Proportionate translation of study materials and measures in a multinational global health trial: methodology development and implementation.

OBJECTIVES: Current translation guidelines do not include sufficiently flexible translation approaches for different study materials. We aimed to develop a proportionate methodology to inform translation of all types of study materials in global health trials. DESIGN: The design included three stages: (1) categorisation of study materials, (2) integration of existing translation frameworks and (3) methodology implementation (Germany, India, Israel, Tanzania and Uganda) and refinement. PARTICIPANTS: The study population comprised 27 mental health service users and 27 mental health workers who were fluent in the local language in stage 7 (pretesting), and 54 bilingual mental health service users, aged 18 years or over, and able to give consent as judged by a clinician for step 9 (psychometric evaluation). SETTING: The study took place in preparation for the Using Peer Support in Developing Empowering Mental Health Services (UPSIDES) randomised controlled trial (ISRCTN26008944). PRIMARY OUTCOME MEASURE: The primary outcome measure was the Social Inclusion Scale (SIS). RESULTS: The typology identifies four categories of study materials: local text, study-generated text, secondary measures and primary measure. The UPSIDES Proportionate Translation Methodology comprises ten steps: preparation, forward translation, reconciliation, back translation, review, harmonisation, pretesting, finalisation, psychometric evaluation and dissemination. The translated primary outcome measure for the UPSIDES Trial (SIS) demonstrated adequate content validity (49.3 vs 48.5, p=0.08), convergent validity and internal consistency (0.73), with minimal floor/ceiling effects. CONCLUSION: This methodology can be recommended for translating, cross-culturally adapting and validating all study materials, including standardised measures, in future multisite global trials. The methodology is particularly applicable to multi-national studies involving sites with differing resource levels. The robustness of the psychometric findings is limited by the sample sizes for each site. However, making this limitation explicit is preferable to the typical practice of not reporting adequate details about measure translation and validation. TRAIL REGISTRATION NUMBER: ISRCTN26008944.

Opposite effects of tissue inhibitor of metalloproteinases-1 (TIMP-1) over-expression and knockdown on colorectal liver metastases.

BACKGROUND: Tissue inhibitors of metalloproteinases (TIMPs) and the corresponding metalloproteinases are integral parts of the protease network and have been shown to be involved in cancer development and metastasis. Paradoxically, for TIMP-1, tumor promoting as well as tumor inhibitory effects have been observed. METHODS: To address this paradox, we utilized the BALB/c/CT26 mouse model that reliably leads to liver metastasis after splenic tumor cell injection and variegated the type of target cells for therapeutic intervention and the modalities of gene transfer. Since we have observed before that over-expression of TIMP-1 in liver host cells leads to efficient tumor growth inhibition in this model, we now examined whether targeting the tumor cells themselves will have a similar effect. RESULTS: In concordance with the earlier results, TIMP-1 over-expression in tumor cells led to a dramatic reduction of tumor growth as well. To evaluate any influence of treatment modality, we further examined whether TIMP-1 knockdown in the same animal model would have the opposite effect on tumor growth than TIMP-1 over-expression. Indeed, TIMP-1 knockdown led to a marked increase in tumor burden. CONCLUSION: These data indicate that in the BALB/c/CT26 model, the modification of TIMP-1 has concordant effects irrespective of the type of target cell or the technique of modulation of TIMP-1 activity, and that TIMP-1 is unequivocally tumor inhibitory in this model.

Serum (-5, -7) proPSA for distinguishing stage and grade of prostate cancer.

BACKGROUND: ProPSA has been suggested for the detection of preferentially aggressive prostate cancer (PCa). We report on the use of proPSA and free PSA to enhance preoperative staging and grading. PATIENTS AND METHODS: Serum samples from 376 PCa patients within the PSA range 1-25 microg/l who underwent radical prostatectomy were analysed for PSA, free PSA (fPSA) and (-5, -7) proPSA. RESULTS: ProPSA was only significantly different between pT2 and pT3 PCa (p = 0.02) in the subgroup of patients with % fPSA < 10%. The ratio proPSA/% fPSA differed between G2 and G3 (p = 0.004), Gleason < 7 and Gleason > or =7 (p = 0.001), and pT2 and pT3 tumors (p < 0.0001) at PSA 1-25 microg/l. However, % fPSA improved differentiation only between Gleason < 7 and Gleason > or = 7 tumors, not between pT2 and pT3 or G2 and G3 tumors. CONCLUSION: ProPSA as a single parameter did not improve the detection of non-organ confined or aggressive PCa whereas proPSA/% fPSA further improved staging and grading within all analysed PSA ranges.