Postoperative serum proteomic profiles may predict recurrence-free survival in high-risk primary breast cancer

Item does not contain fulltextPURPOSE: Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective longitudinal study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence-free survival. METHODS: Sera of 82 breast cancer patients obtained after surgery, but prior to the administration of adjuvant therapy, were fractionated using anion-exchange chromatography, to facilitate the detection of the low-abundant serum peptides. Selected fractions were subsequently analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS), and the resulting protein profiles were searched for prognostic markers by appropriate bioinformatics tools. RESULTS: Four peak clusters (i.e. m/z 3073, m/z 3274, m/z 4405 and m/z 7973) were found to bear significant prognostic value (P </= 0.01). The m/z 3274 candidate marker was structurally identified as inter-alpha-trypsin inhibitor heavy chain 4 fragment(658-688) in serum. Except for the m/z 7973 peak cluster, these peaks remained independently associated with recurrence-free survival upon multivariate Cox regression analysis, including clinical parameters of known prognostic value in this study population. CONCLUSION: Investigation of the postoperative serum proteome by, e.g., anion-exchange fractionation followed by SELDI-TOF MS analysis is promising for the detection of novel prognostic factors. However, regarding the rather limited study population, validation of these results by analysis of independent study populations is warranted to assess the true clinical applicability of discovered prognostic markers. In addition, structural identification of the other markers will aid in elucidation of their role in breast cancer prognosis, as well as enable development of absolute quantitative assays

Haptoglobin phenotype is not a predictor of recurrence free survival in high-risk primary breast cancer patients

Contains fulltext : 70104tjan-heijnen.pdf (publisher's version ) (Open Access)BACKGROUND: Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective follow-up study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence free survival. METHODS: Two sample sets of high-risk primary breast cancer patients participating in a randomised national trial investigating the effectiveness of high-dose chemotherapy were analysed. Sera in set I (n = 63) were analysed by surface enhanced laser desorption ionisation time-of-flight mass spectrometry (SELDI-TOF MS) for biomarker finding. Initial results were validated by analysis of sample set II (n = 371), using one-dimensional gel-electrophoresis. RESULTS: In sample set I, the expression of a peak at mass-to-charge ratio 9198 (relative intensity 20), identified as haptoglobin (Hp) alpha-1 chain, was strongly associated with recurrence free survival (global Log-rank test; p = 0.0014). Haptoglobin is present in three distinct phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2), of which only individuals with phenotype Hp 1-1 or Hp 2-1 express the haptoglobin alpha-1 chain. As the expression of the haptoglobin alpha-1 chain, determined by SELDI-TOF MS, corresponds to the phenotype, initial results were validated by haptoglobin phenotyping of the independent sample set II by native one-dimensional gel-electrophoresis. With the Hp 1-1 phenotype as the reference category, the univariate hazard ratio for recurrence was 0.87 (95% CI: 0.56 - 1.34, p = 0.5221) and 1.03 (95% CI: 0.65 - 1.64, p = 0.8966) for the Hp 2-1 and Hp 2-2 phenotypes, respectively, in sample set II. CONCLUSION: In contrast to our initial results, the haptoglobin phenotype was not identified as a predictor of recurrence free survival in high-risk primary breast cancer in our validation set. Our initial observation in the discovery set was probably the result of a type I error (i.e. false positive). This study illustrates the importance of validation in obtaining the true clinical applicability of a potential biomarker

Involving people with dementia in developing an interactive web tool for shared decision-making: experiences with a participatory design approach

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Involvement of people with dementia in making decisions about their lives: a qualitative study that appraises shared decision-making concerning daycare

Objective To explore how people with dementia, their informal caregivers and their professionals participate in decision making about daycare and to develop a typology of participation trajectories.Design A qualitative study with a prospective, multiperspective design, based on 244 semistructured interviews, conducted during three interview rounds over the course of a year. Analysis was by means of content analysis and typology construction.Setting Community settings and nursing homes in the Nethearlands.Participants 19 people with dementia, 36 of their informal caregivers and 38 of their professionals (including nurses, daycare employees and case managers).Results The participants&rsquo; responses related to three critical points in the decision-making trajectory about daycare: (1) the initial positive or negative expectations of daycare; (2) negotiation about trying out daycare by promoting, resisting or attuning to others; and (3) trying daycare, which resulted in positive or negative reactions from people with dementia and led to a decision. The ways in which care networks proceeded through these three critical points resulted in a typology of participation trajectories, including (1) working together positively toward daycare, (2) bringing conflicting perspectives together toward trying daycare and (3) not reaching commitment to try daycare.Conclusion Shared decision making with people with dementia is possible and requires and adapted process of decision making. Our results show that initial preferences based on information alone may change when people with dementia experience daycare. It is important to have a try-out period so that people with dementia can experience daycare without having to decide whether to continue it. Whereas shared decision making in general aims at moving from initial preferences to informed preferences, professionals should focus more on moving from initial preferences to experienced preferences for people with dementia. Professionals can play a crucial role in facilitating the possibilities for a try-out period

The challenges of shared decision making in dementia care networks

Decision making is an important part of managing one's life with dementia. Shared decision making is the preferred way of involving people in decisions. Our study aimed to describe the challenges of shared decision making in dementia care networks

Clinical impact of PCR-based Aspergillus and azole resistance detection in invasive aspergillosis. A prospective multicenter study

BACKGROUND: Invasive aspergillosis(IA) by a triazole resistant Aspergillus fumigatus is associated with a high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study in the Netherlands and Belgium, we evaluated the clinical value of the multiplex AsperGenius®PCR in hematology patients from 12 centers. This PCR detects the most frequent cyp51A mutations in A. fumigatus conferring azole-resistance. Patients were included when a CT-scan showed a pulmonary infiltrate and bronchoalveolar lavage(BALf) sampling was performed. The primary endpoint was antifungal treatment failure in patients with azole-resistant IA. Patients with mixed azole-susceptible/resistant infections were excluded. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available in 276/323(94%) and probable IA diagnosed in 99/276(36%). Sufficient BALf for PCR testing was available in 293/323(91%). Aspergillus DNA was detected in 116/293(40%) and A.fumigatus DNA in 89/293(30%). The resistance PCR was conclusive in 58/89(65%) and resistance detected in 8/58(14%). Two had a mixed azole-susceptible/resistant infection. In the 6 remaining patients, treatment failure was observed in one. Galactomannan positivity was associated with higher mortality(p=0.004). In contrast, mortality of patients with an isolated positive Aspergillus PCR was comparable to those with a negative PCR(p=0.83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (e.g. minimum Ct-value and/or PCR positive on >1 BALf sample)