Fibroblast activation protein targeted radiotherapy induces an immunogenic tumor microenvironment and enhances the efficacy of PD-1 immune checkpoint inhibition.

PURPOSE: FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a radiopharmaceutical in clinical development for solid tumors that consists of two functional elements: a FAP-targeting peptide and a chelator used to attach radioisotopes. Preclinically, we evaluated the immune modulation and anti-tumor efficacy of FAP-2287, a murine surrogate for FAP-2286, conjugated to the radionuclide lutetium-177 (177Lu) as a monotherapy and in combination with a PD-1 targeting antibody. METHODS: C57BL/6 mice bearing MCA205 mouse FAP-expressing tumors (MCA205-mFAP) were treated with 177Lu-FAP-2287, anti-PD-1, or both. Tumor uptake of 177Lu- FAP-2287 was assessed by SPECT/CT scanning, while therapeutic efficacy was measured by tumor volume and survival. Immune profiling of tumor infiltrates was evaluated through flow cytometry, RNA expression, and immunohistochemistry analyses. RESULTS: 177Lu-FAP-2287 rapidly accumulated in MCA205-mFAP tumors leading to significant tumor growth inhibition (TGI) and longer survival time. Significant TGI was also observed from anti-PD-1 and the combination. In flow cytometry analysis of tumors, 177Lu-FAP-2287 increased CD8+ T cell infiltration which was maintained in the combination with anti-PD-1. The increase in CD8+ T cells was accompanied by an induction of STING-mediated type I interferon response and higher levels of co-stimulatory molecules such as CD86. CONCLUSION: In a preclinical model, FAP-targeted radiotherapy enhanced anti-PD-1-mediated TGI by modulating the TME and increasing the recruitment of tumor-infiltrating CD8+ T cells. These findings provide a rationale for clinical studies of combined 177Lu-FAP-2286 radiotherapy and immune checkpoint inhibition in FAP-positive tumors.

Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy.

PURPOSE: Fibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor microenvironment of many solid cancers. FAP-2286 is a FAP-binding peptide coupled to a radionuclide chelator that is currently being investigated in patients as an imaging and therapeutic agent. The potency, selectivity, and efficacy of FAP-2286 were evaluated in preclinical studies. METHODS: FAP expression analysis was performed by immunohistochemistry and autoradiography on primary human cancer specimens. FAP-2286 was assessed in biochemical and cellular assays and in in vivo imaging and efficacy studies, and was further evaluated against FAPI-46, a small molecule-based FAP-targeting agent. RESULTS: Immunohistochemistry confirmed elevated levels of FAP expression in multiple tumor types including pancreatic, breast, and sarcoma, which correlated with FAP binding by FAP-2286 autoradiography. FAP-2286 and its metal complexes demonstrated high affinity to FAP recombinant protein and cell surface FAP expressed on fibroblasts. Biodistribution studies in mice showed rapid and persistent uptake of 68Ga-FAP-2286, 111In-FAP-2286, and 177Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. 177Lu-FAP-2286 exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts, with no significant weight loss. In addition, FAP-2286 maintained longer tumor retention and suppression in comparison to FAPI-46. CONCLUSION: In preclinical models, radiolabeled FAP-2286 demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. These results support clinical development of 68Ga-FAP-2286 for imaging and 177Lu-FAP-2286 for therapeutic use in a broad spectrum of FAP-positive tumors.

Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2.

OBJECTIVE: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2. METHODS: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model. RESULTS: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05). CONCLUSION: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.

Tourism and the Highlands: A cross-sectional study on trauma and orthopaedic service use by tourists in 2017.

BACKGROUND: NHS Highland covers a wide geographical region encompassing the Isle of Skye, and Ben Nevis. Tourism is a significant contributor to the local economy and in 2017 the Highlands welcomed 534,000 visitors. Health services across the region treat tourists in addition to the local population. We investigated how many tourists accessed the Trauma and Orthopaedic (T&O) Department at Raigmore Hospital, Inverness. METHODS: We conducted a cross-sectional study with data collected over one year (2017). The number of tourists referred to T&O including patient demographics, country of origin, type of injury and their clinical outcome were recorded. A freedom of information (FOI) request to NHS Highland was sought to investigate associated costs incurred by tourists. RESULTS: 376 tourists accessed T&O services in 2017. Country of origin: 47 (12.5%) Scotland; 177 (47.1%) rest of UK; 74 (19.7%) EU; 45 (12.0%) non-EU. Highest referral month August (61), lowest referral month November (8). Injuries: 224 (59.6%) fracture; 62 (16.5%) soft tissue injury; 20 (5.3%) laceration. Commonest sites of injury were ankle, distal radius and finger. OUTCOMES: 28 (7.4%) Virtual clinic; 137 (36.4%) hospital admission; 193 (51.3%) advice to referring team and discharge; 13 (3.5%) direct discharge by T&O; 4 (1.1%) missing. No. of trauma cases booked: tourists 133 (9%), local population 1415 (91%). CONCLUSIONS: Tourists account for fewer than ten percent of the T&O surgical workload over one year with common injuries being fractures affecting the extremities. Seasonal variation was observed with more referrals occurring in the summer months. Just under half of tourists originated from outside the UK and EU. Health boards should consider increasing resources over the summer months to deal with expected increases in tourist numbers and should be able to recover the cost of treatment from the patient or their travel insurance companies directly at point of care.

Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose) polymerase inhibitor.

1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterised in vitro.2. Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalysed by CYP (fm,CYP) of 0.27 and 0.64, respectively. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3As (IC50, 3.55, 12.9, 5.42, 41.6, and 17.2-22.9 µM [2 substrates], respectively), but not CYP2B6 or CYP2C8 (>190 µM). No time-dependent inhibition of any CYP was observed. In cultured human hepatocytes, rucaparib showed concentration-dependent induction of CYP1A2 mRNA and downregulation of CYP3A4 and CYP2B6 mRNA. In transfected cells expressing drug transporters, rucaparib was a substrate for P-gp and BCRP, but not for OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Rucaparib inhibited P-gp and BCRP (IC50, 169 and 55 µM, respectively) and slightly inhibited OATP1B1, OATP1B3, OAT1, and OAT3 (66%, 58%, 58%, and 42% inhibition, respectively) at 300 µM. Rucaparib inhibited OCT1, OCT2, MATE1, and MATE2-K (IC50, 4.3, 31, 0.63, and 0.19 µM, respectively).3. DDI risk assessment using static models suggested potential CYP-related DDIs, with rucaparib as a perpetrator. Caution is advised when co-administering rucaparib with sensitive substrates of MATEs, OCT1, and OCT2.

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. FINDINGS: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4-22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4-6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16-0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9-16·2) versus 5·4 months (5·1-5·6; 0·32 [0·24-0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3-11·4) versus 5·4 months (5·3-5·5; 0·36 [0·30-0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). INTERPRETATION: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. FUNDING: Clovis Oncology.

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. METHODS: ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. FINDINGS: 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8-10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0-14·7) in the BRCA mutant subgroup, 5·7 months (5·3-7·6) in the LOH high subgroup, and 5·2 months (3·6-5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high (0·62, 0·42-0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. INTERPRETATION: In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. FUNDING: Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.

Quantitative imaging of airway liquid absorption in cystic fibrosis.

New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ∼ 50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.

Adsorption of naphthenic acids on high surface area activated carbons.

In oil sands mining extraction, water is an essential component; however, the processed water becomes contaminated through contact with the bitumen at high temperature, and a portion of it cannot be recycled and ends up in tailing ponds. The removal of naphthenic acids (NAs) from tailing pond water is crucial, as they are corrosive and toxic and provide a substrate for microbial activity that can give rise to methane, which is a potent greenhouse gas. In this study, the conversion of sawdust into an activated carbon (AC) that could be used to remove NAs from tailings water was studied. After producing biochar from sawdust by a slow-pyrolysis process, the biochar was physically activated using carbon dioxide (CO2) over a range of temperatures or prior to producing biochar, and the sawdust was chemically activated using phosphoric acid (H3PO4). The physically activated carbon had a lower surface area per gram than the chemically activated carbon. The physically produced ACs had a lower surface area per gram than chemically produced AC. In the adsorption tests with NAs, up to 35 mg of NAs was removed from the water per gram of AC. The chemically treated ACs showed better uptake, which can be attributed to its higher surface area and increased mesopore size when compared with the physically treated AC. Both the chemically produced and physically produced AC provided better uptake than the commercially AC.

Unequal staffing: A snapshot of nurse staffing in critical care units in New South Wales, Australia.

Abstract A growing body of research provides evidence of the link between nurse-to-patient ratios (NTPRs) and skill mix with adverse patient outcomes. This paper reports an investigation into nurse staffing patterns, skill mix and patient movement in critical care units in NSW, Australia. A 'snapshot' of staffing patterns and patient movement over 1 week in October 2012 was obtained by use of a cross-sectional design using retrospective survey and administrative data. A wide variation was found in NTPRs, skill mix and the number of nursing staff vacancies in coronary care and high dependency units. These variations suggest that the quality of patient care may vary between facilities in New South Wales.

The impact of pre-biopsy MRI and additional testing on prostate cancer screening outcomes: A rapid review.

Objective: This work aims to examine the latest evidence on the impact of pre-biopsy MRI, in addition to prostate-specific antigen (PSA) testing, on health outcomes and quality of life. Methods: We conducted a literature search including PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases, with a limited scan of (i) guidelines and (ii) references from trial reports, from January 2005 to 25th January 2023. Two independent reviewers selected randomised controlled trials (RCT) and cohort studies which met our inclusion criteria. Results: One hundred thirty-seven articles were identified, and seven trial articles were selected. Trial interventions were as follows: (i) PSA blood test, (ii) additional tests such as pre-biopsy multiparametric magnetic resonance imaging (mpMRI) and Biparametric MRI (bpMRI), and (iii) MRI targeted biopsy and standard biopsy. Compared with standard biopsy, MRI-based interventions led to increased detection of clinically significant cancers in three studies and decreased detection of clinically insignificant cancer (Gleason grade 3 + 3) in four studies. However, PROstate Magnetic resonance Imaging Study (PROMIS) and Stockholm3 with MRI (STHLM3-MRI) studies reported different trends depending on the scenario studied in PROMIS (MRI triage and MRI directed biopsy vs. MRI triage and standard biopsy) and thresholds used in STHLM3-MRI (≥0·11 and ≥0·15). MRI also helped 8%-49% of men avoid biopsy, in six out of seven studies, but not in STHLM3-MRI at ≥0.11. Interestingly, the proportion of men who experienced sepsis and UTI was low across studies. Conclusion: This review found that a combination of approaches, centred on the use of pre-biopsy MRI, may improve the detection of clinically significant cancers and reduce (i) the diagnosis of clinically insignificant cancers and (ii) unnecessary biopsies, compared with PSA testing and standard biopsy alone. However, the impact of such interventions on longer term outcomes such as prostate cancer-specific mortality has not yet been assessed.

Variation in harms and benefits of prostate-specific antigen screening for prostate cancer by socio-clinical risk factors: A rapid review.

Objective: To analyse the latest evidence on the relative harms and benefits of screening and diagnostic pathways with close examination of (i) men aged 50 years or older, (ii) men whose ethnicity places them at higher risk and (iii) men with a family history. Methods: We conducted a literature search using PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases and other sources, from January 1990 to 25 January 2023. Two independent reviewers selected for randomised controlled trials (RCTs) and cohort studies which met our inclusion criteria. Results: Twenty-eight articles were selected, from six trials, including the Göteborg trial-reported separately from European Randomised Study of Screening for Prostate Cancer (ERSPC). Prostate-specific antigen (PSA)-based screening led to the increased detection of low-grade cancer and reduction of advanced/metastatic disease but had contradictory effects on prostate cancer (PCa)-specific mortality (no difference or reduced), possibly due to issues of contamination or compliance. Screening men from a relatively young age (50-55) reduced risk of PCa-specific mortality in a subanalysis of an 18-year follow-up study and in a 17-year cohort study from the main Göteborg trial. Moreover, one Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial analysis reported a trend of reduced risk of PCa-specific mortality for men with a family history who were screened. [Correction added on 05 March 2024, after first online publication: "Cancer Screening Trial" has been added to the preceding sentence.] However, we did not find relevant studies for ethnicity. Conclusion: Under current UK practice, the choice to conduct a PSA test relies on a shared decision-making approach guided by known risk factors. However, we found there was a lack of strong evidence on the harms and benefits of PSA screening by socio-clinical risk factors and suggest further research is required to understand the long-term impact of screening on high-risk populations in the current diagnostic setting.

Deep learning-based ultrasound auto-segmentation of the prostate with brachytherapy implanted needles.

BACKGROUND: Accurate segmentation of the clinical target volume (CTV) corresponding to the prostate with or without proximal seminal vesicles is required on transrectal ultrasound (TRUS) images during prostate brachytherapy procedures. Implanted needles cause artifacts that may make this task difficult and time-consuming. Thus, previous studies have focused on the simpler problem of segmentation in the absence of needles at the cost of reduced clinical utility. PURPOSE: To use a convolutional neural network (CNN) algorithm for segmentation of the prostatic CTV in TRUS images post-needle insertion obtained from prostate brachytherapy procedures to better meet the demands of the clinical procedure. METHODS: A dataset consisting of 144 3-dimensional (3D) TRUS images with implanted metal brachytherapy needles and associated manual CTV segmentations was used for training a 2-dimensional (2D) U-Net CNN using a Dice Similarity Coefficient (DSC) loss function. These were split by patient, with 119 used for training and 25 reserved for testing. The 3D TRUS training images were resliced at radial (around the axis normal to the coronal plane) and oblique angles through the center of the 3D image, as well as axial, coronal, and sagittal planes to obtain 3689 2D TRUS images and masks for training. The network generated boundary predictions on 300 2D TRUS images obtained from reslicing each of the 25 3D TRUS images used for testing into 12 radial slices (15° apart), which were then reconstructed into 3D surfaces. Performance metrics included DSC, recall, precision, unsigned and signed volume percentage differences (VPD/sVPD), mean surface distance (MSD), and Hausdorff distance (HD). In addition, we studied whether providing algorithm-predicted boundaries to the physicians and allowing modifications increased the agreement between physicians. This was performed by providing a subset of 3D TRUS images of five patients to five physicians who segmented the CTV using clinical software and repeated this at least 1 week apart. The five physicians were given the algorithm boundary predictions and allowed to modify them, and the resulting inter- and intra-physician variability was evaluated. RESULTS: Median DSC, recall, precision, VPD, sVPD, MSD, and HD of the 3D-reconstructed algorithm segmentations were 87.2 [84.1, 88.8]%, 89.0 [86.3, 92.4]%, 86.6 [78.5, 90.8]%, 10.3 [4.5, 18.4]%, 2.0 [-4.5, 18.4]%, 1.6 [1.2, 2.0] mm, and 6.0 [5.3, 8.0] mm, respectively. Segmentation time for a set of 12 2D radial images was 2.46 [2.44, 2.48] s. With and without U-Net starting points, the intra-physician median DSCs were 97.0 [96.3, 97.8]%, and 94.4 [92.5, 95.4]% (p < 0.0001), respectively, while the inter-physician median DSCs were 94.8 [93.3, 96.8]% and 90.2 [88.7, 92.1]%, respectively (p < 0.0001). The median segmentation time for physicians, with and without U-Net-generated CTV boundaries, were 257.5 [211.8, 300.0] s and 288.0 [232.0, 333.5] s, respectively (p = 0.1034). CONCLUSIONS: Our algorithm performed at a level similar to physicians in a fraction of the time. The use of algorithm-generated boundaries as a starting point and allowing modifications reduced physician variability, although it did not significantly reduce the time compared to manual segmentations.

Optimising the use of the prostate- specific antigen blood test in asymptomatic men for early prostate cancer detection in primary care: report from a UK clinical consensus.

BACKGROUND: Screening is not recommended for prostate cancer in the UK. Asymptomatic men aged ≥50 years can request a prostate-specific antigen (PSA) test following counselling on potential harms and benefits. There are areas of clinical uncertainty among GPs, resulting in the content and quality of counselling varying. AIM: To produce a consensus that can influence guidelines for UK primary care on the optimal use of the PSA test in asymptomatic men for early prostate cancer detection. DESIGN AND SETTING: Prostate Cancer UK facilitated a RAND/UCLA consensus. METHOD: Statements covering five topics were developed with a subgroup of experts. A panel of 15 experts in prostate cancer scored (round one) statements on a scale of one (strongly disagree) to nine (strongly agree). Panellists met to discuss statements before rescoring (round two). A lived experience panel of seven men scored a subset of statements with outcomes fed into the main panel. RESULTS: Of the initial 94 statements reviewed by the expert panel, a final 48/85 (56%) achieved consensus. In the absence of screening, there was consensus on proactive approaches to initiate discussions about the PSA test with men who were at higher-than-average risk. CONCLUSION: Improvements in the prostate cancer diagnostic pathway may have reduced some of the harms associated with PSA testing; however, several areas of uncertainty remain in relation to screening, including optimal PSA thresholds for referral and intervals for retesting. There is consensus on proactive approaches to testing in higher-than-average risk groups. This should prompt a review of current guidelines.

Experimental and modeling study of residual liquid recovery from spent sand in bitumen extraction processes from oil sands.

Disposing solid residue with high liquid content into the environment may impact the immediate ecosystem and its surroundings. In bitumen recovery process from oil sands, it is environmentally and economically desirable to effectively recover as much of the liquid trapped in the spent solids as possible, prior to releasing it into the environment. An experiment was designed to investigate the effect of capillary force to enhance liquid recovery by using a thin, semipermeable layer as the membrane. The results indicate that by employing a membrane at the outlet, and pressurizing the air above the sand bed, the average liquid saturation can be decreased by 50%; however, the maximum pressure applied is restricted by the physical characteristics of the membrane. A mathematical model is developed to predict the liquid saturation profile along the sand pack during transient and steady-state conditions, and results are validated against measured average saturation using two different sand types. Results suggest that more liquid can be recovered from the spent sand bed by increasing the height of the bed; however, the required time to achieve the maximum recovery is increased as well. This method can be applied to reduce the liquid content of spent sand from any process before it is disposed of, thereby reducing possible hazards which may affect the environment.

Cultural safety: a vital element for nursing ethics.

This paper argues that the globalisation of nursing and the internationalisation of nursing education have lead to Western values being embedded into nursing curricula in nations where the cultural values and beliefs may be based in quite different philosophies. It argues for critical examination of assumptions underpinning ethics education in nursing and proposes that the principles of cultural safety need to be incorporated into ethics education to create a culturally safe ethic for both nurses and patients in a multicultural healthcare environment.

Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. FINDINGS: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. INTERPRETATION: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. FUNDING: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.

The role of Gender in Operative Autonomy in orthopaedic Surgical Trainees (GOAST).

Aims: Global literature suggests that female surgical trainees have lower rates of independent operating (operative autonomy) than their male counterparts. The objective of this study was to identify any association between gender and lead/independent operating in speciality orthopaedic trainees within the UK national training programme. Methods: This was a retrospective case-control study using electronic surgical logbook data from 2009 to 2021 for 274 UK orthopaedic trainees. Total operative numbers and level of supervision were compared between male and female trainees, with correction for less than full-time training (LTFT), prior experience, and time out during training (OOP). The primary outcome was the percentage of cases undertaken as lead surgeon (supervised and unsupervised) by UK orthopaedic trainees by gender. Results: All participants gave permission for their data to be used. In total, 274 UK orthopaedic trainees submitted data (65% men (n = 177) and 33% women (n = 91)), with a total of 285,915 surgical procedures logged over 1,364 trainee-years. Males were lead surgeon (under supervision) on 3% more cases than females (61% (115,948/189,378) to 58% (50,285/86,375), respectively; p < 0.001), and independent operator (unsupervised) on 1% more cases. A similar trend of higher operative numbers in male trainees was seen for senior (ST6 to 8) trainees (+5% and +1%; p < 0.001), those with no time OOP (+6% and +8%; p < 0.001), and those with orthopaedic experience prior to orthopaedic specialty training (+7% and +3% for lead surgeon and independent operator, respectively; p < 0.001). The gender difference was less marked for those on LTFT training, those who took time OOP, and those with no prior orthopaedic experience. Conclusion: This study showed that males perform 3% more cases as the lead surgeon than females during UK orthopaedic training (p < 0.001). This may be due to differences in how cases are recorded, but must engender further research to ensure that all surgeons are treated equitably during their training.

BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

BRCA1 splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of BRCA1 exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs), predicted in silico to drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots and BRCA1 minigene modelling. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. We demonstrate that SSMs drive BRCA1 exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.