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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]

Background: The U.S. Food and Drug Administration (FDA) revised the labels of sodium-glucose transporter 2 (SGLT2) inhibitors in December 2015 to inform users regarding the risk of diabetic ketoacidosis (DKA). As more drugs of this class are approved and their indications are expanded, this serious adverse effect has been increasingly reported., Objective: This review evaluated observational studies to inform the prevalence of SGLT2-inhibitor-associated DKA compared with other antihyperglycemic agents., Methods: A systematic review was conducted in PubMed and EMBASE until 19 July 2022 (PROSPERO: CRD42022385425). We included published retrospective cohort active comparator/new user (ACNU) and prevalent new user studies assessing SGLT2-inhibitor-associated DKA prevalence in adult patients with type 2 diabetes mellitus (T2DM) against active comparators. We excluded studies which lacked 1:1 propensity score matching. The JBI Checklist for Cohort Studies guided the risk-of-bias assessments. Meta-analysis was conducted based on the inverse variance method in R software., Results: Sixteen studies with a sample of 2,956,100 nonunique patients met the inclusion criteria. Most studies were conducted in North America (n = 9) and adopted the ACNU design (n = 15). Meta-analysis of 14 studies identified 33% higher DKA risk associated with SGLT2 inhibitors (HR = 1.33, 95% CI: 1.14-1.55, P < 0.01). Meta-regression analysis identified the study location (P = 0.02), analysis principle (P < 0.001), exclusion of chronic comorbidities (P = 0.007), and canagliflozin (P = 0.04) as significant moderator variables., Conclusions: Despite limitations related to heterogeneity, generalizability, and misclassification, the results of this study show that SGLT2 inhibitors increase the prevalence of DKA among adult T2DM patients in the real world. The findings supplement evidence from randomized controlled trials (RCTs) and call for continued vigilance., Competing Interests: Disclosure The authors declare no conflict of interest., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

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.

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]

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.

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., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

In this article the author discusses the study deficiencies in the article by Stupp and colleagues. She points out that the authors neglected to put any reference to Weller and colleagues' article, and that their published article did not receive a peer review. She also poses that the title of the article was criticized since it does not only talk about patients with glioblastoma but also patients with other histologies.

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]

Objective: We investigated whether cognitive performance between ages 43 and 69 years was associated with timing of menopause, controlling for hormone replacement therapy, childhood cognitive ability, and sociobehavioral factors., Methods: We used data from 1,315 women participating in the Medical Research Council National Survey of Health and Development (a British birth cohort study) with known age at period cessation and up to 4 assessments of verbal memory (word-learning task) and processing speed (letter-cancellation task) at ages 43, 53, 60-64, and 69. We fitted multilevel models with linear and quadratic age terms, stratified by natural or surgical menopause, and adjusted for hormone replacement therapy, body mass index, smoking, occupational class, education, and childhood cognitive ability., Results: Verbal memory increased with later age at natural menopause (0.17 words per year, 95% confidence interval [CI]: 0.07-0.27, p = 0.001); an association remained, albeit attenuated, after full adjustment (0.09, 95% CI: 0.02-0.17, p = 0.013). Verbal memory also increased with later age at surgical menopause (0.16, 95% CI: 0.06-0.27, p = 0.002), but this association was fully attenuated after adjustment. Search speed was not associated with age at menopause., Conclusion: Our findings suggest lifelong hormonal processes, not just short-term fluctuations during the menopause transition, may be associated with verbal memory, consistent with evidence from a variety of neurobiological studies; mechanisms are likely to involve estrogen receptor β function. Further follow-up is required to assess fully the clinical significance of these associations., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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, co-treatment 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., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Nimustine hydrochloride [systematic name: 4-amino-5-({[N-(2-chloroethyl)-N-nitrosocarbamoyl]amino}methyl)-2-methylpyrimidin-1-ium chloride], C(9)H(14)ClN(6)O(2)(+)·Cl(-), is a prodrug of CENU (chloroethylnitrosourea) and is used as a cytostatic agent in cancer therapy. Its crystal structure was determined from laboratory X-ray powder diffraction data. The protonation at an N atom of the pyrimidine ring was established by solid-state NMR spectroscopy.

A quadruple combination chemotherapy with ACNU, adriamycin, methotrexate and prednisolone (AAAP), was performed on 9 patients with non-Hodgkin's lymphoma, who had been previously treated with a VEPA (P) regimen. Complete remission rate was 44% (4/9) and, in four other patients, the tumor was decreased in size. Complete remission duration was from 30 days to over 390 days. Median survival time was 105 days. Myelosuppressive toxicity was severe. In eight patients, WBC counts were less than 3,000/mm3. In six patients, platelet counts were less than 100,000/mm3. An AAAP regimen is useful in relapse or for resistant forms of non-Hodgkin's lymphoma.

Local blood flow and capillary permeability of the rats with meningeal carcinomatosis were studied with macroautoradiography, and relationship between blood flow, permeability and effects of chemotherapy is discussed. Experimental meningeal carcinomatosis was induced in the Wistar rats by inoculating Walker 256 tumor into cisterna magna. One to 12 days after inoculation, rats were used for measurements of blood flow (by 14C- iodoantipyrine) and capillary permeability (by 14C-alpha-aminoisobutyric acid). Images of autoradiography and corresponding histological appearances were analyzed. In the early stage of tumor growth (2 to 3 days after inoculation), a few layers of tumor cells were identified in the ambient cistern. Blood flow in the vicinity of the tumor cell layer was noted, but no increase in capillary permeability was found. In the middle stage of tumor growth (3 to 5 days after inoculation), 10 to 20 layers of the tumor cell was noted in the ambient cistern. Blood flow in the tumor was evident and capillary permeability began to increase. In the late stage of tumor growth (6 to 12 days after inoculation), a mass of the tumor cells was noted in the ambient cistern. In this stage, blood flow in the tumor was similar to that of cerebral gray matter and capillary permeability increased markedly. Brain adjacent to the tumor also showed increase in capillary permeability. The result correlated well to the previous result of experimental chemotherapy. Form those data, lipid soluble drugs which cross blood-brain barrier readily are recommended for the early stage of meningeal carcinomatosis, and water soluble drugs which has limitations to cross blood-brain barrier can not be recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

The immunosuppressive effect of a water-soluble nitrosourea derivative, 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), was evaluated in terms of the cytotoxicity of spleen lymphocytes, and the restoring effect of lymphokine-activated killer (LAK) cells and/or human recombinant interleukin-2 (rIL-2) on the cytotoxicities of spleen lymphocytes was examined in ACNU-treated C57BL/6 mice. In addition, we tested whether the administration of LAK cells and/or rIL-2 could reduce the increased numbers of pulmonary metastases in ACNU-treated mice. The maximum effective dose of ACNU suppressed the cytotoxicity of spleen lymphocytes and pretreatment with ACNU enhanced the induction of artificial pulmonary metastases. The administration of LAK cells and/or human rIL-2 restored the cytotoxicity of spleen lymphocytes against YAC-1 and syngeneic B-16 melanoma cells in ACNU-treated mice, and these treatments partially suppressed the increased numbers of artificial pulmonary metastases of B-16 melanoma cells in ACNU-treated mice. These results are extremely important in providing a rationale for the introduction of adoptive immunotherapy using LAK cells and rIL-2 in patients with advanced cancer who are being treated with anticancer agent(s).

A 60-year-old woman was referred to us because of tumors on the occipital and the bilateral submaxillary areas. Biopsy proved them to be well-differentiated lymphosarcoma. On admission, systemic lymphadenopathy was noted and there was 26% of plasmacytoid cells in the bone marrow of the sternum. Monoclonal gammopathy of IgM,K type was found; her disease was diagnosed as a macroglobulinemia (IgM: 8,460 mg/dl). VENP-therapy consisted of vincristine 1 mg/w, cyclophosphamide 50 mg/d procarbazine 50 mg/d and prednisolone 30 mg/d was applied for about four weeks, but in vain. Transaminase levels were elevated (GOT 575 U, GPT 480 U) and the superficial lymphnodes did hardly diminish. Therefore, after improvement of the liver dysfunctions, 5 courses of AAAP-therapy, which was consisted of ACNU 50 mg/d (IV drip over 4 hrs), adriamycin 20 mg/d (IV push), methotrexate 25 mg/d (IV push) and prednisolone 60 mg/d (IV push) once a week or three were employed with excellent clinical effects. The superficial lymphnodes disappeared, M-protein and plasmacytoid cells in the bone marrow markedly decreased. An interval of the initial remission reached to 17 months. As previously reported, AAAP-therapy was also effective to multiple myeloma and acute lymphocytic leukemia of B-cell type. Therefore, AAAP-therapy would be one of the best chemotherapies for B-cell malignancy including macroglobulinemia.

Using our new in vitro antitumor sensitivity assay, the basis of which depends on predictive analysis of morphological findings of L1210 leukemia cells under the influence of antitumor agents, 5 kinds of nitrosoureas including MCNU were comparatively tested for antitumor activity. A cell killing effect became apparent very soon under BCNU and CCNU, rather late under Methyl-CCNU and MCNU, and intermediately under ACNU. Various cellular biological effects were apparently induced in L1210 cells by MCNU and its mechanism of action seemed to be broader than that of any other members of the nitrosoureas.

The effects of two different combination chemotherapies, i.e. cyclophosphamide (CPM) + vincristine (VCR) + methotrexate (MTX) and ACNU + VCR, with or without radiotherapy, were studied in twenty patients with untreated small cell carcinoma of the lung. Respective response rates were 66.7% for CVM and 50% for AV. Median survival time was 51 weeks for CVM and 27 weeks for AV. There was no statistically significant difference between the survival probability curves of CVM and AV. Concerning toxicity, two hazardous side effects, myelosuppression and interstitial pneumonitis, were observed although the incidences were low. We concluded that both regimens are useful as chemotherapy of small cell carcinoma.

We examined the sensitivity to the lethal effects of methylating agents and the O6-methylguanine methyltransferase (MTR) activities of in vitro transformed NIH3T3 cell clones. The sensitivities to the lethal effects of MNNG were not different among all 49 transformed cell clones examined and do not correlate with the MTR activities. All 8 spontaneously transformed cell clones showed the same sensitivities to ACNU as the parental cell line. 2 of 20 transformants induced by UV or MNNG showed higher sensitivities to the ACNU although the MTR activity was normal. One cell clone transformed by UV was sensitive to ACNU and showed about half MTR activity. 5 of 19 cell clones transformed by oncogenes (Ha-ras or SV40 ori-) were sensitive to the lethal effects of ACNU and showed the low MTR activities, but were not as much sensitive as a Ha-MuSV transformed cell clone, Ha821.

Present study was undertaken to reveal the effects of total parenteral nutrition (TPN) on the immunocompetence associated with nutritional status and on the tumor growth. The 4-nitro-quinoline-1-oxide induced Sato Lung Carcinoma was transplanted subcutaneously on the back of Donryu rats. Rats were controlled by TPN, low calorie infusion or oral feeding for one or two weeks. Each group was subdivided into chemotherapy and non chemotherapy group. Chemotherapy was performed with adriamycin or ACNU. Tumor bulk was bigger in the well nourished TPN rats than in malnourished group, revealing an accelerated tumor growth by TPN. Despite no significant change in polyamine level and phosphorylation activity, thymidine kinase activity and mitotic index in tumor were significantly higher in TPN than in low calorie infusion. Compared to the results of low calorie infusion, higher activity of IgG, IgM plaque forming cells and lymphocytic blastformation by PHA was suggested the good maintenance of both cellular and humoral immunity in well nourished rats. There was no positive evidence to support the facilitated effect of chemotherapeutic agents in TPN. However, TPN decreased an incidence of adverse reactions of chemotherapy such as loss of weight, leukopenia. Survival rate of rats at nine weeks after treatment also showed the favorable effect of TPN on chemotherapy.

In vitro decomposition of ACNU, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros ourea hydrochloride, in various conditions was studied with the use of the 14C-labeled compound. Metabolite A, 3,4-dihydro-7-methylpyrimido[4,5-d]pyrimidin-2(1H)-one (an intramolecular cyclized product), was formed spontaneously in the phosphate buffer (pH 7.4) with simultaneous liberation of the alkylating moiety. With rat liver enzyme preparations, formation of three metabolites was observed. Those were metabolite B, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)urea (a denitrosated product), metabolite C, 1-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-5-hydroxy-3-nitroso-2-imidazolidinone (a product via oxidative dechlorination), and metabolite D, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-hydroxy-2-imidazolidinone (a denitrosated product of metabolite C). Formation of metabolite B was catalyzed with both cytosolic and microsomal enzymes, not inhibited with SKF-525A, and partly dependent on nicotinamide adenine dinucleotide phosphate (NADPH). These results suggest that at least two enzymatic steps would be involved in the formation of this product. Metabolites C and D were produced by the microsomal preparation, being dependent on O2 and NADPH, inhibited by CO and SKF-525A, and enhanced by phenobarbital pretreatment. When metabolite C was incubated with cytosolic and microsomal preparations, more efficient formation of metabolite D with the former than the latter was observed. From these results, it was assumed that oxidative dechlorination of ACNU to metabolite C would be catalyzed with the microsomal mixed function oxidase, and metabolite D would be produced via denitrosation process of metabolite C.

A new quadruple combination chemotherapy for acute leukemia with ACNU, Adriamycin, methotrexate, and prednisolone was developed and codenamed AAAP in 1978. We have obtained excellent chemotherapeutic results with AAAP for conventional chemotherapy-resistant leukemia in Japan. Recently we have treated three adults with erythroleukemia with an AAAP regimen. In Case I, a 45-year-old woman attained a complete remission after only one course of AAAP, which was maintained for 21 months. The patient has been alive for over 32 months. In Case 2, a 52-year-old woman, and Case 3, a 38-year-old man, a complete remission was achieved after two courses of AAAP. Both patients have been alive over 21 and 13 months, respectively, with an initial remission duration of 14 months and 11+ months respectively. We conclude that AAAP therapy would be useful for remission induction of erythroleukemia.

The 9L-2, 9L-7, and 9L-8 cell lines, derived from the 9L in vivo rat brain tumor, were treated with nitrosoureas that can alkylate and cross-link DNA and carbamoylate intracellular molecules to various extents. Compared to 9L cells, 9L-2 cells were very resistant to the cytotoxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, and to 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-deoxyglucopyranose. The sensitivity of 9L-7 and 9L-8 cell lines to these drugs was intermediate between 9L and 9L-2. Treatment of 9L, 9L-2, 9L-7, and 9L-8 cell lines with 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea produced approximately the same level of cell kill. Compared to 9L cells, 9L-2 cells are 10-fold more resistant to the cytotoxic effects, 34-fold more resistant to the induction of sister chromatid exchanges, and have 40% fewer DNA interstrand cross-links caused by treatment with 3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-1-nitrosourea . In contrast, treatment of 9L and 9L-2 cells with 1-ethylnitrosourea produced approximately the same level of cell kill and induction of sister chromatid exchanges. Our results suggest that the resistance of 9L-2, 9L-7, and 9L-8 cells is related to DNA cross-linking and not to alkylation or carbamoylation. We studied the effects of other agents that form DNA cross-links with structures different from those formed by treatment with chloroethylnitrosoureas (CENUs) in 9L and 9L-2 cells. In contrast to results obtained with CENUs, 9L-2 cells were 2-fold more sensitive to the cytotoxic effects, 2-fold more sensitive to the induction of sister chromatid exchanges, and had 3-fold more cross-links formed than 9L cells treated with nitrogen mustard. However, the amount of cell kill, number of sister chromatid exchanges induced, and the DNA cross-linking were the same for 9L and 9L-2 cells treated with cis-diamminedichlorplatinum(II). Our results indicate that cellular resistance to CENUs is highly specific and that the mechanism of resistance does not allow cross-resistance with other DNA cross-linking agents. These and other results suggest that when DNA repair processes mediate cellular resistance to CENUs, other cross-linking agents will not be cross-resistant unless they form alkylation products that are affected by repair processes that mediate resistance to CENUs.

A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxicity of ACNU in vitro in rat C6 glioma, 9L gliosarcoma and their ACNU-resistant sublines (C6/ACNU and 9L/ACNU). Uptake and retention of ACNU in these cells were studied with [14C]ACNU in the absence or presence of trifluoperazine. The results indicated that intracellular uptake and retention of ACNU in C6 and 9L cells were larger than those in C6/ACNU and 9L/ACNU cells, and that trifluoperazine increased the cellular uptake and retention of ACNU in C6 and 9L, especially in C6/ACNU and 9L/ACNU cells. The amounts of ACNU in C6/ACNU and 9L/ACNU cells reached almost the same level as those detected in C6 and 9L cells. When trifluoperazine were added along with ACNU to the culture in vitro at a concentration of 10 and 20 microM, ACNU resistance was completely overcome. Furthermore, treatment of C6 and C6/ACNU cells with 20 microM trifluoperazine did not change the cellular uptake rate of [14C]AIB (alpha-aminoisobutyric acid), which might indicate that the membrane permeability of the cells was kept intact during the drug treatment. The same phenomenon was observed in 9L and 9L/ACNU cells. It might be concluded that the enhanced effect of cytotoxicity of ACNU in ACNU-resistant rat brain tumor cells presented in this study is presumably due to the increase of intracellular concentration of ACNU resulting from the inhibition of the efflux of ACNU by trifluoperazine from the resistant cells. It was also suggested that ACNU resistance in malignant brain tumors could be overcome by combination chemotherapy with ACNU and calmodulin inhibitors.

For the early diagnosis of recurrence of acute leukemia, differential count of the 5000 leukocytes was found very effective. In 29 cases out of 30 cases whose leukemic cells were elevated to the level higher than 10/5000 from the level of 0-4/5000 in stable stage of remission, overt recurrence was diagnosed by peripheral blood or bone marrow examination after 3-12 weeks. Prevention of overt recurrence was observed in several cases, in which an intensive treatment was administered at the early stage of recurrence. For the treatment of cases with overt recurrence, it is important to plan the treatment with drugs different from those used in previous treatment. AAAP therapy or new drugs such as mitoxantrone might be considered. In cases in which leukemic cells proliferate earlier than normal cells after intensive treatment, a sustained small dose Ara-C therapy was often effective.

The authors reported the clinical course and the postmortem examination of a unique case of neurocutaneous melanosis with numerous anomalies and complications, which included congenital dislocation of lenses, hypogonadism, ectopia of prostatic duct, genuine phimose, retentio testis, psina bifida and neurogenic bladder. This 13-year-old boy with a large hairy nevus in a bathing trunk configulation and multiple small nevi over the whole body since his birth was admitted to our hospital for evaluation of headache and vomiting. Neurological examination showed bilateral papilledema and slight left hemiparesis. A CT scan revealed a large right frontal mass and craniotomy was performed with subtotal removal of this tumor which was confirmed as a malignant leptomeningeal melanoma. He initially made uneventful postoperative recovery, and two courses of chemotherapy with DTIC, ACNU and VCR were given; however, the currence of brain tumor ensued shortly thereafter, and he died in approximately six months after the onset of intracranial symptoms despite of the third course of chemotherapy. Thirty five cases of neurocutaneous melanosis associated with or without malignant melanoma have been reported in Japan. Twenty-eight cases were male and 7 female. Two cases showed the evidence of primary malignant melanoma outside of the central nervous system, whereas twenty eight leptomeningeal melanoma, in which 22 were solid and 6 diffuse, were shown intracranially. Other 5 cases had epileptic seizure and/or hydrocephalus caused by wide spreaded leptmeningeal melanosis. This high incidence of intracranial malignant melanoma in this disorder was remarkable compaired with the previous reports in other countries. Mean duration between deaths and the onset of symptoms of intracranial hypertension or focal neurological signs was 7 months, ranging from 1 to 24 months, showing the rapidly deteriorating course in this disorder.(ABSTRACT TRUNCATED AT 250 WORDS)