Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S): a randomized pilot clinical trial.

BACKGROUND: Ticagrelor is a reversibly binding, direct-acting, oral, P2Y12 antagonist used for the prevention of atherothrombotic events in patients with coronary artery disease (CAD). Ticagrelor blocks adenosine reuptake through the inhibition of equilibrative nucleoside transporter 1 (ENT-1) on erythrocytes and platelets, thereby facilitating adenosine-induced physiological responses such as an increase in coronary blood flow velocity. Meanwhile, adenosine plays an important role in triggering ischemic preconditioning through the activation of the A1 receptor. Therefore, an increase in ticagrelor-enhanced adenosine bioavailability may confer beneficial effects through mechanisms related to preconditioning activation and improvement of coronary microvascular dysfunction. METHODS: To determine whether ticagrelor can trigger ischemic preconditioning and influence microvascular function, we designed this prospective, open-label, pilot study that enrolled patients with stable multivessel CAD requiring staged, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI). Participants will be randomized in 1:1 ratios either to ticagrelor (loading dose (LD) 180 mg, maintenance dose (MD) 90 mg bid) or to clopidogrel (LD 600 mg, MD 75 mg) from 3 to 1 days before the scheduled PCI. The PCI operators will be blinded to the randomization arm. The primary endpoint is the delta (difference) between ST segment elevations (in millimeters, mm) as assessed by intracoronary electrocardiogram (ECG) during the two-step sequential coronary balloon inflation in the culprit vessel. Secondary endpoints are 1) changes in coronary flow reserve (CFR), index of microvascular resistance (IMR), and FFR measured in the culprit vessel and reference vessel at the end of PCI, and 2) angina score during inflations. This study started in 2018 with the aim of enrolling 100 patients. Based on the rate of negative FFR up to 30% and a drop-out rate up to 10%, we expect to detect an absolute difference of 4 mm among the study arms in the mean change of ST elevation following repeated balloon inflations. All study procedures were reviewed and approved by the Ethical Committee of the Catholic University of Sacred Heart. DISCUSSION: Ticagrelor might improve ischemia tolerance and microvascular function compared to clopidogrel, and these effects might translate to better long-term clinical outcomes. TRIAL REGISTRATION: EudraCT No. 2016-004746-28. No. NCT02701140.  TRIAL STATUS: Information provided in this manuscript refers to the definitive version (n. 3.0) of the study protocol, dated 31 October 2017, and includes all protocol amendments. Recruitment started on 18 September 2018 and is currently ongoing. The enrollment is expected to be completed by the end of 2019. TRIAL SPONSOR: Fondazione Policlinico Universitario A. Gemelli - Roma, Polo di Scienze Cardiovascolari e Toraciche, Largo Agostino Gemelli 8, 00168 Rome, Italy.

Individual participant data pooled-analysis of risk factors for recurrence after neoadjuvant radiotherapy and transanal local excision of rectal cancer: the PARTTLE study.

BACKGROUND: An organ-preserving strategy may be a valid alternative in the treatment of selected patients with rectal cancer after neoadjuvant radiotherapy. Preoperative assessment of the risk for tumor recurrence is a key component of surgical planning. The aim of the present study was to increase the current knowledge on the risk factors for tumor recurrence. METHODS: The present study included individual participant data of published studies on rectal cancer surgery. The literature was reviewed according to according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data checklist (PRISMA-IPD) guidelines. Series of patients, whose data were collected prospectively, having neoadjuvant radiotherapy followed by transanal local excision for rectal cancer were reviewed. Three independent series of univariate/multivariate binary logistic regression models were estimated for the risk of local, systemic and overall recurrence, respectively. RESULTS: We identified 15 studies, and 7 centers provided individual data on 517 patients. The multivariate analysis showed higher local and overall recurrences for ypT3 stage (OR 4.79; 95% CI 2.25-10.16 and OR 6.43 95% CI 3.33-12.42), tumor size after radiotherapy > 10 mm (OR 5.86 95% CI 2.33-14.74 and OR 3.14 95% CI 1.68-5.87), and lack of combined chemotherapy (OR 3.68 95% CI 1.78-7.62 and OR 2.09 95% CI 1.10-3.97), while ypT3 was the only factor correlated with systemic recurrence (OR 5.93). The analysis of survival curves shows that the overall survival is associated with ypT and not with cT. CONCLUSIONS: Local excision should be offered with caution after neoadjuvant chemoradiotherapy to selected patients with rectal cancers, who achieved a good response to neoadjuvant chemoradiotherapy.

Multicentre randomized clinical trial of colonic J pouch or straight stapled colorectal reconstruction after low anterior resection for rectal cancer.

BACKGROUND: Colonic J pouch reconstruction has been found to be associated with a lower incidence of anastomotic leakage than straight anastomosis. However, studies on this topic are underpowered and retrospective. This randomized trial evaluated whether the incidence of anastomotic leakage was reduced after colonic J pouch reconstruction compared with straight colorectal anastomosis following anterior resection for rectal cancer. METHODS: This multicentre RCT included patients with rectal carcinoma who underwent low anterior resection followed by colorectal anastomosis. Patients were assigned randomly to receive a colonic J pouch or straight colorectal anastomosis. The main outcome measure was the occurrence of major anastomotic leakage. The incidence of global (major plus minor) anastomotic leakage and general complications were secondary outcomes. Risk factors for anastomotic leakage were identified by regression analysis. RESULTS: Of 457 patients enrolled, 379 were evaluable (colonic J pouch arm 190, straight colorectal arm 189). The incidence of major and global anastomotic leakage, and general complications was 14·2, 19·5 and 34·2 per cent respectively in the colonic J pouch group, and 12·2, 19·0 and 27·0 per cent in the straight colorectal anastomosis group. No statistically significant differences were observed between the two arms. In multivariable logistic regression analysis, male sex (odds ratio 1·79, 95 per cent c.i. 1·02 to 3·15; P = 0·042) and high ASA fitness grade (odds ratio 2·06, 1·15 to 3·71; P = 0·015) were independently associated with the occurrence of anastomotic leakage. CONCLUSION: Colonic J pouch reconstruction does not reduce the incidence of anastomotic leakage and postoperative complications compared with conventional straight colorectal anastomosis. Registration number NCT01110798 (http://www.clinicaltrials.gov).

Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study.

BACKGROUND: Rectum-sparing approaches appear to be appropriate in rectal cancer patients with a major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The aim of the present study is to evaluate the effectiveness of rectum-sparing approaches at 2 years after the completion of neoadjuvant treatment. STUDY DESIGN: Patients with rectal adenocarcinoma eligible to receive neoadjuvant therapy will be prospectively enrolled. Patients will be restaged 7-8 weeks after the completion of neoadjuvant therapy and those with mCR (defined as absence of mass, small mucosal irregularity no more than 2 cm in diameter at endoscopy and no metastatic nodes at MRI) or cCR will be enrolled in the trial. Patients with mCR will undergo local excision, while patients with cCR will either undergo local excision or watch and wait policy. The main end point of the study is to determine the percentage of rectum preservation at 2 years in the enrolled patients. CONCLUSION: This protocol is the first prospective trial that investigates the role of both local excision and watch and wait approaches in patients treated with neoadjuvant therapy for rectal cancer. The trial is registered at clinicaltrials.gov (NCT02710812).

In-hospital mortality, 30-day readmission, and length of hospital stay after surgery for primary colorectal cancer: A national population-based study.

INTRODUCTION: The simultaneous assessment of multiple indicators for quality of care is essential for comparisons of performance between hospitals and health care systems. The aim of this study was to assess the rates of in-hospital mortality and 30-day readmission and length of hospital stay (LOS) in patients who underwent surgical procedures for colorectal cancer between 2005 and 2014 in Italy. METHODS: All patients in the National Italian Hospital Discharge Dataset who underwent a surgical procedure for colorectal cancer during the study period were included. The adjusted odd ratios for risk factors for in-hospital mortality, 30-day readmission, and LOS were calculated using multilevel multivariable logistic regression. RESULTS: Among the 353 941 patients, rates of in-hospital mortality and 30-day readmission were 2.5% and 6%, respectively, and the median LOS was 13 days. High comorbidity, emergent/urgent admission, male gender, creation of a stoma, and an open approach increased the risks of all the outcomes at multivariable analysis. Age, hospital volume, hospital geographic location, and discharge to home/non-home produced different effects depending on the outcome considered. The most frequent causes of readmission were infection (19%) and bowel obstruction (14.6%). CONCLUSIONS: We assessed national averages for mortality, LOS and readmission and related trends over a 10-year time. Laparoscopic surgery was the only one that could be modified by improving surgical education. Higher hospital volume was associated with a LOS reduction, but our findings only partially support a policy of centralization for colorectal cancer procedures. Surgical site infection was identified as the most preventable cause of readmission.

Routine preoperative chest computed tomography does not influence therapeutic strategy in patients with colorectal cancer.

AIM: Patients with lung metastasis from colorectal cancer (CRC) may benefit from surgical resection. Chest computed tomography (CT) is often included in the preoperative staging. Interpretation of the nature of pulmonary lesions is not always easy and many question its clinical value. METHOD: Clinical data for all patients treated at our institution for CRC have been collected prospectively in a dedicated database. Since August 2008 chest CT has been routinely performed for preoperative staging. The outcome of 147 patients operated on since then (Group A) was compared with a numerically equal group of patients (147) (Group B) treated before the introduction of preoperative routine chest CT. RESULTS: Pulmonary lesions were identified in 45 (30%) patients in Group A and 10 (6.8%) in Group B. Ten and nine lesions, respectively, were interpreted as metastases. In 28 (19%) patients in Group A, the lesions were considered to be indeterminate and only four were confirmed as malignant. Overall metastases were present after 1 year of follow-up in 5 (50%) of 10 patients in Group A and 5 (55%) of 9 in Group B. The global incidence of synchronous and metachronous metastases was 6.8%, with no statistical difference between the two groups. CONCLUSION: This study shows that chest CT reveals a higher number of pulmonary lesions, only a small proportion of which were malignant. The investigation does not add value to routine staging methods in patients with CRC.

Does long-course radiotherapy influence postoperative perineal morbidity after abdominoperineal resection of the rectum for cancer?

AIM: The aim of the study was to define risk factors for perineal wound complications after abdominoperineal resection (APR), with particular reference to preoperative radiotherapy. METHOD: Patients undergoing APR at our institution between 1985 and 2009 were reviewed. Wound complications were classified according to the Center for Disease Control and Prevention classification of surgical site infection (SSI). Perineal complications were identified in patients who had preoperative long-course radiotherapy (Group 1) and those who had surgery alone (Group 2). RESULTS: One hundred and fifty-seven patients met the inclusion criteria. Preoperative radiotherapy was performed in 68 (44.7%) patients (Group 1), and 89 (65.3%) patients (Group 2) underwent surgery alone. The overall rate of perineal wound complications was 14.8%. The wound infection rate was similar in each group (Group 1, 10/68, 14.7%; Group 2, 13/89, 14.9%; P = 0.9). An elevated BMI (>30) was the only factor correlated with perineal morbidity on univariate analysis (P = 0.01). CONCLUSION: Preoperative radiotherapy does not influence perineal healing other than in patients with obesity.

Willingness of gynecologic cancer patients to participate in clinical trials.

OBJECTIVES: Fewer than 5% of cancer patients enroll in clinical trials, delaying their completion and the progress of patient care. Patients who are elderly or members of ethnic minorities participate at even lower rates than the general population. The objective of this study was to identify the factors that motivate or inhibit patient enrollment specifically within the gynecologic oncology population. METHODS: An anonymous, voluntary survey was administered to all new patients presenting in the outpatient gynecologic oncology office for an initial consultation. The questionnaire was developed based on prior surveys in the general oncology literature and included questions about age, demographic information, interest in participation in research, and reasons for declining or desiring participation. Groups were compared with Fisher's Exact Test. RESULTS: There were 98 surveys submitted, of which 79 surveys were completed and included for analysis. The median age of patients was 50 years and the majority (86%) was Caucasian. Only 38% stated they would be unwilling to participate in clinical research, while 20% of the patient population stated they would be willing to participate in clinical trials and 42% were unsure. Factors that reached statistical significance (p=.05) in willingness to participate were age less than 50 years, education level beyond high school, and possession of private insurance. CONCLUSIONS: The percentage of women with gynecologic malignancies willing to participate in clinical trials greatly exceeds the number enrolled. Increasing the use of educational materials, improving patient awareness of clinical trials, and offering enrollment to all patients may increase accrual.

Leukotrienes play protective roles early during experimental VSV encephalitis.

Leukotrienes (LT) are potent lipid mediators of inflammation. 5-Lipoxygenase (5-LO) is the key enzyme in the conversion of arachidonic acid to LT. There are four LT: LTB(4), LTC(4), LTD(4) and LTE(4). LT have been extensively studied in airway inflammation but little is known about their roles in viral infection in the CNS. LTB(4) is a chemoattractant for neutrophils. In this work, we studied the roles of LT in acute vesicular stomatitis virus (VSV) encephalitis. Two methods were used to disrupt 5-LO activity: mice were treated with Zileuton, an enzyme antagonist, or 5-LO genetic knockout mice were used. We found that inhibition or deletion of 5-LO resulted in: (a) impaired process of neutrophil infiltration into the CNS early during viral infection; (b) fewer neurons expressed nitric oxide synthase-1 (NOS-1); (c) higher viral titers 1 day after viral infection; and (d) increased disruption of blood brain barrier (BBB). Our studies suggest that LT are important innate immune players during VSV pathogenesis and are beneficial to the host in early control of viral replication in the CNS.

Expression of rat thrombin receptor and mutants in the baculovirus-infected insect cell system.

The rat thrombin receptor (TR-1) has been expressed in Sf9 cells. Two mutant receptors, one lacking a thrombin cleavage site (RTRM), and the other containing only the extracellular domain of the receptor (ECD), have been expressed. Antibodies to the thrombin receptor activating peptide (TRAP) and to the fibrinogen-binding exosite have been prepared. On Western blots these antibodies bound to TR-1 bands of 65-70 kDa and 44 kDa, similar bands for RTRM, and a doublet of about 10 and 12 kDa for ECD. The free cytosolic Ca++ concentration, measured by Fura-2, increased after thrombin or TRAP stimulation in the cells expressing TR-1. The RTRM cells did not respond to thrombin and had an attenuated response to TRAP. The ECD protein was found in the medium; it was not glycosylated. Both the mutants and the antibodies should be useful for studies of TR-1 structure and function.

Tumor necrosis factor-driven formation of disulfide-linked receptor aggregates.

We have characterized, by ligand blotting, solubilized tumor necrosis factor receptors (TNFR) from K562 cells. Preparations that had been partially purified by gel filtration chromatography yielded two prominent bands of M(r) 60,000 and 75,000 corresponding to the two known TNFR (types I and II, respectively). In addition to these, types I and II TNFR-related species of M(r) > 100,000 were detected after purification by tumor necrosis factor (TNF)-affinity chromatography, suggesting that TNF had driven receptor aggregation during this step. To test this hypothesis ligand blots were performed on receptor preparations that had been partially purified by gel filtration chromatography and incubated with TNF before electrophoretic separation. Indeed, type II TNFR aggregates, but not type I TNFR aggregates, were generated at optimal TNF concentrations. Formation of type II TNFR aggregates in this last experimental setting and of both type I and type II TNFR aggregates during affinity purification could be prevented if an alkylating agent (N-ethylmaleimide) was added during the TNFR-TNF incubation step. Similar results were obtained when intact K562 cells were incubated with TNF and then analyzed for receptor aggregation; type II TNF receptor aggregates were generated at TNF concentrations ranging from 10(-9) to 10(-10) M and their formation was prevented in the presence of N-ethylmaleimide.

Inhibitory effect of suramin on receptor binding and cytotoxic activity of tumor necrosis factor alpha.

The effect of suramin on the binding of human Tumor Necrosis Factor alpha (huTNF alpha) to specific cell-surface receptors as well as on its cytotoxic activity in vitro was investigated. Suramin inhibited both activities in a dose-dependent manner. Experiments designed to discriminate if suramin exerted its inhibitory activity on the ligand or on the receptor showed that the ligand (huTNF alpha) was the most likely target for suramin in this system. These results may explain, in part, the immunosuppressive activities of suramin that have been observed in vivo and suggest that suramin could be useful in those disease states in which hyperproduction of huTNF alpha has been shown to play a pathogenic role.

[Anesthetic management for airway endoscopy in pediatrics]. / Condotta anestesiologica nelle endoscopie respiratorie in età pediatrica.

We describe our experience with anesthesia for airway endoscopy in 60 patients, aged to 10 years. Urgent or out-patient endoscopies were performed during removal of foreign bodies from the airway tract or during "dynamic" pathological diagnosis (laryngomalacia, vocal cord paralysis, tracheomalacia, tracheal/bronchial dyskinesia). Isoflurane induction and local anesthesia of the vocal cords allowed sufficient ventilation and oxygenation of anesthetized spontaneously breathing patients. This anesthetic procedure is suitable in high risk patients like newborns and small children. This technique supports the cardiocirculatory and blood gas analytic parameters, maintaining low airway pressures while depressing respiratory reflexes.

Normal variations in the relationship of the tricuspid valve to the membranous septum in the human heart.

The anatomy of the antero-septal commissure of the tricuspid valve and its relationship to the membranous part of the septum are described in 72 normal hearts from subjects ranging in age from 25 weeks gestation to 13 months. Three major patterns were found. According to whether the contiguous leaflets were fused at the commissure, joined at the circumference of the orifice, or left a gap at the commissural site, the varieties are described as undivided, annular, or gap commissure, respectively. Commissures of annular type showed further morphological varieties, as did the patterns of division of the membranous septum into its atrioventricular and interventricular components. Dominance of the atrioventricular component and/or absence of the interventricular membranous septum were encountered in 38 cases out of 72 (52%). This finding demonstrates that dominance of the atrioventricular membranous septum during fetal life and infancy is not universal. The variability noted in the morphology and position of the antero-septal commissure was not associated with other positional variations of the tricuspid valve.

The medial papillary muscle complex and its related septomarginal trabeculation. A normal anatomical study on human hearts.

The morphology of the medial papillary muscle complex of the right ventricle was studied in 81 normal hearts from subjects ranging in age from 20 weeks of gestation to 13 months. The position of the main medial papillary muscle (of Lancisi) was differentiated in terms of a root and a belly. The anterior aspect of the root was found in a constant position at the basal bifurcation of the septomarginal trabeculation, whereas its belly showed considerable positional variation. Three groups of minor papillary muscles were identified and localised in specific areas in the base of the right ventricle. Taken overall, they formed part of the medial papillary complex. The complex itself was found to be constantly related to the antero-septal commissure of the tricuspid valve. A separate group of septal papillary muscles could be differentiated from the medial papillary complex. The anchorage of the septal leaflet of the tricuspid valve to the ventricular septum was also studied. The antero-superior and postero-inferior portions of this leaflet were found to be supported by the medial and posterior papillary complexes, respectively. Its midportion was connected to the septal group of papillary muscles but much variability was evident. The portion of the septomarginal trabeculation supporting the medial papillary complex, namely the postero-basal division, was studied further. This showed considerable variability and did not form a continuous anatomical spectrum.

The pathology of mitral papillary muscles in mitral regurgitation associated with discrete subaortic stenosis.

Two patients needed mitral valve replacement for severe mitral regurgitation after surgical relief of subaortic stenosis. A third, much older patient (who died) also had mitral regurgitation after surgery to relieve subaortic stenosis and to close a ventricular septal defect. All the mitral valves showed both macroscopic and microscopic abnormalities, the latter being characterized by myocytolysis, vasculitis, and fibrosis. The severity of these abnormalities was inversely proportional to the age of the patient. The findings were compared with those (surgical and necropsy specimens) of five patients with congenital "left-sided" anomalies (group 1) and five with "right-sided" lesions (group 2). Coagulation necrosis and ischemic changes were observed in both of the control groups, but none demonstrated the combination of features observed in the patients with subaortic stenosis. The observation of myocytolysis, vasculitis, and fibrosis suggests that there may be a pathologic substrate for mitral valve malfunction in patients, especially very young ones, with subaortic stenosis.