Summary Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and ...pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging–Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. Funding US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).
Summary Background Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received ...radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. Methods We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov , number NCT01295827. Findings Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8–34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio HR 0·56 95% CI 0·34–0·91, p=0·019; median progression-free survival 4·4 months 95% CI 2·1–8·6 vs 2·1 months 1·6–2·3) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 0·30–0·84, p=0·0084; median progression-free survival 6·3 months 95% CI 2·1–10·4 vs 2·0 months 1·8–2·1). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 95% CI 0·36–0·94, p=0·026; median overall survival 10·7 months 95% CI 6·5–18·9 vs 5·3 months 2·7–7·7) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 95% CI 0·36–0·96, p=0·034; median overall survival 11·6 months 95% CI 6·5–20·5 vs 5·3 months 3·0–8·5). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). Interpretation Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. Funding US National Institutes of Health.
Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of ...terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes.
Background Approximately 40% of patients in medical ICUs require mechanical ventilation (MV). Approximately 20% to 25% of these patients will encounter difficulties in discontinuing MV. Multiple ...studies have suggested that MV has an unloading effect on the respiratory muscles that leads to diaphragmatic atrophy and dysfunction, a process called ventilator-induced diaphragmatic dysfunction (VIDD). VIDD may be an important factor affecting when and if MV can be discontinued. A sensitive and specific diagnostic test for VIDD could provide the physician with valuable information that might influence decisions regarding extubation or tracheostomy. The purpose of this study was to quantify, using daily sonographic assessments, the rate and degree of diaphragm thinning during MV. Methods Seven intubated patients receiving MV during acute care were included. Using sonography, diaphragm muscle thickness was measured daily from the day of intubation until the patient underwent extubation or tracheostomy or died. We analyzed our data using standard descriptive statistics, linear regression, and mixed-model effects. Results The overall rate of decrease in the diaphragm thickness of all seven patients over time averaged 6% per day of MV, which differed significantly from zero. Similarly, the diaphragm thickness decreased for each patient over time. Conclusion Sonographic assessment of the diaphragm provides noninvasive measurement of diaphragmatic thickness and the degree of diaphragm thinning in patients receiving MV. Our data show that diaphragm muscle thinning starts within 48 h after initiation of MV. However, it is unclear if diaphragmatic thinning correlates with diaphragmatic atrophy or pulmonary function. The relationship between diaphragm thinning and diaphragm strength remains to be elucidated.
2009 Focused Update Writing Group Members Kirsten E. Fleischmann, MD, MPH, FACC, Chair Joshua A. Beckman, MD, FACC**SVM Representative; Christopher E. Buller, MD, FACCdaggerdaggerACCF/AHA Task Force ...on Practice Guidelines Liaison; Hugh Calkins, MD, FACC, FAHAdouble dagger Lee A. Fleisher, MD, FACC, FAHAdouble daggerdouble daggerACCF/AHA Representative William K. Freeman, MD, FACC¶ James B. Froehlich, MD, MPH, FACCdouble daggerdouble dagger Edward K. Kasper, MD, FACC, FAHAdouble daggerdouble dagger Judy R. Kersten, MD, FACC# John F. Robb, MD, FACC, FAHA|| R. James Valentine, MD§ Task Force Members Alice K. Jacobs, MD, FACC, FAHA, Chair 2009-2011 Sidney C. Smith, Jr, MD, FACC, FAHA, Immediate Past Chair 2006-2008§§Former Task Force member during this writing effort Jeffrey L. Anderson, MD, FACC, FAHA, Vice Chair Christopher E. Buller, MD, FACC Mark A. Creager, MD, FACC, FAHA Steven M. Ettinger, MD, FACC Robert A. Guyton, MD, FACC, FAHA Jonathan L. Halperin, MD, FACC, FAHA Judith S. Hochman, MD, FACC, FAHA Harlan M. Krumholz, MD, FACC, FAHA§§ Frederick G. Kushner, MD, FACC, FAHA Bruce W. Lytle, MD, FACC, FAHA§§ Rick Nishimura, MD, FACC, FAHA§§ Richard L. Page, MD, FACC, FAHA§§ William G. Stevenson, MD, FACC, FAHA Lynn G. Tarkington, RN Clyde W. Yancy, MD, FACC, FAHA Table of Contents Preamble (UPDATED)...e15 Introduction/Definition of the Problem (UPDATED)...e16 Methodology and Evidence Review (UPDATED)...e17 Organization of Committee and Relationships With Industry and Other Entities (NEW)...e17 Document Review and Approval (UPDATED)...e18 Epidemiology...e18 Practice Patterns...e19 Financial Implications...e19 General Approach to the Patient...e19 Role of the Consultant...e19 History...e20 Physical Examination...e20 Comorbid Diseases...e21 Pulmonary Disease...e21 Diabetes Mellitus...e21 Renal Impairment...e22 Hematologic Disorders...e22 Ancillary Studies...e22 Multivariable Indices to Predict Preoperative Cardiac Morbidity...e23 Clinical Assessment...e23 Stepwise Approach to Perioperative Cardiac Assessment...e23 Disease-Specific Approaches...e26 Coronary Artery Disease...e26 Patients With Known CAD...e26 Influence of Age and Gender...e26 Hypertension...e26 Heart Failure...e28 Cardiomyopathy...e28 Valvular Heart Disease...e28 Arrhythmias and Conduction Defects...e29 Implanted Pacemakers and ICDs...e30 Pulmonary Vascular Disease and Congenital Heart Disease...e30 Surgery-Specific Issues...e30 Urgency...e31 Surgical Risk...e31 Supplemental Preoperative Evaluation...e34 Assessment of LV Function...e34 Assessment of Risk for CAD and Assessment of Functional Capacity...e35 The 12-Lead ECG...e35 Exercise Stress Testing for Myocardial Ischemia and Functional Capacity...e35 Noninvasive Stress Testing...e37 Radionuclide Myocardial Perfusion Imaging Methods...e37 Dobutamine Stress Echocardiography...e40 Stress Testing in the Presence of Left Bundle-Branch Block...e42 Ambulatory ECG Monitoring...e43 Recommendations: If a Test Is Indicated, Which Test?...e43 Implications of Guidelines and Other Risk Assessment Strategies for Costs and Outcomes...e44 Perioperative Therapy...e45 Preoperative Coronary Revascularization With CABG or Percutaneous Coronary Intervention...e45 Rationale for Surgical Coronary Revascularization...e45 Preoperative CABG...e46 Preoperative PCI...e48 PCI Without Stents: Coronary Balloon Angioplasty...e50 PCI: DES...e52 Stent Thrombosis and DES...e53 Perioperative Management of Patients With Prior PCI Undergoing Noncardiac Surgery...e56 Perioperative Management in Patients Who Have Received Intracoronary Brachytherapy...e57 Risks Associated With Perioperative Antiplatelet Agents...e57 Strategy of Percutaneous Revascularization in Patients Needing Urgent Noncardiac Surgery...e58 Perioperative Medical Therapy (UPDATED)...e59 Recommendations for Perioperative Beta-Blocker Therapy (UPDATED)...e59 Evidence on Efficacy of Beta-Blocker Therapy (UPDATED)...e61 Recent Data Regarding Perioperative Beta-Blocker Therapy (NEW)...e64 Titration of Beta Blockers (UPDATED)...e66 Withdrawal of Beta Blockers (UPDATED)...e67 Risks and Caveats (NEW)...e67 Summary (NEW)...e68 Perioperative Statin Therapy...e68 Alpha-2 Agonists...e70 Perioperative Calcium Channel Blockers...e70 Prophylactic Valvular Intervention Before Noncardiac Surgery...e71 Perioperative Arrhythmias and Conduction Disturbances...e71 Intraoperative Electromagnetic Interference With Implanted Pacemakers and ICDs...e72 Preoperative Intensive Care...e73 Venothromboembolism/Peripheral Arterial Disease...e73 Anesthetic Considerations and Intraoperative Management...e74 Choice of Anesthetic Technique and Agent...e74 Perioperative Pain Management...e76 Prophylactic Intraoperative Nitroglycerin...e76 Use of TEE...e77 Maintenance of Body Temperature...e77 Intra-Aortic Balloon Counterpulsation Device...e77 Perioperative Control of Blood Glucose Concentration...e78 Perioperative Surveillance...e78 Intraoperative and Postoperative Use of PACs...e80 Intraoperative and Postoperative Use of ST-Segment Monitoring...e80 Surveillance for Perioperative MI...e81 Postoperative Arrhythmias and Conduction Disorders...e83 Postoperative and Long-Term Management...e84 MI:
Breast cancer is the most common female malignancy and the second leading cause of female cancer death in the United States. Although the majority of palpable breast lumps are benign, a new palpable ...breast mass is a common presenting sign of breast cancer. Any woman presenting with a palpable lesion should have a thorough clinical breast examination, but because many breast masses may not exhibit distinctive physical findings, imaging evaluation is necessary in almost all cases to characterize the palpable lesion. Recommended imaging options in the context of a palpable mass include diagnostic mammography and targeted-breast ultrasound and are dependent on patient age and degree of radiologic suspicion as detailed in the document Variants. There is little role for advanced technologies such as MRI, positron emission mammography, or molecular breast imaging in the evaluation of a palpable mass. When a suspicious finding is identified, biopsy is indicated. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
The ACR BI-RADS experience: learning from history Burnside, Elizabeth S; Sickles, Edward A; Bassett, Lawrence W ...
Journal of the American College of Radiology,
12/2009, Letnik:
6, Številka:
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The Breast Imaging Reporting and Data System (BI-RADS) initiative, instituted by the ACR, was begun in the late 1980s to address a lack of standardization and uniformity in mammography practice ...reporting. An important component of the BI-RADS initiative is the lexicon, a dictionary of descriptors of specific imaging features. The BI-RADS lexicon has always been data driven, using descriptors that previously had been shown in the literature to be predictive of benign and malignant disease. Once established, the BI-RADS lexicon provided new opportunities for quality assurance, communication, research, and improved patient care. The history of this lexicon illustrates a series of challenges and instructive successes that provide a valuable guide for other groups that aspire to develop similar lexicons in the future.
2009 ACCF/AHA Focused Update on Perioperative Beta Blockade Fleischmann, Kirsten E., MD, MPH, FACC; Beckman, Joshua A., MD, FACC; Buller, Christopher E., MD, FACC ...
Journal of the American College of Cardiology,
11/2009, Letnik:
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The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient. ...there are ...circumstances in which deviations from these guidelines may be appropriate.\n42 1.14 to 1.76 Appendix 3 Perioperative Beta Blockade in Noncardiac Surgery Studies: Summary Table AAA indicates abdominal aortic aneurysm; bpm, beats per minute; CAD, coronary artery disease; CHF, congestive heart failure; CI, confidence interval; DSE, dobutamine stress echocardiography; HR, hazard ratio; MI, myocardial infarction; n, number; NNT, number needed to treat; NWMA, new wall-motion abnormality; OR, odds ratio; RCRI, Revised Cardiac Risk Index; RCT, randomized controlled trial; and RR, relative risk.
Abstract Background Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to ...standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. Methods We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. Results A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. Conclusions These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. Trial registry ClinicalTrials.gov ; No. NCT00321906 ; URL: www.clinicaltrials.gov
Predisposing risk factors, clinical course, and prognosis of spontaneous coronary artery dissection (SCAD) remain poorly understood. We reviewed medical records and coronary angiograms of patients ...admitted to our institution with the diagnosis of SCAD from 1999 through 2010. A definite diagnosis of SCAD required the agreement of 2 blinded board-certified interventional cardiologists who reviewed all images separately. Baseline characteristics of patients (n = 23) included mean age 45 ± 11 years, female gender in all (100%), history of hypertension in 13 (57%), and postpartum in 7 (30%). Eleven (48%) had ST-segment elevation on initial electrocardiogram. SCAD involved the left main in 5 patients (21.7%), left anterior descending coronary artery in 16 (70%), left circumflex coronary artery in 8 (35%), and right coronary artery in 6 (26%). Four patients (17%) underwent coronary stenting and 6 (26%) required urgent bypass surgery. Comparison between postpartum and nonpostpartum patients revealed significant differences in mean peak troponin levels: 50 ± 34 ng/ml vs 21 ± 23, p = 0.04, mean left ventricular ejection fraction: 34 ± 6% vs 49 ± 9, p <0.01, proximal coronary segment distribution: 6 (86%) vs 3 (19%), p = 0.004, and left anterior descending coronary artery distribution: 7 (100%) vs 9 (56%), p = 0.04, respectively. Repeat coronary angiographies were performed in 11 patients (46%) during a mean follow-up of 39 ± 38 months and 10 (91%) were found to have healed SCAD, including those who had undergone bypass surgery. In conclusion, our patients with SCAD were characterized by female gender, absence of coronary risk factors, and a high rate of vascular healing without residual stenosis. Larger infarct was found in postpartum patients.
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