Dysembryoplastic neuroepithelial tumor
Dysembryoplastic neuroepithelial tumors are rare, indolent, low-grade tumors found in children and young adults. Most commonly affecting the temporal
Mar. 22, 2021
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Ganglioglioma is an uncommon, usually low-grade, central nervous system tumor with neuronal tissue and glial cells. In this article, the authors discuss diagnosis and treatment of ganglioglioma.
• Gangliogliomas are well-differentiated, slow-growing, mixed neuronal-glial tumors composed of dysplastic ganglion cells (neurons) and neoplastic glial cells.
• They should be suspected in any child or young adult with temporal-lobe epilepsy and a temporal lobe cortical-based lesion on imaging, although these tumors can be found throughout the central nervous system.
• Though mostly low grade, World Health Organization (WHO) grade I, 5% are classified anaplastic ganglioglioma (WHO III or high grade). No criteria for WHO II gangliogliomas have been established.
• Gross total resection of the tumor remains the only effective treatment in most cases, and prognosis is excellent when a grade I ganglioglioma is gross totally resected.
• Identification of IDH1/2, TP53, or PTEN mutations or of CDK4 or EGFR amplification strongly argues against the diagnosis of ganglioglioma.
• Gangliogliomas are characterized by mitogen-activated protein kinase (MAPK) pathway activation through different genetic alterations, most commonly BRAF V600E mutation (20%–80% of gangliogliomas). BRAF V600E status should be determined for possible targeted therapy in case of residual and/or recurrent tumor.
Gangliogliomas and gangliocytomas comprise a spectrum of low-grade tumors characterized by a dysplastic neuronal (or ganglion) cell types. In gangliogliomas, the dysplastic neuronal cells are accompanied by neoplastic glial cells, whereas in gangliocytomas, large, multipolar binucleated well-differentiated neurons are the unique neoplastic component.
The term ganglioglioma was originally described in 1926 (29). Diagnosis was initially based on gross histopathology and light microcopy with additional use of electron microscopy. Histochemistry and immunocytoreactivity are currently used to demonstrate the ganglion cells component. The oncofetal marker CD34 and detection of BRAF V600E mutation or other MAPK pathway alterations characterize gangliogliomas.
Ganglioglioma is the top differential diagnosis in any patient presenting with chronic, medically refractory epilepsy during the first 3 decades of life, in which a temporal mass isointense to gray matter on T1-weighted images is found on brain MRI. Eighty percent of all gangliogliomas present by 30 years of age, with majority (63%) after age 10 and less than 5% before the first year of life (06). Median age at diagnosis is 19 years old for low-grade gangliogliomas and about 40 years for anaplastic gangliogliomas, with a slight male predominance for either grade.
Gangliogliomas can occur anywhere in the brain or spinal cord, though are most commonly found in superficial hemispheres (greater than 90%), especially temporal lobes (greater than 45%). They have been reported in the pineal and sellar regions, basal ganglia, ventricles, and, less frequently, infratentorially and within the cranial nerves. Multifocal intracranial gangliogliomas at diagnosis have also been described (22).
Focal seizure is the most frequent presenting symptom of cerebral ganglioglioma (occurring in greater than 75% of patients), and long-standing epilepsy is not uncommon; in fact, ganglioglioma represents 1 of the most common epilepsy-associated tumors and even may be an incidental finding on temporal lobectomies performed for epilepsy management (Moris et al Epilepsia 1998). Otherwise, the locus of the ganglioglioma in the brain often determines the presenting symptoms or signs. In posterior fossa gangliogliomas, obstructive hydrocephalus, with symptoms of increased intracranial pressure such as headache or depressed consciousness, is the most frequent presentation. For spinal gangliogliomas, the most common presenting symptoms are back pain and extremity weakness (08).
Prognostic factors associated with aggressive behavior include grade III histology, older age, and loss of p16 or CDKN2A mutation (41).
LT, a 30-year-old, right-handed mechanical engineer, had a history of focal seizures since 12 years of age; these seizures were characterized by odd smell, spreading discomfort, and “déjà-vu” lasting less than a minute, with postictal anxiety and no altered consciousness. Seizure frequency increased over the years from a few annually to a few daily and went unmanaged.
Over the next several years, he experienced intermittent short-time memory loss and increasing word finding difficulties. At 30 years of age, he had a generalized tonic-clonic seizure with postictal speech production difficulty. On ensuing brain MRI, he was found to have a nonenhancing left mesial temporal mass. The lesion was hyperintense on T2/FLAIR weighted-imaging and contained a small cyst.
Imaging differential diagnosis included dysembryoplastic neuroepithelial tumor and ganglioglioma. He was started on antiepileptic drug and referred to neurosurgery. A preoperative comprehensive neuropsychological testing reported baseline impaired naming and reduction in auditory attention, suggesting some compromise of the left temporal lobe. An interictal EEG showed continuous left temporal slowing.
Given his course, the patient accepted to proceed with surgical resection. He was considered at risk of postoperative language deficits because of the location of the lesion; thus, awake craniotomy with speech mapping and intraoperative electrocorticography was done to localize extra lesional epileptiform activity, and the lesion was completely resected. The pathology was consistent with a WHO grade I ganglioglioma. The patient experienced postoperative transient word finding difficulties that resolved with time. Postsurgery, he remained seizure free for 3 years, though remained on antiseizure medication; he continued semiannual MRI follow up without recurrence to date.
The etiology and the molecular pathogenesis of ganglioglioma remain unclear. The cell of origin is suggested to be a common glioneural precursor with clonal neoplastic proliferation of the glial cell population.
Although no specific mutation has been identified as a solely causative genetic aberration, gangliogliomas have been characterized by alterations that activate the MAPK signaling pathway, similar to pilocytic astrocytomas, dysembryoplastic neuroepithelial tumors, rosette-forming glioneural tumors, polymorphous low-grade neuroepithelial tumors, and multinodular and vacuolating neuronal tumors (28). In a cohort of 40 gangliogliomas on which targeted next-generation sequencing was performed, 36 had mutations activating MAPK signaling pathway (18 BRAF V600E mutation, 5 other BRAF mutation, 4 BRAF fusion, 2 KRAS mutation, 1 RAF1 fusion, 1 NF1 biallelic mutation, and 5 FGFR1/2 alterations). In the majority, genetic alterations with MAPK pathway was the solitary genetic alteration identified. None had IDH, TP52, ATRX, TERTp, CIC, or FUBP1 mutation; MYB-MYBL1 rearrangement; or TSC1-TSC2 mutation (28).
Somatic BRAF V600E mutation in developing neurons have been implicated in the intrinsic epileptogenicity in ganglioglioma (13; 03). The BRAF V600E–induced epileptogenesis seems to be mediated by RE1-silencing transcription factor, which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy (13). In that study, seizure control in mice was significantly improved with a BRAF inhibitor, vemurafenib.
Genetic susceptibility. Rare cases of gangliogliomas have been described in patients with cancer predisposition syndromes such as neurofibromatosis types 1 and 2 and Peutz-Jeghers syndrome (STK11 mutation) (35; 04; 36; 07).
Pathology. Macroscopically, gangliogliomas are well-circumscribed solid or cystic lesions with minimal mass effect and occasional calcifications. Microscopically, gangliogliomas, as suggested by their name, consist of a combination of 2 cell populations, in varying proportion:
(1) Ganglion cells (ganglio-) are large mature dysplastic neurons. Dysplastic neurons are characterized by lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, and binucleated or clustering appearance.
(2) Neoplastic glial cells (-glioma) can resemble pilocytic astrocytoma, fibrillary astrocytoma, or oligodendroglioma.
Other prominent features include perivascular lymphocytic infiltrates, important capillary network, dystrophic calcifications, and mild to moderate cellularity (occasional mitoses and small foci of necrosis are compatible with the diagnosis). In less than 5% of cases, these tumors show aggressive histopathological features such as increased cellularity, nuclear pleomorphism, increased mitosis, vascular proliferation, and necrosis, and they are then called anaplastic gangliogliomas (WHO grade III). In such cases, exclusion of diffuse glioma with entrapped neurons is mandatory. Also, note that the 2016 WHO classification does not define criteria for WHO II gangliogliomas (19).
The neuronal elements are demonstrated by positive immunostaining for neuronal markers such as microtubule-associated protein 2, neurofilament, chromogranin-A, synaptophysin, and CD34. CD34 is positive in about 80% of ganglioglioma and is not present in neurons of adult brain (19). Glial elements are demonstrated by cytoplasmic positivity for GFAP. The mean MiB1 labelling index, calculated from the glial component, is less than 3%.
Genetic profile. About 30% of gangliogliomas have chromosomal abnormalities, with gain of chromosome 7 being the most frequently described. Firm associations between cytogenetic data and clinical outcome is lacking (19). BRAF V600E mutation is the most common genetic alteration found in 20% to 60% of gangliogliomas, both WHO grade I and III (27). BRAF V600E is not specific for ganglioglioma because this mutation is also found in pleomorphic xanthoastrocytoma, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumors, and epithelioid glioblastoma. Identification of IDH1/2, TP53, or PTEN mutations or of CDK4 or EGFR amplification strongly argues against the diagnosis of ganglioglioma.
Gangliogliomas account for 0.4% to 1.3% of all central nervous system tumors (19), and for up to 10% of all pediatric central nervous system tumors (12; 25). In population-based epidemiological data on newly diagnosed and histologically confirmed gangliogliomas from 2006 to 2011 in France, worldwide adjusted incidence rate was estimated to be less than 0.2 out of 100,000 person-years for WHO grade I ganglioglioma, and less than 0.02 out of 100,000 person-years for WHO grade III ganglioglioma (05). About 80% of WHO grade I gangliogliomas are diagnosed in patients less than 30 years of age (37). Median age at diagnosis is 19 years for low-grade ganglioglioma and almost 40 years for anaplastic gangliogliomas, but they can occur at any age. There is a slight male predominance (1.14:1) (05).
The clinical differential diagnosis of ganglioglioma is broad and varies with patients and imaging characteristics. Most importantly, ganglioglioma should be considered high on the list of causes in any child/young adult presenting with temporal lobe epilepsy with an intra-axial temporal lesion seen on MRI, especially if it is a cortically-based, partially cystic enhancing mass. However, ganglioglioma should also be included in the differential of all lesions with unusual imaging characteristics seen in the optic pathway, sellar, pineal, intraventricular, and cerebellar-pontine angle regions.
In supratentorial tumors, the main differential diagnosis includes dysembryoplastic neuroepithelial tumor (DNET), pleomorphic xanthoastrocytoma (PXA), pilocytic astrocytoma, desmoplastic infantile astrocytoma and ganglioglioma, diffuse astrocytoma, and oligodendroglioma. If the lesion is hemispheric and cortically-based, the differential diagnosis is further restricted to DNET, PXA, and oligodendroglioma. DNET can be differentiated from ganglioglioma due to the DNET’s multicystic “bubbly” appearance and milder, infrequent contrast enhancement; oligodendroglioma may be more heterogeneous due to frequent calcifications and hemorrhagic components; PXA usually shows prominent contrast-enhancement of both the cystic wall and its mural nodule abutting the pia. In case of a superficial mass associated with skull remodeling, meningioma needs also to be considered. Desmoplastic infantile astrocytoma and ganglioglioma, as its name implies, most commonly occurs in children below 2 years of age and manifests as an exceptionally large cerebral hemispheric cystic and solid mass, most commonly in frontal and parietal lobes. In infratentorial tumors, the differential diagnosis includes pilocytic astrocytoma, diffuse astrocytoma, medulloblastoma, and hemangioblastoma.
Histologically, the neoplastic glial component of the tumor can resemble pilocytic astrocytoma, fibrillary astrocytoma, or oligodendroglioma and may, therefore, be mistaken for such tumors, among others. The presence of anaplastic features such as mitoses, increased proliferative activity, necrosis, and/or vascular proliferations expands the differential diagnosis to include high-grade astrocytic tumors. In a pathological review of 22 anaplastic gangliogliomas, 9 (41%) cases were reclassified (40).
As with all neoplasms, the workup for ganglioglioma includes cerebral imaging (CT or MRI) followed by surgical resection. Imaging characteristics are highly variable due to the various pattern of growth and possible locations of these tumors. Supratentorial gangliogliomas present as a sharply demarcated lesion, either as a solid-only (in approximately 50% of cases) or as a cystic or solid-cystic mass. Over 60% demonstrate contrast-enhancement, with either a nodular, rim, or solid enhancement pattern. Compared to supratentorial gangliogliomas, infratentorial gangliogliomas have less cystic changes (about 20% compared to 50%) and more contrast-enhancement (over 70% compared to less than 50%), especially when located in the cervicomedullary junction (100% are enhancing) (18; 10).
On CT, approximately 30% of gangliogliomas show calcifications, and bony remodeling can be seen (19). Gadolinium-enhanced MRI is the imaging modality of choice, and both the brain and spine should be performed if leptomeningeal dissemination or ventricular seeding of ganglioglioma is suspected. On MRI, the solid component is iso- to hypointense to grey matter on T1-weighted imaging (T1WI), hyperintense on T2WI, and the solid component shows variable enhancement intensity and pattern on T1WI post-contrast imaging. Cystic component has variable T2WI signal depending on the presence of blood products and the amount of proteinaceous material. Peritumoral T2/FLAIR edema is distinctly uncommon in ganglioglioma, arguing against the diagnosis. On susceptibility weighted imaging, about 30% of gangliogliomas will show blooming signal loss corresponding to calcified areas, and rarely to blood products. Anaplastic gangliogliomas seem to lose the typical radiological characteristics of grade I gangliogliomas, especially their cystic and well-circumscribed features, and they gain characteristics of anaplastic gliomas and glioblastomas, such as necrosis, surrounding cerebral edema and mass effect (40).
It must be emphasized that the diagnosis of a ganglioglioma cannot be excluded by a negative CT or MRI examination only. There are reports of histologically confirmed ganglioglioma without a recognizable tumor on either CT or MRI images.
Gross total surgical resection (GTR) followed by close observation with serial MRI is the treatment of choice for ganglioglioma, as extent of resection is considered to be the single most important prognosis factor (10). Fluorescence-guided tumor resection has been used to improve intraoperative visualization and extent or resection during resection of gangliogliomas (09). In cases of subtotal resection (STR), the role of adjuvant therapies, either radiation therapy and/or chemotherapy, is uncertain, but preferably reserved for grade III ganglioglioma. On recurrence or tumor regrowth, surgical resection should be repeated whenever feasible. Targeted therapy against the BRAF/MEK pathway represents a novel and promising therapeutic option in gangliogliomas harboring BRAF V600E mutation.
After gross total resection, there is no clear benefit of adjuvant radiation therapy (32). For those with subtotal resection or biopsy, the role of radiation is controversial, as it may improve progression-free survival but not overall survival in both low- and high-grade gangliogliomas; this point was illustrated in a large study comparing 4 therapies for local control and overall survival in 402 patients with ganglioglioma (33). The 10-year local control and overall survival rates were 89% and 95% after gross total resection, 90% and 95% after gross total resection plus radiotherapy, 52% and 62% after subtotal resection, and 65% and 74% after subtotal resection plus radiotherapy, respectively. After subtotal resection, irradiation significantly improved local control but not overall survival. After gross total resection, irradiation did not significantly improve local control or overall survival. Given that majority of gangliogliomas are found in young adults and are located in temporal lobe, the benefit of radiation must be carefully considered against the long-term toxicity, especially its neurocognitive impact. In addition, some in the field have expressed concern that radiation therapy may contribute to transformation to a more anaplastic tumor (39). As such, adjuvant radiation after a subtotal resection should be reserved for those with a high risk of recurrence, such as anaplastic gangliogliomas, in whom a retrospective review showed a 3 times increased rate of recurrence among gangliogliomas with highly anaplastic features, compared to those with moderate anaplastic features (15). However, there are insufficient data to make a firm recommendation about the role of radiation therapy after subtotal resection of low-grade gangliogliomas.
Chemotherapy may also be considered for prevention of ganglioglioma recurrence, although the agent of choice and the optimal duration are unknown. A variety of chemotherapeutics agents have been used as adjuvant therapy, including temozolomide, vincristine, procarbazine, and the nitrosoureas.
Bevacizumab, an anti-VEGF antibody, has been described to rapidly shrink the cystic component of a low-grade ganglioglioma (17).
Targeted therapy with oral selective BRAF V600E inhibitors represents a promising therapeutic option in the 20% to 60% gangliogliomas harboring BRAF V600E mutation. BRAF is a member of the RAS/RAF/MEK/ERK pathway, and the BRAF V600E mutation activates MERF-ERK signaling, promoting cell proliferation, differentiation, and survival. BRAF V600E mutation in some tumors can be sensitive to BRAF V600E mutant-specific inhibitors such as vemurafenib and dabrafenib. In a review summarizing the available data on BRAF V600 point mutations and the antineoplastic activity and toxicity profiles of BRAF inhibitors in neuroepithelial brain tumors such as gangliogliomas, BRAF inhibitors were active and well tolerated in recurrent tumors after failure of other therapies in both pediatric and adult patients (31). A report on the use of dabrafenib in 3 children with unresectable brainstem ganglioglioma observed rapid and durable clinical and radiological improvement, but with a rapid relapse within days to weeks following treatment discontinuation. Notably, all 3 patients showed similar rapid and sustained therapeutic response when dabrafenib was reintroduced, with good tolerability despite up to 5.5 years of use (30). A partial response has been noted in a patient with anaplastic ganglioglioma treated with vemurafenib in the prospective VE-BASKET trial (11).
Intolerance and, more frequently, acquired resistance to BRAF inhibitor have been reported, and a combination of BRAF and MEK inhibitors seems to improve both tolerance and efficacy (14). A case of anaplastic gangliogliomas intolerant to vemurafenib demonstrated tumor response to the BRAF/MEK inhibitor combination dabrafenib and trametinib (23). Another case of anaplastic ganglioglioma that progressed on vemurafenib alone reportedly responded to a combination of vemurafenib and cobimetinib (41). As 90% of ganglioglioma harbor mutations activating the MAPK pathway (28), acquired resistance to vemurafenib may result from persistent MAPK activation downstream to BRAF V600E, and the combination of BRAF/MEK inhibition could overcome resistance.
Nonetheless, the status for BRAF V600E mutation should be tested for all gangliogliomas to at least allow for the possibility of dual targeted therapy in case of tumor regrowth or of incomplete resection, as recommended by the National Comprehensive Cancer Network Guidelines for central nervous system cancers (14).
Lastly, adequate symptom management of increased intracranial pressure and epilepsy is important. When hydrocephalus is present, ventricular shunting may be necessary. Although seizures due to ganglioglioma can usually be controlled with appropriate antiepileptic medications, surgical resection of the tumor is curative in most patients (01).
The typical patient with ganglioglioma generally follows a “manageable” clinical course, but tumor recurrence, malignant progression, and secondary glioblastoma have been observed in some cases. Good prognosis has been associated with lower-grade, temporal location, epilepsy, and gross total resection. Greater extent of resection is the most important variable associated with long-term disease-free survival (20; 33; 02; 10).
The overall prognosis of patients with low-grade ganglioglioma is favorable, with a 95% 7.5-year recurrence-free survival rate (06). Survival rates of 93% at 5 year, 98% at 7.5 year, and 94% at 15 year have been reported from large series (20; 02; 06).
Brainstem and spinal cord gangliogliomas tend to have worse prognosis than supratentorial tumors because of increased subtotal resection and operative morbidity (16). In 1 retrospective review including only patients with brainstem gangliogliomas, the 3-year survival rate was 91%, with a 3-year event-free survival rate of 68% and a mean recurrence-free survival rate of 5.5 months (26). The 5-year survival rate for brainstem gangliogliomas compared to non-brainstem gangliogliomas was reported in 2 large studies showing 79% to 81% versus 93% to 97%, respectively (16; 06). Brainstem gangliogliomas also exhibited a 3-year event-free survival rate and a 5-fold increase risk of recurrence (16).
Anaplastic ganglioglioma. More aggressive behavior may be indicated by anaplastic changes in the glial component. Unfortunately, due to the rarity of anaplastic ganglioglioma, there are scarce data to assess long-term outcomes or prognostic factors, or accurately predict the risk of recurrence in both pediatric and adult populations. As such, varying outcomes have been reported in the literature, ranging from 25% to 88% 5-year survival rate, and 38% to 100% 5-year recurrence rates, with up to 45% of those progressing to secondary glioblastoma (21; Karreman et al 2009; 37; 40). In the largest multicenter retrospective analysis of 43 adults with pathologically confirmed anaplastic ganglioglioma, survival was only slightly improved compared to glioblastomas despite gross total resection and adjuvant therapy (40). Patients who had undergone gross total resection followed by the radiation plus temozolomide were the subgroup with the best median overall survival (37 months).
Epilepsy. The prognosis for epilepsy in the setting of ganglioglioma is excellent. The meta-review of patients after ganglioglioma resection on epilepsy outcomes, including 20 retrospective articles since 1995, with a total of 553 patients, concluded that resection leaves most patients seizure free and many with freedom from antiepileptic therapy, regardless of patients’ demographic, tumor characteristic, and operative variables (01). Although there exist wide variations in reporting standards, the most consistent finding across studies was the correlation of increased seizure freedom with increased extent of resection. Other prognostic factors associated with seizure freedom included shorter duration of epilepsy and younger age at surgery. Reported rates of seizure freedom following surgery ranged from 63% to 100%, with mean follow-up intervals ranging from 3 to 10 years. Many of the included studies had follow-up time of greater than 5 years, suggesting durable response. Between 17% to 77% of seizure-free patients were weaned from antiepileptic drugs in the studies reporting this measure.
Epilepsy associated with anaplastic ganglioglioma has been far less studied. Yet, a 2017 retrospective monocentric series of 18 patients with supratentorial anaplastic ganglioglioma suggested a lower rate of epilepsy in high-grade gangliogliomas compared to low-grade gangliogliomas (35% to 67% vs. 70% to 100%, respectively) (42). However, increasing prevalence of seizures was noted during the natural course of anaplastic ganglioglioma: 44% at imaging discovery, 67% at histopathological diagnosis, 86% at tumor progression, and 100% at the end-of-life. Predictors of seizures at diagnosis were mostly related to tumor location (temporal lobe and/or cortical involvement), but occurrence of seizure at diagnosis did not affect time-to-progression or survival. Regarding low-grade gangliogliomas, extent of resection appears to be associated with increased epilepsy control.
No data are available to suggest any correlation of this tumor with pregnancy. Nonenhanced MRI is the imaging modality of choice and has been demonstrated safe for both the mother and the fetus as gadolinium crosses the placenta, although it has not been associated with birth defects at conventional doses (38). Symptomatic relief of headache and seizures can be accomplished with well-known medications accepted as being of low fetal risk. Hydrocephalus, if serious enough to produce papilledema or other significant effects, can be surgically corrected during pregnancy, as demonstrated in 1 review (34).
No special anesthetic precautions are mandated by the presence of this tumor. General symptoms of increased intracranial pressure may require an alteration in patient preparation for anesthesia.
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Novocure for advisory board membership, and research support from BMS.See Profile
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