Citations

The etiology of intraneural ganglion cysts has been poorly understood. This has resulted in the development of multiple surgical treatment strategies and a high recurrence rate. We sought to analyze these recurrences in order to provide a pathoanatomic explanation and staging classification for intraneural cyst recurrence. An expanded literature search was performed to identify frequencies and patterns in cases of intraneural ganglion cyst recurrences following primary surgery. Two univariate analyses were completed to identify associations between the type of revision surgery and repeat cyst recurrences. The expanded literature search found an 11% recurrence rate following primary surgery, including 64 recurrences following isolated cyst decompression (Group 1); six after articular branch resection (Group 2); and none following surgical procedures that addressed the joint (Group 3). Eight cases did not specify the type of primary surgery. In group 1, forty‐eight of the recurrences (75%) were in the parent nerve, three involved only the articular branch, and one travelled along the articular branch in a different distal direction without involving the main parent nerve. In group 2, only one case (17%) recurred/persisted within the parent nerve, one recurred within a persistent articular branch, and one formed within a persistent articular branch and travelled in a different distal direction. Intraneural recurrences most commonly occur following surgical procedures that only target the main parent nerve. We provide proven or theoretical explanations for all identified cases of intraneural recurrences for an occult or persistent articular branch pathway. Clin. Anat. 28:1058–1069, 2015. © 2015 Wiley Periodicals, Inc.

Background: Intraoperative computed tomography and image-guided navigation improve the accuracy of screw placement. Radiation exposure to the patient remains a primary drawback. The objective of the present study was to compare the total intraoperative radiation dose and assess the resultant image quality for O-arm-assisted pedicle screw insertion, among 3 protocols: default (manufacturer recommended), institutional (reduced dose utilized in our institution), and pediatric (new protocol with lowest dose). Methods: Thirty-seven consecutive patients under the age of 18 years underwent posterior instrumentation of the spine and underwent an intraoperative O-arm scan. Techniques (kV and mAs) for default and institutional dose settings were manually adjusted based on spinal level and body weight. Pediatric dose techniques were 80 kV/80 mAs with no adjustment for level or weight. The number of scans repeated because of inadequate imaging was assessed, and the mean estimated effective dose between the 3 protocols was compared. Results: Sixty-eight scans were performed in 37 consecutive patients with mean age of 14 years and mean weight of 55 kg. For reference, the effective radiation dose of a chest x-ray is approximately 0.10 mSv. Use of the default protocol resulted in higher mean effective dose per scan of 4.65 mSv, whereas institutional protocol resulted in 2.37 mSv. The pediatric protocol reduced the mean dose to 0.65 mSv. The total effective dose per surgery was: 1.17 mSv (pediatric), 3.83 mSv (institutional), and 12.79 mSv (default) (P<0.0001 each). All scans lead to satisfactory image quality except in 1 patient >100 kg with stainless steel implants. There were no neurological or other implant-related complications. The pediatric protocol resulted in satisfactory image quality with the lowest total radiation dose, only 1/10 of that of the default protocol. Conclusions: We successfully switched to a pediatric low-dose O-arm protocol in clinical practice, reducing the dose to <1/4 of the mean annual natural background radiation. This may allow use of intraoperative computed tomography and navigation for pedicle screw placement without excessive radiation exposure to young patients. Level of Evidence: Level III—retrospective comparative study.

Abstract Multiple myeloma (MM) cells are the malignant counterpart of post-germinal center (GC) long-lived PCs, characterized by strong BM dependence, somatic hypermutation (SHM) of immunoglobulin (Ig) genes, and isotype class switch recombination (CSR) resulting in absence of IgM expression in all but 1% of tumors. Virtually every case of MM is preceded by a pre-malignant PC tumor called monoclonal gammopathy of undetermined significance (MGUS) that, like MM, produces a typical M-spike by SPEP or free light chain in the urine. Translocations involving the immunoglobulin heavy chain (IgH) locus are present in at least half of MM cases and are thought to result from errors during the physiological process of CSR or SHM. These translocations result in dysregulated expression of an oncogene that is juxtaposed to the strong Ig enhancers. There are three recurrent primary IgH translocation groups in MM: CYCLIN D (11q13-CYCLIN D1; 12p13-CYCLIN D2; 6p25-CYCLIN D3) MAF (16q23-MAF; 20q12-MAFB; 8q24.3-MAFA; MMSET/(FGFR3)-4p16-(MMSET in all but also FGFR3 in 80% of these tumors. Multiple trisomies represent an alternative pathogenetic pathway. There is a consensus that chromosome content reflects at least two pathways of pathogenesis. Nearly half of MGUS and MM tumors are hyperdiploid (HRD), usually with extra copies of three or more specific chromosomes (3,5,7,9,11,15,19, 21). Strikingly, HRD tumors rarely (~10%) have a primary IgH translocation, whereas Non-hyperdiploid (NHRD) tumors usually (~70%) have an IgH translocation. Almost all cases of plasma cell neoplasm starting from the MGUS stage and independently on the chromosome content aberrantly express one or more of the CYCLIN D genes and it has been proposed that dysregulation of a CYCLIN D gene provides a unifying, early oncogenic event in MGUS and MM. Consistently, the dysregulation of CYCLIN D1 in mouse B cells is sufficient to induce a monoclonal gammopathy that does not progress to MM. Secondary oncogenic events drive MGUS and MM progression MYC dysregulation. There is increased expression of c-MYC in most newly diagnosed MM tumors compared to MGUS tumor. Recently, it was shown that sporadic activation of a MYC transgene (Vk*MYC) in GC B cells in an MGUS prone mouse strain led to the universal development of MM tumor. Hence, increased MYC expression may be responsible for progression from MGUS to MM. Complex translocations involving MYC appear to be secondary progression events that often do not involve Ig loci, but rather other super enhancers that are very active in plasma cells. They are rare or absent in MGUS, but recently identified in over 40% of untreated MM, and 90% of MM cell lines. Activating mutations of RAS and BRAF. The prevalence of activating NRAS or KRAS mutations is about 15-18% each in newly diagnosed and relapsed MM tumors, and recently, BRAF mutations were described in 4% of MM tumors. Expression of an activated of KRAS in mouse B cells is sufficient to induce a monoclonal gammopathy but it does not progress to MM. Not surprisingly, dysregulating pairs of CYCLIN D1, KRAS and/or MYC in mouse B cells accelerated the progression of MM. Activating mutations of NFkappaB pathway. Extrinsic ligands (APRIL and BAFF) produced by BM stromal cells provide critical survival signals to long-lived PCs by stimulating TACI, BCMA, and BAFF receptors to activate the NFKB pathways. Most MGUS and MM tumors highly express NFKB target genes, suggesting a continued role of extrinsic signaling in PC tumors and at least in part explaining the constant dependency of MM cells on the BM microenvironment. Activating mutations in positive regulators and inactivating mutations in negative regulators of the NFKB pathway have been identified in at least 20% of untreated MM tumors and ~50% of HMCLs, rendering the cells less dependent on ligand-mediated NFKB activation and most likely contributing to extra-medullary spread of the disease. Additional changes include monosomy 13 (DIS3, mir15/16, RB1), del17p (TP53), add1q (MCL1) and del1p (CDKN2C, FAM46C). While the role of these putative tumor suppressor/oncogene remain to be defined, we found that loss of one copy of miR15/16 cooperated with MYC to cause the progression of MM in mice, while loss of one copy of RB1 did not, implicating loss of miR15/16 as one driving force behind selection for monosomy 13 in human MM. High-risk MM is associated with intra-clonal tumor heterogeneity Recent evidence indicates that tumor heterogeneity is prevalent in MM, as in many other cancers, and that different subclones are present within the tumor population, characterized by distinct genetic mutations that contributed independently to the tumor progression. The degree of clonal heterogeneity is presumably related to the degree of genomic instability, and appears to correlate with the presence of high-risk genetics. Three patterns of relapse are seen following successful therapy. A third of the time the dominant clone at diagnosis predominates, unchanged, at relapse. A third of the time the diagnostic clone has acquired additional genetic changes at relapse. And a third of the time an ancestral clone to the one dominant at diagnosis emerges, lacking some of the genetic changes present in the diagnostic clone, and having acquired additional genetic changes. Activating the immune system to overcome tumor heterogeneity MM cells develop a malignant relationship with components of the innate immune system in the BM. Initially inflammatory macrophages support MM tumor development, but over time convert to an immunosuppressive M2 phenotype. This relationship can be disrupted by activating signaling downstream of TLR and TNFR receptors in macrophages through the use of IAP antagonists which target for destruction negative regulators of these pathways (cIAP1/2). In MM bearing mice with a mature (but not those with an immature) immune system this results in a complete response, with no evidence of a direct anti-tumor effect of IAP antagonists on the tumor cells at clinically relevant doses. This has led to a phase II clinical trial of IAP antagonists to activate the innate immune system in patients with MM. The treatment is associated with dramatic activation and mobilization of macrophages, with cytokine release and early evidence of anti-tumor effects. Conclusion Significant progress has been made is understanding the molecular pathogenesis and biology of MM. Oncogenic pathways can be activated through cell intrinsic or extrinsic mechanisms. Similar to other cancers, MM is characterized by multi-stage accumulation of genetic abnormalities deregulating different pathways. Much of this knowledge is already being utilized for diagnosis, prognosis and risk-stratification of patients. Importantly, from a clinical standpoint, this knowledge has led to development of novel therapeutic strategies, some of which are already in clinical use, and many others showing promise in pre-clinical and early clinical studies. Citation Format: Marta Chesi, P. Leif Bergsagel. Targeting genetic heterogeneity in multiple myeloma through immune activation. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA25.

Abstract The t(8;21) chromosomal translocation produces AML1-ETO, an oncogenic fusion protein that compromises the function of AML1, a transcription factor critical for the myeloid cell differentiation. The differentiation arrest and self-renewal phenotypes of cells expressing AML1-ETO have been chiefly studied at the single gene level. In order to understand how the genome-wide occupancy of AML1-ETO and associated co-regulators contributes to the leukemic properties of Kasumi-1 cells, a model system for human t(8;21) leukemia, chromatin immunoprecipitation-sequencing (ChIP-seq) experiments were employed. Genome-wide DNA binding profiles for AML1 and AML1-ETO in Kasumi-1 cells showed that both proteins were enriched at introns and distal upstream regulatory regions, the latter implying that distal elements are likely important for target gene regulation. Importantly, A substantial fraction of AML1/AML1-ETO-p300 co-localization occurs near transcriptional start sites (TSSs) in promoter regions associated with transcriptionally active loci, as indicated by an observed enrichment of the H3K4me3 histone modification. A significant discovery of the current study is the co-localization of AML1/AML1-ETO with N-CoR on regions that are primarily distal to TSSs. Analyses of both gene expression data and gene ontology suggest that the AML1/AML1-ETO co-localization with N-CoR, more so than with p300, is associated with the leukemic phenotype of Kasumi-1 cells. De novo motif discovery reveals that PU.1 motifs are over-represented in regions co-occupied by AML1-ETO and N-CoR compared to other AML1-ETO bound regions. Our findings establish a novel and predominant AML leukemia signature characterized by occupancy of the AML1-ETO/N-CoR complex at genomic regions enriched in motifs for myeloid differentiation factors. We propose that this property is critical for maintenance of the leukemic phenotype. Citation Format: Daniel J. Trombly, Troy W. Whitfield, Srivatsan Padmanabhan, Jonathan A. Gordon, Jane B. Lian, Andre J. van Wijnen, Sayyed K. Zaidi, Janet L. Stein, Gary S. Stein. Co-occupancy of AML1-ETO and N-CoR defines a dominant phenotypic signature in leukemic cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B28.