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Background: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1–3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients. Methods: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents. Results: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age 5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1. Conclusions: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

Electrospray ionization – ion mobility spectrometry – mass spectrometry (ESI–IMS–MS) allows the identification of protein polymorphic distribution of protein conformers and oligomers. We report the detailed identification of the species observed with commercially available pharmaceutical preparation of wild-type, regular human insulin.

Background: Patients with HER2-positive breast cancer have a significant risk of developing brain metastases (BrM), which have detrimental effects on survival outcomes and quality of life. Although there are several systemic treatment options available that may delay the appearance of BrM and secondary progression of previously treated BrM, there are still substantial unmet needs for this patient population and primary prevention remains elusive., Methods: A group of experts created consensus statements, through a modified Delphi process, to bridge the gap between current unmet needs, available evidence, and international guidelines., Results: The steering committee reviewed all relevant literature and formed research questions to be answered by the subsequent consensus statements. In total, 61 contributors provided feedback on the consensus statements, with 34 statements reaching agreement out of the 55 statements that were voted on altogether. Statements with consensus aimed to define BrM primary and secondary prevention, screening procedures, assessment of symptoms, treatment efficacy, and preventing the occurrence and progression of BrM, while acknowledging the possibilities and limitations in daily clinical practice. Some statements did not reach agreement for a variety of reasons, mostly due to lack of evidence., Conclusions: The consensus statements outlined in this publication provide a point of reference for daily clinical practice and can act as recommendations for clinical trial procedures and future guidelines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Smoker's paradox usually refers to the observation of a favorable outcome of smoking patients in acute myocardial infarction., Methods: From April 2006 to December 2018 a population of 2456 patients with ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI) were prospectively enrolled in the MATRIX registry. Ischemic time, clinical, demographics, angiographic data, and 1-year follow-up were collected., Results: Among 2546 patients admitted with STEMI, 1007 (41 %) were current smokers. Smokers were 10 years younger and had lower crude in-hospital and 1-year mortality (1.5 % vs 6 %, p < 0.0001 and 5 % vs 11 %, p < 0.0001), shorter ischemic time (203 [147-299] vs 220 [154-334] minutes, p = 0.002) and shorter decision time (60 [30-135] vs 70 [36-170] minutes, p = 0.0063). Smoking habit [OR:0.37(95 % CI:0.18-0.75)-p < 0.01], younger age [OR 1.06 (95%CI:1.04-1.09)-p < 0.001] and shorter ischemic time [OR:1.01(95%CI:1.01-1.02)-p < 0.05] were associated to lower in-hospital mortality. Only smoking habit [HR:0.65(95 % CI: 0.44-0.9)-p = 0.03] and younger age [HR:1.08 (95%CI:1.06-1.09)-p < 0.001] were also independently associated to lower all-cause death at 1-year follow-up. After propensity matching, age, cardiogenic shock and TIMI flow <3 were associated with in-hospital mortality, while smoking habit was still associated with reduced mortality. Smoking was also associated with reduced mortality at 1-year follow-up (HR 0.54, 95 % CI [0.37-0.78]; p < 0.001)., Conclusions: Smoking patients show better outcome after PCI for STEMI at 1-year follow-up. Although "Smoking paradox" could be explained by younger age of patients, other factors may have a role in the explanation of the phenomenon., Competing Interests: Declaration of competing interest Sergio Berti is proctor for St. Jude Medical and Edwards Lifesciences LLC. The remaining authors report no financial relationships or conflicts of interest regarding the con-tent herein., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the first 2 wk after hatching, broiler chickens are vulnerable to enteric pathogens due to underdeveloped gastrointestinal and immune systems. Carvacrol has been reported to improve digestive and immune functions. This study aimed to optimize immune development of broiler chickens by delivering carvacrol in ovo. Effects of 2 in ovo treatments delivered at embryonic day (E)17.5 (saline or carvacrol) were evaluated at 3 stages (E19.5, hatch, and d 14 posthatch). Hatchability, performance parameters, lymphoid organ and yolk sac weights were determined. Histomorphology assessment was performed for jejunal samples at hatch and bursa of Fabricius samples at hatch and d 14. Gene expression of immune-relevant genes was determined for jejunal, bursal, and yolk sac samples over time. At hatch, BW was 0.85% lower (P = 0.02) after in ovo carvacrol delivery compared to the controls. Interactions between in ovo treatment and age were found for gene expression. At hatch, carvacrol treatment resulted in lower expression of proinflammatory cytokines IL-8 and IFN-γ in the yolk sac compared to the controls (P = 0.05 and < .001, respectively) suggesting a potential role for carvacrol-mediated immune modulation. At d 14, carvacrol treatment led to lower expression of proinflammatory cytokine IL-6 in the bursa compared to the controls (P = 0.002). In ovo carvacrol delivery led to bursal histomorphometric changes, including a larger cortex in the bursal follicles (P = 0.03), and a higher cortex/medulla ratio (P = 0.04) compared to the controls, indicating increased B-cell stimulation and maturation. Main effects were found for carvacrol treatment in the jejunum, with overall higher expression of proinflammatory mediators IL-1β and NF-κB, and anti-inflammatory IL-10 compared to the controls (P = 0.04, 0.02, and 0.02 respectively) from E19.5 to d 14. Age-related main effects showed various alterations in expression dynamics of immune-related genes across all tissues over time. Our findings suggest changes in immune parameters occur as the chicken develops, but these mostly do not interact with in ovo carvacrol treatment. In ovo carvacrol treatment alters immune activity of broiler chickens independent of age., Competing Interests: DISCLOSURES The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The outcomes of minor ischemic stroke resulting from small artery occlusion (SAO-MIS) have not yet been characterized after dual antiplatelet treatment (DAPT) has become the standard of care. We provided updated figures on the short-term prognosis of SAO-MIS treated with early short-term DAPT and compared the outcomes of SAO-MIS versus non-SAO-MIS patients., Methods: This is a prespecified sub-analysis from a prospective multicentric real-world study (READAPT, NCT05476081) including patients with minor (NIHSS≤5) non-cardioembolic ischemic stroke treated with DAPT. The primary outcome was a composite of 90-day symptomatic ischemic stroke or major cardiovascular events. Secondary outcomes were the 90-day ordinal distribution of modified Rankin Scale (mRS) scores, 90-day excellent functional outcome (mRS of 0 to 1), and 24-h early neurological deterioration (END). Safety outcomes were 90-day intracerebral hemorrhage, moderate-to-severe and any bleedings. All outcomes were compared between SAO-MIS and non-SAO-MIS patients., Results: We included 678 MIS, of whom 253 (37.3 %) were SAO-related. At 90 days, 3 patients with SAO-MIS had primary outcome (1.2 % [95 % CI 0.2 %-3.5 %]), which were all SAO-related ischemic strokes. For the secondary outcomes, most SAO-MIS patients (n = 191, 75.5 %) had 90-day excellent functional outcome and 12 had 24-h END (4.7 % [95 % CI 2.5 %-8.3 %]). Referring to safety outcomes, 90-day intracerebral hemorrhage occurred only in one patient with SAO-MIS (0.4 % [95 % CI 0.0 %- 2.2 %]). Compared to non-SAO-MIS, the 90-day risk of recurrent vascular events was significantly lower among SAO-MIS (aHR 0.24 [95 % CI 0.08-0.68]; p = 0.007), while there were not significant differences in other secondary outcomes, nor in the risk of safety events., Conclusions: Our findings show overall favorable short-term prognosis after SAO-MIS treated with DAPT. Future studies should investigate factors associated with residual stroke risk and long-term outcomes of SAO-MIS., Competing Interests: Declaration of competing interest Andrea Zini reports compensation from Angels Initiative, Boehringer-Ingelheim, Daiichi Sankyo for consultant services; from Angels Initiative, Boehringer-Ingelheim, CSL Behring for speaking honoraria or other education services; from Daiichi Sankyo for meeting; from Bayer, and Astra Zeneca for participation on a Data Safety, Monitoring Board or Advisory Board; and he is member of ESO guidelines, ISA-AII guidelines, and IRETAS steering committee. Raffaele Ornello reports grants from Novartis and Allergan; compensation from Teva Pharmaceutical Industries, Eli Lilly and Company, and Novartis for other services; and travel support from Teva Pharmaceutical Industries. Simona Sacco reports compensation from Novartis, NovoNordisk, Allergan, AstraZeneca, Pfizer Canada, Inc., Eli Lilly and Company, Teva Pharmaceutical Industries, H. Lundbeck A/S, and Abbott Canada for consultant services; employment by University of L'Aquila; and compensation from Novartis for other services. Maurizio Paciaroni reports compensation from Daiichi Sankyo Company, Bristol Myers Squibb, Bayer, and Pfizer Canada, Inc., for consultant services. Danilo Toni reports compensation from Alexion, Astra Zeneca, Medtronic, and Pfizer for consultant services and participation on a Data Safety, Monitoring Board or Advisory Board. The other authors report no conflicts., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Since 2019, Braile Biomédica® introduced a novel custom-made abdominal endograft tailored to the aorta's anatomy, featuring sizing every 3 mm and a diameter change from 50 mm to 8 mm. This design permits uncovered fenestrations around a single Z stent, eliminating the need for bridging stents to visceral vessels. Utilizing triple stent technology, optimal neck fixation is ensured, enabling treatment of necks shorter than 2 mm, with three 360° fenestrations optimizing graft fixation. This paper aims to analyze the initial experience with this custom-made infrarenal graft for abdominal aorta aneurysm (AAA), concerning procedural success and post-procedural short-term outcomes., Results: Among 12 patients treated from May 2022 to January 2024, technical success was achieved in 91.7 %, with only one intra-procedural complication. Follow-up CT scans at 1-3 months revealed resolution of an intraoperative endoleak and two late complications: a late type III endoleak and right renal artery occlusion., Conclusions: The recent experience with Braile Biomédica® custom-made abdominal endograft demonstrates promising outcomes, particularly in treating AAAs with challenging anatomical features., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An 84-year-old man with extensive calcified atherosclerosis of the infrarenal abdominal aorta was diagnosed with severe aortic valve stenosis, presenting with dyspnea. To facilitate transfemoral approach during the TAVI procedure, IVUS-guided intravascular lithotripsy was successfully performed using Kissing Shockwave Balloon Technique., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Measuring 1,25-dihydroxyvitamin D (1,25(OH) 2 D), parathyroid hormone 1-84 (PTH 1-84) and intact FGF23 (iFGF23) is crucial for diagnosing a variety of diseases affecting bone and mineral homeostasis. Biological variability (BV) data are important for defining analytical quality specifications (APS), the usefulness of reference intervals, and the significance of variations in serial measurements in the same subject. The aim of this study was to pioneer the provision of BV estimates for 1,25(OH)2D and to improve existing BV estimates for iFGF23 and PTH 1-84., Materials and Methods: Serum and plasma-EDTA samples of sixteen healthy subjects have been collected for seven weeks and measured in duplicate by chemiluminescent immunoassay on the DiaSorin Liaison platform. After variance verification, within-subject (CV I ) and between-subject (CV G ) BV estimates were assessed by either standard ANOVA, or CV-ANOVA. The APSs were calculated according to the EFLM-BV-model., Results: We found the following CV I estimates with 95% confidence intervals:1,25(OH) 2 D, 22.2% (18.9-26.4); iFGF23, 16.1% (13.5-19.5); and PTH 1-84, 17.9% (14.8-21.8). The CV G were: 1,25(OH) 2 D, 21.2% (14.2-35.1); iFGF23, 21.1% (14.5-35.8); and PTH 1-84, 31.1% (22.1-50.8)., Conclusions: We report for the first time BV estimates for 1,25(OH) 2 D and enhance existing data about iFGF23-BV and PTH 1-84-BV through cutting-edge immunometric methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: To assess the reproducibility of coronary tissue characterization by an Artificial Intelligence Optical Coherence Tomography software (OctPlus, Shanghai Pulse Medical Imaging Technology Inc.)., Methods: 74 patients presenting with multivessel ST-segment elevation myocardial infarction (STEMI) underwent optical coherence tomography (OCT) of the infarct-related artery at the end of primary percutaneous coronary intervention (PPCI) and during staged PCI (SPCI) within 7 days thereafter in the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and angioX) Treatment-Duration study (ClinicalTrials.gov, NCT01433627). OCT films were run through the OctPlus software. The same region of interest between either side of the stent and the first branch was identified on OCT films for each patient at PPCI and SPCI, thus generating 94 pairs of segments. 42 pairs of segments were re-analyzed for intra-software difference. Five plaque characteristics including cholesterol crystal, fibrous tissue, calcium, lipid, and macrophage content were analyzed for various parameters (span angle, thickness, and area)., Results: There was no statistically significant inter-catheter (between PPCI and SPCI) or intra-software difference in the mean values of all the parameters. Inter-catheter correlation for area was best seen for calcification [intraclass correlation coefficient (ICC) 0.86], followed by fibrous tissue (ICC 0.87), lipid (ICC 0.62), and macrophage (ICC 0.43). Some of the inter-catheter relative differences for area measurements were large: calcification 9.75 %; cholesterol crystal 74.10 %; fibrous tissue 5.90 %; lipid 4.66 %; and macrophage 1.23 %. By the intra-software measurements, there was an excellent correlation (ICC > 0.9) for all tissue types. The relative differences for area measurements were: calcification 0.64 %; cholesterol crystal 5.34 %; fibrous tissue 0.19 %; lipid 1.07 %; and macrophage 0.60 %. Features of vulnerable plaque, minimum fibrous cap thickness and lipid area showed acceptable reproducibility., Conclusion: The present study demonstrates an overall good reproducibility of tissue characterization by the Artificial Intelligence Optical Coherence Tomography software. In future longitudinal studies, investigators may use discretion in selecting the imaging endpoints and sample size, accounting for the observed relative differences in this study., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd., Patients and Methods: Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded., Results: Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred., Conclusion: In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration., Competing Interests: Disclosure CP reports grant funding support: Pfizer, Daiichi Sankyo, Exact Sciences, Gilead and Seagen. Honoraria for advisory boards: Pfizer, Roche, Daiichi Sankyo, Novartis, Exact Sciences, Gilead, SeaGen and Eli Lilly. Support for travel and conferences: Roche, Novartis and Gilead. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preservation by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD., Methods: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplantation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP., Results: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid status and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups., Conclusions: Overall, compared to current clinical SCS, recipient outcomes following transplantation are not adversely impacted by extending HMP to 8 hours. These results have important implications for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A Campylobacter species was first described as the etiological agent of Spotty Liver Disease (SLD) in 2015 and subsequently named as Campylobacter hepaticus in 2016. The bacterium predominantly affects barn and/or free-range hens at peak lay, is fastidious and difficult to isolate, which has impeded elucidation of its sources, means of persistence and transmission. Ten farms from South-Eastern Australia, of which 7 were free range entities participated in the study. A total of 1,404 specimens from layers and 201 from environmental sources, were examined for the presence of C. hepaticus. In this study, our principal findings included the continuing detection of C. hepaticus infection in a flock following an outbreak, indicating a possible transition of infected hens to asymptomatic carriers, that was also characterized by no further occurrence of SLD in the flock. We also report that the first outbreaks of SLD on newly commissioned free-range farms affected layers ranging from 23 to 74 wk of age, while subsequent outbreaks in replacement flocks on these farms occurred during the more conventional peak lay period (23-32 wk of age). Finally, we report that in the on-farm environment, C. hepaticus DNA was detected in layer feces, inert elements such as stormwater, mud, soil, as well as in fauna such as flies, red mites, Darkling beetles, and rats. While in off-farm locations, the bacterium was detected in feces from a variety of wild birds and a canine., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]., Patients and Methods: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961)., Results: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance., Conclusions: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibition is an established treatment in programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined., Materials and Methods: The tumour-infiltrating lymphocytes (TILs) and the messenger RNA (mRNA) levels of 770 immune-related genes (NanoString™, nCounter™ Immuno-oncology IO360) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcripts and protein expression in primary BCs and its association with outcome was determined., Results: There was a significant reduction of TILs in the BCBMs in comparison to primary BCs. 11.5% of BCs presented a high immune infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate). 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. One hundred and twelve immune-related genes including PD-L1 and CTLA4 were decreased in BCBM compared to the primary BCs (false discovery rate <0.01, log2 fold-change >1.5). These genes are involved in matrix remodelling and metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion and migration. Immuno-modulators such as PD-L1 (CD274), CTLA4, TIGIT and CD276 (B7H3) were decreased in BCBMs. However, PD-L1 and CTLA4 expression was significantly higher in TN BCBMs (P = 0.01), with CTLA4 expression also high in human epidermal growth factor receptor 2-positive (P < 0.01) compared to estrogen receptor-positive BCBMs. ARG2 was one of four genes up-regulated in BCBMs. High ARG2 mRNA expression in primary BCs was associated with worse distant metastasis-free survival (P = 0.038), while ARG2 protein expression was associated with worse breast-brain metastasis-free (P = 0.027) and overall survival (P = 0.019). High transcript levels of ARG2 correlated to low levels of cytotoxic and T cells in both BC and BCBM (P < 0.01)., Conclusion: This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and clinical outcome., Competing Interests: Disclosures The authors have declared no conflicts of interest. Data sharing The data generated in this study are available within the article and its supplementary data files., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Neutralizing monoclonal antibodies (moAbs) improves clinical outcomes in patients with COVID-19 when administered during the initial days of infection. The action of moAbs may impair the generation or maintenance of effective immune memory, similar to that demonstrated in other viral diseases. We aimed to evaluate short-term memory T-cell responses in patients effectively treated with bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab (SOT)., Methods: Spike (S)-specific T-cell responses were analyzed in 23 patients with COVID-19 (vaccinated or unvaccinated) before and after a median of 50 (range: 28-93) days from moAb treatment, compared with 11 vaccinated healthy controls. T-cell responses were measured by interferon-γ-enzyme-linked immunospot and flow cytometric activation-induced marker assay., Results: No statistically significant difference in S-specific T-cell responses was observed between patients treated with moAb and vaccinated healthy controls. Bamlanivimab/etesevimab and casirivimab/imdevimab groups showed significant increases in cellular responses in paired baseline/postrecovery series, as well as vaccinated patients receiving SOT. In contrast, unvaccinated patients prescribed SOT presented no statistically significant increases in T-cell-responses, suggesting diverse impacts of different moAbs on the evolution of S-specific T-cell responses in vaccinated and unvaccinated patients., Conclusion: The moAbs did not hinder short-term memory S-specific T-cell responses in the overall group of patients; however, differences among moAbs must be further investigated both in vaccinated and unvaccinated individuals., Competing Interests: Conflict of interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Infection with Chlamydia pecorum is one of the main causes of progressive decline of koala (Phascolarctos cinereus) populations in Eastern Australia. Pathological changes associated with the chlamydial infection in the genital tract of female and male koalas have been widely described with reports of acute and chronic lymphoplasmacytic inflammation and the description of the cystic dilatation of the ovarian bursa. Although these disease manifestations can result in severe chronic inflammation, structural changes and even sterility, only limited data is currently available on the organism's distribution and associated histopathological and ultrastructural changes within the upper genital tract of affected females. This study examined the pathogenesis of the most common pathological lesion associated with chlamydiosis in female koalas, the cystic dilation of the ovarian bursa starting from the evidence that Chlamydia spp. induces disruption of the intercellular junctions in the epithelium of the reproductive organs in humans. Histology, immunohistochemistry (IHC) and transmission electron microscopy (TEM) were performed to evaluate the structural features and the expression of epithelial cell and cellular junctions' markers in affected bursae from 39 Chlamydia-infected female koalas. Epithelial cells from the ovarian bursae of one affected animal examined by transmission electron microscopy showed severe widening of the intercellular space, as morphologic evidence of disrupted permeability of the epithelial barrier. The epithelial cell-cell junctions markers E-cadherin, β-catenin and ZO-1 expressions were significantly reduced in samples from cystic bursae when compared to normal tissue samples (P < 0.0001). On the other end, a significantly higher expression of the proliferation marker Ki67 was observed in cystic bursae compared to control samples (P < 0.0001). As these proteins are required to maintain epithelial functional integrity and cell-cell adhesive interactions, their loss may permanently impair and affect female koala fertility and suggest the molecular basis of the pathogenesis of the cystic accumulation of bursal fluid within this tissue., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Approximately 70% of patients with metastatic breast cancer (MBC) develop bone metastases. Despite advances in systemic treatment options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further treatment options. Radium-223 (Ra 223 ) is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumour effect on bone metastases. Here we evaluate the safety, feasibility and efficacy findings of the combination of Ra 223 with capecitabine chemotherapy in patients with MBC with bone involvement., Methods: CARBON is a multi-centre, open-label phase IB/IIA study evaluating the combination of Ra 223 (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m 2 bd days 4-17 every 21 days) in patients with bone metastases from MBC (± other disease sites). Other eligibility criteria included ECOG performance status 0-2, ≤2 lines of chemotherapy for MBC and current bisphosphonate or denosumab use for ≥ 6 weeks. The phase IB part of the trial (6 patients) was conducted to provide preliminary feasibility and safety of capecitabine + Ra 223 . Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra 223 or capecitabine alone to further characterise the safety profile and evaluate efficacy, the primary efficacy endpoint being the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to first symptomatic skeletal event, and disease progression at extra-skeletal and bone disease., Results: In addition to bone metastases, 10/23 [44%] and 13/23 [57%] capecitabine + Ra 223 and 2/11 [18%] and 9/11 [82%] capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra 223 patients had received prior chemotherapy for MBC: 11/23 [48%] vs 2/11 [18%]. The analysis populations comprise 34 patients (23 capecitabine + Ra 223 , 11 capecitabine); 2 patients randomised to capecitabine + Ra 223 received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra 223 (range 3-12) and 12 in the capecitabine arm (range 1-12). 94/95 prescribed Ra 223 cycles were administered. No dose limiting toxicities were seen in phase IB and no patients developed grade ≥ III diarrhoea. Gastrointestinal, haematological and palmer-planter erthyrodysesthesia adverse events were similar in both arms. Although formal statistical comparisons were not made, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the two treatment arms., Conclusion: Capecitabine + Ra 223 at the planned dose was safe and feasible in MBC patients with bone metastases. However, no efficacy signals were seen that might suggest greater efficacy of the combination over capecitabine alone clinically or biochemically., Competing Interests: Janet Brown declared research grants (to her institution) from Amgen, AstraZeneca and Bayer and personal fees from Amgen, Novartis, BMS, Ipsen, Sandoz, MSD and Bayer and support for attending meetings from Ipsen.  Matthew Winter declared consulting fees from Gilead, Novartis and Eli Lilly, payment for lectures/presentations/speakers bureaus from Eli Lilly, Pfizer, Novartis and Easai and support for attending meetings and/or travel from Eli Lilly, Gilead, Novartis and Easai. Robert Coleman declared consulting fees from AstraZeneca,  Boehringer Ingelheim, ITM and Sanofi; speaker fees from Amgen, ITM, Novartis and Pierre Fabre; and has a patent pending and share options with Inbiomotion.  Caroline Wilson declared consultancy fees from Pfizer, Novartis, Amgen and Roche Iain MacPherson declared consultancy fees from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer and Roche and travel support from Eisai and Roche. Richard Eastell declared consultancy funding from IDS, Sandoz, Samsung, Haoma Medica, CL Bio, Biocon, Takeda, meeting presentations from Pharmacosmos, Alexion and Amgen and grant funding from Amgen, Roche, Pharmacosmos and Alexion. Chris Twelves declared fees from AstraZenenca, Pfizer, Novartis, MSD and Eisai.  Sacha Howell declared speaker fees and advisory board fees from Pfizer. Carlo Palmieri declared grant funding from Daiichi Sankyo, Pfizer and Seagen, travel support from Gilead and Roche and honoraria from Astrazeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, Novartis, Pfizer and Roche. All other authors declared no conflicts of interests., (© 2022 Published by Elsevier GmbH.)

Importance: The introduction of human epidermal growth factor receptor 2 (HER2) directed therapy has transformed the outcomes of patients with advanced breast cancer (BC). However, HER2 positive breast cancer has a predilection for the central nervous system (CNS) which is associated with significant morbidity and mortality. Understanding the intracranial activity of novel HER2 directed agents is key to developing treatments as well as possible preventative strategies for HER2-positive CNS disease., Observations: Using protocols and data from published phase III clinical trials for locally advanced/metastatic HER2-positive breast cancer since the licensing of single agent trastuzumab for advanced BC we review the central nervous system related aspects. This includes CNS related entry criteria, use of baseline and on study cross-sectional imaging of the CNS and protocol and non-protocol defined CNS end points and reported data., Conclusions: and Relevance: This review found heterogeneity between studies with regard to the entry criteria, use of CNS imaging and reported end points within the pivotal phase III studies. Based on these data, a standardisation of both entry criteria and end points with regard to the CNS should be developed and applied to future studies of HER2-positive advanced BC. Such an approach would enable the generation of comparable data and allow a meaningful analysis of different treatment approaches with regard to the CNS. This in turn would allow the development of the most optimal treatment approaches for HER2 positive CNS disease and ultimately the development of preventative strategies., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Background: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally., Patients and Methods: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site., Results: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific., Conclusions: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area., Competing Interests: Disclosure ER reports consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, and Pfizer; research funding from Novartis, Demo Pharmaceutical, Celldex, Radius Health, Tesaro, Parexel, and AnaBIOsis Pharmaceuticals; travel funding from Sanofi, Ipsen, Genesis Pharmaceuticals, LEO Pharma, Merck, Roche, and GENEKOR. CP reports grant funding from Pfizer and Daiichi Sankyo; honoraria from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, Seagen, and Eli Lilly. VM reports honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Seagen, Novartis, Roche, Teva, Janssen-Cilag, and Gilead; playing an advisory role for Hexal, Roche, Pfizer, Amgen, Daiichi-Sankyo, Nektar, Seagen, Gilead, and Eisai; research funding from Roche, Novartis, Seagen, Pfizer, and Genentech. RB reports advisory role for Astra-Zeneca, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, and Seagen; lecture honoraria from Astra-Zeneca, Daiichi, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, and Seagen; research support from Daiichi, MSD, Novartis, and Roche. GR reports research funding (institution) from AstraZeneca, Roche/Genentech, Tesaro, Novartis, Pfizer, Servier, Biovica, GlaxoSmithKline, and Sanofi/Aventis; and patents, royalties, other intellectual property from Agendia for MammaPrint due to the collaboration on the conduct of the MINDACT trial (Institution). SPG reports honoraria from Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; advisory/consultancy roles with Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; research grant from Roche; travel/accommodation/expenses from Roche, Amgen, Shire, Novartis, Pfizer, Bayer, Celgene, and Daiichi Sankyo. HCK reports honoraria and travel support from AstraZeneca, Pfizer, Roche, Daiichi Sankyo, Tesaro, MSD, Onkowissen, Eli Lilly, SurgVision, Exact Sciences, and Genomic Health; and Stock ownership from Theraclion and Phaon scientific. NZ is on the advisory board for Lilly, Eisai, and AstraZeneca; reports receiving honorarium from Roche, Pfizer, Eisai, and Amgen; research funding (institutional) from Pfizer, Roche, and GSK; education funding from Roche, Novartis, and Amgen (none considered relevant to the current work). MP is on the advisory boards, and has participated in educational programs and conferences for Pfizer, BMS, Novartis, Astellas, Janssen, MD Serono, Merck, Amgen, and Sanofi; reports research funding (institutional) from Astellas, Novartis, Roche, Merck, BMS, Sanofi, and AstraZeneca. RMC has received (to institution) an unrestricted educational grant from Pfizer; and research funds from MSD Ireland and Pfizer. HT reports employment or management position with Partner and Medical Director Oncology Practice at Bethanien Hospital, Frankfurt; honoraria from Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science; consulting activities for Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science. AM reports advisory/consultant role, honoraria, and research grant from Lilly and Roche; advisory/consultant role for Novartis, Merck, Seagen, and Daiichi-Sankyo. LDM reports grants from Eli Lilly during the conduct of the study; personal fees from Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Seagen, Ipsen, and Gilead; personal fees and nonfinancial support from Roche, Pfizer, and Eisai, outside the submitted work. CC reports honoraria from Amgen, AstraZeneca, BMS, Genesis, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche. SO reports lecture fees, honoraria, or other fees paid by a single company or for-profit organization for the time or labor of a researcher engaged for conference attendance from Chugai, Lilly, AstraZeneca, and Pfizer. IM reports performing consultancy roles for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer, and Roche; travel/conference registration activities for Eli Lilly, Daiichi Sankyo, Gilead, and Novartis. ME serves on the advisory boards of Pfizer and Novartis; lecturing for Astra Zeneca (institution), but has no conflicts of interest related to this publication. KZ serves on the advisory board or performs talk for AstraZeneca, Daiichi, Exact Sciences, Lilly, Pierre Fabre, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Viatris/Mylan; unrestricted funding for organization of academic symposium from Agendia, AstraZeneca-MSD, Daiichi, Eisai, Exact Sciences, Lilly, Pierre Fabre, Gilead, Novartis, Pfizer, Roche, Seagen, Viatris/Mylan, and Vifor; support for participation in international congress from AstraZeneca, Daiichi, Pierre Fabre, and Roche; is a member of steering committee of Eleanor study (Pierre Fabre); and research funding from Roche. MV reports honoraria from Roche, Novartis, Pfizer, and Daiichi; consulting or advisory role for Novartis and Roche; travel funds from Roche and Pfizer. DF’s institution receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi, and Pfizer for the conduct of clinical trials outside the submitted work. MG-G reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Novartis, and Pierre Fabre; travel/attending meetings for Pfizer, Roche, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo and AstraZeneca. BL reports consulting or advisory role for AstraZeneca, Pfizer, Merck, Eli Lilly, Pierre Fabre, and Daiichi Sankyo. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is growing evidence that Chlamydia pecorum infection of the male koala reproductive tract causes inflammation and pathology of the urogenital tract. Previous studies have revealed that male koalas exhibiting severe clinical signs of urogenital chlamydial disease had an increased incidence of sperm DNA fragmentation and abnormal sperm morphology, suggestive of chronic exposure to C. pecorum infection and/or inflammation in the testis and epididymis, with residual pathology and lesions disrupting spermatogenesis and maturation of spermatozoa. This study specifically aimed to determine whether pathology associated with chlamydial infection in different regions of the male koala reproductive tract had an adverse effect on classical seminal parameters, sperm DNA quality and endocrine function (testosterone secretion) of naturally infected males. Semen from 58 sexually mature male koalas deemed not suitable for rehabilitation or treatment was assessed, in addition to undertaking a GnRH challenge to determine the androgenic capacity of the testis. Following euthanasia, tissue samples from testes, epididymis and prostate were evaluated for histopathology and real time polymerase chain reaction (qPCR). A significant difference in sperm concentration was observed between males with unilateral and bilateral testicular atrophy and C. pecorum infection (P = 0.011); and between males with unilateral atrophy and C. pecorum infection in one testis and bilateral normal testes with no C. pecorum infection (P = 0.008). No significant association was found for any other semen parameters when categorised by histopathology and C. pecorum tissue presence within the testes, epididymis and prostate. Plasma testosterone concentrations did not significantly differ between testicular histopathology diagnosis and/or C. pecorum infection status. This study suggests Chlamydia infection and inflammation may not be the predominant reason of disruption to spermatogenesis in the wild koala but rather testicular degeneration and atrophy, irrespective of Chlamydia infection, appears to be the primary reason of decreased sperm concentration., Competing Interests: Declaration of competing interest No conflicts of interest occurred to carry out this experiment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

As the liver is vital for the metabolism of many anticancer drugs, determining the correct starting doses in cancer patients with liver impairment is key to safe prescription and prevention of unnecessary adverse effects. Clinicians typically use liver function tests when evaluating patients; however, prescribing information and summaries of product characteristics often suggest dosing of anticancer drugs in patients with liver impairment based on the Child-Pugh criteria, even though the criteria were not developed for this purpose. In this review, we assessed all the oncological small molecule and cytotoxic drugs approved by the United States Food and Drug Administration (FDA) over a 5-year period from 2014 to 2018. The various entry criteria related to these drugs-with respect to hepatic function-in key pivotal studies were compared with their approved dosing recommendations found in prescribing information and summaries of product characteristics. We found that 46% of drugs have dosing recommendations based on Child-Pugh criteria alone, despite the fact that only 8% of these drugs were tested within studies that used the Child-Pugh criteria as entry criteria. Moreover, we note that the data used to make recommendations based on Child-Pugh criteria are typically from small studies that may lack an appropriate patient population. We propose that these findings, along with details surrounding the development of the Child-Pugh criteria, call into question the validity and appropriateness of using Child-Pugh criteria for dosing recommendations of anticancer drugs., Competing Interests: Disclosure IRM has participated in advisory boards for Celldex Therapeutics, Daiichi-Sankyo, Eisai, Genomic Health, Novartis, Roche, and Pfizer. CP has received funding from AstraZeneca, Pfizer, and Genomic Health, and has participated in advisory boards for Daiichi-Sankyo, Eisai, Genomic Health, Pfizer, Novartis, and Roche., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bladder pain syndrome (BPS) is a debilitating disease in humans, particularly women, with patients experiencing chronic, intractable, lower urinary and pelvic pain. Although rodent models have been used, feline idiopathic cystitis (FIC) is a naturally occurring bladder disease of cats that is frequently considered to be the preferred model for BPS. Histologically, FIC is most similar to the non-Hunner BPS subtype. Histology is unnecessary for the clinical diagnosis of FIC but is of great value in elucidating the pathogenesis of this disease so that prevention and therapeutic interventions can be optimized. Further study of the histological features of FIC and BPS is required to determine the significance of Von Brunn's nests, which are invaginations of hyperplastic urothelium that have been associated with irritative bladder stimuli in animals and have been observed in FIC. We review the possible pathogenesis, histopathological similarities and differences between FIC and BPS, and highlight the potential of FIC as a model of BPS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

People with metastatic breast cancer face many challenges and disparities in obtaining optimal cancer care. These challenges are accentuated in underserved patient populations across Europe, who are less likely to receive quality healthcare for reasons including socioeconomic inequalities, educational or cultural status, or geographic location. While there are many local and national initiatives targeted to address these challenges, there remains a need to reduce disparities and improve access to healthcare to improve outcomes, with a focus on multidisciplinary stakeholder engagement. In October 2019, a range of experts in metastatic breast cancer, including healthcare professionals, patient representatives, policymakers and politicians, met to discuss and prioritize the critical needs of underserved patient populations with metastatic breast cancer in Europe. Six key challenges faced by these communities were identified: the need for amplification of the metastatic breast cancer patient voice, better and wider implementation of high-quality guidelines for metastatic breast cancer, more collaboration between stakeholders, tailored support for patients from different cultural and ethnic backgrounds, improved data sharing, and work-related issues. The Expert Panel then conceived and discussed potential actionable goals to address each key challenge. Their conclusions present a set of interrelated approaches to address the different challenges and could serve as the basis for concerted improvement of the lives of patients with metastatic breast cancer in Europe., Competing Interests: Declaration of competing interest Emilio Alba: None. Concepción Biurrún: None. Fatima Cardoso:. Consultancy role for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seattle Genetics, Teva. PierFranco Conte: Speaker (Novartis, Roche, AstraZeneca); Travel grant (Novartis, Celgene, Tesaro); Institutional research grant (Novartis, Merck KGa, Roche, Bristol Myers Squibb) Rosanna D’Antona: None. Jacques De Grève: None. Joseph Gligorov: None. Françoise Meunier: None. Carlo Palmieri: Advisory boards and funding for clinical studies (Pfizer). Oriol Sola-Morales: Dr. Sola-Morales has consulted for most of the multinational pharmaceutical companies, including all ‘top 10’. He has received fees and honoraria for such consultancies and is currently engaged in several projects with many of these companies. He holds ownership of several start-up companies in the healthcare field and has had in the past stock ownership of ‘Top 10’ pharmaceutical companies. Luzia Travado: None. Catherine Ubaysi: Compensation for representing Patients en réseau at events. Roberta Ventura: None. Eduard Vrdoljak: Support for clinical trials and scientific projects (Pfizer, Roche, Bristol Myers Squibb, AstraZeneca); Speaker fees and consulting (Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Novartis, PharmaSwiss, Pfizer, Roche, Sanofi, MSD, Merck). Andrew Walker: Pharmaceutical & biotechnology companies (Abbvie, Akcea, Albireo, Alexion, Allergan, Astellas, AstraZeneca, Autolus, Avexis, Biocrysta, Bristol Myers Squibb, Calico, Celgene, Chiesi, Daiichi-Sankyo, Deciphera, Eli Lilly, Ferring, Galapagos, GSK, GW Pharma, Intercept, Ipsen, Janssen, Jazz, Kite/Gilead, Les Laboratories Servier, Lundbeck, Merck Serono, Mundibiopharma, Mylan, Norgine, Novartis, NovoNordisk, Pfizer, Pierre Fabre, RegenXBio, Takeda, UCB, Vertex). Consultancy companies (Adeptfield, Atheneum Partners, Bresmed, CB Partners, Charles Rivers Associates, Creativ Ceutical, Datamonitor, de Facto Research, Dolon, DRG, Evidera, Executive Insight, Fiecon, Fingerpost Consulting, Galbraith Wight, Guidehouse, Health Advances, HiTT, Huron Consulting Group, Inbeeo, Informa/Data Monitor, IQVIA, M2Econ, Market Access Transformation, Miller Economics, Mirador, Mtech Access, Navigant, Open Access, Pagoda S&L Int. Services, Parexel, Partners 4 Access, Plich Advisory Services, Precision Xtract, PRMA, PWC, QualWorld, Remap, Research Partnership, RJW Partners, SAI Med Partners, Simon Kucher, Therapeutic Challenges, Two Labs, Valid Insight, Verto, Wellmera, Windrose, ZS Associates). Public sector: University of Aberdeen. Theresa Wiseman: None. Lieve Wierinck: None. Rachel Wuerstlein: Agendia, Amgen, Aristo, AstraZeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Onkowissen, Paxman, Palleos, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro, Teva., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome., Patients and Methods: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method., Results: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O 2 ) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission., Conclusion: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity., Competing Interests: Disclosure RJL speaker fees BMS and Astrazeneca, MR honoraria from Astellas Pharma, speaker fees MSD and Servier. CW consultancy and speaker fees Pfizer, Amgen, Novartis, AA conference fee Merck, spouse shares in Astrazeneca. TR financial support to attend educational workshops from Amgen and Daiichi-Sankyo. JT is now working at Astra Zeneca. CD, outside of this scope of work, has received research funding from AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, Clearbridge Biomedics, Angle PLC, Menarini Diagnostics, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Thermofisher. CD is on advisory boards for, and has received consultancy fees/honoraria from, AstraZeneca, Biocartis and Merck KGaA. The remaining authors have no conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Organisms belonging to the Family Chlamydiaceae are responsible for a broad range of diseases in humans, livestock, companion animals and non-domestic species. Infection of the reproductive organs can cause a range of syndromes of which sub- and infertility are the most frequently observed clinical manifestations. While the gross and histological lesions associated with the isolation of Chlamydiaceae from the non-human female reproductive tract are well documented, little attention has been given to the pathological effects of this infection in the male genital system. As such, the occurrence and importance of Chlamydia-associated disease in male non-human mammalian species is less well documented. In order to improve our understanding of the significance of chlamydiosis in domestic, laboratory and wild animals, this review provides an up-to-date summary of Chlamydia-associated male reproductive pathology, whether that infection occurs naturally or experimentally. Although most lesions in males are described as incidental and of minor significance, results of recent studies suggest that infection with Chlamydiaceae can adversely impact male fertility and/or be instrumental in disease transmission. Although in humans, bulls and mice Chlamydia infection has been associated with morphological and functional abnormalities of the spermatozoa, this review will focus on the gross and histological findings linked to the colonisation of the genital system by this pathogen. Advances in our understanding of male reproductive chlamydiosis are necessary for diagnostic and therapeutic strategies, as well as epidemiological and conservation studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Coronary no-reflow phenomenon in ST-segment elevation myocardial infarction (STEMI) is associated with a poor clinical prognosis. Although its pathophysiology is not fully elucidated, a deregulated systemic inflammatory response plays an important role. Specifically, the relationship between age-associated differences in inflammatory markers and either no-reflow or mortality in STEMI patients undergoing primary percutaneous coronary intervention (pPCI) has never been investigated., Methods and Results: We retrospectively enrolled 625 consecutive STEMI patients undergoing pPCI for whom a complete laboratory inflammatory pattern was available. Routinely blood measured laboratory parameters were collected at the moment of admission. No reflow was defined as Thrombolysis in Myocardial Infarction (TIMI) flow-grade lower than 3. The population was divided into two groups using a cut-off centered at 65 years. Compared to younger patients, elderly patients had higher mean values of fibrinogen, brain natriuretic peptide (BNP), leukocytes, neutrophil-to-lymphocyte ratio (NLR), C reactive protein/albumin ratio (CAR). Conversely, lymphocyte count and albumin levels were higher in young patients. In elderly patients, the values of NLR, CAR as well as leukocytes, fibrinogen and neutrophils were associated with no-reflow, while in young patients only BNP value was associated. At multivariate Cox regression analysis, only BNP and NLR resulted as independent predictors of all-cause mortality in the whole population and in elderly patients., Conclusions: Elderly STEMI patients on admission had a higher acute pro-inflammatory profile than young patients, associated to coronary no-reflow and mortality outcome. These results suggest that a different therapeutic approach between elderly and young STEMI patients should be agreed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The terminology applied to canine prostatic epithelial lesions, especially carcinomas, is currently not standardized and this hampers the ability of pathologists to study the biological and clinical significance of these lesions. The aim of this review is to present the essential histomorphological diagnostic attributes of a wide spectrum of prostatic epithelial lesions in dogs. In addition to the traditionally recognized prostatic hyperplasia, hormonal atrophy, prostatitis, squamous metaplasia, adenocarcinoma and transitional cell (urothelial) carcinoma, new entities are described and discussed in order to provide veterinary pathologists with a basic atlas of common histological lesions of the canine prostate that is comprehensive and easy to use., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The 21-gene recurrence score (Oncotype DX) (RS) informs systemic therapy decision making in ER-positive HER2-negative early breast cancer (BC). To date no study has described the more nuanced discussions that take place regarding systemic therapy or the impact of the RS on concordance in such decision making. Here we utilized a novel decision making tool to assess the impact of the RS on decision making as well as concordance of treatment recommendations., Patients and Methods: The clinicopathological information (CPI) of 50 BCs without and with the RS were presented to a panel of breast oncologists in a simulated MDT. The Liverpool Adjuvant Systemic Therapy Decision Tool (LASTDT) was developed and used to categorize treatment recommendations. Outcome measures included the impact of the RS on decisiveness and concordance in decision making and its impact on treatment recommendations., Results: Availability of the RS increased definitive decision making from 8% (4/50) to 56% (28/50) [χ 2  = 79.35, p < 0.001] and altered the LASTDT category in 68% (34/50) of cases (p < 0.001), 74% of which were to forgo chemotherapy. With knowledge of RS, universal concordance rose from 14% to 64% [K = 0.328: K = 0.729]., Conclusions: The RS improves certainty of decision making as well as concordance amongst oncologists. This provides evidence that the availability of the RS can improve consistency of decision making amongst oncologists and thus helps to ensure patients are managed consistently. This is particularly important when patients are managed in a loco-regional, multidisciplinary team manner where heterogeneous decisions can lead to disparity in care., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The cancer cell population is heterogeneous, and cancer stem cells (CSCs) are important for tumor growth and maintenance. The CSC population is associated with different neoplastic characteristics, such as cell migration, resistance to apoptosis, radiation therapy and chemotherapy. To increase the knowledge of CSCs in canine prostate cancer (PC), we characterized CSC markers in canine PC tissues and tumorspheres. We performed immunohistochemistry of OCT3/4, Nestin, NANOG, CD44 and CD24 in 10 normal canine prostatic tissue samples, 10 prostatic hyperplastic (PH) tissue samples and 28 PC tissue samples. Then, we established two canine prostate cancer cell cultures and characterized the CSC profile of tumorspheres grown from these cultures. Normal and PH tissues were positive for Nestin, NANOG, CD44 and CD24 only in the basal cell layer. OCT3/4 was expressed in the luminal cells of normal and PH tissues. There was no significant difference in Nestin expression among the prostatic tissues. However, we found higher expression of NANOG and CD44 in canine PC tissues than that in normal and PH tissues. Tumorspheres from canine prostate cancer cells express OCT3/4, Nestin, NANOG and CD44, indicating that these markers may be potential cancer stem cell markers in canine PC. The results obtained can be useful to better characterize the stem cell population in canine prostatic cancer and to guide future studies in comparative oncology., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Elderly treated with dual antiplatelet therapy after percutaneous coronary intervention (PCI) represent a challenging population because of increased risk of both ischemic and bleeding events. We aimed to investigate the association between high on-treatment platelet reactivity (HPR) and long-term outcome in elderly with non-ST-elevated acute coronary syndromes (NSTE-ACS) undergoing PCI., Methods: Platelet reactivity was measured by vasodilator-stimulated phosphoprotein (VASP) assay at three time-points (baseline, discharge, 1 month after PCI) in 1053 NSTE-ACS patients (311 elderly) treated with clopidogrel. Major adverse cardiac events (MACE) were assessed up to 1 year-follow-up., Results: Elderly with HPR at discharge showed a significantly higher incidence of overall MACE (13 vs 4%, p = .006), cardiac death (6 vs 0.7%, p = .020), myocardial infarction (MI, 12 vs 4%, p = .031) and a trend for higher stent-thrombosis (5 vs 0.7%, p = .068). Similarly, elderly with 1-month-HPR showed between 1 month and 1 year significantly higher incidence of MACE (10 vs 4%, p = .012), cardiac death (6 vs 0.7%, p = .019) and composite cardiac death/MI (11 vs 4%, p = .014). Up to 1 year, elderly with HPR showed a 4-fold increased risk of MACE compared to both elderly without HPR (for discharge-HPR: p = .005; for 1-month-HPR: p = .01) and non-elderly with HPR (for discharge-HPR: p < .001; for 1-month-HPR: p < .0001). At multivariable analysis, HPR could independently predict 1-year-MACE in elderly (for discharge-HPR: HR = 3.191, CI: 1.373-7.417, p = .007; for 1-month-HPR: HR = 3.542, CI: 1.373-9.137, p = .009)., Conclusions: In elderly with NSTE-ACS undergoing PCI and treated with clopidogrel, HPR was independently associated with an increased risk of MACE up to 1 year., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this study was to perform a systematic review of morphological alterations in the condyles after orthographic surgery involving a sagittal split ramus osteotomy (SSRO), with or without surgery on the maxilla. Searches were performed on three databases and registered in the PROSPERO. The selected studies fulfilled the criteria established by the following PICO model: (1) population: individuals with skeletal dentofacial deformities (class II or III facial patterns), without asymmetry; (2) intervention: orthognathic surgery for mandibular setback using an SSRO, with or without a Le Fort I osteotomy, and fixed with bicortical screws or plates and screws; (3) comparison: orthognathic surgery for mandibular advancement using an SSRO, with or without a Le Fort I osteotomy, and fixed with plates and screws or bicortical screws; and (4) outcome: condylar resorption rate and relapse. Initially, 1,371 articles were identified and 636 articles were screened after elimination of duplicates, and 6 articles were selected for qualitative analysis based on the inclusion and exclusion criteria. Five studies had data regarding the rate of condylar resorption, varying from 0.0% to 4.2%. In conclusion, condylar resorption and relapses were present in a small percentage of patients studied., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Nanoparticles (NPs) are a promising tool for in vivo multimodality imaging and theranostic applications. Hyaluronic acid (HA)-based NPs have numerous active groups that make them ideal as tumor-targeted carriers. The B-lymphoma neoplastic cells express on their surfaces a clone-specific immunoglobulin receptor (Ig-BCR). The peptide A20-36 (pA20-36) selectively binds to the Ig-BCR of A20 lymphoma cells. In this work, we demonstrated the ability of core-shell chitosan-HA-NPs decorated with pA20-36 to specifically target A20 cells and reduce the tumor burden in a murine xenograft model. We monitored tumor growth using high-frequency ultrasonography and demonstrated targeting specificity and kinetics of the NPs via in vivo fluorescent reflectance imaging. This result was also confirmed by ex vivo magnetic resonance imaging and confocal microscopy. In conclusion, we demonstrated the ability of NPs loaded with fluorescent and paramagnetic tracers to act as multimodal imaging contrast agents and hence as a non-toxic, highly specific theranostic system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Proliferative inflammatory atrophy (PIA), which is comprised of highly proliferative but atrophic prostate epithelial cells in association with chronic inflammation, is considered a risk lesion for prostate cancer in men, while its role in canine prostate carcinogenesis is still unknown. We evaluated the value of immunohistochemical labelling for the basal cell marker cytokeratin-5 (CK5) in identifying PIA lesions in 87 samples of formalin-fixed and paraffin wax-embedded canine prostate. Canine PIA showed cytological features identical to the human counterpart and in most cases was associated with chronic lymphoplasmacytic inflammation. PIA lesions were identified in a higher number of CK5-labelled slides (43 out of 87) compared with slides stained by haematoxylin and eosin (HE) (24 out of 87). This lesion was frequently present in normal, hyperplastic and neoplastic canine prostates, although it was underestimated on evaluation of HE-stained slides. Therefore, CK5 can be considered a useful basal cell marker with high sensitivity and specificity for PIA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The substitution of ewe milk with more economic cow milk is a common fraud. Here we present a capillary electrophoresis method for the quantification of ewe milk in ovine/bovine milk mixtures, which allows for the rapid and inexpensive recognition of ewe milk adulteration with cow milk. We utilized a routine CE method for human blood and urine proteins analysis, which fulfilled the separation of skimmed milk proteins in alkaline buffer. Under this condition, ovine and bovine milk exhibited a recognizable and distinct CE protein profiles, with a specific ewe peak showing a reproducible migration zone in ovine/bovine mixtures. Based on ewe specific CE peak, we developed a method for ewe milk quantification in ovine/bovine skimmed milk mixtures, which showed good linearity, precision and accuracy, and a minimum amount of detectable fraudulent cow milk equal to 5%., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the outcome of patients with an established indication for oral anticoagulation (OAC) undergoing coronary stent implantation (PCI-S) and stratified by the baseline risk of bleeding., Material and Methods: The database of the prospective, multicentre, observational WAR-STENT registry (ClinicalTrials.gov identifier NCT00722319) was analyzed and patients with atrial fibrillation and CHA 2 DS 2 -VASc score ≥2, mechanical heart valve, prior cardiac embolism, intra-cardiac thrombus and recent venous thromboembolism who were treated with either triple (warfarin, aspirin and clopidogrel) or dual (warfarin and clopidogrel) or dual antiplatelet (aspirin and clopidogrel) therapy, identified. Patients were then sorted into two groups at non-low and low risk of bleeding, as defined by an ATRIA score >3 and ≤3 respectively, and compared regarding major adverse cardiac and vascular events (MACVE) and bleeding., Results: At 12-month follow up, MACVE were comparable in the two groups, whereas total, major and minor bleeding, as well as combined MACVE and total bleeding, were significantly more frequent in the non-low bleeding risk group. Upon Cox univariate and multivariable analysis, non-low bleeding risk category confirmed as an independent predictor of major bleeding. The choice of antithrombotic therapy however, appeared not to be influenced by the bleeding risk category at baseline., Conclusions: In patients with an established indication for OAC undergoing PCI-S, non-low bleeding risk category is the most potent independent predictor of major bleeding. Stratification of the bleeding risk at baseline should therefore be regarded as an indispensable process to be carried out before selection of the antithrombotic therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like 'structure' information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients., Methods: A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score >14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1month, compared to TSMs., Results: ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59-66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1month)., Conclusions: Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Chlamydiosis is a common infectious disease of koalas (Phascolarctos cinereus), but Chlamydia spp. have not yet been demonstrated to cause pneumonia in these animals. A juvenile male koala died following an episode of respiratory disease. At necropsy examination, the lung tissue was consolidated. Microscopical lesions in the lung included pyogranulomatous bronchopneumonia, proliferation of bronchiolar and alveolar epithelium and interstitial fibrosis. Hyperplastic bronchiolar epithelial cells contained aggregates of small basophilic punctate organisms, which were confirmed as chlamydiae by transmission electron microscopy and immunohistochemistry. Real-time polymerase chain reaction identified these as Chlamydia pecorum. This report provides the best evidence to date of chlamydial infection causing pneumonia in a koala, and the first evidence that C. pecorum is capable of infecting the bronchiolar epithelium of the koala., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Signal transducer and activator of transcription 3 (STAT3) and phosphatase and tensin homologue (PTEN) are, respectively, an oncogene and tumour suppressor gene whose dysregulated expression in human prostate cancer is associated with increased malignancy and poor prognosis. Both markers were evaluated in 12 samples of canine benign prostatic hyperplasia (BPH) and 17 canine prostatic carcinomas (PCs) by immunohistochemistry, to understand their possible role in canine prostate carcinogenesis. STAT3 was expressed in 25% and 82.35% of BPH and PC, respectively, with a significantly higher number of STAT3-positive cells in malignant compared with hyperplastic lesions. Three PCs had occasional nuclear expression of STAT3. PTEN was expressed in BPH and PC with a similar distribution and percentage of positive cells; however, four PCs were PTEN negative. Solid PCs contained more STAT3-positive and fewer PTEN-positive cells compared with the other subtypes. A reduced number of PTEN-positive cells was observed in PCs with a high Gleason score (GS10), while no association was demonstrated between STAT3 expression and Gleason score. The data suggest that overexpression of STAT3 and downregulation of PTEN may be an important step in canine prostate carcinogenesis and both markers may be related to the histological subtypes of PC and the degree of differentiation of neoplastic cells., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Sex-determining region Y box9 gene (SOX9) protein plays a pivotal role in male sexual development. It regulates the transcription of the anti-Müllerian hormone gene promoting development of testis cords, multiplication, and maturation of Sertoli cells (SCs) and maintenance of spermatogenesis in adult testis. The immunohistochemical expression of SOX9 in normal testes has been reported in humans, mice, and rats. The present study aimed to investigate the expression of SOX9 in canine SCs during testicular maturation and neoplastic transformation. Canine testicular samples derived from three fetuses, four newborns, four prepubertal puppies, five adult dogs, 31 Sertoli cell tumors (SCTs) (one metastasizing), and five Leydig cell tumors (LCTs) were selected from departmental archive and tested immunohistochemically with a polyclonal antibody against SOX9 (1:150). All SCs from fetal, neonatal, and adult testes had a strong and exclusively nuclear labeling for SOX9. In SCs from prepubertal testes, SOX9 staining was highly variable with one negative sample (one of four), two samples with exclusively nuclear staining (two of four), and one with both nuclear and cytoplasmic labeling (one of four). Leydig cells (LCs) and LCTs were always negative. All 31 SCTs were positive for SOX9. The expression of SOX9 was nuclear, nuclear and cytoplasmic, and exclusively cytoplasmic in 18 of 31, 11 of 31, and two of 31 SCTs, respectively. This first report on the immunohistochemical expression of SOX9 in canine testes reports that in normal SCs from fetal, neonatal, and adult testes SOX9 labeled the nucleus, as in humans and laboratory animals. The cytoplasmic labeling observed in one prepubertal pairs of testes and in 11 SCTs could reflect SC immaturity or dedifferentiation, paralleling results observed in rat testes. The expression of SOX9 in SCs and SCTs and its absence in LCs and LCTs suggests that SOX9 is a reliable diagnostic marker for both normal and neoplastic SCs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

An 8.5-year-old, neutered female ferret (Mustela putorius furo) was presented with tachypnoea, polyuria, polydipsia, anorexia and depression. Radiographs revealed multiple osteolytic lesions of the bone, characterized cytologically by the infiltration of medium- to large-sized lymphocytes. The animal was humanely destroyed and post-mortem examination revealed multifocal masses obliterating the bone marrow of the mandible, right and left humeri and femur, and consisting of an infiltrative population of neoplastic lymphocytes. Immunohistochemical labelling for CD3 and CD79a revealed a CD3-positive neoplastic population. A diagnosis of polyostotic T-cell lymphoma was made, which is the first report of this condition in a ferret., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: Self-expanding stents represent a re-emerging option for percutaneous coronary interventions. Their application covers a wide spectrum of angiographic situations, i.e., coronary bifurcations, acute coronary syndromes with large thrombotic burden and stenosis of ectatic coronaries. We review our experience with self-expanding stents for different clinical and angiographic indications, with long clinical follow-up., Methods: From 2011 to 2013 we used self-expanding STENTYS® stents in 40 consecutive patients followed-up for death from any cause and from cardiovascular cause, myocardial infarction, target lesion revascularization (TLR), stent thrombosis (mean 21±13months). We also revised rate of procedural outcomes, acute stent thrombosis and TLR in patients treated with conventional stents for similar clinical/angiographic situations, in the same period at our institution., Results: We identified three anatomical settings of STENTYS® use: coronary bifurcations with proximal/distal main branch diameter discrepancy (55% of cases), massive thrombotic burden in the setting of acute coronary syndrome (35% of cases) and stenosis of ectatic coronaries (15%). We observed one death related to acute heart failure and 1 case (2.5%) of acute stent thrombosis (2.5% in the control group). During follow-up 2 cases of stent restenosis leading to TLR (5%) occurred (6.25% in the control group)., Conclusions: According to our real life experience, self-expanding STENTYS® stents appear to be an effective tool for different angiographic situations in which they may be preferable to balloon-expandable stents, showing a low rate of complications and good results at long term follow-up., (Copyright © 2016 Elsevier Inc. All rights reserved.)