Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling.

PURPOSE: To develop a genome-based classification scheme for clear-cell sarcoma (CCS), also known as melanoma of soft parts (MSP), which would have implications for diagnosis and treatment. This tumor displays characteristic features of soft tissue sarcoma (STS), including deep soft tissue primary location and a characteristic translocation, t(12;22)(q13;q12), involving EWS and ATF1 genes. CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases. MATERIALS AND METHODS: RNA samples from 21 cell lines and 60 pathologically confirmed cases of STS, melanoma, and CCS/MSP were examined using the U95A GeneChip (Affymetrix, Santa Clara, CA). Hierarchical cluster analysis, principal component analysis, and support vector machine (SVM) analysis exploited genomic correlations within the data to classify CCS/MSP. RESULTS: Unsupervised analyses demonstrated a clear distinction between STS and melanoma and, furthermore, showed that CCS/MSP cluster with the melanomas as a distinct group. A supervised SVM learning approach further validated this finding and provided a user-independent approach to diagnosis. Genes of interest that discriminate CCS/MSP included those encoding melanocyte differentiation antigens, MITF, SOX10, ERBB3, and FGFR1. CONCLUSION: Gene expression profiles support the classification of CCS/MSP as a distinct genomic subtype of melanoma. Analysis of these gene profiles using the SVM may be an important diagnostic tool. Genomic analysis identified potential targets for the development of therapeutic strategies in the treatment of this disease.     

Vascular endothelial growth factor and p53 expressions in liver and abdominal metastases from colon cancer.

OBJECTIVE: To determine the relationship between p53 overexpression and vascular endothelial growth factor (VEGF) upregulation in liver and abdominal metastases from colon cancer. The analysis in the two metastatic sites was carried out to evaluate the potential role of microenvironment in the molecular regulation of VEGF. METHODS: Bioptic specimens of liver and abdominal metastases from colon carcinomas were examined by immunohistochemistry for p53 and VEGF expressions. Consecutive cases with assessable tumor tissue were selected. RESULTS: The study population consisted of 24 cases having liver metastases and 34 cases having abdominal metastases. Abdominal metastases showed a higher number of VEGF-positive cases and a higher intensity of VEGF immunoreactivity than liver metastases did (p = 0.01). The combined analysis of p53 and VEGF showed a strong association between the two markers in the 24 liver metastases; 9 cases were VEGF positive/p53 positive and 15 cases were VEGF negative/p53 negative. This relationship was not found in the 34 abdominal metastases, which showed concordance between the two markers in 9 VEGF-positive/p53-positive cases only. CONCLUSIONS: Microenvironment factors like hypoxia may have a predominant role in inducing VEGF expression and they can override the molecular control of p53 on VEGF.     

Fully synthetic carbohydrate-based vaccines in biochemically relapsed prostate cancer: clinical trial results with alpha-N-acetylgalactosamine-O-serine/threonine conjugate vaccine.

PURPOSE: We report the synthesis of a mucin-related O-linked glycopeptide, alpha-N-acetylgalactosamine-O-serine/threonine (Tn), which is highly simplistic in its structure and can induce a relevant humoral response when given in a trimer or clustered (c) formation. We tested for an antitumor effect, in the form of a change in the posttreatment versus pretreatment prostate-specific antigen (PSA) slopes, that might serve as a surrogate for effectiveness of vaccines in delaying the time to radiographic progression. METHODS: We compared the antibody response to immunization with two conjugates, Tn(c)-keyhole limpet hemocyanin (KLH) and Tn(c)-palmitic acid (PAM) with the saponin immunologic adjuvant QS21, in a phase I clinical trial in patients with biochemically relapsed prostate cancer. Patients received Tn(c)-KLH vaccine containing either 3, 7, or 15 microg of Tn(c) per vaccination. Ten patients received 100 microg of Tn(c)-PAM. QS21 was included in all vaccines. Five vaccinations were administered subcutaneously during 26 weeks with an additional booster vaccine at week 50. RESULTS: Tn(c), when given with the carrier molecule KLH and QS21, stimulated the production of high-titer immunoglobulin M (IgM) and IgG antibodies. Inferior antibody responses were seen with T(c)-PAM. There was no evidence of enhanced immunogenicity with increasing doses of vaccine. An antitumor effect in the form of a decline in posttreatment versus pretreatment PSA slopes was also observed. CONCLUSION: A safe synthetic conjugate vaccine in a trimer formation was developed that can break immunologic tolerance by inducing specific humoral responses. It seemed to affect the biochemical progression of the disease as determined by a change in PSA log slope.     

High Serum Levels of Soluble IL-2 Receptor, Cytokines, and C Reactive Protein Correlate with Impairment of T Cell Response in Patients with Advanced Epithelial Ovarian Cancer

The serum levels of interleukin-(IL-)1α, IL-1β, IL-2, IL-6, TNFα, and sIL-2R and the proliferative response of peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA), anti-CD3 monoclonal antibody (mAb), recombinant IL-2 (rIL-2), and the combination of PHA or anti-CD3 mAb with rIL-2 were studied and correlated with serum levels of C-reactive protein (CRP) in women with advanced epithelial ovarian cancer. The expression of CD25 and CD122 subunities of membrane-bound IL-2R on PHA- or anti-CD3 mAb-stimulated PBMC was also studied. In comparisons with the controls, PBMC response to PHA, anti-CD3 mAb, and rIL-2 was significantly lower in the cancer patients. The addition of exogenous rIL-2 to the PBMC cultures increased response in both controls and patients but did not modify the significance of the differences. After stimulation with PHA or anti-CD3 mAb, the percentage of PBMC CD25⁺or CD122⁺was significantly lower in patients. The serum levels of IL-1α, IL-1β, IL-6, TNFα, sIL-2R, and CRP were significantly increased in patients compared to the controls. Instead, no differences were observed for serum levels of IL-2. A strong association was found between high serum levels of the above-mentioned cytokines, sIL-2R, and CRP. The results of our study on advanced stage (IIIb–IV) ovarian cancer patients are consistent with the previously reported hypothesis that high IL-6 and/or CRP serum levels may represent an important and independent prognostic factor of the likely outcome in cancer patients.     

Daptomycin: a novel cyclic lipopeptide antimicrobial.

PURPOSE: The development, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, and dosage and administration of daptomycin are reviewed. SUMMARY: Daptomycin, a novel cyclic lipopeptide antimicrobial, is bactericidal against a range of gram-positive bacteria, including many multiple-drug-resistant isolates. It has only minimal activity against anaerobic bacteria and no activity against gram-negative bacteria. Daptomycin exhibits linear pharmacokinetics, and the plasma concentration-versus-time relationship is best described by a two-compartment model with first-order elimination. The initial bactericidal activity is rapid, extensive, and concentration related. In clinical trials, daptomycin has shown efficacy in treating complicated skin and skin-structure infections (CSSSIs); the drug carries FDA-approved labeling for same. The adverse effects of daptomycin appear comparable to those of vancomycin and semisynthetic penicillins. The dosage for CSSSIs is 4 mg/kg by i.v. infusion every 24 hours. CONCLUSION: Daptomycin is bactericidal against gram-positive organisms and offers an option in the treatment of CSSSIs.     

Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes.

PURPOSE: Nemorubicin (3'-deamino-3'-[2'(S)-methoxy-4'-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3',4'-anhydro-[2'(S)-methoxy-3'(R)-oxy-4'-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682. EXPERIMENTAL DESIGN: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. RESULTS: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. CONCLUSIONS: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.     

Exclusion Diets in Functional Dyspepsia

Functional dyspepsia represents one of the most common and prevalent disorders of the brain–gut interaction, with a large number of widespread risk factors being identified. With an intricate pathogenesis and symptomatology, it heavily impacts the quality of life and, due to the limited efficacy of traditional pharmacological agents, patients are likely to seek other medical and non-medical solutions to their problem. Over the last few years, significant research in this domain has emphasized the importance of various psychological therapies and nutritional recommendations. Nevertheless, a correlation has been established between functional dyspepsia and food intolerances, with more and more patients adopting different kinds of exclusion diets, leading to weight loss, restrictive eating behaviour and an imbalanced nutritional state, further negatively impacting their quality of life. Thus, in this systematic review, we aimed at analysing the impact and efficiency of certain exclusion diets undertook by patients, more precisely, the gluten-free diet and the low-FODMAP diet.     

Ozone Therapy for Dermatological Conditions: A Systematic Review

BackgroundKnown in the past for its toxic aspect as the main urban pollutant, in the last few decades, ozone has been gaining greater visibility for its possible antimicrobial, antiviral, and antioxidant effects when used in human dermatological pathologies. Despite the reports of clinical benefits, the standard dosage for clinical efficacy and safety are yet not clear, nor are its means of application and its true acting mechanism.ObjectiveWe conducted a review to determine the efficacy and safety of ozone therapy for a variety of dermatological conditions.MethodsWe considered clinical trials (both randomized and non-randomized) published between December 2020 and March 2021 as long as they provided some PICO information, i.e., population (P), intervention (I), and study design. The skin dermatological conditions researched were: acne, dermatitis, psoriasis, systemic sclerosis, herpes, aging, ulcers, and skin scarring.ResultsA total of 326 articles were identified and 150 remained after duplicates were removed. After titles, abstracts and full articles were read, 17 articles were included in the systematic review (with 643 patients). ConclusionOzone therapy seems promising for some dermatological conditions; however, the articles included in this review had methodological limitations and did not sufficiently demonstrate sound evidence for safe therapy. Therefore, more studies with better methodological standards and longer-term assessments of side effects should be conducted to achieve better standards and safety in ozone therapy for dermatological conditions.     

Zoonotic Transmission of Diphtheria from Domestic Animal Reservoir,Spain

Toxigenic Corynebacterium ulcerans is as an emerging zoonotic agent of diphtheria. We describe the zoonotic transmission of diphtheria caused by toxigenic C. ulcerans from domestic animals in Spain, confirmed by core-genome multilocus sequence typing. Alongside an increasing number of recent publications, our findings highlight the public health threat posed by diphtheria reemergence.