Publications by authors named "Philip D Walson"

50 Publications

In response to Du et al., 2020, 42(9):1799-1810.

Authors:
Philip D Walson

Clin Ther 2021 Feb 21. Epub 2021 Feb 21.

Departments of Clinical Pharmacology and Laboratory Medicine, University Medical Center Goettingen, Goettingen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clinthera.2021.01.023DOI Listing
February 2021

Time-Dependent Apparent Increase in dd-cfDNA Percentage in Clinically Stable Patients Between One and Five Years Following Kidney Transplantation.

Clin Chem 2020 Oct;66(10):1290-1299

Department of Clinical Pharmacology, University Medical Center Goettingen, Goettingen, Germany.

Background: Donor-derived cell-free DNA (dd-cfDNA) is reportedly a valuable tool for graft surveillance following kidney transplantation (KTx). Possible changes in dd-cfDNA(%) reference values over time have not been evaluated. For long-term monitoring after KTx, changes in host cfDNA might represent a biasing factor in dd-cfDNA(%) determinations.

Methods: Plasma samples were obtained (n = 929) 12-60 months after engraftment in a cross-sectional cohort of 303 clinically stable KTx recipients. Total cfDNA(copies/mL), dd-cfDNA(%), and dd-cfDNA(copies/mL) were determined using droplet-digital PCR. Stability of threshold values in these stable KTx recipients over time was assessed by 80th, 85th, and 90th quantile regression.

Results: Upper percentiles of total cfDNA showed a significant decline of -1902, -3589, and -4753 cp/mL/log(month) (P = 0.014, <0.001, and 0.017, respectively), resulting in increasing dd-cfDNA(%) percentiles by 0.25, 0.46, and 0.72%/log(month) (P = 0.04, 0.001, and 0.002, respectively), with doubling of the 85th percentile value by 5 years. In contrast, dd-cfDNA(cp/mL) was stable during the observation period (P = 0.52, 0.29, and 0.39). In parallel increasing white blood cell counts and decreasing tacrolimus concentrations over time were observed. After 5 years, the median total cfDNA was still 1.6-fold (P < 0.001) higher in KTx recipients than in healthy controls (n = 135) and 1.4-fold (P < 0.001) higher than patients with other medical conditions (n = 364).

Conclusions: The time-dependent decrease of host cfDNA resulted in an apparent increase of dd-cfDNA fraction in stable KTx patients. For long-term surveillance, measurement of absolute dd-cfDNA concentrations appears to be superior to percentages to minimize false positive results.
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http://dx.doi.org/10.1093/clinchem/hvaa175DOI Listing
October 2020

Donor-Derived Cell-Free DNA Testing in Solid Organ Transplantation: A Value Proposition.

J Appl Lab Med 2020 09;5(5):993-1004

Department of Clinical Pharmacology, University Medical Center Goettingen, Goettingen, Germany.

Background: There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. More efficient biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and to prevent immune activation is also important. Donor-derived cell-free DNA (dd-cfDNA) has become available for comprehensive monitoring of allograft integrity. A value proposition concept was applied to assess the potential benefits of dd-cfDNA to stakeholders (patient, transplant physician, laboratory medicine specialist, hospital management, insurance companies) involved in solid organ transplantation care.

Content: There is robust clinical evidence from more than 48 published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. The value proposition framework was used to evaluate published key evidence regarding clinical validity, economic implications, and limitations of this approach. It has been shown that dd-cfDNA testing is essential for guiding earlier transplant injury intervention with potential for improved long-term outcome.

Summary: Monitoring dd-cfDNA offers a rapid and reproducible method to detect graft injuries at an early actionable stage without protocol biopsies and allows for more effective personalized immunosuppression. The appropriate use of dd-cfDNA testing can provide both clinical and economic benefits to all transplantation stakeholders.
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http://dx.doi.org/10.1093/jalm/jfaa062DOI Listing
September 2020

In Memoriam: Professor Folke Sjöqvist.

Ther Drug Monit 2020 Jun;42(3):353

Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge, Stockholm, Sweden.

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http://dx.doi.org/10.1097/FTD.0000000000000762DOI Listing
June 2020

Drug Exposure and Effects in Pregnancy and Lactation.

Authors:
Philip D Walson

Ther Drug Monit 2020 04;42(2):169-171

Georg-August-Universitat, Hannover, Niedersachsen Germany.

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http://dx.doi.org/10.1097/FTD.0000000000000732DOI Listing
April 2020

From Research to the Bedside: Challenges for Pediatric Academic Researchers.

Authors:
Philip D Walson

Curr Ther Res Clin Exp 2019 28;90:123-127. Epub 2018 Dec 28.

Department of Clinical Pharmacology, University Medical Center, Göttingen, Germany.

Background: Although improving, development of drugs and devices for children is still less effective than for adults. Pediatric academicians play an important role in the bench-to-bedside research process, but much remains to be done to improve their contributions.

Objective: To provide a non-comprehensive review of selected literature based on my own personal experience as a U.S. based academic researcher who has spent over 4 decades doing pediatric drug and device development.

Methods: This commentary presents a summary of a talk given at a recent pediatric drug development conference. The observations and conclusions reached were based on the author's (largely US) experience and review of past history, the role of academicians in this process, some successful models of public-private collaboration, available funding, and barriers that remain to be overcome.

Results: Pediatric-specific legislation and more available funding have increased participation from and successes of US academicians in the pediatric drug and device development process. Incentive based public-private collaborations have been particularly successful. However, academicians still face both attitude and practical barriers to success.

Conclusions: Changes are needed if academicians are to maximize their involvement in pediatric drug and device development.
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http://dx.doi.org/10.1016/j.curtheres.2018.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677781PMC
December 2018

Are Regulatory Age Limits in Pediatric Melanoma Justified?

Curr Ther Res Clin Exp 2019 18;90:113-118. Epub 2019 Jan 18.

Department of Clinical Pharmacology, University Medical Center, Goettingen, Germany.

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http://dx.doi.org/10.1016/j.curtheres.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677782PMC
January 2019

Plasma EGFR mutation testing in non-small cell lung cancer: A value proposition.

Clin Chim Acta 2019 Aug 21;495:481-486. Epub 2019 May 21.

Department of Clinical Pharmacology, University Medical Center Goettingen, Goettingen, Germany.

Genomics-driven precision medicine using targeted therapies requires advanced molecular diagnostic tests. Decisions about the use and reimbursement for such tests are increasingly being made on the basis of more outcome-based and value-based approaches. The value proposition concept is a tool to assess the benefits of laboratory testing to each stakeholder of the care pathway with respect to outcomes. This concept was applied to the use of noninvasive plasma epidermal growth factor receptor (EGFR) mutation testing in patients with advanced or metastatic non-small cell lung cancer (NSCLC) to guide treatment with EGFR tyrosine kinase inhibitors (TKIs). Using the value proposition framework, we evaluated published key evidence regarding clinical validity, economic implications, and limitations of this approach. It has been shown that plasma EGFR mutation testing is essential for guiding clinical decisions regarding prediction of eligibility of individual patients for TKI treatment, real-time monitoring, or adjustment of treatment regimens and tracking resistance. The appropriate use of plasma EGFR mutation testing has been shown to deliver both clinical and economic benefits to stakeholders across the entire care pathway; especially in clinical situations where biopsy material is inadequate or unavailable and where it leads to fewer tissue biopsies.
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http://dx.doi.org/10.1016/j.cca.2019.05.019DOI Listing
August 2019

Absolute quantification of donor-derived cell-free DNA as a marker of rejection and graft injury in kidney transplantation: Results from a prospective observational study.

Am J Transplant 2019 11 28;19(11):3087-3099. Epub 2019 May 28.

Chronix Biomedical, Goettingen, Germany.

Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd-cfDNA quantification of copies/mL plasma (dd-cfDNA[cp/mL]) was compared to dd-cfDNA fraction (dd-cfDNA[%]) at prespecified visits in 189 patients over 1 year post KTx. In patients (N = 15, n = 22 samples) with biopsy-proven rejection (BPR), median dd-cfDNA(cp/mL) was 3.3-fold and median dd-cfDNA(%) 2.0-fold higher (82 cp/mL; 0.57%, respectively) than medians in Stable Phase patients (N = 83, n = 408) without rejection (25 cp/mL; 0.29%). Results for acute tubular necrosis (ATN) were not significantly different from those with biopsy-proven rejection (BPR). dd-cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. Receiver operating characteristic (ROC) analysis showed superior performance (P = .02) of measuring dd-cfDNA(cp/mL) (AUC = 0.83) compared to dd-cfDNA(%) (area under the curve [AUC] = 0.73). Diagnostic odds ratios were 7.31 for dd-cfDNA(cp/mL), and 6.02 for dd-cfDNA(%) at thresholds of 52 cp/mL and 0.43%, respectively. Plasma creatinine showed a low correlation (r = 0.37) with dd-cfDNA(cp/mL). In a patient subset (N = 24) there was a significantly higher rate of patients with elevated dd-cfDNA(cp/mL) with lower tacrolimus levels (<8 μg/L) compared to the group with higher tacrolimus concentrations (P = .0036) suggesting that dd-cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd-cfDNA(cp/mL) allowed for better discrimination than dd-cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies.
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http://dx.doi.org/10.1111/ajt.15416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899936PMC
November 2019

Circulating Cell-Free DNA-Diagnostic and Prognostic Applications in Personalized Cancer Therapy.

Ther Drug Monit 2019 04;41(2):115-120

Department of Clinical Pharmacology, University Medical Center Goettingen, Goettingen, Germany.

Genomic analyses in oncologic care allow for the development of more precise clinical laboratory tests that will be critical for personalized pharmacotherapy. Traditional biopsy-based approaches are limited by the availability of sequential tissue specimens to detect resistance. Blood-based genomic profiling ("liquid biopsy") is useful for longitudinal monitoring of tumor genomes and can complement biopsies. Tumor-associated mutations can be identified in cell-free tumor DNA (ctDNA) from patient blood samples and used for monitoring disease activity. The US Food and Drug Administration approved a liquid biopsy test for EGFR-activating mutations in patients with non-small-cell lung cancer as a companion diagnostic for therapy selection. ctDNA also allows for the identification of mutations selected by treatment such as EGFR T790M in non-small-cell lung cancer. ctDNA can also detect mutations such as KRAS G12V in colorectal cancer and BRAF V600E/V600K in melanoma. Chromosomal aberration pattern analysis by low-coverage whole genome sequencing is a new, broader approach. Genomic imbalances detected in cell-free DNA (cfDNA) can be used to compute a copy number instability (CNI) score. In clinical studies, it was demonstrated that the change in CNI score can serve as an early predictor of therapeutic response to chemotherapy/immunotherapy of many cancer types. In multivariable models, it could be shown that the CNI score was superior to clinical parameters for prediction of overall survival in patients with head and neck cancer. There is emerging evidence for the clinical validity of ctDNA testing regarding identification of candidates for targeted therapies, prediction of therapeutic response, early detection of recurrence, resistance mutation detection, measuring genetic heterogeneity, tumor burden monitoring, and risk stratification. Improvement of sensitivity to detect tumors at very early stages is difficult due to insufficient mutant DNA fraction of ≤0.01%. Further developments will include validation in prospective multicenter interventional outcome studies and the development of digital platforms to integrate diagnostic data.
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http://dx.doi.org/10.1097/FTD.0000000000000566DOI Listing
April 2019

Cell-Free Plasma DNA for Disease Stratification and Prognosis in Head and Neck Cancer.

Clin Chem 2018 06 16;64(6):959-970. Epub 2018 Apr 16.

Clinic of Otorhinolaryngology, Ludwig-Maximilian University of Munich, Germany.

Background: Clinicians face many challenges in disease stratification and outcome prediction in head and neck squamous cancer cell (HNSCC) patients. Given the limitations of currently used clinical scoring, repetitive biopsies, and imaging techniques, liquid biopsy approaches may provide valuable additional diagnostic and prognostic information.

Methods: A noninterventional, single-center observational study was performed with clinical data and plasma samples from HNSCC patients. Cell-free tumor DNA-derived copy number aberrations (CNAs) were determined in 116 patients by low-coverage next-generation sequencing (NGS). Significant CNAs were combined in a genome-wide copy number instability score (CNI), which was evaluated with respect to conventional clinical staging and patient outcome.

Results: Receiver-operating characteristic (ROC) curve analysis comparing the presurgery CNI in patients (n = 103) with that in tumor-free controls (n = 142) yielded an area under the ROC curve of 87.2% (95% CI, 79.4%-93.3%). At a specificity of 95%, the sensitivity to detect tumors varied between 46% (pT1) and 94% (pT4). A CNI above the median (i.e., >72) had a positive predictive value of 90% (95% CI, 79%-96%) for lymph node involvement (LNI), while the negative predictive value was 57% (95% CI, 43%-70%). For a CNI >72, overall survival (OS) was worse (hazard ratio, 4.89; 95% CI, 1.39-17.17; = 0.01) with 62% and 90% survivors 3 years after surgery for a CNI >72 and ≤72, respectively. In multivariable models, the CNI was a superior predictor of OS compared to established disease features, including LNI.

Conclusions: The CNI may assist in predicting LNI and prognosis in HNSCC with direct therapeutic implications concerning the need for neck dissection or more aggressive treatment.
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http://dx.doi.org/10.1373/clinchem.2017.285668DOI Listing
June 2018

Diagnostic value of alpha-1-fetoprotein (AFP) as a biomarker for hepatocellular carcinoma recurrence after liver transplantation.

Clin Biochem 2018 Feb 17;52:20-25. Epub 2017 Oct 17.

Department of Clinical Pharmacology, University Medical Center Göttingen, Kreuzbergring 36, 37075 Göttingen, Germany. Electronic address:

Background: Alpha-1-fetoprotein (AFP) is used to monitor progression, evaluate response to therapy and predict recurrence of hepatocellular carcinoma (HCC) in liver transplantation (LTx) patients. To date, the diagnostic value of serum AFP determinations for detecting tumor recurrence in HCC patients after LTx is unclear.

Objective: A retrospective, single-center, cross-sectional, non-interventional study was performed with the objective of determining post-transplant cut-off AFP values for detecting HCC recurrence post LTx.

Methods: Using receiver operating characteristic (ROC) analyses, post-transplant serum AFP values were evaluated against HCC recurrences in 63 HCC patients who had LTx between November 1995 and December 2011 at the University Medical Center Göttingen (UMG). Optimal and application-independent cut points for predicting tumor recurrence at 1, 3, and 5years after LTx were determined.

Results: Post-LTx serum AFP was found to represent an independent risk factor (predictor) for HCC relapse. Post-operative AFP cut-off values of 7μg/l, 6μg/l, and 6μg/l, respectively, were determined to be optimal at 1, 3, and 5years after LTx respectively for predicting a HCC relapse. Using these cut-off values, patients were correctly classified as relapse-positive with a diagnostic sensitivity of 79%, 81%, and 77%, and as relapse-free with a specificity of 82%, 79%, and 69%. The diagnostic accuracy measured by area under the curve (AUC) values ranged from 0.813 to 0.886. However, a limitation is that at a clinically relevant specificity of ≥95%, the analyses showed sensitivity values of only 50%, 52%, and 50%, respectively.

Conclusion: Post-transplant serum AFP may have diagnostic value to detect HCC recurrence after LTx.
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http://dx.doi.org/10.1016/j.clinbiochem.2017.10.011DOI Listing
February 2018

Do Paediatric Investigation Plans (PIPs) Advance Paediatric Healthcare?

Paediatr Drugs 2017 Dec;19(6):515-522

Walson Consulting, LLC, Seattle, Washington, USA.

Since 2007, new drugs need a paediatric investigation plan (PIP) for EU registration. The PIPs' justifications can be traced back to concerns expressed by Shirkey that label warnings against paediatric use made children "therapeutic orphans", and the American Academy of Pediatrics' claim that all children differ considerably from adults. US legislation first encouraged, then also required, separate, adult-style safety and efficacy studies in all paediatric subpopulations. This triggered paediatric regulatory studies by the pharmaceutical industry. There were also negative outcomes, as a result of using the legal definition of childhood as a medical/physiological term. The "therapeutic orphans" concept became dogma that supported/expanded adult-style regulatory testing into all age groups even when poorly justified in adolescents or where other methods are available to generate needed data. PIPs are especially problematic because they lack the limitations imposed on the Food and Drug Administration's (FDA's) regulatory actions and more practical approaches used in the USA. Many PIP studies are medically senseless or even questionable and/or unfeasible with poor risk/benefit ratios. For example, physiologically mature adolescents have been exposed to treatments and doses known to be suboptimal in adults. Unfeasible PIP studies in rare diseases may harm patients by preventing their participation in more beneficence-driven studies. PIP-required studies can prevent effective treatment of allergic rhinitis during years of placebo treatment, exposing minors to the risk of disease progression to asthma. The PIP system should be revised; more should be done by key players, including institutional review boards/ethics committees, to ensure that all paediatric clinical studies are medically justified, rather than legislation driven, and can produce scientifically valid results.
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http://dx.doi.org/10.1007/s40272-017-0260-2DOI Listing
December 2017

Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study.

PLoS Med 2017 04 25;14(4):e1002286. Epub 2017 Apr 25.

Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany.

Background: Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection.

Methods And Findings: Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits.

Conclusions: In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients.
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http://dx.doi.org/10.1371/journal.pmed.1002286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404754PMC
April 2017

Using circulating cell-free DNA to monitor personalized cancer therapy.

Crit Rev Clin Lab Sci 2017 05 10;54(3):205-218. Epub 2017 Apr 10.

a Department of Clinical Pharmacology , University Medical Center Göttingen , Göttingen , Germany.

High-quality genomic analysis is critical for personalized pharmacotherapy in patients with cancer. Tumor-specific genomic alterations can be identified in cell-free DNA (cfDNA) from patient blood samples and can complement biopsies for real-time molecular monitoring of treatment, detection of recurrence, and tracking resistance. cfDNA can be especially useful when tumor tissue is unavailable or insufficient for testing. For blood-based genomic profiling, next-generation sequencing (NGS) and droplet digital PCR (ddPCR) have been successfully applied. The US Food and Drug Administration (FDA) recently approved the first such "liquid biopsy" test for EGFR mutations in patients with non-small cell lung cancer (NSCLC). Such non-invasive methods allow for the identification of specific resistance mutations selected by treatment, such as EGFR T790M, in patients with NSCLC treated with gefitinib. Chromosomal aberration pattern analysis by low coverage whole genome sequencing is a more universal approach based on genomic instability. Gains and losses of chromosomal regions have been detected in plasma tumor-specific cfDNA as copy number aberrations and can be used to compute a genomic copy number instability (CNI) score of cfDNA. A specific CNI index obtained by massive parallel sequencing discriminated those patients with prostate cancer from both healthy controls and men with benign prostatic disease. Furthermore, androgen receptor gene aberrations in cfDNA were associated with therapeutic resistance in metastatic castration resistant prostate cancer. Change in CNI score has been shown to serve as an early predictor of response to standard chemotherapy for various other cancer types (e.g. NSCLC, colorectal cancer, pancreatic ductal adenocarcinomas). CNI scores have also been shown to predict therapeutic responses to immunotherapy. Serial genomic profiling can detect resistance mutations up to 16 weeks before radiographic progression. There is a potential for cost savings when ineffective use of expensive new anticancer drugs is avoided or halted. Challenges for routine implementation of liquid biopsy tests include the necessity of specialized personnel, instrumentation, and software, as well as further development of quality management (e.g. external quality control). Validation of blood-based tumor genomic profiling in additional multicenter outcome studies is necessary; however, cfDNA monitoring can provide clinically important actionable information for precision oncology approaches.
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http://dx.doi.org/10.1080/10408363.2017.1299683DOI Listing
May 2017

Do the European Medicines Agency Decisions Hurt Pediatric Melanoma Patients?

Clin Ther 2017 Feb 31;39(2):253-265. Epub 2017 Jan 31.

Department of Clinical Pharmacology, University Medical School, Goettingen, Germany.

Purpose: US pediatric legislation was introduced in 1997 and was followed by European Union pediatric legislation that, since 2007, requires a European Medicines Agency (EMA)-approved pediatric investigation plan (PIP) for registration of new medicines unless they are PIP exempted. In 2008, the EMA decided that enough adolescent patients with melanoma existed and removed melanoma from the list of PIP-exempted diseases (class waiver list). We examined the logic and the results of this decision.

Methods: We analyzed the EMA class waiver decision, the melanoma PIP decisions, the wording of the European Union pediatric legislation, and melanoma trials listed in www.clinicaltrials.gov and www.clinicaltrialsregister.eu that recruit adults and minors or only minors.

Findings: There are 12 melanoma PIP decisions. Two apparently PIP-triggered melanoma trials were terminated in 2016 because of slow recruitment, and 4 are ongoing. Numerous non-PIP-driven trials are recruiting both adults and minors with melanoma worldwide, thus competing with PIP-triggered melanoma trials.

Implications: Revoking the melanoma class waiver was not based on science but on flawed logic. It resulted in PIP-demanded pediatric trials that do not make medical sense, fail to recruit adequately, and prevent participants from more promising off-label treatment or treatment in clinically, scientifically, and ethically superior non-PIP-triggered studies. Institutional review boards and ethics committees should consult both www.clinicaltrials.gov and www.clinicaltrialsregister.eu for competing trials in the same population and reject or withdraw approval for questionable trials. A major revision or replacement of the European Union pediatric legislation is needed to prevent children from being enrolled in unnecessary, unfeasible, or scientifically invalid trials.
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http://dx.doi.org/10.1016/j.clinthera.2017.01.009DOI Listing
February 2017

Therapeutic drug monitoring - Key to personalized pharmacotherapy.

Clin Biochem 2017 May 14;50(7-8):375-379. Epub 2017 Jan 14.

Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clinbiochem.2017.01.007DOI Listing
May 2017

To the Editor.

Authors:
Philip D Walson

Clin Ther 2016 08 4;38(8):1922. Epub 2016 Jul 4.

Department of Clinical Pharmacology, University Medical School, Goettingen, Germany.

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http://dx.doi.org/10.1016/j.clinthera.2016.06.013DOI Listing
August 2016

The contributions of the European Medicines Agency and its pediatric committee to the fight against childhood leukemia.

Risk Manag Healthc Policy 2015 5;8:185-205. Epub 2015 Nov 5.

Department of Clinical Pharmacology, University Medical School, Goettingen, Germany.

Background: Although the diagnosis of childhood leukemia is no longer a death sentence, too many patients still die, more with acute myeloid leukemia than with acute lymphoblastic leukemia. The European Union pediatric legislation was introduced to improve pharmaceutical treatment of children, but some question whether the European Medicines Agency (EMA) approach is helping children with leukemia. Some have even suggested that the decisions of EMA pediatric committee (PDCO) are counterproductive. This study was designed to investigate the impact of PDCO-issued pediatric investigation plans (PIPs) for leukemia drugs.

Methods: All PIPs listed under "oncology" were downloaded from the EMA website. Non-leukemia decisions including misclassifications, waivers (no PIP), and solid tumors were discarded. The leukemia decisions were analyzed, compared to pediatric leukemia trials in the database http://www.clinicaltrials.gov, and discussed in the light of current literature.

Results: The PDCO leukemia decisions demand clinical trials in pediatric leukemia for all new adult drugs without prioritization. However, because leukemia in children is different and much rarer than in adults, these decisions have resulted in proposed studies that are scientifically and ethically questionable. They are also unnecessary, since once promising new compounds are approved for adults, more appropriate, prioritized pediatric leukemia trials are initiated worldwide without PDCO involvement.

Conclusion: EMA/PDCO leukemia PIPs do little to advance the treatment of childhood leukemia. The unintended negative effects of the flawed EMA/PDCO's standardized requesting of non-prioritized testing of every new adult leukemia drug in children with relapsed or refractory disease expose these children to questionable trials, and could undermine public trust in pediatric clinical research. Institutions, investigators, and ethics committees/institutional review boards need to be skeptical of trials triggered by PDCO. New, better ways to facilitate drug development for pediatric leukemia are needed.
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http://dx.doi.org/10.2147/RMHP.S63029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640230PMC
November 2015

Mycophenolic acid reverses TGF beta-induced cell motility, collagen matrix contraction and cell morphology in vitro.

Cell Biochem Funct 2015 Oct 8;33(7):503-8. Epub 2015 Oct 8.

Department of Clinical Chemistry, University Medical Center Goettingen, Goettingen, Germany.

The aim of this study was to elucidate functional and molecular effects of mycophenolic acid (MPA) on non-lymphatic, kidney epithelial cells treated with transforming growth factor (TGF). MPA effects were studied using HK2 cells incubated with EGF and TGF. The reversibility of these effects was verified using guanosine and 8-aminoguanosine. The following assays were applied: cell proliferation, viability, collagen matrix contraction, scratch wound closure, spindle index, FACS with anti-CD29 and anti-CD326, promoter demethylation of RAS protein activator like 1 (RASAL1), as well as gene expression of RASAL1, integrin 1ß (ITGB1) (CD29) and epithelial cell adhesion molecule (EpCam) (CD326). Cell proliferation was inhibited by increasing concentrations of MPA, whereas neither apoptosis nor cytotoxicity was detected. Stimulation with EGF and/or TGF led to a significant collagen matrix contraction that was successfully inhibited by MPA. In addition, scratch wound closure was inhibited by incubation with TGF alone or with EGF. Under the same conditions, cell morphology (spindle shape) and molecular phenotype (ITGB1(High)EpCam(Low)/ITGB1(Low)EpCam(High)) were both significantly changed, suggesting an epithelial to mesenchymal transformation. Cell morphology and motility, as well as molecular phenotype, were reversible after MPA treatment with TGF transformation in both presence/absence of EGF, thereby suggesting a correlation with the previously described antifibrotic effects of MPA. Dysregulation of TGF signal transduction appears to be related to progression of fibrosis. A TGF-transformed kidney epithelial cell line derived from human proximal tubules was used to study whether the immunosuppressive drug: MPA possesses any functional or molecular antifibrotic effects. Functional and morphological in vitro changes induced by both the TGF and epithelial-growth-factor were reversible by treatment with MPA. An inhibitory effect of MPA on the TGF pathway appears to be responsible for the previously described antifibrotic effects of the MPA in the COL4A3-deficient mouse model of renal fibrosis.
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http://dx.doi.org/10.1002/cbf.3149DOI Listing
October 2015

Graft-Derived Cell-Free DNA as a Marker of Transplant Graft Injury.

Ther Drug Monit 2016 Apr;38 Suppl 1:S75-9

*Institute of Clinical Pharmacology, University Medicine Göttingen, Göttingen, Germany; †Chronix Biomedical GmbH, Göttingen, Germany; and ‡Department of General, Visceral and Pediatric Surgery, University Medicine Go[Combining Diaeresis]ttingen, Göttingen, Germany.

Although short-term success after solid organ transplantation is good, long-term graft and recipient survival are both not satisfactory. Despite therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISDs), both excessive and insufficient immunosuppression still do occur. There is a need for new biomarkers that, when combined with TDM, can be used to provide more effective and less toxic, personalized immunosuppression to improve long-term survival. Currently used methods are insufficient to rapidly, cost-effectively, and directly interrogate graft integrity after solid organ transplantation. However, because organ transplants are also genome transplants, measurement of graft-derived circulating cell-free DNA (GcfDNA) has shown promise as a way to improve both graft and recipient outcomes after solid organ transplantation through the early detection of severe graft injury, enabling an early intervention. A newly developed droplet digital polymerase chain reaction (ddPCR) method has advantages over expensive high-throughput sequencing methods to rapidly quantify GcfDNA percentages and absolute amounts. This procedure does not require donor DNA and therefore can be applied to any organ donor/recipient pair. The droplet digital polymerase chain reaction method allows for the early, sensitive, specific, and cost-effective direct assessment of graft integrity and can be used to define individual responses to ISDs including the minimal ISD exposures necessary to prevent rejection. This is especially important in patients undergoing ISD switches due to ISD toxicity, infections, or malignancies. Although prospective, multicenter clinical trials in liver, heart, and kidney transplantation have not been completed, early results suggest that GcfDNA can be combined with TDM to guide changes in immunosuppression to provide more effective, and less toxic treatment. Personalized immunosuppression will shift emphasis in transplantation from reaction to prevention and could improve outcome at lower health care costs.
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http://dx.doi.org/10.1097/FTD.0000000000000239DOI Listing
April 2016

Pediatric Obesity.

Authors:
Philip D Walson

Clin Ther 2015 Sep 28;37(9):1895-6. Epub 2015 Aug 28.

Department of Clinical Pharmacology, Georg-August Universität Medical School Goettingen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clinthera.2015.08.010DOI Listing
September 2015

Lack of correlation between Treg quantification assays in inflammatory bowel disease patients.

World J Gastroenterol 2015 Mar;21(11):3325-9

Gunnar Brandhorst, Darinka Todorova Petrova, Sebastian Weigand, Christoph Eberle, Nicolas von Ahsen, Department of Clinical Chemistry, University Medical Center, 37075 Goettingen, Germany.

Aim: To compare the number of regulatory T-cells (Tregs) measured by flow cytometry with those obtained using a real-time quantitative PCR (qPCR) method in patients suffering from inflammatory bowel disease (IBD).

Methods: Tregs percentages obtained by both flow cytometry and qPCR methods in 35 adult IBD patients, 18 out of them with Crohn´s disease (CD) and 17 with ulcerative colitis (UC) were compared to each other as well as to scores on two IBD activity questionnaires using the Harvey Bradshaw Index (HBI) for CD patients and the Simple Colitis Clinical Activity Index (SCCAI) for UC patients. The Treg percentages by flow cytometry were defined as CD4(+)CD25(high)CD127(low)FOXP3(+) cells in peripheral blood mononuclear cells, whereas the Treg percentages by qPCR method were determined as FOXP3 promoter demethylation in genomic DNA.

Results: We found an average of 1.56% ± 0.78% Tregs by using flow cytometry, compared to 1.07% ± 0.53% Tregs by using qPCR in adult IBD patients. There were no significant correlations between either the percentages of Tregs measured by flow cytometry or qPCR and the HBI or SCCAI questionnaire scores in CD or UC patients, respectively. In addition, there was no correlation between Treg percentages measured by qPCR and those measured by flow cytometry (r = -0.06, P = 0.73; Spearman Rho). These data suggest that, either Treg-related immune function or the clinical scores in these IBD patients did not accurately reflect actual disease activity. Until the cause(s) for these differences are more clearly defined, the results suggest caution in interpreting studies of Tregs in various inflammatory disorders.

Conclusion: The two methods did not produce equivalent measures of the percentage of total Tregs in the IBD patients studied which is consistent with the conclusion that Tregs subtypes are not equally detected by these two assays.
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http://dx.doi.org/10.3748/wjg.v21.i11.3325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363763PMC
March 2015

Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice.

Proteome Sci 2014 10;12(1):56. Epub 2014 Dec 10.

Department of Clinical Pharmacology, University Medical Center Goettingen, Goettingen, Germany.

Background: We investigated the effects of mycophenolate mofetil (MMF) on kidney function and on protein phosphorylation in a mouse model for the human Alport syndrome.

Methods: COL4A3-deficient (COL4A3-/-) mice were randomly allocated to receive a placebo (PLC COL4A3-/-) or MMF treatment (MMF COL4A3-/-). Wild type mice (WT) were used as controls. Changes in serum creatinine, total protein and blood urea nitrogen (BUN), concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG), serum protein electrophoresis, urine dipstick chemistry and sediment were measured. Changes in the phosphorylation status of renal proteins and histology were analyzed.

Results: MMF influenced kidney function and protein phosphorylation. Serum creatinine and BUN were lower in MMF treated compared to PLC treated COL4A3-/- mice. Serum albumin and alpha-1 globulins were significantly decreased while serum creatinine, alpha-2 globulins, urine dipstick protein, leukocyte esterase, hemoglobin and red blood cells were all increased in both COL4A3-/- groups compared to WT. Differential 2DE-gel analysis identified six phosphorylated kidney protein spots that were significantly altered by MMF.

Conclusions: These data suggest that the MMF treatment in this murine model moderately improved kidney function and reversed the phosphorylation status of six renal phosphoprotein spots to that seen in WT mice.
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http://dx.doi.org/10.1186/s12953-014-0056-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269973PMC
December 2014

Graft-derived cell-free DNA as an early organ integrity biomarker after transplantation of a marginal HELLP syndrome donor liver.

Transplantation 2014 Sep;98(5):e43-5

1 Department of Clinical Chemistry University Medical Center Goettingen Goettingen, Germany 2 Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany 3 Chronix Biomedical, Goetheallee Goettingen, Germany.

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http://dx.doi.org/10.1097/TP.0000000000000303DOI Listing
September 2014

Pediatric drug development.

Authors:
Philip D Walson

Clin Ther 2014 Feb;36(2):154-5

Institute for Clinical Chemistry, University Medical Center, Goettingen, Germany.

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http://dx.doi.org/10.1016/j.clinthera.2014.01.012DOI Listing
February 2014

Use of graft-derived cell-free DNA as an organ integrity biomarker to reexamine effective tacrolimus trough concentrations after liver transplantation.

Ther Drug Monit 2014 Apr;36(2):136-40

*Department of Clinical Chemistry, University Medical Center Göttingen; †Chronix Biomedical, Göttingen; and ‡Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Germany.

Background: Immunosuppressant therapeutic ranges for transplant patients have traditionally been established by indirect clinical means. However, "liquid biopsy" methods measuring graft-derived cell-free DNA (GcfDNA) in blood directly interrogate donor organ integrity. This study was performed to determine whether GcfDNA quantification could be used to reexamine minimally effective trough tacrolimus (Tacro) concentrations in liver transplantation (LTx) patients.

Methods: As part of a large prospective study to demonstrate the ability of GcfDNA to identify early graft rejection, 10 adult white LTx patients [8 men, 2 women, 3 hepatitis C virus (HCV) positive; mean ± SD age (years) = 56 ± 9.4] had simultaneous GcfDNA and whole-blood trough Tacro concentrations measured between days 5 and 30 after LTx. Samples were analyzed using droplet digital polymerase chain reaction for GcfDNA and liquid chromatography tandem mass spectrometry for Tacro. GcfDNA and trough Tacro concentrations were then compared to identify Tacro concentrations associated with intact graft integrity.

Results: Although there were large individual differences, there was a highly significant (Fisher P = 0.00002) segregation between whole-blood Tacro concentrations of ≥8 μg/L and normal (≤10%) GcfDNA percentages. The best discrimination in this population between effective and ineffective trough Tacro concentrations was estimated to be at 6.8 μg/L (P < 10(-7)). Compared with HCV- patients (n = 7), the 3 HCV+ patients had more variable associations between GcfDNA percentages and Tacro concentrations.

Conclusions: Direct measurement of graft integrity using GcfDNA was useful to confirm the lower limit of the therapeutic ranges for trough Tacro concentrations after LTx. It would probably be useful to do so also for other immunosuppressant drugs and after other solid organ transplants. The method might be especially useful to detect graft injury during immunosuppressant dose minimization strategies.
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http://dx.doi.org/10.1097/FTD.0000000000000044DOI Listing
April 2014

FoxP3 demethylation is increased in human colorectal cancer and rat cholangiocarcinoma tissue.

Clin Biochem 2014 Feb 26;47(3):201-5. Epub 2013 Nov 26.

Department of Clinical Chemistry, University Medical Center Goettingen, Goettingen, Germany. Electronic address:

Objectives: FoxP3 expression is a marker for Tregs which are known to be involved in tumor immunity. We aimed to evaluate FoxP3 promoter demethylation in human colorectal cancer (CRC) and rat intrahepatic cholangiocarcinoma (ICC).

Design And Methods: Bisulfite-treated genomic DNA templates of shock frozen paired samples were studied from 13 anonymous CRC patients and from 10 male rats (n=6 ICC induced by thioacetamide and n=4 age-matched controls). Real-time PCR was carried out using a LightCycler 480 system. Human FoxP3 and CD3 promoter demethylations were estimated using previously described assays; and rat FoxP3 promoter demethylation using a newly developed assay.

Results: A significant 3.5-fold increase of the demethylation in FoxP3 promoter region was found in human CRC and rat ICC (P<0.05). The average frequency of cells with FoxP3 demethylation in patients suffering from CRC was 0.26% in normal tissue and 0.92% in tumor tissue (n=11 paired samples). Although, no significant difference was found between the mean frequency of CD3 demethylation in normal tissue (4.80%, n=6) and in tumor tissue (4.14%, n=6) from CRC patients, the ratio of demethylated CD3/FoxP3 promoter areas was significantly lower in tumor specimens (P<0.05). Using our novel assay, we found a significant increase in mean frequencies of cells with FoxP3 demethylation in rats with ICC (7.42%, n=6) in comparison to controls (2.14%, n=4).

Conclusion: FoxP3 seems to be an interesting biomarker for immune response to epithelial tumors. Functional consequences from the increase of Tregs remain to be demonstrated. Further studies with outcome data are necessary.
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http://dx.doi.org/10.1016/j.clinbiochem.2013.11.013DOI Listing
February 2014

Can the Roche hemolysis index be used for automated determination of cell-free hemoglobin? A comparison to photometric assays.

Clin Biochem 2013 Sep 2;46(13-14):1298-301. Epub 2013 Jul 2.

Department of Clinical Chemistry, University Medical Center Goettingen, Goettingen, Germany.

Objectives: The aim of this study was to develop a novel method for automated quantification of cell-free hemoglobin (fHb) based on the HI (Roche Diagnostics).

Methods: The novel fHb method based on the HI was correlated with fHb measured using the triple wavelength methods of both Harboe [fHb, g/L = (0.915 * HI + 2.634)/100] and Fairbanks et al. [fHb, g/L = (0.917 * HI + 2.131)/100]. fHb concentrations were estimated from the HI using the Roche Modular automated platform in self-made and commercially available quality controls, as well as samples from a proficiency testing scheme (INSTAND). The fHb using Roche automated HI results were then compared to results obtained using the traditional spectrophotometric assays for one hundred plasma samples with varying degrees of hemolysis, lipemia and/or bilirubinemia.

Results: The novel method using automated HI quantification on the Roche Modular clinical chemistry platform correlated well with results using the classical methods in the 100 patient samples (Harboe: r = 0.9284; Fairbanks et al.: r = 0.9689) and recovery was good for self-made controls. However, commercially available quality controls showed poor recovery due to an unidentified matrix problem.

Conclusions: The novel method produced reliable determination of fHb in samples without interferences. However, poor recovery using commercially available fHb quality control samples currently greatly limits its usefulness.
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http://dx.doi.org/10.1016/j.clinbiochem.2013.06.018DOI Listing
September 2013