Postoperative disappearance of leptomeningeal enhancement around the brainstem in glioblastoma.

PURPOSE: Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is a complication of end-stage glioblastoma, and is associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indications, we aimed to analyze the clinical significance of preoperative LME of the brainstem in glioblastoma. METHODS: We retrospectively collected clinical and radiological data from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. RESULTS: Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. In comparison with tumors without LME, tumor size was significantly associated with the preoperative LME of the brainstem (p = 0.016). In addition, there was a trend toward significance for a relationship between deep tumor location and preoperative LME of the brainstem (p = 0.058). Notably, among six patients who underwent surgical resection for glioblastoma with LME of the brainstem, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. However, this LME disappearance was not observed after biopsy or chemoradiotherapy. CONCLUSIONS: These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.

Importance of Age and Noncontrast-Enhancing Tumor as Biomarkers for Isocitrate Dehydrogenase-Mutant Glioblastoma: A Multicenter Study.

PURPOSE: This study aimed to investigate the most useful clinical and magnetic resonance imaging (MRI) parameters for differentiating isocitrate dehydrogenase (IDH)-mutant and -wildtype glioblastomas in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. METHODS: This multicenter study included 327 patients with IDH-mutant or IDH-wildtype glioblastoma in the 2016 World Health Organization classification who preoperatively underwent MRI. Isocitrate dehydrogenase mutation status was determined by immunohistochemistry, high-resolution melting analysis, and/or IDH1/2 sequencing. Three radiologists independently reviewed the tumor location, tumor contrast enhancement, noncontrast-enhancing tumor (nCET), and peritumoral edema. Two radiologists independently measured the maximum tumor size and mean and minimum apparent diffusion coefficients of the tumor. Univariate and multivariate logistic regression analyses with an odds ratio (OR) were performed. RESULTS: The tumors were IDH-wildtype glioblastoma in 306 cases and IDH-mutant glioblastoma in 21. Interobserver agreement for both qualitative and quantitative evaluations was moderate to excellent. The univariate analyses revealed a significant difference in age, seizure, tumor contrast enhancement, and nCET ( P < 0.05). The multivariate analysis revealed significant difference in age for all 3 readers (reader 1, odds ratio [OR] = 0.960, P = 0.012; reader 2, OR = 0.966, P = 0.048; reader 3, OR = 0.964, P = 0.026) and nCET for 2 readers (reader 1, OR = 3.082, P = 0.080; reader 2, OR = 4.500, P = 0.003; reader 3, OR = 3.078, P = 0.022). CONCLUSIONS: Age and nCET are the most useful parameters among the clinical and MRI parameters for differentiating IDH-mutant and IDH-wildtype glioblastomas.

Safety and efficacy of depatuxizumab mafodotin in Japanese patients with malignant glioma: A nonrandomized, phase 1/2 trial.

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).

Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study.

BACKGROUND: An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma. METHODS: Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%. RESULTS: Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27-66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4-17.7) and 1.5 (1.4-1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3-4 and 2.0% for Grade 5; most adverse events resolved and were manageable. CONCLUSIONS: The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types. CLINICAL TRIAL REGISTRATION: JapicCTI-152967.

Anthropogenic Osmium in Macroalgae from Tokyo Bay Reveals Widespread Contamination from Municipal Solid Waste.

Human activity is influencing the global osmium cycle, driving the Os isotopic composition (187Os/188Os) of the hydrosphere and associated sedimentary material to lower values. Here, we present the Re and Os abundance and isotope systematics of macroalgae, a proxy for seawater, from Tokyo Bay to elucidate the potential sources of anthropogenic Os to the Pacific Ocean. Macroalgae from the Uraga Channel, which connects Tokyo Bay to the Pacific Ocean, record relatively low Os abundances (∼10.1 pg/g) and an 187Os/188Os of ∼0.9, indicative of surface ocean seawater. Contrastingly, macroalgae within the bay closest to central Tokyo record the highest Os abundances (∼22.8 pg/g) and lowest 187Os/188Os values (∼0.47), suggesting contamination from human activity. To determine the source of anthropogenic Os, we have developed the first Os emission inventory, based on the East Asian Air Pollutant Emission Grid database (EAGrid2010). The close relationship (R2 = 0.67 and p-value = <0.05) between Os inventories and macroalgal data suggests that municipal solid waste incinerators (MSWIs) are the dominant source of Os to Tokyo Bay. Projections for Japan estimate that 26-18+38 ng Os/m2/yr is released from MSWI smokestacks, leading to a concentration in precipitation of 26-18+38 fg/g, identifying MSWIs as a major contributor of anthropogenic Os to the hydrological cycle.

BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B-cell lymphoma.

PURPOSE: Primary central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS-DLBCL. METHODS: Pretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS-DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients' statuses for various markers, which were also evaluated for associations with survival outcomes. RESULTS: According to the Hans criteria, 26 patients (32.9%) had the germinal center B-cell subtype and 53 patients (67.1%) had the activated B-cell subtype. Forty-one cases (51.9%) were positive for MYC (expression of ≥ 40%), 33 cases (41.8%) were positive for BCL2 (expression of ≥ 70%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B-cell subtypes. Furthermore, MYC positivity was not associated with overall survival (p = 0.369) or progression-free survival (PFS) (p = 0.253). However, BCL2 positivity was significantly associated with poor overall survival (p = 0.039) and PFS (p = 0.036). Co-expression of MYC and BCL2 was not associated with survival. CONCLUSION: Our data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS-DLBCL.

A Cenozoic record of the equatorial Pacific carbonate compensation depth.

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.

A case of an epithelioid glioblastoma with the BRAF V600E mutation colocalized with BRAF intact low-grade diffuse astrocytoma.

Epithelioid glioblastomas are one of the rarest histological variants of glioblastomas, which are not formally recognized by the World Health Organization (WHO) classification. Epithelioid glioblastomas usually occur as primary lesions, but there have been several reports of secondary epithelioid glioblastomas or epithelioid glioblastomas with pre- or co-existing lesions to date. The serine/threonine-protein kinase B-Raf (BRAF) V600E mutation has been found at a high frequency of 54% in epithelioid glioblastomas. We present a case of a 26-year-old female patient with an epithelioid glioblastoma with the BRAF V600E mutation in her right frontal lobe. In the present case, a low-grade diffuse astrocytoma component had colocalized with the epithelioid glioblastoma. The component presented prominent calcification on neuroimages as well as by histology, and low-grade diffuse astrocytoma was considered to be a precursor lesion of an epithelioid glioblastoma. However, the BRAF V600E mutation was detected only in epithelioid glioblastoma but not in low-grade diffuse astrocytoma. To the best of our knowledge, this is the first report demonstrating a discrepancy in the BRAF V600E mutation states between epithelioid glioblastoma and colocalized low-grade astrocytoma.

Prognostic impact of completion of initial high-dose methotrexate therapy on primary central nervous system lymphoma: a single institution experience.

BACKGROUND: This retrospective single-center study assessed the feasibility, outcomes, and side-effects of high-dose methotrexate (HD-MTX) plus procarbazine in the treatment of immunocompetent patients with primary central nervous system lymphoma (PCNSL). METHODS: Ninety-one patients diagnosed with PCNSL between January 2001 and December 2011 were treated with HD-MTX plus procarbazine. To reduce neurotoxicity in patients aged ≥60 years, only those not responding to chemotherapy and patients with relapse underwent whole-brain irradiation. RESULTS: All 91 consecutive patients were scheduled to receive HD-MTX. Their median age was 66 years (range 32-88 years) and their median Karnofsky performance score was 40 (range 20-100). While 56 patients (61.5 %) completed 3 cycles of HD-MTX chemotherapy and 48 (52.7 %) showed a complete response, treatment was stopped in 11 patients (12.1 %) due to toxicity. The median overall survival and progression-free survival were 40.6 and 11.7 months, respectively. Overall survival was significantly improved in patients who completed 3 cycles of chemotherapy compared with those did not (56.4 vs 24.0 months; p = 0.013 by univariate and p = 0.022 by multivariate analysis). CONCLUSIONS: Initial treatment with HD-MTX plus procarbazine was effective in patients with PCNSL. Completion of 3 cycles of HD-MTX chemotherapy was a significant independent prognostic factor for patient survival.

The origin of Cretaceous black shales: a change in the surface ocean ecosystem and its triggers.

Black shale is dark-colored, organic-rich sediment, and there have been many episodes of black shale deposition over the history of the Earth. Black shales are source rocks for petroleum and natural gas, and thus are both geologically and economically important. Here, we review our recent progress in understanding of the surface ocean ecosystem during periods of carbonaceous sediment deposition, and the factors triggering black shale deposition. The stable nitrogen isotopic composition of geoporphyrins (geological derivatives of chlorophylls) strongly suggests that N2-fixation was a major process for nourishing the photoautotrophs. A symbiotic association between diatoms and cyanobacteria may have been a major primary producer during episodes of black shale deposition. The timing of black shale formation in the Cretaceous is strongly correlated with the emplacement of large igneous provinces such as the Ontong Java Plateau, suggesting that black shale deposition was ultimately induced by massive volcanic events. However, the process that connects these events remains to be solved.

Antitumor effect of fibrin glue containing temozolomide against malignant glioma.

Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma.

NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin.

Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg/kg) and epirubicin (10 mg/kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL/6 mice that were given NC-6300 (10 mg/kg) or epirubicin (10 mg/kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers.

An epileptogenic intracranial cystic lesion lined with fallopian tube-type epithelium: illustrative case.

BACKGROUND: Intracranial cystic lesions are often a trigger for epileptic seizures. However, there has never been a report of a cystic lesion lined with fallopian tube-type epithelium. OBSERVATIONS: A 48-year-old female presented with a cystic lesion in the right occipital lobe, which gradually grew over 8 years. Right occipital lobe epilepsy was diagnosed based on visual aura, convulsive seizures, and electroencephalogram findings and the cyst was surgically removed. Further examination revealed the cyst was lined with ciliated cells, which had morphological and immunohistochemical features similar to those of fallopian tube epithelium. LESSONS: The characteristics of the cyst did not conform to any known types of benign cystic lesion. To the authors' knowledge, no such cyst has been reported before. The authors discuss the origins and pathogenesis of this unfamiliar cystic lesion.

A multicenter, randomized, placebo-controlled phase IIb trial of an autologous formalin-fixed tumor vaccine for newly diagnosed glioblastomas.

OBJECTIVE: An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV. METHODS: Eligible patients were adults with supratentorial GBMs, 16-75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate. RESULTS: Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed. CONCLUSIONS: The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry).

Fatty acid synthase is a predictive marker for aggressiveness in meningiomas.

Meningiomas are the most frequent intracranial tumors. Although most are benign WHO grade I tumors, grade II and III tumors are aggressive and survival is poor. Treatment options for grade II and III meningiomas are limited, and molecular targets are few. The re-programming of metabolic pathways including glycolysis, lipogenesis, and nucleotide synthesis is a hallmark of the physiological changes in cancer cells. Because fatty acid synthase (FAS), the enzyme responsible for the de-novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers, we investigated its involvement in meningiomas. We subjected 92 paraffin-embedded samples from 57 patients with grade I, 18 with grade II and III, and six with radiation-induced tumors to immunohistochemical study of FAS. Whereas its expression was increased in grade II and III meningiomas (62.9 %) compared with grade I tumors (29.8 %) (chi-squared test: p < 0.001), FAS was expressed in grade I tumors with a high MIB-1 index and infiltration into surrounded tissues. All radiation-induced meningiomas expressed FAS and its expression was positively correlated with the MIB-1 index (p < 0.005). Our findings suggest that increased FAS expression reflects the aggressiveness of meningiomas and that it may be a novel therapeutic target for treatment of unresectable or malignant tumors.

Higher incidence of epilepsy in meningiomas located on the premotor cortex: a voxel-wise statistical analysis.

BACKGROUND: A substantial number of patients with brain tumors develop recurrent seizures, known as tumor-associated epilepsy. It is important to identify specific subgroups of brain tumor patients with higher incidences of epilepsy because a meta-analysis failed to certify the effectiveness of prophylactic anti-epileptic drugs (AEDs) to abort tumor-associated epilepsy as a whole. METHODS: To investigate the relationship between tumor location and incidence of epilepsy, we performed voxel-wise comparison between 3D MRI scans obtained from patients with meningioma-associated epilepsy and those from control patients using spatial normalization techniques on neuroimaging data. Variables such as age, tumor size, the degree of edema, and pathological diagnosis were also compared between the two groups. RESULTS: Our results showed the highest incidence of epilepsy when the tumor was located on the premotor cortex in the frontal lobe (Z-scores >2.0, Liebermeister's quasi-exact test). The stepwise multiple regression analysis on the clinical data revealed that the tumor diameter (p < 0.001) and the patient's age (p = 0.024) were positive and negative predictors, respectively, for the onset of epilepsy. CONCLUSIONS: The incidence of epilepsy was higher in meningiomas located on the premotor cortex than on the other cortex. Larger volume also contributed to the onset of epilepsy. We suggest that variations of epilepsy incidence dependent on tumor characteristics can be considered when treating tumor-associated epilepsy.

[Dystrophia myotonica Type 1 associated with glioblastoma: a case report].

This case involved a 65-year-old woman, who had been suffered from weakness in both legs for 10 years. She had not been diagnosed of dystrophia myotonica type 1 (DM1) despite her son's diagnosis of DM and her distinct facial features and gait anomaly. During her son's recent clinical visit, she was finally suspected of having DM. She was sent to our institution, where a distinct muscle atrophy and grip myotonia were observed and a genetical examination was performed. The sequencing data confirmed her diagnosis of DM1 due to the distinct 230-900 CTG repeats found in the dystrophia myotonica protein kinase gene 3' untranslated region. A brain MRI revealed an abnormal lesion with irregular ring-enhancement at the right temporal lobe. Because of the steady growth of the lesion during one month observation, a surgical intervention was performed in our institution. The histopathological examination gave a diagnosis of glioblastoma multiforme (GBM). The clinical management of the patient required special cares during the perioperative periods due to the distinct pathological manifestation of DM. The risk of developing cancer in DM patients has been estimated about twice as much as general population. Since GBM developed in the DM patient is rarely reported, we present this rare case with a few insights: the difficulties of the clinical management of DM patients under the perioperative stress; the pathological contribution of DM to the malignant transformation of the glial cells.

A prospective comparison of adaptive and fixed boost plans in radiotherapy for glioblastoma.

PURPOSE: To analyze the efficacy of adaptive radiotherapy (ART) for glioblastoma. METHODS: Sixty-one glioblastoma patients who received ART were prospectively evaluated. The initial clinical target volume (CTVinitial) was represented by T2 hyperintensity on postoperative MRIs (pre-RT MRI [MRIpre])plus 10 mm. The initial planning target volume (PTVinitial) was the CTVinitial plus a 5-mm margin. The PTVinitial received 40 Gy. An MRI and a second planning CT were performed during radiotherapy (MRImid). Two types of boost CTVs (the resection cavity and residual tumor on enhanced T1-weighted MRI plus 10 mm) were created based on the MRIpre and MRImid (CTVboost-pre and -mid). The boost PTV (PTVboost) was the CTVboost plus 5 mm. Two types of boost plans (fixed and adaptive boost plans in the first and second planning CT, respectively) of 20 Gy were created. The PTV based on the post-RT MRI (PTVboost-post) was created, and the dose-volume histograms of the PTVboost-post in the fixed and adaptive boost plans were compared. Additionally, the conformity indices (CIs) of the fixed and adaptive boost plans were compared. RESULTS: The median V95 of the PTVboost-post of the fixed and adaptive boost plans (V95pre and V95mid) were 95.6% and 98.3%, respectively (P < 0.01). The median V95pre and V95mid of patients after gross total resection (GTR) were 97.4% and 98.8%, respectively (P = 0.41); in contrast, the median values of patients after non-GTR were 91.9% and 98.2%, respectively (P < 0.01). The median CIs of the fixed and adaptive boost plans in all patients were 1.45 and 1.47, respectively (P = 0.31). The median CIs of the fixed and adaptive boost plans in patients after GTR were 1.61 and 1.48, respectively (P = 0.01); in contrast, those in patients after non-GTR were 1.36 and 1.44, respectively (P = 0.13). CONCLUSION: ART for glioblastoma improved the target coverage and dose reduction for the normal brain. By analyzing the results according to the resection rate, we can expect a decrease in normal brain dose in patients with GTR and an increase in coverage in those with partial resection or biopsy.

Mid-Cretaceous marine Os isotope evidence for heterogeneous cause of oceanic anoxic events.

During the mid-Cretaceous, the Earth experienced several environmental perturbations, including an extremely warm climate and Oceanic Anoxic Events (OAEs). Submarine volcanic episodes associated with formation of large igneous provinces (LIPs) may have triggered these perturbations. The osmium isotopic ratio (187Os/188Os) is a suitable proxy for tracing hydrothermal activity associated with the LIPs formation, but 187Os/188Os data from the mid-Cretaceous are limited to short time intervals. Here we provide a continuous high-resolution marine 187Os/188Os record covering all mid-Cretaceous OAEs. Several OAEs (OAE1a, Wezel and Fallot events, and OAE2) correspond to unradiogenic 187Os/188Os shifts, suggesting that they were triggered by massive submarine volcanic episodes. However, minor OAEs (OAE1c and OAE1d), which do not show pronounced unradiogenic 187Os/188Os shifts, were likely caused by enhanced monsoonal activity. Because the subaerial LIPs volcanic episodes and Circum-Pacific volcanism correspond to the highest temperature and pCO2 during the mid-Cretaceous, they may have caused the hot mid-Cretaceous climate.