Pediatric patients with a malignant bone tumor: when does functional assessment make sense?

Purpose  

The diagnosis of a malignant bone tumor in the lower limb is a risk factor for physical disability, limiting physical performance. Walking ability especially, which is essential for most activities of daily living, is limited in those patients. In the present study, the extent of limitations during the course of treatment was investigated to determine when the assessment of functional parameters is meaningful in those patients.     

Surgical Difficulties Encountered With Use of Modular Endoprosthesis for Limb Preserving Salvage of Failed Allograft Reconstruction After Malignant Tumor Resection

We reviewed outcomes and discussed surgical difficulties encountered in 10 patients who had modular endoprosthesis for limb preserving salvage of failed allograft reconstruction after malignant tumor resection. Mean allograft survival time before failure was 127.4 months (range, 14-264 months). Mean length of follow-up since endoprosthesis revision surgery was 62.8 months (range, 16-132 months). There was one endoprosthesis failure, resulting in a mean endoprosthesis survival time of 56.9 months (range, 16-132). Complications included arterial laceration, nerve injury, periprosthetic crack fracture, aseptic loosening, and infection. Modular endoprosthesis remain a viable option that should be considered in any limb preserving salvage of failed allograft reconstructions. However, altered anatomy, poor/short remnant host bone, periprosthetic fractures, inadequate soft tissue coverage and infection remain important difficulties encountered.     

The primary stability of pelvic reconstruction after partial supraacetabular pelvic resection due to malignant tumours of the human pelvis: A biomechanical in vitro study

BackgroundUp until now, reconstructions after partial supraacetabular pelvic resection have been done with the use of megaprostheses or allo-/autografs, including screws. The literature states complications in up to 100%. Therefore, the university hospital of Muenster has successfully established a reconstruction using poly-axial screws and titanium rods in combination with a Palacos^® shroud. The aim of this study was to gather data on primary stability of five different types of reconstruction.MethodsUsing a biomechanical model Load (N), displacement (mm) and stiffness (N/mm) were recorded in load cycles from 100 N up to 1050 N.FindingsThe data shows that reconstructions with poly-axial screws, titanium rods and Palacos^® can bear a load of up to 1050 N without structural damages. The same is valid with an additional bone graft and for a full metal prosthesis. Referring to reconstructions with just bone graft or without graft and Palacos^® the load-bearing capacity is significantly worse. Additionally, structural damages were recorded in those reconstructions from 700 N onwards.InterpretationDue to the biomechanical results and the save and easy handling, reconstructions with poly-axial screws, titanium rods and Palacos^® (and, if necessary, bone graft) can be recommended achieving high primary stability for pelvic ring reconstruction after partial supraacetabular pelvic resection.     

Distal femur and proximal tibia replacement with megaprosthesis in revision knee arthroplasty: a limb-saving procedure

Purpose

The aim of the present study was to assess whether using megaprostheses in revision knee arthroplasty procedures allows limb salvage with an acceptable outcome and complication rate, in comparison with other limb-saving procedures.

Methods

Between 2000 and 2010, megaprosthesis implantation was required for non-oncologic indications in 20 patients (21 knees) (average age 73 years). Reconstructions involved the distal femur (n = 15), proximal tibia (n = 4), and both femur and tibia (n = 2). The indications, type, and numbers of previous operations and implants, as well as complications associated with megaprosthesis implantation, were reviewed, and the clinical and radiographic outcomes after an average follow-up period of 34 months (range 10–84 months) were evaluated.

Results

The indications for megaprosthesis implantation were periprosthetic infection (n = 5), fracture (n = 9), nonunion (n = 5), and aseptic loosening (n = 2). The types of implant placed before the megaprosthetic reconstruction were a cemented rotating-hinge arthroplasty (n = 16) and a primary total knee arthroplasty (n = 5). Six patients had an additional osteosynthesis of the distal femur. An average of 3.8 operations (range 1–7) had been carried out before megaprosthesis implantation. Complications developed in 11 patients. The Knee Society Score improved significantly, from 43 (±15) to 68 (±16.8); P < 0.05.

Conclusions

Megaprosthesis implantation in revision knee arthroplasty is an exceptional indication. Despite the high complication rate, the patients can be spared amputation in most cases, and rapid mobilization with full weight-bearing is possible.     

Effects of Moderate Hepatic Impairment on the Pharmacokinetic Properties and Tolerability of Umeclidinium and Vilanterol in Inhalational Umeclidinium Monotherapy and Umeclidinium/Vilanterol Combination Therapy: An Open-Label,Nonrandomized Study

Background

The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β₂-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver.

Objectives

The objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg.

Methods

This open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7–9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment.

Results

All 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified.

Conclusions

The administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.     

Activating mutations in the MAP-kinase pathway define non-ossifying fibroma of bone

Non-ossifying fibroma (NOF), which occasionally results in pathologic fracture, is considered the most common benign and self-limiting lesion of the growing skeleton. By DNA sequencing we have identified hotspot KRAS, FGFR1 and NF1 mutations in 48 of 59 patients (81.4%) with NOF, at allele frequencies ranging from 0.04 to 0.61. Our findings define NOF as a genetically driven neoplasm caused in most cases by activated MAP-kinase signalling. Interestingly, this driving force either diminishes over time or at least is not sufficient to prevent autonomous regression and resolution. Beyond its contribution to a better understanding of the molecular pathogenesis of NOF, this study adds another benign lesion to the spectrum of KRAS- and MAP-kinase signalling-driven tumours. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Structural basis for allosteric cross-talk between the asymmetric nucleotide binding sites of a heterodimeric ABC exporter

ATP binding cassette (ABC) transporters mediate vital transport processes in every living cell. ATP hydrolysis, which fuels transport, displays positive cooperativity in numerous ABC transporters. In particular, heterodimeric ABC exporters exhibit pronounced allosteric coupling between a catalytically impaired degenerate site, where nucleotides bind tightly, and a consensus site, at which ATP is hydrolyzed in every transport cycle. Whereas the functional phenomenon of cooperativity is well described, its structural basis remains poorly understood. Here, we present the apo structure of the heterodimeric ABC exporter TM287/288 and compare it to the previously solved structure with adenosine 5′-(β,γ-imido)triphosphate (AMP-PNP) bound at the degenerate site. In contrast to other ABC exporter structures, the nucleotide binding domains (NBDs) of TM287/288 remain in molecular contact even in the absence of nucleotides, and the arrangement of the transmembrane domains (TMDs) is not influenced by AMP-PNP binding, a notion confirmed by double electron-electron resonance (DEER) measurements. Nucleotide binding at the degenerate site results in structural rearrangements, which are transmitted to the consensus site via two D-loops located at the NBD interface. These loops owe their name from a highly conserved aspartate and are directly connected to the catalytically important Walker B motif. The D-loop at the degenerate site ties the NBDs together even in the absence of nucleotides and substitution of its aspartate by alanine is well-tolerated. By contrast, the D-loop of the consensus site is flexible and the aspartate to alanine mutation and conformational restriction by cross-linking strongly reduces ATP hydrolysis and substrate transport.ABC exporters are found in every organism (1, 2). They minimally consist of four domains and exist as homodimers or heterodimers. Two transmembrane domains (TMDs) span the membrane with a total of 12 transmembrane helices and form the substrate permeation pathway by alternating between inward- and outward-oriented states (Fig. S1A). A pair of nucleotide binding domains (NBDs) is connected to the TMDs via coupling helices and drive conformational cycling of the transporter by binding and hydrolysis of ATP, a process which is linked to NBD dimerization and dissociation (3).In their closed state, the NBDs sandwich two ATP molecules at the dimer interface by composite ATP binding sites involving conserved sequence motifs contributed by both subunits (4, 5). The A-loop and Walker A motif of one NBD and the ABC signature motif of the opposite NBD are involved in nucleotide binding. The Walker B glutamate and the switch-loop histidine constitute a catalytic dyad required for ATP hydrolysis (6, 7). In heterodimeric ABC exporters with asymmetric ATP binding sites, these catalytic residues are noncanonical at the degenerate site and ATP is therefore primarily, if not exclusively, hydrolyzed at the consensus site (8). The Q- and D-loops were associated with interdomain communication (3, 9–11), but their functional role remains poorly understood.Recently, we reported the structure of the heterodimeric ABC exporter TM287/288 from the thermophilic bacterium Thermotoga maritima, which was crystallized in the presence of adenosine 5′-(β,γ-imido)triphosphate (AMP-PNP) and was shown to transport drugs and dyes when expressed in Lactococcus lactis (12). The transporter adopted an inward-facing state with a nucleotide bound exclusively to the degenerate site. In contrast to the inward-oriented structures of MsbA (13), ABCB10 (14), and P-glycoprotein (15–17) in which the NBDs are separated or twisted (18), we found that the NBDs of TM287/288 remain in close contact and do not shift in the NBD dimerization plane (Fig. S1). The current transport mechanism of TM287/288 envisages the binding of a second nucleotide to the consensus site for the transition to the outward-facing NBD-closed state, which subsequently is hydrolyzed to permit resetting of the transporter (12).Here, we present the high-resolution structure of the nucleotide-free state of TM287/288. Despite high ATP concentrations in the cell, this state is transiently adopted during transport; at the consensus site, the hydrolysis product ADP is replaced by ATP in each transport cycle, and at the degenerate site, the bound nucleotide is occasionally exchanged. We show that the asymmetric NBDs of TM287/288 remain in contact even in the absence of nucleotides. By comparing the apo state with the AMP-PNP–bound structure, we unravel the structural basis for allosteric coupling between the ATP binding sites.     

Early decrements in bone density after completion of neoadjuvant chemotherapy in pediatric bone sarcoma patients

Background  

Bone mineral density (BMD) accrual during childhood and adolescence is important for attaining peak bone mass. BMD decrements have been reported in survivors of childhood bone sarcomas. However, little is known about the onset and development of bone loss during cancer treatment. The objective of this cross-sectional study was to evaluate BMD in newly diagnosed Ewing's and osteosarcoma patients by means of dual-energy x-ray absorptiometry (DXA) after completion of neoadjuvant chemotherapy.