PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that comprises up to 6% of non-Hodgkin lymphomas diagnosed annually and is associated with a poor prognosis. The average overall survival of patients with MCL is 5 years, and for most patients who progress on targeted agents, survival remains at a dismal 3 to 8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The protein arginine methyltransferase 5 (PRMT5) enzyme is overexpressed in MCL and promotes growth and survival. Inhibition of PRMT5 drives antitumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of prosurvival AKT signaling, which led to the nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing identified multiple proapoptotic BCL-2 family members as FOXO1-bound genomic loci. We identified BAX as a direct transcriptional target of FOXO1 and demonstrated its critical role in the synergy observed between the selective PRMT5 inhibitor, PRT382, and the BCL-2 inhibitor, venetoclax. Single-agent and combination treatments were performed in 9 MCL lines. Loewe synergy scores showed significant levels of synergy in most MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with an increased survival advantage in 2 patient-derived xenograft models (P ≤ .0001, P ≤ .0001). Our results provide mechanistic rationale for the combination of PRMT5 inhibition and venetoclax to treat patients with MCL.

PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.

Characterization of a PIP Binding Site in the N-Terminal Domain of V-ATPase a4 and Its Role in Plasma Membrane Association.

Vacuolar ATPases (V-ATPases) are multi-subunit ATP-dependent proton pumps necessary for cellular functions, including pH regulation and membrane fusion. The evidence suggests that the V-ATPase a-subunit's interaction with the membrane signaling lipid phosphatidylinositol (PIPs) regulates the recruitment of V-ATPase complexes to specific membranes. We generated a homology model of the N-terminal domain of the human a4 isoform (a4NT) using Phyre2.0 and propose a lipid binding domain within the distal lobe of the a4NT. We identified a basic motif, K234IKK237, critical for interaction with phosphoinositides (PIP), and found similar basic residue motifs in all four mammalian and both yeast a-isoforms. We tested PIP binding of wildtype and mutant a4NT in vitro. In protein lipid overlay assays, the double mutation K234A/K237A and the autosomal recessive distal renal tubular-causing mutation K237del reduced both PIP binding and association with liposomes enriched with PI(4,5)P2, a PIP enriched within plasma membranes. Circular dichroism spectra of the mutant protein were comparable to wildtype, indicating that mutations affected lipid binding, not protein structure. When expressed in HEK293, wildtype a4NT localized to the plasma membrane in fluorescence microscopy and co-purified with the microsomal membrane fraction in cellular fractionation experiments. a4NT mutants showed reduced membrane association and decreased plasma membrane localization. Depletion of PI(4,5)P2 by ionomycin caused reduced membrane association of the WT a4NT protein. Our data suggest that information contained within the soluble a4NT is sufficient for membrane association and that PI(4,5)P2 binding capacity is involved in a4 V-ATPase plasma membrane retention.

CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis.

High mortality of prostate cancer patients is primarily due to metastasis. Understanding the mechanisms controlling metastatic processes remains essential to develop novel therapies designed to prevent the progression from localized disease to metastasis. CdGAP plays important roles in the control of cell adhesion, migration, and proliferation, which are central to cancer progression. Here we show that elevated CdGAP expression is associated with early biochemical recurrence and bone metastasis in prostate cancer patients. Knockdown of CdGAP in metastatic castration-resistant prostate cancer (CRPC) PC-3 and 22Rv1 cells reduces cell motility, invasion, and proliferation while inducing apoptosis in CdGAP-depleted PC-3 cells. Conversely, overexpression of CdGAP in DU-145, 22Rv1, and LNCaP cells increases cell migration and invasion. Using global gene expression approaches, we found that CdGAP regulates the expression of genes involved in epithelial-to-mesenchymal transition, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice shows a delayed tumor initiation and attenuated tumor growth. Orthotopic injection of CdGAP-depleted PC-3 cells reduces distant metastasic burden. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a potential biomarker and target for prostate cancer treatments.

Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the spontaneous canine model of non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of blood cancers arising in lymphoid tissues that commonly effects both humans and dogs. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the symmetric di-methylation of arginine residues, is frequently overexpressed and dysregulated in both human solid and hematologic malignancies. In human lymphoma, PRMT5 is a known driver of malignant transformation and oncogenesis, however, the expression and role of PRMT5 in canine lymphoma has not been explored. To explore canine lymphoma as a useful comparison to human lymphoma while validating PRMT5 as a rational therapeutic target in both, we characterized expression patterns of PRMT5 in canine lymphoma tissue microarrays, primary lymphoid biopsies, and canine lymphoma-derived cell lines. The inhibition of PRMT5 led to growth suppression and induction of apoptosis, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric dimethylation. We performed ATAC-sequencing and gene expression microarrays with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility and whole-transcriptome changes in canine lymphoma cells lines upon PRMT5 inhibition. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued use of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.

Transducin ß-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma and is characterized by a remarkable heterogeneity with diverse variants that can be identified histologically and molecularly. Large-scale gene expression profiling studies have identified the germinal center B-cell (GCB-) and activated B-cell (ABC-) subtypes. Standard chemo-immunotherapy remains standard front line therapy, curing approximately two thirds of patients. Patients with refractory disease or those who relapse after salvage treatment have an overall poor prognosis highlighting the need for novel therapeutic strategies. Transducin ß-like protein 1 (TBL1) is an exchange adaptor protein encoded by the TBL1X gene and known to function as a master regulator of the Wnt signalling pathway by binding to ß-CATENIN and promoting its downstream transcriptional program. Here, we show that, unlike normal B-cells, DLBCL cells express abundant levels of TBL1 and its overexpression correlates with poor clinical outcome regardless of DLBCL molecular subtype. Genetic deletion of TBL1 and pharmacological approach using tegavivint, a first-in-class small molecule targeting TBL1 (Iterion Therapeutics), promotes DLBCL cell death in vitro and in vivo. Through an integrated genomic, biochemical, and pharmacologic analyses, we characterized a novel, ß-CATENIN independent, post-transcriptional oncogenic function of TBL1 in DLBCL where TBL1 modulates the stability of key oncogenic proteins such as PLK1, MYC, and the autophagy regulatory protein BECLIN-1 through its interaction with a SKP1-CUL1-F-box (SCF) protein supercomplex. Collectively, our data provide the rationale for targeting TBL1 as a novel therapeutic strategy in DLBCL.

SOX2 activation predicts prognosis in patients with head and neck squamous cell carcinoma.

SOX2 copy number and mRNA expression were analysed to examine the clinical significance of SOX2 activation in HNSCC. Gene expression signatures reflecting SOX2 activation were identified in an HNSCC cohort. Patients with HNSCC were classified into two subgroups according to the gene expression signature: SOX2-high and SOX2-low. The clinical significance of SOX2 activation was further validated in two independent cohorts. Moreover, clinical significance of SOX2 activation in response to radiotherapy was assessed in patients with HNSCC. The relationship between SOX2 activation and radiotherapy was validated in an in vitro experiment. Patients in the SOX2-high subgroup had a better prognosis than patients in the SOX2-low subgroup in all three patient cohorts. Results of multivariate regression analysis showed that SOX2 signature was an independent predictor of the overall survival of patients with HNSCC (hazard ratio, 1.45; 95% confidence interval, 1.09-1.92; P = 0.01). Interestingly, SOX2 activation was a predictor of therapy outcomes in patients receiving radiotherapy. Moreover, SOX2 overexpression enhanced the effect of radiotherapy in HNSCC cell lines. SOX2 activation is associated with improved prognosis of patients with HNSCC and might be used to predict which patients might benefit from radiotherapy.

A comparison of postoperative pain after transumbilical single-port access and conventional three-port total laparoscopic hysterectomy: a randomized controlled trial.

INTRODUCTION: The objective of this study was to compare postoperative pain between single-port access total laparoscopic hysterectomy (SPA-TLH) using a transumbilical single-port system and conventional multi (three)-port access total laparoscopic hysterectomy (MPA-TLH). MATERIAL AND METHODS: A randomized controlled trial was conducted on 60 women who underwent SPA-TLH and MPA-TLH for benign gynecologic diseases between March 2014 and January 2015. Patients were randomly assigned to undergo SPA-TLH (n = 30) or MPA-TLH (n = 30). The variables measured included surgical outcomes and postoperative pain at 30 min and 1, 12, 24, and 48 h after surgery, assessed by the visual analog scale, bolus requirement of intravenous patient-controlled analgesia, and additional analgesic use. RESULTS: The two study groups did not differ in terms of patient demographics or surgical outcomes except for operative time. The SPA-TLH group had a longer operative time (p < 0.0001) compared with the MPA-TLH groups. There were no differences in pain scores between the two groups. The SPA-TLH group had significantly more intravenous analgesia requests during the 12-24 h after surgery (2.17 ± 3.05 vs. 0.79 ± 1.99; p = 0.047), more 24-48 h postoperative analgesics (0.21 ± 0.41 vs. 0.03 ± 0.19; p = 0.045), and more total additional analgesics (0.97 ± 0.94 vs. 0.45 ± 0.87; p = 0.034). CONCLUSION: SPA-TLH was feasible compared with MPA-TLH but the SPA-TLH group had a longer operative time. Although there is no difference in pain based on the visual analog scale pain score, the SPA-TLH group required more analgesia to give the same postoperative pain control.

Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation.

Epigenetic events that are essential drivers of lymphocyte transformation remain incompletely characterized. We used models of Epstein-Barr virus (EBV)-induced B-cell transformation to document the relevance of protein arginine methyltransferase 5 (PRMT5) to regulation of epigenetic-repressive marks during lymphomagenesis. EBV(+) lymphomas and transformed cell lines exhibited abundant expression of PRMT5, a type II PRMT enzyme that promotes transcriptional silencing of target genes by methylating arginine residues on histone tails. PRMT5 expression was limited to EBV-transformed cells, not resting or activated B lymphocytes, validating it as an ideal therapeutic target. We developed a first-in-class, small-molecule PRMT5 inhibitor that blocked EBV-driven B-lymphocyte transformation and survival while leaving normal B cells unaffected. Inhibition of PRMT5 led to lost recruitment of a PRMT5/p65/HDAC3-repressive complex on the miR96 promoter, restored miR96 expression, and PRMT5 downregulation. RNA-sequencing and chromatin immunoprecipitation experiments identified several tumor suppressor genes, including the protein tyrosine phosphatase gene PTPROt, which became silenced during EBV-driven B-cell transformation. Enhanced PTPROt expression following PRMT5 inhibition led to dephosphorylation of kinases that regulate B-cell receptor signaling. We conclude that PRMT5 is critical to EBV-driven B-cell transformation and maintenance of the malignant phenotype, and that PRMT5 inhibition shows promise as a novel therapeutic approach for B-cell lymphomas.

Neurotological parameters and prognosis of Bell's palsy patients.

BACKGROUND: To investigate the relationship with prognosis, various neurotological examinations evaluating all four nerves within the internal auditory canal were performed in patients with Bell's palsy. METHODS: A total of 69 consecutive patients with Bell's palsy were included. They were treated uniformly with steroid and an antiviral agent and underwent neurotological examinations consisting of electronystagmography, pure-tone audiometry (PTA), electroneurography (ENoG), caloric test, rotatory chair test and cervical vestibular evoked myogenic potentials (cVEMP). According to the final recovery state, patients were divided into two groups: a complete recovery group and an incomplete recovery group. The incidence of abnormal findings in each test was compared between the two groups. RESULTS: Fifty-six patients recovered completely and 13 patients recovered incompletely. No association was observed between the rate of ipsilesional PTA threshold and the rate of abnormal caloric test, function tests and recovery state. However, the initial state of facial palsy, ENoG and the rate of abnormal cVEMP were significantly correlated with the rate of recovery. CONCLUSION: The results indicate that Bell's palsy may be more comparable to mononeuritis multiplex and that cVEMP could be a useful tool for predicting the prognosis of Bell's palsy.

Hearing loss as a function of aging and diabetes mellitus: a cross sectional study.

BACKGROUND: Although hearing loss may be caused by various factors, it is also a natural phenomenon associated with the aging process. This study was designed to assess the contributions of diabetes mellitus (DM) and hypertension, both chronic diseases associated with aging, as well as aging itself, to hearing loss in health screening examinees. METHODS: This study included 37,773 individuals who underwent health screening examinations from 2009 to 2012. The relationships between hearing threshold and subject age, hearing threshold at each frequency based on age group, the degree of hearing loss and the presence or absence of hypertension and DM were evaluated. RESULTS: The prevalence of hearing loss increased with age, being 1.6%, 1.8%, 4.6%, 14.0%, 30.8%, and 49.2% in subjects in their twenties, thirties, forties, fifties, sixties, and seventies, respectively (p<0.05). Hearing value per frequency showed aging-based changes, in the order of 6000, 4000, 2000, 1000 and 500 Hz, indicating greater hearing losses at high frequencies. The degree of hearing loss ranged from mild to severe. Aging and DM were correlated with the prevalence of hearing loss (p<0.05). There was no statistically significant association between hearing loss and hypertension after adjusting for age and DM. CONCLUSIONS: The prevalence of hearing loss increases with age and the presence of DM. Hearing loss was greatest at high frequencies. In all age groups, mild hearing loss was the most common form of hearing loss.

Comparison of sudden deafness in adults and children.

OBJECTIVES: Although many studies have assessed sudden deafness in adults, sudden deafness has not been evaluated in children. We therefore evaluated the differences in sudden deafness between children and adults. METHODS: We compared clinical manifestations, including gender, audiogram pattern of initial hearing loss, and recovery rate after treatment in 87 children and 707 adults diagnosed with sudden deafness from September 2003 and August 2012. RESULTS: There were no differences in sex, side, or audiogram between children and adults (P>0.05 each). Hearing recovery rates in children and adults were 72.4% and 70.6%, respectively (P>0.05). Both children and adults with mild hearing loss showed significantly greater hearing recovery rates than individuals with profound hearing loss (P<0.05 each). The percentage with initially mild and moderate hearing loss was higher in children than in adults, as were the recovery rates of children compared to adults with initially mild, moderate-severe, and profound hearing loss (P<0.05 each). In regard to final hearing outcome after treatment, a low percentage of children showed no improvement whereas a high percentage showed complete recovery; a higher percentage of children than of adults showed complete recovery (P<0.05). Recovery rate from profound hearing loss was significantly higher in children than in adults (60.0% vs. 45.4%, P<0.05). CONCLUSION: Degree of hearing loss, gender, side, and recovery rate were similar in children and adults, but the rate of complete recovery was higher in children.

Human dopamine receptor nanovesicles for gate-potential modulators in high-performance field-effect transistor biosensors.

The development of molecular detection that allows rapid responses with high sensitivity and selectivity remains challenging. Herein, we demonstrate the strategy of novel bio-nanotechnology to successfully fabricate high-performance dopamine (DA) biosensor using DA Receptor-containing uniform-particle-shaped Nanovesicles-immobilized Carboxylated poly(3,4-ethylenedioxythiophene) (CPEDOT) NTs (DRNCNs). DA molecules are commonly associated with serious diseases, such as Parkinson's and Alzheimer's diseases. For the first time, nanovesicles containing a human DA receptor D1 (hDRD1) were successfully constructed from HEK-293 cells, stably expressing hDRD1. The nanovesicles containing hDRD1 as gate-potential modulator on the conducting polymer (CP) nanomaterial transistors provided high-performance responses to DA molecule owing to their uniform, monodispersive morphologies and outstanding discrimination ability. Specifically, the DRNCNs were integrated into a liquid-ion gated field-effect transistor (FET) system via immobilization and attachment processes, leading to high sensitivity and excellent selectivity toward DA in liquid state. Unprecedentedly, the minimum detectable level (MDL) from the field-induced DA responses was as low as 10 pM in real- time, which is 10 times more sensitive than that of previously reported CP based-DA biosensors. Moreover, the FET-type DRNCN biosensor had a rapid response time (<1 s) and showed excellent selectivity in human serum.

Effectiveness of transcutaneous electrical stimulation for chronic tinnitus.

CONCLUSION: Based on the Tinnitus Handicap Inventory (THI) and visual analog scale (VAS) scores, transcutaneous electrical stimulation (TENS) can provide relief from tinnitus. Response to electrical stimulation was best seen in patients with low-frequency tinnitus and with mild hearing loss. OBJECTIVE: TENS is known to alleviate symptoms of tinnitus. However, study of the effectiveness of TENS for tinnitus has produced variable results, and it is still unclear what kind of patients with tinnitus would respond best to TENS. Here, we assessed the effects of TENS on the perception of tinnitus using the THI and VAS questionnaires. METHODS: A total of 65 patients with tinnitus were divided into two groups: 45 patients received TENS and 20 patients received placebo (sham stimulation) twice a week over 4 weeks. THI and VAS scores were assessed before and after electrical stimulation. We also evaluated the effects of TENS on the degree of initial hearing loss and tinnitus frequency. RESULTS: Twenty-eight of 45 patients (62.2%) revealed subjective improvement in tinnitus with TENS. TENS was more effective in patients with low-frequency tinnitus or with mild hearing loss. Symptomatic improvement in the electrical stimulation group was achieved for 1 month in most patients.

Clinical bacteriology of recurrent otitis media with effusion.

CONCLUSIONS: Staphylococcus species were the most common bacterial isolates from patients with otitis media with effusion (OME). Unexpectedly, however, there was no difference in the identity or antibiotic resistance of bacteria isolated from patients with recurrent and non-recurrent OME. OBJECTIVES: Antibiotic resistance has increased due to indiscriminate overuse and misuse of antibiotics. Bacterial strains isolated from patients with recurrent OME seem to be more pathogenic and more resistant to antibiotics than strains isolated from patients with non-recurrent OME. The aim of this study was to evaluate the differences in identity and antibiotic sensitivity profiles of bacterial strains isolated from patients with recurrent and non-recurrent OME. METHODS: We collected 900 middle ear fluid (MEF) samples from 654 pediatric patients who underwent ventilation tube insertion due to OME, then compared the identity and antibiotic sensitivity profiles of bacterial strains. Recurrent OME was defined as a requirement for ventilation tube reinsertion after tube extrusion. RESULTS: There was no difference in the identity of bacterial isolates from patients with non-recurrent and recurrent OME regardless of the number of ventilation tubes inserted. Antibiotic sensitivity tests showed that the two groups differed in sensitivity to penicillin and erythromycin, but not to other antibiotics.

Agreement between the Facial Nerve Grading System 2.0 and the House-Brackmann Grading System in Patients with Bell Palsy.

OBJECTIVES: We have analyzed the correlation between the House-Brackmann (HB) scale and Facial Nerve Grading System 2.0 (FNGS 2.0) in patients with Bell palsy, and evaluated the usefulness of the new grading system. METHODS: Sixty patients diagnosed with Bell palsy from May 2009 to December 2010 were evaluated using the HB scale and FNGS 2.0 scale during their initial visit, and after 3 and 6 weeks and 3 months. RESULTS: The overall intraclass correlation coefficient (ICC) was 0.908 (P=0.000) and the Spearman correlation coefficient (SCC) was 0.912 (P<0.05). ICC and SCC displayed differences over time, being 0.604 and 0.626, respectively, at first visit; 0.834 and 0.843, respectively, after 3 weeks; 0.844 and 0.848, respectively, after 6 weeks; and 0.808 and 0.793, respectively, after 3 months. There was a significant difference in full recovery, depending on the scale used (HB, P=0.000; FNGS 2.0, P<0.05). The exact agreements between regional assessment and FNGS 2.0 for the mouth, eyes, and brow were 72%, 63%, and 52%, respectively. CONCLUSION: FNGS 2.0 shows moderate agreement with HB grading. Regional assessment, rather than HB grading, yields stricter evaluation, resulting in better prognosis and determination of grade.

Toll-like receptors, cytokines & nitric oxide synthase in patients with otitis media with effusion.

BACKGROUND & OBJECTIVES: Microbial infections in the normally sterile environment of the middle ear cavity in patients with otitis media trigger expression of Toll-like receptors (TLRs), cytokines, and nitric oxide. We evaluated the expression levels of TLR-1, -2, -4, -5, -6, and -9, interleukin (IL)-6, -8, -10, and -12, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and nitric oxide (NO), in paediatric patients with otitis media with effusion (OME). METHODS: The levels of TLR, cytokine, and nitric oxide synthase (NOS) mRNAs in middle ear effusion were assessed by real-time polymerase chain reaction in 96 children with OME, 24 prone and 72 not prone to otitis. The level of expression of each mRNA was compared in the otitis-prone and non-otitis-prone groups, in patients with and without bacteria, and by frequency of ventilation tube insertion. RESULTS: The expression of TLR-1, -2, -4, -5, -6, and -9; IL-6, -8, -10, and -12; IFN-γ; TNF-α; and NOS mRNAs in the effusion fluid of both the otitis-prone and non-otitis-prone groups were measured. The expression levels of TLR-2, -4, -6, and -9 mRNA were significantly lower in the otitis-prone than in the non-otitis-prone group (P<0.05). Although higher levels of TLR, cytokine, and NOS mRNAs were generally observed in culture positive than in culture negative patients, none of these differences was statistically significant. No differences were observed in the expressions relative to the frequencies of ventilation tube insertion. INTERPRETATION & CONCLUSIONS: TLRs, cytokines, and NOS, which act cooperatively in the innate immune response, were closely associated with OME. Decreased expression of TLRs may be associated with increased susceptibility to OME.

Anesthetic management of a parturient for combined cesarean section and surgical removal of pituitary tumor -A case report-.

A 40-year-old woman was referred to our hospital because of bitemporal hemianopsia at 23 weeks of gestation. A brain magnetic resonance imaging showed a pituitary tumor having suprasellar extension. At 30 weeks of gestation, she complained of rapidly deteriorating vision and bitemporal hemianopsia in both eyes and the ensuing radiological examination revealed increased tumor size, displaced tumor location and compressed optic chiasm. The cesarean section was performed at 31 weeks and 3 days of gestation and simultaneous surgical removal of pituitary tumor was carried out due to the risk of irreversible blindness. Anesthetic management for combined cesarean section and brain surgery can be more complex and challenging for anesthesiologists, and the aim was to achieve both the control of intracranial pressure and fetal well being at the same time. In this case, maternal outcome was somewhat improved after the procedure, and neonatal complications were not detected.

Anesthetic experience in patient for single lung transplantation with previous contralateral pneumonectomy -A case report-.

A 48-year-old woman with cystic fibrosis and a previous left pneumonectomy had surgery planned for single lung transplantation under general anesthesia. Due to progressive dyspnea and recurrent respiratory infection, she could not maintain her normal daily life without lung transplantation. The anesthetic management and surgical procedure was expected to be difficult because of the left mediastinal shift and an asymmetric thorax after the left pneumonectomy, but the single lung transplantation was successfully done under cardiopulmonary bypass.

Epidural hematoma occurred by massive bleeding intraoperatively in cesarean section after combined spinal epidural anesthesia -A case report-.

We describe a case of acute lumbar epidural hematoma at the L2-3 level complicated by paraplegia, which occurred after coagulation disorder because of massive bleeding intraoperatively in cesarean section. The preoperative coagulation laboratory finding was in normal range and so we tried combined spinal epidural anesthesia. Uterine atony occurred in the operation, and there was persistant bleeding during and after the operation. After the operation, she complained of paresthesia on her both legs and was diagnosed with epidural hematoma (EDH) by radiologic examination. Emergency laminectomy on lumbar spine was carried out for hematoma evacuation and decompression of the epidural space at once. In our experience, massive bleeding during surgery may potentially increase the risk of EDH postoperatively.