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Background: Animal models of para-renal cancer can provide useful information for the evaluation of tumor response to loco-regional therapy experiments in solid tumors. The aim of our study was to establish a rabbit para-renal cancer model using locally implanted VX2 tumors. Methods: In order to generate a rabbit model of para-renal cancer, we established four hind limb donor rabbits by using frozen VX2 tumor samples. Following inoculation, rabbits were monitored for appetite and signs of pain. Viable tumors appeared as palpable nodules within 2 weeks of inoculation. Tumor growth was confirmed in all rabbits by high-resolution ultrasound analysis and histology. Once tumor growth was established, hind limb tumors extraction was used for tumor line propagation and para-renal tumor creation. Twenty-one rabbit models bearing para-renal cancer were established by implanting VX2 tumor into the para-renal capsula. Tumors developed into discreet 2-3 cm nodules within 1-3 weeks of implantation. Serial renal ultrasonography follow-up, starting 1 week after tumor implantation, was performed. Two weeks after tumor implantation, rabbits were euthanized and tumors and other organs were collected for histopathology. Results: Tumor growth after VX2 tumor fragment implantation was confirmed in all rabbits by high-resolution ultrasound (US) imaging examinations of the para-renal regions and was measured with digital caliper. The para-renal injection of VX2 tumor fragments, achieved tumor growth in 100% of cases. All data were confirmed by histological analysis. Conclusions: We generated for the first time, a model of para-renal cancer by surgical tumor implantation of VX2 frozen tumor fragments into rabbit's para-renal region. This method minimizes the development of metastases and the use of non-necrotic tumors and will optimize the evaluation of tumor response to loco-regional therapy experiments. [ABSTRACT FROM AUTHOR]

Background Fibrin sealants are currently used in a variety of surgical and endoscopic settings to improve time to haemostasis, reduce blood loss and complications. However, the application of sealants (composed of two essential components: fibrinogen and thrombin) is not without difficulties. These sealants are normally applied to the resected area using dual-chamber delivery systems. Administration of these substances with different viscosities and diverse flow rates through a long catheter means that a certain amount of force needs to be applied and clot formation and clogging at the distal end of the catheter can occur. Methods We designed a novel dual-lumen catheter to facilitate the optimal application of fibrin sealant after diagnostic and therapeutic percutaneous procedures and assessed the efficacy and tolerability of this dual-lumen kit when used in a model of hepatic fine needle aspiration (FNA) biopsy and radiofrequency ablation (RFA) in an in vivo, preclinical porcine study. Results The experimental was performed on nine pigs (mean body weight 85 ± 7 kg) and with the exception of one pig, all animals survived in good conditions until the day of hepatectomy and euthanasia. The premature death of this animal was in the veterinarian's judgment caused by a common, non-infective disease. In all nine pigs, bleeding was stopped within 3 minutes of the application of the fibrin sealant and no cases of recurrent bleeding occurred. Conclusions The new dual aspect catheter increased ease of delivery of the sealant and FNA liver biopsy and RFA procedures were successfully and safely performed. [ABSTRACT FROM AUTHOR]

Background: The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial Methods: A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-a2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-a2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-a2b (groups A+C vs. B+D) Results: Addition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-a2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-a2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events. Conclusions: No significant improvement in outcomes were observed with the addition of either fotemustine or IFN-a2b to dacarbazine. [ABSTRACT FROM AUTHOR]

Introduction: Leptomeningeal metastases are occurring at higher frequency in cancer patients. The prognosis of leptomeningeal metastases is poor and standard treatment, which includes radiotherapy and chemotherapy, is mostly ineffective. Melanoma represents one of the tumors with the highest incidence of leptomeningeal metastases. For such a disease, the BRAF inhibitors have recently been demonstrated to be effective on melanoma brain metastases harboring the V600EBRAF mutation.Case Presentation: We report a case of a 39-year-old Italian woman with advanced melanoma with brain, lung and peritoneum metastases harboring the V600EBRAF mutation. In August 2010 she was enrolled into the BRIM3 trial and after the randomization process she received dacarbazine. After two cycles, there was evidence of disease progression in her peritoneum and lung. For this reason, she was enrolled into another clinical trial with the GSK2118436 BRAF inhibitor, dabrafenib, as a second line of therapy. She had a partial response that was maintained until 13 weeks of treatment. In January 2011 she developed symptoms typical for brain metastases and received a diagnosis of leptomeningeal involvement of melanoma cells after an examination of her cerebral spinal fluid; magnetic resonance imaging was negative for meningitis or brain metastases. Analysis of her cerebral spinal fluid sample confirmed that the melanoma cells still carried the V600EBRAF mutation. After a few days, our patient went into a coma and died.Conclusion: Starting with a clinical case, we discuss the pathogenesis of leptomeningeal metastases and whether the leptomeninges may represent a sanctuary where melanoma cells may generate resistance and/or BRAF inhibitors cannot reach an adequate concentration for significant activity. We assess whether treatment with BRAF inhibitors in melanoma patients should be interrupted as soon as disease progression appears or continued beyond progression, through the administration of additional compounds. [ABSTRACT FROM AUTHOR]

Background: The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial.Methods: A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D).Results: Addition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events.Conclusions: No significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine.Trial Registration: ClinicalTrials.gov: NCT01359956. [ABSTRACT FROM AUTHOR]

Background: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy., Methods/design: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project., Discussion: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Background: RFA is a safe and effective procedure for treating unresectable primary or secondary liver malignancies, but it is not without complications. The most common reported complications include abdominal hemorrhage, bile leakage, biloma formation, hepatic abscesses, and neoplastic seeding. The aim of this study is to evaluate the feasibility of percutaneous use of surgical sealant with a new coaxial bilumen catheter, to prevent the perihepatic bleeding and dissemination of cancer cells through the needle-electrode (neoplastic seeding) or along the needle track., Methods: We designed a novel dual-lumen catheter to facilitate the optimal application of fibrin sealant after diagnostic and therapeutic percutaneous procedures. Percutaneous RFA has been performed using mask ventilation or neuroleptanalgesia. The main aims of this study, after the ablation procedure, in the treatment of unresectable liver cancer were to prevent major adverse events: a) the perihepatic bleeding; b) dissemination of cancer cells through the needle-electrode and or needle track., Results: A total of 181 patients were evaluated for this study at National Cancer Institute of Naples from January 2012 to January 2014. The association of blood loss (≤1 g/dl; ≥1 g/dl) with age, gender, histological diagnosis were analyzed. No statistical significance was observed between bleeding and age (p = 0.840), gender (p = 0.607) and histological diagnosis (p = 0,571), respectively., Conclusions: This study demonstrated that fibrin sealant or other surgical sealant injection, after any locoregional procedure such as biopsy or ablation, could make adverse events even more rare.

Background: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target., Methods/design: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT., Discussion: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28., Trial Registration: ClinicalTrials.gov number, NCT01898104.

Background: Parathyroid carcinoma is a rare malignancy, with an incidence of 0.5 to 4% of all cases of primary hyperparathyroidism. Surgery is the only curative treatment., Case Presentation: We report the case of a 66-year-old man referred for a large suspicious substernal goitre associated with severe hypercalcemia due to hyperparathyroidism. After normalization of serum calcium levels, patient underwent surgery. The voluminous cervicomediastinal firm mass could not be removed through the cervical incision; therefore a cervicothoracic approach was employed. Histopathology revealed a giant parathyroid cancer of 450 grams. A review of the literature was also undertaken to summarize the current treatment approaches for this rare malignancy., Conclusion: Parathyroid cancer is usually not recognized either preoperatively or intra-operatively. En bloc resection of the tumour with the adjacent tissue is the treatment of choice and it is very important to avoid the rupture of the capsule during operation. Neither tumour size, nor the lymph node status appears to play a role in prognosis. The management of parathyroid carcinoma is a challenge even for experienced surgeons.