Outcomes of Wilms tumor treatment in western Kenya

Background/objectives Wilms tumor (WT) is a curable type of cancer with 5-year survival rates of over 90% in high-income countries, whereas this is less than 50% in low- and middle-income countries. We assessed treatment outcomes of children with WT treated at a large Kenyan teaching and referral hospital. Design/methods We conducted a retrospective record review of children diagnosed with WT between 2013 and 2016. Treatment protocol consisted of 6 weeks of preoperative chemotherapy and surgery, and 4–18 weeks of postoperative chemotherapy depending on disease stage. Probability of event-free survival (pEFS) and overall survival (pOS) was assessed using Kaplan–Meier method with Cox regression analysis. Competing events were analyzed with cumulative incidences and Fine–Gray regression analysis. Results Of the 92 diagnosed patients, 69% presented with high-stage disease. Two-year observed EFS and OS were, respectively, 43.5% and 67%. Twenty-seven percent of children died, 19% abandoned treatment, and 11% suffered from progressive or relapsed disease. Patients who were diagnosed in 2015–2016 compared to 2013–2014 showed higher pEFS. They less often had progressive or relapsed disease (p = .015) and borderline significant less often abandonment of treatment (p = .09). Twenty-nine children received radiotherapy, and 2-year pEFS in this group was 86%. Conclusion Outcome of children with WT improved over the years despite advanced stage at presentation. Survival probabilities of patients receiving comprehensive therapy including radiation are approaching those of patients in high-income countries. Additional improvement could be achieved by ensuring that patients receive all required treatment and working on earlier diagnosis strategies

Randomized controlled trial on the effect of 1-hour infusion of vincristine versus push injection on neuropathy in children with cancer (final analysis)

Introduction: Vincristine is an integral component of treatment for children with cancer. Its main dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1-hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short-term outcomes (median follow-up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1-hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow-up 20 months), which includes treatment outcome as a secondary objective (follow-up 3 years). Methods: VIPN was measured 1–7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed.Results: Forty-five participants per randomization group were included. There was no significant effect of 1-hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one-hour group (rate ratio 0.52, 95% confidence interval 0.33–0.80, p = 0.003). Four patients in the one-hour group and one patient in the push group relapsed. Two patients in the one-hour group died. Conclusion:1-hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1-hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.</p

Outcomes of Wilms tumor treatment in western Kenya

Background/objectives: Wilms tumor (WT) is a curable type of cancer with 5-year survival rates of over 90% in high-income countries, whereas this is less than 50% in low- and middle-income countries. We assessed treatment outcomes of children with WT treated at a large Kenyan teaching and referral hospital. Design/methods: We conducted a retrospective record review of children diagnosed with WT between 2013 and 2016. Treatment protocol consisted of 6 weeks of preoperative chemotherapy and surgery, and 4–18 weeks of postoperative chemotherapy depending on disease stage. Probability of event-free survival (pEFS) and overall survival (pOS) was assessed using Kaplan–Meier method with Cox regression analysis. Competing events were analyzed with cumulative incidences and Fine–Gray regression analysis. Results: Of the 92 diagnosed patients, 69% presented with high-stage disease. Two-year observed EFS and OS were, respectively, 43.5% and 67%. Twenty-seven percent of children died, 19% abandoned treatment, and 11% suffered from progressive or relapsed disease. Patients who were diagnosed in 2015–2016 compared to 2013–2014 showed higher pEFS. They less often had progressive or relapsed disease (p =.015) and borderline significant less often abandonment of treatment (p =.09). Twenty-nine children received radiotherapy, and 2-year pEFS in this group was 86%. Conclusion: Outcome of children with WT improved over the years despite advanced stage at presentation. Survival probabilities of patients receiving comprehensive therapy including radiation are approaching those of patients in high-income countries. Additional improvement could be achieved by ensuring that patients receive all required treatment and working on earlier diagnosis strategies

Development of a Therapeutic Drug Monitoring Strategy for the Optimization of Vincristine Treatment in Pediatric Oncology Populations in Africa

Background:Recent studies have reported ethnic differences in vincristine exposure and outcomes such as toxicity. This resulted in the hypothesis of subtherapeutic dosing in African children. To optimize individual treatment, a strategy to identify subtherapeutic exposure using therapeutic drug monitoring is essential. The aim of the current study was to develop a strategy for therapeutic drug monitoring of vincristine in African children to meet the following criteria: (1) identify patients with low vincristine exposure with sufficient sensitivity (>70%), (2) determine vincristine exposure with a limited sampling strategy design of 3 samples, and (3) allow all samples to be collected within 4 hours after administration.Methods:An in silico simulation study was performed using a previously described population pharmacokinetic model and real-life demographic dataset of Kenyan and Malawian pediatric oncology patients. Two different therapeutic drug monitoring strategies were evaluated: (1) Bayesian approach and (2) pharmacometric nomogram. The sampling design was optimized using the constraints described above. Sensitivity analysis was performed to investigate the influence of missing samples, erroneous sampling times, and different boundaries on the nomogram weight bands.Results:With the Bayesian approach, 43.3% of the estimated individual exposure values had a prediction error of ≥20% owing to extremely high shrinkage. The Bayesian approach did not improve with alternative sampling designs within sampling constraints. However, the pharmacometric nomogram could identify patients with low vincristine exposure with a sensitivity, specificity, and accuracy of 75.1%, 76.4%, and 75.9%, respectively. The pharmacometric nomogram performed similarly for different weight bands.Conclusions:The pharmacometric nomogram was able to identify patients with low vincristine exposure with high sensitivity, with 3 blood samples collected at 1, 1.5, and 4 hours after administration. Missing samples should be avoided, and the 3 scheduled samples should be collected within 15, 5, and 15 minutes of 1, 1.5, and 4 hours after administration, respectively

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy in Children with Cancer: A Systematic Review and Meta-Analysis

Vincristine-induced peripheral neuropathy (VIPN) is a debilitating side-effect of vincristine. It remains a challenge to predict which patients will suffer from VIPN. Pharmacogenomics may explain an individuals’ susceptibility to side-effects. In this systematic review and meta-analysis, we describe the influence of pharmacogenomic parameters on the development of VIPN in children with cancer. PubMed, Embase and Web of Science were searched. In total, 1597 records were identified and 21 studies were included. A random-effects meta-analysis was performed for the influence of CYP3A5 expression on the development of VIPN. Single-nucleotide polymorphisms (SNPs) in transporter-, metabolism-, cytoskeleton-, and hereditary neuropathy-associated genes and SNPs in genes previously unrelated to vincristine or neuropathy were associated with VIPN. CYP3A5 expression status was not significantly associated with VIPN. The comparison and interpretation of the results of the included studies was limited due to heterogeneity in the study population, treatment protocol and assessment methods and definitions of VIPN. Independent replication is essential to validate the clinical significance of the reported associations. Future research should aim for prospective VIPN assessment in both a discovery and a replication cohort. Ultimately, the goal would be to screen patients upfront to determine optimal vincristine dosage with regards to efficacy and risk of VIPN

Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium

OBJECTIVE: To determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE). METHODS: We assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways. RESULTS: There were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression. CONCLUSION: Our observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC

The interaction between cannabis use and the Val158Met polymorphism of the COMT gene in psychosis: A transdiagnostic meta - analysis

Neither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive. A meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met). PubMed, Embase, PsychInfo. All observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome. A meta-analysis was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines and forest plots were generated. Thirteen articles met the selection criteria: 7 clinical studies using a case-only design, 3 clinical studies with a dichotomous outcome, and 3 studies analysing a continuous outcome of psychotic symptoms below the threshold of psychotic disorder. The three study types were analysed separately. Validity of the included studies was assessed using "A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions". For case-only studies, a significant interaction was found between cannabis use and COMTVal158Met, with an OR of 1.45 (95% Confidence Interval = 1.05-2.00; Met/Met as the risk genotype). However, there was no evidence for interaction in either the studies including dichotomous outcomes (B = -0.51, 95% Confidence Interval -1.72, 0.70) or the studies including continuous outcomes (B = -0.04 95% Confidence Interval -0.16-0.08). A substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects. The interaction term between cannabis use and COMTVal158Met was only statistically significant in the case-only studies, but not in studies using other clinical or non-clinical psychosis outcomes. Future additional high quality studies might change current perspectives, yet currently evidence for the interaction remains unconvincin

Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients

Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype–trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment

Evidence for interaction between genetic liability and childhood trauma in the development of psychotic symptoms

PURPOSE: Whilst childhood trauma (CT) is a known risk factor across the spectrum of psychosis expression, little is known about possible interplay with genetic liability. METHODS: The TwinssCan Study collected data in general population twins, focussing on expression of psychosis at the level of subthreshold psychotic experiences. A multilevel mixed-effects linear regression analysis was performed including 745 subjects to assess the interaction between genetic liability and CT. The Symptom Checklist-90 (SCL-90-R) score of the co-twin was used as an indirect measure of genetic liability to psychopathology, while the Childhood Trauma Questionnaire Short-Form (CTQ-SF) was used to assess CT in the domains of physical, emotional and sexual abuse, as well as physical and emotional neglect. The Community Assessment of Psychic Experience (CAPE) questionnaire was used to phenotypically characterize psychosis expression. RESULTS: In the model using the CAPE total score, the interaction between CT and genetic liability was close to statistical significance (χ2 = 5.6, df = 2, p = 0.06). Analyses of CAPE subscales revealed a significant interaction between CT and genetic liability (χ2 = 8.8, df = 2, p = 0.012) for the CAPE-negative symptoms subscale, but not for the other two subscales (i.e. positive and depressive). CONCLUSION: The results suggest that the impact of CT on subthreshold expression of psychosis, particularly in the negative subdomain, may be larger in the co-presence of significant genetic liability for psychopathology.status: publishe

PubMed search results (July 18, 2017).

<p>PubMed search results (July 18, 2017).</p