levels of telomerase and shorter telomeres than those with no chromosomal aberration or the sole 13q deletion (P < 0.001). Telomere length/telomerase level profiles identified subgroups of patients with different clinical outcomes (P < 0.0001), even within the subsets of chronic lymphocytic leukemia defined by IGVH mutational status or chromosomal aberrations. Short telomere/high telomerase profile was independently associated with more rapid disease progression.

Conclusions: Comprehensive analyses of telomeres, telomerase, chromosomal aberrations, and IGVH mutational status delineate groups of chronic lymphocytic leukemias with distinct biological characteristics and clinical outcomes. The telomere/telomerase profile may be particularly useful in refining the prognosis of chronic lymphocytic leukemia patients with mutated IGVH and no high-risk chromosomal aberrations.
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http://dx.doi.org/10.3324/haematol.2011.049874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248931PMC
January 2012

Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis.

Blood 2011 Jun 29;117(25):6793-800. Epub 2011 Mar 29.

Department of Hematology and Oncology L. e A. Seràgnoli, University of Bologna, Bologna, Italy.

Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a "warning" for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a "warning" category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.
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http://dx.doi.org/10.1182/blood-2011-01-328294DOI Listing
June 2011

Prognostic and predictive implications of EGFR mutations, EGFR copy number and KRAS mutations in advanced stage lung adenocarcinoma.

Anticancer Res 2010 Dec;30(12):5121-8

Department of Medical Oncology 2, Istituto Oncologico Veneto-IRCCS, 64, I-35128 Padua, Italy.

Background/aim: Gefitinib and erlotinib were shown to be particularly effective in a clinically selected subpopulation of non-small cell lung cancer patients (NSCLC): adenocarcinoma histology, non-smoking status, Asian origin and female gender have been associated with improved clinical benefit compared to the unselected NSCLC population. The aim of the present study was to investigate the prognostic and predictive role of EGFR and KRAS analysis in advanced lung adenocarcinomas, selected according to clinical features associated to better response to EGFR tyrosine kinase inhibitors (TKIs), namely female gender and non-smoker or former light smoker status.

Patients And Methods: EGFR and KRAS mutations and EGFR FISH status were assessed in 67 surgical samples.

Results: EGFR and KRAS mutations were found in 16 (26.7%) and 12 (17.9%) patients, respectively. FISH analysis was positive in 34 (56.7%) patients. EGFR-mutated patients showed significantly longer survival when treated with EGFR TKIs (p = 0.002, hazard ratio (HR) = 0.036, 95% confidence interval (CI): 0.004 -0.303). KRAS mutations was found to be an independent negative prognostic factor in multivariate analysis (p = 0.008, HR = 3.52, 95% CI: 1.39-8.9). The prognostic value of EGFR FISH status was not confirmed in multivariate analysis (p = 0.048, HR = 0.47, 95%CI: 0.22-0.99).

Conclusion: In a group of clinically selected patients, EGFR and KRAS analysis was able to define distinct molecular subsets of lung adenocarcinoma.
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December 2010

DNA copy number alterations correlate with survival of esophageal adenocarcinoma patients.

Mod Pathol 2009 Jan 26;22(1):58-65. Epub 2008 Sep 26.

Oncology Section, Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy.

Despite recent advances in surgical and multidisciplinary treatment, prognosis for patients with esophageal adenocarcinoma remains poor, and the low prognostic significance of pTNM staging suggests that additional parameters are needed. To identify genomic abnormalities characteristic of esophageal adenocarcinoma, a panel of 33 samples obtained at surgery from previously untreated patients were analyzed by muliplex ligation-dependent probe amplification technique. We detected frequent gains of 6p, 8q, 13q, 17q, 20q, and losses of 4q, 5q, 15q, and 18q. When DNA copy number changes were correlated to clinicopathological features of patients no association was found between the number of chromosomal aberrations and gender, age, tumor grade or pTNM staging. However, interestingly, a significant correlation between patient survival and total number of chromosomal aberrations was found when esophageal adenocarcinoma cases were stratified according to the median of survival (20 months) (P=0.002) or the median of aberrations (12 aberrations) (P=0.014). Evaluation of the distribution of gains and losses at the level of single chromosomes indicated that gains on chromosomes 5, 6, 8, 11, 20 and losses on chromosomes 1, 3, 5, 11, and 18 were significantly different in the two survival groups. Furthermore, when single gene imbalances were analyzed in further details, we found that besides alterations that involve genes shared by both survival groups, a few genes (KIAA0170, EMS1, ABCC4, F3, and MIF) were altered only in samples from patients with poor survival. Thus, we established a good correlation between the total number of chromosomal alterations and survival, suggesting that the estimation of total imbalances might represent an additional indicator of disease outcome. In addition, the finding of alterations specific for the more aggressive esophageal adenocarcinoma subset might represent promising biomarkers to increase the accuracy of clinical outcome prediction.
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http://dx.doi.org/10.1038/modpathol.2008.150DOI Listing
January 2009

FISH analysis of chromosomes 3 and 6 on fine needle aspiration biopsy samples identifies distinct subgroups of uveal melanomas.

J Cancer Res Clin Oncol 2008 Oct 2;134(10):1123-7. Epub 2008 Apr 2.

U.O.C. Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto, IRCCS, Via Gattamelata 64, Padua, Italy.

Purpose: Circumstantial evidence suggests that development of uveal melanoma may be associated to two different pathogenetic pathways, either loss of chromosome 3 or extra copies of 6p (+6p). Chromosome 3 monosomy (-3) is detected in approximately half of uveal melanomas, and is strongly linked to metastatic disease, whereas +6p accounts for one-fourth of uveal melanomas with no clear clinical correlations. The aim of our study was to verify if the analysis of chromosomes 3 and 6 was able to distinguish two groups of patients for translating this approach in the clinical practise as prognostic tool.

Methods: Fluorescence in situ hybridisation (FISH) with probes for chromosome 3, 6p and 6q was used to analyze cytological material obtained by fine needle aspiration biopsy (FNAB) from 28 primary uveal melanomas, just before brachytherapy.

Results: Abnormalities affecting 6p and 6q were found in 14 tumors (50%), and -3 in 16 cases (57%). Interestingly, -3 and +6p were mutually exclusive in 23 cases (82%), whereas in two cases only (7%) they coexisted. In particular, +6p alone was present in 9 lesions (32%), -3 was the sole aberration in 11 cases (39%), and concomitant -3 and -6q in 3 other cases (11%).

Conclusions: Although the patient cohort is limited, our findings confirm the hypothesis of a bifurcated pathogenetic model of uveal melanoma. Moreover, our results suggest that investigation of both markers on FNAB samples obtained in vivo could provide a clearer clinical picture of genetic lesions when no histological material is available for prognostic evaluation.
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http://dx.doi.org/10.1007/s00432-008-0382-6DOI Listing
October 2008

In vivo monosomy 3 detection of posterior uveal melanoma: 3-year follow-up.

Graefes Arch Clin Exp Ophthalmol 2008 Apr 13;246(4):609-14. Epub 2007 Oct 13.

Department of Ophthalmology, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.

Background: Monosomy 3 is a highly specific marker for poor prognosis in posterior uveal melanoma. Unfortunately, cytogenetic prognostication is limited to enucleated eyes or resected tumors. The aim of this study was to evaluate mid-term natural history and safety of in vivo detection of chromosome 3 status in posterior uveal melanomas undergoing plaque brachytherapy.

Methods: A 25-gauge transscleral fine needle aspiration biopsy (FNAB) was performed in 32 eyes affected by posterior uveal melanoma undergoing plaque brachytherapy, just before applying the radioactive plaque. Sampled material underwent fluorescence in situ hybridization (FISH) with centromeric probes for chromosome 3. All patients had a follow-up of at least 36 months.

Results: Mean follow-up was 47.1 +/- 8.5 months. Mean largest basal diameter and mean thickness of the tumors were 12.5 +/- 2.7 mm and 8 +/- 2.3 mm respectively. FNAB yielded sufficient material in 26 of 32 cases (81.2%). Adequacy of the sample ranged from 91.1% (ciliary body tumors) to 76.8% (choroidal tumors). Seventeen cases had monosomy 3 (65.3%). No correlation was found between monosomy 3 and tumor dimensions or location (ciliary body vs choroidal tumors). No early and mid-term local complications were documented. Seven patients (21.8%) died during follow-up: five (15.6%) of them died due to metastatic disease (all had monosomy 3 tumors).

Conclusions: Posterior uveal melanomas may be adequately and safely sampled, by intra-operative transscleral FNAB, to detect in vivo monosomy 3.
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http://dx.doi.org/10.1007/s00417-007-0692-4DOI Listing
April 2008

hTERT inhibits the Epstein-Barr virus lytic cycle and promotes the proliferation of primary B lymphocytes: implications for EBV-driven lymphomagenesis.

Int J Cancer 2007 Aug;121(3):576-87

Department of Oncology and Surgical Sciences, Section of Oncology, University of Padova, Padova, Italy.

Transformation of primary B lymphocytes by Epstein-Barr Virus (EBV) requires the establishment of a latent infection, the expression of several latent viral proteins and a sustained telomerase activity. We investigated the interplay between the activation of human telomerase reverse transcriptase (hTERT), the catalytic rate-limiting component of the telomerase complex, and the expression of latent/lytic EBV genes during the establishment of a stably latent EBV infection of normal B lymphocytes. Cell cultures at early passages after EBV infection greatly differed in their timing of hTERT expression and telomerase activation. Induction of hTERT was dependent on the balance between latent and lytic EBV gene expression, being positively associated with a high ratio of latent/lytic isoforms of latent membrane protein 1, and negatively associated with the expression of BZLF1 gene, the main activator of the viral lytic cycle. In turn, hTERT expression was followed by a decrease in EBV lytic gene expression and virus production. Ectopic expression of hTERT in BZLF1-positive B cell cultures resulted in BZLF1 down-regulation, increased resistance to lytic cycle induction, and enhanced in vitro growth properties, whereas hTERT inhibition by siRNA triggered the activation of the EBV lytic cycle. These findings indicate that hTERT contributes by multiple mechanisms to the EBV-driven transformation of B lymphocytes and suggest that hTERT may constitute a therapeutic target for EBV-associated B cell lymphomas.
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http://dx.doi.org/10.1002/ijc.22661DOI Listing
August 2007

Correlations between O6-methylguanine DNA methyltransferase promoter methylation status, 1p and 19q deletions, and response to temozolomide in anaplastic and recurrent oligodendroglioma: a prospective GICNO study.

J Clin Oncol 2006 Oct 5;24(29):4746-53. Epub 2006 Sep 5.

Department of Medical Oncology, Bellaria Hospital, Via Altura 3, Bologna, Italy.

Purpose: To date, no data are available on the relationship between 1p/19q deletions and the response to temozolomide (TMZ) in primary anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) recurrent after surgery and standard radiotherapy. The aim of this study was to evaluate correlations between 1p/19q deletions, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, and response rate to TMZ in this setting.

Patients And Methods: From June 2000 to February 2005, 67 patients were enrolled; 39 patients (58%) had AO and 28 patients (42%) had AOA. All patients received 150 to 200 mg/m2 of TMZ every 28 days. Chromosome 1p and 19q deletions were detected by fluorescence in situ hybridization and MGMT promoter methylation was analyzed using methylation specific polymerase chain reaction.

Results: The overall response rate was 46.3% (17 complete responses and 14 partial responses). The response rate was higher in patients with AO than in those with AOA (61.5% v 25%, P = .003). Combined 1p/19q allelic loss was found in 32 patients (47.8%), while MGMT methylation occurred in 37 (68.5%) of 54 assessable patients. 1p/19q loss was significantly correlated with response rate (P = .04), time-to-progression (P = .003), and overall survival (P = .0001). Despite the significant concordance found between MGMT promoter methylation and 1p/19q deletions (P = .02), MGMT promoter methylation showed only a borderline correlation with overall survival (P = .09).

Conclusion: TMZ is active in anaplastic oligodendroglial tumors treated at first recurrence. In this setting, 1p/19q allelic loss is an important predictive and prognostic factor. Further studies on MGMT promoter methylation should be performed in randomized trials to test its correlation with survival.
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http://dx.doi.org/10.1200/JCO.2006.06.3891DOI Listing
October 2006

Parasagittal cranial fasciitis after irradiation of a cerebellar medulloblastoma: case report.

Neurosurgery 2004 May;54(5):1263-6; discussion 1266-7

Neurosurgical Department, Regional Hospital, Treviso, Italy.

Objective And Importance: Cranial fasciitis is a very rare, nontumoral lesion of the cranium with potential intracranial expansion typical of childhood. Radiotherapy has not been reported among the possible causes or factors associated with this condition. We present a case of cranial fasciitis in an 11-year-old patient previously admitted for cranial radiotherapy of a cerebellar medulloblastoma. Cytogenetic analysis revealed a pattern of chromosomal abnormalities suggestive of a radiation-induced lesion.

Clinical Presentation: An 11-year-old patient, who had been treated previously with craniospinal radiotherapy for a medulloblastoma, presented with a tumor resembling a parasagittal meningioma.

Intervention: At surgery, the tumor apparently had eroded the cranium and was deemed to originate from the external layer of the sagittal sinus. A distinct line of cleavage permitted total removal. Histological analysis was suggestive of cranial fasciitis. Cytogenetic analysis revealed the presence of a polyclonal karyotype in a background of nonclonal changes.

Conclusion: Cranial fasciitis should be included in the differential diagnosis of intracranial tumors infiltrating the cranium. Treatment of these lesions is easier than that of other parasagittal lesions because the sinus is compressed but not infiltrated. This case is associated with previous radiotherapy; thus, cranial fasciitis could be considered one of the more common radiation-induced lesions.
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http://dx.doi.org/10.1227/01.neu.0000119604.10923.63DOI Listing
May 2004