Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

Genomic landscape of glioblastoma without IDH somatic mutation in 42 cases: a comprehensive analysis using RNA sequencing data.

PURPOSE: Glioblastoma is a malignant brain tumor with a poor prognosis. Genetic mutations associated with this disease are complex are not fully understood and require further elucidation for the development of new treatments. The purpose of this study was to comprehensively analyze genetic mutations in glioblastomas and evaluate the usefulness of RNA sequencing. PATIENTS AND METHODS: We analyzed 42 glioblastoma specimens that were resected in routine clinical practice and found wild-type variants of the IDH1 and IDH2 genes. RNA was extracted from frozen specimens and sequenced, and genetic analyses were performed using the CLC Genomics Workbench. RESULTS: The most common genetic alterations in the 42 glioblastoma specimens were TP53 mutation (28.6%), EGFR splicing variant (16.7%), EGFR mutation (9.5%), and FGFR3 fusion (9.5%). Novel genetic mutations were detected in 8 patients (19%). In 12 cases (28.6%), driver gene mutations were not detected, suggesting an association with PPP1R14A overexpression. Our findings suggest the transcription factors SOX10 and NKX6-2 are potential markers in glioblastoma. CONCLUSION: RNA sequencing is a promising approach for genotyping glioblastomas because it provides comprehensive information on gene expression and is relatively cost-effective.

Derivation of Coagulation Phenotypes and the Association with Prognosis in Traumatic Brain Injury: A Cluster Analysis of Nationwide Multicenter Study.

BACKGROUND: The pathogenesis and pathophysiology of traumatic coagulopathy during traumatic brain injury is not well understood, and the appropriate treatment strategy for this condition has not been established. This study aimed to evaluate the coagulation phenotypes and their effect on prognosis in patients with isolated traumatic brain injury. METHODS: In this multicenter cohort study, we retrospectively analyzed data from the Japan Neurotrauma Data Bank. Adults with isolated traumatic brain injury (head abbreviated injury scale > 2; abbreviated injury scale of any other trauma < 3) who were registered in the Japan Neurotrauma Data Bank were included in this study. The primary outcome was the association of coagulation phenotypes with in-hospital mortality. Coagulation phenotypes were derived using k-means clustering with coagulation markers, including prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen (FBG), and D-dimer (DD) on arrival at the hospital. Multivariable logistic regression analyses were conducted to calculate the adjusted odds ratios of coagulation phenotypes with their 95% confidence intervals (CIs) for in-hospital mortality. RESULTS: In total, 556 patients were enrolled and five coagulation phenotypes were identified. The median (interquartile range) score for the Glasgow Coma Scale was 6 (4-9). Cluster A (n = 129) had the closest to normal coagulation values; cluster B (n = 323) had a mild high DD phenotype; cluster C (n = 30) had a prolonged PT-INR phenotype with a higher frequency of antithrombotic medication in elderly patients than in younger patients; cluster D (n = 45) had a low amount of FBG, high DD, and prolonged APTT phenotype with a high incidence of skull fracture; and cluster E (n = 29) had a low amount of FBG and extremely high DD phenotype with high energy trauma and a high incidence of skull fracture. In the multivariable logistic regression analysis, the association of clusters B, C, D, and E with in-hospital mortality yielded the corresponding adjusted odds ratios of 2.17 (95% CI 1.22-3.86), 2.61 (95% CI 1.01-6.72), 10.0 (95% CI 4.00-25.2), and 24.1 (95% CI 7.12-81.3), respectively, relative to cluster A. CONCLUSIONS: This multicenter, observational study identified five different coagulation phenotypes of traumatic brain injury and showed associations of these phenotypes with in-hospital mortality.

Iatrogenic Vertebral Arteriovenous Fistula Involving Brachiocephalic Vein Due to Central Venous Catheterization: A Case Report.

PURPOSE: To report a case of vertebral arteriovenous fistula (VAVF) caused by iatrogenic trauma of central venous catheterization (CVC) involving brachiocephalic vein (BCV). CASE REPORT: A 79-year-old female was referred for assessment of a vertebral artery (VA) aneurysm at the V1 segment. The patient had no signs other than a vascular murmur on the right neck and was diagnosed 20 years after undergoing CVC. Right vertebral angiography revealed a high-flow shunt from the V1 segment of the right VA and draining into the right BCV. The fistula had a single communication between a pseudoaneurysm and large varix. We diagnosed the patient with CVCinduced VAVF (CIVAVF) involving BCV and obliterated the shunt by selective transarterial and transvenous embolization of the pseudoaneurysm under flow control using a balloon catheter with no complications. CONCLUSION: This case highlights the point that CIVAVF involving BCV is rare but possible. In addition, there is a possibility that CIVAVF involving BCV does not demonstrate the findings of arterial steal or retrograde venous drainage and is undiagnosed for a long term due to lack of neurological manifestation and other subjective symptoms. We also showed that endovascular treatment can be feasible and useful for CIVAVF involving BCV.

Assessing floor contamination by antineoplastic agents in a Japanese medical institution specializing in cancer treatment.

INTRODUCTION: This study investigated the extent of contamination with antineoplastic agents on floor surfaces of the ward and the outpatient chemotherapy center of a Japanese cancer center to evaluate healthcare workers' risk of occupational exposure to antineoplastic agents outside of the designated drug preparation areas. METHODS: In this study conducted at Aichi Cancer Center, the amount of fluorouracil detected on various floor surfaces was measured using liquid chromatography-tandem quadrupole mass spectrometry. Areas around the toilets were cleaned with a surfactant two or three times a day, whereas other floor surfaces were cleaned only with dry and wet mops. RESULTS: Fluorouracil was detected on all surveyed floor surfaces, with particularly high amounts detected around the toilet areas in the ward. Additionally, areas with more human traffic tended to have higher fluorouracil contamination. CONCLUSIONS: This survey suggested that antineoplastic agent contamination occurring through patient excretions might spread throughout the hospital with human traffic. Therefore, controlling the spread of antineoplastic agent contamination in hospitals should include the review of measures to mitigate contamination around toilets and to implement effective cleaning methods for floor surfaces.

Effectiveness of Administration of Fibrinogen Concentrate as Prevention of Hypofibrinogenemia in Patients with Traumatic Brain Injury with a Higher Risk for Severe Hyperfibrinolysis: Single Center Before-and-After Study.

BACKGROUND: Coagulopathy is often observed in severe traumatic brain injury (sTBI), and hyperfibrinolysis (HF) is associated with a poor prognosis. Although the efficacy of fibrinogen concentrate (FC) in multiple trauma has been reported, its efficacy in sTBI is unclear. Therefore, we delineated severe HF risk factors despite fresh frozen plasma transfusion. Using these risk factors, we defined high-risk patients and determined whether FC administration to this group improved fibrinogen level. METHODS: In the first part of this study, successive adults with sTBI treated at our hospital between April 2016 and March 2019 were reviewed. Patients underwent transfusion as per our conventional protocol and were divided into two groups based on whether fibrinogen levels of ≥ 150 mg/dL were maintained 3-6 h after arrival to delineate the risk factors of severe HF. In the second part of the study, we conducted a before-and-after study in patients with sTBI who were at a higher risk for severe HF (presence of at least one of the risk factors identified in the first part of the study), comparing those treated with FC between April 2019 and March 2021 (FC group) with those treated with conventional transfusion before FC between April 2016 and March 2019. The primary outcome was maintenance of fibrinogen levels, and the secondary outcome was 30-day mortality. RESULTS: In the first part of the study, 78 patients were included. Twenty-three patients did not maintain fibrinogen levels ≥ 150 mg/dL. A D-dimer level on arrival > 50 µg/mL, a fibrinogen level on arrival < 200 mg/dL, depressed skull fracture, and multiple trauma were severe HF risk factors. In the second part, compared with 46 patients who were identified as being at high risk for severe HF but were not administered FC (non-FC group), fibrinogen levels ≥ 150 mg/dL 3-6 h after arrival were maintained in 14 of 15 patients in the FC group (odds ratio: 0.07; 95% confidence interval: 0.01-0.59). Although there were significant differences in fibrinogen levels, no significant differences were observed in terms of 30-day mortality between the groups. CONCLUSIONS: Coagulation abnormalities on arrival, severe skull fracture, and multiple trauma are severe HF risk factors. FC administration may contribute to rapid correction of developing hypofibrinogenemia.

Maintenance of WT1 expression in tumor cells is associated with a good prognosis in malignant glioma patients treated with WT1 peptide vaccine immunotherapy.

We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4+/CD8+ tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3+ or CD8+ T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4+ T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy.

Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib.

PURPOSE: Adverse events after the use of the CDK4/6 inhibitor abemaciclib are dose-dependent. However, its pharmacokinetics varies among individuals. Abemaciclib is reportedly transported by P-glycoprotein and breast cancer resistance protein. Therefore, we evaluated whether ABCB1 and ABCG2 polymorphisms are pharmacokinetic predictive factors of abemaciclib. METHODS: A total of 45 patients with breast cancer taking abemaciclib (150 mg twice per day) for 2 weeks were evaluated to determine the associations among abemaciclib concentration; adverse events; and ABCB1 1236 T > C, 2677G > T/A, 3435C > T, and ABCG2 421C > A gene polymorphisms. RESULTS: The trough concentration of abemaciclib was significantly higher in the group with grade 2 or greater neutropenia and thrombocytopenia than in those with grades 0 or 1. For ABCB1 2677G > T/A polymorphisms, the concentration of abemaciclib tended to be higher in the homozygous group (TT + AT) than in the wild-type + heterozygous group (GG + GA + GT) (median [range], 222.8 [80.5-295.8] ng/mL vs. 113.5 [23.6-355.2] ng/mL, P = 0.09), Moreover, the ABCB1 2677G > T/A homozygous group had a higher tendency of abemaciclib withdrawal or dose reduction within 4 weeks than the wild-type + heterozygous group (odds ratio, 4.22; 95% confidence interval, 0.86-20.7; P = 0.08). No significant association was observed among abemaciclib concentration; adverse reactions; and ABCB1 1236 T > C, 3435C > T, and ABCG2 421C > A polymorphisms. CONCLUSION: ABCB1 2677G > T/A polymorphism might be a predictor of the pharmacokinetics and tolerability of abemaciclib.

Super-selective balloon test occlusion with electrophysiological monitoring to occlude angiographically invisible posterior communicating artery perforators with unruptured aneurysm.

Balloon test occlusion (BTO) can predict the ischemic complication risk associated with arterial occlusion. We present a case of an unruptured, broad-necked internal carotid artery-posterior communicating artery (PcomA) aneurysm that was successfully embolized after super-selective BTO of fetal PcomA with electrophysiological monitoring. The proximal portion of the PcomA was internally occluded without causing major neurological deficits, although we observed a small new infarction in the ipsilateral anterior thalamus postoperatively. We recognized small perforators arising from the proximal PcomA during a previous clipping surgery. Super-selective BTO with electrophysiological monitoring could be useful for functional preservation after infarction from angiographically invisible perforators.

The Association Between D-dimer Levels and Long-Term Neurological Outcomes of Patients with Traumatic Brain Injury: An Analysis of a Nationwide Observational Neurotrauma Database in Japan.

BACKGROUND: We evaluated the association between D-dimer (DD) levels and long-term neurological prognoses among patients with isolated traumatic brain injury. METHODS: Using data from multiple centers in the Japanese Neurotrauma Data Bank, we conducted an observational retrospective cohort study. Patients with isolated traumatic brain injury (head Abbreviated Injury Scale score > 2; any other Abbreviated Injury Scale score < 3) who were registered in the Japanese Neurotrauma Data Bank from 2015 to 2017 were recruited. We excluded patients younger than age 16 years and those who developed cardiac arrest at hospital admission. We also excluded patients with unknown Glasgow Outcome Scale (GOS) scores at 6 months after injury and those with unknown DD levels. The primary outcome was the association of DD levels with GOS scores at 6 months. We defined GOS scores 1 to 3 as poor and GOS scores 4 and 5 as good. The secondary outcome was the association of DD levels with mortality at 6 months after injury. We conducted multivariate logistic regression analyses to calculate the adjusted odds ratios of DD levels at hospital admission and GOS scores at 6 months as tertiles with 95% confidence intervals (CIs). A total of 293 patients were enrolled (median age 67 years; interquartile range 51-79 years). The median DD level was 27.1 mg/L (interquartile range 9.7-70.8 mg/L), and 58.0% (n = 170) had poor GOS scores at 6 months. RESULTS: The multivariable logistic regression analysis indicated that the adjusted odds ratios were 2.52 (95% CI 1.10-5.77) for middle DD levels with poor GOS scores at 6 months and 5.81 (95% CI 2.37-14.2) for high DD levels with poor GOS scores at 6 months. CONCLUSIONS: We revealed an association between DD levels and poor long-term neurological outcomes among patients with isolated traumatic brain injury.

Identification of two distinct populations of WT1-specific cytotoxic T lymphocytes in co-vaccination of WT1 killer and helper peptides.

Simultaneous induction of tumor antigen-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) is required for an optimal anti-tumor immune response. WT1332, a 16-mer WT1-derived helper peptide, induce HTLs in an HLA class II-restricted manner and enhance the induction of WT1-specific CTLs in vitro. However, in vivo immune reaction to WT1332 vaccination in tumor-bearing patients remained unclear. Here, a striking difference in WT1-specific T cell responses was shown between WT1 CTL + WT1 helper peptide and WT1 CTL peptide vaccines in patients with recurrent glioma. WT1-specific CTLs were more strongly induced in the patients who were immunized with WT1 CTL + WT1 helper peptide vaccine, compared to those who were immunized with WT1 CTL vaccine alone. Importantly, a clear correlation was demonstrated between WT1-specific CTL and WT1332-specific HTL responses. Interestingly, two novel distinct populations of WT1-tetramerlow WT1-TCRlow CD5low and WT1-tetramerhigh WT1-TCRhigh CD5high CTLs were dominantly detected in WT1 CTL + WT1 helper peptide vaccine. Although natural WT1 peptide-reactive CTLs in the latter population were evidently less than those in the former population, the latter population showed natural WT1 peptide-specific proliferation capacity comparable to the former population, suggesting that the latter population highly expressing CD5, a marker of resistance to activation-induced cell death, should strongly expand and persist for a long time in patients. These results demonstrated the advantage of WT1 helper peptide vaccine for the enhancement of WT1-specific CTL induction by WT1 CTL peptide vaccine.

Serum concentration of the CKD4/6 inhibitor abemaciclib, but not of creatinine, strongly predicts hematological adverse events in patients with breast cancer: a preliminary report.

Purpose The CKD4/6 inhibitor abemaciclib is related to adverse events such as hematological toxicity and increase in serum creatinine levels associated with abemaciclib pharmacokinetics. Increase in serum creatinine levels is considered a result of competition with abemaciclib via organic cation transporter 2 and multidrug and toxic compound extrusion. Therefore, we evaluated the association among serum creatinine levels, serum abemaciclib concentrations, and adverse events and whether increase in serum creatinine levels is a useful indicator for predicting the onset of the adverse events of abemaciclib. Methods In total, the data of 12 patients with breast cancer who were treated with abemaciclib (150 mg twice daily) were evaluated to determine the association between increased serum creatinine levels and abemaciclib concentrations and hematological toxicity. Results Grade 3 neutropenia, thrombocytopenia, and anemia were observed at 4 weeks in four (33%), two (17%), and one (8%) patients, respectively. A significant association was observed between steady-state abemaciclib concentrations and the rate of decrease in neutrophil and platelet counts (r = - 0.80, P = 0.003 and r = - 0.70, P = 0.016, respectively). Compared with baseline levels (0.61 [0.53-0.82] mg/mL), serum creatinine levels significantly increased and reached a steady state in at least 2 weeks (0.84 [0.61-1.02] mg/mL, P = 0.01). However, we did not find a significant association between increase in serum creatinine levels and abemaciclib concentrations and hematological toxicity. Conclusions Abemaciclib concentrations are associated with neutropenia and thrombocytopenia. However, increase in serum creatinine levels may not be a useful predictor for estimating abemaciclib pharmacokinetics and hematological toxicity.

Association of skull fracture with in-hospital mortality in severe traumatic brain injury patients.

INTRODUCTION: To identify the association between skull fracture (SF) and in-hospital mortality in patients with severe traumatic brain injury (TBI). MATERIALS AND METHODS: This multicenter cohort study included a retrospective analysis of data from the Japan Trauma Data Bank (JTDB). JTDB is a nationwide, prospective, observational trauma registry with data from 235 hospitals. Adult patients with severe TBI (Glasgow Coma Scale <9, head Abbreviated Injury Scale (AIS) ≥ 3, and any other AIS < 3) who were registered in the JTDB between January 2004 and December 2017 were included in the study. Patients who (a) were < 16 years old, (b) developed cardiac arrest before or at hospital arrival, and (c) had burns and penetrating injuries were excluded from the study. In-hospital mortality was the primary outcome assessed. Multivariable logistic regression analyses were performed to calculate the adjusted odds ratios (ORs) of SF and their 95% confidence intervals (CIs) for in-hospital mortality. RESULTS: A total of 9607 patients were enrolled [median age: 67 (interquartile range: 50-78) years] in the study. Among those patients, 3574 (37.2%) and 6033 (62.8%) were included in the SF and non-SF groups, respectively. The overall in-hospital mortality rate was 44.1% (4238/9607). A multivariate analysis of the association between SF and in-hospital mortality yielded a crude OR of 1.63 (95% CI: 1.47-1.80). A subgroup analysis of the association of skull vault fractures, skull base fractures, and both fractures together with in-hospital mortality yielded adjusted ORs of 1.60 (95% CI: 1.42-1.98), 1.40 (95% CI: 1.16-1.70), and 2.14 (95% CI: 1.74-2.64), respectively, relative to the non-SF group. CONCLUSIONS: This observational study showed that SF is associated with in-hospital mortality among patients with severe TBI. Furthermore, patients with both skull base and skull vault fractures were associated with higher in-hospital mortality than those with only one of these injuries.

Radiologic-pathologic association of tumor-like lesions with inflammation in cerebral white matter: Comparison of two cases with distinct clinical outcomes.

Here, we report two cases showing tumor-like white matter lesions; one case was diagnosed as having inflammatory disease, and the other was diagnosed as having astrocytoma. Their outcomes were completely distinct despite similar pathology. Prior to biopsy, perfusion computed tomography (CT) and magnetic resonance imaging (MRI) were conducted. The two mass-forming lesions were distinct in edema level and vascularity patterns on CT and MRI. However, pathological examination of brain biopsy specimens revealed commonalities, including (1) proliferation of glial cells, (2) perivascular lymphocytic infiltration, and (3) appearance of numerous macrophages. Although atypical astrocytes proliferated in both cases, nuclear atypia was more distinct in case 2 than in case 1. The immunohistochemical results were the same for both cases: isocitrate dehydrogenase 1 (IDH1) R132H mutation was negative, and alpha thalassaemia mental retardation X-linked (ATRX) was retained. Faint immunoreactivity for p53 was observed in a few glial cells, and Ki-67 immunoreactive cells were markedly reduced in numbers (< 1%). Inflammatory reactions were evident in both cases: T cells dominantly infiltrated over B cells in the perivascular area in case 1, whereas both T and B cells infiltrated in case 2. Molecular analysis revealed wild-type IDH1 and IDH2 in both cases. However, a telomerase reverse transcriptase (TERT) sequence mutation was detected in case 2 but not in case 1. Eventually, case 1 was diagnosed as having inflammatory lesions, whereas case 2 was diagnosed as having diffuse astrocytoma associated with inflammatory reactions. The prognosis was favorable for case 1, whereas case 2 died 10 months following biopsy. These data indicated the diagnostic value of molecular analysis, for example, a TERT mutation, in association with the radiological findings. Although in case 2, histopathological evidence did not suggest high-grade glioma, the case met the new diagnostic criteria: "diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma, World Health Organization (WHO) grade IV," according to cIMPACT-NOW, update 3. Thus, interdisciplinary approaches are essential for accurate diagnosis of newly categorized white matter diseases.

[Posterior Surgical Techniques for Cervical Spine].

Currently, various posterior surgical techniques are available for cervical spondylotic myelopathy. These techniques include laminoplasty and laminectomy with or without fusion, and are often used in patients with multilevel cervical stenosis. They were developed with the intent to reduce the risk of complications such as injury to the spinal cord and nerve roots, C5 palsy, postlaminectomy membrane, and postoperative kyphosis. Posterior decompression for cervical spondylotic myelopathy is effective in improving neurological function in patients with appropriate surgical indications.

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

PURPOSE: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonß (IFNß) plus temozolomide (TMZ) with that of TMZ alone. EXPERIMENTAL: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. RESULTS: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNß + Radiotherapy (RT) group were found. CONCLUSION: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNß addition were identified.

[A Case of Miliary Brain Metastases Molecularly Diagnosed as Silent Lung Adenocarcinoma Origin].

A 60-year-old woman was referred to our hospital because of possible miliary brain metastases of unknown primary origin. On admission, she was alert and had no apparent motor weakness. Neuroradiological examinations revealed more than 100 small enhancing lesions, some of which had undergone cystic changes, suggesting multiple metastases. However, plain chest and abdominal CT revealed no abnormalities, and fluorodeoxyglucose-positron emission tomography could not reveal the primary origin of the cancer. Blood examination revealed no apparent abnormalities, except for tumor markers, including pro-gastrin-releasing peptide and carcinoembryonic antigen. On day 22, the patient underwent a biopsy through right frontal craniotomy. Histopathological findings indicated metastases from cancer. Immunohistochemistry was positive for cytokeratin(CK)7 and thyroid transcription factor-1 while negative for CK20(-), CK5/6, and p40, resulting in the diagnosis of lung adenocarcinoma. Genetic testing showed negative for EGFR mutation and positive for ALK fusion gene. From the day 48, whole brain radiotherapy was started, and the ALK inhibitor was prescribed from day 64. Metastatic brain tumors of unknown primary are rare. Miliary brain metastases from an unknown primary origin are rare. To our knowledge, this is the first case of military brain metastases of an unknown primary origin, which was later determined to have originated from ALK fusion-positive lung cancer.

A Prospective Trial Evaluating the Safety of a Shortened Infusion of Ramucirumab in Patients with Gastrointestinal Cancer.

LESSONS LEARNED: A shortened infusion of ramucirumab (from 60 to 20 minutes) was safe and feasible without infusion-related reactions.Twenty-minute infusions of ramucirumab can be an option for patients with no infusion-related reactions during the first 60-minute treatment. BACKGROUND: Ramucirumab is usually administered over 60 minutes, during which it is unlikely to cause infusion-related reactions (IRRs). This prospective study evaluated the safety of a shortened infusion of ramucirumab. METHODS: Patients who received their first dose of ramucirumab in a 60-minute infusion without developing IRRs were eligible and received their second ramucirumab dose for 20 minutes. The primary study endpoint was incidence of IRR during the first short-term infusion, and the secondary endpoints were incidence of IRR at any time and adverse events other than IRR. RESULTS: Of the 40 patients enrolled (median age, 68.5 years), 20 (55%) were male, 27 (67.5%) had stage IV gastric cancer, 25 (62.5%) received ramucirumab in combination with taxane-based chemotherapy, and 24 (60%) received only a single administration of ramucirumab prior to their enrollment. Notably, no IRR was observed during the first short-term infusion (IRR rate, 0%; 95% confidence interval [CI], 0%-0.72%). Among the 149 short-term infusions performed, there were no instances of IRRs or unexpected adverse events related to the treatment (Table 1). CONCLUSION: For patients without development of IRRs upon the first ramucirumab administration, shortening infusion time (from 60 to 20 minutes) is safe and feasible.

A phase I clinical study of a cocktail vaccine of Wilms' tumor 1 (WT1) HLA class I and II peptides for recurrent malignant glioma.

PURPOSE: The safety and clinical efficacy of WT1 human leukocyte antigen (HLA) class I peptide vaccine have been established, but the safety of a cocktail vaccine of WT1 HLA class I and II peptides has not. To verify its safety, we performed a phase I clinical trial for patients with recurrent malignant gliomas and assessed the immunological responses and survival data. PATIENTS AND METHODS: Fourteen HLA-A*24:02-positive patients with recurrent malignant glioma (2 with grade 3, 12 with grade 4) were enrolled. Every week, the patients received alternately a vaccine containing 3 mg of WT1 HLA-A*24:02-restricted (HLA class I) peptide and a cocktail vaccine of the HLA class I peptide and one of 0.75, 1.5 or 3 mg of the WT1 HLA class II peptide. For patients who showed no significant adverse effects within 6 weeks, the WT1 vaccine was continued at 2-4-week intervals. RESULTS: Eleven of the 14 patients completed WT1 vaccination for 6 weeks, while 3 patients dropped out earlier due to disease progression. All patients showed grade I level of skin disorders at the injection sites. No grade III/IV toxicity or dose-limiting toxicity was observed for any dose of WT1 HLA class II peptide. Six of the 14 patients had stable disease at 6 weeks. Median OS and 1-year OS rates were 24.7 weeks and 36%, respectively. CONCLUSION: The safety of a cocktail vaccine of WT1 HLA class I and II peptides for malignant gliomas was verified. This vaccine is, therefore, considered promising for patients with recurrent malignant glioma.

MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma.

BACKGROUND: MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment. METHODS: Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs' expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan-Meier method were performed. RESULTS: We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan-Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level. CONCLUSIONS: STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.