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Image-based data mining (IBDM) and voxel-based analysis (VBA) have shown great promise in the retrospective analysis of routine clinical data, offering a way to analyze a patient population without selection. In radiation therapy, IBDM analyzes whole dose distributions for their effect on a given outcome with no prior assumptions. Recent extensions in IBDM methodologies include per voxel survival analyses, allowing the generation of more robust and testable hypotheses. An essential aspect to produce solid conclusions includes applying the correct statistical techniques to account for multiple testing. There is a growing interest in applying IBDM/VBA techniques in radiation therapy, which is a relatively new area with limited examples in the literature. We present this editorial to discuss guidelines for best practice. In doing so, we highlight 3 recently published papers applying IBDM techniques to radiation therapy data 1 , 2 , 3 and suggest alternative, more robust analysis methods.

PurposeTo evaluate the feasibility and sensitivity of multimodality PET/CT and MRI imaging for non-invasive characterization of brain microglial/macrophage activation occurring during the acute phase in a mouse model of relapsing remitting multiple sclerosis (RR-MS) using [18F]DPA-714, a selective radioligand for the 18-kDa translocator protein (TSPO), superparamagnetic iron oxide particles (SPIO), and ex vivo immunohistochemistry.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice by immunization with PLP139–151. Seven symptomatic EAE mice and five controls underwent both PET/CT and MRI studies between 11 and 14 days post-immunization. SPIO was injected i.v. in the same animals immediately after [18F]DPA-714 and MRI acquisition was performed after 24 h. Regional brain volumes were defined according to a mouse brain atlas on co-registered PET and SPIO-MRI images. [18F]DPA-714 standardized uptake value (SUV) ratios (SUVR), with unaffected neocortex as reference, and SPIO fractional volumes (SPIO-Vol) were generated. Both SUVR and SPIO-Vol values were correlated with the clinical score (CS) and among them. Five EAE and four control mice underwent immunohistochemical analysis with the aim of identifying activated microglia/macrophage and TSPO expressions.ResultsSUVR and SPIO-Vol values were significantly increased in EAE compared with controls in the hippocampus (p p p p p p ConclusionsThese preliminary results suggest that both activated microglia and infiltrated macrophages are present in vulnerable brain regions during the acute phase of PLP-EAE and contribute to disease severity. Both [18F]DPA-714-PET and SPIO-MRI appear suitable modalities for preclinical study of neuroinflammation in MS mice models.

Purpose Radiation pneumonitis (RP) is commonly associated with thoracic radiation therapy, and its incidence is related to dose and volume of the normal lung in the path of radiation. Our aim was to investigate dose patterns associated with RP in patients enrolled in a randomized trial of intensity modulated radiation therapy (IMRT) versus passive scattering proton therapy (PSPT) for locally advanced non-small cell lung cancer. Methods We analyzed 178 patients prospectively treated with PSPT or IMRT for non-small cell lung cancer to a prescribed dose of 66 or 74 Gy in conventional daily fractionation with concurrent chemotherapy. Forty patients (22%) developed clinically symptomatic RP. Voxel-based analysis of local dose differences was done with a nonparametric permutation test accounting for multiple comparisons. From the obtained 3-dimensional significance maps, we derived clusters of voxels that exhibited dose differences between groups at a statistical significance level of 0.05. Results The voxel-based analysis highlighted that (1) significant dose differences between patients with and without RP were found in the lower part of the lungs and in the heart and (2) the anatomic regions significantly spared by PSPT and the clusters in which doses were significantly correlated with RP development were disjoint. Conclusions The analyzed trial data provide an unprecedented opportunity to substantiate previous hypotheses regarding the role of the heart and the lower lungs in the development of RP. Knowledge of this relationship between RP and thoracic regional radiosensitivity should be considered in clinical practice and in the design of future trials.

Purpose To investigate thoracic dose–response patterns for pericardial effusion (PCE) and mortality in patients treated for locally advanced Non-Small-Cell Lung Cancer (NSCLC) by Intensity Modulated RT (IMRT) or Passive-Scattering Proton Therapy (PSPT). Methods Among 178 patients, 43.5% developed grade ≥ 2 PCE. Clinical and dosimetric factors associated with PCE or overall survival (OS) were identified via multi-variable Cox proportional hazards modeling. The Voxel-Based Analyses (VBAs) of local dose differences between patients with and without PCE and mortality was performed. The robustness of VBA results was assessed by a novel characterization of spatial properties of dose distributions based on probabilistic independent component analysis (PICA) and connectograms. Results Several non-dosimetric variables were selected by the multivariable analysis for the considered outcomes, while the time-dependent PCE onset was uncorrelated with the OS (p = 0.34) at a multi-variable Cox analysis. Despite the significant PSPT dosimetric advantage, the RT technique did not affect the occurrence of PCE or OS. VBAs highlighted largely overlapping clusters significantly associated with PCE endpoints in heart and lungs. No significant dosimetric patterns related to mortality endpoints were found. PICA identified 43 components homogeneously scattered within thorax, while connectograms showed modest correlations between doses in main cardio-pulmonary substructures. Conclusions Spatially resolved analysis highlighted dose patterns related to radiation-induced cardiac toxiciy and the observed organ-based dose–response mismatch in PSPT and IMRT. Indeed, the thoracic regions spared by PSPT poorly overlapped with the areas involved in PCE development, as highlited by VBA. PICA and connectograms proved valuable tools for assessing the robusteness of obtained VBA inferences.

Simple Summary The pathophysiology of radiation pneumonitis (RP) after thoracic cancer radiation treatments is still not completely understood although the identification of underlying RP mechanisms may improve the therapeutic window of thoracic cancer patients. The aim of our retrospective study was to explore the dose–response patterns associated with RP by a multi-center voxel-based analysis. In a heterogeneously treated population of 382 thoracic cancer patients, we confirmed the previously described heart–lung interaction in the development of RP. The empowerment of VBA with a novel description of dose map spatial properties based on probabilistic independent component analysis (PICA) and connectograms provided valuable additional and independent information on the radiobiology of RP. Abstract This study investigates the dose–response patterns associated with radiation pneumonitis (RP) in patients treated for thoracic malignancies with different radiation modalities. To this end, voxel-based analysis (VBA) empowered by a novel strategy for the characterization of spatial properties of dose maps was applied. Data from 382 lung cancer and mediastinal lymphoma patients from three institutions treated with different radiation therapy (RT) techniques were analyzed. Each planning CT and biologically effective dose map (α/β = 3 Gy) was spatially normalized on a common anatomical reference. The VBA of local dose differences between patients with and without RP was performed and the clusters of voxels with dose differences that significantly correlated with RP at a p-level of 0.05 were generated accordingly. The robustness of VBA inference was evaluated by a novel characterization for spatial properties of dose maps based on probabilistic independent component analysis (PICA) and connectograms. This lays robust foundations to the obtained findings that the lower parts of the lungs and the heart play a prominent role in the development of RP. Connectograms showed that the dataset can support a radiobiological differentiation between the main heart and lung substructures.

editorial comment of the potential effect of COVID 19 on radiation related lung toxicity

Background/aim Our group has previously demonstrated, in in vitro and in vivo studies on triple-negative breast cancer, that morphine promoted breast cancer progression whereas naloxone was able to reduce it. In this subsequent investigation, we aimed to assess the combinatorial effects of these two drugs in an animal model of triple negative breast cancer. Materials and methods In order to evaluate the in vivo effects of the combination of morphine and naloxone in human breast cancer, a mouse model of human triple-negative breast cancer was generated by injecting the MDA-MB-231 cells subcutaneously in nude mice. Naloxone and morphine were daily intraperitoneally co-injected in mice for 4 weeks at two different doses. Micro-vessel formation was detected by fluorescein isothiocyanate-dextran (100 μl) injected into the lateral tail vein of mice and confirmed by immunohistochemistry for PECAM-1 on mice tumor sections. Results In vivo experiments showed that naloxone was able to counteract the promoting effects of morphine on tumor growth. No impairment of micro-vessel formation in tumors of mice treated with the two drugs was observed. Conclusion Herein, we demonstrated that naloxone was able to counteract the promoting effects of morphine on tumor growth without impairing micro-vessel formation.

Introduction: Aim of this study is to elucidate possible mechanisms of extrapyramidal damage in Fabry Disease (FD), a condition in which involvement of the motor system has been recently suggested, by simultaneously assessing morphometric and susceptibility changes of striatonigral pathway and their possible correlations with clinical variables. Methods: In this cross-sectional study, we investigated possible differences in terms of Quantitative Susceptibility Mapping (QSM) values and volumes of different extrapyramidal relays, including striatum and substantia nigra (SN), in 30 FD patients (M/F = 11/19, mean age 42.6 +/- 12.2) and 37 healthy controls (HC) (M/F = 16/21, mean age 43.2 +/- 14.6). Patients underwent a clinical examination for the study of different motor functions, and the relationship between MRI and clinical variables was tested using the Spearman's coefficient. Results: Compared to HC, FD patients showed an increase in susceptibility values of the SN (p < 0.001) and striatum (p = 0.001), while no difference emerged for the other tested extrapyramidal structures, suggesting their relative sparing. The increased susceptibility was coupled to a reduced volume of the SN (p < 0.001), but not of the striatum (p = 0.34). Finally, no significant correlation emerged when probing the relationship between these modifications and the clinical variables. Conclusion: In FD patients, susceptibility and volumetric alterations are present throughout the extrapyramidal pathway, with the SN being particularly affected by these changes. Such results are in line with the subtle extrapyramidal involvement recently suggested in FD, and could further contribute to the understanding of the physiopathological bases of cerebral involvement in FD.

Gut microbiota, a group of 1014 bacteria, eukaryotes and virus living in gastrointestinal tract, is crucial for many physiological processes in particular plays an important role in inflammatory and immune reactions. Several internal and external factors can influence this population, and shifts in their composition, have been demonstrated to contribute and affect different diseases. During dysbiosis several bacteria related to inflammation, one of the most necessary factors in carcinogenesis; it has been shown that some bacterial strains through deregulation of different signals/pathways may affect tumor development through the production of many factors. Gut microbiota might be considered as a holistic hub point for cancer development: direct and indirect involvements have been studying in several neoplasms such as colon rectal cancer, hepatocellular carcinoma and breast cancer. This review discuss over the evidence of crosstalk between gut microbiota and cancer, its ability to modulate chemotherapy, radiotherapy and immunotherapy, and the possibility that the intestinal microbial is a new target for therapeutic approaches to improve the prognosis and quality of life of cancer patients.

Radiation therapy (RT) of thoracic cancers may cause severe radiation dermatitis (RD), which impacts on the quality of a patient's life. Aim of this study was to analyze the incidence of acute RD and develop normal tissue complication probability (NTCP) models for severe RD in thoracic cancer patients treated with Intensity-Modulated RT (IMRT) or Passive Scattering Proton Therapy (PSPT). We analyzed 166 Non-Small-Cell Lung Cancer (NSCLC) patients prospectively treated at a single institution with IMRT (103 patients) or PSPT (63 patients). All patients were treated to a prescribed dose of 60 to 74 Gy in conventional daily fractionation with concurrent chemotherapy. RD was scored according to CTCAE v3 scoring system. For each patient, the epidermis structure (skin) was automatically defined by an in house developed segmentation algorithm. The absolute dose-surface histogram (DSH) of the skin were extracted and normalized using the Body Surface Area (BSA) index as scaling factor. Patient and treatment-related characteristics were analyzed. The Lyman-Kutcher-Burman (LKB) NTCP model recast for DSH and the multivariable logistic model were adopted. Models were internally validated by Leave-One-Out method. Model performance was evaluated by the area under the receiver operator characteristic curve, and calibration plot parameters. Fifteen of 166 (9%) patients developed severe dermatitis (grade 3). RT technique did not impact RD incidence. Total gross tumor volume (GTV) size was the only non dosimetric variable significantly correlated with severe RD (p = 0.027). Multivariable logistic modeling resulted in a single variable model including S 20Gy, the relative skin surface receiving more than 20 Gy (OR = 31.4). The cut off for S 20Gy was 1.1% of the BSA. LKB model parameters were TD50 = 9.5 Gy, m = 0.24, n = 0.62. Both NTCP models showed comparably high prediction and calibration performances. Despite skin toxicity has long been considered a potential limiting factor in the clinical use of PSPT, no significant differences in RD incidence was found between RT modalities. Once externally validated, the availability of NTCP models for prediction of severe RD may advance treatment planning optimization.

Purpose To develop normal tissue complication probability (NTCP) models for radiation-induced alopecia (RIA) in brain tumor patients treated with proton therapy (PT). Methods and materials We analyzed 116 brain tumor adult patients undergoing scanning beam PT (median dose 54 GyRBE; range 36–72) for CTCAE v.4 grade 2 (G2) acute (≤90 days), late (>90 days) and permanent (>12 months) RIA. The relative dose-surface histogram (DSH) of the scalp was extracted and used for Lyman-Kutcher-Burman (LKB) modelling. Moreover, DSH metrics (Sx: the surface receiving ≥ X Gy, D2%: near maximum dose, Dmean: mean dose) and non-dosimetric variables were included in a multivariable logistic regression NTCP model. Model performances were evaluated by the cross-validated area under the receiver operator curve (ROC-AUC). Results Acute, late and permanent G2-RIA was observed in 52%, 35% and 19% of the patients, respectively. The LKB models showed a weak dose-surface effect (0.09 ≤ n ≤ 0.19) with relative steepness 0.29 ≤ m ≤ 0.56, and increasing tolerance dose values when moving from acute and late (22 and 24 GyRBE) to permanent RIA (44 GyRBE). Multivariable modelling selected S21Gy for acute and S25Gy, for late G2-RIA as the most predictive DSH factors. Younger age was selected as risk factor for acute G2-RIA while surgery as risk factor for late G2-RIA. D2% was the only variable selected for permanent G2-RIA. Both LKB and logistic models exhibited high predictive performances (ROC-AUCs range 0.86–0.90). Conclusion We derived NTCP models to predict G2-RIA after PT, providing a comprehensive modelling framework for acute, late and permanent occurrences that, once externally validated, could be exploited for individualized scalp sparing treatment planning strategies in brain tumor patients.

Background Platelet-rich-plasma (PRP) is largely used, thanks to its properties, as wound therapy after surgical resection. Several studies and clinical findings have demonstrated that the PRP can accelerate the regeneration and the repair of tissues through the action of the platelet-derived growth factors. Material and methods Our study aimed to investigate the effects of PRP-gel on the rate of tumor relapse by using a mouse model of Human Fibrosarcoma (HF). The radical resection of tumors of mice was conducted under fluorescence-guidance (FGR) by using MacroFluo microscope, after a primary tumor removal with bright-light surgery (BLS). Results It was found that the lesion recurrence and the tumor growth were reduced in mice treated with PRP observed in each group of treatment (50%) after 30 days from tumor excision, respect to controls (without statistical significance; p = 0.12). The histopathological and immune-histochemical analysis did not report differences in cellular morphology between the tumors of control and PRP-treated mice. Conclusion Our data suggest that PRP-gel, used as an adjuvant treatment for the stimulation of tissue repair and speed up recovery, can impair tumor growth and slow the tumor.

Thoracic radiation therapy (RT) is often associated with lung side effects, whose etiology is still controversial. Our aim was to explore correlations between local dose in the thoracic anatomy and the radiation-induced lung damage (RILD). To this end, we designed a robust scheme for voxel-based analysis (VBA) to explore dose patterns associated with RILD in non-small-cell lung cancer (NSCLC) patients receiving stereotactic body RT (SBRT). We analyzed 106 NSCLC SBRT patients (median prescription dose: 50 Gy; range: [40-54] Gy) in 4 fractions (range: [3-5]) with clinical and dosimetric records suitable for the analysis. The incidence of acute G1 RILD (RTOG grade ⩾ 1) was 68%. Each planning CT and dose map was spatially normalized to a common anatomical reference using a B-spline inter-patient registration algorithm after masking the gross tumor volume. The tumor-subtracted dose maps were converted into biologically effective dose maps (α/β = 3 Gy). VBA was performed according to a non-parametric permutation test accounting for multiple comparison, based on a cluster analysis method. The underlying general linear model of RILD was designed to include dose maps and each non-dosimetric variable significantly correlated with RILD. The clusters of voxels with dose differences significantly correlated with RILD at a given p -level (S p ) were generated. The only non-dosimetric variable significantly correlated with RILD was the chronic obstructive pulmonary disease (p = 0.034). Patients with G1 RILD received significantly (p ⩽ 0.05) higher doses in two voxel clusters S 0.05 in the lower-left lung (14 cm3) and in an area (64 cm3) largely included within the ventricles. The applied VBA represents a powerful tool to probe the dose susceptibility of inhomogeneous organs in clinical radiobiology studies. The identified subregions with dose differences associated with G1 RILD in both the heart and lower lungs endorse a trend of previously reported hypotheses on lung toxicity radiobiology.

The contemporary approach to the management of a cancer patient requires an "ab initio" involvement of different medical domains in order to correctly design an individual patient's pathway toward cure. With new therapeutic tools in every medical field developing faster than ever before the patient care outcomes can be achieved if all surgical, drug, and radiation options are considered in the design of the appropriate therapeutic strategy for a given patient. Radiation therapy (RT) is a clinical discipline in which experts from different fields continuously interact in order to manage the multistep process of the radiation treatment. RT is found to be an appropriate intervention for diverse indications in about 50% of cancer patients during the course of their disease. Technologies are essential in dealing with the complexity of RT treatments and for driving the increasingly sophisticated RT approaches becoming available for the treatment of Cancer. High conformal techniques, namely intensity modulated or volumetric modulated arc techniques, ablative techniques (Stereotactic Radiotherapy and Stereotactic Radiosurgery), particle therapy (proton or carbon ion therapy) allow for success in treating irregularly shaped or critically located targets and for the sharpness of the dose fall-off outside the target. The advanced on-board imaging, including real-time position management systems, makes possible image-guided radiation treatment that results in substantial margin reduction and, in select cases, implementation of an adaptive approach. The therapeutic gains of modern RT are also due in part to the enhanced anticancer activity obtained by coadministering RT with chemotherapy, targeted molecules, and currently immune checkpoints inhibitors. These main clinically relevant steps forward in Radiation Oncology represent a change of gear in the field that may have a profound impact on the management of cancer patients.

Background: Different modern radiation therapy treatment solutions for breast cancer (BC) and regional nodal irradiation (RNI) have been proposed. In this study, we evaluate the potential reduction in radiation-induced skin morbidity obtained by intensity modulated proton therapy (IMPT) compared with intensity modulated photon therapy (IMXT) for left-side BC and RNI. Material and Methods: Using CT scans from 10 left-side BC patients, treatment plans were generated using IMXT and IMPT techniques. A dose of 50 Gy (or Gy [RBE] for IMPT) was prescribed to the target volume (involved breast, the internal mammary, supraclavicular, and infraclavicular nodes). Two single filed optimization IMPT (IMPT1 and IMPT2) plans were calculated without and with skin optimization. For each technique, skin dose-metrics were extracted and normal tissue complication probability (NTCP) models from the literature were employed to estimate the risk of radiation-induced skin morbidity. NTCPs for relevant organs-at-risk (OARs) were also considered for reference. The non-parametric Anova (Friedman matched-pairs signed-rank test) was used for comparative analyses. Results: IMPT improved target coverage and dose homogeneity even if the skin was included into optimization strategy (HIIMPT2 = 0.11 vs. HIIMXT = 0.22 and CIIMPT2 = 0.96 vs. CIIMXT = 0.82, p < .05). A significant relative skin risk reduction (RR = NTCPIMPT/NTCPIMXT) was obtained with IMPT2 including the skin in the optimization with a RR reduction ranging from 0.3 to 0.9 depending on the analyzed skin toxicity endpoint/model. Both IMPT plans attained significant OARs dose sparing compared with IMXT. As expected, the heart and lung doses were significantly reduced using IMPT. Accordingly, IMPT always provided lower NTCP values. Conclusions: IMPT guarantees optimal target coverage, OARs sparing, and simultaneously minimizes the risk of skin morbidity. The applied model-based approach supports the potential clinical relevance of IMPT for left-side BC and RNI and might be relevant for the setup of cost-effectiveness evaluation strategies based on NTCP predictions, as well as for establishing patient selection criteria.

Simple Summary Dyspnea is a common symptomatic side-effect of thoracic radiation therapy. The aim of this study is to build a predictive model of any-grade radiation-induced dyspnea within six months after stereotactic body radiation therapy in patients treated for non-small cell lung cancer. The occurrence of pre-treatment chronic obstructive pulmonary disease and higher relative lungs volume receiving more than 15 Gy as well as heart volume were shown to be risk factors for dyspnea. The obtained results encourage further studies on the topic, which could validate the present organ-based findings and explore the voxel-based landscape of radiation dose sensitivity in the development of dyspnea. Abstract In this study, we investigated the prognostic factors for radiation-induced dyspnea after hypo-fractionated radiation therapy (RT) in 106 patients treated with Stereotactic Body RT for Non-Small-Cell Lung Cancer (NSCLC). The median prescription dose was 50 Gy (range: 40–54 Gy), delivered in a median of four fractions (range: 3–12). Dyspnea within six months after SBRT was scored according to CTCAE v.4.0. Biologically Effective Dose (α/β = 3 Gy) volume histograms for lungs and heart were extracted. Dosimetric parameters along with patient-specific and treatment-related factors were analyzed, multivariable logistic regression method with Leave-One-Out (LOO) internal validation applied. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC) and calibration plot parameters. Fifty-seven patients (53.8%) out of 106 developed dyspnea of any grade after SBRT (25/57 grade ≥ 2 cases). A three-variable predictive model including patient comorbidity (COPD), heart volume and the relative lungs volume receiving more than 15 Gy was selected. The model displays an encouraging performance given by a training ROC-AUC = 0.71 [95%CI 0.61–0.80] and a LOO-ROC-AUC = 0.64 [95%CI 0.53–0.74]. Further modeling efforts are needed for dyspnea prediction in hypo-fractionated treatments in order to identify patients at high risk for developing lung toxicity more accurately.

Different studies showed correlations between gadolinium-based contrast agent (GBCA) administrations and dentate nucleus (DN) T1-weighted hyperintensity. The clinical impact of gadolinium retention, however, is still largely unknown. The aim of this study was to investigate relations between MRI and clinical disability in relapsing–remitting multiple sclerosis (RR-MS) patients. In this retrospective study, clinical data were obtained from 74 RR-MS patients at baseline and after a mean follow-up time of 3.6 years, including the expanded disability status scale (EDSS) score and its change (ΔEDSS). Patients were considered showing clinical worsening if they score a ΔEDSS ≥ 1 (for baseline EDSS ≤ 5.5) or ΔEDSS ≥ 0.5 (for baseline EDSS > 5.5). From the MRI data, the presence of bilateral DN hyperintensity was recorded along with the calculation of longitudinal relaxation rate (R1) maps. Patients with DN hyperintensity showed similar ΔEDSS change compared to those without visible changes on T1-weighted images (p = 0.32). Similarly, no DN-R1 difference was found comparing stable patients with those showing a significant clinical worsening (p = 0.54). Finally, no significant effect of DN-R1 values explained the variance in ΔEDSS (p = 0.76), thus suggesting their independence from the clinical outcome. MS patients with DN hyperintensity show similar EDSS changes compared to subjects without DN high-signal intensity. Furthermore, mean DN-R1 values of patients with significant clinical worsening were comparable to those of stable subjects and were unrelated to clinical disability. Taken together, these findings suggest that gadolinium retention in the brain of MS patients does not affect their clinical worsening, expressed by the EDSS change.

Ulcerative dermatitis (UD) is an idiopathic, spontaneous and progressive disease typically affecting C57BL/6 aged mice with an unknown aetiopathogenesis. For this study, we evaluated 25 cases of UD in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice. Formalin-fixed, paraffin-embedded skin samples were submitted to morphological investigations. Immunohistochemical analysis was performed to characterize and quantify inflammatory cells using CD3, CD45/B220, CD4, CD8 and IL-17 antibodies. Mast cell-bound IgE was investigated by immunofluorescence, whereas serum and cryopreserved skin samples were collected for molecular analysis. Student's t-test (two-tailed) was performed to assess significant differences between the two groups. Affected skin showed extensive areas of ulceration and diffuse, severe and mixed inflammatory infiltrates. No relevant changes were observed in control mice. Immunohistochemical analysis showed a predominant CD3 + CD4 + leukocyte population with fewer CD45/B220 and IL-17 immunolabelled cells and mast cell-bound IgE. Increases in TNFα, IL-1β and Il-6 mRNA expression were observed in the skin of affected animals compared to controls. Serum TNFα and IL-6 did not vary between affected and control mice. Inflammatory infiltrates and cytokine expression were consistent with both Th2/IgE and Th17 differentiation, a typical pattern of a type I hypersensitivity reaction. Overall, our data suggest an allergic-based aetiopathogenesis of UD in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice.

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is an emerging cancer-related gene that is downregulated in different human malignancies, including thyroid cancer, where its levels gradually decrease going from papillary thyroid carcinomas (PTC) to poorly differentiated and undifferentiated highly aggressive anaplastic carcinomas (ATC). The restoration of PATZ1 expression in thyroid cancer cells reverted their malignant phenotype by inducing mesenchymal-to-epithelial transition, thus validating a tumor suppressor role for PATZ1 and suggesting its involvement in thyroid cancer progression. Here, we investigated the consequences of the homozygous and heterozygous loss of PATZ1 in the context of a mouse modeling of PTC, represented by mice carrying the RET/PTC1 oncogene under the thyroid specific control of the thyroglobulin promoter RET/PTC1 (RET/PTC1TG). The phenotypic analysis of RET/PTC1TG mice intercrossed with Patz1-knockout mice revealed that deficiency of both Patz1 alleles enhanced thyroid cancer incidence in RET/PTC1TG mice, but not the heterozygous knockout of the Patz1 gene. However, both RET/PTC1TG;Patz1+/- and RET/PTC1TG;Patz1-/- mice developed a more aggressive thyroid cancer phenotype-characterized by higher Ki-67 expression, presence of ATCs, and increased incidence of solid variants of PTC-than that shown by RET/PTC1TG; Patz1+/+ compound mice. These results confirm that PATZ1 downregulation has a critical role in thyroid carcinogenesis, showing that it cooperates with RET/PTC1 in thyroid cancer progression.

The so called “Triple Negative Breast Cancer” (TNBC) represents approximately 15-20% of breast cancers. This acronym simply means that the tumour does not express oestrogen receptor (ER) and progesterone receptor (PR) and does not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene. Despite this unambiguous definition, TNBCs are an heterogeneous group of tumours with just one common clinical feature: a distinctly aggressive nature with higher rates of relapse and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Because of the absence of well-defined molecular targets, cytotoxic chemotherapy is currently the only treatment option for TNBC. In the last decades, the use of more aggressive chemotherapy has produced a clear improvement of the prognosis in women with TNBC, but this approach results in an unacceptable deterioration in the quality of life, also if some support therapies try to relieve patients from distress. In addition, there is the general belief that it is impossible to further improve the prognosis of TNBC patients with chemotherapy alone. In view of that, there is a feverish search for new “clever drugs” able both to rescue chemo-resistant, and to reduce the burden of chemotherapy in chemo-responsive TNBC patients. A major obstacle to identifying actionable targets in TNBC is the vast disease heterogeneity both inter-tumour and intra-tumour and years of study have failed to demonstrate a single unifying alteration that is targetable in TNBC. TNBC is considered the subtype that best benefits from the neoadjuvant model, since the strong correlation between pathological Complete Response and long-term Disease-Free-Survival in these patients. In this review, we discuss the recent discoveries that have furthered our understanding of TNBC, with a focus on the subtyping of TNBC. We also explore the implications of these discoveries for future treatments and highlight the need for a completely different type of clinical trials.

We report the assessment of Dentate Nuclei (DN) R1 (1/T1) and R2* (1/T2*) values in a patient with relapsing-remitting Multiple Sclerosis, exposed to 22 standard (0.1 mmol/kg) doses of gadobutrol, who underwent eight relaxometric MR measurements within 2 years. DN R1 did not significantly increase nor correlated with cumulative gadobutrol administration, even after a total dose of 130 ml. Likewise, DN R2* relaxometry remained unchanged. In conclusion, massive gadobutrol exposure did not induce significant DN relaxometry changes.

Breast cancer is considered the most common cancer for women worldwide and it is now the second leading cause of cancer-related deaths among females in the world. Since breast cancer is highly resistant to chemotherapy, alternative anticancer strategies have been developed. In particular, many studies have demonstrated that curcumin, a derivative of turmeric, can be used as natural agent in treatment of some types of cancer by playing antiproliferative and antioxidant effects. In our study, we assessed the antitumor activities of curcumin in ER-negative human breast cancer cell line resistant to chemotherapy, MDA.MB231 byin vitroandin vivoexperiments.In vitrodata allowed us to demonstrate that curcumin played a role in regulation of proliferation and apoptosis in MDA.MB231 cells.In vivo, by generation of mouse model of breast cancer, we showed that treatment of curcumin inhibited tumor growth and angiogenesis. Specifically, we showed that curcumin is able to deregulate the expression of cyclin D1, PECAM-1, and p65, which are regulated by NF-κB. Our data demonstrated that curcumin could be used as an adjuvant agent to chemotherapy in treatment of triple negative breast cancer.

Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Severalin vitroandin vivostudies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performedin vitrostudies on ER-negative human breast carcinoma cells, MDA.MB231 andin vivostudies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphinein vitroenhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells.In vivostudies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

Proton beam therapy represents a promising modality for left-side breast cancer (BC) treatment, but concerns have been raised about skin toxicity and poor cosmesis. The aim of this study is to apply skin normal tissue complication probability (NTCP) model for intensity modulated proton therapy (IMPT) optimization in left-side BC.Ten left-side BC patients undergoing photon irradiation after breast-conserving surgery were randomly selected from our clinical database. Intensity modulated photon (IMRT) and IMPT plans were calculated with iso-tumor-coverage criteria and according to RTOG 1005 guidelines. Proton plans were computed with and without skin optimization. Published NTCP models were employed to estimate the risk of different toxicity endpoints for skin, lung, heart and its substructures.Acute skin NTCP evaluation suggests a lower toxicity level with IMPT compared to IMRT when the skin is included in proton optimization strategy (0.1% versus 1.7%, p 0.001). Dosimetric results show that, with the same level of tumor coverage, IMPT attains significant heart and lung dose sparing compared with IMRT. By NTCP model-based analysis, an overall reduction in the cardiopulmonary toxicity risk prediction can be observed for all IMPT compared to IMRT plans: the relative risk reduction from protons varies between 0.1 and 0.7 depending on the considered toxicity endpoint.Our analysis suggests that IMPT might be safely applied without increasing the risk of severe acute radiation induced skin toxicity. The quantitative risk estimates also support the potential clinical benefits of IMPT for left-side BC irradiation due to lower risk of cardiac and pulmonary morbidity. The applied approach might be relevant on the long term for the setup of cost-effectiveness evaluation strategies based on NTCP predictions.

The quest for alternative drugs with respect to the well-known cis-platin and its derivatives, which are still used in more than 50% of the treatment regimens for patients suffering from cancer, is highly needed. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct covalent metal-carbon bond, have recently been found to be promising anticancer drug candidates. A series of new metallocene complexes with scandium, yttrium, and neodymium have been prepared and characterized. Some of these compounds show a very interesting anti-proliferative activity in triple negative breast cancer cell line (MDA.MB231) and the non-hormone sensitive prostate cancer cell line (DU145). Moreover, the interaction of some of them with biological membranes, evaluated using liposomes as bio-membrane mimetic model systems, seems to be relevant. The biological activity of these compounds, particularly those based on yttrium, already effective at low concentrations on both cancer cell lines, should be taken into account with regard to new therapeutic approaches in anticancer therapy.

Several studies have established that pseudogene mRNAs can work as competing endogenous RNAs and, when deregulated, play a key role in the onset of human neoplasias. Recently, we have isolated two HMGA1 pseudogenes, HMGA1P6 and HMGA1P7. These pseudogenes have a critical role in cancer progression, acting as micro RNA (miRNA) sponges for HMGA1 and other cancer-related genes. HMGA1 pseudogenes were found overexpressed in several human carcinomas, and their expression levels positively correlate with an advanced cancer stage and a poor prognosis. In order to investigate the molecular alterations following HMGA1 pseudogene 7 overexpression, we carried out miRNA sequencing analysis on HMGA1P7 overexpressing mouse embryonic fibroblasts. Intriguingly, the most upregulated miRNAs were miR-483 and miR-675 that have been described as key regulators in cancer progression. Here, we report that HMGA1P7 upregulates miR-483 and miR-675 through a competing endogenous RNA mechanism with Egr1, a transcriptional factor that positively regulates miR-483 and miR-675 expression.

Background Brain MRI plays an essential role in both diagnosis and follow-up of the JCV infection of the brain. Recently, MR studies with Susceptibility-Weighted Imaging (SWI) sequences have shown hypointensities in U-fibers adjacent to white matter (WM) lesions of Progressive Multifocal Leukoencephalopathy (PML). This finding has been confirmed with the use of quantitative susceptibility mapping (QSM), allowing to hypothesize a paramagnetic effect in these regions. Here we report the first longitudinal assessment of QSM and R2* maps in natalizumab-associated PML, to evaluate serial changes in susceptibility contrast images and their role in PML diagnosis and follow-up. Case presentation We report the case of a 42-year old woman with Multiple Sclerosis (MS) who eventually developed, after the 28th natalizumab infusion, sub-acute cognitive decline and received a laboratory-confirmed diagnosis of PML, leading to immediate drug discontinuation. Three months later she suffered a new clinical exacerbation, with a brain scan revealing significant inflammatory activity compatible with the radiological diagnosis of an Immune Reconstitution Inflammatory Syndrome (IRIS). She was then treated with corticosteroids until the clinico-radiological spectrum became stable, with the final outcome of a severe functional impairment. Quantitative maps obtained in the early symptomatic stage clearly showed increased QSM and R2* values in the juxtacortical WM adjacent to PML lesions, which persisted during the subsequent disease course. Discussion and Conclusions High QSM and R2* values in U-fibers adjacent to WM lesions was an early and seemingly time-independent radiological finding in the presented PML case. That, coupled to the known absence of significant paramagnetic effect of new active MS lesions, could support the use of quantitative MRI as an additional tool in the diagnosis and follow-up of natalizumab-related PML in MS.

The risk of radiation-induced toxicity in patients treated for head and neck (HN) cancer with radiation therapy (RT) is traditionally estimated by condensing the 3D dose distribution into a monodimensional cumulative dose-volume histogram which disregards information on dose localization. We hypothesized that a voxel-based approach would identify correlations between radiation-induced morbidity and local dose release, thus providing a new insight into spatial signature of radiation sensitivity in composite regions like the HN district. This methodology was applied to a cohort of HN cancer patients treated with RT at risk of radiation-induced acute dysphagia (RIAD). We implemented an inter-patient elastic image registration framework that proved robust enough to match even the most elusive HN structures and to provide accurate dose warping. A voxel-based statistical analysis was then performed to test regional dosimetric differences between patients with and without RIAD. We identified a significantly higher dose delivered to RIAD patients in two voxel clusters in correspondence of the cricopharyngeus muscle and cervical esophagus. Our study goes beyond the well-established organ-based philosophy exploring the relationship between radiation-induced morbidity and local dose differences in the HN region. This approach is generally applicable to different HN toxicity endpoints and is not specific to RIAD.

Morphine, a highly potent analgesic agent, is widely used to relieve pain and suffering of patients with cancer. Additionally, it has been reported that morphine is important in the regulation of cancerous tissue. Morphine relieves pain by acting directly on the central nervous system, although its activities on peripheral tissues are responsible for many adverse side effects. For these reasons, it is very important also to understand the role of morphine in cancer treatment. The published literature reporting the effect of morphine on tumor growth presents some discrepancies, with reports suggesting that morphine may either promote or inhibit the tumor growth. It has been also demonstrated that morphine modulates angiogenesis which is important for primary tumour growth, invasiveness, and the development of metastasis. This review will focus on the latest findings on the role of morphine in the regulation of cancer cell growth and angiogenesis.

We aimed to evaluate the presence of venous stenosis and blood flow abnormalities in the neck vessels of patients with multiple sclerosis (MS), in respect to a group of age- and sex-matched healthy controls (HC), and their possible relations with clinical variables using a semi-automated quantitative MRI method.45 patients with relapsing remitting MS and 40 HC were enrolled in this study. Flow rates and cross-sectional areas of arterial and venous neck vessels were assessed by phase-contrast MRI at two different neck levels (C2-C3 and C6-C7), and differences between groups were evaluated with an unpaired t-test. Correlation between blood flow variables and clinical parameters was analyzed with Spearman's test.A significant internal jugular vein (IJV) stenosis was found in 23/45 (51.1%) patients with MS and 18/40 (45.0%) HC. No differences were observed between patients with MS and HC for any of the flow measures obtained. No correlations were found between MRI measures and any of the tested clinical variables.No differences in the IJV area emerged at quantitative MRI evaluation, suggesting that stenosis of the extracranial veins is unrelated to MS. Furthermore, no flow differences in the neck vessels were found between patients with MS and HC in any of the tested flow measures, with no correlation with clinical variables. Our results confirm that the hypothesis of the presence of extracranial venous abnormalities in MS, both in terms of stenosis or flow measures, is not suitable.Neck venous drainage abnormalities have been claimed to be associated with MS. Conversely, our quantitative MRI analysis seems to exclude that extracranial venous alterations are related to the disease.

CpG-oligodeoxynucleotide (CpG-ODN; CpG), a Toll-like receptor-9 ligand, has been widely studied as a potential antitumor adjuvant. Toll-like receptor-9 is highly expressed on lung carcinoma tissues and some immune cells, such as plasmacytoid dendritic cells and B cells.The aim of our study was to elucidate the effect of CpG on B cells in a mouse model of lung carcinoma.C57Bl/6j, B cell-deficient, and Nude mice were intravenously implanted with the lung metastatic B16-F10 melanoma cells and killed 3 and 7 days after CpG administration.Administration of CpG increased lung tumor growth in B16-F10-implanted C57BL/6J mice. The genetic absence of B cells strongly facilitated CpG-induced tumor progression. In contrast, the adoptive transfer of CpG-activated B cells induced tumor arrest, associated with a reduced suppressive immune environment due to the lower recruitment of regulatory T cells, myeloid-derived suppressor cells, and CD8(+) regulatory T cells along with the reduced expression of suppressive cytokines such as IL-10 and transforming growth factor-β. Furthermore, concomitant with higher production of IFN-γ, the apoptosis rate in the lungs of mice adoptively transferred with CpG-activated B cells was increased. Depletion of mature CD20(+) B cells increased the lung tumor burden in CpG-treated C57BL/6J mice and nude mice. Moreover, nude mice had the same lung tumor burden as B cell-deficient mice when mature CD20(+) B cells were depleted.Our data demonstrate the protective antitumor activity of CpG-activated B cells and shed light on CpG as an antitumor adjuvant for lung cancer therapy.

With the aim to find novel therapeutical approaches for triple-negative breast cancer (TNBC) treatment, we have developed a powder for i.v. injection based on cyclodextrins and docetaxel (DTX)-loaded polyethyleneglycol-poly(epsilon-caprolactone) nanoparticles (DTX-NPs). Nanoparticles are designed to concentrate at tumor level by enhanced permeability and retention effect and release drug cargo at a sustained rate in the blood and in tumor interstitium. DTX-NPs of around 70 nm, shielding proteins and allowing a sustained DTX release for about 30 days, were produced by melting sonication technique. DTX-NPs were associated to hydroxypropyl-β-cyclodextrin to give a powder for injection with excellent dispersibility and suitable for i.v. administration. DTX-NPs were as efficient as free DTX in inhibiting cell growth of MDA-MB231 cells, even at low concentrations, and displayed a comparable in vivo antitumor efficacy and better survival in a TNBC animal model as compared with DTX commercial formulation (Taxotere®). In conclusion, PEGylated biodegradable DTX-NPs highlighted their potential in the treatment of aggressive TNBC providing a foundation for future clinical studies.

Despite the advancement of clinical and preclinical research on PCa, which resulted in the last five years in a decrement of disease incidence by 3-4%, it remains the most frequent cancer in men and the second for mortality rate. Based on this evidence we present a brief dissertation on numerous preclinical models, comparing their advantages and disadvantages; among this we report the PDX mouse models that show greater fidelity to the disease, in terms of histopathologic features of implanted tumor, gene and miRNA expression, and metastatic pattern, well describing all tumor progression stages; this characteristic encourages the translation of preclinical results. These models become particularly useful in meeting the need of new treatments identification that eradicate PCa bone metastases growing, clarifying pathway of angiogenesis, identifying castration-resistant stem-like cells, and studying the antiandrogen therapies. Also of considerable interest are the studies of 3D cell cultures derived from PDX, which have the ability to maintain PDX cell viability with continued native androgen receptor expression, also showing a differential sensitivity to drugs. 3D PDX PCa may represent a diagnostic platform for the rapid assessment of drugs and push personalized medicine. Today the development of preclinical models in vitro and in vivo is necessary in order to obtain increasingly reliable answers before reaching phase III of the drug discovery.

To evaluate changes in T1 and T2* relaxometry of dentate nuclei (DN) with respect to the number of previous administrations of Gadolinium-based contrast agents (GBCA). In 74 relapsing-remitting multiple sclerosis (RR-MS) patients with variable disease duration (9.8±6.8 years) and severity (Expanded Disability Status Scale scores:3.1±0.9), the DN R1 (1/T1) and R2* (1/T2*) relaxation rates were measured using two unenhanced 3D Dual-Echo spoiled Gradient-Echo sequences with different flip angles. Correlations of the number of previous GBCA administrations with DN R1 and R2* relaxation rates were tested, including gender and age effect, in a multivariate regression analysis. The DN R1 (normalized by brainstem) significantly correlated with the number of GBCA administrations (p

BACKGROUND: Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients. PATIENTS AND METHODS: We evaluated 140 consecutive BC patients undergoing conventional three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman's Rs coefficient and ROC area. RESULTS: By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two-variable model including the skin receiving ≥30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p

The metastatic process is the most serious cause of cancer death. Norepinephrine, secreted in chronic stress conditions, stimulates the motility of breast and colon cells through β-adrenergic receptor. On these bases, we examined its possible role in metastasis formation and development in vitro and in vivo. Treatments with norepinephrine (β2-adrenoreceptor agonist) in mice xenografted with human DU145 prostate cancer cells increased the metastatic potential of these cells. Specifically, we showed that treatment of mice with norepinephrine induced a significant increase of the migratory activity of cancer cells in a concentration-dependent manner and that this process was blocked by propanolol (β-adrenergic antagonist). Mice treated with norepinephrine, displayed an increased number of metastatic foci of DU145 cells in inguinal lymph nodes and also showed an increased expression of MMP2 and MMP9 in tumor samples compared to controls. Moreover, we demonstrated that propanolol induced in norepinephrine treated DU145 cells a E-cadherin finger-like membrane protrusions driven by vimentin remodeling. Altogether these data suggest that β2-AR plays an important role in prostate cancer metastasis formation and that the treatment with antagonist propanolol, could represents an interesting tool to control this process in cells overexpressing β2AR.

We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80 −/− mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80 −/− mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.

Colorectal cancer is one of the most common and aggressive cancers arising from alterations in various signaling pathways, such as the WNT, RAS-MAPK, PI3K and transforming growth factor-beta (TGF-beta) pathways. Cripto (also called Teratocarcinoma-derived growth factor), the original member of the vertebrate EGF-CFC family, plays a key role in all of these pathways and is deeply involved in early embryo development and cancer progression. The role of Cripto in colon and breast cancer, in particular, has been investigated, as it is still not clearly understood. In this article, we provide the first in vivo functional evidence of a role of Cripto in colon cancer development. We analyzed the effect of Cripto haploinsufficiency on colon tumor formation by treating Cripto heterozygous mice with the colonotropic carcinogen azoxymethane (AOM). Of note, in our model system, Cripto haploinsufficiency increased tumorigenesis. Moreover, we revealed a Correlation between the differential AOM response found in wt and Cripto(+/-) mice and the expression levels of glucose regulated protein-78 (Grp78), a heat shock protein required for Cripto signaling pathways. We hypothesize that the balance between Cripto and Grp78 expression levels might be crucial in cancer development and may account for the increased tumorigenesis in Cripto heterozygous mice. In summary, our results highlight the heterogeneous effect of Cripto on tumorigenesis and the consequent high level of complexity in the Cripto regulatory pathway, whose imbalance causes tumors.

// Gennaro Chiappetta 1, * , Teresa Valentino 2, * , Michela Vitiello 2 , Rosa Pasquinelli 1 , Mario Monaco 1 , Giuseppe Palma 3 , Romina Sepe 2, 4 , Antonio Luciano 3 , Pierlorenzo Pallante 2 , Dario Palmieri 5 , Concetta Aiello 1 , Domenica Rea 3 , Simona Nunzia Losito 1 , Claudio Arra 3 , Alfredo Fusco 2, 4 , Monica Fedele 2 1 Department of Experimental Oncology, Functional Genomic Unit, National Cancer Institute “Fondazione Giovanni Pascale”, IRCCS, 80131 Naples, Italy 2 Institute of Experimental Endocrinology and Oncology (IEOS), National Research Counsil (CNR), 80131 Naples, Italy 3 Animal Facility, National Cancer Institute “Fondazione Giovanni Pascale”, IRCCS, 80131 Naples, Italy 4 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy 5 Departments of Molecular Virology, Immunology and Human Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA * These authors have contributed equally to this work Correspondence to: Monica Fedele, e-mail: mfedele@unina.it Gennaro Chiappetta, e-mail: g.chiappetta@istitutotumori.na.it Keywords: thyroid cancer, PATZ1, Epithelial-Mesenchymal Transition, cell migration Received: July 22, 2014 Accepted: November 18, 2014 Published: December 16, 2014 ABSTRACT PATZ1, a POZ-Zinc finger protein, is emerging as an important regulator of development and cancer, but its cancer-related function as oncogene or tumor-suppressor is still debated. Here, we investigated its possible role in thyroid carcinogenesis. We demonstrated PATZ1 is down-regulated in thyroid carcinomas compared to normal thyroid tissues, with an inverse correlation to the degree of cell differentiation. In fact, PATZ1 expression was significantly further down-regulated in poorly differentiated and anaplastic thyroid cancers compared to the papillary histotype, and it resulted increasingly delocalized from the nucleus to the cytoplasm proceeding from differentiated to undifferentiated thyroid carcinomas. Restoration of PATZ1 expression in three thyroid cancer-derived cell lines, all characterized by fully dedifferentiated cells, significantly inhibited their malignant behaviors, including in vitro proliferation, anchorage-independent growth, migration and invasion, as well as in vivo tumor growth. Consistent with recent studies showing a role for PATZ1 in the p53 pathway, we showed that ectopic expression of PATZ1 in thyroid cancer cells activates p53-dependent pathways opposing epithelial-mesenchymal transition and cell migration to prevent invasiveness. These results provide insights into a potential tumor-suppressor role of PATZ1 in thyroid cancer progression, and thus may have potential clinical relevance for the prognosis and therapy of thyroid cancer.

Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells.In vitrostudies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observedin vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-κB and NF-κB-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-κB pathway.

"In the last few years, the field of tumor immunology has significantly expanded and its boundaries, never particularly clear, have become less distinct. Although the immune system plays an important role in controlling tumor growth, it has also become clear that tumor growth can be promoted by inflammatory immune responses. A good example that exemplifies the ambiguous role of the immune system in cancer progression is represented by interleukin 18 (IL-18) that was first identified as an interferon-γ-inducing factor (IGIF) involved in T helper type-1 (Th1) immune response. The expression and secretion of IL-18 have been observed in various cell types from immune cells to circulating cancer cells. In this review we highlighted the multiple roles played by IL-18 in immune regulation, cancer progression and angiogenesis and the clinical potential that may result from such understanding"