PrimerX: A Bayesian Multistage Cohort Embedded Randomised Trial to Evaluate the Role of Deferred Local Therapy of the Primary Tumour in Combination with Immune Checkpoint Inhibitor-based First-line Therapy in Metastatic Renal Cell Carcinoma Patients.

Background: Historically, patients with metastatic renal cell carcinoma (mRCC) have been offered upfront cytoreductive nephrectomy (CN) followed by systemic therapy. Currently, CN is no longer the standard of care (SOC) based on the randomised phase 3 CARMENA study performed in the vascular endothelial growth factor receptor tyrosine kinase inhibitor era. With the advent of immune checkpoint inhibitor (ICI) combination therapy in first line, the role of CN needs to be reassessed.

Early Detection of Ovarian Cancer Using Cell-Free DNA Fragmentomes and Protein Biomarkers.

There is an unmet need for effective ovarian cancer screening and diagnostic approaches that enable earlier-stage cancer detection and increased overall survival. We have developed a high-performing accessible approach that evaluates cfDNA fragmentomes and protein biomarkers to detect ovarian cancer.

Biochemical Response of <0.1 ng/ml Predicts Therapy-free Survival of Prostate Cancer Patients following Prostate-specific Membrane Antigen-targeted Salvage Surgery.

Background: In a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value.

Objective: To evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS.

A Dutch Survey on Medication Adjustments after Metabolic and Bariatric Surgery: Experiences of Bariatric Surgeons, Internists, Pharmacists, and General Practitioners.

Background: As metabolic and bariatric surgery (MBS) can alter the pharmacokinetics of drugs, post-bariatric surgery patients may require medication adjustments and monitoring. To improve pharmacotherapy in these patients, we aimed to understand the beliefs, attitudes, knowledge, and concerns of healthcare professionals who treat these patients.

Methods: A survey by means of an online questionnaire was divided into six sections.

The use of microtracers in food-effect trials: An alternative study design for toxic drugs with long half-lives exemplified by the case for alectinib.

The traditional design of food-effect studies has a high patient burden for toxic drugs with long half-lives (e.g., anticancer agents).

Impact of Bariatric Surgery in the Short and Long Term: A Need for Time-Dependent Dosing of Drugs.

Sparse information is available on pharmacokinetic changes of drugs over time after bariatric surgery. By reviewing the literature on the short- and long-term pharmacokinetic changes of drugs, several patterns were identified for 39 drugs. No relevant pharmacokinetic changes were identified for roughly a third of the drugs.

Higher Preoperative Maximum Standardised Uptake Values (SUV) Are Associated with Higher Biochemical Recurrence Rates after Robot-Assisted Radical Prostatectomy for [Ga]Ga-PSMA-11 and [F]DCFPyL Positron Emission Tomography/Computed Tomography.

This study aimed to investigate the association between the Ga- or F-radiolabeled prostate-specific membrane antigen (PSMA) tracer expression, represented by the maximum standardised uptake value (SUV) of the dominant intraprostatic lesion, and biochemical recurrence (BCR) in primary prostate cancer (PCa) patients prior to robot-assisted radical prostatectomy (RARP). This was a retrospective, multi-centre cohort study of 446 patients who underwent [Ga]Ga-PSMA-11 ( = 238) or [F]DCFPyL ( = 206) Positron Emission Tomography/Computed Tomography (PET/CT) imaging prior to RARP. SUV was measured in the dominant intraprostatic PCa lesions.

Patients with bariatric surgery: Urgent need for accurate registration of the contraindication to enable safe pharmacotherapy in hospital and primary care.

Purpose: To enable the use of automatic clinical decision support for pharmacotherapy in patients with bariatric surgery, it is necessary to register the contraindication "bariatric surgery" in the hospital, general practitioner (GP), and community pharmacy electronic health record systems. The aim of this research was to quantify the correct registration of this contraindication in hospital, GP, and community pharmacy records. Furthermore, we investigated whether the registration status in primary care was dependent on the registration status in the hospital.

Development and validation of an ultra-high performance liquid chromatography coupled to tandem mass spectrometry method for the quantification of the antileishmanial drug paromomycin in human skin tissue.

Bioanalytical assay development and validation procedures were performed to quantify antiprotozoal drug paromomycin in human skin tissue by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Paromomycin, an aminoglycoside drug, is administered intra-muscularly and used in the treatment of multiple clinical presentations of the neglected tropical disease leishmaniasis. It is currently studied in the treatment of post-kala-azar dermal leishmaniasis, a disease where the Leishmania parasites divide and reside in the skin.

Bioanalytical methods for pharmacokinetic studies of antileishmanial drugs.

Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to conduct pharmacokinetic (PK) analysis. This review provides a comprehensive overview of published validated bioanalytical assays for the quantification of antileishmanial drugs amphotericin B, miltefosine, paromomycin, pentamidine, and pentavalent antimonials in human matrices. The applicability of the assays for leishmaniasis clinical trials as well as their relevance to PK studies with emphasis on the choice of matrix, calibration range, sample volume, sample preparation, choice of internal standards, separation, and detection was discussed for each antileishmanial drug.

Development and validation of a high-performance liquid chromatography tandem mass spectrometry method for the quantification of the antiparasitic and antifungal drug amphotericin B in human skin tissue.

Amphotericin B is an antifungal and antiparasitic drug used in first-line treatment of the parasitic neglected tropical disease leishmaniasis. Liposomal amphotericin B is currently studied for the treatment of cutaneous and post-kala-azar dermal leishmaniasis, where the dermis of the skin is infected with Leishmania parasites. For the optimization of known treatment regimens, accurate target-site concentrations of the drug are required.

Cohort Study of Oligorecurrent Prostate Cancer Patients: Oncological Outcomes of Patients Treated with Salvage Lymph Node Dissection via Prostate-specific Membrane Antigen-radioguided Surgery.

Background: In a subset of patients with recurrent oligometastatic prostate cancer (PCa) salvage surgery with prostate-specific membrane antigen (PSMA)-targeted radioguidance (PSMA-RGS) might be of value.

Objective: To evaluate the oncological outcomes of salvage PSMA-RGS and determine the predictive preoperative factors of improved outcomes.

Design, Setting, And Participants: A cohort study of oligorecurrent PCa patients with biochemical recurrence (BCR) after radical prostatectomy and imaging with PSMA positron emission tomography (PET), treated with PSMA-RGS in two tertiary care centers (2014-2020), was conducted.

Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis.

Introduction: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown.

Development and validation of an HPLC-MS/MS method for the quantification of the anti-leishmanial drug miltefosine in human skin tissue.

Miltefosine is the only oral drug approved for the treatment of various clinical presentations of the neglected parasitic disease leishmaniasis. In cutaneous leishmaniasis and post-kala-azar dermal leishmaniasis, Leishmania parasites reside and multiply in the dermis of the skin. As miltefosine is orally administered and this drug is currently studied for the treatment of these skin-related types of leishmaniasis, there is an urgent need for an accurate assay to determine actual miltefosine levels in human skin tissue to further optimize treatment regimens through target-site pharmacokinetic studies.

Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty-Related Diseases: A Systematic Review.

Background: Patients affected by poverty-related infectious diseases (PRDs) are disproportionally affected by malnutrition. To optimize treatment of patients affected by PRDs, we aimed to assess the influence of malnutrition associated with PRDs on drug pharmacokinetics, by way of a systematic review.

Methods: A systematic review was performed on the effects of malnourishment on the pharmacokinetics of drugs to treat PRDs, including HIV, tuberculosis, malaria, and neglected tropical diseases.

Blood Parasite Load as an Early Marker to Predict Treatment Response in Visceral Leishmaniasis in Eastern Africa.

Background: To expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes.

Methods: Data from 3 clinical trials were combined in this study, in which Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative polymerase chain reaction (qPCR) before, during, and up to 6 months after treatment.

Noninvasive, in vivo assessment of the cervical microcirculation using incident dark field imaging.

Aim: This study evaluates the feasibility of handheld vital microscopy for noninvasive, objective assessment of the microcirculation of the human uterine cervix. We qualitatively and quantitatively describe the microcirculation in healthy subjects in order to provide a basis for its application in cervical pathology.

Methods: Incident dark field imaging was used to image the microcirculation in four quadrants of the uterine ectocervix in ten healthy participants.

Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy.

Background: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be delineated accurately.

Objective: To describe and evaluate surgical technique, biochemical response, and therapy-free survival (TFS) after salvage surgery in patients with local recurrence in the seminal vesicle bed.

Design, Setting, And Participants: We retrospectively assessed 40 patients treated with open salvage surgery in two centres (11/2014-02/2020).

Intracellular Pharmacokinetics of Pyrimidine Analogues used in Oncology and the Correlation with Drug Action.

Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves several metabolic steps including sequential phosphorylation to its monophosphate, diphosphate and triphosphate. The intracellularly formed nucleotides are responsible for the pharmacological effects.

Highly sensitive UPLC-MS/MS method for the quantification of paromomycin in human plasma.

A highly sensitive method was developed to quantitate the antileishmanial agent paromomycin in human plasma, with a lower limit of quantification of 5 ng/mL. Separation was achieved using an isocratic ion-pair ultra-high performance liquid chromatographic (UPLC) method with a minimal concentration of heptafluorobutyric acid, which was coupled through an electrospray ionization interface to a triple quadrupole - linear ion trap mass spectrometer for detection. The method was validated over a linear calibration range of 5 to 1000 ng/mL (r≥0.

Optimizing algorithm development for tissue classification in colorectal cancer based on diffuse reflectance spectra.

Diffuse reflectance spectroscopy can be used in colorectal cancer surgery for tissue classification. The main challenge in the classification task is to separate healthy colorectal wall from tumor tissue. In this study, four normalization techniques, four feature extraction methods and five classifiers are applied to nine datasets, to obtain the optimal method to separate spectra measured on healthy colorectal wall from spectra measured on tumor tissue.