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Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15 years, with only a 37% OS rate at 20 years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors. [ABSTRACT FROM AUTHOR]

An 11-year-old spayed female French bulldog was referred on suspicion of nasal tumor. Anaplastic oligodendroglioma in the olfactory bulb that was suspected to have invaded the nasal cavity was diagnosed from imaging and histopathology. Metastasis to cervical lymph nodes was suspected, with no other metastases identified. The brain-to-nasal lesion and lymph nodes were treated with hypo-fractionated radiation therapy. Nasal congestion soon resolved. About 3 months later, follow-up computed tomography revealed multiple hepatic and splenic masses, which were cytologically suspected as metastatic oligodendroglioma. Nimustine, followed by toceranib phosphate, seemed to have no effect, and the dog died on day 167. Postmortem examination revealed the primary tumor disappearance and systemic metastases. Canine oligodendroglioma can grow outside the cranial vault, and systemically metastasize. [ABSTRACT FROM AUTHOR]

Abstract 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.

An 11‐year‐old spayed female American Cocker Spaniel was presented with a 4‐week history of anorexia and a 1‐week history of abdominal distension. Clinicopathologic and imaging abnormalities included intra‐abdominal hemorrhage, granular lymphocytes (GLs) in abdominal fluid smears, a splenic mass, and hepatomegaly with diffuse multiple hypoechogenic nodules. Based on the cytologic, histologic, and immunohistochemical evaluation of the spleen and liver, the diagnosis was hepatosplenic T‐cell lymphoma (HSTCL) of GLs. Postoperatively, the dog was maintained in good condition with chemotherapy (ACNU [nimustine], L‐asparaginase, and prednisolone). However, on day 85, ultrasound‐guided fine‐needle aspiration of the liver revealed a proliferation in neoplastic mast cells not associated with the GLs. The dog was diagnosed with a visceral mast cell tumor (MCT) originating from the liver. The chemotherapy was switched to vinblastine and toceranib. The dog remained in good condition until day 141 but died due to the progression of MCT on day 158. Liver cytology on day 155 showed no GLs, although HSTCL is thought to be resistant to chemotherapy. After the definitive diagnosis of HSTCL, we monitored this patient's response to chemotherapy with blood tests, including complete blood counts, ultrasound imaging, and cytologic aspirates of liver. Although canine HSTCL has a poor prognosis, the possibility of a new neoplasm, including visceral MCT, should be considered. Periodic liver cytology might be worthwhile in dogs receiving chemotherapy for HSTCL. [ABSTRACT FROM AUTHOR]

A 10-year-old female Cavalier King Charles Spaniel presented with hematuria, pollakiuria and skin rash. Based on the histopathological and cytological examination of the skin and bladder mucosa, the dog was diagnosed with large granular lymphocytic (LGL) lymphoma of the bladder and skin. The dog responded well to the initial chemotherapy with nimustine for 3 months. Since recurrence of skin erosion and bladder wall thickening were observed, the dog was subsequently administered chemotherapy with other anticancer drugs, including chlorambucil, vincristine, doxorubicin, L-asparaginase, cytosine arabinoside, and cyclophosphamide. The dog survived for 11 months and died due to tumor-related disseminated intravascular coagulation. This is the first report of a canine case of LGL lymphoma in the skin and bladder. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lymph node metastasis (LNM) has a significant impact on cancer prognosis, emphasizing the need for effective treatment strategies. This study investigated the potential use of high osmotic pressure drug solutions with low viscosity administration using a lymphatic drug delivery system (LDDS) to improve LNM treatment outcomes. The hypothesis was that injection of epirubicin or nimustine at high osmotic pressure but without altered viscosity would enhance drug retention and accumulation in LNs, thereby improving the efficacy of treatment. Biofluorescence analysis revealed enhanced drug accumulation and retention in LNs after administration using LDDS compared to intravenous (i.v) injection. Histopathological results demonstrated minimal tissue damage in the LDDS groups. Pharmacokinetic analysis revealed an improved treatment response with higher drug accumulation and retention in LNs. The LDDS approach offers the potential for greatly reduced side effects of chemotherapy drugs, lower dosage requirements and crucially increased drug retention in LNs. The results highlight the promise of high osmotic pressure drug solutions with low viscosity administrated using the LDDS for enhancing the treatment efficacy of LN metastasis. Further research and clinical trials are warranted to validate these results and optimize the clinical translation of this novel treatment technique. [Display omitted] • Lymph node metastasis: leads to poor prognosis and causes most cancer deaths. • Systemic chemotherapy often leads to adverse effects and poor response rates. • LDDS permits direct injection of chemotherapy drugs into lymph nodes. • Osmotic pressure and viscosity are the main factors that improve treatment outcomes. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a highly invasive and challenging primary tumor of the central nervous system (CNS), and currently available treatments provide limited benefits to patients with this disease. Therefore, the development of novel therapeutic targets and effective treatment strategies is essential. Nimustine hydrochloride (ACNU) is widely used as the standard chemotherapeutic agent and is frequently administered together with other chemotherapeutic agents in clinical studies. Curcumin, a natural polyphenolic compound, could potentially be combined with chemotherapeutics for cancer treatment; however, there are no reports of studies where ACNU and curcumin were combined for GBM treatment, and the mechanisms underlying their activity remain poorly understood. In the present study, we investigated the effects of combined treatment with curcumin and ACNU on GBM cells and found that it significantly enhanced the inhibition of cell proliferation, colony formation, migration, and invasion. In addition, cotreatment with curcumin increased ACNU-induced apoptosis through enhancing the release of cytochrome c from the mitochondrial intermembrane space into the cytosol. Further, curcumin and ACNU acted synergistically in their antitumor effects by targeting N-cadherin/MMP2/9, PI3K/AKT, and NF-κB/COX-2 signaling. These results indicate that curcumin can enhance the anti-proliferation, anti-migration, and proapoptotic activities of ACNU against GBM, and provide strong evidence that combined treatment with curcumin and ACNU has the potential to be an effective therapeutic option for GBM. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of hyperbaric oxygen (HBO) on the survival of C57 mice implanted with GL261 gliomas after chemotherapy with nimustine (ACNU). Methods Forty adult male C57 mice were divided into four groups: control, HBO, ACNU and HBO + ACNU randomly by SPSS 10, and planted with GL261 glioma cell suspension in their caudate nucleus to form tumors. From the 7th day after implantation, these groups (except control group) began to receive different treatments (HBO, ACNU and HBO + ACNU), in order to observe the effects of different treatments on the survival time of tumor bearing mice. Results There were no significant differences in the tumor volume, mass effect, severe compression of normal brain tissue and midline shift (F = 0.602, P = 0.618). The average survival time was significant with one⁃way ANOVA (F = 12.177, P = 0.000) and with the Kaplan⁃ Meier survival analysis of log⁃rank (χ2 = 13.604, P = 0.003), while multiple comparisons between groups showed HBO (χ2 = 0.365, P = 0.546) and single⁃time ACNU (χ2 = 0.884, P = 0.347) had no effect on the survival of mice; the effect of HBO + ACNU (χ2 = 9.962, P = 0.002) was better than that of HBO (χ2 = 6.925, P = 0.008) and single⁃ time ACNU (χ2 = 7.152, P = 0.007). Conclusion The HBO had no effect on survival time of C57 mice with implantation of GL261 and could not promote the growth of the GL261 glioma. However, combining the treatment with ACNU could extend the survival time of tumor bearing mice, suggesting that HBO could strengthen the therapeutic effects of ACNU． DOI：10.3969/j.issn.1672⁃6731.2012.06.014

Nimustine, a chloroethyl nitrosourea derivative (CENU), is an antineoplastic agent, which is used for the treatment of various types of cancer. The present study focuses on the prediction and investigation of binding properties of nimustine with DNA using molecular modeling and UV-Visible spectroscopic technique. The docking study show that nimustine plausibly binds within the major groove of DNA. Further analysis of docking suggests direct interaction of nimustine with the moieties of heterocyclic nitrogenous bases of DNA. The free binding energy value of the best nimustine-DNA docked conformer is predicted as −4.31 kcal/mol using docking results.The molecular modeling study also reveals that the interaction between nimustine and DNA is majorly governed by van der Waals forces, hydrogen bonding and hydrophobic interactions, whereas the contribution of electrostatic forces stands negligible. Further, UV-Visible spectra of free calf thymus DNA and its complexes with varying concentration of nimustine indicate the binding constant ( K ) value as 3.27 × 10 M, which suggests moderate interaction of nimustine with DNA. The spectroscopic results are further used to calculate the binding free energy of the complex using the relation Δ G = − RT ln ( K ). This accounts for a value of −4.79 kcal/mol. It corroborates well with the docking outcomes. The results of present study may help in designing and synthesis of new chloroethyl nitrosourea derivatives with improved efficacy and specificity for the target molecules. [ABSTRACT FROM AUTHOR]

We report surface-enhanced Raman spectroscopic (SERS) studies on free calf thymus DNA and its complexes with anti-tumor chloroethyl nitrosourea derivatives; semustine and nimustine. Since, first incident of SERS in 1974, it has rapidly established into an analytical tool, which can be used for the trace detection and characterization of analytes. Here, we depict yet another application of SERS in the field of drug–DNA interaction and thereby, its promising role in rational designing of new chemotherapeutic agents. Vibrational spectral analysis has been performed in an attempt to delineate the anti-cancer action mechanism of above mentioned nitrosourea derivatives. Strong SERS bands associated with the complexation of DNA with semustine and nimustine have been observed, which reveal binding of nitrosourea derivatives with heterocyclic nitrogenous base pair of DNA duplex. Formation of dG–dC interstrand cross-link in DNA double helices is also suggested by the SERS spectral outcomes of CENUs–DNA adduct. Results, demonstrated here, reflect recent progress in the newly developing field of drug–DNA interaction analysis via SERS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Transferrin receptor (TfR) has been used as a target for antibody-based therapy of cancer. Anti-TfR antibody together with chemotherapeutic drugs has potential for cancer therapy. In this study, we investigated the in vitro anti-tumor effects of the anti-TfR monoclonal antibody (mAb), 7579, alone or in combination with Nimustine, a chemotherapeutic drug, on the gliomas cell lines U251 and U87MG. Our results indicated that 7579 alone dramatically down-regulated surface expression of TfR on tumor cells and induced S phase accumulation and apoptosis of tumor cells. Compared with 7579 or Nimustine used alone, the combination of 7579 with Nimustine demonstrated enhanced growth inhibitory effect on tumor cells. PI (Propidium iodide)/Annexin V staining analyzed by FCM (flow cytometry) demonstrated that 7579 enhanced the cytotoxic effects of chemotherapeutic drug on tumor cells, indicating the therapeutic effect of 7579 was mediated mainly by promoting tumor cell necrosis. Using the median-effect/combination-index isobologram method, we further evaluated the nature of 7579/chemotherapeutic drug interactions. Synergistic interaction was observed for combination of 7579 with Nimustine. Our study provides additional evidence to develop combination therapies of anti-TfR mAbs-plus chemoimmunotherapy for gliomas. [Copyright &y& Elsevier]

Non-invasive loco-regional electro-hyperthermia (EHT) plus alkylating chemotherapy is occasionally used as salvage treatment in the relapse of patients with high-grade gliomas. Experimental data and retrospective studies suggest potential effects. However, no prospective clinical results are available. We performed a single-center prospective non-controlled single-arm Phase I trial. Main inclusion criteria were recurrent high-grade glioma WHO Grade III or IV, age 18–70, and Karnofsky performance score ≥70. Primary endpoints were dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) with the combined regimen. Groups of 3 or 4 patients were treated 2–5 times a week in a dose-escalation scheme with EHT. Alkylating chemotherapy (ACNU, nimustin) was administered at a dose of 90 mg/m2 on day 1 of 42 days for up to six cycles or until tumor progression (PD) or DLT occurred. Fifteen patients with high-grade gliomas were included. Relevant toxicities were local pain and increased focal neurological signs or intracranial pressure. No DLT occurred. In some patients, the administration of mannitol during EHT or long-term use of corticosteroids was necessary to resolve symptoms. Although some patients showed responses in their primarily treated sites, the pattern of response was not well defined. EHT plus alkylating chemotherapy is tolerable in patients with relapse of high-grade gliomas. Episodes of intracranial pressure were, at least, possibly attributed to EHT but did not cause DLTs. A Phase II trial targeting treatment effects is warranted on the basis of the results raised in this trial. [ABSTRACT FROM AUTHOR]

Abstract: 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 50mg/m2 plus paclitaxel 110mg/m2 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. [Copyright &y& Elsevier]

Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukaemia in humans. In contrast, the efficacy of this therapy is extremely limited in the treatment of leptomeningeal dissemination of various solid tumours. Pharmacokinetic studies of the commonly intraventricularly applied anticancer agents in humans have demonstrated that, using low drug doses, very high drug concentrations can be achieved in the cerebrospinal fluid (CSF) and relatively high concentrations in the leptomeninges but not in the brain tissue and the plasma. Therefore, this approach is not an effective treatment for bulky disease of brain tissue, and results in minimal systemic toxicity. In comparison with intralumbar administration, lower interpatient variability of CSF drug concentrations and improved clinical efficacy were observed. ‘Concentration × time’ schedules, i.e. frequent small drug doses over a short period, enable long-term CSF exposure to cytotoxic drug concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. The technique of ventriculolumbar cerebrospinal perfusion delivers continuously high drug concentrations throughout the CSF for several hours, but its widespread use is limited by the technical complexities of this approach. In this article, the dosages, schedules and pharmacokinetic data of routinely used intraventricular agents in humans, e.g. methotrexate, cytarabine, glucocorticoids and thiotepa, are outlined in detail. In addition, pharmacokinetic data of investigational agents for intraventricular administration (diaziquone, DTC 101, mercaptopurine, mafosfamide, etoposide, topotecan, nimustine [ACNU] and bleomycin) are presented. Better understanding of the CSF pharmacology of these drugs is an essential prerequisite for safe, effective administration of these drugs. Investigational efforts are underway to verify the feasibility and efficacy of different dosages, schedules and combination therapies of these new intra-CSF agents. Current and future clinical research should also focus on methods allowing the delivery of tumoricidal drug concentrations for extended periods into the CSF and the brain tissue while minimising neurotoxicity and systemic toxicity (e.g. liposomal drug preparations, monoclonal antibodies, immunotoxins and gene therapy). [ABSTRACT FROM AUTHOR]

In recurrent malignant gliomas, we scheduled a protocol by adding to systemic temozolomide a local treatment delivered through a reservoire positioned in the surgically created cavity, consisting of either mitoxantrone, liposome-loaded doxorubicine or nimustine (ACNU). The progression—free survival (PFS) and survival time (ST) of the whole group of 112 patients were 8.3 and 11 months, respectively, in GBM patients, and 14 and 18 months in AA patients. To limit the selection bias in recruitment we matched locally treated patients with the whole group of patients treated for 3 years and having undergone the same protocol with the exception of local drug delivery. Variables such as age, histology and local chemotherapy delivery were proved to be statistically significant independent factors on adjunctive PFS and ST. Another group of 12 recurrent malignant gliomas with further progression was locally managed according to convection-enhanced delivery (CED) of mitoxantrone; the preliminary results show good tolerability of the schedule. [ABSTRACT FROM AUTHOR]