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- Fatal CTLA-4 Heterozygosity With Autoimmunity and Recurrent Infections: a De Novo MutationPublication . Moraes-Fontes, MF; Hsu, AP; Caramalho, I; Martins, C; Araújo, AC; Lourenço, F; Taulaigo, AV; Lladó, A; Holland, SM; Uzel, GPrimary immunodeficiency disorders are rarely diagnosed in adults but must be considered in the differential diagnosis of combined recurrent infections and autoimmune disease. We describe a patient with CTLA-4 haploinsufficiency and an abnormal regulatory T-cell phenotype. Unusually, infections were more severe than autoimmunity, illustrating therapeutic challenges in disease course.
- Parenteral Nutrition-Associated Cholestasis and Triglyceridemia in Surgical Term and Near-Term Neonates: A Pilot Randomized Controlled Trial of Two Mixed Intravenous Lipid EmulsionsPublication . Pereira-da-Silva, L; Nóbrega, S; Rosa, ML; Alves, M; Pita, A; Virella, D; Papoila, AL; Serelha, M; Cordeiro-Ferreira, G; Koletzko, BBACKGROUND: Cholestasis is a common complication in infants receiving prolonged parenteral nutrition (PN). We studied the effects of two intravenous lipid emulsions composed with either 30% soybean oil, 30% medium-chain triglycerides (MCT), 25% olive oil, and 15% fish oil (SMOF) or with 50% MCT and 50% soybean oil n-6 (MCT/SOY) on the incidence of cholestasis in surgical term and near-term neonates. METHODS: A single-center, double-blinded, randomized controlled trial compared the incidence of cholestasis using either SMOF or MCT/SOY in neonates born at gestational age ≥34 weeks undergoing major surgery. The primary outcome was the incidence of conjugated serum bilirubin >1 mg/dL. Other liver enzymes were assessed as secondary outcomes. A post-hoc analysis assessed serum triglycerides levels. Odds ratios were estimated by mixed-effects regression models. RESULTS: Enrollment was prematurely interrupted because the MCT/SOY became unavailable, thus 49 infants (SMOF 22, MCT/SOY 27) completed the study. The exposure (time on PN, cumulative dose of lipids) was similar in both groups. Similar cumulative incidence rates were found for elevated conjugated bilirubinemia and other liver enzymes. Hypertriglyceridemia >250 mg/dL (12/49) was more frequent in MCT/SOY (37.0%, 95% CI 21.53-55.77) than in SMOF (9.1%, 95% CI 2.53-27.81, p = 0.024). Triglyceridemia at the first assessment (median 8 postnatal days) was significantly higher with MCT/SOY than with SMOF (181 vs. 134 mg/dL, p = 0.006). Over the whole study period, mean triglyceride concentration was 36.5 mg/dL higher with MCT/SOY compared with SMOF (p = 0.013). CONCLUSION: Both emulsions had similar effects on the incidence of cholestasis and markers of liver integrity, but MCT/SOY induced higher serum triglyceride concentrations.
- Switching Biologics in Severe Pediatric Psoriasis: a Retrospective AnalysisPublication . Ramos Pinheiro, R; Diamantino, F; Cabete, J; Brasileiro, A; Baptista, J; Paiva Lopes, MJ
- Dakin's Solution: Is There a Place for it in the 21st Century?Publication . Duarte, B; Cabete, J; Formiga, A; Neves, JDakin's solution (DS) is a time-honoured antiseptic that still remains part of the wound care armamentarium. In spite of its cytotoxicity, some question its use in the current era. We report the case of a 52-year-old diabetic woman who was admitted for sepsis because of a severely infected diabetic foot. Urgent surgical drainage and debridement left a 9 × 9-cm deep, complex, infected wound with both bone and tendon involvement. Treatment with local negative pressure was unsuccessful. DS was regularly instilled through a tube left in the wound dressing. A marked improvement was observed with this strategy as the wound bed was much cleaner and fully granulated after 6 weeks. No adverse effects were noted. This case debunks the myth that topical antiseptics necessarily impair wound healing. DS can still be considered an option for difficult-to-treat, complex and heavily infected wounds.
- Targeting DNA Damage in SCLCPublication . Foy, V; Schenk, MW; Baker, K; Gomes, F; Lallo, A; Frese, KK; Forster, M; Dive, C; Blackhall, FSCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's. The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints. Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy. This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.
- Neuroendocrine Liver Metastasis: Prognostic Implications of Primary Tumor Site on Patients Undergoing Curative Intent Liver SurgeryPublication . Spolverato, G; Bagante, F; Aldrighetti, L; Poultsides, G; Bauer, TW; Field, RC; Pinto Marques, H; Weiss, M; Maithel, SK; Pawlik, TMBACKGROUND: Neuroendocrine tumors typically arise from pancreatic (PNET) vs. gastrointestinal or thoracic origins (non-PNET). The impact of primary tumor site on long-term prognosis following resection of neuroendocrine liver metastasis (NELM) remains poorly defined. The objective of the current study was to define the association of primary tumor location on prognosis of patients undergoing curative intent liver resection for NELM. METHODS: Between 1990 and 2014, 421 patients who underwent resection of NELM were identified from a multi-institutional database. Clinicopathological characteristics, operative details, and outcomes were stratified and analyzed by location of the primary tumor (PNET vs. non-PNET). A propensity score-matched analysis was utilized to assess the impact of primary tumor location on long-term survival. RESULTS: Among the 421 patients, 197 (46.8%) patients had NELM from a PNET primary while 224 (53.2%) had a non-PNET primary (small bowel, n = 145; rectal, n = 10; bronchial, n = 22; other, n = 47). There were no differences in tumor burden and tumor site, while presence of extrahepatic disease was more common among patients with non-PNET NELM (extrahepatic disease, PNET NELM, n = 11 27.5% vs. non-PNET NELM, n = 29 72.5%; p = 0.010). Patients with PNET NELM were more likely to have non-functional disease compared with patients who had non-PNET NELM (non-functional, PNET NELM, n = 117 54.9% vs. non-PNET NELM, n = 96 45.1%; p = 0.011). On the final pathological specimen of the resected NELM, patients with PNET NELM were more likely to have a moderately differentiated tumor (59.3%), while patients with non-PNET NELM were more likely to have a poorly differentiated tumor (67.8%) (p = 0.005). Patients with PNET NELM had a worse 5-year DFS and 5-year OS compared with patients who had non-PNET NELM (DFS, PNET 36.2% vs. non-PNET 55.2%; p = 0.001 and OS, PNET 79.5% vs. non-PNET 83.4%; p = 0.008). After propensity score matching, both 5-year DFS and 5-year OS of the PNET and non-PNET groups were comparable (DFS, PNET 46.2% vs. non-PNET 55.9%; p = 0.22 and OS, PNET 81.5% vs. non-PNET 84.3%; p = 0.19). CONCLUSION: PNET patients more often present with non-functional NELM and moderately differentiated tumors. On propensity-matched analysis, factors such as extrahepatic disease and tumor grade, but not primary tumor location, were associated with prognosis of patients undergoing curative intent liver surgery for NELM.
- Performance of Prognostic Scores and Staging Systems in Predicting Long-Term Survival Outcomes After Surgery for Intrahepatic CholangiocarcinomaPublication . Buettner, S; Galjart, B; van Vugt, JL; Bagante, F; Alexandrescu, S; Pinto Marques, H; Lamelas, J; Aldrighetti, L; Gamblin, TC; Maithel, SK; Pulitano, C; Margonis, GA; Weiss, M; Bauer, TW; Shen, F; Poultsides, GA; Marsh, JW; IJzermans, JN; Groot Koerkamp, B; Pawlik, TMINTRODUCTION: We sought to validate the commonly used prognostic models and staging systems for intrahepatic cholangiocarcinoma (ICC) in a large multi-center patient cohort. METHODS: The overall (OS) and disease free survival (DFS) prognostic discriminatory ability of various commonly used models were assessed in a large retrospective cohort. Harrell's concordance index (c-index) was used to determine accuracy of model prediction. RESULTS: Among 1054 ICC patients, median OS was 37.7 months and 1-, 3-, and 5-year survival, were 78.8%, 51.5%, and 39.3%, respectively. Recurrence of disease occurred in 454 (43.0%) patients with a median DFS of 29.6 months. One-, 3- and 5- year DFS were 64.6%, 46.5 % and 44.4%, respectively. The prognostic models associated with the best OS prediction were the Wang nomogram (c-index 0.668) and the Nathan staging system (c-index 0.639). No model was proficient in predicting DFS. Only the Wang nomogram exceeded a c-index of 0.6 for DFS (c-index 0.602). The c-index for the AJCC staging system was 0.637 for OS and 0.582 for DFS. CONCLUSIONS: While the Wang nomogram had the best discriminatory ability relative to OS and DFS, no ICC staging system or nomogram demonstrated excellent prognostic discrimination. The AJCC staging for ICC performed reasonably, although its overall discrimination was only modest-to-good.
- What Happens to Non-Responders in Cardiac Resynchronization Therapy?Publication . Rio, P; Oliveira, MM; Cunha, PS; Nogueira da Silva, M; Branco, LM; Galrinho, A; Soares, R; Feliciano, J; Pimenta, R; Cruz Ferreira, RINTRODUCTION AND OBJECTIVES: Left ventricular reverse remodeling (LVRR) is strongly related to the long-term prognosis of patients undergoing cardiac resynchronization therapy (CRT). The aim of this study was to assess the long-term clinical outcome of patients without LVRR at six months after CRT implantation and to determine the prognostic impact of clinical response in this population. METHODS: We analyzed 178 consecutive patients who underwent successful CRT device implantation (age 64±11 years; 69% male; 89% in New York Heart Association [NYHA] functional class III; 35% with ischemic cardiomyopathy). Clinical status and echocardiographic parameters were determined before and six months after CRT implantation. We identified those without criteria for LVRR (≥10% increase in left ventricular ejection fraction with ≥15% reduction in left ventricular end-systolic diameter compared to baseline). Clinical responders were defined by a sustained improvement of at least one NYHA functional class. RESULTS: At six-month assessment after CRT, 109 (61%) patients showed LVRR. During a mean follow-up of 56±21 months, 47 (26%) patients died, with higher mortality in the group without LVRR (36% vs. 20%, p=0.023). Clinical response was greater in patients with LVRR (88% vs. 55%, p<0.001). In patients without LVRR, clinical response to CRT was the strongest independent predictor of survival (hazard ratio: 0.120; 95% confidence interval: 0.039-0.366; p<0.001). CONCLUSION: Although patients without LVRR six months after CRT implantation had a worse prognosis, with higher all-cause mortality, clinical response can be an independent predictor of survival in this population.
- Kidney Allocation: New Contributions to an Ongoing ChallengePublication . Moreira Fonseca, N; Nolasco, F
- Progressive Deafness-Dystonia due to SERAC1 Mutations: A Study of 67 casesPublication . Maas, RR; Iwanicka-Pronicka, K; Kalkan Ucar, S; Alhaddad, B; AlSayed, M; Al-Owain, MA; Al-Zaidan, HI; Balasubramaniam, S; Barić, I; Bubshait, DK; Burlina, A; Christodoulou, J; Chung, WK; Colombo, R; Darin, N; Freisinger, P; Garcia Silva, MT; Grunewald, S; Haack, TB; van Hasselt, PM; Hikmat, O; Hörster, F; Isohanni, P; Ramzan, K; Kovacs-Nagy, R; Krumina, Z; Martin-Hernandez, E; Mayr, JA; McClean, P; De Meirleir, L; Naess, K; Ngu, LH; Pajdowska, M; Rahman, S; Riordan, G; Riley, L; Roeben, B; Rutsch, F; Santer, R; Schiff, M; Seders, M; Sequeira, S; Sperl, W; Staufner, C; Synofzik, M; Taylor, RW; Trubicka, J; Tsiakas, K; Unal, O; Wassmer, E; Wedatilake, Y; Wolff, T; Prokisch, H; Morava, E; Pronicka, E; Wevers, RA; de Brouwer, AP; Wortmann, SBOBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015