World Antibody Drug Conjugate Summit Europe: February 21–23, 2011; Frankfurt,Germany

The World Antibody Drug Conjugate Summit Europe, organized by Biorbis/Hanson Wade was held in Frankfurt, Germany February 21–23, 2011. Antibody drug conjugates (ADCs), also called immunoconjugates, are becoming an increasingly important class of therapeutics as demonstrated by the attendance of nearly 100 delegates at this highly focused meeting. Updates on three ADCs that are in late-stage clinical development, trastuzumab emtansine (T-DM1), brentuximab vedotin (SGN-35) and inotuzumab ozogamicin (CMC-544), were presented by speakers from ImmunoGen, Genentech, Roche, Seattle Genetics and Pfizer. These ADCs have shown encouraging therapeutic effects against solid tumors (T-DM1) and hematological malignancies (SGN-35, CMC-544). The key feature of the new generation of ADCs is the effective combination of the cytotoxicity of natural or synthetic highly potent antineoplastic agents, tumor selective monoclonal antibodies and blood-stable optimized linkers. Early clinical data for ADCs were showcased by Progenics Pharmaceuticals (PSMA ADC), Celldex (CDX-011) and Biotest (BT-062). Takeda, MedImmune and sanofi-aventis outlined their strategies for process development and analytical characterization. In addition, presentations on duocarmycin based-ADCs, α emitting immunoconjugates and antibody-conjugated nanoparticles were given by representatives from Syntarga, Algeta and the University of Stuttgart, respectively.Key words: antibody drug conjugates, immunoconjugates, trastuzumab emtansine, brentuximab vedotin, inotuzumab ozogamicin, oncology, cancer     

Bronchiectasis-Associated Hospitalizations in Germany, 2005–2011: A Population-Based Study of Disease Burden and Trends

Background

Representative population-based data on the epidemiology of bronchiectasis in Europe are limited. The aim of the present study was to investigate the current burden and the trends of bronchiectasis-associated hospitalizations and associated conditions in Germany in order to inform focused patient care and to facilitate the allocation of healthcare resources.

Methods

The nationwide diagnosis-related groups hospital statistics for the years 2005–2011 were used in order to identify hospitalizations with bronchiectasis as any hospital discharge diagnosis according to the International Classification of Diseases, 10th revision, code J47, (acquired) bronchiectasis. Poisson log-linear regression analysis was used to assess the significance of trends. In addition, the overall length of hospital stay (LOS) and the in-hospital mortality in comparison to the nationwide overall mortality due to bronchiectasis as the primary diagnosis was assessed.

Results

Overall, 61,838 records with bronchiectasis were extracted from more than 125 million hospitalizations. The average annual age-adjusted rate for bronchiectasis as any diagnosis was 9.4 hospitalizations per 100,000 population. Hospitalization rates increased significantly during the study period, with the highest rate of 39.4 hospitalizations per 100,000 population among men aged 75–84 years and the most pronounced average annual increases among females. Besides numerous bronchiectasis-associated conditions, chronic obstructive pulmonary disease (COPD) was most frequently found in up to 39.2% of hospitalizations with bronchiectasis as the primary diagnosis. The mean LOS was comparable to that for COPD. Overall, only 40% of bronchiectasis-associated deaths occurred inside the hospital.

Conclusions

The present study provides evidence of a changing epidemiology and a steadily increasing prevalence of bronchiectasis-associated hospitalizations. Moreover, it confirms the diversity of bronchiectasis-associated conditions and the possible association between bronchiectasis and COPD. As the major burden of disease may be managed out-of-hospital, prospective patient registries are needed to establish the exact prevalence of bronchiectasis according to the specific underlying condition.     

Epidemiology and Management of Cysticercosis and Taenia solium Taeniasis in Europe,Systematic Review 1990–2011

Background

Cysticercosis is caused by the invasion of human or pig tissues by the metacestode larval stage of Taenia solium. In Europe, the disease was endemic in the past but the autochthonous natural life cycle of the parasite is currently completed very rarely. Recently, imported cases have increased in parallel to the increased number of migrations and international travels. The lack of specific surveillance systems for cysticercosis leads to underestimation of the epidemiological and clinical impacts.

Objectives

To review the available data on epidemiology and management of cysticercosis in Europe.

Methods

A review of literature on human cysticercosis and T. solium taeniasis in Europe published between 1990–2011 was conducted.

Results

Out of 846 cysticercosis cases described in the literature, 522 cases were autochthonous and 324 cases were imported. The majority (70.1%) of the autochthonous cases were diagnosed in Portugal from 1983 and 1994. Imported cases of which 242 (74.7%) diagnosed in migrants and 57 (17.6%) in European travellers, showed an increasing trend. Most of imported cases were acquired in Latin America (69.8% of migrants and 44.0% of travellers). The majority of imported cases were diagnosed in Spain (47.5%), France (16.7%) and Italy (8.3%). One third of neurosurgical procedures were performed because the suspected diagnosis was cerebral neoplasm. Sixty eight autochthonous and 5 imported T. solium taeniasis cases were reported.

Conclusions

Cysticercosis remains a challenge for European care providers, since they are often poorly aware of this infection and have little familiarity in managing this disease. Cysticercosis should be included among mandatory reportable diseases, in order to improve the accuracy of epidemiological information. European health care providers might benefit from a transfer of knowledge from colleagues working in endemic areas and the development of shared diagnostic and therapeutic processes would have impact on the quality of the European health systems.Key words: cysticercosis, neurocysticercosis, Taenia solium, taeniasis, Europe, travellers, migrants.     

Radiotherapy facilities,equipment, and staffing in Poland: 2005–2011

Background and purpose

To evaluate the current status of radiotherapy facilities, staffing, and equipment, treatment and patients in Poland for the years 2005–2011 following implementation of the National Cancer Programme.

Methods

A survey was sent to the radiotherapy centres in Poland to collect data on available equipment, staffing, and treatments in the years 2005–2011.

Results

In 2011, 76,000 patients were treated with radiotherapy at 32 centres vs. 63,000 patients at 23 centres in 2005. Number of patients increased by 21%. In 2011, there were 453 radiation oncologists – specialists (1 in 168 patients), 325 medical physicists (1 in 215 patients), and 883 radiotherapy technicians (1 in 86 patients) vs. 320, 188, and 652, respectively, in 2005. The number of linear accelerators increased by 60%, from 70 units in 2005 to 112 in 2011. The current linac/patient ratio in Poland is 1 linac per 678 patients. Waiting times from diagnosis to the start of treatment has decreased.

Conclusion

Compared to 2005, there are more treatment facilities, more and better equipment (linacs), and more cancer care specialists. There are still large differences between the 16 Polish provinces in terms of equipment availability and ease of access to treatment. However, radiotherapy services in Poland have improved dramatically since the year 2005.     

Food Marketing towards Children: Brand Logo Recognition,Food-Related Behavior and BMI among 3–13-Year-Olds in a South Indian Town

Objectives

To assess exposure to marketing of unhealthy food products and its relation to food related behavior and BMI in children aged 3–13, from different socioeconomic backgrounds in a south Indian town.

Methods

Child-parent pairs (n = 306) were recruited at pediatric clinics. Exposure to food marketing was assessed by a digital logo recognition test. Children matched 18 logos of unhealthy food (high in fat/sugar/salt) featured in promotion material from the food industry to pictures of corresponding products. Children''s nutritional knowledge, food preferences, purchase requests, eating behavior and socioeconomic characteristics were assessed by a digital game and parental questionnaires. Anthropometric measurements were recorded.

Results

Recognition rates for the brand logos ranged from 30% to 80%. Logo recognition ability increased with age (p<0.001) and socioeconomic level (p<0.001 comparing children in the highest and lowest of three socioeconomic groups). Adjusted for gender, age and socioeconomic group, logo recognition was associated with higher BMI (p = 0.022) and nutritional knowledge (p<0.001) but not to unhealthy food preferences or purchase requests.

Conclusions

Children from higher socioeconomic groups in the region had higher brand logo recognition ability and are possibly exposed to more food marketing. The study did not lend support to a link between exposure to marketing and poor eating behavior, distorted nutritional knowledge or increased purchase requests. The correlation between logo recognition and BMI warrants further investigation on food marketing towards children and its potential role in the increasing burden of non-communicable diseases in this part of India.     

Big game hunting in New Zealand: per capita effort,harvest and expenditure in 2011–2012

Recreational big game hunters make a significant contribution to conservation through kills of deer, pigs, chamois and tahr. New opportunities for managing recreational hunting through the proposed Game Animal Council underscore the need to understand the implications of potential changes in recreational hunting participation and harvests. Based on a survey of hunters' recall over a year, hunters averaged 15.63 (SEM = 0.58) big game hunts per year, spending 30.53 (SEM = 0.85) days hunting and killing 8.92 (SEM = 0.69) big game animals. Hunters commonly targeted several species on a single hunt, with highly skewed distributions for hunter effort and kills. Mean monthly expenditure on big game hunting items was $296.78 (SEM = $8.95). Results demonstrate that big game hunting is a significant activity in New Zealand, but this varies considerably among hunters with a small number responsible for the vast majority of kills. These are important considerations for future big game hunting management.     

Applying new tools to cephalopod trophic dynamics and ecology: perspectives from the Southern Ocean Cephalopod Workshop, February 2–3, 2006

A two day workshop on Southern Ocean cephalopods was held in Hobart, Tasmania, Australia prior to the triennial 2006 Cephalopod International Advisory Council (CIAC) symposium. The workshop provided a second international forum to present the current state of research and new directions since the last Southern Ocean cephalopod meeting held in 1993. A major focus of the workshop was trophic ecology and the use of a variety of tools that can be applied in Southern Ocean trophic studies for both cephalopod and predator researchers. New tools that are being used as trophic indicators and tracers in food chain pathways include stable isotope, heavy metal and fatty acid signature analysis. Progress is also being made on understanding squid population dynamics in relation to other key components of the ecosystem by incorporating squid data in ecosystem models. Genetic barcoding is now of great value to fish taxonomy as well as other groups and it is expected that a cephalopod barcoding initiative will be an important tool for cephalopod taxonomy. There is a current initiative to produce a new cephalopod beak identification guide to assist predator biologists in identifying cephalopod prey items. There were also general discussions on specific taxonomic issues, Southern Ocean Cephalopod paralarvae and parasites, and suggestions for future CIAC workshop topics.     

Typhoid Outbreak in Songkhla,Thailand 2009–2011: Clinical Outcomes,Susceptibility Patterns,and Reliability of Serology Tests

Objective

To determine the clinical manifestations and outcomes, the reliability of Salmonella enterica serotype Typhi (S ser. Typhi) IgM and IgG rapid tests, and the susceptibility patterns and the response to treatment during the 2009–2011 typhoid outbreak in Songkhla province in Thailand.

Method

The medical records of children aged <15 years with S ser. Typhi bacteremia were analysed. The efficacy of the typhoid IgM and IgG rapid tests and susceptibility of the S ser. Typhi to the current main antibiotics used for typhoid (amoxicillin, ampicillin, cefotaxime, ceftriaxone, co-trimoxazole, and ciprofloxacin), were evaluated.

Results

S ser. Typhi bacteremia was found in 368 patients, and all isolated strains were susceptible to all 6 antimicrobials tested. Most of the patients were treated with ciprofloxacin for 7–14 days. The median time (IQR) of fever before treatment and duration of fever after treatment were 5 (4, 7) days and 4 (3, 5) days, respectively. Complications of ascites, lower respiratory symptoms, anemia (Hct <30%), and ileal perforation were found in 7, 7, 22, and 1 patients, respectively. None of the patients had recurrent infection or died. The sensitivities of the typhoid IgM and IgG tests were 58.3% and 25.6% respectively, and specificities were 74.1% and 50.5%, respectively.

Conclusion

Most of the patients were diagnosed at an early stage and treated with a good outcome. All S ser. Typhi strains were susceptible to standard first line antibiotic typhoid treatment. The typhoid IgM and IgG rapid tests had low sensitivity and moderate specificity.     

2nd Charles Richet et Jules Héricourt Workshop: Therapeutic antibodies and anaphylaxis; May 31–June 1, 2011; Tours,France

The Charles Richet and Jules Héricourt workshops honor the memory of Jules Héricourt (1850–1938) and Charles Richet (1850–1935) who described the principle of serotherapy in 1888 and made the very first attempts to fight cancer with serotherapy in 1895. In 1902, Charles Richet and Paul Portier described “anaphylaxis,” a discovery awarded the Nobel Prize in 1913. The first workshop, “Towards the clinical use of monoclonal antibodies with higher cytolytic efficacy in cancer” was held in Tours, France on November 20–21, 2008. The second Charles Richet and Jules Héricourt workshop, held May 31–June 1, 2011 at the University of Tours, France, was also organized by the Cancéropôle Grand Ouest. The topic of the workshop was therapeutic antibodies and anaphylaxis, a subject rarely addressed in congresses focused on mAbs. To have discussions about mAb side effects with complete objectivity, the congress was organized independently of any sponsorship from pharmaceutical companies. This academic event was motivated by the high incidence of shocks to cetuximab and the need to compile and evaluate scattered information. This growing public health concern was thus analyzed from different scientific and medical angles. The first session was devoted to acute infusion reactions, with an emphasis on deconvolution of the terms “cytokine-release syndrome,” “cytokine storms,” “anaphylaxis” and their epidemiology. This session concluded with the Charles Richet lecture on cetuximab anaphylaxis and anti-αGal IgE by Thomas Platts-Mills, its discoverer. In the next session, the involvement of anti-glycan antibodies in both anaphylaxis and delayed hypersensitivity reactions to therapeutic antibodies was discussed. A gala dinner was held in the gardens of the beautiful château of Villandry, which was acquired and restored by Joachim Carvalho, a pupil of Charles Richet''s and great-grandfather of the present owner. The final session focused on strategies to prevent cetuximab anaphylaxis in clinical practice included a variety of topics, e.g., premedication, biobetters and biosimilars, skin testing and predictive assays. All speakers and attendees enjoyed this very stimulating and rewarding meeting, which gathered many people with divergent scientific backgrounds and medical specialties.Key words: cetuximab, anaphylaxis, α-Gal epitope, anti-αGal IgE, anti-cetuximab IgE, allergy, monoclonal antibodies, glycosylation     

Guillain-Barré Syndrome,Influenza Vaccination,and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009–2011

Background

Guillain-Barré Syndrome (GBS) can be triggered by gastrointestinal or respiratory infections, including influenza. During the 2009 influenza A (H1N1) pandemic in the United States, monovalent inactivated influenza vaccine (MIV) availability coincided with high rates of wildtype influenza infections. Several prior studies suggested an elevated GBS risk following MIV, but adjustment for antecedent infection was limited.

Methods

We identified patients enrolled in health plans participating in the Vaccine Safety Datalink and diagnosed with GBS from July 2009 through June 2011. Medical records of GBS cases with 2009–10 MIV, 2010–11 trivalent inactivated influenza vaccine (TIV), and/or a medically-attended respiratory or gastrointestinal infection in the 1 through 141 days prior to GBS diagnosis were reviewed and classified according to Brighton Collaboration criteria for diagnostic certainty. Using a case-centered design, logistic regression models adjusted for patient-level time-varying sources of confounding, including seasonal vaccinations and infections in GBS cases and population-level controls.

Results

Eighteen confirmed GBS cases received vaccination in the 6 weeks preceding onset, among 1.27 million 2009–10 MIV recipients and 2.80 million 2010–11 TIV recipients. Forty-four confirmed GBS cases had infection in the 6 weeks preceding onset, among 3.77 million patients diagnosed with medically-attended infection. The observed-versus-expected odds that 2009–10 MIV/2010–11 TIV was received in the 6 weeks preceding GBS onset was odds ratio = 1.54, 95% confidence interval (CI), 0.59–3.99; risk difference = 0.93 per million doses, 95% CI, −0.71–5.16. The association between GBS and medically-attended infection was: odds ratio = 7.73, 95% CI, 3.60–16.61; risk difference = 11.62 per million infected patients, 95% CI, 4.49–26.94. These findings were consistent in sensitivity analyses using alternative infection definitions and risk intervals for prior vaccination shorter than 6 weeks.

Conclusions

After adjusting for antecedent infections, we found no evidence for an elevated GBS risk following 2009–10 MIV/2010–11 TIV influenza vaccines. However, the association between GBS and antecedent infection was strongly elevated.     

TLR3, TLR4 and TLRs7–9 Induced Interferons Are Not Impaired in Airway and Blood Cells in Well Controlled Asthma

Defective Rhinovirus induced interferon-β and interferon-λ production has been reported in bronchial epithelial cells from asthmatics but the mechanisms of defective interferon induction in asthma are unknown. Virus infection can induce interferon through Toll like Receptors (TLR)3, TLR7 and TLR8. The role of these TLRs in interferon induction in asthma is unclear. This objective of this study was to measure the type I and III interferon response to TLR in bronchial epithelial cells and peripheral blood cells from atopic asthmatics and non-atopic non-asthmatics. Bronchial epithelial cells and peripheral blood mononuclear cells from atopic asthmatic and non-atopic non-asthmatic subjects were stimulated with agonists to TLR3, TLR4 & TLRs7–9 and type I and III interferon and pro-inflammatory cytokine, interleukin(IL)-6 and IL-8, responses assessed. mRNA expression was analysed by qPCR. Interferon proteins were analysed by ELISA. Pro-inflammatory cytokines were induced by each TLR ligand in both cell types. Ligands to TLR3 and TLR7/8, but not other TLRs, induced interferon-β and interferon-λ in bronchial epithelial cells. The ligand to TLR7/8, but not those to other TLRs, induced only type I interferons in peripheral blood mononuclear cells. No difference was observed in TLR induced interferon or pro-inflammatory cytokine production between asthmatic and non-asthmatic subjects from either cell type. TLR3 and TLR7/8,, stimulation induced interferon in bronchial epithelial cells and peripheral blood mononuclear cells. Interferon induction to TLR agonists was not observed to be different in asthmatics and non-asthmatics.     

The Prevalence and Endemic Nature of Dengue Infections in Guangdong,South China: An Epidemiological,Serological, and Etiological Study from 2005–2011

Objectives

Frequent outbreaks of dengue are considered to be associated with an increased risk for endemicity of the disease. The occurrence of a large number of indigenous dengue cases in consecutive years indicates the possibility of a changing dengue epidemic pattern in Guangdong, China.

Methods

To have a clear understanding of the current dengue epidemic, a retrospective study of epidemiological profile, serological response, and virological features of dengue infections from 2005–2011 was conducted. Case data were collected from the National Notifiable Infectious Diseases Reporting Network. Serum samples were collected and prepared for serological verification and etiological confirmation. Incidence, temporal and spatial distribution, and the clinical manifestation of dengue infections were analyzed. Pearson''s Chi-Square test was used to compare incidences between different age groups. A seroprevalence survey was implemented in local healthy inhabitants to obtain the overall positive rate for the specific immunoglobulin (Ig) G antibody against dengue virus (DENV).

Results

The overall annual incidence rate was 1.87/100000. A significant difference was found in age-specific incidence (Pearson''s Chi-Square value 498.008, P<0.001). Children under 5 years of age had the lowest incidence of 0.28/100000. The vast majority of cases presented with a mild manifestation typical to dengue fever. The overall seroprevalence of dengue IgG antibody in local populations was 2.43% (range 0.28%–5.42%). DENV-1 was the predominant serotype in circulation through the years, while all 4 serotypes were identified in indigenous patients from different outbreak localities since 2009.

Conclusions

A gradual change in the epidemic pattern of dengue infection has been observed in recent years in Guangdong. With the endemic nature of dengue infections, the transition from a monotypic to a multitypic circulation of dengue virus in the last several years will have an important bearing on the prevention and control of dengue in the province and in the neighboring districts.     

Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai–Myanmar Border, 1999–2011: An Observational Study

Background

The Shoklo Malaria Research Unit has been working on the Thai–Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria. Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged. We expanded malaria activities through EDT and evaluated the impact over a 12-y period.

Methods and Findings

Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations. Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys. In vivo and in vitro antimalarial drug efficacy were monitored. Over this period, the number of malaria cases detected increased initially, but then declined rapidly. In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76–80) (1,048/1,344 consultations) to 7% (95% CI 6.2–7.1) (767/11,542 consultations), p<0.001. The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3–1.4) to 0.7 (95% CI 0.7–0.8). The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04–0.07]). The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year. The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0–28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8–4.3) (76/2,207 pregnant women), p<0.001. The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20–62]). The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13–45) (8/29 patients) in 2011.

Conclusions

Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai–Myanmar border. Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area. Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate. Please see later in the article for the Editors'' Summary