The role of MRI biomarkers in evaluation of symptomatic pineal cysts - a retrospective analysis.

BACKGROUND: Our aim was to determine whether the Apparent Diffusion Coefficient is able to predict the presence of a symptomatic pineal cyst by detecting cerebral edema. METHODS: We retrospectively analyzed MRIs of 45 patients with pineal cysts before and after resection and 51 patients without pineal cysts, comparing ADC values of thalamus, central, periventricular and subcortical white matter. Furthermore we evaluated cyst size and morphology and analyzed its correlation to ADC values in corresponding patients. RESULTS: Differences between patients with symptomatic pineal cyst and control group were not significant (p = 0.200 - 0.968). ADC ratios did not change significantly after resection of the cyst (p = 0.575 - 0.862). Cyst size showed no significant correlation to ADC ratios (p = 0.071 - 0.918). Raw data analyses revealed more significance, especially periventricularly and in central white matter, which resulted in significant interhemispheric differences in ADC ratios in both subgroups (p < 0.001 and p = 0.031). MRI of 1.5T showed consistently higher values than 3T but mostly insignificant. CONCLUSION: Our analysis revealed no evidence that pineal cysts lead to intracerebral edema caused by venous compression. Since variability was higher than the differences seen, ADC sequences do not appear to be an appropriate diagnostic tool for symptomatic pineal cysts.

Petroclival meningiomas: update of current treatment and consensus by the EANS skull base section.

BACKGROUND: The optimal management of petroclival meningiomas (PCMs) continues to be debated along with several controversies that persist. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the management of these tumors. To achieve this, the task force reviewed in detail the literature in this field and had formal discussions within the group. RESULTS: The constituted task force dealt with the existing definitions and classifications, pre-operative radiological investigations, management of small and asymptomatic PCMs, radiosurgery, optimal surgical strategies, multimodal treatment, decision-making, and patient's counselling. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the management of PCMs.

Platelet transfusion to reverse antiplatelet therapy before decompressive surgery in patients with intracranial haemorrhage.

BACKGROUND: Platelet concentrates (PC) are transfused to improve primary haemostasis before urgent neurosurgery in patients with intracranial haemorrhage (ICH) receiving antiplatelet therapy (APT). It is unresolved, whether PCs increase the risk for major cardio- and cerebrovascular adverse events. We evaluated a standardized transfusion regimen to reverse APT in patients with ICH who required decompressive neurosurgery. METHODS: Analysed were consecutive patients between 2012 and 2014. The primary outcome was the frequency of new arterial thrombotic complications. The secondary outcome was the frequency of recurrent ICH. RESULTS: Of 72 patients, 14 received acetylsalicylic acid and a P2Y12 inhibitor, 53 received acetylsalicylic acid and five clopidogrel. No acute coronary syndrome (95% CI: 0-5·07) and one ischaemic stroke occurred (1·4%; 95% CI: 0·25-7·46). In contrast, 26·4% of patients developed recurrent ICH (95% CI: 17·59-37·58). The risk of bleeding was significantly higher compared to the risk of arterial thrombosis (P < 0·00001) and was increased for patients with chronic ICH (OR: 4·78; 95% CI: 1·57-14·55) and those receiving clopidogrel (OR: 2·78; 95% CI: 0·90-8·57). CONCLUSION: Platelet concentrate transfusion before cranial decompressive surgery in patients with ICH complicating APT showed a low risk for cardio-cerebral thrombotic complications. However, the risk of rebleeding remains high, especially in patients with chronic ICH and those pretreated with clopidogrel.

[Comprehensive review on rhino-neurosurgery]. / Rhino-Neurochirurgie.

In the past 2 decades, an innovative and active field of surgical collaboration has been evolved and established combining the expertise of Neurosurgery and Rhinosurgery in treatment of different lesions affecting the anterior skull base together with the adjacent intranasal and intradural areas. Important prerequesites for this development were improvements of technical devices, definitions of transnasal surgical corridors and approvements in endonasal reconstruction e. g. by use of pedicled nasal mucosal flaps. Interdisciplinary surgical teams have been established constituting specialized centers of "rhino-neurosurgery". With growing experience of these groups, it could be shown that oncological results and perioperative complications were comparable to traditional surgery while at the same time, patient's morbidity could be reduced.The present review encompasses the recent literature focussing on the development, technical details, results and complications of "rhino-neurosurgery".

Through the orbit and beyond: Current state and future perspectives in endoscopic orbital surgery on behalf of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Introduction: Orbital surgery has always been disputed among specialists, mainly neurosurgeons, otorhinolaryngologists, maxillofacial surgeons and ophthalmologists. The orbit is a borderland between intra- and extracranial compartments; Krönlein's lateral orbitotomy and the orbitozygomatic infratemporal approach are the historical milestones of modern orbital-cranial surgery. Research question: Since its first implementation, endoscopy has significantly impacted neurosurgery, changing perspectives and approaches to the skull base. Since its first application in 2009, transorbital endoscopic surgery opened the way for new surgical scenario, previously feasible only with extensive tissue dissection. Material and methods: A PRISMA based literature search was performed to select the most relevant papers on the topic. Results: Here, we provide a narrative review on the current state and future trends in endoscopic orbital surgery. Discussion and conclusion: This manuscript is a joint effort of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Regulation of interferon-inducible proteins by doxorubicin via interferon γ-Janus tyrosine kinase-signal transducer and activator of transcription signaling in tumor cells.

Activation of the immune system is a way for host tissue to defend itself against tumor growth. Hence, treatment strategies that are based on immunomodulation are on the rise. Conventional cytostatic drugs such as the anthracycline doxorubicin can also activate immune cell functions of macrophages and natural killer cells. In addition, cytotoxicity of doxorubicin can be enhanced by combining this drug with the cytokine interferon-γ (IFNγ). Although doxorubicin is one of the most applied cytostatics, the molecular mechanisms of its immunomodulation ability have not been investigated thoroughly. In microarray analyses of HeLa cells, a set of 19 genes related to interferon signaling was significantly over-represented among genes regulated by doxorubicin exposure, including signal transducer and activator of transcription (STAT) 1 and 2, interferon regulatory factor 9, N-myc and STAT interactor, and caspase 1. Regulation of these genes by doxorubicin was verified with real-time polymerase chain reaction and immunoblotting. An enhanced secretion of IFNγ was observed when HeLa cells were exposed to doxorubicin compared with untreated cells. IFNγ-neutralizing antibodies and inhibition of Janus tyrosine kinase (JAK)-STAT signaling [aurintricarboxylic acid (ATA), (E)-2-cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide (AG490), STAT1 small interfering RNA] significantly abolished doxorubicin-stimulated expression of interferon signaling-related genes. Furthermore, inhibition of JAK-STAT signaling significantly reduced doxorubicin-induced caspase 3 activation and desensitized HeLa cells to doxorubicin cytotoxicity. In conclusion, we demonstrate that doxorubicin induces interferon-responsive genes via IFNγ-JAK-STAT1 signaling and that this pathway is relevant for doxorubicin's cytotoxicity in HeLa cells. Immunomodulation is a promising strategy in anticancer treatment, so this novel mode of action of doxorubicin may help to further improve the use of this drug among different types of anticancer treatment strategies.

Review of intravenous immunoglobulin replacement therapy trials for primary humoral immunodeficiency patients.

An available supply of intravenous immunoglobulin (IVIG) is essential for individuals with primary humoral immunodeficiency. A shortage in 1997 prompted the Food and Drug Administration (FDA) to revise guidelines for the licensure, production, and distribution of new IVIG products, including the standardization of United States clinical trials regarding endpoints for safety, efficacy, and pharmacokinetics. The following review is intended to present current information and results of clinical trials in patients with primary immunodeficiency treated with IVIG products currently licensed or awaiting licensure in the United States. The data presented are compiled from published clinical trials and prescribing information generated by manufacturers.

Membranous glomerulopathy in an adult patient with X-linked agammaglobulinemia receiving intravenous gammaglobulin.

BACKGROUND: Immune complex deposition in the subepithelial zone of glomerular capillaries can lead to membranous glomerulopathy. OBJECTIVE: To present the case of a 23-year-old man with X-linked agammaglobulinemia (XLA) who developed idiopathic membranous glomerulopathy while receiving intravenous immunoglobulin (IVIG). METHODS: We performed an immunological workup, genetic testing, and a renal biopsy. RESULTS: XLA was confirmed with less than 0.02% CD19+ cells in the blood after sequence analysis revealed a nonfunctional BTK gene. The patient presented with microhematuria, which persisted for 3 years and spanned treatment with 5 different preparations of intravenous gammaglobulin. Immunohistochemistry revealed membranous glomerulopathy. CONCLUSION: Although endogenous serum immunoglobulin (Ig) production is severely impaired in XLA, rare B lymphocytes that have managed to mature can produce functional IgG antibodies. The pathogenic immune complexes could reflect IVIG reacting with polymorphic autoantigens, an endogenous IgG-producing clone reacting with a common idiotype present in the IVIG, or both.

Genetic control of the B cell response to LPS: opposing effects in peritoneal versus splenic B cell populations.

Lipopolysaccharide (LPS) from gram-negative bacteria activates B cells, enabling them to proliferate and differentiate into plasma cells. This response is critically dependent on the expression of TLR4; but other genes, such as RP105 and MHC class II, have also been shown to contribute to B cell LPS response. Here, we have evaluated the role of genetic control of the B cell response to LPS at the single cell level. We compared the response to LPS of peritoneal cavity (PEC) and splenic B cells on the BALB/c genetic background (LPS-low responder) to those on the C57BL/6J background (LPS-high responder) and their F1 progeny (CB6F1). Both PEC and splenic B cells from B6 exhibited 100% clonal growth in the presence of LPS; whereas, BALB/c PEC and splenic B cells achieved only 50% and 23% clonal growth, respectively. Adding CpG to the LPS stimulus pushed PEC B cell clonal growth in the low responder strain BALB/c up to 90%, showing that the nonresponse to LPS is a specific effect. Surprisingly, PEC B cells on the F1 background behaved as high responders, while splenic B cells behaved as low responders to LPS. The data presented here reveals a previous unsuspected behavior in the genetic control of the B cell response to LPS with an opposing impact in splenic versus peritoneal cavity B cells. These results suggest the existence of an, as yet, unidentified genetic factor exclusively expressed by coelomic B cells that contributes to the control of the LPS signaling pathway in the B lymphocyte.

Composition of the immunoglobulin classic antigen-binding site regulates allergic airway inflammation in a murine model of experimental asthma.

BACKGROUND: When bound to mast cell FcepsilonRI, IgE serves as antigen receptor for allergic reactions, permitting specific identification of the allergen. Although the core of the classic antigen-binding site is heavy chain complementarity determining region 3 (CDR-H3), recent studies suggest that allergens might also bind IgE in a superantigen-like fashion outside the classic antigen-binding site. OBJECTIVE: We sought to evaluate the contribution of the classic CDR-H3-centric antigen-binding site to the development of an allergic phenotype. METHODS: Using a murine model of experimental asthma, we characterized a gene-targeted mouse strain expressing an altered range of CDR-H3s (DeltaD-iD mice) in response to the hydrophobic allergen ovalbumin (OVA). Mutant and wild-type (wt) mice were sensitized intraperitoneally with OVA; non-sensitized mice served as controls. RESULTS: We found the composition of the classic CDR-H3-centric antigen-binding site to be critical for the development of characteristic aspects of allergic asthma. (i) Compared with wt animals, DeltaD-iD mice showed a significantly less pronounced OVA-induced rise in allergen-specific IgE levels and hence in total serum IgE levels. (ii) In addition, DeltaD-iD mice demonstrated a significant reduction in eosinophilic airway inflammation, as well as in interleukin-4 (IL-4), IL-5 and IL-13 levels in BAL fluids. CONCLUSION: Allergic sensitization and airway inflammation depend on the composition of the predominant CDR-H3 repertoire, suggesting that the classic CDR-H3-centric antigen-binding site plays a crucial role in creating the immunological interface between allergen and IgE. Our results further emphasize a central role of IgE, not only in mediating but also in regulating the allergic immune response.

Early restriction of the human antibody repertoire.

Diversification of the antibody repertoire in mammals results from a series of apparently random somatically propagated gene rearrangement and mutational events. Nevertheless, it is well known that the adult repertoire of antibody specificities is acquired in a developmentally programmed fashion. As previously shown, rearrangement of the gene segments encoding the heavy-chain variable regions (VH) of mouse antibodies is also developmentally ordered: the number of VH gene segments rearranged in B lymphocytes of fetal mice is small but increased progressively after birth. In this report, human fetal B-lineage cells were also shown to rearrange a highly restricted set of VH gene segments. In a sample of heavy-chain transcripts from a 130-day human fetus the most frequently expressed human VH element proved to be closely related to the VH element most frequently expressed in murine fetal B-lineage cells. These observations are important in understanding the development of immunocompetence.

Preoperative platelet transfusions to reverse antiplatelet therapy for urgent non-cardiac surgery: an observational cohort study.

Essentials An increasing number of patients requiring surgery receive antiplatelet therapy (APT). We analyzed 181 patients receiving presurgery platelet transfusions to reverse APT. No coronary thrombosis occurred after platelet transfusion. This justifies a prospective trial to test preoperative platelet transfusions to reverse APT. SUMMARY: Background Patients receiving antiplatelet therapy (APT) have an increased risk of perioperative bleeding and cardiac adverse events (CAE). Preoperative platelet transfusions may reduce the bleeding risk but may also increase the risk of CAE, particularly coronary thrombosis in patients after recent stent implantation. Objectives To analyze the incidence of perioperative CAE and bleeding in patients undergoing non-cardiac surgery using a standardized management of transfusing two platelet concentrates preoperatively and restart of APT within 24-72 h after surgery. Methods A cohort of consecutive patients on APT treated with two platelet concentrates before non-cardiac surgery between January 2012 and December 2014 was retrospectively identified. Patients were stratified by the risk of major adverse cardiac and cerebrovascular events (MACCE). The primary objective was the incidence of CAE (myocardial infarction, acute heart failure and cardiac troponine T increase). Secondary objectives were incidences of other thromboembolic events, bleedings, transfusions and mortality. Results Among 181 patients, 88 received aspirin, 21 clopidogrel and 72 dual APT. MACCE risk was high in 63, moderate in 103 and low in 15 patients; 67 had cardiac stents. Ten patients (5.5%; 95% CI, 3.0-9.9%) developed a CAE (three myocardial infarctions, four cardiac failures and three troponin T increases). None was caused by coronary thrombosis. Surgery-related bleeding occurred in 22 patients (12.2%; 95% CI, 8.2-17.7%), making 12 re-interventions necessary (6.6%; 95% CI, 3.8-11.2%). Conclusion Preoperative platelet transfusions and early restart of APT allowed urgent surgery and did not cause coronary thromboses, but non-thrombotic CAEs and re-bleeding occurred. Randomized trials are warranted to test platelet transfusion against other management strategies.

Endoscopic Third Ventriculostomy before Posterior Fossa Tumor Surgery in Adult Patients.

OBJECTIVE: Obstructive hydrocephalus in patients with posterior fossa tumors is frequently seen. Treatment options include immediate tumor removal or prior cerebrospinal fluid (CSF) diversion procedures. The necessity and feasibility of an ETV in these situations has not yet been proven in adult patients. METHODS: We retrospectively reviewed our prospectively maintained database for ETVs before surgery of posterior fossa tumors in adults. The primary focus of data analyses was the question of whether the ETV was suitable to treat the acute situation of hydrocephalus without an increased rate of complications due to the special anatomical situation with a posterior fossa tumor. We also analyzed whether any further CSF diverting procedures were necessary. RESULTS: A total of 40 adult patients who underwent an ETV before posterior fossa tumor surgery were analyzed. Overall, 33 patients (82.5%) had clinical signs of hydrocephalus, and all of them improved in their clinical course after ETV. Seven patients (17.5%) did not demonstrate clinical signs of hydrocephalus, but ETV was performed with prophylactic or palliative intent in six patients and one patient, respectively. No complications were observed due to ETV itself. No permanent shunting procedure was necessary in a mean follow-up of 76.5 months. Early additional CSF diverting procedures (redo ETV, external ventricular drain) were performed in five patients (12.5%). CONCLUSION: The present series confirms the feasibility and safety of ETV before posterior fossa tumor surgery in adult patients. If patients had symptomatic hydrocephalus before tumor surgery, an ETV can be performed, followed by early elective tumor surgery. A prophylactic ETV in asymptomatic patients is not advised. Early elective tumor surgery should be performed in these patients.

Evidence of antigen receptor-influenced oligoclonal B lymphocyte expansion in the synovium of a patient with longstanding rheumatoid arthritis.

Plasma cell infiltration of synovium is common in longstanding rheumatoid arthritis (RA). The mechanism(s) underlying synovial B cell proliferation remains unclear. One theory invokes nonspecific polyclonal stimuli; another implicates antigen as the driving force. Antigen-driven repertoires are characteristically enriched for related sets of V gene segments containing similar sequence in the antigen binding site (complementarity-determining regions; CDRs). To study the forces shaping B cell proliferation, we analyzed V kappa transcripts expressed in the synovium of an RA patient. We found Humkv325, a developmentally regulated V kappa III gene segment associated with autoantibody reactivity, in > 10% of randomly-chosen synovial C kappa cDNAs. Two sets of sequences contained identical charged amino acid residues at the V kappa-J kappa join, apparently due to N region addition. We generated "signature" oligonucleotides from these CDR3s and probed PCR amplified V kappa products from the synovium and PBLs of the same patient, and from PBLs and spleen of individuals without rheumatic disease. Significant expression of transcripts containing these unique CDR3 sequences occurred only in the patient's synovium. Thus, in this synovium there is expansion of a limited set of B cell clones expressing antigen receptors that bear evidence of antigen selection.

Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency.

We have proposed that significant subsets of individuals with IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) may represent polar ends of a clinical spectrum reflecting a single underlying genetic defect. This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles. Here we present our analysis of the MHC haplotypes of 12 IgA-D and 19 CVID individuals from 21 families and of 79 of their immediate relatives. MHC haplotypes were defined by analyzing polymorphic markers for 11 genes or their products between the HLA-DQB1 and the HLA-A genes. Five of the families investigated contained more than one immunodeficient individual and all of these included both IgA-D and CVID members. Analysis of the data indicated that a small number of MHC haplotypes were shared by the majority of immunodeficient individuals. At least one of two of these haplotypes was present in 24 of the 31 (77%) immunodeficient individuals. No differences in the distribution of these haplotypes were observed between IgA-D and CVID individuals. Detailed analysis of these haplotypes suggests that a susceptibility gene or genes for both immunodeficiencies are located within the class III region of the MHC, possibly between the C4B and C2 genes.

Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals.

Immunoglobulin secretion by plasma cells infiltrating synovial membranes is a prominent feature of RA. Previous analyses of a cDNA library generated from synovium of RA patient BC revealed immunoglobulin kappa light chain transcripts with extensive somatic mutation, frequent N region addition, and unexpected variation in the lengths of CDR3 regions which form the center of the antigen binding site. To determine if these characteristics are present in other individuals, we performed reverse transcription-polymerase chain reaction amplification and sequenced > or = 10 V kappa-containing amplicons from nine tissue samples: synovia of three individuals with long-standing RA (including patient BC), PBLs of two of these individuals, and PBLs or splenocytes of four normal individuals. Increased levels of somatic mutation in PBLs appeared to correlate with increased age, which may reflect accumulation of circulating memory cells and/or decreased bone marrow production of naive B lymphocytes. Two of three RA synovial samples and both RA PBL samples exhibited increased proportions of clones with unusual CDR3 lengths. Enrichment for these antibody binding sites could be due to abnormal regulation of the emerging repertoire or to selection for B lymphocytes bearing antibodies of unusual specificity, and may play a role in the pathogenesis of RA.

Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors.

To better understand the stage(s) of differentiation reached by B-type chronic lymphocytic leukemia (B-CLL) cells and to gain insight into the potential role of antigenic stimulation in the development and diversification of these cells, we analyzed the rearranged VH genes expressed by 83 B-CLL cells (64 IgM+ and 19 non-IgM+). Our results confirm and extend the observations of a bias in the use of certain VH, D, and JH genes among B-CLL cells. In addition, they indicate that the VH genes of approximately 50% of the IgM+ B-CLL cells and approximately 75% of the non-IgM+ B-CLL cells can exhibit somatic mutations. The presence of mutation varies according to the VH family expressed by the B-CLL cell (VH3 expressers displaying more mutation than VH1 and VH4 expressers). In addition, the extent of mutation can be sizeable with approximately 32% of the IgM+ cases and approximately 68% of the non-IgM+ cases differing by > 5% from the most similar germline gene. Approximately 20% of the mutated VH genes display replacement mutations in a pattern consistent with antigen selection. However, CDR3 characteristics (D and JH gene use and association and HCDR3 length, composition, and charge) suggest that selection for distinct B cell receptors (BCR) occurs in many more B-CLL cells. Based on these data, we suggest three prototypic BCR, representing the VH genes most frequently encountered in our study. These data suggest that many B-CLL cells have been previously stimulated, placing them in the "experienced" or "memory" CD5(+) B cell subset.

Endoscopic Biopsy for Intra- and Paraventricular Tumors: Rates of Complications, Mortality, and Tumor Cell Dissemination.

BACKGROUND AND STUDY AIM: Intra- and paraventricular tumors are frequently associated with cerebrospinal fluid (CSF) pathway obstruction. Thus the aim of an endoscopic approach is to restore patency of the CSF pathways and to obtain a tumor biopsy. Because endoscopic tumor biopsy may increase tumor cell dissemination, this study sought to evaluate this risk. PATIENTS, MATERIALS, AND METHODS: Forty-four patients who underwent endoscopic biopsies for ventricular or paraventricular tumors between 1993 and 2011 were included in the study. Charts and images were reviewed retrospectively to evaluate rates of adverse events, mortality, and tumor cell dissemination. Adverse events, mortality, and tumor cell dissemination were evaluated. RESULTS: Postoperative clinical condition improved in 63.0% of patients, remained stable in 30.4%, and worsened in 6.6%. One patient (2.2%) had a postoperative thalamic stroke leading to hemiparesis and hemineglect. No procedure-related deaths occurred. Postoperative tumor cell dissemination was observed in 14.3% of patients available for follow-up. CONCLUSIONS: For patients presenting with occlusive hydrocephalus due to tumors in or adjacent to the ventricular system, endoscopic CSF diversion is the procedure of first choice. Tumor biopsy in the current study did not affect safety or efficacy.