Olav Dahl

Background and purpose: European Society for Hyperthermic Oncology (ESHO) 2–85 is a multicenter randomized trial investigating hyperthermia (HT) as an adjuvant to radiotherapy (RT) in treatment of locally advanced neck nodes. The trial never fulfilled recruitment and was stopped prematurely, and has not previously been published. Patients and methods: Between January 1987 and February 1993, 64 evaluable neck nodes in 54 patients were included. Tumors were stratified according to institution and nodal size and randomly assigned to receive RT alone (2 Gy/fx, 5 fx/wk) to a total dose of 60–70 Gy, including boost, or the same RT followed once weekly by HT (aimed for 43°C for 60 min). The primary endpoint was persistent complete response (local control). Results and interpretation: Sixty-four tumors in 54 patients were evaluable, with a median observation of 17 months. Thirty-four tumors were randomized to RT alone and 30 to RT+HT. Compliance with RT was good. HT was associated with moderate to severe pain and discomfort in 38% of the treatments. In 57% of the heated patients at least one treatment achieved the target temperature. HT did not significantly increase radiation morbidity. The complete response rate was 53% in the RT versus 80% in the RT+HT group, and 3-year persistent local control rate was 32% for RT alone versus 53% for RT+HT; HR: 0.48 [0.23–0.98]. The ESHO 2–85 study demonstrated that addition of a weekly HT treatment to RT of advanced neck nodes significantly enhanced the persistent tumor control. The results substantiate the potential clinical benefit of hyperthermic oncology.

The SWENOTECA-MIR prospective multicenter study aims to assess the clinical value of miR-371a-3p as a novel marker in metastatic germ cell tumor patients undergoing retroperitoneal lymph node dissection (RPLND), to predict the presence of viable residual tumor. A total of 114 patients (86 nonseminomas, 28 seminomas) who underwent surgery for presumed metastatic disease pre-chemotherapy (primary RPLND), and post-chemotherapy RPLND were included. The expression of miR-371a-3p was evaluated using RT-digital droplet PCR before and after RPLND. Pre- and post-operative miR-371a-3p levels were statistically compared, and optimism-corrected performance calculations compared with conventional serum tumor markers. Associations were evaluated by logistic regression. Patients who underwent primary RPLND were categorized into seminoma and nonseminoma groups. Among the seminoma patients (n = 24) undergoing primary RPLND, all had normal conventional markers. Six patients received adjuvant treatment before surgery. miR-371a-3p exhibited a sensitivity of 74%, specificity of 100%, PPV of 100% and NPV of 21% for viable tumor. The levels of miR-371a-3p significantly decreased after surgery. In the nonseminoma group (n = 18) treated with primary RPLND, 22% had elevated conventional markers, and 3 had received prior adjuvant treatment. miR-371a-3p showed a sensitivity of 34%, specificity of 88%, PPV of 67% and NPV of 62% for the primary nonseminoma patients. No association was observed between stage or prior adjuvant treatment, and the outcome of the miR-test. In the post-chemotherapy group (n = 72), the miR-371a-3p sensitivity was 9%, reducing to 0 when excluding patients with seminoma (n = 4). Teratomas and benign histology were essentially negative. Our study highlights miR-371a-3p as a fairly sensitive and highly specific marker for pre-chemotherapy seminomas, outperforming conventional markers. However, in pre-chemotherapy non-seminomas as well as in post-chemotherapy patients, we observed low sensitivity and no significant differences in miR-371a-3p levels before and after surgery, suggesting limited utility for miR-371a-3p in this context.

Background: MicroRNA (MiR) influences the growth of cancer by regulation of mRNA for 50–60% of all genes. We present as per our knowledge the first global analysis of microRNA expression in anal cancer patients and their prognostic impact. Methods: Twenty-nine patients with T1-4 N0-3 M0 anal cancer treated with curative intent from September 2003 to April 2011 were included in the study. RNA was extracted from fresh frozen tissue and sequenced using NGS. Differentially expressed microRNAs were identified using the R-package DEseq2 and the endpoints were time to progression (TTP) and cancer specific survival (CSS). Results: Five microRNAs were significantly associated with 5-year progression free survival (PFS): Low expression of two microRNAs was associated with higher PFS, miR-1246 (100% vs. 55.6%, p = 0.008), and miR-135b-5p (92.9% vs. 59.3%, p = 0.041). On the other hand, high expressions of three microRNAs were associated with higher PFS, miR-148a-3p (93.3% vs. 53.6%, p = 0.025), miR-99a-5p (92.9% vs. 57.1%, p = 0.016), and let-7c-3p (92.9% vs. 57.1%, p = 0.016). Corresponding findings were documented for CSS. Interpretation: Our study identified five microRNAs as prognostic markers in anal cancer. MiR-1246 and microRNA-135b-5p were oncoMiRs (miRs with oncogene effects), while miR-148a-3p, miR- 99a-5p, and let-7c-3p acted as tumour suppressors in anal cancer patients.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

S100A12 is a calcium‐binding protein predominantly found in neutrophil granulocytes and monocytes. Its usefulness in monitoring inflammatory disease states depends on documentation that assay results are reliable. This study aimed at defining guidelines for blood sampling, selection of optimal material handling and reference intervals in healthy controls while taking into account the basic features of S100A12. An enzyme linked immunosorbent assay was developed based upon antibodies induced in rabbits by injection of recombinant S100A12. Our studies confirm that oligomers of S100A12 are generated in the presence of calcium. Structural changes in S100A12 mediated by calcium influence the interaction with antibody. This is proposed as the background for our very low readings of S100A12 in Ethylene Diamine Tetraacetic Acid (EDTA) plasma. Individual S100A12 levels did not change substantially over a 5‐week sampling period. Based upon testing of 150 blood donors we suggest reference intervals of S100A12 in serum to be 49–1340 μg/l for women and 27–1750 μg/l for men. The estimated mean concentrations were 234 μg/l in serum samples (range 12–15791), 114 μg/l (range 3–17282) in re‐calcified EDTA plasma and 48 μg/l (range 2–14843) in heparin plasma. Without adding calcium to EDTA plasma before running the assay, concentrations were around 2 μg/l (16 persons). S100A12 quantification is assumed to become relevant for diagnostic use in many disease states. The importance of the handling and analysing conditions for a reliable result was examined. We recommend serum collected in gel‐containing tubes as the preferred sample material and have suggested reference intervals for healthy individuals.