Publications by authors named "Mariantonia Carosi"

46 Publications

Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors.

J Exp Clin Cancer Res 2021 Jan 23;40(1):37. Epub 2021 Jan 23.

Department of Infectious Diseases, Istituto Superiore di Sanità, 00161, Rome, Italy.

Background: The oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells.

Methods: Envisioning clinical application of the best characterized anti-HPV16 E6 and -HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed.

Results: We showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway.

Conclusion: Based on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.
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http://dx.doi.org/10.1186/s13046-021-01841-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825221PMC
January 2021

Schwannomas of the sciatic nerve: A rare and neglected diagnosis. A review of the literature with two illustrative cases.

Clin Neurol Neurosurg 2020 Aug 6;195:105889. Epub 2020 May 6.

UOC Plastic Surgery, IRCSS National Cancer Institute "Regina Elena", Rome, Italy.

Objective: Schwannomas of the sciatic nerve, which is the largest nerve of the human body, are very rare accounting for ≤ 1% of all schwannomas. They often may raise confusion with other more common causes of sciatica, such as lumbar degenerative and inflammatory diseases or spinal tumors, which may often lead to a late correct diagnosis.

Patients And Methods: We present two cases of sciatic nerve schwannomas that were recently treated at our Institution, and we review the pertinent English literature on this topic over the last 15 years, yielding twenty three cases to analyze.

Results: Even if sciatic nerve schwannomas are a rare occurrence, a thorough clinical and radiological evaluation of the sciatic nerve should be considered whenever a sciatic pain is not otherwise explained. A positive Tinel sign and a palpable mass along the course of the sciatic nerve may be strong clues to achieve the diagnosis. Combined morphological and advanced functional MRI imaging may help to differentiate benign from malignant peripheral nerve sheath tumors, avoiding unnecessary preoperative biopsy.

Conclusions: A standard microsurgical technique guided by ultrasound and neurophysiologic monitoring, allows in most of the cases a safe removal of the tumor and very satisfactory post-operative results for the patients.
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http://dx.doi.org/10.1016/j.clineuro.2020.105889DOI Listing
August 2020

Sister Mary Joseph's nodule in endometrial cancer: A case report and review of the literature.

J Cancer Res Ther 2019 Oct-Dec;15(6):1408-1410

Department of Women and Children Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Università Cattolica del Sacro Cuore, Roma, Italia.

Sister Mary Joseph's nodule (SMJN) is an umbilical mass referring to an intraabdominal and/or pelvic tumor's metastasis. SMJN is frequently associated with gynecological malignancies, but only 30 cases of SMJN originated from endometrial cancer have been described in the literature. We reported a case of SMJN detected within the primary diagnosis of endometrial cancer, in which a 1-year vaginal relapse occurs. A robotic single-site total hysterectomy and a bilateral salpingo-oophorectomy were performed to treat the primary tumor, followed by an adjuvant radiotherapy. The SMJN was resected during the surgical procedure. The relapse was treated by a partial colpectomy. No evidence of disease has been observed to date, and an overall survival of 31 months has been achieved. Due to the rare occurrence of an umbilical metastasis from an endometrial carcinoma, SMJN is difficult to recognize in this contest; nevertheless, its diagnosis is becoming increasingly important in relation to the choice of a proper treatment.
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http://dx.doi.org/10.4103/jcrt.JCRT_523_18DOI Listing
May 2020

The effect of CELLFOOD on radiotherapy or combined chemoradiotherapy: preclinical evidence.

Ther Adv Med Oncol 2019 13;11:1758835919878347. Epub 2019 Oct 13.

Preclinical Models and New Therapeutic Agent Unit, IRCCS Regina Elena National Cancer Institute, Via Chianesi, Rome 00144, Italy.

Background: Based on previous observations that the nutraceutical CELLFOOD™ (CF), the 'physiological modulator' that aimed to make oxygen available 'on demand', inhibits the growth of cancer cells, this study was designed to investigate the role of CF in the regulation of hypoxia-inducible factor 1 alpha (HIF1α) and its correlated proteins, phosphoglycerate kinase 1 and vascular endothelial growth factor. Our idea was that CF, acting on HIF1α, in combination with current anticancer therapies could improve their effectiveness.

Methods: To evaluate the effect of CF in association with radiotherapy and chemotherapy, different human cancer cell lines and mice with mesothelioma were analysed by tumour growth, clonogenic assay, western blot and immunohistochemical analysis.

Results: CF in combination with radiation with or without cisplatin increases the death rate of cancer cells. , 70% of mice treated with CF before the mesothelioma graft did not show any tumour growth, indicating a possible preventive effect of CF. Moreover, in mouse mesothelioma xenografts, CF improves the effect of radiotherapy also in combination with chemotherapy treatment. Immunohistochemical analysis of tumour explants showed that HIF1α expression was reduced by the combination of CF and radiotherapy treatment and even more by the combination of CF and radiotherapy and chemotherapy treatment. Mechanistically, CF increases the fraction of oxygenated cells, making the radiotherapy more effective with a greater production of reactive oxygen species (ROS) that in turn, reduce the HIF1α expression. This effect is amplified by further increase in ROS from chemotherapy.

Conclusions: Collectively, results from preclinical trials suggest that CF could be a useful intervention to improve the efficacy of radiotherapy or combined treatment strategies and could be a promising treatment modality to counteract cancer.
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http://dx.doi.org/10.1177/1758835919878347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792276PMC
October 2019

Correction to: Phase II study of weekly carboplatin in pretreated adult malignant gliomas.

J Neurooncol 2019 Oct;145(1):189

Division of Medical Oncology, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.

In the original article, the names of authors Mariantonia Carosi and Tatiana Koudriavtseva were incorrectly captured, and author Francesco Cognetti's affiliation was incorrect. The information is correctly shown here.
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http://dx.doi.org/10.1007/s11060-019-03285-xDOI Listing
October 2019

Neurocognitive evaluation in older adult patients affected by glioma.

J Geriatr Oncol 2020 05 2;11(4):701-708. Epub 2019 Jul 2.

Neuro-Oncology Unit, I.R.C.C.S. Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy.

Background: Glioblastoma (GBM) has an increasing incidence and dismal prognosis in older adults. This study evaluated neurocognitive status of an older adult population with GBM and its correlation with clinical and demographical variables.

Methods: Each patient underwent an extended neuropsychological evaluation by means of a battery of standardized tests describing eight cognitive domains: global function; verbal learning; short- and long-term memory (LTM); executive functions (EFs); abstract reasoning (AR); attention; and visuo-constructional abilities (CA).

Results: We assessed 79 patients with GBM (median age: 74 years). Out of this initial sample, a subgroup of seventeen patients with six-month median time underwent a follow-up test session. 46 out of the 79 patients (58.2%) presented multi-domain cognitive impairment, 24 patients (30.3%) showed single-domain cognitive impairment and only seven (9%) showed no cognitive impairment. Kaplan Meier estimator showed that patients with AR deficit had a poorer prognosis in terms of progression-free survival and overall survival (p < .001). At the multivariate analysis AR (deficit vs non; hazard ratio (HR) = 5.07, 95%; confidence interval (CI): 1.91-13.46; p < .001) was correlated with disease progression and overall survival, AR (deficit vs non; HR = 7.24, 95% CI: 2.58-20.32; p < .001). Eight out of seventeen patients who underwent follow-up test session showed cognitive improvement, five resulted in further deterioration, and four patients remained stable. LTM, EF, and CA were the most affected functions at follow-up, while verbal learning was the most improved one in patients with cognitive improvement.

Conclusions: Cognitive functioning evaluation should be included among the standard clinical endpoints in the treatment of older adult neuro-oncology patients.
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http://dx.doi.org/10.1016/j.jgo.2019.06.015DOI Listing
May 2020

Phase II study of weekly carboplatin in pretreated adult malignant gliomas.

J Neurooncol 2019 Aug 4;144(1):211-216. Epub 2019 Jul 4.

Division of Medical Oncology, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.

Purpose: Patients with relapse of recurrent glioma have a poor outcome and limited treatment options. The aim of this study is to investigate the clinical benefit and tolerability of weekly intravenous administration of carboplatin-based monotherapy in adult glioma patients who had progressed from previous chemotherapy lines based on temozolomide and nitrosoureas.

Methods: This was a single-arm, phase II study. Eligibility criteria included progressive or recurrent glioma after radiotherapy and chemotherapy-based treatments and Karnofsky performance status (KPS) > 60.

Results: Thirty-two patients (median age 43.5 years) were enrolled to receive weekly carboplatin monotherapy in an intravenous method of administration. The median duration of response was 7.3 months with an overall disease control rate of 31.3%. Median progression-free survival was 2.3 months while overall survival was 5.5 months. Pre-treatment with corticosteroids (i.e. dexamethasone) was associated to clinical benefit in 43.8% of patients. Patients achieving clinical benefit exhibited a longer progression-free survival (4.6 vs. 1.5 months; p > 0.001) and overall survival (7.9 vs. 3.2 months; p = 0.041) compared with those not achieving clinical benefit.

Conclusions: Our findings show that single agent, weekly, intravenous administration of carboplatin may have a role in patients with recurrent glioma and suggest that pre-treatment with corticosteroids may confer survival benefit.
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http://dx.doi.org/10.1007/s11060-019-03223-xDOI Listing
August 2019

A multicenter real-world study of bevacizumab in heavily pretreated malignant gliomas: clinical benefit is a plausible end point?

Future Oncol 2019 May 12;15(15):1717-1727. Epub 2019 Apr 12.

Neuroncology Unit, IRCCS Regina Elena National Cancer Institute, via Elio Chianesi 53 00144, Rome, Italy.

This multicenter, retrospective study evaluates the clinical benefit (CB) of bevacizumab, alone or in combination, in recurrent gliomas (RG).  The CB was measured as a reduction of corticosteroid dosage and an improvement ≥20 points in the Karnofsky Performance Status lasting ≥3 months. We collected data of 197 RG patients. A CB was observed in 120, patients without significant differences between patients treated with bevacizumab alone or in combination. The rate of patients who achieved a CB and free from progression at 1 year was 21.5 versus 1.4% in patients who did not report CB. The majority of RG patients treated with bevacizumab reported CB. Moreover, patients with CB showed improved survival.
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http://dx.doi.org/10.2217/fon-2018-0826DOI Listing
May 2019

The prognostic significance of positive peritoneal cytology in endometrial cancer and its correlations with L1-CAM biomarker.

Surg Oncol 2019 Mar 5;28:151-157. Epub 2019 Jan 5.

Department of Women and Children Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy. Electronic address:

Background: The aim of this study was to evaluate the prognostic role of positive peritoneal cytology (PPC) in a cohort of patients with endometrial cancer (EC). The secondary objective was to correlate the PPC and the expression of L1CAM in a group of patients with recurrence endometrial disease.

Methods: All women diagnosed with EC and who performed a peritoneal cytology at "Regina Elena" National Cancer Institute of Rome from 2001 to 2013 were included in the study. Patients were divided into two groups according to positivity at peritoneal cytology. Moreover, patients with a recurrence disease and whose a tissue microarray (TMA) tumor sample was available underwent a L1CAM analysis.

Results: Seven hundred sixty six patients underwent to EC staging in our Institute: 696 (90.8%) with negative and 70 (9.2%) with positive cytology. Five-year recurrence rate was higher in women with PPC (46.9% vs 18.4%, p = 0 < 0.0001) and, in particular, distant recurrence (86.7% vs 53.4%, p = 0.03). Moreover, we found an interesting pattern of recurrence disease in the group of early stage of EC with NPC and positive L1CAM.

Conclusions: Our results support the data that PPC may be a potential prognostic factor in early EC, due to its significant association with other risk factors and its significant influence on survival. Our findings confirm the need for large studies that point out the role of PPC and new prognostic factors, including biomarkers as L1CAM.
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http://dx.doi.org/10.1016/j.suronc.2019.01.001DOI Listing
March 2019

Comorbidities in elderly patients with glioblastoma: a field-practice study.

Future Oncol 2019 Mar 18;15(8):841-850. Epub 2019 Jan 18.

Neuro-Oncology Unit, 'Regina Elena' National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy.

Aim: This single-center study evaluated the effect of comorbidities on progression-free and overall survival in elderly patients with glioblastoma multiforme (GBM).

Patients & Methods: Comorbid conditions were identified in each patient with the modified version of the cumulative illness rating scale (CIRS).

Results:  Total of 118 patients with GBM were enrolled. An age of >75 years at diagnosis, high CIRS, comorbidity index and performance status play a predictive role on survival.

Conclusion: Comorbidities play an important prognostic role in elderly patients with GBM, a factor too often neglected in clinical practice. If the prognostic role of comorbidity measured by CIRS on outcome will be confirmed, it would be interesting to add it in the algorithm for treatment choice in elderly GBM patients.
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http://dx.doi.org/10.2217/fon-2018-0524DOI Listing
March 2019

Endometrial cancer prognosis correlates with the expression of L1CAM and miR34a biomarkers.

J Exp Clin Cancer Res 2018 Jul 6;37(1):139. Epub 2018 Jul 6.

Department of Experimental Clinical Oncology, Gynecologic Oncology Unit, IRCCS - Regina Elena National Cancer Institute, Via Elio chianesi, 53 -, 00144, Rome, Italy.

Background: Patients with endometrial cancer (EC) and presumably with good prognosis may develop a recurrence indicating that the classification of this tumor is still not definitive and that new markers are needed to identify a subgroup at risk of relapse. The cell adhesion molecule L1CAM is highly expressed in several human carcinomas and has recently been described as a new marker for endometrial and ovarian carcinomas. The aim of this study was to determine the relevance of L1CAM in recurrent EC.

Methods: In this work we have analyzed, by immunohistochemical and RT-qPCR analysis, the expression of L1CAM in a cohort of 113 endometrial cancers at different stages, which 50% have relapsed. As a predictor of good outcome, the tumors were also analyzed for the expression of miR-34a, a post-transcriptional regulator of L1CAM.

Results: Among metastatic EC, the highest levels (60%) and the median level (24%) of L1CAM in tumors correlate with the progression, suggesting that the expression of this molecule is linked to the tumor component most involved in metastatic processes. We also found an inverse correlation between miR-34a and L1CAM protein expression, suggesting that miR-34a is a positive prognostic marker of EC.

Conclusions: Our results demonstrate the expression of L1CAM and miR-34a in EC as prognostic factors that identify subgroup of patients at high risk of recurrence suggesting for them more aggressive schedules of treatment.
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http://dx.doi.org/10.1186/s13046-018-0816-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035393PMC
July 2018

Circulating Micrornas Predict Survival of Patients with Tumors of Glial Origin.

EBioMedicine 2018 Apr 21;30:105-112. Epub 2018 Mar 21.

Dept. of Cancer Biology and Genetics (CBG), The Ohio State University, Columbus, OH, United States. Electronic address:

The World Health Organization has recently introduced molecular prognostic-diagnostic biomarkers in the classification of Central Nervous System (CNS) tumors. In order to characterize subclasses of tumors that cannot find a precise location in the current classification, and, or cannot be tested because of scant material, it is important to find new molecular biomarkers in tissue and, or biological fluid samples. In this study, we identified serum microRNAs that could serve as biomarkers for the diagnosis and prognosis of patients with tumors of glial origin. We retrospectively analyzed microRNA expression in the serum extracellular vesicles of patients with tumors of glial origin. Extracellular vesicles RNA was analyzed by Nanostring. qRT-PCR confirmed 6 overexpressed microRNAs: hsa-miR-4443, hsa-miR-422a, hsa-miR-494-3p, hsa-miR-502-5p, hsa-miR-520f-3p, and hsa-miR-549a. Hsa-miR-4443 was the only microRNA that showed significant differences in most comparisons. In situ hybridization (ISH), confirmed that our signature was mostly expressed in cancer cells. Importantly, hsa-miR-549a and hsa-miR-502-5p expression predicted prognosis in patients with tumors of glial origin. Although more studies are needed, we demonstrated that serum vesicles microRNA profiles are promising diagnostic and prognostic molecular biomarkers that will find an actual application in the clinical practice of CNS tumors.
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http://dx.doi.org/10.1016/j.ebiom.2018.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952410PMC
April 2018

A predictive value of von Willebrand factor for early response to Bevacizumab therapy in recurrent glioma.

J Neurooncol 2018 Jul 28;138(3):527-535. Epub 2018 Mar 28.

Clinical Pathology, Department of Clinical Experimental Oncology, Regina Elena National Cancer Institute, IFO, Via Elio Chianesi 53, 00144, Rome, Italy.

Bevacizumab (BV), a neutralizing monoclonal antibody against the vascular endothelial growth factor ligand, is recognized as a potent anti-angiogenic agent with antitumor activity. The aim of this single-center, retrospective, longitudinal study was to investigate the possible predictive value of baseline demographic, clinical and laboratory parameters for early 3-month response to BV therapy in patients with recurrent glioma. Forty-nine patients with recurrent glioma received BV at 10 mg/kg intravenously every 3 weeks alone or in association with chemotherapy were included in this study. Blood samples were collected from all patients before the first (baseline), the second and the third administration of BV. After 3 months of BV therapy, patients with partial response were defined as responders whereas patients with stable or progressive disease were defined as non-responders. The median overall follow-up was 8 months (range 1-73), the median overall survival (OS) was 8 months (95% CI 6-10) and the median progression free survival (PFS) was 4 months (95% CI 3-5). Thirty-five % of patients were responders and showed significantly lower von Willebrand factor (VWF) levels than non-responders at all sample times (p < .02 for all). Also, on multivariate analysis the baseline VWF value was the only predictor for an early response to BV therapy. Furthermore, D-dimer and prothrombin fragment 1+2 were predictive factors for OS while Karnofsky performance status resulted predictive for PFS. VWF antigen value is a possible predictive biomarker for an early 3-month response to BV therapy in recurrent glioma.
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http://dx.doi.org/10.1007/s11060-018-2820-xDOI Listing
July 2018

Correction to: Serum DNA integrity index as a potential molecular biomarker in endometrial cancer.

J Exp Clin Cancer Res 2018 02 20;37(1):35. Epub 2018 Feb 20.

Department of Experimental Clinical Oncology, Gynecologic Oncology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Correction: In the publication of this article [1], there is an error in the first sentence of the Acknowledgements section.
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http://dx.doi.org/10.1186/s13046-018-0708-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820798PMC
February 2018

Serum DNA integrity index as a potential molecular biomarker in endometrial cancer.

J Exp Clin Cancer Res 2018 Jan 30;37(1):16. Epub 2018 Jan 30.

Department of Experimental Clinical Oncology, Gynecologic Oncology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background: Circulating cell-free DNA (cfDNA) and its integrity index may represent a rapid and noninvasive "liquid biopsy" biomarker, which gives important complementary information for diagnosis, prognosis, and treatment stratification in cancer patients. The aim of our study was to evaluate the possible role of cfDNA and its integrity index as a complementary tool for endometrial cancer (EC) management.

Methods: Alu-quantitative real-time PCR (qPCR) analysis wasprformed on 60 serum samples from preoperative EC patients randomly recruited. Both cfDNA content and DNA integrity index were measured by qPCR-Alu115 (representing total cfDNA) and qPCR-Alu247 (corresponding to high molecular weight DNA) and correlated with clinicopathologic characteristics. Lymphovascular space invasion (LVSI) was detected by hematoxylin and eosin staining. In case of doubt, LVSI status was further evaluate by immunohistochemistry using anti-CD31 and anti-CD34 antibodies.

Results: Total cfDNA content significantly increases in high grade EC. A significant decrease of DNA integrity index was detected in the subset of hypertensive and obese high grade EC. Serum DNA integrity was higher in samples with LVSI. The ordinal regression analysis predicted a significant correlation between decreased integrity index values and hypertension specifically in tumors presenting LVSI.

Conclusions: Our study supports the utility of serum DNA integrity index as a noninvasive molecular biomarker in EC. We show that a correlation analysis between cfDNA quantitative and qualitative content and clinicopathologic features, such as blood pressure level, body mass index (BMI) and LVSI status, could represent a potential predictive signature to help stratification approaches in EC.
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http://dx.doi.org/10.1186/s13046-018-0688-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791183PMC
January 2018

The small molecule SI113 synergizes with mitotic spindle poisons in arresting the growth of human glioblastoma multiforme.

Oncotarget 2017 Dec 18;8(67):110743-110755. Epub 2017 Nov 18.

Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Cellular Networks and Therapeutic Targets, "Regina Elena" National Cancer Institute, IRCCS, Rome, Italy.

Glioblastoma multiforme (GBM) is the deadliest brain tumor. State-of-art GBM therapy often fails to ensure control of a disease characterized by high frequency of recurrences and progression. In search for novel therapeutic approaches, we assayed the effect of compounds from a cancer drug library on the ADF GBM cell line, establishing their elevated sensitivity to mitotic spindle poisons. Our previous work showed that the effectiveness of the spindle poison paclitaxel in inhibiting cancer cell growth was dependent on the expression of RANBP1, a regulatory target of the serine/threonine kinase SGK1. Recently, we developed the small molecule SI113 to inhibit SGK1 activity. Therefore, we explored the outcome of the association between SI113 and selected spindle poisons, finding that these drugs generated a synergistic cytotoxic effect in GBM cells, drastically reducing their viability and clonogenic capabilities , as well as inhibiting tumor growth . We also defined the molecular bases of such a synergistic effect. Because SI113 displays low systemic toxicity, yet strong activity in potentiating the effect of radiotherapy in GBM cells, we believe that this drug could be a strong candidate for clinical trials, with the aim to add it to the current GBM therapeutic approaches.
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http://dx.doi.org/10.18632/oncotarget.22500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762281PMC
December 2017

MicroRNA-128-3p-mediated depletion of Drosha promotes lung cancer cell migration.

Carcinogenesis 2018 02;39(2):293-304

Oncogenomic and Epigenetic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.

Alteration in microRNAs (miRNAs) expression is a frequent finding in human cancers. In particular, widespread miRNAs down-regulation is a hallmark of malignant transformation. In the present report, we showed that the miR-128-3p, which is up-regulated in lung cancer tissues, has Drosha and Dicer, two key enzymes of miRNAs processing, as the main modulation targets leading to the widespread down-regulation of miRNA expression. We observed that the miRNAs downregulation induced by miR-128-3p contributed to the tumorigenic properties of lung cancer cells. In particular, miR-128-3p-mediated miRNAs down-regulation contributed to aberrant SNAIL and ZEB1 expression thereby promoting the epithelial-to-mesenchymal transition (EMT) program. Drosha also resulted to be implicated in the control of migratory phenotype as its expression counteracted miR-128-3p functional effects. Our study provides mechanistic insights into the function of miR-128-3p as a key regulator of the malignant phenotype of lung cancer cells. This also enforces the remarkable impact of Drosha and Dicer alteration in cancer, and in particular it highlights a role for Drosha in non-small-cell lung cancer cells migration.
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http://dx.doi.org/10.1093/carcin/bgx134DOI Listing
February 2018

tsRNA signatures in cancer.

Proc Natl Acad Sci U S A 2017 07 10;114(30):8071-8076. Epub 2017 Jul 10.

Department of Cancer Biology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;

Small, noncoding RNAs are short untranslated RNA molecules, some of which have been associated with cancer development. Recently we showed that a class of small RNAs generated during the maturation process of tRNAs (tRNA-derived small RNAs, hereafter "tsRNAs") is dysregulated in cancer. Specifically, we uncovered tsRNA signatures in chronic lymphocytic leukemia and lung cancer and demonstrated that the cluster (now called "" and "," respectively), , and are down-regulated in these malignancies. Furthermore, we showed that tsRNAs are similar to Piwi-interacting RNAs (piRNAs) and demonstrated that and can associate with PiwiL2, a protein involved in the silencing of transposons. In this study, we extended our investigation on tsRNA signatures to samples collected from patients with colon, breast, or ovarian cancer and cell lines harboring specific oncogenic mutations and representing different stages of cancer progression. We detected tsRNA signatures in all patient samples and determined that tsRNA expression is altered upon oncogene activation and during cancer staging. In addition, we generated a knocked-out cell model for and in HEK-293 cells and found significant differences in gene-expression patterns, with activation of genes involved in cell survival and down-regulation of genes involved in apoptosis and chromatin structure. Finally, we overexpressed and in two lung cancer cell lines and performed a clonogenic assay to examine their role in cell proliferation. We observed a strong inhibition of colony formation in cells overexpressing these tsRNAs compared with untreated cells, confirming that tsRNAs affect cell growth and survival.
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http://dx.doi.org/10.1073/pnas.1706908114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544330PMC
July 2017

Overexpression of syndecan-1, MUC-1, and putative stem cell markers in breast cancer leptomeningeal metastasis: a cerebrospinal fluid flow cytometry study.

Breast Cancer Res 2017 04 11;19(1):46. Epub 2017 Apr 11.

Regina Elena National Cancer Institute, Neuro-Oncology Division, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Cancer is a mosaic of tumor cell subpopulations, where only a minority is responsible for disease recurrence and cancer invasiveness. We focused on one of the most aggressive circulating tumor cells (CTCs) which, from the primitive tumor, spreads to the central nervous system (CNS), evaluating the expression of prognostic and putative cancer stem cell markers in breast cancer (BC) leptomeningeal metastasis (LM).

Methods: Flow cytometry immunophenotypic analysis of cerebrospinal fluid (CSF) samples (4.5 ml) was performed in 13 consecutive cases of BCLM. Syndecan-1 (CD138), MUC-1 (CD227) CD45, CD34, and the putative cancer stem cell markers CD15, CD24, CD44, and CD133 surface expression were evaluated on CSF floating tumor cells. The tumor-associated leukocyte population was also characterized.

Results: Despite a low absolute cell number (8 cell/μl, range 1-86), the flow cytometry characterization was successfully conducted in all the samples. Syndecan-1 and MUC-1 overexpression was documented on BC cells in all the samples analyzed; CD44, CD24, CD15, and CD133 in 77%, 75%, 70%, and 45% of cases, respectively. A strong syndecan-1 and MUC-1 expression was also documented by immunohistochemistry on primary breast cancer tissues, performed in four patients. The CSF tumor population was flanked by T lymphocytes, with a different immunophenotype between the CSF and peripheral blood samples (P ≤ 0.02).

Conclusions: Flow cytometry can be successfully employed for solid tumor LM characterization even in CSF samples with low cell count. This in vivo study documents that CSF floating BC cells overexpress prognostic and putative cancer stem cell biomarkers related to tumor invasiveness, potentially representing a molecular target for circulating tumor cell detection and LM treatment monitoring, as well as a primary target for innovative treatment strategies. The T lymphocyte infiltration, documented in all CSF samples, suggests a possible involvement of the CNS lymphatic system in both lymphoid and cancer cell migration into and out of the meninges, supporting the extension of a new form of cellular immunotherapy to LM. Due to the small number of cases, validation on large cohorts of patients are warranted to confirm these findings and to evaluate the impact and value of these results for diagnosis and management of LM.
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http://dx.doi.org/10.1186/s13058-017-0827-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387324PMC
April 2017

Prognostic role of NF-YA splicing isoforms and Lamin A status in low grade endometrial cancer.

Oncotarget 2017 Jan;8(5):7935-7945

Department of Experimental Clinical Oncology, Gynecologic Oncology Unit, Regina Elena National Cancer Institute, Rome, Italy.

Although most cases of low grade (G1) endometrial cancer (EC) do not behave aggressively, in rare instances, can progress in a highly aggressive manner. In this study we analyzed formalin-fixed, paraffin-embedded (FFPE) EC tissues to find novel clinical and biological features to help diagnosis and treatment of G1 ECs s in order to better stratify patient risk of recurrence. A retrospective cohort of FFPE specimens from patients with EC (n=87) and benign tissue specimens (NE) from patients who underwent a hysterectomy to treat other benign disease (n = 13) were collected. Total RNA and proteins were extracted and analyzed, respectively, by quantitative PCR and western blotting. NF-YAs is expressed and lamin A is down-modulated in all high grade (G2 and G3) ECs. In G1 ECs, NF-YAs expression is heterogeneous being expressed only in a subset of these tumours. Interestingly, the G1 ECs that express NF-YAs display low levels of lamin A similar to those present in G2 and G3 ECs. Of note, this pattern of NF-YAs and lamin A expression correlates with tumor aggressiveness assessed by comparative analysis with estrogen receptor (ER) status and epithelial-mesenchymal transition (EMT) markers thus suggesting its potential role as biomarker of tumour aggressiveness in G1 EC. In all grade ECs, lamin A is strongly downmodulated, being its expression inversely correlated with tumor aggressiveness and its loss of expression. We identified NF-YAs and lamin A expression levels as novel potential biomarkers useful to identify G1 ECs patients with risk of recurrence.
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http://dx.doi.org/10.18632/oncotarget.13854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352372PMC
January 2017

Temozolomide low-dose chemotherapy in newly diagnosed low-grade gliomas: activity, safety, and long-term follow-up.

Tumori 2017 May 22;103(3):255-260. Epub 2016 Sep 22.

 Neuro-Oncology Unit, "Regina Elena" National Cancer Institute, Rome - Italy.

Purpose: To explore the efficacy and toxicity of an extended schedule of temozolomide (50 mg/mq 1 week on/1 week off) in a population of newly diagnosed low-grade gliomas (LGG).

Methods: Primary endpoints were progression-free survival (PFS) at 12 and 24 months and response rate evaluated with Response Assessment in Neuro-Oncology Criteria. Secondary endpoints were clinical benefit (reduction of seizures frequency), reduction of steroid, and modifications of Karnofsky Performance Status.

Results: From 2006 to 2009, we enrolled 14 consecutive patients with newly diagnosed LGG: 8 grade II astrocytomas, 2 oligodendroglioma, and 4 oligo-astrocytoma. Temozolomide was administered for 18 cycles (mean) per patient (range 3-24 cycles). In 57.5% (n = 8), we observed stable disease, 28.5% (n = 4) presented a minor response, and 14% (n = 2) showed progression. Five patients presented early progression during the first year of treatment and the study was stopped. A relevant clinical benefit was observed in 85% of patients (seizure control). After 6 years of follow-up, only 4 patients died. Prolonged PFS was associated with 1p-19q codeletion over 1p-19q intact (35 vs 4 months; p<0.04) and IDH1 mutation over IDH1 wild-type (36 vs 6 months; p<0.009).

Conclusions: The study was interrupted for the high rate of progression observed in the first 14 patients enrolled. However, our results show that an extended low dose of temozolomide presents interesting activity with objective response and clinical benefit, but does not seem to prevent progression in patients presenting unfavorable molecular prognostic factors.
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http://dx.doi.org/10.5301/tj.5000565DOI Listing
May 2017

Brain stereotactic biopsy flow cytometry for central nervous system lymphoma characterization: advantages and pitfalls.

J Exp Clin Cancer Res 2016 08 27;35(1):128. Epub 2016 Aug 27.

Neurosurgery, Regina Elena National Cancer Institute, Rome, Italy.

Background: Brain stereotactic biopsy (SB) followed by conventional histopathology and immunohistochemistry (IHC) is the gold standard approach for primary central nervous system lymphoma (PCNSL) diagnosis. Flow cytometry (FCM) characterization of fine-needle aspiration cytology and core needle biopsies are increasingly utilized to diagnose lymphomas however, no biological data have been published on FCM characterization of fresh single cell suspension from PCNSL SB. The aim of this study was to establish the feasibility and utility of FCM for the diagnosis and characterization of brain lymphomas from a tissue samples obtained by a single SB disaggregation.

Methods: Twenty-nine patients with a magnetic resonance suggestive for PCNSL entered the study. A median of 6 SB were performed for each patient. A cell suspension generated from manual tissue disaggregation of a single, unfixed, brain SB, was characterized by FCM. The FCM versus standard approach was prospectively compared.

Results: FCM and IHC showed an high degree of agreement (89 %) in brain lymphoma identification. By FCM, 16 out of 18 PCNSL were identified within 2 h from biopsy. All were of B cell type, with a heterogeneous CD20 mean fluorescence intensity (MFI), CD10 positive in 3 cases (19 %) with surface Ig light chain restriction documented in 11 cases (69 %). No false positive lymphomas cases were observed. Up to 38 % of the brain leukocyte population consisted of CD8 reactive T cells, in contrast with the CD4 positive lymphocytes of the peripheral blood samples (P < 0.001). By histopathology, 18 B-PCNSL, only one CD10 positive (5 %), 1 primitive neuroectodermal tumor (PNET) and 10 gliomas were diagnosed. A median of 6 days was required for IHC diagnosis.

Conclusion: Complementary to histopathology FCM can contribute to a better characterization of PCNSL, although necrosis and previous steroid treatment can represent a pitfall of this approach. A single brain SB is a valid source for accurate FCM characterization of both lymphoma and reactive lymphocyte population, routinely applicable for antigen intensity quantification and consistently documenting an active mechanism of reactive CD8 T-lymphocytes migration in brain lymphomas. Moreover, FCM confirmed to be more sensitive than IHC for the identification of selected markers.
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http://dx.doi.org/10.1186/s13046-016-0404-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002320PMC
August 2016

A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas.

J Exp Clin Cancer Res 2016 07 30;35(1):124. Epub 2016 Jul 30.

Department of Research, Advanced Diagnostics and Technological Innovation, Genomic and Epigenetic Unit, Translational Research Area, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Malignant gliomas are the most common primary brain tumors in adults and challenging cancers for diagnosis and treatment. They remain a disease for which non-invasive, diagnostic and/or prognostic novel biomarkers are highly desirable. Altered microRNA (miRNA) profiles have been observed in tumor tissues and biological fluids. To date only a small set of circulating/serum miRNA is found to be differentially expressed in brain tumors compared to normal controls. Here a restricted signature of circulating/serum miRNA including miR-15b*,-23a, -99a, -125b, -133a, -150*, -197, -340, -497, -548b-5p and let-7c were investigated as potential non-invasive biomarkers in the diagnosis of glioma patients.

Methods: Serum and tissues miRNAs expression in patients with brain cancers (n = 30) and healthy controls (n = 15) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Relative expression was calculated using the comparative Ct method. Statistical significance (p ≤ 0,05) was determined using the Mann-Whitney rank sum and Fisher's exact test. Diagnostic accuracy of miRNAs in distinguishing glioblastoma multiforme (GBM) from lower grade cancer was assessed by the Receiver Operating Characteristic (ROC) curve analysis. To validate the role of the identified miRNAs in cancer a comprehensive literature search was conducted using PubMed, Web of Science (Core Collection) and Scopus databases.

Results: We observed a decrease of miR-497 and miR-125b serum levels depending on tumor stages with reduced level in GBM than lower grade tumors. The ROC curve analysis distinguishing GBM from lower grade cases yielded an area under the curve (AUC) of 0.87 (95 % confidence interval (CI) = 0.712-1) and of 0.75 (95 % CI = 0.533-0.967) for miR-497 and -125b, respectively. GBM patients are more likely to show a miR-497 and -125b down-regulation than the lower grade group (p = 0.002 and p = 0.024, respectively). These results were subsequently compared with evidence from 19 studies included in the final systematic review.

Conclusions: Although multiple biomarkers are currently leveraged in the clinic to detect specific cancer types, no such standard blood biomolecules are used as yet in gliomas. Our data suggest that serum miR-497 and -125b could be a novel diagnostic markers with good perspectives for future clinical applications in patients with glioma.
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http://dx.doi.org/10.1186/s13046-016-0393-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967504PMC
July 2016

Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment.

Oncoimmunology 2016 Jun 28;5(6):e1160187. Epub 2016 Mar 28.

Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy; Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.

Hippo is a tumor-suppressor pathway that negatively regulates the oncoproteins TAZ and YAP. Moreover, Hippo affects the biology of a variety of non-neoplastic cells in the tumor microenvironment, even including immune cells. We herein assessed the predictive role of TAZ and YAP, assessed by immunohistochemistry, in 50 cervical cancer patients prevalently treated with neoadjuvant chemotherapy. Tumors were classified as positive or negative according to the percentage of tumor-expressing cells and cellular localization. TAZ/YAP were also evaluated in non-neoplastic cells, namely endothelial cells, non-lymphocytic stromal cells and tumor-infiltrating lymphocytes (TILs). TAZ expression in cancer cells (TAZ(pos)) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZ(TIL+) and YAP(TIL+)) seemed to be associated with increased pCRs (p = 0.083 and p = 0.018, respectively). When testing the predictive significance of the concomitant expression of TAZ in cancer cells and its absence in TILs (TAZ(pos)/TAZ(TIL-)), patients with TAZ(pos)/TAZ(TIL-) showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZ(pos)/TAZ(TIL-): OR 8.67, 95% CI: 2.31-32.52, p = 0.001). Sensitivity analysis carried out in the 41 patients treated with neoadjuvant chemotherapy yielded comparable results (TAZ(pos)/TAZ(TIL-): OR 11.0, 95% CI: 2.42-49.91, p = 0.002). Internal validation carried out with two different procedures confirmed the robustness of this model. Overall, we found evidence on the association between TAZ expression in cervical cancer cells and reduced pCR rate. Conversely, the expression of the Hippo transducers in TILs may predict increased treatment efficacy, possibly mirroring the activation of a non-canonical Hippo/MST pathway necessary for T-cells activation and survival.
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http://dx.doi.org/10.1080/2162402X.2016.1160187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938371PMC
June 2016

Development and validation of a microRNA-based signature (MiROvaR) to predict early relapse or progression of epithelial ovarian cancer: a cohort study.

Lancet Oncol 2016 08 9;17(8):1137-1146. Epub 2016 Jul 9.

Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Background: Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer.

Methods: We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model.

Findings: We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months [95% CI 15-22]) and a low-risk group (90 patients; median progression-free survival 38 months [24-not estimable]; hazard ratio [HR] 1·85 [1·29-2·64], p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33-4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11-1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03-2·13, p=0·036; OC263: adjusted HR 3·09 [2·24-4·28], p<0·0001; and OC452: HR 1·41 [1·11-1·79], p=0·0047).

Interpretation: MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay.

Funding: AIRC and CARIPLO Foundation.
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http://dx.doi.org/10.1016/S1470-2045(16)30108-5DOI Listing
August 2016

Human papillomavirus 16 E2 interacts with neuregulin receptor degradation protein 1 affecting ErbB-3 expression in vitro and in clinical samples of cervical lesions.

Eur J Cancer 2016 May 7;58:52-61. Epub 2016 Mar 7.

Laboratory of Virology, Regina Elena National Cancer Institute, Rome, Italy; HPV-Unit, Regina Elena National Cancer Institute, Rome, Italy. Electronic address:

The ErbB tyrosine kinase receptors play a key role in regulating many cellular functions and human papillomaviruses (HPVs) may interact with transductional pathway of different growth factor receptors. Here, these interactions were analysed in W12 cell line carrying HPV 16 genome and in clinical samples. W12 cells, in which HPV16 becomes integrated during passages, were utilised to detect viral and ErbB family expression at early (W12E) and late passages (W12G). Interestingly, a strong reduction of ErbB-3 expression was observed in W12G. Loss of the E2 and E5 viral genes occurs in W12G and this may affect ErbB-3 receptor expression. E2 and E5 rescue experiments demonstrated that only E2 gene was able to restore ErbB-3 expression. E2 is a transcriptional factor but the expression levels of ErbB3 were unaffected and ErbB-3 promoter did not show any consensus sequence for E2, thus E2 may interact in another way with ErbB3. Indeed, HPV 16 E2 can modulate ErbB-3 by interacting with the ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp-1) that is involved in the regulation of this receptor, via ubiquitination and degradation. E2 co-immunoprecipitated in a complex with Nrdp-1 leading to hypothesise an involvement of this interaction in ErbB-3 regulation. In addition, 90% of the clinical samples with integrated virus and E2 loss showed no or low ErbB-3 positivity, confirming in vitro results. In conclusion, the new discovered interaction of HPV-16 E2 with Nrdp-1 may affect ErbB-3 expression.
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http://dx.doi.org/10.1016/j.ejca.2016.02.001DOI Listing
May 2016

Metabolic Determinants and Anthropometric Indicators Impact Clinical-pathological Features in Epithelial Ovarian Cancer Patients.

J Cancer 2016 10;7(5):516-22. Epub 2016 Feb 10.

1. Division of Medical Oncology 2, Regina Elena National Cancer Institute, Rome, Italy; 12. Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.

Background: Over the last twenty years, the efforts of the scientific community devoted to the comprehension and treatment of ovarian cancer have remained poorly remunerative, with the case-fatality ratio of this disease remaining disappointedly high. Limited knowledge of the basic principles regulating ovarian carcinogenesis and factors impacting the course of disease may significantly impair our ability to intervene in early stages and lessen our expectations in terms of treatment outcomes. In the present study, we sought to assess whether metabolic factors and anthropometric indicators, i.e., pre-treatment fasting glucose and body mass index, are associated with renown cancer related prognostic factors such as tumour stage and grade at diagnosis.

Materials And Methods: Study participants were 147 women diagnosed with epithelial ovarian cancer and treated with platinum based regimens and/or surgery at the Regina Elena National Cancer Institute of Rome, Italy. Glucose levels were assessed at the institutional laboratories on venous blood collected in overnight fasting conditions and prior to any therapeutic procedure. Stage was coded according to the FIGO staging system based on the results of the diagnostic workup, while tumour grade was locally assessed by an expert pathologist. Participants' characteristics were descriptively analyzed for the overall study population and in a subgroup of 70 patients for whom data on body mass index (BMI) were available. FIGO stage and grade were compared by categories of pre-treatment fasting glucose defined upon the median value, i.e., 89 mg/dl. The association of interest was tested in regression models including BMI.

Results: For the overall study population, patients in the lowest category of fasting glucose were significantly more likely to exhibit a FIGO stage III-IV at diagnosis compared with their counterpart in the highest glucose category (81.3 vs 66.7%, p: 0.021). Subgroup analysis in 70 patients with BMI data confirmed this association (81.5 vs 55.8, p: 0.049), which remained significant when tested in regression models including BMI (OR: 0.28 95% CI 0.086-0.89, p: 0.031). No relevant evidence emerged when testing the association between fasting glucose and tumour grade.

Conclusions: In patients diagnosed with epithelial ovarian cancer, pre-treatment glucose levels appear to be inversely associated with FIGO stage. Further studies are warranted to eventually confirm and correctly interpret the implications of this novel finding.
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http://dx.doi.org/10.7150/jca.13578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780127PMC
March 2016

DNA Damage and Repair Biomarkers in Cervical Cancer Patients Treated with Neoadjuvant Chemotherapy: An Exploratory Analysis.

PLoS One 2016 1;11(3):e0149872. Epub 2016 Mar 1.

Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.

Cervical cancer cells commonly harbour a defective G1/S checkpoint owing to the interaction of viral oncoproteins with p53 and retinoblastoma protein. The activation of the G2/M checkpoint may thus become essential for protecting cancer cells from genotoxic insults, such as chemotherapy. In 52 cervical cancer patients treated with neoadjuvant chemotherapy, we investigated whether the levels of phosphorylated Wee1 (pWee1), a key G2/M checkpoint kinase, and γ-H2AX, a marker of DNA double-strand breaks, discriminated between patients with a pathological complete response (pCR) and those with residual disease. We also tested the association between pWee1 and phosphorylated Chk1 (pChk1), a kinase acting upstream Wee1 in the G2/M checkpoint pathway. pWee1, γ-H2AX and pChk1 were retrospectively assessed in diagnostic biopsies by immunohistochemistry. The degrees of pWee1 and pChk1 expression were defined using three different classification methods, i.e., staining intensity, Allred score, and a multiplicative score. γ-H2AX was analyzed both as continuous and categorical variable. Irrespective of the classification used, elevated levels of pWee1 and γ-H2AX were significantly associated with a lower rate of pCR. In univariate and multivariate analyses, pWee1 and γ-H2AX were both associated with reduced pCR. Internal validation conducted through a re-sampling without replacement procedure confirmed the robustness of the multivariate model. Finally, we found a significant association between pWee1 and pChk1. The message conveyed by the present analysis is that biomarkers of DNA damage and repair may predict the efficacy of neoadjuvant chemotherapy in cervical cancer. Further studies are warranted to prospectively validate these encouraging findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149872PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773222PMC
July 2016

The Prognostic Value of Pyrosequencing-Detected MGMT Promoter Hypermethylation in Newly Diagnosed Patients with Glioblastoma.

Dis Markers 2015 11;2015:604719. Epub 2015 Aug 11.

Division of Pathology, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy.

O6-methylguanine-DNA-methyltransferase (MGMT) has emerged as a relevant predictor of therapeutic response and good prognosis in patients with glioblastoma (GBM). Transcriptionally active MGMT rapidly removes the alkyl adducts, preventing the formation of cross-links and thereby causing resistance to alkylating drugs. Studies with pyrosequencing (PSQ) showed that this technique has a higher reproducibility and sensitivity than other techniques. However, the definition of a prognostically relevant threshold for the percentage of MGMT methylation remains one of the most critical issues in the use of PSQ analysis. The aim of this study was to define the cut-off value correlated with good favourable prognostic outcomes. We retrospectively analyzed 51 patients (33 males, 18 females) with GBM who underwent surgery or biopsy. The Receiver Operating Characteristics analysis showed that the best possible criteria for PSQ-detected percentage of MGMT methylation that predicted progression-free survival (PFS) and overall survival (OS) were 19% and 13%, respectively. Patients with ≤ 19% of PSQ-detected MGMT had a shorter PFS (HR: 0.24, p < 0.01); those ones with ≤ 13% had a shorter OS (HR: 0.33, p < 0.05). Our study reinforces the importance of MGMT in the management of GBM patients, but future studies with larger sample sizes are warranted to confirm our findings.
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http://dx.doi.org/10.1155/2015/604719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548097PMC
April 2016

A differentially expressed set of microRNAs in cerebro-spinal fluid (CSF) can diagnose CNS malignancies.

Oncotarget 2015 Aug;6(25):20829-39

MVIMG, The Ohio State University, Columbus, OH, USA.

Central Nervous System malignancies often require stereotactic biopsy or biopsy for differential diagnosis, and for tumor staging and grading. Furthermore, stereotactic biopsy can be non-diagnostic or underestimate grading. Hence, there is a compelling need of new diagnostic biomarkers to avoid such invasive procedures. Several biological markers have been proposed, but they can only identify specific prognostic subtype of Central Nervous System tumors, and none of them has found a standardized clinical application.The aim of the study was to identify a Cerebro-Spinal Fluid microRNA signature that could differentiate among Central Nervous System malignancies.CSF total RNA of 34 neoplastic and of 14 non-diseased patients was processed by NanoString. Comparison among groups (Normal, Benign, Glioblastoma, Medulloblastoma, Metastasis and Lymphoma) lead to the identification of a microRNA profile that was further confirmed by RT-PCR and in situ hybridization.Hsa-miR-451, -711, 935, -223 and -125b were significantly differentially expressed among the above mentioned groups, allowing us to draw an hypothetical diagnostic chart for Central Nervous System malignancies.This is the first study to employ the NanoString technique for Cerebro-Spinal Fluid microRNA profiling. In this article, we demonstrated that Cerebro-Spinal Fluid microRNA profiling mirrors Central Nervous System physiologic or pathologic conditions. Although more cases need to be tested, we identified a diagnostic Cerebro-Spinal Fluid microRNA signature with good perspectives for future diagnostic clinical applications.
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http://dx.doi.org/10.18632/oncotarget.4096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673232PMC
August 2015