Significance of Wilms' tumor 1 antigen as a cancer vaccine for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a very poor prognosis, despite novel chemotherapeutic treatments. Moreover, the majority of PDA patients with complete surgical resection show recurrence within 5 years of resection. Therefore, new targeted cancer vaccines are urgently needed to extend PDA patient survival. The Wilms' tumor 1 (WT1) antigen was identified as an excellent antigen in a list of 75 tumor-associated antigens by a National Cancer Institute prioritization project based on several factors, such as therapeutic function. WT1-targeted cancer vaccines are not only efficient in the regression of PDA cells but also angiogenesis and immune suppressive cells, such as myeloid-derived suppressor cells (MDSCs), in the PDA microenvironment. Moreover, WT1 is increased in PDA cells; thus, WT1 may represent an effective therapeutic target for PDA, resulting in a survival benefit for PDA patients. A novel WT1 peptide with increased immunogenicity was developed and used in clinical trials to induce more successful clinical results. This review summarizes the clinical trials of PDA patients receiving WT1-targeted cancer vaccines.

Respiratory-gated bilateral pulmonary radiotherapy for Ewing's sarcoma and nephroblastoma in children and young adults: Dosimetric and clinical feasibility studies.

PURPOSE: Bilateral pulmonary radiotherapy in children and young adults aims to reduce the recurrence of lung metastases. The radiation field includes liver tissue, which is sensitive to even low radiation doses. We investigated the feasibility of respiratory gating radiotherapy using voluntary deep inspiration breath hold and its toxicity in these patients. PATIENTS AND METHOD: A retrospective clinical review was conducted for all patients who had undergone bilateral pulmonary radiotherapy, with or without deep inspiration breath hold, treated in our institution between October 1999 and May 2012. A dosimetric study was conducted on seven consecutive children using 4D-scan data on free-breathing and a SpiroDyn'RX-system-scan on deep inspiration breath hold. A radiation treatment of 20Gy was simulated. RESULTS: Concerning the clinical study, seven patients of mean age 11.9 years (range: 4.9-21.1 years) were treated with free-breathing and ten patients of mean age 15.6 years (range: 8.6-19.7 years) were treated with deep inspiration breath hold for mainly Ewing sarcoma and nephroblastoma. Within six months of radiotherapy, all patients experienced mild liver toxicity (grade 1 or 2 altered levels of alanine/aspartate aminotransferase [n=8 of 9] or cholestasis [n=1 of 9]), which resolved completely with no difference between deep inspiration breath hold and free-breathing technique. Over a median follow-up of 2.6 years (range: 0.1-9.3 years), four patients died from disease progression (mean 1.5 years post-radiotherapy [range: 1.1-1.6 years]) and three experienced grade III-V lung toxicity. Concerning the dosimetric study, the irradiated liver volume was significantly lower with deep inspiration breath hold than free-breathing, for each isodose (V5: 73.80% versus 86.74%, P<0.05; V20: 5.70% versus 26.44%, P<0.05). CONCLUSIONS: The dosimetric data of respiratory-gated bilateral pulmonary radiotherapy showed a significantly spare of normal liver tissue. Clinical data showed that this technique is feasible even in young children. However, no liver toxicity difference between deep inspiration breath hold and free-breathing was shown.

La oncología pediátrica: pasado, presente y futuro / Paediatric oncology: Past, present and future

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Silencing of hypoxia inducible factor-1α by RNA interference inhibits growth of SK-NEP-1 Wilms tumour cells in vitro, and suppresses tumourigenesis and angiogenesis in vivo.

Wilms tumour is the most common tumour of the pediatric kidney. Elevation of hypoxia-inducible factor 1α (HIF-1α) has been detected in 93% to 100% of human Wilms tumour specimens, suggesting a potential value of HIF-1α as a therapeutic target for Wilms tumour. In the present study, a stable HIF-1α-silenced Wilms tumour cell strain was established by introducing HIF-1α short-hairpin RNA (shRNA) into SK-NEP-1 cells. Silencing of HIF-1α significantly reduced single-cell growth capacity, suppressed proliferation and arrested cell cycle of SK-NEP-1 cells. In addition, reduction of HIF-1α expression induced apoptosis in SK-NEP-1 cells, which was accompanied by increased levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP) and Bax as well as downregulation of Bcl-2 in the cells. Furthermore, when inoculated subcutaneously in nude mice, HIF-1α-silenced SK-NEP-1 cells displayed retarded tumour growth and impaired tumour angiogenesis. In summary, the findings of this study suggest that HIF-1α plays a critical role in the development of Wilms tumour, and it may serve as a candidate target of gene therapy for Wilms tumour.

Genetic variation frequencies in Wilms' tumor: A meta-analysis and systematic review.

Over the last few decades, numerous biomarkers in Wilms' tumor have been confirmed and shown variations in prevalence. Most of these studies were based on small sample sizes. We carried out a meta-analysis of the research published from 1992 to 2015 to obtain more precise and comprehensive outcomes for genetic tests. In the present study, 70 out of 5175 published reports were eligible for the meta-analysis, which was carried out using Stata 12.0 software. Pooled prevalence for gene mutations WT1, WTX, CTNNB1, TP53, MYCN, DROSHA, and DGCR8 was 0.141 (0.104, 0.178), 0.147 (0.110, 0.184), 0.140 (0.100, 0.190), 0.410 (0.214, 0.605), 0.071 (0.041, 0.100), 0.082 (0.048, 0.116), and 0.036 (0.026, 0.046), respectively. Pooled prevalence of loss of heterozygosity at 1p, 11p, 11q, 16q, and 22q was 0.109 (0.084, 0.133), 0.334 (0.295, 0.373), 0.199 (0.146, 0.252), 0.151 (0.129, 0.172), and 0.148 (0.108, 0.189), respectively. Pooled prevalence of 1q and chromosome 12 gain was 0.218 (0.161, 0.275) and 0.273 (0.195, 0.350), respectively. The limited prevalence of currently known genetic alterations in Wilms' tumors indicates that significant drivers of initiation and progression remain to be discovered. Subgroup analyses indicated that ethnicity may be one of the sources of heterogeneity. However, in meta-regression analyses, no study-level characteristics of indicators were found to be significant. In addition, the findings of our sensitivity analysis and possible publication bias remind us to interpret results with caution.

Nephrogenic remnants: occasional ultrasound diagnosis and follow-up.

Nephrogenic remnants (NRs) are nodular collections of undifferentiated renal blastema cells in the postnatal kidney that are recognized as putative precursor lesions of Wilms tumor (WT). NRs may remain stationary, undergo regression, or proliferate. In the last case, there is a high risk for the development of a WT. During infancy, they are most frequently of microscopic size, to be found only at autopsy in approximately 1% of infant kidneys. Approximately 1 out of 100 microscopic lesions persist and grow developing lesions large enough to be seen by ultrasound in the first months of life. We report on a case of NRs in a six year old child, as incidental finding during abdominal ultrasound performed for other purposes. In consideration of the potential evolution in WT, after a period of close surveillance of 14 months, the lesion was resected. Histological examination revealed the presence of NRs, no neoplastic lesions were found. Currently the patient is 16 years old, in good health, and there have been no signs of recurrence.

Is there a role for FDG-PET for the assessment of treatment efficacy in Wilms' tumor? A case report and literature review.

BACKGROUND: The role of FDG-PET in Wilms' tumor has not been well established. The aim of this report is to describe the role of FDG-PET to assess chemotherapy efficacy and to show potential correlations between different Standardized Uptake Values (SUVs) and histopathological features in a patient with persisting metastatic disease. CASE DESCRIPTION: A 3-year-old boy was diagnosed with Wilms' tumor without anaplasia. The patient underwent treatment as according to the AIEOP-TW-2003 protocol, for stage III tumors. Therapy was discontinued with no evidence of disease, yet 9 months later thorax metastases were found. Although second and third line treatments were administered, conventional imaging demonstrated stable disease. Metronomic chemotherapy as well was employed for 44 months and FDG-PET was annually performed basing on responsible local physician choice trying to better describe the disease status. Four months after fourth line treatment was stopped, the patient manifested clinical symptoms; lesions began to increase their metabolic activity inhomogeneously. Therapy was hence restarted and SUVs decreased. Metastasectomies were then performed and histology revealed a correlation between viable disease shown by higher FDG-PET uptake and viable tumor areas. CONCLUSIONS: Our case discussion demonstrates that FDG-PET is potentially valuable in Wilms' tumor correlating SUV values and histological features of the tumor after chemotherapy. This case suggests that FDG-PET is a valid tool to assess chemotherapy response in relapsed Wilms' tumor even in case of no evidence of significant dimensional changes under conventional imaging.

Enhanced tumor immunity of WT1 peptide vaccination by interferon-ß administration.

To induce and activate tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs) for cancer immunity, it is important not only to select potent CTL epitopes but also to combine them with appropriate immunopotentiating agents. Here we investigated whether tumor immunity induced by WT1 peptide vaccination could be enhanced by IFN-ß. For the experimental group, C57BL/6 mice were twice pre-treated with WT1 peptide vaccine, implanted with WT1-expressing C1498 cells, and treated four times with WT1 peptide vaccine at one-week intervals. During the vaccination period, IFN-ß was injected three times a week. Mice in control groups were treated with WT1 peptide alone, IFN-ß alone, or PBS alone. The mice in the experimental group rejected tumor cells and survived significantly longer than mice in the control groups. The overall survival on day 75 was 40% for the mice treated with WT1 peptide+IFN-ß, while it was 7, 7, and 0% for those treated with WT1 peptide alone, IFN-ß alone or PBS alone, respectively. Induction of WT1-specific CTLs and enhancement of NK activity were detected in splenocytes from mice in the experimental group. Furthermore, administration of IFN-ß enhanced expression of MHC class I molecules on the implanted tumor cells. In conclusion, our results showed that co-administration of WT1 peptide+IFN-ß enhanced tumor immunity mainly through the induction of WT1-specific CTLs, enhancement of NK activity, and promotion of MHC class I expression on the tumor cells. WT1 peptide vaccination combined with IFN-ß administration can thus be expected to enhance the clinical efficacy of WT1 immunotherapy.

Pediatric cancer rates after universal folic acid flour fortification in Ontario.

Following the introduction of mandatory Canadian folic acid flour fortification in mid-1997, the incidence of selected childhood cancers that declined in Ontario prior to and subsequent to this public policy initiative was examined. A population-based cohort study of all incident cases of childhood malignancy in Ontario between the years 1985 and 2006 was conducted. Participants were identified from a database provided by the Pediatric Oncology Group of Ontario and included children 0 to 4 years of age and 5 to 9 years of age who were diagnosed with cancer. Among children aged 0 to 4 years, the incidence rate of Wilms' tumor declined from 1.94 to 1.43 per 100,000 (incidence rate ratio 0.74, 95% confidence interval, 0.57-0.95). No significant change was seen in the prefortification vs postfortification time periods for acute lymphoblastic leukemia, brain cancers, or embryonal cancers among the 0- to 4-year or 5- to 9-year age groups. There was an approximately 30% reduction in risk of Wilms' tumor following introduction of the initiative. This corroborates a recent case-control study from Germany. These data may also provide some reassurance that universal flour fortification does not heighten the risk of pediatric cancer.

Loss of 11q and 16q in Wilms tumors is associated with anaplasia, tumor recurrence, and poor prognosis.

Allele loss of chromosome arms 11q and 16q in Wilms tumors has been associated with different clinical parameters in prior studies. To substantiate these findings in a large collection of tumors treated according to the GPOH/SIOP protocol and to narrow down critical regions, we performed loss of heterozygosity (LOH) analyses of chromosome arms 11q and 16q on 225 Wilms tumors. On chromosome arm 11q an overall rate of allele loss of 19.6% (44 of 225 tumors) was found using eleven markers that were almost evenly distributed along the long arm. Chromosome arm 16q was analyzed with six markers selected from gene-rich regions that identified an LOH rate of 18.4% (41/223). Evaluation of LOH with respect to clinical data revealed significant associations of LOH 11q with histology: LOH 11q was 3-4 times more frequent in mixed type and diffuse anaplastic tumors. In contrast, epithelial as well as stromal type tumors never exhibited allele loss on 11q. Furthermore, a significant correlation with tumor recurrence and death was detected, but only for tumors that lost the entire long arm of chromosome 11. Similarly, LOH 16q was correlated with higher risks of later relapse, especially in tumors with complete loss of the long arm. Hence, analyses of LOH on 11q and 16q appear to be helpful to identify tumors with a higher risk of relapse and adverse outcome, which need adjusted therapeutic approaches.

Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice.

BACKGROUND: Most Wilms tumours occur in otherwise healthy children, but a small proportion occur in children with genetic syndromes associated with increased risks of Wilms tumour. Surveillance for Wilms tumour has become widespread, despite a lack of clarity about which children are at increased risk of these tumours and limited evidence of the efficacy of screening or guidance as to how screening should be implemented. METHODS: The available literature was reviewed. RESULTS: The potential risks and benefits of Wilms tumour surveillance are finely balanced and there is no clear evidence that screening reduces mortality or morbidity. Prospective evidence-based data on the efficacy of Wilms tumour screening would be difficult and costly to generate and are unlikely to become available in the foreseeable future. CONCLUSIONS: The following pragmatic recommendations have been formulated for Wilms tumour surveillance in children at risk, based on our review: (1) Surveillance should be offered to children at >5% risk of Wilms tumour. (2) Surveillance should only be offered after review by a clinical geneticist. (3) Surveillance should be carried out by renal ultrasonography every 3-4 months. (4) Surveillance should continue until 5 years of age in all conditions except Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and some familial Wilms tumour pedigrees where it should continue until 7 years. (5) Surveillance can be undertaken at a local centre, but should be carried out by someone with experience in paediatric ultrasonography. (6) Screen-detected lesions should be managed at a specialist centre.

Breast-feeding and Wilms tumor: a report from the Children's Oncology Group.

OBJECTIVE: Previous research has shown that breast-feeding offers many nutritional benefits to children including protection against infection and possibly a decreased risk of childhood cancer. We investigated the association between breast-feeding and Wilms tumor, a childhood kidney tumor. METHODS: We used data from a large case-control study in the United States and Canada. Cases were children under age 16 years who were diagnosed with Wilms tumor from 1999 to 2002 and were participating in the National Wilms Tumor Study. Controls were identified by random-digit dialing and were age and region matched to cases. Mothers of 501 cases and 480 controls provided information on breast-feeding by telephone interviews. RESULTS: Breast-feeding was associated with a reduced risk of Wilms tumor [adjusted odds ratio (OR) = 0.7; 95% confidence interval (CI) = 0.5-0.9]. Longer duration did not provide any additional reduction in risk. When stratified by maternal education, breast-feeding lowered risk among children whose mothers had less than a college education (OR = 0.6; 95% CI = 0.4-0.8) but not for mothers who had a college degree or more (OR = 1.1; 95% CI = 0.6-1.9). CONCLUSIONS: The results of this study are suggestive of an association between breast-feeding and Wilms tumor, but further research is needed to confirm this relationship.

Radiation therapy for favorable histology Wilms tumor: prevention of flank recurrence did not improve survival on National Wilms Tumor Studies 3 and 4.

PURPOSE: To determine whether radiation therapy (RT) of patients with Wilms tumor of favorable histology prevented flank recurrence and thereby improved the survival outcomes. METHODS AND MATERIALS: Recurrence and mortality risks were compared among groups of patients with Stage I-IV/favorable histology Wilms tumor enrolled in the third (n = 1,640) and fourth (n = 2,066) National Wilms Tumor Study Group studies. RESULTS: Proportions of patients with flank recurrence were 0 of 513 = 0.0% for 20 Gy, 12 of 805 = 1.5% for 10 Gy, and 44 of 2,388 = 1.8% for no flank RT (p trend = 0.001 adjusted for stage and doxorubicin); for intra-abdominal (including flank) recurrence they were 5 of 513 = 1.0%, 30 of 805 = 3.7%, and 58 of 2,388 = 2.4%, respectively (p trend = 0.02 adjusted). Survival percentages at 8 years after intra-abdominal recurrence were 0 of 5 = 0% for 20 Gy, 10 of 30 = 33% for 10 Gy, and 34 of 58 = 56% for no RT (p trend = 0.0001). NWTS-4 discontinued use of 20 Gy RT, and the 8-year flank recurrence risk increased to 2.1% from 1.0% on NWTS-3 (p = 0.013). However, event-free survival was unaltered (88% vs. 86%, p = 0.39), and overall survival was better (93.8% vs. 90.8%, p = 0.036) on NWTS-4. CONCLUSIONS: Partly because of lower postrecurrence mortality among nonirradiated patients, prevention of flank recurrence by RT did not improve survival. It is important to evaluate entire treatment policies with regard to long-term outcomes.

[A case of Denys-Drash syndrome with prophylactic bilateral nephrectomy].

Denys-Drash syndrome is a rare disorder consisting of pseudohermaphrodism, Wilms' tumor and nephropathy. We describe here a boy with severe hypospadias and undescended testes, who presented with end-stage renal failure at the age of 1 year and 8 months when he was referred to our hospital. Emergency hemodialysis was performed because of oliguria, edema and severe hypertension, and then peritoneal dialysis was started. The findings of the renal biopsy showed diffuse mesangial sclerosis, consistent with the characteristic change in Denys-Drash syndrome. The analysis of WT1 gene revealed a G-to-A point mutation at 1,186 resulting in a change from Asp to Asn at 396 in exon 9. Since he had no urine output and his kidneys were not functional and in addition, patients with this mutation have been reported to have a high risk of Wilms' tumor, bilateral nephrectomy was performed. The removed kidneys showed no malignancies. Since Denys-Drash syndrome is frequently associated with Wilms' tumor, renal biopsy and gene analysis should be performed on male patients with gonadal anomaly, such as hypospadias and/or undescended testes, and proteinuria.

Prevention of childhood leukemia by BCG vaccination in newborns? A population-based case-control study in Lower Saxony, Germany.

Data from a case-control study in Lower Saxony, Germany, were used to assess whether the risk for childhood cancer may be reduced by bacille Calmette-Guérin (BCG) vaccination in the neonatal period. There were 420 newly diagnosed childhood cancer cases from the German cancer registry and 613 controls eligible for this study. A mailed questionnaire was completed during a telephone interview with parents. Details on the perinatal history were abstracted from the birth charts by nurses blinded to the children's case-control status. Complete information was available for 259 cases and for 323 controls. A total of 85% of the controls had been BCG vaccinated in the newborn period. The adjusted odds ratios for BCG vaccination were 0.90 (95% confidence interval; 0.51-1.61) for leukemia and 0.61 (95% confidence interval; 0.25-1.50) for other cancers. Based on these data the probability of a 50% or more reduction of more reduction of the cancer risk by BCG vaccination in the newborn period is small. The statistical power of this study, however, was not high enough to rule out a smaller, still relevant reduction in cancer risk.

Effect of Avemar and Avemar + vitamin C on tumor growth and metastasis in experimental animals.

Because of the observed immunostimulatory actions of a new fermented wheat germ extract--with standardized benzoquinone composition--we have investigated the eventual tumor growth- and metastasis-inhibiting effects of this preparation (Avemar) applied alone or in combination with vitamin C. Tumor models of different origin [a highly metastatic variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice were applied. The metastasis-inhibiting effects of the treatments have been studied both in the presence and in the absence (following surgical removal) of the transplanted primary tumors. Combined treatments with Avemar and vitamin C--administered synchronously--profoundly inhibited the metastasis formation in all the applied tumor models while, treatments with vitamin C alone did not exert such an inhibiting effect on the metastasizing process. The degree of the observed metastasis inhibition in certain models was significant, while in others--although it was meaningful--did not prove to be significant. It is noteworthy that treatment with Avemar alone in certain models exerted a more pronounced inhibiting effect on metastasis formation than the synchronous combined treatment with Avemar and vitamin C. Furthermore, if the time schedule of the combined treatment was changed (vitamin C--instead of being administered synchronously--was given one hour after the treatments with Avemar), the vitamin C rather decreased the metastasis inhibiting effect of Avemar. It should be mentioned however, that in the case of rat nephroblastoma, a different response was observed: while, in the case of synchronous combination significant inhibition of metastasis formation was observed, treatment with Avemar alone did not produce metastasis-inhibition. It is noteworthy that in this model the metastasis-inhibiting effect of the synchronous combination treatment proved to be even more pronounced if Avemar was administered in a 100 times smaller dose than its regularly applied dosage. Treatment with Avemar and vitamin C--administered in combination or separately--in the majority of experimental models (with the exception of rat nephroblastoma) did not inhibit the growth of the primary tumors. It is reasonable, therefore, to suppose that in the observed metastasis-inhibiting effect the eventual proliferation inhibiting effect of these remedies does not play an important role. According to the results of other experiments--carried out in our laboratory in parallel with those described here--Avemar proved to have a meaningful immunostimulatory effect. It might therefore be suggested that the observed metastasis-inhibiting effect of this preparation may be mainly due to its immunostimulatory properties. The possible therapeutic benefits of Avemar and Avemar plus vitamin C are also discussed.

Screening for Wilms' tumor in children with high-risk congenital syndromes: considerations for an intervention trial.

Screening for cancer in children is uncommon. However, in children with congenital syndromes associated with Wilms' tumor, conditions exist that potentially make screening effective. This select population of children 1) are relatively easily identified; 2) have a high incidence of Wilms' tumor; 3) if identified before development of Wilms' tumor, may have a decrement in morbidity/mortality; and 4) are amenable to a simple and acceptable screening technology, renal sonography exams. Many clinicians have recommended screening for cancer in children with congenital syndromes associated with Wilms' tumor. However, neither costs nor effectiveness of such recommendations have been evaluated systematically. The strongest evidence for or against Wilms' tumor screening in this select population would be provided by a randomized screening trial. Prior to undertaking such a trial, the key parameters that dominate the cost and effectiveness of screening should be identified. Simulation models, such as cost effectiveness analysis, offer a starting point for deciding whether cancer screening is appropriate, and if so, under what set of conditions. We review basic conditions required for a successful screening trial in children with syndromes that are at increased risk of Wilms' tumor. We also discuss the use of cost-effectiveness analysis as a preliminary step in determining the feasibility of an intervention trial.

Inhibition of the progression of human and rat Wilms' tumor by Tiazofurin.

We monitored the antitumoral and antimetastatic effects of tiazofurin (2-beta-Dribofuranosylthiazole-4-carboxamide, TR) on human (HWT) and rat (RWT) Wilms' tumor grafts transplanted orthotopically underneath the renal capsule of scid mice and in rat Wilms' tumour, immunocompetent F344 rats. Treatment with different doses of Tiazofurin, twice a week proved therapeutically effective, since they resulted in a significant decrease in inhibition of both human and rat nephroblastoma grafts. We also applied combined surgical and chemotherapeutic treatment using orthotopic rat Wilms' tumor. The primary tumor was removed 13 days after tumor implantation. TR treatment was started immediately after the implantation of the isograft or following surgical removal of the primary tumor and chemotherapy was followed for 13 days. A high cure rate was found from combined treatment compared to surgery alone. TR treatment resulted in a significant inhibition of the growth of the primary tumor. TR decreased also the frequency and size of recurrent tumors, and appeared to exert selective antimetastatic effects, unrelated to cytotoxicity toward tumor cells. Our results indicate that TR may be a potential alternative chemotherapeutic in the treatment of human Wilms' tumor.