High‐frequency p16INK4A promoter methylation is associated with histone methyltransferase SETDB1 expression in sporadic cutaneous melanoma

Epigenetic mechanisms participate in melanoma development and progression. The effect of histone modifications and their catalysing enzymes over euchromatic promoter DNA methylation in melanoma remains unclear. This study investigated the potential association of p16^INK4A promoter methylation with histone methyltransferase SETDB1 expression in Greek patients with sporadic melanoma and their correlation with clinicopathological characteristics. Promoter methylation was detected by methylation‐specific PCR in 100 peripheral blood samples and 58 melanoma tissues from the same patients. Cell proliferation (Ki‐67 index), p16^INK4A and SETDB1 expression were evaluated by immunohistochemistry. High‐frequency promoter methylation (25.86%) was observed in tissue samples and correlated with increased cell proliferation (P = 0.0514). p16^INK4A promoter methylation was higher in vertical growth‐phase (60%) melanomas than in radial (40%, P = 0.063) and those displaying epidermal involvement (P = 0.046). Importantly, p16^INK4A methylation correlated with increased melanoma thickness according to Breslow index (P = 0.0495) and marginally with increased Clark level (I/II vs III/IV/V, P = 0.070). Low (1–30%) p16^INK4A expression was detected at the majority (19 of 54) of melanoma cases (35.19%), being marginally correlated with tumor lymphocytic infiltration (P = 0.078). SETDB1 nuclear immunoreactivity was observed in 47 of 57 (82.46%) cases, whereas 27 of 57 (47.37%) showed cytoplasmic immunoexpression. Cytoplasmic SETDB1 expression correlated with higher frequency of p16^INK4A methylation and p16^INK4A expression (P = 0.033, P = 0.011, respectively). Increased nuclear SETDB1 levels were associated with higher mitotic count (0–5/mm² vs >5/mm², P = 0.0869), advanced Clark level (III‐V, P = 0.0380), epidermal involvement (P = 0.0331) and the non‐chronic sun exposure‐associated melanoma type (P = 0.0664). Our data demonstrate for the first time the association of histone methyltransferase SETDB1 with frequent methylation of the euchromatic p16^INK4A promoter and several prognostic parameters in melanomas.     

Successful intravenous regional sympathetic blockade (Bier's Block) with guanethidine and lidocaine in a patient with advanced Buerger's Disease (thromboangiitis obliterans)--a case report

A 65-year-old man, a heavy smoker with Buerger's disease (thromboangiitis obliterans), presented to this department with persistent severe ischemic rest pain at the fingers of his right hand, not responding to oral treatment with vasodilators and analgesics. Critical blood flow was discovered in the middle, ring, and little finger, with ischemic ulcerations apparent in the fingertips of these 3 fingers. The distal phalanx of the little finger had been amputated 6 months before because of gangrenous necrosis. In an attempt to avoid further disabling amputations, the patient received 3 series of Bier's block sessions with guanethidine and lidocaine according to a specific protocol. Marked increase in finger blood flow was induced even after the first series, and complete disappearance of both fingertip ulcerations and ischemic rest pain was achieved. No side effects were observed. The above-described method in a patient with advanced Buerger's disease resulted in excellent pain relief and full restoration of both blood flow and function of the affected fingers.     

Delusional parasitosis: a rare cause of pruritus in hemodialysis patients

Uremic pruritus is a common symptom in patients undergoing hemodialysis (HD) or peritoneal dialysis, but its exact pathogenesis remains rather unclear. However, severe or "intractable" pruritus may be the manifestation of another underlying disease or disorder other than uremia. Delusional parasitosis, or Ekbom syndrome, is a rare psychiatric disorder characterized by the false conviction of being infested with parasites, and it can be primary, or secondary to several medical and psychiatric disorders. We report 2 elderly HD patients who presented one after another, with delusional parasitosis. At some point in time, the delusional beliefs of the first patient were adopted by the second patient who was waiting to start his HD session on the same bed and HD machine, on a subsequent shift. They were both diagnosed with Ekbom syndrome and described as having monosymptomatic hypochondriac delusion. They were both prescribed antipsychotic medications. During follow-up they admitted feeling better than before; however, they remained concerned about the "insects/parasites."     

Two icodextrin exchanges per day in peritoneal dialysis patients with ultrafiltration failure: one center’s experience and review of the literature

Background  

At present, only one exchange of an icodextrin-based solution is recommended to increase peritoneal ultrafiltration (UF) during long-dwell exchanges in peritoneal dialysis (PD) patients with impaired UF.     

Encapsulating peritoneal sclerosis: a single-center experience and review of the literature

Encapsulating peritoneal sclerosis (EPS) is a serious and often fatal complication of long-term PD with severe malnutrition and poor prognosis. It causes progressive obstruction and encapsulation of the bowel. This retrospective study reviews our experience and that reviewed in the literature concerning EPS. It refers to a total of 1966 patients treated with chronic PD between 1974 and 2008. Twenty one of them (1.1%) developed EPS, with the incidence increasing with the duration of PD. Mean age of our patients with EPS was 43, ranging from 18 to 71 years, 8 were men and 13 women with a mean body mass index (BMI) of 21.6 kg/m². Only one patient had Type II diabetes, 15 patients had glomerular disease, and six of these 15 had an autoimmune disease such as Wegener’s granulomatosis and SLE. Thirteen patients developed EPS while on PD, 7 within 2 years after transfer to HD, and only one after renal transplantation. However, 7 patients had a previous renal transplant before returning to PD and subsequently developing EPS. Interestingly, we did not observe more episodes of EPS after transplantation. In the patients who developed EPS, the peritonitis rate over the period of observation was 1/15.6 pt-months and was due to Staphylococcus aureus, coagulase-negative staphylococcus, Pseudomonas and fungi. A history of peritonitis was not a prerequisite for developing EPS, since one patient had no episodes of peritonitis and 4 had just one previous episode. Fifteen patients presented with peritonitis within 4 months before the diagnosis of EPS with particularly virulent micro-organisms such as S. aureus, Candida, Pseudomonas, Corynebacterium, and Peptostreptococcus. Eleven patients were treated with hypertonic dextrose solutions (4.25 g/dl of dextrose) and seven with icodextrin, indirectly suggesting problems with ultrafiltration. Nine of 21 patients were on beta-blockers. The diagnosis of EPS was made either surgically or radiologically with signs of small bowel obstruction in combination with severe malnutrition. Eleven of our patients (52%) had evidence of small bowel obstruction and 14 patients required total parenteral nutrition (TPN). Tamoxifen (10–20 mg daily) was started in 6 patients, 4 of whom are alive and 2 deceased 3 and 5 years after EPS was diagnosed. Of the 12 patients who were not given tamoxifen, 2 are alive and 10 died. No side effects of tamoxifen were reported. Only 7 of our patients (33%) died during the first year after the diagnosis of EPS. Currently, 4 patients are on HD and 3 have had a renal transplant. Six patients of the fourteen who underwent surgery (42.8%) died within the first 6 months after operation and five died after an average of 6.6 years, mostly due to cardiovascular causes, three are still alive. As EPS becomes more prevalent with longer duration of PD, large multicenter prospective studies are needed to establish its incidence and identify risk factors, therapeutic approach, and prognosis.     

Phosphorylated 4E-binding protein 1 (p-4E-BP1): a novel prognostic marker in human astrocytomas

Korkolopoulou P, Levidou G, El‐Habr E A, Piperi C, Adamopoulos C, Samaras V, Boviatsis E, Thymara I, Trigka E‐A, Sakellariou S, Kavantzas N, Patsouris E & Saetta A A
(2012) Histopathology  61, 293–305 Phosphorylated 4E‐binding protein 1 (p‐4E‐BP1): a novel prognostic marker in human astrocytomas Aims: To investigate the significance of the mammalian target of rapamycin (mTOR) pathway in astrocytic tumours, published information in this context being limited, especially regarding phosphorylated 4E‐binding protein (p‐4E‐BP) 1. Methods and results: Paraffin‐embedded tissue from 111 patients with astroglial tumours (grades II–IV) was investigated for the association of phosphorylated mTOR (p‐mTOR) signalling components with phosphorylated extracellular signal‐related kinase 1/2 (p‐ERK1/2) and phosphorylated AKT (p‐AKT) expression, clinicopathological features, angiogenesis, isocitrate dehydrogenase 1 (IDH1)‐R132H, and survival. Expression was also quantified by western blot analysis in 12 cases and in three primary glioma cell cultures following rapamycin treatment. p‐mTOR expression correlated with p‐4E‐BP1 expression and marginally with p‐p70S6K expression. p‐4E‐BP1 expression increased with tumour grade. Rapamycin induced a decline in phosphorylation levels of all three proteins. Nuclear p‐AKT and cytoplasmic p‐ERK1/2 immunoexpression correlated with p‐4E‐BP1 expression, whereas cytoplasmic p‐AKT expression correlated with p‐p70S6K expression. All three proteins were associated with increased angiogenesis but not with IDH1‐R132H expression status. p‐mTOR adversely affected overall and disease‐free survival in univariate analysis. In multivariate survival analysis, the presence of p‐4E‐BP1 predicted shortened overall survival in the entire cohort and glioblastomas. Conclusions: mTOR signalling components are differentially involved in the acquisition of a more aggressive and angiogenic phenotype in astrocytic tumours. Moreover, p‐4E‐BP1 emerges as a novel prognostic marker, which might aid in the selection of patients who are more likely to benefit from therapy with mTOR inhibitors.     

Icodextrin and peritoneal dialysis: advantages and new applications

The impact of icodextrin (ico) on peritoneal dialysis (PD) extension and patient survival is well established. Predominantly, ico-based solutions were prescribed in high-transporter PD patients. Advantages of the ico-based solutions include increased biocompatibility, avoidance of glucotoxicity, enhanced ultrafiltration failure (UF), sodium removal rates, better metabolic and blood pressure control. Bimodal solutions and twice daily exchanges of ico-based solutions are two newly introduced strategies to avoid glucose exposure and/or enhance UF in PD patients with UF failure. In addition, a simplified schedule of PD using a single nocturnal exchange of ico in patients with refractory congestive heart failure may represent an alternative option to manage fluid removal and azotaemia. The use of a simplified schedule of PD with only two ico exchanges or a single ico exchange is a challenging approach for end-stage renal disease patients with preserved residual function who desire to initiate PD.     

Replication protein A: a reliable biologic marker of prognostic and therapeutic value in human astrocytic tumors

Replication protein A is a single-stranded DNA–binding protein that is required for the stabilization of single-stranded DNA and identified in replication foci where members of cyclin-dependent kinases–cyclin complexes are also present. In this study, we investigated the expression of replication protein A1 and replication protein A2 subunits of replication protein A protein in correlation with cyclins D2 and D3 and nuclear factor κB expression and assessed their prognostic significance in 66 patients with astrocytomas. Statistically significant positive associations emerged between (a) replication protein A1 and replication protein A2 protein expression (P < .0001); (b) cyclins D2 and D3 expression (P < .0001); (c) replication protein A1, replication protein A2, and cyclins D2 and D3 expression and histologic grade (P = .0001 in all correlations); (d) replication protein A1 and cyclin D2 or D3 expression (P < .0001 in both relationships); and (e) replication protein A2 and cyclin D2 or D3 expression (P < .0001 in both relationships). Nuclear factor κB1/p50 expression was positively correlated with replication protein A1, replication protein A2, and cyclins D2 and D3 expression, although these relationships failed to retain statistical significance when they were adjusted for histologic grade. Replication protein A2 expression seemed to independently affect survival in grade IV (P = .005) as well as in the entire cohort (P = .006). None of the molecules under study seemed to influence survival in lower grades (II/III), either by univariate or by multivariate analysis. In conclusion, replication protein A1, replication protein A2, and cyclins D2 and D3 seem to have a parallel role in the promotion of cell cycle in astrocytic tumors being implicated in the malignant progression of these neoplasms. Moreover, replication protein A2 protein seems to be a useful prognostic indicator in patients with astrocytomas.