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.

Protein arginine methyltransferase 5 represses tumor suppressor miRNAs that down-regulate CYCLIN D1 and c-MYC expression in aggressive B-cell lymphoma.

Protein arginine methyltransferase-5 (PRMT5) is overexpressed in aggressive B-cell non-Hodgkin's lymphomas, including mantle cell lymphoma and diffuse large B-cell lymphoma, and supports constitutive expression of CYCLIN D1 and c-MYC. Here, we combined ChIP analysis with next-generation sequencing to identify microRNA (miRNA) genes that are targeted by PRMT5 in aggressive lymphoma cell lines. We identified enrichment of histone 3 dimethylation at Arg-8 (H3(Me2)R8) in the promoter regions of miR33b, miR96, and miR503. PRMT5 knockdown de-repressed transcription of all three miRNAs, accompanied by loss of recruitment of epigenetic repressor complexes containing PRMT5 and either histone deacetylase 2 (HDAC2) or HDAC3, enhanced binding of co-activator complexes containing p300 or CREB-binding protein (CBP), and increased acetylation of specific histones, including H2BK12, H3K9, H3K14, and H4K8 at the miRNA promoters. Re-expression of individual miRNAs in B-cell lymphoma cells down-regulated expression of PRMT5, CYCLIN D1, and c-MYC, which are all predicted targets of these miRNAs, and reduced lymphoma cell survival. Luciferase reporter assays with WT and mutant 3'UTRs of CYCLIN D1 and c-MYC mRNAs revealed that binding sites for miR33b, miR96, and miR503 are critical for translational regulation of the transcripts of these two genes. Our findings link altered PRMT5 expression to transcriptional silencing of tumor-suppressing miRNAs in lymphoma cells and reinforce PRMT5's relevance for promoting lymphoma cell growth and survival.

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.

Protein arginine methyltransferase 5 (PRMT5) promotes survival of lymphoma cells via activation of WNT/ß-catenin and AKT/GSK3ß proliferative signaling.

Epigenetic regulation by the type II protein arginine methyltransferase, PRMT5, plays an essential role in the control of cancer cell proliferation and tumorigenesis. In this report, we investigate the relationship between PRMT5 and WNT/ß-CATENIN as well as AKT/GSK3ß proliferative signaling in three different types of non-Hodgkin's lymphoma cell lines, clinical samples, and mouse primary lymphoma cells. We show that PRMT5 stimulates WNT/ß-CATENIN signaling through direct epigenetic silencing of pathway antagonists, AXIN2 and WIF1, and indirect activation of AKT/GSK3ß signaling. PRMT5 inhibition with either shRNA-mediated knockdown or a specific small molecule PRMT5 inhibitor, CMP-5, not only leads to derepression of WNT antagonists and decreased levels of active phospho-AKT (Thr-450 and Ser-473) and inactive phospho-GSK3ß (Ser-9) but also results in decreased transcription of WNT/ß-CATENIN target genes, CYCLIN D1, c-MYC, and SURVIVIN, and enhanced lymphoma cell death. Furthermore, PRMT5 inhibition leads to reduced recruitment of co-activators CBP, p300, and MLL1, as well as enhanced recruitment of co-repressors HDAC2 and LSD1 to the WNT/ß-CATENIN target gene promoters. These results indicate that PRMT5 governs expression of prosurvival genes by promoting WNT/ß-CATENIN and AKT/GSK3ß proliferative signaling and that its inhibition induces lymphoma cell death, which warrants further clinical evaluation.

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.

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.

Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing.

Epigenetic regulation mediated by lysine- and arginine-specific enzymes plays an essential role in tumorigenesis, and enhanced expression of the type II protein arginine methyltransferase PRMT5 as well as the polycomb repressor complex PRC2 has been associated with increased cell proliferation and survival. Here, we show that PRMT5 is overexpressed in three different types of non-Hodgkin lymphoma cell lines and clinical samples as well as in mouse primary lymphoma cells and that it up-regulates PRC2 expression through inactivation of the retinoblastoma proteins RB1 and RBL2. Although PRMT5 epigenetically controls RBL2 expression, it indirectly promotes RB1 phosphorylation through enhanced cyclin D1 expression. Furthermore, we demonstrate that PRMT5 knockdown in non-Hodgkin lymphoma cell lines and mouse primary lymphoma cells leads to RBL2 derepression and RB1 reactivation, which in turn inhibit PRC2 expression and trigger derepression of its CASP10, DAP1, HOXA5, and HRK pro-apoptotic target genes. We also show that reduced PRMT5 expression leads to cyclin D1 transcriptional repression via loss of TP53K372 methylation, which results in decreased BCL3 expression and enhanced recruitment of NF-κB p52-HDAC1 repressor complexes to the cyclin D1 promoter. These findings indicate that PRMT5 is a master epigenetic regulator that governs expression of its own target genes and those regulated by PRC2 and that its inhibition could offer a promising therapeutic strategy for lymphoma patients.

Retro superior costotransverse ligament space block as an effective analgesia after laparoscopic gastrectomy -a case report.

BACKGROUND: The retro superior costotransverse ligament space (RSS) block, reported as a novel target in paraspinal block, involves the spreading of local anesthetics into the thoracic paravertebral space through slits around the superior costotransverse ligament . This blocks not only the dorsal rami but also the ventral rami, achieving a reliable complete sensory blockade. CASE: We performed an RSS block at the T5, T7, and T9 levels on both sides for postoperative analgesia in two patients who underwent laparoscopic gastrectomy. Both patients showed complete sensory blockade from T4 to L1 on the anterior, lateral, and posterior chest walls in the recovery room. The resting and dynamic pain scores were 0 at 30 min and 6 h postoperatively. The pain score consistently remained below 3 throughout postoperative period. CONCLUSIONS: The RSS block provided effective postoperative analgesia in laparoscopic gastrectomy through definitive complete sensory blockade.

Actinomycosis Confined to the Nasal Septum.

Actinomycosis is common in the head and neck region but rarely occurs in the nasal septum. A 75-year-old male patient with an edentulous maxilla, hypertension, and diabetes developed actinomycosis confined to the nasal septum and showed mucosal necrosis and septal bony sequestration. The patient underwent surgery and medication therapy; this case was reported using endoscopic photographs and radiographs and a literature review was conducted to provide further context and understanding of the condition of the patient.

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.

Intraglandular Ordinary Lipoma of the Submandibular Gland.

Lipomas are the most common soft tissue lesions occurring in the salivary glands but have a very low incidence. Lipomas commonly occur in the parotid gland, and lipomas in the submandibular gland (SMG) are rare. Until recently, ordinary lipomas of the parotid gland and some variants of lipomas of the SMG have been reported. However, few reports of ordinary lipomas occurring within the SMG exist in the literature. We report an extremely rare case of ordinary lipoma within the right SMG of a 65-year-old man. The tumor measured a 2.0 × 1.8 × 2.7 cm, was a well-capsulated homogenous yellow mass, which was composed of mature adipose tissue. A partially mixed area with salivary gland tissue was observed. There has not been much research on lipomatous tumors from the SMG because of their rareness. Most lipomatous tumors in the parotid gland are known as ordinary lipomas, but more research is needed to determine whether they can be applied to the SMG. Thus, this report will be instrumental in the understanding of lipomatous tumors of the SMG.

Postoperative Urinary Retention Following General Anesthesia for Endoscopic Nasal Surgery in Men Aged Older Than 60 Years: A Retrospective Study.

OBJECTIVES: Postoperative urinary retention (POUR) is influenced by many factors, and its reported incidence rate varies widely. This study aimed to investigate the occurrence and risk factors for urinary retention following general anesthesia for endoscopic nasal surgery in male patients aged >60 years. METHODS: A retrospective review of medical records between January 2015 and December 2019 identified 253 patients for inclusion in our study. Age, body mass index (BMI), a history of diabetes/hypertension, American Society of Anesthesiologists (ASA) classification, and urologic history were included as patient-related factors. Urologic history was subdivided into 3 groups according to history of benign prostate hyperplasia (BPH)/lower urinary tract symptoms (LUTS) and current medication. The following was analyzed as perioperative variables for POUR development: duration of anesthesia and surgery; amount of fluid administered; rate of fluid administration; intraoperative requirement for fentanyl, ephedrine, and dexamethasone; postoperative pain; and analgesic use. Preoperatively measured prostate size and uroflowmetry parameters of patients on medication for symptoms were compared according to the incidence of urinary retention. RESULTS: Thirty-seven (15.7%) patients developed POUR. Age (71.4 vs 69.6 years), BMI (23.9 vs 24.9 kg/m2), a history of diabetes/hypertension, ASA classification, and perioperative variables were not significantly different between patients with and without POUR. Only urologic history was identified as a factor affecting the occurrence of POUR (P = .03). The incidence rate among patients without urologic issues was 5.9%, whereas that among patients with BPH/LUTS history was 19.8%. Among patients taking medication for symptoms, the maximal and average velocity of urine flow were significantly lower in patients with POUR. CONCLUSIONS: General anesthesia for endoscopic nasal surgery may be a potent trigger for urinary retention in male patients aged >60 years. The patient's urological history and urinary conditions appear to affect the occurrence of POUR.

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.

Eagle syndrome after a fracture of complete ossified stylohyoid ligament from indirect trauma treated using local steroid injection: A case report.

RATIONALE: Stylohyoid complex syndrome is characterized by various cervicopharyngeal symptoms related to the ossification and abnormality of the styloid process, stylohyoid ligament, and the lesser horn of the hyoid bone. Eagle syndrome is the most well-known of the spectra of these diseases. Although surgical treatment is considered effective, conservative treatment may be beneficial if symptoms arise because of inflammation of the soft tissues attached to the styloid process or hyoid bone. PATIENT CONCERNS: A 68-year-old man presented with pain in the right side of the neck and odynophagia after trauma on his philtrum. He was diagnosed with Eagle syndrome elicited by a fracture from indirect trauma. Despite analgesic medication and physiotherapy, the pain had somewhat relieved but persisted for 1 year. DIAGNOSIS: Computed tomography revealed complete ossification of the bilateral stylohyoid complex. A fracture was observed in the ampulla on the right side of the neck. One year later, the fracture resolved by complete union. INTERVENTIONS: Ultrasonography was performed and abnormal ossification was observed on the right side of the neck. Five milligrams of dexamethasone at a concentration of 1 kg/m was slowly injected into the tender point under ultrasonographic guidance. OUTCOMES: The patient reported immediate reduction of pain and was satisfied with the resolution. No recurrence was observed during a 6-month follow-up period. LESSONS: Although traumatic fracture of the ossified ligament elicited the syndrome, the results were satisfactory because the origin of the patient's pain was presumed to arise from inflammatory conditions. This case demonstrates that treatment with local steroid injection may be appropriate for patients who present with pain originating from muscles and ligaments.

Postoperative expressive aphasia associated with intravenous midazolam administration: a 5-year retrospective case-control study.

OBJECTIVES: This study aimed to investigate the epidemiology of intravenous midazolam-induced postoperative expressive aphasia (EA). METHODS: The incidence rate, risk ratio, and contributing factors to intravenous midazolam-induced postoperative EA were analyzed retrospectively in 6756 orthopedic patients. A telephone interview was conducted with patients with EA after surgery. RESULTS: Patients were allocated to either the midazolam group (n = 6178) or no-midazolam group (n = 578). Twelve patients developed EA in the midazolam group, with an incidence of 0.19%, and no patient developed EA in the no-midazolam group. The mean age of EA patients was 70 years, and 92% were women. Among them, 75% received general anesthesia, and the mean dose of midazolam was 1.8 mg. EA was reversed in nine of 12 (75%) patients within 4 minutes of flumazenil administration, and >60 minutes were required to reverse EA in the other three patients (25%). CONCLUSION: Intravenous midazolam administration for preoperative sedation caused transient EA in 0.19% of patients, especially elderly women who received general anesthesia, and EA could be reversed by flumazenil.

MicroRNAs modulate the chemosensitivity of tumor cells.

MicroRNAs are strongly implicated in such processes as development, carcinogenesis, cell survival, and apoptosis. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. In the experimental system, we increased the expression of individual microRNAs by transfecting their precursors (which are active) or suppressed the expression by transfection of antisense oligomers. In three NCI-60 human cancer cell lines, a panel of 60 lines used for anticancer drug discovery, we assessed the growth-inhibitory potencies of 14 structurally diverse compounds with known anticancer activities. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growth-inhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that approximately 30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Ten of those microRNAs have already been implicated in cancer biology. Our results support a substantial role for microRNAs in anticancer drug response, suggesting novel potential approaches to the improvement of chemotherapy.

Multimodal analgesia with multiple intermittent doses of erector spinae plane block through a catheter after total mastectomy: a retrospective observational study.

BACKGROUND: Although case reports have suggested that the erector spinae plane block (ESPB) may help analgesia for patients after breast surgery, no study to date has assessed its effectiveness. This retrospective observational study analyzed the analgesic effects of the ESPB after total mastectomy. METHODS: Forty-eight patients were divided into an ESPB group (n = 20) and a control group (n = 28). Twenty patients in the control group were selected by their propensity score matching the twenty patients in the ESPB group. Patients in the ESPB group were injected with 30 mL 0.375% ropivacaine, followed by catheter insertion for further injections of local anesthetics every 12 hours. Primarily, total fentanyl consumption was compared between the two groups during the first 24 hours postoperatively. Secondary outcomes included pain intensity levels (visual analogue scale) and incidence of postoperative nausea and vomiting (PONV). RESULTS: Median cumulative fentanyl consumption during the first 24 hours was significantly lower in the ESPB (33.0µg; interquartile range [IQR], 27.0-69.5µg) than in the control group (92.8µg; IQR, 40.0-155.0µg) (P = 0.004). Pain level in the early postoperative stage (<3 hr) and incidence of PONV (0% vs. 55%) were also significantly lower in the ESPB group compared to the control (P = 0.001). CONCLUSIONS: Intermittent ESPB after total mastectomy reduces fentanyl consumption and early postoperative pain. ESPB is a good option for multimodal analgesia after breast surgery.

Erector spinae plane block for multimodal analgesia after wide midline laparotomy: A case report.

RATIONALE: The most commonly used regional techniques for analgesia following laparotomy thoracic epidural analgesia and paravertebral blocks are technically difficult to perform and carry a risk of severe complications. Recently, the erector spinae plane block (ESPB) has been reported to effectively treat neuropathic pain. The ultrasound-guided ESPB is an easily performed fascial plane block that can provide sensory blockade from T2-4 to T12-L1. Moreover, the ESPB reportedly blocks both the ventral rami of spinal nerves and the rami communicants, which contain sympathetic nerve fibres, through spread into the thoracic paravertebral space. PATIENT CONCERNS: We report the case of a 35-year-old female patient who underwent excision of a larger ovarian mass via laparotomy with a wide, midline incision from the xiphoid process to the pubic tubercle. DIAGNOSES: They were diagnosed with mucinous cystadenoma originated from the right ovary and fallopian tube, and a right oophorectomy and salpingectomy were performed. INTERVENTIONS: The ESPB was performed for postoperative pain control at the level of the T8 transverse process. Postoperative multimodal analgesia was provided according to the acute pain service protocol of our hospital. The patient was prescribed oral acetaminophen 175 mg every 6 hours and intravenous patient-controlled analgesia (PCA) with fentanyl 7 µg/mL. A 1:1 mixture of 0.75% ropivacaine (20 mL) and saline (20 mL) with epinephrine (1: 200,000) was manually injected through the indwelling catheter every 8 hours (20 mL per side). OUTCOMES: The first demand dose of fentanyl was administered at 9 hours and 39 minutes after the surgery. There were no reported resting pain scores >4, nor were any rescue analgesics needed during the first 5 postoperative days. LESSONS: The ESPB provided highly effective analgesia as a part of multimodal analgesia after laparotomy with a wide midline incision.

Extended Stability of Reconstituted and Diluted SB3 (Trastuzumab Biosimilar) Assessed by Physicochemical and Biological Properties.

INTRODUCTION: Stability information for the trastuzumab biosimilar SB3 is limited to 48 h at 2-8 °C for the reconstituted solution and 24 h at up to 30 °C for diluted solutions. Extended physicochemical stability and biological activity were assessed to evaluate the advanced preparation of reconstituted and diluted SB3. METHODS: Under controlled and aseptic conditions, the stability of reconstituted and diluted SB3 was evaluated using several assessments and according to the UK's National Health Service guidance. Reconstituted SB3 was stored at 25 ± 2 °C with 60 ± 5% relative humidity for 3 days, and subsequently diluted SB3 (0.32-4 mg/mL) was stored in an infusion bag in the absence of light at 25 ± 2 °C with 60 ± 5% relative humidity for 28 days and 5 ± 3 °C for 28 days, respectively. Physicochemical stability (appearance, pH, protein concentration, size exclusion high-performance liquid chromatography, non-reducing capillary electrophoresis-sodium dodecyl sulfate, imaged capillary isoelectric focusing), biological activity (competitive inhibition binding assay to human epidermal growth factor receptor 2 by fluorescence resonance energy transfer, anti-proliferation assay), and properties with a potential safety impact (subvisible particulates, submicronic aggregation by dynamic light scattering) were determined. RESULTS: No physicochemical instability signs or biological activity changes were observed for either reconstituted or diluted SB3 up to 28 days; all stability acceptance criteria were met. No major change was noted in the proportion of molecular weight variants (high molecular weight impurity, total purity) or relative percentages of acidic, main, and basic charge isoforms of the protein. No increases in particulates or aggregates in terms of a potential safety impact were noted. CONCLUSION: The physicochemical stability and biological activity of reconstituted and diluted SB3 are maintained for extended time periods beyond those denoted in the product labeling, which allows for advanced SB3 preparation and may reduce drug wastage and preparation time. FUNDING: Samsung Bioepis Co., Ltd.