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Editor's Choice : The Neurotoxicity and Pharmacokinetics of Oral Ifosfamide
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Abstract: Purpose:Ifosfamide can cause an unexplained encephalopathy. The incidence after intravenous infusion is 10%, but is much higher after oral administration. This study assesses the pharmacokinetics of oral ifosfamide in relation to neurotoxicity. Patients and Methods:Eleven patients received oral ifosfamide 500 mg twice daily for 14 days, with concurrent oral mesna. The concentrations of ifosfamide, isophosphoramide mustard, 2-dechloroethylifosfamide, 3-dechloroethylifosfamide, carboxyifosfamide, ketoifosfamide, chloroethylamine and 3-oxazolidine-2-one were measured using GC-MS. Patients were evaluated clinically, and also with the EEG, psychometric testing, the national adult reading test, and the mini-mental state examination. Results:A decrease in the electroencephalogram alpha frequency was observed, with the development of pathological slow wave activity. Psychometric performance was also impaired. Neurotoxicity was progressive during treatment, and the incidence of grade 3 neurotoxicity was 22%. The mean day 14 / day 1 Cmax ratios for 2-dechloroethylifosfamide and 3-dechloroethylifosfamide were 2.73 (± 2.11) and 2.04 (± 1.32) respectively. The metabolite with the lowest ratio was isophosphoramide mustard 1.07 (± 0.39). High chloroethylamine Cmax values were associated with lower alpha frequencies, and increased clinical neurotoxicity. Conclusion:Oral ifosfamide 500 mg twice daily for 14 days causes unacceptable neurotoxicity. It was not possible to identify one particular metabolite responsible for the neurotoxicity, although the dechloroethyl metabolites and chloroethylamine are implicated. Keywords: Oral ifosfamide, metabolites, pharmacology, encephalopathy, electroencephalogram, lung neoplasms, cervical neoplasmsa.Download Full Article |
Editor's Choice : The Role of the IGF Axis in Epithelial-to-Mesenchymal Transition during the Progression of Prostate Cancer
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Abstract: Prostate cancer is the second most common lethal cancer in men worldwide. Despite the fact that the prognosis for patients with localized disease is good, many patients succumb to metastatic disease with the development of resistance to hormone treatments. This is normally termed castration-resistant prostate cancer (CRPC). The development of metastatic, castration-resistant prostate cancer has been associated with epithelial-to-mesenchymal transition (EMT), a process where cancer cells acquire a more mesenchymal phenotype with enhanced migratory potential, invasiveness and elevated resistance to apoptosis. The main event in EMT is the repression of epithelial markers such as E-cadherin and upregulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin. The insulin-like growth factor (IGF) signalling axis is essential for normal development and maintenance of tissues, including that of the prostate, and dysregulation of this pathway contributes to prostate cancer progression and malignant transformation. It is becoming increasingly clear that one of the ways in which the IGF axis impacts upon cancer progression is through promoting EMT. This review will explore the role of EMT in prostate cancer progression with a specific focus on the involvement of the IGF axis and its downstream signalling pathways in regulating EMT in prostate cancer. Keywords: Epithelial-to-mesenchymal transition, insulin-like growth factor family, prostate cancer progression, lifestyle factors.Download Full Article |
Editor's Choice : Metastatic Bone Marrow Tumors Manifested by Hematologic Disorders: Study of Thirty-Four Cases and Review of Literature
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Abstract: Purpose: Bone marrow metastasis of cancer is a sign of extensively hematogenous spreading of cancer and may be a terminal event of those patients. With the improvement of systemic chemotherapy for malignant disease, some patients may have longer survival. We plan to find out the clinical hematologic presentation and prognostic factors in cancer patients with bone marrow metastasis. Materials & Methods: In this retrospective study, we reviewed the results of 162 bone marrow examination carried out in adult malignancy patients (colon, lung, gastric, breast and prostate cancers) between January 2002 and December 2012 in Changhua Christian Hospital. The indication for bone marrow study for those patients with hematologic disorders included: leukoerythroblastosis, microangiopathic hemolytic anemia, unknown etiology of anemia, thrombocytopenia, bicytopenia and pancytopenia. Statistics analysis used SPSS 18.0 and overall survival was analyzed with the use of Kaplan–Meier curves and the log-rank test. Results: Thirty-four patients (20.9%) had evidence of involvement of the bone marrow by a solid tumor, most common cancers were prostate and lung. At the time of diagnosis, the most common hematologic disorders were leukoerythroblastosis and microangiopathic hemolytic anemia. Median survival after the diagnosis of bone marrow metastasis with supportive care only compared with definite treatments was 0.3 months and 20.6 months (p<0.0001). Patients with visceral organ metastasis (0.4 months vs 6.4 months, respectively; p <0.002) and anemia (2.1 months vs 6.4 months, p=0.031) had inferior survival. Patents without any cytopenia had better survival (12.5 months vs 4.1 months, p=0.029). Initial level of thrombocyte and neutrophil, bone marrow infiltration type (focal or diffuse) and disease status were not significant prognostic factor. Conclusions: Visceral metastasis and anemia are most poor prognostic factors in solid cancers with bone marrow metastasis. Since the improvement of the diagnosis and treatment for cancers during the recent decades, a portion of patients can be had better disease control after definite treatment especially in breast and prostate cancers with bone marrow metastasis. Keywords: Bone marrow metastasis, leukoerythroblastosis, microangiopathic hemolytic anemia, bone marrow involvement, adenocarcinoma.Download Full Article |
Editor’s Choice : Pathological Complete Response Induced by the Combination Therapy of Gemcitabine and 24-h Infusion of Cisplatin in Two Cases Initially Diagnosed as Node-Positive Advanced Urothelial Carcinomas
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Abstract: We report on two patients, successfully treated by the combination therapy of gemcitabine and 24-h intravenous infusion of cisplatin, who were initially diagnosed with node-positive advanced urothelial cancer. Each patient had a very good clinical response and underwent curative radical surgery after gemcitabine/cisplatin chemotherapy. A microscopically detailed examination of surgically obtained specimens showed the complete disappearance of malignant cells in the two cases. As a pilot study, we have used the regimen of gemcitabine plus 24-h continuous infusion of cisplatin, instead of bolus injection, for the treatment of 20 patients with node-positive or metastatic urothelial cancer. The clinical response rate in this regimen was 75% (complete response 7/20; 35%, partial response 8/20; 40%). The median overall survival was 665 days. As for the adverse effects, the incidences of severe neutropenia and thrombocytopenia (grade 3-4) were 20% and 15%, which might be less toxic than conventional gemcitabine plus cisplatin therapy. The 24-h infusion of cisplatin combined with gemcitabine can be highly recommended as neoadjuvant chemotherapy for locally advanced urothelial cancer. Keywords: Urothelial carcinoma, cisplatin, gemcitabine, pathological complete response.Download Full Article |
