Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer : A low cost effective regimen

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m−2 i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m−2 i.v. followed by 5-fluorouracil 400 mg m−2 i.v. bolus and 600 mg m−2 i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m−2 i.v. bolus on day 2, every 6 weeks. Grades 3–4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1–61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials

Justified Concern or Exaggerated Fear: The Risk of Anaphylaxis in Percutaneous Treatment of Cystic Echinococcosis—A Systematic Literature Review

Percutaneous treatment (PT) emerged in the mid-1980s as an alternative to surgery for selected cases of abdominal cystic echinococcosis (CE). Despite its efficacy and widespread use, the puncture of echinococcal cysts is still far from being universally accepted. One of the main reasons for this reluctance is the perceived risk of anaphylaxis linked to PTs. To quantify the risk of anaphylactic reactions and lethal anaphylaxis with PT, we systematically searched MEDLINE for publications on PT of CE and reviewed the PT-related complications. After including 124 publications published between 1980 and 2010, we collected a total number of 5943 PT procedures on 5517 hepatic and non-hepatic echinococcal cysts. Overall, two cases of lethal anaphylaxis and 99 reversible anaphylactic reactions were reported. Lethal anaphylaxis occurred in 0.03% of PT procedures, corresponding to 0.04% of treated cysts, while reversible allergic reactions complicated 1.7% of PTs, corresponding to 1.8% of treated echinococcal cysts. Analysis of the literature shows that lethal anaphylaxis related to percutaneous treatment of CE is an extremely rare event and is observed no more frequently than drug-related anaphylactic side effects

Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder

Children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD) experience functional impairment and poor health-related quality of life (HRQoL) in addition to symptoms of inattention/hyperactivity-impulsivity. To synthesize qualitatively the published evidence from randomized, double-blind, placebo-controlled trials of the effectiveness of pharmacotherapy on functional impairment or HRQoL in patients with ADHD, a systematic PubMed searching and screening strategy was designed to identify journal articles meeting pre-specified criteria. Post hoc analyses and meta-analyses were excluded. HRQoL outcomes, functional outcomes and the principal ADHD symptom-based outcome were extracted from included studies. An effect size of 0.5 versus placebo was used as a threshold for potential clinical relevance (unreported effect sizes were calculated when possible). Of 291 records screened, 35 articles describing 34 studies were included. HRQoL/functioning was usually self-rated in adults and proxy-rated in children/adolescents. Baseline data indicated substantial HRQoL deficits in children/adolescents. Placebo-adjusted effects of medication on ADHD symptoms, HRQoL and functioning, respectively, were statistically or nominally significant in 18/18, 10/12 and 7/9 studies in children/adolescents and 14/16, 9/11 and 9/10 studies in adults. Effect sizes were ≥0.5 versus placebo for symptoms, HRQoL and functioning, respectively, in 14/16, 7/9 and 4/8 studies in children/adolescents; and 6/12, 1/6 and 1/8 studies in adults. Effect sizes were typically larger for stimulants than for non-stimulants, for symptoms than for HRQoL/functioning, and for children/adolescents than for adults. The efficacy of ADHD medication extends beyond symptom control and may help reduce the related but distinct functional impairments and HRQoL deficits in patients with ADHD

Potentially threatened: a Data Deficient flag for conservation management

Data Deficient species (DD) comprise a significant portion of the total number of species listed within the IUCN Red List. Although they are not classified within one of the threat categories, they may still face high extinction risks. However, due to limited data available to infer their extinction risk reliably, it is unlikely that the assessment of the true status of Data Deficient species would be possible before many species decline to extinction. An appropriate measure to resolve these problems would be to introduce a flag of potentially threatened species within the Data Deficient category [i.e., DD(PT)]. Such a flag would represent a temporary Red List status for listed Data Deficient species that are, based on the available direct evidence and/or indirect indices, likely to be assigned to one of the threat categories, but where current data remains insufficient for a complete classification. The use of such a flag could increase the focus of the scientific community and conservation decision-makers on such species, thus avoiding the risk that necessary conservation measures are implemented too late. As such, establishment of the DD(PT) category as a kind of alarm for priority species could be beneficial

Role of novel targeted therapies in the clinic

The number and variety of novel, molecular-targeted agents offers realistic hope for significant advances in cancer treatment. The potential of these new treatment approaches is unquestionable, but the reality is something that only thorough clinical evaluation and experience can reveal. Clinical experience of targeted therapies is at an early stage but it is likely that we will have an increasing number of treatment options available to us in the near future. This manuscript explores our current understanding of molecular-targeted therapies and considers: What approach should be used? (single vs multitarget agents); When should they be administered? (identifying the optimal point for intervention); How should they be used? (monotherapy or combination therapy regimens); and Who should we be giving them to? (acknowledging the need for patient selection)

A phase II study of paclitaxel and capecitabine as a first-line combination chemotherapy for advanced gastric cancer

Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, have each shown high activity as single agents in gastric cancer. Synergistic interaction between these two drugs was suggested by taxane-induced upregulation of thymidine phosphorylase. We, therefore, evaluated the antitumour activity and toxicities of paclitaxel and capecitabine as first-line therapy in patients with advanced gastric cancer (AGC). Patients with histologically confirmed unresectable or metastatic AGC were treated with capecitabine 825 mg m−2 p.o. twice daily on days 1–14 and paclitaxel 175 mg m−2 i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicities. Between June 2002 and May 2004, 45 patients, of median age 57 years (range=38–73 years), were treated with the combination of capecitabine and paclitaxel. After a median 6 cycles (range=1–9 cycles) of chemotherapy, 43 were evaluable for toxicity and response. A total of 2 patients showed complete response and 20 showed partial response making the overall response rate 48.9% (95% CI=30.3–63.5%). After a median follow-up of 42.2 months (range=31.2–54.3 months), median time to progression was 5.6 months (95% CI=3.9–7.2 months) and median overall survival was 11.3 months (95% CI=8.1–14.4 months). Grade 3 or 4 adverse events include neutropaenia (46.5% of patients), hand–foot syndrome (9.3%), arthralgia (9.3%), and asthenia (4.7%). There was no neutropaenic fever or treatment-related deaths. Paclitaxel and capecitabine combination chemotherapy was active and highly tolerable as a first-line therapy for AGC

Sporangiospore Size Dimorphism Is Linked to Virulence of Mucor circinelloides

Mucor circinelloides is a zygomycete fungus and an emerging opportunistic pathogen in immunocompromised patients, especially transplant recipients and in some cases otherwise healthy individuals. We have discovered a novel example of size dimorphism linked to virulence. M. circinelloides is a heterothallic fungus: (+) sex allele encodes SexP and (−) sex allele SexM, both of which are HMG domain protein sex determinants. M. circinelloides f. lusitanicus (Mcl) (−) mating type isolates produce larger asexual sporangiospores that are more virulent in the wax moth host compared to (+) isolates that produce smaller less virulent sporangiospores. The larger sporangiospores germinate inside and lyse macrophages, whereas the smaller sporangiospores do not. sexMΔ mutants are sterile and still produce larger virulent sporangiospores, suggesting that either the sex locus is not involved in virulence/spore size or the sexP allele plays an inhibitory role. Phylogenetic analysis supports that at least three extant subspecies populate the M. circinelloides complex in nature: Mcl, M. circinelloides f. griseocyanus, and M. circinelloides f. circinelloides (Mcc). Mcc was found to be more prevalent among clinical Mucor isolates, and more virulent than Mcl in a diabetic murine model in contrast to the wax moth host. The M. circinelloides sex locus encodes an HMG domain protein (SexP for plus and SexM for minus mating types) flanked by genes encoding triose phosphate transporter (TPT) and RNA helicase homologs. The borders of the sex locus between the three subspecies differ: the Mcg sex locus includes the promoters of both the TPT and the RNA helicase genes, whereas the Mcl and Mcc sex locus includes only the TPT gene promoter. Mating between subspecies was restricted compared to mating within subspecies. These findings demonstrate that spore size dimorphism is linked to virulence of M. circinelloides species and that plasticity of the sex locus and adaptations in pathogenicity have occurred during speciation of the M. circinelloides complex