Citations

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

There have been major advances in the diagnosis, staging, risk‐stratification, and management of multiple myeloma (MM). In addition to established CRAB (hypercalcemia, renal failure, anemia, and lytic bone lesions) features, new diagnostic criteria include three new biomarkers to diagnose the disease: bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain ratio ≥100, and >1 focal lesion on magnetic resonance imaging. MM can be classified into several subtypes based on baseline cytogenetics, and prognosis varies according to underlying cytogenetic abnormalities. A Revised International Staging System has been developed which combines markers of tumor burden (albumin, beta‐2 microglobulin) with markers of aggressive disease biology (high‐risk cytogenetics and elevated serum lactate dehydrogenase). Although the approach to therapy remains largely the same, the treatment options at every stage of the disease have changed. Carfilzomib, pomalidomide, panobinostat, daratumumab, elotuzumab, and ixazomib have been approved for the treatment of the disease. These drugs combined with older agents such as cyclophosphamide, dexamethasone, thalidomide, bortezomib, and lenalidomide dramatically increase the repertoire of regimens available for the treatment of MM. This review provides a concise overview of recent advances in MM, including updates to diagnostic criteria, staging, risk‐stratification, and management. Am. J. Hematol. 91:90–100, 2016. © 2015 Wiley Periodicals, Inc.

OBJECT In this clinically based systematic review of cervical facet fractures, the authors’ aim was to determine the optimal clinical care for patients with isolated fractures of the cervical facets through a systematic review. METHODS A systematic review of nonoperative and operative treatment methods of cervical facet fractures was performed. Reduction and stabilization treatments were compared, and analysis of postoperative outcomes was performed. MEDLINE and Scopus databases were used. This work was supported through support received from the Association for Collaborative Spine Research and AOSpine North America. RESULTS Eleven studies with 368 patients met the inclusion criteria. Forty-six patients had bilateral isolated cervical facet fractures and 322 had unilateral isolated cervical facet fractures. Closed reduction was successful in 56.4% (39 patients) and 63.8% (94 patients) of patients using a halo vest and Gardner-Wells tongs, respectively. Comparatively, open reduction was successful in 94.9% of patients (successful reduction of open to closed reduction OR 12.8 [95% CI 6.1–26.9], p < 0.0001); 183 patients underwent internal fixation, with an 87.2% success rate in maintaining anatomical alignment. When comparing the success of patients who underwent anterior versus posterior procedures, anterior approaches showed a 90.5% rate of maintenance of reduction, compared with a 75.6% rate for the posterior approach (anterior vs posterior OR 3.1 [95% CI 1.0–9.4], p = 0.05). CONCLUSIONS In comparison with nonoperative treatments, operative treatments provided a more successful outcome in terms of failure of treatment to maintain reduction for patients with cervical facet fractures. Operative treatment appears to provide superior results to the nonoperative treatments assessed.

We recently defined event‐free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age‐ and sex‐matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline‐based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c‐statistic = 0.671) in the validation dataset compared to the IPI (c‐statistic = 0.649) or the NCCN‐IPI (c‐statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12–88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps. Am. J. Hematol. 91:179–184, 2016. © 2015 Wiley Periodicals, Inc.

Symptoms of post-traumatic stress disorder are common in fibromyalgia patients. This study compared post-traumatic stress disorder symptoms in fibromyalgia patients and healthy controls and determined whether patient-control differences in post-traumatic stress disorder symptoms mediated differences in mental health. In all, 30 patients and 30 healthy controls completed questionnaires assessing symptoms of post-traumatic stress disorder and mental health. Fibromyalgia patients had greater symptoms of post-traumatic stress disorder and mental health than controls. Patient-control differences in mental health symptoms were fully or partially mediated by differences in post-traumatic stress disorder symptoms. Healthcare providers should understand the role of trauma as management of trauma symptoms may be one strategy for improving mental health.

The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi‐institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe. Though dysmorphic features were commonly reported, patients do not have consistent and recognizable features. Cardiac, ophthalmologic, growth, behavioral, and other abnormalities were each present in a subset of patients. The newly associated features potentially resulting from 17q12 duplication include height and weight above the 95th percentile, cataracts, microphthalmia, coloboma, astigmatism, tracheomalacia, cutaneous mosaicism, pectus excavatum, scoliosis, hypermobility, hypospadias, diverticulum of Kommerell, pyloric stenosis, and pseudohypoparathryoidism. The majority of duplications were inherited with some carrier parents reporting learning disabilities or microcephaly. We identified additional, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing to phenotypic variability. © 2015 Wiley Periodicals, Inc.

Aberrant intracellular calcium levels and increased cAMP signaling contribute to the development of polycystic kidney disease (PKD). cAMP can be hydrolyzed by various phosphodiesterases (PDEs). To examine the role of cAMP hydrolysis and the most relevant PDEs in the pathogenesis of PKD, we examined cyst development in Pde1 - or Pde3 -knockout mice on the Pkd2 −/WS25 background (WS25 is an unstable Pkd2 allele). These PDEs were selected because of their importance in cross-talk between calcium and cyclic nucleotide signaling ( PDE1 ), control of cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR) –driven fluid secretion (PDE3), and response to vasopressin V2 receptor activation (both). In Pkd2 −/WS25 mice, knockout of Pde1a , Pde1c , or Pde3a but not of Pde1b or Pde3b aggravated the development of PKD and was associated with higher levels of protein kinase A–phosphorylated (Ser133) cAMP–responsive binding protein (P-CREB), activating transcription factor-1, and CREB–induced CRE modulator proteins in kidney nuclear preparations. Immunostaining also revealed higher expression of P-CREB in Pkd2−/ WS25 ; Pde1a −/− , Pkd2− /WS25 ; Pde1c −/− , and Pkd2−/ WS25 ; Pde3a −/− kidneys. The cystogenic effect of desmopressin administration was markedly enhanced in Pkd2 −/WS25 ; Pde3a −/− mice, despite PDE3 accounting for only a small fraction of renal cAMP PDE activity. These observations show that calcium- and calmodulin-dependent PDEs ( PDE1A and PDE1C ) and PDE3A modulate the development of PKD, possibly through the regulation of compartmentalized cAMP pools that control cell proliferation and CFTR–driven fluid secretion. Treatments capable of increasing the expression or activity of these PDEs may, therefore, retard the development of PKD.