Three dimensional primary cultures for selecting human breast cancers that are sensitive to the anti-tumor activity of ipatasertib or taselisib in combination with anti-microtubule cytotoxic drugs.

Two inhibitors of phosphatidylinositol 3-kinase (PI3K) pathway taselisib, targeting the mutant PI3K-subunit-alpha (PI3KA) and ipatasertib, AKT-inhibitor, are currently under clinical investigation in breast cancer (BC) patients. We have previously demonstrated the anti-tumor efficacy of these anti-PI3K/AKT-inibitors in combination with anti-microtubule drugs in human BC cell lines, through a complete cytoskeleton disorganization. In this work, we generated ex-vivo three-dimensional (3D) cultures from human BC as a model to test drug efficacy and to identify new molecular biomarkers for selection of BC patients suitable for anti-PI3K/AKT-inibitors treatment. We have established 3D cultures from 25/27 human BC samples, in which the ability of growth in vitro replicates the clinical and biological aggressiveness of the original tumors. According to the results of next generation sequencing analysis, a direct correlation was found between PI3KA mutations and the sensitivity in 3D models in vitro to taselisib and ipatasertib alone and combined with anti-microtubule agents. Moreover, mutations in HER and MAPK families related genes, including EGFR, KRAS and BRAF, were found in resistant samples, suggesting their potential role as negative predictive factors of response to these agents. Thus, we demonstrated that ex vivo 3D cultures from human BC patients allow a rapid and efficient drug screening for chemotherapies and targeted agents in genetically selected patients and represent an innovative model to identify new biomarkers of drug resistance.

Electrochemotherapy in the Treatment of Cutaneous Metastases from Breast Cancer: A Multicenter Cohort Analysis.

BACKGROUND: The management of breast cancer (BC) skin metastases represents a therapeutic challenge. Electrochemotherapy (ECT) combines the administration of bleomycin with temporary permeabilization induced by locally administered electric pulses. Preliminary experience with ECT in BC patients is encouraging. METHODS: A total of 125 patients with BC skin metastases who underwent ECT between 2010 and 2013 were enrolled onto a multicenter retrospective cohort study. The treatment was administered following the European Standard Operative Procedures of Electrochemotherapy. Tumor response was clinically assessed adapting the Response Evaluation Criteria in Solid Tumors, and toxicity was evaluated according to Common Terminology Criteria for Adverse Events 4.0. Cox regression analysis was used to identify predictive factors. RESULTS: Response was evaluable in 113 patients for 214 tumors (median 1 per patient, range 1-3). The overall response rate after 2 months was 90.2 %, while the complete response (CR) rate was 58.4 %. In multivariate analysis, small tumor size (P < 0.001), absence of visceral metastases (P = 0.001), estrogen receptor positivity (P = 0.016), and low Ki-67 index (P = 0.024) were significantly associated with CR. In the first 48 h, 10.4 % of patients reported severe skin pain. Dermatologic toxicity included grade 3 skin ulceration (8.0 %) and grade 2 skin hyperpigmentation (8.8 %). Tumor 1-year local progression-free survival was 86.2 % (95 % confidence interval 79.3-93.8) and 96.4 % (95 % confidence interval 91.6-100) in the subgroup of those with CR. CONCLUSIONS: In this study, small tumor size, absence of visceral metastases, estrogen receptor positivity, and low Ki-67 index were predictors of CR after ECT. Patients who experienced CR had durable local control. ECT represents a valuable skin-directed therapy for selected patients with BC.

Mesh fixation with human fibrin glue (Tissucol) in open tension-free inguinal hernia repair: a preliminary report.

BACKGROUND: The Lichtenstein technique for inguinal hernia repair is easy to learn and associated with few complications. However, recent studies have suggested that this technique is inferior to some 'sutureless' repair systems in terms of perceived difficulty, operating time, surgeon satisfaction, etc. METHODS: We employed a sutureless Lichtenstein technique in 80 consecutive patients with primary unilateral inguinal hernia, to assess patient and trainee surgeon outcomes. Human fibrin glue was used in place of conventional sutures. RESULTS: The mean operating time was 36 min and all patients were discharged 5-6 h after the operation. On a 100-point visual analogue scale, the surgeons rated the difficulty of the operation as low (mean score, 31), and perceived satisfaction as high (mean score, 84). No complications were observed at 12-month follow-up. CONCLUSION: This study confirms the efficacy of mesh fixation with human fibrin glue, and supports the viability of a sutureless Lichtenstein procedure.

[Interstitial laser treatment of small hepatocarcinoma on cirrhosis without anesthesia: feasibility study]. / Laserterapia interstiziale del piccolo epatocarcinoma su cirrosi senza alcuna anestesia: studio di fattibilità.

OBJECTIVE: We evaluated if interstitial laser photocoagulation (ILP) under ultrasound (US) guidance of intraparenchymal small HCC (<2 cm) in cirrhosis can be safely and effectively performed without any anesthesia. PATIENTS AND METHODS: Twelve cirrhotic patients with 14 nodules of HCC (diameter 1.2-2.0 cm; mean: 1.7) underwent ILP. All procedures were performed without local or general anesthesia. Necrosis of the nodules was evaluated with triphasic contrast-enhanced CT. RESULTS: Post-treatment CT showed complete necrosis in all cases. Pain occurred in 5 patients during the treatment was treated with iv pain-killer and only in 1 case the procedure was stopped before the scheduled time. No major complication occurred. CONCLUSIONS: ILP under US guidance is feasible without any anesthesia in patients with small intraparenchymal HCC.

[Blood coagulation changes in patients with post-splenectomy persistent thrombocytosis]. / Le alterazioni emocoagulative nei pazienti con trombocitosi persistente post-splenectomia.

To clarify the possible role of persistent thrombocytosis after splenectomy as being a predisposing factor causing thromboembolism. Blood coagulation profiles were studied in 35 patients (20 M and 15 F, mean age 42 +/- 17.5) suffering from thrombocytosis (> 500,000/dl) who underwent splenectomy for non-malignant and non-traumatic diseases. Seventy healthy subjects acted as a control group. Tests were performed 6 months after the operation and for both groups (patients and controls) blood samples were collected for: platelets, fibrinogen, PT, APTT, AT III, plasminogen, F1 + 2, t-PA and DNA analysis for F V, F II and MTHFR. After one year all subjects were controlled for thrombocytosis, genomic abnormalities and venous thrombosis. All the analyses were performed according to the Statistical Package for Social Science. The significance of the differences in means was evaluated by non-parametric tests, differences with a P value < 0.05 being considered significant. Increased plasma levels of fibrinogen, D-dimer, F1 + 2 and PAI-1 were found in the patients compared with the control group. TPA was significantly lower in the patients than in the controls. At the one year follow-up, two patients with genetic polymorphism had suffered deep venous thrombosis. Our findings indicate that splenectomy contributes to abnormal platelet aggregation and endothelial cell activation with hypercoagulability.

Sutureless skin closure in varicose vein surgery: preliminary results.

OBJECTIVE: To describe the preliminary results of a special method of wound closure in varicose vein surgery using the tissue adhesive butyl-2-cyanoacrylate. METHODS: Eighteen consecutive young women (mean age 23 years) underwent partial stripping of the greater saphenous vein for varicose veins of the lower limbs by an external phleboextractor. Their wounds were closed without sutures by means of the adhesive butyl-2-cyanoacrylate. The cutaneous edges were drawn together by linear traction between forceps and the adhesive was applied and allowed to set. Less than 0.5 ml of adhesive was required to complete the entire procedure. Wounds were evaluated at 7 days for infection, dehiscence, and tissue reactions. At 6 months all wounds were rated for cosmesis using a validated visual analog scale, that is, a 100 mm line with "worst scar" at the right end of the line and "best scar" at the left end. All patients were interviewed about their acceptance of tissue adhesive skin closure. RESULTS: The mean time required to close the epidermis with the adhesive was 117 seconds. All patients were followed up for 6 months. At 7 days no adverse outcomes had occurred. Results of wound evaluation at 6 months by the visual analog scale showed scores of 22.2 +/- 13.8 mm (optimal). The percentage of optimal scores was 94.4%, and only one patient (5.6%) had a suboptimal score. Inquiry into the patient's opinions suggested that this procedure was very acceptable. CONCLUSION: Preliminary results with sutureless skin closure in varicose vein surgery have been very encouraging. This fast and cosmetic method of wound repair can replace the need for skin sutures in varicose vein surgery.

Inguinal hernia repair in patients with coagulation problems: prevention of postoperative bleeding with human fibrin glue.

BACKGROUND: Our purpose was to establish the efficacy of human fibrin glue (HFG) in preventing coagulative complications after inguinal hernia repair in patients with coagulation disorders. METHODS: A randomized controlled trial of 50 patients with coagulation disorders undergoing hernia repair was performed. Patients had concurrent coagulopathies as a consequence of liver disease or long-term treatment with anticoagulants. Coagulopathies were defined according to the following criteria: prothrombin time < 10.5 seconds, activated partial thromboplastin time < 21 seconds, and fibrinogen < 230 mg/dL. Patients were randomized in a 1:1 ratio with (group A) or without (control group B) use of HFG. RESULTS: Postoperative hemorrhagic complications were significantly reduced in group A (4%) compared with group B (24%). CONCLUSION: This study shows that HFG is effective in preventing local hemorrhagic complications after herniorrhaphy in patients with concurrent coagulation disorders. This implies that the use of HFG reduces the costs of prolonged hospitalization related to such complications.

[Ultrasonically guided percutaneous treatment of renal cysts using ethanol and human fibrin glue (tissucol)]. / Il trattamento percutaneo eco-guidato delle cisti renali con etanolo e colla di fibrina umana (tissucol).

The sclerosant agents to be employed in the percutaneous treatment of renal cysts, according to the world wide published reports, are still topic of debate. The authors report the satisfying results obtained, once the cyst has been emptied under ultrasonographic control, by the injection into the cyst of ethanol 95% immediately followed by human fibrin glue (tissucol). In all ten patients so treated the complete and rapid disappearance of the cyst occurred without relapse after 6 months. The proposed procedure is also particularly suitable due to the lack of local and/or general complications deriving from the synergic, yet unprecedented, use of the two substances.