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Background Crizotinib was the first oral targeted therapy approved by the US Food and Drug Administration (FDA), on 11 March 2016, for c-ros oncogene 1 (ROS1)-positive advanced non-small-cell lung cancer (NSCLC). Data to support long-term clinical benefit in a real-world setting are limited. Objective This study aimed to assess real-world clinical outcomes among patients with ROS1-positive advanced NSCLC treated with crizotinib in the US community oncology setting. Patients and Methods We conducted a retrospective cohort study using iKnowMed electronic health record data to identify adult patients with ROS1-positive advanced NSCLC who initiated crizotinib between 17 January 2013 (time of the addition of crizotinib for ROS1-positive NSCLC to National Comprehensive Cancer Network (NCCN) treatment guidelines) and 1 June 2019 with a potential follow-up period through 1 December 2019. Patient characteristics were assessed descriptively. Kaplan–Meier analyses were used to evaluate time to treatment discontinuation (TTD), time to next treatment (TTNT), and overall survival (OS). A Cox proportional hazards model was conducted to determine factors associated with OS. Results The study cohort included 38 ROS1-positive patients treated with crizotinib. The median age was 68 years (interquartile range 60.0–73.0) and 65.8% were female. Over 50% were current/former smokers, and 18.4% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Overall, 21 (55.3%) patients remained on crizotinib, 10 (26.3%) had evidence of subsequent treatment, and 16 (42.1%) died. The median TTD, TTNT, and OS were 25.2 months [95% confidence interval (CI): 5.2–not reached (NR)], 25.0 months (95% CI 5.2–61.0), and 36.2 months (95% CI 15.9–NR), respectively. In a multivariate Cox regression model, ECOG performance status of 2 was associated with a 4.9-fold higher risk of death (hazard ratio = 4.9; 95% CI 1.1–21.4) compared to ECOG performance status of 0 or 1. Conclusions This ROS1-positive NSCLC real-world population was older and had a higher proportion of smokers and of patients with poorer ECOG performance status than those investigated in clinical trials. Nevertheless, our findings support the clinical benefit of crizotinib in this patient population with ROS1-positive advanced NSCLC. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00860-z.

PURPOSE: Treatment goals for patients with metastatic cancer include prolongation and maintenance of quality of life. Patients and oncologists have questioned the current paradigm of initial dose selection for systemic therapy; however, data on oncologists' dose selection strategies and beliefs are lacking. METHODS: We conducted an electronic international survey of medical oncologists who treat patients with breast and/or gastrointestinal cancers. Survey questions addressed experiences with, and attitudes toward, dose reduction at initiation (DRI) of a new systemic therapy for patients with metastatic cancer. RESULTS: Among 3,099 eligible oncologists, 367 responded (response rate 12%). Most (52%) reported using DRI at least 10% of the time to minimize toxicities. Gastrointestinal specialists were more likely to report DRI ≥ 10% of the time (72% v 50% of generalists and 51% of breast specialists, P < .005). Of those who dose reduced ≥ 10% of the time, 89% reported discussing potential tradeoffs between efficacy and toxicity with patients. Overall, 65% agreed it is acceptable to lower starting doses to reduce side effects even if it compromises efficacy; younger clinicians were more likely to agree ( P < .005). There was strong support (89%) for future trials to determine optimal effective, rather than maximum tolerated, dose. CONCLUSION: Oncology practice varies with regard to discussion and individualized selection of starting doses in the metastatic setting. This study demonstrates a need for consideration of shared decision making regarding initial dose selection and strong support among oncologists for clinical studies to define optimal dosing and best practices for individualizing care.

Planning organ-at-risk volume (PRV) margins can be applied to the bladder and rectum in prostate external beam radiation therapy (EBRT), in order to incorporate the uncertainties resulting from their inter-fraction motion. For each of a total of 16 patients, the bladder and rectum were delineated on CBCT images for five treatment fractions in addition to the planning CT image set. The bladder and rectum boundary displacements across the images were measured and the frequency and size of organ boundary displacements were evaluated. Subsequently, PRV margins were created to cover a specific percentage of organ boundary motion for a specified percentage of the population. In this investigation, two bladder PRV margins were generated to deal with two bladder conditions of low and high-volume variation among fractions. A combined PRV margin was also generated for the rectum by separating the rectum into three parts and deriving independent PRV margins for each segment. Outward coverage and effectiveness metrics allowed evaluation of the margins.

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (

The ACPSEM radiation oncology medical physics workforce modelling project task group was formed to acquire a snapshot of practices in Australia and New Zealand and to develop an activity-based workforce model. To achieve this, two surveys were carried out, capturing the work practices of 98 radiation oncology departments and 182 college members. The member survey provided a snapshot of the current workforce: their demographics, work conditions, professional recognition, and future plans. The facility survey provided an Australian and New Zealand contextualisation of the volume-based activities defined in the International Atomic Energy Agency activity-based radiation oncology staffing model at a granular level. An ACPSEM ROMP workforce model was developed to be a modelling tool applicable at both the facility and sector levels.

Background Ivermectin is being considered for mass drug administration for malaria, due to its ability to kill mosquitoes feeding on recently treated individuals. In a recent trial, 3-day courses of 300 and 600 mcg/kg/day were shown to kill Anopheles mosquitoes for at least 28 days post-treatment when fed patients’ venous blood using membrane feeding assays. Direct skin feeding on humans may lead to higher mosquito mortality, as ivermectin capillary concentrations are higher. We compared mosquito mortality following direct skin and membrane feeding. Methods We conducted a mosquito feeding study, nested within a randomized, double-blind, placebo-controlled trial of 141 adults with uncomplicated malaria in Kenya, comparing 3 days of ivermectin 300 mcg/kg/day, ivermectin 600 mcg/kg/day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. On post-treatment day 7, direct skin and membrane feeding assays were conducted using laboratory-reared Anopheles gambiae sensu stricto. Mosquito survival was assessed daily for 28 days post-feeding. Results Between July 20, 2015, and May 7, 2016, 69 of 141 patients participated in both direct skin and membrane feeding (placebo, n = 23; 300 mcg/kg/day, n = 24; 600 mcg/kg/day, n = 22). The 14-day post-feeding mortality for mosquitoes fed 7 days post-treatment on blood from pooled patients in both ivermectin arms was similar with direct skin feeding (mosquitoes observed, n = 2941) versus membrane feeding (mosquitoes observed, n = 7380): cumulative mortality (risk ratio 0.99, 95% confidence interval [CI] 0.95–1.03, P = .69) and survival time (hazard ratio 0.96, 95% CI 0.91–1.02, P = .19). Results were consistent by sex, by body mass index, and across the range of ivermectin capillary concentrations studied (0.72–73.9 ng/mL). Conclusions Direct skin feeding and membrane feeding on day 7 resulted in similar mosquitocidal effects of ivermectin across a wide range of drug concentrations, suggesting that the mosquitocidal effects seen with membrane feeding accurately reflect those of natural biting. Membrane feeding, which is more patient friendly and ethically acceptable, can likely reliably be used to assess ivermectin’s mosquitocidal efficacy. Clinical Trials Registration NCT02511353., Ivermectin is being considered for mass drug administration for malaria, due to its ability to kill mosquitoes feeding on recently-treated individuals. Membrane feeding, which is more patient friendly, likely reflects the effects of direct-skin feeding in assessing ivermectin’s mosquitocidal efficacy.

Introduction The aim of this study was to evaluate the suitability of using cone‐beam computed tomography (CBCT) obtained with a mobile C‐arm X‐ray fluoroscopy unit as a single modality for planning of high‐dose‐rate (HDR) prostate brachytherapy treatments. Methods The feasibility of using CBCT images obtained using a Siemens Arcadis Orbic 3D mobile C‐arm was evaluated. A retrospective clinical study was undertaken of six participants undergoing HDR prostate brachytherapy. Plans generated using images from a Toshiba Aquilion One LB CT were compared with those generated using CBCT images. After rigid spatial registration, the plans were compared based on various parameters such as dose‐volume histograms, overlap quantities and metrics, and dose constraints. Results Provided they were within the limited field of view, the brachytherapy catheters and fiducial markers were clearly visible in the CBCT images and thus, localisable and identifiable in the treatment planning process. The Siemens CBCT underestimated CT numbers leading to poorer tissue contrast which exacerbated the difficulties in delineation of the target tumour and the surrounding organs at risk. Between CT‐ and CBCT‐based plans, the mean difference of CTV‐D 90 was 1.58 Gy, CTV‐V 100 was 12.13%, rectum‐V 80 was 0.06% and urethra‐V 120 was −0.70%. Conclusion It was not feasible to solely utilise the Siemens Arcadis Orbic 3D for HDR prostate brachytherapy treatment planning due to suboptimal organ delineation. However, the methods in this study could be used to evaluate other mobile CBCT imaging devices for feasibility in HDR brachytherapy treatment planning since the results indicated that it may not be necessary to have standard quality CT images for treatment planning.

A dosimetric study was undertaken to assess the ability of Cyberknife (CK), Volumetric Modulated Arc Therapy (VMAT), and TomoTherapy (Tomo) to generate treatment plans that mimic the dosimetry of high dose-rate brachytherapy (HDR BT) for prostate cancer. The project aimed to assess the potential of using stereotactic body radiotherapy (SBRT) for boost treatment of high-risk prostate cancer patients where HDR BT in combination with conformal external beam radiotherapy (EBRT) is the standard of care. The datasets of 6 prostate patients previously treated with HDR BT were collated. VMAT, CK, and TomoTherapy treatment plans were generated for each dataset using the target and organ-at-risk structures as defined by the Radiation Oncologist during the HDR BT treatment process. The HDR BT plan isodoses were also converted into planning structures to assist the other modalities to achieve a HDR BT-like dose distribution. CK plans were created using both the iris collimator (IC) and a multileaf collimator (MLC). Comparison of the techniques was made based on dose-volume indices. Each plan was created at centres experienced using the respective treatment planning systems (TPS). Planning target volume (PTV V100%), i.e., the volume of the planning target volume (PTV) receiving 100% of the relative dose, in VMAT and TomoTherapy SBRT plans was higher than HDR BT plans. PTV V150% and V200%, i.e., volume of the PTV receiving 150% and 200% of the relative dose, were approached on all the CK MLC and TomoTherapy SBRT plans. However, it is not presently achievable for "virtual brachytherapy" SBRT to replicate the same high intraprostatic doses as HDR BT while meeting the constraints on the organs-at-risk (OARs). Half of the CK IC plans achieved PTV V150% but this was at the expense of high rectal dose. TomoTherapy and CK MLC plans achieved PTV V150% and V200% but the bladder dose was higher compared to CK IC plans. VMAT exhibited excellent PTV coverage based on V100 and OAR sparing, but without any ability to achieve the high intra-prostatic doses of HDR (V150% and V200%). SBRT techniques can be used to deliver hypofractionated radiotherapy to the PTV V100%. Based on the comparison of "physical" dose distributions, SBRT cannot presently achieve the same high intraprostatic doses as HDR BT while respecting the OAR constraints. SBRT still remains an attractive treatment option for delivering hypofractionated treatments for prostate cancer compared to HDR BT, in particular as it is less invasive and less resource intensive. Long-term outcomes of clinical trials comparing HDR BT and SBRT "prostate boosts" may show whether the high intraprostatic doses are clinically significant and correlate with outcomes.

PURPOSE The use of three-dimensional (3D) printing to develop custom phantoms for dosimetric studies in radiotherapy is increasing. The process allows production of phantoms designed to evaluated specific geometries, patients, or patient groups with a defining feature. The ability to print bone-equivalent phantoms has, however, proved challenging. The purpose of this work was to 3D print a series of three similar spine phantoms containing no surgical implants, implants made of titanium, and implants made of carbon fiber, for future dosimetric and imaging studies. Phantoms were evaluated for (a) tissue and bone equivalence, (b) geometric accuracy compared to design, and (c) similarity to one another. METHODS Sample blocks of PLA, HIPS, and StoneFil PLA-concrete with different infill densities were printed to evaluate tissue and bone equivalence. The samples were used to develop CT to physical (PD) and effective relative electron density (REDeff ) conversion curves and define the settings for printing the phantoms. CT scans of the printed phantoms were obtained to assess the geometry and densities achieved. Mean distance to agreement (MDA) and DICE coefficient (DSC) values were calculated between contours defining the different materials, obtained from design and like phantom modules. HU values were used to determine PD and REDeff and subsequently evaluate tissue and bone equivalence. RESULTS Sample objects showed linear relationships between HU and both PD and REDeff for both PLA and StoneFil. The PD and REDeff of the objects calculated using clinical CT conversion curves were not accurate and custom conversion curves were required. PLA printed with 90% infill density was found to have a PD of 1.11 ± 0.03 g.cm-3 and REDeff of 1.04 ± 0.02 and selected for tissue- equivalent phantom elements. StoneFil printed with 100% infill density showed a PD of 1.35 ± 0.03 g.cm-3 and REDeff of 1.24 ± 0.04 and was selected for bone-equivalent elements. Upon evaluation of the final phantoms, the PLA elements displayed PD in the range of 1.10 ± 0.03 g.cm-3 -1.13 ± 0.03 g.cm-3 and REDeff in the range of 1.02 ± 0.03-1.06 ± 0.03. The StoneFil elements showed PD in the range of 1.43 ± 0.04 g.cm-3 -1.46 ± 0.04 g.cm-3 and REDeff in the range of 1.31 ± 0.04-1.33 ± 0.04. The PLA phantom elements were shown to have MDA of ≤1.00 mm and DSC of ≥0.95 compared to design, and ≤0.48 mm and ≥0.91 compared like modules. The StoneFil elements displayed MDA values of ≤0.44 mm and DSC of ≥0.98 compared to design and ≤0.43 mm and ≥0.92 compared like modules. CONCLUSIONS Phantoms which were radiologically equivalent to tissue and bone were produced with a high level of similarity to design and even higher level of similarity of one another. When used in conjunction with the derived CT to PD or REDeff conversion curves they are suitable for evaluating the effects of spinal surgical implants of varying material of construction.

Planning organ-at-risk volume (PRV) margins can be applied to the bladder and rectum in prostate external beam radiation therapy (EBRT), in order to incorporate the uncertainties resulting from their inter-fraction motion. For each of a total of 16 patients, the bladder and rectum were delineated on CBCT images for five treatment fractions in addition to the planning CT image set. The bladder and rectum boundary displacements across the images were measured and the frequency and size of organ boundary displacements were evaluated. Subsequently, PRV margins were created to cover a specific percentage of organ boundary motion for a specified percentage of the population. In this investigation, two bladder PRV margins were generated to deal with two bladder conditions of low and high-volume variation among fractions. A combined PRV margin was also generated for the rectum by separating the rectum into three parts and deriving independent PRV margins for each segment. Outward coverage and effectiveness metrics allowed evaluation of the margins.

Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [

High‐dose ivermectin, co‐administered for 3 days with dihydroartemisinin‐piperaquine (DP), killed mosquitoes feeding on individuals for at least 28 days posttreatment in a recent trial (IVERMAL), whereas 7 days was predicted pretrial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae s.s. Three days of ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28 days of follow‐up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito‐cluster mortality rates, and 524 QTcF‐intervals were collected. Using pharmacokinetic/pharmacodynamic (PK/PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal‐effects throughout the 28‐day study duration, without invoking an unidentified mosquitocidal metabolite or drug‐drug interaction. Ivermectin had no effect on piperaquine's PKs or QTcF‐prolongation. The PK/PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.

Background: Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (2 ; women: 2 ), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353. Findings: Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93–2·65, p

Summary Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators’ discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov , number NCT00567190 . Findings Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. Interpretation Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Funding F Hoffmann-La Roche and Genentech.

1555 Background: Screening every patient for clinical trials is time-consuming, costly and inefficient. Developing an automated method for identifying patients who have potential disease progression, at the point where the practice first receives their radiology reports, but prior to the patient’s office visit, would greatly increase the efficiency of clinical trial operations and likely result in more patients being offered trial opportunities. Methods: Using Natural Language Processing (NLP) methodology, we developed a text parsing algorithm to automatically extract information about potential new disease or disease progression from multi-institutional, free-text radiology reports (CT, PET, bone scan, MRI or x-ray). We combined semantic dictionary mapping and machine learning techniques to normalize the linguistic and formatting variations in the text, training the XGBoost model particularly to achieve a high precision and accuracy to satisfy clinical trial screening requirements. In order to be comprehensive, we enhanced the model vocabulary using a multi-institutional dataset which includes reports from two academic institutions. Results: A dataset of 732 de-identified radiology reports were curated (two MDs agreed on potential new disease/dz progression vs stable) and the model was repeatedly re-trained for each fold where the folds were randomly selected. The final model achieved consistent precision (>0.87 precision) and accuracy (>0.87 accuracy). See the table for a summary of the results, by radiology report type. We are continuing work on the model to validate accuracy and precision using a new and unique set of reports. Conclusions: NLP systems can be used to identify patients who potentially have suffered new disease or disease progression and reduce the human effort in screening or clinical trials. Efforts are ongoing to integrate the NLP process into existing EHR reporting. New imaging reports sent via interface to the EHR will be extracted daily using a database query and will be provided via secure electronic transport to the NLP system. Patients with higher likelihood of disease progression will be automatically identified, and their reports routed to the clinical trials office for clinical trial screening parallel to physician EHR mailbox reporting. The over-arching goal of the project is to increase clinical trial enrollment. 5-fold cross-validation performance of the NLP model in terms of accuracy, precision and recall averaged across all the folds.[Table: see text]

Well type chambers are used for radioactive source calibrations in brachytherapy, but do not provide radiation shielding. Routine constancy checks on a well chamber are required between periodic secondary standard laboratory calibrations to ensure consistent device performance, and ultimately to ensure accurate patient dose delivery. In this work, a method is described to provide suitable shielding for a Cs-137 rod-type point source to enable use for constancy checks. A novel plunger-type shielded housing was designed and constructed for the Cs-137 source that when combined with a suitably shielded well-chamber container minimised user exposure during constancy checks. The designed shielding proved effective, and a constancy test routine was established and used for the past 16 months. The well chamber showed consistent performance (0.12 ± 0.18 % from the baseline) and no increased exposure was reported on users' radiation badges.

Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks.

Background: Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food. Objectives: This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB. Methods: Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non-fasting states using LC-MS methods. Results: Sixty patients participated in the study. The median rifampicin Cmax and AUC0–6 were higher during fasting than non-fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg·h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02–1.28, P

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25-40 mg/Kg regimen is bioequivalent to a clinically effective 100-200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.

Significance Filarial nematode infections, caused by Wuchereria bancrofti , Brugia malayi (elephantiasis), and Onchocerca volvulus (river blindness) infect 150 million of the world’s poorest populations and cause profound disability. Standard treatments require repetitive, long-term, mass drug administrations and have failed to interrupted transmission in certain sub-Saharan African regions. A drug cure using doxycycline, which targets the essential filarial endosymbiont Wolbachia , is clinically effective but programmatically challenging to implement due to long treatment durations and contraindications. Here we provide proof-of-concept of a radical improvement of targeting Wolbachia via identification of drug synergy between the anthelmintic albendazole and antibiotics. This synergy enables the shortening of treatment duration of macrofilaricidal anti- Wolbachia based treatments from 4 wk to 7 d with registered drugs ready for clinical testing.

Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks.

A placebo-controlled trial that compares the outcomes of immediate vs. deferred initiation of antiretroviral therapy in HIV +ve tuberculous meningitis (TBM) patients was conducted in Vietnam in 2011. Here, the pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol were investigated in the presence and absence of anti-HIV treatment in 85 patients. Pharmacokinetic analyses show that HIV therapy has no significant impact on the pharmacokinetics of TB drugs in this cohort. The same population, however, displayed generally low cerebrospinal fluid (CSF) and systemic exposures to rifampicin compared to previously reported HIV -ve cohorts. Elevated CSF concentrations of pyrazinamide, on the other hand, were strongly and independently correlated with increased mortality and neurological toxicity. The findings suggest that the current standard dosing regimens may put the patient at risk of treatment failure from suboptimal rifampicin exposure, and potentially increasing the risk of adverse central nervous system events that are independently correlated with pyrazinamide CSF exposure.

Purpose Low-dose-rate brachytherapy using iodine-125 seeds is a highly efficacious treatment for low-risk prostate cancer. We propose a bioeffect model may be used to target an ablative dose to the tumor with a lower, therapeutic dose to low-risk regions to maintain high rates of tumor control with reduced toxicity. We report on the validation of the model and derivation of the optimal cutpoint value of tumor control probability (TCP) that predicts for freedom from biochemical failure. Methods and Materials The TCP was calculated from postimplant dosimetry data for 423 prostate cancer patients from three Australian institutions. To apply the model, the prostate was mathematically divided into 12 subsections with tumor characteristics, including a nonuniform distribution of tumor cell density, derived from the literature. Results When TCP values were above and below 0.62, the 5-year freedom from biochemical failure were 93.7% (95% confidence interval [CI], 90.4, 96.4%) and 88.8% (95% confidence interval, 81.3, 94.5%), respectively ( p = 0.004). Conclusions Using postimplant dosimetry data, the TCP model was able to predict for freedom from biochemical failure. The cutpoint value that would be used clinically depends on the selection of the model parameters, but the potential for the model to be used in the optimization of treatment planning is demonstrated.

Introduction A survey was designed to establish a baseline data set for the current routine practice of high-dose-rate prostate brachytherapy (HDR-PB) in Australia and New Zealand. Existing treatment protocols and clinical implementations are not generally known. Methods The survey, for the 2010 and 2011 calendar years, collected data including number of patients treated; equipment used; imaging modalities; applicator verification and correction methods; dose prescriptions and normal tissue dose constraints. The number of HDR-PB patients treated was compared with the most recently published prostate cancer incidence data in Australia and in New Zealand. Total biologically equivalent doses in 2.0 Gy fractions (EQD2) were calculated for each prescription regime reported. Results There were reductions, of 25–60%, in patients treated with HDR-PB from 2010 to 2011 in four departments. Prostate cancer patients are two to six times more likely to be prescribed HDR-PB in Western Australia than elsewhere in the region. There were 12 different treatment prescriptions, with EQD2 doses ranging from 73.5 to 97.6 Gy, among the 18 reported by survey respondents. Normal tissue definition methodology and dose constraints varied, and 13 of 15 departments reported that no particular published external guidelines were followed in full. Conclusion The high survey response rate, 15 of 17 departments, has provided a representative baseline data set of contemporary HDR-PB practice in Australia and New Zealand that may assist government and professional bodies, such as the Australasian Brachytherapy Group, in formulating recommendations, setting standards and future planning.

Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children., IMPORTANCE Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers.

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.

A highly sensitive and rapid liquid chromatography tandem mass spectrometry (LC–MS/MS) method has been developed to measure the levels of the antitubercular drug rifampicin (RIF) in human plasma and cerebrospinal fluid (CSF). The analyte and internal standard (IS) were isolated from plasma and CSF by a simple organic solvent based precipitation of proteins followed by centrifugation. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring (MRM) mode. The assay was linear in the concentration range 25–6400ng/mL with intra- and inter-day precision of

We examined catheter displacement in patients treated with fractionated high-dose rate (HDR) brachytherapy boost for prostate cancer and the impact this had on tumor control probability (TCP). These data were used to make conclusions on an acceptable amount of displacement.The last 20 patients treated with HDR brachytherapy boost for prostate cancer at our center in 2007 were replanned using simulated interstitial catheter displacements of 3, 6, 9, and 12 mm with originally planned dwell times. The computer-modeled dose-volume histograms for the clinical target volumes were exported and used to calculate the TCP of plans with displaced needles relative to the original plan. Actual catheter displacements were also measured before and after manual adjustment in all patients treated in 2007.In the 20 patients who were replanned for caudal catheter displacements of 3, 6, 9, and 12 mm, the median relative TCP was 0.998, 0.964, 0.797, and 0.265, respectively (p0.01 when all medians were compared). All patients replanned with a 3-mm displacement, compared with only 75% with a 6-mm displacement, had a relative TCP greater than 0.950. In the 91 patients treated in 2007, before adjustment, 82.3% of fractions had a displacement greater than 3 mm compared with 12.2% of fractions after adjustment.Catheter displacement in HDR brachytherapy significantly compromises the TCP. The tolerance for these movements should be small (or =3 mm). Correcting these displacements to within acceptable limits is feasible.

Accurate and reproducible patient positioning is fundamental to the success of fractionated radiotherapy. Poor patient positioning could result in geographic misses. We have recently reported on an improved method of customized face mask production using laser surface scanning. In this report, we sought to identify and develop a method to routinely make customized neck supports for patients prescribed radiotherapy to the brain or head and neck regions. We identified a potentially suitable product--sealed packs containing two liquids that produce expanding polyurethane foam when mixed--and developed a method for their use. The neck supports are inexpensive and simple to produce (taking less than 5 min of radiation therapist labour). We assessed the customized neck supports in several ways. The effect on setup accuracy was assessed by comparing two consecutive cohorts of patients. Statistically significant differences favouring the customized neck supports included a reduced total displacement error (mean 3.4 vs. 2.1 mm) and a reduced left-right setup error (mean 1.8 vs. 1.1 mm). This is consistent with the greater support provided by the customized neck supports. This method could easily be undertaken by other departments.

For safe and accurate dose delivery in brachytherapy, associated equipment is subject to commissioning and ongoing quality assurance (QA). Many centres depend on the use of a well-type chamber ('well chamber') for performing brachytherapy dosimetry. Documentation of well chamber commissioning is scarce despite the important role the chamber plays in the whole brachytherapy QA process. An extensive and structured commissioning of the HDR 1000 plus well chamber (Standard Imaging Inc, Middleton WI) for HDR and LDR dosimetry was undertaken at Sir Charles Gairdner Hospital. The methodology and outcomes of this commissioning is documented and presented as a guideline to others involved in brachytherapy. The commissioning tests described include mechanical integrity, leakage current, directional dependence, response, length of uniform response, the influence of insert holders, ion collection efficiency, polarity effect, accuracy of measured air kerma strength (S(K)) or reference air kerma rate (K(R)) and baseline setting (for ongoing constancy checks). For the HDR 1000 plus well chamber, some of the insert holders modify the response curve. The measured sweet length was 2.5 cm which is within 0.5% of that specified by the manufacturer. Correction for polarity was negligible (0.9999) and ion recombination was small (0.9994). Directional dependence was small (less than 0.2%) and leakage current was negligible. The measured K(R) for (192)Ir agreed within 0.11% compared with a second well chamber of similar model and was within 0.5% of that determined via a free-in-air measurement method. Routine constancy checks over a year agreed with the baseline within 0.4%.

Introduction To report long-term prostate-specific antigen (PSA) and toxicity outcomes for patients with localised prostate cancer treated with Iodine-125 permanent implantation at a single Australian centre. Methods Between September 1994 and November 2007, 207 patients at Sir Charles Gairdner Hospital with localised prostate cancer were consecutively treated with Iodine-125 permanent interstitial implantation. Post-therapy assessment was performed three times a month and included clinical review and biochemical (PSA) evaluation. PSA progression was evaluated using the Phoenix (nadir + 2.0) definition. Treatment-related morbidity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 guidelines. The rate of biochemical failure was calculated by Kaplan–Meier plots. Univariate and multivariate analyses were performed to evaluate outcomes by pre-treatment clinical prognostic factors and radiation dosimetry. Results Median follow-up was 7.8 years. The 10-year biochemical disease-free survival (bDFS) for the entire cohort was 89%. Ten-year bDFS estimates by pre-treatment risk group were 96% for low-risk, 83% for intermediate-risk and 50% for high-risk disease. On multivariate analysis, pre-treatment PSA was an independent predictor of bDFS. D90 dose did not show a statistically significant effect on bDFS. The peak incidences of late grade 3 or higher urinary and rectal toxicities were 10.7% and 1.1% respectively. Conclusion Excellent long-term biochemical control was demonstrated with Iodine-125 permanent interstitial implantation in appropriately selected patients with prostate cancer. The results of our single centre experience are comparable with those of other single institutions.

Tritium radiopharmaceuticals are often used in drug development because of their desirable specific activity. The inherent instability of these radioactive tracers often leads to a requirement to purify prior to use. Purification methodologies such as preparative chromatography and solid/liquid extractions often utilize water as a solvent, which is not suitable for long-term storage and necessitates removal. Rotary evaporation has traditionally been utilized for the removal of this unwanted solvent, however, this method has been shown to lead to decomposition of the tritium species in some cases. Centrifugal evaporation is a milder concentration method which has been demonstrated to effectively remove solvents. In this study, we show that centrifugal evaporation leads to effective concentration of tritium samples without the decomposition typically observed by rotary evaporation.

Purpose This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. Patients and Methods Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry. Results Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed. Conclusion CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

In this paper, we examine the effect of treatment parameters in a model used to evaluate permanent prostate implants. The model considers the prostate to be composed of 12 sub-sections, each sub-section is assigned a cell density based on the probability of finding cancer foci in that sub-section. Wasted dose as a result of the dose rate from the implant falling below a level adequate to counteract repopulation was found to vary by 2-16% over the range of radiosensitivity and repopulation rates considered. Within the model, applied to five dose distributions, the uncertainty in the tumour control probability (TCP) values calculated for each sub-section as a result of differences in the model parameters, was found to be less than 12% in most cases for the good quality implants. The difference in TCP values was much larger for the poor quality implant. Substituting a heterogeneous distribution of alpha for a single mean value resulted in generally lower TCP values though introducing a cutoff value with a Gaussian distribution had a profound effect on the calculated values. Despite uncertainties in the parameters, the model was able to identify sub-sections at risk of local recurrence but as a result of these uncertainties, the TCP values can only be considered in the relative rather than absolute sense.

Secondary-electron emission (SEE) from LiF films deposited on Si(0 0 1) surface was studied using time-of-flight two-electron coincidence spectroscopy. A set of energy-distribution curves (EDCs) of secondary electrons excited from a LiF film by electrons with energies in the range of 20–50 eV exhibits emission features at about 7 and 11 eV. The energy positions of these maxima do not depend on the incident energy. To reveal the origin of these features, each of the EDCs was spanned in the second dimension E2 using two-electron coincidence spectroscopy. Two-dimensional mapping of the energy sharing between correlated electrons shows that above 25 eV incident energy, one electron of the pair is preferentially emitted with E1 ¼ 7:2 � 0:3 eV energy and the second one with energy E2 ¼ð Ep � 23:3 Þ� 0:5 eV, where Ep is the incident electron energy. At about 30 eV incident energy, a second favoured emission energy of 10.9 ± 0.3 eV is observed. The unique capability of (e,2e) spectroscopy established the links between electron energy loss process and emission features in the EDCs. It is suggested that the mechanism of SEE from LiF film includes the excitation of two collective excitations with subsequent decay via electron ejection. It was shown that the mechanism of secondary emission from LiF film depends on the film thickness and its structure. � 2003 Elsevier B.V. All rights reserved.

A highly efficient time-of-flight electron spectrometer is described. An incident electron current of the order of 10−14 A makes it suitable for studying secondary emission from dielectric surfaces. A microchannel plate position-sensitive detector allows flight distance correction while keeping a large acceptance angle. Measured energy distribution curves of secondary electrons generated from a LiF film by 19–31 eV incident electrons demonstrate good energy resolution and reveal reproducible and stable emission features at 2.6±0.3 eV, 7.2±0.3 eV, and 10.3±0.3 eV.

The influence of electron spectrometer alignment on the momentum resolution of electron-impact ionisation (e,2e) experiments is quantified. We show that for coplanar measurements with circular detector apertures, the azimuthal spectrometer alignment should be determined with an accuracy of ±0.001 rad to optimise the momentum resolution of an (e,2e) apparatus. Using this criterion, we predict an improvement in the (e,2e) momentum resolution of ∼30% near q =0 a.u., where quantum-mechanical scattering models predict a minimum in the triple differential cross-section (TDCS) of atomic p states. This result will assist in determining an upper limit on the effects of second order scattering processes that contribute to small momentum transfers.

Metformin is currently prescribed worldwide to treat type 2 diabetes, and therefore, radiolabeled [(14) C] metformin is often prepared for clinical comparisons of new drug candidates. Prior to using the radiolabeled metformin, the purity needs to be determined to ensure the quality of the material. While typical reversed-phase LC methods are often the first choice for purity analysis, they are not suitable for this determination because the compound is poorly retained under these conditions. Mixed-mode chromatography has been demonstrated to overcome these retention issues, and therefore, this methodology was utilized for the purity determination of radiolabeled metformin.

SUMMARYWithin the World Health Organization 2012–2020 roadmap for control and elimination of schistosomiasis, the scale-up of mass drug administration with praziquantel is set to change the epidemiological landscape across Africa and Arabia. Central in measuring progress is renewed emphasis upon diagnostics which operate at individual, community and environmental levels by assessing reductions in disease, infections and parasite transmission. However, a fundamental tension is revealed between levels for present diagnostic tools, and methods applied in control settings are not necessarily adequate for application in elimination scenarios. Indeed navigating the transition from control to elimination needs careful consideration and planning. In the present context of control, we review current options for diagnosis of schistosomiasis at different levels, highlighting several strengths and weaknesses therein. Future challenges in elimination are raised and we propose that more cost-effective diagnostics and clinical staging algorithms are needed. Using the Kingdom of Saudi Arabia as a contemporary example, embedding new diagnostic methods within the primary care health system is discussed with reference to both urogenital and intestinal schistosomiasis.