Comparison of Athletes and Nonathletes Undergoing Thoracic Outlet Decompression for Neurogenic Thoracic Outlet Syndrome.

BACKGROUND: Neurogenic thoracic outlet syndrome (NTOS) is the most common form of thoracic outlet syndrome (TOS) and may occur from injury, occupational stress, or athletic endeavors. Although most patients with NTOS will improve after first-rib resection and scalenectomy (FRRS), the prognostic risk factors for success remain unclear. Athletes are a very motivated and disciplined demographic and therefore should be a group more likely to respond to FRRS for NTOS than nonathletes. We hypothesized that athletes would do better after FRRS than nonathletes despite the added physical stress that sporting activity imposes. METHODS: We reviewed our office records for all patients treated for TOS from July 2009 to May 2014 and extracted demographic, historical, procedural, and follow-up data. We contacted these patients to complete a survey to assess patient-centered outcomes of FRRS and compared athlete versus nonathlete survey responses. RESULTS: Five hundred sixty-four patients had FRRS for NTOS, and 184 (33%) responded to the survey. Of the 184 who responded, 97 were athletes (53%) and 87 were nonathletes (47%). Survey results suggested that 87% were improved in pain medication use (athletes 93% vs. nonathletes 80%, P = 0.013), 77% would undergo FRRS on the contralateral side if needed (athletes 75% vs. nonathletes 79%, P = 0.49), 73% had resolution of TOS symptoms (athletes 80% vs. nonathletes 65%, P = 0.02), and 86% could perform activities of daily living without limitation (athletes 95% vs. nonathletes 77%, P = 0.0004). Although 24% of respondents required another non-TOS procedure (athletes 27% vs. nonathletes 22%, P = 0.6), 89% felt that they had made the right decision (athletes 93% vs. nonathletes 80%, P = 0.09). Multivariable analysis of age, race, gender, previous surgery, preoperative physical therapy, preoperative narcotic use, and athletic status confirmed that athletic status was a significant predictor for improvement in pain medication use, complete TOS resolution, and the ability to perform activities of daily living. CONCLUSIONS: Most patients undergoing FRRS for NTOS are improved and satisfied with the result and indicate they made the correct choice to have FRRS. Although being an athlete was an independent variable for better outcomes in activity and pain medication use, their satisfaction after FRRS was similar to that in nonathletes. Further investigation is needed to determine if these findings are due to physical and/or psychosocial factors.

Midterm and long-term follow-up in competitive athletes undergoing thoracic outlet decompression for neurogenic thoracic outlet syndrome.

BACKGROUND: Neurogenic thoracic outlet syndrome (NTOS) results from compression of the brachial plexus by the clavicle, first rib, and scalene muscles and may develop secondary to repetitive motion of the upper extremity. Athletes routinely perform repetitive motions, and sports requiring significant arm and shoulder use may put the participant at increased risk for NTOS. Competitive athletes who develop NTOS may require first rib resection and scalenectomy (FRRS) for symptomatic relief. However, the effectiveness of FRRS has not previously been studied in this vulnerable population. METHODS: This is a cross-sectional study of competitive athletes with NTOS who received FRRS by the senior author between 2009 and 2014. Eligible patients were contacted by phone and invited to complete a nine-item survey assessing the long-term effects of FRRS on pain medication use, postoperative physical therapy duration, patient satisfaction, symptom relief, activities of daily living, athletic performance, time to return of athletic performance, and need for other operations. Multivariate analyses of the following risk factors were performed: age, pectoralis minor release, preoperative narcotic use, athletic shutdown, and involvement in a throwing sport. RESULTS: There were 232 competitive athletes who met the inclusion criteria, and 67 of these (age, 14-48 years; 35 male; 99% white) responded to the survey. The average time between surgery and survey completion was 3.9 years (range, 2.2-7.0 years). The most frequent sports conducted by this group were baseball and softball (n = 44 [66%]), volleyball (n = 7 [10%]), and cheerleading and gymnastics (n = 5 [7%]), ranging from high-school to professional levels. The survey results revealed that 96% were improved in pain medication use, 75% would undergo FRRS on the contralateral side if needed, 82% had resolution of symptoms, and 94% were able to perform activities of daily living without limitation; 70% returned to the same or better level of athletic activity after FRRS, and this occurred within 1 year in 50%. Multivariate regression analysis identified younger age as a predictor of the length of physical therapy and preoperative narcotics use as a predictor of symptom resolution. CONCLUSIONS: At our center, >40% of patients requiring FRRS for NTOS are competitive athletes. The results of this study show that the majority of them are able to return to their precompetitive state after FRRS, and few experience limitations in their daily living activities. Half can return to competition at or exceeding their premorbid ability level within 6 months of surgery. The majority are pleased with their decision to undergo FRRS. Further investigation is needed to identify predictive factors for successful return to competitive athletics.

The incidence and outcome of endothermal heat-induced thrombosis after endovenous laser ablation.

BACKGROUND: Endovenous laser ablation (EVLA) of the saphenous vein has become one of the preferred treatments for treating saphenous vein reflux that has resulted in symptomatic lower extremity venous insufficiency or varicose veins. This procedure was noted during initial reports to have a low incidence of postoperative thrombosis of the femoral or popliteal vein adjacent to the treated great saphenous vein (GSV) or small saphenous vein (SSV). Later clinical experience suggested that the actual incidence of this event is higher and it was subsequently termed endothermal heat-induced thrombosis (EHIT). METHODS: We reviewed the office records and the pre- and post-treatment ultrasounds of patients undergoing EVLA in our office from 2005 to 2010 to determine the frequency of EHIT in patients we had treated and then graded them according to a previously published classification. RESULTS: There were 528 veins treated in 192 men and 336 women. The clinical, etiology, anatomy, pathophysiology (CEAP) class for these patients was 1 (0), 2 (291), 3 (65), 4 (104), 5 (26), and 6 (40), respectively. The GSV was treated in 496 patients, the SSV in 22, and both were treated in 10 patients. EHIT occurred in 29 of the legs treated for an incidence of 5.1%. The EHIT in the femoral vein were of level 3 (3), 4 (7), 5 (12), and 6 (3), respectively. Two patients developed EHIT in the popliteal vein after EVLA of the SSV. Treatment for the EHIT consisted of observation (13), anticoagulation (9), antiplatelet therapy (2), and nonsteroidal anti-inflammatory agents (1). Duration of therapy was usually 1 week, but 7 patients were treated for periods ranging from 1 to 7 weeks. No pulmonary emboli occurred in any of these patients. The EHIT resolved completely in all patients. CONCLUSIONS: EHIT after EVLA occurs frequently and mainly consists of low-risk level 3, 4, and 5 deep vein thrombosis. The risk of pulmonary embolism is low and the EHIT typically resolves after 1 week. It can be treated with a short course of antiplatelet or anticoagulation therapy, although observation appears to be sufficient as well for lesser grades of EHIT.

Four-year randomized prospective comparison of percutaneous ePTFE/nitinol self-expanding stent graft versus prosthetic femoral-popliteal bypass in the treatment of superficial femoral artery occlusive disease.

BACKGROUND: This is a randomized prospective study comparing the treatment of superficial femoral artery occlusive disease percutaneously with an expanded polytetrafluoroethylene (ePTFE)/nitinol self-expanding stent graft (stent graft) versus surgical femoral to above-knee popliteal artery bypass with synthetic graft material. METHODS: One hundred limbs in 86 patients with superficial femoral artery occlusive disease were evaluated from March 2004 to May 2005. Patient symptoms included both claudication and limb threatening ischemia with or without tissue loss. Trans-Atlantic InterSociety Consensus (TASC II) A (n = 18), B (n = 56), C (n = 11), and D (n = 15) lesions were included. Patients were randomized prospectively into one of two treatment groups; a percutaneous treatment group (group A; n = 50) with angioplasty and placement of one or more stent grafts, or a surgical treatment group (group B; n = 50) with a femoral to above-knee popliteal artery bypass using synthetic conduit (Dacron or ePTFE). Patients were followed for 48 months. Follow-up evaluation included clinical assessment, physical examination, ankle-brachial indices, and color flow duplex sonography at 3, 6, 9, 12, 18, 24, 36, and 48 months. RESULTS: Mean total lesion length of the treated arterial segment in the stent graft group was 25.6 cm (SD = 15 cm). The stent graft group demonstrated a primary patency of 72%, 63%, 63%, and 59% with a secondary patency of 83%, 74%, 74%, and 74% at 12, 24, 36, and 48 months, respectively. The surgical femoral-popliteal group demonstrated a primary patency of 76%, 63%, 63%, and 58% with a secondary patency of 86%, 76%, 76%, and 71% at 12, 24, 36, and 48 months, respectively. No statistical difference was found between the two groups with respect to primary (P = .807) or secondary (P = .891) patency. CONCLUSION: Management of superficial femoral artery occlusive disease with percutaneous stent grafts exhibits similar primary patency at 4-year (48 month) follow up when compared with conventional femoral-popliteal artery bypass grafting with synthetic conduit. This treatment method may offer an alternative to treatment of the superficial femoral artery segment for revascularization when prosthetic bypass is being considered or when autologous conduit is unavailable.

Randomized comparison of ePTFE/nitinol self-expanding stent graft vs prosthetic femoral-popliteal bypass in the treatment of superficial femoral artery occlusive disease.

BACKGROUND: A randomized prospective study comparing the treatment of superficial femoral artery occlusive disease percutaneously with an expanded polytetrafluoroethylene (ePTFE)/nitinol self-expanding stent graft (stent-graft) vs surgical femoral to above knee popliteal artery bypass with synthetic graft material. METHODS: One hundred limbs in 86 patients with superficial femoral artery occlusive disease were evaluated from March 2004 to May 2005. Patient symptoms included both claudication and limb threatening ischemia with or without tissue loss. The TransAtlantic InterSociety Consensus (TASC) II A (N = 18), B (N = 56), C (N = 11), and D (N = 15) lesions were included. Patients were randomized prospectively into one of two treatment groups; a percutaneous treatment group (group A; N = 50) with angioplasty and placement of one or more stent-grafts or a surgical treatment group (group B; N = 50) with a femoral to above knee popliteal artery bypass using synthetic conduit (Dacron graft or ePTFE). Patients were followed for a total of 24 months. Follow-up evaluation included clinical assessment and physical examination, ankle-brachial indices (ABI), and color flow duplex sonography at 3, 6, 9, 12, 18, and 24 months. RESULTS: The mean total lesion length of the treated arterial segment in the stent-graft group was 25.6 cm (SD +/- 15 cm). The stent-graft group demonstrated a primary patency of 81%, 72%, and 63% with a secondary patency of 86%, 83%, and 74% at 6, 12, and 24 months, respectively. The surgical femoral-popliteal group demonstrated a primary patency of 84%, 77%, and 64% with a secondary patency of 89%, 86%, and 76% at 6, 12, and 24 months, respectively. No statistical difference was found between the two groups with respect to primary (P = .716) or secondary patency (P = .695). Grouping of less severe (TASC II A/B) vs more severe (TASC II C/D) lesions demonstrated patency at 24 months for the femoral-popliteal arm of 63% and 67%, respectively while that of the stent-graft arm was 64% and 47%, respectively. Secondary patency was 76% in both TASC classifications for the femoral-popliteal arm with 78% and 47% patency found respectively in the stent-graft group. These resulted in no significant difference for primary (P = .978) or secondary (P = .653) patency overall, although there is a trend for decreased patency with higher TASC II lesions. CONCLUSION: Management of superficial femoral artery occlusive disease with percutaneous stent-grafts exhibits similar primary patency at 24-month follow-up when compared with conventional femoral-popliteal artery bypass grafting with synthetic conduit. This treatment method may offer an alternative to treatment of the superficial femoral artery segment for revascularization when prosthetic bypass is being considered or when autologous conduit is unavailable.

The Rule of Five revisited: applying log D in place of log P in drug-likeness filters.

The much publicized "Rule of 5" has been widely adopted among the pharmaceutical industry. It is used as a first step filter to perform virtual screening of compound libraries, in an effort to quickly eliminate lead candidates that have poor physicochemical properties for oral bioavailabilty. One of the key parameters used therein is log P, which is a useful descriptor, but one that fails to take into account variation in the lipophilicity of a drug with respect to the ionic states present at key biological pH values. Given that the majority of commercial pharmaceuticals contain an ionizable moiety, we propose that log D is a better descriptor for lipophilicity in the context of the Rule of 5. It gives more physiologically relevant results, thereby reducing the number of potential false-negatives incorrectly eliminated in screening. Using a series of commercial compound libraries, this study showed that the adapted Rule of 5 using log D instead of log P provides notable improvement in pass rate for compounds that have the desired lipophilicity at a relevant physiological pH.

Probabilistic neural network multiple classifier system for predicting the genotoxicity of quinolone and quinoline derivatives.

Quinolone and quinoline are known to be liver carcinogens in rodents, and a number of their derivatives have been shown to exhibit mutagenicity in the Ames test, using Salmonella typhimurium strain TA 100 in the presence of S9. Both the carcinogenicity and the mutagenicity of quinolone and quinoline derivatives, as determined by SAS, can be attributed to their genotoxicity potential. This potential, which is measured by genotoxicity tests, is a good indication of carcinogenicity and mutagenicity because compounds that are positive in these tests have the potential to be human carcinogens and/or mutagens. In this study, a collection of quinolone and quinoline derivatives' carcinogenicity is determined by qualitatively predicting their genotoxicity potential with predictive PNN (probabilistic neural network) classification models. In addition, a multiple classifier system is also developed to improve the predictability of genotoxicity. Superior results are seen with the multiple classifier system over the individual PNN classification models. With the multiple classifier system, 89.4% of the quinolone derivatives were predicted correctly, and higher predictability is seen with the quinoline derivatives at 92.2% correct. The multiple classifier system not only is able to accurately predict the genotoxicity but also provides an insight about the main determinants of genotoxicity of the quinolone and quinoline derivatives. Thus, the PNN multiple classifier system generated in this study is a beneficial contributor toward predictive toxicology in the design of less carcinogenic bioactive compounds.

Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical molecules.

Computational models are currently being used by regulatory agencies and within the pharmaceutical industry to predict the mutagenic potential of new chemical entities. These models rely heavily, although not exclusively, on bacterial mutagenicity data of nonpharmaceutical-type molecules as the primary knowledge base. To what extent, if any, this has limited the ability of these programs to predict genotoxicity of pharmaceuticals is not clear. In order to address this question, a panel of 394 marketed pharmaceuticals with Ames Salmonella reversion assay and other genetic toxicology findings was extracted from the 2000-2002 Physicians' Desk Reference and evaluated using MCASE, TOPKAT, and DEREK, the three most commonly used computational databases. These evaluations indicate a generally poor sensitivity of all systems for predicting Ames positivity (43.4-51.9% sensitivity) and even poorer sensitivity in prediction of other genotoxicities (e.g., in vitro cytogenetics positive; 21.3-31.9%). As might be expected, all three programs were more highly predictive for molecules containing carcinogenicity structural alerts (i.e., the so-called Ashby alerts; 61% +/- 14% sensitivity) than for those without such alerts (12% +/- 6% sensitivity). Taking all genotoxicity assay findings into consideration, there were 84 instances in which positive genotoxicity results could not be explained in terms of structural alerts, suggesting the possibility of alternative mechanisms of genotoxicity not relating to covalent drug-DNA interaction. These observations suggest that the current computational systems when applied in a traditional global sense do not provide sufficient predictivity of bacterial mutagenicity (and are even less accurate at predicting genotoxicity in tests other than the Salmonella reversion assay) to be of significant value in routine drug safety applications. This relative inability of all three programs to predict the genotoxicity of drugs not carrying obvious DNA-reactive moieties is discussed with respect to the nature of the drugs whose positive responses were not predicted and to expectations of improving the predictivity of these programs. Limitations are primarily a consequence of incomplete understanding of the fundamental genotoxic mechanisms of nonstructurally alerting drugs rather than inherent deficiencies in the computational programs. Irrespective of their predictive power, however, these programs are valuable repositories of structure-activity relationship mutagenicity data that can be useful in directing chemical synthesis in early drug discovery.

Predicting the genotoxicity of polycyclic aromatic compounds from molecular structure with different classifiers.

Classification models were developed to provide accurate prediction of genotoxicity of 277 polycyclic aromatic compounds (PACs) directly from their molecular structures. Numerical descriptors encoding the topological, geometric, electronic, and polar surface area properties of the compounds were calculated to represent the structural information. Each compound's genotoxicity was represented with IMAX (maximal SOS induction factor) values measured by the SOS Chromotest in the presence and absence of S9 rat liver homogenate. The compounds' class identity was determined by a cutoff IMAX value of 1.25-compounds with IMAX > 1.25 in either test were classified as genotoxic, and the ones with IMAX < or = 1.25 were nongenotoxic. Several binary classification models were generated to predict genotoxicity: k-nearest neighbor (k-NN), linear discriminant analysis, and probabilistic neural network. The study showed k-NN to provide the highest predictive ability among the three classifiers with a training set classification rate of 93.5%. A consensus model was also developed that incorporated the three classifiers and correctly predicted 81.2% of the 277 compounds. It also provided a higher prediction rate on the genotoxic class than any other single model.

Predicting the genotoxicity of thiophene derivatives from molecular structure.

We report several binary classification models that directly link the genetic toxicity of a series of 140 thiophene derivatives with information derived from the compounds' molecular structure. Genetic toxicity was measured using an SOS Chromotest. IMAX (maximal SOS induction factor) values were recorded for each of the 140 compounds both in the presence and in the absence of S9 rat liver homogenate. Compounds were classified as genotoxic if IMAX >or= 1.5 in either test or nongenotoxic if IMAX < 1.5 for both tests. The molecular structures were represented by numerical descriptors that encoded the topological, geometric, electronic, and polar surface area properties of the thiophene derivatives. The classification models used were linear discriminant analysis (LDA), k-nearest neighbor classification (k-NN), and the probabilistic neural network (PNN). These were used in conjunction with either a genetic algorithm or a generalized simulated annealing to find optimal subsets of descriptors for each classifier. The quality of the resulting models was determined by the number of misclassified compounds, with preference given to models that produced fewer false negative classifications. Model sizes ranged from seven descriptors for LDA to three descriptors for k-NN and PNN. Very good classification results were obtained with all three classifiers. Classification rates for the LDA, k-NN, and PNN models were 80, 85, and 85%, respectively, for the prediction set compounds. Additionally, a consensus model was generated that incorporated all three of the basic model types. This consensus model correctly predicted the genotoxicity of 95% of the prediction set compounds.

Predicting the genotoxicity of secondary and aromatic amines using data subsetting to generate a model ensemble.

Binary quantitative structure-activity relationship (QSAR) models are developed to classify a data set of 334 aromatic and secondary amine compounds as genotoxic or nongenotoxic based on information calculated solely from chemical structure. Genotoxic endpoints for each compound were determined using the SOS Chromotest in both the presence and absence of an S9 rat liver homogenate. Compounds were considered genotoxic if assay results indicated a positive genotoxicity hit for either the S9 inactivated or S9 activated assay. Each compound in the data set was encoded through the calculation of numerical descriptors that describe various aspects of chemical structure (e.g. topological, geometric, electronic, polar surface area). Furthermore, five additional descriptors that focused on the secondary and aromatic nitrogen atoms in each molecule were calculated specifically for this study. Descriptor subsets were examined using a genetic algorithm search engine interfaced with a k-Nearest Neighbor fitness evaluator to find the most information-rich subsets, which ultimately served as the final predictive models. Models were chosen for their ability to minimize the total number of misclassifications, with special attention given to those models that possessed fewer occurrences of positive toxicity hits being misclassified as nontoxic (false negatives). In addition, a subsetting procedure was used to form an ensemble of models using different combinations of compounds in the training and prediction sets. This was done to ensure that consistent results could be obtained regardless of training set composition. The procedure also allowed for each compound to be externally validated three times by different training set data with the resultant predictions being used in a "majority rules" voting scheme to produce a consensus prediction for each member of the data set. The individual models produced an average training set classification rate of 71.6% and an average prediction set classification rate of 67.7%. However, the model ensemble was able to correctly classify the genotoxicity of 72.2% of all prediction set compounds.