Experience With Tirabrutinib in the Treatment of Primary Central Nervous System Lymphoma that Is Difficult to Treat With Standard Treatment.

BACKGROUND/AIM: Standard treatment options for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based drug therapy and whole-brain radiation therapy. However, there are many cases in which these standard treatment options are not tolerated for various reasons. In the present study, five cases of refractory/relapsed PCNSL that are difficult to treat with standard treatment were successfully treated by tirabrutinib. PATIENTS AND METHODS: A total of 5 patients (4 women, 1 man) with refractory (n=3) and relapsed (n=2) PCNSL were included. The patients had a median age of 76 years and a median Karnofsky performance status (KPS) of 40. The reasons why standard treatment cannot be given to these patients are the low KPS, renal dysfunction, and resistance to HD-MTX. Administration of a drug via the oral route was challenging in three patients; thus, these patients were administered tirabrutinib in suspension through a nasogastric tube. RESULTS: Imaging findings showed that the patients achieved a 100% response rate to tirabrutinib, with a median survival of 8 months. As symptoms improved, 2 of the 3 patients who were initially administered tirabrutinib via a nasogastric tube were able to receive the drug via the oral route. Three patients developed adverse reactions; however, treatment was not interrupted because they were manageable. CONCLUSION: Tirabrutinib was effective in the treatment of patients who were unable to receive standard treatment options. Tirabrutinib may be considered one of the novel treatment strategies that could improve the prognosis of PCNSL patients in the future.

High 11 C-Methionine Uptake in a Parasellar Inflammatory Pseudotumor.

ABSTRACT: A 20-year-old man had left visual impairment and homonymous hemianopsia. MRI findings suggested enlargement of an optic glioma, because optic glioma was indicated by MRI 14 years earlier without a definite pathological diagnosis. 11 C-methionine (MET) PET showed high uptake in the tumor in the parasellar region. Transnasal endoscopic biopsy was performed, and an inflammatory pseudotumor (IPT) was diagnosed based on histopathological findings. High MET uptake in a parasellar IPT has apparently not been previously reported. Clinicians should be aware of the possibility of high MET uptake in IPT, because this image could provide an interpretation pitfall.

Experience with nasogastric tube administration of tirabrutinib in the treatment of an elderly patient with primary central nervous system lymphoma.

We report that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient's level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia.

Japanese local government management of compulsory hospitalization for patients with mental disorders and comorbid COVID-19.

Administering medical treatment or managing quarantine for a patient is particularly difficult when a patient harming others or causing self-harm because of severe depression, a manic state, or psychomotor agitation is also infected with COVID-19. Kanazawa University Hospital is the only facility able to manage such difficult cases occurring in Ishikawa prefecture, a local administrative area in Japan. The hospital has arranged a negative pressure apparatus in a psychiatric ward with two protection rooms. This report describes an urgently established but viable system in one prefecture of Japan for treating COVID-19-infected patients with severe psychiatric symptoms during the COVID-19 pandemic.

Remote Reminiscence Using Immersive Virtual Reality May Be Efficacious for Reducing Anxiety in Patients with Mild Cognitive Impairment Even in COVID-19 Pandemic: A Case Report.

To prevent cognitive decline, non-pharmacological therapies such as reminiscence for mild cognitive impairment (MCI) are required, however, the use of nursing homes was limited due to coronavirus disease 2019 (COVID-19). Therefore, the demand for remote-care is increasing. We hypothesized that immersive virtual reality (iVR) could be used more effectively than conventional reminiscence for anxiety. We first examined the effectiveness and safety of reminiscence using iVR (iVR reminiscence session) in patients with MCI. After COVID-19 imposed restriction on visiting nursing homes, we conducted online iVR reminiscence session (remote iVR reminiscence session) and compared its effectiveness with that of interpersonal iVR reminiscence session (face-to-face iVR reminiscence session). The results of two elderly with MCI suggested that iVR reminiscence could reduce anxiety and the burden of care without serious side effects. The effects of remote iVR reminiscence might be almost as effective as those of face-to-face one.

Effectiveness of Palliative Cerebrospinal Fluid Shunting for Patients With Leptomeningeal Carcinomatosis-related Hydrocephalus.

BACKGROUND/AIM: Leptomeningeal carcinomatosis (LMC) with hydrocephalus is particularly difficult to treat, and its prognosis is extremely poor. The therapeutic outcomes of 14 patients with LMC-associated hydrocephalus who were treated with cerebrospinal fluid shunting are reported. PATIENTS AND METHODS: The study subjects were 14 LMC patients with solid primary cancer who had developed hydrocephalus. RESULTS: Postoperatively, both symptoms and Karnofsky performance status improved in 100% of patients. Postoperative therapy consisted of whole-brain radiotherapy in 4 cases and molecular targeted therapy in 4, with 6 patients not receiving any postoperative treatment. Median overall survival was 3.7 months, with no significant difference between those who underwent postoperative therapy and those who did not. However, two of those who received molecular targeted therapy survived for more than one year. CONCLUSION: Cerebrospinal fluid shunting for LMC-associated hydrocephalus is an effective therapeutic procedure from the palliative viewpoint. Patients for whom molecular targeted therapy is indicated may have better long-term survival.

Surgical outcome and graded prognostic assessment of patients with brain metastasis from adult sarcoma: multi-institutional retrospective study in Japan.

BACKGROUND: Brain metastasis (BM) is an uncommon complication of sarcomas with a poor prognosis. Little information is available about the feasibility and prognostic factors of surgical resection of BM from sarcomas. METHODS: This study involved a retrospective analysis of 22 patients with BM from sarcomas who underwent resection at six institutes in Japan. Prognostic factors were analyzed to develop a graded prognostic assessment (GPA) using the log-rank test and Cox regression analysis. For validation of this GPA, we collected data on 100 surgical cases from 48 published reports. RESULTS: Postoperative Karnofsky Performance Status (KPS) improved in 50% of our patients. Median overall survival (OS) was 21 months. Multivariate analysis showed age and alveolar soft part sarcoma (ASPS) were significant preoperative prognostic factors (P < 0.05). RTOG-RPA classification had no significant prognostic value. We developed a GPA system for OS after resection of BM. A score of 0 was assigned to patients aged 18-29 years with non-ASPS, 2 to patients aged 18-29 years with ASPS or 30-76 years with non-ASPS, and 4 to patients aged 30-76 years with ASPS. Median OS for patients with GPA scores of 0, 2, and 4 were 6.5, 16.0, and 44.0 months, respectively (P = 0.002). The results were validated by the data of 100 cases compiled (P < 0.001). CONCLUSION: Median OS of patients with BM from sarcomas was comparable to that from carcinomas after resection. A new sarcoma-specific GPA may help patients and clinicians to select resection as an option for treatment of BM from sarcomas.

Clinical Outcomes of Surgical Resection for Brain Metastases from Non-small Cell Lung Cancer.

BACKGROUND/AIM: Recent advances in systemic chemotherapy, including molecularly targeted therapy, have dramatically improved survival for patients with advanced non-small cell lung cancer. We retrospectively analyzed the clinical outcomes of surgical resection for brain metastases of non-small cell lung cancer cases performed at the Department of Neurosurgery of Kindai University Hospital, Osaka, Japan. PATIENTS AND METHODS: Craniotomy and tumor resection were performed for 56 patients with brain metastases of non-small cell lung cancer. Adenocarcinoma was the most common histological type, appearing in 40 cases, of which 18 were positive for driver gene mutations. RESULTS: Median survival for all 56 patients was 14.5 months, and single brain metastasis and adenocarcinoma were identified as favorable prognostic factors. Analysis limited to the 40 cases of adenocarcinoma identified single brain metastasis as a favorable prognostic factor. Although no significant difference was found for systemic chemotherapy, patients who received molecularly targeted therapy showed a better prognosis than those who received cytotoxic chemotherapy. Analyses of both the entire group and of adenocarcinoma patients alone found that whole-brain radiotherapy showed no significant association with survival. CONCLUSION: Single brain metastasis and adenocarcinoma were identified as favorable prognostic factors, but did not confirm any benefit from whole-brain radiotherapy. These results suggest that multimodal treatment strategies utilizing various methods of treatment, including systemic chemotherapy, may help prolong patient survival in the future.

Epstein-Barr Virus-Induced Post-Transplant Lymphoproliferative Disorder of the Central Nervous System Successfully Treated with Chemo-immunotherapy.

Aplastic anemia is a rare blood disease characterized by the destruction of the hematopoietic stem cells (HSC) in the bone marrow that, in the majority of cases, is caused by an autoimmune reaction. Patients with aplastic anemia are treated with immunosuppressive drugs and some of them, especially younger individuals with a donor available, can be successfully treated with hematopoietic stem cell transplantation (HSCT). We report here a rare case of post-transplant lymphoproliferative disorder (PTLD) associated with Epstein-Barr virus (EBV) reactivation in a 30-year-old female patient who underwent allogeneic HSCT for severe aplastic anemia. The PTLD, which was diagnosed 230 days after transplantation, was localized exclusively in the central nervous system (specifically in the choroid plexus) and manifested with obvious signs of intracranial hypertension. After receiving three cycles of high dose methotrexate (HD-MTX) combined with rituximab, the patient achieved a complete clinical recovery with normalization of blood cell counts, no evidence of EBV reactivation, and no associated neurotoxicity.

Immersive Virtual Reality Reminiscence Reduces Anxiety in the Oldest-Old Without Causing Serious Side Effects: A Single-Center, Pilot, and Randomized Crossover Study.

Background: Dementia is one the major problems of aging societies, and, novel and effective non-drug therapies are required as interventions in the oldest-old to prevent cognitive decline. Objective: This study aims to examine the efficacy and safety of reminiscence using immersive virtual reality (iVR reminiscence) focusing on anxiety that often appears with cognitive decline. The secondary objective is to reveal the preference for VR image types for reminiscence: live-action (LA) or computer graphics (CG). Methods: This was a pilot, open-label, and randomized crossover study which was conducted on January 2020 at a single nursing home. The subjects were randomly divided into two groups (A or B) in equal numbers, and they alternately viewed two types of VR images (LA and CG) themed on the mid- to late Showa era (A.D. 1955-1980) in Japan. In group A, the CG images were viewed first, and then the LA images were viewed (CG→ LA). In group B, the images were viewed in the opposite order (LA→ CG). Before VR viewing, subjects responded to Mini-Mental State Examination (MMSE) Japanese version and State-Trait Anxiety Inventory (STAI) Japanese version. After viewing the first and second VR, subjects responded to STAI and the numerical rating scale (NRS) for satisfaction and side effects (nausea, dizziness, headache, and tiredness). Results: Ten subjects participated in this study. The values of analyses are presented in the mean (SD). The age was 87.1 years (4.2), and the MMSE was 28.5 (1.8). The total STAI score before VR viewing was 36.1 (7.2), but it significantly decreased to 26.8 (4.9) after the first VR viewing (P = 0.0010), and further decreased to 23.4 (2.8) after the second VR viewing (P < 0.001). The NRS score for satisfaction tended to be higher after viewing LA in group A (CG→ LA) (CG vs. LA; 7.0 (2.3) vs. 8.6 (1.5), P = 0.0993), while in group B (LA→ CG), the score after CG was slightly lower than that after LA. There were no serious side effects. Conclusions: This study suggests that iVR reminiscence can reduce anxiety in the oldest-old without causing serious side effects. Furthermore, the impacts might be better with LA images.

A case of leptomeningeal metastases of human epidermal growth factor receptor 2-positive breast cancer that responded well to lapatinib plus capecitabine.

BACKGROUND: Leptomeningeal metastases (LM) pose the most difficult form of cancer metastasis to treat and portend a poor prognosis. Standard treatment has yet to be established, and intrathecal chemotherapy and whole- brain radiotherapy are administered on an empirical basis. CASE DESCRIPTION: We report on a 46-year-old woman with LM from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. She was suffering from intractable headaches, severe nausea and vomiting, and cerebellar ataxia. Contrast-enhanced magnetic resonance imaging (MRI) revealed diffuse enhancement of the meninges, mainly in the posterior cranial fossa, and compression of the cerebellum by the profoundly thickened meninges. The first step in the treatment was decompression of the posterior cranial fossa to relieve intracranial hypertension. After surgery, her symptoms immediately improved. The second step was treatment with lapatinib at 1250 mg and capecitabine 1200 mg, which dramatically improved her symptoms and disappeared diffuse abnormal signal enhancement on MRI. CONCLUSION: We treated a patient with LM from primary HER2-positive breast cancer who responded well to lapatinib plus capecitabine.

Significance of Elevated HMGB1 Expression in Pituitary Apoplexy.

BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation. PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens. RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478). CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.

Intravascular Lymphoma Presenting as a Cavernous Sinus Tumor.

Intravascular lymphoma (IVL) is a malignant lymphoma that lacks the expression of cell surface adhesion molecules so that cells fluidly migrate within the blood vessels. The patient in the present study had restricted eye movement caused by IVL, mimicking a cavernous sinus tumor. Because the cavernous sinus lumen is divided into multiple compartments by trabeculae and venous channels, IVL tumor cells were trapped in these compartments, thus forming a mass, which subsequently extended into the contralateral cavernous sinus via the anterior and posterior intercavernous sinuses. This is a rare case of IVL forming a mass inside the cavernous sinus.

Seizures and Tumor Progression in Glioma Patients with Uncontrollable Epilepsy Treated with Perampanel.

BACKGROUND/AIM: Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy. PATIENTS AND METHODS: Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed. RESULTS: Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER. CONCLUSION: PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.

Clinical outcomes of brain metastases from hepatocellular carcinoma: a multicenter retrospective study and a literature review.

INTRODUCTION: The introduction of systemic chemotherapy for advanced hepatocellular carcinoma in recent years has led to the prediction that cases of brain metastases from hepatocellular carcinoma will increase. However, because brain metastases from hepatocellular carcinoma are relatively rare, the characteristics of this pathology are poorly understood. METHODS: We carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan. RESULTS: A total of 38 patients were enrolled and patient characteristics were poor general condition in many patients due to the progression of primary cancers. Stereotactic radiosurgery/stereotactic radiotherapy alone was the most common treatment (39.5%), with best supportive care provided for 10.5%. Median survival was 6 months, the neurological death rate was 28%, and the rate of brain hemorrhage was high (39.5%). Overall survival was analyzed for correlations with age, etiology of chronic liver disease, albumin-bilirubin (ALBI) grade, RPA classification, control of the primary tumor, number of brain metastases, brain hemorrhage, surgical resection, and radiotherapy. In multivariate analysis, ALBI grade, number of brain metastases and brain hemorrhage showed statistically significant correlation. CONCLUSIONS: A multivariate analysis extracted three items-ALBI grade, number of brain metastases, and brain hemorrhage-as prognostic factors for survival of brain metastases from hepatocellular carcinoma.

Efficacy of Combination Therapy with MET and VEGF Inhibitors for MET-overexpressing Glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a malignant brain tumor with an extremely poor prognosis. GBM tissues frequently express mesenchymal-epithelial transition factor (MET), which induces cell division, growth and migration. In addition, angiogenesis is a significant feature of GBM, attributable to the overexpression of vascular endothelial growth factor (VEGF). Although the VEGF inhibitor bevacizumab was recently highlighted as the second-line drug for GBM treatment, GBMs often recur even with bevacizumab therapy. Based on these findings, we hypothesized that inhibition of both MET and VEGF would exhibit a synergistic effect on MET-overexpressing GBM. MATERIALS AND METHODS: As we observed MET expression at high levels in some patients with GBM, we designed GL261 murine glioma-based experiments. GL261 cells were transfected with siRNAs specific for MET and VEGF in vitro, and the cell growth ratios were evaluated. Simultaneously, transfected GL261 cells were transplanted into the brain of C57BL/6 mice, and their survival was monitored. RESULTS: GBM tissues frequently overexpressed MET protein at high levels compared with lower-grade gliomas. These GBMs at first responded to bevacizumab, but often eventually recurred. When GL261 cells were co-transfected with both MET-specific siRNA and VEGF-specific siRNA, the in vitro tumor cell growth significantly decelerated compared to single siRNA transfection. Consistently, when mice were transplanted with co-transfected GL261 cells, their survival was significantly prolonged compared to those given cells transfected with single siRNA. CONCLUSION: The current data indicate that the inhibition of both MET and VEGF exhibits efficient therapeutic effects of GBM-bearing hosts.

Surgical Site Infection after Malignant Brain Tumor Resection: A Multicenter Study for Induction of a Basic Care Bundle.

Patients with malignant brain tumors are possibly at increased risk for surgical site infections (SSIs) considering the various medical situations associated with the disease. However, the actual rate of SSI after malignant brain tumor resection has not been well established, despite the potential impact of SSI on patient outcome. To investigate the incidence of SSI following malignant brain tumor surgery, we performed a retrospective study in 3 neurosurgical units. Subsequently, aiming at the reduction of incidence of SSI, we performed a prospective study using a care bundle technique in the same units. The SSI incidence in the retrospective (n = 161) and prospective studies (n = 68) were 4.3% and 4.4%, respectively, similar to the previously reports on general craniotomies. A care bundle does not appear to enhance prevention of SSI. However, future, large studies with a new care bundle should be planned based on a zero tolerance policy.

A nationwide multi-institutional retrospective study to identify prognostic factors and develop a graded prognostic assessment system for patients with brain metastases from uterine corpus and cervical cancer.

BACKGROUND: The prevalence of brain metastases (BM) from uterine cancer has recently increased because of the improvement of overall survival (OS) of patients with uterine cancer due to its early detection and improved local control as a result of new effective treatments. However, little information is available regarding their clinical characteristics and prognosis, because oncologists have encountered BM from uterine cancer on rare occasions. METHODS: Records from 81 patients with uterine BM were collected from 10 institutes in Japan. These were used in a multi-institutional study to identify prognostic factors and develop a graded prognostic assessment (GPA) for patients with BM from uterine cancer. RESULTS: Median OS after the development of BM was 7 months (95% confidence interval, 4 to 10 months). Multivariate analysis revealed that there were survival differences according to the existence of extracranial metastases and number of BM. In the present uterine-GPA, a score of 0 was assigned to those patients with ≥5 BM and extracranial metastasis, a score of 2 was assigned to those patients with one to four BM or without extracranial metastasis, and a score of 4 was assigned to those patients with one to four BM and without extracranial metastasis. The median OS for patients with a uterine-GPA scores of 0, 2, and 4 was 3, 7, and 22 months, respectively. A survival analysis confirmed the presence of statistically significant differences between these groups (p < 0.05). The results were validated by data obtained from the National Report of Brain Tumor Registry of Japan. CONCLUSION: Uterine GPA incorporates two simple clinical parameters of high prognostic significance and can be used to predict the expected survival times in patients with BM from uterine cancer. Its use may help in determining an appropriate treatment for individual patients with BM.

[Diagnosis of Cochleovestibular Neurovascular Compression Syndrome:A Scoring System Based on Five Clinical Characteristics].

The optimal method for diagnosing cochleovestibular neurovascular compression syndrome(CNVC)remains controversial, and the aim of this study is to develop a standard diagnostic instrument for the condition. The clinical features of 53 sides of 50 patients with a combination of vertigo, tinnitus, and/or hearing loss were retrospectively evaluated. The following five clinical features were evaluated and given a score of 1 or 0:1)a long history of recurrent vertigo, tinnitus, or hearing loss;2)neurological findings related to positional vertigo, nystagmus, tinnitus, or hearing loss;3)neuro-otological findings involving tinnitus, audiometry, or vestibular testing;4)auditory brainstem response(ABR)evaluation with the detection of a low 25-75% II wave amplitude on the contralateral side and delayed interpeak latency in the I-III or I-V waves(usually low II wave amplitude combined with double peaks and a wide-based form)during ABR evaluation using 80 and 90dB clicks;and 5)the detection of vascular contact with the eighth cranial nerve on magnetic resonance imaging-constructive interference in steady state or air computed tomography imaging. Finally, the sum of these scores was evaluated. For cases in which more than one of the features of the items 1), 2), or 3) were present, the score was evaluated based on the most representative of the items. RESULTS: The patients were divided into those with scores of 4-5 and those with scores of 2-3. All the patients with scores of 4-5 exhibited CNVC, while those with scores of 2-3 had other diseases. Therefore, CNVC should be suspected in patients with scores of 4-5, but can be ruled out in those with scores of 2-3.

Clinical outcome of node-negative oligometastatic non-small cell lung cancer.

INTRODUCTION: The concept of "oligometastasis" has emerged as a basis on which to identify patients with stage IV non-small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. PATIENTS AND METHODS: Consecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study. Patients with regional lymph node-negative disease and a limited number of metastatic lesions (≤5) per organ site and a limited number of affected organ sites (1 or 2) were eligible. RESULTS: Eighteen patients were identified for analysis during the study period. The most frequent metastatic site was the central nervous system (CNS, 72%). Most patients (83%) received systemic chemotherapy, with only three (17%) undergoing surgery, for the primary lung tumor. The CNS failure sites for patients with CNS metastases were located outside of the surgery or radiosurgery field. The median overall survival for all patients was 15.9 months, with that for EGFR mutation-positive patients tending to be longer than that for EGFR mutation-negative patients. CONCLUSION: Cure is difficult to achieve with current treatment strategies for NSCLC patients with synchronous oligometastases, although a few long-term survivors and a smaller number of patients alive at last follow-up were present among the study cohort. There is an urgent clinical need for prospective evaluation of surgical resection as a treatment for oligometastatic NSCLC, especially negative for driver mutations.