Van Leeuwenhoek Research Articles

Spontaneous electrical low-frequency oscillations: a possible role in Hydra and all living systems.

As one of the first model systems in biology, the basal metazoan Hydra has been revealing fundamental features of living systems since it was first discovered by Antonie van Leeuwenhoek in the early eighteenth century. While it has become well-established within cell and developmental biology, this tiny freshwater polyp is only now being re-introduced to modern neuroscience where it has already produced a curious finding: the presence of low-frequency spontaneous neural oscillations at the same frequency as those found in the default mode network in the human brain. Surprisingly, increasing evidence suggests such spontaneous electrical low-frequency oscillations (SELFOs) are found across the wide diversity of life on Earth, from bacteria to humans. This paper reviews the evidence for SELFOs in diverse phyla, beginning with the importance of their discovery in Hydra, and hypothesizes a potential role as electrical organism organizers, which supports a growing literature on the role of bioelectricity as a ‘template’ for developmental memory in organism regeneration.This article is part of the theme issue ‘Basal cognition: conceptual tools and the view from the single cell’.

Comparative evaluation of antimicrobial properties of piperidine and apple cider vinegar on Streptococcus mutans and in-silico demonstration of the mechanism of action

In the seventeenth century, Antonie van Leeuwenhoek first observed “animalcules” swarming on living and dead matter out of curiosity he discovered these “animalcules” on his own teeth, it is reasonable to suggest that this early study of dental plaque was the first documented evidence of the existence of microbial biofilms. Biofilm is an association of micro-organisms in which microbial cells adhere to each other on a wide range surfaces i.e. biological and inert surfaces within a self-produced matrix of extracellular polymeric substances (EPS). Bacterial biofilm is infectious in nature and can result in infections. The microbial biofilm of caries is diverse and contains many facultative and obligate anaerobic bacteria, S. mutans, is the most common acid producer, primarily associated with caries. Due to increased resistance to antibiotics and other antimicrobial agents there is a need for effective and economical way to control the oral biofilm. Chlorhexidine is the most commonly used antimicrobial agent in dentistry as they destroy wide spectrum of microrganisms. Black pepper (Piper nigrum L.) is used in traditional medicinal systems as an antimicrobial due to presence of volatile compounds, tannins, phenols and various unknown substances. Similarly, acetic acid in apple cider vinegar effective against several types of bacteria and acts as an antimicrobial agent. Methodology: The current study focuses on In-vitro studies on biofilm establishment by S. mutans followed by competitive quenching of the biofilm by Piperidine from black pepper and apple cider vinegar which was carried out at 50,100 150µL concentrations using bacterial growth assessment by spectrophotometer and crystal violet assay. Chlorhexidine has been used as the positive control. Conclusion: Statistical analysis of the results was carried out to determine the correlation between the intensity of biofilm and the concentration of the test materials to evaluate the competence of the three candidate materials tested. The mechanism of anti-biofilm activity has been demonstrated through insilico docking between Piperidine and S. mutans. The study predicts the prospects of Piperidine based product formulations for dental treatments.

Oral microflora: Varied habitats, niche and their disparity in systemic health

The discovery of microbes dates back to the 1700s when Dutchman Antony Van Leeuwenhoek observed his own dental plaque and reported 'little living animalcules prettily moving' further named them as microbes “Dierken”, meaning small lively objects. Since then, the understanding of oral microflora has become profound. Oral microflora is the aggregation of microorganism inhabiting the oral cavity which include bacteria, fungi, viruses and protozoa. The term “microbiome” is defined as the collective genome of microorganisms that reside in the oral cavity. The mouth is an exceedingly complex habitat with its variable niches where microbes settle down and colonize. At present, the connection that has taken a limelight is the link between the oral microbial community and their interactions with the host in the maintenance of homeostasis and in the pathogenesis of many diseases. In today's urbanized society, change in lifestyle, diet along with other environmental factors and distinct health habits, there is precise switching in the composition of the oral microbiota with a remarkable increase in the frequency of systemic diseases. Recently there are few advancements made in the field of 16S RNA sequencing and other technologies. Here in this review, we emphasize on the varied habitats and niches that microorganisms colonize along with their disparity in systemic health and the use of currently available methods to determine the oral microflora.

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

PurposeOlaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR).MethodsWe retrospectively identified patients using olaparib at the Netherlands Cancer Institute – Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012).ResultsIn total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) μmol/L before/off treatment to 82 (IQR: 20) μmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C–derived eGFR (p = 0.918).ConclusionsThis study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C–derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.

Leeuwenhoek and his little animals

Antoine van Leeuwenhoek (1632-1723) was a Dutch cloth merchant and self-taught microscopist who is considered the father of Microbiology. His marvellous lenses and keen microscopic observations over nearly five decades made it possible for the first time to unravel the secrets of the microcosm. The main objective of this work is that the reader can directly access some of his famous letters addressed to the Royal Society of London, announcing the discovery of his famous little animals.

The anatomy, movement, and functions of human sperm tail: an evolving mystery.

Sperms have attracted attention of many researchers since it was discovered by Antonie van Leeuwenhoek in 1677. Though a small cell, its every part has complex structure and different function to play in carrying life. Sperm tail is most complicated structure with more than 1000 proteins involved in its functioning. With the advent of three-dimensional microscopes, many studies are undergoing to understand exact mechanism of sperm tail movement. Most recent studies have shown that sperms move by spinning rather than swimming. Each subunit of tail, including axonemal, peri-axonemal structures, plays essential roles in sperm motility, capacitation, hyperactivation, fertilization. Furthermore, over 2300 genes are involved in spermatogenesis. A number of genetic mutations have been linked with abnormal sperm flagellar development leading to motility defects and male infertility. It was found that 6% of male infertility cases are related to genetic causes, and 4% of couples undergoing intracytoplasmic sperm injection for male subfertility have chromosomal abnormalities. Hence, an understanding of sperm tail development and genes associated with its normal functioning can help in better diagnosis of male infertility and its management. There is still a lot that needs to be discovered about genes, proteins contributing to normal human sperm tail development, movement, and role in male fertility. Sperm tail has complex anatomy, with surrounding axoneme having 9 + 2 microtubules arrangement along its entire length and peri-axonemal structures that contribute in sperm motility and fertilization. In future sperm tail-associated genes, proteins and subunits can be used as markers of male fertility.

Sukshmjeevanu in Vedas: The Forgotten Past of Microbiology in Indian Vedic Knowledge.

No one questions the existence of presumptive knowledge of invisible organisms causing disease, decay and destruction mentioned before the discovery of the microbial world by Antonie Van Leeuwenhoek, who was the first to describe the invisible world as per literature available today. However, the knowledge about microbial world by Indian Rishis presented in Sanskrit shlokas or suktas of our traditional manuscripts such as Vedas remained unseen, where the Rishis had predicted the role of microorganisms known as Krimi or Jeevanu years before Leeuwenhoek. This note is an attempt to bring an emphasis to revisit our traditional Vedic knowledge and establish them through research based facts for wider acceptance globally.

A cost analysis study of the implementation of fixed-dosing of monoclonal antibodies in the Netherlands Cancer Institute.

Background There is a strong rationale for fixed-dosing of monoclonal antibodies in oncology. Although fixed-dosing of recently introduced monoclonal antibodies is well accepted, the rationale is also applicable for other monoclonal antibodies that already have been used for years, but are still body-size-based dosed in many hospitals. In the Netherlands Cancer Institute, Antoni van Leeuwenhoek (NKI-AVL), fixed-dosing has been implemented now for all monoclonal antibodies and, therefore, this site offers an ideal opportunity for a cost analysis study. Objective To investigate the financial impact of switching to fixed-dosing in the NKI-AVL. Setting The NKI-AVL. Method Information on the preparations of monoclonal antibodies was collected from August 2017 to February 2020. We compared the number of vials needed during preparation for fixed-dosing and body-size -based dosing strategies. The economic impact was calculated for 2 scenarios: scenario 1 assumed clustering of all preparations per day and scenario 2 assumed no clustering of preparations. Main outcome measure Number of saved vials and the correlating savings in health care costs. Results The implementation of fixed-dosing resulted in a substantial reduction in vials used for almost all monoclonal antibodies. The economic savings were calculated to be €0,8 and €3,1 million per year for scenario 1 and 2, respectively. Conclusion Fixed-dosing resulted in substantial savings in health care costs.

SenX3-RegX3, an Important Two-Component System, Regulates Strain Growth and Butenyl-spinosyn Biosynthesis in Saccharopolyspora pogona.

SummaryButenyl-spinosyn produced by Saccharopolyspora pogona exhibits strong insecticidal activity and a broad pesticidal spectrum. Currently, important functional genes involved in butenyl-spinosyn biosynthesis remain unknown, which leads to difficulty in efficient understanding of its regulatory mechanism and improving its production by metabolic engineering. Here, we present data supporting a role of the SenX3-RegX3 system in regulating the butenyl-spinosyn biosynthesis. EMSAs and qRT-PCR demonstrated that RegX3 positively controls butenyl-spinosyn production in an indirect way. Integrated proteomic and metabolomic analysis, regX3 deletion not only strengthens the basal metabolic ability of S. pogona in the mid-growth phase but also promotes the flow of the acetyl-CoA produced via key metabolic pathways into the TCA cycle rather than the butenyl-spinosyn biosynthetic pathway, which ultimately leads to continued growth but reduced butenyl-spinosyn production. The strategy demonstrated here may be valuable for revealing the regulatory role of the SenX3-RegX3 system in the biosynthesis of other natural products.

Association of Image-Guided Navigation With Complete Resection Rate in Patients With Locally Advanced Primary and Recurrent Rectal Cancer

The percentage of tumor-positive surgical resection margin rates in patients treated for locally advanced primary or recurrent rectal cancer is high. Image-guided navigation may improve complete resection rates. To ascertain whether image-guided navigation during rectal cancer resection improves complete resection rates compared with surgical procedures without navigation. This prospective single-center nonrandomized controlled trial was conducted at the Netherlands Cancer Institute-Antoni van Leeuwenhoek in Amsterdam, the Netherlands. The prospective or navigation cohort included adult patients with locally advanced primary or recurrent rectal cancer who underwent resection with image-guided navigation between February 1, 2016, and September 30, 2019, at the tertiary referral hospital. Clinical results of this cohort were compared with results of the historical cohort, which was composed of adult patients who received rectal cancer resection without image-guided navigation between January 1, 2009, and December 31, 2015. Rectal cancer resection with image-guided navigation. The primary end point was the complete resection rate, measured by the amount of tumor-negative resection margin rates. Secondary outcomes were safety and usability of the system. Safety was evaluated by the number of navigation system-associated surgical adverse events. Usability was assessed from responses to a questionnaire completed by the participating surgeons after each procedure. In total, 33 patients with locally advanced or recurrent rectal cancer were included (23 men [69.7%]; median [interquartile range] age at start of treatment, 61 [55.0-69.0] years). With image-guided navigation, a radical resection (R0) was achieved in 13 of 14 patients (92.9%; 95% CI, 66.1%-99.8%) after primary resection of locally advanced tumors and in 15 of 19 patients (78.9%; 95% CI, 54.4%-94.0%) after resection of recurrent rectal cancer. No navigation system-associated complications occurred before or during surgical procedures. In the historical cohort, 142 patients who underwent resection without image-guided navigation were included (95 men [66.9%]; median [interquartile range] age at start of treatment, 64 [55.0-70.0] years). In these patients, an R0 resection was accomplished in 85 of 101 patients (84.2%) with locally advanced rectal cancer and in 20 of 41 patients (48.8%) with recurrent rectal cancer. A significant difference was found between the navigation and historical cohorts after recurrent rectal cancer resection (21.1% vs 51.2%; P = .047). For locally advanced primary tumor resection, the difference was not significant (7.1% vs 15.8%; P = .69). Surgeons stated in completed questionnaires that the navigation system improved decisiveness and helped with tumor localization. Findings of this study suggest that image-guided navigation used during rectal cancer resection is safe and intuitive and may improve tumor-free resection margin rates in recurrent rectal cancer. Netherlands Trial Register Identifier: NTR7184.

Comparison of Myelotoxicity and Nephrotoxicity Between Daily Low-Dose Cisplatin With Concurrent Radiation and Cyclic High-Dose Cisplatin in Non-Small Cell Lung Cancer Patients.

AimAntineoplastic effect of cisplatin, the first line treatment in non-small cell lung cancer (NSCLC), is hindered by its nephrotoxicity and myelotoxicity. Both low-dose and high-dose regimens are used in the management of NSCLC. The aim of this study is to assess the risk on myelotoxicity and nephrotoxicity from the daily low-dose cisplatin (DLD) treatment as compared to cyclic high-dose cisplatin (CHD).MethodsA retrospective cohort study was conducted. NSCLC patients treated with cisplatin between 2011 and 2018 in the Amsterdam UMC or Antoni van Leeuwenhoek cancer hospital were studied. Myelotoxicity and nephrotoxicity were defined based on common terminology criteria (CTCAE v4.03) and categorized as ≥grade 1 and ≥grade 2. Modified Poisson regression and Cox proportional hazards model were used to estimate relative risks and cumulative hazard respectively.ResultsOf the 115 NSCLC patients receiving DLD (N=62) and CHD (N=53), 60% had ≥grade 1 anemia, 33.9% leukopenia, 31.3% neutropenia, 27.8% thrombocytopenia, 32.2% acute nephrotoxicity with combined definition (Cr-electrolyte nephrotoxicity), and 58.3% chronic nephrotoxicity. The DLD group was older, had an earlier cancer stage, had more comorbidities, and had higher baseline albumin levels. In the DLD group less ≥grade 2 toxicities were reported compared to the CHD group except for Cr-electrolyte nephrotoxicity. However, there was a stronger association in the DLD group with ≥grade 1 leukopenia, thrombocytopenia, and Cr-electrolyte nephrotoxicity. The DLD group developed significantly more ≥grade 1 leukopenia [adjusted relative risk (adjRR)=1.83, 95% CI 1.02–3.27], thrombocytopenia (adjRR=3.43, 95% CI 1.64–7.15), and ≥grade 2 Cr-electrolyte nephrotoxicity (adjRR=3.02, 95% CI 1.20–7.56). The DLD group had a lower adjusted cumulative hazard for developing ≥grade 2 myelotoxicity and chronic nephrotoxicity but not for Cr-electrolyte nephrotoxicity [adjusted hazard ratio (adjHR)=3.90, 95% CI 1.35–11.23]. In contrast, DLD showed protective effect to ≥grade 2 nephrotoxicity when definition was restricted to the traditional creatinine-based definition (adjRR=0.07, 95% CI 0.01–0.86; adjHR=0.05, 95% CI 0.01–0.56).ConclusionsOverall, the DLD regimen was safer than the CHD regimen when assessing the risk of ≥grade 2 myelotoxicity and nephrotoxicity. However, this might not be the case in patients with a higher risk of electrolyte abnormalities.

Antoni van Leeuwenhoek and measuring the invisible: The context of 16th and 17th century micrometry

This article explores the impact of 16th and 17th-century developments in micrometry on the methods Antoni van Leeuwenhoek employed to measure the microscopic creatures he discovered in various samples collected from his acquaintances and from local water sources. While other publications have presented Leeuwenhoek's measurement methods, an examination of the context of his techniques is missing. These previous measurement methods, driven by the need to improve navigation, surveying, astronomy, and ballistics, may have had an impact on Leeuwenhoek's methods. Leeuwenhoek was educated principally in the mercantile guild system in Amsterdam and Delft. He rose to positions of responsibility within Delft municipal government. These were the years that led up to his first investigations using the single-lens microscopes he became expert at creating, and that led to his first letter to the Royal Society in 1673. He also took measures to train in surveying and liquid assaying practices existing in his time, disciplines that were influenced by Pedro Nunes, Pierre Vernier, Rene Descartes, and others. While we may never know what inspired Leeuwenhoek's methods, the argument is presented that there were sufficient influences in his life to shape his approach to measuring the invisible.

Genomic research delivering on promises: From rejuvenation to vaccines and pharmacogenetics.

What is known and ObjectiveThere has been astounding progress made in the treatment of disease over recent years. This progress is particularly marked in cell therapy and in the personalization of therapy based on genetic insight, an approach known as genomic medicine. Our objective is to comment on the progress made in cell and genomic medicine against an historical backcloth of the search for rejuvenation.CommentIn 1741, close to seven decades after Antoine van Leeuwenhoek first saw his microscopic animalcules, Abraham Trembley, a tutor in Leiden, reported on an organism that could regenerate itself. The strange organism was thought to hold the secret of life. If it does, we have yet to prise the secret out. However, the ensuing study of cell programming and induced stem cells has shed considerable light on cellular development and provided new insights on the rejuvenative capacity of organisms. Inventive scientists have provided a deeper understanding of cell replication and, from this, developed new medicines for an increasing range of diseases. Targeted therapies, oligonucleotide therapy, therapeutic monoclonal antibodies and pharmacogenetics are all new therapeutic areas originating from the improved insights. More will surely follow.What is new and conclusionImmortality is for the gods, but man's search for its elusive secrets, perhaps as old as man himself, will continue. Huge leaps have been made, and effective medicines have been developed from our improved insights into the mechanism of life. However, only the foolish will predict how far this new knowledge will lead us, and more particularly, at what speed new therapies will follow.

The prognostic value of the tumor-stroma ratio is most discriminative in patients with grade III or triple-negative breast cancer.

The tumor–stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin‐stained tissue slides of 1,794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence‐free survival (RFS; HR 1.35, 95% CI 1.10–1.66, p = 0.004). The interaction term was statistically significant for grade and triple‐negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43–2.51, p < 0.001) and triple‐negative tumors (HR 1.86, 95% CI 1.10–3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple‐negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma‐high tumor had a worse prognosis compared to patients with a stroma‐low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple‐negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.

Eggs, Sperm and Desire: Sex and Science in the Dutch Golden Age

AbstractWithin the seventeenth‐century Dutch Republic, humanism, empiricism and liberalism thrived. This social and intellectual liberty allowed for numerous studies on sex, from anatomical treatises on generation to philosophical tracts about lust, published by Reinier de Graaf, Antoni van Leeuwenhoek, Jan Swammerdam, Johannes van Beverwijck, Hadriaan Beverland and Bernhard Mandeville. This article compares the main intellectual traditions in which sex became a popular topic, natural philosophy and medical works versus theological and moralistic treatises, and demonstrates that the Dutch Republic boasted a fertile environment for the science of sex owing to its tolerant intellectual setting and social freedom regarding sexual behaviour.

899TiP - Addition of an oral docetaxel treatment (ModraDoc006/r) to androgen deprivation therapy (ADT) and intensity-modulated radiation therapy (IMRT) in patients with high risk N+M0 prostate cancer

BackgroundHigh risk lymph node positive non-metastatic (N+M0) prostate cancer (PCa) patients (pts) are treated with pelvic radiotherapy (RT) and androgen deprivation therapy (ADT), which can lead to significant toxicity. Docetaxel (Doc) has been acknowledged for its radiosensitizing activity. Chemoradiation with RT on the primary tumour could improve local and systemic control, while avoiding toxicity of pelvic RT. This has been investigated in 6 trials with weekly intravenous Doc. Oral chemotherapy is often preferred, improves cost-effectiveness and avoids dexamethasone prophylaxis. However, oral Doc treatment is challenging due to a low systemic uptake. Co-administration of ritonavir (r), a Cyp3A4 and P-glycoprotein inhibitor, and formulation of water soluble tablets (ModraDoc006), increased the bioavailability of orally given Doc (ModraDoc006/r). This phase I study assesses the pharmacokinetics (PK), safety and maximum tolerated dose (MTD) of ModraDoc006/r, given with IMRT and ADT in high risk N+M0 PCa. Trial designHigh risk PCa is defined as newly diagnosed N+M0 disease (>4 radiologic pathologic pelvic lymph nodes), Gleason score ≥4+3=7, ≥cT2c and any PSA, with an indication for (pelvic) RT and ADT. Pts are treated with ADT (28mo), Image-guided Arc Therapy on the primary tumour (77Gy in 35 fractions) and weekly ModraDoc006/r for 7 (Part 1A) or 18 weeks (Part 1B). Sampling for PK of ModraDoc006/r, measured by a validated liquid chromatography with tandem mass spectrometry assay, is done up to 48h after intake. Adverse events (AEs) are evaluated with the National Cancer Institute’s Common Terminology Criteria for AEs and RT Oncology Group/European Organization for Research and Treatment of Cancer scale. Efficacy is assessed by Prostate Specific Antigen and Magnetic Resonance Imaging. In Part 1A, three dose levels are investigated. Dose-escalation is based on acute (within 3mo) and late (within 12mo) dose limiting toxicities (DLTs), evaluated in a Time-to-Event Continual Reassessment Method model. The MTD is the highest dose at which ≤15% of≥6 pts experience DLTs. The number of pts is currently 19 in Part 1A and will be≥9 in Part 1B. Clinical trial identificationNCT03066154. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL). FundingNetherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL). DisclosureJ.H. Beijnen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Modra Pharmaceuticals B.V. All other authors have declared no conflicts of interest.

904PD - Pre-operative ipilimumab and nivolumab in locoregionally advanced, stage III, urothelial cancer (NABUCCO)

BackgroundStage III (cT3-4aN0M0 or ≥cT1N+M0) urothelial cancer (UC) patients (pts) have a poor prognosis. Despite high response rates, pre-operative chemo shows limited survival benefit. Immunotherapy targeting PD-1/PD-L1 is active in metastatic UC; the combination of ipilimumab (ipi) and nivolumab (nivo) appears to increase response rates. Encouraging path Complete Response (pCR) rates are observed in trials testing neoadjuvant anti-PD-1/PD-L1 (mostly cT2-T3N0 pts). Here, we present the first clinical trial data on preoperative ipi+nivo. MethodsThis is a single-arm phase 1B trial testing the feasibility (primary endpoint) of pre-operative ipi+nivo in stage III UC pts (cis unfit/refusal). To mitigate the risk of immune-related toxicity, pts were treated with (based on melanoma data): ipi 3mg/kg (day 1), ipi 3 + nivo 1mg/kg (day 22), and nivo 3mg/kg (day 43), followed by resection. Secondary endpoints were efficacy (pCR) and translational parameters: PD-L1, TMB (by WES), and immune cell infiltrates at baseline vs on-treatment using multiplex immunofluorescence (mIF; pan-CK/CD3/CD8/FOXP3/CD20/CD68). Results24 pts (14 cT3-4N0; 10 cN+) were enrolled, of whom 23 (96%) had resection <12 weeks from 1st cycle. 1pt, responding radiologically, had a delay in surgery because of an irAE (hemolysis). 18/24 pts received all 3 cycles, 6 pts received 2 cycles due to irAEs. Grade 3/4 irAEs occurred in 54% of pts; 42% when excluding clinically insignificant lab deviations. 22 pts were available for efficacy assessment (1pt resection delayed, 1pt had resection 1day before abstract submission). 10/22 pts (45%) achieved a pCR. 3 additional pts (14%) had noninvasive cancer at resection (2 ypTis, 1 ypTa), resulting in an overall path downstaging (≤ypT1N0) rate of 59% (13/22). In recent neoadjuvant IO studies in melanoma and NSCLC, major path response (MPR) has been defined as≤10% vital tumor cells in the tumor bed. MPR was seen in 5/22 pts (23%). Nonresponse was seen in 4/22 (17%). Response was associated with massive infiltration of CD8+ T-cells in the tumour bed. ConclusionsPreoperative ipi+nivo is feasible (96% surgery <12 weeks) and shows promising efficacy in stage III UC pts. Updated results on all 24 pts, including mIF, PDL1 and TMB, will be presented. Clinical trial identificationNCT03387761, January 2, 2018. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek. FundingBMS. DisclosureM.S. Van der Heijden: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Janssen. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA. P. Kvistborg: Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Personalis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: GenMab; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): NanoString. B.W. van Rhijn: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ferring. All other authors have declared no conflicts of interest.

1666TiP - COMPRAYA: Dutch nationwide infrastructure for COMPRehensive health outcome and intervention research among patients with adolescent and young adult cancer

BackgroundCompared to children, Adolescent and Young Adult (AYA) cancer patients, diagnosed with cancer between 18-39 years old, more often suffer from delay in diagnosis and lack of centralization of care, age-specific expertise and structured follow-up. This group presents with a unique spectrum of cancers with distinctive tumor biology, cancer risk factors, and psychosocial developmental challenges. The potential burden of medical and psychosocial problems could result in compromised quality of life and reduced life expectancy. Given the differences, findings derived from childhood cancer patients cannot be extrapolated to AYA cancer patients. It is imperative for advances in the field of AYA oncology to pool data sources (patient-reported outcomes, clinical, genetic and biological data) across institutions and create large cohorts that include the full range of AYA ages and diagnoses to be able to address the many pressing questions that remain unanswered in this vulnerable population. Therefore, we will create a unique nationwide infrastructure (COMPRAYA) for research into the prevalence, predictive and prognostic markers and underlying mechanisms of early and late medical and psychosocial outcomes, and to facilitate the development and testing of (early) intervention strategies to improve these outcomes for patients (at risk). Trial designAn observational cohort of 1-year AYA cancer survivors (N=4000), recruited over 4 years, followed prospectively, will be established. Patients are asked to (1) complete validated patient-reported outcome measures; (2) donate a blood, hair, urine and stool sample; (3) consent for biobanking of tumor tissue and serial clinical data extraction from medical records and Netherlands Cancer Registry; (4) visit an outpatient clinic (vital and phenotypic parameters); (5) be approached for ancillary studies. The established Dutch AYA cancer care network forms an optimal collaborating environment. Next to the COMPRAYA research infrastructure, an online AYA platform will be created together with and for AYA cancer patients where age-specific information, support and interventions will become available. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek Hospital. FundingKWF Kanker Bestrijding. DisclosureAll authors have declared no conflicts of interest.

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.

1486PD - Exposure-response analyses of ALK-inhibitors crizotinib and alectinib in NSCLC patients

BackgroundCrizotinib and alectinib are first and second generation ALK-inhibitors, respectively, indicated for the treatment of ALK+ NSCLC. At the currently used fixed doses, interpatient variability in exposure is high (40%), while the registration studies suggest that exposure might be linked to efficacy (FDA Reviews). Therefore, the aim of this study was to explore whether exposure to crizotinib and alectinib is related to efficacy in a real life patient (pt) cohort. MethodsA retrospective observational study was performed. ALK+ NSCLC pts who were treated with crizotinib or alectinib and of whom pharmacokinetic (PK) samples were drawn as part of routine care were included. Calculated minimum plasma concentration (Cmin) was taken as a measure of exposure. Efficacy endpoint was progression free survival (PFS). Univariable and multivariable exposure-response analyses were performed using previously proposed thresholds of 235 µg/L for crizotinib and 435 µg/L for alectinib (Verheijen 2017). Variables taken into account were WHO performance status (PS) and previous lines of therapy for crizotinib, and WHO PS and previous treatment with ALK-inhibitors for alectinib. ResultsIn total, 100 pts were included in this study (48 crizotinib, 52 alectinib), of whom 376PK samples were eligible for analysis (235 crizotinib, 141 alectinib). Median number of samples per pt was 3 (range 1 – 15). Median Cmin per pt was 244 µg/L (IQR 176 – 344 µg/L) for crizotinib and 517 µg/L (IQR 369 – 659 µg/L) for alectinib. For crizotinib, median PFS was 5.7 vs 17.4 months (mo) for pts with median Cmin < 235 µg/L (48%) and ≥ 235 µg/L, respectively (log rank test, p=0.08). In multivariable analysis Cmin < 235 µg/L resulted in a HR of 1.79 (95% CI 0.90 – 3.59, p=0.10). For alectinib, median PFS was 12.6mo vs not reached yet after 20mo for pts with Cmin < 435 µg/L (37%) and ≥ 435 µg/L, respectively (log rank test, p=0.04). Multivariable analysis resulted in a HR of 3.86 (95% CI 1.19 – 12.58, p=0.025). Thus far, this could not be explained by bias. ConclusionsThis study shows that exposure to alectinib is associated with efficacy in a real life patient cohort. Therefore, therapeutic drug monitoring might be appropriate to individualize treatment and improve treatment outcomes. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek Hospital. FundingHas not received any funding. DisclosureS.A. Burgers: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche Advisory / Consultancy: MSD. 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): Genentech; 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): 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.