-
Alzheimer's Research & Therapy Sep 2021Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid...
BACKGROUNDS
Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies.
OBJECTIVES
We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs).
METHODS
We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 10 cells/2 mL), and six patients received a high dose (3.0 × 10 cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study.
RESULTS
After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed.
CONCLUSIONS
Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02054208. Registered on 4 February 2014. ClinicalTrials.gov NCT03172117. Registered on 1 June 2017.
Topics: Alzheimer Disease; Animals; Fetal Blood; Follow-Up Studies; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells
PubMed: 34521461
DOI: 10.1186/s13195-021-00897-2 -
The Lancet. Oncology May 2023Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated...
BACKGROUND
Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity.
METHODS
In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0-21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov, NCT01419067.
FINDINGS
Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39-13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28-8·53) for patients who did not have progression and 7·62 years (IQR 6·48-8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4-99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3-4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff.
INTERPRETATION
Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared.
FUNDING
American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness.
Topics: Child; Humans; Male; Adolescent; Female; United States; Craniopharyngioma; Proton Therapy; Endocrine System Diseases; Progression-Free Survival; Pituitary Neoplasms
PubMed: 37084748
DOI: 10.1016/S1470-2045(23)00146-8 -
Child's Nervous System : ChNS :... Jun 2021Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are debilitating tumors that account for 3-5% of all pediatric brain tumors. They are most commonly... (Review)
Review
BACKGROUND
Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are debilitating tumors that account for 3-5% of all pediatric brain tumors. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of these tumors results in visual loss and blindness, endocrine and hypothalamic dysfunction, hydrocephalus, and premature death. Their involvement of the visual pathways and proximity to other eloquent brain structures typically precludes complete resection or optimal radiation dosing without incurring significant neurological injury. There are various surgical interventions that can be performed in relation to these lesions including biopsy, cerebrospinal fluid diversion, and partial or radical resection, but their role is a source of debate. This study catalogues our surgical experience and patient outcomes in order to support decision-making in this challenging pathology.
METHODS
A retrospective review of all cases of OPGs treated in a single center from July 1990 to July 2020. Data was collected on patient demographics, radiographic findings, pathology, and management including surgical interventions. Outcome data included survival, visual function, endocrine, and hypothalamic dysfunction.
RESULTS
One hundred twenty-one patients with OPG were identified, and 50 of these patients underwent a total of 104 surgical procedures. These included biopsy (31), subtotal or gross total resection (20 operations in 17 patients), cyst drainage (17), Ommaya reservoir insertion (9), or cerebrospinal fluid diversion (27). During the study period, there was 6% overall mortality, 18% hypothalamic dysfunction, 20% endocrine dysfunction, and 42% had some cognitive dysfunction. At diagnosis 75% of patients had good or moderate visual function in at least one eye, and overall, this improved to 83% at the end of the study period. In comparison the worst eye had good or moderate visual function in 56%, and this reduced to 53%. Baseline and final visual function were poorer in patients who had a surgical resection, but improvements in vision were still found-particularly in the best eye.
DISCUSSION/CONCLUSION
OPG are debilitating childhood tumor that have lifelong consequences in terms of visual function and endocrinopathies/hypothalamic dysfunction; this can result in substantial patient morbidity. Decisions regarding management and the role of surgery in this condition are challenging and include cerebrospinal fluid diversion, biopsy, and in highly select cases cystic decompression or surgical resection. In this paper, we review our own experience, outcomes, and surgical philosophy.
Topics: Astrocytoma; Brain Neoplasms; Child; Humans; Neurofibromatosis 1; Neurosurgical Procedures; Optic Nerve Glioma; Retrospective Studies; Treatment Outcome
PubMed: 33532921
DOI: 10.1007/s00381-021-05060-8 -
Cureus Apr 2020Ommaya reservoir insertion is an elective neurosurgical procedure to deliver repeated intraventricular therapy, but placement can be complicated by malposition of the...
Ommaya reservoir insertion is an elective neurosurgical procedure to deliver repeated intraventricular therapy, but placement can be complicated by malposition of the catheter, clogging, infection or poor postoperative cosmesis. Here, we describe the technique used by the senior author for accurate placement including preassembly of the reservoir and catheter, and recessing of the reservoir so that others may consider the technique for their practice. Results in a consecutive series of 27 Ommaya placements were reviewed. Catheter tip placement accuracy, complications and surgical times were reported. Indications were leptomeningeal cancer or infection. Postoperative imaging showed the catheter tip was located in the frontal horn (96%) or body (4%) of the ipsilateral lateral ventricle. The median surgical time was 36 minutes (range 17-63 minutes). There were no parenchymal or subarachnoid hemorrhages. Infections occurred in 7% (n=2) of cases, and both infections presented greater than 60 days postoperative. In conclusion, we have found that image guidance can optimize accuracy in placement, that preassembly of the reservoir and catheter may be used with a 25-gauge spinal needle stylet to minimize risk of clogging during placement, and that recessing of the reservoir produces the best aesthetic result.
PubMed: 32432009
DOI: 10.7759/cureus.7731 -
Cancer Control : Journal of the Moffitt... Jan 2017Advancements in cancer treatment have led to more cases of leptomeningeal disease, which requires a multimodal approach. (Review)
Review
BACKGROUND
Advancements in cancer treatment have led to more cases of leptomeningeal disease, which requires a multimodal approach.
METHODS
Treatment modalities are reviewed from a neurosurgical standpoint, focusing on intrathecal chemotherapy and shunting devices. Potential complications and how to avoid them are discussed.
RESULTS
The Ommaya reservoir and the chemoport are used for administering intrathecal chemotherapy. Use of ventriculo-lumbar perfusion can efficiently deliver chemotherapeutic agents and improve intracerebral pressure. Shunting systems, in conjunction with all of their variations, address the challenge of hydrocephalus in leptomeningeal carcinomatosis. Misplaced catheters, malfunction of the system, and shunt-related infections are known complications of treatment.
CONCLUSIONS
From an oncological perspective, the surgical treatment for leptomeningeal disease is limited; however, neurosurgery can be used to aid in the administration of chemotherapy and address the issue of hydrocephalus. Minimizing surgical complications is important in this sensitive patient population.
Topics: Humans; Meningeal Neoplasms; Prognosis
PubMed: 28178712
DOI: 10.1177/107327481702400107 -
Neurology India 2021Endoscopic third ventriculostomy (ETV) has become a proven modality for treating obstructive and selected cases of communicating hydrocephalus. (Review)
Review
BACKGROUND
Endoscopic third ventriculostomy (ETV) has become a proven modality for treating obstructive and selected cases of communicating hydrocephalus.
OBJECTIVE
This review aims to summarize the indications, preoperative workup, surgical technique, results, postoperative care, complications, advantages, and limitations of an ETV.
MATERIALS AND METHODS
A thorough review of PubMed and Google Scholar was performed. This review is based on the relevant articles and authors' experience.
RESULTS
ETV is indicated in obstructive hydrocephalus and selected cases of communicating hydrocephalus. Studying preoperative imaging is critical, and a detailed assessment of interthalamic adhesions, the thickness of floor, arteries or membranes below the third ventricle floor, and prepontine cistern width is essential. Blunt perforation in a thin floor, while bipolar cautery at low settings and water jet dissection are preferred in a thick floor. The appearance of stoma pulsations and intraoperative ventriculostomography reassure stoma and basal cistern patency. The intraoperative decision for shunt, external ventricular drainage, or Ommaya reservoir can be taken. Magnetic resonance ventriculography and cine phase-contrast magnetic resonance imaging can determine stoma patency. Good postoperative care with repeated cerebrospinal fluid drainage enhances outcomes in selected cases. Though the complications mostly occur in an early postoperative phase, delayed lethal ones may happen. Watching live surgeries, assisting expert surgeons, and practicing on cadavers and models can shorten the learning curve.
CONCLUSION
ETV is an excellent technique for managing obstructive and selected cases of communicating hydrocephalus. Good case selection, methodical technique, and proper training under experts are vital.
Topics: Cerebral Ventricles; Humans; Hydrocephalus; Magnetic Resonance Imaging; Third Ventricle; Ventriculostomy
PubMed: 35103009
DOI: 10.4103/0028-3886.332253 -
Brain Pathology (Zurich, Switzerland) Nov 2016If cancer is hard to be treated, brain cancer is even more, caused by the inability of many effective drugs given systemically to cross the blood brain and blood tumor... (Review)
Review
If cancer is hard to be treated, brain cancer is even more, caused by the inability of many effective drugs given systemically to cross the blood brain and blood tumor barriers and reach adequate concentrations at the tumor sites. Effective delivery of drugs to brain cancer tissues is thus a necessary, albeit not sufficient, condition to effectively target the disease. In order to analyze the current status of research on drug delivery to high grade gliomas (HGG-WHO grades III and IV), the most frequent and aggressive brain cancers, a literature search was conducted in PubMed using the terms: "drug delivery and brain tumor" over the publication year 2015. Currently explored drug delivery techniques for HGG include the convection and permeabilization-enhanced deliveries, drug-releasing depots and Ommaya reservoirs. The efficacy/safety ratio widely varies among these techniques and the success of current efforts to increase this ratio widely varies as well.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Convection; Drug Delivery Systems; Glioma; Humans
PubMed: 27488680
DOI: 10.1111/bpa.12423 -
Paediatric Drugs Aug 2018Prophylactic eradication of central nervous system (CNS) leukaemia is the current standard of care in treating childhood acute lymphoblastic leukaemia (ALL). This is... (Review)
Review
Prophylactic eradication of central nervous system (CNS) leukaemia is the current standard of care in treating childhood acute lymphoblastic leukaemia (ALL). This is conventionally achieved through regular lumbar punctures with intrathecal injections of methotrexate into the cerebrospinal fluid (CSF). Ommaya reservoirs are subcutaneous implantable devices that provide a secure route of drug delivery into the CSF via an intraventricular catheter. They are an important alternative in cases where intrathecal injection via lumbar puncture is difficult. Among UK Paediatric Principal Treatment Centres for ALL we found considerable variation in methotrexate dosing when using an Ommaya reservoir. We review the current safety and theoretical considerations when using Ommaya reservoirs and evidence for methotrexate dose adjustments via this route. We conclude by summarising the pragmatic consensus decision to use 50% of the conventional intrathecal dose of methotrexate when it is administered via Ommaya reservoir in front-line ALL therapy.
Topics: Antineoplastic Agents; Catheters, Indwelling; Child, Preschool; Drug Delivery Systems; Humans; Infusions, Intraventricular; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 29850985
DOI: 10.1007/s40272-018-0298-9 -
Clinical Lung Cancer Mar 2023Leptomeningeal metastasis (LM) is a highly fatal and debilitating complication of lung adenocarcinoma (LUAD) with limited therapeutic options. This study aimed to...
Safety, Pharmacokinetic and Clinical Activity of Intrathecal Chemotherapy With Pemetrexed via the Ommaya Reservoir for Leptomeningeal Metastases From Lung Adenocarcinoma: A Prospective Phase I Study.
INTRODUCTION
Leptomeningeal metastasis (LM) is a highly fatal and debilitating complication of lung adenocarcinoma (LUAD) with limited therapeutic options. This study aimed to evaluate the efficacy and toxicities of intrathecal chemotherapy (IC) with pemetrexed via Ommaya reservoir in LUAD with refractory LM.
METHODS
In this prospective, single-arm, phase I trial (ChiCTR2000028936), LUAD-LM patients who had progressed after at least two prior treatments were recruited. Pemetrexed from 30 mg to 50 mg was administered on Days 1 and 8 every 3 weeks via Ommaya reservoir. Serial samples of cerebrospinal fluid (CSF) and plasma were obtained for pharmacokinetic studies. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and therapeutic toxicities.
RESULTS
Twenty-three patients were enrolled and analyzed, revealing an ORR of 43.5% (95% CI, 23.2%-63.8%) and DCR of 82.6% (95% CI, 61.2%-95.0%). The median PFS and OS were 6.3 and 9.5 months, respectively. Dose-limiting toxicity was only observed in 2 patients (2/23, 8.7%), and 30 mg pemetrexed was considered as the recommended dose for IC. Pharmacokinetic analysis showed that using Ommaya reservoirs, higher pemetrexed concentrations and prolonged half-lives were achieved in the CSF compared with lumbar puncture (LP).
CONCLUSIONS
Intrathecal pemetrexed at a dose of 30 mg via Ommaya reservoirs on Days 1 and 8 every 21 days achieved promising disease control and satisfactory survival with moderate toxicities in resistant LUAD-LM, providing a feasible and effective option, especially for the patients who cannot tolerate LP.
Topics: Humans; Pemetrexed; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Prospective Studies; Adenocarcinoma of Lung; Meningeal Carcinomatosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36588048
DOI: 10.1016/j.cllc.2022.11.011