The Potential Role of Immunotherapy in Wilms' Tumor: Opportunities and Challenges.

Wilms' tumor (WT) is the most common renal malignancy in children, accounting for more than 90% of all pediatric renal cancers. Although this tumor is generally responsive to treatment, relapses and deaths still occur in a significant proportion of patients. The genetic alterations commonly found in WT and also its unique histological features and the tumor microenvironment suggest that the immune system may play a crucial role in the disease's development and progression. The limitations of conventional therapies, including surgery, chemotherapy, and radiotherapy, in preventing recurrence in WT patients and their potential for exerting long-term side effects, necessitate the application of novel therapeutic strategies, like immunotherapy, in this disease. Immunotherapy is an emerging cancer treatment approach based on the concept of harnessing the patient's immune system to fight tumor cells. This approach has demonstrated promising results in various types of cancers due to its relatively high specificity, efficacy, and tolerability. However, the precise effects of immunotherapy in WT remain to be explored. For this purpose, this review highlights the potential implication of different immunotherapy approaches, like monoclonal antibodies, adoptive cell therapy, and immune checkpoint inhibitors, in patients with WT, with a particular emphasis on the tumor's genetic and histological features. Although much remains to be learned about the optimal use of immunotherapy for this disease, the available evidence suggests that immunotherapy has the potential to significantly improve outcomes for patients with WT. However, there is still a substantial need for conducting further studies, especially randomized controlled trials, to determine the most effective immunotherapy strategy for this tumor. Moreover, the potential beneficiary roles of the combination of immunotherapy and conventional treatments should be investigated in future research.

Exposure to pesticides and pediatric Wilms' tumor. A meta-analysis on pre-conception and pregnancy parental exposure with an IARC/WHO commentary.

BACKGROUND: There are hereditary types of nephroblastoma or Wilms' tumor associated with exposure of the germ cells of either parent to harmful environmental factors. Some studies have examined the exposure of compounds used pesticides and herbicides as a risk factor for Wilms' tumor. METHODS: A systematic review and meta-analysis were carried out on case-control studies to establish the potential link between exposure to these organic molecules and Wilms' tumor occurrence in children rigorously. We examined the monographs on some organo-phosphate insecticides and herbicides issued by the International Association for the Research on Cancer (IARC) under the auspices of the World Health Organization (WHO). PUBMED, SCOPUS, and Google Scholar studies (1960-2021) were identified and systematically reviewed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Subgroup analyses were conducted after stratification for occupational versus residential exposure and before birth (prenatal) vs. after birth (postnatal) exposure. In addition, we revised the monographs on chemical compounds issued recently by the IARC/WHO. RESULTS: Our findings seem to consolidate that parental pesticide exposure during the preconception or pregnancy period is correlated with an increased occurrence risk for Wilms' tumor. We confirm the validity of the WHO essays on certain organophosphate herbicides and insecticides, which support these compounds, may be highly relevant in future cancer prevention policies. CONCLUSION: Parental exposure to pesticides, particularly in household settings, is poorly emphasized in our society. There is a strong association between these organophosphate compounds and pediatric cancer. Public health agencies may need to take stronger action than in the past.

Recurrent vincristine-associated fever in a child with Wilms tumor.

BACKGROUND: Fever is a common complaint among children with an underlying oncologic diagnosis, especially during chemotherapy courses and periods of neutropenia. Chemotherapy-induced fever is well described in relation to specific chemotherapy agents. However, fever induced by vincristine (VCR) has only been rarely reported. CASE: We describe a case of a 5-year-old female with stage III Wilms tumor who had recurrent VCR-associated fever that was controlled with prophylactic dexamethasone and acetaminophen. CONCLUSION: In patients developing recurrent fever following chemotherapy with VCR, febrile allergic reaction and prophylactic treatment should be considered after exhaustion of appropriate investigations.

Bilateral Warthin tumor in psoriatic patients in therapy with multiple immunosuppressive therapy.

Anti-TNFα drugs have strongly changed the way in which we deal with moderate and severe psoriasis. However, it is debatable whether biological drugs could increase the risk of developing cancer. The correlation between anti-TNFα drugs and lymphomas is well-known and is reported in all the technical details of biologic drugs. However, the association between anti-TNFα agents and solid tumors is still controversial. The authors report a case of bilateral salivary gland tumor in a psoriatic patient treated with several immunosuppressive therapies including anti-TNFα inhibitors.

The effect of vitamin A deficiency in maternal rats on tumor formation in filial rats.

PURPOSE: We established a vitamin A-deficient (VAD) model of pregnant rats to evaluate the effect of vitamin A deficiency in maternal rats on tumor formation in filial rats. METHODS: Ten pregnant Wistar rats were divided into 2 groups: (1) VAD group, 6 rats were given nonvitamin A diet from 2 weeks before mating till delivery and (2) normal diet (ND) group, 4 rats were given normal diet. Twenty random neonatal rats from each group were killed on the next day of delivery. The rest neonates were given normal diet for 1 year until killed. Serum levels of vitamin A, morphology of the kidney, incidence of tumor formation, and retinoid X receptor (RXR) alpha messenger RNA (mRNA) expression in renal tissue were assessed for the filial rats. RESULTS: Fifty-six and 49 neonatal rats were born for VAD group and ND group, respectively. The detection rate of nephrogenic rests (NRs) from neonates in VAD group (50%) was significantly higher than that in ND group (20%; P < .05). The incidence of nephroblastoma was 13.9% in filial rats of VAD group and 0% for ND group. The detection rate of NRs for filial rats of VAD group (30.6%) was significantly higher than that of ND group (6.9%; P < .01). The expression of RXRalpha mRNA in tumor tissue of the filial rats of VAD group (3.17 +/- 0.15) was significantly lower than that in kidney tissue of ND group (3.58 +/- 0.20; P < .01). CONCLUSION: Deficiency in vitamin A for pregnant rats resulted in renal dysplasia, increased NRs, and higher incidence of nephroblastoma.

The enhancing role of vitamin A deficiency on chemically induced nephroblastoma in rats.

PURPOSE: Vitamin A plays an important role in the prevention of neoplasia. The occurrence of nephroblastoma, a common renal malignancy of childhood, is said to be closely correlated with retardation of differentiation of metanephric blastema. The aim of this study was to clarify the effect of vitamin A deficiency (VAD) in experimental nephroblastoma. METHODS: Sixty weaning outbred female Wistar rats weighing 40 to 50 g were injected with 0.35% dimethylhydrazine dihydrochloride (DMH) subcutaneously and divided into 2 groups. Animals were fed with diets containing vitamin A, normal diet (ND group; n = 30), and vitamin A-deficient diet (VAD group; n = 30). Serum concentrations of vitamin A on day 120 after DMH injection were assayed. The incidence of nephroblastomas in 2 groups was recorded. The renal tissues were prepared for morphological studies and WT1 messenger RNA (mRNA) detection on day 365 after DMH injection. RESULTS: The average serum concentrations of vitamin A in the ND group (2.60 +/- 0.53 mumol/L) were significantly higher than that in the VAD group (0.51 +/- 0.26 mumol/L, P < .05) 120 days after DMH injection. On day 365, the incidence of renal tumors in the VAD group (36.7%) was significantly higher than that of the ND group (13.3%, P < .05). Certain histological and ultrastructural features and WT1 mRNA expression patterns observed in these tumors showed that they had a resemblance to human nephroblastomas. Nephrogenic rests (NRs) could be seen in the adjacent normal renal parenchyma. The incidence of NRs in the VAD group (16.7%) was significantly higher than that in the ND group (3.3%, P < .05). The mutant WT1 mRNA expression levels in the VAD group (0.75 +/- 0.11) were significantly higher than those in the ND group (0.24 +/- 0.06, P < .05). CONCLUSIONS: Vitamin A deficiency can increase development of nephroblastomas in rats, probably via a mechanism of elevated NR remnants and WT1 expression.

Down-regulation of von Hippel-Lindau protein in N-nitroso compound-induced rat non-clear cell renal tumors.

Non-clear cell rat kidney tumors, inducible by N-nitroso compounds but lacking mutations in the von Hippel--Lindau (VHL) coding sequence, were examined for other VHL alterations. Neither mutations nor DNA methylation was detected in a putative promoter region. By immunohistochemistry, however, VHL protein level was evidently reduced in six of the eight eosinophilic renal epithelial tumors and in all the ten nephroblastomas. Immunoblotting of normal kidney detected two VHL proteins of 20 and 22kDa in a 16-day-old fetal rat but only 20kDa protein in an adult rat. This is the first demonstration of VHL alteration at the protein level.

Long-term outcome of acute renal injury induced by Aristolochia manshuriensis Kom in rats.

AIM: To investigate the long-term functional and morphological changes of the kidney induced by acute intoxication of Aristolochia manshuriensis Kom in rats. METHODS: Experimental model of acute renal injury was established in the Sprague-Dawley rats with oral administration of decoctions of Chinese herb, Aristolochia manshuriensis Kom, at dosages of 50 g.kg-1.d-1 and 30 g.kg-1.d-1 for 7 consecutive days, and 20 g.kg-1.d-1 for 15 consecutive days. Renal function was assayed at months 0 (right after treatment), 1, 3, and 6 of the experiment. Renal histological examination was also performed. RESULTS: 1) At month 0, the renal functional changes of acute renal injury included azotemia, low molecular weight proteinuria, glycosuria, hypoosmotic urine, and NAG enzymuria. Histopathological changes showed acute tubular necrosis, predominantly at the corticomedullary junction. 2) At months 1 and 3, the renal function of rats of the experiment was gradually restored and histopathologic examination suggested that the tubular lesions gradually recovered. In HE sections, basophilic deposits were observed in the tubular cytoplasm. And interstitial infiltration of inflammatory cells was not prominent. 3) At months 6, renal preneoplastic lesions, renal tumors, and extrarenal tumors occurred in rats. The occurrence of renal preneoplastic lesions at dosages of 50 g.kg-1.d-1, 30 g.kg-1.d-1, and 20 g.kg-1.d-1 were 100.0% at all three doses, renal tumors 42.8%, 25.0%, and 0%, respectively, extrarenal tumors 14.4%, 12.5%, and 12.5%, respectively, and systemic tumors 57.2%, 37.5%, and 12.5%, respectively. The occurrence of basophilic deposits, renal preneoplastic lesions, renal tumors, and extrarenal tumors in normal control group was nil. CONCLUSIONS: 1) Administration of large dosage of Aristolochia manshuriensis Kom induces acute renal failure in rats. 2) The long-term renal function and histopathologic changes of acute renal injury induced by Aristolochia manshuriensis Komrecover spontaneously. 3) Aristolochia manshuriensis Kom has been proved to be oncogenic for the first time.

Deficient expression of mRNA for the putative inductive factor bone morphogenetic protein-7 in chemically initiated rat nephroblastomas.

Wilms' tumor, or nephroblastoma, arises from metanephric blastema and caricatures renal organogenesis. An alteration in at least one of the genes involved in control of renal differentiation is therefore a likely event in tumorigenesis, and indeed some of the genes involved in renal development, for example, hepatocyte growth factor (HGF) and its receptor c-met, the transcription factor Wilms' tumor gene (WT1), and transforming growth factor-beta family member bone morphogenetic protein (BMP)-7, have also been implicated in various models of tumorigenesis. In a comparison of mRNA expression patterns for these genes in normal rat embryonic or fetal kidney and nephroblastoma, we found that the patterns for HGF, met, and WT1 detected by in situ hybridization or ribonuclease protection assay (RPA) in the nephroblastomas were similar to those of normal developing kidney. BMP-7 expression, on the other hand, was lower in most tumors examined both by in situ hybridization and RPA than in normal tissues. This deficiency in a defined inductive factor that has been shown to function in renal tubulogenesis may play a role in tumorigenesis by allowing the accumulation of blastemal populations typical of nephroblastomas.

Pesticides and childhood cancer.

Children are exposed to potentially carcinogenic pesticides from use in homes, schools, other buildings, lawns and gardens, through food and contaminated drinking water, from agricultural application drift, overspray, or off-gassing, and from carry-home exposure of parents occupationally exposed to pesticides. Parental exposure during the child's gestation or even preconception may also be important. Malignancies linked to pesticides in case reports or case-control studies include leukemia, neuroblastoma, Wilms' tumor, soft-tissue sarcoma, Ewing's sarcoma, non-Hodgkin's lymphoma, and cancers of the brain, colorectum, and testes. Although these studies have been limited by nonspecific pesticide exposure information, small numbers of exposed subjects, and the potential for case-response bias, it is noteworthy that many of the reported increased risks are of greater magnitude than those observed in studies of pesticide-exposed adults, suggesting that children may be particularly sensitive to the carcinogenic effects of pesticides. Future research should include improved exposure assessment, evaluation of risk by age at exposure, and investigation of possible genetic-environment interactions. There is potential to prevent at least some childhood cancer by reducing or eliminating pesticide exposure.

Parental occupational exposures and risk of childhood cancer.

Occupational exposures of parents might be related to cancer in their offspring. Forty-eight published studies on this topic have reported relative risks for over 1000 specific occupation/cancer combinations. Virtually all of the studies employed the case-control design. Occupations and exposures of fathers were investigated much more frequently than those of the mother. Information about parental occupations was derived through interviews or from birth certificates and other administrative records. Specific exposures were typically estimated by industrial hygienists or were self-reported. The studies have several limitations related to the quality of the exposure assessment, small numbers of exposed cases, multiple comparisons, and possible bias toward the reporting of positive results. Despite these limitations, they provide evidence that certain parental exposures may be harmful to children and deserve further study. The strongest evidence is for childhood leukemia and paternal exposure to solvents, paints, and employment in motor vehicle-related occupations; and childhood nervous system cancers and paternal exposure to paints. To more clearly evaluate the importance of these and other exposures in future investigations, we need improvements in four areas: a) more careful attention must be paid to maternal exposures; b) studies should employ more sophisticated exposure assessment techniques; c) careful attention must be paid to the postulated mechanism, timing, and route of exposure; and d) if postnatal exposures are evaluated, studies should provide evidence that the exposure is actually transferred from the workplace to the child's environment.

Polymerase chain reaction-single-strand conformation polymorphism analysis for the VHL gene in chemically induced kidney tumors of rats using intron-derived primers.

von Hippel-Lindau (VHL) gene mutations occur throughout three exons including the exon-intron boundaries in human VHL disease-associated and sporadic renal cell carcinomas. To explore the possible role of the VHL gene in chemically induced rat kidney tumors originating from various cell types, more than 150 bp of Fischer 344 and Noble rat VHL intron sequences flanking the three exons was determined by dideoxy sequencing. Five primer sets were selected for polymerase chain reaction amplification of the coding regions of rat VHL exons 1-3 and the exon-intron boundaries. Tissues from 10 renal eosinophilic epithelial tumors induced by N-nitrosoethyl(2-hydroxyethyl)amine, 10 nephroblastomas induced by N-nitroso-N-ethylurea, and seven renal mesenchymal tumors induced by N-nitrosomethyl(methoxymethyl)amine were examined for VHL mutations by polymerase chain reaction-single-strand conformation polymorphism analysis. No mutation was detected in any tumor type, indicating that VHL mutations are not involved in the pathogenesis of rat kidney tumors arising from the distal region of the renal tubules, the metanephric blastema, or stromal tissues of the cortex.

Use of dipyrone during pregnancy and risk of Wilms' tumor. Brazilian Wilms' Tumor Study Group.

We evaluated the risk of Wilms' tumor in the offspring of women taking various medications during pregnancy in a case, control study conducted in Brazil. The study accrued 109 cases and 218 age- and gender-matched hospital controls. After adjustment for known confounders, we found a strong association with ingestion of dipyrone (odds ratio = 10.9; 95% confidence interval = 2.4-50) particularly in women from low-income families. Although dipyrone-containing analgesics are banned in Europe and North America, they are widely prescribed in Brazil and are given as free samples in neighborhood clinics providing free health care. The strong effect specific to low-income women may result from higher individual consumption compared with women at higher income levels.

Effect of stage of development on frequency and pathogenesis of kidney tumors induced in Noble (Nb) rats exposed prenatally or neonatally to N-nitrosoethylurea.

Wilms' tumor of kidney, a common human childhood neoplasm, is modeled by nephroblastomas induced by prenatal exposure of some rodents to alkylating agents. Noble (Nb) rats are especially susceptible. We studied the ontogeny of susceptibility by treatment with N-nitrosoethylurea (NEU) on gestation day 10, 12, 14, 16 or 18 or neonatal day 1, 3, 5, 7, or 10. No nephroblastomas were observed in offspring exposed to NEU on day 10 or 12 of gestation. In contrast, nephroblastomas commonly occurred in rats exposed on gestation day 14, 16 or 18 of gestation, with the highest incidence (48%) after treatment on day 18. Nephroblastomas were rare ( < 10%), but renal mesenchymal tumors were common (25-30%) in rats exposed to NEU on day 1 or 3 after birth. In rats exposed to NEU on day 7 or 10 only renal mesenchymal tumors were seen. Thus our results suggest that the stage of differentiation of fetal and neonatal kidneys at the time of NEU administration determines the frequency and type of kidney tumors induced in Nb rats. Since NEU induces both nephroblastomas and mesenchymal tumors in this strain, this experimental model may prove useful for the study of molecular mechanisms involved in the development of these two histogenetically different types of kidney tumors.

A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea.

Embryonal kidney cell tumors develop in rats given the alkylating agent N-nitroso-N'-methylurea as neonates. These tumors resemble the childhood Wilms tumors in their histopathology. Deletions and mutations in the Wilms tumor suppressor gene, WT1, are present in up to 6% of childhood nephroblastomas. To investigate the role of WT1 in rat kidney tumorigenesis, we studied the genetic alterations in WT1 and its target genes. Point mutations were found in WT1 cDNA in 7 of 18 kidney tumors. Mesenchymal tumors contained G-->A transition mutations in codons 128, 364, and 372, typical of the methylating action of N-nitroso-N'-methylurea on DNA. Each of the four nephroblastomas contained the same T-->A mutation at codon 111 of WT1, reflective of transversion mutagenesis by N-nitroso-N'-methylurea in vivo. Like Wilms tumors, mRNA levels of WT1, IGF2, Pax-2, and MK genes were higher than newborn kidney in the majority of the tumors. The histopathology of the rat kidney tumors and the genetic alterations are reminiscent of those observed in Wilms tumors, establishing this as a relevant model system for the human disease.

Promoting effects of ethinyl estradiol on development of renal proliferative lesions induced by N-nitrosobis (2-oxopropyl)amine in female Syrian golden hamsters.

The modulating effects of female sex hormones, ethinylestradiol and levonorgestrel, on the development of renal proliferative lesions after initiation with N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Three groups of female Syrian golden hamsters, each comprising 30 animals, were given four weekly s.c. injections of BOP (10 mg/kg body weight) and then fed diet containing 1 ppm ethinylestradiol (group 1: BOP/EE), diet containing 10 ppm levonorgestrel (group 2) or basal diet (group 3) for the next 27 weeks. As hormone controls, two groups of 20 female hamsters each received diet containing 1 ppm ethynylestradiol (group 4) and 10 ppm levonorgestrel (group 5) from week 3 for 27 weeks without the prior initiation treatment. The severity of diffuse anisokarya, characterized by varied nuclear size and the incidence of dysplasias of the proximal tubular epithelia induced by BOP, were significantly increased in the BOP/EE group, indicating the promoting effects of the hormone. In the renal dysplastic lesions (small-cluster, cystic, clear-cell and acidophilic cell types), adenomas and nephroblastomas, increases in the numbers of argyrophilic proteins associated with nucleolar organizer regions (NOR) in the nucleus, suggesting a high proliferative activity, were seen in dysplasia of acidophilic cell types and adenomas. In addition, the number of bizarre NOR per nucleus was significantly higher in adenomas than in dysplasias and highest in nephroblastomas. This morphological change in NOR should therefore be a useful parameter for the diagnosis of malignancy of renal tumors.

Tumors produced in rats with a single dosage of 1,2-dimethylhydrazine.

To evaluate possible nephroblastoma induction in young Sprague-Dawley male rats by 1,2-dimethylhydrazine (DMH), agents including inhibitors and stimulators of the carcinogenesis were tested concurrently in 2 experiments. In series A, rats, 27 days of age, were fed the following as supplements in a basal diet at the final wt% given: hydralazine (0.035%), disulfiram (250 ppm), ferrous sulfate heptahydrate (0.55%; 0.11 g% Fe), isotretinoin (240 ppm), dehydroepiandrosterone (0.30%) in addition to selenium (2 ppm; drinker). At day 15, DMH was injected s.c. at 108 mg base/kg; duration on the diets: 51 weeks. Series B comprised 33 day-old males which were partially hepatectomized (control and indomethacin at 10 mg/l by drinker) or bilaterally gonadectomized for comparison vs sham-operated, and intact groups on s.c. injection of estradiol benzoate (15 micrograms/kg), progesterone (30 mg/kg) and diallyl sulfide (100 mg/kg), the respective controls receiving the peanut oil vehicle. Treatments were begun 8 days post-operative and 17 days later, the single dosage of DMH as in the above was injected. The oil solutions were administered at the specified weekly levels for a total of 52 injections, 2 doses being introduced per week for the 1st 3 weeks. Colon adenocarcinomas comprised the main tumors and occurred in about 15-50% of the rats with total frequencies in the respective control ranges except for decrements with the disulfiram- and iron-fed groups. Renal changes were more involved with series B and nephroblastomas of the left kidney occurred in one animal each of the estradiol benzoate- and diallyl sulfide-injected groups. Of interest, bilateral nephroblastomas were present in one of the saline-injected controls which was gonadectomized. Under the conditions explored, concurrent treatment with DMH inhibitors or synergists had a minimal effect on nephroblastoma induction.

Characterization of experimental rat nephroblastoma and its cell line.

Rat nephroblastoma (Wilms' tumor) was induced by transplacental administration of N-ethyl-nitrosourea (ENU). The induced renal tumors were histologically compatible with human nephroblastoma. A cultured cell line (ENU-T-1) established from a xenotransplant, showed similar morphological and biological features to cultured embryonal kidney cells. Introduction of normal human chromosome #11 (#11) bearing Wilms' tumor suppressor gene(s) (WT) suppressed colony-forming ability on soft agar plates (CFA) but tumorigenicity of ENU-T-1 was not affected. Whereas tumorigenicity of human nephroblastoma cell line, SK-NEP-1 was completely suppressed, CFA was unchanged. These facts indicated that pathogenetic mechanism is different between human and experimental rat nephroblastomas.

Selective mutation of codons 204 and 213 of the p53 gene in rat tumors induced by alkylating N-nitroso compounds.

Kidney and esophageal tumors induced by alkylating N-nitroso compounds in rats contain a high incidence (75-100%) of G----A transition mutations in the p53 gene. These are almost selectively (89%) located in the first base of codon 204 and the second base of 213, leading to amino acid substitutions Glu----Lys and Arg----Gln, respectively. In contrast to human neoplasms, a considerable fraction of rat kidney and esophageal tumors carries multiple p53 mutations. All nephroblastomas induced by transplacental exposure to N-nitrosoethylurea and 56% of esophageal tumors induced by N-nitrosomethylurea showed double mutations in codons 204 and 213 of exon 6. The selective targeting of p53 codons by alkylating nitrosamines may provide a basis for molecular epidemiological studies on this class of chemical carcinogens.