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Emanuela Arvat,
Laura Gianotti,
Roberta Giordano,
Fabio Broglio,
Mauro Maccario,
Fabio Lanfranco,
Giampiero Muccioli, Mauro Papotti,
Andrea Grazian,
Ezio Ghigo,
Romano Deghenghi
[show abstract]
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ABSTRACT: Growth hormone-releasing hormone (GHRH) and somatostatin are the most important hypothalamic neurohormones controlling growth
hormone (GH) secretion. Several neurotransmitters and neuropeptides also play an important role in the control of GH secretion,
mainly acting via modulation of GHRH and somatostatin. In the past two decades, particular attention has been given to a new
family of substances showing a strong GH-releasing effect: GH secretagogues (GHSs). GHSs increase GH secretion in a dose-and
age-related manner after iv and even oral administration. The endocrine effects of GHSs, are not fully specific for GH; they
show, in fact, prolactin- (PRL), adenocorticotropic hormone- and cortisol-releasing effects. Specific GHS receptors are present
in both the central nervous system and peripheral tissues, where they mediate several extraendocrine effects of GHSs. The
isolation of these “orphan” receptors suggested the existence of an endogenous GHS-like ligand that could be represented by
a recently discovered gastric peptide, named ghrelin. The interaction between GHSs and GHRH at the central level and in the
pituitary gland, but not at peripheral level, has clearly been shown. Because GHRH and GHS receptors share the same localization
in some peripheral tissues, they may have some interactions even at this level.
Endocrine 04/2012; 14(1):35-43. · 1.42 Impact Factor
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ABSTRACT: Ghrelin has been discovered as a natural ligand of the receptor specific for synthetic GH secretagogues (GHS). Ghrelin as
well as synthetic GHS not only possess a remarkable GH-releasing activity but are also endowed with other endocrine and nonendocrine
activities including orexigenic action, influence on gastro-enteropancreatic functions, and cardiovascular and anti-proliferative
effects. Based on these data, particular effort has been focused on the isolation of new putative natural ligands of the GHS-receptors
(GHS-R) and on the identification of synthetic compounds endowed with agonistic or antagonistic activity. For instance, ghrelin
analogs acting as agonists or antagonists would be able to enhance or reduce appetite and food intake; these molecules would
receive obvious interest for treatment of eating disorders and obesity, respectively. Ghrelin and its orally active, agonistic
analogs could have prespectives for diagnosis and treatment of GH insufficiency. In this context, EP1572, a selective, orally
active, peptidomimetic GHS as well as cortistatin, another putative, natural ligand of the GHS-R, and its analogs, are currently
under investigation.
Endocrine 04/2012; 22(1):13-18. · 1.42 Impact Factor
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Ezio Ghigo,
Emanuela Arvat,
Roberta Giordano,
Fabio Broglio,
Laura Gianotti,
Mauro Maccario,
Gianni Bisi,
Andrea Graziani, Mauro Papotti,
Giampiero Muccioli,
Romano Deghenghi,
Franco Camanni
[show abstract]
[hide abstract]
ABSTRACT: Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible
growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R)
at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime
enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender
but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty,
which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors
probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their
slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing
activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains
the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other
central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep
pattern, stimulated food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular
derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin,
a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research
in this field.
Endocrine 04/2012; 14(1):87-93. · 1.42 Impact Factor
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ABSTRACT: As pulmonary sarcomatoid carcinomas (PSCs) are life-threatening tumors, an improvement in their recognition in small-sized tumor samples is clinically warranted.
Preoperative biopsy samples and paired surgical specimens from 20 pleomorphic carcinomas, two pulmonary blastomas and one carcinosarcoma (training set) were studied for vimentin immunohistochemistry. A modified vimentin histologic score (M-VHS) was devised by multiplying three independently assessed parameters, i.e. the percentage of positive cells (from 0 to 5+, by quintiles), the intensity of immunostaining (low=1 vs. strong=2) and the distribution pattern within the cytoplasm (partial=1 vs. diffuse=2), so ranging from 0 to 20. Forty-eight consecutive and independent cases of non-small cell lung carcinoma (NSCLC), including two additional cases of PSC, were used as control groups (validation set).
No differences in M-VHS were found between biopsies and surgical specimens of PSC, thus confirming the occurrence of stable epithelial mesenchymal transition (EMT) and hence the specific diagnosis of PSC. All types of PSC shared the same M-VHS. The M-VHS of 46 conventional NSCLC was by far lower (p<0.0001), whereas two additional cases of PSC showed the same results as the training set. Poorly differentiated NSCLC with marked pleomorphism but not stable EMT did not exhibit significantly increased M-VHS values.
M-VHS helped in morphological analysis to render more definite diagnoses on small biopsies of PSC.
Anticancer research 04/2012; 32(4):1463-73. · 1.73 Impact Factor
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Enrico Bollito,
Stefano De Luca,
Matteo Cicilano,
Roberto Passera,
Susanna Grande,
Carmen Maccagnano,
Susanna Cappia,
Angela Milillo,
Francesco Montorsi,
Roberto Mario Scarpa, Mauro Papotti,
Donato Franco Randone
[show abstract]
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ABSTRACT: To determine an optimal prostate cancer gene 3 (PCA3) cutoff in predicting prostate cancer in Italian patients undergoing first or repeat biopsy.
In this observational multicenter study 1246 men with elevated prostate specific antigen (PSA) and negative digital rectal examination, with prostate biopsy after PCA3 assessment, were divided into two groups submitted to PCA3 testing before or after previous negative biopsies. Ideal PCA3 cutoff was identified using area under the curve of the receiver operating characteristic analysis. Various cutoff values were used to determine the best predictive score. Univariate and multivariate logistic regression models compared age, PSA, free-PSA, and PCA3 score to predict prostate cancer.
PCA3 cutoff 39-50 had the highest accuracy in the repeat biopsy group in which cutoff of 39 could have avoided 51.9% negative repeat biopsies, eventually missing 7.8% of cancers (all low risk); cutoff of 50 would have prevented 56.5% of negative repeat biopsies, missing 29 tumors (10.3%), 5 potentially aggressive. The PCA3 test performed poorly in the first biopsy group.
We confirm the usefulness of PCA3 in Italian men with a previous negative biopsy. We achieved the best performance at a cutoff of 39. PCA3 did not perform better than PSA in non-biopsy-selected men.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology 04/2012; 34(2):96-104. · 0.41 Impact Factor
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ABSTRACT: Neuroendocrine (NE) breast carcinoma is defined by morphological features similar to those of NE tumors of other organs and NE marker expression in at least 50 % of neoplastic cells. However, a NE morphology may be observed even in breast carcinomas lacking NE markers. Human achaete-scute homolog-1 (hASH-1) is a transcription factor that plays a key role in the regulation of mammalian neural and NE cell development and has been identified in several human NE tumors. The aim of this study was to investigate hASH-1 expression in human breast cancers. hASH-1 expression was evaluated in 482 consecutive non-NE invasive breast carcinomas, in a series of 84 breast cancers with >50 % NE marker expression (high NE differentiation) and 21 carcinomas with NE histology but negative or focally (<50 %) positive for NE markers (low NE differentiation). hASH-1 protein was evaluated by a specific monoclonal antibody using immunohistochemistry and gene expression by real-time polymerase chain reaction. None of the non-NE invasive breast carcinomas expressed hASH-1 at any levels. hASH-1 was expressed in tumor cell nuclei of 63 and 38 % of cases with high and low NE differentiation, respectively. Strong correlation with protein and gene expression levels was observed (p < 0.0001). hASH-1 expression was correlated to a low mitotic count (p = 0.02) and a low Ki67 proliferative index (p = 0.0062). hASH-1 expression occurs in breast cancers with NE differentiation regardless of the extent of the NE cell population, and it is restricted to a subset of tumor cells having a low proliferative potential.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2012; 460(4):415-21. · 2.49 Impact Factor
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American Journal of Respiratory and Critical Care Medicine 02/2012; 185(3):341; author reply 341-2. · 11.08 Impact Factor
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ABSTRACT: Inflammatory reactions, known to promote tumor growth and invasion, have been found associated with colorectal carcinoma (CRC). Macrophages are the chief component of the inflammatory infiltration that occurs early in the progression from non-invasive to malignant tumor, with a switch from the pro-inflammatory phenotype to the tumor-promoting phenotype. Tumor and stroma are additional sources of inflammation-related molecules. The study aimed to evaluate, during colorectal carcinogenesis from benign to malignant phases: i) the trend of serum levels of IL-8, IL-6, TGFβ1, VEGF and MMPs; ii) the parallel trend of CRP serum levels; iii) derangement of the principal TGFβ1 receptors (TGFβ1RI/RII) in tumor tissues.
96 patients with colon adenomas or CRC at different stages of progression, and 17 controls, were recruited. Serum IL-8, IL-6, TGFβ1, VEGF, MMPs and CRP levels were analyzed before endoscopy or surgery. TGFβ1 receptors were evaluated in adenoma biopsies and surgically-removed colorectal adenocarcinomas. Serum levels of IL-8 in adenocarcinoma patients were increased from stage II, when also the enzymatic activity of MMP-9 increased. Of note, the increasing trend of the two serum markers was found significantly correlated. Trend of serum CRP was also very similar to that of IL-8 and MMP-9, but just below statistical significance. TGFβ1 levels were lower at stage III CRC, while IL-6 and VEGF levels had no significant variations. In tissue specimens, TGFβ1 receptors were already absent in about 50% of adenomas, and this percentage of missing receptors markedly increased in CRC stages III and IV.
Combined quantification of serum IL-8, MMP-9 and CRP, appears a reliable and advanced index of inflammation-related processes during malignant phase of colorectal carcinogenesis, since these molecules remain within normal range in colorectal adenoma bearing patients, while consistently increase in the blood of CRC patients, even if from stage II only.
PLoS ONE 01/2012; 7(7):e41839. · 4.09 Impact Factor
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Alfredo Berruti,
Paola Sperone,
Anna Ferrero,
Antonina Germano,
Arianna Ardito,
Adriano Massimiliano Priola,
Silvia De Francia,
Marco Volante,
Fulvia Daffara,
Daniele Generali,
Sophie Leboulleux,
Paola Perotti,
Eric Baudin, Mauro Papotti,
Massimo Terzolo
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ABSTRACT: There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells.
We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro.
Multicenter, prospective phase II trial. Setting Referral centers for ACC.
Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity.
Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel.
Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.
European Journal of Endocrinology 12/2011; 166(3):451-8. · 3.42 Impact Factor
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ABSTRACT: Differentiation-inducing factor-1 (DIF-1) is a morphogen originally identified in the amoebozoan Dictyostelium discoideum. In mammalian cells, it has been shown to activate GSK3β, which in turn is expected to reduce levels of β-catenin and cyclin D1, thus mediating DIF-1 antiproliferative properties. Since this could alter the expression and activity of E2F1 transcription factor and consequently those of the prognostic marker/chemotherapy target thymidylate synthase (TS), we evaluated (1) whether DIF-1 could effectively regulate these genes, (2) whether it could interfere with cell viability, and (3) whether DIF-1 activity could enhance the efficacy of the TS inhibitor 5-fluorouracil (5-FU).
We investigated the effects of DIF-1 in continuous human cell lines derived from two oral tumor histotypes (corresponding to an adenosquamous and a squamous carcinoma) and a gingival epithelium. We evaluated mRNA accumulation by means of quantitative real-time PCR and efficacy of drugs on cell viability by means of MTT assay.
DIF-1 inhibited the accumulation of E2F1 mRNA and reduces TS mRNA levels in tumor cell lines, but did not alter mRNA levels in the gingival counterpart. As a result, it inhibited proliferation preferentially of tumor cell in time- and concentration-dependent manner. Moreover, it enhanced cytotoxic effects of 5-FU only in tumor cell, whereas reduced them in the gingival counterpart.
These findings suggest a tumor-specific action of DIF-1 on oral carcinoma cells. Thus, interfering with E2F1 and TS transcription, DIF-1 potentiates TS enzymatic inhibitors.
Cancer Chemotherapy and Pharmacology 12/2011; 69(4):983-9. · 2.83 Impact Factor
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Eleonora Duregon,
Marco Volante,
Susanna Cappia,
Alessandra Cuccurullo,
Michele Bisceglia,
Daniel D Wong,
Dominic V Spagnolo,
Sylwia Szpak-Ulczok,
Enrico Bollito,
Fulvia Daffara,
Alfredo Berruti,
Massimo Terzolo, Mauro Papotti
[show abstract]
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ABSTRACT: The pathologic diagnosis of adrenocortical carcinoma (ACC) relies on microscopic features that are sometimes equivocal in special variants, including oncocytic adrenocortical tumors (OACTs). We report a series of 27 unpublished OACTs (15 pure and 12 mixed or focal) and assess for the first time in OACTs the diagnostic utility of an algorithm recently proposed by our group ("reticulin" algorithm) for conventional ACCs on the basis of a combination of reticulin staining and assessment of only 3 Weiss parameters. Overall, 12 cases were malignant according to the Lin-Weiss-Bisceglia (L-W-B) system for pure tumors and the original Weiss system for mixed or focal tumors; extensive or focal disruption of the reticulin network was found in 16 of 27 OACTs. This was associated with either a high mitotic index, presence of necrosis, and/or vascular invasion in 14 of these, which were thus considered malignant according to our algorithm. From a clinical standpoint, OACTs, at least in the pure form, are "low grade" lesions with a low mean Weiss score, mitotic and Ki-67 indices, and uncommon capsular or vascular invasion. They, including unequivocal morphologically malignant cases, generally pursue an indolent clinical course. In addition, the 4977 bp mitochondrial DNA "common deletion" was detected using real-time polymerase chain reaction in 54% of cases from this study and an additional validation series of 23 OACTs, with a heterogenous (heteroplasmic) intratissue and intracellular distribution (as detected by a modified FISH procedure) and a marked association with the presence of intact reticulin framework.
The American journal of surgical pathology 12/2011; 35(12):1882-93. · 4.06 Impact Factor
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ABSTRACT: The pathological diagnosis of adrenocortical carcinoma (ACC) is still challenging for its rarity and the presence of special variants (pediatric, oncocytic, myxoid, and sarcomatoid). It is based on the recognition at light microscopy of at least three among nine morphological parameters, according to the Weiss scoring system, which has been introduced 27 years ago and nowadays is the most widely employed. Nevertheless, the diagnostic performance of this system is very high but does not reach a sensitivity and specificity of 100%, its diagnostic applicability is potentially low among non-expert pathologists, and a group of borderline cases with only one or two criteria exist of uncertain behavior. Moreover, it is scarcely reproducible in the ACC morphological variants. In fact, specifically for the pure oncocytic neoplasms that seem to have a better prognosis in comparison to the conventional ACCs, a modified system (the Lin-Weiss-Bisceglia) has been proposed. With the aim to simplify the ACC diagnosis, 2 years ago, the "reticulin" diagnostic algorithm has been proposed, based on the observation that the tumoral reticulin framework (highlighted by reticulin silver-based histochemical staining) is consistently disrupted in malignant cases but only in a small subset of benign cases. Following this algorithm, in the presence of reticulin alterations, malignancy is further defined through the identification of at least one of the following parameters: necrosis, high mitotic rate, and venous invasion. As a complement to the morphological approach, some immunohistochemical markers (such as steroidogenic factor 1) have been proposed as diagnostic and prognostic adjuncts but still lack wide clinical validation.
Hormones and Cancer 12/2011; 2(6):333-40.
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Giuseppe Pelosi,
Alessandra Fabbri,
Fabrizio Bianchi,
Patrick Maisonneuve,
Giulio Rossi,
Mattia Barbareschi,
Paolo Graziano,
Alberto Cavazza,
Natasha Rekhtman,
Ugo Pastorino,
Paolo Scanagatta, Mauro Papotti
[show abstract]
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ABSTRACT: Diagnosing non-small cell lung cancer on biopsy/cellblock samples by morphology may be demanding. As sparing material for molecular testing is mandatory, a minimalist immunohistochemistry (IHC)-based diagnostic approach is warranted by means of novel, reliable, and easy-to-assess biomarkers.
Forty-six consecutive biopsy/cellblock samples and the corresponding resection specimens (as the gold standard for morphology and IHC) from 30 adenocarcinomas (AD), 10 squamous carcinomas (SQC), 5 adenosquamous carcinomas (ADSQC), and 1 sarcomatoid carcinoma (SC) were IHC-evaluated for p40 [corresponding to nontransactivating ΔNp63 isoforms] and thyroid transcription factor-1 (TTF1) by semiquantitative assessment. For p40, also immunodecoration intensity was taken into account and dichotomized as strong or low.
Nonrandom and overlapping distributions of the relevant markers were found in biopsy/cellblock and surgical specimens, which closely correlated with each other and the diverse tumor categories, with no differences in area under curve-receiver-operating-characteristic curves for each marker between any two samples, including p40 and p63. Diagnostic combinations were p40-/TTF1+ or TTF1- for AD (where p40 was negative, apart from 5/30 AD showing at the best 1-2% tumor cells with low intensity); p40+/TTF1- (p40 strong and by far higher than 50%) for SQC; and p40+/TTF1+ or p40+/TTF1- (p40 strong and less than 50%) for ADSQC. The single SC case was p40-/TTF1-, suggesting glandular lineage. Practically, 41/46 (89%) tumors were correctly classified by IHC on small samples, including 30 AD, 10 SQC, 1/5 ADSQC, and no SC. Underdiagnosis of ADSQC was actually because of sampling error of biopsies/cellblocks rather than insufficient biomarker robustness, whereas underdiagnosis of SC was really because of the failure of either marker to highlight epithelial-mesenchymal transition.
This minimalist IHC-based model of p40 and TTF1 on biopsy/cellblock samples was effective to correctly subtype most cases of lung cancer.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2011; 7(2):281-90. · 4.55 Impact Factor
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Mattia Barbareschi,
Chiara Cantaloni,
Valerio Del Vescovo,
Alberto Cavazza,
Valentina Monica,
Rodolfo Carella,
Giulio Rossi,
Luca Morelli,
Alberto Cucino,
Massimo Silvestri,
Giuseppe Tirone,
Giuseppe Pelosi,
Paolo Graziano, Mauro Papotti,
Paolo Dalla Palma,
Claudio Doglioni,
Michela Alessandra Denti
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ABSTRACT: Large cell carcinomas (LCCs) of the lung are heterogeneous and may be of different cell lineages. We analyzed 56 surgically resected lung tumors classified as LCC on the basis of pure morphologic grounds, using a panel of immunophenotypic markers (adenocarcinoma [ADC]-specific, thyroid transcription factor-1, cytokeratin 7, and napsin A; squamous cell carcinoma [SQCC]-specific, p63, cytokeratin 5, desmocollin 3, and Δnp63) and the quantitative analysis of microRNA-205 (microRNA sample score [mRSS]). Based on immunoprofiles 19 (34%) of the cases were reclassified as ADC and 14 (25%) as SQCC; 23 (41%) of the cases were unclassifiable. Of these 23 cases, 18 were classified as ADC and 5 as SQCC according to the mRSS. Our data show that an extended panel of immunohistochemical markers can reclassify around 60% of LCCs as ADC or SQCC. However, a relevant percentage of LCCs may escape convincing immunohistochemical classification, and mRSS could be used for further typing, but its clinical relevance needs further confirmation.
American Journal of Clinical Pathology 11/2011; 136(5):773-82. · 2.60 Impact Factor
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Giovanni N Berta,
Andrea E Sprio,
Manuela Iezzi,
Michela Spadaro,
Susanna Cappia,
Paolina Salamone,
Federica Di Scipio,
Barbara Mognetti, Mauro Papotti,
Piero Musiani,
Guido Forni,
Federica Cavallo
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ABSTRACT: Vaccines against oncoantigens halt early neoplastic lesions in several cancer-prone, genetically engineered mouse models, whereas their ability to prevent chemical carcinogenesis has not been explored. This is a significant issue, as exposure to chemical mutagens is responsible for a substantial percentage of cancers worldwide. Here, we show that the archetypal oncoantigen ERBB2 is transiently overexpressed in Syrian hamsters during the early stages of 7,12-dimethylbenz[α]anthracene (DMBA)-induced oral carcinogenesis. Repeated DNA vaccinations against ERBB2 significantly reduce the number, size, and severity of oral lesions in a manner directly proportional to the anti-ERBB2 antibody response. These results support the prospects of vaccines as a fresh strategy in the management of individuals at risk for exposure to defined carcinogenic agents.
Cancer Prevention Research 07/2011; 4(7):994-1001. · 4.91 Impact Factor
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ABSTRACT: Aurora kinase A (AURKA) is a member of serine/threonine kinase family. Several kinases belonging to this family are activated in the G2/M phase of the cell cycle being involved in mitotic chromosomal segregation. AURKA overexpression is significantly associated with neoplastic transformation in several tumors and deregulated Aurora Kinases expression leads to chromosome instability, thus contributing to cancer progression. The purpose of the present study was to investigate the expression of AURKA in non small cell lung cancer (NSCLC) specimens and to correlate its mRNA or protein expression with patients' clinico-pathological features.
Quantitative real-time PCR and immunohistochemistry analysis on matched cancer and corresponding normal tissues from surgically resected non-small cell lung cancers (NSCLC) have been performed aiming to explore the expression levels of AURKA gene.
AURKA expression was significantly up-modulated in tumor samples compared to matched lung tissue (p<0.01, mean log2(FC)=1.5). Moreover, AURKA was principally up-modulated in moderately and poorly differentiated lung cancers (p<0.01), as well as in squamous and adenocarcinomas compared to the non-invasive bronchioloalveolar histotype (p=0.029). No correlation with survival was observed.
These results indicate that in NSCLC AURKA over-expression is restricted to specific subtypes and poorly differentiated tumors.
Journal of Translational Medicine 06/2011; 9:100. · 3.41 Impact Factor
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ABSTRACT: To analyse the surgical margins status of prostatic glands, resected by laparoscopic radical prostatectomy (LRP) for prostate cancer, and to correlate it with biochemical free survival rate (BFSR).
Data were collected prospectively from 405 patients undergoing LRP from 2000 to 2009 at a single institution. Patients undergoing neoadjuvant and/or adjuvant therapy were excluded from the study. Three hundred patients matched all the criteria: 232 of these had negative surgical margins (NSM) and 68 positive surgical margins (PSM). The median follow-up was 62 months. PSM were classified based on the following: (a) the number of margins, monofocal and multifocal, (b) the location, apical or non-apical and (c) the extension, ≤2.8 mm or >2.8 mm. These data were then entered into a multivariate analysis.
Overall BFSR rate was 67.6% in PSM group and 88.8% in NSM group (P < 0.001). We registered a HR of 3.78 in multivariate analysis (P < 0.001). In terms of the extension, BFSR in univariate survival analysis was 77.8% in ≤2.8 mm PSM and 38.9% in >2.8 mm PSM (P = 0.003), with a HR of 5.68 (P = 0.011) in multivariate analysis. BFSR was 59% for apical margins and 77% for non-apical margins (P = 0.038). In monofocal margins, BFSR was 73%, while 53% in multifocal (P = 0.014).
We recommend careful evaluation of patients with PSM following LRP, especially if they are more than 2.8 mm, and in these cases, adjuvant therapy should be considered after radical surgery.
World Journal of Urology 06/2011; 30(2):245-50. · 2.41 Impact Factor
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Giuseppe Pelosi,
Giulio Rossi,
Fabrizio Bianchi,
Patrick Maisonneuve,
Domenico Galetta,
Angelica Sonzogni,
Giulia Veronesi,
Lorenzo Spaggiari, Mauro Papotti,
Mattia Barbareschi,
Paolo Graziano,
Andrea Decensi,
Alberto Cavazza,
Giuseppe Viale
[show abstract]
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ABSTRACT: More detailed typing of non-small cell lung cancer on small biopsy specimens is increasingly required, albeit sometimes demanding with morphology alone. Little, however, is known about the likelihood of immunohistochemistry (IHC)-assessed small biopsies to effectively parallel profiling and, hence, eventual diagnoses of surgical specimens.
Sixty-three preoperative biopsies and the corresponding surgical specimens from 30 consecutive squamous cell carcinomas, 22 adenocarcinomas, 2 adenosquamous carcinomas, eight sarcomatoid carcinomas, and one yolk sac tumor were jointly evaluated semiquantitatively for cytokeratins 5/6 and 7, p63, thyroid transcription factor-1, and vimentin immunoreactivity. Surgical specimens were the gold standard for morphology and IHC.
Hierarchic clustering analysis of both surgical specimens and biopsies showed a nonrandom and overlapping distribution of the relevant markers, which closely correlated with each other and the diverse tumor categories, as confirmed by mosaic plot analysis. There were no differences in area under the curve-receiver operating characteristic curves for each marker between any two samples, with the exception of p63 that paralleled more effectively squamous cell carcinoma on biopsies than surgical specimens. Fifty-nine of 63 (94%) lesions were correctly classified by IHC on biopsy compared with 53 of 63 (84%) by revised morphology, with the predictive positive value being 97% for squamous cell carcinoma, 88% for adenocarcinoma, and 100% for sarcomatoid and adenosquamous carcinoma. Yolk sac tumor and three of eight sarcomatoid carcinomas, however, failed any diagnostic recognition.
Diverse cell differentiation lineages of non-small cell lung cancer may be consistently detected by IHC in small biopsies, making the eventual typing of tumors effective in most cases.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2011; 6(6):1039-49. · 4.55 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs which regulate gene expression by base-pairing to the 3'-UTR of the target mRNA. Recently, miRNAs have been shown to regulate cancer metastasis, however, central molecular mechanisms of this ability still need to be investigated. Epithelial to mesenchymal transition (EMT), which is characterized especially by repression of E-cadherin expression and increased cell motility, is an essential component of cancer metastasis and progression. In the present study, we found that Snai1, a known transcriptional repressor of E-cadherin and modulator of EMT, is post-transcriptionally targeted by miRNA-30a in non-small cell lung cancer (NSCLC). Consistent with this, microRNA-30a expression was found inversely proportional to the invasive potential of various NSCLC cell lines, correlating positively with E-cadherin (epithelial marker) and negatively with N-cadherin (mesenchymal marker) expression. Forced re-introduction of miR-30a significantly altered cell morphology, in vitro invasion and migration of invasive cell lines, this being paralleled by a downregulation of Snai1 and upregulation of E-cadherin expression. Using a chicken embryonic metastasis assay, we found that miR-30a suppresses in vivo distant metastasis to the lungs and liver. Finally, we screened the expression of miR-30a in 64 consecutively resected NSCLC patients and found that, in 81% of the patients, expression of miR-30a was downregulated significantly (p < 0.0001) in tumors compared to corresponding normal tissues. These results suggest that miR-30a targets Snai1, inhibits invasion and metastasis, and is downregulated in NSCLC.
International Journal of Cancer 06/2011; 130(9):2044-53. · 5.44 Impact Factor
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ABSTRACT: The combination of cytotoxic chemotherapy with signaling pathway inhibitors represents a potential strategy to improve the treatment of nonsmall cell lung cancer (NSCLC). Thymidylate synthase (TS) is an enzyme essential for DNA synthesis, and its overexpression has been associated with the reduced sensitivity to antifolate agents. Src is a tyrosine kinase that modulates the cytotoxicity of cancer cells after drug treatment, and in vitro data indicate that its inhibition could revert the resistance to TS-inhibiting drugs. Our study investigated the significance of TS and Src expression in NSCLC tissues, and the effects of their pharmacological inhibition in cell lines. In tumor and normal tissues from 94 resected NSCLC patients, TS and Src transcript levels were found positively correlated (R(S) = 0.66), associated with patients smoking history and overall survival. At multivariate analysis, TS gene expression was an independent prognostic factor (relative risk (RR) = 1.78, from 1.16 to 2.72; p < 0.01). Immunohistochemical detection in tumor specimens confirmed that Src kinase activation, evaluated by phospho-specific antibody, was associated to a higher TS expression. In cell lines, dasatinib, a Src-inhibiting agent, synergistically enhanced pemetrexed-cytotoxicity of A549 cells, as evaluated by MTT and apoptosis assays. The biological explanation for this interaction was based on the upregulation of TS messenger RNA and protein levels induced by pemetrexed, which was significantly prevented by dasatinib cotreatment. The data of our study suggest that TS and Src may belong to a common pathway that bears prognostic significance in NSCLC, and that Src represents a potential target to improve the efficacy of TS-inhibiting agents.
International Journal of Cancer 05/2011; 130(8):1777-86. · 5.44 Impact Factor
