Conjunctival Leiomyosarcoma, a Rare Neoplasm Always Originating at the Limbus? Report of a New Case and Review of 11 Published Cases.

PURPOSE OF THE STUDY: To describe the differential diagnosis and management of a rare conjunctival malignancy. PROCEDURES: A 79-year-old man presented with a conjunctival mass at the limbus. Excisional biopsy revealed a malignant mesenchymal tumor with myogenic differentiation. Six months later, three suspect lesions developed at the border of the previous excision. Pathological diagnosis pointed to a leiomyosarcoma. Adjuvant radiotherapy with strontium-90 brachytherapy was applied. After 3 years, there was neither recurrence nor distant metastases. A literature review revealed 11 cases of conjunctival leiomyosarcoma. RESULTS: All 12 cases seemed to originate at the limbal conjunctiva. Scleral invasion was found only in one patient with multiple previous resections. Corneal invasion was reported in two patients. Four patients had a globe-sparing resection. In two of them, margins were not tumor free and additional brachytherapy gave a tumor-free follow-up of 1 and 3 years. Four cases underwent an exenteration. CONCLUSION AND MESSAGE: Primary conjunctival leiomyosarcoma is a rare tumor with a favorable prognosis due to early detection and consequently limited size. Diagnosis involves histopathological investigation including immunohistochemistry. If possible, complete resection has the best prognosis. Adjunctive radiotherapy can be effective when the margins are not free and should be considered.

Posterior malleolar fracture morphology determines outcome in rotational type ankle fractures.

INTRODUCTION: Rotational type ankle fractures with a concomitant fracture of the posterior malleolus are associated with a poorer clinical outcome as compared to ankle fractures without. However, clinical implications of posterior malleolar (PM) fracture morphology and pattern have yet to be established. Many studies on this subject report on fragment size, rather than fracture morphology based on computed tomography (CT). The overall purpose of the current study was to elucidate the correlation of PM fracture morphology and functional outcome, assessed with CT imaging and not with -unreliable- plain radiographs. METHODS: Between January 2010 and May 2014, 194 patients with an operatively (ORIF) treated ankle fracture, were prospectively included in the randomized clinical EF3X-trial at our Level-I trauma center. The current study retrospectively included 73 patients with rotational type ankle fractures and concomitant fractures of the posterior malleolus. According to the CT-based Haraguchi fracture morphology, all patients were divided into three groups: 20 Type I (large posterolateral-oblique), 21 Type II (transverse medial-extension) and 32 Type III (small-shell fragment). At 12 weeks, 1 year and 2 years postoperatively the Foot and Ankle Outcome Scores (FAOS) and SF-36 scores were obtained, with the FAOS domain scores at two years postoperative as primary study outcome. Statistical analysis included a multivariate regression and secondary a mixed model analysis. RESULTS: Haraguchi Type II PM ankle fractures demonstrated significantly poorer outcome scores at two years follow-up compared to Haraguchi Types I and III. Mean FAOS domain scores at two years follow-up showed to be significantly worse in Haraguchi Type II as compared to Type III, respectively: Symptoms 48.2 versus 61.7 (p = 0.03), Pain 58.5 versus 84.4 (p < 0.01), Activities of Daily Living (ADL) 64.1 versus 90.5 (p < 0.01). CONCLUSION: Posterior malleolar ankle fractures with medial extension of the fracture line (i.e. Haraguchi Type II) are associated with significantly poorer functional outcomes. The current dogma to fix PM fractures that involve at least 25-33% of the tibial plafond may be challenged, as posterior malleolar fracture pattern and morphology - rather than fragment size - seem to determine outcome.

The correlation between intra-operative 2D- and 3D fluoroscopy with postoperative CT-scans in the treatment of calcaneal fractures.

OBJECTIVES: The aim of this study was to determine the correlation of the intra-operative fluoroscopic 2D- and 3D-images compared with a postoperative CT-scan, in terms of quality of reduction and fixation of calcaneal fractures. METHODS: Patients requiring open reduction and internal fixation (ORIF) of a calcaneal fracture were recruited as part of the EF3X-trial. During surgery, intra-operative images of fluoroscopic 2D- and 3D-imaging were obtained to assess the quality of the reduction and implant position. All patients received a postoperative CT-scan within one week. The operating surgeon evaluated intra-operatively both 2D- and 3D-images according to a 23-item scoring protocol on a 3-point Likert scale. A scoring panel, consisting of three clinical experts, evaluated all images in a blinded and independent fashion. Intraclass correlation coefficients (ICC) with their 95% confidence intervals (CI) were calculated using a two-way-random model with absolute agreement. RESULTS: A total of 102 calcaneal fractures were included. Agreement of 3D-imaging for the quality of reduction was better than 2D-imaging, although still fair, but for fixation moderate to good. Agreement between the 2D-images and the CT-scans was poor to fair. Intra-operative 2D-imaging received the highest ratings for image quality and interpretability, followed by CT-scanning. CONCLUSION: Implant position can be evaluated satisfactory with the aid of intra-operative 3D imaging. Although intra-operative 3D imaging had a better agreement with postoperative CT-scanning than 2D-imaging, there is a need to improve image quality and suppress scattering from implants to improve the additional value of intra-operative 3D imaging in calcaneal fracture reduction and fixation.

Systematic CT evaluation of reduction and hardware positioning of surgically treated calcaneal fractures: a reliability analysis.

INTRODUCTION: Up to date, there is a lack of reliable protocols that systematically evaluate the quality of reduction and hardware positioning of surgically treated calcaneal fractures. Based on international consensus, we previously introduced a 23-item scoring protocol evaluating the reduction and hardware positioning in these fractures based on postoperative computed tomography. The current study is a reliability analysis of the described scoring protocol. METHODS: Three raters independently and systematically evaluated anonymized postoperative CT scans of 102 surgically treated calcaneal fractures. A selection of 25 patients was scored twice by all individual raters to calculate intra-rater reliability. The scoring protocol consisted of 23 items addressing quality of reduction and hardware positioning. Each of these four-option questions was answered as: 'optimal', 'suboptimal (but not needing revision)', 'not acceptable (needing revision)' or 'not judgeable'. We used intraclass correlation coefficients (ICC's) to calculate inter- and intra-rater reliability. RESULTS: Inter-rater reliability of the overall 23-item protocol was good (ICC 0.66, 95% CI 0.64-0.69). Individual items that scored an inter-rater ICC ≥0.60 included evaluation of the calcaneocuboid joint, the posterior talocalcaneal joint, the anterior talocalcaneal joint, the position of the plate and sustentaculum screws and screws protruding the tuber and medial wall. The intra-rater reliability for the overall protocol was good for all three individual raters with ICC's between 0.60 and 0.70. CONCLUSION: Our scoring protocol for the radiological evaluation of operatively treated calcaneal fractures is reliable in terms of inter- and intra-rater reliability.

New Paradigm for Translational Modeling to Predict Long-term Tuberculosis Treatment Response.

Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology. Simulations of recent trials testing 4-month regimens predicted 65% (95% confidence interval [CI], 55-74) relapse-free patients vs. 80% observed in the REMox-TB trial, and 79% (95% CI, 72-87) vs. 82% observed in the Rifaquin trial. Simulation of 6-month regimens predicted 97% (95% CI, 93-99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials.

Epidemiology of extremity fractures in the Netherlands.

INTRODUCTION: Insight in epidemiologic data of extremity fractures is relevant to identify people at risk. By analyzing age- and gender specific fracture incidence and treatment patterns we may adjust future policy, take preventive measures and optimize health care management. Current epidemiologic data on extremity fractures and their treatment are scarce, outdated or aiming at a small spectrum of fractures. The aim of this study was to assess trends in incidence and treatment of extremity fractures between 2004 and 2012 in relation to gender and age. METHODS: We used a combination of national registries of patients aged ≥ 16 years with extremity fractures. Fractures were coded by the International Classification of Diseases (ICD) 10, and allocated to an anatomic region. ICD-10 codes were used for combining the data of the registries. Absolute numbers, incidences, number of patients treated in university hospitals and surgically treated patients were reported. A binary logistic regression was used to calculate trends during the study period. RESULTS: From 2004 to 2012 the Dutch population aged ≥16 years grew from 13,047,018 to 13,639,412 inhabitants, particularly in the higher age groups of 46 years and older. The absolute number of extremity fractures increased significantly from 129,188 to 176,129 (OR 1.308 [1.299-1.318]), except for forearm and lower leg fractures. Incidences increased significantly (3-4%) for wrist, hand/finger, hip/upper leg, ankle and foot/toe fractures. In contrast to the older age categories from 66 years and older, in younger age categories from 16 to 35 years, fractures of the extremities were more frequent in men than in women. Treatments gradually moved towards non-university hospitals for all except forearm fractures. Both relative and absolute numbers increased for surgical treatments of clavicle/shoulder, forearm, wrist and hand/finger fractures. Contrarily, lower extremity fractures showed an increase in non-surgical treatment, except for lower leg fractures. CONCLUSION: During the study period, we observed an increasing incidence of extremity fractures and a shift towards surgical treatment. Patient numbers in university hospitals declined. If these trends continue, policy makers would be well advised to consider the changing demands in extremity fracture treatment and pro-actively increase capacity and resources.

Three-dimensional virtual planning of corrective osteotomies of distal radius malunions: a systematic review and meta-analysis.

The purpose of this study was to summarize and evaluate results of three-dimensional (3D-) planned corrective osteotomies of malunited distal radius fractures. 3D-planning techniques provide the possibility to address 3D-deformity that conventional planning methods might not address. We systematically searched PubMed, EMBASE and the Cochrane library for studies that performed a 3D-planned corrective osteotomy on patients with a malunited distal radius fracture. Fifteen studies with a total of 68 patients were included in the analysis. In 96% of cases, the preoperatively present palmar tilt, radial inclination and ulnar variance showed statistically significant improvement postoperatively with restoration to within 5° or 2 mm of their normal values. Mean flexion-extension, pro-supination and grip strength showed statistically significant improvement (p < 0.05). Complications were reported in 11 out of 68 patients (16%). With the current advances in 3D printing technology, 3D-planned corrective osteotomies seem a promising technique in the treatment of complex distal radius malunions. Level of evidence IV Systematic review of case series, Level IV.

"Turn laterally to the left!". The need for uniform C-arm communication terminology during orthopaedic trauma surgery.

To avoid disturbed teamwork, unnecessary radiation exposure, and procedural delays, we designed and tested a uniform communication language for use in fluoroscopy-assisted surgical procedures. Input of surgeons and radiographers was used to create a set of commands. The potential benefit of this terminology was explored in an experimental setting. There was a tremendous diversity in the currently used terminology. Use of the newly designed terminology showed a reduction of procedural time and amount of images needed. Our first standardized Dutch language terminology can reduce total fluoroscopy time, number of images acquired, and potentially radiation exposure. For Dutch speaking colleagues, the developed terminology is freely available for use in their OR.

Computer-assisted 3D planned corrective osteotomies in eight malunited radius fractures.

In corrective osteotomy of the radius, detailed preoperative planning is essential to optimising functional outcome. However, complex malunions are not completely addressed with conventional preoperative planning. Computer-assisted preoperative planning may optimise the results of corrective osteotomy of the radius. We analysed the pre- and postoperative radiological result of computer-assisted 3D planned corrective osteotomy in a series of patients with a malunited radius and assessed postoperative function. We included eight patients aged 13-64 who underwent a computer-assisted 3D planned corrective osteotomy of the radius for the treatment of a symptomatic radius malunion. We evaluated pre- and postoperative residual malpositioning on 3D reconstructions as expressed in six positioning parameters (three displacements along and three rotations about the axes of a 3D anatomical coordinate system) and assessed postoperative wrist range of motion. In this small case series, dorsopalmar tilt was significantly improved (p = 0.05). Ulnoradial shift, however, increased by the correction osteotomy (6 of 8 cases, 75 %). Postoperative 3D evaluation revealed improved positioning parameters for patients in axial rotational alignment (62.5 %), radial inclination (75 %), proximodistal shift (83 %) and volodorsal shift (88 %), although the cohort was not large enough to confirm this by statistical significance. All but one patient experienced improved range of motion (88 %). Computer-assisted 3D planning ameliorates alignment of radial malunions and improves functional results in patients with a symptomatic malunion of the radius. Further development is required to improve transfer of the planned position to the intra-operative bone. Level of evidence IV.

Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice.

BACKGROUND: Infliximab (IFX) is effective in the treatment of inflammatory bowel diseases (IBD). Currently, IFX is administered at fixed doses and intervals; however, costs are high and optimisation is necessary. Several publications indicate that IFX should be dosed on trough levels ≥3.0 mg/L. For optimising IFX dosing, the use of a pharmacokinetic model is important. Population pharmacokinetics of IFX have been described earlier; however, these models were not used for dose optimising. AIMS: To develop a pharmacokinetic model for IFX in IBD patients that can be used for dose-optimisation of IFX and to predict serum trough levels in this population. METHODS: An observational retrospective study was performed in 42 IFX-treated IBD patients. Serum samples were drawn before infusion at T = 0, 2, 6, 14, 22 and 54 weeks and analysed for IFX and antibodies against IFX (ATI). Relevant covariates were recorded and a population pharmacokinetic model was developed. RESULTS: Individual plots created using the final model showed good correspondence between observed and model predicted values. Serum levels were influenced by ATI, disease activity, sex and albumin. Our results show that in patients without ATI target trough levels ≥3.0 mg/L can be achieved by increasing dosing intervals from 8 to 12 weeks combined with a dose increase. This results in a reduction of 33% in concomitant costs. CONCLUSIONS: In IBD patients without ATI, trough level dosing based on longer intervals can reduce IFX therapy-related visits to the hospital with one-third. Trough level based dose intensification should always be justified by disease activity parameters.

Modeling and Simulation Workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose.

Several software tools are available that facilitate the use of the NONMEM software and extend its functionality. This tutorial shows how three commonly used and freely available tools, Pirana, PsN, and Xpose, form a tightly integrated workbench for modeling and simulation with NONMEM. During the tutorial, we provide some guidance on what diagnostics we consider most useful in pharmacokinetic model development and how to construct them using these tools.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e50; doi:10.1038/psp.2013.24; advance online publication 26 June 2013.

Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor®): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety.

From 1997, plasma-derived C1-inhibitor concentrate (Cetor®) has been available to HAE and AAE patients. Recently, a virus reducing 15 nm nanofiltration step has been introduced in the production process. A randomized, double-blind controlled cross-over study was performed to compare the pharmacokinetics (PK) of nanofiltered (C1-INH-NF) with conventional C1-inhibitor (C1-INH). Efficacy and safety were investigated in an open-label, on-demand and a prophylactic study. No differences in pharmacokinetic parameters between C1-INH and C1-INH-NF were found (13 non-symptomatic HAE patients). Both C1-inhibitor products equally increased plasma C4 levels. In the on-demand study, 14 acute angioedema attacks in 8 patients were analyzed. In the prophylactic study, 1 AAE and 5 HAE patients experienced in total 31 attacks during 748 observation days. In total 180,000 units of C1-INH-NF were administered. No product-related adverse events occurred, and no anti-C1-antibodies were induced. Nanofiltration in the production process of C1-inhibitor did not affect the pharmacokinetics, efficacy, and safety.

Chromosomal aberrations in iris melanomas.

BACKGROUND: Uveal melanomas can develop in the choroid, ciliary body and iris. In choroidal and ciliary body melanomas, specific chromosomal changes correlate with metastatic disease. Iris melanomas have a better prognosis than choroidal melanomas, and it would be interesting to know if they share chromosomal changes. In addition, iris melanomas might harbour UV-induced mutations of tumour suppressor genes, such as PTEN and CDKN2A. METHODS: Twenty iris melanomas were analysed for chromosome 1p, 3, 6, 8, 9p and 10q abnormalities using fluorescence in situ hybridisation. These results were correlated to clinical follow-up data using statistical analyses. RESULTS: (Partial) loss of chromosome 3 was observed in nine iris melanomas, and gain of 8q was present in seven tumours. Loss of chromosome 9p was demonstrated in seven tumours, but no deletions of the PTEN region on chromosome 10 were found. Three patients died of metastatic disease, and one patient developed liver metastases, but is still alive. Univariate analysis indicated a lower disease-free survival for patients with diffuse growing melanomas (p=0.01), melanomas that lost a copy of chromosome 3 (p=0.03), or invading the ciliary body (p=0.01). In a multivariate analysis, none of the correlations were significant. CONCLUSION: Loss of chromosome 3 as well as loss of chromosomal region 9p21 (that entails tumour suppressor gene CDKN2A) plays a role in iris melanoma. A firm correlation with disease-free survival could not be established, possibly due to the small sample size.

Epistaxis or epiphora as a sign for extension of a conjunctival melanoma. A series of six patients with nasolacrimal recurrence.

PURPOSE: To characterise malignant conjunctival melanomas with extension and recurrence in the nasolacrimal system. METHODS: Localisation of the primary tumour and recurrences of 210 conjunctival melanomas treated in The Netherlands were reviewed for orbital and nasal tumours (1978-2008). Based of these cases and literature data, characteristics for nasolacrimal system extension and metastasis were reviewed. RESULTS: Six patients (3%) showed a recurrence of the primary conjunctival melanoma in the nasolacrimal system. Two of the six primary tumours were limbal tumours; the other four were diffuse tumours involving the fornix. In all six patients, the primary conjunctival melanomas were associated with primary acquired melanosis. During the follow-up period (11.6±3 years, range 3.4-28.5 years, median 8.7 years) two patients developed metastases and died. CONCLUSIONS: Patients should be advised to contact their treating ophthalmologist in the case of symptoms of epiphora, nose obstructions and epistaxis, especially non-bulbar and diffuse cases associated with primary acquired melanosis.

IL-10 promotor haplotypes associated with susceptibility to and severity of bacterial corneal ulcers.

Interleukin-10 plays an important role in modulating inflammation and antimicrobial defences. In animal models for bacterial corneal ulcers, high IL-10 levels were associated with a better clinical outcome. We investigated whether IL-10 promotor haplotypes, known to determine IL-10 expression in vitro, are associated with susceptibility to and/or clinical outcome of bacterial corneal ulcers in patients. IL-10 promotor polymorphisms C-819T, G-1082A, A-2763C, and A-2849G for 83 patients with bacterial corneal ulcers and 115 healthy controls were determined by restriction fragment length PCR analysis. For 63 patients and all healthy controls the most frequently occurring IL-10 promotor haplotypes were inferred from these data using the program SNPHAP. A significant underrepresentation of the A-2849A genotype was observed in patients as compared to healthy controls. Both the -2763A allele and the IL-10.1 promotor haplotype were associated with a poor clinical outcome, whereas a favourable clinical outcome was seen in patients carrying the IL-10.2 promotor haplotype. Together, IL-10 promotor haplotypes associated with low IL-10 levels seem to protect against the onset of bacterial corneal ulcers. Once a corneal ulcer has developed, patients carrying IL-10 haplotypes associated with a high IL-10 expression may have a favourable outcome.

Cutaneous allergy testing in patients suspected of an allergic reaction to eye medication.

PURPOSE: Our aim was to determine the usefulness of allergy testing in patients with possible allergic reactions to an eye medication. METHODS: This retrospective study analyzed the usefulness of allergy testing in 90 patients who on the basis of their complaints were under suspicion of having an allergic response to eye medication. RESULTS: Among the 90 patients suspected of an allergic reaction to eye medication, the most common complaint was itching, while hyperemic conjunctivae were the most common symptom. Skin testing revealed an allergy to eye medication in 32 (36%) of the patients tested, which seemed to be the causal factor of the complaints in 22 cases (24%). The most frequent medication-associated allergies were directed against tobramycin, neomycin sulfate and thimerosal. Clinically relevant non-drug-related allergies occurred in 26 cases and were directed against nickel sulfate, Myroxylon pereirae and fragrance mix. Twenty-three patients were atopic and had positive skin prick tests against inhalation allergens such as house dust mites or dogs. CONCLUSION: Allergy testing was helpful to obtain a diagnosis of a clinically relevant allergy in 48 of the 90 patients who were referred under suspicion of having a contact allergy to eye medication.