Suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cell gene delivery vehicles in recurrent glioblastoma multiforme: a first-in-human, dose-escalation, phase I clinical trial.

BACKGROUND: Glioblastoma multiforme (GBM) is associated with remarkably poor prognosis, and its treatment is challenging. This investigation aimed to evaluate the safety of suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cells (ADSCs) carrying herpes simplex virus-thymidine kinase (HSV-TK) gene for the first time in patients with recurrent GBM. METHODS: This study was a first-in-human, open-label, single-arm, phase I clinical trial with a classic 3 + 3 dose escalation design. Patients who did not undergo surgery for their recurrence were included and received this gene therapy protocol. Patients received the intratumoral stereotactic injection of ADSCs according to the assigned dose followed by prodrug administration for 14 days. The first dosing cohort (n = 3) received 2.5 × 105 ADSCs; the second dosing cohort (n = 3) received 5 × 105 ADSCs; the third dosing cohort (n = 6) received 10 × 105 ADSCs. The primary outcome measure was the safety profile of the intervention. RESULTS: A total of 12 patients with recurrent GBM were recruited. The median follow-up was 16 (IQR, 14-18.5) months. This gene therapy protocol was safe and well tolerated. During the study period, eleven (91.7%) patients showed tumor progression, and nine (75.0%) died. The median overall survival (OS) was 16.0 months (95% CI 14.3-17.7) and the median progression-free survival (PFS) was 11.0 months (95% CI 8.3-13.7). A total of 8 and 4 patients showed partial response and stable disease, respectively. Moreover, significant changes were observed in volumetric analysis, peripheral blood cell counts, and cytokine profile. CONCLUSIONS: The present clinical trial, for the first time, showed that suicide gene therapy using allogeneic ADSCs carrying the HSV-TK gene is safe in patients with recurrent GBM. Future phase II/III clinical trials with multiple arms are warranted to validate our findings and further investigate the efficacy of this protocol compared with standard therapy alone. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20200502047277N2. Registered 8 October 2020, https://www.irct.ir/ .

Safety and feasibility of autologous olfactory ensheathing cell and bone marrow mesenchymal stem cell co-transplantation in chronic human spinal cord injury: a clinical trial.

STUDY DESIGN: This is a phase I clinical trial. OBJECTIVES: Our objective was to assess the safety and feasibility of autologous mucosal olfactory ensheathing cell (OEC) and bone marrow mesenchymal stem cell (MSC) co-transplantation in people with chronic, complete (American Spinal Injury Association (ASIA) Impairment Scale (AIS) classification A) spinal cord injury (SCI). SETTING: This study was performed at Shohada Tajrish Hospital, Tehran, Iran. METHODS: Three individuals with the traumatic SCI of the thoracic level were enrolled. They received the autologous OEC and MSC combination through the lumbar puncture. All adverse events and possible functional outcomes were documented performing pre- and post-operative general clinical examination, magnetic resonance imaging (MRI), neurological assessment based on the International Standard of Neurological Classification for SCI, and functional evaluation using Spinal Cord Independence Measure version III (SCIM III). RESULTS: No serious safety issue was recorded during the 2 years of follow-up. MRI findings remained unchanged with no neoplastic tissue formation. AIS improved from A to B in one of the participants. SCIM III evaluation also showed some degrees of progress in this participant's functional ability. The two other research participants had negligible or no improvement in their sensory scores without any changes in the AIS and SCIM III scores. No motor recovery was observed in any of the participants. CONCLUSIONS: Overall, this 2-year trial was not associated with any adverse findings, which may suggest the safety of autologous OEC and bone marrow MSC combination for the treatment of human SCI.

Changed pattern of hospital admission in stroke during COVID-19 pandemic period in Iran: a retrospective study.

BACKGROUND: Some previous reports have shown a reduced number of admission in stroke cases during the coronavirus disease 2019 (COVID-19) pandemic period. The present study aimed to investigate this changing pattern and the potential causes behind it at an academic neurology and neurosurgery center in Iran. METHODS: Patients admitted to our center with the diagnosis of ischemic and hemorrhagic stroke, between March 1, 2019, Jun 1, 2019, and the similar 3-month period in 2020 (COVID-19 pandemic period), were compared in terms of clinical characteristics and outcome. Poisson regression was also conducted to assess the correlation between daily admissions and the COVID-19 pandemic period. RESULTS: A total of 210 patients with stroke (ischemic and hemorrhagic) in 2019 were compared with 106 patients in 2020. COVID-19 pandemic period was significantly associated with the decline in the number of daily admissions in ischemic stroke (IRR, 0.51 [95% CI, 0.4-0.64]). A significant reduction (P = 0.003) in time from onset to arrival at hospital from median 12 h [IQR, 5-32] in 2019 to median 6 h [IQR, 4-16] in 2020 was found in ischemic stroke cases. National Institute of Health Stroke Scale (NIHSS) was significantly increased (P < 0.001) from median 4 [IQR, 2-7] in 2019 to median 9 [IQR, 4-14] in 2020. Glasgow coma scale (GCS) was significantly decreased from 13.9 (SD, 2) in 2019 to 12.8 (SD, 2.9) in 2020 (P < 0.001). CONCLUSIONS: The present study provided new pieces of evidence regarding the changed pattern of hospital admission in stroke especially the possible reasons for its decline.

Grafted human chorionic stem cells restore motor function and preclude cerebellar neurodegeneration in rat model of cerebellar ataxia.

Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. Cell replacement therapy (CRT) has been considered as a potential treatment for neurological disorders. In this report, we investigated the neuro-restorative effects of human chorionic stem cells (HCSCs) transplantation on rat model of CA induced by 3-acetylpyridine (3-AP). In this regard, HCSCs were isolated and phenotypically determined. Next, a single injection of 3-AP was administered for ataxia induction, and bilateral HCSCs implantation was conducted 3 days after 3-AP injection, followed by expression analysis of a number of apoptotic, autophagic and inflammatory genes as well as vascular endothelial growth factor (VEGF) level, along with assessment of cerebellar neurodegeneration, motor coordination and muscle activity. The findings revealed that grafting of HCSCs in 3-AP model of ataxia decreased the expression levels of several inflammatory, autophagic and apoptotic genes and provoked the up-regulation of VEGF in the cerebellar region, prevented the degeneration of Purkinje cells caused by 3-AP toxicity and ameliorated motor coordination and muscle function. In conclusion, these data indicate in vivo efficacy of HCSCs in the reestablishment of motor skills and reversal of CA.

Evaluating the Effects of Time From Brain Death and Type of Inotrope Usage on Result of Heart Transplant: Results of 1-Year Follow-Up.

OBJECTIVES: Heart transplant is the most effective treatment in patients with advanced heart failure who are refractory to medical treatment. The brain death interval and type of inotrope We assessed the effects of these parameters on heart transplant outcomes. MATERIALS AND METHODS: In this follow-up study, we followed heart transplant recipients for 1 year to study patient survival, ejection fraction, adverse events, and organ rejection. We evaluated follow-up results on time from brainstem death test to the cross-clamp placement, as well as the type of inotrope used. RESULTS: Our study enrolled 54 heart transplant candidates. The inotrope dose was 3.66 ± 0.99 µg/kg/min, and the most used inotrope, with 28 cases (51.9%), was related to dopamine. Six cases (11.1%) of death and 1 case of infection after transplant were observed in recipients. The average ejection fraction of transplanted hearts before transplant, instantly at time of transplant, and 1 month, 6 months, and 1 year after transplant was 54.9 ± 0.68, 52.9 ± 10.4, 51.9 ± 10.7, 50.1 ± 10.9, and 46.8 ± 17, respectively; this decreasing trend over time was significant (P =.001). Furthermore, ejection fraction changes following transplant did not differ significantly in transplanted hearts regarding brain death interval and type of inotrope used. CONCLUSIONS: Our study revealed that cardiac output of a transplanted heart may decrease over time and the time elapsed from brain death, and both dopamine and norepinephrine could have negligible effects on cardiac function.

Epidemiology of malignant gliomas in Iran: first report of Iranian National Population-based Cancer Registry, 2009-2017.

OBJECTIVE: Malignant gliomas constitute the most common type of primary malignant brain tumors. Most previous studies have evaluated the epidemiology of malignant gliomas in developed countries. Hence, there is a lack of evidence in this regard from developing countries. This study is the first epidemiological report on the status of malignant glioma in Iran between 2009 and 2017. METHODS: Data from the Iranian National Population-based Cancer Registry (covering 98% of the Iranian population) on CNS tumors recorded from 2009 to 2017 were used for analysis. Age-adjusted incidence rates were calculated by sex, tumor histology, tumor site, and year of diagnosis. Trend analysis of incidence rates was also performed. Survival data were recorded and the Cox proportional hazards model was used to evaluate underlying risk factors. RESULTS: A total of 8484 patients were diagnosed with malignant glioma between 2009 and 2017 in Iran. The overall age-adjusted incidence rate of malignant gliomas over the 9-year period was 1.71 per 100,000 persons. The most common histology of malignant gliomas was glioblastoma (81.4%). A significant increase in the incidence of malignant gliomas was found between 2009 and 2012. The median overall survival was 13.0 (95% CI 12.6-13.5) months over the study period. Older age groups, higher tumor grade, male sex, the first half of the study period, and receiving no treatment were significantly associated with worse prognoses. CONCLUSIONS: This study is the latest epidemiological report on the status of malignant gliomas in Iran. Although the overall incidence rate was lower than the rates in developed countries, several findings were consistent with those in prior reports.

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.

First Successful Human Coronary Artery Bypass Surgery Postoperative Heart Transplant: A Case Report.

Heart transplant is now the treatment of choice for patients with advanced heart failure who are refractory to medical treatment. With a small number of candidates who meet the traditional criteria of a heart donor, we aimed to alleviate this shortage. In this article, we report a 43-year-old woman with a highly urgent heart requirement, according to acute decompensated heart failure, who received a heart with coronary artery grafts from a 50-year-old woman with the diagnosis of 3-vessel disease. Our review of her 1-year follow-up demonstrated the absence of any cardiac or other problems and survival of the patient. There have been no reports in the relevant literature of transplanting marginal hearts from donors who have previously undergone coronary artery bypass graft before transplant. According to our findings, transplant of a marginal heart with coronary artery grafts can be successful; additional studies with larger samples are warranted to further investigate the results of transplanting marginal hearts from donors who have previously undergone coronary artery bypass graft procedures.

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.

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.