Summation Effects of Uracil and Other Promoters on Epithelial Lesion Development in the F344 Rat Urinary Bladder Initiated by N-Butyl-N-(4-hydroxybutyl)nitrosamine

Five non-genotoxic chemicals previously demonstrated to be bladder cancer promoters in 36-week in vivo assays for carcinogenesis were reevaluated in a 20-week experiment in order to assess the summation influence of dietary nracil, a component of RNA, on the development of (pre)neoplastic lesions. The test chemicals, sodium bicarbonate, sodium L-ascorbate, sodium citrate, butylated hydroxytoluene and ethoxyquin, were mixed into the diet at concentrations of 3%, 5%, 5%, 1% and 0.8%, respectively, and administered to male F344 rats after initiation with 0,05% N-butyl-N-(4-hydroxybutyDnitrosamine (BBN) in their drinking water for 4 weeks. The test chemicals were given from the 4th to the 8th and the llth to 20th experimental weeks, uracil being administered at the level of 3% in the diet during the intervening period. Rats in the control group received only BBN and uracil. All animals were killed at week 20 and the bladders were evaluated for the occurrence of putative preneoplastic papillary or nodular (PN) hyperplasia and tumors. Significant increase in the occurrence of FN hyperplasia was observed in all groups initiated with BBN and fed uracil and test chemicals. Quantitative values for papillomas were also significantly increased except in the ethoxyquin-treated group. The results confirm that uracil given in the middle of the post-initiation stage enhances the promoting activity of chemicals and suggest that the use of this chemical might be useful to reduce the duration of current bioassays for bladder chemical carcinogens.     

Sequential Observation of Rat Prostate Lesion Development Induced by 3,2'-Dimethyl-4-aminobiphenyl and Testosterone

3,2'-Dimethyl-4-aminobiphenyl (DMAB), when combined with high doses of testosterone propionate (TP) induces invasive adenocarcinomas with metastatic potential in the rat prostate. The processes underlying this tumor development, including the involvement of atypical hyperplasias, were sequentially investigated in F344 rats. DMAB was given subcutaneously at a dose of 50 mg/kg body weight 10 times at 2-week intervals. TP was administered chronically (in Silastic tubes) from the beginning of the experiment or after the DMAB administration until termination (week 60). Invasive adenocarcinomas were induced in the lateral and anterior prostate as well as the seminal vesicles. Atypical hyperplasias appeared from an early stage, with the later appearance of cancers being closely associated with such foci of morphological alteration. The findings confirm that combined administration of DMAB and pharmacological doses of TP yields invasive adenocarcinomas in the rat prostate and provide further support for the conclusion that atypical hyperplasias are premalignant lesions.     

Effects of Phenobarbital and Carbazole on Carcinogenesis of the Lung, Thyroid, Kidney, and Bladder of Rats Pretreated with N-Bis(2-hydroxypropyl)nitrosamine

Studies were made on potential modifying effects of phenobarbital (PB) and carbazole on tumor development induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN), a wide-spectrum carcinogen in rats. Effects on the lung, thyroid, kidney, bladder and liver were investigated. Male F344 rats were given 0.2% DHPN in their drinking water for 1 week and then 0.05% PB or 0.6% carbazole in their diet for 50 weeks. Control animals were treated with either DHPN or PB or carbazole only. Neither PB nor carbazole affected the incidence or histology of lung tumors. However, PB promoted the development of thyroid tumors and preneoplastic lesions of the liver, while carbazole promoted the induction of renal pelvic tumors.     

Infrequent Mutations of the WT1 Gene in Primary Cancers of the Adult Urinary Tract

Polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP) analysis of all of the ten exons of the WT1 geneand restriction fragment length polymorphism (RFLP) analysisof the WT1 locus were performed on primary urinary tract cancers:seven renal pelvic cancers, one ureteral cancer, 11 bladdercancers, and 22 renal cell cancers. Four human bladder cancercell lines (T24, JTC30, JTC32, and HUB41) and three human prostatecancer cell lines (PC-3, DU145, and LNCaP) were also examined.None of the primary cancers showed any apparent mutations ofthe gene, whereas one base substitution of exon 5 was foundin DU145 and gross alteration of the gene was recognized inHUB41. Heterozygosity of polymorphic exon 7 was retained inall of the 12 informative cases, and none of 10 informativecases showed loss of heterozygosity at the WT1 locus in RFLPanalysis. It is concluded that mutations of the WT1 gene maynot be involved in the formation of malignant tumors of theadult urinary tract.     

经腹与经腹膜后腹腔镜肾输尿管全长切除治疗上尿路尿路上皮癌的临床研究

目的探讨经腹膜后入路腹腔镜肾输尿管全长切除联合膀胱袖状切除术治疗上尿路尿路上皮癌的可行性和安全性。方法将62例尿路上皮癌患者分为经腹腔入路组和经腹膜后入路组。经腹腔入路组患者均接受经腹腔入路腹腔镜肾输尿管全长切除联合膀胱袖状切除术治疗;而经腹膜后入路组患者则接受经腹膜后入路肾输尿管全长切除联合下腹部小切口膀胱袖状切除术治疗。观察并记录2组患者手术时间、术中出血量和住院时间等手术相关指标。术后观察2组患者术后并发症、肿瘤复发和转移情况,并于术前和术后3个月采用SF-36量表对患者的生活质量进行评分。结果经腹膜后入路组患者的手术时间、术中出血量和住院时间分别为(118.74±22.68)min、(124.69±43.78)mL和(8.12±2.21)d,均显著低于经腹腔入路组的,组间差异有统计学意义(P<0.05);经腹膜后入路组患者术后3个月的生理功能、生理职能、躯体疼痛、总体健康、社会功能、活力、情感职能和精神健康共8个维度的评分均高于经腹腔入路组(P<0.05);经腹膜后入路组患者术后的并发症发生率为3.12%,显著低于经腹腔入路组的13.33%(P<0.05)。2组患者术后彩超和膀胱镜检查均未发现肿瘤复发情况;2组患者术后远处转移发生率比较,差异无统计学意义(P>0.05)。结论经腹膜后入路肾输尿管全长切除联合下腹部小切口膀胱袖状切除术治疗上尿路尿路上皮癌,创伤小,利于患者的康复,同时可提高患者的生活质量,安全有效,值得应用于临床。     

膀胱肿瘤切除术后尿路感染病原菌分布及相关因素分析

目的 对经尿道行膀胱肿瘤切除术(TURBT)的患者进行术后尿路感染情况调查,并探讨其相关因素及相应的预防措施.方法 采用回顾性调查法对接受TURBT的患者的尿路感染情况以及其他有关的临床数据资料进行统计分析.结果 92例患者在术后留置尿液中的细菌培养有阳性41例,总发生率44.6％;共检测出45株病原菌,其中革兰阳性球菌10株,占22.2％;革兰阴性杆菌35株,占77.8％;主要菌种是肺炎克雷伯菌、大肠埃希菌及肠球菌属,未检测到真菌.TURBT术后发生尿路感染除与手术操作及留置导尿管有关外,还与高龄、糖尿病、肿瘤位点多发、术前已有留置导尿管有关.结论 手术全程无菌操作,手术用器械、纱布严格消毒,手术过程尽量防止损伤组织黏膜,选择合适的导管,确保留置的导尿位置合适,妥善放置和固定尿管,确保其通畅,对其他一些基础疾病加强治疗,能有效地减少TURBT术后的尿路感染现象发生.     

Disturbance of the Cell Cycle with Colchicine Enhances the Growth Advantage of Diethylnitrosamine-initiated Hepatocytes in Rats

The effect of cell cycle disturbance due to colchicine on the induction of enzyme-altered foci during liver regeneration in rats was studied. For initiation, diethylnitrosamine (DEN) at a dose of 10 mg/ kg was injected intraperitoneally and partial hepatectomy (PH) was performed 4 h thereafter. Colchicine at doses of 0, 0.1, 0.25 and 0.5 mg/kg was injected intraperitoneally 1 and 3 days after the initiation, followed by application of selection pressure consisting of 2-acetylaminofluorene (AAF) and carbon tetrachloride (CCl₄) administration. As end point lesions, γ–glutamyltransferase (GGT)-positive enzyme-altered foci were assayed at week 5. There was no significant effect of colchicine on numbers of foci. However, a significant, dose-dependent increase in the area of GGT-positive lesions in the groups treated with colchicine was observed. Bromodeoxyuridine labeling indices were higher in foci induced in colchicine-treated rats than in the untreated rats. In a separate experiment, serum glutamic pyruvic transaminase was not increased significantly after DEN and colchicine treatment, and the mitotic index at 6 days after PH was increased in the liver of colchicine-treated rats. These results suggest that the cell cycle disturbance induced by colchicine causes more pronounced selective growth of cells initiated by DEN and colchicine, and this experimental model may be useful for analyzing the mechanisms underlying that growth advantage and the effects of cell cycle abnormalities in liver carcinogenesis.     

镇痛药联合双膦酸盐治疗恶性肿瘤骨转移的相关进展

骨转移是晚期恶性肿瘤最常见的并发症之一.最常见的发生骨转移的恶性肿瘤,主要包括肺癌、乳腺癌、前列腺癌、肾癌、胃肠道肿瘤等.晚期肿瘤一旦发生骨转移,会引起局部的骨质破坏,从而引起骨痛、病理性骨折、神经压迫、高钙血症等一系列骨相关事件(SREs),严重影响患者的生活质量,甚至导致患者脊髓压迫,引起截瘫.晚期恶性肿瘤骨转移的...     

老年卵巢癌患者术后尿路感染常见病原菌分析及药敏实验

目的 调查与分析老年卵巢癌患者术后尿路感染常见病原菌及药敏实验结果 .方法 选取68例老年卵巢癌术后尿路感染患者为研究对象,对其尿液病原菌检出情况进行分析与比较,并对病原菌的药敏实验结果 进行分析与比较.结果 68例老年卵巢癌术后尿路感染患者共检出75株病原菌,其中革兰阴性菌检出率明显高于革兰阳性菌及真菌的检出率,革兰阳性菌检出率则显著高于真菌的检出率,革兰阴性菌对氨苄西林、哌拉西林及环丙沙星的耐药率显著高于对其他药物的耐药率,革兰阳性菌对青霉素、红霉素及苯唑西林的耐药率显著高于对其他药物的耐药率,差异均有统计学意义(P均<0.05).结论 老年卵巢癌患者术后尿路感染常见病原菌为革兰阴性菌,且革兰阴性菌及革兰阳性菌对常规抗菌药物的耐药性均较为突出,应针对其病原菌分布及耐药性情况给予针对性干预.     

尿路移行细胞癌微转移的检测

目的 探讨尿路移行细胞癌患者外周血CK20的表达及临床意义.方法 采用逆转录聚合酶链反应(RT-PCR)检测47例尿路移行细胞癌患者和14例健康志愿者以及18例非肿瘤患者外周血CK20的表达.以GAPDH作为内参照.结果 14例健康志愿者和18例非肿瘤患者外周血CK20的表达均为阴性;47例尿路移行细胞癌患者外周血CK20阳性表达率为21.3%(10/47):T1为0(0/29),T2为20%(2/10),T3为100%(4/4),T4为100%(4/4).随访12个月,6例(T2～T3)外周血CK20阳性的尿路移行细胞癌有3例(T3G2膀胱癌1例,TaG2和T3G2输尿管癌各1例)发生远处转移.结论 检测外周血CK20表达,可以提示癌细胞的血行播散,对判断预后以及指导治疗具有一定临床价值.     

Effects of Age on Multiple Organ Carcinogenesis Induced by 3,2'-Dimethyl-4-aminobiphenyl in Rats, with Particular Reference to the Prostate

The effects of age on multi-organ carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) in male F344 rats were examined. Groups of 5-, 35-, and 65-week-old animals were given 4 weekly sc injections of DMAB at a dose of 200 or 150 mgAg body weight. Prostate carcinomas were induced in 8 to 19% of rats treated, no significant differences in the incidence between different ages being observed. Tumors in the small intestine, skin, pancreas and peritoneum, however, developed more frequently in young than in old animals, whereas higher incidences of testis, preputial and mammary gland lesions were found in the 35- and/or 65-week-old groups. Colon and Zymbal gland carcinogenesis did not reveal any age dependence.     

Urothelial Damage and Tumor Initiation by Urinary Metabolites of Sodium o-Phenylphenate in the Urinary Bladder of Female Rats

Intravesical instillation of 2-phenyl-1,4-benzoquinone (PBQ), a metabolite of sodium o -phenylphenate (Na-OPP), at a concentration of 0.1% in saline caused acute epithelial injury, prolonged inflammation and epithelial hyperplasia in female F344 rats. Ten such instillations of PBQ within 5 weeks resulted in the development of preneoplastic lesions of the urinary bladder epithelium when followed by 5% sodium saccharin feeding for 31 weeks. Since neither urothelial damage nor tumor-initiating activity was observed with either Na-OPP itself or another metabolite, phenylhydroquinone, PBQ may play an essential role in Na-OPP urinary bladder carcinogenesis.     

Sparse Distribution of Hepatocyte Growth Factor-producing Cells inside Hepatocellular Foci in Rats Treated with Hepatocarcinogens

The distribution of hepatocyte growth factor (HGF)–synthesizing cells in rat liver during development of glutathione S –transfcrasc P form (GST–P)–positive nodules after diethylnitrosamine initiation followed hy promotion with 2–acetylaminofluorene plus partial hepatectomy (PH) was investigated using in situ hybridization, HGF–produclng cells were iioii–parenchymal in nature, and were suspected to be mainly of Kupffer type. They were mostly located outside GST–P–positive lesions, in the surrounding parenchyma. In the oval cell proliferation phase 1 week after PH, they increased and they were mainly localized around the portal triads. It is concluded that HGF is directly involved in an endogenous paracrine growth pathway controlling proliferation in oval cells and in normal, hut not GST–P–positive, hepatocytes.     

Modifying Effects of Soybean Trypsin Inhibitor on Development of Eosinophilic Nodules and Basophilic Foci in the Exocrine Pancreas of Male Sprague-Dawley Rats Treated with 4-Hydroxyaminoquinoline 1-Oxide

Administration of 4-liydroxyaniinoquiiioline 1-oxide (HAQO) to rats results in development of 2 types of pancreatic acinar lesions, namely eosinophilic nodules and basophilic foci. To cast light on the biological character of these lesions, 5-week-old male Sprague-Dawley rats were given a single intravenous injection of HAQO at a dose of 7 mg/kg and, thereafter, fed soybean trypsin inhibitor (SBTI) at dose levels of 10% and 5%. At week 57, all rats were killed for pathological examination of pancreatic tissue. The incidence of eosinophilic nodules was significantly higher in the HAQO/ SBTI group than in the HAQO-alone group, whereas the basophilic acinar foci were observed to occur less frequently and to be smaller in the HAQO/SBTI-treated animals. Administration of SBTI is known to increase the blood level of cholecystokinin, a trophic factor for pancreatic acinar cells. Thus, the present findings suggest that long-term elevation of this endocrine factor can affect the two types of pancreatic acinar lesions in essentially different ways, namely enhancing development of eosinophilic nodules, while suppressing the occurrence of basophilic foci.     

Comparison of the Minimum Inhibitory,Mutant Prevention and Minimum Bactericidal Concentrations of Ciprofloxacin,Levofloxacin and Garenoxacin Against Enteric Gram-negative Urinary Tract Infection Pathogens

Abstract

Acute, uncomplicated urinary tract infections (UTIs) are among the most commonly encountered bacterial infections and management has been made more complicated in the last decade due to the trend toward increasing antimicrobial resistance to ampicillin and trimethoprim/sulfamethoxazole (TMP/SMX). Fluoroquinolones are suggested as alternative antimicrobials for the treatment of UTIs in communities for which TMP/SMX resistance is ≥10%. The mutant-prevention concentration (MPC) is a novel susceptibility parameter designed to minimize the selection of first-step resistant mutants present in large, ≥10¹⁰ CFU/mL, heterogeneous bacterial populations and is a distinct measurement from minimum inhibitory concentration testing. We measured MPC results for 80 enteric Gramnegative and 20 Pseudomonas aeruginosa urinary isolates against ciprofloxacin, levofloxacin and garenoxacin. Ciprofloxacin, levofloxacin and garenoxacin MPC results for Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Klebsiella pneumoniae and P. aeruginosa respectively were 0.5, 1, 1, 1 and 4 mg/L; 1, 2, 4, 2 and 16 mg/L; 1, 8, >8, 4 and ≥32 mg/L. By comparison, minimum inhibitory concentration (MIC)₉₀ results for the Enterobacteriaceae organisms ranged from ≤0.06-4 mg/L for the three drugs and 1-4 mg/L against P. aeruginosa. Similarly, MBC₉₀ results ranged from ≤0.06-4 mg/L and 2-8 mg/L respectively. For ciprofloxacin against E.coli, E. cloacae and K. pneumoniae and for levofloxacin against E.coli, C. freundii and K. pneumoniae, MPC results were below susceptible breakpoints and within clinically achievable and sustainable drug concentrations for >24 hours of the dosing interval against. For garenoxacin, urine drug concentrations are expected to be in excess of MPC results for the entire length of the dosing interval for E.coli. Application of MPCs to fluoroquinolones and management of UTIs represents a situation where high levels of in vitro activity, based on low MICs, is reflected in correspondingly low MPC values for most of the organisms tested. Incorporation of MPC strategies into current fluoroquinolone dosing in UTI represents a realistic approach for preventing the further selection of resistant organisms associated with UTIs.     

Time-dependent Modulation of Liver Lesion Development in Opisthorchis-infected Syrian Hamster by an Antihelminthic Drug, Praziquantel

In the North-east of Thailand, repeated antihelminthic therapy has been introduced for control of the opisthorchiasis known to be a major risk factor for cholangiocellular carcinomas. What influence this may have on tumorigenesis, however, remains unclear. The effects of administration of praziquantel, an antihelminthic drug, at different time points subsequent to infection with Opisthorchis viverrini (OV) on 2,2'-dihydroxy-di- n -propylnitrosamine (DHPN)-initiated lesion development in the liver of female Syrian hamsters were therefore investigated. Praziquantel (250 mg/kg body weight, i.p.) was given 4, 12 or 20 weeks after infection of DHPN-treated animals (two 1000 mg/kg i.p. injections at weeks 0 and 2) with 60 OV metacercariae (at week 4). Survivors at week 38 were killed and examined. It was found that whereas praziquantel administration at the earlier two time points was effective at reducing hepatocellular nodule development, the results for cholangiocellular lesions were less pronounced, significant reduction only being evident in hamsters treated 4 weeks after parasite infestation. The findings thus indicate that enhancement of DHPN-initiated bile duct carcinogenesis by opisthorchiasis is both rapid and to a large degree irreversible. Hepatocellular lesion development in this model, on the other hand, appears to correlate more closely with the duration of parasite-associated proliferative stimulus.     

Development of Androgen-independent Carcinomas from Androgen-dependent Preneoplastic Lesions in the Male Accessory Sex Organs of Rats Treated with 3,2'-Dimethyl-4-aminobiphenyl and Testosterone Propionate

Two kinds of cancer can be induced in rat male accessory sex organs, one a non-invasive carcinoma arising in the ventral lobe and the other an invasive lesion which develops in the dorsolateral and anterior lobe as well as the seminal vesicles. In the present study, one group of male rats were given biweekly s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) for 20 weeks for induction of non-invasive carcinomas and the other group received DMAB with 40-week testosterone propionate for induction of invasive carcinomas. Half of the animals in each group were then subjected to bilateral orchiectomy at week 41 to remove testicular androgen, in order to examine the androgen dependence of both types of carcinomas as well as precancerous lesions. Animals were killed at weeks 41, 46 and 60. All parts of the prostate complex showed involution and significant weight reduction after castration, with a complete disappearance of atypical hyperplasias and carcinomas of the ventral prostate. However, in spite of suppression of development of atypical hyperplasias in the anterior prostate and seminal vesicles, the incidence of invasive carcinomas was not changed. Normal epithelial cells and atypical hyperplasias of all parts of the prostate and seminal vesicles and carcinomas of the ventral prostate were immunohistochemically positive for nuclear androgen receptor, while invasive carcinomas that developed in either castrated or non-castrated animals were negative. These findings suggest that in the ventral prostate, both precancerous and cancerous lesions are androgen-dependent, but in the anterior and seminal vesicles, cancerous lesions (invasive carcinomas) are androgen-independent while precancerous lesions are hormone-dependent.     

Selective Induction of Prostate Carcinomas in F344 Rats Treated with Intraperitoneal Injections of N-Hydroxy-3,2'-dimethyl-4-aminobiphenyl

Groups of F344 and Wistar rats were given an intraperitoneal injection of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl (N-OH-DMAB) at a dose of 5 mg/kg body weight with a 1-week dietary pretreatment with ethinyl estradiol (EE), and this regimen was repeated 10 times at one-week intervals. Additional groups were given N-OH-DMAB 10 times without the dietary EE pretreatment. The total experimental period was 60 weeks. Carcinomas and atypical hyperplasias of the prostate developed in 8 (42%) and 16 (84%) of 19 F344 rats without the dietary EE treatment and in 1 (6%) and 7 (39%) of 18 rats with the EE diet, respectively. No prostatic tumors were found in Wistar rats, although atypical hyperplasias were observed in 6 of 18 rats with and 4 of 8 rats without the EE supplementation. Tumor yields in other organs were extremely low, resulting in good survival of the animals. A comparison of the results with those obtained for DMAB suggests that intraperitoneal administration of N-OH-DMAB in F344 provides a better induction method for models of prostate carcinogenesis.     

Dose Dependence of 1-O-Hexyl-2,3,5-trimethylhydroquinone Promotion of Forestomach Carcinogenesis in Rats Pretreated with N-Ethylnitrosourethane

Post-initiation dose-dependent effects of the chemopreventive antioxidant 1- O -hexyl-2,3,5-trimethylhydroquinone (HTHQ), a potent inhibitor of heterocyclic amine-induced mutagenesis and carcinogenesis, on the development of forestomach and tongue tumors were investigated in male F344 rats. Groups of 22 rats were treated with 0.01% ethylnitrosourethane (ENUR) as an initiator in the drinking water for 4 weeks, then placed on diet containing 1.0%, 0.5%, 0.25% or 0.125% HTHQ, or basal diet alone for 36 weeks. Further groups of 12 rats each were similarly treated with the different doses of HTHQ or given basal diet alone for 36 weeks without prior ENUR treatment. All animals were killed at week 40. Tongue papillary hyperplasia and papillomas tended to be increased in the groups treated with ENUR followed by 0.5–0.125% HTHQ, though there was no effect at the highest dose, in line with increased bromodeoxyuridine labeling indices. In the forestomach, the incidences of papillomas and carcinomas were also significantly elevated only in the group treated with ENUR followed by 0.125% HTHQ. Without ENUR pretreatment, papillary hyperplasia was found in the 1–0.125% HTHQ groups and the labeling index was also increased, though without clear dose dependence. The results indicate that HTHQ may have very weak or weak promotion potential for tongue and forestomach carcinogenesis, but that both minimum and maximum thresholds for active dose levels may exist.