Sacroiliac joint fusion navigation: how accurate is pin placement?

OBJECTIVE: Sacroiliac joint (SIJ) fusion utilizing intraoperative navigation requires a standard reference frame, which is often placed using a percutaneous pin. Proper placement ensures the correct positioning of SIJ fusion implants. There is currently no grading scheme for evaluation of pin placement into the pelvis. The purpose of this study was to evaluate the occurrence of ideal percutaneous pin placement into the posterior ilium during navigated SIJ fusion. METHODS: After IRB approval was obtained, electronic medical records and intraoperative computed tomography images of patients who underwent navigated SIJ fusion by the senior author between October 2013 and January 2020 were reviewed. A pin placement grading scheme and the definition of "ideal" placement were developed by the authors and deemed acceptable by fellow attending surgeons. Six attending surgeons completed two rounds of pin placement grading, and statistical analysis was conducted. RESULTS: Of 90 eligible patients, 73.3% had ideal pin placement, 17.8% medial/lateral breach, and 8.9% complete miss. Male patients were 3.7 times more likely to have ideal placement than females (p < 0.05). There was no relationship between BMI, SIJ fusion laterality, or pin placement laterality and ideal placement. Interobserver reliability was 0.72 and 0.70 in the first and second rounds, respectively, and defined as "substantial agreement." Intraobserver reliability ranged from 0.74 (substantial agreement) to 0.92 (almost perfect agreement). CONCLUSIONS: Nonideal pin placement occurred in 26.7% of cases, but a true "miss" into the sacrum was rare. Ideal pin placement was more likely in males and was not associated with BMI, SIJ fusion laterality, or pin placement laterality. The grading scheme developed has high intraobserver and interobserver reliability, indicating that it is reproducible and can be used for future studies. When placing percutaneous pins, surgeons must be aware of factors that can decrease placement accuracy, regardless of location.

Threshold-Responsive Colorimetric Sensing System for the Continuous Monitoring of Gases.

Colorimetric sensors are widely used because of their inherent advantages including accuracy, rapid response, ease-of-use, and low costs; however, they usually lack reusability, which precludes the continuous use of a single sensor. We have developed a threshold-responsive colorimetric system that enables repeated analyte measurements by a single colorimetric sensor. The threshold responsive algorithm automatically adjusts the sensor exposure time to the analyte and measurement frequency according to the sensor response. The system registers the colorimetric sensor signal change rate, prevents the colorimetric sensor from reaching saturation, and allows the sensor to fully regenerate before the next measurement is started. The system also addresses issues common to colorimetric sensors, including the response time and range of detection. We demonstrate the benefits and feasibility of this novel system, using colorimetric sensors for ammonia and carbon dioxide gases for continuous monitoring of up to (at least) 60 detection cycles without signs of analytical performance degradation of the sensors.

The 2021 Association Research Circulation Osseous Classification for Early-Stage Osteonecrosis of the Femoral Head to Computed Tomography-Based Study.

BACKGROUND: The Association Research Circulation Osseous developed a novel classification for early-stage (precollapse) osteonecrosis of the femoral head (ONFH). We hypothesized that the novel classification is more reliable and valid when compared to previous 3 classifications: Steinberg, modified Kerboul, and Japanese Investigation Committee classifications. METHODS: In the novel classification, necrotic lesions were classified into 3 types: type 1 is a small lesion, where the lateral necrotic margin is medial to the femoral head apex; type 2 is a medium-sized lesion, with the lateral necrotic margin being between the femoral head apex and the lateral acetabular edge; and type 3 is a large lesion, which extends outside the lateral acetabular edge. In a derivation cohort of 40 early-stage osteonecrotic hips based on computed tomography imaging, reliabilities were evaluated using kappa coefficients, and validities to predict future femoral head collapse by chi-squared tests and receiver operating characteristic curve analyses. The predictability for future collapse was also evaluated in a validation cohort of 104 early-stage ONFH. RESULTS: In the derivation cohort, interobserver reliability (k = 0.545) and intraobserver agreement (63%-100%) of the novel method were higher than the other 3 classifications. The novel classification system was best able to predict future collapse (P < .05) and had the best discrimination between non-progressors and progressors in both the derivation cohort (area under the curve = 0.692 [0.522-0.863], P < .05) and the validation cohort (area under the curve = 0.742 [0.644-0.841], P = 2.46 × 10-5). CONCLUSION: This novel classification is a highly reliable and valid method of those examined. Association Research Circulation Osseous recommends using this method as a unified classification for early-stage ONFH. LEVEL OF EVIDENCE: Level III, diagnostic study.

Endoscopic Evaluation of Radiologic Distal Esophageal Thickening.

GOALS: We aim to determine the incidence of esophagogastroduodenoscopies (EGDs) primarily performed for imaging findings of distal esophageal thickening (DET). We also aim to determine if patients with imaging findings of DET have a higher incidence of cancer, and to evaluate the risk factors associated with findings of malignancy. BACKGROUND: The growth of diagnostic imaging has led to an increase in incidental findings of DET. This nonspecific finding frequently prompts an EGD for evaluation-many of which demonstrate benign conditions. There may be a misuse of valuable resources. STUDY: We performed a retrospective chart review of 1080 EGDs from January 2016 to July 2018 at the Veterans Affairs Medical Center, comparing EGDs for the indication of imaging report of DET with EGDs for other indications. Patient demographics, clinical history, imaging, procedure, and pathology reports were collected. Descriptive analysis and biostatistical analysis with χ2, Fisher exact, Wilcoxon rank sum, and Kruskal-Wallis tests were utilized in analyzing the data. RESULTS: Of the 1080 total endoscopies, 8.2% (n=88) were done specifically because of the imaging findings of DET. Those who had EGDs performed because of DET had a higher percentage of abnormal esophageal findings and of cancer. A history of Barrett's esophagus, tobacco use, and having gastrointestinal symptoms were not significant predictors of abnormal findings or of cancer for EGDs done for DET. CONCLUSIONS: There may be a role for EGDs performed for radiologic findings of DET. Even those without risk factors for malignancy should have EGDs performed for DET. Radiologists should consider reporting the DET size in order to determine if significant endoscopic findings correlate with wall thickness.

ARCO Consensus on the Pathogenesis of Non-traumatic Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is a devastating disease frequently leading to femoral head collapse and hip arthritis. Specifically, non-traumatic ONFH primarily affects young and middle-aged adults. Although compromised local circulation of the femoral head seems to be pathognomonic for the disease, the pathogenesis is perplexing and continues to be an area of scrutiny and research. Comprehension of the pathogenesis is of crucial importance for developing and guiding treatments for the disease. Therefore, we provide an up-to-date consensus on the pathogenesis of non-traumatic ONFH.

Osteonecrosis of the Femoral Head: an Updated Review of ARCO on Pathogenesis, Staging and Treatment.

Non-traumatic osteonecrosis of the femoral head (ONFH) usually affects adults younger than 50 years and frequently leads to femoral head collapse and subsequent arthritis of the hip. It is becoming more prevalent along with increasing use of corticosteroids for the adjuvant therapy of leukemia and other myelogenous diseases as well as management of organ transplantation. This review updated knowledge on the pathogenesis, classification criteria, staging system, and treatment of ONFH.

Diagnosis and Treatment of Femoral Head Osteonecrosis: A Protocol for Development of Evidence-Based Clinical Practice Guidelines.

INTRODUCTION: There are many treatment options for patients who have osteonecrosis of the femoral head (ONFH) and management strategies vary widely both among and within individual countries. Although many researchers have attempted to elucidate the optimal strategies for managing this disease, the lack of large-scale randomized control trials and the lack of agreement on disease staging have curtailed the development of clear-cut guidelines. MATERIALS AND METHODS: The Association Research Circulation Osseous (ARCO) group sought to address three questions for the management of patients who have ONFH: 1) What imaging studies are most sensitive and specific for the diagnostic evaluation of patients who have ONFH?; 2) What is the best treatment strategy for preventing disease progression in patients who have pre-collapse lesions?; and 3) What is the best treatment strategy for patients who have post-collapse disease? The Patient, Intervention, Comparison, and Outcome (PICO) format was used to formulate the search strategy for each research question. A systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ARCO participants have been allocated to three groups, each representing one of the PICO questions. After qualitative and quantitative analysis of the data extracted from studies pertaining to each of the three research questions, a set of evidence-based clinical practice guidelines will be proposed for the management of patients who have ONFH. DISCUSSION: It is not always clear which treatment method is optimal for the management of ONFH. Thus, many surgeons have developed and performed various procedures based on patient-specific factors. As there is no consensus on the optimal treatment for various stages of disease, it was clear that developing evidence-based clinical practice guidelines would provide more structure and uniformity to management of these patients. Therefore, the results of this systematic review will lead to the development guidelines that may improve patient-care strategies and result in better outcomes for patients who have ONFH.

Inpatient hospital procedural volume and outcomes following catheter ablation of atrial fibrillation.

INTRODUCTION: The real-world distribution of hospital atrial fibrillation (AF) ablation volume and its impact on outcomes are not well-established. We sought to examine patient characteristics, complications, and readmissions after AF ablation stratified by hospital procedural volume. METHODS AND RESULTS: Using the nationally representative inpatient Nationwide Readmissions Database, we evaluated 54 597 admissions for AF ablation between 2010 and 2014. Hospitals were categorized according to tertiles of annual AF ablation volume. Index complications, 30-day readmissions, and early mortality were examined. Multivariable logistic regression was performed to assess the predictors of adverse outcomes. Between 2010 and 2014, low volume tertile hospitals accounted for 79.3% of hospitals performing AF ablations. When stratified by first, second, and third volume tertiles, complication and early mortality rates were higher in low volume centers (8.9% and 0.67% vs 6.1% and 0.33%, vs 4.5% and 0.16%, respectively; P < .001). Patients undergoing AF ablation at low volume centers were older and had a higher prevalence of congestive heart failure, coronary artery disease, and other comorbidities. Low volume hospitals were associated with increased cardiac perforation (adjusted odds ratio [aOR], 4.79; P < .001), vascular complications (aOR 1.49; P < .001), and any complication (aOR 2.06; P < .001) during index admission as well as increased early mortality (aOR 2.43; P = .039). CONCLUSIONS: Among patients hospitalized for AF ablation, low inpatient AF ablation hospital volume was associated with worse outcomes following ablation, which was exacerbated by a greater comorbidity burden among patients at these centers.

Sex-based differences in outcomes, 30-day readmissions, and costs following catheter ablation of atrial fibrillation: the United States Nationwide Readmissions Database 2010-14.

AIMS: Although catheter ablation has emerged as an important therapy for patients with symptomatic atrial fibrillation (AF), there are limited data on sex-based differences in outcomes. We sought to compare in-hospital outcomes and 30-day readmissions of women and men undergoing AF ablation. METHODS AND RESULTS: Using the United States Nationwide Readmissions Database, we analysed patients undergoing AF ablation between 2010 and 2014. Based on ICD-9-CM codes, we identified co-morbidities and outcomes. Multivariable logistic regression and inverse probability-weighting analysis were performed to assess female sex as a predictor of endpoints. Of 54 597 study patients, 20 623 (37.7%) were female. After adjustment for age, co-morbidities, and hospital factors, women had higher rates of any complication [adjusted odds ratio (aOR) 1.39; P < 0.0001], cardiac perforation (aOR 1.39; P = 0.006), and bleeding/vascular complications (aOR 1.49; P < 0.0001). Thirty-day all-cause readmission rates were higher for women compared to men (13.4% vs. 9.4%; P < 0.0001). Female sex was independently associated with readmission for AF/atrial tachycardia (aOR 1.48; P < 0.0001), cardiac causes (aOR 1.40; P < 0.0001), and all causes (aOR 1.25; P < 0.0001). Similar findings were confirmed with inverse probability-weighting analysis. Despite increased complications and readmissions, total costs for AF ablation were lower for women than men due to decreased resource utilization. CONCLUSIONS: Independent of age, co-morbidities, and hospital factors, women have higher rates of complications and readmissions following AF ablation. Sex-based differences and disparities in the management of AF need to be explored to address these gaps in outcomes.

The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head.

BACKGROUND: The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification. METHODS: In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale. RESULTS: Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I-X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II-X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III-fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV-X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression. CONCLUSION: A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.

Effect of chemotherapy on cancer stem cells and tumor-associated macrophages in a prospective study of preoperative chemotherapy in soft tissue sarcoma.

BACKGROUND: Cancer stem cells (CSC) may respond to chemotherapy differently from other tumor cells. METHODS: This study examined the expression of the putative cancer stem cell markers ALDH1, CD44, and CD133; the angiogenesis marker CD31; and the macrophage marker CD68 in soft tissue sarcomas (STS) before and after 4 cycles of chemotherapy with doxorubicin and ifosfamide in 31 patients with high-grade soft tissue sarcoma in a prospective clinical trial. RESULTS: None of the markers clearly identified CSCs in STS samples. Macrophages represented a prominent component in viable tumor areas in pre-treatment STS biopsies, ranging from < 5 to > 50%. Furthermore, macrophages expressed CD44 and ALDH1. Macrophage density correlated with baseline maximum standardized uptake value (SUVmax) on fluoro-deoxyglucose positron emission tomography (PET) imaging. Pre-chemotherapy CD68 staining correlated positively with the baseline SUVmax, and negatively with the percent of viable tumor cells in post-chemotherapy resection samples. In particular, cases with more CD68-positive cells at biopsy had fewer viable tumor cells at resection, suggesting a better response to chemotherapy. CONCLUSIONS: In conclusion, ALDH1, CD44, and CD133 are not likely to be useful markers of CSCs in STS. However, our observation of infiltrating macrophages in STS specimens indicates that these immune cells may contribute significantly to STS biology and response to chemotherapy, and could provide a potential target of therapy. Future studies should investigate macrophage contribution to STS pathophysiology by cytokine signaling.

Reconstruction of the Shoulder and Humerus in Metastatic Bone Disease.

Metastatic disease involving the skeleton most often affects the spine, pelvis, and proximal long bones of the extremities. In the upper extremity, the proximal humerus is frequently affected. Although many of the principles of managing metastatic bone disease are similar, regardless of the metastatic site, the upper extremity has some unique anatomic and functional traits that warrant consideration when making management decisions. The main anatomic differences from the lower extremity pertain to the smaller bone size, rotator cuff function, and proximity to major neurologic structures, and the important functional differences that relate to activities of daily living have a greater dependence on the upper, rather than lower, extremity; greater range of motion of the shoulder; side dominance; limited weight-bearing function; and marked propensity of the elbow to develop stiffness. Clinicians should consider aspects of the shoulder and humerus as they relate to the overall management of metastatic bone disease, either monostotic or polyostotic, when evaluating and managing metastatic lesions at this site.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 1: Glucocorticoid-Associated Osteonecrosis.

BACKGROUND: Glucocorticoid usage, a leading cause of osteonecrosis of the femoral head (ONFH), and its prevalence was reported in 25%-50% of non-traumatic ONFH patients. Nevertheless, there have been no unified criteria to classify glucocorticoid-associated ONFH (GA-ONFH). In 2015, the Association Research Circulation Osseous addressed the issue of developing a classification scheme. METHODS: In June 2017, a task force was set up to conduct a Delphi survey concerning ONFH. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey consists of questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, the panel reached a consensus on the classification criteria. The response rates were 100% (Round 1), 96% (Round 2), and 100% (Round 3), respectively. RESULTS: The consensus on the classification criteria of GA-ONFH included the following: (1) patients should have a history of glucocorticoid use >2 g of prednisolone or its equivalent within a 3-month period; (2) osteonecrosis should be diagnosed within 2 years after glucocorticoid usage, and (3) patients should not have other risk factor(s) besides glucocorticoids. CONCLUSION: Association Research Circulation Osseous established classification criteria to standardize clinical studies concerning GA-ONFH.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 2: Alcohol-Associated Osteonecrosis.

BACKGROUND: Although alcohol is a leading risk factor for osteonecrosis of the femoral head (ONFH) and its prevalence reportedly ranges from 20% to 45%, there are no unified classification criteria for this subpopulation. In 2015, Association Research Circulation Osseous decided to develop classification criteria for alcohol-associated ONFH. METHODS: In June of 2017, Association Research Circulation Osseous formed a task force to conduct a Delphi survey. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey included questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, consensus was reached on the classification criteria. The response rates for the 3 Delphi rounds were 100% (round 1), 96% (round 2), and 100% (round 3). RESULTS: The consensus on the classification criteria of alcohol-associated ONFH included the following: (1) patients should have a history of alcohol intake >400 mL/wk (320 g/wk, any type of alcoholic beverage) of pure ethanol for more than 6 months; (2) ONFH should be diagnosed within 1 year after alcohol intake of this dose; and (3) patients should not have other risk factor(s). CONCLUSION: ARCO-established classification criteria to standardize clinical studies concerning AA-ONFH.

Drug-induced immune hemolytic anemia associated with anti-vancomycin complicated by a paraben antibody.

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is rare, but potentially life-threatening. A high index of clinical suspicion is required for diagnosis, since the number of medications known to induce DIIHA continues to expand. Additionally, in vitro antibody reactivity against reagent additives has been reported, which may complicate test interpretation. CASE REPORT: A 61-year-old group A, D+ woman with a history of negative antibody detection tests developed hemolytic anemia on Postoperative Day 7 after repeat incision and drainage of a chronically infected right knee prosthesis. She was treated with multiple antibiotics in the postoperative period, including three cephalosporins and vancomycin intravenously as well as vancomycin and gentamicin-containing intraarticular cement spacers. STUDY DESIGN AND METHODS: A workup for possible DIIHA was performed. Testing was performed using vancomycin and cephalosporin antibiotics. Initially, gentamicin injection solution was used for testing, followed by testing with its component ingredients. RESULTS: A vancomycin antibody was detected and anemia resolved after vancomycin was discontinued. Reactivity was seen when gentamicin injection solution was used for testing, raising the possibility of a gentamicin antibody as well. However, testing with purified gentamicin as well as methylparaben and propylparaben demonstrated a paraben antibody that reacted with the paraben-containing gentamicin solution. The patient also demonstrated an anti-N. Neither the paraben antibody nor the anti-N appeared to cause in vivo hemolysis. CONCLUSION: This is the second reported case of DIIHA associated with anti-vancomycin. It is the fourth report describing a paraben antibody.

CT-based Structural Rigidity Analysis Is More Accurate Than Mirels Scoring for Fracture Prediction in Metastatic Femoral Lesions.

BACKGROUND: Controversy continues regarding the appropriate assessment of fracture risk in long bone lesions affected by disseminated malignancy. QUESTIONS/PURPOSES: The purpose of this ongoing Musculoskeletal Tumor Society-sponsored, multi-institutional prospective cross-sectional clinical study is to compare CT-based structural rigidity analysis (CTRA) with physician-derived Mirels scoring for predicting pathologic fracture in femoral bone lesions. We hypothesized CTRA would be superior to Mirels in predicting fracture risk within the first year based on (1) sensitivity, specificity, positive predictive value, and negative predictive value; (2) receiver operator characteristic (ROC) analysis; and (3) fracture prediction after controlling for potential confounding variables such as age and lesion size. METHODS: Consented patients with femoral metastatic lesions were assigned Mirels scores by the individual enrolling orthopaedic oncologist based on plain radiographs and then underwent CT scans of both femurs with a phantom of known density. The CTRA was then performed. Between 2004 and 2008, six study centers performed CTRA on 125 patients. The general indications for this test were femoral metastatic lesions potentially at risk of fracture. The enrolling physician was allowed the choice of prophylactic stabilization or nonsurgical treatment, and the local treating oncology team along with the patient made this decision. Of those 125 patients, 78 (62%) did not undergo prophylactic stabilization and had followup sufficient for inclusion, which was fracture through the lesion within 12 months of CTRA, death within 12 months of CTRA, or 12-month survival after CTRA without fracture, whereas 15 (12%) were lost to followup and could not be studied here. The mean patient age was 61 years (SD, 14 years). There were 46 women. Sixty-four of the lesions were located in the proximal femur, 13 were in the diaphysis, and four were distal. Osteolytic lesions prevailed (48 lesions) over mixed (31 lesions) and osteoblastic (15 lesions). The most common primary cancers were breast (25 lesions), lung (14 lesions), and myeloma (11 lesions). CTRA was compared with Mirels based on sensitivity/specificity analysis, ROC, and fracture prediction by multivariate analysis. For the CTRA, reduction greater than 35% in axial, bending, or torsional rigidities at the lesion was considered at risk for fracture, whereas a Mirels score of 9 or above, as suggested in the original manuscript, was used as the definition of impending fracture. RESULTS: CTRA provided higher sensitivity (100% versus 66.7%), specificity (60.6% versus 47.9%), positive predictive value (17.6% versus 9.8%), and negative predictive value (100% versus 94.4%) compared with the classic Mirels definition of impending fracture (≥ 9), although there was considerable overlap in the confidence intervals. ROC curve analysis found CTRA to be better than the Mirels score regardless of what Mirels score cutoff was used. After controlling for potential confounding variables including age, lesion size, and Mirels scores, multivariable logistic regression indicated that CTRA was a better predictor of fracture (likelihood ratio test = 10.49, p < 0.001). CONCLUSIONS: CT-based structural rigidity analysis is better than Mirels score in predicting femoral impending pathologic fracture. CTRA appears to provide a substantial advance in the accuracy of predicting pathological femur fracture over currently used clinical and radiographic criteria. LEVEL OF EVIDENCE: Level III, diagnostic study.

Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels.

Ca(2+) influx via L-type Ca(v)1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca(2+) signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Ca(v)1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca(2+) influx and excitation-contraction coupling. Light-induced fusion of WT Ca(v)1.2 channels with Ca(v)1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca(v)1.2-TS) increased Ca(2+) currents, diastolic and systolic Ca(2+) levels, contractility and the frequency of arrhythmogenic Ca(2+) fluctuations in ventricular myocytes. Our data indicate that these changes in Ca(2+) signaling resulted from Ca(v)1.2-TS increasing the activity of adjoining WT Ca(v)1.2 channels. Collectively, these data support the concept that oligomerization of Ca(v)1.2 channels via their C termini can result in the amplification of Ca(2+) influx into excitable cells.

Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8).

Ca(2+) flux through l-type CaV1.2 channels shapes the waveform of the ventricular action potential (AP) and is essential for excitation-contraction (EC) coupling. Timothy syndrome (TS) is a disease caused by a gain-of-function mutation in the CaV1.2 channel (CaV1.2-TS) that decreases inactivation of the channel, which increases Ca(2+) influx, prolongs APs, and causes lethal arrhythmias. Although many details of the CaV1.2-TS channels are known, the cellular mechanisms by which they induce arrhythmogenic changes in intracellular Ca(2+) remain unclear. We found that expression of CaV1.2-TS channels increased sarcolemmal Ca(2+) "leak" in resting TS ventricular myocytes. This resulted in higher diastolic [Ca(2+)]i in TS ventricular myocytes compared to WT. Accordingly, TS myocytes had higher sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) spark activity, larger amplitude [Ca(2+)]i transients, and augmented frequency of Ca(2+) waves. The large SR Ca(2+) release in TS myocytes had a profound effect on the kinetics of CaV1.2 current in these cells, increasing the rate of inactivation to a high, persistent level. This limited the amount of influx during EC coupling in TS myocytes. The relationship between the level of expression of CaV1.2-TS channels and the probability of Ca(2+) wave occurrence was non-linear, suggesting that even low levels of these channels were sufficient to induce maximal changes in [Ca(2+)]i. Depolarization of WT cardiomyocytes with a TS AP waveform increased, but did not equalize [Ca(2+)]i, compared to depolarization of TS myocytes with the same waveform. We propose that CaV1.2-TS channels increase [Ca(2+)] in the cytosol and the SR, creating a Ca(2+)overloaded state that increases the probability of arrhythmogenic spontaneous SR Ca(2+) release.

An unusual case of Ewing sarcoma: a middle-aged woman with multiple recurrences over 36 years.

Ewing sarcoma (EWS) is a primary bone tumor that most often occurs in the long bones of young patients. EWS is typically an aggressive tumor that is highly sensitive to radiation therapy; recurrences often occur, usually within a year of treatment. We present a case of EWS that first presented in a patient at the age of 40 with extraosseous disease. The patient was treated initially with radiation and surgery. Over the following 36-year period, the tumor recurred once and metastasized twice. The morphologic, immunohistochemical, and cytogenetic features of this tumor were typical of EWS, and the tumor was highly responsive to radiation therapy. The unusually prolonged course in this patient demonstrates significant heterogeneity in the biological behavior of EWS, and the importance of randomized trials in cancer therapy.

Chemotherapy influences the pseudocapsule composition in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are a heterogeneous group of malignant tumors. Standard treatment for soft tissue sarcoma of the extremity is surgical excision and adjuvant therapy; however, the role of neoadjuvant chemotherapy is controversial. QUESTIONS/PURPOSES: We sought to (1) define the histologic characteristics of the pseudocapsule in soft tissue sarcomas; (2) compare the appearance of this structure in chemotherapy-treated versus untreated soft tissue sarcomas; and (3) evaluate the effect of chemotherapy on the presence and viability of tumor cells at the host-sarcoma interface. METHODS: Twenty-eight patients with biopsy-proven, deep, high-grade extremity soft tissue sarcomas greater than 5 cm (AJCC stage III) treated with chemotherapy and surgical excision were compared histologically with 47 matched control subjects treated with surgery alone. RESULTS: A pseudocapsule was identifiable in the majority of tumors and consisted of two identifiable layers, each with specific histological characteristics suggesting the biologic processes occurring in these layers are different. The pseudocapsule was more frequently observed in the group treated with chemotherapy and it was more frequently continuous, thicker, and better developed in this group. Chemotherapy decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CONCLUSIONS: Neoadjuvant chemotherapy contributed to the development of a pseudocapsule and decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CLINICAL RELEVANCE: These findings may provide a histological explanation for the clinical effect of chemotherapy in soft tissue sarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.