Timing of Primary Surgery for Cleft Palate.

BACKGROUND: Among infants with isolated cleft palate, whether primary surgery at 6 months of age is more beneficial than surgery at 12 months of age with respect to speech outcomes, hearing outcomes, dentofacial development, and safety is unknown. METHODS: We randomly assigned infants with nonsyndromic isolated cleft palate, in a 1:1 ratio, to undergo standardized primary surgery at 6 months of age (6-month group) or at 12 months of age (12-month group) for closure of the cleft. Standardized assessments of quality-checked video and audio recordings at 1, 3, and 5 years of age were performed independently by speech and language therapists who were unaware of the trial-group assignments. The primary outcome was velopharyngeal insufficiency at 5 years of age, defined as a velopharyngeal composite summary score of at least 4 (scores range from 0 to 6, with higher scores indicating greater severity). Secondary outcomes included speech development, postoperative complications, hearing sensitivity, dentofacial development, and growth. RESULTS: We randomly assigned 558 infants at 23 centers across Europe and South America to undergo surgery at 6 months of age (281 infants) or at 12 months of age (277 infants). Speech recordings from 235 infants (83.6%) in the 6-month group and 226 (81.6%) in the 12-month group were analyzable. Insufficient velopharyngeal function at 5 years of age was observed in 21 of 235 infants (8.9%) in the 6-month group as compared with 34 of 226 (15.0%) in the 12-month group (risk ratio, 0.59; 95% confidence interval, 0.36 to 0.99; P = 0.04). Postoperative complications were infrequent and similar in the 6-month and 12-month groups. Four serious adverse events were reported (three in the 6-month group and one in the 12-month group) and had resolved at follow-up. CONCLUSIONS: Medically fit infants who underwent primary surgery for isolated cleft palate in adequately resourced settings at 6 months of age were less likely to have velopharyngeal insufficiency at the age of 5 years than those who had surgery at 12 months of age. (Funded by the National Institute of Dental and Craniofacial Research; TOPS ClinicalTrials.gov number, NCT00993551.).

Awareness, referral and age at Kasai surgery for biliary atresia in Europe: A survey of the Quality-of-Care Task Force of ESPGHAN.

OBJECTIVES: To identify infants with biliary atresia (BA), European Society of Paediatric Gastroenteroloy and Nutrition (ESPGHAN)/North American Society of Pediatric Gastroenteroloy and Nutrition (NASPGHAN) guidelines recommend measurement of conjugated/direct bilirubin in infants with prolonged jaundice and using a stool colour card (SCC). The 'Quality of Care' Task Force of ESPGHAN performed two surveys to assess current case finding for BA and age at Kasai portoenterostomy (KPE). METHODS: The first survey approached 26 European hepatology centres to report age at referral and age at KPE of all infants diagnosed with BA from 2015 to 2019. The second survey targeted paediatricians in France to assess awareness and compliance with the recently introduced SCC. RESULTS: Data from 785 patients with BA from 18 centres in 15 countries revealed a mean age at referral to tertiary centre of 55 days (median 53, IQR 48-60) (n = 636). The mean age at KPE was 61 days (median 60; IQR 54-67) (n = 772). For 6% of patients, cirrhosis was too advanced for surgery. Of 392 paediatricians answering the second survey, 53% felt familiar with the target diseases, 80% correctly identified cholestasis and 59% always inquired about the infant's stool colour. If abnormal, 93% would order blood tests and 85% call for advice. The SCC screening was considered helpful for case finding and improving knowledge of cholestatic diseases by 62% and 45% paediatricians, respectively. CONCLUSIONS: Referral of infants for KPE remains late, indicating low adherence to search for cholestasis in icteric infants by age 2-3 weeks. Knowledge and structures need improvement to allow earlier guideline conform case finding, diagnosis and therapy.

Inter-rater reliability in classification of canonical babbling status based on canonical babbling ratio in infants with isolated cleft palate randomised to Timing of Primary Surgery for Cleft Palate (TOPS).

Canonical babbling (CB) is commonly defined as present when at least 15% of all syllables produced are canonical, in other words a canonical babbling ratio (CBR) ≥0.15. However, there is limited knowledge about inter-rater reliability in classification of CB status based on CBR and inter-rater differences in assessment of CBR. We investigated inter-rater reliability of experienced Speech Language Therapists (SLTs) on: classification of CB status based on CBR ≥ 0.15, CBRs and the total number of syllables per infant used to calculate CBR.Each infant (n = 484) was video-recorded at a clinical site in play interaction with their parent as part of the randomised controlled trial Timing of Primary Surgery for Cleft Palate. Each recording was subsequently assessed by three independent SLTs, from a pool of 29 SLTs. They assessed the recordings in real time.The three assessing SLTs agreed in classification of CB status in 423 (87.4%) infants, with higher complete agreement for canonical (91%; 326/358) than non-canonical (77%; 97/126). The average difference in CBR and total number of syllables identified between the SLT assessments of each infant was 0.12 and 95, respectively.This study provided new evidence that one trained SLT can reliably classify CB status (CBR ≥ 0.15) in real time when there is clear distinction between the observed CBR and the boundary (0.15); however, when the observed CBR approaches the boundary multiple SLT assessments are beneficial. Thus, we recommend to include assessment of inter-rater reliability, if the purpose is to compare CBR and total syllable count across infants or studies.Trial registration number here: www.clinicaltrials.gov, identifier NCT00993551.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Multiple myeloma in elderly patients-a Portuguese multicentric real-life study.

Patients older than 75 years old with multiple myeloma (MM) have shorter survival and are usually treated differently from what features in clinical trials. In this study, the authors characterized the Portuguese population of MM patients above 75 years old, treated between 2009 and 2016. We compared the outcomes obtained with bortezomib-based protocols (BBP), thalidomide-based protocols (TBP), and chemotherapy (CT) using univariate and multivariate controlling for age, performance status, International Staging System score, renal impairment, and number of comorbidities. We retrieved data from 386 patients, treated in 12 hospitals. Three hundred thirty-one cases were analyzed: 119 patients treated with BBP, 65 with TBP, 147 with CT. Median age was 79 years; CT-treated patients were older, had a worse performance status, and have more comorbidities. The median follow-up was 25 months. The 2-year OS was 58% and the median OS was 29.5 months. Patients treated with BBP had more frequently very good partial response (VGPR) or better response, and the subgroup of more fit patients had a significantly longer progression-free survival (PFS) and OS. The most frequently grade 3-4 toxicities were hematologic, infectious, and neurologic and were significantly lower in TBP and CT groups vs BBP. The most common second line was CT, followed by lenalidomide. Patients treated with lenalidomide had a higher probability of VGPR or better and a superior 1-year PFS. Despite the limitations of a retrospective study, our cohort represents the reality of older patients with MM in a western country. The hazard of death or progression was higher for old, fit patients treated, in first line, with CT and with TBP compared with that of BBP.

Post-catheterisation arterial thrombosis in children--pathophysiology, prevention, and treatment.

Lower limb ischaemia is the most frequent complication of cardiac catheterisation in children. It is often overlooked, but it can cause significant disability and may limit arterial access sites to repeat diagnostic or interventional catheterisations. A narrative review of the literature on arterial access site thrombosis in children was carried out with a special focus on current evidence that supports preventive and treatment strategies. Anticoagulation, thrombolysis, and thrombectomy have been used successfully to treat arterial access site thrombosis. However, it is not completely established which is the role of each treatment modality and what is the most appropriate timing to deliver it. Therefore, diagnostic and therapeutic strategies have to be prospectively investigated, particularly for clarifying the role of new pharmacologic interventions and of percutaneous and surgical thrombectomy in the current era.

Hepatitis C Virus Infection in Europe.

The Hepatitis C Virus (HCV) is a significant public health challenge in European countries. Historically, healthcare-related procedures were the primary source of HCV infection in Europe. However, with the implementation of blood safety programs, injection drug use has become the main transmission route. The infection's distribution and genotype prevalence vary widely across the continent. Even with the availability of highly effective direct-acting antiviral (DAA) therapies, HCV infection is far from being controlled. A significant proportion of patients remain undiagnosed, contributing to the ongoing transmission of the virus. Additionally, several barriers hinder the widespread use of DAAs, including high treatment costs, stigma, poor linkage to care, and considerable geographical variations in prevalence and transmission routes. The World Health Organization has set ambitious targets to reduce liver-related deaths, decrease new viral hepatitis infections, and ensure that 90% of infected individuals are diagnosed by 2030. However, most European countries face challenges, highlighting the need for screening programs, funding mechanisms, and public health strategies to effectively control HCV infection in Europe.

Fosfomycin increases chromosome instability in lymphocytes from Fanconi Anemia patients.

Fanconi Anemia (FA) is a chromosome instability (CI) syndrome, clinically characterized by progressive bone marrow failure and increased cancer predisposition. Lymphocytes from FA patients have hypersensitivity to alkylating agents, particularly to diepoxybutane (DEB). The antibiotic fosfomycin (FOM) is an alkylating agent. FOM is used as a large spectrum antibiotic and also as a prophylactic pre-surgery agent. FOM has been considered non-genotoxic. However, no specific genotoxic evaluation directed to patients with hypersensitivity to alkylating agents was performed. As FA patients are very susceptible to infections and may be submitted to several surgeries, FOM can eventually be prescribed to them during their lifetime. In the present study we evaluated the putative genotoxic effect of FOM in cultured lymphocytes from FA patients, compared to cultured lymphocytes from healthy donors (HD). Cultures from FA patients and HD were treated with 0.5mM FOM or with 0.6mM DEB and CI was evaluated. Results showed that FOM significantly increases CI in cultured lymphocytes from FA patients, compared to lymphocytes from HD, in which no effect was found. Additionally, a direct correlation between DEB and FOM toxicity was observed in lymphocytes from FA patients, indicating similar susceptibility to both agents.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Pediatric Acute Liver Failure in Sickle Cell Disease.

Introduction: Sickle cell intrahepatic cholestasis (SCIC) is one of the rarest and the most severe acute hepatic manifestations of sickle cell disease (SCD) and it can rapidly progress to acute liver failure. It is associated with a high mortality rate, demanding prompt recognition and management. Case Presentation: We report a case of a 7-year-old boy with a history of homozygous HbS SCD who presented to the emergency department with fever, increasing abdominal pain, and jaundice. His course was complicated by acute liver injury (AST 9,472 IU/L, ALT 2,683 IU/L, total bilirubin 15.4 mg/dL; conjugated bilirubin 8.69 mg/dL, hypoalbuminemia 2.6 g/dL, and persistent hypoglycemia), with acute liver failure (coagulopathy not corrected by vitamin K administration with INR 3.26, decreased factors V 10% and VII 28%, and West Haven grade I hepatic encephalopathy associated with mild hyperammonemia of 71 µmol/L). After excluding other causes of acute liver failure, the patient was diagnosed as having SCIC and was successfully treated with manual exchange transfusion. Conclusion: This case reinforces that exchange transfusion is an effective treatment for SCIC and that it should be introduced promptly to prevent fulminant and potentially fatal liver failure.

Introdução: A colestase intra-hepática falciforme (CIHF) é uma das manifestações hepáticas agudas mais raras e graves da doença de células falciformes (DCF), que pode progredir rapidamente para falência hepática aguda. Associa-se a uma elevada taxa de mortalidade, que exige identificação e intervenção imediatas. Caso clínico: Descreve-se o caso de um rapaz de 7 anos com DCF, homozigótico para a HbS, que recorreu ao serviço de urgência por febre, dor abdominal de agravamento progressivo e icterícia. Verificou-se evolução para lesão hepática aguda (AST 9,472 UI/L, ALT 2,683 UI/L, bilirrubina total 15.4 mg/dL; bilirrubina conjugada 8.69 mg/dL, hipoalbuminemia 2.6 g/dL, hipoglicemia persistente), com falência hepática aguda (coagulopatia não corrigida por administração de vitamina K com INR 3.26, diminuição dos fatores V 10% e VII 28%, assim como encefalopatia grau I (critérios de West Haven) e hiperamoniemia ligeira 71 µmol/L). Após exclusão de outras etiologias de falência hepática aguda, o doente foi diagnosticado com CIHF e realizada exsanguineo-transfusão manual, com sucesso. Discussão/Conclusão: Este caso reforça que a exsanguineotransfusão é uma terapêutica eficaz na CIHF, que deve ser instituída precocemente para prevenir falência hepática fulminante e potencialmente fatal.

Ketogenic Diet and Drug-Induced Hepatotoxicity During Tuberculosis Treatment.

When therapy with hepatotoxic drugs is being considered, all other possible contributing agents of liver damage should be held to account. While not generally considered a risk factor, we present 2 cases in which ketogenic diet (KD) may have played a role in liver injury due to antituberculosis drugs. Ketogenic diet has been linked to liver injury, and while its pathophysiology remains obscure, carnitine depletion could play a role, as it is a mechanism of liver damage common to KD and antituberculosis drug regimens.

Otologic and audiologic outcomes with the Furlow and von Langenbeck with intravelar veloplasty palatoplasties in unilateral cleft lip and palate.

OBJECTIVE: Cleft palate increases the risk of chronic middle ear disease and hearing loss. The goal of this report was to determine which of two palate surgeries and which timing of palate surgery were associated with better otologic and audiologic outcomes in children with unilateral cleft lip and palate at 5 to 6 years of age. DESIGN: Subjects were randomly assigned to the von Langenbeck with intravelar veloplasty or Furlow palate repair, to palate surgery at 9 to 12 months or 15 to 18 months of age, and to the Spina or Millard lip repair. SETTING: Centralized, tertiary care craniofacial treatment center. PATIENTS: A total of 673 infants with unilateral cleft lip and palate. INTERVENTIONS: Palate and lip were repaired using established techniques. Serial otoscopic and audiometric evaluations were performed. MAIN OUTCOME MEASURES: Hearing and otoscopic findings at 5 to 6 years old. RESULTS: There were 370 children available for analysis. Hearing and need for tympanostomy tube placement did not differ by palatoplasty, age at palatoplasty, cheiloplasty, or surgeon. Risk of developing cholesteatoma or perforation was higher with Millard cheiloplasty (odds ratio  =  5.1, 95% confidence interval  =  1.44 to 18.11, p  =  .012). Type and age at palatoplasty were not significantly associated with either the rate of developing these sequelae or the rate of achieving bilaterally normal hearing and ear examinations. CONCLUSIONS: Type of palatoplasty did not influence otologic and audiologic outcomes in 5- to 6-year-olds with unilateral cleft lip and palate. The potential influence of lip repair on otologic outcomes warrants further investigation.

Oxymestane, a cytostatic steroid derivative of exemestane with greater antitumor activity in non-estrogen-dependent cell lines.

A new promising steroid derivative of Exemestane (Exe), the drug used for the treatment of estrogen-dependent breast cancer, was synthesized and evaluated against a set of human cancer cell lines. The new compound (Oxymestane-D1, Oxy) was tested comparatively with Exe against colon (C2BBe1, WiDr), liver (HepG2, HuH-7), lung (A549, H1299) and prostate (LNCaP, PC3) human cancer cell lines. Likewise, its effect on human colon normal cells (CCD-841 CoN) and human normal fibroblast cells (HFF-1) was studied. The cytostatic activity of Oxy was also compared with that of the reference cytostatic drugs used in chemotherapy protocols, namely carboplatin, cisplatin, doxorubicin, epirubicin, etoposide, flutamide, 5-fluorouracil, irinotecan, oxaliplatin and sorafenib. In all cell lines tested, Oxy proved to be more powerful cytostatic than Exe. Additionally, the IC50 at 72 h showed a three-fold activity greater than 5-fluorouracil in the WiDr cell line, twice as high as cisplatin for cell line A549 and five times higher than cisplatin for cell line H1299. Also, Oxy surprisingly revealed to induce DNA damage and inhibit the DNA damage response (DDR) proteins ATM, ATR, CHK1 and CHK2. The results obtained allow concluding that Oxy can be a promising anticancer agent to be used in chemotherapy protocols. Furthermore, its ability to inhibit crucial components of DDR can also be useful for the monotherapy or for combination with chemo and/or radiotherapy of cancer.

Multispacer Sequence Typing for Mycobacterium bovis Genotyping.

The molecular typing of Mycobacterium bovis, which causes bovine tuberculosis, can be accomplished by combining different polymorphic markers, contributing to its epidemiological investigation. Multispacer sequence typing (MST) is a sequencing-based method that employs intergenic regions susceptible to higher mutation rates given the low selection pressure. It has been applied to M. tuberculosis, but not to M. bovis. The aim of this study was to evaluate a MST for M. bovis. A total of 58 strains isolated from tissues with lesions suggestive of bovine tuberculosis, coming from cattle herds in six Brazilian states and four standard samples of M. bovis were typified employing the MST technique. Fourteen intergenic regions were used, and four types of genetic events were reported: single nucleotide mutation (SNP), insertion, deletion, and tandem repeat (TR). Seven loci were chosen for typing. Twenty-eight type sequences (ST) were identified, indicating type sequences (ST) were identified, indicating a 92.9% HGDI (Hunter Gaston Discriminatory Index). The data were used to analyze the evolutionary patterns of these isolates and correlate them to phylogeographic lineages based on the formation of clonal complexes generated from eBURST software. Later, we associated the MST with spoligotyping technique, currently considered the gold standard for classification of M. bovis. The results support the MST as an alternative method for genotyping of M. bovis. The method has the advantage of sequencing and the availability of sequences analyzed in public databases, which can be used by professionals around the world as a tool for further analysis. This was the first study to identify the variability of isolates of M. bovis by the MST method.

Current Practices on Diagnosis, Prevention and Treatment of Post-Transplant Lymphoproliferative Disorder in Pediatric Patients after Solid Organ Transplantation: Results of ERN TransplantChild Healthcare Working Group Survey.

(1) Background: Post-transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation (SOT). However, there is lack of consensus in PTLD management. Our aim was to establish a present benchmark for comparison between international centers and between various organ transplant systems and modalities; (2) Methods: A cross-sectional questionnaire of relevant PTLD practices in pediatric transplantation was sent to multidisciplinary teams from 17 European center members of ERN TransplantChild to evaluate the centers' approach strategies for diagnosis and treatment and how current practices impact a cross-sectional series of PTLD cases; (3) Results: A total of 34 SOT programs from 13 European centers participated. The decision to start preemptive treatment and its guidance was based on both EBV viremia monitoring plus additional laboratory methods and clinical assessment (61%). Among treatment modalities the most common initial practice at diagnosis was to reduce the immunosuppression (61%). A total of 126 PTLD cases were reported during the period 2012-2016. According to their histopathological classification, monomorphic lesions were the most frequent (46%). Graft rejection after PTLD remission was 33%. Of the total cases diagnosed with PTLD, 88% survived; (4) Conclusions: There is still no consensus on prevention and treatment of PTLD, which implies the need to generate evidence. This might successively allow the development of clinical guidelines.

Iodine­131 metabolic radiotherapy leads to cell death and genomic alterations through NIS overexpression on cholangiocarcinoma.

Cholangiocarcinoma (CC) is an aggressive liver tumor with limited therapeutic options. Natrium­iodide symporter (NIS) mediates the uptake of iodine by the thyroid, representing a key component in metabolic radiotherapy using iodine­131 (131I) for the treatment of thyroid cancer. NIS expression is increased in CC, providing the opportunity for a novel therapeutic approach for this type of tumor. Thus, in this study, we aimed to evaluate therapeutic efficacy of 131I in two human CC cell lines. Uptake experiments analyzed the 131I uptake profiles of the tumor cell lines under study. The cells were irradiated with various doses of 131I to evaluate and characterize the effects of metabolic radiotherapy. NIS protein expression was assessed by immunofluorescence methods. Cell survival was evaluated by clonogenic assay and flow cytometry was used to assess cell viability, and the type of death and alterations in the cell cycle. The genomic and epigenetic characterization of both CC cells was performed before and after irradiation. NIS gene expression was evaluated in the CC cells by RT­qPCR. The results revealed that CC cells had a higher expression of NIS. 131I induced a decrease in cell survival in a dose­dependent manner. With the increasing irradiation dose, a decrease in cell viability was observed, with a consequent increase in cell death by initial apoptosis. Karyotype and array comparative genomic hybridization (aCGH) analyses revealed that both CC cell lines were near­triploid with several numerical and structural chromosomal rearrangements. NIS gene expression was increased in the TFK­1 and HuCCT1 cells in a time­dependent manner. On the whole, the findings of this study demonstrate that the presence of NIS in cholangiocarcinoma cell lines is crucial for the decreased cell viability and survival observed following the exposure of cholangiocarcinoma cells to 131I.

[The impact of selective clamping of portal vein in hepatocellular function. An experimental study]. / Estudo experimental do impacto da clampagem selectiva da veia porta na função hepatocelular.

UNLABELLED: The influence of selective clamping of the elements of hepatic pedicle in the hepatocellular function and viability were evaluated in our department. AIM: Study the effect of selective clamping of the portal vein (CPV) in hepatocellular function in an animal model with normal liver. METHOD: Three groups of Wistar rats (males, 2 months) were subjected a CPV for 60 min: group A (n=21) submitted to a continuous inflow occlusion; group B (n=12) underwent to a CPV for 30 min with 5 min of reperfusion; group C (n=10) underwent a CPV for 15 min with 5 min of reperfusion. The group D (n=9) was not subjected to a CPV. A hepatic biopsy was done at the end of surgery. The degree of tissue injury was evaluated using: 1) blood markers: AST, ALT, total bilirubin (TB), GGT alkaline-phosphatase, LDH and hepatic extraction fraction (HEF) by radioisotopic methods three days before laparotomy (BS) and after surgery (AS); 2) apoptosis, necrosis were investigated after collagenase cell isolation from hepatectomy pieces by flow-cytometry using the followed probes: propidium-iodide and annexin-V. STATISTICAL ANALYSIS: variance analysis, post-hoc comparisons by Turkey-test (p<0.05). RESULTS: 1) Mortality: Group A - 62%, Group B - 17%, Group C - 30%, Group D - 0% (p<0.03). 2) We observed statistical differences in these parameters: ALT (p<0,025) and LDH (p<0,002) preferentially in groups A but without differences between the A,B,C and D Groups (ns). 3) We also verified a significant decrease in HEF values (p<0,0001) preferentially in group A without differences between the groups. 4) No difference were observed when analysed apoptosis and necrosis and cell viability between the groups. CONCLUSIONS: Postoperative liver failure is the leading cause of mortality after hepatectomy, however selective clamping of the portal vein, is reflected in an increase in cell viability and a decrease in the type of cell death (necrosis ou apoptosis) compared to studies carried out previously by us and thus may be regarded as an alternative to the Pringle maneuver. However, selective clamping of the portal vein for periods above 30' should be avoided, given the high mortality verified.

Update on the approach to smoking in patients with respiratory diseases.

Smoking is the leading cause of respiratory disease (RD). The harmful effects of smoking on the respiratory system begin in utero and influence immune responses throughout childhood and adult life. In comparison with "healthy" smokers, smokers with RD have peculiarities that can impede smoking cessation, such as a higher level of nicotine dependence; nicotine withdrawal; higher levels of exhaled carbon monoxide; low motivation and low self-efficacy; greater concern about weight gain; and a high prevalence of anxiety and depression. In addition, they require more intensive, prolonged treatment. It is always necessary to educate such individuals about the fact that quitting smoking is the only measure that will reduce the progression of RD and improve their quality of life, regardless of the duration and severity of the disease. Physicians should always offer smoking cessation treatment. Outpatient or inpatient smoking cessation treatment should be multidisciplinary, based on behavioral interventions and pharmacotherapy. It will thus be more effective and cost-effective, doubling the chances of success.