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The objective of the article is to underline the importance of community-based participatory research, which involves institutional researchers and community practitioners, in establishing local and regional research priorities in relation to HIV/AIDS. We describe an 11-month-long reflection process conducted by a research collective in the Abitibi-Témiscamingue region of northern Quebec. The significant results of the joint reflection and discussion process included: the development of local capacities for research and collective action, involving academics and practitioners; the valorization of participatory research; and the increased accessibility of research-based knowledge for community actors involved in the fight against HIV/AIDS. In contrast with more traditional research methods, the participatory approach situates the balance of power within a research collective that jointly determines, throughout the course of the project, the priorities that best reflect local needs for HIV/AIDS research. This initial process of discussion resulted also in the joint validation of a forthcoming grant application to be submitted to the Canadian Institutes of Health Research (CIHR)., L’objectif de l’article est de souligner l’importance de la recherche participative communautaire, impliquant des acteurs locaux et les chercheurs institutionnels, dans l’établissement des priorités de recherche locales et régionales en matière de VIH/SIDA. Les auteurs décrivent un processus de réflexion de 11 mois mené par un collectif de recherche dans la région de l’Abitibi-Témiscamingue, dans le Nord du Québec. Parmi les résultats importants du processus de réflexion et de discussion conjoint, mentionnons : le développement des capacités locales de recherche et d’action collective, impliquant des universitaires et des praticiens; la valorisation de la recherche participative; et l’accessibilité accrue des connaissances issues de la recherche pour les acteurs communautaires impliqués dans la lutte contre le VIH/SIDA. Contrairement aux méthodes de recherche plus traditionnelles, l’approche participative situe le pouvoir au sein d’un collectif de recherche qui détermine conjointement, tout au long du projet, les priorités qui reflètent le mieux les besoins locaux en matière de recherche sur le VIH/SIDA. Ce processus initial de discussion a également abouti à la validation conjointe d’une prochaine demande de subvention qui sera soumise aux Instituts de recherche en santé du Canada (IRSC).

espanolLa fistula colecistocolonica (FCC) es una complicacion poco comun de la colelitiasis. A menudo son asintomaticas, de dificil diagnostico preoperatorio a pesar del apoyo radiologico, y se descubren de manera incidental perioperatoriamente. Presentamos el caso de una mujer con un cuadro de colecistitis aguda, la cual fue intervenida por laparoscopia, y se evidencio una FCC, la cual fue resuelta mediante conversion a cirugia abierta. La FCC puede complicarse y simular cuadros abdominales agudos. Se debe tener en cuenta en adultos mayores, con historia de colelitiasis, y vesiculas escleroatroficas con adherencias. En la literatura se han descrito muy pocos casos, y ninguno en nuestro medio. Presentamos un caso de FCC que ingreso como una colecistitis aguda, y su diagnostico y tratamiento fueron durante su cirugia EnglishCholecystocolonic fistula (CCF) is a rare complication of cholelithiasis. They are often asymptomatic, difficult to diagnose preoperatively, it despite radiological support, and they are discovered incidentally perioperatively. We present the case of a woman with acute cholecystitis, who was operated by laparoscopy, and a CCF was evidenced, it was resolved by conversion to open surgery. FCC can be complicated and simulate acute abdominal symptoms. It should be taken into account in older adults with a history of cholelithiasis and scleroatrophic vesicles with adhesions. Very few cases have been described in the literature, and none in our country. We present a case of FCC that was admitted as acute cholecystitis, and the diagnosis and treatment of it were during her surgery.

Item does not contain fulltext BACKGROUND: Sepsis is a leading cause of morbidity and mortality after surgery. Most studies regarding sepsis do not differentiate between patients who have had recent surgery and those without. Few data exist regarding the risk factors for poor outcomes in pediatric postsurgical sepsis. Our hypothesis is pediatric postsurgical, and medical patients with severe sepsis have unique risk factors for mortality. METHODS: Data were extracted from a secondary analysis of an international point prevalence study of pediatric severe sepsis. Sites included 128 pediatric intensive care units from 26 countries. Pediatric patients with severe sepsis were categorized into those who had recent surgery (postsurgical sepsis) versus those that did not (medical sepsis) before sepsis onset. Multivariable logistic regression models were used to determine risk factors for mortality. RESULTS: A total of 556 patients were included: 138 with postsurgical and 418 with medical sepsis. In postsurgical sepsis, older age, admission from the hospital ward, multiple organ dysfunction syndrome at sepsis recognition, and cardiovascular and respiratory comorbidities were independent risk factors for death. In medical sepsis, resource-limited region, hospital-acquired infection, multiple organ dysfunction syndrome at sepsis recognition, higher Pediatric Index of Mortality-3 score, and malignancy were independent risk factors for death. CONCLUSIONS: Pediatric patients with postsurgical sepsis had different risk factors for mortality compared with medical sepsis. This included a higher mortality risk in postsurgical patients presenting to the intensive care unit from the hospital ward. These data suggest an opportunity to develop and test early warning systems specific to pediatric sepsis in the postsurgical population.

Introduction Continuous renal replacement therapies (CRRT) are frequently used in critically ill children and may increase the risk of infection. However, the incidence, characteristics and prognosis of infection in critically ill children on CRRT have not been studied. Methods Data from a prospective, single-center register of critically ill children treated with CRRT was analyzed. Results 55 children (40% under 1 year of age) were treated with CRRT between June 2008 and January 2012; 43 patients (78.2%) presented 1 or more infections. The most common condition of patients requiring CRRT was heart disease (69%). Infection occurred a median of 11 days after the initiation of CRRT (IQ range: 4 to 21 days). A total of 21 patients (48.8 %) developed 1 infection, 7 (16.2%) developed 2 infections and 15 (34.9%) developed 3 or more infections. The most frequent infection was catheter-related bacteremia, with no differences in catheter location. CRRT duration longer than 4.5 days was the only risk factor for infection. Patients with infection had a longer length of stay (LOS) in the Pediatric Intensive Care Unit (PICU) than patients without it (37.8 vs. 17.6, p = 0.019), but there were no differences in mortality (30.2% vs. 33.3%; p = 0.84). Conclusions Infection rate is high in critically ill children treated with CRRT. More than 4 days of CRRT increases the risk of infection. Infection in these patients entails a longer stay in the PICU but did not increase mortality.

Breast cancer surgery can benefit from regional anaesthesia techniques, which can be used as a sole anaesthetic procedure in some cases where risk for general anaesthesia is high. Regional anaesthesia allows early recovery, reduces postoperative opioid and non opioid analgesics consumption and helps early home discharge, reducing thus costs. We present a case of an 87-year-old woman with multiple comorbidities who underwent breast cancer surgery. The patient was successfully surgically treated under serratus intercostal plane block anaesthesia. We discuss the use and benefits of the serratus intercostal plane block in thoracic procedures.

Snoezelen terapia, zentzumen anitzeko terapia (ZAT) ez-farmakologiko eta psikosoziala da; zazpi funtsezko zentzumenen estimulazioan edo erlaxazioan oinarritzen dena, hain zuzen ere. Pertsonon ongizatea eta norberaren bizi-kalitatea hobetzea du helburu nagusia.Ikusmen, entzumen, ukimen, dastamen, oreka, propriozepzio eta usaimen zentzumenak hainbat objekturen bitartez kitzikatzen dira: argiztapen artifizialaren, musika lasaigarri edo terapeutikoaren, ehundura ezberdinen eta hainbat lurrinen eta elikagaien bidez, besteak beste. Terapia honen erabilera dementziaren sintoma fisiologikoak eta portaera-aldaketak arintzeko hautabide eraginkor gisa bistaratu da azken hamarkadan. Dementziaetengabeko narriadura kognitiboa eragiten duen gaixotasun kronikoa eta atzeraezina da; baita sintoma fisiko, fisiologiko eta portaera-aldaketa nabarmenak eragiten dituen gaitz neurologikoa ere. Oldarkortasuna, depresioa, antsietatea, gogogabezia, loezina eta elikadura-nahasmendua dira dementzia gaixotasunean deskribatu izan diren eta Snoezelen terapiak hobetzen dituen sintoma fisiologiko eta portaera-aldaketa ohikoenak. Horrez gain, aipatzekoak dira Rett sindromean, garun-lesio traumatikoan, zainketa aringarrietako programetan eta garun-paralisian Snoezelen terapiak eragiten dituen onura nabarmenak. Azterlan honek Snoezelen terapiaren inguruko hainbat ikerketa biltzen ditu. Kontzeptuaren deskribapen zehaztua eta Euskal Herriko udalerrietan azken urteotan terapia honi eman zaion erabilera terapeutikoaren zein pedagogikoaren azalpen orokorra azaltzen dira. Horrez gain, hainbat gaixotasunen aurrean terapia honek ekar ditzakeen efektu mesedegarrien edo mugen eta gabezien deskribapena jorratuko da ikuspuntu kritiko batetik.

Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.Objectives: To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. Design: Secondary analysis of a prospective, cross-sectional, point prevalence study. Setting: International, multicenter PICUs. Patients: Pediatric patients with severe sepsis identified on five separate days over a 1-year period. Interventions: None. Measurements and Main Results: Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001). Conclusions: Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts are needed to validate whether reducing new or progressive multiple organ dysfunction syndrome leads to improvements in more definitive morbidity and mortality endpoints.

Barnes syndrome is a rare entity observed among thoracic dysplasia/hypoplasia with or without polydactyly. It is a very low frequency disease of autosomal dominant transmission with variable penetrance. It is characterized by a laryngeal stenosis, costal narrowing and reduced pelvic dimensions. We present the case of a 5-month-old patient who is admitted to our Intensive Care Unit for progressive respiratory failure. She was diagnosed in utero with probable asphyxiating thoracic using Magnetic Resonance Imaging. When the patient was two months old, a whole-body bone scan was made and ruled out the disease, diagnosing the patient with spondyloepiphyseal dysplasia congenita. On admission to our unit, she presented progressive worsening, despite non-invasive mechanical ventilation, requiring intubation. This intubation was not possible due to significant subglottic stenosis. A tracheostomy was performed, and the patient was connected to mechanical ventilation. Fibrobronchoscopy was performed and showed significant laryngeal stenosis and a Chest CT showed severe obliteration of the proximal tracheal lumen. The bone scan showed chest narrowing and hypoplasia of the pelvis which, together with laryngeal stenosis, allowed the diagnosis of Barnes Syndrome. We proposed thoracic surgery in order to increase the size of the rib cage, thereby improving the lung function. The family refused consent and the patient died a month later after removal of ventilation (at the request of parents).

The prevalence of primary hyperparathyroidism (PHPT) is about 0.1–0.4%. It consists of an elevated serum calcium level, or elevated serum ionised calcium with an inappropriately normal, or more com...

Purpose Sunitinib is a tyrosine kinase inhibitor indicated for the treatment of gastrointestinal stromal tumor, advanced renal cell carcinoma, and pancreatic neuroendocrine tumors. The aim of this article is to describe the pharmacological interactions between sunitinib and commonly prescribed drugs. Method We reviewed available information on pharmacological interactions between sunitinib and concomitantly prescribed drugs. Drugs were grouped into different therapeutic groups according to the Anatomical Therapeutic Chemical (ATC) classification. Results Sunitinib interacts with CYP3A4 inducers or inhibitors and with P-glycoprotein and ABCG2 substrates. Pharmacodynamic interactions with drugs have also been found. Conclusion Current information on drug interactions between sunitinib and other drugs is scarce and most of the times it is difficult to apply to clinical practice. Even so, this difficulty in managing drug interactions should not be a reason to ignore them as they can help to explain intolerances and treatment failures.

Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.Objectives: Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies. Design: We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality. Setting: European and U.S. PICUs. Patients: Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study. Interventions: None. Measurements and Main Results: European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days. Conclusions: Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future international clinical trials in pediatric severe sepsis.

A 28-year-old female with history of chest wall extraskeletal myxoid chondrosarcoma (EMC) presented to the emergency department complaining of two weeks of lightheadedness and fatigue. Laboratories showed hemoglobin of 7.6 g/dL and a positive hemoccult test. Upper and lower endoscopies were unremarkable, and the patient was discharged after blood transfusion. The next day she returned to the ED with left-sided weakness and perioral numbness. Brain CT scan revealed a 6 cm right frontal mass with midline shift and edema that required urgent craniotomy with resection of a hemorrhagic tumor. The patient continued dropping her hemoglobin, and CT scans showed a rounded 3 cm small bowel mass in the mid ileum. Repeat upper endoscopy revealed a 2 × 2 cm ulcerated mass in the fourth portion of the duodenum. The patient was taken to the operating room and was found to have two lesions; one in the distal duodenum and a second one in the mid ileum causing small bowel intussusception. Pathology was consistent with metastatic EMC grade 2/3, involving the bowel and mesenteric fat. Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft-tissue sarcoma with unique features that distinguishes, it from other sarcomas. It has been often described as a low-grade sarcoma although there are certain characteristics like high mitotic activity and the presence of focal regions of Ki67 staining above 25% that correlate with aggressive behavior of the tumor. This is the first case of EMC metastatic to the small bowel to be reported to the medical community.

The Ras family of genes is involved in the cellular regulation of proliferation, differentiation, cell adhesion and apoptosis. The K-ras gene is mutated in over 90% of pancreatic cancer cases. Salirasib (S-trans,trans-farnesylthiosalycilic acid [FTS]) is a synthetic small molecule that acts as a potent Ras inhibitor. It is a farnesylcysteine mimetic that selectively disrupts the association of active RAS proteins with the plasma membrane. Animal studies demonstrated that salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of salirasib combined with standard doses of gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. The salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer.

We studied 298 patients with severe aplastic anaemia (SAA) allografted in four Latin American countries. The source of cells was bone marrow (BM) in 94 patients and PBSCs in 204 patients. Engraftment failed in 8.1% of recipients with no difference between BM and PBSCs (P=0.08). Incidence of acute GvHD (aGvHD) for BM and PBSCs was 30% vs 32% (P=0.18), and for grades III-IV was 2.6% vs 11.6% (P=0.01). Chronic GvHD (cGvHD) between BM and PBSCs was 37% vs 59% (P=0.002) and extensive 5% vs 23.6% (P=0.01). OS was 74% vs 76% for BM vs PBSCs (P=0.95). Event-free survival was superior in patients conditioned with anti-thymocyte globulin (ATG)-based regimens compared with other regimens (79% vs 61%, P=0.001) as excessive secondary graft failure was seen with other regimens (10% vs 26%, P=0.005) respectively. In multivariate analysis, aGvHD II-IV (hazard ratio (HR) 2.50, confidence interval (CI) 1.1-5.6, P=0.02) and aGvHD III-IV (HR 8.3 CI 3.4-20.2, P

Data regarding the prevalence of metabolic syndrome (MTS) in Andean populations are limited. We evaluated the prevalence of MTS according to American Heart Association/National Heart, Lung and Blood Institute criteria among 1878 subjects in the PREVENCION study in Peru. In women, the most common component was low HDL cholesterol (60.9%) followed by abdominal obesity (36.9%). In men, the most common component was elevated triglycerides (52.0%) followed by low HDL cholesterol (32.5%), whereas the prevalence of abdominal obesity was 14%. Abnormal fasting glucose was the least common component in men (5.4%) and women (5.0%). The prevalence of MTS was significantly higher in women compared to men (23.2% versus 14.3%) and increased steeply with age, particularly in women (p0.0001). Using body mass index (BMIor=30kg/m2) instead of waist circumference as a component of the MTS lead to equivalent prevalence estimates of MTS in men but significantly underestimated the prevalence in women. The MTS is highly prevalent among Peruvian Andeans, particularly in older women. The pattern of MTS components in this Andean population is characterized by a high prevalence of dyslipidemia and a relatively low prevalence of elevated fasting glucose. Further studies are required to characterize genetic and environmental determinants of these patterns.

The potential role of oncogenic viruses mediating development of proliferative skin lesions in patients treated with RAF inhibitors is poorly understood. The objective of this study was to investigate human papilloma virus (HPV) and Merkel cell polyomavirus (MCPyV) in skin lesions among patients treated with RAF inhibitors with the help of a case series describing prevalence of HPV, MCPyV, and RAS mutations in skin biopsies obtained from patients receiving RAF inhibitors and developing cutaneous lesions. HPV-DNA was amplified by PCR utilizing multiple nested primer systems designed for detection of a broad range of HPV types. MCPyV copy number determination with real time PCR technology was performed by a "Quantification of MCPyV, small t region" kit. Thirty-six patients were tested (squamous cell carcinoma (SCC) = 14; verruca vulgaris = 15; other = 11). Nine of 12 SCCs (75 %) and eight of 13 verruca vulgaris lesions (62 %) tested positive for MCPyV whereas none of the normal skin biopsies obtained from nine of these patients tested positive for MCPyV (p = 0.0007). HPV incidence in cutaneous SCCs was not different compared to normal skin (50 vs. 56 %, p = 0.86). The association between MCPyV and proliferative skin lesions after RAF inhibitor therapy merits further investigation.

Introduction Nosocomial infections (NI) are a major healthcare problem. National surveillance systems enable data to be compared and to implement new measures to improve our practice. Methods A multicentre, prospective, descriptive and observational study was conducted using the data from surveillance system for nosocomial infections created in 2007 for Spanish pediatric intensive care units. Data were collected for one month, between 01 and 31 March, for every study year (2008–2012). The objective was to report 5-years of NI surveillance data, as well as trends in infections by multidrug resistant organisms in Spanish pediatric intensive care units. Results A total of 3667 patients were admitted to the units during the study period. There were 90 (2.45%) patients with nosocomial infections. The mean rates during the 5 years study were: central line-associated bloodstream infection, 3.8/1000 central venous catheter-days, Ventilator-associated pneumonia 7.5/1000 endotracheal tube-days, and catheter-associated urinary tract infections 4.1/1000 urinary catheter-days. The comparison between the 2008 and 2009 rates for nosocomial infections did not show statistically significant differences. All rates homogeneously decreased from 2009 to 2012: central line-associated bloodstream infection 5.83 (95% CI 2.67–11.07) to 0.49 (95% CI 0.0125–2.76), P = 0.0029; ventilator-associated pneumonia 10.44 (95% CI 5.21–18.67) to 4.04 (95% CI 1.48–8.80), P = 0.0525; and Catheter-associated urinary tract infections 7.10 (95% CI 3.067–13.999) to 2.56 (95% CI 0.697–6.553), P = 0.0817; respectively. The microorganism analysis: 63 of the 99 isolated bacteria (63.6%) were Gram-negative bacteria (36.5% were resistant), 19 (19.2%) Gram-positive bacteria, and 17 (17.2%) were Candida spp. infections. Conclusions The local surveillance systems provide information for dealing with nosocomial infections rates.

To study the efficacy and tolerance of transpyloric enteral nutrition (TEN) in the critically ill child with acute renal failure (ARF). Prospective observational study. Paediatric intensive care unit. Critically ill children with ARF who received TEN were included in the study. They were compared with the remaining 473 critically ill children receiving TEN in this period. Tolerance of nutrition and gastrointestinal complications were assessed. Transpyloric enteral nutrition. Fifty-three critically ill children with ARF aged between 3 days and 17 years received TEN. Children with ARF more frequently received parenteral nutrition before TEN (56.6%) than the other patients (17.5%). The incidence of shock, hepatic alterations and mortality was significantly higher in patients with ARF than in the remaining children. In children with ARF the mean duration of the TEN was 16.5 ± 27.3 days and the maximum caloric intake was 77 ± 26.7 kcal/kg/day. Thirteen patients (24.5%) presented gastrointestinal complications, 9 (17%) abdominal distension and/or excessive gastric residue, 5 (9.4%) diarrhoea, 1 necrotising enterocolitis and 1 duodenal perforation. The frequency of gastrointestinal complications was significantly higher in children with ARF. TEN was definitive suspended in five patients due to gastrointestinal complications. Four of these patients were treated with continuous renal replacement therapy. Thirty percent of patients died during TEN. In only one patient was the death related to complications of the nutrition. Critically ill children with ARF tolerate TEN, although the incidence of gastrointestinal complications is higher than in other critically ill children.

Item does not contain fulltext Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

A pesar de los avances terapéuticos recientes la mortalidad del shock séptico sigue siendo muy elevada. Las causas más importantes de mortalidad son el shock refractario, la alteración incontrolable de la coagulación y el fallo multiorgánico. Algunos autores han propuesto la utilización precoz de plasmafiltración y hemodiafiltración de elevado flujo como tratamiento del shock séptico refractario, realizando la mayoría la plasmafiltración en sesiones cortas y a continuación la hemodiafiltración de forma continua. Una niña de 13 años de edad presentó shock séptico meningocócico refractario a tratamiento con expansión y dosis elevadas de adrenalina y noradrenalina, coagulación intravascular diseminada (CID) e insuficiencia renal aguda. Se realizó tratamiento simultáneo con plasmafiltración y hemodiafiltración venovenosa continua durante 30 h, utilizando dos bombas de depuración extrarrenal colocadas en paralelo a través del mismo catéter de doble luz, consiguiendo una rápida estabilización hemodinámica y control de la coagulopatía. La paciente sobrevivió recuperando de manera progresiva la función renal, pero se tuvo que realizar amputación de miembro inferior izquierdo. La plasmafiltración continua y la hemodiafiltración venovenosa pueden utilizarse simultáneamente como tratamiento de niños mayores con shock séptico, coagulopatía e hipervolemia grave. : Despite recent therapeutic advances, mortality due to septic shock remains high. The most important causes of mortality are refractory shock, uncontrollable alterations of coagulation, and multiorgan failure. Some authors have proposed the early use of plasmafiltration and high flow hemodiafiltration for refractory septic shock. Most authors initiate treatment with a short session of plasmafiltration followed by continuous hemodiafiltration. A 13-year-old girl presented refractory meningococcal septic shock, disseminated intravascular coagulation, and acute renal failure unresponsive to volume expansion and high doses of adrenalin and noradrenaline. She received simultaneous treatment with plasmafiltration and continuous venovenous hemodiafiltration for 30 hours. Two pumps of extrarenal purification placed in parallel through the same double line catheter were used. Fast hemodynamic stabilization and control of the coagulopathy were achieved. The patient survived with progressive recovery of renal function but required amputation of the inferior left limb. Continuous plasmafiltration and venovenous hemodiafiltration can be used simultaneously for the treatment of older children with septic shock, severe coagulopathy, and hypervolemia.

Objective To report a case of peripheral and intestinal ischemia associated with arterial catheterization and terlipressin treatment in a child. Design Case report. Setting Pediatric intensive care unit of a university hospital. Patient The patient was a 2-month-old female infant with shock refractory to treatment with catecholamines, who received treatment with terlipressin (20 microg/kg/4 hrs). In order to monitor her cardiac output, the right femoral artery was catheterized with a 4-Fr PiCCO catheter. At 60 hrs, the patient presented progressive ischemia of the right lower limb and intestinal ischemia. The ischemia did not improve despite withdrawal of the catheter and interruption of the terlipressin administration; it progressed to massive intestinal ischemia, and the patient died. Conclusions Arterial catheterization combined with the administration of vasoconstrictor drugs, particularly vasopressin or terlipressin, can lead to local ischemic complications and severe intestinal ischemia in infants in shock.

Summary The acute respiratory distress syndrome (ARDS) secondary to tuberculosis in adults carries a high mortality. Its presentation in children is exceptional. We report the case of a pregnant 15-year-old adolescent with no immunodeficiency who developed ARDS secondary to tuberculosis, requiring mechanical ventilation and inhaled nitric oxide treatment and presenting a favourable clinical course. We conclude that, although very infrequent, tuberculosis must be excluded in any child with ARDS of unknown cause as early diagnosis and treatment significantly improves the prognosis.

The Peruvian health system is limited in providing specialized care for patients with clefts because there are an insufficient number of hospitals and few specially trained doctors in rural areas of the country. The most common model of care in these areas is the surgical mission wherein experienced cleft surgeons perform surgeries and teach local doctors. The purpose of this research was to identify the differences in outcome between the surgical mission trip and the referral center model of care provided by the same team. A retrospective analysis (2002–2012) was performed on data from surgical outcomes provided by the Outreach Surgical Center Lima that utilized both models of care (surgical mission and referral center). A total of 935 procedures were performed in 680 patients with clefts who were treated by the Outreach Surgical Center Program Lima since 2002. Patients in both groups were identified from our records (medical records and screening-day registries). All patients underwent a physical examination, had photographs taken, and any unfavorable results and complications were documented. Comparison of categorical variables (including outcomes) between care models was performed using Pearson’s χ 2 test or Fisher’s exact test when appropriate. In all cases a two-tailed test was performed and the p value for rejecting the null hypothesis (no difference or no association) was set at 0.05. We found significant differences between the two models of care with respect to unilateral cleft lip and cleft palate dehiscence (p = 0.02 and p = 0.04, respectively), palate postoperative hemorrhage (p

Purpose The combination of DNA methylation inhibitors and histone deacetylase inhibitors is synergistic in gene expression activation and may overcome platinum resistance. Sequential treatment with azacitidine and valproic acid (VPA) in combination with carboplatin may overcome resistance to platinum-based therapy, and we conducted a phase I trial to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental Design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received azacitidine for 5 days from days 1 to 5, VPA for 7 days from days 5 to 11, and carboplatin starting in the second cycle on days 3 and 10. Clinical correlates included evaluation of epigenetic changes, methylation patterns, and histone acetylation levels in peripheral blood mononuclear cells. Results Thirty-two patients were treated. The MTD was 75 mg/m2 azacitidine, 20 mg/kg VPA, and AUC 3.0 carboplatin. Minor responses or stable disease lasting ≥4 months were achieved by six patients (18.8 %), including three with platinum-resistant or platinum-refractory ovarian cancer. The most common adverse events grade ≥3 were fatigue (81 %) and neutropenia (69 %). Dose-limiting toxicity occurred in six patients (18.8 %), including four patients with grade 3 altered mental status. Death receptor 4 (DR4) methylation was shown to decrease in a subset of patients, but there was no relationship with tumor response or number of cycles received. Conclusions Combination of azacitidine, VPA, and carboplatin demonstrates decreased DR4 methylation and modest evidence of antitumor activity in patients with heavily treated advanced malignancies.

Context: Neonatal diabetes mellitus, a rare condition occurring in approximately 1 in 500 000 live births, is defined as insulin-requiring hyperglycemia presenting in the first months of life. Neonatal diabetes can be transient or permanent, with studies characterizing the condition as a monogenic disorder. Case Report: We describe a case of a 9-week-old infant with neonatal diabetes who presented in diabetic ketoacidosis due to a mutation affecting the ABCC8 gene that encodes the SUR1 subunit of the potassium ATP channel. Conclusion: This genetic diagnosis has therapeutic implications regarding the initiation of sulfonylurea administration as 85% of patients with neonatal diabetes due to ABCC8 gene mutations can be successfully treated with oral sulfonylurea treatment.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- CIMBA et al., BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., The study was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341), grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure; Cancer Research UK grants C12292/A11174 and C1287/A10118; the European Commission's Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175). Breast Cancer Family Registry Studies (BCFR): supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), and University of Melbourne (U01 CA69638). The Australian BCFR was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. Melissa C. Southey is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Carriers at FCCC were also identified with support from National Institutes of Health grants P01 CA16094 and R01 CA22435. The New York BCFR was also supported by National Institutes of Health grants P30 CA13696 and P30 ES009089. The Utah BCFR was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1 RR025764, and by Award Number P30 CA042014 from the National Cancer Institute. Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-19/2010, and Hereditary Cancer Association (Paveldimo vėžio asociacija)., Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/​016.BRCA-gene mutations and breast cancer in South African women (BMBSA): BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. Beckman Research Institute of the City of Hope (BRICOH): Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship. BRICOH was supported by NIH R01CA74415 and NIH P30 CA033752. Copenhagen Breast Cancer Study (CBCS): The CBCS study was supported by the NEYE Foundation. Spanish National Cancer Centre (CNIO): This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. City of Hope Cancer Center (COH): The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: Jeffrey N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): CONSIT TEAM was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”), Italian Association for Cancer Research (AIRC, IG 8713), Italian Minitry of Health (Extraordinary National Cancer Program 2006, “Alleanza contro il Cancro” and “Progetto Tumori Femminili), Italian Ministry of Education, University and Research (Prin 2008) Centro di Ascolto Donne Operate al Seno (CAOS) association and by funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’). German Cancer Research Center (DKFZ): The DKFZ study was supported by the DKFZ. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005, and the BBMRI grant CP46/NWO., Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Rosalind A. Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Canter (FCCC): The authors acknowledge support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): The GEMO study was supported by the Ligue National Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award and the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program. Gynecologic Oncology Group (GOG): This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), Statistical and Data Center (CA 37517), and GOG's Cancer Prevention and Control Committtee (CA 101165). Drs. Mark H. Greene and Phuong L. Mai were supported by funding from the Intramural Research Program, NCI, NIH. Hospital Clinico San Carlos (HCSC): HCSC was supported by RETICC 06/0020/0021, FIS research grant 09/00859, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitivity, and the European Regional Development Fund (ERDF)., Helsinki Breast Cancer Study (HEBCS): The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary (HUNBOCS): HUNBOCS was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/ÖP-9. Institut Català d'Oncologia (ICO): The ICO study was supported by the Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Ramón Areces Foundation, Carlos III Health Institute, Catalan Health Institute, and Autonomous Government of Catalonia and contract grant numbers: ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, and 2009SGR283. International Hereditary Cancer Centre (IHCC): Supported by the Polish Foundation of Science. Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. Iceland Landspitali–University Hospital (ILUH): The ILUH group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): INHERIT work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance grant 019511 and the Ministry of Economic Development, Innovation and Export Trade grant PSR-SIIRI-701. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics., Istituto Oncologico Veneto (IOVHBOCS): The IOVHBOCS study was supported by Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero della Salute (“Progetto Tumori Femminili” and RFPS 2006-5-341353,ACC2/R6.9”). Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Amanda B. Spurdle is an NHMRC Senior Research Fellow. The Clinical Follow Up Study was funded from 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333. Mayo Clinic (MAYO): MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. McGill University (MCGILL): The McGill Study was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation, and Export Trade. Memorial Sloan-Kettering Cancer Center (MSKCC): The MSKCC study was supported by Breast Cancer Research Foundation, Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Family Foundation, and Lymphoma Foundation. Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Women's College Research Institute, Toronto (NAROD): NAROD was supported by NIH grant: 1R01 CA149429-01. National Cancer Institute (NCI): Drs. Mark H. Greene and Phuong L. Mai were supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. National Israeli Cancer Control Center (NICCC): NICCC is supported by Clalit Health Services in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N. N. Petrov Institute of Oncology (NNPIO): The NNPIO study has been supported by the Russian Foundation for Basic Research (grants 11-04-00227, 12-04-00928, and 12-04-01490), the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780), and through a Royal Society International Joint grant (JP090615). The Ohio State University Comprehensive Cancer Center (OSU-CCG): OSUCCG is supported by the Ohio State University Comprehensive Cancer Center., South East Asian Breast Cancer Association Study (SEABASS): SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): The SMC study was partially funded through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium. Swedish Breast Cancer Study (SWE-BRCA): SWE-BRCA collaborators are supported by the Swedish Cancer Society. The University of Chicago Center for Clinical Cancer Genetics and Global Health (UCHICAGO): UCHICAGO is supported by grants from the US National Cancer Institute (NIH/NCI) and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. University of California Los Angeles (UCLA): The UCLA study was supported by the Jonsson Comprehensive Cancer Center Foundation and the Breast Cancer Research Foundation. University of California San Francisco (UCSF): The UCSF study was supported by the UCSF Cancer Risk Program and the Helen Diller Family Comprehensive Cancer Center. United Kingdom Familial Ovarian Cancer Registries (UKFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. University of Pennsylvania (UPENN): The UPENN study was supported by the National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855), Breast Cancer Research Foundation, Rooney Family Foundation, Susan G. Komen Foundation for the Cure, and the Macdonald Family Foundation. Victorian Familial Cancer Trials Group (VFCTG): The VFCTG study was supported by the Victorian Cancer Agency, Cancer Australia, and National Breast Cancer Foundation. Women's Cancer Research Initiative (WCRI): The WCRI at the Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN).

We report the case of an African American male with no significant past medical history presenting with recurrent, rapidly relapsing episodes of thrombotic thrombocytopenic purpura (TTP) despite aggressive treatment with several lines of treatment. Incidentally, these episodes were associated with severe abdominal pain which eventually developed into acute abdomen and prompted exploratory laparotomy, revealing diffuse carcinomatosis with a tumor located on the left pelvis that was encasing the distal sigmoid colon. Pathology made a final diagnosis of peritoneal mesothelioma. TTP-like syndrome (TTP-LS) has been described as a paraneoplastic phenomenon in several malignancies but never before in the setting of malignant mesothelioma. Paraneoplastic TTP-like syndrome has historically been associated with a dismal prognosis and particular clinical and laboratory abnormalities described in this paper. It is of utmost importance to make a prompt determination whether TTP is idiopathic or secondary to an underlying condition because of significant differences in their prognosis, treatment, and response. This paper also reviews the current literature regarding this challenging condition.

PMCID: PMC3319317.-- et al., [Background]: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). [Methods]: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. [Results]: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). [Conclusions]: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. [Impact]: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers., This research was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341), and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. This work was also supported by Cancer Research UK (CR-UK) grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175). Support was also provided by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and by the Canadian Breast Cancer Research Alliance-grant #019511., A.C. Antoniou is a CR-UK Senior Cancer Research Fellow. D.F. Easton is CR-UK Principal Research Fellow. G. Chenevix-Trench6 is a NHMRC Senior Principal Research Fellow. BFBOCC was supported by the Research Council of Lithuania grant LIG-19/2010 to R. Janavicius. BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to E.J. van Rensburg. BCFR was supported by the National Cancer Institute, NIH under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (formerly the Northern California Cancer Center; U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). CBCS was supported by The Neye Foundation. CNIO was partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, the Spanish Ministry of Science and Innovation (FIS PI08 1120), and the Basque Foundation for Health Innovation and Research (BIOEF): BIO07/CA/006. CONSIT TEAM was supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 “Alleanza contro il Cancro” to L. Varesco and P. Radice, and “Progetto Tumori Femminili” to P. Radice), Ministero dell'Universita' e Ricerca (RBLAO3-BETH to P. Radice), Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors” to P. Radice), Associazione Italiana per la Ricerca sul Cancro (4017 to P. Pujol), and by funds from Italian citizens who allocated the 5 × 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”)., The DKFZ study was supported by funds from the DKFZ. EMBRACE was supported by CR-UK Grants C1287/A10118 and C1287/A11990. D.G. Evans and Fiona Lalloo were supported by an NIHR grant to the Biomedical Research Centre, Manchester, UK. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R.A. Eeles, Elizabeth Bancroft, and Lucia D'Mello were supported by CR-UK Grant C5047/A8385. GC-HBOC was supported by a grant of the German Cancer Aid (grant 109076) and by the Centre of Molecular Medicine Cologne (CMMC). The GEMO study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association “Le cancer du sein, parlons-en!” Award. The Georgetown study was supported by the Familial Cancer Registry at Georgetown University (NIH/NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure. GOG was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program—COPTRG) NCI programs. K. Phillips is the Cancer Council Victoria, Colebatch Clinical Research Fellow. HEBCS was supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HEBON study was supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, and the ZonMW grant 91109024. HUNBOCS was supported by the Hungarian Research Grant KTIA-OTKA CK-80745. ICO was supported by Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; contract grant numbers ISCIIIRETIC RD06/0020/1051, PI10/01422, PI10/31488, and 2009SGR290. IHCC was supported by a Polish Foundation of Science award to K. Jaworska, a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. ILUH was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund., INHERIT was supported with J. Simard, Chairholder of the Canada Research Chair in Oncogenetics. IOVHBOCS was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), and “Ministero della Salute” (“Progetto Tumori Femminili and grant numbers RFPS 2006-5-341353, ACC2/R6.9”). kConFab was supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow-Up Study was funded by the NHMRC [145684, 288704, 454508]. A.-B. Skytte is supported by a NHMRC Senior Research Fellowship. A.K. Godwin was funded by U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund while at FCCC. The author acknowledges support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor. The McGill study was supported by the Jewish General Hospital Weekend to End Breast Cancer. M. Thomassen holds a Fonds de la Recherche en Santé du Québec clinician-scientist award. The MSKCC study was supported by the Starr Cancer Consortium, the Breast Cancer Research Foundation, the Norman and Carol Stone Cancer Research Initiative, the Kate and Robert Niehaus Clinical Cancer Research Initiative, the Lymphoma Foundation, and the Sabin Family Research Initiative. The NCI study was supported by the Intramural Research Program of the U.S. National Cancer Institute and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc. NNPIO was supported by the Russian Federation for Basic Research (grants 10-04-92601, 10-04-92110, 11-04-00227) and the Federal Agency for Science and Innovations (contract 16.512.11.2237)., OCGN was supported by Cancer Care Ontario and the U.S. National Cancer Institute, NIH under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators. OSU-CCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS was supported by an Instituto Toscano Tumori grant to M.A. Caligo. SEABASS was supported by CARIF and University Malaya. The UCSF study was supported by the Helen Diller Family Comprehensive Cancer Center at UCSF, the Avon Foundation, and the Center for Translational and Policy Research in Personalized Medicine (TRANSPERS), NIH/NCI P01 CA130818-02A1. UKFOCR was supported by a project grant from CRUK to P.P.D. Pharoah. The UPENN study was supported Komen Foundation for the Cure to S.M. Domchek, the Breast Cancer Research Foundation to K.L. Nathanson, and NIH grants R01-CA083855 and R01-CA102776 to T.R. Rebbeck. WCRI was supported by the American Cancer Society Clinical Research Professorship #SIOP-06-258-06-COUN.

Severe disease caused by Clostridium difficile is frequently encountered in transplant recipients and carries a high mortality. Numerous studies have been published on this subject in the adult population, but few in the pediatric setting. A 4-year-old boy who had undergone heart transplant 20 months earlier was admitted to the pediatric intensive care unit after humoral rejection. Seven days after admission, he developed septic shock, abdominal distension, and paralytic ileus without diarrhea. Pseudomembranous colitis due to C. difficile was confirmed by microbiological and radiological studies. Despite treatment with rectal vancomycin and intravenous metronidazole, the patient did not improve and required decompressive laparotomy; because of the poor subsequent clinical course, terminal ileostomy and cecostomy were performed in a second operation. Recovery was satisfactory, and surgical reconstruction of intestinal tract was performed 3 months later without complications. Although early surgery with total colectomy is indicated, when there is a poor response to medical treatment in cases of C. difficile toxic megacolon, the case we present responded favorably to a conservative surgical approach that enabled intestinal integrity to be restored 3 months later. In the pediatric population, less aggressive therapeutic options should be considered, as they have benefits on the subsequent quality of life of the patient.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P

Item does not contain fulltext Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Contains fulltext : 81601.pdf (Publisher’s version ) (Closed access) Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Endogenous NO synthase inhibitors (end-NOSIs) have been associated with cardiovascular risk factors and atherosclerosis. In addition, end-NOSIs may directly cause hypertension through hemodynamic effects. We aimed to examine the association between end-NOSI asymmetrical dimethylarginine (ADMA) and N -guanidino-monomethyl-arginine (NMMA), subclinical atherosclerosis, and arterial hemodynamics. We studied 922 adults participating in a population-based study (PREVENCION Study) and examined the correlation between end-NOSI/ l -arginine and arterial hemodynamics, carotid-femoral pulse wave velocity, and carotid intima-media thickness using linear regression. ADMA, NMMA, and l -arginine were found to be differentially associated with various classic cardiovascular risk factors. ADMA and NMMA (but not l -arginine) were significant predictors of carotid intima-media thickness, even after adjustment for cardiovascular risk factors, C-reactive protein, and renal function. In contrast, ADMA and NMMA did not predict carotid-femoral pulse wave velocity, blood pressure, or hemodynamic abnormalities. Higher l -arginine independently predicted systolic hypertension, higher central pulse pressure, incident wave amplitude, central augmented pressure, and lower total arterial compliance but not systemic vascular resistance or cardiac output. We conclude that ADMA and NMMA are differentially associated with cardiovascular risk factors, but both end-NOSIs are independent predictors of carotid atherosclerosis. In contrast, they are not associated with large artery stiffness, hypertension, or hemodynamic abnormalities. Our findings are consistent with a role for asymmetrical arginine methylation in atherosclerosis but not in large artery stiffening, hypertension, or long-term hemodynamic regulation. l -Arginine is independently associated with abnormal pulsatile (but not resistive) arterial hemodynamic indices, which may reflect abnormal l -arginine transport, leading to decreased intracellular bioavailability for NO synthesis.

Introduction: Identification of patients with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to activation of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR) signaling. The RADIANT-3 trial of everolimus in advanced PNETs demonstrated a significant prolongation of progression-free survival (PFS) from 4.6 months with placebo versus 11 months with everolimus. Despite the improvement in PFS, the response rate was only 5% among patients receiving everolimus. The index case for our study was an exceptional responder who had a significant radiological response as well as a PFS of 24 months, which were both better than expected from the literature. This led to the hypothesis that there may be mutational changes in genes affecting the mTOR pathway that could predict sensitivity to mTOR inhibitors. In this study, we specifically explored the role of PTEN loss as a potential predictive marker. Methods and Materials: Between 2010 and 2014, patients with well-differentiated unresectable and metastatic PNETs treated at the University of Miami/Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital with everolimus were identified. Eight patients had pathology specimens available for testing. PTEN loss detected by Fluorescence In Situ Hybridization (FISH) was carried out using a commercially available probe for cytoband 10q23. Patients' response to everolimus was evaluated through June 2014. The primary outcome was PFS. PTEN expression by immunohistochemistry (IHC) will also be performed and the results will be compared to those obtained by FISH. Results: The median age was 60 years (range 45-78). 50% of the patients were females and 50% were males. Two patients had gastrinomas, 1 patient had an insulinoma, and five patients had non-functional PNETs. All patients had unresectable metastases to the liver. In addition to sandostatin LAR, the patients received everolimus starting at a dose of 10mg daily. Three patients were found to have deletion of PTEN. Of those, one patient did not tolerate everolimus and the PFS for the other two was 8 and 24 months respectively. Detection of PTEN loss by FISH yielded no results in 2 patients due to insufficient tumor left in the specimen. PFS in these 2 patients was 24 and 4 months respectively. Testing is ongoing in the last 3 patients and the PFS for these patients is 3, 10 and 13 months. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusion: The index case for this study had a PTEN deletion and had a partial response to treatment and prolonged disease control for 2 years with everolimus. Testing is ongoing in additional cases to determine if there is a consistent correlation between PTEN loss by FISH and PFS. Citation Format: Moh'd Khushman, Joyce Slingerland, Yao-Shan Fan, Monica Garcia-Buitrago, Ernesto Bustinza, Maria Restrepo, Daniel Sussman, Caio Rocha-Lima, Peter Hosein. Exploring phosphatase and tensin homolog (PTEN) loss as a potential predictive marker for response to everolimus in patients with pancreatic neuroendocrine tumors (PNETs). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A01.

Background Patients with tuberous sclerosis often develop facial angiofibromas that can be successfully treated with topical 1% sirolimus ointments. Nevertheless, this ointment’s greasy nature can produce acne, causing patients to refuse the treatment. Purpose To devise a non-oily formula for topical sirolimus for patients with tuberous sclerosis and facial angiofibromas who develop acne due this ointment. Material and methods We reviewed the literature searching for standard procedures for making alternative topical formulations of sirolimus. In addition, the physicochemical properties of sirolimus were considered in order to find the most suitable formulation for this particular case. Results No standard ways were found of producing oil-free formulations of sirolimus. We decided to compound a 0.2% sirolimus gel with the following procedure. First, prepare a 2% carmellose gel. For this, heat aqua conservans (Nipagin 0.25 g + Nipasol 0.11 g + distilled water 500 mL) to 50°C. In a mortar, mix 2 g of sodium carboxymethylcellulose and 10 g of glycerol. Then, add the content of the mortar to 88 g of heated aqua conservans and stir the mixture until room temperature is reached. Once the carmellose gel has been prepared, weigh 0.2 g of sirolimus and add a few drops of glycerol to it. Slowly, pour the carmellose gel onto the sirolimus, mixing them by stirring, until 100 g has been added. Let it stand for 12 h until the gel is homogeneous. We give it an expiry date of 2 months, stored in an opaque container and at room temperature (below 25°C). Mask and gloves must be used throughout the procedure. Conclusion We found a way to formulate sirolimus in non-oily excipients in order to diminish the development of acne with its use. Further studies will be needed to determine the efficacy of this formula in the treatment of facial angiofibromas of patients with tuberous sclerosis and the improvement of the acne presented by these patients. References and/or acknowledgements No conflict of interest.

Cardiovascular disease is emerging as a leading cause of morbidity and mortality in Latin America. Population-based data regarding the prevalence of hypertension and hypertension subtypes in Andean Hispanic populations are scarce. The authors performed a population-based study that included 1878 Peruvian Andean adults to determine: (1) the prevalence, awareness, and control of hypertension and (2) the relative frequency of hypertension subtypes (systolic vs. diastolic). The prevalence of hypertension was 15.7% (95% confidence interval [CI], 14.0%–17.4%), did not differ by gender, and increased steeply with age, particularly in women. Awareness, treatment, and control rates were 47.9%, 39.5%, and 14%, respectively. Diastolic blood pressure increased until age 50 years and reached a plateau thereafter, whereas mean arterial pressure continued to increase with age even after age 50 years. Furthermore, in sharp contrast with the United States population, the predominant type of hypertension was systodiastolic (41.7%; 95% CI, 35.1%–48.5%). Isolated systolic hypertension accounted for only 29.3% of cases (95% CI, 23.9%–35.4%) and was responsible for a minority of cases in all age groups before age 70 years. Hypertension subtypes in this Andean population seem to differ significantly from those present in the United States population, with a much larger proportion of systodiastolic and diastolic hypertension even with advanced age. These differences result from interactions between hemodynamic and structural factors, and further studies aimed at characterizing their genetic and environmental determinants and implications in end-organ damage and prognosis in this population may contribute to understanding the pathophysiology of hypertension.

OBJECTIVE: The objective of this study was to analyze the incidence and significance of hepatic dysfunction after cardiac surgery in children. DESIGN: Prospective, observational study. SETTING: Pediatric intensive care unit of a university hospital. PATIENTS: The study consisted of 232 children ranging in age from newborn to 17 years with no history of liver disease. MEASUREMENTS AND MAIN RESULTS: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gammaglutamyltranspeptidase (GGT), alkaline phosphatase, total and conjugated bilirubin, blood glucose, urea, creatinine, and coagulation studies were determined at admission, at 24 and 48 hrs, and at 7 days. Hepatic dysfunction was taken as an ALT of100 IU/L or a moderate or high hepatic score. The statistical study included bivariate analysis and multivariate logistic regression to study the risk factors for hepatic dysfunction. Twenty-one patients (9%) showed an ALT100 IU/L, and 29.3% had a moderate or high hepatic score. A relationship was found between hepatic dysfunction and the type of cardiopathy (D-transposition of the great arteries and coarctation of the aorta), shock, the administration of dopamine or epinephrine, renal insufficiency, the presence of pulmonary changes (pulmonary edema, atelectasis, pulmonary hypertension, hypoxemia), hematologic disturbances (prothrombin time, kaolin-cephalin time, fibrinogen, and platelets), and the need for a greater number of transfusions of packed cells, plasma, and platelets. Compared with 7.6% of the rest of the patients (p.001), 38% of patients with an ALT100 IU/L died. The hepatic score of those patients who died was 4.2 (2.3)-higher than that of the survivors at 1.5 (1.8), (p.001). Shock and renal insufficiency were the factors most significantly related to the development of hepatic dysfunction. CONCLUSIONS: Hepatic dysfunction is an uncommon complication in children after cardiac surgery. This complication is related mainly to hemodynamic disturbances and renal insufficiency and is an indicator of poor prognosis.

333 Background: Identification of pts with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Exceptional responders to everolimus in NET including pancreatic (PNET) were observed in our cohort of pts. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt and mammalian target of rapamycin (mTOR) pathway. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to PI3K/Akt/mTOR pathway activation. Inthis study, we explored the role of PTEN as a potential predictive marker of everolimus in pts with NET including PNET. Methods: Between 2010 and 2014, pts with well-differentiated unresectable and metastatic gastrointestinal NET treated at our institution with everolimus were identified. 17 patients had pathology specimens available for testing. PTEN loss detection by FISH was carried out using a commercially available probe for cytoband 10q23, and by IHC using a commercially available antibody. Patients’ response to everolimus was evaluated through August 2014. The primary outcome was PFS and PTEN status was correlated with PFS for any potential association. Results: The median age was 59 years (range 45-78); 7 were male; 8 had PNET (2 gastrinomas, 1 insulinoma and 5 non-functional); 7 had small bowel NET and 2 unknown primary. All pts received everolimus starting at 10mg daily and octreotide LAR. Of the pts with PNETs, 3 had PTEN loss by FISH. Of those, one did not tolerate everolimus. The PFS for the other two pts was 8 and 24 months respectively. Among the 4 pts with intact PTEN; PFS was 14, 26, 3 and 12 months. 1 patient had insufficient tumor for testing. PTEN FISH is ongoing in the 9 non-pancreatic NET pts. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusions: Testing for PTEN loss by FISH is feasible. Due to the small sample size, the role of PTEN loss could not be defined as a predictive marker in PNET. Testing on additional cases is ongoing and will be presented at the meeting.

Introduction Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). Methods We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients Results Of the 706 patients, 301 (42.6 %) met both definitions. The inter-rater agreement (κ ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician’s diagnosis of severe sepsis, only 69 % (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria. Conclusions Physician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis.

Severe aplastic anemia (SAA) is characterized by the absence of progenitor hematopoietic cells in bone marrow caused mainly by autoimmunity. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for young newly diagnosed patients with SAA. The preferred source of stem cells is bone marrow (BM) due to improved overall survival (OS) and lower incidence of graft versus host disease (GVHD). In Latin American countries, many patients have received peripheral blood stem cell transplantation (PBSCT) for several reasons: lower cost, apheresis without anesthesia, no bone punctures and faster hematological recovery. Moreover, due to patient family or donors idiosyncratic factors, there is a lack of acceptance to surgical harvesting of bone marrow. Therefore we describe the Latin American experience with allo-HSCT using PBSC in SAA patients. One hundred and ninety patients with acquired SAA that received allo-HSCT using PBSC between 1997- 2014 were included. The allo-HSCT was performed at 4 centers of Perú, Colombia and México. All donors were HLA-identical siblings mobilized with G-CSF. The choice of the conditioning regimens was made on each institution. Primary outcome was OS; incidence of GVHD, outcome of patients > 40 years old and effect of conditioning regimens on survival were studied. The median of CD 34+ cells administered was 4.22 X 10⁶/kg (range 0.70-22.28). Median of neutrophil and platelet recovery was 11 days (range 7-35) and 12 days (range 8-25) respectively. Neutrophil recovery for anti-thymocyte globulin (ATG)-based regimens presented at a median of 11 days (range 7-28) and for non-ATG based regimens 14 days (range 9-35) (P The incidence of acute graft versus host disease (aGVHD) was 19.5% (8.4% was grade III-IV). Chronic GVHD (cGVHD) was 24.7% and extensive manifestations presented in 5.9% of patients. No relation between the conditioning regimen used (ATG vs non-ATG based regimens) and the incidence of aGVHD (P=0.066) or cGVHD (p=0.613) was found. The administration of ≥3.0X10⁶ CD 34/Kg related to higher incidence of aGVHD grade III and IV (P=0.05), but not cGVHD (P=0.709) or extensive cGVHD (P=0.428). The presence of aGVDH and cGVHD was associated with higher mortality (P Time from diagnosis to transplant ≥ 100 days was not a predictor of death (P=0.458). A total of 63% of patients were considered heavily transfunded and this factor was not related to relapse (P=0.96), aGVHD (P=0.75) or cGVHD (P=0.39). Nineteen patients (10%) lost their grafts; most of them had received non-ATG conditioning regimens (P=.016). Four patients (2%) developed secondary malignancies after transplant: acute myeloid leukemia (2), myelodisplastic syndrome (1) and hairy cell leukemia (1). In multivariate analysis, the use of non-ATG based regimens (P3 X10⁶/kg CD34(P=0.04) were independent negative predictors of survival. Infections were the leading cause of death. The second cause was GVDH and related complications. The transplant was successful in 95% of patients. The OS achieved in this study at 10 years with ATG-based regimens and PBSC (82%) is comparable to that (84%) reported from the WPSAA-EBMT (Haematologica 2009) using BM. In the study reported by EBMT-CIBMTR (Blood 2007) the 5 years OS was 85% using BM in patients ≤20 years and 64% in patients > 20 years. In our study the incidence of aGVHD and cGVHD was similar the aforementioned study of WPSAA-EBMT using PBSC (19.5% vs 17%) and (24.5 vs 22%) respectively. In conclusion allo-HSCT in SAA patients using PBSC is an effective treatment resulting in cure in the majority of cases. Patients conditioned with ATG had a 10-year OS similar to that reported with BM as the source of stem cells, a prospective and comparative study is needed to definitively establish if it is safe to perform a HSCT using peripheral blood as a source of stem cells. Disclosures No relevant conflicts of interest to declare.

Se puede iniciar el tratamiento temprano de la maloclusión clase II división 2 en la dentición mixta, usando diferentes tipos de aparatología, el objetivo en esa fase es lograr una función muscular equilibrada, una relación molar clase I y mejorar el entrecruzamiento vertical y horizontal.Se reporta el caso de un niño de 9 años 4 meses, en dentición mixta primera fase con maloclusión clase II división 2 y discrepancia alveolo dentaria superior de -7,3 mm e inferior de -8,4mm. El tratamiento incluyó el uso de una placa de expansión con plano de mordida anterior, aparato extraoral ortodóntico de tracción cervical y lip bumper, obteniendo resultados satisfactorios en 18 meses.

Background: Nutrition is important in childhood because the child has a lower energy reserve than the adult and a higher demand for calories because of ongoing growth. In this study, the utility of transpyloric enteral feeding (TEF) in critically ill children was evaluated. Methods: A prospective, descriptive study was made in a pediatric intensive care unit of a tertiary pediatric center of 41 critically ill children. 30 after surgical procedures and 11 with nonsurgical illness, aged 8 days to 12 years, who received transpyloric enteral feeding with 8- or 10-Fr weighted feeding tubes. Analysis was made of tolerance and complications (vomiting, abdominal distension, excessive gastric residual, diarrhea, and pulmonary aspiration) of TEF. Results: The mean duration of TEF was 19.5 ± 26.8 days (range, 1-120 days). The administration of sedative agents or inotropic drugs did not alter toleration of TEF. Eight of 12 patients treated with continuous infusion of vecuronium tolerated TEF without complications. Eleven gastrointestinal complications occurred in 10 patients, abdominal distension and excessive gastric residual in 7 (17%), and diarrhea in 4 (9.7%). In 7 patients gastrointestinal complications improved, with decreasing use or transitory interruption of TEF, but in 4 patients (9.7%), TEF had to be withdrawn. Gastrointestinal complications were more frequent in postsurgical than in nonsurgical patients (p < 0.001). No patients suffered from pulmonary aspiration, and the incidence of pulmonary infection and hepatic dysfunction diminished during TEF. Conclusions: Transpyloric enteral feeding is a good method of nutritional support in critically ill children and can be used in patients treated with neuromuscular blocking agents. The frequency and severity of complications and the risks of pulmonary infection and hepatic dysfunction related to TEF are low.

BACKGROUND Sepsis and septic shock represent up to 30% of admitted patients in pediatric intensive care units, with a mortality that can exceed 10%. The objective of this study is to determine the prognostic factors for mortality in sepsis. METHODS Multicenter prospective descriptive study with patients (aged 7 days to 18 years) admitted to the pediatric intensive care units for sepsis, between January 2011 and April 2012. RESULTS Data from 136 patients were collected. Eighty-seven were male (63.9%). The median age was a year and a half (P25-75 0.3-5.5 years). In 41 cases (30.1%), there were underlying diseases. The most common etiology was Neisseria meningitidis (31 cases, 22.8%) followed by Streptococcus pneumoniae (16 patients, 11.8%). Seventeen cases were fatal (12.5%). In the statistical analysis, the factors associated with mortality were nosocomial infection (P = 0.004), hypotension (P

Background Omalizumab’s labelled indication is the treatment of IgE-mediated asthma. It has been used in our hospital since 2008. In 2011 it became necessary to develop a protocol that clarified patient selection and criteria for withholding treatment. Purpose To describe the patients treated with omalizumab, focusing on whether they match our protocol’s use criteria or not. Materials and Methods All patients treated with omalizumab for asthma in our hospital were included. Data were obtained in October 2012 from electronic clinical records: treatment period, patient smoker or not, other medicines for asthma, basal IgE, adherence to treatment, omalizumab dosage and hospitalizations and emergency department visits before and after treatment. Our omalizumab use protocol states these patient selection criteria: uncontrolled severe asthma with previous optimised therapy, basal IgE > 76 IU/mL and at least three emergency department visits or one hospitalisation in the previous year. Treatment withholding criteria are: evaluation after 16 weeks and stop if treatment shows no benefit. Two different pharmacists examined each patient’s information to establish if treatment was being effective and whether the hospital’s protocol was being followed. Results 31 patients were studied, 7 children and 24 adults. Treatment was stopped in 9 patients, due to lack of efficacy in 8 of them and to adverse effects in the other (diarrhoea, fever and skin reaction). Previous treatments included montelukast or theophylline in 19 patients (61%). Basal IgE was below 76 IU/mL in one patient. Median duration of treatment was 637 days (72–1624). Regarding patients’ adherence to treatment, 23% of patients missed a dose, 13% missed two and 6% missed three or more. 13 patients had had no pre-treatment hospitalizations or emergency department visits. Treatment was evaluated as effective in 14 of the 22 patients who continued receiving omalizumab (64%). Conclusions Our patients still need to be selected better. Protocol compliance is lower than desirable. No conflict of interest.

Background Glucarpidase (Voraxaze) is effective in the treatment of methotrexate (MTX)-induced renal dysfunction but many cases this can be handled with standard treatment. Purpose To describe the progress of a patient with MTX-induced renal failure in whose management glucarpidase was not used. Materials and Methods A 13 year-old girl with acute lymphoblastic leukaemia treated with high-dose MTX. Baseline laboratory tests were normal, except for elevated transaminases and GGT. Results The patient received her first consolidation cycle with 500 mg/m2 of MTX in 30 minutes, followed by 4500 mg/m2 in 23.5 hours, oral mercaptopurine 30 mg/m²/day and triple intrathecal therapy. Simultaneously, she received hyperhydration/alkalinisation (3000 ml/m²/day).There was no pharmacological interaction to MTX. 24 hours after the MTX infusion stared, the serum creatinine level (Cr) had tripled (see the table below).The following measures were taken: hyperhydration/alkalinisation (4500 ml/m²/day), colestyramine (3 g/6 h) and folinic acid rescue at 500 mg/m²/6 h 31 hours after the start of the MTX infusion. Although the protocol provides for the possibility of administering glucarpidase, it was decided not to do this because the methotrexate level was Conclusions An early intervention with supportive treatment based on folinic acid, hyperhydration and urine alkalinisation was effective in the management of MTX-induced renal toxicity. No conflict of interest.

Background Valproic acid (VPA) is 90–95% protein bound to albumin; this binding can be saturated so other parameters that can modify the free fraction of VPA should be taken into account. Purpose To identify areas for improvement in VPA use and monitoring in a tertiary hospital where the pharmacy service does not routinely send pharmacokinetic dose adjustment recommendations. Materials and Methods A retrospective study was conducted from February to April 2012. All patients treated with VPA were included and grouped depending on whether VPA was part of their home treatment or not. Variables collected were: dose, indication, total VPA serum concentration (C), drug interactions classified as ≥C by Lexi-Comp, glomerular filtration rate (GFR), Child-Pugh score, albumin and bilirubin. Results 30 patients were treated with VPA, 24 of whom were on VPA before admission (15 epilepsy, 9 psychiatric disorders and 1 unknown reason). Reasons for admission were: 5 convulsions, 12 psychiatric disorders and 13 causes unrelated to VPA. At discharge 27 patients continued on VPA with a mean dose similar to the dose at admission. C was determined in 14 patients: 5 were within the reference range (50–100 mg/L); 2 above, achieving therapeutic levels before discharge and 7 below. In these latter cases, 3 had an albumin 50 mg/L after correcting it with the J. Hermida formula which is a theoretical method for normalising C in hypoalbumenic patients. GFR, Child-Pugh score and bilirubin were normal. Mean time between changes in dose and C determinations was 1.5 days (0–5 days). 21 drug interactions were detected in 15 patients, involving a total of 10 drugs. Only 2 interactions were reported: VPA meropenem and VPA lamotrigine. Conclusions Changes in free fraction of VPA, due to hypoalbuminaemia, liver or kidney disease and hyperbilirubinaemia, must be detected. C should be measured once a steady state has been achieved (3–5 days). Drug interactions affecting VPA should be added to the pharmacy service’s interaction notification programme. No conflict of interest.

Background: Phase I trials seek to determine the maximum-tolerated drug dose that will be used in future efficacy studies and are often criticized for their inability to clinically benefit patients. This study examined whether time to progression (TTP) in patients with head and neck cancer enrolled in phase I trials at M. D. Anderson Cancer Center was inferior to TTP with last FDA-approved drug prior to inclusion in the phase I trial. We also examined the molecular profile of these patients including: PI3CA mutations and PTEN deletions Methods: We retrospectively reviewed medical chart data from head and neck cancer patients enrolled in phase I trials at M. D. Anderson, including age, gender, performance status, tumor histology, hemoglobin, LDH, albumin, platelets, clinical response and TTP while on phase I trials and TTP to their last FDA-approved therapy prior to inclusion on phase I. We conducted univariate and multivariate analysis using SPSSv17. Results: 62 patients with head and neck cancer were enrolled in phase I trials from 2003 to 2009. Of these, 39 (63%) had squamous head and neck cancers, 12 (19%) had adenocystic carcinomas, and 4 (6%) had oropharyngeal adenocarcinomas. Median age was 54.2 years (range 26-80); 52 (83%) were male. 58 patients had an ECOG performance status of 0-1. Median and standard deviation values of hemoglobin, LDH, albumin and platelets were: 12.5 (1.8) g/dL, 689 (772), 4.02 (0.43) g/dL and 299 (113.96), respectively. Univariate survival analysis results showed that a hemoglobin level of ≤10.5 g/dL, LDH ≤700 and partial response (PR) or stable disease (SD) on phase I trials were associated with survival (p Conclusion: We show that clinical outcome for patients with head and neck cancers treated in phase I trials is not inferior to outcome with last treatment line based on a FDA-approved drug. We will be also presenting data regarding the molecular profile of these patients including PI3CA mutations and PTEN deletions and correlation with response to trials including drugs targeting mTOR/PI3K pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2773.