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Purpose: Magnetic resonance image-guided brachytherapy is essential in the management of locally advanced cervical cancer. This study compares disease and toxicity outcomes in cervical cancer patients treated with 24 Gy/3 fractions (Fr) versus the conventional 28 Gy/4 Fr., Methods and Materials: This retrospective study included 241 consecutive patients with International Federation of Gynecology and Obstetrics 2018 stage IB to IVA cervical cancer treated with definitive chemoradiation between April 2014 and March 2021. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of local failure (LF), distant failure (DF), and G2+ gastrointestinal (GI), urinary and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using Gray's test., Results: Of the 241 patients, 42% received 24 Gy/3 Fr and 58% received 28 Gy/4 Fr. With a median follow-up of 3.2 (range, 0.2-9.2) years, there were 14 local, 41 regional nodal, and 51 distant failures in 63 (26%) patients. No significant differences were found between the 24 Gy/3 Fr and 28 Gy/4 Fr groups in 3-year DFS (77% vs 68%, P = .21), the 3-year cumulative incidence of LF (5% vs 7%, P = .57), DF (22% vs 25%, P = .86), G2+ GI toxicity (11% vs 20%, P = .13), or G2+ vaginal toxicity (14% vs 17%, P = .48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = .03)., Conclusions: Patients with cervical cancer treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI, and vaginal toxicity rates and a trend toward a lower G2+ urinary toxicity rate compared with those treated with 28 Gy/4 Fr. A less resource-intensive brachytherapy fractionation schedule of 24 Gy/3 Fr is a safe alternative to 28 Gy/4 Fr for definitive treatment of cervical cancer., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Patients with liver cirrhosis are prone to develop severe bacterial infections. Pharmacokinetics (PK) of antibiotics in cirrhosis are potentially affected by impaired biotransformation phases 0-3 and consequences of portal hypertension such as portovenous shunting, ascites formation and/or acute kidney injury (AKI). We aimed to elucidate to what extent PK of selected antibiotics and, therefore, dosage recommendations are affected in adults with cirrhosis., Methods: We performed a systematic search in PubMed, Embase, Cochrane and CINAHL on effects of cirrhosis on PK profiles of ceftriaxone, fosfomycin, gentamicin, meropenem, nitrofurantoin, piperacillin/tazobactam and vancomycin in adults. Antibiotics were selected based on the lack of specific dosing recommendations for adults with cirrhosis. We included studies reporting on ≥1 of the following PK parameters: AUC, half-life (t½), CL, volume of distribution (Vd), peak (Cmax) or trough concentrations (Cmin)., Results: We identified 15 studies (ceftriaxone, n = 5; gentamicin, n = 3; meropenem n = 5; vancomycin, n = 2), including 379 patients with cirrhosis, of which two were of high quality. No eligible studies were identified for fosfomycin, nitrofurantoin or piperacillin/tazobactam. Ceftriaxone unbound concentration increased in cirrhosis, but was mitigated by increased renal CL. Gentamicin levels in ascitic fluid were comparable to those in plasma. Meropenem PK parameters were not altered in cirrhosis without AKI, but in the presence of AKI a decrease in CL was observed. In contrast, vancomycin CL decreased in advanced cirrhosis., Conclusions: Available data in studies of mostly moderate quality suggest that PK of ceftriaxone, meropenem and vancomycin are altered in cirrhosis. More advanced PK studies are needed to provide specific dosing recommendations., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Magnetic resonance imaging (MRI) is the gold standard for delineating cancerous lesions in soft tissue. Catheter-based interventions require the accurate placement of multiple long, flexible catheters at the target site. The manual segmentation of catheters in MR images is a challenging and time-consuming task. There is a need for automated catheter segmentation to improve the efficiency of MR-guided procedures., Purpose: To develop and assess a machine learning algorithm for the detection of multiple catheters in magnetic resonance images used during catheter-based interventions., Methods: In this work, a 3D U-Net was trained to retrospectively segment catheters in scans acquired during clinical MR-guided high dose rate (HDR) prostate brachytherapy cases. To assess confidence in segmentation, multiple AI models were trained. On clinical test cases, average segmentation results were used to plan the brachytherapy delivery. Dosimetric parameters were compared to the original clinical plan. Data was obtained from 35 patients who underwent HDR prostate brachytherapy for focal disease with a total of 214 image volumes. 185 image volumes from 30 patients were used for training using a five-fold cross validation split to divide the data for training and validation. To generate confidence measures of segmentation accuracy, five trained models were generated. The remaining five patients (29 volumes) were used to test the performance of the trained model by comparison to manual segmentations of three independent observers and assessment of dosimetric impact on the final clinical brachytherapy plans., Results: The network successfully identified 95% of catheters in the test set at a rate of 0.89 s per volume. The multi-model method identified the small number of cases where AI segmentation of individual catheters was poor, flagging the need for user input. AI-based segmentation performed as well as segmentations by independent observers. Plan dosimetry using AI-segmented catheters was comparable to the original plan., Conclusion: The vast majority of catheters were accurately identified by AI segmentation, with minimal impact on plan outcomes. The use of multiple AI models provided confidence in the segmentation accuracy and identified catheter segmentations that required further manual assessment. Real-time AI catheter segmentation can be used during MR-guided insertions to assess deflections and for rapid planning of prostate brachytherapy., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: The popularity of direct oral anticoagulants (DOACs) is increasing among patients with cirrhosis. Cirrhosis has a major impact on the pharmacokinetics of drugs, potentially increasing adverse events. Safe use of drugs in cirrhosis requires a diligent risk-benefit analysis. The aim of this study is to develop practice recommendations for safe use of DOACs in cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data., Methods: We conducted a systematic literature search to identify studies on pharmacokinetics, pharmacodynamics and safety of DOACs in cirrhosis. Data were collected and presented in summary tables by severity of cirrhosis using the Child-Turcotte-Pugh (CTP) classification. A multidisciplinary expert panel evaluated the results and classified the DOACs according to safety., Results: Fifty four studies were included. All DOACs were classified as 'no additional risks known' for CTP A. For CTP B, apixaban, dabigatran and edoxaban were classified as 'no additional risks known'. Apixaban and edoxaban showed fewer adverse events in patients with cirrhosis, while dabigatran may be less impacted by severity of cirrhosis based on its pharmacokinetic profile. Rivaroxaban was classified as 'unsafe' in CTP B and C based on significant pharmacokinetic alterations. Due to lack of data, apixaban, dabigatran and edoxaban were classified as 'unknown' for CTP C., Conclusion: DOACs can be used in patients with CTP A cirrhosis, and apixaban, dabigatran and edoxaban can also be used in CTP B. It is recommended to avoid rivaroxaban in CTP B and C. There is insufficient evidence to support safe use of other DOACs in CTP C cirrhosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Significance: Photodynamic therapy (PDT) and photothermal therapy (PTT) show promise as cancer treatments, but challenges in generating large ablative volumes for deep-seated tumours persist. Using simulations, this study investigates combined PDT and PTT to increase treatment volumes, including the impact of a temperature-dependent PDT dose on the treatment volume radius., Approach: A finite-element model, using the open-source SfePy package, was developed to simulate combined interstitial photothermal and photodynamic treatments. Results compared an additive dose model to a temperature-dependent dose model with enhanced PDT dosimetry and examined typical clinical scenarios for possible synergistic effects., Results: Findings revealed that the temperature-dependent dose model could significantly expand the damage radius compared to the additive model, depending on the tissue and drug properties., Conclusions: Characterizing synergistic effects of PDT and PTT could enhance treatment planning. Future work is ongoing to implement additional variables, such as photosensitizer photobleaching, and spatial and temporally varying oxygenation., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

To investigate the effect of using non-uniform loading and notched plaques on dose distribution for eye plaques. Using EGSnrc Monte Carlo (MC) simulations, we investigate eye plaque dose distributions in water and in an anatomically representative eye phantom. Simulations were performed in accordance with TG43 formalism and compared against full MC simulations which account for inter-seed and inhomogeneity effects. For standard plaque configurations, uniformly and non-uniformly loaded plaque dose distributions in water showed virtually no difference between each other. For standard plaque, the MC calculated dose distribution in planes parallel to the plaque is narrower than the TG43 calculation due to attenuation at the periphery of the plaque by the modulay. MC calculated the dose behind the plaque is fully attenuated. Similar results were found for the notched plaque, with asymmetric attenuation along the plane of the notch. Cumulative dose volume histograms showed significant reductions in the calculated MC doses for both tumor and eye structures, compared to TG43 calculations. The effect was most pronounced for the notch plaque where the MC dose to the optic nerve was greatly attenuated by the modulay surrounding the optic nerve compared to the TG43. Thus, a reduction of optic nerve D95% from 14 to 0.2 Gy was observed, when comparing the TG43 calculation to the MC result. The tumor D95% reduced from 89.2 to 79.95 Gy for TG43 and MC calculations, respectively. TG43 calculations overestimate the absolute dose and the lateral dose distribution of both standard and notched eye plaques, leading to the dose overestimation for the target and organs at risk. The dose matching along the central axis for the non-uniformly loaded plaques to that of uniformly loaded ones was found to be sufficient for providing comparable coverage and can be clinically used in eye-cancer-busy centers., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Safe and appropriate use of medicines is essential to improve health outcomes in cirrhosis. However, little is known about the number and type of medicines dispensed to people with cirrhosis in Australia, as this predominantly occurs in the community. We aimed to characterise the prescriptions dispensed to people with cirrhosis and explore changes in the use of medication groups over time., Methods: Pharmaceutical Benefits Scheme data between 1 January 2016 and 30 June 2020 was extracted for consenting CirCare participants (multi-site, prospective, observational study). Prescriptions dispensed from cirrhosis diagnosis until liver transplant or death were included. Safety classifications for dispensed medicines were defined using published evidence-based recommendations. The pattern of medication use was analysed in 6-monthly time intervals. Generalised estimating equations models were used to estimate the change in consumption of medicines over time., Results: Five hundred twenty-two patients (mean age 60 years, 70% male, 34% decompensated at recruitment) were dispensed 89,615 prescriptions during the follow-up period, representing a median of 136 [interquartile range (IQR) 62-237] prescriptions and a median of 16 (IQR 11-23) unique medicines per patient (total n = 9306 medicines). The most commonly used medicines were proton pump inhibitors (PPIs) (dispensed at least once to 73% of patients), opioids (68%) and antibiotics (89%). Polypharmacy was prevalent, with 59-69% of observed participants in each time period dispensed five or more unique medicines. Prescription medication use increased over time (p < 0.001) independently of age, comorbidity burden and liver disease aetiology. The likelihood of taking PPIs, opioids, antidepressants and inhaled medicines also increased with each successive time period. Use of angiotensin therapies, metformin and statins differed over time between patients with compensated versus decompensated cirrhosis. General practitioners prescribed 69% of dispensed medicines, including a higher proportion of 'unsafe' and 'safety unknown' medicines compared with consultants/specialists (p < 0.001)., Conclusions: Polypharmacy is common in people with cirrhosis and some medication groups may be overused. Pharmacovigilance is required and future medication safety efforts should target high-risk prescribing practices and promote medication rationalisation in the community., (© 2023. The Author(s).)

Tumoricidal photodynamic (PDT) and photothermal (PTT) therapies harness light to eliminate cancer cells with spatiotemporal precision by either generating reactive oxygen species or increasing temperature. Great strides have been made in understanding biological effects of PDT and PTT at the cellular, vascular and tumor microenvironmental levels, as well as translating both modalities in the clinic. Emerging evidence suggests that PDT and PTT may synergize due to their different mechanisms of action, and their nonoverlapping toxicity profiles make such combination potentially efficacious. Moreover, PDT/PTT combinations have gained momentum in recent years due to the development of multimodal nanoplatforms that simultaneously incorporate photodynamically- and photothermally active agents. In this review, we discuss how combining PDT and PTT can address the limitations of each modality alone and enhance treatment safety and efficacy. We provide an overview of recent literature featuring dual PDT/PTT nanoparticles and analyze the strengths and limitations of various nanoparticle design strategies. We also detail how treatment sequence and dose may affect cellular states, tumor pathophysiology and drug delivery, ultimately shaping the treatment response. Lastly, we analyze common experimental design pitfalls that complicate preclinical assessment of PDT/PTT combinations and propose rational guidelines to elucidate the mechanisms underlying PDT/PTT interactions.

Objective. Laser interstitial thermal therapy (LITT) is an evolving hyperthermia-based technology that may offer a minimally invasive alternative to inoperable lung cancer. LITT of perivascular targets is challenged by higher risk of disease recurrence due to vascular heat sinks, as well as risk of damage to these vascular structures. The objective of this work is to examine the impact of multiple vessel parameters on the efficacy of the treatment and the integrity of the vessel wall in perivascular LITT. Approach. A finite element model is used to examine the role of vessel proximity, flow rate, and wall thickness on the outcome of the treatment . Main result . The simulated work indicates that vessel proximity is the major factor in driving the magnitude of the heat sink effect. Vessels situated near the target volume may act as a protective measure for reducing healthy tissue damage. Vessels with thicker walls are more at risk of damage during treatment. Interventions to reduce the flow rate may reduce the vessel's heat sink effect but may also result in increased risk of vascular wall damage. Lastly, even at reduced blood flow rates, the volume of blood reaching the threshold of irreversible damage (>43 °C) is negligible compared to the volume of blood flow throughout the treatment duration. Significance. This investigative simulation yields results that may help guide clinicians on treatment planning near large vessels., (Creative Commons Attribution license.)

Purpose: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims., Methods and Materials: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTV HR and T stage., Results: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTV HR (median 28 vs. 26 cm 3 , p = 0.04), CTV IR D 98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D 2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D 2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D 2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005)., Conclusions: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Stereotactic body radiation therapy (SBRT) has shown promising results in the treatment of pancreatic cancer and other solid tumors. However, wide adoption of SBRT remains limited largely due to uncertainty about the treatment's optimal fractionation schedules to elicit maximal tumor response while limiting the dose to adjacent structures. A small animal irradiator in combination with a clinically relevant oncological animal model could address these questions. Accurate delivery of X rays to animal tumors may be hampered by suboptimal image-guided targeting of the X-ray beam in vivo. Integration of bioluminescence imaging (BLI) into small animal irradiators in addition to standard cone-beam computed tomography (CBCT) imaging improves target identification and high-precision therapy delivery to deep tumors with poor soft tissue contrast, such as pancreatic tumors. Using bioluminescent BxPC3 pancreatic adenocarcinoma human cells grown orthotopically in mice, we examined the performance of a small animal irradiator equipped with both CBCT and BLI in delivering targeted, hypo-fractionated, multi-beam SBRT. Its targeting accuracy was compared with magnetic resonance imaging (MRI)-guided targeting based on co-registration between CBCT and corresponding sequential magnetic resonance scans, which offer greater soft tissue contrast compared with CT alone. Evaluation of our platform's BLI-guided targeting accuracy was performed by quantifying in vivo changes in bioluminescence signal after treatment as well as staining of ex vivo tissues with γH2AX, Ki67, TUNEL, CD31 and CD11b to assess SBRT treatment effects. Using our platform, we found that BLI-guided SBRT enabled more accurate delivery of X rays to the tumor resulting in greater cancer cell DNA damage and proliferation inhibition compared with MRI-guided SBRT. Furthermore, BLI-guided SBRT allowed higher animal throughput and was more cost effective to use in the preclinical setting than MRI-guided SBRT. Taken together, our preclinical platform could be employed in translational research of SBRT of pancreatic cancer., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

Percutaneous needle-based interventions such as transperineal prostate brachytherapy require the accurate placement of multiple needles to treat cancerous lesions within the target organ. To guide needle placement, magnetic resonance imaging (MRI) offers excellent visualization of the target lesion without the need for ionizing radiation. To date, multi-needle insertion relies on a grid template, which limits the ability to steer individual needles. This work describes an MR-compatible robot designed for the sequential insertion of multiple non-parallel needles under MR guidance. The 6-DOF system is designed with an articulated arm to extend the reach of the robot. This strategy presents a novel approach enabling the robot to maneuver around existing needles while minimizing the footprint of the robot. Forward kinematics as well as optimization-based inverse kinematics are presented. The impact of the robot on image quality was tested for four sequences (T1w-TSE, T2w-TSE, THRIVE and EPI) on a 3T Philips Achieva system. Quantification of the signal-to-noise ratio showed a 46% signal loss in a gelatin phantom when the system was powered on but no further adverse effects when the robot was moving. Joint level testing showed a maximum error of 2.10 ± 0.72°s for revolute joints and 0.31 ± 0.60 mm for prismatic joints. The theoretical workspace spans the proposed clinical target surface of 10 x 10 cm. Lastly, the feasibility of multi-needle insertion was demonstrated with four needles inserted under real-time MR-guidance with no visible loss in image quality., Competing Interests: AA received support from Mitacs Accelerate Program. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This research was supported by Siemens Healthcare Canada Ltd., and the Natural Sciences and Engineering Research Council., (Copyright © 2022 Aleong, Looi, Luo, Zou, Waspe, Singh, Drake and Weersink.)

Significance: Our work demonstrates in preclinical models that continuous-wave transrectal diffuse optical tomography (TRDOT) can be used to accurately monitor photothermal therapy (PTT) and, in particular, the progression of the photocoagulation boundary toward the rectum. When used in patients, this should prevent rectal damage during PTT, thereby achieving maximum treatment efficacy while ensuring safety, using a technology platform suitable for wide dissemination., Aim: We aim to validate that TRDOT measurements analyzed using a shape-based image-reconstruction algorithm (SBDOT) allow localization of the photocoagulation boundary during PTT within ±1  mm toward the rectum in the transverse plane., Approach: TRDOT measurements were performed in tissue-simulating phantoms, ex vivo tissues, and an in vivo canine prostate model. The accuracy and sensitivity of reconstructing the size and location of the coagulation zone were determined, based on changes in the tissue absorption and reduced scattering coefficients upon photocoagulation. The reconstruction also yields the native and coagulated tissue optical properties., Results: The TRDOT measurements and SBDOT reconstruction algorithm were confirmed to perform sufficiently well for clinical translation in PTT monitoring, recovering the location of the coagulation boundary within ±1  mm compared to the true value as determined by direct visualization postexcision and/or MRI., Conclusions: Implementing previously described TRDOT instrumentation and SBDOT image reconstruction in different tissue models confirms the potential for clinincal translation, including required refinements of the system and reconstruction algorithm.

Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65 years) were categorized according to age: "young" (< 65 years); "young-old" (65-74 years); "middle-old" (75-84 years); and "oldest-old" (≥ 85 years). All elderly groups had an increasingly higher comorbidity burden (P < 0.001) and polypharmacy (P < 0.001). There was a relationship between jaundice and hospitalization (P < 0.001), and both were more prevalent in the older age groups, especially in the oldest-old (88% and 69%, respectively), and the DILI episode was more severe (P = 0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin-clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65 years. Older patients had increased non-liver-related mortality (P = 0.030) as shown by the predictive capacity of the Model for End-Stage Liver Disease score (odds ratio (OR) = 1.116; P < 0.001), and comorbidity burden (OR = 4.188; P = 0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin-clavulanate, with increased non-liver-related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations., (© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

One of the largest geometric uncertainties in designing radiotherapy treatment plans for squamous cell cancers of the head and neck is contouring the gross tumor volume. We have previously described a method of projecting mucosal disease contours, visible on endoscopy, to volumetrically reconstructed planning computed tomography (CT) datasets, using electromagnetic (EM) tracking of a flexible endoscope, enabling rigid registration between endoscopic and CT images.However, to achieve better accuracy for radiotherapy planning, we propose refining this initial registration with image-based registration methods. In this paper, several types of cost functions are evaluated based on accuracy and robustness. Three phantoms and eight clinical cases are used to test each cost function, with initial registration of endoscopy to CT provided by the pose of the flexible endoscope recovered from EM tracking. Cost function classes include: cross correlation, mutual information and gradient methods. For each test case, a ground truth virtual camera pose was first defined by manual registration of anatomical features visible in both real and virtual endoscope images. A new set of evenly spaced fiducial points and a sample contour were created and projected onto the CT image to be used in assessing image registration quality. A new set of 5000 displaced poses was generated by random sampling displacements along each translational and rotational dimension. At each pose, fiducial and contour points in the real image were again projected on the CT image. The cost function, fiducial registration error and contouring error values were then calculated.While all cost functions performed well in select cases, only the normalized gradient field function consistently had registration errors less than 2 mm, which is the accuracy needed if this application of registering mucosal disease identified on optical image to CT images is to be used in the clinical practice of radiation treatment planning.(Registration: ClinicalTrials.gov NCT02704169)., (© 2020 Institute of Physics and Engineering in Medicine.)

The liver has a major role in the pharmacokinetics and pharmacodynamics of medicines and hepatic impairment could therefore lead to increased plasma levels and adverse drug reactions. Due to the large overcapacity of the liver, medication adjustments are only needed when a chronic liver disease has progressed to cirrhosis. Important pharmacokinetic alterations that could occur in cirrhosis are: (a) a decreased first-pass effect, (b) impaired metabolism by liver enzymes, and (c) in an advanced stage also impairment of renal elimination. Patients with cirrhosis could also be more sensitive to certain adverse drug reactions at normal drug levels, such as renal impairment due to NSAIDs or the sedative effect of morphinomimetics and psychotropic drugs. Prescribing in patients with cirrhosis is complex, which we illustrate by 5 common pitfalls. In practice, healthcare professionals could use a website with guidance for prescribing almost 300 medicines (www.geneesmiddelenbijlevercirrose.nl).

Patients with chronic liver disease (CLD) are becoming increasingly complex due to the rising prevalence of multimorbidity and polypharmacy. Medications are often essential to manage the underlying liver disease, complications of cirrhosis and portal hypertension, and comorbidities. However, medication-related problems (MRPs) have been associated with adverse patient outcomes, including hospitalization and mortality. Factors that can contribute to MRPs in people with CLD are variable and often entwined. This narrative literature review discusses key barriers and opportunities to modify risk factors and improve medication-related outcomes for people with CLD., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

We describe the rationale, design, fabrication and performance of a clinical transrectal diffuse optical tomography (TRDOT) system for in vivo monitoring of photothermal therapy (PTT) of localized prostate cancer. The system comprises a 32-channel fiberoptic-based, MRI-compatible transrectal probe connected to a computer-controlled instrument that includes laser diode sources, an optical fiber switch and photomultiplier tube detectors. Performance tests were performed in tissue-simulating phantoms and in ex vivo muscle tissue during PTT treatment. The safety and technical feasibility of in vivo transrectal use were tested in a canine prostate model and in a first-in-human study in a patient before PTT treatment. Limitations of the system are discussed, as well as further developments to translate it into planned clinical trials for monitoring the photocoagulation boundary in the prostate during PTT.

Aims: To study community pharmacists' level of knowledge on medication safety in patients with hepatic impairment and their practice in caring for these patients., Methods: Pharmacists from Dutch community pharmacies (n = 1545) were invited to participate in an online survey. The survey consisted of 27 questions covering 2 main topics: knowledge and current practice. The level of knowledge was measured by a 6-item knowledge test. Multiple linear regression was used to identify predictors of correctly answered responses., Results: In total, 338 pharmacists (22%) completed the questionnaire. The mean knowledge score was 2.8 (standard deviation 1.6). Only 30.3% of respondents were able to appropriately advise on use of analgesics in severe cirrhosis. Postgraduate education on hepatic impairment, knowledge of recently developed practical guidance, and fewer years of practice were associated with a higher level of knowledge. In total, 70.4% indicated to evaluate medication safety in a patient with hepatic impairment at least once weekly. In the past 6 months, 83.3% of respondents consulted a prescriber about a patient with hepatic impairment. Frequently encountered barriers in practice were insufficient knowledge on the topic and a lack of essential patient information (i.e. diagnosis and severity of the impairment)., Conclusion: Community pharmacists regularly evaluate the safety of medication in patients with hepatic impairment, yet their level of knowledge was insufficient and additional education is needed. Pharmacists experienced several difficulties in providing pharmaceutical care. If these issues are resolved, pharmacists can play a more active role in ensuring medication safety in their patients with hepatic impairment., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

In Chinese philosophy, yin and yang ("dark-bright," "negative-positive") describe how seemingly opposite or contrary forces may actually be complementary, interconnected and interdependent. This paper provides this perspective on photodynamic and photothermal therapies, with a focus on the treatment of solid tumors. The relative strengths and weaknesses of each modality, both current and emerging, are considered with respect to the underlying biophysics, the required technologies, the biological effects, their translation into clinical practice and the realized or potential clinical outcomes. For each specific clinical application, one or the other modality may be clearly preferred, or both are effectively equivalent in terms of the various scientific/technological/practical/clinical trade-offs involved. Alternatively, a combination may the best approach. Such combined approaches may be facilitated by the use of multifunctional nanoparticles. It is important to understand the many factors that go into the selection of the optimal approach and the objective of this paper is to provide guidance on this., (© 2019 American Society for Photobiology.)

Purpose: To evaluate the electromagnetic (EM) tracking of endoscopes and applicators as a method of positioning a high dose rate (HDR) luminal applicator., Method: An anatomical phantom consisting of a rigid trachea and flexible esophagus was used to compare applicator placement measurements using EM tracking vs the traditional method using two-dimensional (2D) fluoroscopy and surface skin markers. The phantom included a tumor in the esophagus and several pairs of optically visible points inside the lumen that were used to simulate proximal and distal ends of tumors of varying lengths. The esophagus tumor and lung points were visible on a computed tomography (CT) image of the phantom, which was used as ground truth for the measurements. The EM tracking system was registered to the CT image using fiducial markers. A flexible endoscope was tracked using the EM system and the locations of the proximal and distal ends of the tumor identified and this position recorded. An EM-tracked applicator was then inserted and positioned relative to the tumor markings. The applicator path was mapped using the EM tracking. The gross tumor length (GTL) and the distance between the first dwell position and distal edge of tumor (offset) were measured using the EM tracking and 2D fluoroscopy methods and compared to the same measurements on the CT image., Results: The errors in GTL using EM tracking were on average -0.5 ± 1.7 mm and 0.7 ± 3.6 mm for esophagus and lung measurements, similar to errors measured using the 2D fluoroscopy method of -0.9 ± 1.2 mm and 3.4 ± 4.4 mm. Offset measurements were slightly larger while using EM tracking relative to the fluoroscopy method but these were not statistically significant., Conclusions: Electromagnetic tracking for placement of lumen applicators is feasible and accurate. Tracking of the endoscope that is used to identify the proximal and distal ends of the tumor and of the applicator during insertion generates accurate three-dimensional measurements of the applicator path, GTL and offset. Guiding the placement of intraluminal applicators using EM navigation is potentially attractive for cases with complex insertions, such as those with nonlinear paths or multiple applicator insertions., (© 2019 American Association of Physicists in Medicine.)

Introduction : The global burden of cirrhosis is rising, and clinicians increasingly face the challenge of safely prescribing medicines for complications of hepatic disease and comorbidities. Prescribing in patients with cirrhosis is complicated by alterations that can occur in the pharmacology of medicines. Areas covered : This paper provides an overview of current knowledge on the pharmacokinetics and pharmacodynamics of medicines in patients with cirrhosis. We describe the pathophysiological changes that occur and their consequences on pharmacokinetic parameters. We explain that the influence of cirrhosis on the pharmacokinetics depends on several drug and patient characteristics. Patients with cirrhosis also have an increased susceptibility to some toxicological effects of medicines, such as renal impairment and hematological toxicity, which we describe in detail. In addition, we discuss approaches to apply this knowledge in practice and improve safe medication use in patients with cirrhosis. Expert opinion : Tailored pharmacotherapy is needed to ensure safe and appropriate use of medicines in patients with cirrhosis. Clinicians are supported by freely available recommendations on safe drug use in cirrhosis published on a website. In addition, a regular evaluation of medication use in patients with cirrhosis could resolve and prevent medication-related problems.

Background: In 2005, the European Medicines Agency (EMA) released guidance on pharmacokinetic studies in patients with hepatic impairment. This guidance describes the design of these studies and what information should be presented in the Summary of Product Characteristics (SmPC). We aim to evaluate the availability and clinical applicability of information on medicine use in patients with hepatic impairment in SmPCs and registrational dossiers of recently approved medicines. Methods: We reviewed SmPC information on use in patients with hepatic impairment of 51 new medicines authorized between 2015 and 2017. Per medicine, we assessed the availability of nine information items derived from the EMA guidance, i.e. type of hepatic disease studied; stratification by severity of hepatic impairment; influence of hepatic impairment on the pharmacokinetics; safety advice in mild, moderate, and severe hepatic impairments; and dosing recommendation in mild, moderate, and severe hepatic impairments. If unavailable, the European Public Assessment Report (EPAR) and study report were consulted consecutively. Of available items, clinical applicability was assessed by labeling information as "clear" or "ambiguous". Results: Of 51 medicines, 15 had no pharmacokinetic study in patients with hepatic impairment described in their SmPC. The other 36 SmPCs contained on average seven of the nine information items (range 4-9). One SmPC contained all 9 items, and after consulting, the study reports, 11 SmPCs were complete. The item "type of hepatic disease studied" was available in one SmPC, though it could be retrieved in 21 study reports. Regarding clinical applicability, there was no medicine with all information items available and clearly formulated in the SmPC. A total of 12 medicines (33%) contained only clearly formulated information, while 24 (67%) contained at least one ambiguously formulated information item (range 0-4). Items often ambiguously formulated were: "definition of mild, moderate, and severe hepatic impairment" (15 ambiguous SmPCs) and "safety advice in severe hepatic impairment" (17 ambiguous SmPCs). Conclusion: While SmPCs contain a large part of information requested by the EMA, clinical applicability seems low, as it is often unclear to which specific type of hepatic disease patient the advice applies. This can negatively influence the practical use by healthcare professionals., (Copyright © 2019 Weersink, Timmermans, Monster-Simons, Mol, Metselaar, Borgsteede and Taxis.)

Purpose: To develop a treatment planning platform for episcleral Collaborative Ocular Melanoma Study plaque therapy in an established treatment planning software and to improve an existing quality assurance (QA) process for nonuniformly loaded plaques that measures air kerma strengths (AKSs) and loading profile., Materials and Methods: Treatment planning is performed in Pinnacle using scripts that let the planner choose plaque size and notching. Scripts load seed positions for each plaque and five source groups corresponding to available stock seeds that can be placed into each seed position. Contours are loaded that display the model eye and the plaque itself. Plaque QA is performed using a modification of our previous pinhole apparatus by replacing x-ray film exposure with an optical camera and scintillating film system. The captured image is processed to remove background and to correct the intensity of seeds on the plaque periphery. Measured total optical counts provide an estimate of total plaque AKS., Results: Treatment planning of eye plaques using Pinnacle, in conjunction with our stock inventory of seeds, is established as standard practice at our center. Planned plaques can vary from uniformly loaded to asymmetrically loaded notched plaques. Using the optical camera system for assessment of the seed loadings has decreased QA time from 40 min/plaque to 10 min/plaque. Total AKS of each plaque can be measured using the optical camera with an accuracy of 10%., Conclusions: Treatment planning is performed on a Health Canada-approved software that accommodates nonuniform plaque loading. Optical imaging of the plaque provides absolute total AKS and the relative seed arrangement in the plaque., (Copyright © 2019 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients with cirrhosis are at risk for adverse drug reactions (ADRs) due to altered pharmacokinetics and pharmacodynamics. We aimed to determine the prevalence of drug prescriptions and the potential safety of these prescriptions in a real-world cohort of patients with cirrhosis., Methods: This was a retrospective cohort study based on linked real-world data from the Out-patient Pharmacy Database and the Hospitalisation Database of the PHARMO Database Network. Patients with a diagnosis of cirrhosis between January 1998 and December 2015 were included. Follow-up ended when the patient underwent a liver transplant, died, transferred out of the database, or on 31 December 2015. Prescription data were derived from a community pharmacy database and were compared with our previously developed safety recommendations for 209 drugs., Results: In total, 5618 patients were included and followed for a median of 3 years (interquartile range [IQR] 1-7). In the first year after the diagnosis, patients used a median of nine drugs (IQR 5-14), with proton pump inhibitors (prevalence 53.9%), aldosterone antagonists (43.6%), and sulfonamide diuretics (41.3%) being the most commonly used drug groups. Almost half (48.3%) of 102,927 prescriptions consisted of drugs with a safety recommendation. The prevalence of potentially unsafe drug use was 60.0% during the total follow-up. Three nonsteroidal anti-inflammatory drugs (NSAIDs) were among the five most commonly used potentially unsafe drugs., Conclusions: Patients with cirrhosis use a large number of drugs. Almost two-thirds of patients in our cohort used potentially unsafe drugs. To prevent ADRs in these frail patients, personalised pharmacotherapy is necessary.

Photodynamic therapy (PDT) following lung-sparing extended pleurectomy for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression levels of folate receptor 1 (FOLR1) have been reported in MPM; therefore, targeting FOLR1 has been considered a novel potential strategy. The present study developed FOLR1‑targeting porphyrin-lipid nanoparticles (folate-porphysomes, FP) for the treatment of PDT. Furthermore, inhibition of activated epidermal growth factor (EGFR)-associated survival pathways enhance PDT efficacy. In the present study, these approaches were combined; FP-based PDT was used together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI). The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1‑targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and therapeutic efficacy were subsequently examined. The effects of EGFR-TKI were also assessed in vitro. The in vivo combined antitumor effect of EGFR-TKI and FP-PDT was then evaluated. The results revealed that FOLR1 and EGFR were expressed in 79 and 89% of MPM samples, respectively. In addition, intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated with FP and then irradiated at 671 nm, there was significant in vitro cell death, which was inhibited in the presence of free folic acid, thus suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pretreatment with EGFR-TKI and FP-PDT induced a marked improvement of treatment responses. In conclusion, FP-based PDT induced selective destruction of MPM cells based on FOLR1 targeting, and pretreatment with EGFR-TKI further enhanced the therapeutic response.

Aims: Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in patients with cirrhosis., Methods: A systematic literature search identified studies on the safety (i.e. adverse events) and pharmacokinetics of PPIs in cirrhotic patients. This evidence and data from the product information was reviewed by an expert panel who classified drugs as safe; no additional risks known; additional risks known; unsafe; or unknown. Guidance was aimed at the oral use of PPIs and categorized by the severity of cirrhosis, using the Child-Turcotte-Pugh (CTP) classification., Results: A total of 69 studies were included. Esomeprazole, omeprazole and rabeprazole were classified as having 'no additional risks known'. A reduction in maximum dose of omeprazole and rabeprazole is recommended for CTP A and B patients. For patients with CTP C cirrhosis, the only PPI advised is esomeprazole at a maximum dosage of 20 mg per day. Pantoprazole and lansoprazole were classified as unsafe because of 4- to 8-fold increased exposure. The use of PPIs in cirrhotic patients has been associated with the development of infections and hepatic encephalopathy and should be carefully considered., Conclusions: We suggest using esomeprazole, omeprazole or rabeprazole in patients with CTP A or B cirrhosis and only esomeprazole in patients with CTP C. Pharmacokinetic changes are also important to consider when prescribing PPIs to vulnerable, cirrhotic patients., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: The presence of liver cirrhosis can have a major impact on pharmacodynamics and pharmacokinetics, but guidance for prescribing is lacking., Objective: The aim of this study is to provide an overview of evidence-based recommendations developed for the safe use of drugs in liver cirrhosis., Methods: Recommendations were based on a systematic literature search combined with expert opinion from a panel of 10 experts. The safety of each drug was classified as safe, no additional risks known, additional risks known, unsafe, unknown or the safety class was dependent on the severity of liver cirrhosis (Child-Pugh classification). If applicable, drug-specific dosing advice was provided. All recommendations were implemented in clinical decision support systems and on a website., Results: We formulated 218 recommendations for a total of 209 drugs. For nine drugs, two recommendations were formulated for different administration routes or indications. Drugs were classified as 'safe' in 29 recommendations (13.3%), 'no additional risks known' in 60 (27.5%), 'additional risks known' in 3 (1.4%), and 'unsafe' in 30 (13.8%). In 57 (26.1%) of the recommendations, safety depended on the severity of liver cirrhosis and was 'unknown' in 39 (17.9%) recommendations. Large alterations in pharmacodynamics were the main reason for classifying a drug as 'unsafe'. For 67 drugs (31%), a dose adjustment was needed., Conclusions: Over 200 recommendations were developed for the safe use of drugs in patients with liver cirrhosis. Implementing these recommendations into clinical practice can possibly enhance medication safety in this vulnerable patient group.

Objective: Despite modest improvements, the prognosis of lung cancer patients has still remained poor and new treatment are urgently needed. Photodynamic therapy (PDT), the use of light-activated compounds (photosensitizers) is a treatment option but its use has been restricted to central airway lesions. Here, we report the use of novel porphyrin-lipid nanoparticles (porphysomes) targeted to folate receptor 1 (FOLR1) to enhance the efficacy and specificity of PDT that may translate into a minimally-invasive intervention for peripheral lung cancer and metastatic lymph nodes of advanced lung cancer., Materials and Methods: The frequency of FOLR1 expression in primary lung cancer and metastatic lymph nodes was first analyzed by human tissue samples from surgery and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA). Confocal fluorescence microscopy was then used to confirm the cellular uptake and fluorescence activation in lung cancer cells, and the photocytotoxicity was evaluated using a cell viability assay. In vivo fluorescence activation and quantification of uptake were investigated in mouse lung orthotopic tumor models, followed by the evaluation of in vivo PDT efficacy., Results: FOLR1 was highly expressed in metastatic lymph node samples from patients with advanced lung cancer and was mainly expressed in lung adenocarcinomas in primary lung cancer. Expression of FOLR1 in lung cancer cell lines corresponded with the intracellular uptake of folate-porphysomes in vitro. When irradiated with a 671nm laser at a dose of 10J/cm 2 , folate-porphysomes showed marked therapeutic efficacy compared with untargeted porphysomes (28% vs. 83% and 24% vs. 99% cell viability in A549 and SBC5 lung cancer cells, respectively). Systemically-administered folate-porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast. Folate-porphysomes mediated PDT successfully inhibited tumor cell proliferation and activated tumor cell apoptosis., Conclusion: Folate-porphysome based PDT shows promise in selectively ablating lung cancer based on FOLR1 expression in these preclinical models., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We develop and demonstrate a simple shape-based approach for diffuse optical tomographic reconstruction of coagulative lesions generated during interstitial photothermal therapy (PTT) of the prostate. The shape-based reconstruction assumes a simple ellipsoid shape, matching the general dimensions of a cylindrical diffusing fiber used for light delivery in current clinical studies of PTT in focal prostate cancer. The specific requirement is to accurately define the border between the photothermal lesion and native tissue as the photothermal lesion grows, with an accuracy of ? 1 ?? mm , so treatment can be terminated before there is damage to the rectal wall. To demonstrate the feasibility of the shape-based diffuse optical tomography reconstruction, simulated data were generated based on forward calculations in known geometries that include the prostate, rectum, and lesions of varying dimensions. The only source of optical contrast between the lesion and prostate was increased scattering in the lesion, as is typically observed with coagulation. With noise added to these forward calculations, lesion dimensions were reconstructed using the shape-based method. This approach for reconstruction is shown to be feasible and sufficiently accurate for lesions that are within 4 mm from the rectal wall. The method was also robust for irregularly shaped lesions.

Introduction: Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis., Methods and Analysis: For each drug, a six-step evaluation process will be followed. (1) Available evidence on the pharmacokinetics and safety of a drug in patients with liver cirrhosis will be collected from the Summary of Product Characteristics (SmPC) and a systematic literature review will be performed. (2) Data regarding two outcomes, namely pharmacokinetics and safety, will be extracted and presented in a standardised assessment report. (3) A safety classification and dosage suggestion will be proposed for each drug. (4) An expert panel will discuss the validity and clinical relevance of this suggested advice. (5) Advices will be implemented in all relevant Clinical Decision Support Systems in the Netherlands and published on a website for patients and healthcare professionals. (6) The continuity of the advices will be guaranteed by a yearly check of new literature and comments on the advices. This protocol will be applied in the evaluation of a selection of drugs: (A) drugs used to treat (complications of) liver cirrhosis, and (B) drugs frequently prescribed to the general population., Ethics and Dissemination: Since this study does not directly involve human participants, it does not require ethical clearance. Besides implementation on a website and in clinical decision support systems, we aim to publish the generated advices of one or two drug classes in a peer-reviewed journal and at conference meetings., Competing Interests: DB has received research grants from BMS, MSD and ViiV and has performed teaching for Abbvie, BMS, Gilead, MSD and ViiV, outside the submitted work. JD has received research grants from Abbvie and Janssen and has been a member of advisory boards of AbbVie, BMS, Gilead, Janssen, and Merck, outside the submitted work. HM has received research grants from AbbVie, Astellas, Novartis and Gilead and has been a member of advisory boards of AbbVie, Astellas and Novartis, outside the submitted work., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Photothermal therapy (PTT) is enhanced by the use of nanoparticles with a large optical absorption at the treatment wavelength. However, this comes at the cost of higher light attenuation that results in reduced depth of heating as well as larger thermal gradients, leading to potential over- and under-treatment in the target tissue. These limitations can be overcome by using photothermal enhancing auto-regulating liposomes (PEARLs), based on thermochromic J-aggregate forming dye-lipid conjugates that reversibly alter their absorption above a predefined lipid phase-transition temperature. Under irradiation by near-infrared light, deeper layers of the target tissue revert to the intrinsic optical absorption, halting the temperature rise and enabling greater light penetration and heat generation at depth. This effect is demonstrated in both nanoparticle solutions and in gel phantoms containing the nanoparticles., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e., gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.

Purpose: Little is known about consumer information needs regarding antipsychotic medicines. Medicines call centre (MCC)-derived data are underutilised; and could provide insight into issues of importance to consumers. This study aimed to explore consumers' information needs about antipsychotic medication sought from a national MCC in Australia., Methods: Questions received by the National Prescribing Service Medicines Line relating to antipsychotic medication from September 2002 to June 2010 were examined by antipsychotic subclass and in relation to other medication queries., Results: We identified 6,295 calls related to antipsychotic medication. While female callers predominated, the percentage of males with antipsychotic questions was statistically significantly higher than for other medication calls (33.9 vs 22.6 %; p < 0.001). There were distinct gender differences in medicines information seeking across age ranges. Younger men asked about second-generation antipsychotics, shifting toward first-generation antipsychotics after 45 years of age. Female interest in both subclasses was comparable, irrespective of age. Most callers asking about antipsychotics sought information for themselves (69.4 %). Callers were primarily concerned about safety (57.0 %), especially adverse drug reactions (28.8 %), and were more often prompted by a worrying symptom (23.8 %) compared with the rest of calls (17.2 %). Trends of antipsychotic questions received corresponded with antipsychotic prescription data., Conclusions: The number of calls received by this MCC over time reveals an ongoing consumer need for additional, targeted information about antipsychotics. Noticeable was the relatively high frequency of young male callers asking about antipsychotics, indicating that call centres could be a way to reach these traditionally poor users of health services.

Purpose: The authors describe the integration of optical imaging with a targeted small animal irradiator device, focusing on design, instrumentation, 2D to 3D image registration, 2D targeting, and the accuracy of recovering and mapping the optical signal to a 3D surface generated from the cone-beam computed tomography (CBCT) imaging. The integration of optical imaging will improve targeting of the radiation treatment and offer longitudinal tracking of tumor response of small animal models treated using the system., Methods: The existing image-guided small animal irradiator consists of a variable kilovolt (peak) x-ray tube mounted opposite an aSi flat panel detector, both mounted on a c-arm gantry. The tube is used for both CBCT imaging and targeted irradiation. The optical component employs a CCD camera perpendicular to the x-ray treatment/imaging axis with a computer controlled filter for spectral decomposition. Multiple optical images can be acquired at any angle as the gantry rotates. The optical to CBCT registration, which uses a standard pinhole camera model, was modeled and tested using phantoms with markers visible in both optical and CBCT images. Optically guided 2D targeting in the anterior/posterior direction was tested on an anthropomorphic mouse phantom with embedded light sources. The accuracy of the mapping of optical signal to the CBCT surface was tested using the same mouse phantom. A surface mesh of the phantom was generated based on the CBCT image and optical intensities projected onto the surface. The measured surface intensity was compared to calculated surface for a point source at the actual source position. The point-source position was also optimized to provide the closest match between measured and calculated intensities, and the distance between the optimized and actual source positions was then calculated. This process was repeated for multiple wavelengths and sources., Results: The optical to CBCT registration error was 0.8 mm. Two-dimensional targeting of a light source in the mouse phantom based on optical imaging along the anterior/posterior direction was accurate to 0.55 mm. The mean square residual error in the normalized measured projected surface intensities versus the calculated normalized intensities ranged between 0.0016 and 0.006. Optimizing the position reduced this error from 0.00016 to 0.0004 with distances ranging between 0.7 and 1 mm between the actual and calculated position source positions., Conclusions: The integration of optical imaging on an existing small animal irradiation platform has been accomplished. A targeting accuracy of 1 mm can be achieved in rigid, homogeneous phantoms. The combination of optical imaging with a CBCT image-guided small animal irradiator offers the potential to deliver functionally targeted dose distributions, as well as monitor spatial and temporal functional changes that occur with radiation therapy.

Introduction: Photodynamic therapy (PDT) can be employed as a focal therapy for prostate cancer. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) can potentially help identify tumour recurrence after failed external-beam radiotherapy (EBRT). The purpose of this study was to determine the ability of DCE-MRI to predict early response to PDT salvage treatment., Methods: Patients with post-EBRT prostate cancer recurrence were prospectively enrolled into a Phase I/II trial of PDT using WST09. A 15-patient subgroup of this cohort undergoing 1.5T DCE-MRI at baseline and 1-week post-PDT was retrospectively analyzed. The reference standard was prostate biopsy obtained 6 months post-PDT. Analysis was performed on a patient-by-patient basis, by prostate gland halves, and by prostate sextants., Results: Biopsy 6 months post-PDT identified cancer in 10/15 patients (66.7%), and in 24/90 sextants (26.7%). Residual cancer was identified in 22/37 sextants (59.5%) identified as being involved at baseline. DCE-MRI at 1 week correctly predicted recurrent disease with a sensitivity of 100% (10/10), specificity of 60% (3/5), positive predictive value of 83.3% (10/12), negative predictive value of 100% (3/3), and an overall accuracy of 86.7%, (13/15). When analysis was performed on prostate halves, the sensitivity and negative predictive value remained at 100%, with an improvement in specificity to 88.2% (15/17). The overall accuracy of DCE-MRI was similar regardless of analysis method: 86.7% on a patient-by-patient basis, 86.7% by prostate half and 83.3% by sextant. Changes in prostate-specific antigen (PSA) did not correlate to response., Conclusion: DCE-MRI shows promise as a tool to predict successful outcome when performed 1 week post-PDT and could potentially be used to inform the need for re-treatment at an early time-point.