There is currently no standard national approach to the management of category II fetal heart rate (FHR) patterns, yet such patterns occur in the majority of fetuses in labor. Under such ...circumstances, it would be difficult to demonstrate the clinical efficacy of FHR monitoring even if this technique had immense intrinsic value, since there has never been a standard hypothesis to test dealing with interpretation and management of these abnormal patterns. We present an algorithm for the management of category II FHR patterns that reflects a synthesis of available evidence and current scientific thought. Use of this algorithm represents one way for the clinician to comply with the standard of care, and may enhance our overall ability to define the benefits of intrapartum FHR monitoring.
Background LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. Objective We sought to ...report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. Methods Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. Results Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA . Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents. Conclusion This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.
Objective Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene, continues to present diagnostic challenges. Newborn screening and an evolving ...understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. Study design To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. Results After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. Conclusions It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project ( http://www.cftr2.org/index.php ) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR - related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR - related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.
Abstract Pulmonary arteriovenous malformations are often included in the differential diagnosis of common clinical presentations, including hypoxemia, hemoptysis, brain abscesses, and paradoxical ...stroke, as well as affecting 30% to 50% of patients with hereditary hemorrhagic telangiectasia (HHT). Various imaging studies are used in the diagnostic and screening settings, which have been reviewed by the ACR Appropriateness Criteria Vascular Imaging Panel. Pulmonary arteriovenous malformation screening in patients with HHT is commonly performed with transthoracic echocardiographic bubble study, followed by CT for positive cases. Although transthoracic echocardiographic bubble studies and radionuclide perfusion detect right-to-left shunts, they do not provide all of the information needed for treatment planning and may remain positive after embolization. Pulmonary angiography is appropriate for preintervention planning but not as an initial test. MR angiography has a potential role in younger patients with HHT who may require lifelong surveillance, despite lower spatial resolution compared with CT. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
Summary Background High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed ...neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. Methods Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m2 ) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m2 ) on days 3–5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov , number NCT00153530. Findings 551 patients (median age 63 years, IQR 55–69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8–39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5–46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80–1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6–25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3–16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). Interpretation No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors. Funding German Cancer Aid.
Background Type B aortic dissections are being successfully treated by thoracic endovascular aortic repair (TEVAR). Postoperative false lumen patency has been associated with aneurysmal dilatation ...and rupture of the thoracic aorta, necessitating further intervention. This is the first volumetric analysis of type B aortic dissections comparing patients with and without false lumen thrombosis (FLT) after TEVAR. We hypothesized that a greater increase in postoperative true lumen volume will lead to FLT, and without this change, false lumen patency will result. Methods Preoperative and postoperative computed tomography angiography (CTA) imaging was analyzed using three-dimensional reconstruction to measure the short- and long-axis diameter and cross-sectional area of the true lumen, false lumen, and total aorta. Measurements were taken at 5-cm intervals from the left subclavian artery to the aortic bifurcation. Pre- and postoperative volumetric data were calculated and compared in patients with and without postoperative FLT. Results Between 2006 and 2010, 132 patients underwent thoracic aortic stent grafting. Of these, 31 (23%) had thoracic endografting for type B aortic dissection. Pre- and postoperative CTA images were available for analysis in 23 patients with a mean age of 59 ± 14 years treated for acute, complicated (n = 8, 35%), and chronic (n = 15, 65%) indications. Mean follow-up imaging was 9 months (range, 1-39 months). Thirteen patients (56%) had postoperative FLT and 10 (43%) had persistent false lumen patency. The dissections involved the left subclavian artery (n = 12), visceral arteries (n = 14), renal arteries (n = 16), and iliac arteries (n = 15). The left subclavian artery was intentionally covered in 15 patients (65%). There were no significant differences in age, acute vs chronic dissection, branch vessel involvement, coverage of the left subclavian artery, or distal extent of the endograft between patients with and without postoperative FLT. Patients with postoperative FLT had a significantly smaller preoperative maximum thoracic aortic diameter (5.05 ± 1.0 vs 6.30 ± 1.4 cm; P = .02). Volumetric analysis demonstrated significantly smaller preoperative true lumen volume (141.3 ± 68 vs 230.5 ± 92 cm3 ; P = .01) in patients with FLT, but no difference in preoperative false lumen volume. Patients with FLT had a significant increase in the volume percentage of the true lumen from 42.7% to 61.7% ( P = .02) after stent graft repair, compared with an increase from 46.7% to 47.7% ( P = .75) in patients with persistent false lumen patency. Conclusions This volumetric study of type B aortic dissection treated with TEVAR suggests that the ability of the endograft to significantly increase the true lumen volume as a percent of the total aorta most accurately predicts postoperative FLT. This is best demonstrated in a nonaneurysmal dissection regardless of timing since dissection.
Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most ...important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic examinations, adoption of a standardized template for radiology reporting, using universally accepted and agreed on terminology for solid pancreatic neoplasms, is needed. A consensus statement describing a standardized reporting template authored by a multi-institutional group of experts in pancreatic ductal adenocarcinoma that included radiologists, gastroenterologists, and hepatopancreatobiliary surgeons was developed under the joint sponsorship of the Society of Abdominal Radiologists and the American Pancreatic Association. Adoption of this standardized imaging reporting template should improve the decision-making process for the management of patients with pancreatic ductal adenocarcinoma by providing a complete, pertinent, and accurate reporting of disease staging to optimize treatment recommendations that can be offered to the patient. Standardization can also help to facilitate research and clinical trial design by using appropriate and consistent staging by means of resectability status, thus allowing for comparison of results among different institutions.
Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed ...to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis.
This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s FEV1 ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205.
Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% 95% CI -0.8 to 6.3; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 95% CI 0.57-1.05; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% -4.0 to 2.1 vs -6.4% -9.8 to -3.7; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events 0.9-1.9 vs 2.18 events 1.6-2.7; rate ratio 0.60 0.42-0.86; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group.
Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin.
PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.
Abstract Background Although renal sympathetic denervation therapy has shown promising results in patients with resistant hypertension, the human anatomy of peri-arterial renal nerves is poorly ...understood. Objectives The aim of our study was to investigate the anatomic distribution of peri-arterial sympathetic nerves around human renal arteries. Methods Bilateral renal arteries were collected from human autopsy subjects, and peri-arterial renal nerve anatomy was examined by using morphometric software. The ratio of afferent to efferent nerve fibers was investigated by dual immunofluorescence staining using antibodies targeted for anti–tyrosine hydroxylase and anti–calcitonin gene–related peptide. Results A total of 10,329 nerves were identified from 20 (12 hypertensive and 8 nonhypertensive) patients. The mean individual number of nerves in the proximal and middle segments was similar (39.6 ± 16.7 per section and 39.9 ± 1 3.9 per section), whereas the distal segment showed fewer nerves (33.6 ± 13.1 per section) (p = 0.01). Mean subject-specific nerve distance to arterial lumen was greatest in proximal segments (3.40 ± 0.78 mm), followed by middle segments (3.10 ± 0.69 mm), and least in distal segments (2.60 ± 0.77 mm) (p < 0.001). The mean number of nerves in the ventral region (11.0 ± 3.5 per section) was greater compared with the dorsal region (6.2 ± 3.0 per section) (p < 0.001). Efferent nerve fibers were predominant (tyrosine hydroxylase/calcitonin gene–related peptide ratio 25.1 ± 33.4; p < 0.0001). Nerve anatomy in hypertensive patients was not considerably different compared with nonhypertensive patients. Conclusions The density of peri-arterial renal sympathetic nerve fibers is lower in distal segments and dorsal locations. There is a clear predominance of efferent nerve fibers, with decreasing prevalence of afferent nerves from proximal to distal peri-arterial and renal parenchyma. Understanding these anatomic patterns is important for refinement of renal denervation procedures.
Objectives This study sought to determine whether ablation of complex fractionated atrial electrograms (CFAEs) after antral pulmonary vein isolation (APVI) further improves the clinical outcome of ...APVI in patients with long-lasting persistent atrial fibrillation (AF). Background Ablation of CFAEs has been reported to eliminate persistent AF. However, residual pulmonary vein arrhythmogenicity is a common mechanism of recurrence. Methods In this randomized study, 119 consecutive patients (mean age 60 ± 9 years) with long-lasting persistent AF underwent APVI with an irrigated-tip radiofrequency ablation catheter. Antral pulmonary vein isolation resulted in termination of AF in 19 of 119 patients (Group A, 16%). The remaining 100 patients who still were in AF were randomized to no further ablation and underwent cardioversion (Group B, n = 50) or to ablation of CFAEs in the left atrium or coronary sinus for up to 2 additional hours of procedure duration (Group C, n = 50). Results Atrial fibrillation terminated during ablation of CFAEs in 9 of 50 patients (18%) in Group C. At 10 ± 3 months after a single ablation procedure, 18 of 50 (36%) in Group B and 17 of 50 (34%) in Group C were in sinus rhythm without antiarrhythmic drugs (p = 0.84). In Group A, 15 of 19 patients (79%) were in sinus rhythm. A repeat ablation procedure was performed in 34 of 100 randomized patients (for AF in 30 and atrial flutter in 4). At 9 ± 4 months after the final procedure, 34 of 50 (68%) in Group B and 30 of 50 (60%) in Group C were in sinus rhythm without antiarrhythmic drugs (p = 0.40). Conclusions Up to 2 h of additional ablation of CFAEs after APVI does not appear to improve clinical outcomes in patients with long-lasting persistent AF.
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