AOSpine Consensus Paper on Nomenclature for Working-Channel Endoscopic Spinal Procedures.

STUDY DESIGN: International consensus paper on a unified nomenclature for full-endoscopic spine surgery. OBJECTIVES: Minimally invasive endoscopic spinal procedures have undergone rapid development during the past decade. Evolution of working-channel endoscopes and surgical instruments as well as innovation in surgical techniques have expanded the types of spinal pathology that can be addressed. However, there is in the literature a heterogeneous nomenclature defining approach corridors and procedures, and this lack of common language has hampered communication between endoscopic spine surgeons, patients, hospitals, and insurance providers. METHODS: The current report summarizes the nomenclature reported for working-channel endoscopic procedures that address cervical, thoracic, and lumbar spinal pathology. RESULTS: We propose a uniform system that defines the working-channel endoscope (full-endoscopic), approach corridor (anterior, posterior, interlaminar, transforaminal), spinal segment (cervical, thoracic, lumbar), and procedure performed (eg, discectomy, foraminotomy). We suggest the following nomenclature for the most common full-endoscopic procedures: posterior endoscopic cervical foraminotomy (PECF), transforaminal endoscopic thoracic discectomy (TETD), transforaminal endoscopic lumbar discectomy (TELD), transforaminal lumbar foraminotomy (TELF), interlaminar endoscopic lumbar discectomy (IELD), interlaminar endoscopic lateral recess decompression (IE-LRD), and lumbar endoscopic unilateral laminotomy for bilateral decompression (LE-ULBD). CONCLUSIONS: We believe that it is critical to delineate a consensus nomenclature to facilitate uniformity of working-channel endoscopic procedures within academic scholarship. This will hopefully facilitate development, standardization of procedures, teaching, and widespread acceptance of full-endoscopic spinal procedures.

Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists.

Immunogenic cell death induced by anticancer chemotherapy is characterized by a series of molecular hallmarks that include the exodus of high-mobility group box 1 protein (HMGB1) from dying cells. HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and engages Toll-like receptor4 (TLR4) on dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. The absence of HMGB1 expression by dying tumor cells exposed to anthracyclines or oxaliplatin compromises DC-dependent T-cell priming by tumor-associated antigens. Here, we show that transplantable tumors exhibiting weak expression of nuclear HMGB1 respond to chemotherapy more effectively if the treatment is combined with the local or systemic administration of a highly purified and physiochemically defined and standardized lipopolysaccharide solution, which acts as a high-potency and exclusive TLR4 agonist, called Dendrophilin (DEN). The synergistic antitumor effects mediated by the combination of chemotherapy and immunotherapy relied upon the presence of the MyD88 (myeloid differentiation primary response gene) adapter of TLR4 (but not that of the TIR-domain-containing adapter-inducing interferon-ß adapter), in line with the well-characterized action of DEN on the MyD88 signaling pathway. DEN and anthracyclines synergized to induce intratumoral accumulation of interferon-γ-producing CD4(+) and CD8(+) T lymphocytes. Moreover, DEN could restore the immunogenicity of dying tumor cells from which HMGB1 had been depleted by RNA interference. These findings underscore the potential clinical utility of combination regimens involving immunogenic chemotherapy and certain TLR4 agonists in advanced HMGB1-deficient cancers.

Transcorporeal tunnel approach for unilateral cervical radiculopathy: a 2-year follow-up review and results.

BACKGROUND: The long-term complications of traditional discectomy and fusion surgery have led to the need for minimally invasive procedures that do not require a complete discectomy and fusion. Jho developed an anterior unco-foraminotomy that we have modified, with the approach being more medial than that of Jho, into an anterior transcorporeal tunnel approach which we use for cervical spondylotic unilateral radiculopathy. METHODS: A retrospective analysis was carried out in 30 patients who underwent a transcorporeal "tunnel" anterior micro-foraminotomy for unilateral radicular symptoms with a follow-up more than 2 years. All were operated by a single surgeon using the same technique from the vertebral body proximal to the lesion and proceeding downwards to the herniation. At final follow-up we reviewed the clinical and radiological results. RESULTS: All patients in the immediate post-operative period showed relief of their symptoms, and there were major complications. 3 patients complained about the numbness in the immediate postoperative period which resolved within 3 months. There was a significant improvement in NDI from pre-operative 55.16% to postoperative 5.82% ( P <0.001). Average pre-operative VAS scores for arm and neck were 8.15 and 4.05, respectively; which improved to 1.05 and 1.23 ( P <0.001) postoperatively. There was an average 9% decrease (from 7.8 mm to 7.3 mm) in the post-operative disc height compared to the preoperative disc height; however, it was clinically and radiologically insignificant. The long-term results were favourable and there were no major complications. CONCLUSION: The transcorporeal tunnel approach can be used as an alternative treatment for cervical spondylotic radiculopathy.

Percutaneous endoscopic lumbar herniectomy for high-grade down-migrated L4-L5 disc through an L5-S1 interlaminar approach: a technical note.

BACKGROUND: L4-L5 disc herniations can be treated with percutaneous endoscopic lumbar discectomy (PELD) using a transforaminal posterolateral approach. Although PELD has some distinct advantages over conventional open discectomy, inadequate decompression is a major cause of failure of the procedure, especially with high-grade migrations. The objective of this technical note is to present a new surgical approach for treating high-grade, down-migrated, L4-L5 disc herniations through an L5-S1 interlaminar endoscopic approach. METHOD: This technical report presents 4 consecutive patients with high-grade, down-migrated, L4-L5 disc herniations, who were treated with PELD through an L5-S1 interlaminar approach under local anesthesia and conscious sedation. All patients were evaluated clinically using both the visual analogue scale (VAS) for back and leg pain and the Oswestry disability index (ODI) and radiologically using MR imaging postoperatively. RESULTS: All 4 patients experienced improvement in their preoperative symptoms and signs immediately postoperatively. The mean VAS scores for back and leg pain improved from 3.75 to 1.75 and from 8.5 to 0.75, respectively. The mean ODI score improved from 65% to 3%. Postoperative MR imaging also depicted L5 root decompression. There were no complications during the procedure. CONCLUSION: This technical note presents a new technique for treating high-grade, down-migrated, L4-L5 disc herniations with PELD using an L5-S1 interlaminar approach.

MMP-7 promoter polymorphisms do not influence CD4+ recovery and changes in plasma viral load during antiretroviral therapy for HIV-1 infection.

Matrix metalloproteinase-7 (MMP-7) generates soluble Fas Ligand (FasL), which is involved in the apoptotic loss of CD4+ T cells during HIV infection. We evaluated whether two polymorphisms in MMP-7 promoter could influence CD4+ recover in response to antiretroviral therapy, and found that these polymorphisms are ineffective.

Cyclo19,31[D-Cys19]-uPA19-31 is a potent competitive antagonist of the interaction of urokinase-type plasminogen activator with its receptor (CD87).

Urokinase-type plasminogen activator (uPA) represents a central molecule in pericellular proteolysis and is implicated in a variety of physiological and pathophysiological processes such as tissue remodelling, wound healing, tumor invasion, and metastasis. uPA binds with high affinity to a specific cell surface receptor, uPAR (CD87), via a well defined sequence within the N-terminal region of uPA (uPA19-31). This interaction directs the proteolytic activity of uPA to the cell surface which represents an important step in tumor cell proliferation, invasion, and metastasis. Due to its fundamental role in these processes, the uPA/uPAR-system has emerged as a novel target for tumor therapy. Previously, we have identified a synthetic, cyclic, uPA-derived peptide, cyclo19,31uPA19-31, as a lead structure for the development of low molecular weight uPA-analogues, capable of blocking uPA/uPAR-interaction [Burgle et al., Biol. Chem. 378 (1997), 231-237]. We now searched for peptide variants of cyclo19,31uPA19-31 with elevated affinities for uPAR binding. Among other tasks, we performed a systematic D-amino acid scan of uPA19-31, in which each of the 13 L-amino acids was individually substituted by the corresponding D-amino acid. This led to the identification of cyclo19,31[D-Cys19]-uPA19-31 as a potent inhibitor of uPA/uPAR-interaction, displaying only a 20 to 40-fold lower binding capacity as compared to the naturally occurring uPAR-ligands uPA and its amino-terminal fragment. Cyclo19,31[D-Cys19]-uPA19-31 not only blocks binding of uPA to uPAR but is also capable of efficiently displacing uPAR-bound uPA from the cell surface and to inhibit uPA-mediated, tumor cell-associated plasminogen activation and fibrin degradation. Thus, cyclo19,31[D-Cys19]-uPA19-31 represents a promising therapeutic agent to significantly affect the tumor-associated uPA/uPAR-system.

Integrin alpha(v)beta(3)/vitronectin interaction affects expression of the urokinase system in human ovarian cancer cells.

The urokinase type plasminogen activator (uPA), together with its receptor uPAR and the plasminogen activator inhibitor type-1 (PAI-1) plays a pivotal role during tumor invasion and metastasis. Integrins, via interaction with the extracellular matrix (ECM), control cell adhesion and motility. The two systems are functionally linked because uPAR and PAI-1 bind to the ECM component vitronectin (VN). Because integrin signaling alters gene expression patterns, we investigated whether the expression levels of uPA, uPAR, and PAI-1 are affected by ECM/integrin interactions. Expression of uPA, uPAR, and PAI-1 was significantly enhanced when human ovarian cancer cells (OV-MZ-6) were cultivated on fibronectin or collagen type IV. In contrast, VN induced down-regulation of uPA and uPAR while increasing PAI-1 by up to 4-fold. VN-dependent decrease of uPA protein was paralleled by a significant reduction of uPA promoter activity that was even more pronounced upon alpha(v)beta(3) overexpression and depended on the presence of intact Rel protein-binding sites. The activity of Rel transcription factors was also significantly reduced upon alpha(v)beta(3)-mediated cell adhesion to VN. The activity of the Rel-unresponsive PAI-1 promoter was up to 5-fold induced as a function of alpha(v)beta(3)/VN interaction. Thus, the balance between available concentrations of uPA, uPAR, PAI-1, and integrins in human ovarian cancer cells might provide a switch within the regulation of their invasive phenotype.

Surgical treatment of submucous cleft palate: a comparative trial of two modalities for palatal closure.

Submucous cleft palate is a congenital malformation with specific clinical and anatomical features. It can be present with or without velopharyngeal insufficiency. Surgical treatment of this malformation is indicated only when velopharyngeal insufficiency has been demonstrated. This article compares two modalities of surgical treatment for submucous cleft palate. The first includes a minimal incision palatopharyngoplasty, as described in a previous report. The second combines the first technique with additional individualized velopharyngeal surgery (individualized pharyngeal flap or sphincter pharyngoplasty) performed simultaneously. The individualized part of the procedure was selected and performed according to the findings of videonasopharyngoscopy and multiview videofluoroscopy, as reported previously. Two hundred and three patients with submucous cleft palate were studied from 1990 to 1999. Videonasopharyngoscopy and multiview videofluoroscopy demonstrated velopharyngeal insufficiency in 72 patients, who were randomly divided into two groups. Those in group 1 (n = 37) underwent a minimal incision palatopharyngoplasty. Patients in group 2 (n = 35) also underwent that procedure but simultaneously received individualized pharyngeal flap or sphincter pharyngoplasty, according to the findings of videonasopharyngoscopy and multiview videofluoroscopy. The median age of the patients from both groups was not significantly different (p > 0.5). The frequency of residual velopharyngeal insufficiency after palatal closure was not significantly different in both groups of patients (14 percent versus 11 percent; p > 0.5). The mean size of the gap at the velopharyngeal sphincter during speech was not significantly different in both groups of patients before surgery (23 percent versus 22 percent; p > 0.5). After the surgical procedures, there was a nonsignificant difference between both groups of patients in mean residual size of the gap in cases of velopharyngeal insufficiency (7 percent versus 8 percent; p > 0.5). It seems that minimal incision palatopharyngoplasty is a safe and reliable procedure for palatal closure in patients with submucous cleft palate. The use of additional individualized velopharyngeal surgery performed simultaneously did not seem to decrease the frequency of residual velopharyngeal insufficiency. Moreover, the residual size of the gap at the velopharyngeal sphincter was not significantly reduced when an additional surgical procedure was performed simultaneously with palatal closure.

(4-aminomethyl)phenylguanidine derivatives as nonpeptidic highly selective inhibitors of human urokinase.

Increased expression of the serine protease urokinase-type plasminogen activator (uPA) in tumor tissues is highly correlated with tumor cell migration, invasion, proliferation, progression, and metastasis. Thus inhibition of uPA activity represents a promising target for antimetastatic therapy. So far, only the x-ray crystal structure of uPA inactivated by H-Glu-Gly-Arg-chloromethylketone has been reported, thus limited data are available for a rational structure-based design of uPA inhibitors. Taking into account the trypsin-like arginine specificity of uPA, (4-aminomethyl)phenylguanidine was selected as a potential P1 residue and iterative derivatization of its amino group with various hydrophobic residues, and structure-activity relationship-based optimization of the spacer in terms of hydrogen bond acceptor/donor properties led to N-(1-adamantyl)-N'-(4-guanidinobenzyl)urea as a highly selective nonpeptidic uPA inhibitor. The x-ray crystal structure of the uPA B-chain complexed with this inhibitor revealed a surprising binding mode consisting of the expected insertion of the phenylguanidine moiety into the S1 pocket, but with the adamantyl residue protruding toward the hydrophobic S1' enzyme subsite, thus exposing the ureido group to hydrogen-bonding interactions. Although in this enzyme-bound state the inhibitor is crossing the active site, interactions with the catalytic residues Ser-195 and His-57 are not observed, but their side chains are spatially displaced for steric reasons. Compared with other trypsin-like serine proteases, the S2 and S3/S4 pockets of uPA are reduced in size because of the 99-insertion loop. Therefore, the peculiar binding mode of the new type of uPA inhibitors offers the possibility of exploiting optimized interactions at the S1'/S2' subsites to further enhance selectivity and potency. Because crystals of the uPA/benzamidine complex allow inhibitor exchange by soaking procedures, the structure-based design of new generations of uPA inhibitors can rely on the assistance of x-ray analysis.

Epitope mapping of monoclonal antibodies directed to PAI-1 using PAI-1/PAI-2 chimera and PAI-1-derived synthetic peptides.

Plasminogen activator inhibitor type-1 is a key regulatory protein of the fibrinolytic system that is involved in a variety of physiological and pathophysiological processes. A panel of 14 monoclonal antibodies directed against plasminogen activator inhibitor type-1 was analyzed regarding epitope specificity on plasminogen activator inhibitor type-1. For this purpose, chimera consisting of plasminogen activator inhibitor type-1 and another plasminogen activator inhibitor, plasminogen activator inhibitor type-2, with different portions of the respective wild-type proteins, were generated and plasminogen activator inhibitor type-1-derived 20-mer and 10-mer linear peptides were synthesized. Nine of the 14 monoclonal antibodies recognized an epitope located in the region between amino acid 76-188 of plasminogen activator inhibitor type-1, which encompasses the binding sites for vitronectin, heparin, and part of the fibrin binding region. Of these nine monoclonal antibodies, six reacted with a quadruple plasminogen activator inhibitor type-1 mutant (N152H, K156T, Q321L, M356I), and seven detected a plasminogen activator inhibitor type-1 deletion mutant (DeltaF111-H114). Two of the remaining five monoclonal antibodies recognized epitopes located between amino acid 209-227 and amino acid 352-371, respectively, while the other three antibodies reacted with wild-type plasminogen activator inhibitor type-1, only. Additional experiments revealed that two of the 14 mAbs neutralized and one monoclonal antibodies increased plasminogen activator inhibitor type-1 activity toward urokinase-type plasminogen activator, one of its target proteases.