5-Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in curatively resected stage III colon cancer: long-term follow-up results of the adjCCA-01 trial.

BACKGROUND: Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and leucovorin in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrences and improves survival. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in a long-term follow-up study in comparison with the effects of 5-FU plus levamisole in the prospective multicenter trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected stage III (International Union Against Cancer) colon cancer were stratified according to tumor, node and grading category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body surface area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days, plus leucovorin 100 mg/m2, 12 cycles (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred and eighty (96.9%) of 702 patients enrolled into this study were eligible. To date, 261 patients have died, 117 on arm A and 144 on arm B (P = 0.007). After a median follow-up time of 82 months, the 5-FU plus leucovorin combination significantly improved disease-free survival [79.8 months in arm A versus 69.3 months in arm B (P = 0.012)] and significantly increased median overall survival (88.9 months in arm A versus 78.6 months in arm B; P = 0.003). Adjuvant treatment with 5-FU plus levamisole as well as 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSIONS: After curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated. This long-term follow-up study demonstrates that adjuvant treatment with 5-FU plus leucovorin given for 12 cycles is significantly more effective than 5-FU plus levamisole (Moertel scheme) in reducing tumor relapse and improving survival.     

阻断乙型肝炎病毒母婴传播对血清病毒转录体的影响

目的进一步探讨阻断乙型肝炎病毒（HBV）母婴垂直传播的效果，明确携带HBV孕妇干预治疗对保护婴儿抗-HBV感染的意义。探讨乙型肝炎病毒转录体（RNA）检测在母婴传播诊断中的意义。方法将91例HBsAg／HBeAg呈阳性孕妇分成两组。其中治疗组为61例，以乙肝免疫球蛋白（HBIG）与左旋咪唑涂布剂阻断治疗；对照组为30例。治疗组在孕26周起开始阻断治疗，自母亲及其婴儿血清和母亲乳汁中提取核酸，经PCR及RT—PCR分别扩增HBV DNA和RNA，Southern—blotting验证反应的特异性，取代表性产物克隆、测序，检测血清HBV DNA及全长型（IRNA）和顿挫性转录体（trRNA）。结果治疗组和对照组新生儿外周血HBV DNA、fRNA和trRNA的阳性率分别为3．3％，3．3％，47．5％和6．7％，13．3％。70．0％。治疗组的前二项指标明显低于对照组，差异有显著意义（P〈0．01），但trRNA差异无显著意义（P〉0．05）。结论携带HBV孕妇于孕晚期给予HBIG和左旋咪唑涂布剂阻断治疗后，婴儿HBV DNA和fRNA携带率明显降低。治疗组和对照组均有超过1／2的患儿携带trRNA。trRNA在HBV母婴垂直传播过程中有可能是一个出现更早期的可检测指标，有助于确定新生儿HBV感染的状态。     

Cocaine adulteration with the anthelminthic tetramisole (levamisole/dexamisole): Long‐term monitoring of its intake by chiral LC–MS/MS analysis of cocaine‐positive hair samples

Recent studies indicate that not only the anthelminthic levamisole but also the racemate tetramisole (R‐/S‐phenyltetraimidazothiazole, PTHIT) was found as an adulterant for cocaine. We herein report on the investigation of the prevalence of PTHIT among cocaine‐positive hair samples and the discrimination of the presence of its stereoisomers levamisole and dexamisole. Cocaine‐positive hair samples were collected in a forensic context in 2015 and mainly 2017 (n = 724). Cocaine and PTHIT concentrations have been determined by achiral liquid chromatography–tandem mass spectrometry (LC–MS/MS). For distinction of levamisole/dexamisole chiral LC–MS/MS was performed. Cocaine hair concentrations ranged from 500 (cut‐off) to approximately 800 000 pg/mg. The study demonstrates a strong prevalence of PTHIT in cocaine users' hair (87%, n = 627). PTHIT hair concentrations ranged from below LLOQ 3.5 to approximately 61 000 pg/mg (median: 260 pg/mg). Surprisingly, enantiomeric ratios of levamisole/dexamisole ranged from 0.17 to 1.34 (median: 0.63). Therefore, PTHIT‐adulterated street cocaine samples (n = 24) seized between 2013 and 2016 were tested. Samples mainly contained racemic tetramisole (87.5%), only one sample contained levamisole only and two samples contained non‐racemic PTHIT. Our experiments suggest that the presence of tetramisole in biological samples may have hitherto been underestimated. Most probably higher dexamisole than levamisole concentrations in hair specimens arise from stereoselective metabolism and/or elimination. This is particularly important in light of the different pharmacological activities of the two enantiomers and potentially different adverse effects. Toxicological interpretations in intoxication cases with adulterated cocaine should not only consider levamisole but also tetramisole and terminology in scientific contributions should be used accordingly.     

Androgen metabolic response to indomethacin and the alkaline phosphatase inhibitor levamisole in fibroblasts

OBJECTIVES: The aim of this investigation is to study the effects of indomethacin (I) and the alkaline phosphatase (ALP) inhibitor levamisole (L) on androgen 5alpha-reductase expression in gingival and periosteal fibroblasts, in the context of repair in the periodontium. Chronically inflamed human gingival fibroblasts (HGF) were used to demonstrate the comparative effects of L on HGF and human oral periosteal fibroblasts (HPF). MATERIAL AND METHODS: Monolayer cultures of six cell lines of HPF of the fifth to ninth passage were incubated in duplicate with 14C-testosterone/14C-4-androstenedione as substrates in Eagle's MEM; I was added at concentrations of 1 and 3 microg/ml in the presence or absence of the established inhibitory concentration of 30 microg/ml L and incubated for 24 h. The medium was solvent extracted for radioactive metabolites, separated by thin layer chromatography and quantified. RESULTS: L caused 50% inhibition of 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase activity in HGF. In HPF, 5alpha-reductase expression was enhanced by I with both substrates, by 65-76% (n = 6; p<0.01), inhibited by 30-50% (n = 6; p<0.01) with L and restored to control values in combination. CONCLUSION: Yields of androgen metabolites may be linked to ALP activity, with implications on healing, during adjunctive treatment of inflammatory periodontal disease with I.     

FFP时辰化疗联合左旋咪唑治疗大肠癌

目的探讨FFP时辰化疗联合左旋咪唑治疗大肠癌的临床疗效。方法8例大肠癌根治术后患者采用FFP时辰化疗联合左旋咪唑治疗治疗：（1）顺铂（DDP）或奥沙利铂（L-OHP）在每天的特定时间注入；（2）5-FU采用微电脑控制的ZZB型全自动注药泵，预先设定给药时间及给药量，以正弦速率在22：00～10：00注入，于每天04：00达到最高峰，亚叶酸钙（CF）则每天在此之前天注入；（3）左旋咪唑（LMS）50mg／次，口服，3次／d。连服3d，每2周重复，持续服用1年。结果所有患者均获随访，随访1～2年，其中1例肺转移的患者随访2年病灶稳定；其余7例患者经B超或CT等影像学检查均未见任何复发转移征象，血清CEA检测均为阴性。3例出现轻度呕吐，所有患者均未出现明显的骨髓抑制。结论大肠癌术后采用FFP时辰化疗联合左旋咪唑治疗副作用小，效果较为满意，值得进一步研究和探索。     

The influence of nonspecific immunotherapy on the course of Murine Melanoma

BCG, Corynebacterium parvum, vitamin A, and levamisole were continuously administered to C57 BL/6 mice bearing B16 melanoma prior to, with, and following tumor implantation as well as before and coincident with surgical excision of the implanted tumor. Only the group given levamisole prophylactically for 8 weeks before tumor inplantation showed a significant difference from control mice but a tenfold increase in dosage in this drug did not exert a comparable effect.     

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.     

Side effects to levamisole given to neoplastic patients as adjuvant to surgery: A new case of agranulocytosis

Side-effects to levamisole given as adjuvant to surgery in a consecutive series of 203 neoplastic patients are reported: Thirty-four patients (16.7%) suffered gastric adverse reactions; 8 (3.9%) allergic; 6 (2.9%) intestinal; 6 (2.9% neurologic; 4 (1.9%) severe hyperthermia (more than 40.5°C); 3 (1.4%) flu-like illness; 1 (0.4%) leucopenia; and 1 (0.4%) agranulocytosis. Withdrawal rate was 5.4% or 11 patients. Side effects appeared sex-related (39.0% in females, 17.7% in males; with seven female dropouts out of 11), unrelated to other eventual adjuvant treatments, and reappearing at a new challenge with levamisole. The opportunity of very close control of patients taking levamisole for at least the first months is discussed.