The perceptions of teenagers, young adults and professionals in the participation of bone cancer clinical trials.

The reasons why teenagers and young adults (TYA) with cancer do, or do not, participate in clinical trials is not wholly understood. We explored the perceptions and experiences of young people with bone cancer, and health professionals involved in their care, with regard to participation in two clinical trials. We conducted semi-structured interviews using narrative inquiry with 21 young people aged 15-24 years and 18 health professionals. New understandings emerged about perceptions of, and factors that influence participation in, clinical trials. These include perceptions about the importance and design of the clinical trial, communicating with young people in an age-specific manner, using language young people are comfortable with, support from family, peers and specialists in teenage and young adult cancer care. We conclude that addressing these factors may increase acceptability of clinical trials and the trial design for TYA with cancer and ultimately improve their participation. Qualitative research has an important role in making explicit the perceptions and practices that ensure trials are patient-centred, appropriate and communicated effectively to TYA. Translating knowledge gained into routine practice, will go some way in ensuring that the disparities affecting this population are more fully understood.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study).

BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.

Long-term adverse outcomes in survivors of childhood bone sarcoma: the British Childhood Cancer Survivor Study.

BACKGROUND: With improved survival, more bone sarcoma survivors are approaching middle age making it crucial to investigate the late effects of their cancer and its treatment. We investigated the long-term risks of adverse outcomes among 5-year bone sarcoma survivors within the British Childhood Cancer Survivor Study. METHODS: Cause-specific mortality and risk of subsequent primary neoplasms (SPNs) were investigated for 664 bone sarcoma survivors. Use of health services, health and marital status, alcohol and smoking habits, and educational qualifications were investigated for survivors who completed a questionnaire. RESULTS: Survivors were seven times more likely to experience all-cause mortality than expected, and there were substantial differences in risk depending on tumour type. Beyond 25 years follow-up the risk of dying from all-causes was comparable to the general population. This is in contrast to dying before 25 years where the risk was 12.7-fold that expected. Survivors were also four times more likely to develop a SPN than expected, where the excess was restricted to 5-24 years post diagnosis. Increased health-care usage and poor health status were also found. Nonetheless, for some psychosocial outcomes survivors were better off than expected. CONCLUSIONS: Up to 25 years after 5-year survival, bone sarcoma survivors are at substantial risk of death and SPNs, but this is greatly reduced thereafter. As 95% of all excess deaths before 25 years follow-up were due to recurrences and SPNs, increased monitoring of survivors could prevent mortality. Furthermore, bone and breast SPNs should be a particular concern. Since there are variations in the magnitude of excess risk depending on the specific adverse outcome under investigation and whether the survivors were initially diagnosed with osteosarcoma or Ewing sarcoma, risks need to be assessed in relation to these factors. These findings should provide useful evidence for risk stratification and updating clinical follow-up guidelines.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

A phase II study to determine the efficacy and safety of oral treosulfan in patients with advanced pre-treated Ewing sarcoma ISRCTN11631773.

We report a prospective Phase II study of efficacy and toxicity for oral treosulfan in advanced Ewing sarcoma. Twenty patients, median age 19 years (range 7-39) from five UK sites, were treated with oral treosulfan 1 g/m(2) daily for 7 days in 28. Primary endpoint was objective response rate. Best response was stable disease in one patient. All patients died of progressive disease, after median 6.41 months. Median progression free survival was 1.8 months. Toxicity was minimal. No activity was demonstrated for treosulfan at this dose. Progression free survival data should be able to be used for comparison when planning future clinical trials.

Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

What is the role of routine follow-up for localised limb soft tissue sarcomas? A retrospective analysis of 174 patients.

BACKGROUND: There are neither prospective data nor agreement on the optimal routine follow-up procedures in patients treated for soft tissue sarcoma of the limb. METHODS: Data on 174 consecutive patients with a soft tissue sarcoma of the limb undergoing follow-up by oncologists at a single centre from 2003 to 2009 were included in this analysis. The rate and site of recurrence and mode of detection were analysed. Outcome of the patients was assessed. RESULTS: Eighty-two patients (47%) experienced relapse of any type. Isolated local recurrence occurred in 26 patients and local relapse with synchronous pulmonary metastases in five patients. Local recurrences were detected clinically in 30 of these 31 patients; magnetic resonance imaging identified only one local recurrence. Twenty-eight patients developed isolated lung metastases; in nine patients these were amenable to resections, seven of whom are currently free of disease after treatment. Lung metastases were detected by chest x-ray (CXR) in 19 patients, computed tomography scanning in 3 patients, and clinically in 11 patients. Twenty-three patients developed non-pulmonary metastases. More than 80% of relapses occurred in the first 2 years of follow-up; however, later recurrences were also observed. CONCLUSIONS: Routine follow-up CXR can detect lung metastases suitable for surgical resection, although the optimal interval of imaging has yet to be defined. Local relapse is almost always detected by patients or physicians, and routine scanning of the primary site is of doubtful benefit. Patient and physician education to detect local relapse may be helpful. Prospective evaluation of follow-up is recommended.

ENCCA WP17-WP7 consensus paper on teenagers and young adults (TYA) with bone sarcomas.

Teenagers and young adults (TYA) cancer contributes substantially to morbidity and mortality in a population with much to offer society. TYA place distinct challenges upon cancer care services, many reporting feeling marginalized and their needs not being met in adult or paediatric cancer services. Bone tumours such as osteosarcoma and Ewing sarcoma, because of their age at presentation and the complexity of their care, are where challenges in managing (TYA) with cancer have often been most readily apparent. Bone sarcomas may be managed by paediatric or medical oncologists, and require fastidious attention to protocol. A lack of recent improvement in survival in TYA with bone tumours may be linked to a lack of specialist care, poor concordance with therapy in some situations and TYA-specific pharmacology. Participation in clinical trials, particularly of young adults, is low, hindering progress. All these requirements may be best met by a concerted effort to create collaborative care between adult and paediatric experts in bone sarcoma, working together to meet TYA patients' needs.

A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study.

BACKGROUND: The prognosis for patients with nonpulmonary metastatic Ewing sarcoma remains poor with survival in the order of 15-20%. The need to introduce effective new agents into clinical practice is clear. Based on a preclinical rationale of responses in xenografts and backed by a phase I study in children, the Euro-E.W.I.N.G consortium planned a phase II window study of irinotecan in newly diagnosed high risk metastatic patients with Ewing sarcoma. PROCEDURES: Patients were recruited between April 2004 and December 2007. Two courses of irinotecan were administered at a dose of 600 mg/m(2) as a 1 hour infusion at 21 day intervals. Response evaluation was determined after the second course of treatment by radiological assessment of primary and metastatic sites and, where appropriate bone marrow sampling. RESULTS: Twenty-three patients were recruited. Two patients were deemed inevaluable for response. Five patients (24%) demonstrated a partial response. Grade 3 or 4 diarrhoea was seen in 4/43 course of treatment and was managed with loperamide. CONCLUSIONS: This is the first report of single agent irinotecan activity in an untreated population of patients with Ewing sarcoma. In common with other paediatric tumours and other camptothecin analogues such as topotecan, single agent activity is only modest. The exact role for the use of irinotecan in patients with ES, dose schedule and combinations with other agents still requires further investigation.

Clustered base substitutions in CTP synthetase conferring drug resistance in Chinese hamster ovary cells.

Dominantly acting mutations that eliminate the allosteric regulation of CTP synthetase confer a form of multidrug resistance and a mutator phenotype to cultured Chinese hamster ovary cells. Mutations responsible for this phenotype have been identified in 23 independent strains selected for resistance to arabinosyl cytosine and 5-fluorouracil. All these mutations were due to base substitutions at seven sites within a highly conserved region of the ctps gene. This clustering should make it feasible to assess the role of such mutations in the development of drug resistance encountered in the treatment of malignant disease.

Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials.

BACKGROUND: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. PATIENTS AND METHODS: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. RESULTS: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. CONCLUSIONS: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.

Visits on 'lamb-viewing days' at a sheep farm open to the public was a risk factor for Q fever in 2009.

Between February and May 2009, 347 laboratory-confirmed cases of acute Q fever were reported in a southern municipal health service region in The Netherlands. Commercial dairy-goat farms were implicated and control measures were initially targeted there. A preliminary investigation also implicated a non-dairy sheep farm, open to the public on 'lamb-viewing days'. This study tested the association between visiting the non-dairy sheep farm and developing Q fever in residents of the region between February and May 2009. A case-control study of 146 cases and 431 address-matched controls was conducted. Multivariable logistic regression analysis confirmed the association between visiting to the sheep farm and Q fever disease (matched odds ratio 43, 95% confidence interval 9-200). Other risk factors were being a smoker, having a past medical history and being aged >40 years. Vaccination of sheep and goats on farms open to the public should help to reduce the number of future human cases.

A scoping exercise of favourable characteristics of professionals working in teenage and young adult cancer care: 'thinking outside of the box'.

A scoping exercise to define the preferred competencies of professionals involved in teenage and young adult (TYA) cancer care. Data were generated during two workshops with health professionals. In groups, they ranked skills, knowledge and attitudes, previously identified through a literature search, onto a diamond template. Data were also used from an education day with TYA professionals, who generated lists of key skills, knowledge and attitudes. Individually, professionals then selected the top five areas of competence to care for young people with cancer. The workshops generated three diamonds, which exhibited agreement of 13 principle skills, knowledge and attitudes. The top two being: 'expertise in treating paediatric and adult cancers' and 'understanding cancer'. The data from the education day suggested communication, technical knowledge and teamwork as being core role features for professionals who care for young people with cancer. Integration of both datasets; one derived inductively, the other deductively provides a comprehensive outline of core skills health professionals require to be proficient in young people's cancer care. These results will form the basis of future discussion around workforce strategies and inform a Delphi survey.

Obesometric factors associated with increased skin-to-stone distances in renal stone patients.

INTRODUCTION: Obese patients are at increased risk for renal stones as well as treatment failures due to increased skin-to-stone distances (SSD) and harder stone compositions. We investigated the relationships between obesometric parameters (body mass index [BMI], body fat distribution and obesity-related hormone levels) with SSD and stone hardness. MATERIALS AND METHODS: We prospectively enrolled patients undergoing stone interventions at our institution. Computed tomography (CT) scans were analyzed; adipose tissue was identified according to Hounsfield units (HU) and separated into subcutaneous (SAT) and visceral (VAT) components. The pixels were averaged at three levels to calculate fat distribution: %VAT = (VAT)/(VAT + SAT). SSD was measured and HU were used as a surrogate for stone hardness. Obesity-related hormones leptin and adiponectin were measured by ELISA. RESULTS: Seventy-nine patients were prospectively enrolled. Mean BMI and %VAT were 30.02 kg/m2 and 40.13 kg/m2. Mean leptin and adiponectin levels were 17.5 ng/mL and 7.67 mcg/mL indicating high risk for metabolic consequences of obesity. Females had greater proportions of subcutaneous fat than males (%VAT 28.4 versus 46.94, p < 0.001) and greater SSD (11.26 cm versus 9.86 cm, p = 0.025). Among obese patients, subcutaneous fat correlated with SSD independently of BMI (r = 0.454, p = 0.008). Obese patients with %VAT > 40 versus < 40 had SSD of 11.35 cm versus 13.7 cm (p = 0.005). Diabetics had harder stone compositions as measured by HU than non-diabetics (982.86 versus 648.86, p = 0.001). CONCLUSION: Obesometric parameters such as BMI, body fat distribution, and the presence of diabetes mellitus are important considerations in the management of renal stone disease. A large proportion of subcutaneous fat, which can be estimated by physical examination, predicts SSD among obese patients and may aid treatment decisions in patients, particularly those without pre-treatment CT scans. Further studies are needed to refine the role of obesometrics in personalizing treatment decisions.

Case registry systems for pandemic influenza A(H1N1)pdm09 in Europe: are there lessons for the future?

Countries across Europe developed a range of database systems to register pandemic influenza A(H1N1)pdm09 cases. Anecdotal reports indicate that some systems were not as useful as expected. This was a cross-sectional, semi-structured survey of health professionals who collected and reported pandemic influenza A(H1N1)pdm09 cases in 23 countries within the 27 European Union (EU) Member States plus Norway. We describe here the experiences of using pandemic case register systems developed before and during the pandemic, whether the systems were used as intended and, what problems, if any, were encountered. We conducted the survey to identify improvements that could be made to future pandemic case registers at national and EU level. Despite many inter-country differences, 17 respondents felt that a standardised case register template incorporating a limited number of simple standard variables specified in advance and agreed between the World Health Organization and the European Centre for Disease Prevention and Control could be useful. Intra- and inter-country working groups could facilitate information exchange, clearer system objectives and improved interoperability between systems.

Patterns of immunodominance in HIV-1-specific cytotoxic T lymphocyte responses in two human histocompatibility leukocyte antigens (HLA)-identical siblings with HLA-A*0201 are influenced by epitope mutation.

Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201-restricted SLYNTVATL and HLA-A3-restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201-restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.

A paramedic study comparing the use of the Airtraq, Airway Scope and Macintosh laryngoscopes in simulated prehospital airway scenarios.

In a randomised, cross-over study, we compared the use of the Airtraq , Airway Scope and Macintosh laryngoscopes by paramedics for tracheal intubation in three simulated prehospital scenarios. Fifty-four paramedics were invited to take part. When evaluated in a difficult airway manikin, median IQR [range] time to intubation with the Airtraq (21 (16-37 [6-80] s) and Airway Scope (16 (5-75 [12-23] s) was shorter than that with the Macintosh laryngoscope (39 (25-54 [7-120] s; p < 0.0001). The success rate within 30 s was greater with the Airtraq (61%) and Airway Scope (93%) than with the Macintosh laryngoscope (22%; p < 0.0001). When used for a standard intubation and in the sitting position, we found minimal differences among the three laryngoscopes. We conclude that the Airway Scope and Airtraq have significant advantages over the Macintosh laryngoscope and that of the two, the Airway Scope is the more effective device to use in the prehospital environment.

National outbreak of Salmonella Typhimurium (Dutch) phage-type 132 in the Netherlands, October to December 2009.

Between October and December 2009, 23 cases of Salmonella Typhimurium (Dutch) phage type 132, each with an identical multiple-locus variable-number tandem-repeat analysis (MLVA) profile (02-20-08-11-212), were reported from across the Netherlands. A case­control study was conducted using the food-consumption component of responses to a routine population-based survey as a control group. The mean age of cases was 17 years (median: 10 years, range: 1­68). Sixteen cases were aged 16 years or under. Raw or undercooked beef products were identified as the probable source of infection. Consumers, in particular parents of young children, should be reminded of the potential danger of eating raw or undercooked meat.

Ongoing mumps outbreak in a student population with high vaccination coverage, Netherlands, 2010.

Since December 2009, mumps incidence has increased in the Netherlands. As of 20 April 2010, 172 cases have been notified on the basis of laboratory confirmation or linkage to a laboratory-confirmed case. Of these, 112 were students, the majority of whom had been vaccinated (81%). Although outbreaks in vaccinated populations have been described before, risk factors for exposure and susceptibility, and dose-dependent vaccine effectiveness in a student population of this nature are relatively unknown.

Conversion of dietary polyunsaturated fats between humans and rodents: A review of allometric scaling models.

The purpose of this research was to explore various allometric scaling models for dietary nutrients to improve translational validity between preclinical experimental rodent models and humans, focusing on polyunsaturated fats. Currently, there is no authoritative document that provides standardized guidelines for which dietary designs can be based on to improve translational fidelity between species. This paper reviews the challenges of using a rodent model, the major allometric scaling models, the use of these mathematical models to extrapolate human equivalent doses, and then tests one of these models using data generated in mice, with comparisons of data generated in human clinical trials. Mice were fed diets containing micro- and macronutrient compositions that approximated the US diet based on energy distribution and were then supplemented with increasing levels of various n-3 and n-6 polyunsaturated fatty acids at human equivalent doses. Changes in plasma and erythrocyte fatty acid phospholipid compositions were determined and compared to corresponding data generated in humans. Our findings suggest that basing lipid composition on percent of energy may result in comparable outcomes between mice and humans and that extrapolation of non-energy producing nutrients between species might be done using differences in energy needs (based on food intake).