Plasma alpha-1-acid glycoprotein as a potential predictive biomarker for non-haematological adverse events of docetaxel in breast cancer patients.

CONTEXT: Rash and oral mucositis are major non-haematological adverse events (AEs) of docetaxel, in addition to fatigue, nausea, vomiting and diarrhoea, which restrict the use of the drug in cancer therapy. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel has extensive binding (>98%) to plasma proteins such as AAG, lipoproteins and albumin. OBJECTIVE: To study the association between plasma AAG level and non-haematological AEs of docetaxel in Malaysian breast cancer patients of three major ethnic groups (Malays, Chinese and Indians). MATERIALS AND METHODS: One hundred and twenty Malaysian breast cancer patients receiving docetaxel as single agent chemotherapy were investigated for AAG plasma level using enzyme-linked immunosorbent assay technique. Toxicity assessment was determined using Common Terminology Criteria of Adverse Events v4.0. The association between AAG and toxicity were then established. RESULTS: There was interethnic variation of plasma AAG level; it was 182 ± 85 mg/dl in Chinese, 237 ± 94 mg/dl in Malays and 240 ± 83 mg/dl in Indians. It was found that low plasma levels of AAG were significantly associated with oral mucositis and rash. CONCLUSIONS: This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.

Pruritus in hemodialysis patients: association with phosphorus intake and serum calcium level. / Prurido no paciente em hemodiálise: associação com ingestão de fósforo e nível sérico de cálcio.

OBJECTIVE: To analyze the association between the occurrence of pruritus and adherence to the prescribed diet, biochemical indicators of renal function and the quality of hemodialysis in chronic renal patients. METHOD: A cross-sectional study performed at a dialysis clinic in the Northeast of Brazil, with 200 patients undergoing hemodialysis in the first half of 2015.To analyze the data, inferential statistics were used, using Chi-Square and Fisher's Exact tests; and Mann Whitney U test. RESULTS: The pruritus was present in 51% of the sample, being associated statistically with phosphorus consumption (P = 0.024) and elevation of serum calcium (P = 0.009). CONCLUSION: Pruritus in chronic renal patients undergoing hemodialysis is influenced by adequate nonadherence to the prescribed diet, in addition to the elevation of biochemical indicators of renal function.

Transmission of chromosomally integrated human herpesvirus 6 via cord blood transplantation.

Chromosomally integrated human herpesvirus 6 (ciHHV-6) can be transmitted via allogeneic hematopoietic cell transplantation. To date, only a few cases have been reported. Here, we report a case identified as transmission of ciHHV-6 via cord blood transplantation. Distinguishing transmission of ciHHV-6 from HHV-6 reactivation in cases with high titer of HHV-6 DNA load after transplantation is important to prevent unnecessary exposure to antiviral drugs that could be toxic.

Pseudozyma and other non-Candida opportunistic yeast bloodstream infections in a large stem cell transplant center.

Non-Candida opportunistic yeasts are emerging causes of bloodstream infection (BSI) in immunocompromised hosts. However, their clinical presentation, management, and outcomes in stem cell transplant (SCT) recipients are not well described. We report the first case to our knowledge of Pseudozyma BSI in a SCT recipient. He had evidence of cutaneous involvement, which has not been previously described in the literature. He became infected while neutropenic and receiving empiric micafungin, which is notable because Pseudozyma is reported to be resistant to echinocandins. He was successfully treated with the sequential use of liposomal amphotericin B and voriconazole. A review of the literature revealed nine reported instances of Pseudozyma fungemia. We performed a retrospective review of 3557 SCT recipients at our institution from January 2000 to June 2015 and identified four additional cases of non-Candida yeast BSIs. These include two with Cryptococcus, one with Trichosporon, and one with Saccharomyces. Pseudozyma and other non-Candida yeasts are emerging pathogens that can cause severe and disseminated infections in SCT recipients and other immunocompromised hosts. Clinicians should have a high degree of suspicion for echinocandin-resistant yeasts, if patients develop breakthrough yeast BSIs while receiving echinocandin therapy.

Avoiding "Rash" Conclusions: Challenge of IgA Vasculitis in Adults.

IgA vasculitis is primarily a pediatric disease that is rarely encountered in adults. With adults, gastrointestinal manifestations are quite common, yet are nonspecific and may overlap with other diseases, particularly Crohn's disease, which can make the diagnosis a challenging task. Treatment is controversial given the disease course is usually self-limited with few serious complications. We present a case of IgA vasculitis in an adult patient with limited extraintestinal findings illustrating the complexity of arriving at the correct diagnosis.

A rash diagnosis: Gemcitabine-associated pseudocellulitis.

Gemcitabine is an antitumor agent with broad clinical application. The most common cutaneous toxicities are mild rash and pruritus; however, a severe 'pseudocellulitis' rash, which resembles infectious cellulitis in clinical presentation, has increasingly been recognized as a rare complication of this agent. Though the specific pathophysiology related to this condition is not clear, it has been observed to occur primarily in regions of significant lymphadenopathy or prior radiation exposure typically after 24-48 h following administration of gemcitabine. It is a self-limiting reaction, with most cases resolving within two to seven days of onset without any specific treatment for the rash. Treatment with gemcitabine may be safely continued in patients with this complication, though recurrence of the rash is common following repeated doses. We report a case of biopsy confirmed gemcitabine associated pseudocellulitis in a patient treated for metastatic pancreatic adenocarcinoma. Knowledge of this complication is important to avoid unwarranted hospitalizations and antibiotic use in patients treated with gemcitabine.

A Term Infant of Neonatal Toxic Shock Syndrome-Like Exanthematous Disease Complicated with Hemophagocytic Syndrome.

Neonatal toxic shock syndrome-like exanthematous disease (NTED) is a newly recognized neonatal infectious disease, caused by the superantigen toxic shock syndrome toxin-1 (TSST-1). TSST-1 is mainly produced by methicillin-resistant Staphylococcus aureus, and the immune responses to TSST-1 are known to cause toxic shock syndrome, a life-threatening infectious disease. The clinical symptoms of NTED are skin rash, fever, and thrombocytopenia, but severe thrombocytopenia is rare in term infants with NTED. Although the cause of NTED is the same as that of toxic shock syndrome, the clinical symptoms of NTED are milder than toxic shock syndrome. The mild phenotype of NTED has been explained by selectively elevated serum levels of anti-inflammatory cytokine interleukin (IL)-10, which suppress immune responses to TSST-1. In the present study, we report a term female infant of NTED complicated with hemophagocytic syndrome (HPS). HPS is characterized by systemic inflammation and hemophagocytosis, caused by uncontrolled activation of T cells and macrophages. The serum IL-10 level of the patient at 4 days of age was relatively low (67 pg/mL) for NTED but still higher than normal controls (< 2.0 pg/mL). The patient also showed severe thrombocytopenia. We speculate that the serum IL-10 level of the patient was enough to supress immune responses to TSST-1, thereby resulting in NTED, but not enough to suppress the onset of HPS. This is the first reported case of NTED complicated with HPS. If a physician encounters an NTED patient with severe cytopenia, microscopic examination of peripheral blood smear should be carried out to exclude HPS.

Anti-C1q in chronic hepatitis C virus genotype IV infection: association with autoimmune rheumatologic manifestations.

A growing body of evidence suggests that anti-complement-1q (anti-C1q) antibodies are elevated in a variety of autoimmune disease. Therefore, we investigated their prevalence and clinical significance in plasma of patients with hepatitis C virus (HCV) genotype IV in the presence and absence of autoimmune extra hepatic manifestations in comparison to normal healthy individuals. Plasma Anti-C1q Abs levels were assessed by an Enzyme Linked Immunosorbant Assay in 91 chronic HCV-infected patients (51 with and 40 without autoimmune rheumatic manifestations) and 40 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. Positive Anti-C1q antibodies were more frequent among HCV patients with extra-hepatic autoimmune involvement, than those without and healthy control subjects. No significant correlations were found between Anti-C1q levels with either the liver activity or the fibrosis scores. In HCV-patients with autoimmune involvements, plasma Anti-C1q levels were significantly higher in patients with positive cryoglobulin, and in those with lymphoma than in those without. These results were confirmed by multivariate analysis. Further large scale longitudinal studies are required to assess and clarify the significance and the pathogenic role of anti-C1q antibodies among HCV infected patients with positive cryoglobulinaemia and lymphoma.

[The comparative characteristic of cytokine production in serum and whole blood in patients with chronic autoimmune nettle rash].

The sampling of 100 patients with chronic autoimmune nettle rash and control group of 30 healthy donors was analyzed for identification of level of interleukin (IL)-4, IL-10, IL-17, IL-18 and γ-interferon (IFN) in serum of patients. The same sampling was examined using method ex vivo for spontaneous and induced production by cells of immune system. In patients with chronic autoimmune nettle rash increasing of spontaneous production of IL-4 and spontaneous and induced production of IL-17 and IFN was identified. The decreasing of spontaneous and induced production of IL-18 was detected too. These occurrences indicate to simultaneous activation of Th1, Th2 and Th17-population of T-lymphocytes. The analysis of level of cytokines in blood serum established only decreasing of level of IL-4 in patients with chronic autoimmune nettle rash as compared with healthy individuals. The level of other analyzed cytokines had no reliable differences that demonstrate both low informativeness of detection ofcontent of cytokines in blood serum and advantage of application of method ex vivo with detection of level of cytokines in whole blood.

Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer.

BACKGROUND: Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival. METHODS: 55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected. RESULTS: 43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did. CONCLUSIONS: Absence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses.

Clinical characteristics of children with positive anti-SSA/SSB antibodies.

This study aimed to characterize the manifestations of clinical symptoms and signs, primary rheumatic diseases, and other autoantibodies in pediatric patients with positive anti-SSA and/or anti-SSB antibodies. Subjects under age 18 with positive anti-SSA and/or anti-SSB antibodies were screened and enrolled in a tertiary hospital in Taiwan. Data were collected via medical records,including age, gender, onset of the primary rheumatic disease, clinical symptoms and signs, and the medication used. Schirmer test for Sjögren's syndrome (SS) screening was performed in all enrolled patients. Among twenty enrolled subjects, seventeen of them had systemic lupus erythematosus; four of them were diagnosed as SS with positive Schirmer test. In addition to antinuclear antibodies and anti-DNA antibodies, other common autoantibodies were anti-RNP antibodies (50 %) and anti-Sm antibodies(30 %). The most common symptoms were arthritis (60 %)followed by malar rash (40 %). In conclusion, we observed that a low proportion of childhood SS (4/20) exists in our patients with positive SSA and/or anti-SSB antibodies. It is suggested that clinicians should focus more on the clinical symptoms in these patients, rather than undertaking invasive diagnostic interventions to rule out Sjögren's syndrome.

Association of creatine kinase and skin toxicity in phase I trials of anticancer agents.

BACKGROUND: We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials. METHODS: We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents. RESULTS: Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 U l(-1)) compared with G1 (median 81 U l(-1)) and no rash (median 55 U l(-1)) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK. CONCLUSION: Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials.

Extremely high serum ferritin levels as a main diagnostic tool of adult-onset Still's disease.

Adult-onset Still's disease is a rare systemic inflammatory disease of unknown aetiology characterised by typical symptoms including daily high spiking fever, evanescent salmon-pink rash, sore throat, arthritis/arthralgias and polyserositis. The laboratory findings usually show neutrophilic leucocytosis, seronegativity and raised serum transaminases. We describe six typical cases. All of them had serum ferritin above 5,000 µg/L. Although there are few theories about the origin of the high ferritin level, an extremely high serum ferritin above 5,000 µg/L should be the main diagnostic tool of adult-onset Still's disease.

Serum Interleukin-18 Provides a Clue to the Diagnosis of Adult-Onset Still's Disease: Findings from 6 Japanese Patients with Adult-Onset Still's Disease.

BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder accompanied by skin eruption. However, typical skin eruptions, such as evanescent, salmon-pink erythema, are not specific to AOSD and dermatologists often face difficulty in diagnosing AOSD. In this study, we examined serum IL-18 levels as well as IL-6, ferritin and C-reactive protein in 6 Japanese patients with AOSD. METHODS: Serum levels of IL-6 and IL-18 were evaluated in the acute phase and at the time of remission. Serum levels of IL-6 were analyzed using a commercial chemiluminescent enzyme immunoassay (CLEIA; SRL, Tokyo, Japan). Serum IL-18 levels were measured using a commercial ELISA kit (Medical & Biological Laboratories Co., LTD. Nagoya, Japan). RESULT: In active AOSD, serum ferritin levels and CRP levels were above normal range in 6 patients. In remission, serum ferritin levels of 3 patients were slightly above the normal range, while CRP serum levels of 6 patients were all normalized. Serum IL-18 levels were markedly elevated in 5 cases during the acute phase. In remission, serum IL-18 levels remained at higher values than the normal range in 5 cases. Serum IL-6 levels were also highly elevated in 5 patients in active AOSD and became normalized in remission except in case 2. CONCLUSION: High levels of serum IL-18 will be a clue to the diagnosis of AOSD. CRP is also useful biomarker for monitoring disease activity compared with IL-6 and IL-18.

C-reactive protein and complement components but not other acute-phase reactants discriminate between clinical subsets and organ damage in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by tissue injury mediated by inflammatory mechanisms. Nonetheless, several acute-phase proteins may remain normal or are decreased. We explore the association of diverse biomarkers with selected clinical features, disease activity, and organ damage in SLE. METHODS: One hundred and fifteen SLE patients were analyzed for clinical manifestations, disease activity, and organ damage. Serum C-reactive protein (CRP), complement C3, C4 and CH50%, alpha-1-antitrypsin (AAT), transferrin (Tf), procalcitonin, erythrosedimentation rate (ESR), and interleukin-6 were measured in patients and twenty-six healthy blood donors. Statistics include chi-square, Kruskal-Wallis (post hoc by Mann-Whitney) or one-way ANOVA tests (post hoc by t tests) as appropriate. Associations were evaluated by the Spearman's correlation coefficient (p). RESULTS: SLE patients have lower C3 (85 vs. 110 mg/dL; p < 0.0001) and C4 (14.2 vs. 24.2 mg/dL; p < 0.0001) than controls, while CRP (4.1 vs. 1.4 mg/L; p = 0.005) and AAT (147 vs. 138 mg/dL; p = 0.03) were higher, other biomarkers were irrelevant. Disease activity score positively correlated with ESR (p = 0.23, 95 % CI 0.04 to 0.4; p = 0.01) and CRP (p = 0.19, 0.0007 to 0.36; p = 0.04), while inverse correlations with C3 (p = -0.26, -0.43 to -0.08; p = 0.004), C4 (p = -0.18, -0.36 to 0.005; p = 0.04), CH50 % (p = -0.20, -0.38 to -0.01; p = 0.02), and Tf (p = -0.35, -0.53 to -0.12; p = 0.002) were found. According to clinical manifestations, patients with arthritis showed higher levels of ESR (34 vs. 20 mm/h), CRP (10 vs. 2.8 mg/L), and AAT (179 vs. 145 mg/dL), but lower Tf (192 vs. 226 mg/dL) than those without arthritis; whereas active nephritis was characterized by lower serum concentrations of complement C3 (73 vs. 92 mg/dL), C4 (10 vs. 15 mg/dL), CH50% (80 vs. 160 U/mL) and Tf (196 vs. 232 mg/dL) than those patients without this manifestation. No other significant differences were found. CONCLUSIONS: In patients with SLE, acute-phase proteins behave differently depending on the kind of organ damage evaluated. Serum complement proteins remained as the most reliable laboratory markers for nephritis, while CRP was determined the best in patients with arthritis. The muted CRP response seen in SLE patients with active nephritis could have important pathogenic implications.