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Due to their rarity and diversity, sarcomas are difficult to diagnose. Consequently, there is an urgent demand for a novel diagnostic test for these cancers. In this study, we investigated serum miRNA profiles from 1002 patients with bone and soft tissue tumors representing more than 43 histological subtypes, including sarcomas, intermediate tumors, and benign tumors, to determine whether serum miRNA profiles could be used to specifically detect sarcomas. Circulating serum miRNA profiles in sarcoma patients were clearly distinct from those in patients with other types of tumors. Using the serum levels of seven miRNAs, we developed a molecular detector, Index VI, that could distinguish sarcoma patients from benign and healthy controls with remarkably high sensitivity (90%) and specificity (95%), regardless of histological subtype. Index VI provides an approach to the early and precise detection of sarcomas, potentially leading to curative treatment and longer survival., Sarcomas are rare malignant tumours of bone and soft tissue whose diagnosis remain difficult. Here, the authors analyse serum samples from over 1000 patients and using separate discovery, training and validation cohorts, identify and validate a 7-microRNA index that distinguishes malignant sarcomas from benign disease.

Gene therapy is a promising technology for genetic and intractable diseases. Drug delivery carriers or systems for genes and nucleic acids have been studied to improve transfection efficiency and achieve sufficient therapeutic effects. Ultrasound (US) and microbubbles have also been combined for use in gene delivery. To establish a clinically effective gene delivery system, exposing the target tissues to US is important. The three-dimensional (3D) diagnostic probe can three-dimensionally scan the tissue with mechanical regulation, and homogenous US exposure to the targeted tissue can be expected. However, the feasibility of therapeutically applying 3D probes has not been evaluated, especially gene delivery. In this study, we evaluated the characteristics of a 3D probe and lipid-based microbubbles (LB) for gene delivery and determined whether the 3D probe in the diagnostic US device could be used for efficient gene delivery to the targeted tissue using a mouse model. The 3D probe RSP6-16 with LB delivered plasmid DNA (pDNA) to the kidney after systemic injection with luciferase activity similar to that of probes used in previously studies. No toxicity was observed after treatment and, therefore, the combined 3D probe and LB would deliver genes to targeted tissue safely and efficiently.

Up to 30% stage I lung cancer patients suffer recurrence within 5 years of curative surgery. We sought to improve existing protein-coding gene and microRNA expression prognostic classifiers by incorporating epigenetic biomarkers.Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of stage I lung adenocarcinoma. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed by Cox regression and Kaplan-Meier survival analysis in both cohorts.Promoters of genes marked by polycomb in embryonic stem cells were methylated de novo in tumors and identified patients with poor prognosis. The HOXA9 locus was methylated de novo in stage I tumors (p0.0005). High HOXA9 promoter methylation was associated with worse cancer-specific survival (hazard ratio [HR], 2.6; p = 0.02) and recurrence-free survival (HR, 3.0; p = 0.01), and identified high-risk patients in stratified analysis of stages IA and IB. Four protein-coding gene (XPO1, BRCA1, HIF1α, and DLC1), miR-21 expression, and HOXA9 promoter methylation were each independently associated with outcome (HR, 2.8; p = 0.002; HR, 2.3; p = 0.01; and HR, 2.4; p = 0.005, respectively), and when combined, identified high-risk, therapy naive, stage I patients (HR, 10.2; p = 3 × 10). All associations were confirmed in two independently collected cohorts.A prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of stage I lung cancer patients at high risk of recurrence.

Purpose: Better understanding of the underlying biology of primary central nervous system lymphomas (PCNSL) is critical for the development of early detection strategies, molecular markers, and new therapeutics. This study aimed to define genes associated with survival of patients with PCNSL. Experimental Design: Expression profiling was conducted on 32 PCNSLs. A gene classifier was developed using the random survival forests model. On the basis of this, prognosis prediction score (PPS) using immunohistochemical analysis is also developed and validated in another data set with 43 PCNSLs. Results: We identified 23 genes in which expressions were strongly and consistently related to patient survival. A PPS was developed for overall survival (OS) using a univariate Cox model. Survival analyses using the selected 23-gene classifiers revealed a prognostic value for high-dose methotrexate (HD-MTX) and HD-MTX–containing polychemotherapy regimen–treated patients. Patients predicted to have good outcomes by the PPS showed significantly longer survival than those with poor predicted outcomes (P < 0.0001). PPS using immunohistochemical analysis is also significant in test (P = 0.0004) and validation data set (P = 0.0281). The gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < 0.0001). Among the genes, BRCA1 protein expressions were most strongly associated with patient survival. Conclusion: We have identified gene expression signatures that can accurately predict survival in patients with PCNSL. These predictive genes should be useful as molecular biomarkers and they could provide novel targets for therapeutic interventions. Clin Cancer Res; 18(20); 5672–81. ©2012 AACR.

Dopamine is related to behaviour (including arousal, motivation and motor control of locomotion), and its turnover in the brain is increased during exercise. We examined the hypothesis that dopamine D2 receptors contribute to exercise hyperpnoea via central neural pathways using the D2-like receptor antagonist, raclopride. We simultaneously measured ventilation and pulmonary gas exchange for the first time in mice. Mice injected with saline and raclopride (2 mg (kg body weight)−1; i.p.) were compared for respiratory responses to constant-load exercise at 6 m min−1. Each mouse was set in an airtight treadmill chamber. In the resting state, raclopride-treated mice had reduced respiratory frequency (fR) and minute ventilation () compared with saline-treated mice, but arterial and pulmonary gas exchange were not affected, showing that alveolar ventilation was maintained. Inhalation of hyperoxic gas maintained in saline-treated mice, and hypercapnic ventilatory responses between the two groups were similar. Treadmill exercise produced an abrupt increase in to a maximal level within 1 min and declined to a steady-state level in both groups. Raclopride-treated mice had reduced fR and compared with saline-treated mice during steady states, but showed a similar increase in fR and at exercise onset. Minute ventilation in the steady state was controlled, along with the increase in pulmonary O2 uptake in both groups, but was lowered in raclopride-treated mice. Thus, D2 receptors participate in resting breathing patterns to raise fR and exercise hyperpnoea in the steady state, probably through behavioural control and not central motor command, at exercise onset.

12019Background: Diagnosis of sarcomas is considered to be quite difficult because of the rarity and diversity of the disease. The development of a novel diagnostic test for sarcoma is eagerly awai...

近年，古レール造跨線橋の耐震診断として，非線形特性をH型断面の鋼部材と仮定し，計算した例があるが，あくまでH型断面の評価，非線形特性も完全弾塑性型としてモデル化したものであり，降伏点以降のモデル化が適切に評価されているかどうかわからない実状がある．本論文では，古レール造乗換え跨線橋の耐震診断を行うにあたり，未解明である古レール柱の復元力特性について明らかにすることを目的とした．具体的には，古レール単柱に一定軸力の下，交番載荷試験を行い，古レール柱の履歴曲線を本試験より求め，復元力特性を適切に評価した．本検討結果について報告する．

Background: Chemotherapy with or without radiotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, either as a single agent or in combination with other drugs. Due to the lack of well-conducted randomized trials, the optimal treatment remains controversial. Available retrospective studies are difficult to discuss, however, some common themes can be found. Methods: One hundred and twelve patients with PCNSL were treated with four different regimens over a period of 24 years. Treatment regimens were: whole-brain irradiation (WBI) alone, MVP (MTX, vincristine, and predonisolone), ProMACE-MOPP hybrid (cyclophosphamide, pirarubicin, etoposide, vincristine, procarbazine, prednisone, and MTX) and R-MTX (rituximab, MTX, pirarubicin, procarbazine, and prednisone) combined-modality therapy. Results: The median failure-free survival was 16 months, and the median overall survival (OS) was 24 months. The 2- and 5-year actuarial probability of survival was 52.4+4.8% [95% confidence intervals (CI)] and 30.2+4.8% (95% CI), respectively. The ProMACEMOPP protocol, Karnofsky performance status (KPS), MTX dose and WBI were associated with good OS by univariate models. By multivariate analysis, MTX dose, WBI dose, and its square dose were significantly associated with good OS. 20‐30 Gy WB, and 500 mg/m 2 of MTX dose appeared important determinants of OS. Conclusions: A modest dose of MTX (500 mg/m 2 ) followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity.

In mice, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces a high incidence of malignant lymphoma and leukemia, but exhibits little, if any, carcinogenic activity in the large intestine after long-term exposure. However, recent studies have revealed that colonic adenocarcinomas can be efficiently and rapidly induced by combined treatment with PhIP and dextran sulfate sodium (DSS), a potent inducer of colitis. In the present study, the authors investigated the effects of inflammation on PhIP-induced carcinogenesis using two mouse strains, C57BL/6J and MSM/Ms, showing distinct temporal profiles of inflammatory responses to DSS. A long-term carcinogenesis experiment conducted with a single i.g. administration of PhIP (200 mg/kg body weight), followed by DSS treatment in drinking water for 4-6 days, revealed an increase in tumor incidence in C57BL/6J mice in accordance with the DSS intake. In contrast, neoplastic lesions were rarely observed in the MSM/Ms strain. From the short-term exposure to DSS for 4 days, C57BL/6J mice demonstrated severe chronic colitis, accompanied by hyperplastic cryptal epithelium and extensive cellular infiltration. Splenomegaly and swelling of mesenteric lymph nodes were also evident for over 1 month as chronic symptoms of systemic immunological disturbance. However, no inflammatory lesions were detected in MSM/Ms mice. The present results provide strong evidence that prolonged chronic inflammatory responses induced by DSS are directly responsible for the observed enhancement of PhIP-induced large bowel carcinogenicity.

To cite this Article: Yamanaka, Ryuya, Homma, Junpei, Sano, Masakazu, Tsuchiya, Naoto, Yajima, Naoki, Shinbo, Yoshikatsu, Hasegawa, Akira, Onda, Kiyoshi and Tanaka, Ryuichi , 'Immuno-chemotherapy with a combination of rituximab, methotrexate, pirarubicin and procarbazine for patients with primary CNS lymphoma A preliminary report', Leukemia and Lymphoma, 48:5, 1019 1022 To link to this article: DOI: 10.1080/10428190701248009 URL: http://dx.doi.org/10.1080/10428190701248009

We report the efficacy of salvage therapy with a modified ProMACE-MOPP combined with radiation in patients with primary central nervous system lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristin, and methotrexate (MTX: 500 mg/m(2)) administered in 21-day cycles. Patients received 20 Gy of whole-brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every four months for two years. Nine patients with CNS relapse were retreated with additional cycles of the ProMACE-MOPP hybrid regimen with a 90% objective response rate. Median complete response (CR) duration was 13.2 months and median survival time (MST) for the nine patients treated after initial relapse was 30 months. One of 17 patients (5.8%) who had less than 20 Gy of whole brain irradiation developed dementia. In contrast, six of seven (85.7%) patients who had more than 30 Gy of whole brain radiotherapy became demented. Maintaining a moderate dose of MTX, while adding chemotherapeutic agents and 20 Gy of whole brain radiation therapy, improved disease control and overall survival and lowered the incidence of delayed neurologic toxicity in patients with PCNSL. Additional treatment with a ProMACE-MOPP hybrid regimen is still effective for relapsed disease.

In this Phase I/II trial, the patient's peripheral blood dendritic cells were pulsed with an autologous tumour lysate of the glioma. Seven patients with glioblastoma and three patients with anaplastic glioma, ranging in age from 20 to 69 years, participated in this study. The mean numbers of vaccinations of tumour lysate-pulsed dendritic cells were 3.7 times intradermally close to a cervical lymph node, and 3.2 times intratumorally via an Ommaya reservoir. The percentage of CD56-positive cells in the peripheral blood lymphocytes increased after immunisation. There were two minor responses and four no-change cases evaluated by radiological findings. Dendritic cell vaccination elicited T-cell-mediated antitumour activity, as evaluated by the ELISPOT assay after vaccination in two of five tested patients. Three patients showed delayed-type hypersensitivity reactivity to the autologous tumour lysate, two of these had a minor clinical response, and two had an increased ELISPOT result. Intratumoral CD4+ and CD8+ T-cell infiltration was detected in two patients who underwent reoperation after vaccination. This study demonstrated the safety and antitumour effects of autologous tumour lysate-pulsed dendritic cell therapy for patients with malignant glioma.

Purpose: To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC). Experimental Design: The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR–based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Results: A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power. Conclusion: The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence. Clin Cancer Res; 20(18); 4784–93. ©2014 AACR.

Dysfunction of the p53 network is a major cause of cancer development, and selective elimination of p53-inactivated cancer cells therefore represents an ideal therapeutic strategy. In this study, we performed a microRNA target screen that identified NEK9 (NIMA-related kinase 9) as a crucial regulator of cell-cycle progression in p53-inactivated cancer cells. NEK9 depletion selectively inhibited proliferation in p53-deficient cancer cells both in vitro and in vivo. The resultant cell-cycle arrest occurred predominantly in G1 phase, and exhibited senescence-like features. Furthermore, NEK9 repression affected expression of a broad range of genes encoding cell-cycle regulators and factors involved in mRNA processing, suggesting a novel role for NEK9 in p53-deficient cells. Lung adenocarcinoma patients with positive staining for NEK9 and mutant p53 proteins exhibited significantly poorer prognoses, suggesting that expression of both proteins promotes tumor growth. Our findings demonstrate that a novel NEK9 network regulates the growth of cancer cells lacking functional p53.

We have shown that constant-load treadmill exercise in mice produces an abrupt ventilatory increase to a maximal level at exercise onset. We examined what caused this abrupt response. We measured ventilation during 30-min constant-load exercise on a treadmill, below the lactate threshold, in conscious mice. Video analysis showed that hyperpnoea started before locomotion began. Incremental changes in speed did not further increase ventilation during the early phase of exercise. Next, we measured ventilatory responses to a sudden movement of the treadmill belt on which the mice were kept in a stationary position by a mesh cover. Hyperpnoea started concurrently with the sudden belt movement. In the absence of locomotion, ventilation increased to the extent reached during exercise hyperpnoea. Finally, the abrupt response showed plasticity but was attenuated by experience. The present study shows the importance of factors independent of limb movements in the hyperpnoeic response during the early phase of treadmill exercise in mice.

Purpose: The primary goal of this phase I study was to assess the safety and immunologic responses of personalized peptide vaccination for patients with advanced malignant glioma.Experimental Design: Twenty-five patients with advanced malignant glioma (8 grade 3 and 17 grade 4 gliomas) were evaluated in a phase I clinical study of a personalized peptide vaccination. For personalized peptide vaccination, prevaccination peripheral blood mononuclear cells and plasma were provided to examine cellular and humoral responses to 25 or 23 peptides in HLA-A24+ or HLA-A2+ patients, respectively; then, only the reactive peptides (maximum of four) were used for in vivo administration.Results: The protocols were well tolerated with local redness and swelling at the injection site in most cases. Twenty-one patients received more than six vaccinations and were evaluated for both immunologic and clinical responses. Increases in cellular or humoral responses specific to at least one of the vaccinated peptides were observed in the postvaccination (sixth) samples from 14 or 11 of 21 patients, respectively. More importantly, significant levels of peptide-specific IgG were detected in the postvaccination tumor cavity or spinal fluid of all of the tested patients who showed favorable clinical responses. Clinical responses were 5 partial responses, 8 cases of stable disease, and 8 cases of progressive disease. The median overall survival for patients with recurrent glioblastoma multiforme in this study (n = 17) was 622 days.Conclusions: Personalized peptide vaccinations were recommended for the further clinical study to malignant glioma patients.

Purpose: To investigate the safety and the immunologic and clinical responses of dendritic cell therapy for patients with recurrent malignant glioma.Experimental Design: Twenty-four patients with recurrent malignant glioma (6 grade 3 and 18 grade 4 patients) were evaluated in a phase I/II clinical study of dendritic cell therapy. All patients were resistant to the standard maximum therapy. The patient's peripheral blood dendritic cells were generated with granulocyte macrophage colony-stimulating factor, plus interleukin 4 with or without OK-432, and pulsed with an autologous tumor lysate. Dendritic cells were injected intradermally, or both intratumorally and intradermally every 3 weeks.Results: The protocols were well tolerated with only local redness and swelling at the injection site in several cases. Clinical responses were as follows: 1 patient with partial response, 3 patients with minor response, 10 patients with stable disease, and 10 patients with progressive disease. The patients whose dendritic cells were matured with OK-432 had longer survival times than the dendritic cells from patients without OK-432 maturation. The patients with both intratumoral and intradermal administrations had a longer survival time than the patients with intradermal administration only. Increased ELISPOT and delayed-type hypersensitivity responses after vaccination could provide good laboratory markers to predict the clinical outcome of patients receiving dendritic cell vaccination. The overall survival of patients with grade 4 glioma was 480 days, which was significantly better than that in the control group.Conclusions: This study showed the safety and clinical response of autologous tumor lysate-pulsed dendritic cell therapy for patients with malignant glioma. Dendritic cell therapy is recommended for further clinical studies in malignant glioma patients.

A 36-year-old woman developed multiple spontaneous arterial dissections in both renal arteries, the carotid artery, superior mesenteric artery, and vertebral artery, but not the aorta, and she suffered a renal infarction and subarachnoid hemorrhage within a short period of time. She had been undergoing frequent injections of human chorionic gonadotropin and human menopausal gonadotropin, together with oral estrogen therapy, during a 5-year infertility treatment regimen. As she had no other history of any disorder affecting the arterial walls, this therapy is suspected to have caused the multiple arterial deformities. Although cases of isolated arterial dissection are occasionally reported, it is rare for multiple dissections and serious symptoms to occur simultaneously. (Circ J 2005; 69: 368 - 372)

✓ The authors report on two patients in whom an increased signal on T1-weighted magnetic resonance images and a high-density signal on computerized tomography scans of the striatum were demonstrated, both of which were associated with nonketotic hyperglycemia. Involuntary movements, which have been present in all previously reported cases, were not observed in either patient at any time during the entire course of illness. One patient displayed hemiparesis, whereas the other had dementia, gait disturbance, and urinary incontinence. Clinical and radiological abnormalities improved on control of blood glucose levels. Invasive studies, including biopsy procedures, should be avoided on encountering this disease given the good prognosis that results from simple medical treatment.

In this Phase I/II trial, the patient's peripheral blood dendritic cells were pulsed with an autologous tumour lysate of the glioma. Fourteen patients with glioblastoma and 4 patients with anaplastic glioma, ranging in age from 20 to 73 years, participated in this study. The mean numbers of vaccinations of tumour lysate-pulsed dendritic cells were 4.8 times intradermally close to a cervical lymph node, and 4.2 times intratumourally via an Ommaya reservoir. The percentage of CD56-positive cells in the peripheral blood lymphocytes increased after immunization. There were 1 partial response, 2 minor responses and 7 no change cases evaluated by radiological findings. Dendritic cell vaccination elicited T-cell-mediated antitumour activity, as evaluated by ELISPOT assay after vaccination in 2 of 5 tested patients. Three patients showed DTH reactivity to the autologous tumour lysate, two of these had a minor clinical response, and two had an increased ELISPOT result. Intratumoural CD4 and CD8 T-cell infiltration was detected in two patients who underwent re-operation after vaccination. This study demonstrated the safety and antitumour effects of autologous tumour lysate-pulsed dendritic cell therapy for patients with malignant glioma.

Despite advances in radiation and chemotherapy along with surgical resectioning, the prognosis of patients with malignant glioma is poor. Among the new treatments currently being investigated for malignant glioma, immunotherapy is theoretically very attractive, since it offers the potential for high tumor-specific cytotoxicity. There are increasing reports demonstrating that systemic immunotherapy using dendritic cells is capable of inducing an antiglioma response. Therefore, dendritic cell-based immunotherapy could be a new treatment modality for patients with glioma. In this review, we will discuss the implications of these findings for glioma therapy. A literature review of dendritic cell-based glioma immunotherapy was used to overview the dendritic cell in immunobiology, in the central nervous system and in tumor immunology, glioma-associated antigens, dendritic cell therapy in animal glioma model, dendritic cell therapy in clinical trials and future directions in dendritic cell therapy. Dendritic cell-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma. Dendritic cell therapy of glioma seems to be safe and without major side effects. Its efficacy should be further determined in randomized, controlled clinical trials. The development of methods for manipulating dendritic cells for the purpose of vaccination will enhance the clinical usefulness of these cells for biotherapy for malignant glioma.