Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Talaromyces sayulitensis, Acidiella bohemica and Penicillium citrinum in Brazilian oil shale by-products.

Fine shale particles and retorted shale are waste products generated during the oil shale retorting process. These by-products are small fragments of mined shale rock, are high in silicon and also contain organic matter, micronutrients, hydrocarbons and other elements. The aims of this study were to isolate and to evaluate fungal diversity present in fine shale particles and retorted shale samples collected at the Schist Industrialization Business Unit (Six)-Petrobras in São Mateus do Sul, State of Paraná, Brazil. Combining morphology and internal transcribed spacer (ITS) sequence, a total of seven fungal genera were identified, including Acidiella, Aspergillus, Cladosporium, Ochroconis, Penicillium, Talaromyces and Trichoderma. Acidiella was the most predominant genus found in the samples of fine shale particles, which are a highly acidic substrate (pH 2.4-3.6), while Talaromyces was the main genus in retorted shale (pH 5.20-6.20). Talaromyces sayulitensis was the species most frequently found in retorted shale, and Acidiella bohemica in fine shale particles. The presence of T. sayulitensis, T. diversus and T. stolli in oil shale is described herein for the first time. In conclusion, we have described for the first time a snapshot of the diversity of filamentous fungi colonizing solid oil shale by-products from the Irati Formation in Brazil.

1,3-Azoles from ortho-naphthoquinones: synthesis of aryl substituted imidazoles and oxazoles and their potent activity against Mycobacterium tuberculosis.

Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 µg/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes.

Specific microbicides in the prevention of HIV infection.

Microbicides are products that are designed for application at vaginal or rectal mucosae to inhibit or block early events in HIV infection and thereby prevent transmission of HIV. Currently, the most advanced microbicides in the development pipeline are based on highly active anti-retroviral drugs (ARVs). Significant protection of women by vaginally applied tenofovir gel, demonstrated in the CAPRISA 004 trial, has provided proof-of-concept that microbicides can be effective. The rationale for investigating ARVs and other compounds as vaginal or rectal microbicides is discussed together with approaches to improve efficacy by the development of combination microbicides and by new formulations that may increase user acceptance.

Re-irradiation with concurrent chemotherapy in recurrent head and neck cancer: a decision analysis model based on a systematic review.

OBJECTIVES: Local recurrence is the major cause of treatment failure in head and neck cancer patients after radiation or combined therapy. If surgically unresectable, management involves supportive care or chemotherapy with palliative intent. Recent studies have assessed the role of re-irradiating these patients with concurrent chemotherapy (CTReRT) and have reported improved local control. The aim of this study was to perform a decision analysis model comparing quality adjusted life years (QALYs) between patients undergoing CTReRT and best supportive care for radio-recurrent head and neck squamous cancer. DESIGN: Outcome data from recent reviews on the topic were used. A decision analysis model was generated. An expert panel arrived at a consensus to assign utility values for the various health state outcomes when CTReRT is administered for recurrent cancer, or in the setting of palliative care for these patients. MAIN OUTCOME MEASURES: Quality adjusted life years from the decision analysis model. RESULTS: Patients who do not suffer a severe complication following CTReRT were assigned by the expert panel to have a utility value of 0.7, and those who suffered one, a utility value of 0.6. A value of 1.0 equates to perfect health and 0 to death. The utility value assigned in the setting of good palliation was 0.8, with 0.6 given when symptom control was less than optimal. The model showed superior QALYs for the CTReRT arm of approximately 5 weeks (20 weeks versus 15 weeks for palliation). CONCLUSIONS: Re-irradiation with concurrent chemotherapy is a modality to be considered in select patients with recurrent head and neck cancer. These results should help to better inform both patients and clinicians when considering this treatment.

Naphthoquinone Derivatives as Scaffold to Develop New Drugs for Tuberculosis Treatment.

Despite being a curable disease, tuberculosis (TB) remains a public health problem worldwide mainly due to lengthy treatment, as well as its toxic effects, TB/HIV co-infection and the emergence of resistant Mycobacterium tuberculosis strains. These barriers reinforcing the need for development of new antimicrobial agents, that ideally should reduce the time of treatment and be active against susceptible and resistant strains. Quinones are compounds found in natural sources and among them, the naphthoquinones show antifungal, antiparasitic, and antimycobacterial activity. Thus, we evaluated the potential antimycobacterial activity of six 1,4-naphthoquinones derivatives. We determined the minimum inhibitory concentration (MIC) of the compounds against three M. tuberculosis strains: a pan-susceptible H37Rv (ATCC 27294); one mono-resistant to isoniazid (ATCC 35822); and one mono-resistant to rifampicin (ATCC 35838); the cytotoxicity in the J774A.1 (ATCC TIB-67) macrophage lineage; performed in silico analysis about absorption, distribution, metabolism, and excretion (ADME) and docking sites. All evaluated naphthoquinones were active against the three strains with MIC between 206.6 and 12.5 µM, and the compounds with lower MIC values have also showed low cytotoxicity. Moreover, two naphthoquinones derivatives 5 and 6 probably do not exhibit cross resistance with isoniazid and rifampicin, respectively, and regarding ADME analysis, no compound violated the Lipinski's rule-of-five. Considering the set of findings in this study, we conclude that these naphthoquinones could be promising scaffolds to develop new therapeutic strategies to TB.

A synthetic peptide adhesion epitope as a novel antimicrobial agent.

The earliest step in microbial infection is adherence by specific microbial adhesins to the mucosa of the oro-intestinal, nasorespiratory, or genitourinary tract. We inhibited binding of a cell surface adhesin of Streptococcus mutans to salivary receptors in vitro, as measured by surface plasmon resonance, using a synthetic peptide (p1025) corresponding to residues 1025-1044 of the adhesin. Two residues within p1025 that contribute to binding (Q1025, E1037) were identified by site-directed mutagenesis. In an in vivo human streptococcal adhesion model, direct application of p1025 to the teeth prevented recolonization of S. mutans but not Actinomyces, as compared with a control peptide or saline. This novel antimicrobial strategy, applying competitive peptide inhibitors of adhesion, may be used against other microorganisms in which adhesins mediate colonization of mucosal surfaces.

Comorbidity in nasopharyngeal carcinoma: a preliminary communication on the prevalence, descriptive distribution and impact on outcome.

OBJECTIVES: Comorbidity has been shown to be a determinant in treatment selection and survival in squamous cell cancer of the head and neck at various subsites. The objective of this study is to analyse the effect of comorbidity burden on outcome of nasopharyngeal cancer using the Adult Comorbidity Evaluation-27 (ACE-27) instrument. DESIGN: Retrospective analysis. SETTING: Tertiary care centres. PARTICIPANTS: This study included 59 patients diagnosed with nasopharyngeal carcinoma between 1989-2003 in the North-East of England. Exclusion criteria included non-squamous neoplasms of the nasopharynx. Comorbidity was assessed retrospectively from the notes using standard validated techniques described earlier. Tumour, treatment and survival data were obtained from prospective databases. Data was analysed using SPSS for Windows. MAIN OUTCOME MEASURES: Comorbidity and outcome of treatment. RESULTS: Comorbid burden was evident in 44% of patients, with moderate or severe comorbidity in 19%. The cardiovascular system was the most commonly affected system (27%). Cox's proportional hazard model showed age and stage of tumour to have an impact on disease specific survival. Comorbidity was not seen to predict the outcome independent of other factors. The sample size of this study is powered to detect only medium to large effects. We estimate that 614 subjects will be needed to detect a correlation coefficient of 0.1 with 80% power, assuming a type 1 error rate of 5%. CONCLUSION: This study shows for the first time that the comorbidity burden seen in nasopharyngeal cancer does not affect prognosis independent of the TNM staging.

Profile of differentially expressed Toll-like receptor signaling genes in the natural killer cells of patients with Sézary syndrome.

Sézary syndrome (SS), an aggressive and leukemic form of cutaneous T-cell lymphoma, usually results in shortened survival. Improving innate immunity in SS by targeting natural killer (NK) cells with Toll-like receptor (TLR) agonists could be an interesting modulatory strategy. We evaluated the NK cell populations in SS patients assessing activating and inhibitory receptors expression and profiled the differential expression of TLR signaling pathway genes in unstimulated NK cells and after TLR7/8 stimulation. We observed preserved CD56bright NK cells and a low percentage of CD56dim NK cells in the peripheral blood of SS patients compared to those in the healthy control group. Both NK cell populations showed down-modulation of NKG2C and NKG2D expression, which was associated with high serum levels of the soluble form of NKG2D ligands. In contrast, an expansion of "memory" CD57+ NKG2C+ NK cells and high cytomegalovirus antibody titers were detected in SS patients. Profiling of the TLR signaling genes in NK cells from SS patients showed an abundance of differentially expressed genes (DEGs) in NK cells in the unstimulated condition, with mostly up-regulation of NFκB/JNK p38 pathway genes, but there was down-regulation of type I (IFN-α/ß) and II (IFN-γ) interferon and IL-12A. After activation of NK cells with TLR7/8 agonist, the down-regulated genes correlated with the IFN response, and IL-12 became up-regulated, together with other antitumor factors. NK cell activation with a dual agonist for TLR7 and TLR8 is able to induce the expression of IFN-γ and type I IFN, which can improve immunity in SS patients.

Chemotherapy: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper summarises the role of chemotherapy in head and neck cancer management, recent advances and what the future holds for this modality.

Antiviral factors and type I/III interferon expression associated with regulatory factors in the oral epithelial cells from HIV-1-serodiscordant couples.

Individuals who remain HIV-seronegative despite repeated unprotected exposure to the virus are defined as exposed seronegative (ESN) individuals. Innate and adaptive immunity, as well as genetic factors, provide ESNs with important advantages that allow for low infection susceptibility. The majority of HIV-1-infected individuals undergo antiretroviral therapy, which can decrease the level of HIV-1 exposure in ESNs. We analyzed type I interferon (IFN)-related antiviral and regulatory factors in peripheral blood mononuclear cells (PBMCs) and oral epithelial cells from serodiscordant couples. Our findings revealed that ESNs did not induce the expression of antiviral factors (APOBEC-3G, TRIM5-α, SAMDH1, STING, TBk1) or regulatory factors (Trex, Foxo3, Socs3, IL-10) in PBMCs, unlike their HIV-1-infected partners. In contrast, ESNs upregulated APOBEC-3G and type I/III IFNs (IFNs-α,-ß/-λ) in oral mucosal epithelial cells similar to their HIV-infected partners. The serodiscordant groups exhibited an increased expression of type I IFN-induced regulators, such as Trex and Foxo3, in oral epithelial cells. TLR7, TLR8 and TLR9 were expressed in oral epithelial cells of both ESNs and HIV-1-infected subjects. These findings revealed evidence of antiviral factors, type I/III interferon and regulatory factor expression only in the oral mucosal compartment of ESNs, while HIV-1-infected partners systemically and oral mucosal expressed the antiviral profile.

Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sézary syndrome.

Sézary syndrome (SS) carries a poor prognosis, and infections represent the most frequent cause of death in SS patients. Toll-like receptors (TLRs) are a family of innate immune receptors that induce protective immune responses against infections. We sought to evaluate the ability of TLR agonists to induce inflammatory cytokine, Th2 cytokine, and type I interferon (IFN-I) production by peripheral blood mononuclear cells (PBMC) of untreated SS patients. We detected impaired IL-6, IL-10 and IL-13 secretion by PBMC induced by the agonists for TLR5, TLR3, TLR7 and TLR9 in SS patients, while it was partially recovered by TLR2/TLR4 and TLR7/8 agonists TNF secretion was restored following stimulation with TLR2/TLR4 agonists. IFN-γ was scarcely produced upon TLR activation in SS cells, albeit TLR 7/8 (CL097) enhanced their secretion at lower levels than the control group. TLR9 agonist efficiently induced IFN-I in SS patients, although this positive regulation was not observed for other cytokines, in direct contrast to the broad activity of CL097. Among the TLR agonists, TLR4 was able to induce pro-inflammatory, IL-10 and Th2 secretion, while TLR7-8 agonist induced the inflammatory cytokines, IFN-I and IFN-γ. These findings reveal a dysfunctional cytokine response upon both extracellular and intracellular TLR activation in SS patients, which was partially restored by TLRs agonists.

Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules.

AIMS: To determine whether palliation of chest symptoms from a 10 Gy single fraction (regimen 1) was equivalent to that from 30 Gy in 10 fractions (regimen 2). MATERIALS AND METHODS: Patients with cytologically proven, symptomatic lung cancer not amenable to curative therapy, with performance status 0-3, were randomised to receive either 30 Gy in 10 fractions or a 10 Gy single fraction. Local symptoms were scored on a physician-assessed, five-point categorical scale and summed to produce a total symptom score (TSS). This, performance status, Hospital Anxiety and Depression (HAD) score and Spitzer's quality-of-life index were noted before treatment, at 1 month after treatment and every 2 months thereafter. Palliation was defined as an improvement of one point or more in the categorical scale. Equivalence was defined as less than 20% difference in the number achieving an improvement in the TSS. RESULTS: We randomised 149 patients and analysed 74 in each arm. According to the design criteria, palliation was equivalent between the two arms. TSS improved in 49 patients (77%) on regimen 1, and in 57 (92%) patients on regimen 2, a difference of 15% (95% confidence interval [CI] 3-28) in the proportion improving between the two regimens. A complete resolution of all symptoms was achieved in three (5%) on regimen 1, and in 14 (23%) patients on regimen 2 (P < 0.001), a difference in the proportion between the two regimens of 21% (95% CI 10-33). A significantly higher proportion of patients experienced palliation and complete resolution of chest pain and dyspnoea with regimen 2. No differences were observed in toxicity. The median survival was 22.7 weeks for regimen 1 and 28.3 weeks for regimen 2 (P = 0.197). CONCLUSIONS: Although this trial met the pre-determined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnoea with the fractionated regimen.

The expression of Fc receptors for immunoglobulin G in human rectal epithelium.

The rectal mucosa is one of the routes of transmission of the HIV virus, although the mechanism of transmission is unknown. We carried out an immunohistological investigation of human rectal epithelium to detect CD4 glycoprotein and Fc receptors (FcR) for immunoglobulin G which may be involved in HIV infection. CD4 was not detected by monoclonal antibodies (MAb) in normal rectal epithelial cells, although CD4+ mononuclear cells were found in the lamina propria of the rectum. FcR3 and FcR2 were, however, detected in surface or crypt epithelial cells of rectal mucosa, using MAb to CD16 and CD32, respectively. In addition, CD16 messenger RNA (mRNA) was found in surface and crypt epithelial cells by in situ hybridization using an RNA probe. FcR3 and FcR2 were also detected in fetal recto-colonic tissue by immunohistology, suggesting that these are constitutive receptors. FcR3 and FcR2 gene transcripts were then demonstrated in fetal recto-colonic tissue using the polymerase chain reaction to amplify a portion of FcR3 and FcR2 coding sequences in complementary DNA (cDNA) prepared from fetal RNA. These findings suggest the possibility that rectal transmission of HIV-antibody complexes might be facilitated by the expression of FcR3 and FcR2 in rectal epithelial cells.

Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules.

BACKGROUND: The optimum dose and fractionation schedule for the palliative irradiation of painful bone metastases is controversial. PURPOSE: To compare the efficacy, side-effects and effect on quality of life of two commonly used radiotherapy schedules in the management of painful bone metastases. MATERIALS AND METHODS: In a prospective trial, 280 patients were randomised to receive either a single 10 Gy treatment or a course of 22.5 Gy in five daily fractions for the relief of localised metastatic bone pain. RESULTS: Response rates have been calculated from 240 assessable treated sites of pain. The overall response rates were 83.7% (single treatment) and 89.2% (five fractions). The complete response rates were 38.8% (single treatment) and 42.3% (five fractions). The median duration of pain control was 13.5 weeks (single treatment) and 14.0 weeks (five fractions). None of these differences was statistically significant. There were no differences between the groups in the effect of treatment on a variety of quality of life parameters. CONCLUSIONS: It is concluded that a single 10 Gy treatment is as effective as a course of 22.5 Gy in five fractions in the management of painful bone metastases.

Anti-adhesive strategies in the prevention of infectious disease at mucosal surfaces.

Binding of microbial cell surface adhesins to host receptor molecules is a critical early step in microbial infection and pathogenesis. Anti-adhesive strategies aimed at blocking this interaction offer an attractive means of preventing infection at an early stage. The strategy should reduce the likelihood of resistant strains of microorganisms emerging, since those that do not bind will not be subjected to sustained selective pressure, as may occur with antibiotic therapy. Three classes of adhesion-blocking agent have been investigated, namely anti-adhesin antibodies, adhesin analogues and receptor analogues. The effectiveness of a number of these adhesion-blocking compounds has been demonstrated in human and animal models of infection. Direct application to the tooth surface of anti-adhesin monoclonal antibody, or a synthetic peptide adhesion epitope, prevented infection with the oral pathogen, Streptococcus mutans in humans. Intranasal administration of a soluble receptor analogue significantly reduced virus production and symptoms following experimental infection with rhinovirus. Similarly, all three types of anti-adhesion agent protected against a variety of infections at other mucosal surfaces in animal models. A common finding from these studies is the long duration of protection, which cannot be due to persistence of the anti-adhesion agent, but may be the result of competitive exclusion by members of the normal flora at specific mucosal surfaces. Development of these novel antimicrobial agents is particularly timely in view of the increasing concern over the spread of antibiotic resistance.

Dissociation of antibody responses during human schistosomiasis and evidence for enhancement of granuloma size by anti-carbohydrate IgM.

Immunoglobulin (Ig) G and IgM antibody levels to soluble egg antigens (SEA), adult worm glycoproteins (AWGP), carbohydrate antigens (CHO) and cationic exchange fraction 6 (CEF6) were measured in serum specimens taken from Brazilian patients with acute, intestinal, hepato-intestinal and hepatosplenic schistosomiasis mansoni. The antibody levels varied among the groups, with the highest anti-egg antigen responses in the acute patients and the highest anti-adult worm responses in patients with chronic disease. The responses to the component parts of the egg antigens were dissociated, with anti-carbohydrate IgG and IgM responses being highest in the acute infection group and anti-CEF6 IgG responses being uniform among the clinical groups. The possibility of a direct role for anti-CHO antibody responses in egg-induced pathology was investigated using the mouse lung model. The anti-carbohydrate monoclonal antibody NIMP/M45 significantly enhanced granuloma formation. Mice given NIMP/M45 produced granulomas larger than those of naive mice or mice given an unrelated monoclonal antibody, and as large as those produced by mice which had been presensitized to egg antigens. The independent regulation of responses to egg antigens may indicate that such responses are minimized to reduce the pathological consequences of infection whilst allowing the development of protective anti-worm responses.