Survival after Stereotactic Radiosurgery in the Era of Targeted Therapy: Number of Metastases No Longer Matters.

Randomised control trial data support the use of stereotactic radiosurgery (SRS) in up to 4 brain metastases (BMs), with non-randomised prospective data complementing this for up to 10 BMs. There is debate in the neuro-oncology community as to the appropriateness of SRS in patients with >10 BMs. We present data from a large single-centre cohort, reporting survival in those with >10 BMs and in a >20 BMs subgroup. A total of 1181 patients receiving SRS for BMs were included. Data were collected prospectively from the time of SRS referral. Kaplan-Meier graphs and logrank tests were used to compare survival between groups. Multivariate analysis was performed using the Cox proportional hazards model to account for differences in group characteristics. Median survival with 1 BM (n = 379), 2-4 BMs (n = 438), 5-10 BMs (n = 236), and >10 BMs (n = 128) was 12.49, 10.22, 10.68, and 10.09 months, respectively. Using 2-4 BMs as the reference group, survival was not significantly different in those with >10 BMs in either our univariable (p = 0.6882) or multivariable analysis (p = 0.0564). In our subgroup analyses, median survival for those with >20 BMs was comparable to those with 2-4 BMs (10.09 vs. 10.22 months, p = 0.3558). This study contributes a large dataset to the existing literature on SRS for those with multi-metastases and supports growing evidence that those with >10 BMs should be considered for SRS.

Simultaneous Focal Boost With Stereotactic Radiation Therapy for Localized Intermediate- to High-Risk Prostate Cancer: Primary Outcomes of the SPARC Phase 2 Trial.

PURPOSE: Dose-escalated radiation therapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiation therapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease while limiting toxicity. This study evaluated the toxicity and quality of life (QoL) with CyberKnife-based SBRT and simultaneous integrated boost in localized prostate cancer. METHODS AND MATERIALS: Eligible participants included newly diagnosed, biopsy-proven unfavorable intermediate- to high-risk localized prostate cancer (at least 1 of the following: Gleason ≥4+3, magnetic resonance imaging(MRI)-defined T3a N0, prostate-specific antigen ≥20) with up to 2 MRI-identified DILs. Participants received 36.25 Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5 Gy as allowed by organ-at-risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2+ genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using Radiation Therapy Oncology Group scoring, biochemical parameters, International Prostate Symptom Score, International Index of Erectile Function 5, and EQ-5D QoL outcomes were assessed. RESULTS: Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43 Gy. Cumulative acute grade 2+ genitourinary and gastrointestinal toxicity were 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. International Prostate Symptom Score and urinary QoL scores recovered to baseline by 6 months. Patient-reported outcomes showed no significant change in EQ-5D QoL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date. CONCLUSIONS: CyberKnife SBRT-delivered dose of 36.25 Gy to the prostate with a simultaneous integrated boost up to 47.5 Gy is well tolerated. Acute and late genitourinary and gastrointestinal toxicity rates are comparable to other contemporary SBRT trials and series with focal boost.

Diagnostic dilemma in a patient with upper arm mass with history of breast cancer and melanoma.

We present a case of upper limb muscle metastasis in a female patient with a history of malignant melanoma. Although melanoma is the fifth most common cancer in the UK, muscle metastases are extremely rare, with only a few cases reported in the literature. We discuss the challenge of diagnosing muscle metastasis on radiological imaging and in particular of distinguishing metastatic lesions to muscle from sarcoma. We also review the imaging findings of other published cases in a literature review. We conclude that although certain characteristic features of melanoma metastases can be identified on imaging (e.g., hyperintensity on T 1-weighted MRI), the radiological appearances are highly variable and histopathological examination is necessary to confirm the diagnosis.

Stereotactic radiotherapy with focal boost for intermediate and high-risk prostate cancer: Initial results of the SPARC trial.

INTRODUCTION: Dose escalation to dominant intraprostatic lesions (DILs) is a novel method to increase the therapeutic ratio in localised prostate cancer. The Stereotactic Prostate Augmented Radiotherapy with Cyberknife (SPARC) trial was designed to determine the feasibility of a focal boost defined with multiparametric magnetic resonance imaging (mpMRI) using stereotactic ablative body radiotherapy (SABR). MATERIALS AND METHODS: Patients were included with newly diagnosed intermediate to high risk prostate cancer with at least one of: Gleason score 4 + 3, stage T3a, or PSA > 20 ng/ml. Visible disease on mpMRI was mandatory and up to 2 separate nodules were allowed. All patients received androgen deprivation. Patients received 36.25 Gy in 5 fractions using CyberKnife® and the DIL received a simultaneous boost to a maximum of 47.5 Gy, as allowed by OAR constraints. Genitourinary (GU) and gastrointestinal (GI) toxicity was reported using the RTOG scoring criteria. International Index of Erectile Function (IIEF) and EQ-5D global health scores were regularly captured. RESULTS: An interim safety analysis was performed on the first 8 patients, recruited between July 2013 and December 2015. Median follow up was 56 months (range 50-74). Median D95 values for the prostate PTV and boost volume were 36.55 Gy (range 35.87-36.99) and 46.62 Gy (range 44.85-48.25) respectively. Of the dose constraints, 10/80 were not achieved but all were minor dose variations. Grade 2+ acute GU and GI toxicities were 37.5% respectively while grade 2+ late GU and GI toxicities were 12.5% and 0% respectively. IIEF and quality of life scores recovered over time and all patients remain in biochemical remission. CONCLUSION: The first patients have been successfully treated with prostate SABR and focal boost on the SPARC trial, with excellent adherence to the planning protocol. Toxicity and efficacy results are promising and further recruitment is underway.

Production and Characterization of Human Macrophages from Pluripotent Stem Cells.

Macrophages are present in most vertebrate tissues and comprise widely dispersed and heterogeneous cell populations with different functions. They are key players in health and disease, acting as phagocytes during immune defense and mediating trophic, maintenance, and repair functions. Although it has been possible to study some of the molecular processes involved in human macrophage function, it has proved difficult to apply genetic engineering techniques to primary human macrophages. This has significantly hampered our ability to interrogate the complex genetic pathways involved in macrophage biology and to generate models for specific disease states. An off-the-shelf source of human macrophages that is amenable to the vast arsenal of genetic manipulation techniques would, therefore, provide a valuable tool in this field. We present an optimized protocol that allows for the generation of macrophages from human induced pluripotent stem cells (iPSCs) in vitro. These iPSC-derived macrophages (iPSC-DMs) express human macrophage cell surface markers, including CD45, 25F9, CD163, and CD169, and our live-cell imaging functional assay demonstrates that they exhibit robust phagocytic activity. Cultured iPSC-DMs can be activated to different macrophage states that display altered gene expression and phagocytic activity by the addition of LPS and IFNg, IL4, or IL10. Thus, this system provides a platform to generate human macrophages carrying genetic alterations that model specific human disease and a source of cells for drug screening or cell therapy to treat these diseases.

Rapid Mast Cell Generation from Gata2 Reporter Pluripotent Stem Cells.

Mast cells are tissue-resident immune cells. Their overgrowth/overactivation results in a range of common distressing, sometimes life-threatening disorders, including asthma, psoriasis, anaphylaxis, and mastocytosis. Currently, drug discovery is hampered by use of cancer-derived mast cell lines or primary cells. Cell lines provide low numbers of mature mast cells and are not representative of in vivo mast cells. Mast cell generation from blood/bone marrow gives poor reproducibility, requiring 8-12 weeks of culture. Here we report a method for the rapid/robust production of mast cells from pluripotent stem cells (PSCs). An advantageous Gata2Venus reporter enriches mast cells and progenitors as they differentiate from PSCs. Highly proliferative mouse mast cells and progenitors emerge after 2 weeks. This method is applicable for rapid human mast cell generation, and could enable the production of sufficient numbers of physiologically relevant human mast cells from patient induced PSCs for the study of mast cell-associated disorders and drug discovery.

An evaluation of systematic errors on marker-based registration of computed tomography and magnetic resonance images of the liver.

We demonstrated a general method to evaluate systematic errors related to Magnetic Resonance (MR) imaging sequences in marker-based co-registration of MR and Computed Tomography (CT) images, and investigated the effect of MR image quality in the co-registration process using clinical MR and CT protocols for stereotactic ablative body radiotherapy (SABR) planning of the liver. Small systematic errors (under 1.6 mm) were detected, unlikely to be a clinical risk to liver SABR. The least favourable marker configuration was found to be a co-planar arrangement parallel to the transaxial image plane.

Intrarater Reliability and Other Psychometrics of the Health Promoting Activities Scale (HPAS).

OBJECTIVE: The Health Promoting Activities Scale (HPAS) measures the self-rated frequency with which adults participate in activities that promote health. We evaluated the internal consistency, construct validity, and intrarater reliability of the HPAS with a cohort of mothers (N = 56) of school-age children. METHOD: We used an online survey that included the HPAS and measures of mental and physical health. Statistical analysis included intraclass correlation coefficients (ICCs), measurement error, error range, limits of agreement, and minimum detectable change (MDC). RESULTS: The HPAS showed good internal consistency (Cronbach's α = .73). Construct validity was supported by a significant difference in HPAS scores among participants grouped by physical activity level; no other differences were significant. Results included a high aggregate ICC of .90 and an MDC of 5 points. CONCLUSION: Our evaluation of the HPAS revealed good reliability and stability, suggesting suitability for ongoing evaluation as an outcome measure.

Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment.

PURPOSE AND OBJECTIVES: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. METHODS AND MATERIALS: Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A "plan of the day" radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 months using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. RESULTS: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). CONCLUSION: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.

A randomized placebo-controlled trial of methotrexate in psoriatic arthritis.

OBJECTIVE: MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. METHODS: A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). RESULTS: Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. CONCLUSIONS: This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151.

Impacts of a fuel oil spill on seagrass meadows in a subtropical port, Gladstone, Australia--the value of long-term marine habitat monitoring in high risk areas.

We used an established seagrass monitoring programme to examine the short and longer-term impacts of an oil spill event on intertidal seagrass meadows. Results for potentially impacted seagrass areas were compared with existing monitoring data and with control seagrass meadows located outside of the oil spill area. Seagrass meadows were not significantly affected by the oil spill. Declines in seagrass biomass and area 1month post-spill were consistent between control and impact meadows. Eight months post-spill, seagrass density and area increased to be within historical ranges. The declines in seagrass meadows were likely attributable to natural seasonal variation and a combination of climatic and anthropogenic impacts. The lack of impact from the oil spill was due to several mitigating factors rather than a lack of toxic effects to seagrasses. The study demonstrates the value of long-term monitoring of critical habitats in high risk areas to effectively assess impacts.

Induction of hematopoietic differentiation of mouse embryonic stem cells by an AGM-derived stromal cell line is not further enhanced by overexpression of HOXB4.

Hematopoietic differentiation of embryonic stem (ES) cells can be enhanced by co-culture with stromal cells derived from hematopoietic tissues and by overexpression of the transcription factor HOXB4. In this study, we compare the hematopoietic inductive effects of stromal cell lines derived from different subregions of the embryonic aorta-gonad-mesonephros tissue with the commonly used OP9 stromal cell line and with HOXB4 activation. We show that stromal cell lines derived from the aorta and surrounding mesenchyme (AM) act at an earlier stage of the differentiation process compared with the commonly used OP9 stromal cells. AM stromal cells were able to promote the further differentiation of isolated brachyury-GFP(+) mesodermal cells into hematopoietic progenitors, whereas the OP9 stromal cells could not support the differentiation of these cells. Co-culture and analyses of individual embryoid bodies support the hypothesis that the AM stromal cell lines could enhance the de novo production of hematopoietic progenitors, lending support to the idea that AM stromal cells might act on prehematopoietic mesoderm. The induction level observed for AM stromal cells was comparable to HOXB4 activation, but no additive effect was observed when these 2 inductive strategies were combined. Addition of a γ-secretase inhibitor reduced the inductive effects of both the stromal cell line and HOXB4, providing clues to possible shared molecular mechanisms.

The outcome of a rapid hepatitis B vaccination programme in a methadone treatment clinic.

AIM: Injecting drug users are a high-risk population for hepatitis B (HBV), but are difficult to engage in vaccination programmes. This study examines the completion rates of a HBV vaccination schedule and seroconversion in a group of patients in methadone maintenance treatment. METHODS: Patients at a public methadone maintenance programme in Sydney, Australia, were screened for viral hepatitis (hepatitis A, B and C) and offered a rapid HBV vaccination schedule (0, 1 and 2 months). Hepatitis B surface antibody (antiHBs) was retested on completion of the vaccination schedule. RESULTS: A total of 143 patients [71.3% male, mean age 33.1 (standard deviation +/- 8.3)] enrolled in the project. Forty-nine per cent of patients were HAV antibody (Ab) positive, 81.1% hepatitis C virus (HCV) antibody (Ab) positive and 38.9% antiHBs positive. Exposure to multiple hepatitis viruses was common, with 24.5% testing positive for all three viruses. Seventy-three (83%) of the 88 antiHBs negative patients completed the vaccination schedule. Post-vaccination serology indicated a seroconversion rate of 75.4% (55 of 73) of completors, or 62.5% of eligible participants (55 of 88). CONCLUSION: While there was a high rate of completion of the rapid vaccination schedule in this population, a moderate seroconversion rate was achieved. Further work is required to identify an optimal vaccination schedule in opioid substitution patients.

Can digitally reconstructed radiographs (DRRS) replace simulation films in prostate cancer conformal radiotherapy?

PURPOSE: To evaluate the precision of using digitally reconstructed radiographs (DRRs) of either 3 mm or 6 mm slice separation vs. using simulator images for the setup verification of patients receiving CT planned conformal radiotherapy to the prostate. To calculate the transfer error between CT and simulator. METHODS AND MATERIALS: Twenty patients were CT scanned (3 mm slice spacing/width). DRRs were generated for both 3 mm (DRR 3) and 6 mm (DRR 6) separations. DRRs and a simulator image of an anterior and a lateral field were used as reference images. Five observers matched each of the reference images to treatment images using the Theraview "Target check" facility. It was assumed that poorer images would lead to a loss of precision of field placement estimations (FPE) between observers. The study was designed to detect a difference greater than 1.5 mm(2) in the precision of image placement. The transfer error was the mean difference in the setup error derived from the DRRs and the simulation films. RESULTS: The precision of evaluations for simulator films and 3 mm DRRs were similar. There was a trend for the DRR 6 mm to achieve less precise results which was greatest for craniocaudal examinations (variance: simulator 1.5 mm(2), DRR6 2.8 mm(2), p = 0.17), but this did not reach statistical significance. A range of transfer errors was identified, with standard deviations ranging from 1.7 to 4.2 mm. There was evidence of a significant systematic bias in anterior craniocaudal (1.3-1.9 mm, p < 0.004) and anterior posterior (-1.9 mm, p = 0.027). CONCLUSION: The precision of setup evaluations using DRRs is similar to that achieved by using simulator fields when planning conformal prostate radiotherapy. The use of DRRs could reduce systematic errors introduced in the planning process.

Characterisation of the rhoph2 gene of Plasmodium falciparum and Plasmodium yoelii.

The high molecular mass protein complex (RhopH) in the rhoptries of the malaria parasite consists of three distinct polypeptides with estimated sizes in Plasmodium falciparum of 155kDa (PfRhopH1), 140kDa (PfRhopH2) and 110kDa (PfRhopH3). Using a number of reagents, including a new mAb 4E10 that is specific for the PfRhopH complex, it was shown that the RhopH complex is synthesised during schizogony and transferred intact to the ring stage in newly invaded erythrocytes. The genes encoding RhopH1 and RhopH3 have already been identified and characterised in both P. falciparum and Plasmodium yoelii. In this report, we describe the identification of the gene for RhopH2 in both these parasite species. Peptide sequences were obtained from purified RhopH2 proteins and used to generate oligonucleotide primers and search malaria sequence databases. In a parallel approach, mAb 4E10 was used to identify a clone coding for RhopH2 from a P. falciparum cDNA library. The sequences of both P. falciparum and P. yoelii genes for RhopH2 were completed and compared. They both contain nine introns and there is a high degree of similarity between the deduced amino acid sequences of the two proteins. The P. falciparum gene is a single copy gene located on chromosome 9, and is transcribed in schizonts.