Dural Tears in Percutaneous Biportal Endoscopic Spine Surgery: Anatomical Location and Management.

OBJECTIVE: To determine the rate and anatomical location of dural tears associated with spinal surgery using a percutaneous biportal endoscopic surgery (PBES) technique. We investigated the relationship between dural tears and the type of procedure and type of instrument used. METHODS: We retrospectively analyzed 643 PBES cases by reviewing the medical records, operative records, and operative videos. Incidental durotomy was identified in 29 cases. We analyzed the size and anatomical location of the dural tears, the surgical instrument that caused the tear, and the technique used to seal the tear. RESULTS: The dural tear incidence was 4.5% (29 of 643 cases). Tears in the exiting nerve area (2 cases; 6.9%) had mainly been caused by curettage, tears in the thecal sac area (18 cases; 62.1%) were associated with electric drill and forceps use; and tears in the traversing nerve area were associated with the use of a Kerrison punch (9 cases; 31%). Of the 29 cases of dural tear, 12 were treated with in-hospital monitoring and bed rest, 14 were treated with a fibrin sealant, 2 were treated with a nonpenetrating titanium clip, and 1 was converted to microscopic surgery. One case of postoperative meningocele after conservative treatment required endoscopic revision surgery to close the dural tear. CONCLUSIONS: Most cases of incidental dural tear during PBES were treated with an endoscopic procedure. The incidence of dural tear was no greater than that associated with microscopic surgery. Our management strategy for incidental dural tears during PBES has been shown to be safe and effective.

Pooled analysis of unsuccessful percutaneous biportal endoscopic surgery outcomes from a multi-institutional retrospective cohort of 797 cases.

BACKGROUND: Spinal percutaneous biportal endoscopic surgery (PBES) is a minimally invasive surgery; however, it is associated with several poor outcomes. This study aimed to analyze unsuccessful PBES outcomes and verify their relationships with patient satisfaction. METHODS: From May 2015 to June 2018, PBES was performed at several institutions. Unsuccessful outcomes (reoperation and prolonged hospital stay) due to various reasons (hematoma, lesion recurrence, incomplete decompression, dural tear, instability, ascites, and infection) were analyzed. To verify the relationships between surgical experience and unsuccessful outcomes, the first 50 cases and the later cases were compared. Logistic regression was used to assess the relationships between unsuccessful outcomes and patient dissatisfaction. RESULTS: Among 866 patients, 797 cases with 1-year follow-up and complete data were analyzed. In total, 82 patients with unsuccessful outcomes were identified (10.29%). The incidences of hematoma (p < 0.04), incomplete operation (p < 0.01), and dural tear (p < 0.01) were significantly higher in the first 50 cases than in the later cases. Analyses of the relationship between unsuccessful outcomes and patient dissatisfaction showed that incomplete decompression (odds ratio (OR) 4.06), postoperative instability (OR 3.64), hematoma (OR 3.25), ascite (OR 3.25), dural tear (OR 3.02), and local recurrence (OR 2.45, 95%) contributed significantly. CONCLUSIONS: Unsuccessful PBES outcomes were mostly associated with hematomas, incomplete decompression, and dural tears; instability, ascites, and infection contributed to a lesser extent. Incomplete decompression, instability, hematoma, ascite, dural tear, and local recurrence were significantly related to patient dissatisfaction. The potential for poor outcomes should be described to the patient and considered prior to surgery.

Radiological and clinical long-term results of heterotopic ossification following lumbar total disc replacement.

BACKGROUND: The long-term results of heterotopic ossification (HO) following lumbar total disc replacement (TDR) and the corresponding clinical and radiological outcomes are unclear. PURPOSE: This study aimed to report the long-term results of HO following lumbar TDR and to analyze the clinical and radiological outcomes. STUDY DESIGN/SETTING: A retrospective case review was performed for the consecutive patients who underwent lumbar TDR. PATIENT SAMPLE: The study included 48 patients (60 segments) who underwent lumbar TDR. OUTCOME MEASURES: The time and location of HO development, segmental range of motion (ROM) of index level, the visual analog scale (VAS), and the Oswestry Disability Index (ODI) were analyzed. METHODS: Forty-eight patients (60 segments) were divided into HO and non-HO groups, and radiographs were used to measure the time and location of HO development. We compared segmental ROM between two groups using flexion-extension radiographs. Clinical outcomes were assessed using the VAS and the ODI. Furthermore, the segmental ROM, VAS, and ODI scores of each HO class were compared with those of the non-HO group. RESULTS: The mean follow-up duration was 104.4 months. Heterotopic ossification was detected in 30 of 60 segments following lumbar TDR, and HO progression was noted in six segments. The mean segmental ROM was significantly lower in the HO group than in the non-HO group. The mean VAS and ODI scores were not significantly different between the two groups. Segmental ROM was significantly lower in the class III and IV of the HO group than in the non-HO group. The VAS and ODI scores were not significantly different among the different classes. CONCLUSIONS: We found that the incidence of HO is the highest within 12 months after lumbar TDR, and the incidence might increase 5 years after surgery. Furthermore, HO progressed over time. Segmental ROM was decreased in the HO groups; however, the limitation in motion might have little clinical influence.

Long-Term Outcomes Following Lumbar Total Disc Replacement Using ProDisc-II: Average 10-Year Follow-Up at a Single Institute.

STUDY DESIGN: A retrospective analysis. OBJECTIVE: To evaluate the long-term clinical and radiographic outcomes and to investigate who achieved the successful outcomes after lumbar total disc replacement (TDR) using ProDisc II. SUMMARY OF BACKGROUND DATA: There are few evidences regarding the long-term efficacy and safety of TDR. Furthermore, it has not been addressed which patients achieved good outcomes in long-term follow-up. METHODS: Data at 1-, 2-, 5-, 7-year, and last follow-up were used for the analysis. According to the presence of combined pathologies, patients were categorized as groups A and B (presumed good and bad candidates, respectively). Clinical outcomes were evaluated using visual analog scale, Oswestry Disability Index, clinical success rate, and subjective satisfaction (four-point scale). Radiographic results included segmental range of motion. RESULTS: Total study population was 54 patients with 69 segments with the average follow-up duration of 120.0 months. There were 39 patients in group A and 15 in group B. Visual analog scale and Oswestry Disability Index scores were improved significantly at all follow-up periods, reaching maximal improvement at the postoperative 2 years. Clinical success rate and satisfaction rate were significantly higher in group A (76.9% and 87.2%, respectively) than those in group B (40.0% and 60.0%, respectively) at the last follow-up. Five patients (9.3%) required revision fusion surgeries, and they are all in group B. The final segmental range of motion was well maintained in monosegmental TDR, but not in bisegmental TDR. CONCLUSION: Lumbar TDR using Prodisc II showed the successful outcomes with the clinical success rate of 76.9% and the satisfaction rate of 87.2% when the patients were presumed as good candidate for TDR. However, the patients who had the combined pathologies showed suboptimal results with high risk of the revision surgeries. Thus, the strict patient selection process is mandatory for the successful outcomes. LEVEL OF EVIDENCE: 4.

Korean Red Ginseng Extract Enhances the Anticancer Effects of Imatinib Mesylate Through Abrogation p38 and STAT5 Activation in KBM-5 Cells.

Although imatinib mesylate (IM) in the treatment of chronic myelogenous leukemia (CML) remains the best example of successful targeted therapy, majority of patients with CML suffer its toxicity profile and develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of CML. Here, we investigated whether Korean red ginseng extract (KRGE) could suppress the proliferation and induce chemosensitization in human CML cells. Also, we used a human phospho-antibody array containing 46 antibodies against signaling molecules to examine a subset of phosphorylation events after treatment. Korean red ginseng extract broadly suppressed the proliferation of five different cell lines, but KRGE was found to be the most potent inducer of apoptosis against KBM-5 cells. It also abrogated the expression of Bcl-2 (B-cell lymphoma 2), Bcl-xL (B-cell lymphoma-extra large), survivin, inhibitors of apoptosis protein 1/2, COX-2 (Cyclooxygenase-2), cyclin D1, matrix metalloproteinase-9, and VEGF (Vascular endothelial growth factor), as well as upregulated the expression of pro-apoptotic gene products. Interestingly, KRGE also enhanced the cytotoxic and apoptotic effect of IM in KBM-5 cells. The combination treatment of KRGE and IM caused pronounced suppression of p38 and signal transducer and activator of transcription 5 phosphorylation and induced phosphorylation of p53 compared with the individual treatment. Our results demonstrate that KRGE can enhance the anticancer activity of IM and may have a substantial potential in the treatment of CML.

The hydrolyzed products of iridoid glycoside with ß-glucosidase treatment exert anti-proliferative effects through suppression of STAT3 activation and STAT3-regulated gene products in several human cancer cells.

CONTEXT: Iridoids belong to a group of monoterpene compounds with cyclopentane ring and found as mostly the glycoside forms in nature. They act primarily as the defense substances and found in various medicinal plants. OBJECTIVE: Although many iridoids exhibit anti-inflammatory and anticancer activities, their molecular targets/pathways are not fully understood. Here, the antiproliferative effect of the hydrolyzed-iridoid product (H-iridoid) form through the STAT3 signaling pathways on tumor cells was investigated. MATERIALS AND METHODS: H-iridoids were obtained from five iridoid glycosides with ß-glucosidase treatment. The effects of several H-iridoids on cell viability and cell proliferation in tumor cells were measured by the MTT assay. The phosphorylation levels of STAT3, its regulatory molecules, and apoptosis by H-geniposide treatment in DU145 cells were investigated by immunoblots and flow cytometry. RESULTS: No single iridoid glycoside exerted any cytotoxicity in the tumor cells, whereas H-iridoids had significant cytotoxic, antiproliferative, and STAT3 inhibitory effects and revealed different potencies depending on their chemical structures. Among the H-iridoids tested, H-geniposide inhibited constitutive STAT3 activation through inhibiting upstream JAK1 and c-Src. Consistent with STAT3 inactivation, H-geniposide downregulated the expressions of Bcl-2, Bcl-xL, survivin, and cyclin D1; this correlated with the accumulation of cells in the sub-G1 phase of the cell cycle and the induction of apoptosis. DISCUSSION AND CONCLUSIONS: Our results indicate that the hydrolysis of the glycosidic bond from iridoid glycoside is required for exhibiting cytotoxicity in tumor cells. H-geniposide is the most potent agent and a novel blocker of STAT3 activation in DU145 cells.

Prospective evaluation of the effectiveness of a home-based program of isometric strengthening exercises: 12-month follow-up.

BACKGROUND: The aim of this prospective randomized clinical trial was to investigate the efficacy of a home-based program of isometric strengthening exercises for the treatment of the lateral epicondylitis (LE) of the distal humerus. We hypothesized that 1) use of isometric strengthening exercises would result in clinical benefits similar to those provided by medication and pain relief and 2) functional improvements after exercise would be time-dependent. METHODS: Patients were assigned to one of two groups: 1) an immediate physical therapy group (group I), or 2) a delayed physical therapy group (group D). Group I patients (n = 16) were instructed how to do the exercises at their first clinic visit and immediately carried out the exercise program. Group D patients (n = 15) learned and did the exercises after being on medications for 4 weeks. RESULTS: Outcomes at the 1-month clinic visit indicated that pain (measured using a visual analogue scale [VAS]) had been significantly reduced in group I compared to group D (p < 0.01). However, significant differences between groups were not found at 3-, 6-, and 12-month follow-up for either VAS scores or Mayo elbow performance scores. For modified Nirschl/Pettrone scores, a significant difference between groups was found only at the 1-month follow-up visit. By then, the number of participants who returned to all activities with no pain or occasional mild pain was six (37%) in Group I and two (13%) in Group D (p = 0.031). At the final follow-up visit, 88% of all participants performed physical activities without pain. CONCLUSIONS: Isometric strengthening exercises done early in the course of LE (within 4 weeks) provides a clinically significant improvement.

Dynamic change of T315I BCR-ABL kinase domain mutation in Korean chronic myeloid leukaemia patients during treatment with Abl tyrosine kinase inhibitors.

We analysed the dynamic change of imatinib-resistant mutations in BCR-ABL kinase domain focusing on T315I mutation during dasatinib or nilotinib therapy. Fifty-five imatinib-resistant chronic myeloid leukaemia patients (32 patients with imatinib-resistant mutations and 23 patients without mutation) in different disease phases were treated with dasatinib (median 17.3 months) or nilotinib (median 6.8 months). Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255K, M351T, H396R, S417Y, E450K and E459K disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459K, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Previous best responses can be re-achieved by resumption after imatinib discontinuation in patients with chronic myeloid leukemia: implication for intermittent imatinib therapy.

Although imatinib is considered as a front line therapy in patients with chronic myeloid leukemia (CML), it is still unclear whether transient imatinib discontinuation may adversely affect the outcome. This study was conducted to investigate long-term outcome after discontinuation and resumption of imatinib, and to determine whether intermittent imatinib therapy can be employed in patients with CML. Twenty six Philadelphia chromosome positive (Ph+) patients with CML discontinued imatinib when they achieved complete cytogenetic response (CCyR) or complete molecular response (CMR), and they were retreated with imatinib in case of hematologic, cytogenetic or molecular relapse. Except one patient who progressed and two patients who are in persistent molecular remission without imatinib resumption, all of 23 patients are maintaining the best response achieved after imatinib resumption with a median follow-up of 44 months. This study shows that although imatinib cannot be discontinued completely, intermittent therapy can be considered for the treatment of patients with CML in particular situations.

Clinical profile of dasatinib in Asian and non-Asian patients with chronic myeloid leukemia.

Resistance and intolerance to imatinib are of particular clinical relevance to Asian patients because of their lower body surface area. Dasatinib is 325-fold more potent than imatinib in inhibiting BCR-ABL in vitro and is indicated for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib. Data from a series of phase I/II research trials were analyzed to compare the efficacy, safety and pharmacokinetic profile of dasatinib 70 mg twice daily in Asian and non-Asian patients. Results from 55 Asian and 615 non-Asian patients demonstrated that the efficacy and safety of dasatinib was comparable. Dasatinib was well tolerated, with no observed toxicities exclusive to Asian patients. A higher incidence of adverse events and lower rate of response observed among Asian patients with myeloid blast phase CML reflected the aggressive nature of the disease. Analyses of noncompartmental pharmacokinetics (5 Asian and 49 non-Asian patients) and population pharmacokinetics (17 Asian and 382 non-Asian patients) were also comparable. The efficacy, safety and pharmacokinetic profile of dasatinib 70 mg twice daily is similar in Asian and non-Asian patients with CML. Dasatinib is therefore an important therapeutic option for this patient population.

Antipathogenic properties of green tea polyphenol epigallocatechin gallate at concentrations below the MIC against enterohemorrhagic Escherichia coli O157:H7.

The inhibitory effects of green tea polyphenol epigallocatechin gallate (EGCG) on virulence phenotypes and gene expression regulated by quorum sensing (QS) in Escherichia coli O157:H7 were demonstrated at concentrations of 1 to 100 microg/ml, which are lower than the MIC (539 +/- 22 microg/ml). At 25 microg/ml, the growth rate was not affected, but autoinducer 2 concentration, biofilm formation, and swarm motility decreased to 13.2, 11.8, and 50%, respectively. Survival at 5 days of nematodes (Caenorhabditis elegans) that were fed the pathogen without and with EGCG were 47.1 and 76%, respectively. Real-time PCR data indicated decreased transcriptional level in many quorum sensing-regulated virulence genes at 25 microg/ml. Our results suggest that EGCG at concentrations below itsMIC has significant antipathogenic effects against E. coli O157:H7.

Analysis of Bcr-Abl kinase domain mutations in Korean chronic myeloid leukaemia patients: poor clinical outcome of P-loop and T315I mutation is disease phase dependent.

Despite durable responses to imatinib in chronic myeloid leukaemia (CML), mutations in Bcr-Abl kinase domain (KD) are known to induce imatinib resistance and cause poor clinical outcome. We characterized Bcr-Abl KD mutations in 137 Korean CML patients with imatinib resistance (n = 111) or intolerance (n = 26) using allele specific oligonucleotide polymerase chain reaction (PCR) and direct sequencing. Seventy (51%) patients harboured 81 mutations of 20 different types with increasing prevalence in advanced phase. Nine (13%) patients had multiple mutations. No mutation was found in intolerant patients. T315I was the most common mutation and P-loop was the hottest spot in Bcr-Abl KD. Patients harbouring P-loop mutation, T315I, or multiple mutations showed poor overall survival and progression free survival compared with patients harbouring other mutations. Survival analysis according to disease phase of mutation being detected and type of mutations provided correlation between P-loop or T315I mutation and poor overall survival in blast crisis, but not in accelerated phase (AP) or chronic phase (CP), indicating poor clinical outcome of particular mutations depends on disease phase. CML patients with imatinib resistance showed high rate (63%) of mutations in Bcr-Abl KD and therefore CML patients who do not respond to imatinib should be the candidates for mutation screening as molecular monitoring.

Structural modeling of V299L and E459K Bcr-Abl mutation, and sequential therapy of tyrosine kinase inhibitors for the compound mutations.

Sequential treatment with different tyrosine kinase inhibitors (TKIs) is one of the strategies for handling chronic myeloid leukemia (CML) in which dynamic change in Bcr-Abl kinase domain mutation is often an obstacle faced during TKI therapy. Here we report successful sequential therapy with different TKIs for the CML patient harboring V299L and E459K compound mutations. Molecular monitoring including quantitative analysis of BCR-ABL transcript level and mutation analysis were performed regularly for successful treatment. Additionally a drug-target complex was structurally modeled to investigate influence of amino acid substitutions on drug resistance, and to choose alternative TKI in sequential therapy, suggesting protein structural modeling can be useful approach in selecting alternative TKIs.

Ethanolic Hwaeumjeon induces mitochondrial dependent apoptosis partly via PI3K/AKT/HSP27/ERK pathways and inhibits PSA and AR in LNCaP cells.

Hwaeumjeon is a classical prescription that has been traditionally used for treatment of urogenital diseases with no scientific evidences until now. Thus, the present study was performed to evaluate antitumor mechanism of ethanolic Hwaeumjeon (EHEJ). 2-Dimensional electrophoresis (2-DE) proteomic analysis, cell culture study, and Western blotting on apoptosis and prostate-specific antigen (PSA) related proteins were carried out in LNCaP prostate cancer cells. Eight spots with significant increased or decreased expression revealed by 2-DE based comparative proteomic analysis were identified as an increased protein ENC-1AS, four decreased proteins such as RAB34, SFRS1, heat shock 27, and proteasome activator, and three novel proteins such as Rho GDP dissociation inhibitor alpha, cytoplasmic antiproteinase, and EIF3EIP protein in EHEJ-treated LNCaP cells. In addition, EHEJ selectively inhibited the growth of LNCaP prostate cancer cells compared to normal human umbilical vein endothelial cells. Furthermore, EHEJ inhibited PSA and androgen receptor (AR) expression in androgen sensitive LNCaP prostate cancer cells at nontoxic concentrations. Also, EHEJ increased sub-G1 apoptotic portion, activated caspase-9 and -3, cleaved poly (ADP-ribose) polymerase (PARP) and increased the ratio of Bax to Bcl-2. Interestingly, EHEJ also attenuated phosphatidylinositol-3 kinase (PI3K) expression and suppressed the phosphorylation of survival gene AKT, ERK, and HSP27 in LNCaP cells. Consistently, PI3K and ERK inhibitors potentiated EHEJ-induced cytotoxicity and overexpression of Bcl-2 attenuated EHEJ-mediated apoptosis in LNCaP cells. These findings suggest that EHEJ induces mitochondrial dependent apoptosis partly via PI3K/AKT/HSP27/ERK pathways and inhibits PSA and AR in LNCaP cells as a prostate cancer chemopreventive candidate.

Comparative analysis of cell surface proteins in chronic and acute leukemia cell lines.

This study was designed to identify the cell surface protein markers that can differentiate between chronic myeloid leukemia (CML) and acute promyelocytic leukemia cells (APL). The differentially expressed plasma membrane proteins were analyzed between CML cell line (K562) and APL cell line (NB4) using the comparative proteomic approach. The cell membrane proteins were enriched by labeling with a membrane-impermeable biotinylation reagent, sulfo-NHS-SS-Biotin, and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS). By comparative proteomic analysis of K562 and NB4 cells, we identified 25 membrane and 14 membrane-associated proteins. The result of LC-MS/MS combined with chemical tagging method was validated by confirming the expression and localization of one of the differentially expressed plasma membrane proteins, CD43, by FACS and confocal microscopy. Our results indicate that CD43 could be a potential candidate for differentiating CML from APL.