Nam D. Tran

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial

IMPORTANCEnGlioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly.nnnOBJECTIVEnTo evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma.nnnDESIGN, SETTING, AND PARTICIPANTSnAfter completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (nu2009=u2009466) or temozolomide alone (nu2009=u2009229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis.nnnINTERVENTIONSnTreatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle.nnnMAIN OUTCOMES AND MEASURESnThe primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (nu2009=u2009280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up.nnnRESULTSnThe interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; Pu2009=u2009.001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (nu2009=u2009196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (nu2009=u200984) (HR, 0.64 [99.4% CI, 0.42-0.98]; Pu2009=u2009.004).nnnCONCLUSIONS AND RELEVANCEnIn this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00916409.

Central Nervous System Cancers, Version 2.2014: Featured Updates to the NCCN Guidelines

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Neurotrophin Signaling via TrkB and TrkC Receptors Promotes the Growth of Brain Tumor-initiating Cells

Background: The role of Trk neurotrophin receptors in glioma is unknown. Results: TrkB and TrkC are required for survival of brain tumor-initiating cells in the absence of EGF and FGF. Conclusion: Trk receptors can control the survival of BTICs in the absence of EGF and FGF. Significance: Trks may be important targets for treatment of malignant gliomas. Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma.

Comparison of polymethylmethacrylate versus expandable cage in anterior vertebral column reconstruction after posterior extracavitary corpectomy in lumbar and thoraco-lumbar metastatic spine tumors

Single-stage posterior corpectomy for the management of spinal tumors has been well described. Anterior column reconstruction has been accomplished using polymethylmethacrylate (PMMA) or expandable cages (EC). The aim of this retrospective study was to compare PMMA versus ECs in anterior vertebral column reconstruction after posterior corpectomy for tumors in the lumbar and thoracolumbar spine. Between 2006 and 2009 we identified 32 patients that underwent a single-stage posterior extracavitary tumor resection and anterior reconstruction, 16 with PMMA and 16 with EC. There were no baseline differences in regards to age (mean: 58.2xa0years) or performance status. Differences between groups in terms of survival, estimated blood loss (EBL), kyphosis reduction (decrease in Cobb’s angle), pain, functional outcomes, and performance status were evaluated. Mean overall survival and EBL were 17xa0months and 1165xa0ml, respectively. No differences were noted between the study groups in regards to survival (pxa0=xa00.5) or EBL (pxa0=xa00.8). There was a trend for better Kyphosis reduction in favor of the EC group (10.04 vs. 5.45, pxa0=xa00.16). No difference in performance status or VAS improvements was observed (pxa0>xa00.05). Seven patients had complications that led to reoperation (5 infections). PMMA or ECs are viable options for reconstruction of the anterior vertebral column following tumor resection and corpectomy. Both approaches allow for correction of the kyphotic deformity, and stabilization of the anterior vertebral column with similar functional and performance status outcomes in the lumbar and thoracolumbar area.

Balloon kyphoplasty in the treatment of metastatic tumors of the upper thoracic spine

OBJECTnBalloon kyphoplasty has recently been shown to be effective in providing rapid pain relief and enhancing health-related quality of life in patients with metastatic spinal tumors. When performed to treat lesions of the upper thoracic spine, kyphoplasty poses certain technical challenges because of the smaller size of the pedicle and vertebral bodies. Fluoroscopic visualization is also difficult due to interference of the shoulder. The authors objective in the present study was to evaluate their approach and the results of balloon kyphoplasty in the upper thoracic spine in patients with metastatic spinal disease.nnnMETHODSnFourteen patients underwent kyphoplasty via an extrapedicular approach to treat metastatic tumors in the upper (T1-5) thoracic spine. Electrodiagnostic monitoring (somatosensory and motor evoked potentials) was used in 5 cases. Three levels were treated in 7 cases, 2 levels in 2 cases, and 1 level in 5 cases. In 3 cases access was bilateral, whereas in 11 cases access was unilateral. The procedure took an average of 25 minutes per treated level, and the mean amount of cement applied was 3 ml per level. Four patients were discharged from the hospital on the day of the procedure, and 10 patients went home after 24 hours.nnnRESULTSnAll patients exhibited marked improvement in mean visual analog scale scores (preoperative score 79 vs postoperative score 30, respectively) and Oswestry Disability Index scores (83 vs 33, respectively). The mean kyphotic angle was 25.03° preoperatively, whereas the mean postoperative angle was 22.65° (p > 0.3). At latest follow-up, the mean kyphotic angle did not differ significantly from the postoperative kyphotic angle (26.3°, p > 0.1). No neurological deficits or lung-related complications (pneumothorax or hemothorax) were encountered in any of the patients. Polymethylmethacrylate cement extravasations were observed in 3 (10%) of 30 treated vertebral bodies without any sequelae. By a mean follow-up of 16 months, no patients had experienced an adjacent-level fracture.nnnCONCLUSIONSnBalloon kyphoplasty of the upper thoracic spine via an extrapedicular approach is an efficient and safe minimally invasive procedure that may provide immediate and long-term pain relief and improvement in functional ability. It is technically challenging and has the potential for serious complications. With a fundamental knowledge of anatomy, as well as an ability to interpret fluoroscopy images, one can feasibly and safely perform balloon kyphoplasty in the upper thoracic spine.

Novel treatments for melanoma brain metastases.

BACKGROUNDnThe development of brain metastases is common in patients with melanoma and is associated with a poor prognosis. Treating patients with melanoma brain metastases (MBMs) is a major therapeutic challenge. Standard approaches with conventional chemotherapy are disappointing, while surgery and radiotherapy have improved outcomes.nnnMETHODSnIn this article, we discuss the biology of MBMs, briefly outline current treatment approaches, and emphasize novel and emerging therapies for MBMs.nnnRESULTSnThe mechanisms that underlie the metastases of melanoma to the brain are unknown; therefore, it is necessary to identify pathways to target MBMs. Most patients with MBMs have short survival times. Recent use of immune-based and targeted therapies has changed the natural history of metastatic melanoma and may be effective for the treatment of patients with MBMs.nnnCONCLUSIONSnDeveloping a better understanding of the factors responsible for MBMs will lead to improved management of this disease. In addition, determining the optimal treatments for MBMs and how they can be optimized or combined with other therapies, along with appropriate patient selection, are challenges for the management of this disease.

Increasing Back and Radicular Pain 2 Years Following Intrathecal Pump Implantation with Review of Arachnoiditis

BACKGROUNDnImplanted intrathecal drug delivery pumps are now regularly used for the treatment of chronic benign and cancer-related pain that is refractory to conservative treatment methods. In most cases, the pumps are successful at reducing the intensity of pain and improving function and quality of life for pain patients. Limited studies have discussed the complications associated with intrathecal pump placement.nnnSETTINGnAcademic tertiary care center.nnnSUMMARYnWe describe an unusual case of a patient who presented with progressive weakness and worsening lumbar and lower extremity pain following implantation of an intrathecal drug delivery system (IDDS). Work-up for the patients symptoms includes a magnetic resonance imaging, which revealed lumbar arachnoiditis. Patient underwent a laminectomy and detethering of spinal cord and nerve roots below level of catheter insertion. There was transient improvement in her pain and weakness. Subsequent surgery for pump explantation revealed a retained Touhy introducer needle from her pump placement procedure.nnnCONCLUSIONnThe entire IDDS was removed including the retained Touhy introducer needle. The patient later went on to receive a successful spinal cord stimulator trial and implantation with moderate relief of her chronic pain.

Role of motor-evoked potential monitoring in conjunction with temporary clipping of spinal nerve roots in posterior thoracic spine tumor surgery

BACKGROUND CONTEXTnThe vascular supply of the thoracic spinal cord depends on the thoracolumbar segmental arteries. Because of the small size and ventral course of these arteries in relation to the dorsal root ganglion and ventral root, they cannot be reliably identified during surgery by anatomic or morphologic criteria. Sacrificing them will most likely result in paraplegia.nnnPURPOSEnThe goal of this study was to evaluate a novel method of intraoperative testing of a nerve roots contribution to the blood supply of the thoracic spinal cord.nnnSTUDY DESIGN/SETTINGnThis is a clinical retrospective study of 49 patients diagnosed with thoracic spine tumors. Temporary nerve root clipping combined with motor-evoked potential (MEP) and somatosensory-evoked potential (SSEP) monitoring was performed; additionally, postoperative clinical evaluation was done and reported in all cases.nnnMETHODSnAll cases were monitored by SSEP and MEPs. The nerve root to be sacrificed was temporarily clipped using standard aneurysm clips, and SSEP/MEP were assessed before and after clipping. Four nerve roots were sacrificed in four cases, three nerve roots in eight cases, and two nerve roots in 22 cases. Nerve roots were sacrificed bilaterally in 12 cases.nnnRESULTSnMost patients (47/49) had no changes in MEP/SSEP and had no neurological deficit postoperatively. One case of a spinal sarcoma demonstrated changes in MEP after temporary clipping of the left T11 nerve root. The nerve was not sacrificed, and the patient was neurologically intact after surgery. In another case of a sarcoma, MEPs changed in the lower limbs after ligation of left T9 nerve root. It was felt that it was a global event because of anesthesia. Postoperatively, the patient had complete paraplegia but recovered almost completely after 6 months.nnnCONCLUSIONSnTemporary nerve root clipping combined with MEP and SSEP monitoring may enhance the impact of neuromonitoring in the intraoperative management of patients with thoracic spine tumors and favorably influence neurological outcome.

Presacral noncommunicating enteric duplication cyst

BackgroundGastrointestinal (GI) tract duplication cysts or enteric duplication cysts are rare congenital malformations sometimes found on the mesenteric aspect of segments of the alimentary tract. ...

Assessing Response of High-Grade Gliomas to Immune Checkpoint Inhibitors

BACKGROUNDnImmunotherapeutic agents, especially checkpoint inhibitors, have emerged as the mainstay of therapy for several solid and hematological malignancies. These therapies are under investigation for the treatment of high-grade gliomas and brain metastases.nnnMETHODSnThis article reviews the unique challenges encountered when evaluating changes on magnetic resonance imaging (MRI) of glioblastomas seen in response to immunotherapy and checkpoint inhibitors and how to effectively incorporate MRI findings into the response assessment of high-grade gliomas to these emerging therapies.nnnRESULTSnAn increase in tumor size or the appearance of new lesions on MRI may represent either an immune-mediated inflammatory response or true tumor progression, which may precede the subsequent stabilization or response of high-grade gliomas to immunotherapy. These MRI findings should not result in the mandatory cessation of immunotherapy in patients with high-grade glioma.nnnCONCLUSIONSnAlthough immunotherapy Response Assessment for Neuro-Oncology criteria have been developed to assist with response assessment of high-grade gliomas to immunotherapy and to provide guidance with treatment decisions, these criteria have not been validated in prospective clinical trials. In patients with brain tumors who are receiving immunotherapy, MRI findings suggestive of disease progression should be evaluated with caution to prevent premature discontinuation of potentially beneficial therapies. Close, clinical monitoring with appropriate short-term, follow-up imaging is often necessary, and histopathological analysis may be required in some cases to confirm disease progression before a decision on continuation of these novel therapies can accurately be made.