Emodialisi Extracorporea Domiciliare:prima esperienza in Campania

L'Emodialisi Extracorporea Domiciliare (HHD) è un’alternativa ancora poco utilizzata, ma in grado di offrire migliori outcomes clinici, una più soddisfacente qualità della vita ed una riduzione dei costi sanitari “diretti” ed “indiretti” del trattamento emodialitico. Al fine di offrire un’ulteriore opzione terapeutica ai pazienti che necessitano di terapia dialitica sostitutiva e per essere in linea col Piano Sanitario della Regione Campania, avente tra le finalità l’implementazione delle cure domiciliari, la Cattedra di Nefrologia dell’Università di Napoli “Federico II” nel 2014 ha dato vita al primo programma di Emodialisi Extracorporea Domiciliare in Campania ed ha stilato un rigoroso modello assistenziale per tale metodica. L’attivazione di un programma di Emodialisi Extracorporea Domiciliare (HHD) difatti richiede un percorso strutturato che ne identifichi i requisiti tecnologici, organizzativi ed assistenziali. Il percorso realizzato considera ed esplicita: (a) criteri di eleggibilità e di idoneità all’HHD del paziente e del caregiver, (b) analisi della letteratura sull’HHD e razionale della scelta della più moderna tecnologia, (c) informazione del paziente/caregiver ed acquisizione del consenso, (d) modalità di copertura assistenziale e di accesso al ricovero ospedaliero, (e) idoneità dei locali adibiti al trattamento emodialitico domiciliare, (f) programma di formazione del paziente e del caregiver, avvio al trattamento domiciliare e follow-up del paziente,(g) analisi dei costi. Dall’ Agosto 2014 sono stati arruolati cinque pazienti in Emodialisi Domiciliare in modalità Short Daily Home Hemodialysis (SDHHD) con in media n. 5 sedute/settimana della durata di 2,5 ore utilizzando il cycler portatile NxStage-System One. I dati raccolti hanno evidenziato che i benefici clinici descritti in letteratura si confermavano nei pazienti arruolati nel nostro programma di HHD. L’effettuazione di sedute emodialitiche più brevi e frequenti permettevano una significativa riduzione dell’incremento ponderale interdialitico ed una maggiore stabilità emodinamica intradialitica. Inoltre, si è ottenuta una significativa riduzione dei valori pressori con possibilità di ridurre la terapia anti-ipertensiva. Il controllo della fosforemia risultava migliore e l’emoglobinemia era a target con una minore dose di eritropoetina settimanale. I pazienti riferivano un maggiore senso di benessere ed una riduzione dell’astenia post-dialitica. Nessuna problematica è insorta utilizzando l’accesso vascolare (CVC e FAV) da parte del paziente e/o del caregiver. L’analisi dei parametri di efficienza dialitica ha documentato come l’adeguatezza dialitica della SDHHD fosse sovrapponibile a quella ottenuta con la HD tradizionale. L’applicazione di un percorso strutturato ha dunque permesso di avviare un programma di HHD di successo: tale metodologia di lavoro ha definito a priori il percorso assistenziale ed analizzato le priorità di rischio. Il processo della terapia emodialitica extracorporea domiciliare è stato analizzato con l’obiettivo di identificare i possibili errori e le criticità prevedibili nell’attività assistenziale domiciliare. L’esperienza fatta con la HHD è incoraggiante per quanto segue: (a) dose dialitica “adeguata” (b) nessuna complicanza insorta nei pazienti (c) buon controllo dell’equilibrio idro-elettrolitico e minerale (d) ridotto uso di farmaci (e) maggiore benessere psicofisico (e) migliore qualità della vita. Per ottenere i vantaggi clinici descritti in letteratura per questo tipo di trattamento, appare di fondamentale importanza, una accurata valutazione e selezione dell’insieme “paziente-caregiver-ambiente” ed un rigoroso follow-up della compliance del paziente/caregiver al programma terapeutico prescritto. La possibilità di offrire concretamente un’ulteriore opzione terapeutica tra le terapie sostitutive dell’insufficienza renale cronica tutela il diritto alla libertà di scelta terapeutica del paziente. Infine, l’istituzione di un programma di HHD realizza le direttive Regionali sulla domiciliarizzazione dei pazienti affetti da MRC allo stadio dialitico, permette l’ottimizzazione delle risorse ed un risparmio economico della spesa sanitaria. Pertanto, questa metodica può essere considerata una ulteriore opzione terapeutica da offrire a pazienti selezionati secondo i criteri di eleggibilità previsti

The double face of Morgana in tumorigenesis

Morgana is a chaperone protein able to bind to ROCK I and II and to inhibit their kinase activity. Rho kinases are multifunctional proteins involved in different cellular processes, including cytoskeleton organization, centrosome duplication, cell survival and proliferation. In human cancer samples Morgana appears to be either downregulated or overexpressed, and experimental evidence indicate that Morgana behaves both as an oncosuppressor and as a proto-oncogene. Our most recent findings demonstrated that if on the one hand low Morgana expression levels, by inducing ROCK II hyperactivation, cause centrosome overduplication and genomic instability, on the other hand, Morgana overexpression induces tumor cell survival and chemoresistance through the ROCK I-PTEN-AKT axis. Therefore, Morgana belongs to a new class of proteins, displaying both oncogenic and oncosuppressor features, depending on the specific cellular context

Targeting few to help hundreds: JAK, MAPK and ROCK pathways as druggable targets in atypical chronic myeloid leukemia

Abstract Atypical Chronic Myeloid Leukemia (aCML) is a myeloproliferative neoplasm characterized by neutrophilic leukocytosis and dysgranulopoiesis. From a genetic point of view, aCML shows a heterogeneous mutational landscape with mutations affecting signal transduction proteins but also broad genetic modifiers and chromatin remodelers, making difficult to understand the molecular mechanisms causing the onset of the disease. The JAK-STAT, MAPK and ROCK pathways are known to be responsible for myeloproliferation in physiological conditions and to be aberrantly activated in myeloproliferative diseases. Furthermore, experimental evidences suggest the efficacy of inhibitors targeting these pathways in repressing myeloproliferation, opening the way to deep clinical investigations. However, the activation status of these pathways is rarely analyzed when genetic mutations do not occur in a component of the signaling cascade. Given that mutations in functionally unrelated genes give rise to the same pathology, it is tempting to speculate that alteration in the few signaling pathways mentioned above might be a common feature of pathological myeloproliferation. If so, targeted therapy would be an option to be considered for aCML patients

Evidence That p-Cresol and IL-6 Are Adsorbed by the HFR Cartridge: Towards a New Strategy to Decrease Systemic Inflammation in Dialyzed Patients?

Introduction Hemodialysis (HD) and hemodiafiltration clear only with a low efficiency the plasma from interleukin-6 and p-cresol, two protein-bound uremic toxins associated with high cardiovascular risk in end stage renal disease. HFR Supra is a double-chamber hemodiafiltration system in which the ultrafiltrate returns to the patient after its regeneration through a resin cartridge that binds hydrophobic and protein-bound solutes. In the present study, we evaluated whether the HFR cartridge can also bind total p-cresol and IL-6 and remove them from the ultrafiltrate. Methods We compared the levels of IL-6 and p-cresol in ultrafiltrate samples collected at the inlet (UFin) and at the outlet (UFout) of the cartridge at the start or at the end of a 240 min HFR session in 12 inflamed chronic HD patients. The pro-inflammatory activity of the ultrafiltrate samples was also determined by evaluating the changes that they induced in IL-6 mRNA expression and protein release in peripheral blood mononuclear cells from 12 healthy volunteers. IL-6 and p-cresol circulating levels were also assessed in peripheral plasma blood samples collected before and after HFR and, for comparison, a control HD. Results p-Cresol and IL-6 were lower in UFout than in UFin both at the start and at the end of the HFR session, suggesting that they were retained by the cartridge. IL-6 mRNA expression and release were lower in PBMC incubated with UFout collected at the end than with UFin collected at the start of HFR, suggesting that passage through the cartridge reduced UF pro-inflammatory activity. Plasma total p-cresol decreased by about 53% after HFR, and 37% after HD. IL-6 circulating values were unmodified by either these dialysis procedures. Conclusions This study shows that the HFR-Supra cartridge retains total p-cresol and IL-6 in the ultrafiltrate and lowers plasma total p cresol but not IL-6 levels. Trial Registration ClinicalTrials.gov NCT0186577

Treatment of Cutaneous Melanoma Harboring SMO p.Gln216Arg Mutation with Imiquimod: An Old Drug with New Results

: Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target

Determinants of worse liver-related outcome according to HDV infection among HBsAg positive persons living with HIV: Data from the ICONA cohort

Objectives: We aimed to study hepatitis D virus (HDV) prevalence and risk of progression to severe liver-related events (SLRE) in HBsAg positive people living with HIV (PLWH) in Italy; role of HDV-RNA copy levels, HCV coinfection and nadir CD4 counts were also investigated.Methods: People living with HIV (PLWH) from Italian Foundation cohort Naive antiretrovirals (ICONA) with available HBsAg and HDV Ab were enrolled. HBsAg, HDV Ab, HDV-RNA and HDV genotypes were tested. Primary end-point: time from first HDV screening to Severe Liver Related Events (SLRE: decompensated cirrhosis, liver transplantation, HCC). Fine-grey regression models were used to evaluate the association of HDV Ab, HDV-RNA, HDV/HCV coinfection, CD4 nadir and outcome. Secondary end-points: time to SLRE or death; HDV Ab and HDV-RNA prevalence.Results: A total of 152/809 (18.8%) HBsAg positive PLWH showed HDV Ab reactivity; 63/93 (67.7%) were HDV-RNA positive. Being male, persons who inject drugs (PWID), HCV Ab positive, with FIB-4 > 3.25 were independent factors of HDV Ab positivity. In a median follow-up of 5 years, 37 PLWH (4.1% at 5-year) developed SLRE and 97 (12.0%) reached the SLRE or death end-point. HDV-RNA positive (independently from HDV-RNA copy level) PLWH had a 4.6-fold (95%CI 2.0-10.5) higher risk of SLRE than HDV negatives. PLWH positive for both HCV Ab and HDV Ab showed the highest independent risk of SLRE (ASHR: 11.9, 95%CI: 4.6-30.9 vs. HCV neg/HDV neg). Nadir CD4 < 200/mL was associated with SLRE (ASHR: 3.9, 95% 1.0-14.5).Conclusions: One-fifth of the HBsAg positive PLWH harbour HDV infection, and are at high risk of progression to advanced liver disease. HCV contributes to worse outcomes. This population needs urgently effective treatments