Tranexamic acid to reduce bleeding after dental extraction in patients treated with non-vitamin K oral anticoagulants: design and rationale of the EXTRACT-NOAC trial.

Bleeding after dental extraction in patients treated with non-vitamin K oral anticoagulants (NOAC) may lead to unplanned reinterventions and interruption of anticoagulation, thereby exposing patients to a risk of thromboembolism. We have designed a study (EXTRACT-NOAC) to investigate whether tranexamic acid (TXA) mouthwash decreases bleeding after extraction in such patients. The study is a randomised, double-blind, placebo-controlled trial. We plan to randomise 236 patients listed for dental extraction and treated with NOAC to 10% TXA mouthwash or placebo. Patients are instructed to use the mouthwash before the dental extraction, and three times a day for three days thereafter. The primary outcome is oral bleeding. Secondary outcomes include type of bleeding, procedural bleeding score, number of reinterventions after oral bleeding, and number of interruptions in NOAC treatment. Any bleeding from sources other than the mouth, and thrombotic events, are recorded as safety outcomes. Patients are followed-up for seven days. This study will provide evidence to guide the management of patients taking NOAC who need teeth extracted.

Reamer-Irrigator-Aspirator bone graft harvesting for treatment of segmental bone loss: analysis of defect volume as independent risk factor for failure.

INTRODUCTION: The management of segmental bone loss poses a significant clinical challenge. The purpose of this study was to conduct a retrospective evaluation of our experience in treating segmental bone loss, using Reamer-Irrigator-Aspirator (RIA)-harvested autologous bone graft. MATERIALS AND METHODS: Between June 2008 and March 2015, 81 patients were treated with the RIA technique for multiple purposes. Inclusion criteria for this study were skeletal mature patients with segmental bone loss, due to acute trauma or non-union, who were treated with RIA-harvested bone graft. Exclusion criteria were skeletal immaturity, pathological fractures and indications for the RIA system other than bone graft harvesting. The primary outcome parameter was clinical and radiographical bone healing. RESULTS: During the study period, 72 patients met the inclusion criteria. In total, 39 patients (54.2%) were classified as having clinical and radiographical bone healing. Although univariate analysis could not reveal any significant influence of specific risk factors to predict the outcome, there was a trend towards statistical significance for defect volume. Further analysis indeed revealed that smaller defect volumes (< 8 cm3) had a lower risk of non-union. CONCLUSIONS: In approximately half of our study population, the use of the RIA technique for autologous bone graft harvesting in cases of segmental bone loss resulted in a successful outcome with bone healing. Defect size seems to be a critical issue regarding the outcome. Although our results are less promising than previously published, the RIA technique has its place in the treatment algorithm of segmental bone defects.

Short- and medium-term outcomes following primary ileocaecal resection for Crohn's disease in two specialist centres.

BACKGROUND: Despite improvements in medical therapy, the majority of patients with Crohn's disease still require surgery. The aim of this study was to report safety, and clinical and surgical recurrence rates, including predictors of recurrence, after ileocaecal resection for Crohn's disease. METHODS: This was a cohort analysis of consecutive patients undergoing a first ileocaecal resection for Crohn's disease between 1998 and 2013 at one of two specialist centres. Anastomotic leak rate and associated risk factors were assessed. Kaplan-Meier estimates were used to describe long-term clinical and surgical recurrence. Univariable and multivariable regression analyses were performed to identify risk factors for both endpoints. RESULTS: In total, 538 patients underwent primary ileocaecal resection (40·0 per cent male; median age at surgery 31 (i.q.r. 24-42) years). Median follow-up was 6 (2-9) years. Fifteen of 507 patients (3·0 per cent) developed an anastomotic leak. An ASA fitness grade of III (odds ratio (OR) 4·34, 95 per cent c.i. 1·12 to 16·77; P = 0·033), preoperative antitumour necrosis factor therapy (OR 3·30, 1·09 to 9·99; P = 0·035) and length of resected bowel specimen (OR 1·06, 1·03 to 1·09; P < 0·001) were significant risk factors for anastomotic leak. Rates of clinical recurrence were 17·6, 45·4 and 55·0 per cent after 1, 5 and 10 years respectively. Corresponding rates of requirement for further surgery were 0·6, 6·5 and 19·1 per cent. Smoking (hazard ratio (HR) 1·67, 95 per cent c.i. 1·14 to 2·43; P = 0·008) and a positive microscopic resection margin (HR 2·16, 1·46 to 3·21; P < 0·001) were independent risk factors for clinical recurrence. Microscopic resection margin positivity was also a risk factor for further surgery (HR 2·99, 1·36 to 6·54; P = 0·006). CONCLUSION: Ileocaecal resection achieved durable medium-term remission, but smoking and resection margin positivity were risk factors for recurrence.

Risk factors for nonunion after intramedullary nailing of femoral shaft fractures: Remaining controversies.

INTRODUCTION: Intramedullary nailing (IMN) is the preferred treatment for femoral shaft fractures in adults. Although previous studies published good outcomes, some controversies remain. The purpose of this retrospective study was to identify factors that influence outcome after IMN for femoral shaft fractures. MATERIALS AND METHODS: Between July 1998 and July 2013, we treated 230 patients with 248 femoral shaft fractures. Statistical analyses were performed to determine predictors of nonunion. The following set of variables was selected based on the speculation that they would contribute to the outcome: sex (male or female), smoking, obesity, polytrauma, fracture type, open fractures, Gustilo type, primary external fixation (EF) and reaming. RESULTS: Initial fracture stabilization was performed by IMN in 161 (64.9%) and by EF in 87 (35.1%) fractures. There were no documented cases of deep infection. Nonunion was diagnosed in 27 patients with 28 fractures (11.3%). Factors affecting nonunion in the univariate analysis were Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) fracture type (odds ratio [OR] 25.0; p<0.0001), Gustilo type (OR 0.64; p=0.0358), and EF (OR 0.42; p=0.0401). Multiple logistic regression analysis only identified AO/OTA fracture type (OR 22.0; p<0.0001) as a risk factor for nonunion. Fracture reaming did not change the outcome (OR 0.80; p=0.6073). A separate analysis showed that damage control EF was not a risk factor in polytrauma patients (OR 0.76; p=0.5825). CONCLUSIONS: Fracture stabilisation with IMN is a good treatment option for femoral shaft fractures in adults. The purpose of this study was to evaluate risk factors of poor outcome after IMN of femoral shaft fractures. The present analysis revealed that there was no difference in the outcome whether the fracture was reamed or not. Univariate and multivariate analysis could only correlate AO/OTA fracture type with the occurrence of nonunion. Therefore, in this study, unreamed nailing and damage control EF were not associated with a negative outcome.

The rs1800716 variant in CYP2D6 is associated with an increased double endometrial thickness in postmenopausal women on tamoxifen.

BACKGROUND: Tamoxifen remains important in the treatment and prevention of estrogen receptor-positive breast cancer. In postmenopausal women, it can lead to endometrial changes such as cystic appearances, hyperplasia, polyps and endometrial cancer. Tamoxifen is metabolized by cytochrome P450 (CYP450) enzymes to the more active metabolite endoxifen. Several genetic variants in the CYP450 enzymes reduce tamoxifen metabolism, leading to reduced endoxifen levels. We hypothesize that carriers of these variants, which are established poor metabolizers of tamoxifen, do not have the typical tamoxifen-induced increase in endometrial thickness. We test the association between genetic variability in CYP450 enzymes and the increase in double endometrial thickness (DET) as measured through transvaginal ultrasound (TVU). PATIENTS AND METHODS: We carried out a retrospective study on postmenopausal tamoxifen users for which germline DNA was available and at least one DET measurement was made between January 2000 and October 2011. Genotyping of 33 single nucleotide polymorphisms in CYP450 genes involved in tamoxifen metabolism was carried out using Sequenom MassARRAY. The association between these variants and TVU outcome (DET ≥5 mm) was assessed by proportional hazards regression. RESULTS: Data were available for 184 women: 47 with a DET of <5 mm on all ultrasounds and 137 with a DET of ≥5 mm on at least one ultrasound. The rs1800716 variant in CYP2D6 showed a statistically significant association with DET. In particular, mutant carriers of rs1800716 had an increased chance of having a DET of ≥5 mm (P = 0.0022, false discovery rate 0.0179). None of the other variants were associated with DET. CONCLUSION: Although mutant carriers of rs1800716 are characterized by reduced CYP2D6 enzyme activity and by low levels of endoxifen, we observed that mutant alleles of rs1800716 were associated with an increased chance of having a DET of ≥5 mm in postmenopausal women on tamoxifen. We conclude that the increase in endometrial thickness seen under tamoxifen cannot be used as a marker for favorable genotypes. CLINICAL TRIAL NUMBER: B32220084284.

Association between recent herpes zoster but not herpes simplex infection and subsequent risk of malignancy in women: a retrospective cohort study.

The association between herpes zoster and subsequent cancer risk is still unclear. Consequently, doubts remain regarding the need for investigation of herpes patients for co-existing or subsequent malignancy. This is a retrospective cohort study comparing cancer risk in patients after herpes zoster and age-/sex-matched non-herpes zoster patients, in a primary care-based continuous morbidity database. We tested for interaction by gender, age, diabetes, HRT use or antiviral therapy. Analyses were repeated for patients with and without herpes simplex. The hazard ratio (HR) comparing cancer risk in herpes zoster vs. control patients was significant in all women, women aged > 65 years and subgroups of breast and colorectal cancer (HRs 1·60, 1·82, 2·14, 2·19, respectively). For men, a significant association was found for haematological cancers (HR 2·92). No associations were found with herpes simplex. No interaction was identified with antiviral therapy, diabetes or HRT treatment. We concluded that there was a moderate significant association between herpes zoster and subsequent cancer risk in women aged > 65 years, without any influence of antiviral therapy. No association was found with herpes simplex. There is insufficient reason for extensively testing older patients with herpes zoster or herpes simplex for the presence of occult cancer.

Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC).

BACKGROUND: To assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy. PATIENTS AND METHODS: Twenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end points). RESULTS: Carriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38). CONCLUSION: Genetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.

Catheter-directed thrombolysis with microplasmin for acute peripheral arterial occlusion (PAO): an exploratory study.

AIM: We performed an open-label, dose-ascending, single-centre, Phase IIa study to explore the safety and efficacy of catheter-directed thrombolysis (CDT) with microplasmin for infrainguinal arterial or bypass occlusions. METHODS: Patients who presented with acute occlusions were subsequently treated with an intrathrombus infusion of five ascending doses of microplasmin: 0.3 mg/kg/h for 4 hours; 0.45 mg/kg/h for 4 hours; 0.6 mg/kg/h for 4 hours; 0.9 mg/kg/h for 4 hours or 0.6 mg/kg/h for 6 hours. Repeat angiograms were obtained to assess the degree of clot lysis. The primary outcome was complete thrombolysis defined as >95% thrombus volume reduction at the end of the microplasmin infusion. Safety evaluation included bleedings, adverse events and coagulation biomarkers. RESULTS: Complete thrombolysis was obtained in 3 of the 19 treated patients at the end of microplasmin infusion. Thrombus volume reduction between 50% and 95% was achieved with all dosing regimens. Clinically significant distal embolization occurred in 8 patients. One major and two non-major bleedings occurred. Microplasmin depleted α2-anti-plasmin and decreased fibrinogen. CONCLUSION: Intrathrombus infusion of microplasmin for 4 or 6 hours resulted in significant clot lysis. Distal embolization appeared the most important limitation.

Willems II. Non-gender-specific dental maturity scores.

Demirjian's dental maturity scoring system has been adapted for a Belgian Caucasian population for males and females. The purpose of this study was to adapt Demirjian's dental maturity scoring system from a Belgian Caucasian population to provide non-gender-specific scores. We selected 2116 orthopantomograms of 1029 boys and 1087 girls aged 3-16 years. A weighted ANOVA was performed in order to adapt the scoring system for this Belgian population. A second test sample of 273 orthopantomograms of individuals with immature dentitions aged 3-16 years was used to evaluate the accuracy of the original method, gender-specific scores and non-gender-specific scores of the adapted method. Mean/median difference between dental age and real age was calculated as well as other measures of accuracy. The adapted scoring system resulted in new age scores expressed in years and in a higher accuracy compared to the original method in Belgian Caucasians.