Concentrations In Cancer Patients Research Articles

Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi-centre factorial randomized trial.

Physical activity and metformin pharmacotherapy are associated with improved clinical outcomes in breast and colorectal cancer survivors. Myokines are cytokines secreted from skeletal muscle that may mediate these associations. This hypothesis-generating analysis used biospecimens collected from a multi-centre 2×2 factorial randomized design of 116 patients with stage I-III breast and colorectal cancer who were randomized to 12weeks of (1) aerobic exercise (moderate intensity titrated to 220min/week); (2) metformin (850mg daily for 2weeks and then titrated to 850mg twice per day); (3) aerobic exercise and metformin; or (4) control. Fourteen myokines were quantified using a multiplex panel. Myokine concentrations were log-transformed, and main effects analyses were conducted using linear mixed-effects regression models. The type I error rate was controlled with the Holm sequential testing procedure. Randomization to exercise increased leukaemia inhibitory factor (1.26pg/mL, 95% confidence interval [CI]: 0.69, 1.84; adjusted P=0.001) and interleukin-15 (2.23pg/mL, 95% CI: 0.87, 3.60; adjusted P=0.013) compared with randomization to no exercise. Randomization to metformin decreased apelin (-2.69pg/mL, 95% CI: -4.31, -1.07; adjusted P=0.014) and interleukin-15 (-1.74pg/mL, 95% CI: -2.79, -0.69; adjusted P=0.013) compared with randomization to no metformin. Metformin decreased myostatin, irisin, oncostatin M, fibroblast growth factor 21 and osteocrin; however, these changes were not statistically significant after correction for multiple comparisons. This pilot study demonstrates that randomization to exercise and metformin elicit unique effects on myokine concentrations in cancer patients. This hypothesis-generating observation warrants further basic, translational and clinical investigation and replication.

Abstract 110: Pro-thrombotic BCR-ABL Tyrosine Kinase Inhibitors Ponatinib And Nilotinib, But Not The Novel Agent Asciminb, Impair Endothelial Cell Wound Healing

Introduction: Tyrosine kinase inhibitors (TKIs) targeting ABL kinase have transformed the treatment of BCR-ABL positive leukemias. First generation imatinib is well tolerated while the newer TKIs, ponatinib and nilotinib, are more effective for leukemia but both substantially increase risk of acute arterial thrombosis, thereby limiting their clinical benefit over imatinib. Asciminib is a new BCR-ABL inhibitor with an unknown safety profile. We previously showed that BCR-ABL inhibitors that increase thrombosis in humans also cause toxicity in endothelial cells (ECs). Hypothesis: We hypothesize that BCR-ABL TKIs that cause EC dysfunction in vitro delay healing at sites of vascular injury in vivo as a potential mechanism of increased risk of thrombosis. Methods: We used the in vitro scratch wound assay and western blot for endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein (HUV)ECs and a mouse carotid artery wire injury model to assess the impact of BCR-ABL TKIs on EC wound healing capacity in vitro and in vivo . Results: ECs were treated with the Cmax concentration in cancer patients, as were mice, as confirmed by serum LC-MS. In vitro , ponatinib and nilotinib significantly decreased HUVEC wound healing compared to both imatinib and asciminib (p<0.001), with no difference between imatinib and asciminib. Ponatinib significantly decreased peNOS compared to both imatinib and nilotinib (<0.05), while asciminib was not significantly different from any of the other TKIs. In vivo , nilotinib significantly decreased carotid EC wound healing compared to imatinib and asciminib (p< 0.05), while ponatinib was not significantly different from any other TKIs. Carotid thrombosis after wire injury was observed in 3/26 mice treated with ponatinib, 5/23 with nilotinib, 1/21 with asciminib, and 0/26 treated with imatinib, with clot-free survival studies ongoing. Conclusions: Ponatinib and nilotinib cause EC toxicity by distinct mechanisms in vitro , which has implications for mitigating their cardiovascular risk. Asciminib causes little vascular toxicity in vitro or in vivo by these assays. Carotid thrombosis developed in some TKI treated mice, suggesting this model can be used to study the link between impaired EC healing and thrombosis.

Plasma Nickel Levels Correlate with Low Muscular Strength and Renal Function Parameters in Patients with Prostate Cancer.

Nickel is associated with cancer in occupational exposure. However, few studies have been devoted to analyzing the effects of nickel at environmental concentrations in cancer patients. In this work, the concentration of nickel in blood samples from patients with prostate cancer (PCa) was evaluated because this metal displays androgenic and estrogenic effects that play a crucial role in prostate carcinogenesis and treatment. We, therefore, compared blood nickel concentration in patients with PCa (non-occupationally exposed) (n = 46) with those in control age-matched individuals (n = 46). We also analyzed if there was any association between sociodemographic factors, clinical variables, geriatric evaluation assessment results, blood cell counts, or biochemical, androgen and estrogen concentrations. Using inductively coupled plasma-mass spectroscopy on the plasma samples, we observed a mean nickel level of 4.97 ± 1.20 µg/L in the PCa group and 3.59 ± 0.49 µg/L in the control group, with a non-significant effect (p = 0.293) between the two groups. The nickel concentration was significantly correlated with patient age (p = 0.005) and reduced handgrip strength (p = 0.003). Regarding biochemical parameters, significant associations were found with the renal glomerular filtration rate (p = 0.024) and blood urea levels (p = 0.016). No significant correlations were observed with other blood analytical parameters or testosterone or estradiol levels. These specific renal function and muscle strength effects were observed at environmental nickel exposure levels believed to be safe or at least far from the high concentrations observed after occupational exposure. Therefore, these parameters deserve further study, given that they could help pinpoint further public health concerns regarding nickel exposure in the general population.

Validation of an LC-MS/MS Method for the Quantification of the CK2 Inhibitor Silmitasertib (CX-4945) in Human Plasma.

Silmitasertib (CX-4945) is currently being investigated in clinical trials against various types of cancer. The U.S. Food and Drug Administration (FDA) has already granted orphan drug designation to the compound for the treatment of advanced cholangiocarcinoma, medulloblastoma, and biliary tract cancer. Silmitasertib inhibits the serine/threonine protein kinase CK2, which exerts a proliferation-promoting and anti-apoptotic effect on cancer cells. In view of current and future applications, the measurement of silmitasertib levels in plasma is expected to play an important role in the evaluation of therapeutic and toxic concentrations in cancer patients. In the present work, we therefore present an LC–MS/MS method for the quantification of silmitasertib in human plasma. Using a simple liquid–liquid extraction with ethyl acetate and a mixture of n-hexane and ethyl acetate, this method can be performed in any laboratory with mass spectrometry. The validation was carried out according to the FDA guideline.

Effect of letrozole on follicular fluid steroids concentrations in cancer patients undergoing oocyte cryopreservation.

To investigate the impact of letrozole administration on follicular steroid hormones during controlled ovarian hyperstimulation for fertility preservation. One hundred and nineteen women with cancer undergoing oocytes retrieval for fertility preservation were recruited. All women underwent ovarian hyperstimulation according to a random start protocol. Those with hormone-sensitive tumors also received letrozole, an aromatase inhibitor aimed at keeping peripheral estrogen levels low. At the time of oocytes retrieval, a sample of follicular fluid was collected and frozen. All samples were assayed concomitantly after thawing, by liquid chromatography tandem mass spectrometry. The concentration of 15 steroid hormones was determined and results were compared between women who did and did not receive letrozole. Fifty-two women were treated with letrozole, while 67 were not. Statistically significant differences emerged for 12 of the 15 tested steroids. They were the following: cortisol, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), estradiol, androstenedione, testosterone, dihydrotestosterone (DHT), 17-hydroxyprogesterone, progesterone and corticosterone. The most striking differences were observed for testosterone that showed a more than 200-time increase in women receiving letrozole. Estradiol was conversely reduced to a third. The endocrine microenvironment surrounding oocytes is markedly perturbed by the concomitant assumption of letrozole. Robust clinical evaluation is pressingly needed to rule out any detrimental effect on the chance of live birth with the use of these oocytes.

Vitamins as Possible Cancer Biomarkers: Significance and Limitations.

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as ‘hidden hunger’), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.

Method Development and Validation for Measuring O6-Methylguanine in Dried Blood Spot Using Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry.

BackgroundCyclophosphamide is a nitrogen mustard chemotherapy drug that damages DNA through alkylation in the DNA base and produces DNA adducts. Alkylation that occurs in the N7 position of guanine base has a cytotoxic effect which is useful for cancer therapy. However, the alkylation that occurs in the O6 position of guanine bases can have mutagenic and carcinogenic effects that can trigger secondary cancer. This carcinogenic compound can be found in very low concentrations in cancer patients who had been receiving alkylating agents as their anticancer therapy. Analysis of O6-methylguanine can be one of the ways of therapeutic drug monitoring to avoid secondary cancer risk. This study aims to develop a sensitive, selective, and validated analytical method using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS).MethodsAnalysis of O6-methylguanine was done in Dried Blood Spot (DBS) and using allopurinol as an internal standard. The optimal analysis conditions were obtained using a C18 Acquity® Bridged Ethylene Hybrid (BEH) column (1.7 µm, 100 mm x 2.1 mm); mobile phase was 0.05% formic acid - acetonitrile (95:5 v/v); flow rate 0.1 mL/minute; gradient elution for 6 minutes; and detection at m/z 165.95 > 149 for O6-methylguanine and m/z 136.9 > 110 for allopurinol.ResultsThe present study has fulfilled the FDA validation parameter requirements. The method provides rapid, sensitive, and selective analysis of O6-methylguanine using UPLC-MS/MS with a linear concentration range between 0.5–20 ng/mL.

The Induction of Antioxidant Catalase Enzyme With Decrease of Plasma Malonidialdehyde: An Important Reactive Oxidative Species Inhibiting Mechanism.

The simultaneous increase of antioxidant CAT (catalase) enzyme and plasma MDA (malonidialdehyde) concentrations versus the numeric rating scale (NRS) pain score following surgery is unknown. Patients and Methods: The study included 114 patients with gallstone disease and 29 patients in the cancer group. Following surgery, the plasma CAT concentrations increased and plasma MDA concentrations decreased in all patients and especially in cancer patients. The linear mixed model time-effect was statistically significant in CAT and MDA (p<0.001 and p=0.02, respectively). In addition, a significant correlation between NRS pain score values and plasma MDA median concentrations in cancer patients was identified (r=0.430, p<0.001). The plasma MDA concentrations decreased and CAT concentrations increased significantly in all patients and especially in cancer patients following surgery. The simultaneous increase of antioxidant CAT enzyme with the decrease of plasma MDA may be an important ROS inhibiting mechanism to help patients return to normal antioxidant-oxidant status.

Prospective Association of Serum Opioid Levels and Clinical Outcomes in Patients With Cancer Pain Treated With Intrathecal Opioid Therapy.

Opioids remain the mainstay of cancer pain management but are associated with systemic toxicity. In refractory cancer pain, intrathecal therapy (ITT) is associated with improved pain control, reduced systemic side effects, and improved survival. It has been assumed that ITT decreases systemic serum opioid levels and their associated toxicity, but there are limited data to support this assumption. This study hypothesizes that serum opioid levels decrease with ITT. Secondary objectives include comparative measures of pain, bowel function, and other cancer-related symptoms. Fifty-one cancer patients undergoing ITT for cancer pain were recruited in a prospective observational study. Daily oral morphine equivalency (OME) dose, serum opioid levels, Brief Pain Inventory (BPI), MD Anderson Symptom Inventory (MDASI), and a constipation questionnaire were obtained at the time of implant, and 4 and 8 weeks postoperatively. Average baseline daily OME was 375 mg (median, 240; interquartile range, 150-405; range, 0-3160), mean serum morphine concentration was 53.7 ng/mL (n = 17), and mean oxycodone concentration was 73.7 ng/mL (n = 20). At 4 weeks, 87.5% of patients had discontinued non-IT opioids, and 53% had undetectable (<2 ng/mL) serum opioid concentrations. At 8 weeks, 92% remained off all non-IT opioids and 59% had undetectable serum opioid levels. IT morphine doses >4.2 mg/d were invariably associated with detectable serum levels; with doses <4.2 mg, morphine was undetectable in 80% of subjects. IT hydromorphone doses >6.8 mg/d were detectable in the serum. Using linear mixed model analyses, there were statistically significant decreases in the mean "worst pain," "average pain," and MD Anderson symptom severity and interference scores at 4 and 8 weeks. This change was independent of serum opioid levels; when analyzed separately, there was no difference in the pain scores of subjects with detectable serum opioid levels compared to those with undetectable levels at 4 and 8 weeks. Constipation ranked as "quite a bit" or "very much" decreased from 58.7% to 19.2% of subjects at week 4 (P < .001) and to 37.5% at 8 weeks (P = .23). A very low complication rate was observed. ITT for cancer pain was associated with a marked reduction in serum opioid concentrations, with the majority of patients having undetectable serum levels. Reducing serum opioid concentrations in cancer patients may have implications with respect to restoring bowel function, improving fatigue, and promoting the integrity of antitumor immune function and warrants further study.

Radiotherapy Treatment Effects on the Energy Metabolism in LUNG, Head and Neck Cancer Patients

Radiotherapy (RT) treatment can produce metabolic changes in cancer patients. The application of metabolomics to the study of energy metabolism in cancer is an underdeveloped issue, and only a few studies have investigated this in lung (LC) and head and neck cancer (HNC) patients exposed to RT, despite its potential relevance in clinical practice. The aims of our study were to analyze the changes produced by RT on the activity and concentration of serum PON1 and the variations in the lipoprotein profile and energy metabolites in LC and HNC patients and to correlate these changes with the clinical and pathological characteristics of patients and tumors, and their response to treatment. The study included LC patients (n=33) and HNC patients (n=28) treated with RT. Control group (n= 50) was formed by Mediterranean health people. Blood samples for analyses were obtained before and after the irradiation procedure. Lipoprotein profile and energy metabolites carried out by nuclear magnetic resonance and gas chromatography-mass spectrometry. Statistical analysis was performed with a statistical analysis software. Relative to control, both cancer groups had significantly lower serum PON1 concentration, and arylesterase activity (p<0.001). However, after RT increased PON1 concentration in cancer patients but also arylesterase activity decreased. This low activity was correlated with an increase of pulmonary toxicity. Intermediate density lipoprotein (IDL), triglycerides linked with different lipoprotein profiles and the VLDL particles size were significantly higher in cancer groups in comparison to control group. Whereas leucine, isoleucine, valine, 3-hydroxybutyrate, and serine metabolites were significantly lower in cancer groups, succinate, malate, aspartate, pyruvate, glutamine and glutamate were significantly higher in the same groups. LC and HNC patients showed significantly differences in leucine, isoleucine, serine, aconitate and citrate metabolites between before and after RT treatment. Our study demonstrates that RT treatment can modulate anti-oxidant defense mechanisms and metabolites related to one carbon metabolism in cancer patients. These results could be useful as a biomarker to predict RT response and the prognosis of patients.

Fecal calprotectin concentrations in cancer patients with Clostridium difficile infection.

Fecal calprotectin (fCPT) has been used as a surrogate marker for assessment of intestinal inflammation. We explore the utility of fCPT values as a diagnostic aid in cancer patients with suspected Clostridium difficile infection (CDI). A total of 232 stool specimens submitted for GeneXpert C. difficile PCR testing were included in the study. All specimens were tested for fCPT and toxin/GDH antigens. Clinical severity of CDI cases was determined by the IDSA/SHEA criteria. Significant differences of median fCPT values between CDI (n = 117, Median 183.6μg/g) and non-CDI (n = 115, 145.6μg/g, p = 0.006) patients were seen. In CDI patents, significantly lower fCPT values were found in patients with mild to moderate (n = 95, 182.1μg/g) than those with severe and severe to complicated (n = 22, 218.5μg/g, p = 0.014) scores, and among those that were toxin positive (n = 24, 200.2μg/g) vs. toxin negative (n = 86, 182.8μg/g, p = 0.044). Despite this overall trend, wide variations in fCPT values were found in all categories examined. A logistic regression analysis revealed that the fCPT values correlated independently with the severity of clinical manifestations (OR = 2.021, 95%CI = 1.132-3.608); however, it did not correlate with other clinical outcomes. Our study findings show that high fecal calprotectin levels correlate with toxin-positive and clinically severe CDI; however, wide variations in individual measurements preclude establishment of reliable cut-offs for routine diagnostic use in cancer patients.

PO-018 Acquired DNA damage in adolescent obesity – a promoter and predictor of cancer?

IntroductionEpidemiological evidence linking obesity with increased risk of cancer is steadily growing, although the causative aspects underpinning this association are only partially understood. Obesity coincides with deficiencies in micronutrients such as Vitamin D, a key player in DNA repair processes. As a result, vitamin D deficiency in obesity may have a marked impact on DNA stability and integrity. 8-hydroxyguanosine (8-OHdG) is a well-established marker of oxidative DNA damage that has been identified in higher concentrations in cancer patients. Here we report, preliminary, unpublished findings from our study on acquired DNA damage in childhood obesity.Material and methodsBody Mass Index (BMI), Waist to Hip ratio (WHR) and body fat percentage via bioelectrical impedance was assessed in over 70 participants, aged 11–18 and recruited from National Health Service (NHS) obesity clinics and schools in London. A non-invasive, integrated evaluation of urinary 8-OHdG and salivary vitamin D was conducted using ELISA based methods and compared to markers of adiposity.Results and discussionsA BMI percentile >99 was found to be associated with decreased salivary vitamin D and increased urinary 8-OHdG when compared to healthy weight controls (BMI=5th-85th percentile). Vitamin D levels in saliva were found to be inversely correlated with BMI and body fat percentage. Urinary 8-OHdG positively correlated with body fat percentage and WHR. Most importantly, an inverse correlation between vitamin D in saliva and 8-OHdG in urine was also identified.Recent evidence has suggested vitamin D in obesity to be a consequence of altered behaviour, reduced intestinal absorption, and sequestration of vitamin D into adipose tissue. As a result, DNA repair processes against oxidative DNA damage in obesity may be impaired, resulting in the excess of lesions including 8-OHdG. The effects of excess 8-OHdG lesions have been well researched to include various mutations that can drive carcinogenesis.ConclusionOur results suggest Vitamin D deficiency in obese adolescents may play a significant role in triggering oxidative DNA damage, thus increasing the likelihood of cancer later in life.

The Clinical Utility of Cell-Free DNA Measurement in Differentiated Thyroid Cancer: A Systematic Review.

Cell-free DNA (cfDNA) can be detected in the circulation of healthy individuals, but is found in higher concentrations in cancer patients. Furthermore, mutations in tumor cells can be identified in circulating DNA fragments. This has been the subject of significant interest in the field of cancer research, but little has been published in thyroid cancer. To assess all available evidence on the use of circulating cfDNA in the diagnosis, management and surveillance of patients with differentiated thyroid cancer, and collate it into a systematic review to guide future research. A comprehensive literature search on the measurement of cfDNA in thyroid cancer was undertaken, and results from relevant studies collated into a systematic review. Nine studies were identified, with varying methodologies and findings. Key techniques and findings are summarized. There is limited but promising evidence that somatic mutations in thyroid cancer can be detected in circulating cfDNA and are associated with more advanced disease. Further research is required to develop a clinically useful tool based on cfDNA to improve the management of thyroid cancers.

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

PurposeEverolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients’ home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients.MethodsPaired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted.ResultsSamples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93–1.35) and a small proportional bias (slope 0.89; 95% CI 0.76–0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of < 20%.ConclusionsDBS is a valid method to determine everolimus concentrations in cancer patients. This can especially be of value for early recognition of over- or underexposure to enable dose adaptations.

Neopterin as a biomarker of immune response in cancer patients.

With the advent of immunotherapy the topic of biomarkers of immune response is of high interest. Along with the expression of programmed death ligand 1 (PD-L1) or tumor infiltrating lymphocytes (TIL), biomarkers of macrophage activation could be of interest. Neopterin is a biomarker of immune activation increased in different disorders associated with immune activation, including cancer. Neopterin synthesis is induced by interferon-γ that also induces indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing catabolism of tryptophan to kynurenine. Increased urinary or serum concentrations of neopterin have been associated with poor prognosis across a spectrum of malignant disorders of different primary location. Neopterin concentration in peripheral blood as well as in the tumor microenvironment correlates with phenotypic and functional changes of lymphocytes, indicating immune dysfunction. Increased neopterin concentrations are also accompanied by increased rate of conversion of tryptophan to kynurenine. Increasing neopterin concentrations also accompany side effects of anticancer treatment and could predict subsequent complications. Although almost four decades have elapsed since the discovery of increased neopterin concentrations in cancer patients, the full potential of neopterin as a biomarker in this setting has not been so far realized.

Measurement of piperacillin plasma concentrations in cancer patients with suspected infection.

Piperacillin (PIP) in combination with tazobactam is commonly used for anti-infective treatment in cancer patients. PIP exerts a time-dependent killing. Thus, the maintenance of plasma concentrations above a pre-defined target concentration for a pre-defined time may be relevant for optimal efficacy. It is assumed that PIP-plasma concentrations above the clinical breakpoint of the target pathogen [Pseudomonas aeruginosa, clinical breakpoint at minimal inhibitory concentration (MIC) 16mg/L] should be reached for 100% of the dosing interval or>4xMIC (64mg/L) for 50% of the dosing interval. Whereas studies in the intensive-care setting have shown underdosing in patients with sepsis, little is known about PIP-plasma concentrations in cancer patients. Data of 56 cancer patients who received piperacillin/tazobactam (PIP/TAZ, 4.5g three times daily) as empiric therapy for suspected infection were analysed at baseline and 4h after the infusion. Median trough concentrations in steady state [median 3days (IQR 3-5) after start of PIP/TAZ] were 4.6mg/L (95% CI 0.3-136.3) and median PIP-plasma concentrations 4h after infusion were 46.2mg/L (95% CI 10.1-285.6). A second evaluation 5days (IQR 4-7) after start of PIP/TAZ confirmed these results: trough concentrations were 2.7mg/L (95% CI 0.5-6.3), concentrations after 4h 28.0mg/L (95% CI 1.7-47.3). A good renal function was associated with lower plasma concentrations (r=-0.388, p<0.003). Detailed pharmacokinetic measurements in six patients showed low maximum plasma concentration (median 165mg/L) and a rapid decline of plasma concentrations (median plasma half time 1.38h). In conclusion, piperacillin plasma concentrations in cancer patients are below target levels warranting prospective trials to investigate therapeutic drug monitoring.

Electron transport through 8-oxoG: NEGF/DFT study

We present a first-principles study of the conductance of Guanine and 8-Oxoguanine (8-oxoG) attached to Au(111) electrodes. Cellular levels of 8-oxoG have been found in larger concentrations in cancer patients. The current through the structure was calculated using a DFT–NEGF formalism. We have compared flat and pyramidal electrode geometries and show that there is a measurable difference between the I–V characteristics of the pristine molecule and the 8-oxoG. For a flat electrode geometry, 8-oxoG produces a 2.57 (18.3) times increase in current than the corresponding counterpart at 3 V with a bond separation of 1.2 Å (2.4 Å). This can be attributed to molecular orbital energies shifting at the junction. Overall the flat geometry produces larger currents. We have also investigated the sensitivity of the current to the electrode molecule separation. For the flat geometry, the current dropped approximately 80% (97%) for 8-oxoG (pristine Guanine) with the doubling of the electrode separation.

Abstract OT1-04-01: Cambridge brain mets trial 1 (CamBMT1): A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy

Abstract Background Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure for patients with brain tumors. For most patients who don't respond to treatment, it is not known whether this is due to inadequate drug concentrations in the tumor, or due to drug resistance. Preliminary data suggest that low-dose radiotherapy may disrupt the BBB, and could facilitate increased drug delivery into brain tumors. Afatinib is a potent, irreversible inhibitor of EGFR / HER2 / HER4 and takes approximately 8 days to achieve steady-state concentrations in cancer patients. Aims CamBMT1 has been designed to investigate the delivery of afatinib into brain metastases and whether this might be enhanced by low dose-radiotherapy. Patient Population Key eligibility criteria Patients with operable brain metastases from breast or lung primaries for whom neurosurgical resection would be standard of care, as determined by the local multi-disciplinary team. ECOG PS 0, 1 or 2. Trial design After a phase 1b safety run- in, the phase 2 part of the trial randomises patients (n=60) into 3 pre-operative arms: Arm 1afatinib alone for 11 days, then neurosurgery on day 12Arm 2afatinib for 11 days plus a single 2 Gy fraction on day 10, then neurosurgery on day 12Arm 3afatinib for 11 days plus a single 4 Gy fraction on day 10, then neurosurgery on day 12 Primary endpoint: to compare steady-state afatinib concentration in resected brain metastases, following afatinib administered alone, or in combination with radiotherapy (2 Gy or 4 Gy). Afatinib concentrations are measured in the resected brain metastases and in plasma. Secondary endpoints: safety of afatinib administration in combination with radiotherapy; and multi-sequence MRI (optional) to detect changes in perfusion, vascular density, blood-brain-barrier permeability and interstitial pressure. Exploratory endpoints: molecular profiling of resected brain metastases, for comparison with paired primary lung and breast cancers; the establishment and study of patient-derived xenografts. Statistical methods With 20 patients randomised in each of 3 arms in the phase 2 part of CamBMT1, the trial has a power of 84% at a significance level of 20% (one-sided) to detect an increase in afatinib concentrations with targeted radiotherapy, measured as a Cohen's D (standardised mean difference) ≥0.5. Accrual By the end of q2 2016, phase 1b had nearly completed enrolment. The randomised phase 2 part of CamBMT1 is due to open by q4 2016 at additional Experimental Cancer Medicine Centres. Acknowledgments CamBMT1 is funded by Cancer Research UK, the Brain Tumour Charity and Boehringer-Ingelheim. Citation Format: Baird RD, Ramenatte N, Watts C, Jonson A, Jones L, Biggs H, Harrison E, Oberg I, Bullen G, Williams M, Qian W, Gilbert F, Jodrell D, Caldas C, Karabatsou K, Dunn L, Jena R, Whitfield G, Chalmers A, Jefferies S, Price S. Cambridge brain mets trial 1 (CamBMT1): A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-01.

Urinary Iodine Concentrations in Cancer Patients

Background:It has been suggested that incidence of some cancers, especially examples in the breast and stomach may be influenced by the iodine intake. However, only few studies are available at present. Therefore, we have conducted the present assessment of iodine status in Iranian patients diagnosed with a malignancy.Materials and Methods:This cross-sectional study was conducted in 85 patients diagnosed with different types of cancer at Shahid Sadoughi Hospital, Yazd, Iran. The method used was based on the Sandell–Kolthoff reaction.Results:The median urinary iodine concentration (UIC) was 17.4 μg/L, with ≤20 μg/L indicative of severe iodine deficiency. According to the WHO/IC C IDD/UNIC EF classification, 88.1%, 7.1% and 2.4% of patients had a UIC <20 (severe), 20–49 (mild), and 50–99 μg/L (moderate), respectively. There was no statistically significant differences in UIC between men and women.Conclusion:The UIC values indicate that Iranian cancer patients were seriously iodine deficient according to WHO/UNIC EF/IC C IDD, and that this is a suitable index to assess iodine status in Iranians. Daily consumption of salt fortified with iodine or other approaches to increase intake might be effective strategies for prevention or reduction of malignancies.

Relationship between the plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain

This study aimed to evaluate the relationship between the concentrations of plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in cancer patients. Thirty-three Japanese cancer patients treated with transdermal fentanyl were enrolled. The concentrations of plasma fentanyl and norfentanyl, and serum 4β-hydroxycholesterol and total cholesterol were determined at day 8 or later after starting the medication. The plasma fentanyl concentration was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. The *3/*3 group had a lower metabolic ratio of fentanyl. The serum 4β-hydroxycholesterol concentration and its ratio to total cholesterol were significantly lower in the CYP3A5*3/*3 group than in the *1 allele carrier group. The concentrations of plasma fentanyl and serum 4β-hydroxycholesterol were significantly higher in women than in men. Gender did not affect the metabolic ratio of fentanyl or the concentration ratio of 4β-hydroxycholesterol. The plasma fentanyl concentration was not correlated with the serum 4β-hydroxycholesterol concentration, while the metabolic ratio of fentanyl was slightly correlated with the serum concentration ratio of 4β-hydroxycholesterol. In conclusion, CYP3A5*3 and gender affected the plasma fentanyl and serum 4β-hydroxycholesterol concentrations in cancer patients. However, the plasma disposition of fentanyl was not determined using the serum 4β-hydroxycholesterol concentration.