Citations

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. Results Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was −3 ± 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was −0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (−0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated–placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. Conclusions Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).

Context.— The classification and prognosis determination in acute leukemia (AL) are complex and it is unclear what testing is being performed in practice. Objective.— To survey physicians describing their current practice of test ordering in the diagnosis of AL. Design.— In anticipation of a guideline by the College of American Pathologists (CAP) and the American Society for Hematology on laboratory testing needed for the initial workup of AL, a baseline survey was designed by an expert panel from CAP. Members of professional societies were asked to describe their current practice of test ordering. Results.— Two hundred ninety-four responses were received with 258 respondents analyzed after the first qualifying survey question regarding initial diagnosis of AL. One hundred seventy-six of 249 respondents (70.7%) were board-certified hematopathologists. Flow cytometry and karyotype analysis were routinely performed for acute myeloid leukemia (AML) (99.1% [232 of 234] and 96.2% [225 of 234], respectively) and acute lymphoblastic leukemia (ALL) (98.3% [229 of 233] and 96.6% [225 of 233], respectively). In addition, fluorescence in situ hybridization studies were routinely performed by 81.2% (190 of 234) of respondents for AML and 85.0% (198 of 233) of respondents for ALL; other molecular studies were performed by 78.2% (183) for AML and 54.9% (128) for ALL; immunohistochemistry by 44.9% (105) for AML and 47.6% (111) for ALL; and cytochemistry by 24.8% (58) for AML and 14.2% (33) for ALL. Conclusions.— While flow cytometry and karyotyping are routinely reported as being performed for the diagnosis of AL, there is marked variation in the reporting of testing patterns for other genetic studies, immunohistochemistry, and cytochemistry.

Objective: To assess concordance between physician assessment and patient-reported symptoms when screening for depression in Parkinson disease (dPD). Background: Depression in Parkinson disease is highly prevalent (∼40%) and has a significant impact on quality of life and disability, yet physician recognition and treatment remain inadequate. Methods: One thousand seventy-six patients with PD completed the Brief Symptom Inventory-18 (BSI-18), a screening questionnaire for psychiatric symptoms, which was compared to item #3 (depression) on the Unified Parkinson’s Disease Rating Scale (UPDRS). Results: The mean BSI-18 depression score was 51.4 (9.7). Of the 170 (16%) patients screening positive for dPD on the BSI-18, 104 (61%) were not recognized as depressed by neurologists on the UPDRS. Factors associated with lower neurologist recognition included male gender, better mental health quality of life, and lack of antidepressant use. Conclusion: More than 60% of patients screening positive for depression on self-report were not recognized by neurologists on the UPDRS. A patient-reported screening tool for depression may improve recognition and management of dPD.

AbstractAfter decades on the margins of primary health care, surgical and anaesthesia care is gaining increasing priority within the global development arena. The 2015 publications of the Disease Control Priorities third edition on Essential Surgery and the Lancet Commission on Global Surgery created a compelling evidenced‐based argument for the fundamental role of surgery and anaesthesia within cost‐effective health systems strengthening global strategy. The launch of the Global Alliance for Surgical, Obstetric, Trauma, and Anaesthesia Care in 2015 has further coordinated efforts to build priority for surgical care and anaesthesia. These combined efforts culminated in the approval of a World Health Assembly resolution recognizing the role of surgical care and anaesthesia as part of universal health coverage. Momentum gained from these milestones highlights the need to identify consensus goals, targets and indicators to guide policy implementation and track progress at the national level. Through an open consultative process that incorporated input from stakeholders from around the globe, a global target calling for safe surgical and anaesthesia care for 80% of the world by 2030 was proposed. In order to achieve this target, we also propose 15 consensus indicators that build on existing surgical systems metrics and expand the ability to prioritize surgical systems strengthening around the world.

To evaluate the clinical utility of cell‐free DNA (cfDNA), we performed whole‐genome sequencing to systematically examine plasma cfDNA copy number variations (CNVs) in a cohort of patients with colorectal cancer (CRC, n = 80), polyps (n = 20), and healthy controls (n = 35). We initially compared cfDNA yield in 20 paired serum–plasma samples and observed significantly higher cfDNA concentration in serum (median = 81.20 ng, range 7.18–500 ng·mL−1) than in plasma (median = 5.09 ng, range 3.76–62.8 ng·mL−1) (P < 0.0001). However, tumor‐derived cfDNA content was significantly lower in serum than in matched plasma samples tested. With ~10 million reads per sample, the sequencing‐based copy number analysis showed common CNVs in multiple chromosomal regions, including amplifications on 1q, 8q, and 5q and deletions on 1p, 4q, 8p, 17p, 18q, and 22q. Copy number changes were also evident in genes critical to the cell cycle, DNA repair, and WNT signaling pathways. To evaluate whether cumulative copy number changes were associated with tumor stages, we calculated plasma genomic abnormality in colon cancer (PGA‐C) score by summing the most significant CNVs. The PGA‐C score showed predictive performance with an area under the curve from 0.54 to 0.84 for CRC stages I‐IV. Locus‐specific copy number analysis identified nine genomic regions where CNVs were significantly associated with survival in stage III‐IV CRC patients. A multivariate model using six of nine genomic regions demonstrated a significant association of high‐risk score with shorter survival (HR = 5.33, 95% CI = 6.76–94.44, P < 0.0001). Our study demonstrates the importance of using plasma (rather than serum) to test tumor‐related genomic variations. Plasma cfDNA‐based tests can capture tumor‐specific genetic changes and may provide a measurable classifier for assessing clinical outcomes in advanced CRC patients.

BACKGROUNDThe use of rapid response systems (RRS), which were designed to bring clinicians with critical care expertise to the bedside to prevent unnecessary deaths, has increased. RRS rely on accurate detection of acute deterioration events. Early warning scores (EWS) have been used for this purpose but were developed using heterogeneous populations. Predictive performance may differ in medical vs surgical patients.OBJECTIVETo evaluate the performance of published EWS in medical vs surgical patient populations.DESIGNRetrospective cohort study.SETTINGTwo tertiary care academic medical center hospitals in the Midwest totaling more than 1500 beds.PATIENTSAll patients discharged from January to December 2011.INTERVENTIONNone.MEASUREMENTSTime‐stamped longitudinal database of patient variables and outcomes, categorized as surgical or medical. Outcomes included unscheduled transfers to the intensive care unit, activation of the RRS, and calls for cardiorespiratory resuscitation (“resuscitation call”). The EWS were calculated and updated with every new patient variable entry over time. Scores were considered accurate if they predicted an outcome in the following 24 hours.RESULTSAll EWS demonstrated higher performance within the medical population as compared to surgical: higher positive predictive value (P < .0001 for all scores) and sensitivity (P < .0001 for all scores). All EWS had positive predictive values below 25%.CONCLUSIONSThe overall poor performance of the evaluated EWS was marginally better in medical patients when compared to surgical patients.

ObjectiveTo develop response criteria for adult dermatomyositis (DM) and polymyositis (PM).MethodsExpert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus.ResultsConsensus was reached for a conjoint analysis–based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0–100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001).ConclusionThe response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

Abstract We describe a series of 102 patients diagnosed from January 1, 1990 to December 31, 2015 with Type 1 monoclonal cryoglobulinemia (MoC). Symptoms were seen in 89 (87%) patients, including: cutaneous symptoms in 64 (63%) patients, with purpura (n = 43, 42%) and ulcers/gangrene (n = 35, 34%) being most common; neurological findings in 33 (32%) patients, most frequently sensory neuropathy (n = 24, 24%); vasomotor symptoms, mainly Raynaud's phenomenon in 25 (25%); arthralgias in 24 (24%); and renal manifestations, primarily glomerulonephritis in 14 (14%) patients. An underlying lymphoproliferative disorder was identified in 94 (92%) subjects; MGUS—39, myeloma—20, lymphoplasmacytic lymphoma—21 and others—14. Treatment was initiated in 73 (72%) patients, primarily for cryoglobulinemia‐related symptoms in 57. Treatment regimens consisted of: steroids ± alkylating agents in 29 (40%), novel myeloma therapies in 16 (22%), rituximab with alkylating agents in 12 (16%) and rituximab ± steroids in 11 (15%) patients; 22 patients received plasmapheresis. Six patients underwent autologous stem cell transplant. Cryocrit at treatment initiation, change in cryocrit and time to nadir cryocrit were predictive of symptom improvement. Treatment directed toward the underlying clonal disorder resulted in improvement (n = 47) or stabilization (n = 16) of symptoms in the majority of patients and disappearance of cryoglobulin in over one‐half.