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.

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.

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.).

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.

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.

An interleukin 5 mutant distinguishes between two functional responses in human eosinophils.

Interleukin 5 (IL-5) is the key cytokine involved in regulating the production and many of the specialized functions of mature eosinophils including priming, adhesion, and survival. We have generated a point mutant of human IL-5, IL-5 (E12K), which is devoid of agonist activity in both a TF-1 cell proliferation assay and a human eosinophil adhesion assay. However, IL-5 (E12K) is a potent and specific antagonist of both these IL-5-dependent functional responses. In both receptor binding and cross-linking studies the wild-type and IL-5 (E12K) mutant exhibit virtually identical properties. This mutant protein was unable to stimulate tyrosine phosphorylation in human eosinophils, and blocked the phosphorylation stimulated by IL-5. In contrast, IL-5 (E12K) is a full agonist in a human eosinophil survival assay, although with reduced potency compared to the wild-type protein. This IL-5 mutant enables us to clearly distinguish between two IL-5-dependent functional responses and reveals distinct mechanisms of receptor/cellular activation.

Establishing relative release kinetics of faecal indicator organisms from different faecal matrices.

AIMS: A laboratory assay for comparative characterization of various faecal matrices with respect to faecal indicator organism (FIO) release using, artificial rain water. METHODS AND RESULTS: Fresh sheep and beef-cattle faeces, dairy cattle slurry and beef cattle farm yard manure (FYM) were collected from commercial units in south-west England and applied to 20 randomized 1 m(2) plots established on permanent grassland. Representative samples from each faecal matrix (n = 5) were collected on four occasions over 16 days. One gram of each sample was transferred to a sterile vial to which 9 ml of standard local rain was carefully pipetted. The vial was then rotated through 360 degrees, 20 times in 60 s to 'simulate' a standardized interaction of the faecal material with rainfall, providing an assay of comparative release potential. Appropriate decimal dilutions were prepared from the eluent. Following agitation, with a sterile spatula, the remaining faecal material and eluent in the vials were vortex mixed for 60 s before decimal dilutions were prepared from the resulting mixture, providing a quantitative assessment of the total FIO in the sample from which percentage release could be determined. Bacterial concentrations were enumerated in duplicate by membrane filtration following standard methods for FIO. Significant differences in release kinetics of Escherichia coli and enterococci from each of the faecal matrices were determined. CONCLUSIONS: Differences in release from each faecal substrate and between FIO type (E. coli and intestinal enterococci) were observed in this laboratory study. The order of release of E. coli from the faecal matrices (greatest to least, expressed as a percentage of the total present) was dairy cattle slurry > beef cattle FYM > beef-cattle faeces > sheep faeces. For intestinal enterococci the order of percentage release was dairy cattle slurry > beef-cattle faeces > beef cattle FYM > sheep faeces. SIGNIFICANCE AND IMPACT OF THE STUDY: This laboratory-based method provides the first data on the relative release kinetics of FIO from different faecal matrices in rain water. This is fundamental information needed to parameterize laboratory-based microbial models and inform approaches to field and catchment risk assessment.

Clostridial typhlitis associated with topical antibiotic therapy in a Syrian hamster.

A Syrian hamster that had been treated with topical antibiotic ointment for 10 days following injuries sustained during fighting was presented moribund. Postmortem and microscopic examinations revealed lesions consistent with clostridial typhlitis and enteritis. Anaerobic culture of caecal contents resulted in the isolation of two Clostridium species, and caecal contents contained Clostridium difficile enterotoxins. Based on these findings, a diagnosis of acute C. difficile enterotoxaemia was made. This report discusses the pathogenesis of C. difficile enterotoxaemia and the potential role of topical antibiotic ointment therapy in initiating the disease.

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.

Reflex increase in blood pressure during the intracoronary administration of adenosine in man.

Infusion of adenosine (0.022-2.2 mg/min) into the left anterior descending (LAD) coronary artery of 26 patients produced a dose-dependent increase in blood pressure without a change in heart rate. At adenosine 2.2 mg/min, systolic pressure rose by 21.0 +/- 2.2 mmHg from 134 +/- 4.3 mmHg (P less than 0.001) and diastolic pressure increased by 10.4 +/- 1.1 mmHg from 76 +/- 1.9 mmHg (P less than 0.001). The rise in arterial pressure was associated with a 22 +/- 3.4% increase in systemic vascular resistance (P less than 0.01) and no change in cardiac output (-2.8 +/- 4.3%, P = NS). Plasma norepinephrine levels rose by 40 +/- 14% from 105 +/- 9 pg/ml (P less than 0.05) and epinephrine levels by 119 +/- 31% from 37 +/- 9 pg/ml (P less than 0.01). Right atrial infusion of adenosine produced insignificant hemodynamic effects, suggesting that systemic spillover of adenosine was not responsible for the observed effects. In 20 cardiac transplant patients with denervated hearts, LAD infusion of adenosine (2.2 mg/min) produced no change in systolic pressure (-0.1 +/- 1.6 mmHg from 139 +/- 3.4 mmHg, P = NS) and a decrement in diastolic pressure (-4.7 +/- 1.2 mmHg from 98 +/- 2.5 mmHg, P less than 0.01). Thus, infusion of adenosine into the LAD coronary artery causes a reflex increase in arterial pressure due to a rise in systemic vascular resistance, probably as a result of increased sympathetic discharge. This reflex pathway may be of importance in disease states such as myocardial ischemia, in which myocardial adenosine levels are elevated.

Responses of coronary arteries of cardiac transplant patients to acetylcholine.

Accelerated coronary atherosclerosis is a major cause of graft failure after heart transplantation. Graft atherosclerosis is typically diffuse and difficult to detect even with coronary arteriography. Recently, acetylcholine was shown to dilate blood vessels by releasing a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). We have demonstrated paradoxical vasoconstriction induced by acetylcholine both early and late in the course of coronary atherosclerosis in patients, suggesting an association of endothelial dysfunction and atherosclerosis. In this report, we tested the hypothesis that coronary arteries of heart transplant patients can show endothelial dysfunction before or in the early stages of angiographically evident coronary atherosclerosis. Acetylcholine was infused into the left anterior descending artery of 13 heart transplant patients at 12 (n = 9) and 24 (n = 4) mo after transplantation. Vascular responses were evaluated by quantitative angiography. Among patients with angiographically smooth coronary arteries, relatively few (6/25) arterial segments had preserved vasodilator responses, while the majority failed to dilate (10/25) or paradoxically constricted (9/25). Angiographically irregular coronary arteries were present in three patients, in whom 8/10 segments showed marked paradoxical constriction and the remaining 2/10 failed to dilate. Only 1 of 13 patients retained appropriate dilation to acetylcholine in all segments. Nitroglycerin, which acts directly on vascular smooth muscle, dilated nearly all segments. No clinical features of the patients, including myocardial rejection appeared to correlate with the impaired functional response of vessels. Thus impaired response to acetylcholine is a common early finding in heart transplant patients and emphasizes the potential importance of endothelial dysfunction in the development of atherosclerosis.

Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise.

We studied the vasomotion of epicardial coronary arteries during exercise and tested the hypotheses that abnormal vasoconstriction is related to the presence of atherosclerosis and may be related to endothelial dilator dysfunction. During cardiac catheterization quantitative coronary angiography was performed in 21 patients during supine bicycle exercise. 21 of 28 smooth, angiographically normal vessel segments dilated (14.0 +/- 1.8%) during exercise; four smooth segments did not change whereas only three constricted. In contrast, 15 of 16 vessel segments with irregularities constricted in response to exercise (17.0 +/- 0.1%) with only one segment dilating. All 10 stenotic segments constricted to exercise (23 +/- 4%). Six patients also received intracoronary acetylcholine before exercise to test endothelium-dependent dilator function. In five of six patients all nine vessel segments showed the same directional response to acetylcholine and exercise. Three irregular and two stenotic segments constricted with acetylcholine (51 +/- 21%) and exercise (9.0 +/- 0.6%). In contrast, four smooth segments dilated to acetylcholine (19 +/- 6%) and exercise (9 +/- 1%). Both exercise and acetylcholine generally dilated smooth but constricted irregular and stenosed coronary segments. It appears likely that atherosclerosis plays an important role in the abnormal vasomotion of diseased coronary arteries during exercise and the pattern of abnormality suggests impairment of vasodilator function.

Characterization of endothelial-like cells derived from human mesenchymal stem cells.

BACKGROUND: Blood-derived endothelial progenitor cells (EPC) have been used to treat ischemic disease. However, the number of EPC that can be obtained from adult blood is limited. OBJECTIVE: To characterize endothelial-like cells obtained from human bone marrow and determine their ability to stimulate new blood vessel formation in vivo. METHODS: Mononuclear cells (MNC) were isolated from human bone marrow or umbilical cord blood and cultured in endothelial growth medium (EGM-2). Mesenchymal stem cells (MSC) were isolated from bone marrow and induced to differentiate into endothelial-like cells (MSCE), or adipocytes or osteocytes by growth in EGM-2, adipogenic or osteogenic medium. RESULTS: Cells obtained by culturing bone marrow MNC in EGM-2 formed cord- or tube-like structures when grown on Matrigel(TM) and expressed several endothelial marker proteins. However, cell morphology and the profile of endothelial marker protein expression were different from those of cord blood-derived EPC (cbEPC). Cells with a similar phenotype were obtained by differentiation of MSC into MSCE, which was accompanied by an increase of endothelial marker proteins and a diminished capacity to differentiate into adipocytes. Subcutaneous implantation of MSCE in collagen plugs in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice resulted in formation of functional blood vessels that had incorporated the MSCE. CONCLUSIONS: Our results show that MSCE and cbEPC are different cell types. The formation of functional blood vessels by MSCE, combined with high yields and a reduced capacity to differentiate into other cell types compared with MSC, makes these cells potentially useful for autologous therapy of ischemic disease.

A genome-based approach for the identification of essential bacterial genes.

We have used comparative genomics to identify 26 Escherichia coli open reading frames that are both of unknown function (hypothetical open reading frames or y-genes) and conserved in the compact genome of Mycoplasma genitalium. Not surprisingly, these genes are broadly conserved in the bacterial world. We used a markerless knockout strategy to screen for essential E. coli genes. To verify this phenotype, we constructed conditional mutants in genes for which no null mutants could be obtained. In total we identified six genes that are essential for E. coli (yhbZ, ygjD, ycfB, yfil, yihA, and yjeQ). The respective orthologs of the genes yhbZ, ygjD, ycfB, yjeQ, and yihA are also essential in Bacillus subtilis. This low number of essential genes was unexpected and might be due to a characteristic of the versatile genomes of E. coli and B. subtilis that is comparable to the phenomenon of nonorthologous gene displacement. The gene ygjD, encoding a sialoglycoprotease, was eliminated from a minimal genome computationally derived from a comparison of the Haemophilus influenzae and M. genitalium genomes. We show that ygjD and its ortholog ydiE are essential in E. coli and B. subtilis, respectively. Thus, we include this gene in a minimal genome. This study systematically integrates comparative genomics and targeted gene disruptions to identify broadly conserved bacterial genes of unknown function required for survival on complex media.

Long-term outcome of patients treated with repeat percutaneous coronary intervention after failure of gamma-brachytherapy for the treatment of in-stent restenosis.

BACKGROUND: Although (192)Ir intracoronary brachytherapy has been demonstrated to dramatically reduce the recurrence of in-stent restenosis, up to 24% of these patients will still require repeat target-vessel revascularization. The short- and long-term outcomes of repeat percutaneous intervention in this population have not been characterized. METHODS AND RESULTS: Analysis was performed of all patients enrolled in the GAMMA-I and GAMMA-II brachytherapy trials who underwent repeat percutaneous target lesion revascularization (TLR) because of restenosis. Subjects were divided into 2 cohorts: those who had received (192)Ir brachytherapy and those randomized to placebo. Forty-five (17.6%) of a total of 256 patients whose index treatment was intracoronary radiation therapy and 36 (29.8%) of 121 patients whose index treatment was placebo required repeat percutaneous TLR. The mean time to this first TLR was 295+/-206 days in the irradiated group and 202+/-167 days in the placebo group (P=0.03). Acute procedural success occurred in 100% of irradiated patients and 94% of placebo controls (P=0.19). After the first TLR, a subsequent TLR was required in 15 (33.3%) of 45 brachytherapy patients versus 17 (47.2%) of 36 placebo failure patients (P=0.26). There was no significant difference in time to second TLR between the 2 groups. Other long-term major adverse event rates in both groups were comparable to those of other contemporary angioplasty/stenting series. CONCLUSIONS: In those patients who "fail" (192)Ir intracoronary brachytherapy for in-stent restenosis, treatment with (192)Ir delays the time to first TLR. Additionally, repeat percutaneous intervention in these patients is safe and efficacious in the short term, with acceptable long-term results.

The adenosine triphosphate test: a bedside diagnostic tool for identifying the mechanism of supraventricular tachycardia in patients with palpitations.

OBJECTIVES: This study assesses the value of the "ATP test" (injection of adenosine triphosphate [ATP] during sinus rhythm) for identifying patients with palpitations of unclear etiology who actually have atrioventricular (AV) nodal re-entry tachycardia (AVNRT) or AV re-entry tachycardia (AVRT). BACKGROUND: Because AVNRT and AVRT can be cured with radiofrequency ablation, documentation of spontaneous AVNRT or AVRT usually prompts referral for electrophysiologic (EP) evaluation. However, these paroxysmal arrhythmias may elude clinical diagnosis. We recently showed that administration of ATP during sinus rhythm often reveals dual AV node physiology or a concealed accessory pathway (AP) in patients with documented AVNRT or AVRT. Thus, we postulated that the ATP test could identify patients with palpitations who actually have AVNRT or AVRT and would therefore benefit from EP evaluation. METHODS: One hundred forty-six patients (54 with "palpitations without documented arrhythmias" and 92 with "documentation of arrhythmias of unclear mechanism") underwent a noninvasive ATP test. ATP was injected during sinus rhythm using 10 mg increments. The ATP test was considered positive when prospectively defined signs of dual AV node physiology or concealed AP were disclosed in the electrocardiogram. These findings were correlated with the results of EP evaluation. RESULTS: A positive ATP test predicted induction of AVNRT or AVRT with a positive predictive value of 93% (sensitivity 71%) but a negative predictive value of 37% (specificity 76%). CONCLUSIONS: A bedside ATP test identifies patients with palpitations who are likely to have AVNRT or AVRT (and who are therefore likely to benefit from EP evaluation) with a high positive predictive value.

Adenosine-5'-triphosphate test for the noninvasive diagnosis of concealed accessory pathway.

OBJECTIVES: This study assessed the use of adenosine triphosphate (ATP) in the noninvasive diagnosis of concealed accessory pathway (AP) and dual atrioventricular (AV) node physiology in patients with inducible AV reentrant tachycardia (AVRT). BACKGROUND: Administration of ATP during sinus rhythm identifies dual AV node physiology in 76% of patients with inducible sustained slow/fast AV nodal reentry tachycardia (AVNRT). METHODS: Incremental doses of ATP were intravenously administered during sinus rhythm to 34 patients with inducible sustained AVRT involving a concealed AP and to 27 control patients without AP or dual AV node physiology. One study group patient could not complete the study and was excluded from analysis. RESULTS: The AV reentrant echo beats (AVRE), or AVRT, suggestive of the presence of concealed AP, were observed after ATP administration in 24 (73%) study patients and in none of the control group. Electrocardiographic signs suggestive of dual AV node physiology were observed after ATP administration in 7 (21%) study patients and in none of the control group. Most instances of AVRE/AVRT were preceded by a slight increase (<50 ms) in PR interval. In 8 of 9 patients tested, neither AVRE nor AVRT was no longer observed following ATP administration after successful radiofrequency ablation of the AP. In the remaining patient, a different AVRE due to the presence of an additional AP was observed. CONCLUSIONS: Administration of ATP during sinus rhythm may be a useful bedside test for identifying patients with concealed AP who are prone to AVRT and those with associated dual AV node pathways.