Background:

Long-term survival is a problem with locally advanced and metastatic renal cell carcinomas. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, but data on sunitinib use as a second line treatment in metastatic renal cell carcinoma (mRCC) are limited. Prognostic and predictive value of peripheral blood markers has been shown for many cancers. Materials and

Methods:

Efficacy and safety profiles of sunitinib after interferon alpha were evaluated based on retrospective data for 23 patients with mRCC. Hematological parameters (neutrophils, lymphocytes, platelets, mean platelet volume, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio) were recorded at the time of metastasis. It was evaluated whether hematological parameters were prognostic and predictive factors.

Results:

Median progression-free survival (PFS) time was 16.5 months (95%CI: 0-34.5). Median overall survival (OS) time was 25.7 months (95%CI: 10.8-40.0). Most common side effects were neutropenia (52.2%), stomatitis (26.1%) and hand-food syndrome (26.1%). PFS was found 3.13 vs 17.1 months in patients with neutrophil / lymphocyte ratio (NLR)>3 vs NLR≤3 (p:0.012). Median OS was 6.96 vs 27.1 months in patients with NLR>3 vs NLR≤3 (p:0.001).While 75% of patients who responded to sunitinib had NLR≤3, in 72% of patients with no response to sunitinib NLR>3 was detected (p:0.036). The association between the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria and NLR was statistically significant (p:0.022).

Conclusions:

Data on second line sunitinib treatment following cytokine in mRCC are limited. In our study, we observed second line sunitinib treatment following IFN-alpha to be effective and tolerable. NLR appeared to have prognostic and predictive value.

Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus, (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of small molecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking entry of HIV-1 pseudotyped with SARS-CoV surface glycoprotein S (SARS-S), but not with Vesicular Stomatitis Virus surface glycoprotein G (VSV-G). Studies on their mechanisms of action revealed that they act by three distinct mechanisms: a) SSAA09E2 (N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide) acts through a novel mechanism of action, by blocking early interactions of SARS-S with the receptor for SARS-CoV, Angiotensin Converting Enzyme-2 (ACE2); b) SSAA09E1 ([(Z)-1-thiophen-2-ylethylideneamino]thiourea), which acts later by blocking cathepsin L, a host protease required for processing of SARS-S during viral entry and c) SSAA09E3 (N-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide)), which also acts later and does not affect interactions of SARS-S with ACE2 or the enzymatic functions of cathepsin L, but prevents fusion of the viral membrane with the host cellular membrane. Our work demonstrates that there are at least three independent strategies to block SARS-CoV entry, validates these mechanisms of inhibition, and introduces promising leads for the development of SARS therapeutics.

Poly(methyl methacrylate) (PMMA) has been widely used as a denture-base acrylic resin due to its excellent physical and mechanical properties. However, the material is highly prone to microbial fouling that often leads to Candida-associated denture stomatitis. Incorporation of phosphate groups into PMMA could facilitate adsorption of salivary antimicrobials and inhibit microbial adherence on the polymer surface. An in vitro study evaluated PMMA polymers containing varying amounts of phosphate group for their efficacy to inhibit Candida albicans adhesion, adsorb salivary histatin 5, and exhibit candidacidal activity.Six PMMA polymers containing 0%, 5%, 15%, 10%, 20%, and 25% of phosphate group were synthesized by bead (suspension) polymerization technique using mixtures of methyl methacrylate and methallyl phosphate as monomers. The efficacy of the polymers to inhibit the adherence of C. albicans was examined by using human saliva-coated polymer beads and radio-labeled C. albicans cells, as compared with that of PMMA. The potency of the phosphated PMMA polymers to adsorb histatin 5 was determined by measuring the radioactivity of the adsorbed labeled-peptide on the polymer surface. The candidacidal activity of the histatin 5-adsorbed polymers was assessed by using the fluorescence technique. The percent release of the fluorescent probe calcein from the C. albicans membrane caused by the disruption of the cell membrane was determined. The data were analyzed statistically by one-way ANOVA followed by Scheffé's test (α = 0.05 and n = 6).The presence of ≥15% phosphate content in PMMA significantly reduced the saliva-mediated adhesion of C. albicans. Phosphated PMMA polymers showed significantly enhanced adsorption of histatin 5 in a phosphate density-dependent manner. The candidacidal activity of the histatin 5-bound polymers increased significantly with the increase in the phosphate content of the polymer.Phosphated PMMA polymers have the potential to serve as novel denture-base resins, which may reduce C. albicans colonization and prevent denture stomatitis.

Activation-induced deaminase converts deoxycytidine to deoxyuridine at the Ig loci. Complementary pathways, initiated by the uracil-DNA glycosylase (UNG) or the mismatch repair factor MSH2/MSH6, must process the deoxyuridine to initiate class-switch recombination (CSR) and somatic hypermutation. UNG deficiency most severely reduces CSR efficiency and only modestly affects the somatic hypermutation spectrum in vitro. This would predict isotype-switching deficiency but normal affinity maturation in Ung(-/-) mice in vivo, but this has not been tested. Moreover, puzzling differences in the amount of circulating Ig between UNG-deficient humans and mice make it unclear to what extent MSH2/MSH6 can complement for UNG in vivo. We find that Ab affinity maturation is indeed unaffected in Ung(-/-) mice, even allowing IgM responses with higher than normal affinity. Ung(-/-) mice display normal to only moderately reduced basal levels of most circulating Ig subclasses and gut-associated IgA, which are elicited in response to chronically available environmental Ag. In contrast, their ability to produce switched Ig in response to immunization or vesicular stomatitis virus infection is strongly impaired. Our results uncover a specific need for UNG in CSR for timely and efficient acute Ab responses in vivo. Furthermore, Ung(-/-) mice provide a novel model for separating isotype switching and affinity maturation during acute (but not chronic) Ab responses, which could be useful for dissecting their relative contribution to some infections. Interestingly, Ung(-/-) mice present with circulating autoantibodies, suggesting that UNG may impinge on tolerance.

BACKGROUND:

The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies.

PATIENTS AND METHODS:

We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m(2), oxaliplatin 85 mg/m(2), and folinate 200 mg/m(2) on day 1, followed by fluorouracil 3000 mg/m(2) as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m(2) after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR).

RESULTS:

Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7-12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered.

CONCLUSIONS:

Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising.

OBJECTIVES:

Recurrent aphthous stomatitis (RAS) is a common ulcerative disease of the oral mucosa. Methylenetetrahydrofolate reductase (MTHFR) gene variants are associated with thrombophilia and vasculopathy that may result in oral ulceration. Oral ulcers are also the most common feature of Behcet's disease (BD). Association of MTHFR gene C677T mutation with BD has been reported in different populations. The aim of the present study was to investigate the possible association between MTHFR gene C677T mutation and RAS and evaluate if there was an association with clinical features in a relatively large cohort of Turkish patients.

MATERIALS AND METHODS:

The study included 188 patients affected by RAS and 200 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR gene C677T mutation.

RESULTS:

The genotype and allele frequencies of C677T mutation showed statistically significant differences between RAS patients and controls (p = 0.002 and p = 0.0004, respectively). After stratifying RAS patients according to clinical characteristics of oral ulcers, a significant association was observed between C677T mutation and number of oral ulcers of RAS patients (p = 0.006).

CONCLUSIONS:

As a result, a high association between MTHFR gene C677T mutation and RAS was observed in the present study. Also number of oral ulcers was found to be associated with MTHFR C677T mutation in RAS patients.

CLINICAL RELEVANCE:

If our observation can be substantiated with further studies, evaluation for MTHFR mutations and perhaps folate supplementation may become necessary in selected patients.

PROJECT: Recurrent aphthous stomatitis (RAS) is a common oral mucosal disorder characterized by recurrent, painful oral aphthae, and oxidative stress presumably contributes to its pathogenesis. The aim of this study is to scrutinize the relationship between oxidative stress and serum trace elements (copper, Cu; zinc, Zn; selenium, Se), and to evaluate the ratios of Cu/Zn and Cu/Se in this disorder.

PROCEDURE:

Patients with RAS (n=33) and age- and sex-matched healthy control subjects (n=30) were enrolled in this study. Malondialdehyde (MDA) concentrations in plasma and the activities of superoxide dismutase (SOD1; CuZnSOD), glutathione peroxidase (GPx) and catalase (CAT) in erythrocyte were determined as spectrophotometric. Also, the levels of Se, Zn and Cu in serum were determined on flame and furnace atomic absorption spectrophotometer using Zeeman background correction.

RESULTS AND CONCLUSIONS:

Oxidative stress was confirmed by the significant elevation in plasma MDA, and by the significant decrease in CAT, SOD1, and GPx (p<0.05). When compared to controls, Zn and Se levels were significantly lower in patients, whereas Cu levels was higher in RAS patients than those in controls (p<0.05). In addition, the correlation results of this study were firstly shown that there were significant and positive correlations between Se-CAT, Se-GPx, and Cu-MDA parameters, but negative correlations between Se-Cu, Se-MDA, Cu-CAT, Cu-SOD1 and Cu-GPx parameters in RAS patients. Furthermore, the ratios of Cu/Zn and Cu/Se were significantly higher in the patients than the control subjects (p<0.05). Our results indicated that lipid peroxidation associated with the imbalance of the trace elements seems to play a crucial role in the pathogenesis of RAS. Furthermore, the serum Cu/Zn and Cu/Se ratios may be used as biochemical markers in these patients.

Recurrent aphthous stomatitis (RAS) has a multifactorial etiopathogenesis, an interaction between predisposing factors and/or systemic conditions and immunological components in genetically predisposed subjects. The Mediterranean fever (MEFV) gene has already been identified as being responsible for familial Mediterranean fever. Because the association between MEFV gene mutations and Behçet's disease has been reported before in several studies, we considered that the role of MEFV gene mutations should be studied in patients with RAS, because of the clinical similarities of both diseases. The aim of this study was to explore the frequency and clinical significance of MEFV gene mutations in a cohort of Turkish patients with RAS. The study population comprised 100 unrelated patients with a clinical diagnosis of RAS and 156 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction and restriction fragment length polymorphism for the four MEFV gene mutations (M694V, M680I, V726A and E148Q). There were statistically significant differences of the MEFV gene mutation carrier rates and allele frequencies between RAS patients and healthy controls (P = 0.042, odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.01-3.41; and P = 0.039, OR = 1.8, 95% CI = 1.02-3.14, respectively). Even if it is not statistically significant, the E148Q allele frequency was higher in patients with RAS than the control group. A statistically significant increased prevalence of MEFV variants in RAS patients was found. This is the first study to report that missense mutations of MEFV is associated with RAS in the Turkish population.

Background:

Hand, foot, and mouth disease is a contagious enteroviral infection occurring primarily in children and characterized by vesicular palmoplantar eruptions and erosive stomatitis. There are very few cases of unilateral acute idiopathic maculopathy associated with hand, foot, and mouth infection. We described a case with unilateral outer retinitis occurring a few days after the onset of disease. 


Methods:

A 30-year-old man with reduced vision in his right eye underwent complete ophthalmologic examination including fluorescein angiography and spectral optical coherence tomography. 


Results:

Fundus fluorescein angiography demonstrated mottled hyperfluorescence in the early phase and leakage in the late phase. Spectral domain optical coherence tomography revealed subretinal fluid suggesting a serous detachment and also showed mild intraretinal cystic changes. The fluid disappeared in 1 week with some retinal pigment epithelium changes in the center of the macula.


Conclusion:

Although this disease is a viral infection associated with reversible symptoms, this case suggests that it can resolve with mild visual loss, and the disease should be considered in the differential diagnosis of acute central serous chorioretinopathy.