Longitudinal health-related quality of life analysis in childhood cancer survivors after proton beam therapy.

PURPOSE: Whilst proton beam therapy (PBT) for children with cancer is expected to reduce their comorbidities, to date only a limited number of studies have been published. To analyze the long-term comorbidity and health-related quality of life (HRQoL) of childhood cancer survivors (CCSs) after PBT, we conducted a questionnaire-based study. METHODS: Questionnaires were sent to CCSs who underwent PBT at the University of Tsukuba Hospital during the period from 1984 to 2020. Scores from 41 CCSs who did not undergo PBT (noPBT-CCSs) and from the general population were used for comparison. RESULTS: In total, 110 individuals who underwent PBT participated in the study. Among them, 40 individuals were longitudinally analyzed. The range of change in the scores was significantly greater in the CCSs whose initial scores were low. Although the comorbidity levels were more severe, HRQoL tended to be better in the PBT-CCSs than in the noPBT-CCSs with central nervous system (CNS) or solid tumors, respectively. When compared with the general population, the psychosocial health summary scores and its components were not different in the noPBT-CNS-CCSs. On the other hand, the psychosocial health summary scores and/or at least one of the scores of emotional, social, and school functioning were significantly higher in the other CCSs groups. CONCLUSIONS: The HRQoL scores of CCSs with low initial scores can be greatly changed over time. Appropriate psychosocial support for this population is warranted. PBT may avoid reduction in HRQoL in terms of the psychosocial functioning of CCSs with CNS tumors.

Cancer-Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan.

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer-predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients' peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

Maximum resection and immunotherapy improve glioblastoma patient survival: a retrospective single-institution prognostic analysis.

Glioblastoma (GBM) is a refractory disease with a poor prognosis and various methods, including maximum resection and immunotherapy, have been tested to improve outcomes. In this retrospective study we analyzed the prognostic factors of 277 newly diagnosed GBM patients over 11 years of consecutive cases at our institution to evaluate the effect of these methods on prognosis. Various data, including the extent of removal (EOR) and type of adjuvant therapy, were examined and prognostic relationships were analyzed. The median overall survival (OS) of the entire 277-case cohort, 200 non-biopsy cases, and 77 biopsy cases was 16.6 months, 19.7 months, and 9.7 months, respectively. Gross total removal (GTR; 100% of EOR) was achieved in 32.9% of the cases. Univariate analysis revealed younger age, right side, higher Karnofsky performance status, GTR, intraoperative magnetic resonance imaging (MRI) use for removal, proton therapy, combination immunotherapy, and discharge to home as good prognostic factors. Intraoperative MRI use and EOR were closely related. In the multivariate analysis, GTR, proton therapy, and a combination of immunotherapies, including autologous formalin-fixed tumor vaccine, were the significant prognostic factors. A multivariate analysis of 91 GTR cases showed that immunotherapy contributed to prognostic improvements. The median OS and 5-year OS % values were 36.9 months and 43.3% in GTR cases receiving immunotherapy. In conclusion, GTR, proton therapy, and immunotherapy were good prognostic factors in single-center GBM cases. Tumor vaccine therapy for GTR cases achieved a notably high median survival time and long-term survival ratio, indicating its usefulness in GTR cases.

Association of Kabuki syndrome and tethered cord syndrome: a report of three cases and literature review.

Kabuki syndrome (KS) is a congenital disorder characterized by distinctive facial features, skeletal and dermatoglyphic abnormalities, mild-to-moderate intellectual disability, and postnatal growth deficiency. Recently, mutations in the KMT2D and KDM6A genes have been identified as the causative factors in most KS cases. In this study, we present three cases of KS associated with tethered cord syndrome. All cases had a sacral dimple, which is a skin stigmata, and radiological abnormalities, including fatty or thickened filum terminale. Untethering surgery was performed and clinical improvement was achieved. Although in the association between KS and closed neural tube defect (NTD) has rarely been discussed, we emphasize that sacral dimples in KS and tethered cord syndrome are not uncommon. The KS patients with sacral dimple must be carefully investigated by radiological examination and urological study if there is abnormality. Further understanding of the genetic mechanism underlying KS might provide a novel insight on the correlation between the genetics and development of closed NTDs.

Involvement of the optic pathway and outcome of visual function in patients with neurohypophyseal germ cell tumor.

BACKGROUND: Patients with neurohypophyseal germ cell tumors (GCTs) typically present with visual problems. Hence, this study aimed to assess optic pathway involvement based on clinical and radiological findings and to validate the outcome of visual function. METHODS: A total of 16 patients with newly diagnosed neurohypophyseal GCTs who were treated at the University of Tsukuba Hospital between 2000 and 2020 were included in this study. RESULTS: The median interval from symptom onset to diagnosis was 173.5 days (range, 33-1588 days). Patients with visual disturbance at diagnosis had a longer time to diagnosis compared with those without. Ophthalmologic abnormalities were frequently observed, with an incidence rate of 69%. Fifty percent of patients exhibited optic pathway involvement detected via magnetic resonance imaging (MRI). Visual impairment was more severe in the patients with optic pathway involvement (p = 0.002). Post-treatment visual impairment was improved but was still significantly severe in patients with optic pathway involvement than in those without involvement (p = 0.010). Visual field deficit more likely remained with an improvement rate of 50%, whereas the improvement rate of visual acuity was 78%. Further, none developed late-onset visual deterioration during the follow-up period. CONCLUSIONS: Visual disturbance and optic pathway involvement are common in neurohypophyseal GCTs. Visual impairment particularly in patients with optic pathway involvement on MRI is more likely to remain at follow-up, although the outcome of visual function is acceptable in most cases.

Quadrigeminal arachnoid cyst with perinatal encephalocele.

INTRODUCTION: Quadrigeminal arachnoid cyst (QAC) associated with encephalocele is rare; and while some treatments have been developed in recent years, no definite therapeutic approach for QAC has been established. Endoscopic treatment for arachnoid cyst is gaining popularity because it is relatively less invasive to the normal brain tissues. CASE PRESENTATION: The patient, a 4-year-old girl, presented with QAC associated with congenital occipital encephalocele. At the age of 1 month, repair of the perinatal encephalocele had been performed at another institute. An asymptomatic arachnoid cyst remained in the posterior fossa, which was closely monitored with follow up. At age 4 years, the patient started to complain of headache, which gradually increased in both strength and frequency. Magnetic resonance imaging (MRI) revealed cerebellar compression due to cyst enlargement. We performed neuroendoscopic cyst fenestration with an occipital bone approach. Post-operative MRI showed reduced size of the cyst, and the headache dramatically improved and resolved. DISCUSSION: The standard treatment of QAC is still controversial; however, our successful use of endoscopic fenestration toward the third ventricle indicates its efficacy and safety. QACs have been classified into 3 types based on their expansion mechanisms; our case might suggest another possible mechanism of QAC development. CONCLUSION: In our case, endoscopic cyst fenestration was successful for QAC with perinatal encephalocele. However, long-term follow-up and analysis of similar cases are needed to determine its effectiveness.

Time to diagnosis and clinical characteristics in pediatric brain tumor patients.

PURPOSE: We aimed to identify factors that affect the time to diagnosis in pediatric brain tumors and investigate the effect of time to diagnosis on clinical outcome. METHODS: A retrospective study of children with brain tumors aged less than 18 years diagnosed at the University of Tsukuba Hospital over a period of 7 years was conducted. RESULTS: Eighty-five consecutive patients, with a mean age of 9.1 years, were included in the study. The median interval from symptom onset to diagnosis was 45 days (range 0-1673); median interval from symptom onset to first presentation was 31.0 days; and median interval from first presentation to diagnosis was 13.5 days. Germinoma had the longest interval from symptom onset to first presentation, and from first presentation to diagnosis. Patients presenting with endocrine disorder had a significantly longer interval from symptom onset to first presentation (p = 0.019); those with visual disturbance (p = 0.016) or endocrine disorder (p = 0.030) had significantly longer intervals from first presentation to diagnosis. CONCLUSION: Pediatric brain tumor patients with germinoma and presenting symptoms of endocrine disorder or visual disturbance have a longer time to diagnosis. Although improved prognosis is not clearly related to a shorter time to diagnosis, we believe that early diagnosis can lead to improved treatment and better quality of life. A detailed medical history and neuroimaging studies at the earliest time possible are important for early diagnosis.

Proton therapy for newly diagnosed pediatric diffuse intrinsic pontine glioma.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a type of brain malignancy with a very poor prognosis. Although various radiation and chemotherapy protocols have been attempted, only conventional radiotherapy has yielded improvements in survival. In this study, we aimed to compare proton therapy versus conventional photon radiotherapy in terms of the outcomes of pediatric patients with DIPG. METHODS: This retrospective review included 12 pediatric patients with newly diagnosed DIPG who received a total proton therapy dose of 54 Gy (relative biological effectiveness) in 30 fractions at the University of Tsukuba Hospital between 2011 and 2017 (proton group). We additionally reviewed the medical records of 10 patients with DIPG who previously underwent conventional photon radiotherapy at our institute (historical cohort). RESULTS: The median progression-free survival (PFS) duration was 5 months (range 1-11 months), and the 6-, 12-, and 18-month PFS rates were 50%, 33%, and 25%, respectively. The median overall survival (OS) duration was 9 months (range 4-48 months), and the 6-, 12-, 18-, and 24-month OS rates were 66.8%, 50%, 41%, and 20%, respectively. There were no significant differences in survival between the proton and historical groups (PFS, p = 0.169 and OS, p = 0.16). CONCLUSIONS: Proton therapy was well tolerated by the majority of patients. No severe adverse events, including radiation necrosis, were recorded. Proton therapy did not yield superior survival outcomes vs. conventional photon radiotherapy in patients with DIPG at our institution. Further research is needed to identify the factors associated with better survival in this population.

Pure germinoma occurring 11 years after total pineal mature teratoma removal: a case report and review of the literature.

Intracranial mature teratomas have good prognoses and are usually treated by total tumor resection. We report a rare case of a germinoma that occurred 11 years after total removal of a pineal mature teratoma. A 5-year-old boy presented with headache and nausea and was diagnosed with a pineal tumor and obstructive hydrocephalus on MRI. He underwent total removal of the lesion, which was pathologically diagnosed as a mature teratoma without any other germ cell tumor components. MR images after 11 years showed a newly developed pineal tumor, which was confirmed as a germinoma after neuroendoscopic biopsy. Chemoradiotherapy resulted in complete remission, without any symptoms. This case demonstrated possible late occurrence of germinoma even after total removal of a mature teratoma had been achieved. A long-term follow-up of 10 years or more should be planned for these patients.

Primary cavernous sinus germinoma with atypical extension pattern: a case report and review of the literature.

Primary intracranial germinoma is a rare central nervous system tumor that usually arises in the pineal and the supra-sellar region. Here, we report a rare case of primary intracavernous sinus germinoma with an atypical extension pattern, with a comparison to germinomas originating from the cavernous sinus as described in the existing literature. A 12-year-old boy was admitted to our hospital with the chief complaint of the left-side ptosis and double vision. Magnetic resonance imaging showed homogenous enhanced mass lesion in the pineal region together with mass lesions in the lateral ventricle, left cavernous sinus, and temporal lobe, extending into the left masticator space. The enhanced mass in the intracavernous sinus originated from the cavernous sinus. Endoscopic third ventriculostomy and tumor biopsy was done. Pathological diagnosis was pure germinoma. After six courses of chemotherapy followed by radiation therapy, all the lesions decreased in size significantly. Only faint enhancement around the masticator space remained. We report a rare case of a germinoma that developed mainly in the cavernous sinus with additional tumor masses in the pineal region, ventricles, and temporal lobe. Although the lesions shrank significantly on the post-chemoradiation imaging, a long follow-up is necessary not only to check for symptoms, but also monitor imaging findings for possible serial changes in the residual region of the masticator space.

Unusual Form of Obstructive Hydrocephalus in Association with 6q Terminal Deletion Syndrome: A Case Report and Literature Review.

INTRODUCTION: Terminal deletion of chromosome 6q is a rare chromosomal abnormality associated with intellectual disabilities and various structural brain abnormalities. We present a case of 6q terminal deletion syndrome with unusual magnetic resonance imaging (MRI) findings in a neonate. CASE PRESENTATION: The neonate, who was prenatally diagnosed with dilation of both lateral ventricles, was born at 38 weeks of gestation. MRI demonstrated abnormal membranous structure continuing to the hypertrophic massa intermedia in the third ventricle that had obscured the cerebrospinal fluid pathway, causing hydrocephalus. G-band analysis revealed a terminal deletion of 6q with the karyotype 46, XY, add(6)(q25.3) or del(6)(q26). He underwent ventriculoperitoneal shunt successfully, and his head circumference has been stable. DISCUSSION/CONCLUSION: 6q terminal deletion impacts the molecular pathway, which is an essential intracellular signaling cascade inducing neurological proliferation, migration, and differentiation during neuronal development. In patients with hydrocephalus in association with hypertrophy of the massa intermedia, this chromosomal abnormality should be taken into consideration. This case may offer an insight into the pathogenesis of hydrocephalus in this rare chromosomal abnormality.

A critical role of noggin in developing folate-nonresponsive NTD in Fkbp8 -/- embryos.

PURPOSE: Maternal folate intake has reduced the incidence of human neural tube defects by 60-70 %. However, 30-40 % of cases remain nonresponsive to folate intake. The main purpose of this study was to understand the molecular mechanism of folate nonresponsiveness in a mouse model of neural tube defect. METHODS: We used a folate-nonresponsive Fkbp8 knockout mouse model to elucidate the molecular mechanism(s) of folate nonresponsiveness. Neurospheres were grown from neural stem cells isolated from the lumbar neural tube of E9.5 Fkbp8 (-/-) and wild-type embryos. Immunostaining was used to determine the protein levels of oligodendrocyte transcription factor 2 (Olig2), Nkx6.1, class III beta-tubulin (TuJ1), O4, glial fibrillary acidic protein (GFAP), histone H3 Lys27 trimethylation (H3K27me3), ubiquitously transcribed tetratricopeptide repeat (UTX), and Msx2, and quantitative real-time (RT)-PCR was used to determine the message levels of Olig2, Nkx6.1, Msx2, and noggin in neural stem cells differentiated in the presence and absence of folic acid. RESULTS: Fkbp8 (-/-)-derived neural stem cells showed (i) increased noggin expression; (ii) decreased Msx2 expression; (iii) premature differentiation--neurogenesis, oligodendrogenesis (Olig2 expression), and gliogenesis (GFAP expression); and (iv) increased UTX expression and decreased H3K27me3 polycomb modification. Exogenous folic acid did not reverse these markers. CONCLUSIONS: Folate nonresponsiveness could be attributed in part to increased noggin expression in Fkbp8 (-/-) embryos, resulting in decreased Msx2 expression. Folate treatment further increases Olig2 and noggin expression, thereby exacerbating ventralization.

H3 K27-altered diffuse midline glioma in adults arising from atypical regions: Two case reports and literature review.

Diffuse midline glioma (DMG), H3 K27-altered, is a newly defined "pediatric-type," diffuse, high-grade glioma under current WHO classifications (updated in 2021). An essential diagnostic criteria of DMG is its occurrence in the midline structures; most intracranial DMG occurs in the brainstem or thalamus but can also occur in other midline structures. We experienced 2 adult cases of intracranial DMGs in areas other than the brainstem and thalamus that were initially difficult to diagnose. Case 1 was a 49-year-old man with extensive T2 high-signal lesions in the bilateral frontal lobes and corpus callosum on brain MRI. A Gd-based contrast medium partially enhanced the lesion and showed marked diffusion restriction, mimicking malignant lymphoma. Case 2 was a 24-year-old man who presented with paroxysmal olfactory abnormalities. The tumor extended mainly to the right temporal lobe, the right basal forebrain, and the bilateral hypothalamus, showing a T2/FLAIR mismatch sign suggestive of IDH-mutant astrocytoma without 1p/19q co-deletion. After a biopsy, both cases were properly diagnosed as DMG, H3 K27-altered (K27M-mutant). Diagnosing adult cases involving atypical midline structures is sometimes challenging before surgery; we discuss this phenomenon with both case details and a literature review.

Epigenetic modification after inhibition of IGF-1R signaling in human central nervous system atypical teratoid rhabdoid tumor (AT/RT).

OBJECTIVE: This study investigated epigenetic modifications in human central nervous system atypical teratoid rhabdoid tumors (AT/RTs), in response to inhibition of insulin-like growth factor receptor 1 (IGF-1R). MATERIALS AND METHODS: Tumor tissue was obtained from two pediatric patients, tissue was dissociated, and primary cultures were established. Cultured cells were treated with picropodophyllin (PPP; 0, 1, and 2 µM for 48 h), a selective IGF-1R inhibitor. Histone acetylation and methylation patterns (H3K9ac, H3K18ac, H3K4me3, H3K27me3) and levels of histone deacetylases (HDACs; HDAC1, HDAC3, and SirT1) and histone acetyl transferases (GCN5 and p300) were examined. H3K9ac and H3K18ac decreased in response to treatment with PPP. HDAC levels showed a biphasic response, increasing with 1 µM PPP, but then decreasing with 2 µM PPP. CONCLUSION: Inhibition of IGF-1R modified epigenetic status in AT/RT. Determining the mechanisms behind these modifications will guide the development of novel therapeutic targets for this malignant embryonal cancer.

Acute cerebral hemorrhage mimicking glioblastoma on intraoperative magnetic resonance imaging: A case report.

Intraoperative magnetic resonance imaging (iMRI) is important in neurosurgical practice, especially for glioma surgery. However, the well-reported possibility to mistake lesions for brain tumors (tumor mimics) with MRI also exists for iMRI. Here, we first report a case of glioblastoma with acute cerebral hemorrhage that mimicked a newly emerged brain tumor on iMRI. A 53-year-old man underwent a second surgery for recurrent glioblastoma. Intraoperatively, iMRI revealed a new, enhanced lesion near the resected area that was absent on preoperative MRI and difficult to differentiate from newly emerged tumors. Here, a recent preoperative MRI was helpful and the new lesion was actually a hematoma. Neurosurgeons must understand that, as acute intracerebral hemorrhaging can mimic brain tumors on iMRI, preoperative MRI should be conducted just before surgery to place iMRI findings in proper context and avoid unnecessary resections.

Hemorrhagic Complications After Brain Tumor Biopsy: Risk-Reduction Strategies Based on Safer Biopsy Targets and Techniques.

OBJECTIVE: Brain tumor biopsies are essential for pathologic diagnosis. However, hemorrhagic complications after biopsies may occur, leading to suboptimal outcomes. This study aimed to evaluate the associated factors of hemorrhagic complications after brain tumor biopsies and propose countermeasures. METHODS: We retrospectively collected data on 208 consecutive patients with brain tumors (malignant lymphoma or glioma) who underwent a biopsy from 2011-2020. We evaluated factors and microbleeds (MBs) in the tumor plus relative cerebral/tumoral blood flow (rCBF) at the biopsy site on preoperative magnetic resonance imaging (MRI). RESULTS: Postoperative all and symptomatic hemorrhage occurred in 21.6% and 9.6% of patients. In univariate analysis, a needle biopsy was significantly associated with the risk of all and symptomatic hemorrhages compared to techniques that allow adequate hemostatic manipulation (i.e., open and endoscopic biopsies). Multivariate analyses revealed that a needle biopsy and gliomas of World Health Organization (WHO) grade III/IV were significantly associated with postoperative all and symptomatic hemorrhages. Multiple lesions were also an independent risk factor for symptomatic hemorrhages. On preoperative MRI, abundant MBs in the tumor and MBs at the biopsy sites, in addition to high rCBF, were significantly associated with postoperative all and symptomatic hemorrhages. CONCLUSIONS: We recommend the following measures to prevent hemorrhagic complications: consider biopsy techniques that allow adequate hemostatic manipulation preferentially; perform more careful hemostasis in cases of suspected gliomas of WHO grade III/IV, multiple lesions, and abundant MBs in the tumors; and, if there are multiple candidate biopsy sites, select areas with lower rCBF and no MBs as a biopsy target.

Sclerosing meningioma with a large peritumoral cyst: Case report.

Meningioma morphology is diverse. Although unlisted in the WHO classification, sclerosing meningioma is a rare variation featuring an extremely low signal intensity on MRI T2-weighted imaging. About 50 cases of sclerosing meningiomas, including spinal tumors, have been reported; however, cases with an accompanying large peritumoral cyst remain unreported. Here, we first report a rare case of sclerosing meningioma with a large peritumoral cyst and review relevant literature.

Spinal cord diffuse midline glioma with postoperative acute swelling: A case report and review of literature.

Background: H3K27-altered diffuse midline glioma (DMG) is a newly classified disease according to the 5th edition of the World Health Organization classification of the central nervous system tumors. However, little is known about its progression pattern and the timing of surgical intervention, especially regarding spinal cord lesions. Case Description: A 26-year-old man presented with rapid muscle weakness progression in both upper and lower extremities and urinary dysfunction. Magnetic resonance imaging showed diffuse swelling of the cervicothoracic spinal cord. He underwent decompressive laminectomy with expansive duroplasty and tumor biopsy. The surgical specimen revealed DMG. Immediately after surgery, deterioration of limb paresis was observed, and the patient developed respiratory failure the day after surgery. Head-and-neck computed tomography on the 7th day after surgery showed spinal cord swelling and acute obstructive hydrocephalus. Conclusion: We report a rare case of a spinal DMG with acute postoperative swelling. Neurological deterioration in patients with spinal cord DMG is often exacerbated, so it is essential to suspect DMG at an early stage based on neuroimaging, and if surgery is performed on the edematous spinal cord, further rapid swelling can occur, as in the present case.

Frontal sinus giant osteoma with radiologically unusual component suggesting blood supply: A case report.

Osteoma is a common, slow growing bone tumor, and often affects the paranasal sinus. Typically, it shows a very hyperdense osseous lesion on computed tomography (CT) scan and low-intensity change on T2-weighted image on magnetic resonance imaging (MRI). No report has mentioned osteomas in blood supply on MRI. A 57-year-old male patient presented with a prolonged declined activity and a gigantic osseous tumor that originated from the frontal sinus, which markedly compressed the bilateral frontal lobe. MRI revealed a slightly enhanced front basal part of the tumor by gadolinium, with blood supply from ethmoidal arteries. The patient underwent surgery, and the diagnosis of osteoma was made based on histological findings. We reported a case of giant osteoma originating from the frontal sinus with unusual blood supply on 4-dimensional MR angiography.