Immunomodulatory treatment for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma)

The pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma has been characterized as a dynamic process driven by lymphoma cell dependency on T-cell signaling, chronic antigenic stimulation of marginal zone B-cells and activation of the nuclear factor-kappa B signaling pathway. This concept is underlined by the strong causal connection of chronic Helicobacter pylori associated gastritis and MALT lymphoma development based on perpetual auto-antigenic stimulation of Helicobacter pylori-specific T-cells, but also its association with further potential infectious triggers and autoimmune disorders for extragastric lymphoma sites. Thus, given the dependency of MALT lymphoma cells on the tumor microenvironment, this specific entity appears highly suitable for immunomodulatory treatment strategies. Several approaches have been assessed in the last years including promising data on immunomodulatory agents “IMiDs” thalidomide and lenalidomide, macrolide antibiotics and antibodies. The aim of the present review is to discuss rationales for immunomodulatory therapies in MALT lymphoma and to present the statu quo on immunomodulatory and therefore chemotherapy-free treatment strategies for these patients.     

C-9 Alkenylidine bridged macrolides: WO2008061189

Ketolides, which represent the third generation of erythromycin A derivatives, were developed as a result of the need for new and potent antibacterial agents. This class of compounds has a significantly improved pharmacokinetic profile and, above all, shows activity against macrolide-resistant strains. When compared with other macrolides, ketolide structural differences are characterized by the removal of the 3-O-cladinose moiety and by a heteroaryl-alkyl side chain attached to the macrocycle by a flexible linker. The bridged bicyclic ketolides (BBK) are one of the three classes of ketolide; the present application from Enanta Pharmaceuticals, Inc. discloses a series of novel C-9 alkenylidine bridged macrolides belonging to BBK. These compounds are 3,6- and 6,11-bicyclolides, which have the alkenylidine second anchor portion attached to C-9 of the molecule.     

Otitis media

Bacterial pathogens are isolated from middle ear fluid in up to 90% of children with acute otitis media (OM). Streptococcus pnuemoniae, Haemophilus influenzae and Moraxella catarrhalis predominate. Acute OM can be classified as uncomplicated, persistent, recurrent or chronic. Patient age, symptom severity, prior treatment history and exposure through day-care attendance in children influences pathogen distribution, antimicrobial susceptibility and anticipated clinical and microbiological responses to empirical and pathogen-directed therapies. The natural history of acute OM without intervention is favourable. However, meta-analysis of clinical trials shows an improvement in symptom and middle ear effusion resolution with antimicrobials. Aminopenicillins, cephalosporins and macrolides are often selected as therapy for acute OM. The various agents have differing activity against acute OM pathogens, particularly organisms with resistance mechanisms and they differ in dosing schedule, side effects and compliance enhancing factors. Consideration should be given to pharmacokinetic and pharmacodynamic principles in antibiotic selection. Selection criteria include antibiotic activity against drug-resistant S. pneumoniae and efficacy against β-lactamase-producing Gram-negative organisms. The necessary duration of treatment for acute OM varies according to multiple factors, including local preferences, but there is growing, compelling data to support short-course therapy. Tympanocentesis has been endorsed in various guidelines as a diagnostic and therapeutic procedure. Best-practice for management of acute OM continues to advocate antibiotic therapy with careful, accurate diagnosis and consideration of the major pathogens and their mechanisms of resistance.     

Treatment of Tularemia in Pregnant Woman,France

A pregnant woman who had oropharyngeal tularemia underwent treatment with azithromycin and lymph node resection and recovered without obstetrical complication or infection in the child. Azithromycin represents a first-line treatment option for tularemia during pregnancy in regions where the infecting strains of Francisella tularensis have no natural resistance to macrolides.     

Azithromycin Enhances Phagocytic Killing of Aggregatibacter actinomycetemcomitans Y4 by Human Neutrophils

Background: Aggregatibacter actinomycetemcomitans resists killing by neutrophils and is inhibited by azithromycin (AZM) and amoxicillin (AMX). AZM actively concentrates inside host cells, whereas AMX enters by diffusion. The present study is conducted to determine whether AZM is more effective than AMX at enhancing phagocytic killing of A. actinomycetemcomitans by neutrophils. Methods: Killing assays were conducted in the presence of either 2 μg/mL AZM or 16 μg/mL AMX (equipotent against A. actinomycetemcomitans). Neutrophils were loaded by incubation with the appropriate antibiotic. Opsonized A. actinomycetemcomitans strain Y4 was incubated with the indicated antibiotic alone, with loaded neutrophils and antibiotic, or with control neutrophils (without antibiotic) at multiplicities of infection (MOIs) of 30 and 90 bacteria per neutrophil. Results: Neutrophil incubation with 2 μg/mL AZM yielded an intracellular concentration of 10 μg/mL. At an MOI of 30, neutrophils loaded with AZM failed to kill significantly more bacteria than control neutrophils during the 60‐ and 90‐minute assay periods. At an MOI of 90, neutrophils loaded with AZM killed significantly more bacteria than either AZM alone or control neutrophils during 60‐ and 90‐minute incubations (P <0.05), and killed significantly more bacteria after 90 minutes than the sum of the killing produced by AZM alone or neutrophils alone. Neutrophils incubated with AMX under identical conditions also killed significantly more bacteria than either AMX alone or control neutrophils, but there was no evidence of synergism between AMX and neutrophils. Conclusions: Neutrophils possess a concentrative transport system for AZM that may enhance killing of A. actinomycetemcomitans. Its effects are most pronounced when neutrophils are greatly outnumbered by bacteria.     

Multicentre surveillance of prevalence of the 23S rRNA A2058G and A2059G point mutations and molecular subtypes of Treponema pallidum in Taiwan, 2009–2013

Resistance mutations A2058G and A2059G, within the 23S rRNA gene of Treponema pallidum, have been reported to cause treatment failures in patients receiving azithromycin for syphilis. Genotyping of T. pallidum strains sequentially isolated from patients with recurrent syphilis is rarely performed. From September 2009 to August 2013, we collected 658 clinical specimens from 375 patients who presented with syphilis for genotyping to examine the number of 60-bp repeats in the acidic repeat protein (arp) gene, T. pallidum repeat (tpr) polymorphism, and tp0548 gene, and to detect A2058G and A2059G point mutations by restriction fragment length polymorphism. Treponemal DNA was identified in 45.2% (n = 298) of the specimens that were collected from 216 (57.6%) patients; 268 (40.7%) specimens tested positive for the 23S rRNA gene, and were examined for macrolide resistance. Two isolates (0.7%) harboured the A2058G mutation, and no A2059G mutation was identified. A total of 14 strains of T. pallidum were identified, with 14f/f (57.5%) and 14b/c (10.0%) being the two predominant strains. Forty patients who presented with recurrent episodes of syphilis had T. pallidum DNA identified from the initial and subsequent episodes, with five cases showing strain discrepancies. One patient had two strains identified from different clinical specimens collected in the same episode. Our findings show that 14f/f is the most common T. pallidum strain in Taiwan, where the prevalence of T. pallidum strains that show A2058G or A2059G mutation remains low. Different genotypes of T. pallidum can be identified in patients with recurrent episodes of syphilis.     

克拉霉素治疗非嗜酸粒细胞型难治性哮喘的疗效分析

目的探讨克拉霉素对于难治性哮喘患者,特别是对非嗜酸粒细胞型哮喘(NEA)亚组患者的疗效。方法难治性哮喘患者(n=45)被随机分配至克拉霉素组(500 mg bid)和安慰剂组,共8周。结果克拉霉素与安慰剂相比,明显降低了气道IL-8的浓度和中性粒细胞的数目,改善了生活质量评分。另外NE和MMP-9的浓度得到降低,这对于NEA患者最为显著。结论克拉霉素可调节难治性哮喘患者气道内IL-8水平和中性粒细胞的聚集和活性,降低非嗜酸粒细胞性炎症反应,特别是中性粒细胞性炎症反应。     

Changing Pattern of Relapse in Osteosarcoma of the Extremities Treated with Adjuvant and Neoadjuvant Chemotherapy

Abstract

In 551 patients with osteosarcoma of the extremities treated between 1980 and 1991 in our Institution with surgery only (35 cases), surgery combined with adjuvant chemotherapy (147 cases) or neoadjuvant chemotherapy (369 cases) the relapse patterns were analyzed. Adjuvant chemotherapy was performed according to 2 different protocols and neoadjuvant chemotherapy according to 3 different protocols successively activated.

In the 252 patients who relapsed, the interval between initial treatment and first relapse was significantly longer in the group treated with adjuvant and neoadjuvant chemotherapy (18.1 and 21.3 mo) than in the group treated with surgery only (5.4 mo). For patients treated with neoadjuvant chemotherapy, a longer interval was seen in the most effective regimen of neoadjuvant chemotherapy (25 mo). No significant differences were seen among the 3 groups, according to the site of first metastasis, although in patients treated with the most effective neoadjuvant regimen there was a higher incidence of bone metastasis.

In patients who relapsed with pulmonary metastases the average number of nodules seen by standard X-rays, as well as CT scans, was significantly higher in patients treated with surgery only (3.6) than in patients treated with adjuvant or neoadjuvant chemotherapy (2.5 and 2.6 nodules).

We conclude that these changes in metastatic pattern in patients treated with adjuvant and neoadjuvant chemotherapy are important, because they may encourage the use of salvage therapy with thoracotomy in a larger number of patients.

Prolongation of time relapsed after more effective regimens of adjuvant and neoadjuvant chemotherapy should be considered when evaluating the preliminary results of new chemotherapy protocols.