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Background: In a previously reported Phase I trial, we observed therapy-associated declines in circulating myeloid-derived suppressor cells (MDSCs) with the administration of white button mushroom (WBM) tablets in prostate cancer (PCa) patients. These observations led us to hypothesise that WBM could mitigate PCa progression by suppressing MDSCs., Methods: We performed bidirectional translational research to examine the immunomodulatory effects of WBM consumption in both syngeneic murine PCa models and patients with PCa participating in an ongoing randomised Phase II trial (NCT04519879)., Results: In murine models, WBM treatment significantly suppressed tumour growth with a reduction in both the number and function of MDSCs, which in turn promoted antitumour immune responses mediated by T cells and natural killer (NK) cells. In patients, after consumption of WBM tablets for 3 months, we observed a decline in circulating polymorphonuclear MDSCs (PMN-MDSCs), along with an increase in cytotoxic CD8 + T and NK cells. Furthermore, single immune cell profiling of peripheral blood from WBM-treated patients showed suppressed STAT3/IRF1 and TGFβ signalling in circulating PMN-MDSCs. Subclusters of PMN-MDSCs presented transcriptional profiles associated with responsiveness to fungi, neutrophil chemotaxis, leukocyte aggregation, and regulation of inflammatory response. Finally, in mouse models of PCa, we found that WBM consumption enhanced the anticancer activity of anti-PD-1 antibodies, indicating that WBM may be used as an adjuvant therapy with immune checkpoint inhibitors., Conclusion: Our results from PCa murine models and patients provide mechanistic insights into the immunomodulatory effects of WBM and provide a scientific foundation for WBM as a nutraceutical intervention to delay or prevent PCa progression., Highlights: White button mushroom (WBM) treatment resulted in a reduction in pro-tumoural MDSCs, notably polymorphonuclear MDSCs (PMN-MDSCs), along with activation of anti-tumoural T and NK cells. Human single immune cell gene expression profiling shed light on the molecular alterations induced by WBM, specifically on PMN-MDSCs. A proof-of-concept study combining WBM with PD-1 blockade in murine models revealed an additive effect on tumour regression and survival outcomes, highlighting the clinical relevance of WBM in cancer management., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background/objectives: Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer., Subjects/methods: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science., Results/conclusion: We argue for the widespread adoption of germline testing in all patients with prostate cancer and for somatic mutations testing in patients at the time of recurrent/metastatic disease. In this first part, we review how genomic testing is performed. We also review how to overcome certain barriers to integrate genetic and biomarker testing into clinical practice., (© 2024. The Author(s).)

Background/objectives: Unfortunately, not all metastatic castration-resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing for prostate cancer., Subjects/methods: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science., Results/conclusions: In this second part, we highlight how genetic testing can lead to improved, life-prolonging mCRPC therapeutic strategies based on a review of the recent phase III trials and subsequent regulatory approvals for PARP inhibitors in mCRPC., (© 2024. The Author(s).)

Background: Circulating biomarkers of bone metabolism are significantly associated with overall survival (OS) in men with advanced prostate cancer. In the SWOG S1216 phase III trial, we showed that elevated bone biomarkers are significantly associated with an increased risk of death in hormone-sensitive prostate cancer (HSPC) regardless of the status of bone metastases, identifying three risk groups with differential OS outcomes based on bone biomarker status. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal metastases as part of a planned subset analysis of S1216., Methods: Bone resorption [C-telopeptide (CTx); Pyridinoline (PYD)] and bone formation markers [C-terminal collagen propeptide (CICP); bone alkaline phosphatase (BAP)] were assessed in blood from men with bone metastatic HSPC. Patients were randomly divided into training (n = 238) and validation (n = 475) sets. In the training set, recursive partitioning that maximizes discrimination of OS was used to identify the dichotomous cut-point for each biomarker and for a combination of biomarker split points to define prognostic groups. In the validation set, Cox proportional hazards models were used to assess the impact of biomarkers on OS, adjusted for patient and tumor characteristics., Results: Of 1279 men, 713 had both baseline bone metastases and evaluable bone biomarkers. Patient characteristics were similar between the overall population and the subset with bone metastases. Elevated levels of CICP, CTX, and PYD were strongly prognostic for OS. Hazard ratios (95% CI) for OS adjusted for treatment arm and baseline clinical variables were: BAP-1.31 (0.93, 1.84), p = 0.12; CICP-1.58 (1.09, 2.29), p < 0.02; CTx - 1.55 (1.12, 2.15), p = 0.008; and PYD-1.66 (1.27, 2.217), p = 0.0002. There was no evidence of interaction between elevated biomarkers and treatment (all p > 0.2). Recursive partitioning algorithms identified four groups of patients with differential OS outcomes based on bone biomarkers, adjusted for baseline clinical variables, with median OS ranging from 2.3 years (highest risk group) to 7.5 years (lowest risk group)., Conclusions: In this planned S1216 subset analysis of men with HSPC and bone metastases, elevated serum markers of bone metabolism were significantly associated with worse OS. Bone biomarker levels alone and in combination with patient and tumor characteristics identify unique subsets of men with differential OS outcomes., Gov Identifier: NCT01809691., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Ukraine has one of the lowest COVID-19 vaccination rates in Europe. This may pose a significant epidemiological risk in the context of the refugee crisis and the fact that, since 2020, SARS-CoV-2 has been spreading and changing globally., Objective: To evaluate determinants of vaccination decision making among Ukrainian female migrants (UFMs)., Methods: A qualitative study with 45 UFMs was conducted between December 2021 and January 2022. UFMs, from 2 Polish provinces, differing in age, education and length of stay were invited with the use of the snowball technique. Using a semi-structured topic guide, eight focus groups were conducted in person, recorded and transcribed. Thematic, qualitative analysis was made; key themes which emerged from the data (with the help of the Working Group Determinants of Vaccine Hesitancy Matrix), were related to contextual, individual/group and contextual vaccine/vaccination-specific influences., Results: Mothers were found to be playing a crucial role in children and adolescent COVID-19 vaccine decision-making process. Universal trust in the Polish healthcare system and vaccination procedures, employer requirements and willingness to preserve jobs, desire to get back to normal and social influences were paramount prerequisites to let UFMs make a decision to get vaccinated. However, COVID-19 vaccines also faced backlash among UFMs. Negative experiences with vaccines provided in Ukraine, doubts about the rapid vaccine development, combined with lack of confidence in vaccine safety, specifically regarding child vaccination, might have a bearing on UFMs' decision about declining COVID-19 vaccine while on migration. Discrimination through HCWs during vaccination visits was also reported. Corrupted Ukrainian healthcare system, which facilitates proof forgery regarding vaccination certificates, could act as a negative influencer of UFMs' vaccine decision-making., Conclusion: The results provide the novel information, expressed in economic UFMs' own words. Findings show that influencers of the decision-making process regarding the COVID-19 vaccination are complex and polarized; elements of hesitancy may persist after migration. Any continuation of UFMs' vaccination with COVID-19 vaccine should be subject to designing accessible information to address modifiable demotivators of the vaccine decision-making process identified in this study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ganczak, Kalinowski, Twardowski, Osicka, Pasek, Duda-Duma, Vervoort, Edelstein and Kowalska.)

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Background: Bone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC)., Objective: Bone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel., Design, Setting, and Participants: Patients were randomly divided into training (n = 316) and validation (n = 633) sets. Recursive partitioning and Cox proportional hazard models were employed., Outcome Measurements and Statistical Analysis: Bone resorption (C-telopeptide and pyridinoline) and bone formation markers (C-terminal collagen propeptide and bone alkaline phosphatase) were assessed from patient sera., Results and Limitations: Of 1279 men, 949 had evaluable baseline bone biomarkers. Optimal cutoffs were identified to define elevated levels of each of the four biomarkers (all p < 0.05) that were associated with worse OS. After adjusting for clinical risk factors in the validation set, elevated bone biomarkers were statistically significantly associated with an increased risk of death (hazard ratios ranging from 1.37 to 1.92). Recursive partitioning algorithms applied to the training set identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 yr, respectively) based on combinations of bone biomarkers. These results were confirmed in the validation set., Conclusions: In men with HSPC initiating androgen deprivation therapy, bone biomarkers are strongly and independently prognostic for OS. Bone biomarker levels alone or in combination with clinical covariates identify unique subsets of men with differential OS outcomes. These results validate the clinical value of bone biomarker assessment in the HSPC state, extending bone biomarker utility beyond the castration-resistant state., Patient Summary: In men with newly diagnosed metastatic prostate cancer, high levels of bone turnover biomarkers are associated with a shorter lifespan., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: SPOTLIGHT (NCT04186845) evaluated diagnostic performance and safety of radiohybrid 18 F-rhPSMA-7.3, a novel high-affinity positron emission tomography radiopharmaceutical., Materials and Methods: Men with prostate cancer recurrence underwent positron emission tomography/CT 50-70 minutes after intravenous administration of 296±20% MBq 18 F-rhPSMA-7.3. To assess the coprimary end points (verified detection rate and combined region-level positive predictive value), 3 blinded, independent central readers evaluated the scans. Verified detection rate is equivalent to the overall detection rate × positive predictive value. Standard of truth was established for each patient using histopathology or confirmatory imaging. Statistical thresholds (lower bounds of the confidence intervals) of 36.5% and 62.5% were prespecified for verified detection rate and combined region-level positive predictive value, respectively . Additional end points included detection rate, verified detection rate, and combined region-level positive predictive value in patients with histopathology standard of truth, and safety., Results: The overall 18 F-rhPSMA-7.3 detection rate among all 389 patients with an evaluable scan was 83% (majority read). Among the 366 patients (median prostate-specific antigen 1.27 ng/mL) for whom a standard of truth (histopathology [n=69]/confirmatory imaging only [n=297]) was available, verified detection rate ranged from 51% (95% CI 46.1-56.6) to 54% (95% CI 48.8-59.3), exceeding the prespecified statistical threshold. Combined region-level positive predictive value ranged from 46% (95% CI 42.0-50.3) to 60% (95% CI 55.1-65.5) across the readers, not meeting the threshold. In the subset of patients with histopathology standard of truth, the verified detection rate and combined region-level positive predictive value were both above the prespecified thresholds (majority read, 81% [95% CI 69.9-89.6] and 72% [95% CI 62.5-80.7], respectively). No significant safety concerns were identified., Conclusions: 18 F-rhPSMA-7.3 offers a clinically meaningful verified detection rate for localization of recurrent prostate cancer. Despite missing the coprimary end point of combined region-level positive predictive value, the totality of the data support the potential clinical utility of 18 F-rhPSMA-7.3.

The paper presents probabilistic aspects of diagnostics of grinding processes with consideration of metrological aspects of evaluation of topography of machined surfaces and selected problems of assessment of machining accuracy. The processes of creating the geometric structure of the ground surface are described. It was pointed out that the distribution of features important for process diagnostics depends on the mechanism of cumulative effects of random disturbances. Usually, there is a multiplicative mechanism or an additive mechanism of the component vectors of relative displacements of the tool and workpiece. The paper describes a method for determining the classification ability of specific parameters used to evaluate stereometric features of ground surfaces. It is shown that the ability to differentiate the geometric structure of a certain set of surfaces using a selected parameter depends on the geometric mean of the differences in normalized and sorted, consecutive values of this parameter. A methodology is presented for evaluating the ability of various parameters to distinguish different geometric structures of surfaces. Further, on the basis of analyses of a number of grinding processes, a methodology was formulated for proceeding leading to a comprehensive evaluation of machining accuracy and forecasting its results. It was taken into account that in forecasting the accuracy of grinding, it is necessary to determine the deviations, arising under the conditions of multiplicative interaction of the effects of various causes of inaccuracy. Examples are given of processes in which, due to the deformation of the technological system, dependent on the position of the zone and machining force, varying temperature fields and tool wear, the distributions of dimensional deviations are not the realization of stationary processes. It was emphasized that on the basis of the characteristics of the dispersion of the deviation value in the sum set of elements, it is not possible to infer its causes. Only the determination of the "instantaneous" values of the deviation dispersion parameters allows a more complete diagnosis of the process.

Dexmedetomidine, a central α-2 agonist, is used for procedural sedation and for conscious sedation influences on heart rate and blood pressure. Authors verified whether it is possible to predict bradycardia and hypotension with the use of heart rate variability (HRV) analysis for an autonomic nervous system (ANS) activity assessment. The study included adult patients of both sexes with an ASA score of I or II scheduled for ophthalmic surgery to be performed under sedation. The loading dose of dexmedetomidine was followed by a 15 min infusion of the maintenance dose. The frequency domain heart rate variability parameters from the 5-min Holter electrocardiogram recordings before dexmedetomidine administration were used for the analysis. The statistical analysis also included pre-drug heart rate and blood pressure as well as patient age and sex. The data from 62 patients were analysed. There was no relationship between the decrease in heart rate (42% of cases) and initial HRV parameters, haemodynamic parameters or sex and age of patients. In multivariate analysis, the only risk factor for a decrease in mean arterial pressure (MAP) > 15% from the pre-drug value (39% of cases) was the systolic blood pressure before dexmedetomidine administration as well as for a >15% decrease in MAP sustained at more than one consecutive time point (27% of cases). The initial condition of the ANS did not correlate with the incidence of bradycardia or hypotension; HRV analysis was not helpful in predicting the abovementioned side effects of dexmedetomidine.

The article presents the technological aspects of the diagnostics of grinding processes. The main features of the grinding process and their importance in diagnostic issues are discussed. Selected issues of research and assessment of the condition of the active surface of grinding wheels are presented. The authors pointed out that the parameters used to assess the topography of the ground surfaces do not have sufficient possibilities to differentiate the surface condition of the grinding wheels. This publication draws attention to the possibility of using new dedicated parameters to assess the properties of the grinding wheel surface. These parameters have a high ability to differentiate changes occurring as a result of the abrasion of grain vertices, their chipping or loading of the grinding wheel surface. The methodology of assessing the processes of abrasive grain wear and changes in the shape and dimensions of the grinding wheel, taking into account the probabilistic features of the grinding process, was formulated. The directions for the development of abrasive tools are presented, pointing to hybrid tools with a multi-phase structure, modified by additions of abrasive aggregates. A new research direction has also been formulated on the use of additive technology to produce specialised abrasive tools, including those with built-in process sensors.

Purpose: External beam radiation therapy (EBRT) to oligometastases may improve outcomes in patients with oligometastatic hormone-sensitive prostate cancer (oHSPC). Follow-up on this cohort has been limited to <5 years and prospective data on de novo patients with oHSPC are lacking. We reviewed the long-term outcomes of patients with oHSPC treated with EBRT and androgen deprivation therapy on a prospective trial., Methods and Materials: From 2006 to 2011, patients with oHSPC with 1 to 5 metastases received 36 weeks of androgen deprivation therapy (luteinizing hormone-releasing hormone agonist + bicalutamide) and up to 53 Gy to all visible metastases. When indicated, the primary tumor or prostate bed was treated with EBRT up to 78 or 66 Gy, respectively., Results: Twenty-nine patients were treated: 15 de novo, 14 oligorecurrent, and 21 patients (72.4%) had bone metastases. Median number of metastases per patient was 1 (range, 1-5). EBRT was administered to 52 lesions (38 bone, 12 pelvic lymph nodes [LNs], 2 nonpelvic LNs) up to 53 Gy (range, 47-66). Median follow-up was 9.9 years (years; range, 0.2-14.4). Median overall survival was 9.7 years (95% confidence interval [CI], 5.8-not reached). Median progression-free survival was 1.9 years (95% CI, 1.6-2.2). Patients who presented with prostate cancer-defined de novo metastases had significantly improved (P = .04) median progression-free survival (2.0 years; 95% CI, 1.3-6.0) compared with oligorecurrent patients (1.8 years; 95% CI, 1.0-2.0). Patients who presented with LN-only metastases had numerically improved (P = .13) median PFS (5.8 years; 95% CI, 1.2-not reached) compared with patients with bony metastases (1.8 years; 95% CI, 1.3-2.0). At last follow-up, 17 patients (58.6%) had local control of all EBRT-treated metastases. The metastases that locally progressed had previously been controlled for median 3.5 years (range, 1.7-10.5)., Conclusions: Our results compare favorably with other reported studies of patients with oHSPC and provide new insights into their long-term outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Ophthalmic surgery is assumed to be safe, but some operations require general anaesthesia which is associated with a number of potential complications. In addition, adverse cardiovascular symptoms, such as severe slowing of the heart rate and, in some cases, cardiac arrest may occur due to the surgical technique. The aim of this study was to determine whether it is possible to predict the occurrence of oculocardiac reflex (OCR) based on heart rate variability (HRV) analysis for autonomic nervous system (ANS) activity assessment measured prior to the induction of anaesthesia and immediately before eyeball traction., Methods: Fifty-two adults of both sexes (age range 18-65 years) with American Society of Anesthesiologists (ASA) physical status class 1 and 2 were enrolled in this study. All patients had underwent episcleral buckling under general anaesthesia. High-frequency (HF) changes in HRV are thought to reflect parasympathetic impulse transmission, whereas low-frequency (LF) changes reflect both sympathetic and parasympathetic activity. However, in practice, LF changes can be considered to reflect sympathetic changes. Thus, the LF/HF ratio reflects the actual balance between sympathetic and parasympathetic activity. Based on that, frequency domain HRV parameters from 5-min Holter electrocardiogram recordings before anaesthesia induction and before eyeball traction were used for the analysis. The statistical analysis also included patient age, sex, ASA status and preanaesthesia and premanoeuvre heart rate and blood pressure., Results: Data from 42 patients were analysed. Oculocardiac reflex was observed in 32 patients (76.2%). No difference was found in the analysed parameters between patients with and without oculocardiac reflex. There was no relationship between the incidence of the OCR and the analysed parameters., Conclusion: The prediction of OCR based on initial ANS tone was not possible, and the initial heart rate, blood pressure, age, sex, and ASA status were not helpful for the identification of patients at risk of this reflex., Trial Registration: ClinicalTrials.gov identifier no.: NCT01714362., (© 2022. The Author(s).)

Background: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction., Methods: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28., Results: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event., Conclusions: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.)., (Copyright © 2022 Massachusetts Medical Society.)

The dynamic development of new technologies enables the optimal computer technique choice to improve the required quality in today's manufacturing industries. One of the methods of improving the determining process is machine learning. This paper compares different intelligent system methods to identify the tool wear during the turning of gray cast-iron EN-GJL-250 using carbide cutting inserts. During these studies, the experimental investigation was conducted with three various cutting speeds vc (216, 314, and 433 m/min) and the exact value of depth of cut a p and federate f . Furthermore, based on the vibration acceleration signals, appropriate measures were developed that were correlated with the tool condition. In this work, machine learning methods were used to predict tool condition; therefore, two tool classes were proposed, namely usable and unsuitable, and tool corner wear VBc = 0.3 mm was assumed as a wear criterium. The diagnostic measures based on acceleration vibration signals were selected as input to the models. Additionally, the assessment of significant features in the division into usable and unsuitable class was caried out. Finally, this study evaluated chosen methods (classification and regression tree, induced fuzzy rules, and artificial neural network) and selected the most effective model.

Background: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor., Objective: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database., Methods: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses., Results: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status., Conclusions: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase., International Registered Report Identifier (irrid): DERR1-10.2196/36261., (©Neill KJ Adhikari, Ruxandra Pinto, Andrew G Day, Marie-Hélène Masse, Julie Ménard, Sheila Sprague, Djillali Annane, Yaseen M Arabi, Marie-Claude Battista, Dian Cohen, Deborah J Cook, Gordon H Guyatt, Daren K Heyland, Salmaan Kanji, Shay P McGuinness, Rachael L Parke, Bharath Kumar Tirupakuzhi Vijayaraghavan, Emmanuel Charbonney, Michaël Chassé, Lorenzo Del Sorbo, Demetrios James Kutsogiannis, François Lauzier, Rémi Leblanc, David M Maslove, Sangeeta Mehta, Armand Mekontso Dessap, Tina S Mele, Bram Rochwerg, Oleksa G Rewa, Jason Shahin, Pawel Twardowski, Paul Jeffrey Young, François Lamontagne, LOVIT Investigators. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 20.05.2022.)

Pectus excavatum (PE) is one of the most frequently reported chest deformities. However, limited studies are available with regard to its CT scan findings in cats. In the present research computed tomographic images of the thoraxes of 14 cats diagnosed with PE has been reviewed. This is one of the first studies exploring the use of CT to characterise PE in animals. The aim of this study was to present characteristic CT features of PE in cats. The introduction of new criteria for better assessing thoracic wall deformity-a correction index (CI) and an asymmetry index (AI)-was also proposed. The study revealed a high variety of morphological features of PE in cats. It was demonstrated that among the 14 cats: cranial PE (an atypical location) occurred in seven cats while seven cats had typical (caudal) PE, long PE occurred in five cats, while short PE had nine cats. Of the 14 cats included in the study eight showed symmetric PE, and asymmetric PE was found insix. Thoracic asymmetry was found in six cats. Six cats had sternal torsion. Based on the Vertebral Index moderate or severe PE was revealed in 11 animals. In the group of cats studied the CI ranged from 12.20 to 32.11. The magnitude of AI did not exceed 10% in any of the cats studied. The study confirmed statistically significant differences in the CI values between groups of cats with different degrees of PE severity (p = 0.02). CT examination showed many PE features that have not been discussed so far. The main benefit of CT examination is its ability to reveal asymmetric PE, thoracic asymmetry and sternal torsion. CI and AI provided a clinically useful tool to quantify thoracic wall deformity in order to obtain comparable results between cats with PE., Competing Interests: The authors have declared that no competing interests exist.

Waveguide based optical combiners for augmented reality (AR) glasses are integrating several surface relief gratings (SRG) whose pitch sizes can be as small as 200 nm for the blue wavelength. All SRG components exploit the first diffraction order to couple in and out or to deviate the light. We present SRG using higher diffraction orders featuring over-wavelength pitch sizes. Our gratings use the edge wave (EW) diffraction phenomenon to steer light in the preferred far field direction.

Intra-operatively placed cryopreserved placental tissue allograft (CPTA) has shown promise in expediting the recovery urinary continence (UC) following robot-assisted radical prostatectomy (RARP). In this retrospective review of a prospectively maintained single-surgeon, single-institution RARP database, we compare three groups of patients: historical controls (C; N = 183 men) that received no allograft versus two different CPTA products (total CPTA N = 162 [A1 N = 81; A2 N = 81]). The CPTA product was intra-operatively placed as an onlay over the area of the neurovascular bundles during RARP. CPTA cases had significantly faster median time to UC (A1 = 1.4 months; A2 = 1.45 months) versus controls (1.64 months), p = 0.01. On multivariable analysis, use of A1 (HR 1.55, 95% CI [1.14-2.09], p = 0.005) and use of A2 (HR 1.53, CI [1.11-2.11], p = 0.01) were significantly associated with quicker return of UC. Older age (HR 0.97, CI [0.96-0.99], p = 0.001) and non-organ-confined clinical stage (HR 0.51, CI [0.26-1.0] p = 0.05), were significantly associated with slower return of UC. In a propensity score-matched analysis of 77 CPTA patients with sufficient follow-up versus controls, there was significantly less biochemical recurrence (BCR; p = 0.01). Our study indicates that CPTA use appears to accelerate time to UC in age- and performance status-matched men undergoing RARP without increased risk of BCR., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd. part of Springer Nature.)

Inconel 718 is a material often used in the aerospace and marine industries due to its properties and ability to work in harsh environments. However, its machining is difficult, and therefore methods are sought to facilitate this process. One of such methods is turn-milling. This paper presents the forces during orthogonal turn-milling of the Inconel 718 alloy. In this machining, both the side and the end edge are involved in the material removal, which causes the tool to be more loaded. The forces during turn-milling can be up to 50% higher than in the case of milling, which causes damage to the tool. Tool wear during machining has a significant impact on the values of the cutting force proportional coefficients. In the case of the tested material, it is important to take it into account when creating cutting force models.

In today's developing aircraft and automotive industry, extremely durable and wear-resistant materials, especially in high temperatures, are applied. Due to this practical approach, conventional materials have been superseded by composite materials. In recent years, the application of metal matrix composites has become evident in industry 4.0. A study has been performed to analyze the surface roughness of aluminum matrix composites named Duralcan ® during end milling. Two roughness surface parameters have been selected: arithmetical mean roughness value Ra and mean roughness depth Rz regarding the variable cutting speed. Due to the classification of aluminum matrix composites as hard-to-cut materials concerning excessive tool wear, this paper describes the possibility of surface roughness prediction using machine learning algorithms. In order to find the best algorithm, Classification and Regression Tree (CART) and pattern recognition models based on artificial neural networks (ANN) have been compared. By following the obtained models, the experiment shows the effectiveness of roughness prediction based on verification models. Based on experimental research, the authors obtained the coefficient R 2 for the CART model 0.91 and the mean square error for the model ANN 0.11.

The paper presents the possibilities of a high-speed camera in recording displacements of thin-walled workpiece during milling made of aluminum alloys, which allowed for an analysis in which it was compared to other methods of testing the deflection of such elements. The tests were carried out during peripheral milling with constant cutting parameters. Deflection of thin-walled workpiece due to cutting forces was measured using a high-speed camera and a laser displacement sensor. Additionally, the experimental results were compared with the theoretical results obtained with the use of the finite element method. The research proved the effectiveness of the use of high-speed camera in diagnostics of thin-walled workpieces during milling with an accuracy of up to 11% compared to measurements made with a displacement laser sensor.

Background: Until the advent of T cell check point inhibitors standard second-line therapy for patients with metastatic urothelial cancer (mUC) was undefined. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of tumor models including modulation of apoptosis in bladder cancer cell lines. We evaluated the efficacy and toxicity of the HDACi vorinostat in patients with mUC failing first-line platinum-based therapy either in the adjuvant/neoadjuvant setting or for recurrent/advanced disease., Methods: Vorinostat was given orally 200 mg twice daily continuously until progression or unacceptable toxicity. The primary end point was RECIST response rate (RR); a RR > 20% was deemed interesting in a 2-stage design requiring one response in the first 12 patients to proceed to 2nd stage for a total of 37 subjects. CT or MRI scan imaging occurred every 6 weeks., Results: Fourteen patients were accrued characterized by: median age 66 years (43-84); Caucasian (79%); males (86%); and Karnofsky performance status ≥90 (50%). Accrual was terminated in the first stage as no responses were observed. Best response was stable disease (3 patients). Progression was observed in 8 patients. Two patients came off therapy prior to re-imaging and a 3rd patient died while on treatment and was not assessed for response. Median number of cycles was 2 (range 1-11). Median disease-free survival and overall survival times were 1.1 (0.8, 2.1) & 3.2 (2.1, 14.5) months, respectively. Toxicities were predominantly cytopenias and thrombocytopenic bleeding. Two pts. had grade 5 toxicity unlikely related to treatment. Two pts. had grade 4 and 6 had grade 3 toxicities observed. Two patients with stable disease remained on therapy for 6+ cycles., Conclusions: Vorinostat on this dose-schedule had limited efficacy and significant toxicity resulting in a unfavorable risk:benefit ratio in patients with mUC. NCT00363883.

Purpose: Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in a RB and cyclin D-dependent manner in preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor and cell cycle with palbociclib would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC)., Patients and Methods: A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD + palbociclib. Primary endpoint was PSA response rate (RR) after 28 weeks of therapy. Secondary endpoints included safety, PSA, and clinical progression-free survival (PFS), as well as PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various timepoints., Results: A total of 72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. A total of 62 of 64 (97%) retained RB expression. A total of 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common grade 3/4 adverse event in Arm 2. Eighty percent of patients (Arm 1: 16/20, Arm 2: 32/40; P = 0.87) met primary PSA endpoint ≤4 ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2, respectively ( P = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively ( P = 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS., Conclusions: Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome., (©2021 American Association for Cancer Research.)

Background: The authors report a case of keratinized squamous cell carcinoma (SCC) in a 14-year-old dog with extensive cranial bone invasion. To our knowledge, this is the first description of such a case of cranial keratinized SCC with aggressive generalized osteolysis described in a dog., Case Presentation: The 14-year-old dog was referred for radiological examination with suspicion of head trauma with clinical signs of head deformation, exophthalmos and nasal discharge. The skull radiographs showed a large osteolytic defect of the frontal bone and parietal bone in the region of the external sagittal crest. Findings from the skull CT scan included generalized osteolysis in the region of parietal bone, frontal bones, maxilla on the right side and the nasal bone including the dorsal nasal concha. In the area of bone loss, new soft tissue formation with multifocal foci of mineralization was visible. The ultrasound examination revealed hypoechogenic changes with hyperechoic foci consistent with mineralization and poor vascularization. The brain and ocular structures were without visible changes. Fine needle aspiration cytology (FNAC) was performed, and squamous cell carcinoma was suspected. After 3 months, the re-presented to the clinic. The dog became progressively listless, his appetite was decreased, and he became acutely blind. Follow-up skull CT scan revealed significant osteolysis, which affected a significant aspect of the cranium. All bone defects had been replaced by new 3.5 cm-thick soft tissue formations with multifocal small 1-2 mm areas of mineralization. There was no evidence of metastasis. Histological examination confirmed the suspicion of squamous cell carcinoma., Conclusions: This paper is the first report of cranial SCC in a dog causing extensive bone osteolysis. The lesions in this dog originated from the frontal and parietal bones including frontal sinuses. There are variants of tumors that arise from squamous epithelium or resemble SCC in the skull. These examples include adenosquamous carcinoma and proliferating trichilemmal tumours. In addition, there is possible malignant transformation caused by papilloma viruses. In the veterinary literature, there is only one similar description of adenosquamous carcinoma in a cat with similar clinical manifestations. It is justified to suspect a process of neoplastic epithelial origin in all cases of aggressive and extensive skull bone lysis. This issue should be subject to further investigation.

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli , pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4 + and CD8 + T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. SIGNIFICANCE: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design. This article is highlighted in the In This Issue feature, p. 521 ., (©2021 American Association for Cancer Research.)

Background: We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported., Methods: In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1 , BRCA2 , or ATM , and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously., Results: The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population., Conclusions: Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1 , BRCA2 , or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.)., (Copyright © 2020 Massachusetts Medical Society.)

This article deals with the phenomenon of tool wear prediction in face milling of aluminum matrix composite materials (AMC), class as hard-to-cut materials. Artificial neural networks (ANN) are one of the tools used to predict tool wear or surface roughness in machining. Model development is applicable when regression models do not give satisfactory results. Because of their mechanical properties based on SiC or Al 2 O 3 reinforcement, AMCs are applied in the automotive and aerospace industry. Due to these materials' abrasive nature, a three-edged end mill with diamond coating was selected to carry out milling tests. In this work, multilayer perceptron (MLP) models were used to predict the tool flank wear VB B and tool corner wear VB C during milling of AMC with 10% SiC content. The signals of vibration acceleration and cutting forces were selected as input to the network, and the tests were carried out with three cutting speeds. Based on the analysis of the developed models, the models with the best efficiency were selected, and the quality of wear prediction was assessed. The main criterion for evaluating the quality of the developed models was the mean square error (MSE) in order to compare measured and predicted value of tool wear.

Background: Radium-223 is approved for treatment of bone metastases in metastatic castration-resistant prostate cancer (mCRPC). After the ALSYMPCA trial showed overall survival benefit with the addition of radium-223 to standard of care in mCRPC in 2013, there have been numerous publications and trials using radium-223 in mCRPC. Recently, there has been interest in using radium-223 earlier in the metastatic prostate cancer timeline, in metastatic castrate-sensitive prostate cancer (mCSPC); however, currently, radium-223 in mCSPC treatment is investigational. Aim: A literature search was conducted to review the use of radium-223 in mCSPC treatment from 1980 to 2019. A review of both radium-223 articles and abstracts was performed. Search terms included metastatic prostate cancer and radium-223, mCSPC, hormone-sensitive metastatic prostate cancer, radium-223, and oligometastatic disease. The results were limited to studies involving multiple patients with mCSPC. Conclusion: There are a limited number of studies of radium-223 in mCSPC treatment and the authors report on these studies (two published studies and four ongoing trials). Trials are currently underway to assess if radium-223 could be used in mCSPC as a treatment for bone metastases and micrometastases. Future data from these trials will be informative as to the benefit of radium-223 in mCSPC treatment and may change treatment paradigms for mCSPC. This review will focus on trials assessing the role of radium-223 in mCSPC.

Background: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers., Methods: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1 , BRCA2 , or ATM ; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review., Results: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib., Conclusions: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.)., (Copyright © 2020 Massachusetts Medical Society.)

Pectus excavatum, thoracic spine deformities, tracheal hypoplasia and lateral heart displacement are frequently described in brachycephalic dog breeds. Pectus carinatum is described sporadically, although the authors' observations demonstrate that it may occur in certain brachycephalic dog breeds. It was hypothesised that dogs of screw-tailed brachycephalic breeds carry a greater risk of these anomalies than normal-tailed brachycephalic breeds, and that there could a relation between the presence of pectus excavatum or pectus carinatum and thoracic spine deformities, tracheal hypoplasia and lateral heart displacement. During retrospective studies, these anomalies were identified in lateral and dorso-ventral radiographs of the thorax in brachycephalic dog breeds. A statistical analysis revealed that the frequency of pectus excavatum occurrence in screw-tailed and normal-tailed brachycephalic dog breeds is similar. The greatest risk of pectus excavatum occurrence is carried by two breeds: Maltese (60%) and English Bulldog (58%), while for pectus carinatum: Pug (41%) and French Bulldog (18%). Dogs of screw-tailed brachycephalic breeds carry a greater risk of kyphosis (p < 0.0001), tracheal hypoplasia occurrence (p < 0.0001), compared to "normal-tailed" breeds. The hypothesis concerning a relation between the presence of pectus excavatum or pectus carinatum and the other anomalies studied was not confirmed (p > 0.05). It was demonstrated that in dogs of brachycephalic breeds there was a greater risk of co-incidence between kyphosis of the thoracic spine and lateral heart displacement (p = 0.038), as well as kyphosis of the thoracic spine and tracheal hypoplasia (p = 0.003)., Competing Interests: The authors have declared that no competing interests exist.

The ability to effectively predict tool wear during machining is an extremely important part of diagnostics that results in changing the tool at the relevant time. Effective assessment of the rate of tool wear increases the efficiency of the process and makes it possible to replace the tool before catastrophic wear occurs. In this context, the value of the effectiveness of predicting tool wear during turning of hardened steel using artificial neural networks, multilayer perceptron (MLP), was checked. Cutting forces and acceleration of mechanical vibrations were used to monitor the tool wear process. As a result of the analysis using artificial neural networks, the suitability of individual physical phenomena to the monitoring process was assessed.

The obesity epidemic is swelling to epic proportions. Obese patients often suffer from a combination of hypertension, dyslipidemia, and type 2 diabetes mellitus (T2DM), also known as the "metabolic syndrome." The metabolic syndrome is an independent predictor of cardiac dysfunction and cardiovascular disease and a risk factor for perioperative morbidity and mortality. In this paper, we discuss the perioperative risk factors and the need for advanced care of obese patients needing general anesthesia for (bariatric) surgical procedures based on physiological principles.

Purpose: Contemporary treatment for metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) plus abiraterone or docetaxel. While these intensified regimens have improved efficacy, they are also associated with increased cost and toxicities. Not all men with mHSPC may be candidates for these intensified regimens, yet there are no clinical models or biomarkers used to optimize treatment selection. Herein, we hypothesized that longer time from prior definitive therapy (DT), either radical prostatectomy, definitive radiotherapy, or both, to onset of metastatic disease is associated with improved survival outcomes in men with newly diagnosed mHSPC., Methods: This multicenter retrospective study included men initiating systemic therapy with ADT for new mHSPC. Kaplan-Meier and COX proportional hazard models assessed time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) by receipt of prior DT., Results: Of the 253 men with new mHSPC, 115 (45%) had received prior DT. In a multivariate analysis, increasing years from DT to the start of ADT was an independent predictor of time to mCRPC (per year: hazard ratio 0.91 95% confidence interval 0.84-0.99, P = 0.020) and improved OS (per year: hazard ratio 0.87, 95% confidence interval 0.74-0.99, P = 0.0025) in patients with new mHSPC, and may assist with risk stratification in these patients at time of mHSPC., Conclusion: Time from DT to start of ADT is an independent predictor of time to mCRPC and OS in men with new mHSPC, and may assist with risk stratification of these patients for systemic therapy selection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/objectives: Caregivers of older adults with cancer assist both with cancer care and other health issues, which may make them vulnerable to consequences of caregiving. Hospitalization may represent a time when a caregiver's ability to provide care at home is exceeded. We sought to characterize caregivers of hospitalized older adults with cancer, determine their quality of life (QOL), and identify factors associated with caregiver QOL., Methods: Patients (n = 100), aged 65 years and older, with an unplanned hospitalization and their caregivers were included. Caregivers completed a questionnaire about their health, social support, caregiving relationship, QOL (Caregiver Quality of Life Index-Cancer [CQOLC] tool), and patient function. Patient medical history was obtained via chart review. The association between patient, caregiving, and caregiver factors and CQOLC was determined using multivariate linear regression., Results: Most patients (73%) had metastatic/advanced disease, and 71% received treatment for their cancer within 30 days of hospitalization. Median Karnofsky Performance Status (KPS) was 60%, and 89% required help with instrumental activities of daily living, as reported by caregivers. Median caregiver age was 65 years (range = 29-84 years). The majority (60%) had no major comorbidities and rated their health as excellent/good (79%), though 22% reported worsening health due to caregiving. Caregivers had a median Mental Health Inventory-18 score of 70 (range = 0-97), a median Medical Outcomes Study (MOS)-social activity score of 56 (range = 0-87.5), and a median MOS-Social Support Survey score of 68 (range = 0-100). Caregivers provided a median of 35 hours of care per week (range = 0-168 hours of care per week). Mean CQOLC was 84.6 ± 23.5. Lower caregiver QOL was associated with poorer caregiver mental health, less social support, and poorer patient KPS (P < .05)., Conclusion: Caregivers of hospitalized older adults with cancer are older but generally in good health. Those with poorer mental health, less social support, and caring for patients with poorer performance status are more likely to experience lower QOL. J Am Geriatr Soc 67:978-986, 2019., (© 2019 The American Geriatrics Society.)

Background: Oral metronomic chemotherapy, which has low toxicity, has demonstrated promising anti-tumor and anti-angiogenic properties that may lead to prolonged progression-free survival and improved response rates in patients with recurrent epithelial ovarian cancer (EOC). These effects may be enhanced by the co-administration of anti-angiogenic agents., Methods: We conducted a randomized phase II clinical trial to evaluate the therapeutic benefit of oral metronomic cyclophosphamide (CTX) alone and with the anti-angiogenic drug celecoxib in patients with gynecological malignancies. 52 patients were randomly assigned to two treatments arms: 50 mg oral CTX daily alone (Arm A) or with 400 mg celecoxib twice daily (Arm B). The primary endpoint was response rate. Secondary endpoints included toxicity, time to treatment failure, and overall survival., Results: In Arm A (n = 26), 3 patients (12%) had stable disease >6 months and 1 (4%) had a partial response. In Arm B, 5 (19%) had stable disease >6 months and 1 patient (4%) had a partial response. There were no significant between-group differences in overall survival (9.69 months [95% CI 3.84-13.18] vs. 12.55 months [6.67-17.61]) or in median time to treatment failure (1.84 months [1.68-2.76] vs. 1.92 months [1.64-5.22]). The most common adverse events were nausea, vomiting, and abdominal pain., Conclusions: Oral metronomic CTX has activity with no major toxicities in heavily pretreated recurrent gynecological cancers and may be considered in patients with indolent disease. We did not observe any additional benefit of celecoxib treatment, though this may be due to small sample sizes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC). Since radiation therapy (RT) can suppress bone marrow function and immune responses, previous studies evaluating sipuleucel-T excluded patients who received RT less than or equal to 28 days prior to sipuleucel-T therapy. Recent evidence suggests that RT may act synergistically with immunotherapy to enhance and broaden antitumor immune response., Methods: Patients who met standard criteria for sipuleucel-T were randomized to receive sipuleucel-T alone (Arm A) or sipuleucel-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B). RT was delivered at 300cGy/day to 3000 cGy total. The primary endpoint was the ability to safely combine sipuleucel-T preceded by RT and generate sipuleucel-T with adequate product immune activation parameters. Secondary endpoints included the measurement of systemic immune responses to prostatic acid phosphatase (PAP), a target for sipuleucel-T immune therapy and PA20204 (recombinant fusion protein utilized in the generation of sipuleucel-T)., Results: 51 pts were enrolled, 2 did not receive any sipuleucel-T because of vascular access problems and were excluded. 24 were treated on Arm A, 25 on Arm B. 47/49 patients received all 3 sipuleucel-T infusions. Median age was 66 yrs (range 45-90). Sipuleucel-T product parameters including: total nucleated cell (TNC) count, antigen presenting cell (APC) count were similar in both groups. Cumulative APC upregulation was higher in Arm A. 1 patient in Arm A demonstrated PSA response. Median progression free survival (PFS) was 2.46 months on Arm A and 3.65 months on Arm B (p = 0.06). Both arms showed similar increases in humoral responses to PA2024 and PAP. IFN-ƴ ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.028). Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (1 patient in Arm A and 3 patients in Arm B)., Conclusions: Sensitizing RT completed 1 week before generation of sipuleucel-T did not affect the majority of product parameters and the ability to deliver sipuleucel-T therapy. RT did not enhance the humoral and cellular responses associated with sipuleucel-T therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In this paper, we present a detailed and rigorous study of cylindrical harmonic Fresnel lenses (HFLs) using the finite difference time domain method (FDTD) and angular spectrum method (ASM). The HFL is a kind of diffractive lens that can have maximum diffraction efficiency at several discrete harmonic wavelengths, which is suitable for some broadband applications. Previous studies on HFLs were investigated mainly in the domain of paraxial approximation. By using our proposed calculation method, we have determined the efficiency, focal length, maximum focus intensity, and full width at half maximum (FWHM) of the focal spot for several harmonic numbers and for F-numbers of 0.5, 1, and 3. To compare with the paraxial approximation, we have presented the response to both s-polarized and p-polarized light with constant refractive index and real dispersive material, BK7. Moreover, we have also analyzed the cases with oblique illumination. We have shown that the harmonic wavelengths do not change with F/# and that the diffraction efficiency and FWHM of the focus increase as F/# increases. New results on harmonic wavelengths shift and oblique angle of incidence response have been detailed.

Background: Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored., Objective: To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity., Design, Setting, and Participants: Multicenter single arm phase 2 study enrolling 36 chemotherapy-naïve patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients., Intervention: Two cycles of GC followed by four cycles of GC plus ipilimumab., Outcome Measurements and Statistical Analysis: The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival., Results and Limitations: Grade ≥3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%, and negative predictive value=38.9%). Limitations are related to the sample size and single-arm design., Conclusions: GC+ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers., Trial Registration: ClinicalTrials.gov NCT01524991., Patient Summary: Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: With the advent of secondary androgen receptor (AR)-targeted therapies in metastatic castration resistant prostate cancer (PC), nonadenocarcinoma PCs are becoming more prevalent. Many of these cancers express neuroendocrine markers, which may provide biomarkers for emergence of this disease state. We aimed to quantify the expression of synaptophysin (Syp) on circulating tumor cells (CTCs) from serial samples of patients being treated with abiraterone acetate or enzalutamide., Methods: CTCs were isolated from 44 patients with castration resistant PC before starting abiraterone or enzalutamide, at 4, 8, and 12 weeks on therapy, and at progression. Patients were stratified into 3 groups: de novo resistance, short response, and long response. CTCs were enumerated on the CellSearch platform and Syp expression was quantified using the open fluorescent channel on the platform. Correlative analyses were performed., Results: A baseline CTC count of 5 or greater was associated with a more rapid time to progression and increasing CTC counts correlated with emergence of drug resistance. Syp was readily detectable on the surface of CTCs, and baseline percentage CTC Syp expression was significantly associated with time to progression. Furthermore, in evaluable patients, percent CTC Syp expression increased with the emergence of drug resistance. We also found that prior exposure to AR-targeted therapies was inversely associated with progression free survival., Conclusions: We have demonstrated that Syp can be quantified on CTCs and that Syp expression correlates with resistance to abiraterone and enzalutamide. Larger studies testing Syp as a biomarker of emergence of nonadenocarcinoma disease and as a marker of response to AR-targeted therapies are warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Two androgen receptor (AR)-targeted therapies, enzalutamide and abiraterone acetate plus prednisone (abiraterone), have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). Many patients respond to these agents, but both de novo and acquired resistance are common. The authors characterized resistant phenotypes that emerge after treatment with abiraterone or enzalutamide., Methods: Patients who received abiraterone or enzalutamide in the course of routine clinical care were consented for serial blood collection. A proprietary system (CellSearch) was used to enumerate and enrich circulating tumor cells (CTCs). RNA-sequencing (RNA-seq) was performed on pools of up to 10 epithelial cell adhesion molecule (EpCAM)-positive/CD45-negative CTCs. The impact of gene expression changes observed in CTCs between patients who responded or were resistant to abiraterone/enzalutamide therapies was further explored in a model cell line system., Results: RNA-seq data from CTCs identified mutations commonly associated with CRPC as well as novel mutations, including several in the ligand-binding domain of AR that could facilitate escape from AR-targeted agents. Ingenuity pathway analysis of differentially regulated genes identified the transforming growth factor β (TGFβ) and cyclin D1 (CCND1) signaling pathways as significantly upregulated in drug-resistant CTCs. Transfection experiments using enzalutamide-sensitive and enzalutamide-resistant LNCaP cells confirmed the involvement of SMAD family member 3, a key mediator of the TGFβ pathway, and of CCND1 in resistance to enzalutamide treatment., Conclusions: The current results indicate that RNA-seq of CTCs representing abiraterone and enzalutamide sensitive and resistant states can identify potential mechanisms of resistance. Therapies targeting the downstream signaling mediated by SMAD family member 3 (SMAD3) and CCND1, such as cyclin-dependent kinase 4/cyclin-dependent kinase 6 inhibitors, could provide new therapeutic options for the treatment of antiandrogen-resistant disease. Cancer 2018;124:1216-24. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

A glass cuboid, embedded inside a dielectric cylinder is studied when illuminated with a monochromatic plane wave. A photonic nanojet (PNJ) with a full-width at half-maximum (FWHM) waist of around 0.25λ 0 is obtained outside the external surface of the cuboid. The influence of the parameters of a square section cuboid is studied. Three particular phenomena can be obtained and are discussed: an ultra-narrow PNJ on the external surface of the cuboid, a long photonic jet and the excitation of whispering gallery modes (WGMs). A parametric study, over the width and the height of a rectangular section cuboid, shows that these parameters can be used to control the photonic jet properties. We also study several other geometries of the insert, which shows that the key parameter is the refractive index of the inserted material. Finally, we show that by changing the incident angle we can obtain a curved photonic jet.

Evidence suggests lower nadir testosterone levels during the first year of androgen deprivation therapy improve advanced prostate cancer clinical outcomes. We evaluated pivotal trials for subcutaneously administered leuprolide acetate (1-, 3-, 4-, and 6-month doses) to determine nadir testosterone levels. Pooled analysis showed 99%, 97%, and 91% of patients reached nadir testosterone ≤20, ≤10, and ≤5 ng/dL respectively (median ≤3 ng/dL). Across all available categories, $88% of patients reached nadir testosterone ≤5 ng/dL, and <3% experienced a microsurge. Achievement and maintenance of low nadir testosterone levels may improve progression-free survival and time to onset of castrate-resistant prostate cancer.

Background: Skeletal metastases often occur in men with castration-resistant prostate cancer (CRPC) where bone biomarkers are prognostic for overall survival (OS). In those with highly elevated markers, there is preferential benefit from bone-targeted therapy. In the phase IIIS0421 docetaxel +/- atrasentan trial, clinical covariates and bone biomarkers were analyzed to identify CRPC subsets with differential outcomes., Subjects and Methods: Markers of bone resorption [N-telopeptide-NTx; pyridinoline-PYD] and formation [C-terminal collagen propeptide-CICP; bone alkaline phosphatase-BAP] were measured in pre-treatment sera. Bone biomarkers and clinical covariates were included in a Cox model for OS; bone markers were added in a stepwise selection process. Receiver operating characteristic (ROC) curves were constructed for risk factor models +/- bone markers. Significant variables were allowed to compete in a classification and regression tree (CART) analysis. Hazard ratios(HR) were calculated by comparing OS in each of the terminal nodes to a reference group in a Cox model., Results: 750 patients were included. Each bone marker significantly contributed to the risk factor-adjusted OS Cox model, with higher levels associated with worse OS. BAP (HR = 1.15, p = 0.008), CICP (HR = 1.27, p < 0.001), and PYD (HR = 1.21, p = 0.047) in combination were significantly associated with OS. Prognostic accuracy was improved by addition of bone markers to clinical covariates. CART analysis selected CICP, BAP, hemoglobin, and pain score for the final OS model, identifying five prognostic groups., Conclusions: Elevated serum bone biomarker levels are associated with worse OS in bone-metastatic CRPC. Bone biomarkers can identify unique prognostic subgroups. These results further define the role of bone biomarkers in the design of CRPC trials., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients., Patients and Methods: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS., Results: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms., Conclusions: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: There are limited long-term data on patients treated with image guided intensity modulated radiation therapy (IG-IMRT) for prostate cancer recurrence or high-risk disease features after radical prostatectomy. We report single-institution results for patients treated with IG-IMRT and identify variables associated with outcome., Methods and Materials: This is a retrospective chart review consisting of 313 consecutive patients who were treated with adjuvant or salvage IG-IMRT from 2004 to 2013. Cox proportional hazards analysis was used to identify factors related to survival and toxicity. Toxicity was graded using the Common Terminology Criteria for Adverse Events Version 4.0., Results: The median follow-up was 55 months (range, 6-131 months). The median pre-radiation therapy (RT) prostate-specific antigen (PSA) was 0.3 ng/mL (range, <0.01-55.4). The vast majority of patients (87%) received elective pelvic nodal irradiation (median dose: 45 Gy). Androgen deprivation therapy (ADT) was given to 39% of patients for a median of 9 months. Five-year biochemical progression-free survival and distant metastasis-free survival were 59% (95% confidence interval, 53%-66%) and 89% (95% confidence interval, 85%-93%), respectively. On multivariate analysis, higher pre-RT PSA (>0.2 ng/mL), biopsy Gleason score (≥7 [4+3]), and duration of ADT (>6 months) were significantly associated ( P < .05) with biochemical progression-free survival. Actuarial late grade 3 genitourinary and gastrointestinal toxicities at 5 years were 10% and 2%, respectively., Conclusion: Our results suggest that lower pre-RT PSA level and longer duration of ADT are associated with improved biochemical control. The incidence of late grade 3 gastrointestinal toxicity was low, but late grade 3 genitourinary toxicity was higher than anticipated.