ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

Heart rate control with landiolol hydrochloride in infants with ventricular dysfunction and pulmonary hypertension.

AIMS: Sinus tachycardia potentially leads to a deterioration of cardiac function in critically ill infants. The ultrashort-acting beta-blocker landiolol hydrochloride is a new pharmacological option for a selective heart rate (HR) control in patients with sinus tachycardia and heart failure. METHODS AND RESULTS: This study was a monocentric retrospective medical chart review study at the University Children's Hospital Bonn (Germany) from 01 January 2018 until 30 June 2020. This study included a cohort of 62 term and preterm infants with a diagnosis of ventricular dysfunction and/or pulmonary hypertension (PH), in combination with preexisting tachycardia and treatment with landiolol hydrochloride. Infants were allocated to subgroups according to weeks of gestational age (GA): born at <35 weeks of GA (Group A) and born at >35 weeks of GA (Group B). Tachycardia was defined depending on GA (<35 weeks of GA: >170 b.p.m.; ≥ 35 weeks of GA: >150 b.p.m.). The primary endpoint was defined as percentage of patients achieving HR normalization during the first 24 h of landiolol treatment. Twenty-nine infants were allocated to Group A and 33 infants to Group B. The overall median GA of the infants was 35.3 (23.3/41.3), with 53% female infants. The primary endpoint was achieved in 57 patients (91.9%). The median time to reach target HR was 1.8 (0.3-24) h. The median starting dose of landiolol was 8.8 (3.9-25.3) µk/kg/min, with a median dosing during the first 24 h of landiolol treatment of 9.9 (2.8-35.4) µk/kg/min. The median landiolol dose while achieving the target HR was 10 (2.4-44.4) µk/kg/min. The right ventricular dysfunction improved significantly in both groups 24 h after onset of landiolol infusion (P = 0.001 in Group A and P = 0.045 in Group B). The left ventricular and biventricular dysfunction improved significantly 24 h after onset of landiolol infusion in infants of Group B (P = 0.004 and P = 0.006, respectively). The severity of PH improved significantly after 24 h in infants of Group A (P < 0.001). During landiolol treatment, no severe drug-related adverse event was noted. CONCLUSIONS: The use of landiolol hydrochloride for HR control of non-arrhythmic tachycardia in critically ill infants is well tolerated. Reduction of HR can be guided quickly and landiolol treatment is associated with an improvement of ventricular dysfunction and PH.

Intra-articular osteoma in the stifle joint of a cat.

Case summary: A 13-year-old male castrated cat was referred to our clinic for a 2-month history of right hindlimb lameness. Radiographs and CT showed a solid bony mass within the stifle joint. The mass was resected by arthrotomy and osteotomy of the tibial tuberosity. Histopathological examination revealed the diagnosis of osteoma. Recovery from surgery was uneventful. At the 8-week follow-up examination, the cat was free of clinical signs. Relevance and novel information: Feline osteomas are rare; only few cases have been reported. To the best of our knowledge, this is the first report of an intra-articular osteoma in the stifle joint of a cat and description of its surgical resection.

Radiographically confirmed outcomes after fracture repair with a PLS polyaxial locking system in 40 dogs and cats.

OBJECTIVE: To report radiographic findings and complications after fracture repair with a new polyaxial locking plate system (PLS polyaxial locking system; Aesculap/B Braun, Tuttlingen, Germany) in dogs and cats. STUDY DESIGN: Retrospective case review from four veterinary practices. SAMPLE POPULATION: Twenty-six dogs and 14 cats (40 long bone fractures). METHODS: Medical and radiographic records of dogs and cats with long bone fractures treated with the PLS were reviewed. Cases were included when operative records were complete and included documentation of radiographic union or complications. Phone interviews of owners were performed for long-term follow-up. Ancillary methods of fracture fixation and associated complications were recorded. RESULTS: Only two complications were recorded, one of which required a revision surgery. Radiographic follow-up was performed for all fractures. Radiographic union without complications was achieved in 38 of 40 (95%) fractures. Radiographic union was documented before 60 days in 19 of 40 (47.5%) fractures, between 61 and 90 days in 15 of 40 (37.5%) fractures, and after 90 days in six of 40 (15%) fractures. A functional union was observed at a mean time ± SD of 70.8 ± 38.9 days (range, 32-182). One or more ancillary fixation methods were used in 27 of 40 (67.5%) fractures. CONCLUSION: The PLS polyaxial locking system was often used with adjunct fixation in this series, and radiographically confirmed healing without complications was documented in most cases. CLINICAL SIGNIFICANCE: Use of the PLS can result in high success rates for fracture repair in dogs and cats, but ancillary fixation should be strongly considered.

How Do the Locking Screws Lock? A Micro-CT Study of 3.5-mm Locking Screw Mechanism.

OBJECTIVE: To quantify the amount of the screw head thread and the plate hole thread connection in two 3.5 mm locking plates: Locking Compression Plate (LCP) and Polyaxial Locking System (PLS). MATERIALS AND METHODS: A micro - CT scan of a screw head - plate hole connection was performed pre- and post destructive tests. Tests were performed on bone surrogates in a fracture gap model. The 3.5 LCP and 3.5 PLS plates, with 3 perpendicular screws per segment were used in a destructive static test. The 3.5 PLS plates with mono- and polyaxial screws were compared in a cyclic fatigue tests in two orthogonal directions. Pre - and post - test scan datasets were compared. Each dataset was converted into serial images depicting sections cut orthogonally to locking screw axis. The amount of engagement was detected through automated image postprocessing. RESULTS: The mean amount of the thread connection for the LCP was 28.85% before and 18.55% after destructive static test. The mean amount of the connection for the PLS was 16.20% before and 14.55% after destructive static test. When inserted monoaxially, the mean amount of the connection for the PLS screws was 14.4% before and 19.24% after destructive cyclic test. The mean amount of the connection for the polyaxial inserted PLS screws when loaded against plate thickness was 2.99% before and 2.08% after destructive cyclic test. The mean amount of the connection for the polyaxial inserted PLS screws when loaded against plate width was 3.36% before and 3.93% after destructive cyclic test. The 3D visualization of the thread connection showed that the initial interface points between screw head and plate hole are different for both LCP and PLS after the destructive testing. Depending on the type of applied force, there was either loss or increase of the contact. CLINICAL RELEVANCE: Micro-CT offers news possibilities in locking implant investigation. It might be helpful in better understanding the nature of locking mechanism and prediction of possible mode of failure in different systems.

Mechanical Performance of a Polyaxial Locking Plate and the Influence of Screw Angulation in a Fracture Gap Model.

OBJECTIVE: The aim of this study was to compare the locking compression plate (LCP) with polyaxial locking system (PLS) using single cycle to failure 4-point bending test and to investigate the behaviour of PLS with screws inserted mono- and polyaxially using cyclic fatigue test in two bending directions. MATERIALS AND METHODS: Tests were performed on bone surrogates in a fracture gap model. The 3.5 LCP and 3.5 PLS plates were tested in single cycle to failure. The 3.5 PLS plates with mono- and polyaxial screws were compared in a cyclic fatigue tests in two orthogonal directions. For both experiments, micro-computed tomography (CT) scans were performed pre- and post-testing to investigate the connections between the screw head and the plate hole. Means of forces and cycles needed to failure were statistically compared. RESULTS: The PLS plates were on average 30% weaker than LCP plates. Mode of failure was plate bending in the single cycle to failure tests, and plate breakage in the cyclic fatigue tests. Neither screw breakage nor loss of the screw-plate interface occurred. Mono- and polyaxial constructs performed similarly when loaded in the same direction. Micro-CT revealed no additional internal cracks in the plates or screws after testing. It also showed for both PLS and LCP that there was only partial contact of the screw head with the plate hole. CLINICAL RELEVANCE: PLS offers a durable locking system, even when the screws are placed polyaxially. The weaker bending properties of the PLS compared with LCP should be considered during preoperative planning.

Open-Label Two-Dose Pilot Study of Landiolol for the Treatment of Atrial Fibrillation/Atrial Flutter in Caucasian Patients.

BACKGROUND: We investigated for the first time the suitability of landiolol, an ultra-short-acting ß1-specific ß-blocker, for the treatment of atrial fibrillation/atrial flutter (AF/AFL) in Caucasian patients.Methods and Results:The 20 study patients received landiolol as a continuous infusion (starting dose 40 µg/kg/min) with (B+CI) or without (CI) a preceding bolus dose (100 µg/kg/min administered over 1 min) in a prospective open-label study. The primary endpoint was the proportion of patients with sustained heart rate (HR) reduction ≥20% or to <90 beats/min within 16 min of starting the CI. Secondary endpoints were the pharmacodynamics, pharmacokinetics, AF/AFL symptoms, safety and tolerability of landiolol. At 16 min, HR was reduced in all patients treated with landiolol. The primary endpoint was met by 60% of patients in the CI group and 40% in the B+CI group without a significant group difference. Overall reduction of AF/AFL symptoms at 16 min was 72%. Safety and local tolerability of landiolol were excellent, and no serious adverse events occurred. CONCLUSIONS: Continuous infusion of landiolol with a starting dose of 40 µg/kg/min is suitable for the acute treatment of tachycardic AF/AFL in Caucasian patients. Administration of a preceding bolus seems unnecessary.

Landiolol in patients with septic shock resident in an intensive care unit (LANDI-SEP): study protocol for a randomized controlled trial.

BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017-002138-22 . Registered on 8 August 2017.

Early Clinical Experience with a Newly Designed Interlocking Nail System-Targon(®) Vet.

OBJECTIVE: To describe early clinical experience with a newly designed interlocking nail system (Targon(®) Vet) in diaphyseal fractures in cats and small dogs. STUDY DESIGN: Retrospective case series. ANIMALS: Client-owned cats (n=49) and dogs (n=8). METHODS: Fifty-seven consecutive cases (49 cats, 8 dogs) with 60 long bone fractures were included in the study. Follow-up radiographs were scheduled at 4 and 8 weeks and again 6 months postoperatively. The end point for each case was determined radiographically by a healed fracture. Complications were defined as minor or major. Clinical outcome was subjectively assessed by a full orthopedic examination and follow-up radiographs. Descriptive data are reported. RESULTS: Median age of cats was 18 months (range, 3-220 months) and of dogs was 28 months (range, 7-115 months). Median body weight was 3.7 kg (range, 1.67-8.41 kg) for cats and 8.15 kg (range, 2.68-13.6 kg) for dogs. Median radiographic follow-up was 16 weeks. All fractures with follow-up radiographs available (n=46) were healed with no infections reported. A total of 12 postoperative complications occurred: 3 minor (slippage of the locking screws) and 9 major (5 femoral-irritation of the sciatic nerve, stress protection, fracture because of a missed fissure, femoral neck fracture, intra-operative revision with a rod and plate; 4 tibial-3 with protrusion of the distal locking screw through the skin and 1 with in-growth of the intramedullary nail). CONCLUSION: Implantation of the Targon(®) Vet System was feasible in all cases. It provides an alternative system for diaphyseal fracture repair in cats and small dogs.