Multimodality imaging in primary hyperparathyroidism.

Institutional variations in parathyroid adenoma localisation are largely dictated by local experience and availability of imaging investigations, with no consensus on the optimal approach. This review evaluates the role of multiple imaging techniques in primary hyperparathyroidism and highlights their advantages and limitations in different clinical contexts. A clinico-radiological review of parathyroid imaging techniques is illustrated with example cases and data from the literature. These include high-resolution ultrasound, 99mTc-sestamibi planar scintigraphy with and without thyroid subtraction techniques, integrated 99mTc-sestamibi single-photon-emission computed tomography (SPECT)/computed tomography (CT), four-dimensional (4D) CT, and other techniques, such as magnetic resonance imaging, integrated 18F-choline/11C-methionine positron-emission tomography (PET)/CT and angiographic selective venous sampling. The crucial role of parathyroid embryological and gross anatomy in informing the surgical approach to parathyroidectomy is discussed. Finally, a systematic approach to imaging is proposed to maximise the accuracy of imaging localisation of parathyroid lesions, which is crucial for optimal patient management.

Machine learning-based FDG PET-CT radiomics for outcome prediction in larynx and hypopharynx squamous cell carcinoma.

AIM: To determine whether machine learning-based radiomic feature analysis of baseline integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) computed tomography (CT) predicts disease progression in patients with locally advanced larynx and hypopharynx squamous cell carcinoma (SCC) receiving (chemo)radiotherapy. MATERIALS AND METHODS: Patients with larynx and hypopharynx SCC treated with definitive (chemo)radiotherapy at a specialist cancer centre undergoing pre-treatment PET-CT between 2008 and 2017 were included. Tumour segmentation and radiomic analysis was performed using LIFEx software (University of Paris-Saclay, France). Data were assigned into training (80%) and validation (20%) cohorts adhering to TRIPOD guidelines. A random forest classifier was created for four predictive models using features determined by recursive feature elimination: (A) PET, (B) CT, (C) clinical, and (D) combined PET-CT parameters. Model performance was assessed using area under the curve (AUC) receiver operating characteristic (ROC) analysis. RESULTS: Seventy-two patients (40 hypopharynx 32 larynx tumours) were included, mean age 61 (range 41-77) years, 50 (69%) were men. Forty-five (62.5%) had chemoradiotherapy, 27 (37.5%) had radiotherapy alone. Median follow-up 26 months (range 12-105 months). Twenty-seven (37.5%) patients progressed within 12 months. ROC AUC for models A, B, C, and D were 0.91, 0.94, 0.88, and 0.93 in training and 0.82, 0.72, 0.70, and 0.94 in validation cohorts. Parameters in model D were metabolic tumour volume (MTV), maximum CT value, minimum standardized uptake value (SUVmin), grey-level zone length matrix (GLZLM) small-zone low grey-level emphasis (SZLGE) and histogram kurtosis. CONCLUSION: FDG PET-CT derived radiomic features are potential predictors of early disease progression in patients with locally advanced larynx and hypopharynx SCC.

Protocol-driven multidetector SPECT/CT: integration of hybrid imaging into the routine workflow of whole-body bone scintigraphy in oncology patients.

AIM: To analyse the additional clinical value of protocol-driven and selective use of multidetector single-photon-emission tomography/computed tomography (SPECT/CT) in oncology patients undergoing whole-body bone scintigraphy (BS) and to analyse reporter confidence in diagnosis with and without SPECT/CT. MATERIALS AND METHODS: During a 2-year period, 2,954 whole-body BS examinations were performed in oncology patients, with 444 (15%) undergoing additional protocol-driven SPECT/CT. Retrospective evaluation of planar BS and SPECT/CT images was performed by two experienced dual-trained nuclear medicine radiologists. The BS and SPECT/CT images were graded blindly using a five-point scale designed to evaluate the likelihood of a lesion being benign or malignant. Interpretation was applied on a per-patient basis. RESULTS: There was a 74.5% increase in definitive diagnostic classification and a 26.6% reduction in equivocal findings with SPECT/CT when compared to BS alone (p<0001). Of cases initially classified as "probably benign" on BS, 5.1% (10/193) were reclassified to "probably malignant" (1%) or "malignant" (4.1%) using the SPECT/CT data. The highest impact in reporter confidence was seen with SPECT/CT in the interpretation of lesions within the pelvis (34%), ribs (23%), lumbar spine (22%), and thoracic spine (21%). CONCLUSION: Protocol-driven, selective use of SPECT/CT imaging to augment planar BS reduces equivocal findings and improves reporter confidence whilst minimising the impact on patient and reporting workflows.

Radiological-pathological correlation of the British Thyroid Association ultrasound classification of thyroid nodules: a real-world validation study.

AIM: To evaluate the real-world performance of the British Thyroid Association (BTA) U classification, specifically focusing on radiology-pathology correlation and to glean learning points. METHODS AND MATERIALS: Adults undergoing a neck ultrasound for thyroid nodules were reviewed over a period of 1-year. Data including demographics, nodule characteristics, BTA grading, and cytology/histopathology were retrieved with a minimum 24-month follow-up. RESULTS: Of 1,225 graded nodules in 964 patients, cytology and/or histology were available for 300 (24%). 57 cancers were detected. Of 24 (2%) U5 nodules, 14 were malignant, of 51 (4%) U4, 22 were malignant, of 256 (21%) U3, 20 were malignant, and from 894 (73%) U2 nodules, one cancer was discovered. BTA U grading with fine-needle aspiration (FNA)/core biopsy achieved 96.5% sensitivity, 93.7% specificity, and 93.9% accuracy compared to excision. There was no association between nodule size and rate of malignancy. CONCLUSION: This is the first study to validate the use of the BTA U-grading system in UK clinical practice. The BTA U-grading system is a robust and reliable method of evaluating the risk of malignancy in thyroid nodules with a high negative predictive value. Key learning points gleaned from the study were accurate assessment of nodule echogenicity, careful evaluation of solid-cystic nodules, optimising ultrasound technique, and the low-risk nature of U3 nodules.

Utility of additional abdominopelvic CT in detecting occult cancer in patients with unprovoked venous thromboembolism.

AIM: To analyse the positive rate for cancer on additional abdominopelvic computed tomography (CT) in patients with unprovoked venous thromboembolism (VTE), evaluate the subsequent emergence of a cancer diagnosis in the clinical follow-up period, and identify any possible predictive factors of cancer in this cohort, which may allow better selection of patients for additional imaging. MATERIALS AND METHODS: Consecutive adult patients with VTE were retrospectively identified in two large teaching hospitals between January 2013 and June 2014, including a subset of those with unprovoked VTE. Relevant demographic data were extracted and analysed. All patients had a minimum of 12 months clinicoradiological follow-up. RESULTS: One thousand four hundred and forty-six patients with VTE were deemed eligible, of which 699 (48%) were male; the median age (range) was 66 (16-102) years. The prevalence of pre-existing cancer in these patients was 343/1446 (24%), and 388/1446 (27%) were classified as unprovoked VTE. In 12/1446 (0.8%), cancer was diagnosed synchronously with VTE on the initial imaging investigation. Additional screening imaging was performed in 232/388 (60%) including abdominopelvic CT in 205 (53%) patients with unprovoked VTE. Only five additional cancers were identified, all of these occurring in patients with clinical symptoms suspicious for cancer. None of the additional CT examinations identified any clinically occult cancer in asymptomatic patients, and subsequent mean follow-up of 22 (SD=6) months also failed to reveal any further cancer diagnosis. CONCLUSION: Contrary to the National Institute of Health and Care Excellence (NICE) guidance, the yield of performing additional abdominopelvic CT as a screening tool for occult cancer in asymptomatic patients with unprovoked VTE is negligible. A more selective and clinically-driven assessment of these patients is recommended.

FDG PET/CT in infection and inflammation--current and emerging clinical applications.

Integrated positron emission tomography/computed tomography (PET/CT) with the glucose analogue, 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG), is an evolving hybrid imaging technique in the evaluation of an important and diverse group of pathological conditions, which are characterised by infection and aseptic inflammation. With a rapidly expanding body of evidence, it is being increasingly recognised that, in addition to its established role in oncological imaging, FDG PET/CT also has clinical utility in suspected infection and inflammation. The technique can identify the source of infection or inflammation in a timely fashion ahead of morphological changes on conventional anatomical imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), map the extent and severity of disease, identify sites for tissue sampling, and assess therapy response. FDG PET/CT exhibits distinct advantages over traditional radionuclide imaging techniques in terms of shorter duration of examination, higher spatial resolution, non-invasive nature of acquisition, ability to perform quantitative analyses, and the provision of a synergistic combination of functional and anatomical imaging. With the use of illustrative clinico-radiological cases, this article discusses the current and emerging evidence for the use of FDG PET/CT in a broad spectrum of disorders, such as fever of unknown origin, sarcoidosis, large vessel vasculitis, musculoskeletal infections, joint prosthesis or implant-related complications, human immunodeficiency virus (HIV)-related infections, and miscellaneous indications, such as IgG4-related systemic disease. It will also briefly summarise the role of more novel tracers such as FDG-labelled leukocytes and gallium-68 PET tracers in this arena.

PAMAM Dendrimers as Quantized Building Blocks for Novel Nanostructures.

The desire to synthesize soft supramolecular structures with size scales similar to biological systems has led to work in assembly of polymeric nanomaterials. Recent advances in the isolation of generationally homogenous poly(amidoamine) (PAMAM) dendrimer enables their use as quantized building blocks. Here, we report their assembly into precise nanoclusters. In this work, click-functional ligands are stochastically conjugated to monomeric generation 5 PAMAM dendrimer and separated via reverse-phase HPLC to isolate dendrimers with precise numbers of click ligands per dendrimer particle. The click-ligand/dendrimer conjugates are then employed as modular building blocks for the synthesis of defined nanostructures. Complimentary click chemistry employing dendrimers with 1, 2, 3, or 4 ring-strained cyclooctyne ligands and dendrimers with 1 azide ligand were utilized to prepare megamer structures containing 2 to 5 ~30,000 kDa monomer units as characterized by mass spectrometry, size exclusion chromatography, and reverse-phase liquid chromatography. The resulting structures are flexible with masses ranging from 60,000 to 150,000 kDa, and are soluble in water, methanol, and dimethylsulfoxide.

Airway dysfunction in nasal polyposis: a spectrum of asthmatic disease?

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) represents an interesting model to investigate the existence of a non-allergic unified airway. The factors associated with airway dysfunction in CRSwNP are not fully understood. OBJECTIVE: To assess the impact of nasal disease on lower airway dysfunction in CRSwNP. METHODS: Fifty-seven patients with CRSwNP underwent spirometry, nasal endoscopy, exhaled nitric oxide, methacholine bronchial challenge, blood sampling for total IgE, eosinophil count and radioallergosorbent testing (NCT00788749). Three phenotypic groups were identified: 'asthma group' (asthma diagnosis); 'inflammatory group' [no asthma diagnosis, but elevated fractionated exhaled nitric oxide (FE(NO)) and/or bronchial-hyperreactivity (BHR)]; and 'non-inflammatory group' (no asthma diagnosis, no BHR and normal FE(NO)). Group comparisons, univariate and multivariate analyses were performed to examine associations with airway dysfunction. RESULTS: FEV(1) and FEF(25-75%) were reduced in asthma, but there was no difference between the non-asthmatic groups. Total IgE and eosinophils were elevated in asthma vs. the non-inflammatory group, but there was no difference for asthma vs. inflammatory groups. BHR was the only significant predictor of FEV(1) (P<0.001). For FEF(25-75), BHR and eosinophil count were independent predictors (P<0.001 and P=0.04). Nasal outcomes were not predictors of spirometry. CONCLUSION AND CLINICAL RELEVANCE: In CRSwNP there is asymptomatic airway dysfunction suggestive of an asthmatic phenotype. Impairment of lung function is significantly associated with BHR and eosinophilia but not parameters of nasal disease suggesting that severity of airway dysfunction relates to the spectrum of asthma rather than rhinosinusitis. Lower airway dysfunction is common in CRSwNP but does not correlate to the severity of nasal disease. Signs and symptoms of asthma should be sought and treated in CRSwNP.

The minimal clinically important difference in allergic rhinitis.

BACKGROUND: When presented with results from clinical measurements or research findings, clinicians must first make an interpretation of their importance, not only in statistical terms, but also the 'clinical importance' given the size of the change observed. To do this, they require an understanding of the relationship between their outcome measures, and the patient's perception of change. The minimal clinically important difference (MCID) illustrates this relationship by calculating the smallest change in a given outcome that is meaningful to a patient. There are few reports of calculated MCIDs in the Rhinology literature. OBJECTIVE: To calculate MCIDs for common subjective and objective outcome measures in allergic rhinitis (AR). METHODS: Nine randomized, blinded, placebo-controlled clinical trials in intermittent and persistent AR (pooled subjects, n=204) were analysed using anchor- and distribution-based approaches, applying regression and meta-analysis techniques. RESULTS: MCIDs were obtained for the Mini Rhinoconjunctivitis Quality of Life Questionnaire: 0.4 units, peak nasal inspiratory flow: 5 L/min and total nasal symptoms score: 0.55 units. Nasal NO measurement changes had no correlation with patient perceptions of benefit. CONCLUSION: Estimates of MCIDs were obtained for common subjective and objective rhinological outcomes. MCIDs can and should be applied by physicians interpreting research findings, as well as researchers reporting their findings. We can then be confident that our changes in practice will be of perceptible benefit to the patient.

Disconnect between standardized field-based testing and mannitol challenge in Scottish elite swimmers.

BACKGROUND: Elite swimmers have high rates of rhinoconjunctivitis and exercise-induced bronchoconstriction. Moreover, exposure to chlorine and chlorine metabolites is known to induce bronchial hyper-reactivity. OBJECTIVE: To assess the early and late effects of chlorine and exercise on the unified airway of elite swimmers, and to compare the response to mannitol and field-based exercise challenge. METHODS: The Scottish national squad underwent exhaled tidal (FE(NO)) and nasal (N(NO)) nitric oxide measurement, peak nasal inspiratory flow (PNIF), and forced expiratory volume in 1 s before, immediately after, and 4-6 h post-swimming. A sport-specific exercise test was carried out during an intensive lactate set (8 min at >/=80% maximum hear rate). All swimmers underwent mannitol challenge, and completed a health questionnaire. RESULTS: N=61 swimmers were assessed: 8/59 (14%) of swimmers had a positive mannitol challenge. Nine out of 57 (16%) of swimmers had a positive exercise test. Only one swimmer was positive to both. Swimmers with a positive mannitol had a significantly higher baseline FE(NO) (37.3 vs. 18.0 p.p.b., P=0.03) than those with a positive exercise challenge. A significant decrease in FE(NO) was observed pre vs. immediate and delayed post-chlorine exposure: mean (95% CI) 18.7 (15.9-22.0) p.p.b. vs. 15.9 (13.3-19.1) p.p.b. (P<0.01), and 13.9 (11.5-16.7) p.p.b. (P<0.01), respectively. There were no significant differences in N(NO.) Mean PNIF increased from 142.4 L/min (5.8) at baseline to 162.6 L/min (6.3) immediately post-exposure (P<0.01). Delayed post-exposure PNIF was not significantly different from pre-exposure. CONCLUSIONS: No association was found between mannitol and standardized field-based testing in elite swimmers. Mannitol was associated with a high baseline FE(NO); however, exercise/chlorine challenge was not. Thus, mannitol may identify swimmers with a 'traditional' inflammatory asthmatic phenotype, while field-based exercise/chlorine challenge may identify a swimmer-specific bronchoconstrictor response. A sustained fall in FE(NO) following chlorine exposure suggests that a non-cellular, perhaps neurogenic, response may be involved in this group of athletes.

Steroid sparing effects of intranasal corticosteroids in asthma and allergic rhinitis.

BACKGROUND: Treating allergic rhinitis may have a downstream anti-inflammatory effect on the lower airways. We conducted a dose ranging study in asthma and persistent allergic rhinitis to evaluate if intranasal corticosteroids exhibit a sparing effect on the dose of inhaled corticosteroid. METHODS: Twenty five participants were randomized to receive two weeks of 100 microg/day (Low dose) or 500 microg/day (High dose) of inhaled fluticasone propionate both with intranasal placebo; or inhaled fluticasone 100 microg/day with intranasal fluticasone 200 microg/day (Combined) in a double-blind cross-over fashion. RESULTS: Low dose fluticasone produced a shift of 1.20 doubling-dilutions (95% CI, 0.63, 1.77); Combined fluticasone, 1.79 doubling-dilutions (95% CI, 0.77, 2.80) and high dose fluticasone, 2.01 doubling-dilutions (95% CI, 1.42, 2.61) in methacholine PC(20) from respective baselines. There was a significant difference between high and low doses: 0.82 doubling dilutions (95%CI, 0.12, 1.50) but not between combined and low dose 0.58 doubling dilutions (95% CI, -0.78, 1.95). Combined treatment alone produced improvements in peak nasal inspiratory flow (P < 0.001), rhinitis quality of life (P = 0.004) and nasal NO (P = 0.01); reduced blood eosinophil count (P = 0.03), and serum eosinophil cationic protein (P = 0.02). All treatments significantly improved tidal NO, FEV(1) and asthma quality of life. CONCLUSIONS: High-dose fluticasone was superior to low dose fluticasone for methacholine PC20, demonstrating room for further improvement. Combined treatment was not significantly different from low dose fluticasone and we could not demonstrate a steroid sparing effect on methacholine PC20. Combined treatment alone produced improvements in upper airway outcomes and suppressed systemic inflammation but not adrenal function.

Effects of chlorine and exercise on the unified airway in adolescent elite Scottish swimmers.

BACKGROUND: Chlorine metabolites and high training load may produce exercise-induced bronchospasm (EIB) in elite swimmers. The aim of this study was to assess the combined effects of chlorine and exercise on the unified airway of adolescent elite swimmers. METHODS: The Scottish Midlands District squad were assessed during an indoor pool session at the National Swimming Academy. Athletes trained at least 8 h per week. Subjects underwent tidal (T(NO)) and nasal (N(NO)) exhaled NO and peak nasal inspiratory flow (PNIF) pre and post a 2 h session. A physiological exercise challenge assessed EIB in n = 36 swimmers (>10% fall in forced expiratory volume in 1 s (FEV(1))). RESULTS: Combined and free chlorine levels (mg/l) were 1.66 and 0.3 respectively. n = 36 swimmers (mean age 13.3 years) were assessed: n = 8 (22%) had known asthma; n = 13 (36%) had a positive physiological challenge; 18 (50%) complained of symptoms suggestive of EIB. n = 10/28 (36%) who did not have asthma were found to have a positive exercise challenge. There was no significant association between reported exercise symptoms and positive exercise test. There was no significant change in T(NO) or N(NO) for pre vs postexposure, irrespective of asthma diagnosis or AHR. n = 15 (42%) swimmers complained of worsening nasal symptoms postexposure, but only n = 7 (14%) had a demonstrable fall in PNIF (mean 33 l/min). No significant association was found between PNIF and symptoms. CONCLUSIONS: Combined exposure to chlorine and exercise did not affect surrogate markers of inflammation in the unified airway. There was a high prevalence of undiagnosed EIB.

Effect of levocetirizine on nasal provocation testing with adenosine monophosphate compared with allergen challenge in allergic rhinitis.

BACKGROUND: End-organ hyperreactivity is an important feature of the allergic airway. There are no data directly comparing the responsiveness to treatment of different nasal provocation tests (NPT). OBJECTIVE: We compared the effect of levocetirizine on nasal adenosine 5'-monophosphate (AMP) with specific allergen challenge in patients with intermittent and persistent allergic rhinitis (AR). METHODS: Patients with AR were randomized in double-blind cross-over fashion to receive single doses of levocetirizine 5 mg or identical placebo, with nasal challenge performed 12 h after dosing. Sixteen participants completed per protocol. Nasal AMP or allergen challenge was conducted on separate days with 1- and 2-week washout periods in between, respectively. Measurements of peak nasal inspiratory flow (PNIF) were made over 60 min after each challenge. The primary end-point was the provocative concentration of AMP or allergen causing a 20% drop in the PNIF (PC(20)). RESULTS: The time-profile for PNIF recovery [area under the 60 min time-response curve as % PNIF change (min)] were significantly attenuated for AMP challenge, as mean difference [95% confidence interval (CI)]: 11.57 (3.87, 19.25), P=0.005 and for allergen challenge: 17.82 (0.11, 35.53), P=0.04. A highly significant correlation was shown between methods for the area under the curve: (R=0.86, P<0.001). A statistically significant correlation was also seen for the PC(20): (R=0.94, P<0.001). PC(20) improvement amounted to a 1.26 (95% CI 0.16, 2.35) and 0.16 (95% CI -0.41, 0.73) doubling-dilution shifts for allergen and AMP challenges, respectively. Bland-Altman plots confirmed good agreement between methods. CONCLUSION: A high correlation and statistical agreement has been demonstrated between AMP and allergen challenge for all outcome measures. In particular, the recovery profile after NPT is a sensitive and discriminatory measure of anti-allergic treatment.

Accuracy of Response Assessment Positron Emission Tomography-Computed Tomography Following Definitive Radiotherapy Without Chemotherapy for Head and Neck Squamous Cell Carcinoma.

AIM: There are few data to inform on the use of response assessment 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography-computed tomography (PET-CT) following radical radiotherapy without chemotherapy for head and neck squamous cell carcinoma (HNSCC). This retrospective study evaluated the accuracy of PET-CT in HNSCC following radical radiotherapy. MATERIALS AND METHODS: In total, 138 patients with HNSCC treated with radical radiotherapy without chemotherapy who underwent a baseline and response assessment FDG PET-CT were identified. FDG PET-CT outcomes were analysed with reference to clinicopathological outcomes. RESULTS: The median follow-up was 26 months. FDG-avid disease at baseline was present for the primary site and lymph nodes in 118 and 86 patients, respectively. With regard to the primary tumour, the negative predictive value (NPV) of a complete metabolic response (CMR) was 95%; the positive predictive value (PPV) of equivocal uptake and a positive scan were 6% and 82%, respectively. The likelihood ratios for a CMR, equivocal and positive scans of the primary site were 0.19, 0.22, 14.8, respectively. With regard to lymph node disease, the NPV of a CMR was 91%, the PPV of equivocal uptake and a positive scan were 33% and 88%, respectively. Likelihood ratios for lymph node disease for CMR, equivocal and positive scans were 0.19, 0.97 and 15.1, respectively. CONCLUSION: Compared with the accuracy reported in the literature following chemoradiotherapy, response assessment FDG PET-CT following radical radiotherapy without chemotherapy had a similarly high NPV, whereas the PPV following a positive scan was higher.

A study of dose-proportionality in the pharmacokinetics of the oral direct renin inhibitor aliskiren in healthy subjects.

OBJECTIVE: To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension. METHODS: This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 - 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and C(max) were analyzed to determine dose-proportionality using the power model, parameter = A*(Dose)(beta), where A = intercept and beta = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 â 600 mg were 90% confidence intervals (CI) for beta contained within the range 0.89 - 1.11. RESULTS: AUC and Cmax values increased with increasing doses of aliskiren. Both AUC and C(max) were associated with high variability (coefficient of variation 55 - 64% for AUC and 59 - 117% for C(max)). The estimated proportionality coefficients (beta) for AUC(0-infiniti), AUC(0-t) and C(max) were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 â 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and C(max), respectively. All doses of aliskiren were well tolerated. CONCLUSIONS: Exposure to aliskiren was greater than proportional over the dose range of 75 - 600 mg. Over the therapeutic dose range of 150 â 300 mg approved for the treatment of hypertension, AUC and Cmax increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.

Evaluation of the pharmacokinetic interaction between fluvastatin XL and cyclosporine in renal transplant recipients.

OBJECTIVE: To assess the pharmacokinetic interaction between cyclosporine and extended-release fluvastatin (fluvastatin XL), 80 mg for 7 days, in stable renal transplant recipients. METHODS: This was a single-center, open-label study. 17 renal transplant recipients received their standard cyclosporine therapy (Days 1 - 9) plus a once-daily single oral dose of fluvastatin XL, 80 mg (Days 2 - 8). Blood samples were collected and cyclosporine (whole blood) and fluvastatin (plasma) concentrations determined by radioimmunoassay and HPLC fluorescence detection, respectively. Pharmacokinetic parameters were calculated using non-compartment analysis and fluvastatin results were compared with historical controls. RESULTS: Treatment with fluvastatin XL, 80 mg for 7 days, had no significant effect on either the AUC0-12 (3,644 ng x h/ml in the absence of fluvastatin vs. 3,534 ng x h/ml in the presence of fluvastatin) or the Cmax of cyclosporine (983 ng/ml in the absence of fluvastatin vs. 945 ng/ml in the presence of fluvastatin). Co-administration of fluvastatin XL also had no effect on the tmax, t1/2 or apparent clearance (CL/F) of cyclosporine in renal transplant patients. The AUC and Cmax for fluvastatin XL in the presence of cyclosporine (AUC0-24 1,192 ng. x h/ml, Cmax 271 ng/ml) were approximately 2-fold higher compared with historical data for fluvastatin XL alone in healthy volunteers (AUC0-24 630 ng x h/ml, Cmax 102 ng/ml) but lower than the historical data for fluvastatin IR, 40 mg b.i.d. alone in healthy volunteers (AUC0-24 1,340 ng x h/ml, Cmax 443 ng/ml). Tmax, t1/2 and trough levels of fluvastatin in the presence of cyclosporine were also similar to the historical controls. Concomitant administration of cyclosporine and fluvastatin XL was well tolerated by renal transplant recipients. CONCLUSIONS: Fluvastatin XL, 80 mg, and cyclosporine do not show clinically relevant pharmacokinetic interactions.

In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis.

Cell cycle genes are often aberrantly expressed in cancer, but how their misexpression drives tumorigenesis mostly remains unclear. From S phase to early mitosis, EMI1 (also known as FBXO5) inhibits the anaphase-promoting complex/cyclosome, which controls cell cycle progression through the sequential degradation of various substrates. By analyzing 7403 human tumor samples, we find that EMI1 overexpression is widespread in solid tumors but not in blood cancers. In solid cancers, EMI1 overexpression is a strong prognostic marker for poor patient outcome. To investigate causality, we generated a transgenic mouse model in which we overexpressed Emi1. Emi1-overexpressing animals develop a wide variety of solid tumors, in particular adenomas and carcinomas with inflammation and lymphocyte infiltration, but not blood cancers. These tumors are significantly larger and more penetrant, abundant, proliferative and metastatic than control tumors. In addition, they are highly aneuploid with tumor cells frequently being in early mitosis and showing mitotic abnormalities, including lagging and incorrectly segregating chromosomes. We further demonstrate in vitro that even though EMI1 overexpression may cause mitotic arrest and cell death, it also promotes chromosome instability (CIN) following delayed chromosome alignment and anaphase onset. In human solid tumors, EMI1 is co-expressed with many markers for CIN and EMI1 overexpression is a stronger marker for CIN than most well-established ones. The fact that Emi1 overexpression promotes CIN and the formation of solid cancers in vivo indicates that Emi1 overexpression actively drives solid tumorigenesis. These novel mechanistic insights have important clinical implications.