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

The effectiveness of monotherapy with PI3K/AKT/mTOR pathway inhibitors in ovarian cancer: A meta-analysis

Objective. To determine the clinical benefit of monotherapy with PI3K/AKT/mTOR inhibitors in patients diagnosed with advanced or recurrent ovarian cancer and to investigate the predictive value of current PI3K/AKT/ mTOR biomarkers on therapy response. Methods. A systematic search was conducted in PubMed, Embase and the Cochrane Library for articles reporting on treatment with PI3K/AKT/mTOR inhibitors in ovarian cancer. The primary endpoint was defined as the clinical benefit rate (CBR), including the proportion of patients with complete (CR) and partial response (PR) and stable disease (SD). Secondary endpoints included the overall response rate (ORR, including CR and PR) and drug-related grade 3 and 4 adverse events. Results. We included 233 patients from 19 studies and observed a pooled CBR of 32% (95% CI 20-44%) and ORR of 3% (95% CI 0-6%) in advanced or recurrent ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors. Subgroup analysis tended to favor the studies who selected patients based on current PI3K/AKT/mTOR biomarker criteria (e.g. genomic alterations or loss of PTEN protein expression), but the difference in CBR was not statistically significant from studies with unselected populations (respectively, CBR of 42% (95% CI 23-62%) and 27% (95% CI 14-42%), P = 0.217). To better reflect true patient benefit, we excluded SD <6 months as a beneficial outcome which resulted in a pooled CBR of 7% (95% CI 2-13%). The overall proportion of patients with drug-related grade 3 and 4 adverse events was 36%. Conclusions. The efficacy of monotherapy with PI3K/AKT/mTOR inhibitors in advanced recurrent ovarian cancer patients is limited to a small subgroup and selection of patients with the use of current biomarkers did not improved the CBR significantly. Given the toxicity profile, we suggest that current treatment with PI3K/AKT/ mTOR inhibitors should not be initiated unless in clinical trials. Furthermore, improved biomarkers to measure functional PI3K/AKT/mTOR pathway activity are needed to optimize patient selection. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)

The effectiveness of monotherapy with PI3K/AKT/mTOR pathway inhibitors in ovarian cancer: A meta-analysis

Objective. To determine the clinical benefit of monotherapy with PI3K/AKT/mTOR inhibitors in patients diagnosed with advanced or recurrent ovarian cancer and to investigate the predictive value of current PI3K/AKT/ mTOR biomarkers on therapy response. Methods. A systematic search was conducted in PubMed, Embase and the Cochrane Library for articles reporting on treatment with PI3K/AKT/mTOR inhibitors in ovarian cancer. The primary endpoint was defined as the clinical benefit rate (CBR), including the proportion of patients with complete (CR) and partial response (PR) and stable disease (SD). Secondary endpoints included the overall response rate (ORR, including CR and PR) and drug-related grade 3 and 4 adverse events. Results. We included 233 patients from 19 studies and observed a pooled CBR of 32% (95% CI 20-44%) and ORR of 3% (95% CI 0-6%) in advanced or recurrent ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors. Subgroup analysis tended to favor the studies who selected patients based on current PI3K/AKT/mTOR biomarker criteria (e.g. genomic alterations or loss of PTEN protein expression), but the difference in CBR was not statistically significant from studies with unselected populations (respectively, CBR of 42% (95% CI 23-62%) and 27% (95% CI 14-42%), P = 0.217). To better reflect true patient benefit, we excluded SD <6 months as a beneficial outcome which resulted in a pooled CBR of 7% (95% CI 2-13%). The overall proportion of patients with drug-related grade 3 and 4 adverse events was 36%. Conclusions. The efficacy of monotherapy with PI3K/AKT/mTOR inhibitors in advanced recurrent ovarian cancer patients is limited to a small subgroup and selection of patients with the use of current biomarkers did not improved the CBR significantly. Given the toxicity profile, we suggest that current treatment with PI3K/AKT/ mTOR inhibitors should not be initiated unless in clinical trials. Furthermore, improved biomarkers to measure functional PI3K/AKT/mTOR pathway activity are needed to optimize patient selection. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)

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

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

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

A sensitive liquid chromatographic-mass spectrometry method for the quantification of vincristine in whole blood collected with volumetric absorptive microsampling

Vincristine is a well-established cytotoxic drug. In paediatric populations blood collection via venipuncture is not always feasible. Volumetric absorptive microsampling (VAMS) is a less invasive method for blood collection. Furthermore, VAMS lacks the haematocrit effect on the recovery known with dried blood spots. Therefore, a liquid chromatography tandem-mass spectrometry method was developed and validated for the quantification of vincristine in whole blood collected with VAMS devices. Sample preparation consisted of solid-liquid extraction with 0.2% formic acid in water and acetonitrile. The final extract was injected on a C18 column (2.0 ×50 mm, 5 µm). Gradient elution was used and quantification was accomplished with a triple quadruple mass spectrometer operating in the positive mode. The validated concentration range was from 1 to 50 ng/mL with an intra- and inter-accuracy and precision of ± 10.3% and ≤ 7.3%, respectively. This method was able to successfully quantify vincristine concentrations in whole blood collected with VAMS from paediatric oncology patients. Vincristine concentrations in whole blood were non-linearly associated with plasma concentrations, which could be described with a saturable binding equilibrium model

Transcription Factors in Mature B Cells During Aging

The purpose of this chapter is to give an overview of the age-related changes in the expression and function of the major transcription factors regulating mature B cells. We also summarize our recent work and show that the age-related defects in Ig class switch are directly related to the decrease in the transcription factor E47 which controls the expression of activation-induced cytidine deaminase (AID), the enzyme needed for class-switch recombination (CSR) and somatic hypermutation (SHM). The age-associated effects on the expression and function of the transcription factors NF-kB and Pax-5 are also described. Blimp-1 seems not to be modified by aging, and only one report has shown age effects on Bach2. For other transcription factors relevant for mature B cell functions, such as IRF4, Notch2, and HoxC4, no effects of aging have been reported so far. The defects presented herein for aged B cells should allow the discovery of mechanisms to improve humoral immune responses in both humans and mice in the near future