Endoscopic sealing of pancreatic fistula by using N-butyl-2-cyanoacrylate

BACKGROUND: The treatment of pancreatic fistula can be difficult. A novel endoscopic approach to sealing pancreatic fistulas by using N-butyl-2-cyanoacrylate is described. METHODS: Twelve patients with pancreatic fistulas underwent endoscopic injection of N-butyl-2-cyanoacrylate into the fistulous tract, in addition to endoscopic drainage. RESULTS: Fistulas were closed successfully in 8 of 12 patients. A single treatment session was successful in 7 patients; a second session was required in one patient. In two patients, closure was temporary, and, in one patient, the treatment failed. One patient died 24 hours after treatment. He developed a pulmonary thromboembolism from a left popliteal vein thrombosis and died from complications of surgical thromboembolectomy. At autopsy, a pulmonary embolus was found, but there was no evidence of N-butyl-2-cyanoacrylate in the lungs. No procedure-related complication occurred over a median follow-up of 20.7 months (range 9-51 months). CONCLUSIONS: In this preliminary study, occlusion of pancreatic fistulas by using N-butyl-2-cyanoacrylate glue was safe and effective, and obviated the need for surgery in a substantial proportion of patients. Further studies of the use of N-butyl-2-cyanoacrylate for closure of pancreatic fistula are warranted.     

Detection of pancreatic metastases by EUS-guided fine-needle aspiration

BACKGROUND: Metastases to the pancreas are usually found incidentally. Tissue diagnosis is imperative because imaging alone is incapable of differentiating them from primary pancreatic tumors. This study tested whether it is possible to differentiate metastases from other focal pancreatic lesions by using EUS-guided fine-needle aspiration (EUS-FNA) for cytodiagnosis. METHODS: One hundred fourteen consecutive patients (mean age 61 years) with focal pancreatic masses, detected on CT, underwent EUS-FNA by using a linear-array echoendoscope and 22-gauge needles. RESULTS: Adequate specimens were obtained from 112 lesions. Carcinomas were identified in 68 cases (60.7%), 56 (50%) of pancreatic origin and 12 (10.7%) from distant primary tumors. The metastases were all located in the head and body of the pancreas and measured 1.8 to 4.0 cm. The echo-texture was heterogeneous or hypoechoic in all cases and resembled that of primary tumors. Six of the 12 patients with metastatic disease had a prior diagnosis of cancer (breast, 3; renal cell, 2; salivary gland, 1), 4 of them with a recurrence and 2 with a second carcinoma metastasizing to the pancreas. Six patients without a prior diagnosis of cancer had metastases from renal cell, colonic, ovarian, and esophageal carcinomas; one metastasis was from an unknown primary and another was from a malignant lymphoma. These findings influenced the therapeutic strategy in 8 patients who underwent nonsurgical palliation. There were no complications. CONCLUSIONS: Pancreatic metastasis is an important cause of focal pancreatic lesions, but the EUS features are not diagnostic. Simultaneous EUS-FNA allows cytodiagnosis and can have a decisive influence on the selection of appropriate therapeutic strategies.     

Splenectomy for the treatment of thrombotic thrombocytopenic purpura

Plasma exchange is the treatment of choice for patients with thrombotic thrombocytopenic purpura (TTP) and results in remission in >80% of the cases. Treatment of patients who are refractory to plasma therapy or have relapsing disease is difficult. Splenectomy has been a therapeutic option in these conditions but its value remains controversial. We report on a series of 33 patients with TTP who were splenectomised because they were plasma refractory (n = 9) or for relapsed disease (n = 24). Splenectomy generated prompt and unmaintained remissions in all except five patients, in whom remission was delayed (n = 4) or who died with progressive disease (n = 1). Four postoperative complications occurred: one pulmonary embolism and three surgical complications. Median follow-up after splenectomy was 109 months (range 28-230 months). The overall postsplenectomy relapse rate was 0.09 relapses/patient-year and the 10-year relapse-free survival (RFS) was 70% (95% CI 50-83%). In the patients with relapsing TTP, relapse rate fell from 0.74 relapses/patient-year before splenectomy to 0.10 after splenectomy (P < 0.00001). Two patients died from first postsplenectomy relapse. Although these results are based on retrospective data and that the relapse rate may spontaneously decrease with time, we conclude that splenectomy, when performed during stable disease, has an acceptable safety profile and should be considered in cases of plasma refractoriness or relapsing TTP to reach durable remissions and to reduce or prevent future relapses.     

Exploratory evaluation of pharmacodynamics,pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study

Background

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.

Methods

This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.

Results

Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.

Conclusions

Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.

Trial registration

ClinicalTrials.gov number, NCT01145859.

     

Pharmacokinetics,clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency

Essentials

• Congenital afibrinogenemia causes a potentially life‐threatening bleeding and clotting tendency.
• Two human fibrinogen concentrates (HFCs) were compared in a randomized pharmacokinetic study.
• Bioequivalence was not shown for AUC_norm, which was significantly larger for the new HFC.
• Increases in clot strength were comparable, and no thromboses or deaths occurred in the study.

Summary

Background

Human fibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a‐/hypofibrinogenemia.

Objectives

To assess pharmacokinetics (PK), effects on thromboelastometry maximum clot firmness (MCF), and safety of a new double virus‐inactivated/eliminated, highly purified HFC vs. active control.

Patients/Methods

In this multinational, randomized, phase II, open‐label, crossover study in 22 congenital afibrinogenemia patients aged ≥ 12 years, 70 mg kg^?1 of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan^® P/RiaSTAP?, CSL Behring GmbH) were administered, followed by crossover to the other concentrate. Fibrinogen activity, PK and MCF in plasma were assessed.

Results

The concentrates were not bioequivalent for the primary endpoint, AUC_norm (mean ratio, 1.196; 90% confidence interval [CI], 1.117, 1.281). Remaining PK parameters (C_maxnorm, IVR, t_1/2, MRT) reflected bioequivalence between concentrates, except for clearance (mean ratio, 0.836; 90% CI, 0.781, 0.895) and V_ss (mean ratio, 0.886; 90% CI, 0.791, 0.994). Mean AUC_norm was significantly larger for the new HFC (1.62 ± 0.45 vs. 1.38 ± 0.47 h kg g L^?1 mg^?1, P = 0.0001) and mean clearance was significantly slower (0.665 ± 0.197 vs. 0.804 ± 0.255 mL h^?1 kg^?1, P = 0.0002). Mean MCF increased from 0 mm to 9.68 mm (new HFC) and 10.00 mm (control) 1‐hour post‐infusion (mean difference, ?0.32 mm; 95% CI, ?1.70, 1.07, n.s.). No deaths, thromboses, viral seroconversions or serious related adverse events occurred.

Conclusions

Bioequivalence was not demonstrated for AUC_norm, clearance and V_ss. Larger AUC_norm and slower clearance were observed for the new HFC. Remaining pharmacokinetic parameters reflected bioequivalence to control. Safety profiles and increases in clot strength were comparable between concentrates.