Ignacio Jusué-Torres

Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma

INTRODUCTION Surgery is first-line therapy for glioblastoma, and there is evidence that gross total resection is associated with improved survival. Gross total resection, however, is not always possible, and relationships among extent (percent) of resection (EOR), residual volume (RV), and survival are unknown. The goals were to evaluate whether there is an association between EOR and RV with survival and recurrence and to establish minimum EOR and maximum RV thresholds. METHODS Adult patients who underwent primary glioblastoma surgery from 2007 to 2011 were retrospectively reviewed. Three-dimensional volumetric tumor measurements were made. Multivariate proportional hazards regression analysis was used to evaluate the relationship between EOR and RV with survival and recurrence. RESULTS Of 259 patients, 203 (78%) died and 156 (60%) had tumor recurrence. The median survival and progression-free survival were 13.4 and 8.9 months, respectively. The median (interquartile range) pre- and postoperative tumor volumes were 32.2 (14.0-56.3) and 2.1 (0.0-7.9) cm(3), respectively. EOR was independently associated with survival (hazard ratio [HR], 0.995; 95% confidence interval [CI]: 0.990-0.998; P = .008) and recurrence (HR [95% CI], 0.992 [0.983-0.998], P = .005). The minimum EOR threshold for survival (P = .0006) and recurrence (P = .005) was 70%. RV was also associated with survival (HR [95% CI], 1.019 [1.006-1.030], P = .004) and recurrence (HR [95% CI], 1.024 [1.001-1.044], P = .03). The maximum RV threshold for survival (P = .01) and recurrence (P = .01) was 5 cm(3). CONCLUSION This study shows for the first time that both EOR and RV are significantly associated with survival and recurrence, where the thresholds are 70% and 5 cm(3), respectively. These findings may help guide surgical and adjuvant therapies aimed at optimizing outcomes for glioblastoma patients.

When Gross Total Resection of a Glioblastoma Is Possible, How Much Resection Should Be Achieved?

OBJECTIVE The efficacy of extensive resection on prolonging survival for patients with glioblastoma (GBM) is controversial because prior studies have included tumors with dissimilar resection capabilities. The true isolated effect of increasing resection on survival for GBM therefore remains unclear. METHODS Adult patients who underwent surgery of an intracranial newly diagnosed GBM at an academic tertiary-care institution from 2007 to 2011 were reviewed. Preoperative images were reviewed by 3 neurosurgeons independently. Tumors considered amenable to gross total resection based on preoperative imaging by all neurosurgeons were included. Multivariate proportional hazards regression analysis was used to identify if an association existed between residual volume (RV) and extent of resection (EOR) with survival. RESULTS Of the 292 patients with newly diagnosed GBM, 84 (29%) were amenable to gross total resection. The median (interquartile range) pre and postoperative tumor volumes were 27 (13.8-54.4) and 0.9 (0-2.7) cm(3), respectively. The mean percent resection was 91.7% ± 1.3%. In multivariate analysis, after controlling for age, functional status, and adjuvant therapies, RV (hazards ratio [HR] [95% confidence interval (CI)] = 1.114 [1.033-1.193], P = 0.006) and EOR (HR [95% CI] = 0.959 [0.934-0.985], P = 0.003) were each independently associated with survival. The RV and EOR with the greatest reduction in the risk of death was <2 cm(3) and >95%, respectively. Likewise, RV (HR [95% CI] = 1.085 [1.010-1.178], P = 0.01) and EOR (HR [95% CI] = 0.962 [0.930-0.998], P = 0.04) each remained independently associated with recurrence. CONCLUSION This is the first study to evaluate RV and EOR in a more uniform population of patients with tumors of similar surgical capabilities. This study shows that achieving a decreased RV and/or an increased EOR is independently associated with survival and recurrence in those patients with tumors with similar resection capacities.

Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum.

Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer–specific gene panel to detect DNA methylation in sputum and plasma. Experimental Design: This is a case–control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non–small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42). Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P < 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 [95% confidence interval (CI), 0.80–0.98] in sputum and 0.77 (95% CI, 0.68–0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection. Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma. Clin Cancer Res; 23(8); 1998–2005. ©2016 AACR.

Synopsis of guidelines for the clinical management of cerebral cavernous malformations: Consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel

BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance (www.angioma.org), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines.

Time Interval Reduction for Delayed Implant-Based Cranioplasty Reconstruction in the Setting of Previous Bone Flap Osteomyelitis

Background: Reinfections following implant-based cranioplasty, in the setting of previous bone flap osteomyelitis, are common and associated with significant morbidity. The timing of reconstruction following initial osteomyelitic bone flap removal remains controversial; most advocate for prolonged time intervals of approximately 6 to 12 months. Thus, the authors investigated their delayed cranioplasty outcomes following both early (between 90 and 179 days) and late (≥180 days) time intervals with custom craniofacial implants to determine whether timing affected outcomes and rates of reinfection. Methods: An institutional review board–approved retrospective cohort review of 25 consecutive cranioplasties, from 2012 to 2014, was conducted. A nonparametric bivariate analysis compared variables and complications between the two different time interval groups, defined as early cranioplasty (between 90 and 179 days) and cranioplasty (≥180 days). Results: No significant differences were found in primary and secondary outcomes in patients who underwent early versus late cranioplasty (p > 0.29). The overall reinfection rate was only 4 percent (one of 25), with the single reinfection occurring in the late group. Overall, the major complication rate was 8 percent (two of 25). Complete and subgroup analyses of specific complications yielded no significant differences between the early and late time intervals (p > 0.44). Conclusions: The results suggest that early cranioplasty is a viable treatment option for patients with previous bone flap osteomyelitis and subsequent removal. As such, a reduced time interval of 3 months—with equivalent outcomes and reinfection rates—represents a promising area for future study aiming to reduce the morbidity surrounding prolonged time intervals. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Outcomes and Experience with Lumbopleural Shunts in the Management of Idiopathic Intracranial Hypertension.

OBJECTIVE To report five patients who underwent lumbopleural (LPl) shunting for the treatment of idiopathic intracranial hypertension (IIH) and to describe the considerations, complications, and outcomes related to this rarely described procedure. METHODS The clinical data of five patients treated with LPl shunting over a 23-year period were retrospectively analyzed. Factors including the age at diagnosis of IIH, age at time of LPl shunting, body mass index (BMI), reason for LPl shunt placement, number of revisions before LPl shunt placement, valve type, time to first revision, presence of overdrainage and its management, complications and their management, survival time of LPl shunt, and clinical course at last follow-up were analyzed. RESULTS All patients were morbidly obese females with an average of 4.6 shunt revisions before an LPl shunt. The average overall survival time of the LPl shunt was 48 months. Two patients experienced failure of their LPl shunts with subsequent replacement within the first year. Four patients experienced complications related to shunt overdrainage, requiring placement of an antisiphon device (ASD) or additional valve. One patient developed a symptomatic pleural effusion, and one patient developed a small pneumothorax, which was managed conservatively. CONCLUSIONS LPl shunting, though rarely used, is a viable option in the treatment of IIH refractory to standard peritoneal shunting. When pursuing this treatment, a valve and ASD are recommended to mitigate the risks of overdrainage and pleural effusion. Chest imaging should be obtained if the patient becomes symptomatic but can be deferred if the patient remains asymptomatic and is doing well.

Prognostic factors associated with pain palliation after spine stereotactic body radiation therapy

OBJECT The number of patients with spinal tumors is rapidly increasing; spinal metastases develop in more than 30% of cancer patients during the course of their illness. Such lesions can significantly decrease quality of life, often necessitating treatment. Stereotactic radiosurgery has effectively achieved local control and symptomatic relief for these patients. The authors determined prognostic factors that predicted pain palliation and report overall institutional outcomes after spine stereotactic body radiation therapy (SBRT). METHODS Records of patients who had undergone treatment with SBRT for either primary spinal tumors or spinal metastases from June 2008 through June 2013 were retrospectively reviewed. Data were collected at the initial visit just before treatment and at 1-, 3-, 6-, and 12-month follow-up visits. Collected clinical data included Karnofsky Performance Scale scores, pain status, presence of neurological deficits, and prior radiation exposure at the level of interest. Radiation treatment plan parameters (dose, fractionation, and target coverage) were recorded. To determine the initial extent of epidural spinal cord compression (ESCC), the authors retrospectively reviewed MR images, assessed spinal instability according to the Bilsky scale, and evaluated lesion progression after treatment. RESULTS The study included 99 patients (mean age 60.4 years). The median survival time was 9.1 months (95% CI 6.9-17.2 months). Significant decreases in the proportion of patients reporting pain were observed at 3 months (p < 0.0001), 6 months (p = 0.0002), and 12 months (p = 0.0019) after treatment. Significant decreases in the number of patients reporting pain were also observed at the last follow-up visit (p = 0.00020) (median follow-up time 6.1 months, range 1.0-56.6 months). Univariate analyses revealed that significant predictors of persistent pain after intervention were initial ESCC grade, stratified by a Bilsky grade of 1c (p = 0.0058); initial American Spinal Injury Association grade of D (p = 0.011); initial Karnofsky Performance Scale score, stratified by a score of 80 (p = 0.002); the presence of multiple treated lesions (p = 0.044); and prior radiation at the site of interest (p < 0.0001). However, when multivariate analyses were performed on all variables with p values less than 0.05, the only predictor of pain at last follow-up visit was a prior history of radiation at the site of interest (p = 0.0038), although initial ESCC grade trended toward significance (p = 0.073). Using pain outcomes at 3 months, at this follow-up time point, pain could be predicted by receipt of radiation above a threshold biologically effective dose of 66.7 Gy. CONCLUSIONS Pain palliation occurs as early as 3 months after treatment; significant differences in pain reporting are also observed at 6 and 12 months. Pain palliation is limited for patients with spinal tumors with epidural extension that deforms the cord and for patients who have previously received radiation to the same site. Further investigation into the optimal dose and fractionation schedule are needed, but improved outcomes were observed in patients who received radiation at a biologically effective dose (with an a/b of 3.0) of 66.7 Gy or higher.

Does CT wand guidance improve shunt placement in patients with hydrocephalus

OBJECT To evaluate the effectiveness of stereotactic navigation in enhancing the accuracy of ventricular shunt placement in patients with hydrocephalus. METHODS A retrospective cohort study at a single institution by a single surgeon was performed. Consecutive patients who underwent implantation of a ventricular shunt for the management of hydrocephalus between July 2001 and December 2011 were included in the study, totaling 535 patients. Patients were classified as either having optimal or sub-optimal placement of the shunt into the ventricle. Multiple logistic regression analysis was used. RESULTS Overall, 93.8% of patients were found to have optimal shunt placement. On multivariate analysis, navigation use was not significantly associated with improved accuracy of shunt placement (odds ratio [OR] = 0.54; 95% confidence interval [CI] = 0.19-1.54; p = 0.25). Pseudotumor cerebri diagnosis was significantly associated with increased odds of sub-optimal shunt placement (OR = 6.41; 95% CI = 1.90-21.59; p=0.003). CONCLUSIONS CT guided navigation did not significantly improve the accuracy of ventricular shunt placement in adults with hydrocephalus for an experienced surgeon. Further studies are required to assess the utility of CT guided navigation for less experienced surgeons and patients with small or dysmorphic ventricles.

Functional gait outcomes for idiopathic normal pressure hydrocephalus after primary endoscopic third ventriculostomy

We evaluated if patients with idiopathic normal pressure hydrocephalus (iNPH) showed functional improvement after primary endoscopic third ventriculostomy (ETV). The efficacy of ETV for iNPH remains controversial. We retrospectively reviewed 10 consecutive patients treated between 2009 and 2011 with ETV for iNPH. Seven patients with a median age of 73 years (range: 60-80) who underwent a primary ETV for iNPH were included for analysis. Median follow-up was 39 months (range: 26-46). Post-ETV stoma and aqueductal and cisternal flows were confirmed via high resolution, gradient echo and phase contrast MRI. Post-ETV timed up and go (TUG) and Tinetti performance oriented mobility assessment scores were compared to pre- and post-lumbar puncture (LP) values. A second LP was performed if ETV failed to sustain the observed improvement after initial LP. Patients who demonstrated ETV failure were subsequently shunted. Compared to pre-LP TUG and Tinetti values of 14.00 seconds (range: 12.00-23.00) and 22 (range: 16-24), post-LP scores improved to 11.00 seconds (range: 8.64-15.00; p=0.06) and 25 (range: 24-28; p=0.02), respectively. ETV failed to sustain this improvement with slight worsening between pre-LP and post-ETV TUG and Tinetti scores. Improvement from pre-LP assessment was regained after shunting and at last follow-up with TUG and Tinetti scores of 12.97 seconds (range: 9.00-18.00; p=0.250) and 25 (range: 18-27; p=0.07), and 11.87 seconds (range: 8.27-18.50; p=0.152) and 23 (range: 18-26; p=0.382), respectively. Despite stoma patency, ETV failed to sustain functional improvement seen after LP, however, improvement was regained after subsequent shunting suggesting that shunt placement remains the preferred treatment for iNPH.

Clinical outcomes after ventriculoatrial shunting for idiopathic normal pressure hydrocephalus

INTRODUCTION Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that classically presents with a triad of progressive gait impairment, urinary incontinence, and cognitive deterioration. Treatment predominantly involves ventriculoperitoneal (VP) shunting, but one alternative is ventriculoatrial (VA) shunting. This study sought to describe and evaluate the clinical outcomes of patients with iNPH primarily treated with VA shunting. MATERIALS AND METHODS A retrospective review of patients with iNPH who were treated with VA shunting at a single institution, from 2003 to 2013, was performed. RESULTS 58 patients with iNPH underwent primary VA shunting at a median age of 74 (IQR: 70-80) years. The most common comorbidities included hypertension (n=39, 67%) and diabetes mellitus (n=11, 19%). Median duration of symptoms prior to VA shunting was 24 (IQR: 12-36) months. All patients had gait impairment, 52 (90%) had cognitive decline, and 43 (74%) had urinary incontinence. Forty-three (74%) patients had all three symptoms. At a median last follow-up of 16 (IQR: 7-26) months, median iNPH score improved from 6 to 3 (p<0.0001), mini mental status exam (MMSE) tended to increase from 26 to 29 (p=0.082), timed up-and-go (TUG) improved from 18 to 13s (p<0.0001), and Tinetti score improved from 19 to 25 (p<0.0001) after VA shunting. 78% of patients had improvement in at least one of their symptoms with 66% of patients having improvement in gait, 53% having improvement in their cognition, and 52% having improved urinary incontinence. A total of 21 patients (36%) had improvement in all 3 symptoms. CONCLUSIONS There were significant improvements in functional outcomes as evaluated via the iNPH score, TUG, and Tinetti score, while improvement in MMSE trended toward significance. Patients also had improvement of clinical symptoms related to gait, urinary function and cognition. These results suggest that VA shunting can be an effective primary treatment alternative to VP shunting for iNPH.