Preliminary findings of German-sourced ONC201 treatment in H3K27 altered pediatric pontine diffuse midline gliomas.

PURPOSE: H3K27 altered pediatric pontine diffuse midline gliomas (pDMG) have a poor prognosis, and conventional treatments offer limited benefits. However, recent advancements in molecular evaluations and targeted therapies have shown promise. The aim of this retrospective analysis was to evaluate the effectiveness of German-sourced ONC201, a selective antagonist of dopamine receptor DRD2, for the treatment of pediatric H3K27 altered pDMGs. METHODS: Pediatric patients with H3K27 altered pDMG treated between January 2016 and July 2022 were included in this retrospective analysis. Tissue samples were acquired from all patients via stereotactic biopsy for immunohistochemistry and molecular profiling. All patients received radiation treatment with concurrent temozolomide, and those who could acquire GsONC201 received it as a single agent until progression. Patients who could not obtain GsONC201 received other chemotherapy protocols. RESULTS: Among 27 patients with a median age of 5.6 years old (range 3.4-17.9), 18 received GsONC201. During the follow-up period, 16 patients (59.3%) had progression, although not statistically significant, the incidence of progression tended to be lower in the GsONC201 group. The median overall survival (OS) of the GsONC201 group was considerably longer than of the non-GsONC201 group (19.9 vs. 10.9 months). Only two patients receiving GsONC201 experienced fatigue as a side effect. 4 out of 18 patients in the GsONC201 group underwent reirradiation after progression. CONCLUSION: In conclusion, this study suggests that GsONC201 may improve OS in pediatric H3K27-altered pDMG patients without significant side effects. However, caution is warranted due to retrospective design and biases, highlighting the need for further randomized clinical studies to validate these findings.

Cutaneous rhabdomyosarcoma with FUS::TFCP2 fusion: A case report emphasizing early detection.

Rhabdomyosarcoma with TFCP2 rearrangement is a recently identified malignant neoplasm characterized by immunohistochemical evidence of rhabdomyoblastic differentiation, keratin expression, upregulation of ALK, and an aggressive clinical course. This neoplasm has a tendency to affect craniofacial bones, with only a few reported cases of extra-osseous tumors. Here, we present a case of cutaneous rhabdomyosarcoma with FUS::TFCP2 fusion in a 35-year-old female. Notably, the tumor exhibited a pathologic spectrum, initially resembling sclerosing dermatitis at presentation but progressing into a high-grade malignant tumor within 8 months. The distinctive immunoprofile of this neoplasm highlights the importance of early molecular studies for diagnosis, even in the presence of low-grade cytomorphology. Early detection may offer an opportunity for timely resection before the tumor becomes unresectable.

Expanding the Spectrum of the Soft Tissue Tumors with Kinase Gene Fusions: A Pediatric Spindle Cell Neoplasm Harboring MTAP-RAF1 Fusion.

Introduction: NTRK-rearranged spindled cell tumors have been increasingly recognized with the widespread use of molecular studies. We describe a pediatric spindle cell neoplasm with MTAP-RAF1 gene fusion that fits into this group. Case report: An 8-year-old girl presented with mandibular mass. Histopathologically, it was a moderate to increased cellular spindle cell tumor with mild-to-moderate nuclear pleomorphism, focal perivascular keloid-like collagen, that was positive for S-100 and CD34. MTAP-RAF1 fusion was detected by next generation sequencing, confirming a low-grade sarcoma with MTAP-RAF1 fusion that is presently included in the category of NTRK-rearranged spindled cell tumors. Discussion: MTAP-RAF1 fusion, in the spectrum of spindle cell neoplasms with kinase gene rearrangements, can occur in the pediatric age group.

Malignant nerve sheath tumor of oculomotor nerve in a pediatric patient.

Malignant nerve sheath tumors are extremely rare pathologies. They tend to occur within peripheral nerves and have close association of neurofibromatosis disease. Here, we present the second case of MNST of oculomotor nerve in literature. The patient was a 2-year-old girl with left sided oculomotor nerve palsy. After resection, the patient immediately had chemotherapy and radiotherapy. One year after surgery disease progressed with extensive intracranial seedings, and she passed away.

Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature.

Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFß and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors' proliferative index (Ki67) increased from 5-6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.

Polymorphous low-grade neuroepithelial tumor of the young: A detailed pathomolecular analysis and discussion of a case.

AIM: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare entity with a diffuse, infiltrative pattern, awaiting to be included in the WHO CNS tumor classification; it occurs in pediatric and young patients with seizures and harbors mutually exclusive BRAFV600E or FGFR mutations. Nonetheless, the presence of these mutations may not be obligatory for diagnosis. The conventional histology of these tumors resembles that of oligodendrogliomas. We aimed to discuss a PLNTY case in a young woman presenting with seizures due to a parietal brain tumor and to provide an analysis of the literature. Histopathologically the tumor was consistent of oligodendroglioma-like neoplastic cells showing almost diffuse CD34 and olig-2 staining, retained ATRX expression, p53-negativity, and a low Ki67 index with no necrosis or microvascular proliferation. MATERIALS AND METHODS: 1p/19q statuswas analyzed with FISH; IDH1 and IDH2 mutations were analyzed with minisequence analysis. Translocations, mutations, and expression analyses were studied for 18, 19, and 21 genes via targeted new-generation deep RNA sequencing, respectively. RESULTS: The tumor did not carry 1p/19q codeletion, was IDH wild-type, and had radiological features compatible with the diagnosis of PLNTY. The tumor did not show BRAF or FGFR alterations but had an EGFR c.2342A>G (p.Asn781Ser) mutation which was likely a non-driver mutation due to its low allele frequency of 4%. CONCLUSION: PLNTYs are rare brain tumors, and their accurate diagnosis is important to avoid improper management. Their prognosis shall be stratified according to their mutations.

Spinal intramedullary H3K27M mutant glioma with vertebral metastasis: a case report.

A new entity of gliomas, named "diffuse midline glioma (DMG), H3K27M mutant (grade IV)," which represents a specific molecular profile, was introduced to the World Health Organization (WHO) classification 2016 of central nervous system tumors. Many midline localizations have been described for this glioma, and mainly the hypothalamus, pons, thalamus, and spinal cord are sites of predilection in pediatric and young adult patients. We report the case of spinal intramedullary DMG, H3K27M mutant (WHO grade IV), that showed an unusual presentation with multiple vertebral metastases.

A pediatric cerebral tumor with MN1 alteration and pathological features mimicking carcinoma metastasis: may the terminology "high grade neuroepithelial tumor with MN1 alteration" still be relevant?

INTRODUCTION: Astroblastoma, MN1-altered (old name: high-grade neuroepithelial tumor/HGNET with MN1 alteration) is a recently described central nervous system tumor mostly affecting pediatric patients and profoundly young girls. Differential pathological diagnoses of these tumors include ependymoma, pleomorphic xanthoastrocytoma, embryonal tumor with multilayered rosettes, meningioma, and even glioblastoma. As the treatment approaches to these tumors differ, it is essential to increase the awareness about these tumors in the neurosurgical community. CLINICAL PRESENTATION: A 7-year-old female patient admitted with a 7-day history of headache, nausea, and vomiting. A contrasted MRI scan revealed a left parietal 4 × 4 × 5 cm mass with central necrosis and peripheral contrast enhancement. The tumor's histopathological findings were suggestive of a metastatic carcinoma with unknown primary, yet further genetic analysis revealed MN1 alteration. Peculiarly, the tumor pathomorphological features were not compatible with astroblastomas and exerted features strongly indicating a metastatic cancer; however, systemic PET and whole-body MRI failed to detect a primary malignancy. OUTCOME AND CONCLUSIONS: Eighteen months after gross-total tumor resection, an in-field and out-field multifocal recurrence developed which required a second surgery and subsequent chemo-radiotherapy. The patient is doing well for 1 year after the second treatment regimen at the time of this report. Despite the final cIMPACT6 classification in 2020 advised to define all MN1 altered brain tumors as astroblastomas, there exist prognostic differences in MN1-altered tumors with and without morphological features of astroblastoma. Rare morphological variants of MN1-altered tumors shall be recognized for their future prognostic and clinical classification. HGNET with MN1 alteration seems still be a more proper definition of such malignancies as an umbrella term.

Is it a new culprit? "TERT promoter mutation" in an aggressive pediatric pilocytic astrocytoma.

Recent advances in the genomic study have revolutionized the discovery of molecular biomarkers in glioma not only to aid in targeted therapy but also to prognosticate character of tumor and outcome of a patient.The usually benign nature of pilocytic astrocytoma (PA) can now be challenged with the discovery of genomic alterations that could promote more aggressive clinical behavior. CDKN2A deletion and ATRX gene inactivation or mutation have been the most common molecular alterations in worse prognosis.We will discuss a case of pilocytic astrocytoma showing the progressive recurrence with pilomyxoid features and the presence of TERT promoter mutation.

Benign leiomyoma with multiple metastases to vertebrae and calvarium: An index case with comprehensive review of endocrine targets.

"Benign" metastatic leiomyomas (BML) are indolently growing metastatic tumors which mostly associate with uterine leiomyomas in women in reproductive ages. The reason to define these lesions as "benign" despite metastasis is their pathological features with low mitotic counts, lack of or minimal nuclear atypia, pseudocyst formation, and coagulative necrosis unlike leiomyosarcomas. Despite lack of pathological malignant features, they may cause significant morbidity and even mortality. Here, we describe a BML case with metastases to vertebrae and skull bones. Vertebral and skull metastases of BMLs were very rarely reported. In treatment of these tumors, hysterectomy and GnRH modifier treatments are widely employed. GnRH agonists act by desensitization and downregulation of the GnRH receptors, while GnRH antagonists act via the canonical competitive blockage. These treatments reduce FSH and LH levels, thereby reducing the systemic levels of sex steroids which stimulate leiomyoma growth. However, leiomyomas inherently harbor aromatase activity and synthesize their own estrogen; hence, treatment with systemic estrogen antagonists may provide better tumor control. Another important factor in BML pathogenesis is progesterone, and both progesterone receptor antagonists and high-dose progesterone receptor agonists may reduce BML growth. Following surgical treatment of the calvarial mass and radiotherapy of the vertebral metastatic foci, our BML case was successfully managed with hysterectomy and anastrozole treatment. Higher awareness of BML cases and their molecular endocrinological features in the neurosurgical community may pave to develop better strategies for treatment of these tumors causing high morbidity.

Is H3K27me3 status really a strong prognostic indicator for pediatric posterior fossa ependymomas? A single surgeon, single center experience.

PURPOSE: Posterior fossa ependymomas (PFE) are among the most frequently occurring solid tumors in children. Their definitive treatment is surgical excision and adjuvant radio-chemotherapy. This study aimed to investigate prognostic effects of age, H3K27me3 status, extent of resection, radiation treatment (RT), Ki67 index, WHO grade, and ATRX and H3K27M mutations in PFE patients. METHODS: This retrospective study included 42 pediatric patients with PFE who had undergone operation at our institution between 1996 and 2018. Patient demographics and treatment information were obtained from patient notes. Information on radiological location of tumors (median vs paramedian), extent of tumor resection, and recurrence was obtained from preoperative and postoperative magnetic resonance imaging. Formalin-fixed paraffin-embedded tumor samples were evaluated for H3K27me3 immunostaining, Ki67 index, WHO grades, and ATRX and H3K27M mutations. Tumor samples with global reduction in H3K27me3 were grouped as posterior fossa ependymoma group A (PFA) and those with H3K27me3 nuclear immunopositivity as posterior fossa ependymoma group B (PFB). We evaluated the cohort's 5-year progression-free survival (PFS) and overall survival (OS). RESULTS: There were 20 (47.6%) female and 22 (52.4%) male patients in the cohort. The mean age of patients was 4.4 (range, 0.71-14.51) years. Overall, tumors in 31 (73.8%) and 11 (26.2%) patients were found to be PFA and PFB, respectively. There was no statistically significant age or sex difference between PFA and PFB. All patients received chemotherapy, whereas only 28 (66.6%) received RT. The WHO grades of PFA were statistically higher than those of PFB. There was no significant difference between PFA and PFB in terms of extent of resection, disease recurrence, and survival parameters. Nine of 42 tumor samples had ATRX mutations. One patient with PFA showed H3K27M mutation. Age, WHO grade, H3K27me3 status, and RT had no effect on patients' PFS and OS. Patients with total surgical excisions had significantly better PFS and OS rates. Those with Ki67 < 50% also had better OS rates. CONCLUSIONS: Determining H3K27me3 status by immunohistochemistry is a widely accepted method for molecular subgrouping of PFEs. Most of the reports in the literature state that molecular subgroups of PFEs have significantly different clinical outcomes. However, in our present series, we have shown that the extent of surgical excision is still the most important prognostic indicator in PFEs. We also conclude that the prognostic effect of H3K27me3 status-based molecular subgrouping may be minimized with a more aggressive surgical strategy followed in PFAs.

The importance of brain banking for dementia practice: the first experience of Turkey.

This study reports the results of the first brain tissue banking experience of Turkey in the Unit for Aging Brain and Dementia at Dokuz Eylul University, Department of Geriatric Medicine, Izmir. Here, we have briefly described our efforts on brain banking in our country, which consist of six brains from autopsies that had at least two years of clinical follow-up in the 2015-2017 period. The evaluation led to the diagnosis of two Alzheimer's disease (AD) with cerebral amyloid angiopathy, one AD with dementia with Lewy bodies, one corticobasal degeneration, one multiple system atrophy, one vascular dementia. We believe that the study is of a special importance because of its potential of becoming a brain banking center in the region and because of its contributing to the international knowledge of the neuropathological features of dementia, while characterizing the epidemiology of these diseases in the region.

Pediatric Diffuse Leptomeningeal Glioneuronal Tumors: Diagnosis, Follow-up, and Treatment Options.

AIM: To highlight the diagnosis, follow-up, and treatment options for diffuse leptomeningeal glioneuronal tumor (DLGNT) by examining pediatric patients diagnosed with DLGNT by molecular pathological evaluation and next generation sequencing at our center. MATERIAL AND METHODS: In this retrospective analysis, patients diagnosed with DLGNT between January 2017 and December 2022 are outlined according to their demographic data, radiological data, pathology results, treatments, and follow-up data. RESULTS: Four patients were diagnosed with DLGNT. All the patients were male. The mean age was 6.5 years. All but one patient had symptoms of increased intracranial pressure. An open biopsy was obtained from all patients for diagnosis. Three patients received radiotherapy and chemotherapy after the diagnosis. Two patients died during their follow-up, one of them in the early postoperative period. Two patients were clinically and radiologically stable in their follow-up after treatment. CONCLUSION: Further work with larger cohorts is required to determine a common algorithm for DLGNT treatment and follow-up. This analysis may keep this entity in mind in patients with pediatric communicating hydrocephalus and may present insight into diagnosis, follow-up, and treatment options.

Prevalence of Rathke Cleft and Other Incidental Pituitary Gland Findings on Contrast-Enhanced 3D Fat-Saturated T1 MPRAGE at 7T MRI.

BACKGROUND AND PURPOSE: A cleftlike nonenhancing hypointensity was observed repeatedly in the pituitary gland at the adenohypophysis/neurohypophysis border on contrast-enhanced 3D fat-saturated T1-MPRAGE using clinical 7T MRI. Our primary goal was to assess the prevalence of this finding. The secondary goals were to evaluate the frequency of other incidental pituitary lesions, MRI artifacts, and their effect on pituitary imaging on the contrast-enhanced 3D fat-saturated T1 MPRAGE at 7T. MATERIALS AND METHODS: One hundred patients who underwent 7T neuroimaging between October 27, 2021, and August 10, 2023, were included. Each case was evaluated for cleftlike pituitary hypointensity, pituitary masses, and artifacts on contrast-enhanced 3D fat-saturated T1 MPRAGE. Follow-up examinations were evaluated if present. The average prevalence for each finding was calculated, as were descriptive statistics for age and sex. RESULTS: A cleftlike hypointensity was present in 66% of 7T MRIs. There were no significant differences between the "cleftlike present" and "cleftlike absent" groups regarding sex (P = .39) and age (P = .32). The cleftlike hypointensity was demonstrated on follow-up MRIs in 3/3 patients with 7T, 1/12 with 3T, and 1/5 with 1.5T. A mass was found in 22%, while 75% had no mass and 3% were indeterminate. A mass was found in 18 (27%) of the cleftlike present and 4 (13%) of the cleftlike absent groups. The most common mass types were Rathke cleft cyst in 7 (31.8%) patients, "Rathke cleft cyst versus entrapped CSF" in 6 (27.3%), and microadenoma in 6 (22.2%) in the cleftlike present group. There were no significant differences in the mass types between the cleftlike present and cleftlike absent groups (P = .23). Susceptibility and/or motion artifacts were frequent using contrast-enhanced 3D fat-saturated T1 MPRAGE (54%). Artifact-free scans were significantly more frequent in the cleftlike present group (P = .03). CONCLUSIONS: A cleftlike nonenhancing hypointensity was frequently seen on the contrast-enhanced 3D fat-saturated T1 MPRAGE images at 7T MRI, which most likely represents a normal embryologic Rathke cleft remnant and cannot be seen in lower-field-strength MRIs. Susceptibility and motion artifacts are common in the sella. They may affect image quality, and the artifacts at 7T may lead to an underestimation of the prevalence of the Rathke cleft and other incidental findings.

Identification of IDH and TERTp mutations using dynamic susceptibility contrast MRI with deep learning in 162 gliomas.

PURPOSE: Isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase gene promoter (TERTp) mutations play crucial roles in glioma biology. Such genetic information is typically obtained invasively from excised tumor tissue; however, these mutations need to be identified preoperatively for better treatment planning. The relative cerebral blood volume (rCBV) information derived from dynamic susceptibility contrast MRI (DSC-MRI) has been demonstrated to correlate with tumor vascularity, functionality, and biology, and might provide some information about the genetic alterations in gliomas before surgery. Therefore, this study aims to predict IDH and TERTp mutational subgroups in gliomas using deep learning applied to rCBV images. METHOD: After the generation of rCBV images from DSC-MRI data, classical machine learning algorithms were applied to the features obtained from the segmented tumor volumes to classify IDH and TERTp mutation subgroups. Furthermore, pre-trained convolutional neural networks (CNNs) and CNNs enhanced with attention gates were trained using rCBV images or a combination of rCBV and anatomical images to classify the mutational subgroups. RESULTS: The best accuracies obtained with classical machine learning algorithms were 83 %, 68 %, and 76 % for the identification of IDH mutational, TERTp mutational, and TERTp-only subgroups, respectively. On the other hand, the best-performing CNN model achieved 88 % accuracy (86 % sensitivity, 91 % specificity) for the IDH-mutational subgroups, 70 % accuracy (73 % sensitivity and 67 % specificity) for the TERTp-mutational subgroups, and 84 % accuracy (86 % sensitivity, 81 % specificity) for the TERTp-only subgroup using attention gates. CONCLUSIONS: DSC-MRI can be utilized to noninvasively classify IDH- and TERTp-based molecular subgroups of gliomas, facilitating preoperative identification of these genetic alterations.

Magnetic resonance spectroscopic correlates of progression free and overall survival in "glioblastoma, IDH-wildtype, WHO grade-4".

Background: The 2021 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification has suggested that isocitrate dehydrogenase wildtype (IDH-wt) WHO grade-2/3 astrocytomas with molecular features of glioblastoma should be designated as "Glioblastoma, IDH-wildtype, WHO grade-4." This study analyzed the metabolic correlates of progression free and overall survival in "Glioblastoma, IDH-wildtype, WHO grade-4" patients using short echo time single voxel 1H-MRS. Methods: Fifty-seven adult patients with hemispheric glioma fulfilling the 2021 WHO CNS Tumor Classification criteria for "Glioblastoma, IDH-wildtype, WHO grade-4" at presurgery time point were included. All patients were IDH1/2-wt and TERTp-mut. 1H-MRS was performed on a 3 T MR scanner and post-processed using LCModel. A Mann-Whitney U test was used to assess the metabolic differences between gliomas with or without contrast enhancement and necrosis. Cox regression analysis was used to assess the effects of age, extent of resection, presence of contrast enhancement and necrosis, and metabolic intensities on progression-free survival (PFS) and overall survival (OS). Machine learning algorithms were employed to discern possible metabolic patterns attributable to higher PFS or OS. Results: Contrast enhancement (p = 0.015), necrosis (p = 0.012); and higher levels of Glu/tCr (p = 0.007), GSH/tCr (p = 0.019), tCho/tCr (p = 0.032), and Glx/tCr (p = 0.010) were significantly associated with shorter PFS. Additionally, necrosis (p = 0.049), higher Glu/tCr (p = 0.039), and Glx/tCr (p = 0.047) were significantly associated with worse OS. Machine learning models differentiated the patients having longer than 12 months OS with 81.71% accuracy and the patients having longer than 6 months PFS with 77.41% accuracy. Conclusion: Glx and GSH have been identified as important metabolic correlates of patient survival among "IDH-wt, TERT-mut diffuse gliomas" using single-voxel 1H-MRS on a clinical 3 T MRI scanner.

A pediatric bithalamic high grade glioma with concomitant H3K27M and EGFR mutations.

BACKGROUND: Despite many treatment approaches, survival rates in high grade glial tumors are still not at the desired level. One of the cause of this failure might be that although having similar histologic features, they may display different biological behaviors depending on molecular heterogeneity. CASE: A 10-year-old girl presented with sudden onset left sided hemiparesis, headache, and ataxia. Physical examination was normal except for left sided hemiparesis and ataxia. A hyperintense mass lesion involving the bilateral thalamus was detected in the axial T2-weighted and coronal FLAIR sequences on brain MRI. There was no enhancement in axial T1-weighted contrast-enhanced sequences. Due to the size and location of the tumor, the patient was considered inoperable. Intensity modulated radiotherapy was intended for curative treatment to the patient because the radiological findings suggested a low-grade glial tumor. Tumor was unresponsive to radiotherapy but biopsy could be performed. The histopathological examination revealed a diffuse glial tumor with increased cellularity, mild nuclear atypia and rare mitosis. Due to the infiltrative pattern of the tumor, it was accepted as a high grade diffuse glial tumor. A chemotherapy protocol including cisplatin and etoposide in the first cycle, vincristine and cyclophosphamide in the second cycle, and carboplatin and vincristine in the third cycle were instituted to the patient. After the third cycle of chemotherapy, the tumor progressed radiologically. H3.1 K27M c.83A > T (HIST1H3C p.Lys28Met), ATRX c.2169_2170del (p.Glu723AspfsTer9), TP53 c.338T > C (p.Phe113Ser), and EGFR c.2300_2308dup (p.Ala767_va1769dup) were detected in the genetic assessment of tumor tissue. The patient`s treatment was changed to vincristine, temozolomide, and irinotecan. Unfortunately, MRI showed progression after three cycles of second-line chemotherapy. The patient`s family refused any further treatment, and the patient died with progressive disease in a short time. CONCLUSIONS: EGFR mutation along with H3.1 K27M mutation is extremely rare in children to our knowledge. It should be kept in mind that if there is a possibility of targeted therapy, there may be a treatment option in this malignant disease with a poor prognosis.

Towards Development of a Standard Terminology of the World Health Organization Classification of Tumors of the Central Nervous System in the Turkish Language, and a Perspective on the Practical Implications of the WHO Classification for Low and Middle Income Countries.

In our manuscript, we propose a common terminology in the Turkish language for the newly adopted WHO classification of the CNS tumors, also known as the WHO CNS 5th edition. We also comment on the applicability of this new scheme in low and middle income countries, and warn about further deepening disparities between the global north and the global south. This division, augmented by the recent COVID-19 pandemic, threatens our ability to coordinate efforts worldwide and may create significant disparities in the diagnosis and treatment of cancers between the "haves" and the "have nots".

Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis.

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.

A 52-Year-Old Man With Progressive Weakness and Incontinence.

Here we report a challenging case of a 52-year-old man presenting with subacute constipation, urinary retention, impotence, absent Achilles reflexes, and hypoesthesia in S2-S5 dermatomes. We review the clinical decision-making as the symptoms evolved and diagnostic testing changed over time. Once the diagnosis is settled, we discuss the sign and symptoms, additional diagnostic tools, treatment options and prognosis.