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.

Machine-Learning Approach for Modeling Myelosuppression Attributed to Nimustine Hydrochloride.

PURPOSE: A major adverse effect arising from nimustine hydrochloride (ACNU) therapy for brain tumors is myelosuppression. Because its timing and severity vary among individual patients, the ACNU dose level has been adjusted in an empiric manner at individual medical facilities. To our knowledge, ours is the first study to develop a machine-learning approach to estimate myelosuppression through analysis of patient factors before treatment and attempts to clarify the relationship between myelosuppression and hematopoietic stem cells from daily clinical data. Adverse effect prediction will allow ACNU dose adjustment for patients predicted to have decreases in blood cell counts and will enable focused follow-up of patients undergoing chemoradiotherapy. PATIENTS AND METHODS: Patients were newly pathologically diagnosed with WHO grade 2 or 3 tumors and were treated with ACNU-based chemoradiotherapy. For detailed analysis of the timing and intensity of adverse effects in patients, we developed a data-weighted support vector machine (SVM) based on adverse event criteria (nadir-weighted SVM [NwSVM]). To evaluate the estimation accuracy of blood cell count dynamics, the determination coefficient ( r2) between real and estimated data was calculated by three regression methods: polynomial, SVM, and NwSVM. RESULTS: Only the NwSVM-based regression enabled estimation of the dynamics of all blood cell types with high accuracy (mean r2 = 0.81). The mean timing of nadir arrival estimated using this regression was 35 days for platelets, 41 days for RBCs, 52 days for lymphocytes, 57 days for WBCs, and 62 days for neutrophils. CONCLUSION: The NwSVM can be used to predict myelosuppression and clearly depicts nadir timing differences between platelets and other blood cells.

High dose of nimustine as an add-on treatment for small cell lung cancer with intracranial metastasis: A case report and literature review.

RATIONALE: Small cell lung cancer (SCLC) characterized by high degree of malignancy and rapid tumor progression. Intracranial metastases often appear at the time of the initial diagnosis or treatment. Besides of radiotherapy, chemotherapy is supposed to have limited effect. PATIENT CONCERNS: A 66-year-old male had blurred vision and unsteady step with moderate headache, nausea, vomit. DIAGNOSES: The patient was diagnosed with SCLC with intracranial metastases. INTERVENTIONS: High dose of nimustine (ACNU) (300 mg/m) add to the regimen containing carboplatin and irinotecan. OUTCOMES: Although the patient suffered severe myelosuppression, the intracranial lesion almost disappeared and maintained half a year. LESSONS: ACNU at a dose of 200 mg/m might be tolerable in combination with other chemotherapeutic drugs for the treatment of SCLC with intracranial metastases besides radiotherapy.

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.

[Selected arterial infusion chemotherapy combined with target drugs for non-small cell lung cancer with multiple brain metastase].

BACKGROUND AND OBJECTIVE: The aim of this study is to evaluate the efficacy of selected arterial infusion chemotherapy in treating non-small cell lung cancer (NSCLC) with multiple brain metastases and corresponding factors to influencing prognosis. METHODS: From September 2008 to October 2011, a total of 31 patients of NSCLC with multiple brain metastases (≥3) received selected incranial, bronchial and corresponding target arterial infusion chemotherapy combined with EGFR-TKIs. Interventional treatment was performed every four weeks, two-six cycles with synchronized or sequential targeted drugs (erlotinib, gefitinib or icotinib). Follow-up CT and MRI were regularly finished at interval of four weeks after two cycles of interventional treatment were finished or during taking targeted drugs in order to evaluate efficacy of the therapy. The procedure was stopped for the tumor disease was worse or the patient could not tolerate the toxity of drugs any longer. RESULTS: 31 patients was performed two to six cycles of interventional therapy, 3 cycles at average. Response assessment showed that 5 (16.1%) patients got a complete response (CR), 7 (22.6%) had a partial response (PR), 11 (35.5%) had a stable disease (SD) and 8 (25.8%) had a progressive disease (PD). The objective response rate (ORR) was 38.7%, and the disease control rate was 74.2%. The median progression free survival (PFS) and overall survival (OS) were 13.1 months and 15.1 months. The 6-month survival rate, one-year survival rate and two-year survival rate were 79%, 61.1%, and 31.1%, respectively. The patients' OS and PFS were influenced by smoking state, tumor pathology, extracranial metastases, period of targeted drug taking and performance status, not by sex, age, before therapy and the total of brain metastases. CONCLUSION: Selected arterial infusion chemotherapy with targeted drugs is one of the most effective and safe treatment to NSCLC with multiple brain metastases. Smoking status, tumor pathology, extracranial metastases, targeted drug taking and performance status are corresponding the patient's prognosis.

Local convection-enhanced delivery of chemotherapeutic agent transiently opens blood-brain barrier and improves efficacy of systemic chemotherapy in intracranial xenograft tumor model.

Recently, local chemotherapy proved its efficacy against malignant gliomas. Under the hypothesis that local delivery of chemotherapeutic agents into the brain parenchyma induce opening of the blood-brain barrier (BBB), we evaluated the opening of BBB after convection-enhanced delivery of nimustine hydrochloride into the brain parenchyma. Local convection-enhanced delivery of nimustine hydrochloride transiently opened the BBB from about 7-12 days after delivery in normal rodent brain. Systemic chemotherapy during this period of BBB disruption had synergistic effects resulting in prolonged survival of tumor-bearing rats. The present strategy may provide a new approach for glioma chemotherapy.

Effectiveness of interferon-beta therapy for recurrent glioblastoma: a case report.

AIMS AND BACKGROUND: Glioblastoma has a poor prognosis, with few therapeutic options if it recurs. We report a case in which we were able to inhibit the growth of a recurrent glioblastoma by weekly single-dose administration of interferon-beta. CASE REPORT: A patient with recurrent glioblastoma after radiation and chemotherapy was treated with nimustine and interferon-beta. After 2 cycles of nimustine, the patient's leukocyte, neutrophil, and platelet counts showed grade 4 toxicity according to the National Cancer Institute's Common Toxicity Criteria. The patient was treated with a weekly single dose of interferon-beta at 6 x 10(6) IU. The tumor showed no remarkable changes after 18 months, and the patient's Karnofsky performance status remained at 50%. CONCLUSIONS: The administration of interferon-beta produced long-term control in one case of glioblastoma and may be an effective therapy.

Regression of recurrent glioblastoma infiltrating the brainstem after convection-enhanced delivery of nimustine hydrochloride.

This 13-year-old boy with a history of cranial irradiation for the CNS recurrence of acute lymphocytic leukemia developed a glioblastoma in the right cerebellum. Resection and chemo- and radiotherapy induced remission of the disease. However, recurrence was noted in the brainstem region 8 months later. Because no effective treatment was available for this recurrent lesion, the authors decided to use convection-enhanced delivery (CED) to infuse nimustine hydrochloride. On stereotactic insertion of the infusion cannula into the brainstem lesion, CED of nimustine hydrochloride was performed with real-time MR imaging to monitor the co-infused chelated gadolinium. The patient's preinfusion symptom of diplopia disappeared after treatment. Follow-up MR imaging revealed the response of the tumor. The authors report on a case of recurrent glioblastoma infiltrating the brainstem that regressed after CED of nimustine hydrochloride.

[Nimotuzumab in combination with chemotherapy for patients with malignant gliomas].

OBJECTIVE: Nimotuzumab is a humanized monoclonal antibody targeted against epidermal growth factor receptor (EGFR). Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment. The aim of the present study was to evaluate the efficacy and side effects of nimotuzumab in combination with chemotherapy for patients with malignant gliomas. METHODS: The patients received 200 mg of nimotuzumab infusion intravenously over 60 minutes once weekly for the first eight weeks and then once every two weeks until unacceptable toxicity or tumor progression occurred. Individualized chemotherapy was administered based on O(6)-methylguanine-DNA methyltransferase (MGMT) expression and previous chemotherapy responses in combined with nimotuzumab. RESULTS: Fourteen patients received a total of 122 times of nimotuzumab ranging from 2 to 20 (median 7.5 times). Combined chemotherapy regimens included: continuous 21-day temozolomide (10 cases), standard 5-day temozolomide (2 cases), teniposide plus cisplatin (1 case), and teniposide plus nimustine (1 case). Partial response (PR) and stable disease (SD) were found in 3 patients (21.4%)and 6 patients (42.9%), respectively. Disease control rate (PR + SD) was 64.3%. The median progression-free survival (PFS) was 4 months (95%CI: 0.7 - 7.3) and PFS at 6 months was 30.6%. The most common toxicities include grade I-II neutropenia (2 cases), thrombocytopenia (2 cases), lymphopenia (1 case), nausea and vomitting (3 case) and asymptomatic transaminase increase (1 case). One patient developed grade IV neutropenia and thrombocytopenia. One patient developed nimotuzumab-related acneiform rash. CONCLUSIONS: Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation.

Therapy-related myelodysplastic syndrome developed by dacarbazine, nimustine hydrochloride and vincristine sulfate (DAV) therapy for patient with malignant melanoma.

Therapy-related myelodysplastic syndrome (t-MDS) is mostly attributed to chemotherapeutic agents of alkylating agents. Few studies have evaluated the late effects of chemotherapy for malignant melanoma (MM). To evaluate whether dacarbazine, nimustine hydrochloride and vincristine sulfate (DAV) therapy for MM related to t-MDS or not, a retrospective analysis was performed. We conducted a retrospective case-control study in a cohort of the 217 patients diagnosed with MM from 1989-2007 in Aichi Medical University Department of Dermatology and Nagoya University Graduate School of Medicine Department of Dermatology. One hundred and fifty-five of the 217 patients with MM were prospectively followed after DAV therapy or with or without local injection of ß-interferon, of whom two patients developed t-MDS. Cytogenetic abnormalities were found in two of the 35 patients by chromosome banding method - leukemia (G-Banding). The karyotypes were found in the chromosome of -5, deletion (5), addition (7) and 7q-. In conclusion, DAV therapy should be used carefully for older patients with MM after satisfactory operation.

Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O(6)-methylguanine-DNA methyltransferase(P140K).

Myelotoxicity is a dose-limiting effect of many chemotherapeutic regimens. Thus, there is great interest in protecting human hematopoietic stem cells by the transfer of drug resistance genes. The main focus of this study was the simultaneous overexpression of multidrug resistance 1 (MDR1) and the O(6)-benzylguanine (O(6)-BG)-resistant mutant MGMT(P140K) (O(6)-methylguanine-DNA methyltransferase) with a bicistronic lentiviral vector (HR'SIN-MDR1-IRES-MGMT(P140K)), with regard to the capability to convey chemoprotection in the leukemia cell line, HL60, and human hematopoietic stem cells (CD34(+)). Combination therapy with O(6)-BG/1-(2-chloroethyl)-3-(4-amino-2-methylpyrimidine-5-yl)methyl-1-nitrosourea) (ACNU) plus paclitaxel showed a significant survival advantage of HL60 cells transduced with this combination vector. In CD34(+) cells, monotherapy with O(6)-BG/temozolomide (TMZ) resulted in an increased percentage of MGMT-positive cells (vs untreated cells) after transduction with HR'SIN-MDR1-IRES-MGMT(P140K) (28.3%). For combination therapy with O(6)-BG/temozolomide plus paclitaxel the increase was higher with the combination vector (52.8%) than with a vector expressing MGMT(P140K) solely (29.1%). With regard to MDR1-positive cells the protective effect of the combination vector (88.5%) was comparable to the single vector HR'SIN-MDR1 (90.0%) for monotherapy with paclitaxel and superior for combination therapy with O(6)-BG/temozolomide plus paclitaxel (84.6 vs 69.7%). In conclusion, the combination vector presents simultaneous protective effects of two drug-resistance genes, offering an opportunity to increase the cancer therapeutic index.

Phase II study of nimustine hydrochloride (ACNU) plus paclitaxel for refractory small cell lung cancer.

PURPOSE: Bi-weekly administrations of nimustine hydrochloride (ACNU) plus paclitaxel were evaluated in this phase II study in patients with refractory small cell lung cancer (SCLC). METHODS: Patients who had disease progression within 3 months after treatment with irinotecan (CPT-11)-containing regimens were entered. They were treated with every other week administrations of ACNU 50 mg/m(2) plus paclitaxel 110 mg/m(2) on day 1 over 2 weeks. RESULTS: Twenty-four patients (20 males and 4 females, median age of 64 years, 17 patients with Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1 and 7 patients with PS 2) participated in the trial. Of the 24 refractory patients after CPT-11 containing regimens, 17 patients had been given etoposide plus platinum. There were six partial responses, and an overall response rate of 25% (95% confidence interval, 10-46%) was obtained. The median time to progression and the median survival time after enrollment into this study were 2.8 and 5.8 months, respectively. The median overall survival from the first-line treatment was 19.5 months. The major toxicity was myelosuppression. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia was observed in 13% of patients. There was one treatment-related death, attributed to pneumonitis. CONCLUSION: Bi-weekly administrations of ACNU plus paclitaxel provided a practical and well-tolerated regimen that was active for CPT-11-refractory SCLC.

Nimustine (ACNU) plus teniposide (VM26) in recurrent glioblastoma.

BACKGROUND: In a previous trial (NOA-01), the combination of nimustine and teniposide showed efficacy in previously untreated glioblastoma (GBM). After establishing temozolomide as standard first-line therapy in GBM patients, the nimustine (ACNU)/teniposide (VM-26) combination has been employed as salvage chemotherapy for recurrent GBM. However, data on the toxicity and efficacy of this regimen in recurrent GBM are lacking. PATIENTS AND METHODS: In two neurooncological centers, all patients with recurrent GBM treated with nimustine (90 mg/m(2), day 1/42) and teniposide (45-70 mg/m(2), days 1-3/42) were analyzed retrospectively for progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Thirty-five patients (median age 51 years, range 25-71 years) were identified. Six months after chemotherapy initiation, PFS was 29% and the median OS 6 months; 23% of patients were alive > or = 1 year after initiation of nimustine-teniposide chemotherapy. Grade 4 hematotoxicity was observed in 12 of 35 patients (34%) and in 14 of 83 evaluable chemotherapy courses (17%). CONCLUSIONS: The benefit of the nimustine-teniposide combination is moderate in patients with recurrent GBM. The data support the efficacy of the nimustine-teniposide chemotherapy, but the rate of high-grade hematotoxicity is increased.

Nitrosourea efficacy in high-grade glioma: a survival gain analysis summarizing 504 cohorts with 24193 patients.

Even though past studies have suggested efficacy of nitrosourea drugs in patients with high-grade glioma and temozolomide has recently been shown significantly to be beneficial, no conclusive comparisons between these agents have been published. We performed a survival gain analysis of 364 studies describing 24,193 patients with high-grade glioma treated in 504 cohorts, and compared the effects of drugs. The most frequent diagnoses were glioblastoma multiforme (GBM) (72%) and anaplastic astrocytoma (22%). The mean overall survival (mOS) was 14.1 months. The outcome was influenced by several of the known prognostic factors including the histological grade, if the tumors were newly diagnosed or recurrent, the completeness of resection, patients' age, and gender. This information allowed the calculation of a predicted mOS for each cohort based on their prognostic factors independent of treatment. Survival gain to characterize the influence of treatment was subsequently defined and validated as the difference between the observed and the predicted mOS. In 62 CCNU-treated cohorts and 15 ACNU-treated cohorts the survival gain was 5.3 months and 8.9 months (P < 0.0005), respectively. No detectable survival gain for patients treated with various BCNU-containing regimens was found. Conclusion CCNU- and ACNU-containing regimens were superior to BCNU containing regiments.

Prospective single-arm study of 72 Gy hyperfractionated radiation therapy and combination chemotherapy for anaplastic astrocytomas.

BACKGROUND: Despite intensive multimodal treatment, outcome of patients with malignant glioma remains poor, and a standard dose of radiotherapy for anaplastic astrocytoma has not been defined. In the past RTOG study (83-02), the arm of 72 Gy hyperfractionated radiotherapy (HFRT) for malignant gliomas showed better outcome than the arms of higher doses (76.8 - 81.6 Gy) and the arms of lower doses (48 - 54.4 Gy). The purpose of this study is to verify the efficacy of this protocol. METHODS: From July 1995, 44 consecutive eligible patients with histologically proven anaplastic astrocytoma were enrolled in this study (HFRT group). The standard regimen in this protocol was post-operative radiotherapy of 72 Gy in 60 fractions (1.2 Gy/fraction, 2 fractions/day) with concurrent chemotherapy (weekly ACNU). The primary endpoint was local control rate (LCR), and the secondary endpoints were overall survival (OS), progression-free survival (PFS) and late toxicity. RESULTS: Three-year OS of the HFRT group was 64.8% (95% confidence interval; 48.4-81.3%). Three-year PFS rate and LCR were 64.4% (95%CI: 48.4-80.3%) and 81.6% (95%CI: 69.2-94.8%), respectively. The number of failures at 5 years in the HFRT group were 14 (32%). The number of failures inside the irradiation field was only about half (50%) of all failures. One (2%) of the patients clinically diagnosed as brain necrosis due to radiation therapy. CONCLUSION: The results of this study suggested that 72 Gy HFRT seemed to show favorable outcome for patients with anaplastic astrocytoma with tolerable toxicity.

Long-term follow-up of busulfan, etoposide, and nimustine hydrochloride (ACNU) or melphalan as conditioning regimens for childhood acute leukemia and lymphoma.

We retrospectively evaluated early and long-term complications of an intensified conditioning regimen consisting of busulfan and etoposide in combination with either nimustine hydrochloride (ACNU) (BVA regimen, n = 18) or melphalan (BVL regimen, n = 34) in 52 children with acute leukemia or non-Hodgkin's lymphoma. With a median follow-up of 13.2 years after the BVA regimen and 8.1 years after the BVL regimen, 61% and 76% of patients, respectively, are in continuous complete remission. Transplantation-related mortality was 17% and 6% after the BVA and BVL regimens, respectively, and the corresponding relapse rates were 17% and 15%. The most common and severe toxicity was pulmonary complication in the BVA regimen, which was seen in 67% of patients and was life-threatening in 20%. Thirty-three percent of patients after the BVA regimen and 24% after BVL died of relapse or disease progression (n = 9), interstitial pneumonia (n = 2), fungal pneumonia (n = 1), or chronic graft-versus-host disease (n = 2). One of the long-term survivors developed secondary leukemia. A significant decrease in the height standard deviation score of more than 2 SD from diagnosis to the last follow-up was seen in 17% of the patients, with hypothyroidism in 15%, and alopecia in 42%. Because our experience is limited to a small heterogeneous population of patients who mainly underwent transplantation in the first remission, we cannot draw conclusions on the treatment's effectiveness. The BVL regimen is tolerable, however, because no regimen-related death was observed, whereas the BVA regimen is not recommended because of the high incidence of pulmonary complications. The effectiveness of the BVL regimen requires further study.

Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy.

OBJECT: To assess whether nimustine (ACNU), a drug that can cross the blood brain barrier, combined with radiotherapy, improved the survival of patients with primary central nervous system lymphoma (PCNSL). CLINICAL MATERIALS AND METHODS: Between 1995 and 2005, we treated 63 immunocompetent PCNSL patients with combination therapy consisting of intra-arterial ACNU (100 mg/m(2)) and whole brain radiotherapy (36-50 Gy). Their median age was 60 years (range 28-81). The median follow-up was 24 months. FINDINGS: With this regimen we achieved a complete response rate of 75% (43 of 57 patients). Kaplan-Meier estimates for median progression-free survival and median overall survival were 26 and 39 months, respectively. The 3- and 5-year survival rates were 51% (95% confidence interval [CI], 36-65%) and 32% (95% CI, 17-47%), respectively. By multivariate analysis, age (<60 vs. > or =60 years) was the only statistically significant prognostic factor; the WBRT dose, sex, and number of tumors were not significant prognostic factors in this study. Myelosuppression was the most frequent side effect, 60% of patients experienced grade 3-4 leukopenia. Late neurotoxicity as a result of treatment was observed in 14 of 43 patients (34%) and higher age (>60) was associated with a high risk of neurotoxicity. CONCLUSION: The intra-arterial administration of ACNU combined with radiation therapy yielded a high response rate at acceptable toxicity levels in younger patients with PCNSL. However, late neurotoxicity was a serious complication in patients above 60 years of age.