Browsing by Subject "Treatment Failure"
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Item Open Access Analysis of Successful Versus Failed Radiographic Outcomes After Cervical Deformity Surgery.(Spine, 2018-07) Protopsaltis, Themistocles S; Ramchandran, Subaraman; Hamilton, D Kojo; Sciubba, Daniel; Passias, Peter G; Lafage, Virginie; Lafage, Renaud; Smith, Justin S; Hart, Robert A; Gupta, Munish; Burton, Douglas; Bess, Shay; Shaffrey, Christopher; Ames, Christopher P; International Spine Study Group (ISSG)Study design
Prospective multicenter cohort study with consecutive enrollment.Objective
To evaluate preoperative alignment and surgical factors associated with suboptimal early postoperative radiographic outcomes after surgery for cervical deformity.Summary of background data
Recent studies have demonstrated correlation between cervical sagittal alignment and patient-reported outcomes. Few studies have explored cervical deformity correction prospectively, and the factors that result in successful versus failed cervical alignment corrections remain unclear.Methods
Patients with adult cervical deformity (ACD) included with either cervical kyphosis more than 10°, C2-C7 sagittal vertical axis (cSVA) of more than 4 cm, or chin-brow vertical angle of more than 25°. Patients were categorized into failed outcomes group if cSVA of more than 4 cm or T1 slope and cervical lordosis (TS-CL) of more than 20° at 6 months postoperatively.Results
A total of 71 patients with ACD (mean age 62 yr, 56% women, 41% revisions) were included. Fourty-five had primary cervical deformities and 26 at the cervico-thoracic junction. Thirty-three (46.4%) had failed radiographic outcomes by cSVA and 46 (64.7%) by TS-CL. Failure to restore cSVA was associated with worse preoperative C2 pelvic tilt angle (CPT: 64.4° vs. 47.8°, P = 0.01), worse postoperative C2 slope (35.0° vs. 23.8°, P = 0.004), TS-CL (35.2° vs. 24.9°, P = 0.01), CPT (47.9° vs. 28.2°, P < 0.001), "+" Schwab modifiers (P = 0.007), revision surgery (P = 0.05), and failure to address the secondary, thoracolumbar driver of the deformity (P = 0.02). Failure to correct TS-CL was associated with worse preoperative cervical kyphosis (10.4° vs. -2.1°, P = 0.03), CPT (52.6° vs. 39.1°, P = 0.04), worse postoperative C2 slope (30.2° vs. 13.3°, P < 0.001), cervical lordosis (-3.6° vs. -15.1°, P = 0.01), and CPT (37.7° vs. 24.0°, P < 0.001). Multivariate analysis revealed postoperative distal junctional kyphosis associated with suboptimal outcomes by cSVA (odds ratio 0.06, confidence interval 0.01-0.4, P = 0.004) and TS-CL (odds ratio 0.15, confidence interval 0.02-0.97, P = 0.05).Conclusion
Factors associated with failure to correct the cSVA included revision surgery, worse preoperative CPT, and concurrent thoracolumbar deformity. Failure to correct the TS-CL mismatch was associated with worse preoperative cervical kyphosis and CPT. Occurrence of early postoperative distal junctional kyphosis significantly affects postoperative radiographic outcomes.Level of evidence
3.Item Open Access Biomechanical comparison of plantar-to-dorsal and dorsal-to-plantar screw fixation strength for subtalar arthrodesis.(Einstein (Sao Paulo, Brazil), 2020-01) Chaudhari, Nileshkumar; Godoy-Santos, Alexandre Leme; Netto, Cesar de Cesar; Rodriguez, Ramon; Dun, Shouchen; He, Jun Kit; McKissack, Haley; Fleisig, Glenn S; Pires, Eduardo Araujo; Shah, AshishOBJECTIVE:To compare screw fixation strength for subtalar arthrodesis. METHODS:Eight matched pairs of cadaver feet underwent subtalar joint arthrodesis with two 7.3mm cannulated screws. Randomization was used to assign screw orientation, such that one foot in each pair was assigned dorsal to plantar screw orientation (DP Group), and the other foot, plantar to dorsal orientation (PD Group). Standard surgical technique with fluoroscopy was used for each approach. Following fixation, each specimen was loaded to failure with a Bionix ® 858 MTS device, applying a downward axial force at a distance to create torque. Torque to failure was compared between DP and PD Groups using Student's t test, with p=0.05 used to determine statistical significance. RESULTS:Statistical analysis demonstrated that the mean torque to failure slightly favored the DP Group (37.3Nm) to the PD Group (32.2Nm). However, the difference between the two groups was not statistically significant (p=0.55). CONCLUSION:In subtalar arthrodesis, there is no significant difference in construct strength between dorsal-to-plantar and plantar-to-dorsal screw orientation. The approach chosen by the surgeon should be based on factors other than the biomechanical strength of the screw orientation.Item Open Access Brincidofovir for Asymptomatic Adenovirus Viremia in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: A Randomized Placebo-Controlled Phase II Trial.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017-03) Grimley, Michael S; Chemaly, Roy F; Englund, Janet A; Kurtzberg, Joanne; Chittick, Gregory; Brundage, Thomas M; Bae, Andrew; Morrison, Marion E; Prasad, Vinod KAdenovirus infection in immunocompromised patients contributes to significant morbidity and mortality, especially after allogeneic hematopoietic cell transplantation (HCT). Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir that has in vitro activity against adenoviruses and other double-stranded DNA viruses. This randomized placebo-controlled phase II trial evaluated pre-emptive treatment with BCV for the prevention of adenovirus disease in pediatric and adult allogeneic HCT recipients with asymptomatic adenovirus viremia. Allogeneic HCT recipients with adenovirus viremia were randomized 1:1:1 to receive oral BCV 100 mg (2 mg/kg if <50 kg) twice weekly (BIW), BCV 200 mg (4 mg/kg if <50 kg) once weekly (QW), or placebo for 6 to 12 weeks, followed by 4 weeks of post-treatment follow-up. For randomization, subjects were stratified by screening absolute lymphocyte count (<300 cells/mm3 versus ≥300 cells/mm3). Assignment to BCV or placebo was double blinded; dose frequency was unblinded. The primary endpoint was the proportion of subjects experiencing treatment failure, defined as either progression to probable or definitive adenovirus disease or confirmed increasing adenovirus viremia (≥1 log10 copies/mL) during randomized therapy. Between June 2011 and December 2012, 48 subjects were randomized to the BCV BIW (n = 14), BCV QW (n = 16), or placebo (n = 18) groups. The proportion of subjects with treatment failure in the BCV BIW group was 21% (odds ratio, .53; 95% confidence interval [CI], .11 to 2.71; P = .45), 38% (odds ratio, 1.23; 95% CI, .30 to 5.05, P = .779) in the BCV QW group, and 33% in the placebo group. All-cause mortality was lower in the BCV BIW (14%) and BCV QW groups (31%) relative to the placebo group (39%), but these differences were not statistically significant. After 1 week of therapy, 8 of 12 subjects (67%) randomized to BCV BIW had undetectable adenovirus viremia (<100 copies/mL), compared with 4 of 14 subjects (29%) randomized to BCV QW and 5 of 15 subjects (33%) randomized to placebo. In a post hoc analysis of subjects with viremia ≥1000 copies/mL at baseline, 6 of 7 BCV BIW subjects (86%) achieved undetectable viremia compared with 2 of 8 placebo subjects (25%; P = .04). Early treatment discontinuation because of adverse events was more common in subjects treated with BCV than with placebo. Diarrhea was the most common event in all groups (57% BCV BIW, 38% BCV QW, 28% placebo), but it led to treatment discontinuation in only 1 subject receiving BCV QW. Events diagnosed as acute graft-versus-host disease, primarily of the gastrointestinal tract, were more frequent in the BCV BIW group (50%) than in the BCV QW (25%) and placebo (17%) groups. There was no evidence of myelotoxicity or nephrotoxicity in BCV-treated subjects. The results of this trial confirm the antiviral activity of BCV against adenoviruses. Further investigation is ongoing to define the optimal treatment strategy for HCT recipients with serious adenovirus infection and disease.Item Open Access Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up.(BMC Infect Dis, 2014-11-07) Dow, Dorothy E; Shayo, Aisa M; Cunningham, Coleen K; Reddy, Elizabeth ABACKGROUND: In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up. METHODS: This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained. RESULTS: 161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01). CONCLUSIONS: After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.Item Unknown Failure of lumbopelvic fixation after long construct fusions in patients with adult spinal deformity: clinical and radiographic risk factors: clinical article.(Journal of neurosurgery. Spine, 2013-10) Cho, Woojin; Mason, Jonathan R; Smith, Justin S; Shimer, Adam L; Wilson, Adam S; Shaffrey, Christopher I; Shen, Francis H; Novicoff, Wendy M; Fu, Kai-Ming G; Heller, Joshua E; Arlet, VincentObject
Lumbopelvic fixation provides biomechanical support to the base of the long constructs used for adult spinal deformity. However, the failure rate of the lumbopelvic fixation and its risk factors are not well known. The authors' objective was to report the failure rate and risk factors for lumbopelvic fixation in long instrumented spinal fusion constructs performed for adult spinal deformity.Methods
This retrospective review included 190 patients with adult spinal deformity who had long construct instrumentation (> 6 levels) with iliac screws. Patients' clinical and radiographic data were analyzed. The patients were divided into 2 groups: a failure group and a nonfailure group. A minimum 2-year follow-up was required for inclusion in the nonfailure group. In the failure group, all patients were included in the study regardless of whether the failure occurred before or after 2 years. In both groups, the patients who needed a revision for causes other than lumbopelvic fixation (for example, proximal junctional kyphosis) were also excluded. Failures were defined as major and minor. Major failures included rod breakage between L-4 and S-1, failure of S-1 screws (breakage, halo formation, or pullout), and prominent iliac screws requiring removal. Minor failures included rod breakage between S-1 and iliac screws and failure of iliac screws. Minor failures did not require revision surgery. Multiple clinical and radiographic values were compared between major failures and nonfailures.Results
Of 190 patients, 67 patients met inclusion criteria and were enrolled in the study. The overall failure rate was 34.3%; 8 patients had major failure (11.9%) and 15 had minor failure (22.4%). Major failure occurred at a statistically significant greater rate in patients who had undergone previous lumbar surgery, had greater pelvic incidence, and had poor restoration of lumbar lordosis and/or sagittal balance (that is, undercorrection). Patients with a greater number of comorbidities and preoperative coronal imbalance showed trends toward an increase in major failures, although these trends did not reach statistical significance. Age, sex, body mass index, smoking history, number of fusion segments, fusion grade, and several other radiographic values were not shown to be associated with an increased risk of major failure. Seventy percent of patients in the major failure group had anterior column support (anterior lumbar interbody fusion or transforaminal lumbar interbody fusion) while 80% of the nonfailure group had anterior column support.Conclusions
The incidence of overall failure was 34.3%, and the incidence of clinically significant major failure of lumbopelvic fixation after long construct fusion for adult spinal deformity was 11.9%. Risk factors for major failures are a large pelvic incidence, revision surgery, and failure to restore lumbar lordosis and sagittal balance. Surgeons treating adult spinal deformity who use lumbopelvic fixation should pay special attention to restoring optimal sagittal alignment to prevent lumbopelvic fixation failure.Item Open Access High prevalence of PI resistance in patients failing second-line ART in Vietnam.(J Antimicrob Chemother, 2016-03) Thao, Vu Phuong; Quang, Vo Minh; Day, Jeremy N; Chinh, Nguyen Tran; Shikuma, Cecilia M; Farrar, Jeremy; Van Vinh Chau, Nguyen; Thwaites, Guy E; Dunstan, Sarah J; Le, ThuyBACKGROUND: There are limited data from resource-limited settings on antiretroviral resistance mutations that develop in patients failing second-line PI ART. METHODS: We performed a cross-sectional virological assessment of adults on second-line ART for ≥6 months between November 2006 and December 2011, followed by a prospective follow-up over 2 years of patients with virological failure (VF) at the Hospital for Tropical Diseases, Vietnam. VF was defined as HIV RNA concentrations ≥1000 copies/mL. Resistance mutations were identified by population sequencing of the pol gene and interpreted using the 2014 IAS-USA mutation list and the Stanford algorithm. Logistic regression modelling was performed to identify predictors of VF. RESULTS: Two hundred and thirty-one patients were enrolled in the study. The median age was 32 years; 81.0% were male, 95.7% were on a lopinavir/ritonavir-containing regimen and 22 (9.5%) patients had VF. Of the patients with VF, 14 (64%) carried at least one major protease mutation [median: 2 (IQR: 1-3)]; 13 (59%) had multiple protease mutations conferring intermediate- to high-level resistance to lopinavir/ritonavir. Mutations conferring cross-resistance to etravirine, rilpivirine, tipranavir and darunavir were identified in 55%, 55%, 45% and 27% of patients, respectively. Higher viral load, adherence <95% and previous indinavir use were independent predictors of VF. The 2 year outcomes of the patients maintained on lopinavir/ritonavir included: death, 7 (35%); worsening virological/immunological control, 6 (30%); and virological re-suppression, 5 (25%). Two patients were switched to raltegravir and darunavir/ritonavir with good HIV control. CONCLUSIONS: High-prevalence PI resistance was associated with previous indinavir exposure. Darunavir plus an integrase inhibitor and lamivudine might be a promising third-line regimen in Vietnam.Item Open Access HIV-1 drug resistance in antiretroviral-naive individuals with HIV-1-associated tuberculous meningitis initiating antiretroviral therapy in Vietnam.(Antivir Ther, 2012) Thao, Vu P; Le, Thuy; Török, Estee M; Yen, Nguyen TB; Chau, Tran TH; Jurriaans, Suzanne; van Doorn, H Rogier; de Jong, Menno D; Farrar, Jeremy J; Dunstan, Sarah JBACKGROUND: Access to antiretroviral therapy (ART) for HIV-infected individuals in Vietnam is rapidly expanding, but there are limited data on HIV drug resistance (HIVDR) to guide ART strategies. METHODS: We retrospectively conducted HIVDR testing in 220 ART-naive individuals recruited to a randomized controlled trial of immediate versus deferred ART in individuals with HIV-associated tuberculous meningitis in Ho Chi Minh City (HCMC) from 2005-2008. HIVDR mutations were identified by population sequencing of the HIV pol gene and were defined based on 2009 WHO surveillance drug resistance mutations (SDRMs). RESULTS: We successfully sequenced 219/220 plasma samples of subjects prior to ART; 218 were subtype CRF01_AE and 1 was subtype B. SDRMs were identified in 14/219 (6.4%) subjects; 8/14 were resistant to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs; T69D, L74V, V75M, M184V/I and K219R), 5/14 to non-nucleoside reverse transcriptase inhibitors (NNRTIs; K103N, V106M, Y181C, Y188C and G190A), 1/14 to both NRTIs and NNRTIs (D67N and Y181C) and none to protease inhibitors. After 6 months of ART, eight subjects developed protocol-defined virological failure. HIVDR mutations were identified in 5/8 subjects. All five had mutations with high-level resistance to NNRTIs and three had mutations with high-level resistance to NRTIs. Due to a high early mortality rate (58%), the effect of pre-existing HIVDR mutations on treatment outcome could not be accurately assessed. CONCLUSIONS: The prevalence of WHO SDRMs in ART-naive individuals with HIV-associated tuberculous meningitis in HCMC from 2005-2008 is 6.4%. The SDRMs identified conferred resistance to NRTIs and/or NNRTIs, reflecting the standard first-line ART regimens in Vietnam.Item Open Access Identification of decision criteria for revision surgery among patients with proximal junctional failure after surgical treatment of spinal deformity.(Spine, 2013-09) Hart, Robert; McCarthy, Ian; Oʼbrien, Michael; Bess, Shay; Line, Brett; Adjei, Oheneba Boachie; Burton, Doug; Gupta, Munish; Ames, Christopher; Deviren, Vedat; Kebaish, Khaled; Shaffrey, Christopher; Wood, Kirkham; Hostin, Richard; International Spine Study GroupStudy design
Multicenter, retrospective, consecutive case series.Objective
This study aims to identify demographic and radiographical characteristics that influence the decision to perform revision surgery among patients with proximal junctional failure (PJF).Summary of background data
Revision rates after PJF remain relatively high, yet the decision criteria for performing revision surgical procedures are not uniform and vary by surgeon. A better understanding of the factors that impact the decision to perform revision surgery is important in order to improve efficiency of surgical treatment of adult spinal deformity.Methods
A cohort of 57 patients with PJF was identified retrospectively from 1218 consecutive patients with adult spinal deformity. PJF was identified on the basis of 10° postoperative increase in kyphosis between upper instrumented vertebra (UIV) and UIV +2, along with 1 or more of the following: fracture of the vertebral body of UIV or UIV +1, posterior osseoligamentous disruption, or pullout of instrumentation at the UIV. Univariate statistical analysis was performed using t tests and Fisher exact tests. Multivariate analysis was performed using logistic regression.Results
Twenty-seven (47.4%) patients underwent revision surgery within 6 months of the index operation. Regression results revealed that patients with combined posterior/anterior approaches at index were significantly more likely to undergo revision (P = 0.001) as were patients with more extreme proximal junctional kyphosis angulation (P = 0.034). Patients sustaining trauma were also significantly more likely to undergo revision (P = 0.019). Variables approaching but not reaching significance as predictors of revision included female sex (P = 0.066) and higher sagittal vertical axis (SVA) (P = 0.090).Conclusion
The decision to perform revision surgery is complicated and varies by surgeon. Factors that seem to influence this decision include traumatic etiology of PJF, severity of proximal junctional kyphosis angulation, higher SVA, and female sex. Factors that were expected to influence revision but had no statistical effect included soft tissue versus bony mode of failure, age, levels fused, and upper thoracic versus thoracolumbar proximal junction.Item Open Access Incidence, mode, and location of acute proximal junctional failures after surgical treatment of adult spinal deformity.(Spine, 2013-05) Hostin, Richard; McCarthy, Ian; OʼBrien, Michael; Bess, Shay; Line, Breton; Boachie-Adjei, Oheneba; Burton, Doug; Gupta, Munish; Ames, Christopher; Deviren, Vedat; Kebaish, Khaled; Shaffrey, Christopher; Wood, Kirkham; Hart, Robert; International Spine Study GroupStudy design
Multicenter, retrospective series.Objective
To analyze the incidence, mode, and location of acute proximal junctional failures (APJFs) after surgical treatment of adult spinal deformity.Summary of background data
Early proximal junctional failures above adult deformity constructs are a serious clinical problem; however, the incidence and nature of early APJFs remain unclear.Methods
A total of 1218 consecutive adult spinal deformity surgeries across 10 deformity centers were retrospectively reviewed to evaluate the incidence and nature of APJF, defined as any of the following within 28 weeks of index procedure: minimum 15° post-operative increase in proximal junctional kyphosis, vertebral fracture of upper instrumented vertebrae (UIV) or UIV + 1, failure of UIV fixation, or need for proximal extension of fusion within 6 months of surgery.Results
Sixty-eight APJF cases were identified out of 1218 consecutive surgeries (5.6%). Patients had a mean age of 63 years (range, 26-82 yr), mean fusion levels of 9.8 (range, 4-18), and mean time to APJF of 11.4 weeks (range, 1.5-28 wk). Fracture was the most common failure mode (47%), followed by soft-tissue failure (44%). Failures most often occurred in the thoracolumbar region (TL-APJF) compared with the upper thoracic region (UT-APJF), with 66% of patients experiencing TL-APJF compared with 34% experiencing UT-APJF. Fracture was significantly more common for TL-APJF relative to UT-APJF (P = 0.00), whereas soft-tissue failure was more common for UT-APJF (P < 0.02). Patients experiencing TL-APJF were also older (P = 0.00), had fewer fusion levels (P = 0.00), and had worse postoperative sagittal vertical axis (P < 0.01).Conclusion
APJFs were identified in 5.6% of patients undergoing surgical treatment of adult spinal deformity, with failures occurring primarily in the TL region of the spine. There is evidence that the mode of failure differs depending on the location of UIV, with TL failures more likely due to fracture and UT failures more likely due to soft-tissue failures.Item Open Access Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings.(AIDS, 2012-07-17) Bartlett, John A; Ribaudo, Heather J; Wallis, Carole L; Aga, Evgenia; Katzenstein, David A; Stevens, Wendy S; Norton, Michael R; Klingman, Karin L; Hosseinipour, Mina C; Crump, John A; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Kallungal, Beatrice A; Kumarasamy, NagalingeswaranOBJECTIVE: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs). DESIGN: An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000 copies/ml. METHODS: Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100 mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. RESULTS: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400 copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40 copies/ml and 30 had levels 40-200 copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400 copies/ml. CONCLUSION: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.Item Open Access Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.(Br J Cancer, 2009-12-15) Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; Sathornsumetee, S; McLendon, RE; Herndon, JE; Marcello, JE; Norfleet, J; Friedman, AH; Bigner, DD; Friedman, HSBACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).Item Open Access Nonoperative Management in Neurologically Intact Thoracolumbar Burst Fractures: Clinical and Radiographic Outcomes.(Spine, 2016-03) Hitchon, Patrick W; Abode-Iyamah, Kingsley; Dahdaleh, Nader S; Shaffrey, Christopher; Noeller, Jennifer; He, Wenzhuan; Moritani, ToshioStudy design
Retrospective cohort study.Objective
The identification of factors that lead to the failure of nonoperative management in neurologically intact thoracolumbar burst fractures.Summary of background data
The treatment of thoracolumbar burst fractures (TLBF) can be controversial, particularly in the neurologically intact. Surgery for intact burst fractures has been advocated for early mobilization and a shorter hospital stay. These goals, however, have not always been achieved, rejuvenating an interest in nonoperative treatment.Methods
Sixty-eight neurologically intact patients with burst fractures of the thoracolumbar junction (T11-L2), and a thoracolumbar injury classification and severity score (TLICS) of 2, were treated at our institution. Based on CT scans, patients were scored based on the load-sharing classification (LSC) scale. Initial treatment consisted of bracing in clamshell thoracolumbar orthosis and gradual mobilization.Results
Owing to pain limiting mobilization, 18 patients failed nonoperative management and required instrumentation. Those who failed nonsurgical management were significantly more kyphotic (8° ± 10) and stenotic (52% ± 14%) than those successfully treated nonoperatively (3° ± 7 and 63 ± 12%, respectively). The LSC score of those undergoing surgery (6.9 ± 1.1) was also greater than those successfully treated nonoperatively (5.8 ± 1.3, P = 0.006). Length of hospitalization was longer, and hospital charges higher in those requiring surgery compared to the nonoperative group. At follow-up there was no difference between groups in the visual analog score for pain (VAS) or the Oswestry disability index.Conclusion
Owing to pain limiting mobilization, a quarter of neurologically intact patients with thoracolumbar burst fractures and a TLICS score of 2 failed nonsurgical management. The greater the kyphosis, stenosis, and fragmentation of the fracture, the more likely patients required surgery. In addition to the TLICS classification, other radiographic and clinical parameters should be included in selecting appropriate treatment strategy. The cost savings with nonoperative treatment of intact burst fractures, when appropriate, are significant.Item Open Access Predicting virologic failure among HIV-1-infected children receiving antiretroviral therapy in Tanzania: a cross-sectional study.(J Acquir Immune Defic Syndr, 2010-08) Emmett, Susan D; Cunningham, Coleen K; Mmbaga, Blandina T; Kinabo, Grace D; Schimana, Werner; Swai, Mark E; Bartlett, John A; Crump, John A; Reddy, Elizabeth ABACKGROUND: Many HIV care and treatment programs in resource-limited settings rely on clinical and immunologic monitoring of antiretroviral therapy (ART), but accuracy of this strategy to detect virologic failure (VF) among children has not been evaluated. METHODS: A cross-sectional sample of HIV-infected children aged 1-16 years on ART >or=6 months receiving care at a Tanzanian referral center underwent clinical staging, CD4 lymphocyte measurement, plasma HIV-1 RNA level, and complete blood count. Associations with VF (HIV-1 RNA >or=400 copies/mL) were determined utilizing bivariable and multivariate analyses; accuracy of current clinical and immunologic guidelines in identifying children with VF was assessed. FINDINGS: Of 206 children (median age 8.7 years, ART duration 2.4 years), 65 (31.6%) demonstrated VF at enrollment. Clinical and immunological criteria identified 2 (3.5%) of 57 children with VF on first-line therapy, exhibiting 3.5% sensitivity and 100% specificity. VF was associated with younger age, receipt of nevirapine vs. efavirenz-based regimen, CD4% < 25%, and physician documentation of maladherence (P < 0.05 on bivariable analysis); the latter 2 factors remained significant on multivariate logistic regression. INTERPRETATION: This study demonstrates poor performance of clinical and immunologic criteria in identifying children with virologic failure. Affordable techniques for measuring HIV-1 RNA level applicable in resource-limited settings are urgently needed.Item Open Access Pulmonary vein isolation for the treatment of drug-refractory atrial fibrillation in adults with congenital heart disease.(Congenit Heart Dis, 2012-07) Philip, Femi; Muhammad, Kamran I; Agarwal, Shikar; Natale, Andrea; Krasuski, Richard ABACKGROUND: Atrial fibrillation (AF) is a common arrhythmia in adults with congenital heart disease (CHD). Long-term antiarrhythmic therapy (AAT) in these patients has significant shortcomings. The safety and efficacy of pulmonary vein antrum isolation (PVAI) for the treatment of AF in CHD is presently unknown. HYPOTHESIS: We hypothesized that PVAI for AF in patients with CHD is effective and safe. METHODS: We reviewed a prospective cohort of 4315 patients (age ≥ 18) undergoing PVAI for drug refractory AF at a single institution and identified 36 consecutive patients with CHD (single ventricle physiology, tetralogy of Fallot, coarctation of the aorta, ventricular septal defects, atrial septal defects (ASD) and cardiomyopathy resulting from anomalous origin of the left main coronary from the pulmonary artery). A second cohort of 355 consecutive patients with noncongenital structural heart disease (NSHD) (coronary artery disease, valvular heart disease, ejection fraction <50%, or prior noncongenital cardiac surgery) undergoing PVAI during the same time period was used as a control. Success was defined as freedom from AF starting two months after PVAI in the absence AAT until the end of follow-up. Partial success was defined as freedom from AF in the presence of AAT until the end of follow-up. Combined success was defined as the sum of success and partial success. We compared the outcomes with the use of propensity-score matching in the overall cohort. RESULTS: Patients with NSHD were older and had higher prevalence of hypertension (P < .01), diabetes (P < .01) and hyperlipidemia (P < .01). The most common CHD lesion was ASD (61%) and the most common NSHD lesion was valvular heart disease (57%). After one PVAI, success was achieved in 42% and 53% at 300 days in the CHD and NSHD groups respectively. Four-year success was achieved in 27% and 36% in the CHD and NSHD groups, respectively. There were no significant differences in the success rates between patients groups (P= .46), nor were there any differences in left atrial size or changes in ejection fraction after one or two PVAI in the respective groups. Complication rates between the CHD and NSHD groups were similar (15% vs. 11%, P= .42) except for a higher risk of vascular site complications in patients with CHD (8% vs. 1%, P < .05). CONCLUSION: PVAI is an attractive treatment modality in drug refractory AF in CHD, with combined success rates in excess of 60%. The maintenance of sinus rhythm after PVAI in CHD appears similar to that of NSHD and warrants prospective validation.Item Open Access Sagittal realignment failures following pedicle subtraction osteotomy surgery: are we doing enough?: Clinical article.(Journal of neurosurgery. Spine, 2012-06) Schwab, Frank J; Patel, Ashish; Shaffrey, Christopher I; Smith, Justin S; Farcy, Jean-Pierre; Boachie-Adjei, Oheneba; Hostin, Richard A; Hart, Robert A; Akbarnia, Behrooz A; Burton, Douglas C; Bess, Shay; Lafage, VirginieObject
Pedicle subtraction osteotomy (PSO) is a surgical procedure that is frequently performed on patients with sagittal spinopelvic malalignment. Although it allows for substantial spinopelvic realignment, suboptimal realignment outcomes have been reported in up to 33% of patients. The authors' objective in the present study was to identify differences in radiographic profiles and surgical procedures between patients achieving successful versus failed spinopelvic realignment following PSO.Methods
This study is a multicenter retrospective consecutive PSO case series. The authors evaluated 99 cases involving patients who underwent PSO for sagittal spinopelvic malalignment. Because precise cutoffs of acceptable residual postoperative sagittal vertical axis (SVA) values have not been well defined, comparisons were focused between patient groups with a postoperative SVA that could be clearly considered either a success or a failure. Only cases in which the patients had a postoperative SVA of less than 50 mm (successful PSO realignment) or more than 100 mm (failed PSO realignment) were included in the analysis. Radiographic measures and PSO parameters were compared between successful and failed PSO realignments.Results
Seventy-nine patients met the inclusion criteria. Successful realignment was achieved in 61 patients (77%), while realignment failed in 18 (23%). Patients with failed realignment had larger preoperative SVA (mean 217.9 vs 106.7 mm, p < 0.01), larger pelvic tilt (mean 36.9° vs 30.7°, p < 0.01), larger pelvic incidence (mean 64.2° vs 53.7°, p < 0.01), and greater lumbar lordosis-pelvic incidence mismatch (-47.1° vs -30.9°, p < 0.01) compared with those in whom realignment was successful. Failed and successful realignments were similar regarding the vertebral level of the PSO, the median size of wedge resection 22.0° (interquartile range 16.5°-28.5°), and the numerical changes in pre- and postoperative spinopelvic parameters (p > 0.05).Conclusions
Patients with failed PSO realignments had significantly larger preoperative spinopelvic deformity than patients in whom realignment was successful. Despite their apparent need for greater correction, the patients in the failed realignment group only received the same amount of correction as those in the successfully realigned patients. A single-level standard PSO may not achieve optimal outcome in patients with high preoperative spinopelvic sagittal malalignment. Patients with large spinopelvic deformities should receive larger osteotomies or additional corrective procedures beyond PSOs to avoid undercorrection.Item Open Access Sagittal spino-pelvic alignment failures following three column thoracic osteotomy for adult spinal deformity.(European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, 2012-04) Lafage, Virginie; Smith, Justin S; Bess, Shay; Schwab, Frank J; Ames, Christopher P; Klineberg, Eric; Arlet, Vincent; Hostin, Richard; Burton, Douglas C; Shaffrey, Christopher I; International Spine Study GroupPurpose
Three column thoracic osteotomy (TCTO) is effective to correct rigid thoracic deformities, however, reasons for residual postoperative spinal deformity are poorly defined. Our objective was to evaluate risk factors for poor spino-pelvic alignment (SPA) following TCTO for adult spinal deformity (ASD).Methods
Multicenter, retrospective radiographic analysis of ASD patients treated with TCTO. Radiographic measures included: correction at the osteotomy site, thoracic kyphosis (TK), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic tilt (PT), and pelvic incidence (PI). Final SVA and PT were assessed to determine if ideal SPA (SVA < 4 cm, PT < 25°) was achieved. Differences between the ideal (IDEAL) and failed (FAIL) SPA groups were evaluated.Results
A total of 41 consecutive ASD patients treated with TCTO were evaluated. TCTO significantly decreased TK, maximum coronal Cobb angle, SVA and PT (P < 0.05). Ideal SPA was achieved in 32 (78%) and failed in 9 (22%) patients. The IDEAL and FAIL groups had similar total fusion levels and similar focal, SVA and PT correction (P > 0.05). FAIL group had larger pre- and post-operative SVA, PT and PI and a smaller LL than IDEAL (P < 0.05).Conclusions
Poor SPA occurred in 22% of TCTO patients despite similar operative procedures and deformity correction as patients in the IDEAL group. Greater pre-operative PT and SVA predicted failed post-operative SPA. Alternative or additional correction procedures should be considered when planning TCTO for patients with large sagittal global malalignment, otherwise patients are at risk for suboptimal correction and poor outcomes.Item Open Access Time to development, clinical and radiographic characteristics, and management of proximal junctional kyphosis following adult thoracolumbar instrumented fusion for spinal deformity.(Journal of spinal disorders & techniques, 2015-03) Reames, Davis L; Kasliwal, Manish K; Smith, Justin S; Hamilton, D Kojo; Arlet, Vincent; Shaffrey, Christopher IStudy design
A retrospective review.Objective
To study time to development, clinical and radiographic characteristics, and management of proximal junctional kyphosis (PJK) following thoracolumbar instrumented fusion for adult spinal deformity (ASD).Summary of background data
PJK continues to be a common mode of failure following ASD surgery. Although literature exists on possible risk factors, data on management remain limited.Methods
A retrospective review of medical records of 289 consecutive ASD patients who underwent posterior segmental instrumentation incorporating at least 5 segments was conducted. PJK was defined as proximal kyphotic angle >10 degrees.Results
PJK occurred in 32 patients (11%) at a mean follow-up of 34 months (range, 1.3-61.9±19 mo). Sixteen (50%) patients were revised (mean, 1.7 revisions; range, 1-3) at a mean follow-up of 9.6 months (range, 0.7-40 mo); primary indications for revision were pain (n=16), myelopathy (n=6), instability (n=4), and instrumentation protrusion (n=2). Comparison of preindex and postindex surgery radiographic parameters demonstrated significant improvement in mean lumbar lordosis (24 vs. 42 degrees, P<0.001), pelvic incidence-lumbar lordosis mismatch (30 vs. 11 degrees, P<0.001), and pelvic tilt (29 vs. 23 degrees, P<0.011). The mean T5-T12 kyphosis worsened (30 vs. 53 degrees, P<0.001) and the mean global sagittal spinal alignment failed to improve (9.6 vs. 8.0 cm, P=0.76). There was no apparent relationship between the absolute PJK angle and revision surgery (P>0.05).Conclusions
The patients in this series who developed PJK had substantial preoperative positive sagittal malalignment that remained inadequately corrected following surgery, likely resulting from a combination of inadequate surgical correction and a significant compensatory increase in thoracic kyphosis. In the absence of direct relationship between a greater PJK angle and worse clinical outcome, clinical symptoms and neurological status rather than absolute reliance on radiographic parameters should drive the decision to pursue revision surgery.Item Open Access What Factors Predict the Risk of Proximal Junctional Failure in the Long Term, Demographic, Surgical, or Radiographic?: Results From a Time-dependent ROC Curve.(Spine, 2019-06) Yang, Jingyan; Khalifé, Marc; Lafage, Renaud; Kim, Han Jo; Smith, Justin; Shaffrey, Christopher I; Burton, Douglas C; Ames, Christopher P; Mundis, Gregory M; Hostin, Richard; Bess, Shay; Klineberg, Eric O; Hart, Robert AA; Schwab, Frank J; Lafage, Virginie; International Spine Study Group (ISSG)Study design
Retrospective review of prospective multicenter database.Objective
To identify an optimal set of factors predicting the risk of proximal junctional failure (PJF) while taking the time dependency of PJF and those factors into account.Summary of background data
Surgical correction of adult spinal deformity (ASD) can be complex and therefore, may come with high revision rates due to PJF.Methods
Seven hundred sixty-three operative ASD patients with a minimum of 1-year follow-up were included. PJF was defined as any type of proximal junctional kyphosis (PJK) requiring revision surgery. Time-dependent ROC curves were estimated with corresponding Cox proportional hazard models. The predictive abilities of demographic, surgical, radiographic parameters, and their possible combinations were assessed sequentially. The area under the curve (AUC) was used to evaluate models' performance.Results
PJF occurred in 42 patients (6%), with a median time to revision of approximately 1 year. Larger preoperative pelvic tilt (PT) (hazard ratio [HR]=1.044, P = 0.034) significantly increased the risk of PJF. With respect to changes in the radiographic parameters at 6-week postsurgery, larger differences in pelvic incidence-lumbar lordosis (PI-LL) mismatch (HR = 0.924, P = 0.002) decreased risk of PJF. The combination of demographic, surgical, and radiographic parameters has the best predictive ability for the occurrence of PJF (AUC = 0.863), followed by demographic along with radiographic parameters (AUC = 0.859). Both models' predictive ability was preserved over time.Conclusions
Over correction increased the risk of PJF. Radiographic along with demographic parameters have shown the approximately equivalent predictive ability for PJF over time as with the addition of surgical parameters. Radiographic rather than surgical factors may be of particular importance in predicting the development of PJF over time. These results set the groundwork for risk stratification and corresponding prophylactic interventions for patients undergoing ASD surgery.Level of evidence
4.