Open versus Closed technique for administration of heated intraperitoneal chemotherapy (HIPEC): Morbidity and Mortality outcomes from a high-volume centre.

BACKGROUND AND AIMS: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is an established treatment in selected patients with peritoneal metastases, delivered in the UK in specialist centres. HIPEC can be administered via the open coliseum technique as first described by Sugarbaker (O-HIPEC) or using a closed technique (C-HIPEC). Data comparing the safety and outcomes of these different approaches is limited. This study aims to compare morbidity and mortality rates of O-HIPEC and C-HIPEC following CRS for peritoneal metastases from colorectal cancer and appendiceal tumours. METHODS: Consecutive patients undergoing CRS with open (05/2019-04/2020) and closed (05/2020-04/2021) HIPEC were identified from a prospectively maintained database. Baseline data including primary pathology, HIPEC agent and major operative procedures were analysed using Chi-squared and Fishers exact tests to ensure comparability of groups. Primary outcomes were 30- and 60-day postoperative mortality and morbidity (Common Terminology Criteria for Adverse Events, CTCAE). Secondary outcomes were length of critical care and overall hospital stay. In addition, morbidity and mortality were compared between HIPEC agents (mitomycin and oxaliplatin/5-fluorouracil). RESULTS: 99 patients (39.3%) and 153 patients (60.7%) underwent O-HIPEC, C-HIPEC respectively. Groups were well matched for baseline demographics, pathology, and HIPEC agent. In the O-HIPEC and C-HIPEC groups respectively, the incidence of 60-day complications (CTCAE 1-4) was 40.4% vs 39.3% (chi squared 0.94) and severe complications (CTCAE 3-4) 14% vs 13% (Fisher's exact p = 1) There was no perioperative mortality but one death in each group within the follow up period. There was no difference in morbidity or mortality between those receiving mitomycin or oxaliplatin. CONCLUSION: Closed administration of HIPEC is safe with no difference in post-operative morbidity or mortality compared to open HIPEC administration. Differences in longer term oncological outcomes including overall survival and disease-free survival between open and closed HIPEC techniques are yet to be determined.

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.

BACKGROUND: Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF. METHODS: This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity. RESULTS: The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L). CONCLUSIONS: The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.

Local chromatin interactions contribute to expression of the fibrinogen gene cluster.

Essentials The fibrinogen gene cluster is flanked by CCCTC-binding factor (CTCF) interaction sites. Chromatin looping of the fibrinogen cluster was demonstrated by chromosome conformation capture. Deleting a CTCF interaction site alters chromatin looping and halves fibrinogen expression. Looping of the human fibrinogen locus is functionally linked to fibrinogen gene expression. SUMMARY: Background The coordinately regulated genes encoding human fibrinogen are clustered. This evolutionarily conserved configuration provides a possible mechanism for co-regulation whereby regulatory elements influence gene expression locally. The cluster is flanked by CCCTC-binding factor (CTCF) interaction sites that are candidate insulator regions mediating chromatin looping. Objectives To further our understanding of fibrinogen gene regulation, we aimed to investigate whether interactions exist between parts of the fibrinogen locus and how these contacts contribute to fibrinogen expression. Methods We used chromosome conformation capture in cultured cell lines to detect chromatin interactions at the fibrinogen gene cluster. We generated clonal cell lines where two CTCF interaction sites at one end of the locus were deleted using CRISPR-Cas9-mediated genome editing. Fibrinogen expression and protein production were measured using qRT-PCR and ELISA, respectively. Results We detected proximity between the ends of the fibrinogen locus, regardless of whether cells express fibrinogen. An interaction between the FGA promoter and the edge of the locus was more frequent in fibrinogen-expressing cells. Deletion of a CTCF site at one edge of the cluster altered chromatin interactions, reduced steady-state expression of FGB and FGG mRNA, and led to a halving of secreted fibrinogen. These phenotypes were completely restored by reintroduction of the CTCF interaction motif in previously motif-deleted clones. Conclusions Chromatin interactions are important for the coordinated regulation of the human fibrinogen genes. This finding furthers our comprehension of how fibrinogen is produced and identifies a possible source of variability in plasma fibrinogen levels seen in populations.

Referral and treatment pathways for pseudomyxoma peritonei of appendiceal origin within a national treatment programme.

AIM: Pseudomyxoma peritonei (PMP) is a rare neoplasm of the appendix, which if untreated disseminates throughout the abdominal cavity and generates considerable morbidity. Since 2002 in the UK, patients with PMP have been managed via two nationally commissioned centres. We evaluated referrals and treatment pathways over time at the Manchester centre. METHOD: Data from all patients referred with suspected PMP were prospectively collected (2002-2015). Definitive treatment was cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy. Disease burden was quantified using the Peritoneal Cancer Index (PCI) (score 0-39) and complete cytoreduction (CC) defined by scores of 0/1. Novel treatment algorithms were developed for patients with low grade appendiceal mucinous neoplasm (LAMN) localized to the peri-appendiceal tissue. RESULTS: In all, 817 patients with confirmed PMP were referred increasing from 11 in 2002 to 103 in 2015. Disease burden was high with a mean PCI of 31 in the first quartile (Q1), levelling off to 15, 15, 17 thereafter (P = 0.002). The proportion of CC0/1 increased from 67% in Q1 to 77% Q2 and 74% Q3/4. Where complete cytoreduction was achieved, 5- and 10-year overall survival was 77% and 66%. The proportion of patients referred with localized LAMN increased over time reaching 25% each year since 2010 (Ptrend  < 0.0001). Two-thirds of localized LAMN now undergo laparoscopically assisted risk-reducing CRS. CONCLUSION: The establishment of a national treatment centre was associated with an initial presentation of patients with advanced disease. The programme has demonstrated a clear trend over time towards earlier referral and adoption of minimally invasive techniques for localized disease.

Systematic review of outcome measures following chemoradiotherapy for the treatment of anal cancer (CORMAC).

AIM: Six Phase III randomized trials have determined the effectiveness of chemoradiotherapy as primary treatment for anal squamous cell carcinoma (ASCC), but outcomes reported in these trials varied widely, hindering evidence synthesis. To improve reporting in all future trials, we aim to develop a core outcomes set (COS). As the first stage of COS development, we undertook a systematic review to summarize the outcomes reported in studies evaluating chemoradiotherapy for ASCC. METHOD: Systematic literature searches identified studies evaluating radiotherapy or chemoradiotherapy for ASCC. Outcomes and accompanying definitions were extracted verbatim and categorized into domains. RESULTS: From 5170 abstracts, we identified 95 eligible studies, reporting 1192 outcomes and 533 unique terms. We collapsed these terms into 86 standardized outcomes and five domains: survival; disease activity; life impact [including quality of life (QoL)]; delivery of care; and toxicity. The most commonly reported domains were survival and disease activity, reported in 74 (86%) and 54 (62%) studies, respectively. No outcome was reported in every publication. Over half (43/86) of the standardized outcome terms were reported in fewer than five studies, and 21 (25%) were reported in a single study only. There was wide variation in definitions of disease-free survival, colostomy-free survival and progression-free survival (PFS). Anal continence was reported in only 35 (41%) studies. CONCLUSION: Outcomes reported in studies evaluating chemoradiotherapy for ASCC were heterogenous and definitions varied widely. Outcomes likely to be important to patients, such as ano-rectal function, toxicity and QoL, have been neglected. A COS for future trials will address these issues.

The "3 in 1" Study: Pooling Self-Taken Pharyngeal, Urethral, and Rectal Samples into a Single Sample for Analysis for Detection of Neisseria gonorrhoeae and Chlamydia trachomatis in Men Who Have Sex with Men.

Triple-site testing (using pharyngeal, rectal, and urethral/first-void urine samples) for Neisseria gonorrhoeae and Chlamydia trachomatis using nucleic acid amplification tests detects greater numbers of infections among men who have sex with men (MSM). However, triple-site testing represents a cost pressure for services. MSM over 18 years of age were eligible if they requested testing for sexually transmitted infections (STIs), reported recent sexual contact with either C. trachomatis or N. gonorrhoeae, or had symptoms of an STI. Each patient underwent standard-of-care (SOC) triple-site testing, and swabs were taken to form a pooled sample (PS) (pharyngeal, rectal, and urine specimens). The PS was created using two methods during different periods at one clinic, but we analyzed the data in combination because the sensitivity of the two methods did not differ significantly for C. trachomatis (P = 0.774) or N. gonorrhoeae (P = 0.163). The sensitivity of PS testing (92%) was slightly lower than that of SOC testing (96%) for detecting C. trachomatis (P = 0.167). For N. gonorrhoeae, the sensitivity of PS testing (90%) was significantly lower than that of SOC testing (99%) (P < 0.001). When pharynx-only infections were excluded, the sensitivity of PS testing to detect N. gonorrhoeae infections increased to 94%. Our findings show that pooling of self-taken samples could be an effective and cost-saving method, with high negative predictive values. (Interim results of this study were presented at the BASHH 2013 summer meeting.).

Transcatheter aortic valve implantation despite challenging vascular access.

We describe transcatheter aortic valve implantation in a patient who had severe peripheral artery disease. The patient's vascular condition required additional preliminary peripheral intervention to enable adequate vascular access. A 78-year-old man with severe aortic stenosis, substantial comorbidities, and severe heart failure symptoms was referred for aortic valve replacement. The patient's 20-mm aortic annulus necessitated the use of a 23-mm Edwards Sapien valve inserted through a 22F sheath, which itself needed a vessel diameter of at least 7 mm for percutaneous delivery. The left common femoral artery was selected for valve delivery. The left iliac artery and infrarenal aorta underwent extensive intervention to achieve an intraluminal diameter larger than 7 mm. After aortic valvuloplasty, valve deployment was successful, and the transaortic gradient decreased from 40 mmHg to less than 5 mmHg. The patient was discharged from the hospital 4 days postoperatively. We conclude that transcatheter aortic valve implantation can be successfully performed in patients with obstructed vascular access, including stenosis of the infrarenal aorta and the subclavian and coronary arteries.

Mortality in perinatally HIV-infected young people in England following transition to adult care: an HIV Young Persons Network (HYPNet) audit.

OBJECTIVES: Mortality in young people with perinatally acquired HIV infection (PHIV) following transfer to adult care has not been characterized in the UK. We conducted a multicentre audit to establish the number of deaths and associated factors. METHODS: Fourteen adult clinics caring for infected young people reported deaths to 30 September 2011 on a proforma. Deaths were matched to the Collaborative HIV Paediatric Study, a clinical database of HIV-infected children in the UK/Ireland, to describe clinical characteristics in paediatric care of those who died post-transition. RESULTS: Eleven deaths were reported from 14 clinics which cared for 248 adults with PHIV. For the 11 deaths, the median age at transfer to adult care was 17 years (range 15-21 years), and at death was 21 years (range 17-24 years). Causes of death were suicide (two patients), advanced HIV disease (seven patients) and bronchiectasis (one patient), with one cause missing. At death, the median CD4 count was 27 cells/µL (range 0-630 cells/µL); five patients were on antiretroviral therapy (ART) but only two had a viral load < 50 HIV-1 RNA copies/mL. Nine had poor adherence when in paediatric care, continuing into adult care despite multidisciplinary support. Eight had ART resistance, although all had potentially suppressive regimens available. Nine had mental health diagnoses. CONCLUSIONS: Our findings highlight the complex medical and psychosocial issues faced by some adults with PHIV, with nine of the 11 deaths in our study being associated with poor adherence and advanced HIV disease. Novel adherence interventions and mental health support are required for this vulnerable cohort.

Modelling the cost-effectiveness of mitigation methods for multiple pollutants at farm scale.

Reductions in agricultural pollution are essential for meeting nationally and internationally agreed policy targets for losses to both air and water. Numerous studies quantify the impact of relevant mitigation methods by field experimentation or computer modelling. The majority of these studies have addressed individual methods and frequently also individual pollutants. This paper presents a conceptual model for the synthesis of the evidence base to calculate the impact of multiple methods addressing multiple pollutants in order to identify least cost solutions for multiple policy objectives. The model is implemented as a farm scale decision support tool that quantifies baseline pollutant losses for identifiable sources, areas and pathways and incorporates a genetic algorithm based multi-objective procedure for determining optimal suites of mitigation methods. The tool is generic as baseline losses can be replaced with measured data and the default library of mitigation methods can be edited and expanded. The tool is demonstrated through application to two contrasting farm systems, using survey data on agricultural practices typical of England and Wales. These examples show how the tool could be used to help target the adoption of mitigation options for the control of diffuse pollution from agriculture. The feedback from workshops where Farmscoper was demonstrated is included to highlight the potential role of Farmscoper as part of the farm advisory process.

Trends in attendances to genitourinary medicine services by older women.

We sought to analyse reasons for attendance of older women (defined as aged 46 years and over) to genitourinary (GU) medicine services at two UK clinics. We used KC60 coding data to count new episode attendances by year from 1998 to 2008 and to further dissect reason for attendance in 2827 new episodes during 2003-2008. The total number of new episodes of attendance in older women increased from 167 in 1998 to 701 in 2008. Within this overall increase, there was a stable proportion of acute sexually transmitted infections (STIs) over time, alongside significant increases in the proportion of women requesting STI screening and HIV testing and those attending GU medicine for other reasons, such as dermatological or gynaecological complaints. In our clinic population it was encouraging to see that older women increasingly use GU medicine services for STI screening and HIV testing. Services may need to adapt to older women's specific health-care needs.

Restoration of microcirculatory patency after myocardial infarction: results of current coronary interventional strategies and techniques.

We sought to evaluate the restoration of microcirculatory patency after primary percutaneous coronary intervention (PCI) in an unselected cohort of patients at a tertiary center.We retrospectively evaluated distributions of the Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG) and the myocardial blush grade (MBG) in all primary PCI procedures performed at our institution during 2008. We defined optimal microvascular perfusion as simultaneous TMPG 3 and MBG 3 at procedure's end.Ninety-nine patients (mean age, 61.5 ± 12.7 yr; 64 men) underwent primary PCI. Microvascular perfusion was optimal in 69 patients (69.7%) and was associated with lower peaks of enzymes than those occurring in patients with suboptimal perfusion. When optimal microvascular perfusion was achieved, early spontaneous recanalization was more frequently observed, as expressed by a higher frequency of TIMI-3 flow (34.8% vs 10%; P=0.006), TMPG 3 (26% vs 3.3%; P=0.004), and MBG 3 (24.6% vs 3.3%; P=0.004) on the initial angiogram before primary PCI. A higher frequency of MBG 3 (50% vs 20%; P=0.005) was seen after initial recanalization in patients with optimal microvascular perfusion. Multiple regression analysis showed that MBG after initial recanalization and the use of drug-eluting stents were associated with optimal perfusion.Despite successful recanalization of the culprit coronary artery, optimal microvascular perfusion was achieved in less than 75% of the patients. Restoration of the microvasculature was associated with smaller infarcts. Procedure-related variables associated with suboptimal perfusion were unlikely to be causative.

Mechanical behavior of fully expanded commercially available endovascular coronary stents.

The mechanical behavior of endovascular coronary stents influences their therapeutic efficacy. Through computational studies, researchers can analyze device performance and improve designs. We developed a 1-dimensional finite element method, net-based algorithm and used it to analyze the effects of radial loading and bending in commercially available stents. Our computational study included designs modeled on the Express, Cypher, Xience, and Palmaz stents.We found that stents that did not fully expand were less rigid than the fully expanded stents and, therefore, exhibited larger displacement. Stents with an open-cell design, such as Express-like or Xience-like stents, had a higher bending flexibility. Stents with in-phase circumferential rings, such as the Xience-like stent, had the smallest longitudinal extension when exposed to radial compression forces. Thus, the open-cell model that had in-phase circumferential rings connected by straight horizontal struts exhibited radial stiffness, bending flexibility, and the smallest change in stent length during radial forcing. The Palmaz-like stent was the most rigid of all. These findings are supported by clinical experience.Computer simulations of the mechanical properties of endovascular stents offer sophisticated insights into the mechanical behavior of different stent designs and should be used whenever possible to help physicians decide which stent is best for treating a given lesion. Our 1-dimensional finite element method model is incomparably simpler, faster, and more accurate than the classical 3-dimensional approaches. It can facilitate stent design and may aid in stent selection in the clinical setting.

Automated blood sampling to identify pharmacodynamics biomarkers of corticotrophin releasing factor receptor 1 antagonism.

INTRODUCTION: The aim of this study was to use an automated blood sampling technique to measure soluble hormones following an ovine corticotrophin releasing factor (oCRF) challenge using pharmacological doses that significantly inhibit brain CRF(1) receptors. METHODS: A high throughput crude homogenate CRF(1) receptor binding assay was used to measure binding affinity, dose and time occupancy and exposure relationships in rat brain. From these studies a 30 mg/kg dose of DMP904 was selected to test in an oCRF challenged hormone release assay using an automated blood sampler. RESULTS: DMP904 dose-dependently displaced [(125)I]oCRF ex vivo binding in crude rat cortex homogenates with a mean ID(50) of 0.4±0.08 mg/kg (n=4). DMP904 receptor occupancy remained greater than 90% over a 24h time period, despite a decrease in free plasma concentration. A dose of 30 mg/kg completely abolished an oCRF stimulated increase in plasma corticosterone and adrenocorticotropic hormone (ACTH), as measured by an automated blood sampler. There were no significant alterations to either basal or stimulated pituitary derived hormones measured. DISCUSSION: In conclusion, we have shown for the first time, an automated blood sampling technique that can be incorporated to identify pharmacodynamic biomarkers in-vivo. This technology can be used successfully to reduce the number of animals and improve the quality of biomarker measures. Furthermore, at least for DMP904, to elicit a marked inhibition on plasma corticosterone levels, doses that produce greater than 95% brain occupancy are required.

Rosuvastatin therapy does not affect serum MMP-13 or TIMP-1 levels in hypercholesterolemic patients.

Matrix metalloproteinases degrade the collagen content of atherosclerotic plaque and reduce plaque stability. In tissue sections of atherosclerotic plaque, the expression of matrix metalloproteinases is increased. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decrease the tissue expression of matrix metalloproteinases-1, -2, -3, and -9 in atheromatous plaque by attenuating the inflammatory process that leads to increased expression. However, it is not known whether statins decrease levels of matrix metalloproteinase-13--an enzyme crucial to the initiation of collagen degradation-as part of their plaque-stabilizing effect.We prospectively examined the effect of statin therapy on serum levels of matrix metalloproteinase-13, tissue inhibitor of metalloproteinase-1, and low-density-lipoprotein cholesterol in 14 patients with hypercholesterolemia. All were at low risk for adverse cardiovascular events and were given 20 mg/d of rosuvastatin for 4 weeks. Post-therapy levels of matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 were compared with baseline levels. Although low-density-lipoprotein cholesterol levels were significantly decreased in the 14 patients (mean baseline level, 152 ± 21 mg/dL vs mean post-therapy level, 73 ± 45 mg/dL; P < 0.001), matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 levels were unchanged (matrix metalloproteinase-13, 0.295 ± 0.06 ng/mL vs 0.323 ± 0.11 ng/mL, P = 0.12; and tissue inhibitor of metalloproteinase-1, 400.8 ± 43.4 ng/mL vs 395.3 ± 47.5 ng/mL, P = 0.26). We conclude that even though there was a decrease in low-density-lipoprotein cholesterol, short-term, high-dose rosuvastatin therapy has no effect on matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 levels in hypercholesterolemic patients. However, further investigation is warranted.

The potential for non-heart beating organ donation within a paediatric intensive care unit.

OBJECTIVE: In the UK, the number of patients waiting for an organ transplant has increased by 30% since 2001. Non-heart beating organ donation (NHBD) programmes are advocated as a means of increasing the number of potential donors. Such programmes remain in their infancy within paediatrics. We examined all deaths in our paediatric intensive care unit (PICU) between January 2005 and December 2008 to establish the number of potential NHB donors. We further obtained data from UK NHS Blood and Transplant detailing all paediatric patients that became heart beating and NHB donors in the UK over the same period. DESIGN: (A) Data obtained from UK NHS Blood and Transplant detailing the number of organ donors within the unit and within the UK. (B) Retrospective review of our paediatric intensive care mortality database and patient notes to identify patients aged 1-16 years who died in the PICU over the same period. Assessment of patient suitability for NHBD was made according to predetermined exclusion criteria. RESULTS: During the study period, 126 children died in the PICU. Three children were referred for heart beating organ donation (two proceeded to be donors). Nine children were referred for NHBD (three proceeded to be donors). Of the remaining 114 patients, 39 (34%) were aged >1 year and died following active withdrawal of treatment. Of these 39, 27 (69%) had relative contraindications, leaving 12 patients that might have been considered as potential NHB donors. If a 50% conversion rate is used, six children may have been realised as actual NHB donors. CONCLUSION: If this situation were replicated in the PICUs throughout the UK, it would represent a significant increase in the number of organs available for transplantation.