Epidural steroid injections, conservative treatment, or combination treatment for cervical radicular pain: a multicenter, randomized, comparative-effectiveness study.

BACKGROUND: Cervical radicular pain is a major cause of disability. No studies have been published comparing different types of nonsurgical therapy. METHODS: A comparative-effectiveness study was performed in 169 patients with cervical radicular pain less than 4 yr in duration. Participants received nortriptyline and/or gabapentin plus physical therapies, up to three cervical epidural steroid injections (ESI) or combination treatment over 6 months. The primary outcome measure was average arm pain on a 0 to 10 scale at 1 month. RESULTS: One-month arm pain scores were 3.5 (95% CI, 2.8 to 4.2) in the combination group, 4.2 (CI, 2.8 to 4.2) in ESI patients, and 4.3 (CI, 2.8 to 4.2) in individuals treated conservatively (P = 0.26). Combination group patients experienced a mean reduction of -3.1 (95% CI, -3.8 to -2.3) in average arm pain at 1 month versus -1.8 (CI, -2.5 to -1.2) in the conservative group and -2.0 (CI, -2.7 to -1.3) in ESI patients (P = 0.035). For neck pain, a mean reduction of -2.2 (95% CI, -3.0 to -1.5) was noted in combination patients versus -1.2 (CI, -1.9 to -0.5) in conservative group patients and -1.1 (CI, -1.8 to -0.4) in those who received ESI; P = 0.064). Three-month posttreatment, 56.9% of patients treated with combination therapy experienced a positive outcome versus 26.8% in the conservative group and 36.7% in ESI patients (P = 0.006). CONCLUSIONS: For the primary outcome measure, no significant differences were found between treatments, although combination therapy provided better improvement than stand-alone treatment on some measures. Whereas these results suggest an interdisciplinary approach to neck pain may improve outcomes, confirmatory studies are needed.

Occipital nerve pulsed radiofrequency treatment: a multi-center study evaluating predictors of outcome.

OBJECTIVE: Occipital neuralgia (ON) is a challenging condition for which there is no reference standard for treatment. The purpose of this study was to provide outcome data on the largest study to date evaluating pulsed radiofrequency (PRF) for ON and to determine whether any demographic, clinical, or treatment characteristics are associated with success. DESIGN: Retrospective data analysis was conducted in 102 subjects evaluating the effect of myriad factors on treatment success. SETTING: This study was conducted in academic civilian and military pain treatment centers. PATIENTS: One hundred and two consecutive patients with a primary diagnosis of ON were treated with PRF of the greater and/or lesser occipital nerve. OUTCOME MEASURES: A positive primary outcome was predefined as ≥50% pain relief lasting at least 3 months. The secondary outcome measure was procedural satisfaction. RESULTS: Fifty-two (51%) patients experienced ≥50% pain relief and satisfaction with treatment lasting at least 3 months. Variables associated with a positive outcome included a traumatic inciting event (65.7% success rate; P=0.03), lower diagnostic block volumes (odds ratio [OR]: 0.72; 95% confidence interval [CI]: 0.62-0.82; P<0.0001), and employment of multiple rounds of PRF (OR: 2.95; 95% CI: 1.77-4.92; P<0.0001). Factors correlating with treatment failure included extension of pain anterior to the scalp apex (OR: 0.32; 95% CI: 0.14-0.73; P=0.006) and ongoing secondary gain issues (OR: 0.19; 95% CI: 0.11-0.33; P<0.0001). CONCLUSION: PRF may provide intermediate-term benefit in ON to a significant proportion of refractory cases. Careful attention to selection criteria and treatment parameters may further improve treatment outcomes.

Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.

BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.

Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

Expression of Drosophila neoplastic tumor suppressor genes discslarge, scribble, and lethal giant larvae in the mammalian ovary.

The similarities and differences in molecular mechanisms regulating invertebrate and mammalian folliculogenesis are starting to be deciphered. In Drosophila, the neoplastic tumor suppressor gene discslarge is crucial for suppressing proliferation and movement of follicle cells relative to the growing oocyte. Lethal giant larvae and scribble play similar roles and have been suggested to collaborate intimately with discslarge. We have identified and determined the expression pattern of murine homologs of these Drosophila genes. In situ data shows that murine discslarge-1, discslarge-3, discslarge-4, lethal giant larvae, and scribble are expressed in both overlapping and distinct patterns in oocytes and granulosa cells in maturing follicles. Disclarge-4 is expressed in the surface epithelium and is lost in mouse carcinogenic surface epithelial cells. All of these genes, as well as discslarge-2 and discslarge-5, are expressed in human ovaries. Our data suggests that as in Drosophila, these tumor suppressors may cooperate during mammalian folliculogenesis, but also have distinct functions.

Facet joint pain--advances in patient selection and treatment.

Facetogenic pain, also known as zygapophysial joint pain, is a frequent cause of mechanical spine pain. Diagnostic blocks (for example, medial branch blocks [MBBs]) are the only reliable approach to identify facet joints as the source of neck or back pain. In the absence of a reference standard, MBBs actually serve more of a prognostic than diagnostic role, enabling the selection of patients who might respond to radiofrequency denervation treatment--the standard treatment for facet joint pain. Using double blocks reduces the false-positive rate of MBBs, but will invariably reduce the overall treatment success rate. No studies have evaluated non-interventional treatments for confirmed facetogenic pain, but data from studies in non-specific back pain suggest a modest, short-term beneficial effect for pharmacotherapy and some non-traditional treatments. Trials of intra-articular steroid injections for lumbar and cervical facet joint pain have yielded disappointing results, but evidence suggests that a subpopulation of patients with acute inflammation derive intermediate-term benefit from this therapy. Radiofrequency denervation provides some benefit for up to a year in approximately 60% of individuals. Increasing this success rate might involve enhancing diagnostic specificity and phenotyping, as well as techniques that increase the likelihood of successful nerve ablation, such as maximizing lesion size.