Navid Redjal

Stem Cells Loaded With Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy

BACKGROUND The current treatment regimen for malignant glioblastoma multiforme (GBM) is tumor resection followed by chemotherapy and radiation therapy. Despite the proven safety of oncolytic herpes simplex virus (oHSV) in clinical trials for GBMs, its efficacy is suboptimal mainly because of insufficient viral spread after tumor resection. METHODS Human mesenchymal stem cells (MSC) were loaded with oHSV (MSC-oHSV), and their fate was explored by real-time imaging in vitro and in vivo. Using novel diagnostic and armed oHSV mutants and real-time multimodality imaging, the efficacy of MSC-oHSV and its proapoptotic variant, oHSV-TRAIL encapsulated in biocompatible synthetic extracellular matrix (sECM), was tested in different mouse GBM models, which more accurately reflect the current clinical settings of malignant, resistant, and resected tumors. All statistical tests were two-sided. RESULTS MSC-oHSVs effectively produce oHSV progeny, which results in killing of GBMs in vitro and in vivo mediated by a dynamic process of oHSV infection and tumor destruction. sECM-encapsulated MSC-oHSVs result in statistically significant increased anti-GBM efficacy compared with direct injection of purified oHSV in a preclinical model of GBM resection, resulting in prolonged median survival in mice (P < .001 with Gehan-Breslow-Wilcoxin test). To supersede resistant tumors, MSC loaded with oHSV-TRAIL effectively induce apoptosis-mediated killing and prolonged median survival in mice bearing oHSV- and TRAIL-resistant GBM in vitro (P < .001 with χ(2) contingency test). CONCLUSIONS Human MSC loaded with different oHSV variants provide a platform to translate oncolytic virus therapies to clinics in a broad spectrum of GBMs after resection and could also have direct implications in different cancer types.

Trends in Peptic Ulcer Disease and the Identification of Helicobacter Pylori as a Causative Organism: Population-based Estimates from the US Nationwide Inpatient Sample.

Background: Peptic ulcer disease can lead to serious complications including massive hemorrhage or bowel perforation. The modern treatment of peptic ulcer disease has transitioned from the control of gastric acid secretion to include antibiotic therapy in light of the identification of Helicobacter pylori as a causative infectious organism. We sought to determine trends related to this discovery by using a national database. Materials and Methods: Patient discharges with peptic ulcer disease and associated sequelae were queried from the Nationwide Inpatient Sample, 1993 to 2007, under the auspices of a data user agreement. To account for the Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used. Standard error was calculated using SUDAAN software (Research Triangle International, NC, USA). Results: Decreases in the incidences of gastrointestinal perforation, gastrointestinal hemorrhage, and surgical procedures most specific to peptic ulcer disease were statistically significant over the study period [range of P value (two tailed) = 0.000 – 0.00353; significant at P < 0.001 to < 0.01]. The incidence of H. pylori rose dramatically, peaking at an estimated 97,823 cases in 1998 [SE = 3155; 95% CI = 6,184]. Since that time it has decreased and then stabilized. Conclusions: The identification of H. pylori as the causative agent in the majority of peptic ulcer disease has revolutionized the understanding and management of the disease. Medical conditions and surgical procedures associated with end-stage peptic ulcer disease have significantly decreased according to analysis of selected index categories. Resident physician education objectives may need to be modified in light of these trends. Review Criteria: We reviewed patients with peptic ulcer disease. The database used was the Nationwide Inpatient Sample, 1993 to 2007. Message for the Clinic: Medical therapy has resulted in decreased morbidity from H. pylori infection as it is the causative agent in the majority of peptic ulcer disease. Aggressive screening and treatment of this infection will lead to further reduction in morbidity.

Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline

Target populationThese recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma).Pathology at recurrenceQuestionDo pathologic and molecular characteristics predict outcome/malignant transformation at recurrence?RecommendationsIDH status and recurrence(Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival.TP53 status and recurrence(Level III)TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis.MGMT status and recurrence(Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylationThe available retrospective reports are conflicting and comparisons between reports are limitedCDK2NA status and recurrence(Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs.Proliferative index and recurrence(Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival.1p/19q status and recurrenceThere is insufficient evidence to make any recommendations.Chemotherapy at recurrenceQuestionWhat role does chemotherapy have in LGG recurrence?RecommendationsTemozolomide and recurrence(Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit.PCV and recurrence(Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas.Carboplatin and recurrence(Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs.Other treatments (Nitrosureas, Hydroxyurea/Imanitib, irinotecan, paclitaxel) and recurrenceThere is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents.Radiation at recurrenceQuestionWhat role does radiation have in LGG recurrence?RecommendationsRadiation at recurrence with no previous irradiation(Level III) Radiation is recommended at recurrence if there was no previous radiation treatment.Re-irradiation at recurrence(Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control.Surgery at recurrenceThere is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence.

Combination of Systemic Chemotherapy with Local Stem Cell Delivered S-TRAIL in Resected Brain Tumors

Despite advances in standard therapies, the survival of glioblastoma multiforme (GBM) patients has not improved. Limitations to successful translation of new therapies include poor delivery of systemic therapies and use of simplified preclinical models which fail to reflect the clinical complexity of GBMs. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) induces apoptosis specifically in tumor cells and we have tested its efficacy by on‐site delivery via engineered stem cells (SC) in mouse models of GBM that mimic the clinical scenario of tumor aggressiveness and resection. However, about half of tumor lines are resistant to TRAIL and overcoming TRAIL‐resistance in GBM by combining therapeutic agents that are currently in clinical trials with SC‐TRAIL and understanding the molecular dynamics of these combination therapies are critical to the broad use of TRAIL as a therapeutic agent in clinics. In this study, we screened clinically relevant chemotherapeutic agents for their ability to sensitize resistant GBM cell lines to TRAIL induced apoptosis. We show that low dose cisplatin increases surface receptor expression of death receptor 4/5 post G2 cycle arrest and sensitizes GBM cells to TRAIL induced apoptosis. In vivo, using an intracranial resection model of resistant primary human‐derived GBM and real‐time optical imaging, we show that a low dose of cisplatin in combination with synthetic extracellular matrix encapsulated SC‐TRAIL significantly decreases tumor regrowth and increases survival in mice bearing GBM. This study has the potential to help expedite effective translation of local stem cell‐based delivery of TRAIL into the clinical setting to target a broad spectrum of GBMs. Stem Cells 2015;33:101–110

Trends in inpatient setting laminectomy for excision of herniated intervertebral disc: Population-based estimates from the US nationwide inpatient sample.

Background: Herniated intervertebral discs can result in pain and neurological compromise. Treatment for this condition is categorized as surgical or non-surgical. We sought to identify trends in inpatient surgical management of herniated intervertebral discs using a national database. Methods: Patient discharges identified with a principal procedure relating to laminectomy for excision of herniated intervertebral disc were selected from the Nationwide Inpatient Sample (Healthcare Cost and Utilization Project - Agency for Healthcare Research and Quality, Rockville, MD), under the auspices of a data user agreement. These surgical patients did not undergo instrumented fusion. To account for the Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used. The estimates of standard errors were calculated using SUDAAN software (Research Triangle International, NC, USA). This software is based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM); a uniform and standardized coding system. Results: Using International Classification of Disease 9th Revision clinical modifier (ICD-9 CM) procedure code 80.51, we were able to identify disc excision, in part or whole, by laminotomy or hemilaminectomy. The incidence of laminectomy for the excision of herniated intervertebral disc has decreased dramatically from 1993 where 266,152 cases were reported [CI = 22,342]. In 2007, only 123,398 cases were identified [CI = 12,438]. The average length of stay in 1993 was 4 days [CI = 0.17], and in 2007 it decreased to just 2 days [CI = 0.17]. Both these comparisons were significantly different at P < 0.001. The average inflation adjusted (2007 buying power) charge of the procedure in 1993 was 14,790.87 USD [CI = 916.85]. This value rose in 2007 to 24,639 USD [CI = 1,485.51]. This difference was significant at P < 0.001. Conclusions: National estimates indicate that the incidence of inpatient laminectomy for the excision of herniated intervertebral disc has decreased significantly. This trend is multifactorial and is likely related to developments in outcomes research, the growing popularity of alternative procedures (intervertebral instrumented fusion), and transition to an ambulatory setting of surgical care.

Cerebrospinal fluid fistula prevention and treatment following frontal sinus fractures: a review of initial management and outcomes

Frontal sinus fractures are heterogeneous, and management of these fractures is often modified based on injury pattern and institutional experience. The optimal initial treatment of frontal sinus fractures is controversial. Treatment strategies are aimed at correcting cosmetic deformity, as well as at preventing delayed complications, including CSF fistulas, mucocele formation, and infection. Existing treatment options include observation, reconstruction, obliteration, cranialization, or a combination thereof. Modalities for treatment encompass both open surgical approaches and endoscopic techniques. In the absence of Class I data, the authors review the existing literature related to treatment strategies of frontal sinus fractures, particularly as they relate to CSF fistulas, to provide recommendations based on the best available evidence.

A novel translaminar crossover approach for pathologies in the lumbar hidden zone.

We report eight patients with disc herniations who underwent sequestrectomy via a crossover translaminar technique. The lateral lumbar spinal canal can be divided into several regions: the subarticular, foraminal and extraforaminal zone. Due to its difficult surgical exposure, some authors refer to part of the subarticular and foraminal region as the hidden zone. Conventional approaches involve partial or total facet joint resection, introducing risk of postoperative instability. Under fluoroscopic guidance, a high speed drill was used to create a small, angled fenestration at the base of the spinous process aimed at the contralateral hidden zone. The nerve root was visualized and disc fragments were removed without facet joint violation. Patients were registered in the International Spine Registry, Spine Tango. Numeric rating scale (NRS), Oswestry disability index (ODI) and core outcome measures index (COMI) were used to evaluate outcome after 6 weeks and 3 months. Outcome was further statistically matched with the Spine Tango pool of patients who underwent sequestrectomy via conventional techniques. Postoperative CT scans showed the translaminar crossover approach with the preserved facet joints. There was significant postoperative improvement of NRS scores and ODI at all follow-up intervals. COMI achieved significant improvement at 3 months. Statistical comparison with Spine Tango data confirmed that the translaminar crossover approach matches the clinical results of the conventional techniques. This series is a proof of principle for a successful translaminar crossover approach to the lumbar hidden zone. The outcome is not inferior to conventional inter- and translaminar routes and the technique potentially offers risk reduction for postoperative instability by preserving facet joint function, especially in the case of recurrent disease.

Adult acute calcific discitis confined to the nucleus pulposus in the cervical spine: case report.

Acute calcific discitis is a rare condition in the pediatric population and has been reported in only 2 instances in the adult population. This report describes a case of acute calcific discitis that uniquely presented in the adult cervical spine. A 22-year-old woman presented with the chief complaint of sudden-onset neck pain. Nonsurgical management, including nonsteroidal antiinflammatory drugs, provided moderate symptom relief. Radiography revealed nucleus pulposus calcification at the C2-3 level. Contrast-enhanced MRI did not reveal any additional abnormalities. Further nonsurgical management, including physical therapy and nonsteroidal antiinflammatory drugs, led to complete symptom relief within 6 months. Follow-up imaging demonstrated that the calcification had nearly resolved. Acute calcific discitis should be managed conservatively; the prognosis for a complete recovery is excellent. The pathophysiology of the disorder is yet to be elucidated, and the disorder is not exclusive to the pediatric population.

Pathological mechanism of lumbar disc herniation resulting in neurogenic muscle hypertrophy

We present a 33-year-old man with 5-year history of low back pain who presented with an enlarging right calf. The patient underwent an extensive workup including biopsy without diagnosis. The patients examination was significant for diminished pinprick sensation in the right L5/S1 dermatome. Reflexes were absent in the right ankle. The circumference of the right calf (58 cm) was twice that of the left. MRI revealed a herniated lumbar disc at the L5/S1 level. He then underwent a L5/S1 microdiscectomy. Following this surgery, the patient noted complete resolution of all sensory deficits in his lower extremity. His calf circumference had decreased by 5 cm at 4 months and by a total of 8 cm at his 2-year post-operative visit. Histological examination of the affected muscle demonstrated severe grouped atrophy of both type I and type II fibers. There was also evidence of compensatory fiber hypertrophy as well as fiber splitting. We concluded that the patient suffered from a herniated lumbar disc causing radiculopathy with calf hypertrophy (neurogenic hypertrophy). To our knowledge this is the first report of both grouped atrophy and compensatory hypertrophy of both muscle fiber types seen in this phenomenon.

Determinants of initial bone graft volume loss in posterolateral lumbar fusion

Bone graft volume decreases postoperatively without known etiology. We sought to determine the bone graft volume over time in 15 consecutive patients undergoing a single-level, instrumented, posterolateral lumbar fusion for degeneration causing mechanical pain or spondylolisthesis, and to identify factors associated with bone graft resorption. Following Institutional Review Board approval, a retrospective analysis was performed. Immediate and 3-month postoperative lumbar spine CT scans were imported into imaging software for volumetric analysis. We found that the 15 patients averaged approximately 11% graft volume loss at 3 months postoperatively. All patients exhibited volumetric graft loss on each side (range, 0.3-45%). A paired t-test revealed that immediate postoperative graft volume on a patients left or right did not reflect graft volume on that side 3 months postoperatively (p=0.0008). Gender, age, history of prior operation, history of regular exercise, body mass index, level fused, operative time, initial graft volume, and laterality did not influence percentage volumetric loss (p=0.1-0.5). Interestingly, people who smoked cigarettes (range, 10-40 pack-years) exhibited 27% graft loss, compared to 7% in those who did not (Spearman p=0.009 graft loss versus pack-years smoked). We concluded that bone graft exhibited resorption 3 months postoperatively on both sides of all patients in this series, and that smoking was significantly associated with increased bone graft resorption.