Increasing C-reactive protein levels in a patient with glioblastoma with lymph node metastasis: a case report.

BACKGROUND: Glioblastoma usually recurs locally and extracranial metastases are rare. Most patients with extracranial metastases experience recurrence of the primary intracranial tumor. Lymph node metastases are often detected based on lymphadenopathy or symptoms caused by other metastatic sites. CASE PRESENTATION: Herein, we report a case of glioblastoma with lymph node metastasis in which the patient was asymptomatic but exhibited gradually increasing C-reactive protein levels prior to becoming febrile 9 months after the initial C-reactive protein increase. Diagnosis of lymph node metastasis that was delayed because the patient had a fever of unknown origin, no signs of infection, and the primary intracranial tumor did not recur. Chest computed tomography indicated supraclavicular, mediastinal, and hilar lymphadenopathy, and biopsy identified lymph node metastasis of glioblastoma. This is the fifth reported case of lymph node metastasis without intracranial recurrence. CONCLUSIONS: C-reactive protein levels may be a diagnostic marker for lymph node metastasis in patients with glioblastoma. Further evaluation is needed to elucidate the role of CRP in glioblastoma with lymph node metastasis.

5-Aminolevulinic acid increases boronophenylalanine uptake into glioma stem cells and may sensitize malignant glioma to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a high-LET particle radiotherapy clinically tested for treating malignant gliomas. Boronophenylalanine (BPA), a boron-containing phenylalanine derivative, is selectively transported into tumor cells by amino acid transporters, making it an ideal agent for BNCT. In this study, we investigated whether the amino acid 5-aminolevulinic acid (ALA) could sensitize glioma stem cells (GSCs) to BNCT by enhancing the uptake of BPA. Using human and mouse GSC lines, pre-incubation with ALA increased the intracellular accumulation of BPA dose-dependent. We also conducted in vivo experiments by intracerebrally implanting HGG13 cells in mice and administering ALA orally 24 h before BPA administration (ALA + BPA-BNCT). The ALA preloading group increased the tumor boron concentration and improved the tumor/blood boron concentration ratio, resulting in improved survival compared to the BPA-BNCT group. Furthermore, we found that the expression of amino acid transporters was upregulated following ALA treatment both in vitro and in vivo, particularly for ATB0,+. This suggests that ALA may sensitize GSCs to BNCT by upregulating the expression of amino acid transporters, thereby enhancing the uptake of BPA and improving the effectiveness of BNCT. These findings have important implications for strategies to improve the sensitivity of malignant gliomas to BPA-BNCT.

Chronic expanding pituitary hematoma with calcification resulting from pituitary adenoma: illustrative case.

BACKGROUND: Pituitary apoplexy (PA) is characterized by sudden headache, vomiting, visual dysfunction, anterior lobe dysfunction, and endocrine disorder due to bleeding or infarction from a pituitary adenoma. PA occurs in approximately 0.6-10% of pituitary adenomas, more commonly in men aged 50-60 years, and more frequently in nonfunctioning and prolactin-producing pituitary adenomas. Further, asymptomatic hemorrhagic infarction is found in approximately 25% of PA. OBSERVATIONS: A pituitary tumor with asymptomatic hemorrhage was detected on head magnetic resonance imaging (MRI). Thereafter, the patient underwent head MRI every 6 months. After 2 years, the tumor was enlarged and visual dysfunction was noticed. The patient underwent endoscopic transnasal pituitary tumor resection and was diagnosed with a chronic expanding pituitary hematoma with calcification. The histopathological findings were very similar to those of chronic encapsulated expanding hematoma (CEEH). LESSONS: CEEH associated with pituitary adenomas gradually increases in size, causing visual dysfunction and pituitary dysfunction. In case of calcification, total removal is difficult due to adhesions. In this case, calcification developed within 2 years. A pituitary CEEH, even when showing calcification, should be operated on, as visual function can be fully recovered.

Multi-Targeted Neutron Capture Therapy Combined with an 18 kDa Translocator Protein-Targeted Boron Compound Is an Effective Strategy in a Rat Brain Tumor Model.

BACKGROUND: Boron neutron capture therapy (BNCT) has been adapted to high-grade gliomas (HG); however, some gliomas are refractory to BNCT using boronophenylalanine (BPA). In this study, the feasibility of BNCT targeting the 18 kDa translocator protein (TSPO) expressed in glioblastoma and surrounding environmental cells was investigated. METHODS: Three rat glioma cell lines, an F98 rat glioma bearing brain tumor model, DPA-BSTPG which is a boron-10 compound targeting TSPO, BPA, and sodium borocaptate (BSH) were used. TSPO expression was evaluated in the F98 rat glioma model. Boron uptake was assessed in three rat glioma cell lines and in the F98 rat glioma model. In vitro and in vivo neutron irradiation experiments were performed. RESULTS: DPA-BSTPG was efficiently taken up in vitro. The brain tumor has 16-fold higher TSPO expressions than its brain tissue. The compound biological effectiveness value of DPA-BSTPG was 8.43 to F98 rat glioma cells. The boron concentration in the tumor using DPA-BSTPG convection-enhanced delivery (CED) administration was approximately twice as high as using BPA intravenous administration. BNCT using DPA-BSTPG has significant efficacy over the untreated group. BNCT using a combination of BPA and DPA-BSTPG gained significantly longer survival times than using BPA alone. CONCLUSION: DPA-BSTPG in combination with BPA may provide the multi-targeted neutron capture therapy against HG.

Influence of surgical position and registration methods on clinical accuracy of navigation systems in brain tumor surgery.

The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm; p < 0.0001; prone position, 4.5 mm vs. 13.9 mm; p = 0.0001; 5.2 mm vs. 11.5 mm; p = 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25-3.85 mm) and in the forehead in the SMR method (3.3-8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region.

Multimodal Management of Combined Posterior and Anterior Surgical Approach and Postoperative Pharmacological Therapy for Giant Cell Tumor of the Cervical Spine Encasing the Vertebral Artery: A Technical Case Report.

Giant cell tumor (GCT) of bone is essentially benign but locally aggressive, and the rate of local recurrence is high when the resection is not enough. En bloc resection is recommended as an ideal solution for GCT to decrease the risk of local recurrence, but it remains challenging for cervical GCT. In this technical case report, we present a case of extensively infiltrating GCT of the cervical spine completely encasing the vertebral artery (VA) on one side. The tumor was distributed to layers A-D, sectors 3-8 based on the Weinstein-Boriani-Biagini staging. Combined posterior and anterior surgical approach for the cervical spine was successfully performed and followed by postoperative adjuvant pharmacological therapy. This kind of multimodal management may be one of the solutions for advanced cervical GCT.

Corrigendum: Evaluation of the Effectiveness of the Tap Test by Combining the Use of Functional Gait Assessment and Global Rating of Change.

[This corrects the article DOI: 10.3389/fneur.2022.846429.].

Evaluation of the Effectiveness of the Tap Test by Combining the Use of Functional Gait Assessment and Global Rating of Change.

Background: Although the tap test for patients with suspected idiopathic normal pressure hydrocephalus (iNPH) is still often performed as part of the preoperative evaluation, it is true that some studies have reported the limitations of the tap test, claiming that it does not provide the additional information for appropriate patient selection for surgery. We aimed to determine whether a better method of pre- and post-tap test assessment could lead to appropriate patient selection for shunting. Methods: We performed the tap test as part of the preoperative evaluation in all 40 patients who underwent lumboperitoneal shunt surgery for iNPH from April 2021 to September 2021. We retrospectively analyzed the patient data. We examined whether a comprehensive evaluation of the effect of the tap test using the Functional Gait Assessment (FGA) and Global Rating of Change (GRC) scales would identify a wider range of patients who would benefit from shunt surgery than the 3-m Timed Up and Go test (TUG) alone. Results: Assuming a prevalence of 1% for iNPH, the TUG had a sensitivity of 0.23, specificity of 0.71, positive likelihood ratio of 0.79, and negative likelihood ratio of 1.09. When improvement in either the FGA or the GRC was used as a criterion for the validity of the tap test, the sensitivity was 0.88, specificity was 0.17, positive likelihood ratio was 1.06, and negative likelihood ratio was 0.71. Conclusion: Improvement in either the FGA or the GRC is a more sensitive criterion for the effectiveness of the tap test for the gait aspect than the TUG. Since the negative likelihood ratio is lower than that for the TUG alone, it is more appropriate to exclude patients with neither FGA nor GRC improvement from surgical indications than to exclude surgical indications based on a negative TUG.

Anatomical Limitation of Posterior Spinal Myelotomy for Intramedullary Hemorrhage Associated with Ependymoma or Cavernous Malformation of the High Cervical Spine.

Spinal intramedullary tumors such as ependymoma or vascular lesions such as cavernous malformation are often at risk of intramedullary hemorrhage. Surgical procedures involving the high cervical spinal cord are often challenging. This technical note included four patients who presented with acute, subacute, or gradual onset of spinal cord dysfunction associated with intramedullary hemorrhage at the C1 or C1/2 level of the high cervical spine. The mean age was 46.3 years (16-74 years). All patients underwent posterior spinal cord myelotomy of the posterior median sulcus or posterolateral sulcus. It was not to exceed the caudal opening of the fourth ventricle (foramen of Magendie) and was assumed to be as high as the caudal medulla oblongata. Total removal of the intramedullary ependymoma or cavernous malformation occurred in three of four cases, and the remaining case had subtotal removal of the ependymoma. None of the patients showed postoperative deterioration of the neurological condition. Pathological examination of all cases revealed intramedullary hemorrhage was associated with ependymoma or cavernous malformation. Posterior spinal myelotomy should be limited to the caudal opening of the fourth ventricle (foramen of Magendie), that is the caudal medulla oblongata, to avoid the significant deterioration after surgery.

Characteristic and Management of Symptomatic Septum Pellucidum Cyst in Extreme Elderly Patient: Case Report and Literature Review.

Septum pellucidum cyst is rare and is defined as a fluid-filled space between the lateral ventricles; it has a width of 10 mm or more. In this case report, a surgical patient of symptomatic septum pellucidum cyst (SPC) in extreme age is described. To the best our knowledge, this is the first report of an extremely aged patient with symptomatic SPC that was successfully treated using a flexible neuroendoscope. An 85-year-old male complained of gradually worsening gait disturbance, dementia, and urinary incontinence without headache and was admitted to our hospital. MRI revealed a huge cyst between the lateral ventricles as well as ventricle dilatation with periventricular hyperintensity in T2-weighted image. The patient was diagnosed with symptomatic hydrocephalus with SPC and underwent neuroendoscopic fenestration of the cyst with the use of a flexible endoscope without cerebrospinal fluid shunt placement. Immediately after the surgery, the patient's gait disturbance and dementia were dramatically improved. In extremely aged patients, SPC tended to develop with idiopathic normal pressure hydrocephalus-like symptoms, including gait disturbance without increasing intracranial pressure, sensorimotor disturbances, and psychological disorders. Neuroendoscopic cyst fenestration with the use of a flexible scope for SPC is a less-invasive procedure and should be considered even for extreme elderly symptomatic patients.

Bilateral Posterolateral Sulcus Approach for the Removal of Spinal Intramedullary Metastatic Adenocarcinoma: A Technical Case Report.

Spinal intramedullary metastasis is an extremely rare event that occurs in advanced cancer. The surgical indications for spinal intramedullary metastasis are highly limited because of surgical difficulty and poor prognosis. In this technical case report, we present a rare case of spinal intramedullary metastasis from the lung that recurred late after local radiation to the spinal cord. The patient progressively experienced relapsed buttock pain and developed gait and urination disorders late after treatment for lung cancer. Imaging examinations suggested the recurrence of spinal intramedullary metastasis in the conus medullaris. Systemic examinations revealed no apparent recurrence in other organs, including the primary lung lesions. Gross total resection of the tumor within the conus medullaris was safely performed using the unilateral posterolateral (PLS) approach and by addition of the contralateral PLS approach. To the best of our knowledge, this is the first case in which a spinal intramedullary metastatic tumor was successfully removed using a bilateral PLS approach.

Boron neutron capture therapy using dodecaborated albumin conjugates with maleimide is effective in a rat glioma model.

Introduction Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. Methods and Results In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 h after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 h after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 h after MID-AC administration. Conclusion MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.

Synthesis and Catalytic Activities of 3-Decyl-ß-proline for Michael Reactions in Water without an Organic Solvent.

3-Decyl-ß-proline, which has a highly lipophilic substituent, was synthesized, and its catalytic activities in Michael addition using water as the solvent were investigated. The decyl substituent promoted the reaction by hydrophobic interactions to afford the Michael adduct in a high yield and with high diastereoselectivity under low catalyst loading.

Pituitary stone resulting in visual dysfunction and spontaneous rhinorrhea in nonfunctioning pituitary adenoma: illustrative case.

BACKGROUND: Calcifications in pituitary adenomas are rare, being found in only 5.4%-25% of reported cases. These are divided into eggshell-like calcifications around the tumor and nodular calcifications at the center of the tumor, the latter of which are called "pituitary stones" (PSs). OBSERVATIONS: The authors report the case of a 60-year-old male with a nonfunctional pituitary adenoma with PSs and asymptomatic ventricular dilatation who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhea and rapid visual aggravation without an increase in tumor size over the course of 4 years. After endoscopic transnasal surgery, his visual acuity immediately improved temporarily. It was believed that the increased intracranial pressure due to secondary hydrocephalus resulted in visual aggravation; thus, a ventriculoperitoneal (VP) shunt was created. After creation of the VP shunt, the patient's visual acuity improved gradually and completely. Histological findings showed that adenoma cells were observed among the lamellar bone trabeculae. To the best of the authors knowledge, this is the first report of osteoid metaplasia-type PSs in nonfunctioning pituitary adenoma. LESSONS: PSs formed near the sellar floor and caused spontaneous CSF rhinorrhea due to direct mechanical stress on the dura mater and optic nerves, which may have caused meningitis and secondary hydrocephalus that resulted in visual impairment independent of tumor size.

The Therapeutic Effects of Dodecaborate Containing Boronophenylalanine for Boron Neutron Capture Therapy in a Rat Brain Tumor Model.

BACKGROUND: The development of effective boron compounds is a major area of research in the study of boron neutron capture therapy (BNCT). We created a novel boron compound, boronophenylalanine-amide alkyl dodecaborate (BADB), for application in BNCT and focused on elucidating how it affected a rat brain tumor model. METHODS: The boron concentration of F98 rat glioma cells following exposure to boronophenylalanine (BPA) (which is currently being utilized clinically) and BADB was evaluated, and the biodistributions in F98 glioma-bearing rats were assessed. In neutron irradiation studies, the in vitro cytotoxicity of each boron compound and the in vivo corresponding therapeutic effect were evaluated in terms of survival time. RESULTS: The survival fractions of the groups irradiated with BPA and BADB were not significantly different. BADB administered for 6 h after the termination of convection-enhanced delivery ensured the highest boron concentration in the tumor (45.8 µg B/g). The median survival time in the BADB in combination with BPA group showed a more significant prolongation of survival than that of the BPA group. CONCLUSION: BADB is a novel boron compound for BNCT that triggers a prolonged survival effect in patients receiving BNCT.

Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats.

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl-closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)-a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21-24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26-36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25-37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28-40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.

Enantioselective α-Benzoyloxylation of Malonic Diesters by Phase-Transfer Catalysis.

A highly enantioselective α-benzoyloxylation of malonic diester has been achieved by phase-transfer catalysis. The reaction of α-monosubstituted tert-butyl methyl malonate with benzoyl peroxide in the presence of aqueous KOH and N-(9-anthracenylmethyl)cinchoninium chloride afforded the corresponding α,α-disubstituted products in generally excellent chemical yields (up to 99% yield) with high enantioselectivities (up to 96% ee). In addition, the utility of this methodology was exhibited by the synthesis of a mineralocorticoid receptor antagonist.

The novel bisphosphonate disodium dihydrogen-4-[(methylthio) phenylthio] methanebisphosphonate increases bone mass in post-ovariectomy rats.

The novel bisphosphonate (BP) disodium dihydrogen-4-[(methylthio) phenylthio] methanebisphosphonate (MPMBP) is a non-nitrogen-containing BP with an antioxidant side chain that possesses anti-inflammatory properties. We investigated the systemic effects of this compound on bone loss induced by ovariectomy (OVX) in adult rats. Micro-computed tomography revealed that MPMBP increased bone mass and density in both the metaphysis and diaphysis, and improved the structural properties important for mechanical strength of osteoporotic bone. Sequential bone labeling with tetracycline and calcein indicated that MPMBP decreased longitudinal growth of the primary spongiosa (PS), but stimulated cortical bone formation in the diaphysis. MPMBP increased type I collagen accumulation in the PS, and decreased the number and size of adipocytes in the bone marrow, suggesting inhibition of increased bone marrow adipogenesis induced by OVX. Furthermore, MPMBP reduced the number of bone resorbing cathepsin K-positive osteoclasts induced by OVX. These results suggest that MPMBP could improve bone loss induced by estrogen deficiency. Both stimulation of bone formation and inhibition of bone resorption might play a role in the increase in bone mass and bone density after MPMBP treatment.

Asymmetric synthesis and catalytic activity of 3-methyl-ß-proline in enantioselective anti-Mannich-type reactions.

Enantiomerically pure 3-methyl-ß-proline was synthesized using an asymmetric phase-transfer-catalyzed alkylation of a cyanopropanoate to establish the all-carbon stereogenic center. The catalytic activity of 3-methyl-ß-proline in the Mannich-type reaction between a glyoxylate imine and ketones/aldehydes was subsequently investigated. The catalyst was designed and found to be more soluble in nonpolar organic solvents relative to the unsubstituted ß-proline catalyst, and as a result allowed for added flexibility during optimization efforts. This work culminated in the development of a highly anti-diastereo- and enantioselective process employing low catalyst loading.