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Background Tumour-treating fields therapy is a locoregional, anti-cancer treatment. Efficacy and safety of tumour-treating fields therapy in adults with newly diagnosed glioblastoma were demonstrated in the pivotal phase 3 EF-14 study (NCT00916409). Here, we report post-approval data of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma. Methods Unsolicited post-marketing surveillance data from Japanese patients with newly diagnosed glioblastoma treated with tumour-treating fields therapy (December 2016–June 2020) were retrospectively analysed. The primary endpoints were skin, neurological and psychiatric adverse events. The secondary endpoints were 1- and 2-year overall survival rates, and the 6-month progression-free survival. adverse events were analysed using MedDRA v24.0. The overall survival and progression-free survival were assessed using the Kaplan–Meier survival analysis (log-rank testing). The Cox proportional hazard regression analyses were also performed. Results Forty patients with newly diagnosed glioblastoma were enrolled (62.5% male; median age 59 years; median baseline Karnofsky Performance Scale score 90). The most common tumour-treating-fields-therapy-related adverse event was beneath-array local skin reaction (60% of patients). The adverse events were mostly mild to moderate in severity. Neurological disorders were observed in 2.5% patients (one patient reported dysesthesia). No psychiatric disorders were reported. The 1- and 2-year overall survival rates were 77.9% (95% CI 60.6–88.3) and 53.6% (35.5–68.7%), respectively. The 6-month progression-free survival was 77.5% (61.2–87.6%). These survival rates compare favourably with those in the EF-14 trial (1- and 2-year overall survival rates: 73% [69–77%] and 43% [39–48%], respectively; 6-month progression-free survival rate: 56% (51–61%). Conclusion This post-approval, real-world evidence study revealed no new safety signals and suggests the safety and efficacy of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma.

To investigate whether texture features from tumor and peritumoral areas based on sequence combinations can differentiate between low- and non-low-grade meningiomas.Consecutive patients diagnosed with meningioma by surgery (77 low-grade and 28 non-low-grade meningiomas) underwent preoperative magnetic resonance imaging including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast-enhanced T1WI (CE-T1WI). Manual segmentation of the tumor area was performed to extract texture features. Segmentation of the peritumoral area was performed for peritumoral high-signal intensity (PHSI) on T2WI. Principal component analysis was performed to fuse the texture features to principal components (PCs), and PCs of each sequence of the tumor and peritumoral areas were compared between low- and non-low-grade meningiomas. Only PCs with statistical significance were used for the model construction using a support vector machine algorithm. k-fold cross-validation with receiver operating characteristic curve analysis was used to evaluate diagnostic performance.Two, one, and three PCs of T1WI, apparent diffusion coefficient (ADC), and CE-T1WI, respectively, for the tumor area, were significantly different between low- and non-low-grade meningiomas, while PCs of T2WI for the tumor area and PCs for the peritumoral area were not. No significant differences were observed in PHSI. Among models of sequence combination, the model with PCs of ADC and CE-T1WI for the tumor area showed the highest area under the curve (0.84).The model with PCs of ADC and CE-T1WI for the tumor area showed the highest diagnostic performance for differentiating between low- and non-low-grade meningiomas. Neither PHSI nor PCs in the peritumoral area showed added value.

Supplementary Figure 3 from The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

Supplementary Figure 2 from The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin αVβ3 and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell–specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin αVβ3–expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas αVβ3-expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA–mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an αVβ3-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the αVβ3-deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted αVβ3-expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/mTOR activation. (Cancer Res 2006; 66(23): 11331-40)

Supplementary Figure 1 from The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

The occipital transtentorial approach (OTA) is one of the most useful approaches to the lesions of the pineal region, dorsal brainstem, and supracerebellar region. However, a wide operative field is sometimes difficult to obtain due to the large tentorial sinus and bridging veins. This study evaluated the usefulness of preoperative simulation of OTA, specifically including the cerebellar tentorium in 9 patients. All patients underwent computed tomography angiography and venography and gadolinium-enhanced three-dimensional T1-weighted magnetic resonance images (Gd-3D-T1WI). The images were fused and the cerebellar tentorium and tumor manually extracted from Gd-3D-T1WI to obtain the preoperative simulation images. Visualization of the cerebellar tentorium could discriminate between bridging veins from the occipital lobe and cerebellum, and recognize the site of bridging to the tentorial sinus and variants which may interfere with the tentorial incision. Simulation of the tentorial incision was also possible based on the relationships between the tumor, tentorial sinus, bridging vein, and cerebellar tentorium. The simulation suggested that safe tentorial incision was difficult in two sides because of the crossed tentorial sinus draining the left basal vein and draining veins from the glioblastoma. The OTA was performed in eight cases and no difficulty was experienced in the tentorial incision in all cases. The simulation findings of the bridging vein and tentorial sinus were consistent with the intraoperative findings. Preoperative simulation including the cerebellar tentorium is useful for determining the optimum and safe side and required extent of the tentorial incision necessary for tumor resection with the OTA.

Background CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. Methods We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. Results Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. Conclusions These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild‐type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular‐targeted therapies is of paramount importance. Fatty acid‐binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild‐type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin‐1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin‐1 promoter through controlling the nuclear acetyl‐CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7. Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin‐1 expression, increased levels of histone acetylation, and increased levels of acetyl‐CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin‐1, and this mechanism is critically important for IDH1wt tumor biology., In this study, we observed high expression and nuclear localization of FABP7 in IDH1wt glioblastoma (GB). Using GB cell lines, we investigated that nuclear FABP7 interacted with ATP citrate lyase (ACYL), as well as the associated increase of nuclear acetyl‐CoA levels, which led to an increase of histone acetylation at the caveolin‐1 promoter. Consequently, the increase in caveolin‐1 expression enhanced caveolae/caveosome function and formation, as well as the intracellular signalling activity in IDHwt cells related to GB tumour proliferation.

INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux‐M), as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second‐line arms, patients with EGFR‐amplified recurrent WHO grade III/IV glioma received Depatux‐M plus chemotherapy (temozolomide) or Depatux‐M alone regardless of EGFR status. In first‐line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux‐M plus chemoradiotherapy. The study was halted following lack of survival benefit with first‐line Depatux‐M in the global trial INTELLANCE‐1. The primary endpoint was 6‐month progression‐free survival (PFS) in patients with EGFR‐amplified tumors receiving second‐line Depatux‐M plus chemotherapy. Common nonocular treatment‐emergent adverse events (TEAEs) with both second‐line and first‐line Depatux‐M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second‐line Depatux‐M plus chemotherapy and all patients receiving second‐line Depatux‐M alone or first‐line Depatux‐M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6‐month PFS estimate was 25.6% (95% confidence interval [CI] 11.4‒42.6), and median PFS was 2.1 months (95% CI 1.9‒3.9) with second‐line Depatux‐M plus chemotherapy in the EGFR‐amplified subgroup. This study showed acceptable safety profile of Depatux‐M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263)., INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin, as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in Japanese patients with World Health Organization grade III/IV glioma. The results of this trial demonstrate an acceptable safety profile of depatuxizumab mafodotin, with ocular side effects being the most common adverse events that were mostly reversible. Second‐line depatuxizumab mafodotin in combination with temozolomide resulted in a 6‐month progression‐free survival estimate of 25.6% (95% confidence interval 11.4‒42.6) in patients with EGFR‐amplified tumors and showed encouraging antitumor activity in this subgroup of patients (NCT02590263).

Aphasic status epilepticus (ASE) is a subtype of focal nonconvulsive status epilepticus, in which language disturbance is the only objective clinical manifestation. We present two cases of patients who experienced delayed onset of temporal aphasia after the removal of glioma at the language-dominant hemisphere. In both cases, arterial spin labeling was useful for diagnosis and antiepileptic drug was effective. ASE should be considered a cause of persistent aphasia after glioma resection at or near the language area.

Object Pulsed water jet is an emerging surgical instrumentation intended to achieve both maximal lesion resection and functional maintenance through preservation of fine vessels and minimal damage to the surrounding tissue. The piezo actuator-driven pulsed water jet (ADPJ) is a new technology that can deliver a precisely controlled uniform and efficient pulsed water jet with minimum water flow. The present study evaluated the ADPJ system in preclinical animal studies in the swine brain, and investigated breaking strength, one of the parameters for mechanical properties, to elucidate the mechanism of tissue selectivity for tissue dissection by the water jet. Methods This system consisted of a pump chamber driven by a piezo actuator, a stainless steel tube, and a nozzle (internal diameter: 0.15 mm). The water was supplied at 6 ml/min. The relationship between input voltage (3-25 V at 400 Hz) and peak pressure was measured using a pressure sensor through a sensing hole. Temporal profile of dissection depth during moving application was evaluated using gelatin brain phantom and swine brain. The dissected specimens were evaluated histologically. The mechanical property (breaking strength) of swine brain was measured by a compact table-top universal tester. Results Peak pressure increased linearly with increase in the input voltage, which reflected dissection depth in both the gelatin brain phantom and swine brain. Small arteries were preserved, and minimum damage to surrounding tissues occurred. The breaking strength of arachnoid membrane (0.12 ± 0.014 MPa) was significantly higher compared to gray matter (0.030 ± 0.010 MPa) and white matter (0.056 ± 0.009 MPa) (p < 0.05). The breaking strength of gray matter corresponded to that of 3 wt% gelatin, and that of white matter corresponded to a value between those of 3.5 and 4 wt% gelatin, and the dissection depth seemed to be estimated by 3-4 wt% gelatin. Conclusion The present study suggests that the ADPJ system has the potential to achieve accurate tissue dissection with preservation of blood vessels in neurosurgery. The difference in breaking strength may explain the tissue selectivity between brain parenchyma and tissue protected by the arachnoid membrane.

In cases of malignant gliomas located at language eloquent area, it is often difficult to preoperatively detect those area with functional MRI. Awake surgery is often used to spare the language eloquent area during surgery for such tumors; it is not available for a patient whose intracranial pressure is elevated due to the malignant tumor. The Wada test involves infusing anesthetic agents into the internal carotid artery to determine language dominancy before surgery for epilepsy or brain tumor. The super-selective Wada test is a technique to detect more detailed functional localization by infusing anesthetics into far distal middle cerebral artery branches. We present a 37-year-old man suffering from a left frontal lobe glioblastoma, in whom detection of an artery supplying Broca's area was attempted by a super-selective Wada test. The super-selective Wada test successfully detected the branch of middle cerebral artery supplying Broca's area. Total resection of the contrast-enhancing area was achieved without damaging the artery supplying Broca's area without any neurological sequelae. This is the first report describing the usefulness of the super-selective Wada test in glioblastoma treatment. Our findings suggest that the super-selective Wada test is a powerful and useful means to distinguish the artery that supplies the language area from the tumor feeding artery in cases of tumors in the language eloquent area.

This study investigated the effectiveness and safety of low-dose salvage craniospinal irradiation (CSI) for recurrent germinoma. We retrospectively reviewed long-term tumor control and late adverse effects in 15 recurrent germinoma patients treated at our hospital between 1983 and 2019. Following the first recurrence of germinoma, seven were treated with 24–30 Gy of salvage CSI, three underwent non-CSI, and five were treated with only chemotherapy. CSI achieved a significantly better recurrence-free survival rate after the first recurrence compared to other strategies (100% vs 33%, p < 0.001: log-rank test). To evaluate the safety of salvage CSI, we assessed the outcomes at the final follow-up of seven patients who received salvage CSI at first recurrence and three patients who received salvage CSI at second recurrence. The median follow-up period was 220 months after initial treatment. Five patients who received 40–50 Gy of radiation therapy or underwent multiple radiation therapy before salvage CSI were classified into Group A, whereas five patients treated with platinum-based chemotherapy and 24–32 Gy of radiation therapy to the primary site, whole ventricle, or whole brain were classified into Group B. In Group A, one had endocrine dysfunction and the other had visual dysfunction. None were socially independent. Meanwhile, in Group B, no endocrine or visual dysfunction was found, and three patients were socially independent. Salvage CSI achieved excellent tumor control in recurrent germinoma and was safe in patients initially treated with low-dose radiation therapy and chemotherapy.

Pneumocephalus is generally secondary to direct damage to the skull base. Spontaneous intracerebral pneumatocele without head injury was extremely rare, but previously reported as a serious complication of shunt procedures. We describe a 40-year-old man with intracerebral pneumocephalus who previously underwent craniotomy for large frontal convexity meningioma and lumbo-peritoneal shunting. He presented with gait disturbance 14 months after tumor resection. Computed tomography and magnetic resonance imaging showed intracerebral pneumocephalus in the right temporal lobe, which continued into the mastoid air cells through a bone defect of the right petrous bone. We performed urgent right temporal craniotomy to reduce the mass effect and to repair the fistula. Intraoperatively, bone defects were identified at the roof petrous bone, into which the encephalocele had penetrated. The herniated cerebral parenchyma was removed, and the pneumocephalus opened. The dura was closed with sutures and covered with fascia. To elucidate the underlying mechanism for the development of intracranial pneumocephalus, the previous images obtained before or immediately after resection of meningioma were reviewed. We founded that multiple preexisting bone defects and encephaloceles, one of which was considered to be the cause of the intracerebral pneumocephalus. This case demonstrates that intracerebral pneumocephalus can be caused by preexisting bone defect and encephalocele, and this finding may be useful for prediction of pneumocephalus after shunt procedures.

Corpus callosum swelling has been reported to occur after ventriculoperitoneal shunting for long-standing hydrocephalus. This report presents a case of corpus callosum swelling after intraventricular tumor resection. A 34-year-old woman presented with a headache that worsened over 1 month. Magnetic resonance (MR) images revealed a mass lesion in the left lateral ventricle and obstructive hydrocephalus. She underwent subtotal resection with a transcallosal approach. After tumor resection, she had long-lasting status epilepticus followed by consciousness disturbance. T2-weighted MR images obtained 8 hr after the operation showed a hyperintense area in the corpus callosum. The patient then presented with bilateral dilated pupils 14 hr after the operation due to acute hydrocephalus and tension pneumocephalus. An emergent re-craniotomy was performed and a ventricular drain was placed. The patient recovered consciousness 3 days after the operation. However, she experienced progressive corpus callosum swelling 25 days after the operation, which improved since then. Approximately 4 months after the operation, she returned to her usual workplace with no neurocognitive functional decline. Two years later, she was doing well with no radiological abnormal findings except corpus callosum thinning. Thus, corpus callosum swelling can develop not only after shunting for chronic hydrocephalus but also after intraventricular tumor resection. It occurred relatively acutely and there was no decline in intelligence after long-term follow-up. This case suggests that corpus callosum swelling after intraventricular tumor resection is a rare but noteworthy complication that can improve without intervention.

Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma. Electronic supplementary material The online version of this article (10.1007/s12035-020-02057-3) contains supplementary material, which is available to authorized users.

Most cases of optic hypothalamic pilocytic astrocytoma (OHPA) develop during childhood, so few cases of histologically verified OHPA have been described in adolescents and young adults (AYA). To elucidate the clinical features of OHPA with histological verification in AYA, we reviewed the clinical and radiological finding of OHPA treated at our institute from January 1997 and July 2017. AYA are aged between 15 and 39 years. The clinical courses of 11 AYA patients with optic hypothalamic glioma (OHG) without neurofibromatosis type 1 were retrospectively reviewed. About six patients were diagnosed in childhood and followed up after 15 years of age, and five patients developed OHPA during AYA. Histological diagnosis, verified at initial presentation or recurrence, was pilocytic astrocytoma in 10 and pilomyxoid astrocytoma in one. After initial treatment including debulking surgery and/or chemotherapy, tumor progression occurred 16 times in seven patients as cyst formation, tumor growth, and intratumoral hemorrhage. Five of 10 patients suffered deterioration of visual function during AYA. One of 10 cases had endocrinopathies requiring hormone replacement at last follow-up examination. In conclusion, histological diagnoses of OHG before and in AYA were pilocytic astrocytoma or pilomyxoid astrocytoma. Both pediatric and AYA-onset OHPA demonstrate high incidences of tumor progression and visual dysfunctions in AYA, so that long-term follow up is essential after the completion of treatment for pediatric and AYA-onset OHPA. The optimal timing of debulking surgery and radiation therapy should be established to achieve the long-term tumor control and to preserve the visual function.

We previously reported that CD133 expression correlated with the recurrence pattern of glioblastoma (GBM). Subventricular zone (SVZ) involvement may also be associated with distant recurrence in GBM. Therefore, we herein investigated whether the combined analysis of SVZ involvement and CD133 expression is useful for predicting the pattern of GBM recurrence. We retrospectively analyzed 167 cases of GBM. Tumors were divided into four groups based on spatial relationships between contrast-enhanced lesions (CEL) and the SVZ or cortex (Ctx) on MRI. The initial recurrence pattern (local/distant) was obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by immunohistochemical, clinical (age, sex, KPS, Ki-67 labeling index, surgery, and MRI characteristics), and genetic (IDH1, MGMT, and BRAF) factors. The CD133 expression rate was higher in SVZ-positive tumors than in SVZ-negative tumors (P = 0.046). Distant recurrence was observed in 21% of patients, and no significant difference was noted in recurrence patterns among the four groups. However, strong CD133 expression was associated with a shorter time to distant recurrence in univariate, multivariate, and propensity-matched scoring analyses (P

Background Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results. Methods Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation. Results Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 123 germinomas, 76 intermediate-prognosis-group cases (including 38 germinoma with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year recurrence-free survival (RFS) for germinoma, intermediate and poor-prognosis-groups were 84/79%, 83/76% and 59/59%, respectively, and overall survival (OS) for each were 97/91%, 92/85% and 57/53%, respectively. Prognosis for germinoma with or without STGC was the same. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, and ages were significantly different depending on causes, such as disease-related (14 years on average) and complications (29 years). OS after recurrence at 5/10/20 years were 64/62/48%.Hormonal supplementation was seen in 82% for neurohypophyseal cases and antidiuretic hormone supplementation was most frequent (82%). Among available cases, 20-out-of-155 cases showed neoplastic/vascular complications, among which cavernous malformation was the most (n=9). Median period until complication presentation was 235 months, and the rate at 20 years was 11%. Conclusions Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.

Introduction : Anaplastic astrocytoma has a dismal prognosis with conventional treatment. Multidisciplinary treatment is needed to control the disease; however, side effects of the treatment reduce a patient's quality of life (QOL). Carmustine-impregnated wafers (Gliadel®, Eisai Co., Ltd., Tokyo, Japan), one of the treatment modalities for anaplastic astrocytoma, has been reported to have drug-induced fever as a side effect. Case Report : A 36-year-old man underwent excision for a recurrent brain tumor. Histopathological examination established a diagnosis of anaplastic astrocytoma and an intracranial carmustine implant was placed for local chemotherapy. Postoperatively, the patient developed high fever, which could not be controlled using antipyretics. The high fever ameliorated dramatically after the administration of Kampo medicines, specifically orengedokuto and shosaikoto, and the patient could continue chemotherapy. Conclusion : To the best of our knowledge, this is the first report of successful treatment of intractable carmustine implant-induced fever using Kampo medicine. In this case, Kampo medicine led to an improvement of QOL.

Clinicopathological risk factors for a poor prognosis were investigated in elderly patients with malignant lymphoma of the central nervous system. A total of 82 pathologically confirmed, CD20-positive, diffuse large B-cell lymphoma patients aged 71 years or older who underwent therapeutic intervention in the Tohoku and Niigata area in Japan were retrospectively reviewed. A univariate analysis was performed by the log-rank test using the Kaplan-Meier method. A Cox proportional hazards model was used for multivariate analysis of risk factors. Of the 82 patients, 39 were male and 43 were female, and their median age at onset was 75 years. At the end of the study, there were 34 relapse-free patients (41.5%), 48 relapse cases (58.5%), median progression-free survival was 18 months, and median overall survival (OS) was 26 months; there were 41 deaths and 41 survivors. Multivariate analysis of median OS showed that Karnofsky Performance Status less than 60% 3 months after treatment (p = 0.022, hazard ratio (HR) = 2.591) was the clinical risk factor, and double expressor lymphoma (p = 0.004, HR = 3.163), expression of programmed death-ligand 1 in tumor infiltrating lymphocytes or tumor-associated macrophages (p 0.001, HR = 5.455), and Epstein-Barr virus infection (p = 0.031, HR = 5.304) were the pathological risk factors.

Background Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs. Methods Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH). Results A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs. Conclusions 12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT.

Objective We developed an actuator-driven pulsed water jet (ADPJ) device to achieve maximal lesion dissection with minimal risk of normal structural damage. Despite the unique dissection characteristics, there is a risk of dissemination of tissue dispersion; however, there is no established method to quantify the dispersion. Hence, this study aimed to assess the factors associated with dispersion and propose a simple experimental method using spectrophotometry to evaluate the degree of dispersion in a wet field. Results Methylene blue-stained brain phantom gelatin was immersed in a chamber with distilled water solution and dissected with an ADPJ. The dispersed gelatin solution was stirred and warmed to dissolve. The absorbance of the solution was measured spectrophotometrically. First, a reference standard curve was constructed to confirm the relationship between the absorbance and the amount of the dispersed gelatin. A clear proportional correlation was observed, which indicated that absorbance measurements can help evaluate the amount of dispersion. Using this method, we revealed that a high dissection force, insufficient suction, and inappropriate long distance between the nozzle tip and the target were associated with increased dispersion. This method might constitute a versatile and reliable approach to evaluate dispersion and aid in the development of surgical devices.