Reliability and validity of handheld structured light scanners and a static stereophotogrammetry system in facial three-dimensional surface imaging.

Several new systems for three-dimensional (3D) surface imaging of the face have become available to assess changes following orthognathic or facial surgery. Before they can be implemented in practice, their reliability and validity must be established. Our aim, therefore, was to study the intra- and inter-system reliability and validity of 3dMD (stereophotogrammetry), Artec Eva and Artec Space Spider (both structured light scanners). Intra- and inter-system reliability, expressed in root mean square distance, was determined by scanning a mannequin's head and the faces of healthy volunteers multiple times. Validity was determined by comparing the linear measurements of the scans with the known distances of a 3D printed model. Post-processing errors were also calculated. Intra-system reliability after scanning the mannequin's head was best with the Artec Space Spider (0.04 mm Spider; 0.07 mm 3dMD; 0.08 mm Eva). The least difference in inter-system reliability after scanning the mannequin's head was between the Artec Space Spider and Artec Eva. The best intra-system reliability after scanning human subjects was with the Artec Space Spider (0.15 mm Spider; 0.20 mm Eva; 0.23 mm 3dMD). The least difference in inter-system reliability after scanning human subjects was between the Artec Eva and Artec Space Spider. The most accurate linear measurement validity occurred with the Artec Space Spider. The post-processing error was 0.01 mm for all the systems. The Artec Space Spider is the most reliable and valid scanning system.

Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway.

Most tumor cells undergo apoptosis in circulation and at the metastatic organ sites due to host immune surveillance and a hostile microenvironment. It remains to be elucidated whether dying tumor cells have a direct effect on live tumor cells during the metastatic process and what the underlying mechanisms are. Here we report that apoptotic cancer cells enhance the metastatic outgrowth of surviving cells through Padi4-mediated nuclear expulsion. Tumor cell nuclear expulsion results in an extracellular DNA-protein complex that is enriched with receptor for advanced glycation endproducts (RAGE) ligands. The chromatin-bound RAGE ligand S100a4 activates RAGE receptors in neighboring surviving tumor cells, leading to Erk activation. In addition, we identified nuclear expulsion products in human patients with breast, bladder and lung cancer and a nuclear expulsion signature correlated with poor prognosis. Collectively, our study demonstrates how apoptotic cell death can enhance the metastatic outgrowth of neighboring live tumor cells.

Eucalypt species drive rhizosphere bacterial and fungal community assembly but soil phosphorus availability rearranges the microbiome.

Soil phosphorus (P) availability may limit plant growth and alter root-soil interactions and rhizosphere microbial community composition. The composition of the rhizosphere microbial community can also be shaped by plant genotype. In this study, we examined the rhizosphere microbial communities of young plants of 24 species of eucalypts (22 Eucalyptus and two Corymbia species) under low or sufficient soil P availability. The taxonomic diversity of the rhizosphere bacterial and fungal communities was assessed by 16S and 18S rRNA gene amplicon sequencing. The taxonomic modifications in response to low P availability were evaluated by principal component analysis, and co-inertia analysis was performed to identify associations between bacterial and fungal community structures and parameters related to plant growth and nutritional status under low and sufficient soil P availability. The sequencing results showed that while both soil P availability and eucalypt species influenced the microbial community assembly, eucalypt species was the stronger determinant. However, when the plants are subjected to low P-availability, the rhizosphere selection became strongest. In response to low P, the bacterial and fungal communities in the rhizosphere of some species showed significant changes, whereas in others remained relatively constant under low and sufficient P. Co-inertia analyses revealed a significant co-dependence between plant nutrient contents and bacterial and fungal community composition only under sufficient P. By contrast, under low P, bacterial community composition was related to plant biomass production. In conclusion, our study shows that eucalypt species identity was the main factor modulating rhizosphere microbial community composition; significant shifts due to P availability were observed only for some eucalypt species.

Patient-reported aesthetic outcomes of upper blepharoplasty: a randomized controlled trial comparing two surgical techniques.

It is not yet established whether additional orbicularis oculi muscle excision leads to better patient-reported aesthetic outcomes (PRO) compared to a skin-only resection blepharoplasty. A double-blind randomized controlled trial of upper blepharoplasty, with or without muscle excision, was performed on 54 White European patients who assessed the procedure via PRO. FACE-Q questionnaires covering eyes in general, upper eyelids, forehead and eyebrows, overall face, age appearance appraisal, age appraisal, social functioning, satisfaction with the outcome, and adverse effects were completed preoperatively and at 6 and 12 months after upper blepharoplasty. The Patient and Observer Scar Assessment Scale was used to assess scarring. The FACE-Q scores for skin-only and skin/muscle upper blepharoplasty were similar regarding the upper eyelids, forehead and eyebrows, overall face, patient perceived aging and age, social functioning, and satisfaction with the results, and also increased for both procedures with time. The FACE-Q score regarding the eyes in general was higher in the skin-only group at the 12-month follow-up. Scarring and adverse effects did not differ between the groups. Additional muscle resection does not seem to influence patient satisfaction. Thus, when performing an upper blepharoplasty, there is no need for additional muscle resection as a routine procedure to improve patient satisfaction.

Mismatch between self-perceived and calculated cardiometabolic disease risk among participants in a prevention program for cardiometabolic disease: a cross-sectional study.

BACKGROUND: The rising prevalence of cardiometabolic diseases (CMD) calls for effective prevention programs. Self-assessment of CMD risk, for example through an online risk score (ORS), might induce risk reducing behavior. However, the concept of disease risk is often difficult for people to understand. Therefore, the study objective was to assess the impact of communicating an individualized CMD risk score through an ORS on perceived risk and to identify risk factors and demographic characteristics associated with risk perception among high-risk participants of a prevention program for CMD. METHODS: A cross-sectional analysis of baseline data from a randomized controlled trial conducted in a primary care setting. Seven thousand five hundred forty-seven individuals aged 45-70 years without recorded CMD, hypertension or hypercholesterolemia participated. The main outcome measures were: 1) differences in cognitive and affective risk perception between the intervention group - who used an ORS and received an individualized CMD risk score- and the control group who answered questions about CMD risk, but did not receive an individualized CMD risk score; 2) risk factors and demographic characteristics associated with risk perception. RESULTS: No differences were found in cognitive and affective risk perception between the intervention and control group and risk perception was on average low, even among high-risk participants. A positive family history for diabetes type 2 (ß0.56, CI95% 0.39-0.73) and cardiovascular disease (ß0.28, CI95% 0.13-0.43), BMI ≥25 (ß0.27, CI95% 0.12-0.43), high waist circumference (ß0.25, CI95% 0.02-0.48) and physical inactivity (ß0.30, CI95% 0.16-0.45) were positively associated with cognitive CMD risk perception in high-risk participants. No other risk factors or demographic characteristics were associated with risk perception. CONCLUSIONS: Communicating an individualized CMD risk score did not affect risk perception. A mismatch was found between calculated risk and self-perceived risk in high-risk participants. Family history and BMI seem to affect the level of CMD risk perception more than risk factors such as sex, age and smoking. A dialogue about personal CMD risk between patients and health care professionals might optimize the effect of the provided risk information. TRIAL REGISTRATION: Dutch trial Register number NTR4277, registered 26th Nov 2013.

Loss of myeloid-specific lamin A/C drives lung metastasis through Gfi-1 and C/EBPε-mediated granulocytic differentiation.

The immune-suppressive tumor microenvironment promotes metastatic spread and outgrowth. One of the major contributors is tumor-associated myeloid cells. However, the molecular mechanisms regulating their differentiation and function are not well understood. Here we report lamin A/C, a nuclear lamina protein associated with chromatin remodeling, was one of the critical regulators in cellular reprogramming of tumor-associated myeloid cells. Using myeloid-specific lamin A/C knockout mice and triple-negative breast cancer (TNBC) mouse models, we discovered that the loss of lamin A/C drives CD11b+ Ly6G+ granulocytic lineage differentiation, alters the production of inflammatory chemokines, decreases host antitumor immunity, and increases metastasis. The underlying mechanisms involve an increased H3K4me3 leading to the upregulation of transcription factors (TFs) Gfi-1 and C/EBPε. Decreased lamin A/C and increased Gfi-1 and C/EBPε were also found in the granulocytic subset in the peripheral blood of human cancer patients. Our data provide a mechanistic understanding of myeloid lineage differentiation and function in the immune-suppressive microenvironment in TNBC metastasis.

Aesthetic outcomes of upper eyelid blepharoplasty: a systematic review.

Although upper blepharoplasty is a common cosmetic surgical intervention, a better scientific understanding of the aesthetic results and the preferred surgical technique to achieve the best aesthetic results is still needed. A systematic search using four search engines (PubMed, Embase, CINAHL, and Cochrane) was performed to identify any study on the aesthetic outcome of a solitary upper blepharoplasty; these were subjected to quality assessment for possible inclusion. Eligible studies were randomized controlled trials, controlled trials, cohort studies, and case series (n ≥ 10). A total of 4043 studies were assessed, of which 26 were included. Aesthetic outcomes included patient-reported outcome measures, scarring, eyebrow height, tarsal platform show, and panel or expert evaluation. Meta-analysis was not possible. Patients were generally satisfied with the aesthetic result and scar formation after an upper blepharoplasty. The amount of tarsal platform show increases, which positively affects the aesthetics. The eyebrow seems to move down slightly. The surgical technique used (skin only or skin/muscle removal) did not influence patient satisfaction or the physician-assessed aesthetic outcomes. Patients are generally satisfied after an upper blepharoplasty. The optimal design of the skin excision is still a matter of debate, especially when addressing lateral hooding. Further objective research is advised.

Functional outcomes of upper eyelid blepharoplasty: A systematic review.

OBJECTIVE: Various functional outcomes after upper blepharoplasty are reported in the literature. We systematically reviewed the literature to assess the objective and subjective functional effects of upper blepharoplasty. METHODS: After a systematic search of four search engines (Pubmed, Embase, Cinahl and Cochraine), any study on objective and subjective (patient reported) functional outcome after upper blepharoplasty was subjected to a quality assessment for possible inclusion in the review. The intervention was defined as a solitary surgical upper blepharoplasty containing the removal of skin, with or without the removal of a strip of orbicularis oculi muscle and/or upper orbital fat. Eligible studies were randomized controlled trials, controlled trials, cohort studies and case series (n ≥ 10). RESULTS: A total of 3525 studies were assessed, of which 28 studies were included in this systematic review. Favorable outcomes after an upper blepharoplasty were reported and included enlarged visual field, enhanced quality of life related to fewer headaches and improved vision. Furthermore, sensitivity of the eyelids decreased, with differences in recovery. Outcomes for eyebrow height, astigmatism, contrast sensitivity and eyelid kinematics were not consistent between the studies. No meta-analysis could be performed due to the limited scope of included studies and the great variety in outcomes and blepharoplasty techniques. CONCLUSIONS: Upper blepharoplasty is accompanied by a great variety of beneficial functional outcomes including an increased visual field and improvement in headache- and vision-related quality of life. Further research is needed, especially where results are conflicting (effects on eye dryness and eyebrow height) and/or the data are limited (contrast sensitivity, astigmatism).

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity.

Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFß signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFß receptor II (TßRII) and are down-regulated in these myeloid cells, leading to increased TßRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFß and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.

Attenuation of Myeloid-Specific TGFß Signaling Induces Inflammatory Cerebrovascular Disease and Stroke.

RATIONALE: Cryptogenic strokes, those of unknown cause, have been estimated as high as 30% to 40% of strokes. Inflammation has been suggested as a critical etiologic factor. However, there is lack of experimental evidence. OBJECTIVE: In this study, we investigated inflammation-associated stroke using a mouse model that developed spontaneous stroke because of myeloid deficiency of TGF-ß (transforming growth factor-ß) signaling. METHODS AND RESULTS: We report that mice with deletion of Tgfbr2 in myeloid cells (Tgfbr2Myeko) developed cerebrovascular inflammation in the absence of significant pathology in other tissues, culminating in stroke and severe neurological deficits with 100% penetrance. The stroke phenotype can be transferred to syngeneic wild-type mice via Tgfbr2Myeko bone marrow transplant and can be rescued in Tgfbr2Myeko mice with wild-type bone marrow. The underlying mechanisms involved an increased type 1 inflammation and cerebral endotheliopathy, characterized by elevated NF-κB (nuclear factor-κB) activation and TNF (tumor necrosis factor) production by myeloid cells. A high-fat diet accelerated stroke incidence. Anti-TNF treatment, as well as metformin and methotrexate, which are associated with decreased stroke risk in population studies, delayed stroke occurrence. CONCLUSIONS: Our studies show that TGF-ß signaling in myeloid cells is required for maintenance of vascular health and provide insight into inflammation-mediated cerebrovascular disease and stroke.

Preventing traumatic childbirth experiences: 2192 women's perceptions and views.

The purpose of this study is to explore and quantify perceptions and experiences of women with a traumatic childbirth experience in order to identify areas for prevention and to help midwives and obstetricians improve woman-centered care. A retrospective survey was conducted online among 2192 women with a self-reported traumatic childbirth experience. Women were recruited in March 2016 through social media, including specific parent support groups. They filled out a 35-item questionnaire of which the most important items were (1) self-reported attributions of the trauma and how they believe the traumatic experience could have been prevented (2) by the caregivers or (3) by themselves. The responses most frequently given were (1) Lack and/or loss of control (54.6%), Fear for baby's health/life (49.9%), and High intensity of pain/physical discomfort (47.4%); (2) Communicate/explain (39.1%), Listen to me (more) (36.9%), and Support me (more/better) emotionally/practically (29.8%); and (3) Nothing (37.0%), Ask for (26.9%), or Refuse (16.5%) certain interventions. Primiparous participants chose High intensity of pain/physical discomfort, Long duration of delivery, and Discrepancy between expectations and reality more often and Fear for own health/life, A bad outcome, and Delivery went too fast less often than multiparous participants. Women attribute their traumatic childbirth experience primarily to lack and/or loss of control, issues of communication, and practical/emotional support. They believe that in many cases, their trauma could have been reduced or prevented by better communication and support by their caregiver or if they themselves had asked for or refused interventions.

[Degloving injury of the mandible]. / Degloving-letsel van de mandibula.

A 13-year-old girl presented at an emergency department after she had fallen on her face when she fell from her horse. During physical examination no apparent extraoral injury was visible, such as lacerations, bruises or oedema. However, intraoral examination revealed extensive laceration of soft tissue. The diagnosis was a degloving injury of the mandible, which is very rare. The treatment consisted of debridement, suturing of the mentalis muscle, the approximate closing of the mucosa, accompanied by treatment with broad-spectrum antibiotics. The injury healed well without any residual complaints. This case underlines the importance of intraoral examination during the evaluation of patients with potential facial injury.

Development and content of the biopsychosocial primary care intervention 'Back on Track' for a subgroup of people with chronic low back pain.

Biopsychosocial interventions provided in multidisciplinary settings are promising for improving functional disability levels in patients with chronic low back pain (CLBP). These multidisciplinary biopsychosocial interventions mainly focus on cognitive-behavioural approaches that aim to change negative cognitions, emotions, behaviour, work and social factors. As some patients with CLBP treated in primary care settings also experience psychosocial factors that influence their level of disability, these patients may benefit from the provision of a biopsychosocial intervention in primary care. This paper will provide a detailed description of the development and content of the biopsychosocial primary care intervention 'Back on Track' for this specific subgroup of patients. The Back on Track intervention was developed based on available scientific evidence and clinical experience from multidisciplinary pain rehabilitation programmes, and its effectiveness is currently being tested. CLINICAL TRIAL REGISTRATION NUMBER: NCT02220543.

Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis.

Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor-promoting microenvironment. However, subsets of myeloid cells have also been reported to have anti-tumor properties. It is not clear whether there is a transition between anti- and pro- tumor function of these myeloid cells, and if so, what are the underlying molecular mechanisms. Here we report platelet factor 4 (PF4), or CXCL4, but not the other family members CXCL9, 10, and 11, was produced at higher levels in the normal lung and early stage premetastatic lungs but decreased in later stage lungs. PF4 was mostly produced by Ly6G+CD11b+ myeloid cell subset. Although the number of Ly6G+CD11b+ cells was increased in the premetastatic lungs, the expression level of PF4 in these cells was decreased during the metastatic progression. Deletion of PF4 (PF4 knockout or KO mice) led an increased metastasis suggesting an inhibitory function of PF4. There were two underlying mechanisms: decreased blood vessel integrity in the premetastatic lungs and increased production of hematopoietic stem/progenitor cells (HSCs) and myeloid derived suppressor cells (MDSCs) in tumor-bearing PF4 KO mice. In cancer patients, PF4 expression levels were negatively correlated with tumor stage and positively correlated with patient survival. Our studies suggest that PF4 is a critical anti-tumor factor in the premetastatic site. Our finding of PF4 function in the tumor host provides new insight to the mechanistic understanding of tumor metastasis.

Changes in heart rate during third molar surgery.

Anxiety is an undesirable psychological phenomenon. Patients are usually anxious when subjected to third molar surgery, but the pattern of anxiety is unknown. The aim of this study was to assess the intensity and course of anxiety during third molar surgery. This study included 48 consecutive patients (mean age 25±6 years) who had a third molar removed surgically under local anaesthesia. The heart rate was monitored continuously during treatment as a measure of anxiety. Preoperative anxiety was scored with the Modified Dental Anxiety Scale. Each patient's anxiety level was assessed when in the waiting room, sitting down in the dental chair, during the application of local anaesthesia, application of surgical drapes, time-out procedure, incision, alveolotomy, removal of the third molar, and suturing, and at the end of the procedure. The lowest heart rates were recorded in the waiting room, in the dental chair, during anaesthesia, when applying surgical drapes, during suturing, and at the end of the procedure. The highest values were obtained during the time-out procedure, incision, and alveolotomy (P<0.005). In conclusion, the intensity and course of anxiety has a specific pattern during third molar surgery, with the lowest levels of anxiety prior to surgery and directly postoperative and the highest during the time-out procedure and the actual surgery.

Changes in the expression of calcitonin gene-related peptide after exposure to injurious stretch-shortening contractions.

UNLABELLED: One of the factors that can result in musculoskeletal injuries, and time off work, is exposure to repetitive motion. The goal of this study was to determine if skeletal muscle injury induced by exposure to injurious stretch-shortening cycles (iSSCs), resulted in hyperalgesia in the hind limb and changes in calcitonin-gene related peptide (CGRP) immunolabeling in the dorsal root ganglia (DRG) in young and old male rats. METHODS: Young (3months) and old (30months) male Fisher 344×BN F1 rats were anesthetized with isoflurane and the left hind limbs were exposed to 15 sets of 10 SSCs. Control animals were exposed to a single bout of SSCs of equal intensity. Sensitivity to mechanical stimulation was assessed using von Frey filaments prior to beginning the experiment, and on days 2 and 9 following exposure to iSSCs. Rats were euthanized one, 3 or 10days after the exposure. The ipsilateral DRG were dissected from the L4-5 region of the spine, along with the left tibialis anterior (LTA) muscle. RESULTS: Rats exposed to iSSCs were more sensitive to mechanical stimulation than control rats 2days after the exposure, and showed a reduction in peak force 3days after exposure. Changes in sensitivity to pressure were not associated with increases in CGRP labeling in the DRG at 3days. However, 9days after exposure to iSSCs, old rats still displayed an increased sensitivity to mechanical stimulation, and this hyperalgesia was associated with an increase in CGRP immunolabeling in the DRG. Young rats exposed to iSSC did not display a change in CGRP immunolabeling and sensitivity to mechanical stimulation returned to control levels at 10days. CONCLUSIONS: These findings suggest that hyperalgesia seen shortly after exposure to iSSC is not influenced by CGRP levels. However, in cases where recovery from injury may be slower, as it is in older rats, CGRP may contribute to the maintenance of hyperalgesia.

CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity.

Chemokines and chemokine receptors have critical roles in cancer metastasis and have emerged as one of the targeting options in cancer therapy. However, the treatment efficacy on both tumor and host compartments needs to be carefully evaluated. Here we report that targeting CXCR3 decreased tumor cell migration and at the same time improved host anti-tumor immunity. We observed an increased expression of CXCR3 in metastatic tumor cells compared to those from non-metastatic tumor cells. Knockdown (KD) of CXCR3 in metastatic tumor cells suppressed tumor cell migration and metastasis. Importantly, CXCR3 expression in clinical breast cancer samples correlated with progression and metastasis. For the host compartment, deletion of CXCR3 in all host cells in 4T1 mammary tumor model significantly decreased metastasis. The underlying mechanisms involve a decreased expression of IL-4, IL-10, iNOs, and Arg-1 in myeloid cells and an increased T cell response. IFN-γ neutralization diminished the metastasis inhibition in the CXCR3 knockout (KO) mice bearing 4T1 tumors, suggesting a critical role of host CXCR3 in immune suppression. Consistently, targeting CXCR3 using a small molecular inhibitor (AMG487) significantly suppressed metastasis and improved host anti-tumor immunity. Our findings demonstrate that targeting CXCR3 is effective in both tumor and host compartments, and suggest that CXCR3 inhibition is likely to avoid adverse effects on host cells.

Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone.

Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.

Rapamycin prevents the development and progression of mutant epidermal growth factor receptor lung tumors with the acquired resistance mutation T790M.

Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers.

Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer.

PURPOSE: Patients treated with sunitinib show substantial inter-patient variability in drug exposure (~30-40 %), which is largely unexplained. Since sunitinib is metabolized by cytochrome P450(CYP)3A4, variability in the activity of this enzyme may explain a considerable proportion of this inter-patient variability. Midazolam is widely used as a phenotyping probe to assess CYP3A4-activity. The objective of this study was to prospectively evaluate the relationship between midazolam and sunitinib exposure. Additionally, the correlation between sunitinib trough levels and exposure and the influence of sunitinib on midazolam exposure was determined. METHODS: Thirteen patients treated with sunitinib in a 4 weeks "on"-2 weeks "off" regimen received twice 7.5 mg midazolam; once with and once without sunitinib. Steady-state sunitinib, its active metabolite SU12662 and midazolam exposures were determined. RESULTS: A significant correlation between midazolam exposure (AUC(0-7h)) and steady-state sunitinib and sunitinib + SU12662 exposure (AUC(0-24h)) was found (p = 0.006 and p = 0.0018, respectively); midazolam exposure explained 51 and 41 % of the inter-patient variability in sunitinib and sunitinib + SU12622 exposure. Furthermore, C trough was highly correlated (r(2) = 0.94) with sunitinib AUC(0-24h). Sunitinib decreased midazolam exposure with 24 % (p = 0.034). CONCLUSION: Midazolam exposure is highly correlated with sunitinib exposure and explains a large proportion of the observed inter-patient variability in sunitinib pharmacokinetics. Consequently, midazolam could be used to identify patients that are at risk of under- or overtreatment, respectively, at the start of sunitinib therapy. Moreover, sunitinib and sunitinib + SU12662 trough levels are highly correlated with drug exposure and can thus be used in clinical practice to individualize sunitinib therapy. The decrease in midazolam exposure by sunitinib needs further investigation.