Local Delivery of Nimustine Hydrochloride against Brain Tumors: Basic Characterization Study.

Convection-enhanced delivery (CED) delivers agents directly into tumors and the surrounding parenchyma. Although a promising concept, clinical applications are often hampered by insufficient treatment efficacy. Toward developing an effective CED-based strategy for delivering drugs with proven clinical efficacy, we performed a basic characterization study to explore the locally delivered characteristics of the water soluble nitrosourea nimustine hydrochloride (ACNU). First, ACNU distribution after CED in rodent brain was studied using mass spectrometry imaging. Clearance of 14C-labeled ACNU after CED in striatum was also studied. ACNU was robustly distributed in rodent brain similar to the distribution of the hydrophilic dye Evans blue after CED, and locally delivered ACNU was observed for over 24 h at the delivery site. Subsequently, to investigate the potential of ACNU to induce an immunostimulative microenvironment, Fas and transforming growth factor-ß1 (TGF-ß1) was assessed in vitro. We found that ACNU significantly inhibited TGF-ß1 secretion and reduced Fas expression. Further, after CED of ACNU in 9L-derived intracranial tumors, the infiltration of CD4/CD8 lymphocytes in tumors was evaluated by immunofluorescence.CED of ACNU in xenografted intracranial tumors induced tumor infiltration of CD4/CD8 lymphocytes. ACNU has a robust distribution in rodent brain by CED, and delayed clearance of the drug was observed at the local infusion site. Further, local delivery of ACNU affects the tumor microenvironment and induces immune cell migration in tumor. These characteristics make ACNU a promising agent for CED.

Granulocyte-macrophage colony stimulating factor enhances efficacy of nimustine rendezvousing with temozolomide plus irradiation in patients with glioblastoma.

BACKGROUND: Glioblastoma is the most common and most aggressive type of primary brain tumor. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intranasal granulocyte-macrophage colony stimulating factor (GM-CSF) administration combined with chemoradiotherapy in patients with glioblastoma who underwent surgery. METHODS: Ninety-two patients were randomly divided into two groups: a control group (n= 46), who received radiotherapy with adjuvant local delivery of nimustine hydrochloride (ACNU) and systemic administration of temozolomide, and an intervention group (n= 46), who received intranasal GM-CSF prior to each cycle of adjuvant chemotherapy in addition to the treatment of the control group. Karnofsky performance status (KPS) scores, progression-free survival (PFS), overall survival (OS), and adverse effects were calculated and compared between the two groups. RESULTS: Compared with the control group, the intervention group had longer PFS (7.8 vs. 6.9 months, P= 0.016) and OS (19.2 vs. 17.1 months, P= 0.045, without adjustment for interim analyses). The KPS scores were also higher in the intervention group than in the control group after 6 months (84.35 ± 8.86 vs. 80.65 ± 7.72; t= 4.552, P= 0.036). Furthermore, the patients in the intervention group had lower incidence of neutropenia and thrombocytopenia (8.7% vs. 29.5%, P= 0.012; 8.7% vs. 18.2%, P= 0.186). Other adverse events were similar in both groups, and most adverse events were grade I/II and resolved spontaneously. CONCLUSION: Intranasal GM-CSF enhances the efficacy of the local ACNU administration combined with oral temozolomide chemotherapy. The survival and performance status were significantly improved in patients with glioblastoma after surgery. Additionally, the GM-CSF therapy was able to reduce the occurrence of chemotherapy-related neutropenia and thrombocytopenia.

Retrospective evaluation of nimustine use in the treatment of feline lymphoma.

BACKGROUND: Nimustine, similar to lomustine, is an alkylating agent from the nitrosourea family. There have been some reports regarding lomustine treatment for tumour-bearing cats. However, information regarding nimustine treatment for tumour-bearing cats is limited. OBJECTIVES: To retrospectively evaluate adverse events and clinical outcomes in tumour-bearing cats receiving nimustine. METHODS: Information regarding diagnosis, treatment condition, adverse events, and clinical outcomes was collected in tumour-bearing cats receiving nimustine through reviews of medical records. RESULTS: Nine cats with lymphoma were treated with nimustine in the primary therapy (n = 2) and in the rescue therapy (n = 7). Median starting dose of nimustine was 25 mg/m2 (range: 20-30 mg/m2 ) with dosing interval of three weeks and 1-11 administrations. Adverse events were mild gastrointestinal toxicity (grade 1) including diarrhoea (n = 2) and vomiting (n = 2) and mild myelosuppression (grade 1 or 2) including thrombocytopenia (n = 3) and neutropenia (n = 1). No severe adverse events were observed. Progression-free survival durations among cats receiving nimustine in the primary therapy and in the rescue therapy were 274-688 days (median: 481 days) and 9-671 days (median: 102 days), respectively. Overall survival durations among cats receiving nimustine in the primary therapy and in the rescue therapy were 275-745 days (median: 510 days) and 14-671 days (median: 109 days), respectively. CONCLUSIONS: Nimustine was well tolerated and showed clinical outcomes similar to lomustine in cats with lymphoma. These findings suggest that nimustine might be an alternative to lomustine in the treatment of feline lymphoma.

Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance.

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM.

Nimustine Treatment of 11 Cases of Canine Histiocytic Sarcoma.

The objective of this retrospective study was to report treatment outcomes in dogs with histiocytic sarcoma (HS) that were treated with nimustine (ACNU). This study evaluated data from 11 dogs including 5 with macroscopic tumors that were treated in the primary setting and 6 that underwent aggressive local therapy while being treated in the adjuvant setting. The median ACNU starting dose was 25 mg/m2 (range, 20-30 mg/m2; 3- to 5-wk intervals, 1-8 administrations). The median overall survival in the primary and adjuvant settings was 120 days (median progression-free survival [PFS], 63 days) and 400 days (median PFS, 212 days), respectively. Neutropenia was observed in eight cases (grade 1, n = 1; grade 2, n = 2; grade 3, n = 2; grade 4, n = 3) with nadir neutrophil count at 1 wk after ACNU administration. Mild gastrointestinal toxicity (grade 1-2) was observed in three cases. ACNU was well tolerated and showed a similar outcome to that seen for lomustine, which is a drug commonly used to treat canine HS, in terms of overall survival and PFS in the current study population. Further investigations will need to be undertaken to definitively determine if ACNU is an appropriate alternative to lomustine for the treatment of HS.

Regression of Recurrent Spinal Cord High-Grade Glioma After Convection-Enhanced Delivery of Nimustine Hydrochloride: Case Reports and Literature Review.

BACKGROUND: Spinal cord high-grade glioma has poor prognosis. Especially, no treatment protocols have been established for recurrent cases. OBJECTIVE: To apply a novel treatment method, convection-enhanced delivery (CED), for recurrent high-grade glioma. CED can deliver chemotherapeutic agents directly into the intramedullary lesion and possibly lead to remarkable regression of enlarging tumors that are, otherwise, difficult to control. METHODS: Two patients developed high-grade glioma in the thoracic spinal cord. Partial resection and chemotherapy and radiotherapy induced remission of the disease. However, following the initial treatment, recurrence was noted in the spinal cord at 6 and 12 mo, respectively. No effective treatment was available for these recurrent lesions. Therefore, the authors decided to use CED to infuse nimustine hydrochloride (ACNU) directly into the spinal cord. During the procedure, the infusion cannula was inserted into the spinal cord lesion under intraoperative computed tomography scan. RESULTS: After ACNU CED, successive magnetic resonance imaging confirmed remarkable shrinkages of the tumors in both cases. However, the patient's preinfusion symptoms, including bilateral lower extremity weakness, did not change after the treatment. Importantly, overall survivals of the 2 patients were as long as 67 and 33 mo. CONCLUSION: The authors report the first 2 cases of recurrent spinal cord high-grade glioma. ACNU CED dramatically regressed enhanced mass lesions and provided local tumor controls in the spinal cord.

Role of a Promoter Mutation in TERT in Malignant Transformation of Pleomorphic Xanthoastrocytoma.

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is categorized as grade II, other astrocytic tumors per the 2016 World Health Organization classification. Despite being a relatively benign type of tumor, PXA often has an aggressive clinical course. The more malignant form of PXA is now known as anaplastic pleomorphic xanthoastrocytoma (A-PXA) and is categorized as a grade III tumor. Clinical and genetic factors associated with malignant transformation remain unclear. In particular, typical genetic expression patterns in PXA and A-PXA remain unidentified. CASE DESCRIPTION: We present a case of recurrent PXA in which malignant transformation followed a promoter mutation in TERT. In this case, genetic chronologic changes accompanying malignant transformation of PXA were thoroughly examined. The promoter mutation was detected in the second operative specimen after stereotactic radiosurgery (SRS) at the first tumor recurrence. Subsequently, a malignant transformation to the A-PXA occurred at the time of the second recurrence, and the tumor repeatedly recurred afterward. CONCLUSIONS: TERT promotor mutations may contribute to the malignant transformation of PXA; the mechanism of this mutation is unknown, but it may have been caused by SRS. Therefore, improvident use of radiation should be avoided to prevent the malignant transformation of PXA.

Convection-enhanced delivery of a hydrophilic nitrosourea ameliorates deficits and suppresses tumor growth in experimental spinal cord glioma models.

BACKGROUND: Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier. OBJECTIVE: To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model. METHODS: Toxicity studies were performed in 42 rats following the administration of 4 µl of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED (n = 8); saline i.v. (n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically. RESULTS: The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses (P < 0.05; log-rank test). CONCLUSIONS: ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma.

Phase I/II Study of Temozolomide Plus Nimustine Chemotherapy for Recurrent Malignant Gliomas: Kyoto Neuro-oncology Group.

The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1-5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70-100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12-35%) and 8% (95% CI, 4-15%). Median PFS was 13 months (95% CI, 9.2-17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67-89%) and 49% (95% CI, 33-57%). Median OS was 11.8 months (95% CI, 8.2-14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.

Proton beam therapy with concurrent chemotherapy for glioblastoma multiforme: comparison of nimustine hydrochloride and temozolomide.

To evaluate the safety and efficacy of postoperative proton beam therapy (PBT) combined with nimustine hydrochloride (ACNU) or temozolomide (TMZ) for glioblastoma multiforme (GBM). The subjects were 46 patients with GBM who were treated with high dose (96.6 GyE) PBT. There were 24 males and 22 females, and the median age was 58 years old (range 24-76). The Karnofsky performance status was 60, 70, 80, 90 and 100 in 5, 10, 12, 11 and 8 patients, respectively. Total resection, partial resection, and biopsy were performed for 31, 14 and 1 patients, respectively. Photon beams were delivered to high intensity areas on T2-weighted magnetic resonance imaging (MRI) in the morning (50.4 Gy in 28 fractions). More than 6 h later, PBT was delivered to the enhanced area plus a 10 mm margin in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume in the second half (23.1 GyE in 14 fraction). Concurrent chemotherapy with ACNU during weeks 1 and 4 or daily TMZ was administered in 23 and 23 patients, respectively. The overall 1 and 2 year survival rates were 82.6 and 47.6 %, respectively. Median survival was 21.1 months (95 % CI 13.1-29.2), with no significant difference in survival between the ACNU and TMZ groups. The patient characteristics were similar in the two groups. Late radiation necrosis occurred in 11 patients (six ACNU, five TMZ), but was controlled by necrotomy and therapy including bevacizumab. PBT concurrent with ACNU or TMZ was tolerable and beneficial for carefully selected patients with GBM.

Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer.

BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors. RESULTS: BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance. CONCLUSIONS: In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms.

Long-term survival after treatment of glioblastoma multiforme with hyperfractionated concomitant boost proton beam therapy.

PURPOSE: Although conventional x-ray therapy of 60 Gy in 30 fractions is generally used in our institute as well as others, the prognosis of patients with glioblastoma multiforme (GBM) is poor. The purpose of this study was to evaluate the characteristics of long-term GBM survivors after postoperative hyperfractionated concomitant boost x-ray radiation therapy and proton beam therapy. METHODS AND MATERIALS: Twenty-three of 81 GBM patients who met the eligible criteria and consented to the protocol were treated with x-ray radiation therapy (50.4 Gy in 28 fractions in T2-high areas) and proton beam therapy (46.2 GyE in 28 fractions in gadolinium-enhanced volumes >6 hours after x-ray radiation therapy) concurrent with nimustine hydrochloride or temozolomide. RESULTS: Treatment was completed in all patients within 38-50 days (median, 43 days). Six currently living patients (median follow-up period, 70.9 months) developed radiation necrosis without tumor recurrence. Of these, 5 underwent necrotomy and 2 received bevacizumab after necrotomy. Compared with the pretreatment status, the Karnofsky performance scale (KPS) for the 6 survivors decreased by 10%-30% at the last follow-up. However, radiation necrosis had been well controlled and 5 of 6 patients maintained a stable KPS without hospital care. CONCLUSIONS: The results suggest that high-dose proton beam therapy could control GBM pathogenesis if the treatment area completely covers tumor infiltration. Although radiation necrosis was inevitable, the remaining brain volume was fairly well preserved in the long-term survivors.

Satisfactory therapy results of combining nimustine with nicardipine against glioma at advanced stage.

Glioblastoma multiforme (GBM) is one of the most frequent brain cancers with a very poor prognosis. According to cancer stem cell (CSC) theory, therapies that are more specifically directed against CSCs might result in much more durable responses. Recently, we treated a case of GBM basing on the conception of CSC and gained a better clinic outcome. A 37-year-old male patient complained weakness of left limbs for 1 month. Magnetic resonance imaging (MRI) showed extensive lesions in the right hemisphere. We performed an intracranial tumor partial resection and the postoperative pathological diagnose was GBM. 1 month later, he received monthly chemotherapies with the combination of nimustine and nicardipine for totally 4 times. At the last chemotherapy, MRI scan showed the cancer almost completely disappeared with significantly improved clinic condition. The combination therapy of chemotherapeutics and nicardipine may be a promising treatment for patients of GBM at advanced stage.

Chemotherapy alleviates subacute recurrent glioma-associated refractory cerebral edema by downregulating vascular endothelial growth factor.

To identify a novel treatment modality for postoperative, glioma-related refractory cerebral edema (RCE), eight patients with postoperative RCE received chemotherapy between January 2008 and July 2012 were enrolled. There were five males and three females aged between 24 and 65 years (mean 45.7 years). Vascular endothelial growth factor (VEGF) levels in the cerebrospinal fluid were measured by enzyme-linked immuno-sorbent assay pre- and postchemotherapy. After 3 days postchemotherapy, midline shift improved from 13.14 ± 0.65 to 7.21 ± 0.55 mm and compressed or effaced basilar cisterns disappeared based on cranial computed tomographic scans. Glascow Coma Scale scores in patients significantly improved from 11.13 ± 0.52 to 14.50 ± 0.27 after chemotherapy. Two patients developed grade 1 leukopenia after 3 weeks, and one patient had grade 1 thrombocytopenia 2 weeks after chemotherapy. No fatal complications occurred. The edematous volume reduced from 77,074 ± 6,813 to 27,874 ± 5,073 mm(3) (p < 0.001). VEGF levels were significantly downregulated after chemotherapy (from 543.8 ± 76.39 to 122.2 ± 59.30 pg/ml, p < 0.001). Chemotherapy may serve to alleviate glioma-related RCE by reducing VEGF levels, especially in patients who were insensitive to decompressive craniectomy.

Phase I dose-escalation study of nimustine in tumor-bearing dogs.

Nimustine (ACNU) is an alkylating agent of the nitrosourea and can be an antineoplastic agent in dogs. But, there has been no report on its dose-limiting toxicity (DLT) in dogs. This study was a phase I dose-escalation clinical trial to determine the maximum tolerated dose (MTD) and DLT of ACNU in tumor-bearing dogs. The starting dosage was 25 mg/m(2), and subsequent dosages were administered in increments of 5 mg/m(2) in cohort of 3 dogs. Eight dogs were included, the MTD was determined to be 25 mg/m(2), DLT was neutropenia, and the optimal interval was considered to be 21 days. The data herein provide a basis for the subsequent phase II trial of ACNU in dogs.

Comparison of the clinical efficacy of temozolomide (TMZ) versus nimustine (ACNU)-based chemotherapy in newly diagnosed glioblastoma.

Although temozolomide (TMZ) replaced nitrosoureas as the standard initial chemotherapy for glioblastoma (GBM), no studies have compared TMZ with nimustine (ACNU), a nitrosourea agent widely used in central Europe and most Asian regions. One hundred thirty-five patients with GBM who underwent extensive tumor resection in our institution received both radiation and chemotherapy as initial treatment, 34 received TMZ and 101 ACNU-based (ACNU plus teniposide or cisplatin) chemotherapy. Efficacy analysis included overall survival (OS) and progression-free survival (PFS). The following prognostic factors were taken into account: age, performance status, extent of resection, and O(6)-methylguanine-DNA-methyltransferase (MGMT) gene status. The median OS was superior in the TMZ versus the ACNU group (p = 0.011), although MGMT gene silencing, which is associated with a striking survival benefit from alkylating agents, was more frequent in the ACNU group. In multivariate Cox analysis adjusting for the common prognostic factors, TMZ chemotherapy independently predicted a favorable outcome (p = 0.002 for OS, hazard ratio [HR], 0.45; p = 0.011 for PFS, HR, 0.56). Given that >40 % of patients in ACNU group did not receive the intensive chemotherapy cycles because of severe hematological and nonhematological toxicity, we performed a further subanalysis for patients who received at least 4 cycles of chemotherapy. Although a modest improvement in survival occurred in this ACNU subgroup, the efficacy was still inferior to that in the TMZ cohort. Our data suggest that the survival benefit of TMZ therapy is superior to that of an ACNU-based regimen in patients with extensive tumor resection, also shows greater tolerability.

Treatment results of glioblastoma during the last 30 years in a single institute.

Treatment results of glioblastoma (GB) during the last 30 years in Tohoku University were analyzed to identify any improvements in patient outcome in all 332 histologically proven cases of newly diagnosed GB treated consecutively in our department between 1982 and 2011. These 30 years was divided into 5 treatment eras, Group 1 (1982-1988, without preoperative evaluation by magnetic resonance [MR] imaging, n = 46), Group 2 (1989-1996, with preoperative MR imaging, n = 41), Group 3 (1997-1999, additionally underwent intraoperative functional brain mapping and neuronavigation system, n = 38), Group 4 (2000-August 2006, underwent 30 Gy of whole brain radiation followed by 30 Gy of extended local accelerated hyperfractionated radiation therapy, n = 96), and Group 5 (September 2006-2011, adjuvant usage of temozolomide [TMZ], n = 111). Overall survival (OS) was calculated from the date of surgery to the death from any cause. The median survival time/2-year OS/5-year OS of Groups 1 to 5 were 10.7 months/10.9%/0%, 17.3 months/26.2%/6.9%, 15.9 months/23.7%/5.3%, 20.1 months/34.8%/15.5%, and 20.9 months/45.5%/19.7%. The prognosis for patients with GB improved significantly after the introduction of MR imaging. Younger GB, defined as patients aged below 60 years, or total tumor resection with all ages in Group 5 had 5-year 0S of 31.0% and 30.1%, respectively. The prognosis of GB was improved significantly after the introduction of TMZ for elderly GB, recursive partitioning analysis class 5, or totally resected GB. Introduction of MR imaging and TMZ, and total resection of the tumor were important in the improvement of outcome for patients with GB.

Human umbilical vein endothelial cell vaccine therapy in patients with recurrent glioblastoma.

We aimed to assess the clinical efficacy of glutaraldehyde-fixed human umbilical vein endothelial cell (HUVEC) vaccine for the treatment of patients with recurrent glioblastoma. Patients of a HUVEC vaccine group received intradermal injections of 5 × 10(7) HUVEC weekly during the first month, and every 2 weeks from the second month, until progression of the disease was observed. Salvage treatment consisted of multimodal chemotherapy, radiation, including gamma-knife therapy, and/or repeated surgery, when feasible. Hazard ratios for death were calculated using a Cox model. A total of 17 patients with recurrent glioblastoma were enrolled in this study. All the patients received the initial treatment consisting of maximal safe surgical resection, followed by radiotherapy of 50-80 Gy or more, with concomitant and adjuvant chemotherapy consisting of temozolomide or nimustine (ACNU). A total of 352 vaccinations were performed for the patients of the HUVEC vaccine group (median number of vaccination = 11 doses; range 3-122 doses). The median progression-free survival and overall survival were 5.5 and 11.4 months, respectively. The median overall survival from the diagnosis was 24.3 months. The HUVEC vaccine therapy significantly prolonged the tumor doubling time and contributed to reducing the tumor growth rate. Hematological adverse reactions due to chemotherapy were recognized: one patient experienced grade III leukocytopenia and one showed grade II lymphocytopenia. Associated with the HUVEC vaccine therapy, a delayed-type hypersensitivity-like skin reaction developed at the injection site. The HUVEC vaccine therapy effectively controlled disease progression, without evident adverse effects, except for a delayed-type hypersensitivity-like skin reaction at the injection site.

Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305).

PURPOSE: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). METHODS: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. RESULTS: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. CONCLUSIONS: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

Radiation-induced spinal cord anaplastic astrocytoma subsequent to radiotherapy for testicular seminoma.

A 54-year-old man presented with a very rare case of radiation-induced intramedullary spinal cord anaplastic astrocytoma, which developed 37 years after radiotherapy for testicular seminoma. The patient presented with weakness and numbness of the left lower extremity that had gradually aggravated for 3 months. Magnetic resonance imaging demonstrated an intramedullary mass lesion with syringomyelia at the T9 to T12 levels. Subtotal removal of the tumor was performed using standard microsurgical technique. Histological examination revealed anaplastic astrocytoma. Although radiotherapy was seriously considered, chemotherapy was employed as adjuvant therapy considering the previous treatment. Although his neurological status improved transiently after surgery, relentless neurological decline occurred and resulted in death 9 months following surgery. Considering that subtotal removal of the tumor and chemotherapy had little influence on the quality of life and the length of survival in our case, cordectomy may be the optimum treatment for patients with radiation-induced spinal intramedullary malignant astrocytoma.