Long-Term Outcomes Using Electron IOERT APBI for Early Stage Breast Cancer: The Verona University Hospital Experience.

METHODS AND MATERIALS: From July 2006 to December 2015, 295 patients suitable for breast-conserving therapy entered a single-arm phase II study and were treated with IOERT as radical treatment. Inclusion criteria were age >50, postmenopausal status, cT1N0M0 stage, grade G1-G2, positive estrogen receptor status; unicentric and unifocal disease, histologically proven invasive ductal carcinoma no previous breast irradiation, good performance status. RESULTS: With a median follow-up of 7.1 years (95% CI, 6.5;7.4) 6 women (2.0%) experienced a true local recurrence (reappearance of the tumour in the same quadrant). Five-year overall survival and local recurrence-free survival were 96% (95% CI, 92.9;97.8) and 94.9% (95% CI, 91.6;97.0) respectively. CONCLUSION: Our trial suggests that, in highly selected early stage breast cancers, a single-dose IOERT can be safely delivered with excellent results and very low long-term recurrence rates.

Predictors of Local Control for Stereotactic Ablative Radiotherapy (SAbR) in Pulmonary Oligometastases from Gastrointestinal Malignancies.

BACKGROUND/AIM: To assess predictors of local control (LC) for stereotactic ablative radiotherapy (SAbR) in pulmonary oligometastatic disease (OMD) from gastrointestinal (GI) malignancies. PATIENTS AND METHODS: Patients with pulmonary OMD treated with SAbR from January 2016 to December 2018 were included in this observational analysis. Primary endpoint was LC. Uni- and multivariate analyses to assess variable correlations were conducted. RESULTS: Thirty-seven patients and 59 lung metastases were evaluated. The delivered dose was 30-60 Gy in 3-8 fractions. After a median follow-up of 23.0 months (range=6.3-50.4 months), LC rate at 1/2 years was 89.7%/85.0%, and increased to 96.0%/91.0% for lesions treated with a biologically effective dose (BED10) ≥100 Gy (p=0.03). RECIST response at 6 months was predictive for LC (p=0.002). CONCLUSION: SAbR is an effective option for pulmonary OMD from GI malignancies. A BED10 ≥100 Gy and radiological response at 6 months can affect LC.

Is there a correlation between 3T multiparametric MRI and molecular subtypes of breast cancer?

OBJECTIVES: To test whether 3 T multiparametric magnetic resonance imaging (mMRI) provides information related to molecular subtypes of breast cancer. METHODS: Women with mammographic or US findings of breast lesions (BI-RADS 4-5) underwent 3 T mMRI (DCE, DWI and MR spectroscopy). The histological type of breast cancer was assessed. Estrogen-receptor (ER), progesterone-receptor (PgR), Ki-67 status and HER-2 expression, assessed by immunohistochemistry (IHC), defined four molecular subtypes: Luminal-A, Luminal-B, HER2-enriched and triple-negative. Non-parametric tests (Kruskal-Wallis, k-sample equality of medians, and Mann-Whitney), logistic regression or ANOVA, and a multivariate analysis were performed to investigate correlations between the four molecular subtypes and mMRI (lesion volume, margins or distribution, enhancement pattern, ADC, type of kinetic curve, and total choline (tCho) signal-to-noise-ratio (SNR)). A ROC analysis was finally performed to test the diagnostic power of a multivariate logistic regression model. RESULTS: 433 patients (453 lesions) were considered. Volume was smaller in Luminal-B and larger in triple-negative tumours compared to the other subtypes combined. Margins were significantly correlated to Luminal-A and Luminal-B. The type of curve was significantly correlated to Luminal-A. ADC values were higher in Luminal-A. tCho SNR was higher in triple-negative tumours. The ROC analysis showed that the area under the curve (AUC) significantly improved when multiple MRI features were used compared to individual parameters. CONCLUSIONS: A significant correlation was found between some MRI features and molecular subtypes of breast tumours. A multiparametric approach improved the diagnostic power of MRI. However, further research is needed in order to predict the molecular subtype on the sole basis of mMRI.

A Dirichlet process mixture model for automatic (18)F-FDG PET image segmentation: Validation study on phantoms and on lung and esophageal lesions.

PURPOSE: The aim of this study was to implement a Dirichlet process mixture (DPM) model for automatic tumor edge identification on (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) images by optimizing the parameters on which the algorithm depends, to validate it experimentally, and to test its robustness. METHODS: The DPM model belongs to the class of the Bayesian nonparametric models and uses the Dirichlet process prior for flexible nonparametric mixture modeling, without any preliminary choice of the number of mixture components. The DPM algorithm implemented in the statistical software package R was used in this work. The contouring accuracy was evaluated on several image data sets: on an IEC phantom (spherical inserts with diameter in the range 10-37 mm) acquired by a Philips Gemini Big Bore PET-CT scanner, using 9 different target-to-background ratios (TBRs) from 2.5 to 70; on a digital phantom simulating spherical/uniform lesions and tumors, irregular in shape and activity; and on 20 clinical cases (10 lung and 10 esophageal cancer patients). The influence of the DPM parameters on contour generation was studied in two steps. In the first one, only the IEC spheres having diameters of 22 and 37 mm and a sphere of the digital phantom (41.6 mm diameter) were studied by varying the main parameters until the diameter of the spheres was obtained within 0.2% of the true value. In the second step, the results obtained for this training set were applied to the entire data set to determine DPM based volumes of all available lesions. These volumes were compared to those obtained by applying already known algorithms (Gaussian mixture model and gradient-based) and to true values, when available. RESULTS: Only one parameter was found able to significantly influence segmentation accuracy (ANOVA test). This parameter was linearly connected to the uptake variance of the tested region of interest (ROI). In the first step of the study, a calibration curve was determined to automatically generate the optimal parameter from the variance of the ROI. This "calibration curve" was then applied to contour the whole data set. The accuracy (mean discrepancy between DPM model-based contours and reference contours) of volume estimation was below (1 ± 7)% on the whole data set (1 SD). The overlap between true and automatically segmented contours, measured by the Dice similarity coefficient, was 0.93 with a SD of 0.03. CONCLUSIONS: The proposed DPM model was able to accurately reproduce known volumes of FDG concentration, with high overlap between segmented and true volumes. For all the analyzed inserts of the IEC phantom, the algorithm proved to be robust to variations in radius and in TBR. The main advantage of this algorithm was that no setting of DPM parameters was required in advance, since the proper setting of the only parameter that could significantly influence the segmentation results was automatically related to the uptake variance of the chosen ROI. Furthermore, the algorithm did not need any preliminary choice of the optimum number of classes to describe the ROIs within PET images and no assumption about the shape of the lesion and the uptake heterogeneity of the tracer was required.

GBA2-encoded ß-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.

Current anti-inflammatory strategies for the treatment of pulmonary disease in cystic fibrosis (CF) are limited; thus, there is continued interest in identifying additional molecular targets for therapeutic intervention. Given the emerging role of sphingolipids (SLs) in various respiratory disorders, including CF, drugs that selectively target the enzymes associated with SL metabolism are under development. Miglustat, a well-characterized iminosugar-based inhibitor of ß-glucosidase 2 (GBA2), has shown promise in CF treatment because it reduces the inflammatory response to infection by P. aeruginosa and restores F508del-CFTR chloride channel activity. This study aimed to probe the molecular basis for the anti-inflammatory activity of miglustat by examining specifically the role of GBA2 following the infection of CF bronchial epithelial cells by P. aeruginosa. We also report the anti-inflammatory activity of another potent inhibitor of GBA2 activity, namely N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (Genz-529648). In CF bronchial cells, inhibition of GBA2 by miglustat or Genz-529648 significantly reduced the induction of IL-8 mRNA levels and protein release following infection by P. aeruginosa. Hence, the present data demonstrate that the anti-inflammatory effects of miglustat and Genz-529648 are likely exerted through inhibition of GBA2.

Regional hyperthermia combined with chemoradiotherapy in primary or recurrent locally advanced pancreatic cancer : an open-label comparative cohort trial.

PURPOSE: To evaluate the therapeutic effect of delivering regional hyperthermia (HT) plus chemoradiotherapy (CRT) in patients suffering from locally advanced unresectable pancreatic cancer (LAPC). METHODS: Between January 2000 and December 2008, 68 patients affected by primary (56/68) or recurrent (12/68) LAPC were treated either with CRT alone or CRT plus HT. Radiotherapy (RT) consisted of 3D conformal irradiation of tumor and regional lymph nodes (dose ranged from 30 Gy/10 fractions to 66 Gy/33 fractions). Chemotherapy (CT) consisted of gemcitabine (GEM) alone or in association with either oxaliplatin, cisplatin, or 5-FU. HT was delivered twice a week, concomitant with RT. RESULTS: In the current study, 60 of the original 68 patients were included. Median overall survival (OS) was 15 months in the HT group versus 11 months in the control group (log-rank test: p = 0.025). HT did not increase CRT toxicity. CONCLUSION: HT can be added safely to CRT in LAPC, thus, resulting in slightly prolonged survival in certain cases.

Modulation of expression of IL-8 gene in bronchial epithelial cells by 5-methoxypsoralen.

Persistent recruitment of neutrophils in the bronchi of cystic fibrosis patients contributes to airway tissue damage, suggesting the importance of intervening on the expression of the neutrophil chemokine IL-8. Extracts from plants have been investigated to select components able to reduce IL-8 expression in bronchial epithelial cells challenged with Pseudomonas aeruginosa. Extracts and purified components have been added to cells 24 h before pro-inflammatory challenge with P. aeruginosa and IL-8 transcription was quantified in the IB3-1 CF cells in vitro. P. aeruginosa-dependent IL-8 mRNA induction was increased by Argemone mexicana and Vernonia anthelmintica whereas no significant modification of transcription was observed with Aphanamixis polystachya, Lagerstroemia speciosa and Hemidesmus indicus. Finally, inhibition of IL-8 was observed with Polyalthia longifolia (IC50=200 microg/ml) and Aegle marmelos (IC50=20 microg/ml). Compounds from A. marmelos were isolated and identified by GC-MS. No significant effect was observed with butyl-p-tolyl sulphate, whereas the inhibition obtained with 6-methyl-4-chromanone concentration was accompanied by an anti-proliferative effect. On the contrary, 5-methoxypsoralen resulted in IL-8 inhibition at 10 microM concentration, without effects on cell proliferation. In synthesis, 5-methoxypsoralen can be taken into consideration to investigate mechanisms of neutrophil chemotactic signalling and for its potential application in modulating the excessive CF lung inflammation.

Late generation lentiviral vectors: evaluation of inflammatory potential in human airway epithelial cells.

Lentiviruses (LVs) are considered one of the most promising tools for gene transfer, however, their potential to induce pro-inflammatory cytokines on delivery into the respiratory tissue remains to be established. Here we tested a third-generation vesicular stomatitis virus (VSV)-G pseudotyped LV vector in the two respiratory epithelial cell lines A549 and CFT1-C2. We observed that the VSV-G LV vector does not induce (a) activation of the nuclear factor (NF)-kappaB, which intervenes in transcription of pro-inflammatory genes; (b) expression of ICAM-1; and (c) transcription of a panel of cytokines, with the exception of a mild and transient (24h) increase of IFN-gamma mRNA. In contrast, an adenovirus-derived vector strongly activated NF-kappaB and different transcripts such as those of ICAM-1, IL-8, RANTES, IP-10, TNF-alpha, IL-6, IL-1 beta. In conclusion, this third-generation VSV-G pseudotyped LV vector does not elicit major pro-inflammatory signals in human airway epithelial cells and appears to be better suited for gene delivery strategies.

Pyrogallol, an active compound from the medicinal plant Emblica officinalis, regulates expression of pro-inflammatory genes in bronchial epithelial cells.

The most relevant cause of morbidity and mortality in cystic fibrosis (CF) patients is the lung pathology characterized by chronic infection and inflammation sustained mainly by Pseudomonas aeruginosa (P. aeruginosa). Innovative pharmacological approaches to control the excessive inflammatory process in the lung of CF patients are thought to be beneficial to reduce the extensive airway tissue damage. Medicinal plants from the so-called traditional Asian medicine are attracting a growing interest because of their potential efficacy and safety. Due to the presence of different active compounds in each plant extract, understanding the effect of each component is important to pursue selective and reproducible applications. Extracts from Emblica officinalis (EO) were tested in IB3-1 CF bronchial epithelial cells exposed to the P. aeruginosa laboratory strain PAO1. EO strongly inhibited the PAO1-dependent expression of the neutrophil chemokines IL-8, GRO-alpha, GRO-gamma, of the adhesion molecule ICAM-1 and of the pro-inflammatory cytokine IL-6. Pyrogallol, one of the compounds extracted from EO, inhibited the P. aeruginosa-dependent expression of these pro-inflammatory genes similarly to the whole EO extract, whereas a second compound purified from EO, namely 5-hydroxy-isoquinoline, had no effect. These results identify Pyrogallol as an active compound responsible for the anti-inflammatory effect of EO and suggest to extend the investigation in pre-clinical studies in airway animal models in vivo, to test the efficacy and safety of this molecule in CF chronic lung inflammatory disease.