Case report: Stem cell-based suicide gene therapy mediated by the herpes simplex virus thymidine kinase gene reduces tumor progression in multifocal glioblastoma.

Introduction: The prognosis for glioblastoma multiforme (GBM), a malignant brain tumor, is poor despite recent advancements in treatments. Suicide gene therapy is a therapeutic strategy for cancer that requires a gene to encode a prodrug-activating enzyme which is then transduced into a vector, such as mesenchymal stem cells (MSCs). The vector is then injected into the tumor tissue and exerts its antitumor effects. Case presentation: A 37-year-old man presented to our department with two evident foci of glioblastoma multiforme at the left frontal and left parietal lobes. The patient received an injection of bone marrow-derived MSCs delivering the herpes simplex virus thymidine kinase (HSV-tk) gene to the frontal focus of the tumor, followed by ganciclovir administration as a prodrug for 14 days. For follow-up, the patient was periodically assessed using magnetic resonance imaging (MRI). The growth and recurrence patterns of the foci were assessed. After the injection on 09 February 2019, the patient's follow-up appointment on 19 December 2019 MRI revealed a recurrence of parietal focus. However, the frontal focus had a slight and unremarkable enhancement. On the last follow-up (18 March 2020), the left frontal focus had no prominent recurrence; however, the size of the left parietal focus increased and extended to the contralateral hemisphere through the corpus callosum. Eventually, the patient passed away on 16 July 2020 (progression-free survival (PFS) = 293 days, overall survival (OS) = 513 days). Conclusion: The gliomatous focus (frontal) treated with bone marrow-derived MSCs carrying the HSV-TK gene had a different pattern of growth and recurrence compared with the non-treated one (parietal). Trial registration: IRCT20200502047277N2. Registered 10 May 2020-Retrospectively registered, https://eng.irct.ir/trial/48110.

Combining cell therapy with human autologous Schwann cell and bone marrow-derived mesenchymal stem cell in patients with subacute complete spinal cord injury: safety considerations and possible outcomes.

BACKGROUND: Cellular transplantations have promising effects on treating spinal cord injury (SCI) patients. Mesenchymal stem cells (MSCs) and Schwann cells (SCs), which have safety alongside their complementary characteristics, are suggested to be the two of the best candidates in SCI treatment. In this study, we assessed the safety and possible outcomes of intrathecal co-transplantation of autologous bone marrow MSC and SC in patients with subacute traumatic complete SCI. METHODS: Eleven patients with complete SCI (American Spinal Injury Association Impairment Scale (AIS); grade A) were enrolled in this study during the subacute period of injury. The patients received an intrathecal autologous combination of MSC and SC and were followed up for 12 months. We assessed the neurological changes by the American Spinal Injury Association's (ASIA) sensory-motor scale, functional recovery by spinal cord independence measure (SCIM-III), and subjective changes along with adverse events (AE) with our checklist. Furthermore, electromyography (EMG), nerve conduction velocity (NCV), magnetic resonance imaging (MRI), and urodynamic study (UDS) were conducted for all the patients at the baseline, 6 months, and 1 year after the intervention. RESULTS: Light touch AIS score alterations were approximately the same as the pinprick changes (11.6 ± 13.1 and 12 ± 13, respectively) in 50% of the cervical and 63% of the lumbar-thoracic patients, and both were more than the motor score alterations (9.5 ± 3.3 in 75% of the cervical and 14% of the lumbar-thoracic patients). SCIM III total scores (21.2 ± 13.3) and all its sub-scores ("respiration and sphincter management" (15 ± 9.9), "mobility" (9.5 ± 13.3), and "self-care" (6 ± 1.4)) had statistically significant changes after cell injection. Our findings support that the most remarkable positive, subjective improvements were in trunk movement, equilibrium in standing/sitting position, the sensation of the bladder and rectal filling, and the ability of voluntary voiding. Our safety evaluation revealed no systemic complications, and radiological images showed no neoplastic overgrowth, syringomyelia, or pseudo-meningocele. CONCLUSION: The present study showed that autologous SC and bone marrow-derived MSC transplantation at the subacute stage of SCI could reveal statistically significant improvement in sensory and neurological functions among the patients. It appears that using this combination of cells is safe and effective for clinical application to spinal cord regeneration during the subacute period.

Intracerebral Administration of Autologous Mesenchymal Stem Cells as HSV-TK Gene Vehicle for Treatment of Glioblastoma Multiform: Safety and Feasibility Assessment.

Widespread investigation has revealed the promising ability of suicidal genes in the treatment of glioma tumors; nevertheless, promoting their effects relies on the ability to apply suitable vehicles and techniques. In this study, the safety and feasibility of using bone marrow-derived mesenchymal stem cells (MSCs) in combination with prodrug for treatment of patients with primary and secondary glioblastoma multiform (GBM) was assessed. Five GBM patients were recruited. Following gross total resection of the tumor and adjuvant radiotherapy and chemotherapy, intracerebral injection of autologous MSCs transduced with lentivirus containing herpes simplex virus thymidine kinase (HSV-TK) was performed followed by intravenous administration of ganciclovir for 2 weeks. The treatment was well tolerated by all patients. Mild-to-moderate fever, headache, and cerebrospinal fluid leukocytosis were evident in three, two, and one patient, respectively. The progression-free survival (PFS) and overall survival (OS) of patients were 95.79 ± 51.40 and 128.85 ± 48.81 weeks, respectively. The 1-year PFS and OS were 60% and 100%, respectively, among our patients, and two patients had more than 3 years of OS and more than 2 years of PFS. It seems that intracerebral administration of bone marrow MSC containing the HSV-TK gene in combination with intravenous ganciclovir would be safe and feasible in the treatment of patients with GBM.

Cauda equina syndrome due to herpes simplex virus type 2-associated meningoradiculitis (Elsberg syndrome) after posterior lumbar spinal fusion surgery: Case report and review of literature.

Elsberg syndrome is a rare but well-defined clinical condition, including acute or subacute lumbosacral meningoradiculitis, which might be accompanied by myelitis and is often associated with herpes simplex virus type 2 (HSV-2) infection. We report the case of an immunocompetent 24-year-old man who presented with perineal pain, saddle hypoesthesia, and urinary retention associated with Elsberg syndrome due to HSV-2 infection 20-day after the posterior lumbar spinal fusion surgery. Lumbar magnetic resonance imaging (MRI) with gadolinium enhancement showed mildly enhanced and swollen right sacral nerve roots. One week after the admission, electromyography and nerve conduction studies (EMG-NCS) demonstrated severe axonal damage and radiculopathy at right S3 and S4 roots. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, elevated protein, positive HSV-2 IgG index, and positive HSV-2 polymerase chain reaction (PCR). The patient was treated with intravenous acyclovir for 14 days and showed a gradual improvement in anal sphincter control and urination. Therefore, according to our findings, surgery might have an immunosuppressing role, and in cases with symptoms of cauda equina syndrome (CES) and systemic infection, in the postoperative setting, viral meningoradiculitis should be considered.

Effect of Protein Supplement on Paraspinal Muscles in Spine Fusion Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Dysfunction and weakness due to atrophy of the paraspinal muscles is a major issue after posterior spinal fusion (PSF) surgery, resulting in pain and disability. Considering the role of protein in muscle regeneration, it seems that protein supplements after surgery may prevent muscle atrophy. To date, to our knowledge, no intervention study has investigated the effect of protein supplementation on the volume of paraspinal muscles, pain, or disability after PSF. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, patients were randomly assigned to a control (placebo + diet with 1.2 g/kg body weight of protein, n = 40) or a protein supplementation (36 g/day + a diet with 1.2 g/kg body weight of protein, n = 40) group, which received intervention from 48 hours before to 1 month after surgery. The cross-sectional area (CSA) of the paraspinal muscles was measured by thin-slice computed tomography, and pain and disability were assessed using the visual analog scale and Oswestry Disability Index. RESULTS: After 4 weeks of protein supplementation, the CSAs of multifidus and psoas muscles on both sides were significantly higher in the supplementation group than the placebo group (P <.001). Less atrophy was seen in the right erector spinae and quadratus lumborum muscles in the group receiving protein supplements than the placebo group (P < .001). In addition, protein supplementation was significantly negatively correlated with both pain (P < .001) and disability (P < .001). CONCLUSIONS: In conclusion, we demonstrated that 36 g/day protein supplementation significantly increased the CSA of muscles and reduced the atrophy, pain, and disability after PSF surgery. LEVEL OF EVIDENCE: 2.

Covering of Plate after Anterior Cervical Fusion in Patients with Complete Spinal Cord Injury to Prevent Esophageal Injury: Technical Note.

BACKGROUND: Esophageal injury after anterior corpectomy and fusion is a rare but life-threatening complication. It may cause mediastinitis due to anatomical continuity between the retropharyngeal space and the mediastinum, with reported high mortality rates. The acute and subacute injuries are most commonly of iatrogenic origin, while late perforation has been described several weeks to years later as a result of continuous friction or pressure of the instruments against the posterior wall of the esophagus, leading to ischemia and necrosis. This phenomenon is more common among quadriplegic patients who have undergone corpectomy and insertion of expandable or mesh cages and plate probably due to chronic erosion by hardware at the supine position. METHODS: Since 2015, we have applied the technique of using a patch of autologous fascia lata to cover the anterior cervical plate by suturing to the longus colli muscles in 58 quadriplegic patients; the mean follow-up was 35.2 (28-41) months. RESULTS: Since we started using this procedure, based on our follow-up at our center, there have been no cases of late esophageal perforation among quadriplegic patients. CONCLUSION: As a technical note, it seems like this method would be able to reduce the prevalence of esophagus injury among quadriplegic patients. However, to substantiate the efficacy of this technique, long-term follow-up and larger sample size are needed because esophageal injury occurs rarely.