The non-steroidal anti-inflammatory drug carprofen negatively impacts new bone formation and antibiotic efficacy in a rat model of orthopaedic-device-related infection.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management during recovery from orthopaedic surgery. NSAID use is associated with increased risk of bone healing complications but it is currently unknown whether NSAIDs increase the risk of developing an orthopaedic-device-related infection (ODRI) and/or affects its response to antibiotic therapy. The present study aimed to determine if administration of the NSAID carprofen [a preferential cyclooxygenase-2 (COX-2) inhibitor] negatively affected Staphylococcus epidermidis (S. epidermidis) bone infection, or its subsequent treatment with antibiotics, in a rodent ODRI model. Sterile or S. epidermidis-contaminated screws (~ 1.5 x 106 CFU) were implanted into the proximal tibia of skeletally mature female Wistar rats, in the absence or presence of daily carprofen administration. A subset of infected animals received antibiotics (rifampicin plus cefazolin) from day 7 to 21, to determine if carprofen affected antibiotic efficacy. Bone changes were monitored using in vivo µCT scanning and histological analysis. The risk of developing an infection with carprofen administration was assessed in separate animals at day 9 using a screw contaminated with 10² CFU S. epidermidis. Quantitative bacteriological analysis assessed bacterial load at euthanasia. In the 28-day antibiotic treatment study, carprofen reduced osteolysis but markedly diminished reparative bone formation, although total bacterial load was not affected at euthanasia. Antibiotic efficacy was negatively affected by carprofen (carprofen: 8/8 infected; control: 2/9 infected). Finally, carprofen increased bacterial load and diminished bone formation following reduced S. epidermidis inoculum (10² CFU) at day 9. This study suggests that NSAIDs with COX-2 selectivity reduce antibiotic efficacy and diminish reparative responses to S. epidermidis ODRI.

Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

ABH-Glycan Microarray Characterizes ABO Subtype Antibodies: Fine Specificity of Immune Tolerance After ABO-Incompatible Transplantation.

Organ transplantation from ABO blood group-incompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century-old assay used clinically, does not discriminate subtype-specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO-glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor-specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO-compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens-the only ABH antigen subtypes expressed in heart tissue-were absent, demonstrating the fine specificity of B cell tolerance to donor/graft blood group antigens. In contrast to the hemagglutination assay, the ABO-glycan microarray allows detailed characterization of donor-specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection.

Successful orthotopic heart transplantation using a donor heart with ALCAPA.

With the imbalance between donation rates and potential recipients growing, transplant programs are increasingly using non-ideal organs from so-called marginal donors. This is the first reported case of the intentional use of a donor heart with ALCAPA. The recipient was aged one yr with restrictive cardiomyopathy who had been supported with BiVAD for over six months. Function of the donor left ventricle was shown to be well preserved, with no obvious signs of ischemia, except for a fibrotic layer on the anterolateral papillary muscle of the mitral valve. To prevent coronary steal, the anomalous left coronary artery ostium from the MPA was oversewn prior to implantation. The transplanted heart spontaneously regained sinus rhythm immediately following cross-clamp release and showed good contractility from the first postoperative echocardiogram. The patient continues to do well 18 months post-transplant, with excellent function on echocardiography, and good flow on coronary angiography.

Chemical Basis for Qualitative and Quantitative Differences Between ABO Blood Groups and Subgroups: Implications for Organ Transplantation.

Blood group ABH(O) carbohydrate antigens are carried by precursor structures denoted type I-IV chains, creating unique antigen epitopes that may differ in expression between circulating erythrocytes and vascular endothelial cells. Characterization of such differences is invaluable in many clinical settings including transplantation. Monoclonal antibodies were generated and epitope specificities were characterized against chemically synthesized type I-IV ABH and related glycans. Antigen expression was detected on endomyocardial biopsies (n = 50) and spleen (n = 11) by immunohistochemical staining and on erythrocytes by flow cytometry. On vascular endothelial cells of heart and spleen, only type II-based ABH antigens were expressed; type III/IV structures were not detected. Type II-based ABH were expressed on erythrocytes of all blood groups. Group A1 and A2 erythrocytes additionally expressed type III/IV precursors, whereas group B and O erythrocytes did not. Intensity of A/B antigen expression differed among group A1 , A2 , A1 B, A2 B and B erythrocytes. On group A2 erythrocytes, type III H structures were largely un-glycosylated with the terminal "A" sugar α-GalNAc. Together, these studies define qualitative and quantitative differences in ABH antigen expression between erythrocytes and vascular tissues. These expression profiles have important implications that must be considered in clinical settings of ABO-incompatible transplantation when interpreting anti-ABO antibodies measured by hemagglutination assays with reagent erythrocytes.

Reduction of adolescent grade IV L5-S1 spondylolisthesis with anterior joystick manipulation during a combined anterior and posterior surgical approach: A case report.

Background: High-grade isthmic spondylolisthesis poses a clinical challenge in the pediatric and adolescent population. Current surgical management using posterior-based approaches may lead to incomplete reduction and restoration of listhesis, disc height, and lordosis. Combined anterior and posterior approach addresses these issues but has been infrequently reported, mainly in the treatment of low-grade isthmic spondylolisthesis. Neither offers good disc space visualization and control of spinal alignment during reduction. Case Description: A healthy 17-year-old female presented with 9 months of progressively worsening lower back pain radiating down the left lower extremity and 3 inches of height loss. Diagnosis of grade IV L5-S1 spondylolisthesis was made using plain radiographs, CT, and MRI. Management with combined anterior and posterior fusion, involving the manual manipulation of segments using an anterior pedicle screw joystick, was pursued. Outcome: Satisfactory alignment, solid arthrodesis, no complications, and improved patient reported outcomes. Conclusions: Combined anterior and posterior fusion with anterior joystick manipulation allowed for full reduction of grade IV spondylolisthesis and restoration of disc/foraminal height and L5-S1 segmental lordosis without neurological complication. Although less commonly performed in children and adolescents, this surgical approach can assist in restoring optimal alignment in isthmic spondylolisthesis.

Incompatible ABO-plasma exchange and its impact on patient selection in paediatric cardiac transplantation.

OBJECTIVES: A decade ago, the first series of ABO-incompatible heart transplants was published, with surprising and extremely promising results; drastically reduced waiting list mortalities of infants listed for heart transplantation. Essential to the procedure was the process of plasma exchange transfusion, required to reduce isohaemagglutinin titres and facilitate the crossing of ABO blood group boundaries. Since then, Great Ormond Street Hospital, London has offered ABO-incompatible heart transplants to infants who potentially would die waiting for a suitable organ. We report the results of a decade of evolving plasma exchange experience and its impact upon patient selection. METHODS: A retrospective analysis was undertaken of all elective ABO-incompatible heart transplants at Great Ormond Street Children's Hospital from January 2001 until January 2011. Data were sought on underlying conditions and demographics of the patients, the isohaemagglutinin titre before and after plasma exchange and survival figures to date. RESULTS: Twenty-one patients underwent ABO-incompatible heart transplantation, ranging from 3 to 44 months, with preoperative isohaemagglutinin titres ranging from 0 to 1:32. All patients underwent a "3 times" plasma exchange before transplantation, requiring exchange volumes of up to 3209 mL. Postoperative isohaemagglutinin titres ranged from 0 to 1:16. One patient died of causes unrelated to organ rejection. CONCLUSIONS: Our data showed that eight patients (38.1%) were older than the previously suggested 12-month cut-off age. Using a combination of adult reservoir/paediatric oxygenator and extracorporeal circuit, ABO-incompatible plasma exchange transfusions can be undertaken safely using a simplified '3 times' method, reducing the circulating levels of isohaemagglutinins whilst providing minimal circuit size. This allows ABO-incompatible heart transplantation in a broader patient population than previously reported.

No Difference in Complication Rates or Patient-Reported Outcomes Between Bone-Patella Tendon-Bone and Quadriceps Tendon Autograft for Anterior Cruciate Ligament Reconstruction.

Purpose: To compare subjective outcomes and complications of anterior cruciate ligament reconstruction (ACLR) using either bone-patellar tendon-bone (BPTB) or quadriceps tendon (QT) autograft. Methods: A retrospective analysis of prospectively collected data identified consecutive cohorts of patients undergoing ACLR with either BPTB or QT autograft. Patients with less than 12-month follow-up and those undergoing concomitant osteotomies, cartilage restoration, and/or other ligament reconstruction procedures were excluded. Pre- and postsurgical patient-reported outcomes including International Knee Documentation Committee, Knee Injury and Osteoarthritis Outcome Score, Patient-Reported Outcomes Measurement Information System (PROMIS), Single Assessment Numeric Evaluation, Tegner, and Marx were compared between groups. Complications requiring reoperation were recorded. Results: One hundred nineteen patients met inclusion criteria, including 39 QT autografts and 80 BPTB autografts. Demographic information was comparable between groups. Mean follow-up was comparable between groups (QT 22.4 ± 10.6 months vs BPTB 28.5 ± 18.5 months, P = .06). At minimum 12-month follow-up (range 12.0-100.8 months), patients in both groups demonstrated statistically significant improvements in International Knee Documentation Committee (QT 60.0%, P < .0001; BPTB 57.7%, P < .0001), all Knee Injury and Osteoarthritis Outcome Score domains, PROMIS Mobility T-Score (QT 27.2%, P = .0001; BPTB 23.2%, P < .0001), PROMIS Global Physical Health (QT 14.4%, P = .002; BPTB 13.4%, P = .001), PROMIS Physical Function (QT 29.6%, P < .0001; BPTB 37.1%, P < .0001), PROMIS Pain Interference (QT -16.5%, P < .0001; BPTB -20.8%, P < .0001), Single Assessment Numeric Evaluation, (QT 76.9%, P < .0001; BPTB 73.3%, P < .0001), Tegner (QT 92.9%, P = .0002; BPTB 101.4%, P < .0001), and Marx (QT -26.6%, P = .02; BPTB -32.0%, P = .0002) with no statistically significant differences between the 2 groups. Overall postoperative reoperation rate did not differ between groups (QT 12.8% vs BPTB 23.8%, P = .2). Revision ACL reconstruction rate did not differ between groups (QT 5.1% vs BPTB 7.5%, P = .6). Conclusions: Patients undergoing autograft ACLR with either BPTB or QT demonstrated significant subjective improvements in patient-reported outcomes from preoperative values and no statistically significant differences in outcomes between the groups. Complication and revision ACLR rates were similar between the 2 groups. Level of Evidence: III, retrospective cohort study.

Late donor cardiectomy after paediatric heterotopic cardiac transplantation.

BACKGROUND: Cardiac transplantation is a life-saving procedure in infants and children with advanced cardiomyopathy. However, it is greatly limited by shortage of paediatric donors and the complications of long-term immunosuppression, including post-transplant lymphoproliferative disorder (PTLD). We report the management of an infant who had heterotopic cardiac transplantation for advanced cardiomyopathy with secondary pulmonary hypertension who developed seemingly incurable PTLD. METHODS: An 8-month-old girl presented in 1994 with signs of severe heart failure, secondary to dilated cardiomyopathy. At age 11 months, the patient underwent a heterotopic cardiac transplantation. FINDINGS: The patient developed many episodes of PTLD associated with Epstein-Barr virus infection that were resistant to several therapies, including reduction of immunosuppression. Native heart recovery enabled removal of the donor heart 10.5 years after the original operation to allow complete cessation of immunosuppression. Her postoperative course was uncomplicated and the outcome was excellent. 3.5 years after surgery, the patient remains well, in complete remission from her PTLD, and has normal cardiac function. INTERPRETATION: This case shows several issues relating to the use of heterotopic cardiac transplantation in infants and the capacity of the heart to recover. It also provides new insights into the interaction between the immune system with several aspects of modern management of post-transplantation PTLD. FUNDING: None.

Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy.

Malonyl coenzyme A (CoA) decarboxylase (EC 4.1.1.9, MCD) deficiency, or malonic aciduria, is a rare inborn error of metabolism characterised by a variable phenotype of developmental delay, seizures, cardiomyopathy and acidosis. There is no consensus for dietary treatment in this condition. This case describes the effect of a long-chain triglyceride (LCT)-restricted/medium-chain triglyceride (MCT)-supplemented diet upon the progress of an affected child. A full-term Asian girl of birth weight 3590 g was screened for malonic aciduria after birth due to a positive family history. She had elevated urine malonic and methylmalonic acids and was presumably homozygous for a deleterious mutation in the MLYCD gene. Her echocardiography showed mild cardiomyopathy at 0.5 months of age, but heart function was good. She was treated with carnitine 100 mg/kg per day and continued a high-energy formula feed, as her growth was slow. At 3 months of age, echocardiography showed deteriorating cardiac function with a fractional shortening of 18%. She started an angiotensin-converting enzyme (ACE) inhibitor (Captopril). Over the next few months, her diet was altered to comprise 1.9% energy from LCT, 25% from MCT and the remainder carbohydrate. Cardiac function improved and was optimal at 23 months of age, with a fractional shortening of 28% and good systolic function. During a period of low MCT intake, her cardiac function was noted to deteriorate. This reversed and stabilised following reinstatement of the diet. This case of malonic aciduria with cardiomyopathy demonstrates improvement in cardiac function attributable to LCT-restricted/MCT-supplemented diet.

Cardiomyopathy in the congenital disorders of glycosylation (CDG): a case of late presentation and literature review.

The congenital disorders of glycosylation (CDG) are a recently described group of inherited multisystem disorders characterized by defects predominantly of N- and O-glycosylation of proteins. Cardiomyopathy in CDG has previously been described in several subtypes; it is usually associated with high morbidity and mortality and the majority of cases present in the first 2 years of life. This is the first case with presentation in late childhood and the article reviews current literature. An 11-year-old female with a background of learning difficulties presented in cardiac failure secondary to severe dilated cardiomyopathy. Prior to the diagnosis of CDG, her condition deteriorated; she required mechanical support (Excor Berlin Heart) and was listed for cardiac transplant. Investigations included screening for glycosylation disorders, and isoelectric focusing of transferrin revealed an abnormal type 1 pattern. Analysis of phosphomannomutase and phosphomannose isomerase showed normal enzyme activity, excluding PMM2 (CDG Ia) and MPI (CDG Ib). Lipid-linked oligosaccharide and mutational studies have not yet defined the defect. Despite aggressive therapy there were persistent difficulties achieving adequate anticoagulation and she developed multiple life-threatening thrombotic complications. She was removed from the transplant list and died from overwhelming sepsis 5 weeks following admission. This case emphasizes the need to screen all children with an undiagnosed cardiomyopathy for CDG, regardless of age, and where possible to exclude CDG before the use of cardiac bridging devices. It highlights the many practical and ethical challenges that may be encountered where clinical knowledge and experience are still evolving.

Patients, pictures, and privacy: managing clinical photographs in the smartphone era.

It is easy to capture and share clinical photographs and x-ray images using modern smartphones. This technology affords health-care providers the ability to rapidly collaborate and facilitate care for their patients. This improvement, however, has increased concerns regarding patient privacy and the safeguarding of protected health information. Health-care providers should understand the deidentification process for patient photographs because this process fundamentally changes the expectations and requirements for how providers are to handle this information. Properly deidentified patient photographs (and other data) are no longer considered identifiable protected health information and are not subject to the handling requirements mandated by the Health Insurance Portability and Accountability Act. This article addresses patient privacy concerns attendant to the acquisition, transmission, and sharing of clinical photographs among health-care providers. It provides guidelines for providers seeking to minimize the risk of noncompliance with privacy requirements as they adopt these new technologies into their practices.

Multicenter experience of ABO-incompatible pediatric cardiac transplantation.

Although ABO blood group incompatible cardiac transplantation in neonates and infants reduces waiting list mortality without compromising outcome, the technique has not been adopted by all centers, and to date Toronto remains the only center to have published results from a large case series. We present a review of ABO-incompatible heart transplantation in the United Kingdom (UK) where current recipient selection criteria differ somewhat from those used in the United States (US) and Canada. Between February 2000 and November 2006, 21 ABO-incompatible cardiac transplants were performed in children aged 2-40 months (median 10.0). Immunosuppression followed standard regimens. Pretransplant donor-specific isohemagglutinins of >1:4, (the UNOS cutoff), were present in five patients and reduced by plasma exchange. After transplantation, 19/21 recipients demonstrated persisting deficiency of donor-specific isohemagglutinins. Significant donor-specific isohemagglutinins levels were detected repeatedly in 2/21 recipients who have shown no clinical or biopsy evidence of rejection. All recipients survive without retransplantation and there have been no episodes of humoral rejection. We conclude it is possible for other centers to replicate the excellent results achieved in Toronto and that ABO-incompatible transplantation may be performed successfully in some patients beyond infancy with established isohemagglutinin production providing preoperative antibody removing strategies are used.

Comparative Study of Pediatric Coronary Allograft Vasculopathy Between Single Centers in North America and United Kingdom.

BACKGROUND: Coronary allograft vasculopathy (CAV) is the leading cause of death after pediatric heart transplantation from 1 year postoperation. Anecdotal evidence suggests a difference in the severity of disease between UK and North America. We performed a comparative study using intravascular ultrasound (IVUS). METHODS: Consecutive IVUS procedures from a single year were included from each center. Using standardized techniques, measurement of the vessel area, lumen area, and maximal intimamedial thickening (IMT) were performed with calculation of intimal index (II) for each slice. Mean II, mean IMT, and absolute maximum IMT were calculated along the left coronary artery for each patient. Transplant demographics and treatment details were included in the analysis. RESULTS: One hundred four patients were included between the 2 centers. Interobserver variability for IVUS analysis was excellent. Patients were aged mean 14.2 (SD 3.3) years at the time of the study and 9.2 (SD 6.0) years earlier post-transplant procedure. UK patients were older, at transplant for a shorter time, and demonstrated more severe CAV. Multiple regression analysis demonstrated the detrimental effect of donor age and time from transplant on CAV severity and benefits of sirolimus use. CONCLUSIONS: The data show more severe CAV in the UK cohort despite significantly shorter time post-transplant. Donor age and time post-transplant were associated with more severe CAV and sirolimus use was associated with a reduction in IMT. This study demonstrates a marked difference in the prevalence of CAV in children between UK and North America. The causes are likely to be multifactorial; however, younger donors and recipients have significantly less disease.

Regulation of expression and localisation of the Na+/H+ exchanger (NHE) 3 and the NHE regulatory factor 2 in baboon placental syncytiotrophoblast by oestrogen.

Our understanding of the regulation of the expression of the sodium hydrogen exchangers (NHE) and their regulatory factors (NHERF), which play important roles in fetal-placental homeostasis, is incomplete. We previously showed that the expression and localisation of NHE3 and NHERF2 in the juxtanuclear compartment of the placental syncytiotrophoblast were markedly decreased between mid and late baboon pregnancy. In the current study, immunocytochemical fluorescence localisation and level of NHE3/NHE1 and NHERF1/NHERF2 proteins were determined in late gestation in baboons untreated or treated throughout the second half of gestation with an aromatase inhibitor CGS 20267 alone (reduced oestrogen levels by >95%) or with oestradiol to determine whether oestrogen regulated antiporter developmental expression. The immunocytochemical expression of NHE3 and NHERF2 in the juxtanuclear compartment was minimal in baboons untreated or treated with CGS 20267 plus oestradiol (i.e. oestrogen-replete) but extensive in oestrogen-suppressed animals. Moreover, the abundant expression of NHERF2 in fetal vascular endothelium of oestrogen-replete baboons was decreased in oestrogen-suppressed animals. In contrast, expression and localisation of NHE1 and NHERF1 in the placental syncytiotrophoblast were not altered by oestrogen deprivation in baboons. Based on our current and previous findings, we propose that oestrogen plays an important role in regulating localisation and expression of components of the NHE system within and consequently development and function of the primate placental syncytiotrophoblast.

Comparison of Segmental Versus Longitudinal Intravascular Ultrasound Analysis for Pediatric Cardiac Allograft Vasculopathy.

Intravascular ultrasound (IVUS) has been routinely used in some centers to investigate cardiac allograft vasculopathy in pediatric heart transplant recipients. We present an alternative method using more sophisticated imaging software. This study presents a comparison of this method with an established standard method. All patients who had IVUS performed in 2014 were retrospectively evaluated. The standard technique consisted of analysis of 10 operator-selected segments along the vessel. Each study was re-evaluated using a longitudinal technique, taken at every third cardiac cycle, along the entire vessel. Semiautomatic edge detection software was used to detect vessel imaging planes. Measurements included outer and inner diameter, total and luminal area, maximal intimal thickness (MIT), and intimal index. Each IVUS was graded for severity using the Stanford classification. All results were given as mean ± standard deviation (SD). Groups were compared using Student t test. A P value <.05 was considered significant. There were 59 IVUS studies performed on 58 patients. There was no statistically significant difference between outer diameter, inner diameter, or total area. In the longitudinal group, there was a significantly smaller luminal area, higher MIT, and higher intimal index. Using the longitudinal technique, there was an increase in Stanford classification in 20 patients. The longitudinal technique appeared more sensitive in assessing the degree of cardiac allograft vasculopathy and may play a role in the increase in the degree of thickening seen. It may offer an alternative way of grading severity of cardiac allograft vasculopathy in pediatric heart transplant recipients.

Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity.

UNLABELLED: Oral squamous cell carcinoma (OSCC) is a cancer subtype that lacks validated prognostic and therapeutic biomarkers, and human papillomavirus status has not proven beneficial in predicting patient outcomes. A gene expression pathway analysis was conducted using OSCC patient specimens to identify molecular targets that may improve management of this disease. RNA was isolated from 19 OSCCs treated surgically at the University of Alabama at Birmingham (UAB; Birmingham, AL) and evaluated using the NanoString nCounter system. Results were confirmed using the oral cavity subdivision of the Head and Neck Squamous Cell Carcinoma Cancer (HNSCC) study generated by The Cancer Genome Atlas (TCGA) Research Network. Further characterization of the in vitro phenotype produced by Notch pathway activation in HNSCC cell lines included gene expression, proliferation, cell cycle, migration, invasion, and radiosensitivity. In both UAB and TCGA samples, Notch pathway upregulation was significantly correlated with patient mortality status and with expression of the proinvasive gene FGF1 In vitro Notch activation in HNSCC cells increased transcription of FGF1 and induced a marked increase in cell migration and invasion, which was fully abrogated by FGF1 knockdown. These results reveal that increased Notch pathway signaling plays a role in cancer progression and patient outcomes in OSCC. Accordingly, the Notch-FGF interaction should be further studied as a prognostic biomarker and potential therapeutic target for OSCC. IMPLICATIONS: Patients with squamous cell carcinoma of the oral cavity who succumb to their disease are more likely to have upregulated Notch signaling, which may mediate a more invasive phenotype through increased FGF1 transcription. Mol Cancer Res; 14(9); 883-91. ©2016 AACR.

Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment of 118 patients.

OBJECTIVES: The purpose of this study was to determine the incidence of cardiologic abnormalities in Noonan syndrome. BACKGROUND: The incidence of cardiac abnormalities in Noonan syndrome remains unknown, largely because of such difficulties as assembling a substantial cohort, ensuring a correct phenotypic diagnosis and providing accurate definitions of the most frequent abnormalities--pulmonary stenosis and left ventricular hypertrophy. METHODS: A cohort of 145 patients was assembled, and before cardiologic assessment two independent geneticists scrutinized the phenotype. The diagnosis was confirmed in 118 patients, and they were studied by two-dimensional and Doppler echocardiography. RESULTS: A dysplastic pulmonary valve was present in eight patients (7%) and was associated with significant stenosis in six (75%) of the eight. Significant stenosis was present in 22 (20%) of 110 patients without dysplasia. Left ventricular hypertrophy was present in 29 patients (25%) without significant pulmonary stenosis. Localized anterior septal hypertrophy was the most common pattern in 12 (41%) of 29 patients. Diffuse hypertrophy involving the entire septum and the free wall was present in nine patients (31%) and was severe (> 1.7 cm) in five. Other abnormalities included secundum atrial septal defects (10%). CONCLUSIONS: The high incidence of cardiac abnormalities suggests that echocardiographic and Doppler evaluation of patients with the Noonan phenotype is important because it will aid in genetic counseling and in the assessment of the natural history of--and, ultimately, identification of the gene(s) responsible for--Noonan syndrome.

Five-year follow-up after balloon pulmonary valvuloplasty.

OBJECTIVES: The aim of this study was to assess results 5 years after balloon pulmonary valvuloplasty. BACKGROUND: Since the technique of balloon pulmonary valvuloplasty was first reported in 1982, it has become the treatment of choice for pulmonary valve stenosis. In contrast to surgical valvotomy, the long-term outcome after balloon pulmonary valvuloplasty is unknown. METHODS: We reviewed the findings in 34 patients 5.2 +/- 0.8 (mean +/- SD) years after balloon pulmonary valvuloplasty: 27 with isolated pulmonary stenosis, 5 with Noonan syndrome and 2 with previous surgical valvotomy. In eight patients (three with Noonan syndrome), a second balloon valvuloplasty was the index procedure for analysis. RESULTS: The transpulmonary gradient (mm Hg) was 74 +/- 34 before balloon pulmonary valvuloplasty, 36 +/- 26 immediately after, 22 +/- 9 at cardiac catheterization in 29 patients 6 +/- 0.6 months later and 19 +/- 10 by Doppler study at 5 years. At 5 years 26 patients (group A) had a residual gradient of < or = 20 mm Hg; the remaining 8 (group B) had a gradient of > 20 mm Hg. Four group B patients had Noonan syndrome (p = 0.01). Balloon/pulmonary valve diameter ratio was larger for group A patients than for group B patients with isolated pulmonary stenosis (1.20 +/- 0.10 vs. 1.00 +/- 0.07, p = 0.005); larger balloons were used in group B patients with Noonan syndrome (1.30 +/- 0.10). Group A patients were more likely than group B patients to have significant pulmonary incompetence (6 of 24 vs. 0 of 8) and had a greater right ventricle/left ventricle long-axis diastolic dimension ratio (0.47 +/- 0.10 vs. 0.35 +/- 0.04, p = 0.05). In the subgroup of five patients with Noonan syndrome and two with prior surgical valvotomy, the transpulmonary gradient was reduced from 74 +/- 24 mm Hg before balloon valvuloplasty to 23 +/- 12 mm Hg at 5 years. In addition, two patients with isolated pulmonary valve stenosis had pulmonary valve dysplasia by angiographic criteria: transpulmonary gradients of 85 and 56 mm Hg were reduced to 20 and 11 mm Hg, respectively, at 5 years. CONCLUSIONS: Relief of obstruction persists at 5 years especially if oversized balloons are used. Acceptable results can be obtained in patients with a dysplastic valve. More complete relief of right ventricular outflow gradient is associated with increased right ventricular dimension, probably because more pulmonary incompetence is induced. This is well tolerated at 5 years but may be important in the longer term.