The Predictors of Surgery for Symptomatic, Atraumatic Full-Thickness Rotator Cuff Tears Change Over Time: Ten-Year Outcomes of the MOON Shoulder Prospective Cohort.

BACKGROUND: A prospective cohort study was conducted to assess the predictors of failure of nonoperative treatment, defined as the patient undergoing surgery for symptomatic, atraumatic full-thickness rotator cuff tears. We present the 10-year follow-up data of this population to determine if predictors for surgery change over time, and secondarily we report the outcomes of the cohort. METHODS: At the time of enrollment, demographic, symptom, rotator cuff anatomy, and patient-reported outcome data were collected in patients with symptomatic, atraumatic full-thickness rotator cuff tears. Patients underwent a standard physical therapy protocol for 6 to 12 weeks. Patient data were then collected at 1, 2, 5, 7, and 10 years. Failure of nonoperative treatment was defined as the patient electing to undergo surgery. RESULTS: Of the 452 patients in the original cohort, 20 patients (5%) withdrew from the study, 37 (9%) died before 10 years, and 40 (9%) were otherwise lost to follow-up. A total of 115 patients (27.0%) underwent a surgical procedure at some point during the 10-year follow-up period. Of these patients, 56.5% underwent surgery within 6 months of enrollment and 43.5%, between 6 months and 10 years. Low patient expectations regarding the efficacy of physical therapy were found to be a predictor of early surgery. Workers' Compensation status and activity level were more important predictors of later surgery. Patient-reported outcome measures all improved following physical therapy. For patients who did not undergo a surgical procedure, patient-reported outcome measures did not decline over the 10-year follow-up period. CONCLUSIONS: Low patient expectations regarding the efficacy of physical therapy were found to be a predictor of early surgery, whereas Workers' Compensation status and activity level were predictors of later surgery. Physical therapy was successful in >70% of patients with symptomatic, atraumatic full-thickness rotator cuff tears at 10 years. Outcome measures improved with physical therapy and did not decline over the 10-year follow-up period. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

2013 Neer Award: predictors of failure of nonoperative treatment of chronic, symptomatic, full-thickness rotator cuff tears.

BACKGROUND: The purpose of this study is to help define the indications for rotator cuff repair by identifying predictors of failure of nonoperative treatment. METHODS: A prospective, multicenter, cohort study design was used. All patients with full-thickness rotator cuff tears on magnetic resonance imaging were offered participation. Baseline data from this cohort were used to examine risk factors for failing a standard rehabilitation protocol. Patients who underwent surgery were defined as failing nonoperative treatment. A Cox proportional hazards model was fit to determinethe baseline factors that predicted failure. The dependent variable was time to surgery. The independent variables were tear severity and baseline patient factors: age, activity level, body mass index, sex, Single Assessment Numeric Evaluation score, visual analog scale score for pain, education, handedness, comorbidities, duration of symptoms, strength, employment, smoking status, and patient expectations. RESULTS: Of the 433 subjects in this study, 87 underwent surgery with 93% follow-up at 1 year and 88% follow-up at 2 years. The median age was 62 years, and 49% were female patients. Multivariate modeling, adjusted for the covariates listed previously, identified patient expectations regarding physical therapy (P < .0001) as the strongest predictor of surgery. Higher activity level (P = .011) and not smoking (P = .023) were also significant predictors of surgery. CONCLUSION: A patient's decision to undergo surgery is influenced more by low expectations regarding the effectiveness of physical therapy than by patient symptoms or anatomic features of the rotator cuff tear. As such, patient symptoms and anatomic features of the chronic rotator cuff tear may not be the best features to use when deciding on surgical intervention.

ResQFoam for the Treatment of Non-Compressible Hemorrhage on the Front Line.

Noncompressible torso hemorrhage is the leading cause of potentially survivable death on the battlefield. While medical advances have decreased the rate of "died of wounds" to less than 5%, significant treatment limitations in pre-hospital care remain. To address this persistent capability gap, the Defense Advanced Research Projects Agency launched the Wound Stasis System program in 2010. Under that program, Arsenal Medical, in collaboration with Massachusetts General Hospital and Harvard Medical School, developed a novel, self-expanding polyurethane foam that rapidly treats major abdominal bleeding due to trauma, for use at the point of care. This foam treatment is envisioned as an emergency "bridge to surgery" for warfighters who would otherwise die in the field. This commentary presents this emerging technology with the objective to bring to the community's attention a potentially promising device for the treatment of noncompressible abdominal hemorrhage.

The duration of symptoms does not correlate with rotator cuff tear severity or other patient-related features: a cross-sectional study of patients with atraumatic, full-thickness rotator cuff tears.

HYPOTHESIS: The purpose of this cross-sectional study is to determine whether the duration of symptoms influences the features seen in patients with atraumatic, full-thickness rotator cuff tears. Our hypothesis is that an increasing duration of symptoms will correlate with more advanced findings of rotator cuff tear severity on magnetic resonance imaging, worse shoulder outcome scores, more pain, decreased range of motion, and less strength. METHODS: We enrolled 450 patients with full-thickness rotator cuff tears in a prospective cohort study to assess the effectiveness of nonoperative treatment and factors predictive of success. The duration of patient symptoms was divided into 4 groups: 3 months or less, 4 to 6 months, 7 to 12 months, and greater than 12 months. Data collected at patient entry into the study included (1) demographic data, (2) history and physical examination data, (3) radiographic imaging data, and (4) validated patient-reported measures of shoulder status. Statistical analysis included a univariate analysis with the Kruskal-Wallis test and Pearson test to identify statistically significant differences in these features for different durations of symptoms. RESULTS: A longer duration of symptoms does not correlate with more severe rotator cuff disease. The duration of symptoms was not related to weakness, limited range of motion, tear size, fatty atrophy, or validated patient-reported outcome measures. CONCLUSIONS: There is only a weak relationship between the duration of symptoms and features associated with rotator cuff disease.

Effectiveness of physical therapy in treating atraumatic full-thickness rotator cuff tears: a multicenter prospective cohort study.

PURPOSE: To assess the effectiveness of a specific nonoperative physical therapy program in treating atraumatic full-thickness rotator cuff tears using a multicenter prospective cohort study design. MATERIALS AND METHODS: Patients with atraumatic full-thickness rotator cuff tears who consented to enroll provided data via questionnaire on demographics, symptom characteristics, comorbidities, willingness to undergo surgery, and patient-related outcome assessments (Short Form 12 score, American Shoulder and Elbow Surgeons score, Western Ontario Rotator Cuff score, Single Assessment Numeric Evaluation score, and Shoulder Activity Scale). Physicians recorded physical examination and imaging data. Patients began a physical therapy program developed from a systematic review of the literature and returned for evaluation at 6 and 12 weeks. At those visits, patients could choose 1 of 3 courses: (1) cured (no formal follow-up scheduled), (2) improved (continue therapy with scheduled reassessment in 6 weeks), or (3) no better (surgery offered). Patients were contacted by telephone at 1 and 2 years to determine whether they had undergone surgery since their last visit. A Wilcoxon signed rank test with continuity correction was used to compare initial, 6-week, and 12-week outcome scores. RESULTS: The cohort consists of 452 patients. Patient-reported outcomes improved significantly at 6 and 12 weeks. Patients elected to undergo surgery less than 25% of the time. Patients who decided to have surgery generally did so between 6 and 12 weeks, and few had surgery between 3 and 24 months. CONCLUSION: Nonoperative treatment using this physical therapy protocol is effective for treating atraumatic full-thickness rotator cuff tears in approximately 75% of patients followed up for 2 years.

Defining the role of PET-CT in staging early breast cancer.

INTRODUCTION: Currently, there is a lack of data on the role of combined positron emission tomography-computed tomography (PET-CT) in the staging of early invasive primary breast cancer. We therefore evaluated the role of (18)F-fluorodeoxyglucose ((18)F-FDG)-PET-CT in this patient population. METHODS: We prospectively recruited 70 consecutive patients (69 women, one man; mean age, 61.9 ± 8.1 years) with early primary breast cancer for staging with (18)F-FDG-PET-CT. All PET-CT images were interpreted by two readers (independently of each other). A third reader adjudicated any discrepancies. All readers had ≥5 years of specific experience. Ethics board approval and informed consent were obtained. RESULTS: The mean clinical follow-up was 22.7 ± 12.6 months. The primary tumor was identified with PET-CT in 64 of 70 patients. Of the unidentified lesions, surgical pathology revealed two intraductal carcinomas, one invasive tubular carcinoma, and three invasive lobular carcinomas. Undiagnosed multifocal breast disease was shown in seven of 70 patients. PET-CT identified avid axillary lymph nodes in 19 of 70 patients, compared with 24 of 70 confirmed during surgery. There were four patients who were axillary node positive on PET but had no axillary disease at surgery. Five patients were reported with avid metastases. Two of those patients were treated for metastatic disease (nodal, lung, and liver in one and bone metastases in the other) following further imaging and clinical assessment. In the other three patients, lesions (lung, n = 1; pleural, n = 1; paratrachael node, n = 1) were subsequently diagnosed as benign lesions. CONCLUSION: Integrated (18)F-FDG-PET-CT may have a role in staging patients presenting with early breast cancer.

Haemophilia imaging: a review.

Haemophilia disorders are characterised by a blood coagulation anomaly leading to prolonged and excessive bleeding. Imaging provides an essential role in the investigation of both the musculoskeletal and the non-musculoskeletal complications of haemophilia. Our institution is home to a large tertiary referral centre for haemophilia treatment. Using our broad experience, we present a multi-modality pictorial review of the musculoskeletal manifestations of haemophilia, including haemophilic arthropathy, intra-muscular haemorrhage and haemophilic pseudotumour. The main imaging features of haemophilic arthropathy are described, including synovial hypertrophy, haemosiderin deposition, sub-chondral cyst formation and loss of joint space.

Identification of biomarkers in human head and neck tumor cell lines that predict for in vitro sensitivity to gefitinib.

Potential biomarkers were identified for in vitro sensitivity to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in head and neck cancer. Gefitinib sensitivity was determined in cell lines, followed by transcript profiling coupled with a novel pathway analysis approach. Eleven cell lines were highly sensitive to gefitinib (inhibitor concentration required to give 50% growth inhibition [GI(50)] < 1 microM), three had intermediate sensitivity (GI(50) 1-7 microM), and six were resistant (GI(50) > 7 microM); an exploratory principal component analysis revealed a separation between the genomic profiles of sensitive and resistant cell lines. Subsequently, a hypothesis-driven analysis of Affymetrix data (Affymetrix, Inc., Santa Clara, CA, USA) revealed higher mRNA levels for E-cadherin (CDH1); transforming growth factor, alpha (TGF-alpha); amphiregulin (AREG); FLJ22662; EGFR; p21-activated kinase 6 (PAK6); glutathione S-transferase Pi (GSTP1); and ATP-binding cassette, subfamily C, member 5 (ABCC5) in sensitive versus resistant cell lines. A hypothesis-free analysis identified 46 gene transcripts that were strongly differentiated, seven of which had a known association with EGFR and head and neck cancer (human EGF receptor 3 [HER3], TGF-alpha, CDH1, EGFR, keratin 16 [KRT16], fibroblast growth factor 2 [FGF2], and cortactin [CTTN]). Polymerase chain reaction (PCR) and enzyme-linked immunoabsorbant assay analysis confirmed Affymetrix data, and EGFR gene mutation, amplification, and genomic gain correlated strongly with gefitinib sensitivity. We identified biomarkers that predict for in vitro responsiveness to gefitinib, seven of which have known association with EGFR and head and neck cancer. These in vitro predictive biomarkers may have potential utility in the clinic and warrant further investigation.

Epidermal growth factor receptor immunohistochemistry: comparison of antibodies and cutoff points to predict benefit from gefitinib in a phase 3 placebo-controlled study in advanced nonsmall-cell lung cancer.

BACKGROUND: The ISEL (Iressa Survival Evaluation in Lung Cancer) clinical trial evaluated the efficacy of gefitinib versus placebo in pretreated nonsmall-cell lung cancer patients. Two different antibodies, scoring systems, and cutoff points of epidermal growth factor receptor (EGFR) protein expression were compared to predict response and survival of enrolled patients. METHODS: EGFR expression was assessed in tumor samples by immunohistochemistry using the Dako EGFR pharmDx kit (scoring percent of tumor cells with positive staining) and Zymed monoclonal antibody clone 31G7 (scoring staining index derived from proportion of positive cells times staining intensity). RESULTS: Data for EGFR expression were available for 379 patients for Dako and 357 patients for Zymed antibody (22% and 21%, respectively, of trial population). Objective response rates in gefitinib-treated EGFR-positive patients defined with various cutpoints with Dako antibody varied between 8% and 12%, and with Zymed antibody between 10% and 13%. Lower cutoff points with Dako antibody provided the best discrimination between EGFR-positive and EGFR-negative patients for survival hazard ratios comparing gefitinib to placebo, with a significant treatment/cutoff point interaction for 10% cutoff point (P = .049). A similar but less apparent trend was noted for Zymed antibody, although the discrimination between hazard ratios was not significant for any cutoff point analyzed. CONCLUSIONS: Assessment with the Dako PharmDx kit and percentage of cells with positive staining may provide more accurate prediction of differential effect on survival with gefitinib than assessment with Zymed antibody and staining index. Using higher cutpoints to define positivity does not improve test discrimination.

Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.

PURPOSE: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. METHODS: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). RESULTS: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. CONCLUSION: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.

Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non-small-cell lung cancer.

Cases of non-small-cell lung cancer (NSCLC) carrying the somatic mutation of epidermal growth factor receptor (EGFR) have been shown to be hyperresponsive to the EGFR tyrosine kinase inhibitor gefitinib (IRESSA). If EGFR mutations can be observed in serum DNA, this could serve as a noninvasive source of information on the genotype of the original tumor cells that could influence treatment and the ability to predict patient response to gefitinib. Serum genomic DNA was obtained from Japanese patients with NSCLC before first-line gefitinib monotherapy. Scorpion Amplified Refractory Mutation System technology was used to detect EGFR mutations. Wild-type EGFR was detected in all of the 27 serum samples. EGFR mutations were detected in 13 of 27 (48.1%) patients and two major EGFR mutations were identified (E746_A750del and L858R). The EGFR mutations were seen significantly more frequently in patients with a partial response than in patients with stable disease or progressive disease (P = 0.046, Fisher's exact test). The median progression-free survival was significantly longer in patients with EGFR mutations than in patients without EGFR mutations (200 versus 46 days; P = 0.005, log-rank test). The median survival was 611 days in patients with EGFR mutations and 232 days in patients without EGFR mutations (P > 0.05). In pairs of tumor and serum samples obtained from 11 patients, the EGFR mutation status in the tumors was consistent with those in the serum of 8 of 11 (72.7%) of the paired samples. Thus, EGFR mutations were detectable using Scorpion Amplified Refractory Mutation System technology in serum DNA from patients with NSCLC. These results suggest that patients with EGFR mutations seem to have better outcomes with gefitinib treatment, in terms of progression-free survival, overall survival, and response, than those patients without EGFR mutations.

Synovial sarcoma mimicking haemophilic pseudotumour.

This is a case of a 36-year-old gentleman with haemophilia A who was presented with an acute atraumatic soft tissue swelling in the right thigh. Open biopsy was performed with the resultant diagnosis of a synovial cell sarcoma. Although the clinical findings were nonspecific they could easily have been found in a bleeding haemophilic pseudotumour. The findings reported on MRI scan initially were highly consistent with those present in patients with mild haemophilia. An important part of orthopaedic management in haemophilia is concerned with intraarticular and intramuscular bleeding. Haematomas are common and sarcomas are rare. However the absence of trauma should alert the clinician to the possibility that the abnormality may represent haemorrhage into a tumour and not just haematoma, even in a haemophilic patient.

Recent developments related to the EGFR as a target for cancer chemotherapy.

Inhibition of the epidermal growth factor receptor as a target for cancer chemotherapy has proven to be an effective treatment in both preclinical and clinical settings. Recent work has indicated that the presence of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor is a major determinant of the response to the tyrosine kinase inhibitors gefitinib and erlotinib. However, this is not the full story, and further work is needed to identify the factors underlying the response in those who do not carry mutations. Mechanisms of innate and acquired resistance to epidermal growth factor receptor inhibitors are also topics under investigation. Crosstalk between the epidermal growth factor receptor and other growth factor receptors involved in tumorigenesis has been implicated, along with downstream signalling molecules such as Ras, Braf and PTEN. A full understanding of these mechanistic aspects could lead to the identification of useful combinations of inhibitors of novel targets.

[Evaluation of scintimammography as an additional test to conventional mammography in detection of breast cancer]. / Wartosc scyntymammografii jako testu wspomagajacego badanie mammograficzne w diagnostyce raka sutka.

OBJECTIVES AND DESIGN: Scintimammography using Tc-99m MIBI is becoming established as a second line diagnostic test for the detection of breast cancer in patients with suspected primary disease. Though most published clinical studies compare scintimammography (SMM) with mammography (XMM), in clinical practice they are likely to be used sequentially with the scintimammography following the mammography. MATERIALS AND METHODS: To determine the possible accuracy of such an approach, receiver operator characteristic (ROC) curves were produced for SMM, XMM and a combination of both studies performed over 2 years period on 162 suspicious lesions in 154 patients with no previous history of breast cancer. Each scan was reported in 5 grades: 1-normal or definitely benign; 2-possibly normal or possibly benign; 3-equivoval; 4-probably cancer; 5-definitely cancer. The results have been verified by pathological examination of biopsy material obtained from each suspicious mass. RESULTS: There were 102 malignant breast tumours and 60 non-malignant breast lesions. SMM correctly diagnosed 89 breast cancers, and was false negative in 13 cases. It was true negative in 36 benign breast lesions. The sensitivity of SMM was 87%, specificity 65%, PPV 81% and NPV 75%. XMM diagnosed correctly 70 malignant tumours. The sensitivity, specificity, PPV and NPV for XMM were respectively: 69%, 72%, PPV 81% and NPV 57%. However, if a combination of the two methods is used the overall diagnostic accuracy was as follows: 92%, 80%, 89% and 86%. Evaluation of index area under ROC curve allows in both diagnostic methods XMM and SMM results as follows: 0.79 and 0.83. Additional sequence imaging allows 0.94. Combined XMM and SMM in suspected primary breast cancer patients has higher diagnostic accuracy than each method separately (p < 0.05). CONCLUSION: This study shows that the combination of mammography and scintimammography produces more accurate results than either modality alone this is how these test should be performed in clinical practice.

Characterization of a novel coronavirus associated with severe acute respiratory syndrome.

In March 2003, a novel coronavirus (SARS-CoV) was discovered in association with cases of severe acute respiratory syndrome (SARS). The sequence of the complete genome of SARS-CoV was determined, and the initial characterization of the viral genome is presented in this report. The genome of SARS-CoV is 29,727 nucleotides in length and has 11 open reading frames, and its genome organization is similar to that of other coronaviruses. Phylogenetic analyses and sequence comparisons showed that SARS-CoV is not closely related to any of the previously characterized coronaviruses.