Hepatocellular carcinoma in children: Hepatic resection and liver transplantation

Hepatocellular carcinoma (HCC) is a rare malignancy in children and at the time of diagnosis up to 80% of pediatric HCC are unresectable due to large and multiple lesions. The majority of pediatric HCC occurs on a background of normal liver, and consequently the absence of concomitant chronic liver disease generally allows tolerating pre-and post-operative chemotherapy. Based on the large experiences of adult HCC and pediatric hepatoblastoma, in the last years a multidisciplinary aggressive treatment composed of surgical resection and chemotherapy (based on cisplatin and doxorubicin) has been proposed, improving patient outcomes and recurrence rate in children with HCC. However, the overall survival rate in children with HCC is not satisfactory yet; while the 5-year survival rate may achieve up to 70-80% in non-metastatic resectable HCC, it remains <20% in children with unresectable HCC. The mainstay of the pediatric HCC therapeutic strategy is the radical tumor resection, weather by hepatic resection or liver transplantation, nevertheless the best surgical approaches as well as the optimal neoadjuvant and adjuvant treatment are still under debate. Different strategies have been explored to convert unresectable HCC into resectable tumors by extending criteria for surgical treatment and/or associating multi-modal treatments, such as systemic and local-regional therapy, but universal recommendation needs to be defined yet. The purpose of this review is to outline the role of different surgical approaches, including hepatic resection and liver transplantation, in pediatric HCC with or without underlying chronic liver disease

How do synchronous lung metastases influence the surgical management of children with hepatoblastoma? An update and systematic review of the literature

Approximately 20% of children with hepatoblastoma (HB) have metastatic disease at diagnosis, most frequently in the lungs. In children with HB, lung metastatic disease is associated with poorer prognosis. Its treatment has been approached with a variety of methods that integrate chemotherapy and surgical resection. The timing and feasibility of complete extirpation of lung metastases, by chemotherapy and/or metastasectomy, is crucial for the surgical treatment of the primary liver tumor, which can vary from major hepatic resections to liver transplantation (LT). In children with unresectable HB, which can be surgically treated only by LT, the persistence of unresectable metastases after neoadjuvant chemotherapy excludes the possibility of recurring to LT with consequent negative impact on patients' outcomes. Due to limited evidence and experience, there is no consensus amongst oncologists and surgeons across institutions regarding the surgical treatment for HB with synchronous metastatic lung disease. This narrative review aimed to update the current management of pulmonary metastasis in children with HB and to define its role in the decision-making strategy for the surgical approach to primary liver tumours

Conformational changes produced by ATP binding to the plasma membrane calcium pump

The aim of this work was to study the plasma membrane calcium pump (PMCA) reaction cycle by characterizing conformational changes associated with calcium, ATP, and vanadate binding to purified PMCA. This was accomplished by studying the exposure of PMCA to surrounding phospholipids by measuring the incorporation of the photoactivatable phosphatidylcholine analog 1-O-hexadecanoyl-2-O-[9-[[[2-[125I]iodo-4-(trifluoromethyl-3H-diazirin-3-yl)benzyl]oxy]carbonyl]nonanoyl]-sn-glycero-3-phosphocholine to the protein. ATP could bind to the different vanadate-bound states of the enzyme either in the presence or in the absence of Ca2+ with high apparent affinity. Conformational movements of the ATP binding domain were determined using the fluorescent analog 2′(3′)-O-(2,4,6-trinitrophenyl)adenosine 5′-triphosphate. To assess the conformational behavior of the Ca2+ binding domain, we also studied the occlusion of Ca2+, both in the presence and in the absence of ATP and with or without vanadate. Results show the existence of occluded species in the presence of vanadate and/or ATP. This allowed the development of a model that describes the transport of Ca2+ and its relation with ATP hydrolysis. This is the first approach that uses a conformational study to describe the PMCA P-type ATPase reaction cycle, adding important features to the classical E1-E2 model devised using kinetics methodology only.Fil: Mangialavori, Irene C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Ferreira Gomes, Mariela S.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Saffioti, Nicolas A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Gonzalez-Lebrero, Rodolfo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Rossi, Rolando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Rossi, Juan Pablo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; Argentin

Same donor laparoscopic liver and kidney procurement for sequential living donor liver-kidney transplantation in primary hyperoxaluria type i

Background: Sequential liver-kidney transplantation (SeqLKT) from the same living donor has shown excellent results in children with primary hyperoxaluria type 1 (PH1), yet its experience is limited due to the invasiveness of two major procedures for liver-kidney procurement in a single donor. Despite laparoscopic nephrectomy and hepatic left lateral sectionectomy (LLS) being considered standard procedures in living donation, the sequential use of the two laparoscopic approaches in the same living donor has never been reported. Methods: Herein, we present the first two case series of laparoscopic liver-kidney procurement in the same living donor for SeqLKT in children with PH1 and review of the current literature on this topic. Results: In the first case, a 15-month-old boy received a SeqLKT from his 32-year-old mother, who underwent a laparoscopic LLS and, after 8 months, a laparoscopic left nephrectomy. In the second case, a 34-month-old boy received a SeqLKT from his 40-year-old father who underwent laparoscopic LLS followed by hand-assisted right nephrectomy after 4 months. Both donors had uneventful postoperative courses and were discharged within 5 days from each surgery. The first recipient had no complication; the second child after liver transplantation developed a partial thrombosis of the inferior vena cava, which did not preclude the sequential kidney transplantation. After 12 months, donors and recipients displayed normal liver and renal functions. Conclusions: Sequential laparoscopic liver-kidney procurement in the same living donor is safe and feasible, and might be considered as a possible strategy to promote SeqLKT in children with PH1 from the same living donor

Primary Prophylaxis for Gastrointestinal Bleeding in Children With Biliary Atresia and Portal Hypertension Candidates for Liver Transplantation: A Single-Center Experience

Background. Cirrhosis for biliary atresia (BA) is associated with risk of gastrointestinal bleeding (GB) from gastroesophageal varices due to portal hypertension. Primary prophylaxis of GB is controversial in children who are candidates for liver transplantation (LT). The aim of the study was to define the management of gastroesophageal varices and to identify the benefit of primary prophylaxis for GB in BA children waiting for LT.Methods. A retrospective single-center study including all BA children listed for LT in 2008-2016. Clinical, endoscopical, and biochemical data were analyzed.Results. Of 82 children, 50 (61%) did not receive primary prophylaxis and did not present any episode of bleeding, 16 (19.5%) underwent primary prophylaxis, and 16 (19.5%) presented spontaneous GB and received secondary prophylaxis. Children without primary prophylaxis and GB were younger than patients with primary prophylaxis and those with GB (7.7 years [range, 4.1-37.9 years] vs 11.2 years [range, 5.1-43 years]; P = .03 vs 10.7 years [range, 6.9-39.9 years], respectively; P = .004). Seventy-five percent of GB occurred in children older than 8 months. Fifteen (93.8%) children with GB presented esophageal varices (grade III = 10 [62.5%]) and 10 (62.5%) required endoscopic treatments, consisting mainly of sclerotherapy. Median time to LT was similar for children with or without bleeding (2 months [range, 0-17.7 months] vs 2.2 months [0-17.9 months], respectively; P = .89). After 45.5 months (range, 13.7-105.5 months) of follow-up, the overall patient survival was 97.6%. At the intention-to-treat analysis, the survival rate was 100% for patients without bleeding episode and 87.5% for children with GB (P = .16).Conclusions. Despite the risk of GB being not clinically predictable in children with BA waiting for LT, our experience suggests that primary prophylaxis of GB might be unnecessary in children younger than 6 months, while it should be considered in older children. Thus, the occurrence of GB does not delay the timing of transplantation

Life-saving vascular access after combined liver and kidney transplantation: A challenging access to the right atrium

Exhaustion of vascular accesses is a major complication in patients undergoing hemodialysis, especially in pediatric setting. We report the case of a boy treated for loss of hemodialysis access after a combined liver-kidney transplantation and transient renal dysfunction. An interventional dilatation of calcific superior vena cava allowed to insert a stable central venous line for dialysis until full graft recovery. Careful management of central lines allows to spare the main vessels and reduces the need for unusual accesses

A disease-associated gene desert directs macrophage inflammation through ETS2

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22—which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3–6—we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities

Use of colistin in adult patients: A cross-sectional study

Objectives: The aim of this study was to assess colistin use in a country endemic for multidrug-resistant Gram-negative bacteria (MDR-GNB). Methods: Colistin prescription patterns were evaluated in 22 Italian centres. Factors associated with use of colistin in combination with other anti-MDR-GNB agents were also assessed. Results: A total of 221 adults receiving colistin were included in the study. Their median age was 64 years (interquartile range 52\u201373 years) and 134 (61%) were male. Colistin was mostly administered intravenously (203/221; 92%) and mainly for targeted therapy (168/221; 76%). The most frequent indications for colistin therapy were bloodstream infection and lower respiratory tract infection. Intravenous colistin was administered in combination with at least another anti-MDR-GNB agent in 80% of cases (163/203). A loading dose of 9 MU of colistimethate was administered in 79% of patients receiving i.v. colistin and adequate maintenance doses in 85%. In multivariable analysis, empirical therapy [odds ratio (OR) = 3.25, 95% confidence interval (CI) 1.24\u20138.53;P = 0.017] and targeted therapy for carbapenem-resistant Enterobacterales infection (OR = 4.76, 95% CI 1.69\u201313.43; P = 0.003) were associated with use of colistin in combination with other agents, whilst chronic renal failure (OR = 0.39, 95% CI 0.17\u20130.88; P = 0.024) was associated with use of colistin monotherapy. Conclusion: Colistin remains an important option for severe MDR-GNB infections when other treatments are not available. Despite inherent difficulties in optimising its use owing to peculiar pharmacokinetic/pharmacodynamic characteristics, colistin was mostly used appropriately in a country endemic for MDR-GNB