Symptomatic rebound methaemoglobinaemia after treatment with dapsone.

A 28-year-old female patient was admitted to our hospital with severe dyspnoea and hypoxemia due to methaemoglobinaemia caused by dapsone. The patient recovered completely after repeated infusions of methylene blue and cessation of dapsone. However, 12 days after cessation of dapsone, the patient was readmitted due to recurrence of symptoms based on a relapse of methaemoglobinaemia. Toxicological analysis revealed a toxic dapsone level at readmission and no other explanation for methaemoglobinaemia. Several possible mechanisms as explanation for the recurrence of methaemoglobinaemia are listed and additional tests were performed. In addition to supportive care, treatment consisted of methylene blue; furthermore, cimetidine and ascorbic acid were added. An overview of the pathophysiology, diagnostics, treatment, and possible explanations for this relapse of methaemoglobinaemia caused by dapsone are given. This case shows the importance of considering the possibility of a late rebound methaemoglobinaemia after discontinuation of dapsone.

Strong CD8+ lymphocyte infiltration in combination with expression of HLA class I is associated with better tumor control in breast cancer patients treated with neoadjuvant chemotherapy.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA). METHODS: Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS). RESULTS: A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (p < 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%, p = 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%, p = 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15-1.10, p = 0.08 and hazard ratio 7.67, 95% CI 0.88-66.4, p = 0.07, respectively). Baseline immune markers were not related to ZA treatment. CONCLUSIONS: Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC.

Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe.

Gene expression profiles with prognostic capacities have shown good performance in multiple clinical trials. However, with multiple assays available and numerous types of validation studies performed, the added value for daily clinical practice is still unclear. In Europe, the MammaPrint, OncotypeDX, PAM50/Prosigna and Endopredict assays are commercially available. In this systematic review, we aim to assess these assays on four important criteria: Assay development and methodology, clinical validation, clinical utility and economic value. We performed a literature search covering PubMed, Embase, Web of Science and Cochrane, for studies related to one or more of the four selected assays. We identified 147 papers for inclusion in this review. MammaPrint and OncotypeDX both have evidence available, including level IA clinical trial results for both assays. Both assays provide prognostic information. Predictive value has only been shown for OncotypeDX. In the clinical utility studies, a higher reduction in chemotherapy was achieved by OncotypeDX, although the number of available studies differ considerably between tests. On average, economic evaluations estimate that genomic testing results in a moderate increase in total costs, but that these costs are acceptable in relation to the expected improved patient outcome. PAM50/prosigna and EndoPredict showed comparable prognostic capacities, but with less economical and clinical utility studies. Furthermore, for these assays no level IA trial data are available yet. In summary, all assays have shown excellent prognostic capacities. The differences in the quantity and quality of evidence are discussed. Future studies shall focus on the selection of appropriate subgroups for testing and long-term outcome of validation trials, in order to determine the place of these assays in daily clinical practice.

Extended adjuvant endocrine therapy in hormone-receptor positive early breast cancer: current and future evidence.

The optimal duration and regimen of adjuvant hormonal therapy for premenopausal and postmenopausal patients with hormone receptor positive early breast cancer has not yet been established. This review will give an overview of published and ongoing studies concerning extended endocrine treatment. Most of the currently published studies are based on the adjuvant treatment regime of 5 years tamoxifen, which has been proven to be inferior compared to aromatase inhibitor (AI)-containing regimes. Therefore, until today, there is no clear evidence for the extension of endocrine therapy after upfront AI-based adjuvant treatment regimes. Multiple clinical trials, which will be discussed in this review, are ongoing to elucidate on this matter. We emphasize the need for tailoring of extended adjuvant endocrine treatment. The quest for predictive biomarkers, which are currently being investigated in the context of decision-making whether or not to start adjuvant chemotherapy, should be expanded to include the feasibility of extended endocrine treatment based on these markers. By tailoring the extension of endocrine treatment, overtreatment, side effects and unnecessary costs will be prevented.