Pathology and genetics of tumours of the urinary system and male genital organs

Context More than a quarter of the human population is likely infected with soil-transmitted helminths (Ascaris lumbricoides, hookworm, and Trichuris trichiura) in highly endemic areas. Preventive chemotherapy is the mainstay of control, but only 4 drugs are available: albendazole, mebendazole, levamisole, and pyrantel pamoate. Objective To assess the efficacy of single-dose oral albendazole, mebendazole, levamisole, and pyrantel pamoate against A lumbricoides, hookworm, and T trichiura infections. Data Sources A systematic search of PubMed, ISI Web of Science, ScienceDirect, the World Health Organization library database, and the Cochrane Central Register of Controlled Trials (1960 to August 2007). Study Selection From 168 studies, 20 randomized controlled trials were included. Data Extraction and Data Synthesis Information on study year and country, sample size, age of study population, mean infection intensity before treatment, diagnostic method used, time between evaluations before and after treatment, cure rate (the percentage of individuals who became helminth egg negative following treatment with an anthelminthic drug), egg reduction rate, adverse events, and trial quality was extracted. Relative risk, including a 95% confidence interval (CI), was used to measure the effect of the drugs on the risk of infection prevalence with a random-effects model. Results Single-dose oral albendazole, mebendazole, and pyrantel pamoate for infection with A lumbricoides resulted in cure rates of 88% (95% CI, 79%-93%; 557 patients), 95% (95% CI, 91%-97%; 309 patients), and 88% (95% CI, 79%-93%; 131 patients), respectively. Cure rates for infection with T trichiura following treatment with single-dose oral albendazole and mebendazole were 28% (95% CI, 13%-39%; 735 patients) and 36% (95% CI, 16%-51%; 685 patients), respectively. The efficacy of single-dose oral albendazole, mebendazole, and pyrantel pamoate against hookworm infections was 72% (95% CI, 59%-81%; 742 patients), 15% (95% CI, 1%-27%; 853 patients), and 31% (95% CI, 19%-42%; 152 patients), respectively. No pooled relative risks could be calculated for pyrantel pamoate against T trichiura and levamisole for any of the parasites investigated. Conclusions Single-dose oral albendazole, mebendazole, and pyrantel pamoate show high cure rates against A lumbricoides. For hookworm infection, albendazole was more efficacious than mebendazole and pyrantel pamoate. Treatment of T trichiura with single oral doses of current anthelminthics is unsatisfactory. New anthelminthics are urgently needed.

https://jamanetwork.com/journals/jama/articlepdf/181819/jrv80005_1937_1948.pdf

Efficacy of Current Drugs Against Soil-Transmitted Helminth Infections: Systematic Review and Meta-analysis

Carcinoma of the urinary bladder is the most common malignancy in the Middle East and parts of Africa where schistosomiasis is a widespread problem. Much evidence supports the association between schistosomiasis and bladder cancer: this includes the geographical correlation between the two conditions, the distinctive patterns of gender and age at diagnosis, the clinicopathological identity of schistosome-associated bladder cancer, and extensive evidence in experimentally infected animals. Multiple factors have been suggested as causative agents in schistosome-associated bladder carcinogenesis. Of these, N-nitroso compounds appear to be of particular importance since they were found at high levels in the urine of patients with schistosomiasis-associated bladder cancer. Various strains of bacteria that can mediate nitrosation reactions leading to the formation of N-nitrosamines have been identified in the urine of subjects with schistosomiasis at higher intensities of infection than in normal subjects. In experimental schistosomiasis, the activities of carcinogen-metabolizing enzymes are increased soon after infection but are reduced again during the later chronic stages of the disease. Not only could this prolong the period of exposure to activated N-nitrosamines, but also inflammatory cells, sitmulated as a result of the infection, may induce the endogenous synthesis of N-nitrosamines as well as generating oxygen radicals. Higher than normal levels of host cell DNA damage are therefore anticipated, and they have indeed been observed in the case of alkylation damage, together with an inefficiency in the capacity of relevant enzymes to repair this damaged DNA. In experimental schistosomiasis, it was also found that endogenous levels of host cell DNA damage were related to the intensity of infection. All of these factors could contribute to an increased risk of bladder cancer in patients with schistosomiasis, and in particular, the gene changes observed may have potential for use as biomarkers in the early detection of bladder cancer that may assist in alleviating the problem.

Relationship between Schistosomiasis and Bladder Cancer

Blastocystis hominis is a unicellular organism found commonly in the intestinal tract of humans and many other animals. Very little is known of the basic biology of the organism, and controversy surrounds its taxonomy and pathogenicity. There morphological forms (vacuolar, granular, and ameboid) have been recognized, but recent studies have revealed several additional forms (cyst, avacuolar, and multivacuolar). The biochemistry of the organism has not been studied to any extent, and organelles and structures of unknown function and composition are present in the cells. Several life cycles have been proposed but not experimentally validated. The form used for transmission has not been defined. Infections with the organism are worldwide and appear in both immunocompetent and immunodeficient individuals. Symptoms generally attributed to B. hominis infection are nonspecific, and the need for treatment is debated. If treatment appears warranted, metronidazole is suggested as the drug of choice, although failures of this drug in eradicating the organism have been reported. Infection is diagnosed by light microscopic examination of stained smears or wet mounts of fecal material. Most laboratories identify B. hominis by observing the vacuolar form, although morphological studies indicate that other forms, such as the cyst form and multivacuolar form, also should be sought for diagnosis.

Blastocystis hominis revisited.

Background: The three major soil-transmitted helminths (STH) Ascaris lumbricoides, Trichuris trichiura andNecator americanus/Ancylostoma duodenale are among the most widespread parasites worldwide. Despite the global expansion of preventive anthelmintic treatment, standard operating procedures to monitor anthelmintic drug efficacy are lacking. The objective of this study, therefore, was to define the efficacy of a single 400 milligram dose of albendazole (ALB) against these three STH using a standardized protocol.
Methodology/Principal Findings : Seven trials were undertaken among school children in Brazil, Cameroon, Cambodia, Ethiopia, India, Tanzania and Vietnam. Efficacy was assessed by the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR) using the McMaster egg counting technique to determine fecal egg counts (FEC). Overall, the highest CRs were observed for A. lumbricoides (98.2%) followed by hookworms (87.8%) and T. trichiura (46.6%). There was considerable variation in the CR for the three parasites across trials (country), by age or the pre-intervention FEC (pre-treatment). The latter is probably the most important as it had a considerable effect on the CR of all three STH. Therapeutic efficacies, as reflected by the FECRs, were very high for A. lumbricoides (99.5%) and hookworms (94.8%) but significantly lower for T. trichiura (50.8%), and were affected to different extents among the 3 species by the pre-intervention FEC counts and trial (country), but not by sex or age.
Conclusions/Significance: Our findings suggest that a FECR (based on arithmetic means) of >95% for A. lumbricoidesand >90% for hookworms should be the expected minimum in all future surveys, and that therapeutic efficacy below this level following a single dose of ALB should be viewed with concern in light of potential drug resistance. A standard threshold for efficacy against T. trichiura has yet to be established, as a single-dose of ALB is unlikely to be satisfactory for this parasite.

/pdf/assessment-of-the-anthelmintic-efficacy-of-albendazole-in-4f4jznxreb.pdf

Assessment of the anthelmintic efficacy of albendazole in school children in seven countries where soil-transmitted helminths are endemic.

200 Egyptian boys and men with urinary schistosomiasis were studied by clinical evaluation, radiography, quantitative egg excretion, bacterial cultures, and tests of renal function. Results were analysed by age, by symptoms (clinical grade), by presence of polypoid vs calcified schistosomal lesions (radiological stage), by presence or absence of obstructive uropathy, and by response to antischistosomal treatment. Age—Increasing age correlated slightly with decreasing egg excretion. Obstructive uropathy, bladder calcification, ureterolithiasis, and bladder retention increased linearly with age; polypoid lesions decreased linearly with age. Clinical grade—Age increased with increasing symptoms. Symptomatic patients excreted more eggs than those without symptoms. Non-functioning kidney was associated only with moderate or severe symptoms; other variables did not correlate with the grades. Radiological stage—Age increased from stage 1 (polypoid lesions only) to stage 2 (polypoid and calcified lesions) to stage 3 (calcified lesions only), as egg excretion decreased. Other variables were not different among the stages. Obstructive uropathy—Patients with obstruction were older than those without, and had higher frequencies of ureteral stenosis, ureterolithiasis, and bladder retention. Maximal urine concentration and phenolsulphonphthalein excretion were decreased in patients with obstruction. Treatment—Patients with improved urograms (including obstructive uropathy) following treatment were younger, excreted more eggs, and more frequently were in radiological stages 1 and 2 than patients without improvement. Improvement did not correlate with specific antischistosomal drugs or with the final percent reduction of egg excretion. These results suggest that the course of urinary schistosomiasis may be from polypoid to calcified lesions (radiological stage 1 to 3), associated with increasing age and decreasing egg excretion. However, clinical grade, bacterial urinary-tract infection, obstructive uropathy, and abnormalities of renal function are not stage-dependent. Although older age is associated with greater severity of symptoms and increasingly frequent radiographic abnormalities, appreciable morbidity occurs at all ages and in all stages of the disease in Egyptians in hospital. Prediction of reversibility of schistosomal uropathy can be made on the basis of age, egg excretion, and radiological stage.

Urinary schistosomiasis in Egypt: Clinical, radiological, bacteriological and parasitological correlations

Treatment of chronic urinary salmonella carriers with chloramphenicol at a dosage of 50 mg. per kg. body weight for 14 days was unsuccessful in 15 patients. All began to excrete salmonella again soon after completing treatment. All had active urinary schistosomiasis. A second group of 14 patients were treated with antimony tartrate or niridazole at a standard dose and 4 weeks of ampicillin at a dosage of 100 mg. per kg. body weight per day. 5 of these 14 patients relapsed but intravenous pyelography revealed that 3 of these 5 patients had advanced irreparably damaged urinary tracts and micturating cystograms showed that the other 2 had an established vesico-ureteric reflux. Though all 26 patients had a urinary carrier history of 12 months before treatment, all had positive blood cultures for the same organisms. It is suggested that chronic urinary salmonella carriers in Egypt be thoroughly examined and those with damaged urinary tracts due to schistosomiasis be given the benefit of anti-schistosomal treatment. Further studies are necessary to determine the exact place of prolonged chloramphenicol or ampicillin given alone or with anti-schistosomal treatment in the management of these patients.

Treatment of chronic urinary salmonella carriers

Clinical improvement was rapid in all 13 patients with enteric fever and one with Brucella abortus infection treated with trimethoprim-sulphamethoxazole. There were no side-effects of the treatment and it was found easy to administer to toxic and delirious patients.

https://www.bmj.com/content/bmj/1/5742/230.1.full.pdf

Trimethoprim-sulphamethoxazole in enteric fevers.

During a 5-year period (1975–1980), 171 male patients aged eight to 58 years infected with Schistosoma mansoni have been treated with oxamniquine on an in-hospital basis. The patients comprised three clinical groups—uncomplicated S. mansoni infection, colonic polyposis due to S. mansoni, and hepatic decompensation due to S. mansoni—all with active infection. After treatment all patients were observed for 12 weeks then evaluated for cure. In the uncomplicated group 40 of 73 children (55%) and 39 of 45 adults (87%) were cured. In the polyps group 24 of 29 patients (83%) were cured and in the decompensated group all 24 patients were cured. The only side effect was a febrile reaction occurring in 65 patients (38%) 3–4 days after treatment was started. This 5 years' experience shows that oxamniquine results in a low cure rate in children but is effective in adults with uncomplicated S. mansoni. In patients with colonic polyposis oxamniquine is safe and well tolerated as initial therapy, particularly in the very ill, debilitated patient. Oxamniquine is clearly the drug of choice in patients with decompensated liver disease and active S. mansoni infection.

Treatment of schistosomiasis mansoni with oxamniquine--five years' experience.

. One hundred sixteen male patients with uncomplicated Schistosoma mansoni infection were randomized to treatment with oxamniquine (20 mg/kg a day for 3 days) or niridazole (15 mg/kg a day for 8 days) in an in-hospital study. Fifty-four patients were treated with oxamniquine; no serious drug side effects were noted. Twenty-six percent of children 16 years old and younger were cured, while 85% of adults were cured. Egg reduction was 89%. Sixty-two patients were treated with niridazole; four patients (one child and three adults) had serious side effects which necessitated discontinuing the drug. Seventy-one percent of children and 84% of adults were cured. Egg reduction was 84%. Minor clinical side effects occurred during therapy with both drugs (26% with oxamniquine, 48% with niridazole) but cleared after completion of therapy. Niridazole is the more effective drug for the child with uncomplicated Schistosomiasis mansoni, but oxamniquine is advised for the adult with this disease.

S. Bassily

Papers

Urinary schistosomiasis in Egypt: Clinical, radiological, bacteriological and parasitological correlations

Treatment of chronic urinary salmonella carriers

Trimethoprim-sulphamethoxazole in enteric fevers.

Treatment of schistosomiasis mansoni with oxamniquine--five years' experience.

Oxamniquine versus niridazole for treatment of uncomplicated Schistosoma mansoni infection.