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Marchesi F.,IRCCS Humanitas Clinical Institute | Locatelli M.,Fondazione IRCCS Ospedale Maggiore Policlinico | Solinas G.,IRCCS Humanitas Clinical Institute | Erreni M.,IRCCS Humanitas Clinical Institute | And 3 more authors.
Journal of Neuroimmunology | Year: 2010

CX3CL1 or Fractalkine is a peculiar chemokine that can exist either in a soluble form, like all the other chemokines, and as a cell membrane molecule. CX3CL1 is one of the most expressed chemokines in the central nervous system, where it regulates the communication between neurons, glia and microglia. CX3CR1-expressing microglia may have an important role in limiting tissue injury during inflammation and neuro-degeneration. Recent evidence has implicated CX3CL1 and its cognate receptor CX3CR1 in cancer. Tumors of neural origin (glioma, neuroblastoma) express CX3CR1 which is involved in the adhesion, transendothelial migration and mobilization of tumor cells. In addition, tumors of non-neural origin, like prostate, pancreas and breast carcinoma express high levels of the CX3CR1 receptor. As for other chemokine receptors, CX3CR1 expression is associated with increased migration and site specific dissemination. In pancreatic cancer, receptor expression is involved in the perineural invasion and dissemination of neoplastic cells along intra- and extra-pancreatic nerves. This peculiar route of tumor spread is used also by other carcinomas (e.g. prostate, head and neck) and may represent a target for therapeutic intervention. © 2010 Elsevier B.V.


Cappuzzo F.,Instituto Toscano Tumori | Finocchiaro G.,Instituto Clinico Humanitas IRCCS | Grossi F.,IRCCS AOU San Martino IST Instituto Nazionale per la Ricerca sul Cancro | Bidoli P.,San Gerardo Hospital | And 7 more authors.
Journal of Thoracic Oncology | Year: 2015

Introduction: Afatinib, an oral irreversible ErbB Family Blocker, has demonstrated efficacy and safety in epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. It is unknown whether such activity also occurs in patients with EGFR gene overexpression, regardless of mutation status. This phase II study investigated the activity and safety of afatinib in advanced non-small-cell lung cancer with increased EGFR gene copy number and/or gene amplification by fluorescence in situ hybridization (FISH), with or without EGFR mutation. Methods: EGFR gene overexpression was assessed by FISH analysis; patients with high polysomy or gene amplification were considered FISH positive. Patients received daily afatinib less than or equal to 50 mg (monotherapy). Endpoints included objective response rate (ORR; primary), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Of 223 patients screened, 69 patients were FISH-positive and met eligibility criteria for treatment. The ORR was 13.0% overall (n =9 of 69). Higher ORRs were observed in patients with gene amplification (20.0%; n =5 of 25) and EGFR mutation-positive tumors (25.0%; n =3 of 12). The DCR was 50.7% overall (n = 35 of 69; median duration: 24.9 weeks) with higher DCRs observed in patients with gene amplification 64.0%; (n = 16 of 25), and in patients with EGFR mutation-positive tumors 66.7% (n = 8 of 12). In the overall population, median PFS was 8.4 weeks and median OS was 50.4 weeks. The most common afatinib-related adverse events were rash/acne (83%) and diarrhea (78%). Conclusions: First- or second-line afatinib demonstrated preliminary activity and manageable safety in EGFR FISH-positive patients with advanced non-small-cell lung cancer. © 2015 by the International Association for the Study of Lung Cancer.


Migliavacca R.,University of Pavia | Nucleo E.,University of Pavia | Asticcioli S.,University of Pavia | Casari E.,IRCCS Humanitas Clinical Institute | And 2 more authors.
New Microbiologica | Year: 2013

Sequence Type 258 (ST258) together with its allelic single- and double-locus variants have mostly been associated with the dissemination of KPC-producing Klebsiella pneumoniae in Europe. A total of 56 nonreplicate K. pneumoniae isolates with decreased carbapenem-susceptibility, collected at 7 different hospitals located in Northern Italy were investigated for the occurrence of blaKPC-type genes. PCR and sequencing results highlighted the presence of blaKPC- 2 or blaKPC-3 determinants in 10/56 and 5/56 cases respectively. Here we describe the intra- and inter-hospital spread in Northern Italy of a K. pneumoniae ST512 clone harboring the blaKPC-3 gene.


Serati M.,University of Insubria | Ghezzi F.,University of Insubria | Cattoni E.,University of Insubria | Braga A.,University of Insubria | And 5 more authors.
European Urology | Year: 2012

Background: One of the most effective and popular current procedures for the surgical treatment of stress urinary incontinence (SUI) is tension-free midurethral slings. Objective: To evaluate the outcomes of women with retropubic tension-free vaginal tape (TVT) for urodynamic stress incontinence (USI) after 10-yr follow-up. Design, setting, and participants: This was a prospective observational study. Consecutive women with proven USI were treated with TVT. Patients with mixed incontinence and/or anatomic evidence of pelvic organ prolapse were excluded. Intervention: Standard retropubic TVT. Measurements: Patients underwent preoperative clinical and urodynamic evaluations. During follow-up examinations, women were assessed for subjective satisfaction and objective cure rates. Multivariable analyses were performed to investigate outcomes. Results and limitations: A total of 63 women were included. After 10 yr, 5 patients (8%) were lost or no longer evaluable. The 10-yr subjective, objective, and urodynamic cure rates were 89.7%, 93.1%, and 91.4%, respectively. These rates were stable across the whole study period (p > 0.99). De novo overactive bladder was reported by 30.1% and 18.9% of patients at 3-mo and 10-yr follow-up, respectively (p for trend = 0.19). A total of 84.2% of women with detrusor overactivity received antimuscarinic drugs, but 43.8% were nonresponders 12 wk later. At multivariable analysis, maximum detrusor pressure during the filling phase >9 cm H 2O (hazard ratio [HR]: 16.2; p = 0.01) and maximum detrusor pressure during the voiding phase ≤29 cm H 2O (HR: 8.0; p = 0.01) were independent predictors for the recurrence of SUI, as well as obesity was for the recurrence of objective SUI (HR: 17.1; p = 0.01) and of USI (HR: 8.9; p = 0.02), respectively. Intraoperatively, bladder perforation occurred in two cases; no severe bleeding or other complications occurred. Conclusions: The 10-yr results of this study seem to demonstrate that TVT is a highly effective option for the treatment of female SUI, recording a very high cure rate with low complications after a 10-yr follow-up. © 2012 European Association of Urology.


Serati M.,University of Insubria | Salvatore S.,University of Insubria | Siesto G.,IRCCS Humanitas Clinical Institute | Cattoni E.,University of Insubria | And 5 more authors.
European Urology | Year: 2011

Background: International official guidelines recommend urodynamic (UDS) evaluation in patients with pelvic organ prolapse (POP). However, the real benefit of this examination is still the subject of heated and controversial debate. Therefore, we aimed to assess the correlation between urinary symptoms and UDS findings in women with POP through the implementation of a sophisticated computer-based technology in the outpatient workup. Design, setting, and participants: A prospective cohort study was performed in a single, tertiary, urogynaecologic referral department, enrolling consecutive women seeking care for pelvic floor dysfunctions. Intervention: Patients underwent clinical and urodynamic evaluation. Data regarding baseline characteristics, symptoms, anatomic, and urodynamic findings were gathered for each patient. Multiple linear regression (MLR) and artificial neural networks (ANNs) were performed to design predicting models. Results and limitations: A total of 802 women with POP were included. POP quantification stages and baseline data poorly correlated to final UDS findings. Stress urinary incontinence and overactive bladder were both independently associated to each UDS diagnosis, including detrusor overactivity (DO), urodynamic stress incontinence (USI), and mixed urinary incontinence (USI plus DO). Receiver operating characteristic comparison confirmed that ANNs were more accurate than MLR in identifying predictors of UDS diagnosis, but none of these methods could successfully overcome UDS. Case-control studies are needed to confirm our findings. Conclusions: Despite the current debate based on the actual value of UDS in women with POP, even the implementation of ANN, a sophisticated computer-based technology, does not permit an accurate diagnosis just on the basis of symptoms or avoiding UDS. Therefore, in women with POP, especially if scheduled for surgery, UDS should be considered as mandatory, since misleading counselling could result in unpleasant unexpected events. © 2011 European Association of Urology.


Nobile-Orazio E.,University of Milan | Nobile-Orazio E.,IRCCS Humanitas Clinical Institute | Giannotta C.,IRCCS Humanitas Clinical Institute | Briani C.,University of Padua
Journal of Neuroimmunology | Year: 2010

Anti-ganglioside complexes (GSCs) IgG antibodies have been reported in patients with Guillain-Barré (GBS) or Fisher syndrome but little is known on their presence in multifocal motor neuropathy (MMN) or other chronic immune-mediated neuropathies. We examined 24 patients with MMN, 34 with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 23 with neuropathy associated with IgM monoclonal gammopathy (PN + IgM), 13 with GBS, 34 with motor neuron disease (MND), 24 with other neuropathies and 20 normal subjects. Patients' sera were tested by ELISA for IgM reactivity to GM1, GM2, GD1a, GD1b and GT1b and with GSCs made by any combination of two of these gangliosides. In all GM1 positive patients with MMN (11), PN + IgM (1), CIDP (1) and POEMS (1), binding to GM1 was abolished or consistently reduced when tested in GSCs also containing GD1a or other gangliosides. This only occurred in one of the three GM1 positive MND patients. In a patient with PN-IgM and anti-GM2 and GD1a IgM, both reactivities were reduced when tested in GSCs also containing GM1. New reactivities were found in a patient with CIDP and anti-GD1b IgM who presented an additional reactivity to GT1b/GM1 and GT1b/GM2 GSCs, and in one with PN-IgM who had reactivity to GM2/GD1b but not to individual gangliosides. Testing for IgM antibodies to GSCs rarely permitted to identify new reactivities in chronic immune neuropathies. IgM binding to gangliosides was however often modified in GSCs suggesting that these reactivities may be affected by contiguous gangliosides possibly influencing their pathogenicity. © 2009 Elsevier B.V.


Germano G.,IRCCS Humanitas Clinical Institute | Mantovani A.,IRCCS Humanitas Clinical Institute | Mantovani A.,University of Milan | Allavena P.,IRCCS Humanitas Clinical Institute
Annals of Medicine | Year: 2011

Different types of cancer take advantage of inflammatory components to improve their life-span in the organs. A sustenance of growth factors and cytokines (e.g. interleukin (IL)-1, tumor necrosis factor, IL-6, vascular endothelial growth factor) supports malignant cell progression and contributes to suppress the body immune defense. Strategies to modulate the host micro-environment offer new approaches for anti-cancer therapies. For these reasons new molecules with anti-tumor and anti-inflammatory features (e.g. trabectedin) are looked at with new eyes in the light of the crucial link between inflammation and cancer. © 2011 Informa UK, Ltd.


Marchesi F.,IRCCS Humanitas Clinical Institute | Piemonti L.,Diabetes Research Institute | Mantovani A.,IRCCS Humanitas Clinical Institute | Mantovani A.,University of Milan | Allavena P.,IRCCS Humanitas Clinical Institute
Cytokine and Growth Factor Reviews | Year: 2010

Invasion and metastasis are key components of cancer progression. Inflammatory mediators, including cytokines and chemokines, can facilitate tumor dissemination. A distinct and largely forgotten path is perineural invasion (PNI), defined as the presence of cancer cells in the perinerium space. PNI is frequently used by many human carcinomas, in particular by pancreas and prostate cancer, and is associated with tumor recurrence and pain in advanced patients. Neurotrophic factors have been identified as molecular determinants of PNI. A role for chemokines in this process has been proposed; the chemokine CX3CL1/Fractalkine attracts receptor positive pancreatic tumor cells to disseminate along peripheral nerves. Better understanding of the neurotropism of malignant cells and of the clinical significance of PNI would help the design of innovative strategies for the control of tumor dissemination and pain in cancer patients. © 2009 Elsevier Ltd. All rights reserved.


Vitali E.,University of Milan | Peverelli E.,University of Milan | Giardino E.,University of Milan | Locatelli M.,Neurosurgery Unit | And 5 more authors.
Molecular and Cellular Endocrinology | Year: 2014

In the pituitary the activation of cyclic adenosine 3'-5'-monophosphate (cAMP) dependent pathways generates proliferative signals in somatotrophs, whereas in pituitary cells of other lineages its effect remains uncertain. Moreover, the specific role of the two main cAMP effectors, protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac), has not been defined. Aim of this study was to investigate the effect of cAMP on pituitary adenomatous cells proliferation and to identify PKA and Epac differential involvement. We found that cAMP increased DNA synthesis and cyclin D1 expression in somatotropinomas, whereas it reduced both parameters in prolactinomas and nonfunctioning adenomas, these effects being replicated in corresponding cell lines. Moreover, the divergent cAMP effects were mimicked by Epac and PKA analogs, which activated Rap1 and CREB, respectively. In conclusion, we demonstrated that cAMP exerted opposite effects on different pituitary cell types proliferation, these effects being mediated by both Epac and PKA. © 2013 Elsevier Ireland Ltd.


Allavena P.,IRCCS Humanitas Clinical Institute | Mantovani A.,IRCCS Humanitas Clinical Institute | Mantovani A.,University of Milan
Clinical and Experimental Immunology | Year: 2012

Mononuclear phagocytes are cells of the innate immunity that defend the host against harmful pathogens and heal tissues after injury. Contrary to expectations, in malignancies, tumour-associated macrophages (TAM) promote disease progression by supporting cancer cell survival, proliferation and invasion. TAM and related myeloid cells [Tie2 + monocytes and myeloid-derived suppressor cells (MDSC)] also promote tumour angiogenesis and suppress adaptive immune responses. These divergent biological activities are mediated by macrophages/myeloid cells with distinct functional polarization, which are ultimately dictated by microenvironmental cues. Clinical and experimental evidence has shown that cancer tissues with high infiltration of TAM are associated with poor patient prognosis and resistance to therapies. Targeting of macrophages in tumours is considered a promising therapeutic strategy: depletion of TAM or their 're-education' as anti-tumour effectors is under clinical investigation and will hopefully contribute to the success of conventional anti-cancer treatments. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.

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