Methotrexate-induced myelopathy responsive to substitution of multiple folate metabolites

Methotrexate (MTX)-associated myelopathy is a rare but serious subacute complication of MTX-based chemotherapy. We report the case of a woman with breast cancer and meningeal carcinomatosis who developed severe progressive myelopathy after four cycles of intrathecal MTX administration. We substituted high doses of the key metabolites of the methyl-transfer pathway: S-adenosylmethionine (SAM), 200 mg three times daily i.v.; folinate, 20 mg four times daily i.v.; cyanocobalamin, 100 μg once daily i.v.; and methionine, 5 g daily p.o. The patient’s paraparesis improved rapidly thereafter, and magnetic resonance (MR) imaging showed resolution of the intramedullary lesions. Genetic analyses revealed homozygosity for the A allele of methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (p.E429A), whereas other genetic variants of folate/methionine metabolism associated with MTX neurotoxicity were not present. Substitution with multiple folate metabolites may be a promising strategy for the treatment of MTX-induced neurotoxicity.     

Methotrexate-induced acute toxic leukoencephalopathy

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX), as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS). Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced 'acute toxic leukoencephalopathy' has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI) is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted) and FLAIR (Fluid-Attenuated Inversion recovery) sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted) sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up over a 2 year period.     

Hodgkin-lymphoma-derived cells show high sensitivity to dactinomycin and paclitaxel

Depending on stage and risk factors, up to 30% of patients with advanced Hodgkin lymphoma (HL) progress or relapse. Patients with pleural effusions have a particularly poor prognosis and this stage of HL is regularly resistant to chemotherapy. All currently available HL cell lines are derived from late stage HL patients. In the present study we measured the sensitivity of these HL lines against the 26 most frequently used cytostatic drugs. We used a novel fluorescent short-term survival assay where the cell was incubated with the drugs for 4 days. The precise number of differentially stained live and dead cells was determined using a custom-built automated laser confocal fluorescent microscope. We found that HL cells, independently of their origin, showed very similar sensitivity patterns for several of the drugs. All HL cell lines were highly sensitive to dactinomycin, paclitaxel and etoposide. Our data suggest that the inclusion of dactinomycin and paclitaxel into chemotherapy protocols against late stage Hodgkin lymphoma with pleural effusion may be justified.     

Methotrexate-induced sudden fatal pulmonary reaction.

A teenage girl in bone marrow remission with acute lymphocytic leukemia died suddenly from pulmonary edema. She had taken her first oral dose of methotrexate and cyclophosphamide 10 hours previously when she was feeling well and was asymptomatic. One week previously she had received the last of four intrathecal injections of methotrexate. Autopsy showed marked pulmonary edema as well as chronic lung changes, as previously described in patients with methotrexate pneumonitis. There is usually at least a 12-day interval from the onset of administration of methotrexate to the onset of the lung toxicity. The authors suggest the patient was sensitized by the intrathecal methotrexate and then reacted with angioneurotic edema of the lung when given the first oral dose of methotrexate. Careful examination for infectious agents, including electron microscopy, was negative.     

4′-甲醚-黄芩素对耐药性人绒毛膜癌的耐药逆转作用

目的:研究4'-甲醚-黄芩素(4'-methylether-scutellarein,4'-M-S)对耐药性人绒毛膜癌的体内耐药逆转作用并探讨其相关作用机制.方法:在BALB/c裸鼠左侧腋窝皮下注射耐药性人绒毛膜癌细胞JAR/VP-16建立耐药性人绒毛膜癌裸鼠皮下移植瘤模型,瘤体直径至1.0 cm时,随机分为空白对照组、依托泊苷(etoposide,VP16)化疗组、4'-M-S组和4'-M-S+VP16联合治疗组,每组10只荷瘤鼠.动态观测各治疗组荷瘤鼠肿瘤生长情况,并记录存活时间.治疗3周后,通过光镜、透射电镜观察移植瘤组织形态学改变,流式细胞术检测移植瘤细胞凋亡率的变化,用RT-PCR、Western blotting检测并比较4组移植瘤组织中多药耐药基因1(multidrug resistance 1,MDR1) mRNA、肺耐药相关蛋白(lung resistance-related protein,LRP)mRNA及其产物P-糖蛋白(permeability-glycoprotein,P-gp)和LRP的表达情况.结果:治疗3周后发现,4'-M-S对耐药性人绒毛膜癌有一定的体内抑制作用,与VP16联合用药可使裸鼠移植瘤生长明显受抑,抑瘤率达48.21％,同时可减轻化疗毒性反应、明显改善荷瘤鼠生活质量,并显著延长其平均存活时间;与其他3组相比,4'-M-S+VP16联合治疗组移植瘤细胞凋亡率显著升高(均P ＜0.05),移植瘤组织中MDR1 mRNA、LRP mRNA及其编码蛋白P-gp和LRP表达水平均显著下降(均P＜0.05).结论:4'-M-S能有效逆转人绒毛膜癌对化疗药物VP16的耐药性,其机制可能与4'-M-S诱导细胞凋亡和下调耐药基因MDR1 mRNA、LRP mRNA及相应产物P-gp和LRP的表达有关.     

Methotrexate-induced oral mucositis and salivary methotrexate concentrations

Summary We examined the plasma and saliva levels of methotrexate (MTX) achieved during the treatment and rescue periods of ten patients receiving 42-h MTX infusions followed by citrovorum rescue. Saliva MTX levels were generally 1%–2% of the simultaneous plasma levels. Four patients developed severe oral mucositis; three patients developed mild to moderate oral toxicity, and three others had no evidence of mucositis. MTX levels in the patients with severe mucositis were not higher and did not persist longer than the levels achieved in patients with mild or absent toxicity. Attempts at reducing the severity of oral mucositis with topical citrovorum mouth-washes or with atropine to suppress salivation were unsuccessful. MTX-induced oral mucositis is not related to salivary MTX concentrations, and the use of topical citrovorum therapy or the supression of salivation does not appear to ameliorate this toxicity.     

Alternating methotrexate and dactinomycin in nonmetastatic gestational trophoblastic disease

Alternating 5-day chemotherapy with methotrexate and dactinomycin as primary therapy for nonmetastatic gestational trophoblastic disease was studied in nine patients. The complete response rate was 100% with follow-up of a median of 80 months. Stomatitis was universal but rarely prevented oral alimentation or delayed therapy. Overall, 94% of toxicity was mild or moderate in severity and all toxicity was reversible. This alternating non-cross resistant regimen, reported in a total of 40 patients in the literature, is the only regimen to result in a 100% response rate. This response rate is statistically improved when compared to historical controls receiving methotrexate/folinic acid or pulse dactinomycin. No patients required hysterectomy for disease control. Cooperative prospective phase III studies are needed to determine the efficacy and toxicity of current regimens.     

ATYPICAL CHORIOCARCINOMA

Atypical choriocarcinoma b a rare type of gestational trophoblastic disease and only 3 cases were diagnosed among a total of 696 patients with chorlocarcinoma admitted to our hospital from 1949 through 1985. Atypical chorlocarcinoma is different from the regular choriocarcinoma in both histopathology and clinical manifestations. Morphologically, the tumor cells are predominantly cyto-trophoblast and clinically, the hCG titer is very low which is undetectable by routine biological or immunologic assays. Therefore, It Is not infrequently misdiagnosed as sarcoma, squamous cell carcinoma or clear cell carcinoma of the uterus. A comprehensive review of the past history and clinical manifestations is most essential to obtain a correct diagnosis.     

Radiation therapy of choriocarcinoma metastatic to the brain

Brain irradiation for metastases was performed in 3 cases of choriocarcinoma of pregnancy and 1 patient with testicular choriocarcinoma of embryonal origin. Treatment failed in 2 cases due to tumor advancement, while the other 2 patients showed marked response. Early diagnosis and proper treatment of intracranial metastases may significantly increase survival.     

Clinical significance of circulating tumor cells in predicting disease progression and chemotherapy resistance in patients with gestational choriocarcinoma

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5-mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non-progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with <4 CTCs (P < 0.001). These findings demonstrates the feasibility of CTC detection in cases of GC by adopting EpCAM/CD147 antibodies together as capturing antibodies. The CTC count is a promising indicator in the evaluation of biological activities and the chemotherapy response in GC patients.     

Chemo-resistant choriocarcinoma metastatic to colon cured by low-anterior resection

The role of surgery in the treatment of patients with metastatic choriocarcinoma has diminished. We present a case of chemo-resistant metastatic choriocarcinoma salvaged by surgery. A 48-year-old patient presented with uterine perforation and severe intractable hemorrhage, and histological examination revealed a choriocarcinoma. After 6 years of disease-free state, recurrence occurred in the rectosigmoid colon. Seven cycles of EMACO chemotherapy was administered, and the human chorionic gonadotropin level was normalized. Three months after the chemotherapy, the rectosigmoid colon metastasis progressed. Low anterior resection with lymphadenectomy up to the level of the inferior mesenteric artery was conducted. After the operation, the human chorionic gonadotropin level decreased to within the normal range. There has been no evidence of disease for 13 months since the operation. Local resection of metastases seems to play a significant role in curing the disease in a small subset of patients.     

Uterine choriocarcinoma in a postmenopausal woman

Uterine choriocarcinoma developing in patients beyond reproductive age is a rare occurrence. We report a case of choriocarcinoma of uterine corpus in a 54-yr-old woman after 7 yr of menopause and 25 yr after last child birth. She presented with pain in the abdomen, and on radiological investigation a left uterine adnexal mass of 3.4×2.8 cm size was detected. Her serum CA 125 level was 40 mIU/mL (normal up to 35 mIU/mL). Hysterectomy revealed an intramural growth in left uterine cornu measuring 3.5×3.0×2.5 cm. Histological features of the tumor were consistent with choriocarcinoma, and immunohistochemistry detected strong reactivity for β-hCG in the tumor cells. Serum β-hCG level 4 wk after surgery was 1345 mIU/mL. The patient was put on combination chemotheraphy (EMACO). She acheived serological remission but showed a rise in serum β-hCG level 4 wk after completion of chemotherapy. We conclude that a high level of suspicion may help in preoperative diagnosis of uterine choriocarcinoma in the postmenopausal age group. However, the response to chemotherapy in these cases may not be as encouraging as in choriocarcinoma of reproductive age.