A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone

Purpose: We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of 186Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC).

Methods: Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of 186Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life.

Results: Thirty-eight patients with a median age of 67 years (range 50–77) and a median PSA of 57 ng/ml (range 4–3,628) received a median activity of 4,978 MBq 186Re-HEDP (range 4,770–5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18–24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66–90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15–49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months.

Conclusion: We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach.

Tooth loss and implant outcomes in patients refractory to treatment in a periodontal practice

Aim: The aim of this study was to investigate the factors associated with continued significant tooth loss due to periodontal reasons during maintenance following periodontal therapy in a specialist periodontal practice in Norway.
Material and Methods: A case-control design was used. Refractory cases were patients who lost multiple teeth during a maintenance period of 13.4 (range 8-19) years following definitive periodontal treatment in a specialist practice. Controls were age- and gender-matched maintenance patients from the same practice. Characteristics and treatment outcomes were assessed, and all teeth classified as being lost due to periodontal disease during follow-up were identified. The use of implants in refractory cases and any complications relating to such a treatment were recorded.
Results: Only 27 (2.2%) patients who received periodontal treatment between 1986 and 1998 in a specialist practice met the criteria for inclusion in the refractory to treatment group. Each refractory subject lost 10.4 (range 4-16) teeth, which represented 50% of the teeth present at baseline. The rate of tooth loss in the refractory group was 0.78 teeth per year, which was 35 times greater than that in the control group. Multivariate analysis indicated that being in the refractory group was predicted by heavy smoking (p=0.026), being stressed (p=0.016) or having a family history of periodontitis (p=0.002). Implants were placed in 14 of the refractory patients and nine (64%) of these lost at least one implant. In total, 17 (25%) of the implants placed in the refractory group were lost during the study period.
Conclusions: A small number of periodontal maintenance patients are refractive to treatment and go on to experience significant tooth loss. These subjects also have a high level of implant complications and failure. Heavy smoking, stress and a family history of periodontal disease were identified as factors associated with a refractory outcome.

Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry

Introduction: Refractory asthma represents a significant unmet clinical need where the evidence base for the assessment and therapeutic management is limited. The British Thoracic Society (BTS) Difficult Asthma Network has established an online National Registry to standardise specialist UK difficult asthma services and to facilitate research into the assessment and clinical management of difficult asthma.
Methods: Data from 382 well characterised patients, who fulfilled the American Thoracic Society definition for refractory asthma attending four specialist UK centres—Royal Brompton Hospital, London, Glenfield Hospital, Leicester, University Hospital of South Manchester and Belfast City Hospital—were used to compare patient demographics, disease characteristics and healthcare utilisation.
Results: Many demographic variables including gender, ethnicity and smoking prevalence were similar in UK centres and consistent with other published cohorts of refractory asthma. However, multiple demographic factors such as employment, family history, atopy prevalence, lung function, rates of hospital admission/unscheduled healthcare visits and medication usage were different from published data and significantly different between UK centres. General linear modelling with unscheduled healthcare visits, rescue oral steroids and hospital admissions as dependent variables all identified a significant association with clinical centre; different associations were identified when centre was not included as a factor.
Conclusion: Whilst there are similarities in UK patients with refractory asthma consistent with other comparable published cohorts, there are also differences, which may reflect different patient populations. These differences in important population characteristics were also identified within different UK specialist centres. Pooling multicentre data on subjects with refractory asthma may miss important differences and potentially confound attempts to phenotype this population.

Clinical management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult Asthma Registry

Refractory asthma represents a significant unmet clinical need. Data from a national online registry audited clinical outcome in 349 adults with refractory asthma from four UK specialist centres in the British Thoracic Society Difficult Asthma Network. At follow-up, lung function improved, with a reduction in important healthcare outcomes, specifically hospital admission, unscheduled healthcare visits and rescue courses of oral steroids. The most frequent therapeutic intervention was maintenance oral corticosteroids and most steroid sparing agents (apart from omalizumab) demonstrated minimal steroid sparing benefit. A significant unmet clinical need remains in this group, specifically a requirement for therapies which reduce systemic steroid exposure.

Investigation of molecular markers in the diagnosis of refractory coeliac disease in a large patient cohort

Some patients with coeliac disease, despite strict adherence to a gluten-free diet, continue to have significant symptoms and/or a severe small intestinal histological lesion. The term "refractory coeliac disease" (rCD) is used to describe this condition. The purpose of this study was to investigate the value of tissue molecular markers reported to help in the diagnosis of rCD.

Refractory cachexia and truth-telling about terminal prognosis; A qualitative study

The purpose of this paper is to examine the consequences that medical practitioners’ decisions about whether or not to be candid about terminal prognosis have for those suffering from refractory cachexia and their families. It presents the findings of a qualitative study which used focus groups and semi-structured interviews of a volunteer sample of doctors, nurses and dieticians in a cancer centre of a large teaching hospital in Northern Ireland. Respondents reported that some physicians tended to avoid discussing terminal prognosis in a direct manner with their patients. Nurses and dieticians tended to be reluctant to engage in conversations about weight loss with patients with cachexia. One of the reasons they reported for their lack of acknowledgement of weight loss concerned the close association between refractory cachexia and terminal prognosis. Because they viewed the telling of bad news as an exclusive prerogative of medical practitioners, they did not feel in a position to discuss cachexia because they were concerned that this had the potential to raise end-of-life issues that lay outside the boundaries of their professional role. This meant patients and their families were provided with little information about how to cope with the distressing consequences of cachexia.

Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum. © 2013 Ferrata Storti Foundation.