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2.  Brain stereotactic biopsy flow cytometry for central nervous system lymphoma characterization: advantages and pitfalls 
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.
doi:10.1186/s13046-016-0404-1
PMCID: PMC5002320  PMID: 27567676
PCNSL; Brain stereotactic biopsy; Flow cytometry; Tumor side population
3.  NI-11THE POTENTIAL ROLE OF 18F-FDOPA PET IMAGING IN THE EVALUATION OF LOW-GRADE GLIOMAS 
Neuro-Oncology  2014;16(Suppl 5):v140.
Brain tumors have been widely evaluated using the 3,4-dihydroxy-6-18fluoro-L-phenylalanine (18F-FDOPA) PET imaging. The aim of the study is to evaluate the role of 18F-FDOPA PET in low-grade glioma (LGG). We enrolled 60 patients (37 males and 23 females) affected with LGG; 23% were newly diagnosed, 45% were studied during treatment; and 32% were observed out of treatment during a periodic follow-up. All patients underwent 18F-FDOPA PET and MRI examination; both FLAIR and contrast-enhanced T1-weighted sequences were considered for the response assessment in according to RANO criteria. The PET images were interpreted as positive when the lesion presented definite tracer accumulation considering background and controlateral site. The slices with a maximal 18F-FDOPA uptake in the ROI were chosen for quantitative measurement of metabolic activity of the tracer [standardized uptake value (SUV)]. The concordance between MRI and 18F-FDOPA PET was evaluated measuring the unweighted kappa statistic and its relative 95% Confidence interval (95%CI). The Kappa statistic for the whole sample was equal to 0.301 (95%CIs from 0.21 to 0.40) showing a fair concordance between the two tests in terms of diagnostic ability. We found a good correlations between residual volume and SUV max (r = 0.435, p = 0.002 by Spearman Rank Correlation Coefficient), indicating that the greater the residual volume, higher the SUV max is. Also multivariate analysis documented that a SUV max greater than 1.75 represents the only independent predictor of disease progression (HR = 4.59, 95% CIs from 0.99 to 21.31, p = .054). This implies that a patient with a SUV max higher than 1.75 yielded an almost 5-fold increased risk of disease progression, regardless of its clinical and MRI characteristics. Present results confirm that 18F-FDOPA PET imaging may assume a relevant role mainly in the prognostic assessment of patients affected with primary and recurrent LGG.
doi:10.1093/neuonc/nou264.11
PMCID: PMC4218336
4.  The Prognostic Value of Pyrosequencing-Detected MGMT Promoter Hypermethylation in Newly Diagnosed Patients with Glioblastoma 
Disease Markers  2015;2015:604719.
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.
doi:10.1155/2015/604719
PMCID: PMC4548097  PMID: 26347581
5.  Maintenance bevacizumab beyond first-line paclitaxel plus bevacizumab in patients with Her2-negative hormone receptor-positive metastatic breast cancer: efficacy in combination with hormonal therapy 
BMC Cancer  2012;12:482.
Background
Data on efficacy of bevacizumab (B) beyond first-line taxane -including regimen (BT) as first-line treatment are lacking. Although preclinical results that anti-angiogenic agents combined with hormonal therapy (HT) could be active, no clinical data exist about combination of maintenance Bevacizumab (mBev) with HT.
Methods
Thirty-five patients who experienced a response after first-line BT, were given mBev at the dose of 15 mg/kg every 3 weeks. Among 30 pts with hormonal receptor-positive metastatic breast cancer (MBC), 20 (66.6%) received HT with mBev (mHTBev). Objective of the study was the outcome and safety of mBev and in two groups of patients receiving HT or not.
Results
Complete response and partial response was achieved/maintained in 4 (11.4%) and 13 (37.1%) patients, respectively (overall response rate: 48.5%). Clinical benefit was obtained on 23 patients (65.7%). Median of mBev PFS and clinical benefit were 6.8 months (95% CI: 0.8-12.7) and 17.1 months (95% CI :12.2-21.9), respectively. Median PFS of patients who received mHTBev was longer than mBev without HT (13 months and 4.1 months, respectively, p = 0.05). The most common severe toxicities were proteinuria (11.4%) and hypertension (8.5%). No additional toxicity was observed with HTBev.
Conclusion
Maintenance bevacizumab with or without anti-hormonal therapy in patients with hormone receptor positive breast cancer is tolerable and associated with long-term clinical outcome; these results encourage the strategy of prolonging bevacizumab until progression in combination with anti-hormonal agents.
doi:10.1186/1471-2407-12-482
PMCID: PMC3488474  PMID: 23083011
Maintenance Bevacizumab; Antiangiogenic agents; HER2 negative metastatic breast cancer
6.  Early perfusion changes in patients with recurrent high-grade brain tumor treated with Bevacizumab: preliminary results by a quantitative evaluation 
Background
To determine whether early monitoring of the effects of bevacizumab in patients with recurrent high-grade gliomas, by a Perfusion Computed Tomography (PCT), may be a predictor of the response to treatment assessed through conventional MRI follow-up.
Methods
Sixteen patients were enrolled in the present study. For each patient, two PCT examinations, before and after the first dose of bevacizumab, were acquired. Areas of abnormal Cerebral Blood Volume (CBV) were manually defined on the CBV maps, using co-registered T1- weighted images, acquired before treatment, as a guide to the tumor location. Different perfusion metrics were derived from the histogram analysis of the normalized CBV (nCBV) maps; both hyper and hypo-perfused sub-volumes were quantified in the lesion, including tumor necrosis. A two-tailed Wilcoxon test was used to establish the significance of changes in the different perfusion metrics, observed at baseline and during treatment. The relationships between changes in perfusion and morphological MRI modifications at first follow-up were investigated.
Results
Significant reductions in mean and median nCBV were detected throughout the entire patient population, after only a single dose of bevacizumab. The nCBV histogram modifications indicated the normalization effect of bevacizumab on the tumor abnormal vasculature. An improvement in hypoxia after a single dose of bevacizumab was predictive of a greater reduction in T1-weighted contrast-enhanced volumes at first follow-up.
Conclusions
These preliminary results show that a quantification of changes in necrotic intra-tumoral regions could be proposed as a potential imaging biomarker of tumor response to anti-VEGF therapies.
doi:10.1186/1756-9966-31-33
PMCID: PMC3583244  PMID: 22494770
Perfusion CT; Anti-angiogenic therapy; Bevacizumab; Brain tumor; Hypoxia
7.  Brain metastases from solid tumors: disease outcome according to type of treatment and therapeutic resources of the treating center 
Background
To evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center.
Methods
Four Cancer centres participated to the survey. Data were collected through a questionnaire filled in by one physician for each centre.
Results
Clinical data regarding 290 cancer patients with BMs from solid tumors were collected. Median age was 59 and 59% of patients had ≤ 3 brain metastases. A local approach (surgery and stereotactic radiosurgery) was adopted in 31% of patients. The local approach demonstrated to be superior in terms of survival compared to the regional/systemic approach (whole brain radiotherapy and chemotherapy, p = <.0001 for survival at 2 years). In the multivariate analysis local treatment was an independent prognostic factor for survival. When patients were divided into 2 groups whether they were treated in centers where local approaches were available or not (group A vs group B respectively, 58% of patients with ≤ 3 BMs in both cohorts), more patients in group A received local strategies although no difference in time to brain progression at 1 year was observed between the two groups of patients.
Conclusions
In clinical practice, local strategies should be integrated in the management of brain metastases. Proper selection of patients who are candidate to local treatments is of crucial importance.
doi:10.1186/1756-9966-30-10
PMCID: PMC3033846  PMID: 21244695
8.  Multi-detector row computed tomography (MDCT) and magnetic resonance imaging (MRI) in the evaluation of the mandibular invasion by squamous cell carcinomas (SCC) of the oral cavity. Correlation with pathological data 
Background
To retrospectively compare the diagnostic accuracy of magnetic resonance imaging (MRI) and multidetector-row computed tomography (MDCT) in the assessment of the mandibular invasion by squamous cell carcinoma (SCC) having histopathological exams as standard of reference.
Materials and methods
Institutional review board approval with a waiver of informed patient consent was obtained. Of the 147 patients selected from our database who underwent surgical excision of a tumour arising into the oral cavity, thirty-six patients (26 men, 10 women; mean age, 56 years; range, 30-75 years) with hystologically proven SCC who performed both a preoperative MRI and MDCT, composed our final study population.
Images were qualitatively analyzed in consensus by two expert radiologist in head and neck imaging. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were assessed for both MRI and MDCT.
Differences in sensitivity, specificity, positive and negative predictive values were calculated at a statistical significance of p < .05.
Results
The sensitivity, the specificity and the accuracy of MRI and MDCT in the detection of the mandibular involvement were respectively 93%, 82%, 86% and 79%, 82%, 81%, while the positive predictive value (PPV) and negative predictive value (NPV) were respectively 76%, 95% and 73%, 86%. There wasn't any statistically significant difference in overall diagnostic accuracy between MRI and MDCT in the evaluation of mandibular tumour invasion (p > .05).
Conclusion
MRI showed to have a higher sensitivity compare to MDCT in the assessment of mandibular involvement from SCC arising in the oral cavity although none statistically significant differences were noted.
doi:10.1186/1756-9966-29-73
PMCID: PMC2907338  PMID: 20565737
9.  Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients 
BMC Cancer  2010;10:22.
Background
Adequate surgery still remains the only curative treatment of chordoma. Interesting clinical data on advanced disease with molecularly targeted therapies were reported.
Methods
We described the clinical outcome of a series of chordoma patients followed at Regina Elena National Cancer Centre of Rome from 2004 to 2008.
Results
Twenty-five consecutive patients with sacral (11 patients), spine (13 patients), and skull base (1 patient) chordoma went to our observation. Six patients (24%) had primary disease, 14(56%) a recurrent disease, and 5(20%) a metastatic spreading. Surgery was the primary option for treatment in 22 out of 25 patients. Surgical margins were wide in 5 (23%) and intralesional in 17(77%) patients; 3 out of 4 in-house treated patients obtained wide margins. After first surgery, radiotherapy (protons or high-energy photons) were delivered to 3 patients. One out of the 5 patients with wide margins is still without evidence of disease at 20 months from surgery; 2 patients died without evidence of disease after 3 and 36 months from surgery. Sixteen out of 17 (94%) patients with intralesional margins underwent local progression at a median time of 18 months with a 2-year local progression-free survival of 47%. The 5-year metastasis-free survival rate was 78.3%. Seventeen patients with locally advanced and/or metastatic disease expressing platelet-derived growth factor receptor (PDGFR) β were treated with imatinib mesylate. A RECIST stabilization of the disease was the best response observed in all treated cases. Pain relief with reduction in analgesics use was obtained in 6 out of 11 (54%) symptomatic patients. The 5- and 10-year survival rates of the entire series of patients were 76.7 and 59.7%, respectively.
Conclusions
Despite progress of surgical techniques and the results obtained with targeted therapy, more effort is needed for better disease control. Specific experience of the multidisciplinar therapeutic team is, however, essential to succeed in improving patients' outcome.
doi:10.1186/1471-2407-10-22
PMCID: PMC2828414  PMID: 20109225
10.  The role side effects play in the choice of antiepileptic therapy in brain tumor-related epilepsy: a comparative study on traditional antiepileptic drugs versus oxcarbazepine 
Background
Seizure control doesn't represent the only challenging goal in patients with brain tumor-related epilepsy. Side effects have often taken precedence for patients' quality of life.
Methods
We performed an observational retrospective study on patients with brain tumor-related epilepsy: 35 who had assumed oxcarbazepine monotherapy and 35 patients who had undergone treatment with traditional antiepileptic drugs. Primary variable of efficacy was the mean seizure frequency per month and safety variables were the drop-out for side effects and total incidence of side effects. We applied the Propensity Score technique to minimize selection bias.
Results
Our results showed a similar efficacy of oxcarbazepine and traditional antiepileptic drugs over time, but the difference in safety and tolerability between the two groups was significant: traditional AEDs caused more side effects, both serious and non serious.
Conclusion
This study highlights the importance of taking into consideration not only seizure control but also the appearance of side effects when choosing antiepileptic drugs in this patients population.
doi:10.1186/1756-9966-28-60
PMCID: PMC2686682  PMID: 19419544
11.  Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation 
BMC Cancer  2009;9:101.
Background
In recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m2 weekly for 3 consecutive weeks followed by triweekly administration after a 5-week rest period). Also, the impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status on fotemustine activity has never been explored in the clinical setting.
Methods
40 patients with recurrent pretreated MG were identified as being treated with fotemustine at doses ranging from 65 mg/m2 to 100 mg/m2. Patients were classified into 3 groups according to the dose of fotemustine received, from the lowest dosage received in group A, to the highest in group C. Analysis of MGMT promoter methylation in tumor tissue was successfully performed in 19 patients.
Results
Overall, 20% of patients responded to treatment, for a disease control rate (DCR, responses plus stabilizations) of 47.5%. Groups A and B experienced a response rate of 40% and 26.5% respectively, while the corresponding value for group C was 10%. Out of 19 patients, MGMT promoter was found methylated in 12 cases among which a DCR of 66.5% was observed. All 7 patients with unmethylated MGMT promoter were progressive to fotemustine.
Conclusion
Low-dose fotemustine at 65–75 mg/m2 (induction phase) followed by 75–85 mg/m2 (maintenance phase) has an activity comparable to that of the conventional schedule. By determination of the MGMT promoter methylation status patients might be identified who are more likely to benefit from fotemustine chemotherapy.
doi:10.1186/1471-2407-9-101
PMCID: PMC2667532  PMID: 19335893
12.  Quantitative analysis of CT-perfusion parameters in the evaluation of brain gliomas and metastases 
Background
The paper reports a quantitative analysis of the perfusion maps of 22 patients, affected by gliomas or by metastasis, with the aim of characterizing the malignant tissue with respect to the normal tissue. The gold standard was obtained by histological exam or nuclear medicine techniques. The perfusion scan provided 11 parametric maps, including Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF), Average Perfusion (Pmean) and Permeability-surface area product (PS).
Methods
The perfusion scans were performed after the injection of 40 ml of non-ionic contrast agent, at an injection rate of 8 ml/s, and a 40 s cine scan with 1 s interval was acquired. An expert radiologist outlined the region of interest (ROI) on the unenhanced CT scan, by using a home-made routine. The mean values with their standard deviations inside the outlined ROIs and the contralateral ROIs were calculated on each map. Statistical analyses were used to investigate significant differences between diseased and normal regions. Receiving Operating Characteristic (ROC) curves were also generated.
Results
Tumors are characterized by higher values of all the perfusion parameters, but after the statistical analysis, only the PS, PatRsq (Patlak Rsquare) and Tpeak (Time to Peak) resulted significant. ROC curves, confirmed both PatRsq and PS as equally reliable metrics for discriminating between malignant and normal tissues, with areas under curves (AUCs) of 0.82 and 0.81, respectively.
Conclusion
CT perfusion is a useful and non invasive technique for evaluating brain neoplasms. Malignant and normal tissues can be accurately differentiated using perfusion map, with the aim of performing tumor diagnosis and grading, and follow-up analysis.
doi:10.1186/1756-9966-28-38
PMCID: PMC2661315  PMID: 19284885

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