Years of life that could be saved from prevention of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour 65 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost

Lessons from genetics: is it time to revise the therapeutic approach to children with steroid-resistant nephrotic syndrome?

Primitive nephrotic syndrome is one of the most common glomerular diseases in childhood and represents the clinical manifestation of various pathologic changes in the kidney. In children, nephrotic syndrome is classified based on the initial response to empiric corticosteroid treatment, which is considered as the best predictor of patients' final outcome. The advent of next-generation sequencing technology showed that genetic alterations in structural genes of the podocyte can be recognized in a significant proportion of not only familial or syndromic patients with steroid-resistant nephrotic syndrome (SRNS), but also of sporadic cases, raising the question of whether it is time to update current protocols of patient care. In this review, we discuss the implications derived from several studies describing a high prevalence in children with SRNS of pathogenic mutations in a group of genes and their unresponsiveness to immunosuppressive therapy. We propose a diagnostic and therapeutic algorithm to reduce the exposure to immunosuppressants in individuals with unresponsive forms of the disease, sparing patients the untoward side effects of prolonged ineffective treatments, and at the same time guaranteeing the optimal immunosuppressive or other new therapy in potentially responsive patients

Plasmapheresis-resistant acute humoral rejection successfully treated with anti-C5 antibody

Even if kidney graft survival has improved during the last decades, sensitized pediatric patients are an emerging problem. We describe a 17-yr-old male who lost his first graft due to chronic rejection becoming hyperimmunized (CDC PRA 99.61%). A desensitization protocol based on high-dose IVIG, PP, and two Mabthera(\uae) infusions was performed with minor response (CDC PRA post-desensitization 80%). One month after his second non-living transplant, he developed a biopsy-proven AMR; post-transplant immunological monitoring showed the presence of donor-specific anti-DQ5 antibodies (DSA, MFI 20.000). He received methylprednisolone pulses and 45 PP sessions without clinical response; eculizumab was then used to salvage a kidney undergoing severe PP-resistant rejection. A biopsy performed after the fourth eculizumab infusion showed complete resolution of AMR. Eculizumab infusions were then continued for the first year post-transplantation. Two yr after transplantation, graft function is stable. Anti-C5 therapy may represent an effective therapeutic option in pediatric patients with PP-resistant AMR

Enhanced therapeutic activity of non-internalizing small-molecule-drug conjugates targeting carbonic anhydrase IX in combination with targeted interleukin-2

Purpose: Antibody-drug conjugates and small-molecule-drug conjugates have been proposed as alternatives to conventional anticancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues.Experimental Design: Here, we describe a novel small-molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload.Results: A potent anticancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering IL2 to the tumor neovasculature), all treated mice in the combination group could be rendered tumor free, in a process that favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small-molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX.Conclusions: These findings may be of clinical significance, because carbonic anhydrase IX is overexpressed in the majority of clear cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of IL2 helps potentiate the action of targeted cytotoxics, leading to cancer eradication in models that cannot be cured by conventional chemotherapy

Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2

ISSN:1078-0432ISSN:1557-326

Expression of Rat Ileal Na+-Sulfate Cotransport in Xenopus-Laevis Oocytes - Functional-Characterization

Small-intestinal sulphate absorption is a Na+-dependent process having its highest rate in the ileum; it involves brush-border membrane Na+-sulphate cotransport. Injection of rat ileal mRNA into Xenopus laevis oocytes induced Na+-dependent sulphate uptake in a dose-dependent manner, with no apparent effect on Na+-independent sulphate uptake. For mRNA-induced transport, the apparent K-m value for sulphate interaction was 0.6 +/- 0.2 mM and that for sodium interaction was 25 +/- 2 mM (Hill coefficient: 2.3 +/- 0.3). mRNA-induced transport, was inhibited by thiosulphate, but not by phosphate or 4,4,'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS). Using a rat renal Nac-sulphate cotransporter cDNA as a probe [NaSi-1; Markovich et al. (1993) Proc Natl Acad Sci USA 90:8073 - 8077], the highest hybridization signals (2.3 kb and 2.9 kb) were obtained in size fractions showing the highest expression of Na+-dependent sulphate transport in oocytes. Hybrid depletion experiments using antisense oligonucleotides (from the NaSi-1 cDNA sequence), provided further evidence that rat small-intestinal (ileal) Na+-sulphate cotransport is closely related to rat proximal-tubular brush-border membrane Na+-sulphate cotranspor

Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression

In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid‐resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner

Encapsulating peritoneal sclerosis in paediatric peritoneal dialysis patients: the experience of the Italian Registry of Pediatric Chronic Dialysis

Paediatric literature about encapsulating peritoneal sclerosis (EPS) is limited and comes primarily from anecdotic experiences. In this study, we described the incidence and characteristics of EPS in a large paediatric chronic peritoneal dialysis (CPD) patient population