Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma.

BACKGROUND: Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma. METHODS: In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy. RESULTS: Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p < .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response. CONCLUSIONS: Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

Prescription of therapeutic exercise in migraine, an evidence-based clinical practice guideline.

The main objective of this clinical practice guideline is to provide a series of recommendations for healthcare and exercise professionals, such as neurologists, physical therapists, and exercise physiologists, regarding exercise prescription for patients with migraine.This guideline was developed following the methodology and procedures recommended in the Appraisal of Guidelines for Research and Evaluation (AGREE). The quality of evidence and strength of recommendations were evaluated with the Scottish Intercollegiate Guidelines Network (SIGN). A systematic literature review was performed and an established appraisal process was employed to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology).The evaluation of the current evidence, the elaboration of the grades of recommendation, and their validation show a B grade of recommendation for aerobic exercise, moderate-continuous aerobic exercise, yoga, and exercise and lifestyle recommendations for the improvement of symptoms, disability, and quality of life in patients with migraine. Relaxation techniques, high-intensity interval training, low-intensity continuous aerobic exercise, exercise and relaxation techniques, Tai Chi, and resistance exercise obtained a C grade of recommendation for the improvement of migraine symptoms and disability.

Group augmentation on trial: helpers in small groups enhance antipredator defence of eggs.

Mechanisms selecting for the evolution of cooperative breeding are hotly debated. While kin selection theory has been the central paradigm to explain the seemingly altruistic behaviour of non-reproducing helpers, it is increasingly recognized that direct fitness benefits may be highly relevant. The group augmentation hypothesis proposes that alloparental care may evolve to enhance group size when larger groups yield increased survival and/or reproductive success. However, there is a lack of empirical tests. Here we use the cooperatively breeding cichlid fish Neolamprologus pulcher, in which group size predicts survival and group stability, to test this hypothesis experimentally by prompting two cooperative tasks: defence against an egg predator and digging out sand from the breeding shelter. We controlled for alternative mechanisms such as kin selection, load lightening and coercion. As predicted by the group augmentation hypothesis, helpers increased defence against an egg predator in small compared with large groups. This difference was only evident in large helpers owing to size-specific task specialization. Furthermore, helpers showed more digging effort in the breeding chamber compared with alternative personal shelters, indicating that digging is an altruistic service to the dominant breeders.

Radiological and histopathological assessment of bone infiltration in soft tissue sarcomas.

BACKGROUND: Deep soft tissue sarcomas are frequently in contact with bone. The therapeutic decision of a composite resection strategy may be challenging, which is usually based on clinical and radiological criteria. The aims of the study were to evaluate the overall frequency of bone and periosteal infiltration in these patients in whom composite resection was indicated, and evaluate the role of magnetic resonance imaging and bone scintigraphy in this scenario. METHODS: Forty-nine patients with a composite surgical resection (soft tissue sarcoma and bone), treated at a single institution between 2006 and 2018, were retrospectively included. Presurgical planning of the resection limits was based on clinical and imaging findings (magnetic resonance imaging and bone scintigraphy). Magnetic resonance imaging was performed in all patients (100%) and bone scintigraphy in 41 (83.7% of the cases). According to magnetic resonance imaging results, patients were divided into two groups: Group A, in which the tumor is adjacent to the bone without evidence of infiltration (n = 24, 48,9%), and Group B, patients with evidence of bone involvement by magnetic resonance imaging (n = 25, 51,1%). BS showed a pathological deposit in 28 patients (68.3%). Histological analysis of the resection specimen was preceded to identify bone and periosteal infiltration. For the analysis of the diagnostic validity of imaging tests, histological diagnosis was considered as the gold standard in the evaluation of STS bone infiltration. RESULTS: Histological bone infiltration was identified in 49% of patients and isolated periosteal infiltration in 14.3%. In terms of diagnostic accuracy, magnetic resonance imaging and bone scintigraphy sensitivity values were 92% and 90%, and their specificity values were 91.7% and 52.4%, respectively. CONCLUSIONS: The incidence of bone and periosteal infiltration of soft tissue sarcomas in contact with bone is high. Presurgical bone assessment by MRI has proven to be a sensitive and specific tool in the diagnosis of bone infiltration. Due to its high negative predictive value, BS is a useful test to rule out it. In those cases, in which there is suspicion of bone infiltration not confirmed by MRI, new diagnostic protocols should be established in order to avoid inappropriate resections.

Prototype Selection Method Based on the Rivality and Reliability Indexes for the Improvement of the Classification Models and External Predictions.

Prototype or instance selection techniques is an important field of research in knowledge discovery, data mining, and machine learning. In QSAR, the use of prototype selection techniques in the preprocessing stage of the construction of the QSAR models favors the data set curation, improving the interpretability and accuracy of the models as well as the performance of the algorithms. In this paper, we propose an efficient method for prototype selection to be used in the preprocessing stage of the construction of QSAR classification models. The proposed method is able to generate very high reduction rates in the cardinality of the training set while maintaining or even increasing the accuracy of the classification models. The validation of the method has been carried out by means of the prediction of external molecules, demonstrating that the prediction of new molecules is also maintained or even improved. The method has been tested using 40 benchmark data sets of different sizes and balancing ratios; the results of the tests have demonstrated the wide applicability domain of the proposed method.

Building Highly Reliable Quantitative Structure-Activity Relationship Classification Models Using the Rivality Index Neighborhood Algorithm with Feature Selection.

Dimensionality reduction of the data set representation for the construction of the quantitative structure-activity relationship classification models is an important research subject for the interpretability of the models and the computational cost efficiency of the classification algorithms. Feature selection techniques are appropriate as only a short number of relevant features should be used in the classification process because irrelevant and redundant features should be discarded, the same as the noninterpretable ones. In this paper, we propose an embedded feature selection technique for the construction of classification models using the rivality index neighborhood (RINH) algorithm. This technique uses a filter selection in the preprocessing stage considering the selectivity of the features as a selection criterion and a wrapper technique in the processing stage based on the improvement of the accuracy and reliability of the models generated using the RINH algorithm with LTN and GTN functions. The results obtained using the RINH algorithm with and without the selection of features and compared with those results obtained using 14 machine learning algorithms have demonstrated that the feature selection technique proposed in this paper is capable of clearly building more accurate and reliable models, reducing the data dimensionality around 90%, and generating high robust and interpretable models.

Medication adherence to rivaroxaban and dabigatran in patients with non-valvular atrial fibrillation: a meta-analysis.

Several real-world studies have evaluated adherence to direct acting oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF); however, these studies have not been systematically summarized. We performed a meta-analysis to compare adherence to rivaroxaban versus dabigatran therapy in United States (US) patients with NVAF in a real-world setting. Medline and Scopus were searched from January 2010 to August 2018 using keywords and MeSH terms related to adherence and oral anticoagulants. We included real-world studies of US adults with NVAF comparing adherence to dabigatran and rivaroxaban. Studies evaluating adherence by a measure other than proportion of days covered (PDC) were excluded. The proportion of patients with a PDC ≥ 80 (a commonly utilized definition of adherence) served as the primary outcome of interest. We conducted meta-analysis of non-overlapping studies using the Hartung-Knapp random-effects model to estimate risk ratios (RRs) with corresponding 95% confidence intervals (CIs). We included 5 studies evaluating 80,230 patients (range 2667-22,571). Median follow-up across studies was 6 months (range 3-12 months). The proportion of patients with a PDC ≥ 80 ranged from 59.5 to 83.5% for rivaroxaban users and 57.3 to 78.3% for dabigatran users. Upon meta-analysis, rivaroxaban use was associated with increased adherence compared with dabigatran use (RR 1.08; 95% CI 1.03-1.12; I2 = 88%). In conclusion, rivaroxaban was associated with increased adherence when compared to dabigatran in ~ 80,000 patients in a real-world setting. Possible explanations for this include dosing frequency or patient tolerance.

Asthma prevalence and risk factors in school children: The RESPIR longitudinal study.

OBJECTIVES: To analyze the incidence of wheezing in the first six years of life; the prevalence of asthma at six years of age; and the associated risk factors, in a population from Valencia, Spain. METHODS: A prospective longitudinal study was made of a cohort of 636 newborn infants, with follow-up of the clinical records and the completion of questionnaires up to the age of six years. RESULTS: The prevalence of asthma at six years of age was 12.8%. Up until that age, 63% of the study population had experienced at least one episode of wheezing, and 35% had suffered recurrent wheezing (three or more episodes). Admission due to wheezing was associated to school asthma. The following risk factors were identified: atopic dermatitis (OR: 2.1; 95%CI: 1.2-3.5), the presence of at least one episode of wheezing in the first year (OR: 1.8; 95%CI: 1.1-2.9), prematurity (OR: 2.5; 95%CI: 1.2-5.1), and a family history of asthma (OR: 2.2; 95%CI: 1.2-4.1). CONCLUSIONS: The prevalence of asthma at six years of age in our population is similar to that described in other longitudinal studies. An important increase is observed in the cumulative incidence of wheezing and of recurrent wheezing up to three years of age, followed by stabilization. The most relevant risk factors for developing asthma at six years were atopic dermatitis, wheezing during the first year, prematurity, and a family history of asthma. Full-term pregnancy and the minimization of respiratory infections at an early age could reduce the prevalence of asthma at six years of age in our population.

Building of Robust and Interpretable QSAR Classification Models by Means of the Rivality Index.

An unambiguous algorithm, added to the study of the applicability domain and appropriate measures of the goodness of fit and robustness, represent the key characteristics that should be ideally fulfilled for a QSAR model to be considered for regulatory purposes. In this paper, we propose a new algorithm (RINH) based on the rivality index for the construction of QSAR classification models. This index is capable of predicting the activity of the data set molecules by means of a measurement of the rivality between their nearest neighbors belonging to different classes, contributing with a robust measurement of the reliability of the predictions. In order to demonstrate the goodness of the proposed algorithm we have selected four independent and orthogonally different benchmark data sets (balanced/unbalanced and high/low modelable) and we have compared the results with those obtained using 12 different machine learning algorithms. These results have been validated using 20 data sets of different balancing and sizes, corroborating that the proposed algorithm is able to generate highly accurate classification models and contribute with valuable measurements of the reliability of the predictions and the applicability domain of the built models.

Saddle pulmonary embolism and in-hospital mortality in patients with cancer.

PURPOSE: Saddle pulmonary embolism (PE) has been associated with an increased risk of 1 year mortality when compared to non-saddle PE among patients with cancer. We sought to evaluate the association between saddle PE and in-hospital outcomes among patients with comorbid cancer. METHODS: The 2013 and 2014 United States National Inpatient Sample was used to identify adult patients hospitalized for acute PE. Only patients with an International Classification Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code indicating comorbid cancer were included. Identified admissions were stratified into the following 2 cohorts: saddle (defined as ICD-9-CM code = 415.13) and non-saddle PE. Multivariable logistic regression was performed to determine the association between saddle PE and the odds of in-hospital mortality after adjustment for age ≥ 80 years and sex. RESULTS: A total of 10,660 admissions for acute PE in patients with comorbid cancer were identified. Of which, 4.5% (n = 475) had a saddle PE. Median age was 67 years (interquartile range = 58-76) and 48.9% were male. In-hospital mortality occurred in 6.1% of patients. Upon multivariable adjustment, the odds of in-hospital mortality were higher in saddle versus non-saddle PE (odds ratio = 1.51; 95% confidence interval 1.08-2.10). CONCLUSION: In this retrospective study of admissions for acute PE in patients with comorbid cancer, saddle PE was associated with a higher odds of in-hospital mortality.

Early Mechanical Failure of a Tumoral Endoprosthesic Rotating Hinge in the Knee: Does Bumper Wear Contribute to Hyperextension Failure?

BACKGROUND: Tumor surgeons use a variety of endoprosthetic designs for reconstruction after bone tumor resection. However, functional results and implant survival have not been evaluated for each design. Because the outcomes and failure modes (for example, implant breakage, loosening) may differ between prosthetic design types, it is important to examine the problems associated with different designs. Because of experiences in our practice, we became concerned about a surprisingly high frequency of device breakage with one particular design, and we wished to report on that experience. QUESTION/PURPOSES: (1) In a small series of patients, what proportion of a particular design (Zimmer® Segmental [Zimmer Inc, Warsaw, IN, USA]) of rotating-hinge endoprosthesis experienced implant breakage at short-term follow-up? (2) What patient symptoms were associated with this finding? (3) What is the function as assessed by Musculoskeletal Tumor Society (MSTS) score with the use of this implant before and after revision? METHODS: We treated 87 patients in our tertiary center from 1987 to 2014 who had sarcomas around the knee with wide resection and reconstruction with tumoral endoprosthesis; five patients were lost to follow-up. In all, 33 of the remanining 82 prostheses, treated from 1987 to 2006, were reconstructed with fixed-hinge designs. From 2006 to 2014, 49 patients were reconstructed with a knee endoprosthesis, and 48 of them had a rotating-hinge prosthesis. In our center, we mostly used four designs: 16 of 49 patients were reconstructed with GMRS (Stryker Howmedica, Kalamazoo, MI, USA), seven received the LPS™ (DePuy Synthes, Warsaw, IN, USA), 20 of 49 had the METS (Stanmore, Hertfordshire, UK), and six of 49 received the Zimmer Segmental. The focus of this report is on the six patients with the Segmental. We retrospectively gathered clinical and radiologic data from these six patients' records and we assessed radiographic images. We evaluated function with the MSTS score of the 49 patients. The median follow-up duration of the Segmental prosthesis reconstruction was 65 months (range 24 to 85). RESULTS: Three of the six patients had posterior instability and recurrent joint effusion on physical examination. Three patients who did not have hyperextension presented with restricted knee ROM. Six revision procedures were performed in three patients. The median MSTS score at 6 months for the Segmental® prosthesis was 15 of 30 (range 6 to 24). The score in the three patients who had posterior instability was 9 of 30 (range 6 to 15) and it improved to median 25 of 30 (range 19 to 30) 6 months after revision. The patients with the Segmental® prosthesis who did not undergo revision had a median MSTS score of 20 (range 16 to 24). CONCLUSIONS: The Zimmer Segmental rotating-hinge tumoral prosthesis underwent revision for implant breakage at short term in three of six patients after tumor resection and reconstruction of the knee. Bumper breakage was associated with posterior instability that was related to wear of the bushing blocking system. We are unaware of reports of these issues by other observers or in other prosthetic designs, but we feel larger registries should be created to see if this failure mechanism has been observed by others. If so, this design needs to be improved or the blocking system should be avoided.Level of Evidence Level IV, therapeutic study.

Regression Modelability Index: A New Index for Prediction of the Modelability of Data Sets in the Development of QSAR Regression Models.

Prediction of the capability of a data set to be modeled by a statistical algorithm in the development of quantitative structure-activity relationship (QSAR) regression models is an important issue that allows researchers to avoid unnecessary tasks, wasted time, and/or the need to depurate the molecule composition of the data set in order to achieve an improvement of the model's accuracy. In this paper, we propose and formulate a new index that correlates with the performance of QSAR models. This index, the regression modelability index, requires very low computational cost and is based on the rivality between the nearest neighbors of the molecules in the data set. This rivality allows measurement of the capability of each molecule of the data set to be correctly predicted by a regression algorithm. In this study, using 40 data sets with very different characteristics regarding the number of molecules and activity values, we prove the high correlation between the proposed regression modelability index and the correlation coefficient in cross-validation ( Q2), reaching r2 values of 0.8. In addition, we describe the ability of this index to discover the outliers detected by the regression algorithms, allowing easy data set depuration in the first stages of the construction of QSAR regression models.

Study of Data Set Modelability: Modelability, Rivality, and Weighted Modelability Indexes.

The knowledge of the capacity of a data set to be modeled in the first stages of the building of quantitative structure-activity relationship (QSAR) prediction models is an important issue because it might reduce the effort and time necessary to select or reject data sets and in refining the data set's composition. The modelability index (MODI) is based on the counting of the first nearest neighbor belonging to the molecules of the data set and is a standardized measurement assumed in the QSAR community. In this paper, we revisit the calculation of the modelability index, proposing a more formal formulation that extends the calculation to the first nearest neighbors that belong to each existing class in the data set. In addition, this new formulation allows the calculation of the rivality index, as a measurement of the presence of correctly classifiable molecules and activity cliffs. By weighting the rivality index considering the cardinality of the neighborhood of each molecule of the data set, the calculated weighted modelability index is highly correlated with the correct classification rate (QSAR_CCR) obtained in the building of QSAR models using different classification algorithms. The results obtained with the weighted modelability index show correlations of r2 higher than 0.9, slopes close to 1, and bias close to zero for different algorithms.

Study of the Applicability Domain of the QSAR Classification Models by Means of the Rivality and Modelability Indexes.

The reliability of a QSAR classification model depends on its capacity to achieve confident predictions of new compounds not considered in the building of the model. The results of this external validation process show the applicability domain (AD) of the QSAR model and, therefore, the robustness of the model to predict the property/activity of new molecules. In this paper we propose the use of the rivality and modelability indexes for the study of the characteristics of the datasets to be correctly modeled by a QSAR algorithm and to predict the reliability of the built model to prognosticate the property/activity of new molecules. The calculation of these indexes has a very low computational cost, not requiring the building of a model, thus being good tools for the analysis of the datasets in the first stages of the building of QSAR classification models. In our study, we have selected two benchmark datasets with similar number of molecules but with very different modelability and we have corroborated the capacity of the predictability of the rivality and modelability indexes regarding the classification models built using Support Vector Machine and Random Forest algorithms with 5-fold cross-validation and leave-one-out techniques. The results have shown the excellent ability of both indexes to predict outliers and the applicability domain of the QSAR classification models. In all cases, these values accurately predicted the statistic parameters of the QSAR models generated by the algorithms.

Advantages of Relative versus Absolute Data for the Development of Quantitative Structure-Activity Relationship Classification Models.

The appropriate selection of a chemical space represented by the data set, the selection of its chemical data representation, the development of a correct modeling process using a robust and reproducible algorithm, and the performance of an exhaustive training and external validation determine the usability and reproducibility of a quantitative structure-activity relationship (QSAR) classification model. In this paper, we show that the use of relative versus absolute data in the representation of the data sets produces better classification models when the other processes are not modified. Relative data considers a reference frame to measure the chemical characteristics involved in the classification model, refining the data set representation and smoothing the lack of chemical information. Three data sets with different characteristics have been used in this study, and classifications models have been built applying the support vector machine algorithm. For randomly selected training and test sets, values of accuracy and area under the receiver operating characteristic curve close to 100% have been obtained for the generation of the models and external validations in all cases.

Reconstruction After Hemipelvectomy With the Ice-Cream Cone Prosthesis: What Are the Short-term Clinical Results?

BACKGROUND: Reconstruction after internal hemipelvectomy resection likely provides better function than hindquarter amputation. However, many reconstruction methods have been used, complications with these approaches are common, and function often is poor; because of these issues, it seems important to investigate alternative implants and surgical techniques. QUESTIONS/PURPOSES: The purposes of this study were (1) to identify the frequency of surgical site complications and infection associated with the use of the Ice-Cream Cone prosthesis for reconstruction after hemipelvectomy for oncological indications; (2) to evaluate the Musculoskeletal Tumor Society (MSTS) outcomes scores in a small group of patients treated with this implant in the short term; and (3) to quantify the surgical margins and frequency of local recurrence in the short term in this group of patients. METHODS: Between 2008 and 2013, one center performed a total of 27 internal hemipelvectomies for oncological indications. Of those, 23 (85%) were treated with reconstruction. Our general indications for reconstruction were patients whose pelvic stability was affected by the resection and whose general condition was sufficiently strong to tolerate the reconstructive procedure. Of those patients undergoing reconstruction, 14 (61%) were treated with an Ice-Cream Cone-style implant (Coned®; Stanmore Worldwide Ltd, Elstree, UK; and Socincer® custom-made implant for the pelvis, Gijón, Spain), whereas nine others were treated with other implants or allografts. The indications during this time for using the Ice-Cream Cone implant were pelvic tumors affecting the periacetabular area without iliac wing involvement. Of those 14, 10 were available for followup at a minimum of 2 years (median, 3 years; range, 2-5 years) unless a study endpoint (wound complication, infection, or local recurrence) was observed earlier. Study endpoints were ascertained by chart review performed by one of the authors. RESULTS: Surgical site complications occurred in five patients. Of those, two developed superficial infections with necrosis, two developed deep infections, and one patient developed wound necrosis without apparent infection. No prostheses were removed as a result of these complications [corrected]. Median MSTS score was 19 out of 30 when 0 is the worst possible result and 30 a perfect function and emotional status. Five of seven primary tumors had wide margin surgery and three of seven developed local recurrences by the end of the followup. CONCLUSIONS: Pelvic reconstruction with the Ice-Cream Cone prosthesis yielded fair functional results at short-term followup. Longer term surveillance is called for to see whether this implant will represent an improvement over available reconstructive alternatives such as allograft, custom-made implants, and saddle prostheses. We are cautiously optimistic and continue to use this implant when we need to reconstruct the periacetabular area in patients without Enneking Zone 1 involvement. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Are Biopsy Tracts a Concern for Seeding and Local Recurrence in Sarcomas?

BACKGROUND: A biopsy is the final step in the diagnosis of sarcomas. Complete resection of the biopsy tract traditionally has been recommended in musculoskeletal oncology guidelines, as that tract is considered potentially seeded with tumor cells. However, to our knowledge, the frequency and implications of contamination of the biopsy tract-specifically with respect to the likelihood of local recurrence-and the factors that affect cell seeding are not well described. QUESTIONS/PURPOSES: We asked: (1) How often are biopsy tracts contaminated with pathologically detectable tumor cells at the time of tumor resection? (2) What factors, in particular biopsy type (open versus percutaneous), are associated with tumoral seeding? (3) Is biopsy tract contamination associated with local recurrence? METHODS: This is a retrospective study of a database with patient data collected from a single center between 2000 and 2013. We treated 221 patients with sarcomas. A total of 27 patients (12%) were excluded and 14 (6%) were lost to followup. One hundred eighty patients finally were included in the analysis who either had biopsies at our center (112) or biopsies at outside institutions (68). Of those performed at our center, 15 (13%) were open and 97 (87%) were percutaneous; of those at outside centers, those numbers were 47 (69%) and 21 (31%) respectively. Median followup was 40 months (range, 24-152 months). During the study period, we generally performed percutaneous biopsies as a standard practice for the diagnosis of bone and soft tissue sarcomas and open biopsies were done when the percutaneous procedure failed to provide a histologic characterization. The mean age of the population was 48 years (range, 7-87 years); 60% were male; 42% had bone sarcomas. Nineteen patients had preoperative radiotherapy and 56 had postoperative radiotherapy. Fifty-seven patients received neoadjuvant chemotherapy and 73 had adjuvant chemotherapy. We determined what proportion of biopsy tracts were contaminated by pathologic analysis of the biopsy tract specimen; during the period in question, our routine practice was to excise the biopsy tract whenever possible at the time of the definitive resection. Using the logistic regression test and Mantel-Haenszel test, we compared open with percutaneous biopsies in terms of the proportion of those that were contaminated at our site and for outside referral biopsies separately, because we do not assume the level of expertise was the same (our site is a referral tumor center). We compared the local recurrence-free survival between patients with and without contamination and between open and percutaneous biopsies using the Kaplan Meier test, again separating those performed at our site from those referred for purposes of this analysis. RESULTS: Twenty-one of 180 biopsy tracts were contaminated (12%). Twenty of 62 (32%) of the open biopsies and one of 118 (0.8%) of the percutaneous core needle biopsies had cell seeding (odds ratio [OR], 56; 95% CI, 7-428; p < 0.001. One of 97 (1%) percutaneous biopsies performed in our center, and none of the 21 (0%) percutaneous biopsies performed in other centers had contaminated biopsy tracts (p = 0.047). Two of 15 (13%) open biopsies performed at our center and 18 of 41(38%) open biopsies performed at other centers had contaminated biopsy tracts (OR, 4; 95% CI, 1-7; p = 0.001). Four of 74 (5%) bone sarcomas and 18 of 106 (17%) soft tissue sarcomas had biopsy tract contamination (OR, 3; 95% CI, 1-10; p = 0.023). The local recurrence-free survival was longer for patients without contaminated tracts (mean, 107 months; 95% CI, 74-141 months) than for those with biopsy tract seeding (mean, 11 months; 95% CI, 1-20 months; p < 0.001). CONCLUSIONS: Open biopsies were associated with an increased risk of tumoral seeding of the biopsy site, and tumoral seeding was associated with an increased risk of local recurrence. However, it is possible that other factors, such as increased complexity of the tumor or a difficult location, influenced the decision to obtain an open biopsy. Even so, based on these results, we believe that higher risk of local recurrence may be caused by an incomplete biopsy tract resection. In our opinion, the percutaneous biopsy with neoadjuvant or adjuvant therapy is the preferred method of biopsy at our center. LEVEL OF EVIDENCE: Level III, therapeutic study.

Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease.

OBJECTIVE: To evaluate the feasibility and toxicity of autologous haematopoietic stem cell transplantation (HSCT) for the treatment of refractory Crohn's disease (CD). DESIGN: In this prospective study, patients with refractory CD suffering an aggressive disease course despite medical treatment, impaired quality of life and in whom surgery was not an acceptable option underwent HSCT. Toxicity and complications during the procedure and within the first year following transplantation were evaluated, along with the impact of the introduction of supportive measures on safety outcomes. RESULTS: 26 patients were enrolled. During mobilisation, 16 patients (62%) presented febrile neutropaenia, including one bacteraemia and two septic shocks. Neutropaenia median time after mobilisation was 5 days. 5 patients withdrew from the study after mobilisation and 21 patients entered the conditioning phase. Haematopoietic recovery median time for neutrophils (>0.5×10(9)/L) was 11 days and for platelets (>20×10(9)/L) 4 days. Twenty patients (95%) suffered febrile neutropaenia and three patients (27%) presented worsening of the perianal CD activity during conditioning. Among non-infectious complications, 6 patients (28.5%) presented antithymocyte globulin reaction, 12 patients (57%) developed mucositis and 2 patients (9.5%) had haemorrhagic complications. Changes in supportive measures over the study, particularly antibiotic prophylaxis regimes during mobilisation and conditioning, markedly diminished the incidence of severe complications. During the first 12-month follow-up, viral infections were the most commonly observed complications, and one patient died due to systemic cytomegalovirus infection. CONCLUSIONS: Autologous HSCT for patients with refractory CD is feasible, but extraordinary supportive measures need to be implemented. We suggest that this procedure should only be performed in highly experienced centres.

Differential lipid metabolism in monocytes and macrophages: influence of cholesterol loading.

The influence of the hypercholesterolemia associated with atherosclerosis on monocytes is poorly understood. Monocytes are exposed to high concentrations of lipids, particularly cholesterol and lysophosphatidylcholine (lyso-PC). Indeed, in line with recent reports, we found that monocytes accumulate cholesteryl esters (CEs) in hypercholesterolemic mice, demonstrating the need for studies that analyze the effects of lipid accumulation on monocytes. Here we analyze the effects of cholesterol and lyso-PC loading in human monocytes and macrophages. We found that cholesterol acyltransferase and CE hydrolase activities are lower in monocytes. Monocytes also showed a different expression profile of cholesterol influx and efflux genes in response to lipid loading and a different pattern of lyso-PC metabolism. In monocytes, increased levels of CE slowed the conversion of lyso-PC into PC. Interestingly, although macrophages accumulated glycerophosphocholine, phosphocholine was the main water-soluble choline metabolite being generated in monocytes, suggesting a role for mono- and diacylglycerol in the chemoattractability of these cells. In summary, monocytes and macrophages show significant differences in lipid metabolism and gene expression profiles in response to lipid loading. These findings provide new insights into the mechanisms of atherosclerosis and suggest potentials for targeting monocyte chemotactic properties not only in atherosclerosis but also in other diseases.

NFκB2/p100 is a key factor for endotoxin tolerance in human monocytes: a demonstration using primary human monocytes from patients with sepsis.

Endotoxin tolerance (ET) is a state of reduced responsiveness to endotoxin stimulation after a primary bacterial insult. This phenomenon has been described in several pathologies, including sepsis, in which an endotoxin challenge results in reduced cytokine production. In this study, we show that the NFκ L chain enhancer of activated B cells 2 (NFκB2)/p100 was overexpressed and accumulated in a well-established in vitro human monocyte model of ET. The p100 accumulation in these cells inversely correlated with the inflammatory response after LPS stimulation. Knocking down NFκB2/p100 using small interfering RNA in human monocytes further indicated that p100 expression is a crucial factor in the progression of ET. The monocytes derived from patients with sepsis had high levels of p100, and a downregulation of NFκB2/p100 in these septic monocytes reversed their ET status.