High Interpatient Variability Research Articles

Tacrolimus treatment in childhood refractory nephrotic syndrome: A retrospective study on efficacy, therapeutic drug monitoring, and contributing factors to variable blood tacrolimus levels

Tacrolimus, an immunosuppressive drug, was recommended by the 2012 KDIGO guidelines to treat nephrotic syndrome (NS) in children and adults. However, it has high interpatient pharmacokinetic variability and exposure levels should be monitored, although there are no specified target concentrations. This retrospective study aimed to review efficacy and safety after concomitant treatment with tacrolimus and prednisone, and to identify factors that contribute to the variable blood-trough-concentration-to-dose (C0/Dose) ratio in children with refractory NS (RNS). A 6-month therapy induced complete or partial remission in 95% of patients. One-year follow-up indicated a high remission rate and low nephrotoxicity. Under maintenance dosages, approximately 95% of the C0 values were 2–7 ng/mL. Body weight (BW), age, CYP3A5 polymorphisms were the factors affecting the C0/Dose ratio. The C0/Dose ratio in patients with a BW of <20 kg was 1.5-fold than that in patients with BW of ≥40 kg. Moreover, the C0/Dose ratio in patients aged 1–≤6 and 6–≤12 years was significantly lower than that in patients aged 12–≤18 years, by 25% and 48%, respectively. There were no significant association between CYP3A5 genotyping and C0/Dose ratio in younger children (1–≤6 years), rather than older children (6–≤18 years). In conclusion, routine CYP3A5 genotyping should be considered in children aged over 6 years and exposure levels (C0) of 2–7 ng/mL may be feasible when tacrolimus is combined with low-dose prednisone to treat childhood RNS.

Exploring the role of transtibial prosthetic use in deep tissue injury development: a scoping review

BackgroundThe soft tissue of the residual limb in transtibial prosthetic users encounters unique biomechanical challenges. Although not intended to tolerate high loads and deformation, it becomes a weight-bearing structure within the residuum-prosthesis-complex. Consequently, deep soft tissue layers may be damaged, resulting in Deep Tissue Injury (DTI). Whilst considerable effort has gone into DTI research on immobilised individuals, only little is known about the aetiology and population-specific risk factors in amputees. This scoping review maps out and critically appraises existing research on DTI in lower-limb prosthetic users according to (1) the population-specific aetiology, (2) risk factors, and (3) methodologies to investigate both.ResultsA systematic search within the databases Pubmed, Ovid Excerpta Medica, and Scopus identified 16 English-language studies. The results indicate that prosthetic users may be at risk for DTI during various loading scenarios. This is influenced by individual surgical, morphological, and physiological determinants, as well as the choice of prosthetic componentry. However, methodological limitations, high inter-patient variability, and small sample sizes complicate the interpretation of outcome measures. Additionally, fundamental research on cell and tissue reactions to dynamic loading and on prosthesis-induced alterations of the vascular and lymphatic supply is missing.ConclusionWe therefore recommend increased interdisciplinary research endeavours with a focus on prosthesis-related experimental design to widen our understanding of DTI. The results have the potential to initiate much-needed clinical advances in surgical and prosthetic practice and inform future pressure ulcer classifications and guidelines.

CORR Synthesis: What Is the Evidence for the Clinical Use of Stem Cell-based Therapy in the Treatment of Osteoarthritis of the Knee?

CORR Synthesis: What Is the Evidence for the Clinical Use of Stem Cell-based Therapy in the Treatment of Osteoarthritis of the Knee?

Multiscale receptive field based on residual network for pancreas segmentation in CT images

Medical image segmentation has made great achievements. Yet pancreas is a challenging abdominal organ to segment due to the high inter-patient anatomical variability in both shape and volume metrics. The UNet often suffers from pancreas over-segmentation, under-segmentation and shape inconsistency between the predicted result and ground truth. We consider the UNet can not extract more deepen features and rich semantic information which can not distinguish the regions between pancreas and background. From this point, we proposed three cross-domain information fusion strategies to solve above three problems. The first strategy named skip network can efficiently restrain the over-segmentation through cross-domain connection. The second strategy named residual network mainly seeks to solve the under- and over- segmentation problem by cross-domain connecting on a small scale. The third multiscale cross-domain information fusion strategy named multiscale residual network added multiscale convolution operation on second strategy which can learn more accurate pancreas shape and restrain over- and under- segmentation. We performed experiments on a dataset of 82 abdominal contrast-enhanced three dimension computed tomography (3D CT) scans from the National Institutes of Health Clinical Center using 4-fold cross-validation. We report 87.57 ± 3.26 % of the mean Dice score, which outperforms the state-of-the-art method, producing 7.87 % improvement from the predicted result of original UNet. Our method is not only superior to the other established methods in terms of accuracy and robustness but can also effectively restrain pancreas over-segmentation, under-segmentation and shape inconsistency between the predicted result and ground truth. Our strategies prone to apply to clinical medicine.

A comparison of methods for adapting dose-voxel-kernels to tissue inhomogeneities

In radionuclide therapies, dosimetry is used for determining patient-individual dose burden. Standard approaches provide whole organ doses only. For assessing dose heterogeneity inside organs, voxel-wise dosimetry based on 3D SPECT/CT imaging could be applied. Often, this is achieved by convolving voxel-wise time-activity-curves with appropriate dose-voxel-kernels (DVK). The DVKs are meant to model dose deposition, and can be more accurate if modelled for the specific tissue type under consideration. In literature, DVKs are often not adapted to these inhomogeneities, or simple approximation schemes are applied.For 26 patients, which had previously undergone a -PSMA or -DOTATOC therapy, decay maps, mass-density maps as well as tissue-type maps were derived from SPECT/CT acquisitions. These were used for a voxel-based dosimetry based on convolution with DVKs (each of size ) obtained by four different DVK methods proposed in literature. The simplest only considers a spatially constant soft-tissue DVK (herein named ‘constant’), while others either take into account only the local density of the center voxel of the DVK (herein named ‘center-voxel’) or scale each voxel linearly according to the proper mass density deduced from the CT image (herein named ‘density’) or considered both the local mass density as well as the direct path between the center voxel and any voxel in its surrounding (herein named ‘percentage’). Deviations between resulting dose values and those from full Monte-Carlo simulations (MC simulations) were compared for selected organs and tissue-types.For each DVK method, inter-patient variability was considerable showing both under- and over-estimation of energy dose compared to the MC result for all tissue densities higher than soft tissue. In kidneys and spleen, ‘constant’ and ‘density’-scaled DVKs achieved estimated doses with smallest deviations to the full MC gold standard (∼ underestimation). For low and high density tissue types such as lung and adipose or bone tissue, alternative DVK methods like ‘center-voxel’- and ‘percentage’- scaled achieved superior results, respectively. Concerning computational load, dose estimation with the DVK method ‘constant’ needs about 1.1 s per patient, center-voxel scaling amounts to 1.2 s, density scaling needs 1.4 s while percentage scaling consumes 860.3 s per patient.In this study encompassing a large patient cohort and four different DVK estimation methods, no single DVK-adaption method was consistently better than any other in case of soft tissue kernels. Hence in such cases the simplest DVK method, labeled ‘constant’, suffices. In case of tumors, often located in tissues of low (lung) or high (bone) density, more sophisticated DVK methods excel. The high inter-patient variability indicates that for evaluating new algorithms, a sufficiently large patient cohort needs to be involved.

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer

To investigate the exposure–safety relationships of afatinib in Japanese population, we performed population pharmacokinetics (PK) analysis of afatinib in Japanese advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutation. Plasma samples were collected at 0.5–1, 2–3, 8–12, and 24 h after oral afatinib (40 mg) administration on day 1 and day 8. Plasma afatinib concentrations were determined using high-performance liquid chromatography. Data was analyzed following the population approach and using the software Phoenix® NLMETM Version 7.0 software (Certara USA, Inc., Princeton, NJ, USA). From 34 patients, a total of 354 afatinib plasma concentration values were available for the population PK analysis. Significant covariates in the population PK model included aspartate aminotransferase and creatinine clearance on CL/F, and age and body mass index on V/F. Results of simulation based on final PK model indicated that hepatic impairment had a significant effect on afatinib levels in plasma after multiple dosing. Afatinib trough plasma concentrations on day 8 were higher in patients with adverse events of grade 3 or higher. The population PK analysis showed that hepatic impairment affected afatinib PK parameters and contributed to the high inter-patient variability and high plasma concentrations of afatinib following multiple treatments.

Act Guided Heparin Administration in Elective Open Abdominal Aortic Aneurysm Repair: Results of A Pilot Study

Introduction: Almost all vascular surgeons use a bolus of 5 000 IU of unfractionated heparin (UFH). However, its dose-response and elimination curves are non-linear, and display a high inter-patient variability. The activated clotting time (ACT) is an established method to measure the level of anticoagulation. The purpose of this study was to evaluate the rate of arterial thrombo-embolic complications (ATEC) and bleeding complications in patients undergoing elective open abdominal aortic aneurysm repair (AAA), in which a bolus of 5 000 IU of UFH was compared to an ACT guided additional UFH dose protocol. Methods: All consecutive patients that underwent primary elective open AAA repair were included from a multicentre (1 academic and 2 peripheral hospitals) prospective study on ACT guided heparinization (MANCO: Measuring the ACT during non-cardiac arterial procedures, Clin. Trials.gov NCT 03426293). ACT measurements were performed as a bedside point-of-care test. During the first part of the study patients received a bolus of 5 000 IU. During the second part of the study patients received an initial bolus of 5 000 IU or 100 IU/kg and additional UFH dosages were administered, with a target ACT of 200 - 250 sec. The primary study endpoints were ATEC (graft thrombosis, embolism, myocardial infarction, transient ischemic attack, minor and major stroke, pulmonary embolism, bowel ischemia) detected during the procedure or during 30 day follow-up or during the same admission of the primary procedure, bleeding complications and mortality during 30 day follow-up. The secondary study endpoints were all other complications, the level of periprocedural anticoagulation as measured by the ACT and the additional and total UFH dosages administered. Results: 46 primary elective open AAA procedures were included, 18 patients in the standard dose group and 28 patients in the additional dose group. In the standard dose group 28% of patients reached an ACT of 200 sec. compared to 100% in the additional dose group. In the additional dose group the mean total periprocedural UFH dose administered was 9874 ± 2909 IU. ATEC occurred in 27.8% of patients in the standard dose group versus 14.3% in the additional dose group (P= 0.26). Bleeding complications did not increase in the additional dose group (38.9 versus 35.7%, P= 0.83). In both groups no patient died during 30 day follow-up. Conclusion: A standard dose of 5000 IU UFH leads to inadequate levels of heparinisation. Higher dosing of UFH aimed at an ACT of 200 sec. is safe, does not lead to increased bleeding, and potentially leads to a reduction in ATEC. A randomized controlled trial is needed to provide evidence on potential reduction in thrombo-embolic complications. Disclosure: Grant of Medtronic to perform the ACT measurements.

High Interpatient Variability in Molecular MRD Response to Consolidation Chemotherapy in Acute Myeloid Leukemia

High Interpatient Variability in Molecular MRD Response to Consolidation Chemotherapy in Acute Myeloid Leukemia

A Phase I Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Tripegfilgrastim (Dulastin®) after Single Administration in Pediatric Patients

Introduction: Chemotherapy-induced neutropenia (CIN) is one of main complications following systemic chemotherapy, which can cause many kinds of opportunistic infections. To overcome CIN, granulocyte colony stimulating factor (G-CSF) is usually administered to reduce neutropenic period. Tripegfilgrastim (Dulastin®) is one of pegfilgrastim drugs, which was approved for adult CIN by Korea Ministry of Food and Drug Safety in 2014. Methods: We have conducted a phase I, open-label, single ascending dose study to investigate the pharmacokinetics, safety, tolerability and pharmacodynamics of Tripegfilgrastim in pediatric patients with lymphoma or solid tumors. The patients were divided by dose of Tripegfilgrastim (60 μg/kg [lower dose, LD] and 100 μg/kg [higher dose, HD]) and age (6≤ and &amp;lt;12 years versus 12≤ and &amp;lt;19 years). Total planned number of patients was 32; 8 patients in each groups. Tripegfilgrastim was injected subcutaneously at 24 hours after the end of chemotherapy, and serial pharmacokinetic/pharmacodynamics blood samplings and safety monitoring were conducted. The trial was registered at ClinicalTrials.gov, NCT02963389. This study was supported by Dong-A ST Co., Ltd., Seoul, Republic of Korea. Results: Twenty-seven patients enrolled on this study, including 4 in LD and younger age group, 7 in LD and older age group, 8 in HD and younger age group, and 8 in HD and older age group. Six malignant germ cell tumors, 5 non-rhabdomyosarcoma soft tissue sarcomas, 4 osteosarcomas, 3 rhabdomyosarcomas, 3 neuroblastomas, 2 medulloblastomas, and 4 others were included. All enrolled patients had previously received the same-regimen chemotherapy, which had induced grade 4 neutropenia. Due to insufficient pharmacodynamics by interim analysis in some patients of LD groups, these were early closed and subsequent enrolled patients received HD of Tripegfilgrastim. The maximum concentration (Cmax) and area under the curve until 312 hours (AUC0-312h) were 89.57 ± 40.97 μg/L and 8371.99 ± 4773.29 μg∙h/L in LD group, and 130.15 ± 72.04 μg/L, 11977.40 ± 7572.29 μg∙h/L in HD group, respectively. The peak concentration was achieved at 24 hours after injection, and the Cmax and AUC0-312h of HD group were increased by 45% compared with LD group. The half-life, clearance, and volume of distribution were 47.22 hours, 0.45 L/h, 28.1 L in LD group, 40.78 hours, 0.52 L/h, 28.78 L in HD group, respectively. When these pharmacokinetics parameters were compared with our previous results of healthy adult volunteers, Cmax of LD group was similar to adult 3.6 mg injection, while Cmax and AUC0-312h of HD group were 36% and 50% of those of adult 6.0 mg injection. To investigate the pharmacodynamics, days when the absolute neutrophil count (ANC) is above 1,000/μL (T above ANC 1000), and days when ANC is below 500/μL (T below ANC 500) were evaluated. The mean T above ANC 1000 (range, days) were 7.1 days (1.6-13.6) in LD group, and 9.3 days (3.4-13.7) in HD group, respectively. Furthermore, the mean T below ANC 500 (range, days) were 4.4 days (0-10.8) in LD group, and 2.5 days (0-10.1) in HD group, respectively, which showed better pharmacodynamics in HD group. However, high inter-patient variability was observed. There was no significant difference between younger and older age groups in each LD and HD groups. There were 2 adverse drug reactions (7.4%) related to Tripegfilgrastim, which were grade 1 back pain and grade 2 arthralgia. Three severe adverse events occurred (2 bacteremia and 1 skin lesion), which resolved with further treatments. Conclusions: Tripegfilgrastim have shown safety and tolerability in pediatric patients between 6 to 19 years old with solid tumors. The pharmacokinetics parameters, Cmax and AUC0-312h of HD group were increased by 45% compared with LD group, which translates into the better pharmacodynamics parameters of HD group without increasing toxicity. Our results suggests that Tripegfilgrastim 100 μg/kg once injection could be feasible to reduce CIN in pediatric patients. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Tripegfilgrastim to investigate the safety, tolerability, and pharmacokinetics/pharmacodynamics

Drug Exposure to Establish Pharmacokinetic-Response Relationships in Oncology.

In the oncology field, understanding the relationship between the dose administered and the exerted effect is particularly important because of the narrow therapeutic index associated with anti-cancer drugs and the high interpatient variability. Therefore, in this review, we provide a critical perspective of the different methods of characterising treatment exposure in the oncology setting. The increasing number of modelling applications in oncology reflects the applicability and the impact of pharmacometrics on all phases of the drug development process and patient management as well. Pharmacometric modelling is a worthy component within the current paradigm of model-based drug development, but pharmacometric modelling techniques are also accessible for the clinician in the optimisation of current oncology therapies. Consequently, the application of population models in a hospital setting by generating close collaborations between physicians and pharmacometricians is highly recommended, providing a systematic means of developing and assessing model-based metrics as 'drivers' for various responses to treatments, which can then be evaluated as predictors for treatment success. Characterising the key determinants of variability in exposure is of particular importance for anticancer agents, as efficacy and toxicity are associated with exposure. We present the different strategies to describe and predict drug exposure that can be applied depending on the data available, with the objective of obtaining the most useful information in the patients' favour throughout the full drug cycle. Therefore, the objective of the present article is to review the different approaches used to characterise a patient's exposure to oncology drugs, which will result in a better understanding of the time course of the response and the magnitude of interpatient variability.

Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer-From Basic Research to Potential Clinical Applications.

Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as well as epigenetic mechanisms are important in CRC pathogenesis, the basis of the most cases of cancer is unknown. High spatial and inter-patient variability of the molecular alterations qualifies this cancer in the group of highly heterogeneous tumors, which makes it harder to elucidate the mechanisms underlying CRC progression. Determination of highly sensitive and specific early diagnosis markers and understanding the cellular and molecular mechanism(s) of cancer progression are still a challenge of the current era in oncology of solid tumors. One of the accepted risk factors for CRC development is overexpression of insulin-like growth factor 2 (IGF2), a 7.5-kDa peptide produced by liver and many other tissues. IGF2 is the first gene discovered to be parentally imprinted. Loss of imprinting (LOI) or aberrant imprinting of IGF2 could lead to IGF2 overexpression, increased cell proliferation, and CRC development. IGF2 as a mitogen is associated with increased risk of developing colorectal neoplasia. Higher serum IGF2 concentration as well as its tissue overexpression in CRC compared to control are associated with metastasis. IGF2 protein was one of the three candidates for a selective marker of CRC progression and staging. Recent research indicates dysregulation of different micro- and long non-coding RNAs (miRNAs and lncRNAs, respectively) embedded within the IGF2 gene in CRC carcinogenesis, with some of them indicated as potential diagnostic and prognostic CRC biomarkers. This review systematises the knowledge on the role of genetic and epigenetic instabilities of IGF2 gene, free (active form of IGF2) and IGF-binding protein (IGFBP) bound (inactive form), paracrine/autocrine secretion of IGF2, as well as mechanisms of inducing dysplasia in vitro and tumorigenicity in vivo. We have tried to answer which molecular changes of the IGF2 gene and its regulatory mechanisms have the most significance in initiation, progression (including liver metastasis), prognosis, and potential anti-IGF2 therapy in CRC patients.

Therapeutic Drug Monitoring of Oral Anticancer Drugs: The Dutch Pharmacology Oncology Group-Therapeutic Drug Monitoring Protocol for a Prospective Study.

Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes. In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase. Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.

442O - Therapeutic drug monitoring of oral anticancer drugs - preliminary results of a prospective study

BackgroundOral anticancer drugs show a high interpatient variability in pharmacokinetics (PK). Even though exposure has been linked to efficacy and toxicity for many of these drugs, they are still dosed using a one-size-fits-all approach. Consequently, individual patients (pts) have a high probability to be either underdosed or overdosed, potentially leading to decreased antitumor efficacy or increased toxicity. Therapeutic drug monitoring (TDM), which is personalised dosing based on measured drug levels, can be used to address these problems and thereby optimize treatment outcomes. MethodsThis prospective clinical study (www.trialregister.nl, NL6695) evaluates the feasibility, tolerability and efficacy of TDM of oral anticancer drugs. In total, 600 pts will be included for 23 different drugs. Pts starting regular treatment with one of these drugs at the approved dose are included. PK sampling is performed 4, 8, and 12 weeks after start of treatment and every 12 weeks thereafter. Drug concentrations are measured and trough concentrations (Cmin) are estimated. In case of Cmin below the predefined target and acceptable toxicity, a PK-guided intervention is recommended. This may include emphasizing compliance, adaptations in concomitant medication (due to drug-drug interactions), concomitant intake with food, splitting intake moments or dose increments. ResultsIn total, 274 pts were included (trametinib (n=43), abiraterone (n=38), enzalutamide (n=35), imatinib (n=33), pazopanib (n=23), other (n=102)), of whom 246 pts had available PK data. 83 pts (34%) were underdosed and had ≥ 1PK samples below the predefined target. In 48 of 246 pts (20%) a PK-guided intervention was performed, which was successful (i.e. target attainment without additional toxicities) in 39 pts (81%). In 35 pts, a PK-guided intervention could not be performed, due to toxicity (17 pts), logistical reasons (13 pts) or lack of physician adherence (5 pts). ConclusionsThis prospective study shows that PK-guided dose optimization of oral anticancer drugs is feasible in clinical practice. A PK-guided intervention was recommended in 20% of the patients and resulted in target attainment without additional toxicities in 81% of these patients. Clinical trial identificationNL6695; release date: 6 December 2017. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek Hospital. FundingUnrestricted research grant of Novartis, Pfizer and Roche. DisclosureS.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. D.J.A.R. Moes: Advisory / Consultancy: Sandoz; Advisory / Consultancy, Research grant / Funding (institution): Chiesi Pharmaceuticals. I.M.E. Desar: Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Eisai. D.J. Touw: Advisory / Consultancy: Sanguin; Research grant / Funding (institution): Chiesi Pharmaceuticals. N.P. van Erp: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Gilead. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (institution), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.

1178PD - A phase I trial of GEN-009, a neoantigen vaccine using ATLAS™, an autologous immune assay, to identify immunogenic and inhibitory tumour mutations

1178PD - A phase I trial of GEN-009, a neoantigen vaccine using ATLAS™, an autologous immune assay, to identify immunogenic and inhibitory tumour mutations

A prospective phase I multicentre randomized cross-over pharmacokinetic study to determine the effect of food on abiraterone pharmacokinetics

PurposeAbiraterone acetate is used at a fixed oral dose of 1000 mg once daily (OD) taken fasted. By administering abiraterone acetate with food, a reduced dose can potentially be given while maintaining equivalent abiraterone exposure. Moreover, administering abiraterone acetate with a breakfast is considered more patient friendly. The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast (CB) compared to the standard intake of 1000 mg OD fasted.MethodsIn this phase I, randomized cross-over, multi-center study, abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic castration-resistant prostate cancer who were treated for 14 days with 1000 mg abiraterone acetate taken fasted, followed by 14 days of treatment with 500 mg taken with a CB.Results14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. The geometric mean ratio (GMR) (fed/fasted) was 0.88 (90% CI 0.73–1.07) for area-under-the-curve (AUC0–24h), 1.03 (90% CI 0.79–1.34) for Cmax and 0.81 (90% CI 0.60–1.10) for Ctrough, respectively. High inter-patient variability (> 50%) was found for all PK parameters under both intake conditions. Patients seemed to be slightly more satisfied about the intake of 500 mg abiraterone acetate when taken with a CB compared to 1000 mg fasted.ConclusionIn conclusion, a bioequivalent lower dose of abiraterone taken with food could not be established in our study. Although based on the absence of a exposure–toxicity relationship, the strict bioequivalence margins as defined by the FDA guidelines could be applied more flexible for abiraterone. Information on the effect of food on abiraterone pharmacokinetics as presented in our study can be used for patients with difficulties taken their medication fasted.

Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients

Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that von Willebrand factor (VWF) half-life, as modified by the ABO blood group, is a strong regulator of FVIII PK. The FVIII-binding activity of VWF positively correlated with FVIII half-life, and the rare or low-frequency nonsynonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, were associated with the FVIII PK profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII PK in a pediatric population. Moreover, this study is the first to identify non-VWF and non-ABO variants that modify FVIII PK in pediatric hemophilia A patients.

Beyond Survival in Solid Organ Transplantation: A Summary of Expert Presentations from the Sandoz 6th Standalone Transplantation Meeting, 2018.

Beyond Survival in Solid Organ Transplantation: A Summary of Expert Presentations from the Sandoz 6th Standalone Transplantation Meeting, 2018.

Layer-Wise Relevance Propagation for Explaining Deep Neural Network Decisions in MRI-Based Alzheimer's Disease Classification.

Deep neural networks have led to state-of-the-art results in many medical imaging tasks including Alzheimer's disease (AD) detection based on structural magnetic resonance imaging (MRI) data. However, the network decisions are often perceived as being highly non-transparent, making it difficult to apply these algorithms in clinical routine. In this study, we propose using layer-wise relevance propagation (LRP) to visualize convolutional neural network decisions for AD based on MRI data. Similarly to other visualization methods, LRP produces a heatmap in the input space indicating the importance/relevance of each voxel contributing to the final classification outcome. In contrast to susceptibility maps produced by guided backpropagation (“Which change in voxels would change the outcome most?”), the LRP method is able to directly highlight positive contributions to the network classification in the input space. In particular, we show that (1) the LRP method is very specific for individuals (“Why does this person have AD?”) with high inter-patient variability, (2) there is very little relevance for AD in healthy controls and (3) areas that exhibit a lot of relevance correlate well with what is known from literature. To quantify the latter, we compute size-corrected metrics of the summed relevance per brain area, e.g., relevance density or relevance gain. Although these metrics produce very individual “fingerprints” of relevance patterns for AD patients, a lot of importance is put on areas in the temporal lobe including the hippocampus. After discussing several limitations such as sensitivity toward the underlying model and computation parameters, we conclude that LRP might have a high potential to assist clinicians in explaining neural network decisions for diagnosing AD (and potentially other diseases) based on structural MRI data.

Novel Methods of Incorporating Time in Longitudinal Multivariate Analysis Reveals Hidden Associations With Disease Activity in Systemic Lupus Erythematosus.

Objective: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. SLE is characterized by high inter-patient variability, including fluctuations over time, a factor which most biomarker studies omit from consideration. We investigated relationships between disease activity and biomarker expression in SLE, using novel methods to control for time-dependent variability, in a proof-of-concept study to evaluate whether doing so revealed additional information.Methods: We measured 4 serum biomarkers (MIF, CCL2, CCL19, and CXCL10) and 13 routine clinical laboratory parameters, alongside disease activity measured by the SLE disease activity index-2k (SLEDAI-2k), collected longitudinally. We analyzed these data with unsupervised learning methods via ensemble clustering, incorporating temporal relationships using dynamic time warping for distance metric calculation.Results: Data from 843 visits in 110 patients (median age 47, 83% female) demonstrated highly heterogeneous time-dependent relationships between disease activity and biomarkers. Unbiased magnitude-based hierarchical clustering of biomarker expression levels isolated a patient subset (n = 9) with distinctively heterogeneous expression of the 17 biological parameters, and who had MIF, CCL2, CCL19, and CXCL10 levels that were higher and more strongly associated with disease activity, based on leave-one-out cross-validated regression analysis. In the remaining subgroup, a time-dependent regression model revealed significantly stronger predictive power of biomarkers for disease activity, compared to a time-agnostic regression model. Despite no significant difference in simple magnitude, using dynamic time warping analysis to align longitudinal profiles revealed a large subset (n = 69) with significantly stronger associations between biological parameters and disease activity. This subgroup had significantly lower flare rates, disease activity and damage scores, suggesting this clustering is clinically meaningful.Conclusions: These results suggest associations between biological parameters and disease activity in SLE exist in a multi-dimensional time-dependent pattern, with implications for the analysis of biomarkers in SLE often used to identify therapeutic targets. Novel methods to analyse high-dimensional data and control for time-dependent variability may have broad utility in the study complex relationships between clinical and biological parameters.

The management of haemoglobin interference for the MALDI-MSI proteomics analysis of thyroid fine needle aspiration biopsies.

MALDI-MSI represents an ideal tool to explore the spatial distribution of proteins directly in situ, integrating molecular and cytomorphological information, enabling the discovery of potential diagnostic markers in thyroid cytopathology. However, red cells present in the fine needle aspiration biopsy (FNAB) specimens caused ion suppression of other proteins during the MALDI-MSI analysis due to large amount of haemoglobin. Aim of this study was to set up a sample preparation workflow able to manage this haemoglobin interference. Three protocols were compared using ex vivo cytological samples collected from fresh thyroid nodules of 9 patients who underwent thyroidectomy: (A) conventional air-dried smears, (B) cytological smears immediately fixed in ethanol, and (C) ThinPrep liquid-based preparation. Protocols C and A were also evaluated using real FNABs. Results show that protocol C markedly decreased the amount of haemoglobin, with respect to protocols A and B. Protein profiles obtained with protocols A and B were characterised by high inter-patient variability, probably related to the abundance of the haemoglobin, whereas similar spectra were observed for protocol C, where haemoglobin contents were lower. Our findings suggest protocol C as the sample preparation method for MALDI-MSI analysis. Graphical abstract.