Combination of high anti-SKI and low anti-TMED5 antibody levels is preferable prognostic factor in esophageal carcinoma.

Given that esophageal cancer is highly malignant, the discovery of novel prognostic markers is eagerly awaited. We performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified SKI proto-oncogene protein and transmembrane p24 trafficking protein 5 (TMED5) as antigens recognized by serum IgG antibodies in patients with esophageal carcinoma. SKI and TMED5 proteins were expressed in Escherichia coli, purified by affinity chromatography, and used as antigens. The serum anti-SKI antibody (s-SKI-Ab) and anti-TMED5 antibody (s-TMED5-Ab) levels were significantly higher in 192 patients with esophageal carcinoma than in 96 healthy donors. The presence of s-SKI-Abs and s-TMED5-Abs in the patients' sera was confirmed by western blotting. Immunohistochemical staining showed that the TMED5 protein was highly expressed in the cytoplasm and nuclear compartments of the esophageal squamous cell carcinoma tissues, whereas the SKI protein was localized predominantly in the nuclei. Regarding the overall survival in 91 patients who underwent radical surgery, the s-SKI-Ab-positive and s-TMED5-Ab-negative statuses were significantly associated with a favorable prognosis. Additionally, the combination of s-SKI-Ab-positive and s-TMED5-Ab-negative cases showed an even clearer difference in overall survival as compared with that of s-SKI-Ab-negative and s-TMED5-Ab-positive cases. The s-SKI-Ab and s-TMED5-Ab biomarkers are useful for diagnosing esophageal carcinoma and distinguishing between favorable and poor prognoses.

Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

JMJD6 Autoantibodies as a Potential Biomarker for Inflammation-Related Diseases.

Inflammation is closely associated with cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers, and it is accompanied by the development of autoantibodies in the early stage of inflammation-related diseases. Hence, it is meaningful to discover novel antibody biomarkers targeting inflammation-related diseases. In this study, Jumonji C-domain-containing 6 (JMJD6) was identified by the serological identification of antigens through recombinant cDNA expression cloning. In particular, JMJD6 is an antigen recognized in serum IgG from patients with unstable angina pectoris (a cardiovascular disease). Then, the serum antibody levels were examined using an amplified luminescent proximity homogeneous assay-linked immunosorbent assay and a purified recombinant JMJD6 protein as an antigen. We observed elevated levels of serum anti-JMJD6 antibodies (s-JMJD6-Abs) in patients with inflammation-related diseases such as ischemic stroke, acute myocardial infarction (AMI), diabetes mellitus (DM), and cancers (including esophageal cancer, EC; gastric cancer; lung cancer; and mammary cancer), compared with the levels in healthy donors. The s-JMJD6-Ab levels were closely associated with some inflammation indicators, such as C-reactive protein and intima-media thickness (an atherosclerosis index). A better postoperative survival status of patients with EC was observed in the JMJD6-Ab-positive group than in the negative group. An immunohistochemical analysis showed that JMJD6 was highly expressed in the inflamed mucosa of esophageal tissues, esophageal carcinoma tissues, and atherosclerotic plaques. Hence, JMJD6 autoantibodies may reflect inflammation, thereby serving as a potential biomarker for diagnosing specific inflammation-related diseases, including stroke, AMI, DM, and cancers, and for prediction of the prognosis in patients with EC.

Serum anti-PCK1 antibody levels are a prognostic factor for patients with diabetes mellitus.

BACKGROUND: Autoantibodies develop in autoimmune diseases, cancer, diabetes mellitus (DM), and atherosclerosis-related diseases. However, autoantibody biomarkers have not been successfully examined for diagnosis and therapy. METHODS: Serological identification of antigens through recombinant cDNA expression cloning (SEREX) was used for primary screening of antigens. The cDNA product was expressed in bacteria and purified. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) was used to evaluate antibody levels in serum samples. RESULTS: Phosphoenolpyruvate carboxykinase 1 (PCK1) was recognized as an antigen by serum IgG antibodies in the sera of patients with atherosclerosis. AlphaLISA showed significantly higher serum antibody levels against recombinant PCK1 protein in patients with DM and cardiovascular disease than in healthy donors, but not in those with acute ischemic stroke, transient ischemic attack, or obstructive sleep apnea syndrome. The area under the receiver operating characteristic curve for anti-PCK1 antibodies was 0.7024 for DM. The serum anti-PCK1 antibody levels were associated with age, platelet count, and blood pressure. Anti-PCK1-antibody-positive patients showed significantly lower overall survival than the negative patients. CONCLUSIONS: Serum anti-PCK1 antibody levels were found to be associated with DM. The anti-PCK1 antibody marker is useful for predicting the overall survival of patients with DM.

[Oligodendroglioma, IDH Mutation and 1p/19q Codeletion].

Oligodendrogliomas were clearly defined as tumors with IDH mutations and 1p/19q codeletion by the World Health Organization(WHO)in 2016. Their prognosis is better than that of morphologic oligodendrogliomas, which might include some other gliomas according to WHO in 2016 and 2021. The term "low-grade gliomas" does not exist in the WHO classification and has changed in meaning over time; prior to WHO 2016, it meant grade I and II gliomas; subsequently, it changed to "lower-grade gliomas," including grade II and III gliomas, with the same molecular features. In the current classification, IDH wild-type grade II and III gliomas have been eliminated, and "lower-grade gliomas" now only include gliomas with IDH mutations. Maximal safe resection is necessary for a proper molecular diagnosis and survival, and awake craniotomy should be aggressively considered to prevent permanent postoperative neurologic deficits for tumors in the eloquent region. Supramarginal resection is an attractive approach for neurosurgeons to improve survival outcomes, but the evidence is still lacking. Chemoradiotherapy with procarbazine, CCNU, and vincristine is recommended for both grade 2 and 3 oligodendrogliomas. However, the risk of radiation-induced neurotoxicity is a concern in long-term survivors, and several clinical trials have tested the efficacy of chemotherapy alone in terms of cognitive function. Since CCNU is not approved in Japan, ACNU-containing regimen as PAV, or temozolomide are commonly used for the tumor.

CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy.

Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cell-mediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients.

Serum anti-DIDO1, anti-CPSF2, and anti-FOXJ2 antibodies as predictive risk markers for acute ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is a serious cause of mortality and disability. AIS is a serious cause of mortality and disability. Early diagnosis of atherosclerosis, which is the major cause of AIS, allows therapeutic intervention before the onset, leading to prevention of AIS. METHODS: Serological identification by cDNA expression cDNA libraries and the protein array method were used for the screening of antigens recognized by serum IgG antibodies in patients with atherosclerosis. Recombinant proteins or synthetic peptides derived from candidate antigens were used as antigens to compare serum IgG levels between healthy donors (HDs) and patients with atherosclerosis-related disease using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay. RESULTS: The first screening using the protein array method identified death-inducer obliterator 1 (DIDO1), forkhead box J2 (FOXJ2), and cleavage and polyadenylation specificity factor (CPSF2) as the target antigens of serum IgG antibodies in patients with AIS. Then, we prepared various antigens including glutathione S-transferase-fused DIDO1 protein as well as peptides of the amino acids 297-311 of DIDO1, 426-440 of FOXJ2, and 607-621 of CPSF2 to examine serum antibody levels. Compared with HDs, a significant increase in antibody levels of the DIDO1 protein and peptide in patients with AIS, transient ischemic attack (TIA), and chronic kidney disease (CKD) but not in those with acute myocardial infarction and diabetes mellitus (DM). Serum anti-FOXJ2 antibody levels were elevated in most patients with atherosclerosis-related diseases, whereas serum anti-CPSF2 antibody levels were associated with AIS, TIA, and DM. Receiver operating characteristic curves showed that serum DIDO1 antibody levels were highly associated with CKD, and correlation analysis revealed that serum anti-FOXJ2 antibody levels were associated with hypertension. A prospective case-control study on ischemic stroke verified that the serum antibody levels of the DIDO1 protein and DIDO1, FOXJ2, and CPSF2 peptides showed significantly higher odds ratios with a risk of AIS in patients with the highest quartile than in those with the lowest quartile, indicating that these antibody markers are useful as risk factors for AIS. CONCLUSIONS: Serum antibody levels of DIDO1, FOXJ2, and CPSF2 are useful in predicting the onset of atherosclerosis-related AIS caused by kidney failure, hypertension, and DM, respectively.

Association of serum levels of antibodies against ALDOA and FH4 with transient ischemic attack and cerebral infarction.

BACKGROUND: Ischemic stroke, including transient ischemic attack (TIA) and acute-phase cerebral infarction (aCI), is a serious health problem in the aging society. Thus, this study aimed to identify TIA and aCI biomarkers. METHODS: In 19 patients with TIA, candidate antigens recognized by serum IgG autoantibodies were screened using a human aortic endothelial cell cDNA library. Through amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA), serum antibody levels against the candidate antigens were examined in healthy donor (HD), TIA, and aCI cohorts (n = 285, 92, and 529). The plasma antibody levels in the Japan Public Health Center-based Prospective Cohort Study (1991-1993) were also examined. RESULTS: The candidate antigens were aldolase A (ALDOA) and fumarate hydratase (FH). In AlphaLISA, patients with TIA or aCI had higher anti-ALDOA antibody (ALDOA-Ab) and anti-FH antibody (FH-Ab) levels than the HDs (P < 0.05). In a multivariate logistic regression analysis, the ALDOA-Ab (odds ratio [OR]: 2.46, P = 0.0050) and FH-Ab (OR: 2.49, P = 0.0037) levels were independent predictors of TIA. According to the case-control study, the ALDOA-Ab (OR: 2.50, P < 0.01) and FH-Ab (OR: 2.60, P < 0.01) levels were associated with aCI risk. In a correlation analysis, both ALDOA-Abs and FH-Abs were well associated with hypertension, coronary heart disease, and habitual smoking. These antibody levels also correlated well with maximum intima-media thickness, which reflects atherosclerotic stenosis. CONCLUSIONS: ALDOA-Abs and FH-Abs can be novel potential biomarkers for predicting atherosclerotic TIA and aCI.

Serum anti-LRPAP1 is a common biomarker for digestive organ cancers and atherosclerotic diseases.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti-human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S-transferase-fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis-related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well-known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking.

Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

INTRODUCTION: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

Eighty percent survival rate at 15 years for 1p/19q co-deleted oligodendroglioma treated with upfront chemotherapy irrespective of tumor grade.

INTRODUCTION: Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification. Although treatment for oligodendroglioma is controversial, upfront chemotherapy is regarded as one of the treatment option for low-grade tumor. We have treated all the 1p/19q co-deleted oligodendrogliomas, both grades II and III, with upfront chemotherapy without conventional radiotherapy for 20 years. The clinical experience from this trial may be suggestive for understanding of the biological features of oligodendroglioma with 1p/19q co-deletion toward precision medicine. METHODS: This is a long-term retrospective data of the non-selected patients with 1p/19q co-deleted oligodendrogliomas uniformly treated with up-front chemotherapy. Seventy consecutive patients (48 with grade II and 22 with grade III tumors) were included. RESULTS: The median follow-up period was 13 years. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 85.7%, 54.8%, and 31.5%, respectively, and the median PFS was 146 months. In most cases, tumor recurrence was remained local and could be controlled by salvage surgery and/or chemotherapy. The 5-, 10-, and 15-year overall survival (OS) rates were 96.8%, 88.7%, and 80.0%, respectively, and the median OS was not reached. These survival data compared favorably with previous large clinical studies employing radiotherapy. Tumor grades based on World Health Organization classification, extent of surgery, and age affected neither PFS nor OS. Most patients were able to return to their premorbid social life. CONCLUSIONS: The long-term results drawn from 20-years of single institution experience show that the patients with 1p/19q co-deleted oligodendrogliomas can be successfully treated with up-front chemotherapy alone without compromising OS.

Molecular imaging of 1p/19q deletion in oligodendroglial tumours with 11C-methionine positron emission tomography.

OBJECTIVE: Chromosome 1p/19q deletion is an established prognostic and predictive marker in the WHO grade III oligodendroglial tumours (OT). To estimate the genetic status preoperatively, the authors investigated the correlation between the uptake of (11)C-methionine in positron emission tomography (PET) and the 1p/19q status in grades II and III OT. METHODS: We retrospectively reviewed 144 patients with gliomas who received (11)C-methionine PET. 66 cases with grades II-III oligodendrogliomas or oligoastrocytomas underwent fluorescence in situ hybridisation to determine the 1p/19q status. The tissue uptake of (11)C-methionine was expressed as the ratio of the maximum standardised uptake value (SUVmax) in tumour areas to the mean SUV (SUVmean) in the contralateral normal brain (tumour-to-normal tissue (T/N) ratio). RESULTS: The T/N ratio in (11)C-methionine PET was significantly higher in grade III OT than in grade II tumours. The mean T/N ratio of the grade II tumours without 1p/19q deletion was significantly higher than that of the grade II tumours with 1p/19q deletion (mean 2.67 vs 1.94, respectively; p=0.0457). In grade III tumours, the mean T/N ratio of the tumours without 1p/19q deletion was also significantly higher than that of the tumours with 1p/19q deletion (mean 4.83 vs 3.49, respectively; p=0.0261). The rate of IDH1 mutation was lower and the rate of contrast enhancement on MRIs was higher in the 1p/19q non-deleted OT than those with 1p/19q deletion, which may contribute to the high T/N ratio. CONCLUSIONS: Among suspected OT, (11)C-methionine PET may help us preoperatively discriminate tumours with and without 1p/19q deletion.

Transforming growth factor-ß and stem cell markers are highly expressed around necrotic areas in glioblastoma.

Invasion into surrounding normal brain and resistance to genotoxic therapies are the main devastating aspects of glioblastoma (GBM). These biological features may be associated with the stem cell phenotype, which can be induced through a dedifferentiation process known as epithelial-mesenchymal transition (EMT). We show here that tumor cells around pseudopalisading necrotic areas in human GBM tissues highly express the most important EMT inducer, transforming growth factor (TGF-ß), concurrently with the EMT-related transcriptional factor, TWIST. In addition, the stem cell markers CD133 and alkaline phosphatase (ALPL) were also highly expressed around necrotic foci in GBM tissues. The high expression of TGF-ß around necrotic regions was significantly correlated with shorter progression-free survival and overall survival in patients with GBM. High expression of stem cell markers, ALPL, CD133, and CD44 was also correlated with poor outcomes. These results collectively support the hypothesis that tissue hypoxia induces the stem cell phenotype through TGF-ß-related EMT and contributes to the poor outcome of GBM patients.

PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.

Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.

A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC-223 in patients with advanced cancer. METHODS: Patients with advanced solid tumors or multiple myeloma received an initial dose of 7.5-60 mg of CC-223, followed by oral daily dosing in 28-day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy. RESULTS: Twenty-eight patients were enrolled and received ≥1 dose of CC-223. The most common treatment-related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose-limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg/d was determined to be the MTD. The pharmacokinetics of CC-223 demonstrated a mean terminal half-life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng/mL in patients who received CC-223 ≥45 mg/d. Phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells was inhibited by CC-223 ≥30 mg/d with an exposure-response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30-mg/d cohort), stable disease (8 patients across ≥15 mg/d cohorts; response duration range, 36-168 days), and progressive disease (12 patients). The disease control rate was 32%. CONCLUSIONS: CC-223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed.

IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy.

Despite accumulating knowledge regarding molecular backgrounds, the optimal management strategy for low-grade gliomas remains controversial. One reason is the marked heterogeneity in the clinical course. To establish an accurate subclassification of low-grade gliomas, we retrospectively evaluated isocitrate dehydrogenase-1 (IDH1) mutation in clinical specimens of diffuse astrocytomas (DA) and oligodendroglial tumors separately. No patients were treated with early radiotherapy, and modified PCV chemotherapy was used for postoperative residual tumors or recurrence in oligodendroglial tumors. Immunohistochemical evaluation of IDH status, p53 status, O(6)-methylguanine methyltransferase expression, and the MIB-1 index were performed. The 1p and 19q status was analyzed with fluorescence in situ hybridization. Ninety-four patients were followed for a median period of 8.5 years. For DAs, p53 was prognostic for progression- free survival (PFS) and IDH1 was significant for overall survival (OS) with multivariate analysis. In contrast, for oligodendroglial tumors, none of the parameters was significant for PFS or OS. Thus, the significance of IDH1 mutation is not clear in oligodendroglial tumors that are homogeneously indolent and chemosensitive. In contrast, DAs are heterogeneous tumors including some potentially malignant tumors that can be predicted by examining the IDH1 mutation status.

Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas.

BACKGROUND: Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers. METHODS: We searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas. RESULTS: FLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients' sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC. CONCLUSIONS: The present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study.

Non-deep-seated primary CNS lymphoma: therapeutic responses and a molecular signature.

The survival of patients with primary CNS lymphoma (PCNSL) has been improved by high-dose methotrexate (HD-MTX). Since the combination therapy of HD-MTX and whole-brain radiotherapy (WBRT) carries a significant risk for delayed neurotoxicity, it is important to know the therapeutic potential and prognostic factors for HD-MTX without WBRT. We retrospectively reviewed 46 consecutive patients with PCNSL treated with a HD-MTX (3.5 g/m(2)) and deferred WBRT. Patients who achieved complete response or partial response after three courses of HD-MTX were cautiously followed-up without additional treatment. Patients who had either stable disease, progressive disease, or disease relapse were offered salvage therapy. The median progression-free survival period was 10 months and the median overall survival period was 52 months, with a 5-year survival rate of 39 %. Nineteen patients (49 % of the evaluable patients) achieved a complete response at the initial response assessment. Involvement of deep structures of the brain (corpus callosum, basal ganglia and brainstem) was significantly associated with the worse progression-free survivals (p = 0.0058) and overall survivals (p = 0.0177). Gene expression profiling analysis by microarray was compared in eight patients between PCNSLs located in the deep structures of the brain and non-deep-seated tumors. The result showed that up-regulation of signal transduction-related genes and down-regulation of catalytic activity-related genes in the non-deep-seated PCNSL compared with the deep-seated tumors. The present study shows that PCNSL located in non-deep structures of the brain responds better to HD-MTX alone than those involved deep-structures.

Metabolic state of glioma stem cells and nontumorigenic cells.

Gliomas contain a small number of treatment-resistant glioma stem cells (GSCs), and it is thought that tumor regrowth originates from GSCs, thus rendering GSCs an attractive target for novel treatment approaches. Cancer cells rely more on glycolysis than on oxidative phosphorylation for glucose metabolism, a phenomenon used in 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography imaging of solid cancers, and targeting metabolic pathways in cancer cells has become a topic of considerable interest. However, if GSCs are indeed important for tumor control, knowledge of the metabolic state of GSCs is needed. We hypothesized that the metabolism of GSCs differs from that of their progeny. Using a unique imaging system for GSCs, we assessed the oxygen consumption rate, extracellular acidification rate, intracellular ATP levels, glucose uptake, lactate production, PKM1 and PKM2 expression, radiation sensitivity, and cell cycle duration of GSCs and their progeny in a panel of glioma cell lines. We found GSCs and progenitor cells to be less glycolytic than differentiated glioma cells. GSCs consumed less glucose and produced less lactate while maintaining higher ATP levels than their differentiated progeny. Compared with differentiated cells, GSCs were radioresistant, and this correlated with a higher mitochondrial reserve capacity. Glioma cells expressed both isoforms of pyruvate kinase, and inhibition of either glycolysis or oxidative phosphorylation had minimal effect on energy production in GSCs and progenitor cells. We conclude that GSCs rely mainly on oxidative phosphorylation. However, if challenged, they can use additional metabolic pathways. Therefore, targeting glycolysis in glioma may spare GSCs.

Serum anti­KIAA0513 antibody as a common biomarker for mortal atherosclerotic and cancerous diseases.

Numerous antibody biomarkers have been reported for cancer and atherosclerosis-related diseases. The major complications of atherosclerosis and diabetes mellitus (DM) are acute ischemic stroke (AIS), cardiovascular disease (CVD) and chronic kidney disease (CKD). Cancer development is accompanied by arterial disorders, such as angiogenesis and atherosclerosis, and DM is a risk factor for the development of certain types of cancer. Atherosclerosis-related diseases and cancers are therefore interrelated and could be detected using a common biomarker. In the present study, the initial screening using the protein array method identified KIAA0513 as an antigen recognized by serum IgG antibodies in patients with atherosclerosis. The amplified luminescent proximity homogeneous assay-linked immunosorbent assay revealed significantly higher serum antibody levels against recombinant KIAA0513 protein in patients with AIS, transient ischemic attack (TIA), DM, CVD, obstructive sleep apnea syndrome (OSAS), CKD and solid cancers, such as esophageal, gastric, colon, lung and breast cancers, compared with healthy donors. A receiver operating characteristic (ROC) analysis revealed that the highest areas under the ROC curves of anti-KIAA0513 antibodies were obtained for esophageal cancer, nephrosclerosis-type CKD and DM. Spearman's correlation analysis revealed that serum anti-KIAA0513 antibody levels were associated with maximum intima-media thickness and plaque score, which are indices of atherosclerosis and stenosis. Serum anti-KIAA0513 antibody markers appear to be useful for diagnosing AIS, TIA, DM, CVD, OSAS, CKD and solid cancers, and may reflect common arterial alterations leading to atherosclerotic and cancerous diseases.