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Background: The aim of the study was to investigate Programmed cell Death protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) and their mRNA expression in thymic epithelial tumors (TETs). Research design and Methods: We analyzed 68 samples of formalin-fixed paraffin embedded tissue (63 thymomas and 5 thymic carcinomas). PD-1 and PD-L1 protein expression was evaluated by immunohistochemistry and mRNA expression was evaluated by Real Time-PCR. Results: M/F ratio was 33/35, and median age was 60.5 years. 20 patients had Myasthenia Gravis (MG). In the subgroup with large tumors (>5 cm), PD-L1 mRNA overexpression was significantly associated with worse prognosis vs. patients with no mRNA overexpression (p =0.0083) and simultaneous PD-L1 immunostaining (>1%); PD-L1 mRNA overexpression was significantly associated with worse prognosis, respect to patient with PD-L1 negative immunostaining and no PD-L1 mRNA overexpression (p = 0.0178). The elderly patients (> 60 years) with large tumors showed worse prognosis (p = 0.0395). PD-L1 immunostaining (>50%) resulted significantly associated with MG. Conclusions: Our data suggest the potential involvement of the PD-1 and PD-L1 pathway in TETs progression. According to our results, it may be helpful to design future trials with anti-PD-1 drugs to establish high-risk patients after surgery.

PURPOSE Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established. PATIENTS AND METHODS We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity. RESULTS Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% v 27%) and compliance with CRT higher in group B (91%, 78%, and 76% v 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 v 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B ( P < .001), but not group A ( P = .210), fulfilled the predefined statistical hypothesis. CONCLUSION Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.

We present a new geometrical method capable of quantifying and illustrating the outcomes of a three-component mixing dynamics. In a three-component mixing scenario, classical algebraic equations and endmember mixing analysis (EMMA) can be used to quantify the contributions from each fraction. Three-component mixing of natural waters, either in an element–element plot or by using the EMMA mixing subspace is described by a triangular shaped distribution of sample points where each endmember is placed on an apex, while each side corresponds to the mixing function of the two endmembers placed at the apex, considering the third endmembers' contribution equal to zero. Along each side, the theoretical mixing fractions can be computed using mass balance equations. Samples with contributions from three endmembers will plot inside the triangle, while the homogeneous barycentric coordinate projections can be projected onto the three sides. The geochemistry observed in the mineralized Ferrarelle aquifer system (southern Italy) results from three-component mixing of groundwater, each with diagnostic geochemical compositions. The defined boundary conditions allow us to parameterize and validate the procedures for modelling mixing, including selection of suitable geochemical tracers.

BACKGROUND: We previously showed that selected single-nucleotide-polymorphisms (SNPs) of genes involved in angiogenesis influence the aggressiveness of thymic epithelial tumors (TETs). This study analyzes their role in TETs and in thymic benign lesions, in order to investigate potential correlation with risk and outcome. METHODS: Genomic DNA was extracted from paraffin-embedded tissue of 92 patients, undergoing surgery at our Institution. We investigated by Real-Time PCR the SNPs of the following genes: platelet-derived growth factor receptor-α (PDGFRα), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor-2 and 3 (VEGF-2, VEGFR-3), excision repair cross-complementation group-1 (ERCC1). RESULTS: Fifty-seven TETs and 35 thymic benign lesions were included into the study. Frequency of SNPs was as follows: rs2057482 C, rs11158358 C and rs11549465 C polymorphisms of HIF1-a: thymomas < general population (P=0.008, P=0.007, and P=0.044 respectively). HIF1-a alleles: general population > study groups, rs1951795C SNP (P=0.026 for benign lesions and P=0.0007 for thymomas), rs10873142T SNP (P=0.008 and P=0.001 respectively), rs12434438 A SNP (P=0.034 and P=0.0007) and rs2301113A SNP (P=0.027 and P=0.010). rs699947C polymorphism of VEGF-A: benign lesions > general population (P=0.012). CONCLUSIONS: This is the first study investigating the angiogenetic polymorphisms in thymic benign lesions and TETs. SNPs analysis may represent a further asset in identification of patients who could benefit from anti-angiogenetic therapy.

A theoretical pattern for Fe and As co-precipitation was tested directly in a groundwater natural system. Several monitoring wells were sampled to identify the different endmembers that govern the hydrodynamics of the Ferrarelle Groundwater System in the Riardo Plain (Southern Italy). In agreement with recent investigations, we found a mix of a deep and a shallow component in different proportions, resulting in a specific chemical composition of groundwater in each well depending on the percentages of each component. The shallow component was characterized by EC ~ 430 µS/cm, Eh ~ 300 mV, Fe ~ 0.06 µmol/L and As ~ 0.01–0.12 µmol/L, while the deep component was characterized by EC ~ 3400 µS/cm, Eh ~ 170 mV, Fe ~ 140 µmol/L and As ~ 0.59 µmol/L. A general attenuation of As and Fe concentration that was not due to a simple dilution effect was observed in the mixing process. The oxidation of Fe(II) to Fe(III) produces solid precipitates which adsorb As from solution and then co-precipitate. The reactions pattern of Fe(II) oxidation and As adsorption gave a linear function between [As] and [Fe], where the angular coefficient depends on the [O2]/[H+] ratio. Chemical data obtained from our samples showed a very good agreement with this theoretical relationship. The investigated geochemical dynamics represented a natural process of attenuation of Fe and As, two undesirable elements that usually affect groundwater quality in volcanic aquifers in central-southern Italy, which are exploited to supply drinking water. Graphic abstract

The Riardo basin hosts groundwater exploited for the production of high quality, naturally sparkling, bottled water (e.g., Ferrarelle water), and circulating in a system constituted by highly fractured Mesozoic carbonates, overlain by more impervious volcanic rocks of the Roccamonfina complex. The two formations are locally in hydraulic connection and dislocated by deep-rooted faults. The study aimed at elucidating groundwater origin and circulation, using isotopic tracers (δ18O, δ2H, δ11B and 87Sr/86Sr) coupled to groundwater dating (Tritium, CFCs and SF6). Besides recharge by local precipitation over the Riardo hydrogeological basin, stable isotope ratios in water indicated an extra-basin recharge, likely from the elevated surrounding carbonate reliefs (e.g., Maggiore and Matese Mts.). The mineralization process, promoted by the deep CO2 flux, controls the B and Sr contents. However, their isotopic ratios did not allow discriminating between circulation in the volcanic and in the carbonate aquifers, as in the latter the isotopic composition differed from the original marine signature. Groundwater model ages ranged from ~ 30 years for the volcanic endmember to > 70 years for the deep, mineralized end-member, with longer circuits recharged at higher elevations. Overall, the results of this study were particularly relevant for mineral water exploitation. A recharge from outside the hydrogeological basin could be evidenced, especially for the more mineralized and valuable groundwater, and an active recent recharge was detected for the whole Riardo system. Both findings will contribute to the refinement of the hydrogeological model and water budget, and to a sustainable development of the resource.

Importance Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. Objective To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. Design, Setting, and Participants This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. Interventions Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. Main Outcomes and Measures The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. Results Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45,P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%,P = .67) and distant metastases (18% vs 16%,P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. Conclusions and Relevance This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. Trial Registration ClinicalTrials.gov identifier:NCT02363374

Cabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in RCC patients treated with second- or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second- or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan&ndash, Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51&ndash, 10.88) and 11.57 months (95% CI 10.90&ndash, not reached (NR)) as second-line and 11.38 months (95% CI 5.79&ndash, NR) and NR (95% CI 11.51&ndash, NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib&ndash, nivolumab and 25.64 months and NR with nivolumab&ndash, cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39, 95% CI 1.24&ndash, 4.60, p = 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04&ndash, 2.87, p = 0.037) were associated with PFS while ECOG-PS (HR = 2.33, 95%CI, 1.16&ndash, 4.69, p = 0.018) and Hb levels (HR = 3.12, 95%CI 1.18&ndash, 8.26, p = 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72, 95%CI 1.04&ndash, 7.09, p = 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.

Thymomas, tumors that arise from epithelial cells of the thymus gland, are the most common neoplasms of the anterior mediastinum, with an incidence rate of approximately 2.5 per million/year. Cytotoxic T Lymphocyte Antigen 4 (CTLA-4 or CD152) exerts inhibitory activity on T cells, and since its oncogenic role in the progression of different types of tumors, it has emerged as a potential therapeutic target in cancer patients. In this study, we assessed the expression of CTLA-4 both at mRNA and protein levels in paraffin embedded-tissues from patients with thymomas. Furthermore, we evaluated the relationship between CTLA-4 expression and the clinical-pathologic characteristics and prognosis in patients with thymomas. Sixty-eight patients with median age corresponding to 62 years were included in this analysis. Thymomas were classified accordingly to the WHO and Masaoka-Koga for histochemical analysis and for prognostic significance. A statistical difference was found between CTLA-4 mRNA levels in human normal thymus compared with thymoma specimens. CTLA-4 expression was statistically found to progressively increase in A, B1, B2, AB and it was maximal in B3 thymomas. According to Masaoka-Koga pathological classification, CTLA-4 expression was lower in I, IIA and IIB, and higher in invasive III and IV stages. By confocal microscopy analysis we identified the expression of CTLA-4 both in tumor cells and in CD45+ tumor-infiltrating leukocytes, mainly in B3 and AB thymomas. Finally, CTLA-4 overexpression significantly correlates with reduced overall survival in thymoma patients and in atypical thymoma subgroup, suggesting that it represents a negative prognostic factor.

The “Antica Fonte” mineral water is a valuable resource with well-known therapeutic effects due to its high magnesium and sulphate contents. Hydrochemical and isotopic data indicate that the water is recharged at an elevation exceeding 1000 m asl, derives its mineral content by dissolution of Triassic gypsum and dolomite, and partially mixes with present day recharge from the alluvial aquifer. The results of this investigation provide valuable information for a sustainable development of the resource.

A local preliminary 2D model was built in the Riardo Plain in order to preliminary evaluate the regional hydrogeological conceptual model. The used finite element code was FeFlow 6.2 and calibration of data was performed via inverse modelling through FePEST (PEST code). A volcanic and a carbonate aquifer can be distinguished at regional scale. The multilayered volcanic aquifer presents a radial flow towards gaining streams and it is recharged by direct infiltration. Regional information about the carbonate aquifer are not available. The basement upraise and the fault systems allow the local mixing between the carbonate and volcanic aquifers. Recharge of the carbonate aquifer is likely to up-flow from the deep reservoir, but no direct information is available about rates and spatial distribution. Therefore, the aim of the 2D numerical model was to test the reliability of the hypothesis of possible bottom recharge through the carbonate basement, proposed in previous groundwater budget research. After a first steady state calibration of the model, transient calibration was performed to fit the groundwater levels of the carbonate and the volcanic aquifer monitored in 2003. The zenithal recharge was applied daily as calculated from the thermo pluviometric data elaborated by Thornthwaite’s method, and the vertical discretization of the aquifers was set according to the stratigraphic information. A constant bottom recharge was set as upflow through the carbonate basement. The calibration, performed over conductivity and specific storage, gave good results. The obtained budget parameters show the higher amount of the zenithal recharge (around 60%) over the carbonate recharge (around 40%), preliminary confirming the supposed recharge model.

Complex hydrogeological systems require detailed knowledge of aquifer dynamics to ensure appropriate and sustainable management of the groundwater resource. The Riardo Plain aquifer, southern Italy, is a strategic resource for conjunctive uses; nevertheless, the conceptual model still suffers some uncertainties due to the presence of a deep lateral inflow through the carbonate basement. Therefore, the realisation of a 3D numerical model at catchment scale needs preliminary tests to constrain the possible additional inflow rate, which is at the moment only estimated through the results of the groundwater budget calculation. A 2D section of the mixing area was modelled using FEFLOW in order to test the hypothesis of a combined recharge. Seven versions of the same model were calibrated over an increasing number of adjustable parameters according to their sensitivity. The most efficient model version was identified according to the calculated information criteria and the sum of squared-weighted residuals. In the second phase of the work, nine model scenarios characterised by different deep inflow rates were calibrated and validated according to the same procedure of the first model, in order to identify the range of possible acceptable solutions. The most likely deep inflow rate is 34 ± 4% of the total recharge, corresponding to an estimated deep inflow of 415 ± 50 L/s in the Riardo Plain aquifer through the carbonate basement. This methodological approach will be the basis of following numerical 3D numerical models of the Riardo Plain and can be a valuable tool in conceptualising similar mineral water areas.

The successful management of carbon in the Earth's crust is critical for mitigating the increase of anthropogenic CO2 in the atmosphere. Carbon Capture and Storage (CCS) requires an understanding of the behavior of carbon in the crust and the development of robust monitoring techniques to constrain the movement, mechanisms, and pathways for any potential CO2 leakage. Here, we examine an aquifer from the Riardo Plain (Campania Region, southern Italy), which serves as a suitable natural analogue for CO2 migration to the critical zone (i.e., shallow crust and aquifers) and as a case study to evaluate the geochemical processes that occur when CO2-saturated fluids mix with freshwater in shallow aquifers. We investigate the behavior of various geochemical constituents (major and trace elements, δ18O–H2O, δ13C-DIC, and Rn content). Water from this area has a high degree of mineralization (EC 2500–3000 μS/cm), high HCO3- (~2.5 g/L), is saturated with respect to CaCO3, and is enriched in alkali ions (e.g., Na+ + K+). The high degree of mineralization occurs in groundwater that discharges from the basal aquifer of the Roccamonfina volcanic edifice (~6 km NW), with vast CO2 inputs that promote host rock leaching. Superficial volcanic aquifers are recharged by fresh meteoric precipitation when groundwater flows from carbonates at the edge of the plain to aquifers hosted in the southeastern slope of the Roccamonfina volcano. The presence of normal faults in this area permits natural upwelling of CO2-rich groundwater, which locally mixes with shallow freshwater present within the upper volcanic succession. Significant (R > 0.8) linear correlations between conservative elements suggest that groundwater geochemistry is dominated by a mixture of two main endmembers: (i) deep/mineralized waters and (ii) shallow/diluted waters. The intrusion of freshwater to volcanic aquifers induces oxidation, leading to adsorption of select elements (e.g., As and Ba) onto Fe-oxyhydroxide precipitates within these aquifers. Geochemical modeling suggests that CO2 saturation approaches 3 g/L, which agrees with direct measurements of CO2 flux. We conclude that our conceptual geochemical model helps to constrain mixing of CO2 with freshwater and to diagnose the secondary geochemical processes that influence aqueous geochemistry within CO2-influenced groundwater.

Groundwater management authorities usually use groundwater budget calculations to evaluate the sustainability of withdrawals for different purposes. The groundwater budget calculation does not always provide reliable information, and it must often be supported by further aquifer monitoring in the case of hydraulic connections between neighboring aquifers. The Riardo Plain aquifer is a strategic drinking resource for more than 100,000 people, water storage for 60 km2 of irrigated land, and the source of a mineral water bottling plant. Over a long period, the comparison between the direct recharge and the estimated natural outflow and withdrawals highlights a severe water deficit of approximately 40% of the total groundwater outflow. A groundwater budget deficit should be a clue to the aquifer depletion, but the results of long-term water level monitoring allowed the observation of the good condition of this aquifer. In fact, in the Riardo Plain, the calculated deficit is not comparable to the aquifer monitoring data acquired in the same period (1992–2014). The small oscillations of the groundwater level and the almost stable streambed spring discharge allows the presumption of an additional aquifer recharge source. The confined carbonate aquifer locally mixes with the above volcanic aquifer, providing an externally stable recharge that reduces the effects of the local rainfall variability. The combined approach of the groundwater budget results and long-term aquifer monitoring (spring discharge and/or hydraulic head oscillation) provides information about significant external groundwater exchanges, even if unidentified by field measurements, and supports the stakeholders in groundwater resource management.

The exploitation of groundwater resources must always keep in account the geology and hydrogeological settings of the catchment basin for the sustainability of withdrawals, in order not to overexploit the aquifer. Especially, in the case of mineral water extraction, even more attention should be paid to understand what are the water-rock-gases interaction mechanisms, which allow obtaining a specific water chemistry. The case of Ferrarelle mineral water (western sector of Riardo Plain, Caserta) is particularly complex. Through the acquisition of a great amount of former geological and hydrogeological data and by new hydrogeological surveys, it has been possible to distinguish the aquifer levels, distinguishing four circulations over the Roccamonfina Volcano and in the Riardo Plain. The presence of volcanic and volcaniclastic deposits deriving from the Roccamonfina Volcano which cover a highlytectonized carbonate bedrock, allows the formation of two aquifers in hydraulic continuity. This mixing between the two aquifers allows, with the ascent of deep CO2 through faults in the carbonate bedrock, the formation of the typical chemical composition of the mineral water Ferrarelle. In the eastern sector of the plain, it is possible to distinguish the volcanic aquifer from the carbonate one, probably due to the presence of low permeability deposits.

Although complicated sigmoid diverticulitis is the most common reason for laparoscopic sigmoidectomy, the level of evidence for preference of the laparoscopic approach is low. A multicenter, randomized clinical trial comparing laparoscopic and open sigmoidectomy for diverticulitis was conducted to evaluate the short- and mid-term outcome after both techniques. Data were assessed from randomized patients and from patients who refused randomization. Results of the here presented interim analysis describe the difficulties in randomization leading to abortion of recruitment. 149 patients were enrolled in the randomized trial within 36 months until the interim analysis. A further 294 nonrandomized patients who preferred one of both surgical approaches were assessed. Several differences between these groups were apparent including simple epidemiological characteristics such as age (65 vs. 60 years, p

367 Background: Incidental gallbladder cancer (IGBC) in T1b-3 stage do profit from radical cholecystectomy but nevertheless the cure rate in T2-3 carcinomas is disappointing. For improvement, following questions are of interest. What is significant regarding adjuvant or multimodal aspects? Which technique of liver resection (LR) and lymph- node dissection (LAD) is meaningful? Role of lymph node ratio (LNR)? Answers based on the data of 975 IGBC of the GR- platform. Methods: For data analysis we used the German- Registry- platform (GR). The GR is a network of more than 300 clinics in Germany. More than 1000 cases of IGBC are registered and to the knowledge of the authors the largest prospective gallbladder registry worldwide. Results: To date more than 1000 IGBC in the GR have been registered, n = 975 analyzed. In 44 of 119 T1b cases there was an IRR, with a significant survival benefit for T1b after IRR. There was also a significant survival benefit for the 244 T2 and 86 T3 with IRR of the 492 T2 and 228 T3 tumors. Comparison of LR showed good results for the wedge resection technique (WRT) in T1b and T2. For T3 more radical techniques showed better results. In 233 patients the LNR could be calculated. Statistic indicates that LNR has a significant influence on prognosis. The results show that the referral of patients from a LV to a HV has no practical relevance. In n = 433 T2 / T3 patients there are data calculated about adjuvant therapy, with a highly significant survival benefit after adjuvant therapy in T2 and a trend for a survival benefit in T3 carcinomas. Positive effect of adjuvant therapy exists in the subgroup with and without re- resection but was more evident in patients without radical resection. Conclusions: IGBC's up to T1b needs radical surgery. The WRT is attractive for T1b / T2 IGBC. LAD and LNR are of prognostic relevance. In 433 T2-3 IGBC's, adjuvant therapy has a positive effect, especially in cases without radical surgery. Regimen will be discussed at the meeting. For further improvement in T2-3 IGBC a multimodal therapy (GAIN-) trial has already been planned by the investigator of the GR under the support of the GR- platform with more than 300 clinics in Germany.

Background: Thymic Hyperplasia refers to an enlargement of the thymus, while thymomas display significant heterogeneity from morphologic point of view, clinical behaviour, expression of immunohistochemical markers and molecular profiling. Therefore improving our understanding of the molecular biology of thymic disorders represents a key challenge in the treatment of these rare diseases. Methods: The genomic DNA of 93 consecutive patients undergoing total thymectomy at our Institution was extracted from paraffin-embedded tissue. We selected the following SNPs: Hypoxia Inducible Factor-1 alpha (HIF1a: rs2057482T>C, rs1951795A>C, rs2301113C>A, rs10873142C>T, rs11158358G>C, rs12434438G>A, rs11549465C>T, rs11549467G>A), Vascular Endothelial Growth Factor-A (VEGF-A: rs2010963G>C, rs699947A>C), VEGF Receptor 2 (VEGFR-2: rs2305948C>T, rs1870377T>A), VEGFR-3 (rs307826T>C, rs307821C>A), Platelet-Derived Growth Factor-A (PDGFR-A: rs35597368C>T). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Results: 93 patients were included into the study, 58 females and 35 males. The patients underwent surgery: 43 for thymomas, 14 for thymic carcinomas, 36 for thymic hyperplasia. The frequency of PDGFRa rs35597368T (95.24%) was significantly higher in thymic malignancies if compared with data available for population (86%, p=0.012), thus suggesting that it may represent a risk factor for this type of disease. On the other hand, the frequency of several HIF-1a polymorphisms (rs2057482C, rs11549465C, rs1951795C, rs2301113A, rs10873142T, rs11158358C, rs12434438A) resulted lower in our study than in the general population (p Furthermore, VEGFR3 rs307821C polymorphism was higher in thymoma than in thymic carcinoma (79.5% vs 72%, p=0.0371), and therefore it seems to be related to a lower grade of malignancy. Finally, the following factors were significantly correlated with a better overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-A rs35597368T/C, HIF1a rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C (p Conclusion: To the best of our knowledge this is the largest monocentric study analyzing the angiogenetic variants in thymic hyperplasia and tumors representing a further asset in the definition of high-risk patients after curative resection, also driving the selection of more aggressive adjuvant treatment in this subgroup of patients. The selection tool deriving from this analysis may allow an optimal use of innovative treatment strategies in thymic malignancies including targeted agents such as sunitinib, sorafenib or pazopanib. Citation Format: Rossana Berardi, Silvia Pagliaretta, Alessandro Brunelli, Vittorio Paolucci, Gaia Goteri, Majed Refai, Cecilia Pompili, Agnese Savini, Giulia Marcantognini, Mariangela Torniai, Michela Tiberi, Consuelo Ferrini, Francesca Morgese, Miriam Caramanti, Silvia Rinaldi, Azzurra Onofri, Antonio Zizzi, Paola Mazzanti, Stefano Cascinu. Impact of single-nucleotide polymorphisms (SNPs) on thymic hyperplasia and tumors outcome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2220. doi:10.1158/1538-7445.AM2014-2220

e18557 Background: Thymomas (T) display heterogeneity from morphologic point of view, clinical behaviour, immunohistochemical markers and molecular profiling. Thus improving our understanding of the molecular biology of thymic malignancies (TM) represents a key challenge in the treatment of these tumors. Methods: The genomic DNA of 93 consecutive patients (pts) undergoing total thymectomy was extracted from paraffin-embedded tissue. We studied the following SNPs: HIF-1a (rs2057482T>C, rs1951795A>C, rs2301113C>A, rs10873142C>T, rs11158358G>C, rs12434438G>A, rs11549465C>T, rs11549467G>A), VEGF-A(rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A), VEGFR-3 (rs307826T>C,rs307821C>A), PDGFR-A (rs35597368C>T) and ERCC1 (rs11615A>G). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Results: 93 pts were included, M/F ratio =35/58. All the pts underwent surgery: 43 for T, 14 for thymic carcinomas (TC) and 36 for TH. The frequency PDGFRa rs35597368T SNPs (95.24%) was significant...

// Rossana Berardi 1 , Alessandro Brunelli 2 , Silvia Pagliaretta 1 , Vittorio Paolucci 1 , Alessandro Conti 4 , Gaia Goteri 5 , Majed Refai 3 , Cecilia Pompili 2 , Giulia Marcantognini 1 , Francesca Morgese 1 , Zelmira Ballatore 1 , Agnese Savini 1 , Mariagrazia De Lisa 1 , Miriam Caramanti 1 , Matteo Santoni 1 , Antonio Zizzi 5 , Francesco Piva 6 , Paola Mazzanti 1 , Azzurra Onofri 1 , Armando Sabbatini 3 , Marina Scarpelli 5 , Stefano Cascinu 1 1 Medical Oncology, Universita Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I – GM Lancisi – G Salesi, Italy 2 Department of Thoracic Surgery, St. James’s University Hospital, Leeds, West Yorkshire, United Kingdom 3 Thoracic Surgery, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I – GM Lancisi – G Salesi, Italy 4 Urology, Universita Politecnica delle Marche, Ancona, Italy 5 Section of Pathological Anatomy and Histopathology, Universita Politecnica delle Marche, Ancona, Italy 6 Department of Specialistic Clinical and Odontostomatological Sciences, Universita Politecnica delle Marche, Ancona, Italy Correspondence to: Rossana Berardi, e-mail: r.berardi@univpm.it Keywords: angiogenesis, prognosis, single nucleotide polymorphism, thymic epithelial tumor, tumor risk Received: April 04, 2015 Accepted: May 26, 2015 Published: June 08, 2015 ABSTRACT We aimed to analyze genotypes of VEGF-A, VEGFR2, Flt4, PDGFRα, HIF-1α and ERCC1 and their correlation with thymic tumor risk and patient outcome. DNA of 57 consecutive patients (43 thymomas and 14 thymic carcinomas) who underwent total thymectomy at our Institution was extracted from paraffin-embedded tissue. We selected polymorphisms in the following genes:HIF1-α (rs2057482T > C, rs1951795A > C, rs2301113C > A, rs10873142C > T, rs11158358G > C, rs12434438G > A, rs11549465C > T, rs11549467G > A), VEGF-A (rs2010963G > C, rs699947A > C), VEGFR-2 (rs2305948C > T, rs1870377T > A), VEGFR-3 (rs307826T > C, rs307821C > A), PDGFR-α (rs35597368C > T) and ERCC1 (rs11615A > G). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. As compared to the general population, the allele frequency of PDGFR-α rs35597368T was significantly higher (95% vs. 87%, p = 0.036), while the frequency of alleles HIF1-α rs2057482C (78% vs. 90%), rs1951795C (69% vs. 87%), rs2301113A (70% vs. 83%), rs10873142T (70% vs. 87%), rs11158358C (75% vs. 88%), rs12434438A (67% vs. 84%) were significantly lower. VEGFR-3 rs307821C frequency was significantly higher in thymomas vs. thymic carcinomas (79% vs. 72%, p = 0.0371). The following factors were significantly correlated with a longer overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-α rs35597368T/C, HIF1-α rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C, ERCC1 rs11615A ( p < 0.05). Our results suggest, for the first time, that PDGFR-α, HIF-1α and VEGFR-3 SNPs are associated with thymic cancer risk and survival.

The volcanic system of Ischia is characterized by an intense hydrothermal activity, documented since the early 16th century by the study of Iasolino (1588), which represents the first systematic analysis of the thermal springs of the island for therapeutic purposes. Later studies partially contributed to the enhancement of knowledge on the volcanic, hydrogeological and hydrothermal features of the island, highlighting the strong interaction between hydrothermal flowpaths and volcano- tectonic processes. The reconstruction of the interplay between hydrothermal and magmatic system becomes, therefore, a fundamental element for territorial planning, not only in terms of management of the huge water and geothermal resource, but also in a perspective of prevention and mitigation of volcanic risk. Thermal springs, fumaroles and mud deposits give beginning clues about deep hydrothermal conditions. Till now at Ischia, the local geochemical characterization of fluids and groundwater has been used for the definition of the origin and structure of the hydrothermal system as a whole, as the hydrogeological information is incomplete. However, volcanic hydrothermal systems, such as that characterizes the island of Ischia, are particularly difficult to analyze and outline, as the groundwater resources are the result of a complex and dynamic mixing among meteoric water, sea water and deep fluids. In such cases, the need for an interdisciplinary approach is evident, involving knowledge and research methods ranging from geology to volcanology, geophysics, geochemistry and hydrogeology. With particular reference to the functional and structural representation of the geothermal system of the Ischia island and the resulting correlations with the volcano-tectonic processes, the examination of previous information highlights the need to update and improve the knowledge on groundwater hydrodynamics and mineralization processes. Therefore, the present study aims at a strongly interdisciplinary action that, starting from the design and implementation of a database on the existing geological/volcanological and hydrogeological information, will contribute to highlight the critical issues, define an operating scheme of the hydro-geo-thermal system of the island of Ischia, and upgrade its hydrogeological, geochemical and volcanic monitoring system. The preliminary results improved the definition of the hydrogeological complexes and advanced knowledge of the groundwater flow conditions.