Background:Despite thousands of papers, the value of quality of life (QoL) in curing disease remains uncertain. Until now, we lacked tools for the diagnosis and specific treatment of diseased QoL. We approached this problem stepwise by theory building, modelling, an exploratory trial and now a definitive randomised controlled trial (RCT) in breast cancer, whose results we report here.Methods:In all, 200 representative Bavarian primary breast cancer patients were recruited by five hospitals and treated by 146 care professionals. Patients were randomised to either (1) a novel care pathway including diagnosis of ‘diseased' QoL (any QoL measure below 50 points) using a QoL profile and expert report sent to the patient's coordinating practitioner, who arranged QoL therapy consisting of up to five standardised treatments for specific QoL defects or (2) standard postoperative care adhering to the German national guideline for breast cancer. The primary end point was the proportion of patients in each group with diseased QoL 6 months after surgery. Patients were blinded to their allocated group.Results:At 0 and 3 months after surgery, diseased QoL was diagnosed in 70% of patients. The QoL pathway reduced rates of diseased QoL to 56% at 6 months, especially in emotion and coping, compared with 71% in controls (P=0.048). Relative risk reduction was 21% (95% confidence interval (CI): 0–37), absolute risk reduction 15% (95% CI: 0.3–29), number needed to treat (NNT)=7 (95% CI: 3–37). When QoL therapy finished after successful treatment, diseased QoL often returned again, indicating good responsiveness of the QoL pathway.Conclusion:A three-component outcome system including clinician-derived objective, patient-reported subjective end points and qualitative analysis of clinical relevance was developed in the last 10 years for cancer as a complex intervention. A separate QoL pathway was implemented for the diagnosis and treatment of diseased QoL and its effectiveness tested in a community-based, pragmatic, definitive RCT. While the pathway was active, it was effective with an NNT of 7.

The suffering cancer patient is the main focus of this QoL diagnosis and therapy system. It will have to pass the rigorous test of a definitive randomized trial.

A system for quality-of-life diagnosis and therapy (QoL system) was implemented for breast cancer patients. The system fulfilled the criteria for complex interventions (Medical Research Council). Following theory and modeling, this study contains the exploratory trial as a next step before the randomised clinical trial (RCT) answering three questions: (1) Are there differences between implementation sample and general population? (2) Which amount and type of disagreement exist between patient and coordinating practitioners (CPs) in assessed global QoL? (3) Are there empirical reasons for a cutoff of 50 points discriminating between healthy and diseased QoL? Implementation was successful: 74% of CPs worked along the care pathway. However, CPs showed preferences for selecting patients with lower age and UICC prognostic staging. Patients and CPs disagreed considerably in values of global QoL, despite education in QoL assessment by outreach visits, opinion leaders and CME: Zero values of QoL were only expressed by patients. Finally, the cutoff of 50 points was supported by the relationship between QoL in single items and global QoL: no patients with values above 50 dropped global QoL below 50, but values below 50 and especially at 0 points in single items, induced a dramatic fall of global QoL down to below 50. The exploratory trial was important for defining the complex intervention in the definitive RCT: control for age and prognostic stage grading, support for a QoL unit combining patient's and CP's assessment of QoL and support for the 50-point cutoff criterion between healthy and diseased QoL.

Using tissue microarrays assembling 465 nevi, primary melanomas and metastases, we investigated whether expression of methylthioadenosine phosphorylase (MTAP), a recently suggested biomarker of malignant melanoma, has prognostic significance and may predict responsiveness to adjuvant interferon therapy in patients with melanoma. Because of its association with MTAP activity and interferon signalling pathways, signal transducer and activator of transcription 1 (STAT1) immunohistochemistry was analysed, too. MTAP expression was significantly reduced in melanomas and metastases compared with nevi (P < 0.001); STAT1 expression significantly increased. In melanomas, loss of MTAP expression was significantly related to Clark level (P < 0.05) and tumor thickness (P < 0.01); whereas STAT1 immunoreactivity was significantly related to gender (p < 0.05) and tumor thickness (P < 0.05). Interestingly, subgroup analysis of patients with a tumor thickness of 1.5-4.0 mm revealed a significant survival benefit from adjuvant interferon treatment regarding recurrence-free survival (RFS; P < 0.05) if MTAP expression was observed in the primary melanoma. Patients with STAT1-positive melanomas also tended to benefit from interferon concerning RFS (P = 0.074) and showed a significant benefit concerning overall survival (OS; P < 0.05). According to Cox analysis, MTAP expression in contrast to STAT1 was an independent positive prognostic marker for RFS and OS. In conclusion, MTAP represents a highly promising immunohistochemical marker for prognosis and interferon response of patients with malignant melanoma.Key words: interferon alpha -malignant melanomamethylthioadenosine phosphorylase -signal transducer and activator of transcription 1Please cite this article as: Methylthioadenosine phosphorylase represents a predictive marker for response to adjuvant interferon therapy in patients with malignant melanoma.

The aim of diagnostic accuracy studies is to evaluate how accurately a diagnostic test can distinguish diseased from nondiseased individuals. Depending on the research question, different study designs and accuracy measures are appropriate. As the prior knowledge in the planning phase is often very limited, modifications of design aspects such as the sample size during the ongoing trial could increase the efficiency of diagnostic trials. In intervention studies, group sequential and adaptive designs are well established. Such designs are characterized by preplanned interim analyses, giving the opportunity to stop early for efficacy or futility or to modify elements of the study design. In contrast, in diagnostic accuracy studies, such flexible designs are less common, even if they are as important as for intervention studies. However, diagnostic accuracy studies have specific features, which may require adaptations of the statistical methods or may lead to specific advantages or limitations of sequential and adaptive designs.In this article, we summarize the current status of methodological research and applications of flexible designs in diagnostic accuracy research. Furthermore, we indicate and advocate future development of adaptive design methodology and their use in diagnostic accuracy trials from an interdisciplinary viewpoint. The term "interdisciplinary viewpoint" describes the collaboration of experts of the academic and nonacademic research.