Current State of Targeted Radiometal-Based Constructs for the Detection and Treatment of Disease in the Brain.

The continual development of radiopharmaceutical agents for the field of nuclear medicine is integral to promoting the necessity of personalized medicine. One way to greatly expand the selection of radiopharmaceuticals available is to broaden the range of radionuclides employed in such agents. Widening the scope of development to include radiometals with their variety of physical decay characteristics and chemical properties opens up a myriad of possibilities for new actively targeted molecules and bioconjugates. This is especially true to further advance the imaging and treatment of disease in the brain. Over the past few decades, imaging of disease in the brain has heavily relied on agents which exploit metabolic uptake. However, through utilizing the broad range of physical characteristics that radiometals offer, the ability to target other processes has become more available. The varied chemistries of radiometals also allows for them to incorporated into specifically designed diverse constructs. A major limitation to efficient treatment of disease in the brain is the ability for relevant agents to penetrate the blood-brain barrier. Thus, along with efficient disease targeting, there must be intentional thought put into overcoming this challenge. Here, we review the current field of radiometal-based agents aimed at either imaging or therapy of brain disease that have been evaluated through at least in vivo studies.

Radiotherapy for recurrent intracranial epidermoid cysts without malignant transformation: a single-institution case series.

INTRODUCTION: Recurrent intracranial epidermoid cysts may be difficult to address surgically given their proximity to critical neurovascular structures of the skull base. There are emerging reports of using radiotherapy (RT) for the treatment of recurrent epidermoid cysts. Here, we report a case series of adjuvant fractionated external beam RT for recurrent intracranial epidermoid cysts. METHODS: A single-institution review of all recurrent epidermoid cysts treated with adjuvant therapy between 2000 and 2017 was performed. RESULTS: Eight patients with recurrent epidermoid cysts who underwent adjuvant external beam RT were identified. Average age at initial diagnosis was 42.2 years, and median clinical follow-up after initial diagnosis and RT was 16.4 and 2.9 years, respectively. The median number of surgical resections prior to RT was 3 (range 2-5). Rationale for RT included multiple recurrent disease, rapid recurrence following prior resection, increased risk of further surgical morbidity, and patient preference. Median dose was 50.4 delivered in 1.8 Gy fractions (median 28 fractions). By the date of last follow-up, no patient has demonstrated progression, and there have been no cases of malignant degeneration. CONCLUSION: Adjuvant RT should be considered in the context of recurrent epidermoid cysts to decrease the likelihood of further recurrences.

Idiopathic giant cell granuloma in the saddle area recurring soon after subtotal resection: a case report.

Giant cell granuloma is non-neoplastic proliferation of multinucleated giant cells and rarely occurs in the intracranial space. Here we report a 40-year-old man presented with left ptosis and impaired vision. Magnetic resonance imaging revealed a mass extending from the intrasellar area to the third ventricular floor, left cavernous sinus, retrochiasmatic area, and the left interpeduncular cistern. The lesion was subtotally resected using the transsphenoidal approach. Three months after the operation, the mass recurred and hormone levels decreased significantly. Radiotherapy and steroid therapy were administered at this time.

Influence of Acquisition Mode of Cone-beam Computed Tomography on Accuracy of Image Registration for Image-guided Radiotherapy.

Half scan can acquire images at the 200° rotation in image-guided radiation treatment using cone-beam CT and is useful to evaluate the influence of the half-scan-imaging start angle and imaging direction on image registration accuracy. The half-scan-imaging start angle is changed from 180° to 340° in the clockwise direction and from 180° to 20° in the counter clockwise direction to calculate the registration error. As a result, registration errors between -0.37 mm and 0.27 mm in the left and right directions occur because of the difference in the imaging start angle and approximately 0.3° in the gantry rotation direction because of the difference in the imaging direction. Because half scan does not have data for 360° rotation, depending on the subject structure, inconsistency of opposing data can lower reconstruction accuracy and cause a verification error. In addition, in image acquisition during rotation, the slower the shutter speed is, the more the actual gantry angle and angle information of the image are apart, which is considered the cause of rotation errors. Although these errors are very minute, it is thought that there is no influence on the treatment effect, but these errors are considered an evaluation item indispensable for ensuring the accuracy of high-precision radiation treatment. In addition, these errors need to be considered for ensuring the quality of high-precision radiation treatment.

Quality of the Patient Experience during Radiosurgery: Measurement toward Improvement.

BACKGROUND: All physicians seek to improve the patient experience. In an awake surgical procedure, the patient has a unique opportunity to comment on all aspects of care. The provision of a positive experience is part of quality health care. Our purpose was to define this experience to determine areas for improvement. METHODS: We evaluated 125 patients who underwent stereotactic radiosurgery using a frame-based, gamma knife technique. Patients were surveyed by a nurse practitioner across all elements of their procedural experience prior to same-day discharge. RESULTS: The radiosurgery was completed in all patients with same-day discharge. In an initial 100-patient cohort, 89 patients said they had received adequate oral and/or intravenous sedation before the procedure. All 100 patients said that they felt comfortable before stereotactic frame application, and all patients later remembered frame application. These patients described frame application as very or adequately comfortable (n = 73), minimally uncomfortable (n = 18), or very uncomfortable (n = 9). Neuroimaging was described as very or adequately comfortable (n = 93), minimally uncomfortable (n = 3), or very uncomfortable (n = 4). Radiosurgery in the gamma knife unit was found to be very or adequately comfortable (n = 99) or very uncomfortable (n = 1). We evaluated how 8 separate factors may have contributed to survey responses related to procedural comfort. These factors included intravenous line placement, delivery of sedation medications, application of the head frame, having the MRI, having radiosurgery on the gamma knife bed, removal of the stereotactic frame, communication with caregivers, and knowing what to expect beforehand. We asked the patients to rate their nursing care during the radiosurgery experience, and 'excellent' was chosen by all initial 100 patients. Other elements of the procedure were also studied as well as suggestions for improvement. As a secondary objective, we then modified our protocol to include sodium bicarbonate added to the local anesthetic for frame application and evaluated an additional cohort of 25 patients. CONCLUSIONS: Utilizing a system of physician and nursing education, together with pharmacological sedation and efficient procedural steps, patients said that intravenous line placement (91%), stereotactic frame application (74%), MRI (93%), receiving radiosurgery in the unit (99%), frame removal (84%), communication with caregivers (100%), and knowing what to expect beforehand (97%) were either very or adequately comfortable. Specific evaluations of care processes can lead to care improvement.

Radiotherapy for recurrent epidermoid cyst.

Intracranial epidermoid cysts are rare benign congenital lesions for which the mainstay of treatment has been surgical resection. Due to a propensity to grow along the skull base, subtotal resection is often elected to avoid excessive surgical morbidity, but it comes with an increased risk of recurrence with its associated treatment difficulties. We here present the cases of three patients with recurrent epidermoid cyst who underwent multiple surgical resections followed by external beam radiation therapy with excellent results to date.

[Pituitary disorders in patients after traumatic brain injury and radiotherapy]. / Choroby przysadki u chorych po urazie i radioterapii.

Traumatic brain injury is an important public health problem all over the world. Cranial radiation is routinely and increasingly used to manage various types of tumors. Both traumatic brain injury and brain radiotherapy are a frequent and overlooked cause of abnormalities in hypothalamic-pituitary axis function or sometimes even of overt pituitary disorders altering patients' health and quality of life. Because clinical manifestations may be subtle and develop insidiously many years after injury or radiotherapy, establishing a correct diagnosis is not always straightforward. Diagnosis of hypopituitarism and accurate treatment of pituitary disorders offers the opportunity to improve mortality and outcome in both groups of patients. The purpose of this paper is to review the pathogenesis, clinical manifestations, diagnosis and treatment of traumatic brain injury- or radiotherapy-induced pituitary disturbances with a special emphasis on the most recent literature.

Transcranial photobiomodulation in the management of brain disorders.

Transcranial photobiomodulation (tPBM) is the process of delivering light photons through the skull to benefit from its modifying effect. Brain disorders are important health problems. The aim of this review was to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Parkinson, and Alzheimer's disease as the common brain disorders. Four online databases, including Cochrane, Pub Med, Embase, and Google scholar were searched according to the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines. 4728 articles were obtained in the initial search. Only those articles that were published until September 2020 and designed as randomized clinical trials (RCTs) or animal-controlled studies were included. 6 RCTs, 2 related supplementary articles, and 38 controlled animal studies met the inclusion criteria of this study. No RCTs were performed in the fields of Alzheimer's and Parkinson's diseases. The human RCTs and animal studies reported no adverse events resulted from the use of tPBM. Useful parameters of tPBM were identified according to the controlled animal studies. Since the investigated RCTs had no homogenous results, making an evidence-based decision for definite therapeutic application of tPBM is still unattainable. Altogether, these data support the need for large confirmatory well-designed RCTs for using tPBM as a novel, safe, and easy-to-administer treatment of brain disorders. EVIDENCE BEFORE THIS STUDY: High prevalence and complications of brain disorders and also side effects of neuropsychiatric medications have encouraged researchers to find alternative therapeutic techniques which tPBM can be one of them. In present review we tried to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Alzheimer, and Parkinson's disease as common brain disorders. Four online databases, including "Cochrane", "Pub Med", "Embase", and "Google scholar" were searched. Only those articles that were published until September 2020 and designed as RCTs or animal-controlled studies were included. Search keywords were the followings: transcranial photobiomodulation" OR "transcranial low-level laser therapy" AND "stroke" OR "traumatic brain injury" OR "Alzheimer" OR "Parkinson". Several studies have confirmed effectiveness of tPBM in treatment of different brain disorders but the level of evidence of its effectiveness remain to be determined. ADDED VALUE OF THIS STUDY: In this study we systematically reviewed human RCTs to determine the existing evidence of tPBM effectiveness in management of four mentioned brain disorders. Since the outcomes of the reviewed RCTs were not homogeneous, further well-designed RCTs are required to decide more definitively on the evidence of this noninvasive and probably safe therapeutic intervention. We hypothesized that non-homogeneous outcomes could be due to inefficiency of PBM parameters. Controlled animal studies have the advantage of using objective tests to evaluate the results and compare them with the control group. We determined useful tPBM parameters based on these studies. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: This research is part of our main project of tinnitus treatment using photobiomodulation (PBM). Evidence of central nervous system involvement in tinnitus led us to believe that treatment protocol of tinnitus should also include transcranial PBM. The determined useful parameters can be helpful in designing more efficient tPBM protocols in the management of brain disorders and tinnitus as a common debilitating symptom that can be associated with these disorders.

Setup error with and without image guidance using two canine intracranial positioning systems for radiation therapy.

Daily image guidance reduces inter-fractional variation in patient position for intracranial radiation therapy. However, the ability to detect and correct positioning errors is limited below a certain level. Because of these limitations, the accuracy achieved with a positioning system prior to image guidance may affect the error remaining after image guidance (the residual setup error). The objective of this study was to compare the setup accuracy achieved before and after megavoltage (MV) and cone-beam computed tomography (CBCT) guidance between two intracranial positioning systems. Equipment included a four degrees-of-freedom couch capable of 1 mm translational moves. Six dog cadavers were positioned 24 times as for clinical treatment in a head re-positioner (HPS), and the coordinates of five fiducial markers were measured before and after image-guided correction. The values obtained for the HPS were compared with those previously reported for the standard positioning system (SPS) used at this facility. The mean three-dimensional distance vector (3DDV) was lower for the HPS than for the SPS when no image guidance was used (P = .019). The mean 3DDV after MV guidance was lower for the HPS than for the SPS (P = .027), but not different after CBCT guidance (P = .231). The 95th percentiles of the 3DDV after MV and CBCT guidance were 2.1 and 2.9 mm, respectively, for the HPS, and 2.8 and 3.6 mm for the SPS. The setup error after MV guidance was lower for the positioning system that achieved a more accurate patient position before image guidance.

Symptomatic intracranial Rosai-Dorfman disease in the suprasellar region treated with conformal radiotherapy - A report of two cases and literature review.

Intracranial Rosai-Dorfman Destombes (RDD) disease is a rare entity. Lesions can lead to cranial nerve palsies and visual loss, especially in suprasellar location. Resection is considered to be definitive treatment; however, complete excision is difficult to achieve in view of the close proximity of critical structures. Radiotherapy (RT) is sometimes used for refractory or progressive disease for local tumor control and amelioration of symptoms. We report two patients with suprasellar RDD's with progressive symptoms treated with conformal RT after subtotal excision. These patients were treated with high precision conformal techniques to a dose of 45 Gy with significant and durable improvement in vision.

Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation.

Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress, which are important factors contributing to the development of brain disease. Ample evidence suggests mitochondria are a promising target for neuroprotection. Recently, methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury. This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration, methylene blue (MB) and photobiomodulation (PBM). MB is a widely studied drug with potential beneficial effects in animal models of brain disease, as well as limited human studies. Similarly, PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation, and has garnered increasing attention in recent years. MB and PBM have similar beneficial effects on mitochondrial function, oxidative damage, inflammation, and subsequent behavioral symptoms. However, the mechanisms underlying the energy enhancing, antioxidant, and anti-inflammatory effects of MB and PBM differ. This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.

Stereotactic interstitial radiosurgery for intracranial Rosai-Dorfman disease. A novel therapeutic approach.

BACKGROUND: Rosai-Dorfman disease is an idiopathic, histoproliferative disorder characterized by massive painless lymphadenopathy. The favorable treatment of Rosai-Dorfman disease affecting the central nervous system is surgical resection. Histological and immunohistochemical confirmation is essential for a definitive diagnosis. CASE REPORT: The authors report on a 10-year-old patient with Rosai-Dorfman disease of the central nervous system who presented with increased intracranial pressure. She was treated by stereotactic interstitial irradiation using iodine-125 seeds (interstitial radiosurgery). RESULT: Stereotactic surgery was performed without complications. The patient recovered well to a normal neurologic status. MR images showed a complete remission 49 months after treatment. CONCLUSION: The presented case demonstrates the high efficacy and safety of interstitial irradiation for intracranial Rosai-Dorfman disease. Hence, interstitial radiosurgery could be an appropriate therapeutic option for high-risk resectable intracranial Rosai-Dorfman disease.

Stereotactic radiosurgery for intracranial IgG4-related disease.

We report the case of a 20-year-old woman with intracranial IgG4-related disease, initially misdiagnosed as a meningioma on biopsy and treated with radiosurgery as it was in an eloquent location and not resectable. Her intracranial IgG4 disease had a near-complete response to radiosurgery and is still controlled six years later, so this case represents what we believe to be the first reported use of radiotherapy in the treatment of intracranial IgG4-related disease.

Frame versus Frameless Leksell Stereotactic Radiosurgery.

For more than 65 years localization of brain targets suitable for stereotactic radiosurgery has been performed after application of an intracranial guiding device to the cranial vault. After imaging and dose planning the same frame is used to secure the target at the focus of the intersection of the ionizing radiation beams that create the radiobiological effect. Non-invasive immobilization systems first proposed for linear accelerator or proton radiation technologies have now been developed for the Leksell Gamma Knife ICON radiosurgical system. The ICON technology adds a cone-beam computed tomography (CBCT) scan to the original Perfexion radiosurgical device in order to define the brain stereotactic space. Marketed since 2015, the ICON can be used for standard radiosurgical procedures, most of which remain frame based, but also coupled with a non-invasive thermoplastic mask for carefully selected patients who undergo standard single-session radiosurgical procedures, as well as multisession procedures using repeat mask fixation. Both at UPMC as well as worldwide, mask immobilization has to date been used for approximately 10% of patients with specific characteristics: relatively simple dose plans, short radiation delivery times, and non-anxious patients, most of whom have metastatic or primary brain cancers. In certain cases, multisession radiosurgery is also performed using the mask. The workflow of frame versus frameless procedures is often altered, and is reliant on high-definition imaging, mostly MRI, done prior to dose planning. Since each CBCT takes 10-12 min to set up and acquire, co-register, and review with the treatment plan, and two CBCT scans are necessary to initiate the treatment plan, this workflow must be added to the beam on time. Although frame-based immobilization remains the predominant method to secure target fixation for problems suitable for single-session radiosurgery, the advent of a mask immobilization technique has proven valuable for a select group of patients. It also provides a non-invasive method to perform multisession or fractionated radiation in patients for whom traditional single-session radiosurgery is not feasible.

A study on the magnetic resonance imaging (MRI)-based radiation treatment planning of intracranial lesions.

The aim of this study is to develop a magnetic resonance imaging (MRI)-based treatment planning procedure for intracranial lesions. The method relies on (a) distortion correction of raw magnetic resonance (MR) images by using an adaptive thresholding and iterative technique, (b) autosegmentation of head structures relevant to dosimetric calculations (scalp, bone and brain) using an atlas-based software and (c) conversion of MR images into computed tomography (CT)-like images by assigning bulk CT values to organ contours and dose calculations performed in Eclipse (Philips Medical Systems). Standard CT + MRI-based and MRI-only plans were compared by means of isodose distributions, dose volume histograms and several dosimetric parameters. The plans were also ranked by using a tumor control probability (TCP)-based technique for heterogeneous irradiation, which is independent of radiobiological parameters. For our 3 T Intera MRI scanner (Philips Medical Systems), we determined that the total maximum image distortion corresponding to a typical brain study was about 4 mm. The CT + MRI and MRI-only plans were found to be in good agreement for all patients investigated. Following our clinical criteria, the TCP-based ranking tool shows no significant difference between the two types of plans. This indicates that the proposed MRI-based treatment planning procedure is suitable for the radiotherapy of intracranial lesions.

Multimodal PET/MRI Imaging Results Enable Monitoring the Side Effects of Radiation Therapy.

Radiotherapy is one of the most frequently applied treatments in oncology. Tissue-absorbed ionizing radiation damages not only targeted cells but the surrounding cells too. The consequent long-term induced oxidative stress, irreversible tissue damage, or second malignancies draw attention to the urgent need of a follow-up medical method by which personalized treatment could be attained and the actually dose-limiting organ could be monitored in the clinical practice. We worked out a special hemisphere irradiation technique for mice which mimics the radiation exposure during radiotherapy. We followed up the changes of possible brain imaging biomarkers of side effects, such as cerebral blood flow, vascular endothelial function, and cellular metabolic processes for 60 days. BALB/c mice were divided into two groups (n=6 per group) based on the irradiation doses (5 and 20 Gy). After the irradiation procedure arterial spin labeling (ASL), diffusion-weighted imaging (DWI) in magnetic resonance modality and [18F]fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) scans of the brain were obtained at several time points (3, 7, 30, and 60 days after the irradiation). Significant physiological changes were registered in the brain of animals following the irradiation by both applied doses. Elevated standard uptake values were detected all over the brain by FDG-PET studies 2 months after the irradiation. The apparent diffusion coefficients from DWI scans significantly decreased one month after the irradiation procedure, while ASL studies did not show any significant perfusion changes in the brain. Altogether, our sensitive multimodal imaging protocol seems to be an appropriate method for follow-up of the health status after radiation therapy. The presented approach makes possible parallel screening of healthy tissues and the effectiveness of tumor therapy without any additional radiation exposure.

Radiotherapy of non-malignant disorders: where do we stand?

During a consensus meeting in Nice the role of radiotherapy in benign disorders was discussed. Based on this meeting we categorized the indication into three categories: (A) accepted indication; (B) only accepted in clinical trial; (C) not accepted. The results of this consensus meeting are presented for disorders of the eye, joints and bones, brain and soft tissue.

[First experience with a Gamma-knife unit used for radiosurgical treatment for intracranial space-occupying lesions].

A Gamma-Knife unit that is currently the gold standard in radiosurgery was first used in clinical practice in 1968. The essence of the radiosurgical treatment is to apply the stereotactic technique to high-precision irradiation of small intracranial targets by narrow beams of ionizing radiation from external sources. Three hundred and six patients with various intracranial diseases (137 with malignant tumors, 136 with benign tumors, and 33 patients with vascular diseases) underwent radiosurgery on a Gamma-Knife unit for over 1.5 years, from May 2005 to October 2006. A total of 329 irradiation sessions were performed. By summing up the first results, it can be noted that stereotactic radiosurgery using a Gamma-Knife unit is an effective and rather safe technique in the treatment of patients with various types of intracranial pathology, which maintains the high quality of life, reduces the likelihood of development of different neurological disorders after treatment and avoids the risk of operative complications. The possibility of performing outpatient treatment for a diversity of diseases without mandatory anesthesiological, ICU, and rehabilitative maintenance, determines the potential economic efficiency of this treatment.

Dosimetric comparison of different treatment modalities for stereotactic radiotherapy.

BACKGROUND: The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) linac, and tomotherapy. In this study, the cone-based linac, FFF-VMAT linac, and tomotherapy modalities were evaluated by measuring the differences in doses delivered during brain SRT and experimentally assessing the accuracy of the output radiation doses through clinical measurements. METHODS: We employed a homemade acrylic dosimetry phantom representing the head, within which a thermoluminescent dosimeter (TLD) and radiochromic EBT3 film were installed. Using the conformity/gradient index (CGI) and Paddick methods, the quality of the doses delivered by the various SRT modalities was evaluated. The quality indicators included the uniformity, conformity, and gradient indices. TLDs and EBT3 films were used to experimentally assess the accuracy of the SRT dose output. RESULTS: The dose homogeneity indices of all the treatment modalities were lower than 1.25. The cone-based linac had the best conformity for all tumors, regardless of the tumor location and size, followed by the FFF-VMAT linac; tomography was the worst-performing treatment modality in this regard. The cone-based linac had the best gradient, regardless of the tumor location and size, whereas the FFF-VMAT linac had a better gradient than tomotherapy for a large tumor diameter (28 mm). The TLD and EBT3 measurements of the dose at the center of tumors indicated that the average difference between the measurements and the calculated dose was generally less than 4%. When the 3% 3-mm gamma passing rate metric was used, the average passing rates of all three treatment modalities exceeded 98%. CONCLUSIONS: Regarding the dose, the cone-based linac had the best conformity and steepest dose gradient for tumors of different sizes and distances from the brainstem. The results of this study suggest that SRT should be performed using the cone-based linac on tumors that require treatment plans with a steep dose gradient, even as the tumor is slightly irregular, we should also consider using a high dose gradient of the cone base to treat and protect the normal tissue. If normal tissues require special protection exist at positions that are superior or inferior to the tumor, we can consider using tomotherapy or Cone base with couch at 0° for treatment.

Worldwide variance in the potential utilization of Gamma Knife radiosurgery.

OBJECTIVE The role of Gamma Knife radiosurgery (GKRS) has expanded worldwide during the past 3 decades. The authors sought to evaluate whether experienced users vary in their estimate of its potential use. METHODS Sixty-six current Gamma Knife users from 24 countries responded to an electronic survey. They estimated the potential role of GKRS for benign and malignant tumors, vascular malformations, and functional disorders. These estimates were compared with published disease epidemiological statistics and the 2014 use reports provided by the Leksell Gamma Knife Society (16,750 cases). RESULTS Respondents reported no significant variation in the estimated use in many conditions for which GKRS is performed: meningiomas, vestibular schwannomas, and arteriovenous malformations. Significant variance in the estimated use of GKRS was noted for pituitary tumors, craniopharyngiomas, and cavernous malformations. For many current indications, the authors found significant variance in GKRS users based in the Americas, Europe, and Asia. Experts estimated that GKRS was used in only 8.5% of the 196,000 eligible cases in 2014. CONCLUSIONS Although there was a general worldwide consensus regarding many major indications for GKRS, significant variability was noted for several more controversial roles. This expert opinion survey also suggested that GKRS is significantly underutilized for many current diagnoses, especially in the Americas. Future studies should be conducted to investigate health care barriers to GKRS for many patients.