Greenville Memorial Hospital

BACKGROUND: The incidence of the neonatal abstinence syndrome, a drug-withdrawal syndrome that most commonly occurs after in utero exposure to opioids, is known to have increased during the past decade. However, recent trends in the incidence of the syndrome and changes in demographic characteristics and hospital treatment of these infants have not been well characterized. METHODS: Using multiple cross-sectional analyses and a deidentified data set, we analyzed data from infants with the neonatal abstinence syndrome from 2004 through 2013 in 299 neonatal intensive care units (NICUs) across the United States. We evaluated trends in incidence and health care utilization and changes in infant and maternal clinical characteristics. RESULTS: Among 674,845 infants admitted to NICUs, we identified 10,327 with the neonatal abstinence syndrome. From 2004 through 2013, the rate of NICU admissions for the neonatal abstinence syndrome increased from 7 cases per 1000 admissions to 27 cases per 1000 admissions; the median length of stay increased from 13 days to 19 days (P<0.001 for both trends). The total percentage of NICU days nationwide that were attributed to the neonatal abstinence syndrome increased from 0.6% to 4.0% (P<0.001 for trend), with eight centers reporting that more than 20% of all NICU days were attributed to the care of these infants in 2013. Infants increasingly received pharmacotherapy (74% in 2004-2005 vs. 87% in 2012-2013, P<0.001 for trend), with morphine the most commonly used drug (49% in 2004 vs. 72% in 2013, P<0.001 for trend). CONCLUSIONS: From 2004 through 2013, the neonatal abstinence syndrome was responsible for a substantial and growing portion of resources dedicated to critically ill neonates in NICUs nationwide.

BACKGROUND: In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. METHODS: In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. RESULTS: All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53). CONCLUSIONS: We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270.

PURPOSE: To evaluate the effectiveness of laser-assisted angioplasty for patients with critical limb ischemia (CLI) who were poor candidates for surgical revascularization. METHODS: A prospective registry at 14 sites in the US and Germany enrolled 145 patients with 155 critically ischemic limbs; the patients were poor candidates for bypass surgery owing to inadequate target vessel or saphenous vein, prohibitive cardiac disease, or significant comorbidities (ASA class 4). Additional comorbid risk factors included diabetes in 66%, hypertension in 83%, previous stroke in 21%, and myocardial infarction in 23%. Endovascular treatment included guidewire traversal and excimer laser angioplasty followed by balloon angioplasty with optional stenting. RESULTS: Occlusions were present in 92% of limbs. A mean of 2.7+/-1.4 lesions were treated per limb; the total median treatment length was 11 cm (mean 16.2, range 0.2-123). Stents were implanted in 45% of limbs. Procedural success, defined as <50% residual stenosis in all treated lesions, was seen in 86% of limbs. At 6-month follow-up, limb salvage was achieved in 110 (92%) of 119 surviving patients or 118 (93%) 127 limbs. CONCLUSION: Excimer laser-assisted angioplasty for CLI offers high technical success and limb salvage rates in patients unfit for traditional surgical revascularization.

OBJECTIVES: The purpose of this study was to assess the diagnostic accuracy of the instantaneous wave-free ratio (iFR) to characterize, outside of a pre-specified range of values, stenosis severity, as defined by fractional flow reserve (FFR) ≤0.80, in a prospective, independent, controlled, core laboratory-based environment. BACKGROUND: Studies with methodological heterogeneity have reported some discrepancies in the classification agreement between iFR and FFR. The ADVISE II (ADenosine Vasodilator Independent Stenosis Evaluation II) study was designed to overcome limitations of previous iFR versus FFR comparisons. METHODS: A total of 919 intermediate coronary stenoses were investigated during baseline and hyperemia. From these, 690 pressure recordings (n = 598 patients) met core laboratory physiology criteria and are included in this report. RESULTS: The pre-specified iFR cut-off of 0.89 was optimal for the study and correctly classified 82.5% of the stenoses, with a sensitivity of 73.0% and specificity of 87.8% (C statistic: 0.90 [95% confidence interval (CI): 0.88 to 0.92, p < 0.001]). The proportion of stenoses properly classified by iFR outside of the pre-specified treatment (≤0.85) and deferral (≥0.94) values was 91.6% (95% CI: 88.8% to 93.9%). When combined with FFR use within these cut-offs, the percent of stenoses properly classified by such a pre-specified hybrid iFR-FFR approach was 94.2% (95% CI: 92.2% to 95.8%). The hybrid iFR-FFR approach obviated vasodilators from 65.1% (95% CI: 61.1% to 68.9%) of patients and 69.1% (95% CI: 65.5% to 72.6%) of stenoses. CONCLUSIONS: The ADVISE II study supports, on the basis rigorous methodology, the diagnostic value of iFR in establishing the functional significance of coronary stenoses, and highlights its complementariness with FFR when used in a hybrid iFR-FFR approach. (ADenosine Vasodilator Independent Stenosis Evaluation II-ADVISE II; NCT01740895).

BACKGROUND: Suture knots present several disadvantages in wound closure, because they are tedious to tie and place ischemic demands on tissue. Bulky knots may be a nidus for infection, and they may extrude through skin weeks after surgery. Needle manipulations during knot-tying predispose the surgeon to glove perforation. A barbed suture was developed that is self-anchoring, requiring no knots or slack management for wound closure. The elimination of knot tying may have advantages over conventional wound closure methods. METHODS: This prospective, randomized, controlled trial was designed to show that the use of barbed suture in dermal closure of the Pfannenstiel incision during nonemergent cesarean delivery surgery produces scar cosmesis at 5 weeks that is no worse than that observed with conventional closure using 3-0 polydioxanone suture. Cosmesis was assessed by review of postoperative photographs by a blinded, independent plastic surgeon using the modified Hollander cosmesis score. Secondary endpoints included infection, dehiscence, pain, closure time, and other adverse events. RESULTS: The study enrolled 195 patients, of whom 188 were eligible for analysis. Cosmesis scores did not significantly differ between the barbed suture group and the control group. Rates of infection, dehiscence, and other adverse events did not significantly differ between the two groups. Closure time and pain scores were comparable between the groups. CONCLUSIONS: The barbed suture represents an innovative option for wound closure. With a cosmesis and safety profile that is similar to that of conventional suture technique, it avoids the drawbacks inherent to suture knots.

Patients admitted to acute care frequently require intravenous access to effectively deliver medications and prescribed treatment. For patients with difficult intravenous access, those requiring multiple attempts, those who are obese, or have diabetes or other chronic conditions, determining the vascular access device (VAD) with the lowest risk that best meets the needs of the treatment plan can be confusing. Selection of a VAD should be based on specific indications for that device. In the clinical setting, requests for central venous access devices are frequently precipitated simply by failure to establish peripheral access. Selection of the most appropriate VAD is necessary to avoid the potentially serious complications of infection and/or thrombosis. An international panel of experts convened to establish a guide for indications and appropriate usage for VADs. This publication summarises the work and recommendations of the panel for the Michigan Appropriateness Guide for Intravenous Catheters (MAGIC).

Insulin-like growth factor I (IGF-I) has been identified in human seminal plasma. This study was conducted to determine whether IGF-I is present in bovine seminal plasma, whether sperm cells express the IGF-I receptor (IGF-IR), and whether IGF-I affects sperm motility. Semen samples were collected from bulls by electroejaculation and maintained at 37 degrees C, and motility of sperm was assessed. After centrifugation to separate sperm cells from seminal plasma, the seminal plasma was submitted to a validated heterologous RIA for IGF-I. Significant concentrations of IGF-I (116.29 +/- 40.83 ng/ml expressed as mean +/- SD) were measured in bovine seminal plasma. Sperm cells were washed with buffer and subjected to either radioreceptor assay (RRA) or immunocytochemistry (IC). RRA revealed a single high affinity for the IGF-IR with a Kd of 0.83 nM as determined by the computer program LIGAND. IC, using three monoclonal antibodies, localized the IGF-IR to the acrosomal region of the sperm. Computer-assisted sperm-motion analysis was used to determine the effects of IGF-I and IGF-II on bovine sperm motility parameters. Both IGF-I and IGF-II increased sperm motility and straight-line velocity (p < 0.05) relative to the control. The presence of IGF-IR on sperm, the presence of IGF-I in semen, and the ability of IGF-I to stimulate sperm motility provide evidence that the IGF system may be involved in the fertilization process in the bovine species.

OBJECTIVE: Necrotizing enterocolitis (NEC) is associated with high morbidity and mortality among infants admitted for intensive care. The factors associated with mortality and catastrophic presentation remain poorly understood. Our objective was to describe the factors associated with mortality in infants with NEC and to quantify the degree to which catastrophic presentation contributes to mortality in infants with NEC. Catastrophic NEC was defined before data analysis as NEC that led to death within 7 days of diagnosis. STUDY DESIGN: We performed a retrospective review of the Pediatrix's Clinical Data Warehouse (1997 to 2009, n=560,227) to compare the demographic, therapeutic and outcome characteristics of infants who survived NEC vs those who died. Associations were tested by bivariate and multivariate analysis. RESULT: We compared the 5594 infants diagnosed with NEC and who were discharged home with 1505 infants diagnosed with NEC who died. In multivariate analysis, the factors associated with death (P<0.01 in analysis) were lower estimated gestational age, lower birth weight, treatment with assisted ventilation on the day of diagnosis of NEC, treatment with vasopressors at the time of diagnosis, and Black race. Patients who received only ampicillin and gentamicin on the day of diagnosis were less likely to die. Two-thirds of NEC deaths occurred quickly (<7 days from diagnosis), with a median time of death of one day from time of diagnosis. Infants who died within 7 days of diagnosis had a higher birth weight, more often were on vasopressors and high frequency ventilation at the time of diagnosis compared with patients who died at 7 or more days. Although mortality decreased with increasing gestational age, the proportion of deaths that occurred within 7 days was relatively consistent (65 to 75% of the patients who died) across all gestational ages. CONCLUSION: Mortality among infants who have NEC remains high and infants who die of NEC commonly (66%) die quickly. Most of the factors associated with mortality are related to immaturity, low birth weight and severity of illness.

The spheno-occipital synchondrosis is the joint between the basal portions of the sphenoid and occipital bones in that portion of the skull base usually designated as the clivus. The articulation is similar to the cartilaginous junction between the epiphyses and metaphyses of long bones. A synchondrosis is a temporary union since the connecting cartilage becomes ossified with advancing age. While the times of union of epiphyses to primary centers of the skeleton have been widely studied, a paucity of information is available concerning the normal closure of the spheno-occipital synchondrosis. Embryologic and Anatomic Considerations In the human embryo the earliest evidence of the cranium is found in dense masses of mesenchyme which surround the cranial end of the notochord. Cartilage formation in the developing mesenchyme in this area is apparent at the beginning of the second month of embryonic life. During the ninth and tenth weeks of embryonic life, ossification centers begin to appear in the occipital area, but most of those in the sphenoid area develop much later. Both the occipital and sphenoid bones are of mixed intracartilaginous and intramembranous development. In both bones the intramembranous portions are more laterally situated, while the primitive skull base is entirely intracartilaginous (Henderson and Sherman; Patten). The basilar portion of the occipital bone forms from two ossification centers which coalesce early during development. The body of the sphenoid develops from four centers, two for the presphenoid and two for the postsphenoid section. At birth the body of the sphenoid exists as a unit formed by junction of the basal portions of the presphenoid and post-sphenoid segments of the bone which occurs at approximately the eighth month of fetal life (Goss). The basilar part of the occipital bone is also well developed at birth. During the early years of life bone growth along the synchondrosis is even but, with growth deceleration, relative narrowing appears along the superior aspect of the articulation. Roentgenologic Investigation Prior reports indicate lack of agreement in respect to the time of closure of the spheno-occipital synchondrosis. Observations as to the time of the beginning of ossification vary from puberty (Caffey) to the third decade of life (Pendergrass, Schaeffer, and Hodes). A particularly clear description of the method of closure from above downward has been given by Goss, although he differs with others as to the age of ossification. As a result of these discrepancies, a study was undertaken, on a limited scale, to ascertain more accurately the appearance of the spheno-occipital synchondrosis at different ages and the time of closure. The subjects for examination were chosen at random, an attempt being made to obtain at least two persons with ages corresponding to each yearly interval between five and twenty-five years of age. A total of 47 persons are included in this report.

Abstract Introduction: Establishing an effective midline program involves more than simply learning an insertion technique for a new product. Midline catheters provide a reliable vascular access option for those patients with difficult venous access who would otherwise require multiple venipunctures or the use of higher-risk central lines to maintain access. An effective midline program establishes a protocol for device selection and includes standing orders to facilitate speed to placement. Methods: Our retrospective descriptive review evaluated the successful integration of midline programs into existing vascular access bedside insertion programs in 2 acute care hospitals. The investigator reviewed a convenience sample of hospital patients. Participants in the study included vascular access team managers and team members from the sample sites. Results: The results of this 2-hospital study demonstrate successful integration of a midline program into a bedside insertion program with 0 midline-related infections since initiation. Documentation of overall central line-associated bloodstream infection rates for hospital 1 changed from 1.7/1000 catheter-days to 0.2/1000 catheter-days, reflecting a 78% reduction in infections and a projected cost avoidance of $531,570 annually. Both hospitals demonstrated reduced rates of infection following implementation of a midline program. Conclusions: Midlines have a history of lower risk for both infection and thrombosis compared with central venous devices. Although more research is needed on the more recently developed midline catheters, available evidence suggests that midlines provide a safe and reliable form of vascular access, reducing costs and the risk of infection associated with central venous catheters, especially those placed solely for patients with difficult venous access.

PURPOSE: Redesigning the system of care for the management of patients with type 2 diabetes mellitus has not been well studied in rural communities with a significant minority population and limited health care resources. This study assesses the feasibility and potential for cost-effectiveness of restructuring care in rural fee-for-service practices for predominantly minority patients with diabetes mellitus. METHODS: This was a feasibility study of implementing case management, group visits, and electronic registry in 5 solo or small group primary care practices in rural North Carolina. The subjects were 314 patients with type 2 diabetes mellitus (mean age = 61 years; 72% African American; 54% female). An advanced practice nurse visited each practice weekly for 12 months, provided intensive diabetes case management, and facilitated a 4-session group visit educational program. An electronic diabetes registry and visit reminder systems were implemented. RESULTS: There was an improvement in the percentage of patients achieving diabetes management goals and an improvement in productivity and billable encounters. The percentage of patients with a documented self-management goal increased from 0% to 42%, a currently documented lipid panel from 55% to 76%, currently documented aspirin use from 25% to 37%, and currently documented foot examination from 12% to 54%. The average daily encounter rate improved from 20.17 to 31.55 on intervention days. CONCLUSIONS: A redesigned care delivery system that uses case management with structured group visits and an electronic registry can be successfully incorporated into rural primary care practices and appears to significantly improve both care processes and practice productivity.

Transient hypoglycemia in the early neonatal period is a common adaptive phenomenon as the newborn changes from the fetal state of continuous transplacental glucose consumption to intermittent nutrient supply following cessation of maternal nutrition at birth. Research has demonstrated that in the term, healthy newborn, this dynamic process is self-limiting and is not considered pathologic. The American Academy of Pediatrics and the World Health Organization recommend that neonatal blood glucose screening be reserved for newborns who are at risk or symptomatic and conclude that universal hypoglycemia screening is inappropriate, unnecessary, and potentially harmful. Nevertheless, many hospital nurseries continue the clinical practice of routine early glucose screening on healthy, term newborns. This results in the misidentification of neonates captured while experiencing the normal, self-correcting physiologic blood glucose nadir who are then diagnosed with pathologic neonatal hypoglycemia. Subsequent to this misdiagnosis, further surveillance and unnecessary, aggressive treatment interventions will follow that are potentially harmful to the successful establishment of positive maternal-infant interactions and the breastfeeding experience. Research studies indicate that routine hypoglycemia screens, treatments, and interventions in the healthy infant are not evidence-based and result in a serious disruption of the initiation process and duration patterns of lactation. Using the perspective of the theory of technology dependency, this inquiry explores the potential adverse sequelae of inappropriate glucose screening in the healthy breastfeeding newborn and describes selected outcome variables including: 1) the consequences of early maternal-infant separation, 2) the influence of early formula supplementation on breastfeeding discontinuance rates, 3) the effect of separation and supplementation on the onset of lactogenesis, and 4) the impact of hospital staff and provider recommendations of formula supplementation on maternal confidence to independently nurture her baby.

IMPORTANCE: Prophylactic vitamin A supplementation has been shown to reduce the incidence of chronic lung disease or death in extremely low-birth-weight infants. Beginning in 2010, a national shortage reduced the supply of vitamin A available. OBJECTIVE: To estimate the association between vitamin A supplementation and death or chronic lung disease in the context of the recent drug shortage. Intercenter variability in vitamin A use was assessed secondarily. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 7925 infants with birth weights between 401 and 1000 g who were cared for in US neonatal intensive care units managed by the Pediatrix Medical Group. Infants were discharged between January 1, 2010, and June 30, 2012, and data were collected from the Pediatrix Clinical Data Warehouse. Infants who had major congenital anomalies, died during the first 3 days of life, or had missing data were excluded from the analysis. EXPOSURES: Vitamin A supplementation. MAIN OUTCOMES AND MEASURES: The primary outcome was either death before hospital discharge or chronic lung disease, defined as receiving any respiratory support at 36 weeks' corrected gestational age. RESULTS: Of the 6210 eligible infants, 3011 (48.5%) experienced the primary outcome. Those who received vitamin A were more immature and more likely to receive mechanical ventilation during the first 3 days of life. During the study period, vitamin A supplementation significantly decreased (27.2% to 2.1%); however, the primary outcome was similar (48.4% to 49.5%; P = .40). Vitamin A was unrelated to death or chronic lung disease in unadjusted or multivariable analyses (relative risk [RR], 0.97; 95% CI, 0.91-1.03; P = .32) when demographic and clinical information were considered. After classifying centers by vitamin A use, the center of birth was significantly associated with the outcome, with birth in low- and medium-use centers related to a reduced likelihood of death or chronic lung disease. CONCLUSIONS AND RELEVANCE: The occurrence of death or chronic lung disease appears unaffected by the recent shortage of vitamin A. However, the center of birth appears to be an important risk factor for these infants' outcomes.

PURPOSE: To report the 6-month outcomes from a prospective multicenter study investigating the use of cryoplasty (cold balloon angioplasty) to treat below-knee occlusive disease in patients with critical limb ischemia (CLI). METHODS: Between August 2004 and October 2005, 108 patients (77 men; mean age 73+/-12 years, range 41-101) with CLI involving 111 limbs were enrolled in a prospective multicenter trial (Below-the-Knee Chill Study), which was conducted at 16 institutions. The primary study endpoints were acute technical success, defined as the ability to achieve < or =50% residual stenosis and continuous inline flow to the foot, and absence of major (above or below-knee) amputation of the target limb 180 days post procedure. RESULTS: Acute technical success was achieved in 108 (97.3%) of the 111 limbs treated, with only 1 (0.9%) clinically significant dissection (> or =type C) and 2 residual stenoses >50%. During the 180-day follow-up, 15 (13.9%) of the initial 108 patients either withdrew or were lost to follow-up. Five (4.6%) deaths occurred, leaving 88 (81.5%) patients with 91 (82.0%) treated limbs available for 180-day assessment. The rate of freedom from major amputation at 180 days was 93.4%. Amputation-free survival was 89.3% at 180 days (5 deaths, 6 major amputations). Stratifying data by diabetics (n=71) versus non-diabetics (n=34), the 180-day death and amputation rates were 4.9% and 10.0%, respectively, for diabetics versus 6.7% and 0.0%, respectively, for non-diabetics. CONCLUSION: Cryoplasty therapy is a safe and effective method of treating infrapopliteal disease, providing excellent acute outcomes and a high rate of limb salvage in patients with CLI. Study outcomes support the use of cryoplasty therapy as a primary treatment option for patients with CLI secondary to below- knee disease.

A pooled data analysis of two double-blind studies encompassing 1137 episodes of community-acquired pneumonia in hospitalised adults, of which 560 were treated with sparfloxacin and 577 were randomised to comparator antibacterial agents (amoxycillin/clavulanic acid, erythromycin or amoxycillin administered at reference dosages), was performed. The global efficacy rate at the end of treatment in evaluable patients treated with sparfloxacin was 88.3% compared with 84.1% in those who received comparator antibacterial agents. This analysis verified the efficacy of this new aminofluoroquinolone, given orally once daily, in the treatment of community acquired pneumonia. The overall outcome favoured sparfloxacin for use in the empirical treatment of community-acquired pneumonia.

Preventing the transmission of human immunodeficiency virus during surgical procedures requires attention to barrier techniques and to measures designed to prevent injury. Measures to prevent injury must focus on minimizing both the number of people at risk and the opportunities for injury to occur. Special rules are suggested to make surgical team movements more choreographed and deliberate to reduce the opportunities for collisions between hands and sharp instruments.

BACKGROUND: Some children have persistent pain and instability following inversion injuries of the ankle. Radiographs may reveal a small osseous fragment distal to the lateral malleolus, suggesting an avulsion injury of the anterior talofibular ligament and/or calcaneofibular ligament. The avulsion injury may involve an os subfibulare, causing ligamentous laxity and chronic pain resulting from nonunion. This situation must be differentiated from an asymptomatic os subfibulare, which is a normal anatomic variant in 1% of children. The purpose of this study was to evaluate the intraoperative findings and long-term outcomes of patients treated operatively for symptomatic avulsion injuries or a symptomatic os subfibulare. METHODS: Twenty-three patients presented with chronic ankle pain and instability, tenderness anterior and distal to the lateral malleolus, and imaging studies (magnetic resonance imaging and/or stress radiographs) suspicious for avulsion injury of the anterior talofibular ligament and/or calcaneofibular ligament. After unsuccessful nonoperative treatment, all patients underwent excision of the osseous fragments, anatomic reconstruction of the anterior talofibular ligament with use of drill holes through the lateral malleolus, and a modified Broström procedure. RESULTS: The mean age of the patients was 10.4 years (range, eight to thirteen years) at the time of injury and 13.6 years (range, eight to seventeen years) at the time of surgery, representing a mean delay in diagnosis and treatment of 3.2 years. At a mean follow-up of 4.5 years (range, 2.1 to 13.2 years), the mean Foot and Ankle Outcome Score was 91.4 (range, 87 to 98) out of 100, with all but one patient returning to the preinjury recreational level. Only one patient had a long-term complication. CONCLUSIONS: In children with chronic pain and instability associated with an os subfibulare, surgical excision of the os subfibulare combined with reconstruction of the anterior talofibular ligament and a modified Broström procedure was effective in restoring ankle stability, eliminating pain, and permitting return to the preinjury functional level.

PURPOSE: To report the 12-month follow-up data from the prospective 16-center Below-the-Knee (BTK) Chill Trial, which examined the use of primary cryoplasty for BTK occlusive disease in patients with critical limb ischemia (CLI). METHODS: The trial included 108 patients (77 men; mean age 73 +/- 11 years, range 41-101) with CLI (Rutherford categories 4-6) involving 111 limbs with 115 target infrapopliteal lesions. Angiographic inclusion criteria were reference vessel diameter > or = 2.5 mm and < or = 5.0 mm and target lesion stenosis > or = 50%. The primary study endpoints were acute technical success (the ability to achieve < or = 50% residual stenosis and continuous inline flow to the foot) and absence of major amputation of the target limb at 6 months. Secondary endpoints were serious adverse events specifically related to use of primary cryoplasty and absence of major amputation of the target limb at 1, 3, and 12 months. RESULTS: Acute technical success was achieved in 108 (97.3%) of treated limbs, with only 1 clinically significant dissection (> or = type C) and 2 residual stenoses >50%; stent placement was required following cryoplasty in only 3 (2.7%) procedures. At 6 months and 1 year, major amputation was avoided in 93.4% (85/91) and 85.2% (69/81) of patients, respectively. Through 1 year, 21% (17/81) of patients underwent target limb revascularization. Rates of major amputation and death at 1 year were 0% for limbs of patients with initial Rutherford category 4; 11.4% and 0%, respectively, for initial category 5; and 40.0% and 31.8% for initial category 6. One-year rates of major amputation and death were 20.4% and 8.8%, respectively, for diabetics, versus 4.0% and 10.7% for non-diabetics. At 1 year, major amputation occurred in 16.7% (2/12) of limbs that were expected to be amputated at the time of treatment. CONCLUSION: Cryoplasty therapy is a safe and effective method of treating infrapopliteal disease, providing excellent results and a high rate of limb salvage in patients with CLI. Study outcomes through 1 year support the use of cryoplasty as a primary treatment option for patients with CLI secondary to BTK occlusive disease.

Abstract Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors. Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486. Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug–drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1–14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days. Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072–80. ©2018 AACR.

OBJECTIVE: As the population of patients with Fontan circulation surviving into adulthood increases, hepatic cirrhosis has grown to be a significant cause of morbidity and mortality. Early detection of advanced hepatic fibrosis is imperative for proper intervention and consideration for heart or combined heart/liver transplantation. Noninvasive biomarkers and elastography have been evaluated for their diagnostic utility with variable results in the Fontan population. DESIGN: The cohort included 14 patients age 26.4 SD 7.5 who underwent Fontan surgery. All patients were evaluated with FibroSURE, shear wave elastography (SWE), hepatic duplex sonography, and liver biopsy. Liver fibrosis on biopsy was evaluated according to the congestive hepatic fibrosis system. RESULTS: In our cohort, 100% of patients had fibrosis with 36% demonstrating advanced fibrosis. FibroSURE agreed with liver biopsy in only 5 out of 14 cases (36%): underestimating in 7 and overestimating in 2 individuals. SWE agreed with liver biopsy in 0% of cases: overestimating in 10 and underestimating in 4 cases. None of the duplex sonography indices predicted the presence or severity of liver fibrosis. CONCLUSION: This study demonstrates that children who have undergone a Fontan procedure universally develop some hepatic fibrosis and a significant number have advanced fibrosis by adulthood. The FibroSURE blood test, SWE, and hepatic duplex sonography were unable to accurately predict the presence or severity of hepatic fibrosis when compared with liver biopsy. Further studies are needed to investigate novel noninvasive methods and/or biomarkers that can adequately detect advanced hepatic fibrosis before the development of cirrhosis and hepatic decompensation.