What is the thalamus? The thalamus, also known as the dorsal thalamus, is the largest oval cluster of gray matter nuclei in the mesencephalon, located on either side of the third ventricle, with the left and right thalamus connected by a gray matter mass (called the middle block). With its deep location and proximity to functional areas with many important nuclei clusters, as well as its own and surrounding structures being important and complex, surgery in the thalamic location has a high risk of limb paralysis and sensory impairment. Due to the deep location and adjacent to important functional areas, surgical resection of thalamic tumors has been a difficult problem in neurosurgery.
The new treatment protocols in Europe, the United States, and China all point out that surgery is the preferred and basic treatment option for brain tumors, and that the best suitable surgical approach should be sought to guarantee the first total surgical resection. The greater the resection rate, while protecting the surrounding normal brain tissue, the higher the likelihood of long-term patient survival. This is also true for glioblastoma, and many studies have confirmed the importance of maximal surgical resection in the treatment of glioblastoma; however, maximal resection of thalamic glioblastoma has been rarely attempted, and its role remains unclear. In the traditional treatment of thalamic glioblastoma, biopsies are often performed to confirm the pathologic diagnosis and molecular features, while surgical resection remains challenging.
In the newly published paper "Maximal surgical resection and adjuvant surgical technique to prolong the survival of adult patients with thalamic glioblastoma" published in February 2021, we have demonstrated through Clinical studies and real-life cases demonstrate the role of maximal surgical resection in the treatment of adult thalamic glioblastoma (GBM) and determine the impact of surgical techniques for safe maximal resection.
Case 1
Sub-total thalamic GBM obtained in a 68-year-old man.
No recurrence for more than 4 years after surgery
A 68-year-old male was admitted to the hospital with headache and blurred vision. Preoperative magnetic resonance imaging (MRI) showed cystic and solid masses in a lateral thalamic lesion with enhancement suggestive of glioma. Postoperative MRI showed gross tumor resection (C) and subtotal tumor resection (D). At the one-year follow-up MRI, there was irregular and blurred enhancement in the T1-enhanced image (E) and high signal in the T2-FLAIR image (F). At the 2-year follow-up MRI, the T1 contrast-enhanced image (G) and the T2-FLAIR image (H) were in a stable state. The patient was alive and survived 1515 days postoperatively.
Case 2
Ms. 52-year-old thalamic GBM.
No recurrence 4 years after subtotal resection, life as usual
A 52-year-old woman was admitted with confusion, diplopia, and motor weakness. Preoperative magnetic resonance imaging (MRI) showed: cystic and solid masses in hypothalamic lesions. Postoperative MRI showed sub-total resection of the tumor on T1-enhanced images (C, D). At the one-year follow-up MRI, there was irregular enhancement on T1-contrast-enhanced images (E) and high signal on T2-FLAIR images (F). At the 2-year follow-up MRI, T1-enhancement (G) and T2-FLAIR images (H) showed steady state. The patient was alive and survived 1469 days postoperatively.
Thalamic glioblastoma treatment strategy
In the case of suspected thalamic glioblastoma, surgical resection is generally the treatment of choice. If possible, the aim of surgery is total resection with preservation of neurological function. Subtotal resection is performed in anticipation of severe neurological complications, suspected corticospinal tract (CST) injury, or possible brainstem injury or vascular injury. Biopsy is the treatment of choice for patients with ventricular wall enhancement, soft meningeal enhancement, or distant multiple enhancing lesions. After the pathological diagnosis was confirmed, all patients in this study received standard treatment for glioblastoma (concurrent radiotherapy and temozolomide chemotherapy).
Treatment strategies and patient selection for thalamic GBM. For suspected thalamic glioblastoma, surgical resection is the treatment of choice. Biopsy-only surgery is considered when there is ventricular wall enhancement, soft meningeal enhancement, or distant multiple enhancing lesions.
Ancillary surgical techniques
Preoperative navigational MRI, diffusion tensor fiber bundle imaging (DTI), and enhanced computed tomography (CT) were routinely performed and fused together. Prior to complete dural opening, a navigation stick (tailed bullet) was inserted through an incision in a small dural incision (<5 mm) into the tumor target, whose primary target areas were the corticospinal tract and midbrain, which were difficult to distinguish during the procedure. The target points for target insertion are marked in the fusion images. Using these targets during surgery, it was possible to confirm the target lesion under the microscope and compare the fusion images with the target points. As the tumor volume shrinks during surgery, the tumor and its surroundings are altered; therefore, intraoperative CT is performed to identify changes in the lesion relative to the fusion image.
5-ALA was used to differentiate tumor lesions in all surgically resected cases. Transcranial motor evoked potentials (MEP) and monopolar direct subcortical stimulation (DSS) were used to confirm intraoperative functional status and the location of the CST. Transcranial MEP was monitored every 5 minutes throughout the cortical procedure at 60-100 mA. DSS was initiated at 10 mA and decreased to 6 mA as the stimulator approached the CST. if the patient's status allowed, awake surgery was performed while the patient was awake to check the patient's intraoperative functional status.
Surgical Approach
The choice of surgical access is based on the location of the tumor center and the adjacent corticospinal tract. Considering the pattern and morphological pattern of tumor invasion and the location of the CST, it is recommended to choose the shortest surgical access from the cortex to the tumor. The transcortical approach is chosen when the tumor is located in the anterolateral or posterior lateral thalamus and extends in an upward lateral direction. When the tumor is located in the postero-lateral thalamus, a transcortical-transventricular approach is chosen. The interhemispheric transcallosal approach was chosen when the tumor was located in the medial and posterior thalamus, while the trans-lateral fissure-transinsular approach was chosen for lateral thalamic lesions. For posterior inferior thalamic and medial posterior inferior lesions, an occipital transcallosal approach was used. A modified lateral supraorbital (MLSO) approach was used to treat anterior thalamic tumors.
Clinical Results
To assess the clinical efficacy of surgical resection compared to biopsy, some investigators estimated the difference in overall survival (OS) and progression-free survival (PFS) between three groups: surgical resection (n=19), physician-selected biopsy (n=17), and patient-selected biopsy (n=6). The surgical resection group showed good OS (median: 676 days, p=0.001) (lower panel A) and PFS (median: 328 days, p=0.001) (lower panel B) compared to the described biopsy group (physician-selected biopsy, median OS: 240 days, median PFS: 134 days; patients who chose biopsy, median OS: 212 days, median PFS: 118 days )
Survival analysis of the surgical resection and biopsy groups. a. Overall survival (OS) was significantly longer in patients who underwent surgery, p < 0.001 in the resection group compared to patients who underwent biopsy according to treatment criteria (physician-selected biopsy group) or patients who chose biopsy (patient-selected biopsy group). b. Progression-free survival (PFS) was significantly longer in the surgical resection group than in the physician-selected biopsy group or patient-selected biopsy group (p < 0.001).
In addition, the study experts said that there was no significant difference between the surgical resection group and the biopsy group in terms of motor-related neurological complications such as motor weakness, sensory impairment, visual impairment, cognitive deterioration and KPS deterioration, although of course the study had significant central variability and a smaller number of cases.
Distribution of surgical and neurological complications between the surgical resection and biopsy groups
Finally, the study concluded that it is important to choose the appropriate surgical resection for patients with glioblastoma of the thalamus. In the absence of enhancing lesions or multiple lesions, longer survival can be expected than with biopsy alone when the maximum surgical resection rate exceeds 80%. The use of several high-tech intraoperative neurosurgical aids can help to remove the tumor more precisely and reduce the incidence of surgical complications, and it is important to check the neurophysiological status by careful monitoring such as MEP and DSS.
Currently, the first treatment for glioblastoma is surgery, supplemented by radiotherapy. The extent of surgical resection is the most important factor affecting the effectiveness of radiotherapy and survival. In the case of brain stem glioblastoma, surgery is extremely difficult, and only highly experienced physicians will recommend surgery. If it is a multiple glioma, the tumor is difficult to be removed by surgery and only decompression surgery and radiotherapy can be done mainly. In conclusion, the specific formulation needs to depend on the tumor condition and the treatment plan of specialists in neurosurgery and neuro-oncology.
Photo from: frontiersin.org
INC International Professor thalamic glioma surgery cases
Pre-operative situation: 26-year-old man, professional soccer player, after a minor head trauma during a soccer match, he was not thought of at the time and only did simple bandaging. He was found to have a huge thalamic occupancy and compression of the brainstem. He was referred to the INI hospital in Germany for treatment after obtaining a consultation with Prof. Barthelenfeld, INC Germany.
Seven foreword treatment techniques for glioblastoma
In addition to traditional treatments such as surgery and radiotherapy, in recent years, research and clinical trials have further developed, giving neurosurgeons more treatment options to choose from in clinical practice and providing patients with greater relief and a higher quality of life. Professor James T. Rutka, editor-in-chief of the Journal of Neurosurgery, a leading journal in neurosurgery, has had many cutting-edge studies and has summarized the seven cutting-edge treatments for glioblastoma in recent years.
1、Targeted therapy: novel targeted inhibitors can selectively block key effector molecules from the cell membrane and even downstream cell signaling pathways, theoretically, each cell signaling pathway can be specifically inhibited. Currently, molecularly targeted drugs for malignant glioblastoma are still in preclinical studies. However, many years of research have confirmed that proto-oncogenes (EGF and PDGF and their receptors) and tumor suppressor oncogenes are closely associated with malignant glioblastoma development and progression, and that common heterozygous deletions of 1p, 10p, 10q, 19q and 22q also affect the genetic expression of malignant glioblastoma. These existing studies have successfully provided research targets for the molecular targeting of malignant glioblastoma.
Molecular immunotherapy: Glioblastoma is known as an immune "cold" tumor because brain tumors contain few immune cells and there is a system called blood-brain barrier in the brain that prevents T cells from entering the brain tissue. It is very difficult to get these immune cells needed to generate an immune response against the tumor. There are several promising tumor lysing viruses and vaccines currently in clinical trials.
3、Electric field therapy: Electric field therapy is to use the electric field environment to block the process of cell mitosis, so as to achieve the effect of interfering with the proliferation of cancer cells. Since the FDA approved TTF therapy for newly diagnosed glioblastoma in 2015, electric field therapy has been gaining attention. In a large clinical trial at the Barrow Neurological Institute, electric field therapy was shown to prolong survival and maintain quality of life in tumor patients. The results of a large clinical study showed that people who added electric fields to chemotherapy had a longer chance of survival than those who used chemotherapy alone.
4. Laser interstitial thermotherapy LITT technique: a paper on LITT for glioblastoma published in the Journal of Oncology (IF: 26) in July 2018 validated that MRI-guided laser interstitial thermotherapy (LITT) is safe and effective for certain patients with glioblastoma, with an average life expectancy of 2 months compared to the current standard treatment This is a significant improvement for patients with malignancies such as this, where the median survival is only about 12 months.
Laser Interstitial Thermal Therapy (LITT), a product of modern precision neurosurgery, is a minimally invasive percutaneous procedure under MRI magnetic resonance that relies on fiber-optic conduction of near-infrared laser light to generate thermal energy to act on a target site, thereby selectively ablating the diseased tissue. The greatest advantage of this technology is that it can achieve precise ablation of deep brain lesions and epileptic lesions without craniotomy under the real-time guidance and monitoring of MRI.INC Canada Prof. James T. Rutka has shared the cutting-edge progress and clinical success stories of LITT technology at several neurosurgery conferences. The professor's clinical research focuses on intracranial tumors and epilepsy in children. He is skilled in awake craniotomy, microsurgery, and is also a world pioneer in the emerging minimally invasive technology, laser interstitial thermotherapy (LITT). It is worth mentioning that Professor has been at the forefront of research and use of cutting-edge technology, and his SickKids Hospital was one of the first children's hospitals to be fully equipped with LITT technology.
Case 1: 68-year-old male with postoperative recurrence of glioblastoma, before (A) and after (B) ablation by LITT. Note that the ablation area is confined to the surrounding brain pool, protecting the adjacent brainstem from damage.
Case 2: 45-year-old male with postoperative recurrence of mesenchymal oligodendroglioma, before (A) and after (B) LITT laser ablation. The ablation area was oriented along the central anterior sulcus, avoiding damage to the primary motor cortex.
Case 3: 51-year-old male with postoperative recurrence of glioblastoma in the right temporal thalamus, before (A) and after (B) LITT ablation showed that the lesion was destroyed.
5. Nanosurgical techniques for resection: Over the past three decades, the application of new technologies and materials in the operating room has led to advances in surgery and improved patient prognosis. In particular, the introduction of new technologies has greatly improved tumor resection rates in cancer patients. Nanosurgical Resection of Malignant Brain Tumors: Beyond the Cutting Edge," Professor James T. Rutka, editor of the world-renowned Journal of Neurosurgery, explains the potential for his surgical team to use a handheld Raman scanner to detect and remove glioblastomas in genetically engineered mouse models. They show that the handheld Raman scanning technique can accurately detect gold silica surface-enhanced Raman scattering (SERS) nanoparticles entering the GBM, thereby assisting in the precise and complete removal of the tumor.
Among the nanotechnology aspects of neurosurgery, the research demonstrates how new systems can be better applied in the operating room by varying the size of nanoparticles, overcoming the barriers posed by the blood-brain barrier, and functionalizing nanoparticle binders in order to achieve therapeutic goals. Finally, by adapting the actual handheld Raman spectroscopy technology itself, one can envision a day when "nanosurgery" will be part of the surgeon's equipment. Experimental data suggests that intraoperative SERS-guided surgical resection of tumors is more advantageous than using a surgical microscope and using 5-ALA technology-derived fluorescence-guided resections. Compared to static Raman microscopy, handheld Raman scanning technology can bring better speed for intraoperative data acquisition and can provide real-time intraoperative operational guidance, and can be used in any angle of the surgical bed. Some handheld Raman scanning techniques are already being used in clinical practice, which facilitates the rapid advancement of nanotechnology in neurosurgery.
6. Glioblastoma treatment using platinum nanoparticle conjugates with targeted delivery enhancement and magnetic resonance-guided focused ultrasound: In another of his research papers on GBM, "Enhancing glioblastoma treatment using cisplatin-gold- nanoparticle conjugates and targeted delivery with magnetic resonance-guided focused ultrasound", he pointed out that glioblastoma (GBM) is the most common and aggressive primary brain tumor with an increasing The incidence and mortality rates are increasing. There is an urgent need for a technology that improves the efficacy of existing drugs and enhances the delivery of chemotherapeutic agents across the blood-brain barrier. The authors investigated the combination of platinum nanocouples with magnetic resonance-guided focused ultrasound to enhance glioblastoma treatment. It was shown that platinum nanocouples greatly inhibited the growth of GBM cells compared to conventional free cisplatin drugs and showed significant synergistic effects with radiation therapy.
In addition, increased DNA damage via γH2AX phosphorylation, as well as increased platinum concentration, was observed in cells treated with platinum-based nanocouplers. In vivo, platinum nanocouplings greatly inhibited glioblastoma tumor growth, and MRI-guided focused ultrasound resulted in enhanced blood-brain barrier permeability and platinum drug delivery uptake in brain tissue. Our study suggests that platinum nanocouplers and MRI-guided focused ultrasound can be used to focus on enhancing the delivery of targeted chemotherapeutic agents to brain tumors.
7. Molecular Biology Gene Therapy Research: Since the completion of the Human Genome Project, non-coding RNAs (ncRNAs) have emerged as an important class of genetic regulators. ncRNAs in Glioblastoma: Emerging Biological Concepts and Potential Therapeutic Implications," discusses the potential role of ncRNAs in regulating glioblastoma (GBM) formation and progression, and strategies to exploit the potential of ncRNAs in the diagnosis and treatment of GBM. The professor noted that in the era of molecular biology, with the development of advanced gene sequencing technologies, several different classes of ncRNAs have been identified, including microRNA (miRNA), non-coding RNA (lncRNA), circular RNA (circRNA), and piwi-interacting RNA (piRNA), which have been linked to many important developmental and disease processes, and are being used as clinical and therapeutic targets.
Reference: https://doi.org/10.1371/journal.pone.0244325
