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1.  Isolation of breast cancer and gastric cancer circulating tumor cells by use of an anti HER2-based microfluidic device 
Lab on a chip  2013;14(1):147-156.
Circulating Tumor Cells (CTCs) have emerged as a reliable source of tumor cells, and their concentration has prognostic implications. CTC capture offers real-time access to cancer tissue without the need of an invasive biopsy, while their phenotypic and molecular interrogation can provide insight into the biological changes of the tumor that occur during treatment. The majority of the CTC capture methods are based on EpCAM expression as surface marker of tumor-derived cells. However, EpCAM protein expression levels can be significantly down regulated during cancer progression as consequence of the process of epithelial to mesenchymal transition.
In this paper, we describe a novel HER2 (Human Epidermal Receptor 2)-based microfluidic device for the isolation of CTCs from peripheral blood of patients with HER2-expressing solid tumors. We selected HER2 as an alternative to EpCAM, as the receptor is biologically and therapeutically relevant in several solid tumors, like breast cancer (BC), where it is overexpressed in 30% of the patients and expressed in 90%, and gastric cancer (GC), in which HER2 presence is identified in more than 60% of the cases. We tested the performance of various anti HER2 antibodies in a panel of nine different BC cell lines with varying HER2 protein expression levels, using immunoblotting, confocal microscopy, live cells imaging and flow cytometry analyses. The antibody associated with the highest capture efficiency and sensitivity for HER2 expressing cells on the microfluidic device, was the one that performed best in live cells imaging and flow cytometry assays as opposed to the fixed cell analyses, suggesting that recognition of the native conformation of HER2 extracellular epitope on living cells was essential for specificity and sensitivity of CTC capture. Next, we tested the performance of the HER2 microfluidic device using blood from metastatic breast and gastric cancer patients. The HER2 microfluidic device exhibited CTC capture in 9/9 blood samples. Thus, the described HER2-based microfluidic device can be considered as a valid clinically relevant method for CTC capture in HER2 expressing solid cancers.
PMCID: PMC3921117  PMID: 24202699
2.  Necrotizing fasciitis as a rare complication of osteonecrosis of the jaw in a patient with multiple myeloma treated with lenalidomide: case report and review of the literature 
SpringerPlus  2014;3:123.
Bisphosphonates (BPs), potent inhibitors of osteoclast-mediated bone resorption, play a major role in the management of patients with multiple myeloma (MM). However, in the case of dental infections, they can lead to bisphosphonate related osteonecrosis of the jaw (BRONJ). This process can be worsened by concomitant antineoplastic therapy. Herein, we present a case of a life-threatening necrotizing fasciitis (NF) as a rare and severe complication of BRONJ after three cycles of lenalidomide and dexamethasone in an MM patient treated with corticosteroid therapy and Ibandronate for 5 years. The patient presented swelling on the right part of the neck, difficulty in swallowing and acute pain, so a magnetic resonance of the head and neck region was performed. It revealed the presence of an NF with a massive extension. Due to the large necrotic area and a rapid progression of the infection, the necrotic tissue had to be removed surgically. Furthermore, a specific antimicrobial treatment as well as 12 sessions of hyperbaric oxygen therapy were needed to cure the patient.
Herein, we highlight the potential serious adverse events associated with the use of bisphosphonates and antiangiogenetic drugs in patients with MM. Future studies are needed to evaluate the potential synergistic effects of BPs, corticosteroids and antiangiogenetic drugs.
PMCID: PMC3977019  PMID: 24711984
Necrotizing fasciitis; BRONJ; Bisphosphonate; Multiple myeloma; Lenalidomide
3.  Cisplatin Induces a Mitochondrial-ROS Response That Contributes to Cytotoxicity Depending on Mitochondrial Redox Status and Bioenergetic Functions 
PLoS ONE  2013;8(11):e81162.
Cisplatin is one of the most effective and widely used anticancer agents for the treatment of several types of tumors. The cytotoxic effect of cisplatin is thought to be mediated primarily by the generation of nuclear DNA adducts, which, if not repaired, cause cell death as a consequence of DNA replication and transcription blockage. However, the ability of cisplatin to induce nuclear DNA (nDNA) damage per se is not sufficient to explain its high degree of effectiveness nor the toxic effects exerted on normal, post-mitotic tissues. Oxidative damage has been observed in vivo following exposure to cisplatin in several tissues, suggesting a role for oxidative stress in the pathogenesis of cisplatin-induced dose-limiting toxicities. However, the mechanism of cisplatin-induced generation of ROS and their contribution to cisplatin cytotoxicity in normal and cancer cells is still poorly understood. By employing a panel of normal and cancer cell lines and the budding yeast Saccharomyces cerevisiae as model system, we show that exposure to cisplatin induces a mitochondrial-dependent ROS response that significantly enhances the cytotoxic effect caused by nDNA damage. ROS generation is independent of the amount of cisplatin-induced nDNA damage and occurs in mitochondria as a consequence of protein synthesis impairment. The contribution of cisplatin-induced mitochondrial dysfunction in determining its cytotoxic effect varies among cells and depends on mitochondrial redox status, mitochondrial DNA integrity and bioenergetic function. Thus, by manipulating these cellular parameters, we were able to enhance cisplatin cytotoxicity in cancer cells. This study provides a new mechanistic insight into cisplatin-induced cell killing and may lead to the design of novel therapeutic strategies to improve anticancer drug efficacy.
PMCID: PMC3834214  PMID: 24260552
4.  Anti-Tumor Activity of a miR-199-dependent Oncolytic Adenovirus 
PLoS ONE  2013;8(9):e73964.
The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR-199 target sites within the 3’ UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity.
PMCID: PMC3771938  PMID: 24069256
5.  Fatal Hepatocellular Carcinoma in a Patient with Occult Hepatitis B Virus Infection following the Administration of R-CHOP for Diffuse Large B-Cell Lymphoma 
Case Reports in Hematology  2012;2012:803298.
Occult hepatitis B (OBI) is caused by a persistent low-level replication of HBV. Like overt HBV infection, OBI can be associated with the integration of HBV sequences into the host genome and has a substantial clinical relevance for patients who are severely immunosuppressed for long durations. We present the case of a patient with a diffuse large B-cell non-Hodgkin lymphoma and OBI who developed a hepatocellular carcinoma with a fulminant clinical course following the administration of rituximab plus CHOP.
PMCID: PMC3541567  PMID: 23326737
6.  Malignant Perivascular Epithelioid Cell Tumor of the Esophagus 
Case Reports in Pathology  2012;2012:438505.
Malignant perivascular epithelioid cell tumor (PEComa) is a rare tumor composed of hybrid tumor cells characterized by immunoreactivity for both melanocytic and smooth muscle markers. This paper describes the uncommon esophageal location of an 8 cm PEComa in a 75-year-old Caucasian man who was presented with ingravescent dysphagia. Although PEComas arising within the gastrointestinal tract are exceptional findings, clinicians should not exclude this class of tumors in the diagnostic investigation of a bulky lesion of the esophageal wall.
PMCID: PMC3432343  PMID: 22957287
7.  Adjuvant chemotherapy of pT1a and pT1b breast carcinoma: results from the NEMESI study 
BMC Cancer  2012;12:158.
The prognosis of pT1a-pT1b breast cancer (BC) used to be considered very good, with a 10-y RFS of 90%. However, some retrospective studies reported a 10-y RFS of 81%–86% and suggested benefit from adjuvant systemic therapy.
To evaluate the variables that determined the choice of adjuvant chemotherapy and the type of chemotherapy delivered in pT1a-pT1b BC, we analysed the small tumours enrolled in the NEMESI study.
Out of 1,894 patients with pathological stage I-II BC enrolled in NEMESI, 402 (21.2%) were pT1a-pT1b. Adjuvant chemotherapy was delivered in 127/402 (31.59%). Younger age, grading G3, high proliferative index, ER-negative and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy. An anthracycline without taxane regimen was administered in 59.1% of patients, anthracycline with taxane in 24.4%, a CMF-like regimen in 14.2% and taxane in 2.4%. Adjuvant chemotherapy was administered in 88.4% triple-negative and 73.46% HER2-positive pT1a-pT1b BC. Adjuvant trastuzumab was delivered in 30/49 HER2-positive BC (61.2%).
Adjuvant chemotherapy was delivered in 31.59% T1a-pT1b BC treated at 63 Italian oncological centres from January 2008 to June 2008. The choice to deliver chemotherapy was based on biological prognostic factors. Anthracycline-based chemotherapy was administered in 83.5% patients.
PMCID: PMC3404902  PMID: 22545982
pT1a and pT1b breast cancer; Adjuvant chemotherapy; Adjuvant hormonal therapy
8.  Secondary Leukemia in a non-Hodgkin's Lymphoma Patient Presenting as Myeloid Sarcoma of the Breast 
Case Reports in Hematology  2011;2011:914613.
As defined by the World Health Organization classification of tumors of hematopoietic and lymphoid tissue, myeloid sarcoma (MS) is a tumor mass of myeloblasts or immature myeloid cells that can arise before, concurrent with, or following acute myeloid leukaemia. We describe a case of secondary leukemia presenting itself as MS of the breast in a patient previously treated for a non-Hodgkin's Lymphoma.
PMCID: PMC3420753  PMID: 22937314
9.  Hypoglycemic Syndrome in a Patient with Proinsulin-Only Secreting Pancreatic Adenoma (Proinsulinoma) 
Case Reports in Medicine  2011;2011:930904.
We describe an unusual case of hypoglycemic syndrome in a 69-year old woman with a proinsulin-only secreting pancreatic endocrine adenoma. The clinical history was highly suggestive of an organic hypoglycemia, with normal or relatively low insulin concentrations and elevated proinsulin levels. Magnetic resonance and computed tomography of the abdomen showed a 1 cm pancreatic nodule and multiple accessory spleens. The diagnosis was confirmed by selective angiography, showing location and vascularization of the nodule, despite no response to intra-arterial calcium. After resection, the hypoglycemic syndrome resolved. The surgical specimen was comprised of a neuroendocrine adenomatous tissue with high proinsulin immunoreactivity. Study of this unusual case of proinsulinoma underlines (i) the need to assay proinsulin in patients with hypoglycemia and normal immunoreactive insulin, (ii) the differential diagnosis in the presence of accessory spleens, (iii) the unresponsiveness to intra-arterial calcium stimulation, and (iv) the extensive evaluation needed to reach a final diagnosis.
PMCID: PMC3135210  PMID: 21765847
10.  A pathological complete response after preoperative chemotherapy with carboplatin and pemetrexed in malignant pleural mesothelioma: A case report. 
Malignant pleural mesothelioma is an aggressive tumour with poor prognosis and short duration of response probably due to the high chemo-refractoriness. Multimodality treatment based on preoperative chemotherapy, surgery and adjuvant radiotherapy seems to be a feasible and effective therapeutic option in selected patients.We report on a case of pathological complete response in a patient affected by malignant pleural mesothelioma who was treated with four cycles of preoperative chemotherapy based on carboplatin plus pemetrexed followed by parietal pleurectomy and lung decortication. Carboplatin plus pemetrexed was a well tolerated regimen without grade 3-4 haematological toxicity, and this confirm the feasibility of such a treatment as an alternative to the current golden standard based on cisplatin plus pemetrexed.Complete resection allows the pathologist to better describe biological markers of mesothelioma cells, in order to select patients with different treatment outcome and prognosis.
PMCID: PMC3256467  PMID: 22263055
mesothelioma; chemotherapy; carboplatin; pemetrexed
11.  Peritoneal carcinomatosis of colorectal origin 
Peritoneal carcinomatosis is, after liver metastases, the second most frequent cause of death in colorectal cancer patients and at the present time, is commonly inserted and treated as a stage IV tumour. Because there is no published data that outlines the impact of new therapeutic regimens on survival of patients with peritoneal surface diffusion, the story of carcinomatosis can be rewritten in light of a new aggressive approach based on the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Also if these treatment perhaps allow to obtain better results than standard therapies, we suggest, that a large prospective randomised control trial is needed to compare long-term and progression-free survival under the best available systemic therapy with or without cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
PMCID: PMC2999161  PMID: 21160927
Colorectal cancer; Peritoneal carcinomatosis; Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy
12.  The Extra Cytoplasmic Function Sigma Factor σE Is Essential for Mycobacterium tuberculosis Virulence in Mice  
Infection and Immunity  2004;72(5):3038-3041.
The virulence of a Mycobacterium tuberculosis H37Rv sigE mutant was studied in immunodeficient and immunocompetent mice. The mutant was strongly attenuated in both animal models and induced formation of granulomas with different characteristics than those induced by the wild-type strain.
PMCID: PMC387853  PMID: 15102817

Results 1-12 (12)