Prognostic and predictive significance of osteopontin and other hypoxia-related plasma proteins in the radiotherapy of locally advanced and metastatic bronchial carcinoma

Tumorhypoxie ist ein kritischer Faktor der Strahlenresistenz, der das Ansprechen auf Bestrahlung und die Prognose limitiert. Die Identifikation von Patienten mit klinisch relevanter Tumorhypoxie vor Radiotherapie könnte helfen, Patienten für gegen Hypoxie gerichtete Therapien zu selektieren, um die Prognose zu verbessern. In dieser prospektiven Studie wurden die hypoxieassoziierten Plasmaproteine Osteopontin (OPN), Carbonanhydrase IX (CAIX) und vaskulärer endothelialer Wachstumsfaktor (VEGF) auf ihre prognostische Auswirkung in der Radiotherapy des Bronchialkarzinoms untersucht. Die Ergebnisse zeigen, dass erhöhte prätherapeutische Plasmaspiegel von OPN, VEGF und CAIX fortgeschritteneTumorerkrankung anzeigen und dass insbesondere OPN Plasmaspiegelveränderungen nach Radiotherapie Prädiktoren der Prognose sind. Die Biomarker Ko-Detektion (Kombination OPN-VEGF-CAIX) ist in prognostischer Hinsicht robuster als die Einzelmarker-Detektion.Tumor hypoxia is a critical factor of radiation resistance, limiting response to radiotherapy and prognosis. Identification of patients with clinically relevant tumor hypoxia before radiotherapy could help selecting patients for treatments directed against hypoxia in order to improve prognosis. In this prospective study, the hypoxia-related plasma proteins osteopontin (OPN), carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) were evaluated for their prognostic impact in the radiotherapy of lung cancer. The results show that elevated pre-treatment plasma levels of OPN, VEGF and CAIX indicate advanced tumor disease and thatparticularly OPN plasma level changes after radiotherapy predict prognosis. Biomarker co-detection (i.e. combination of OPN-VEGF-CAIX) is more robust in terms of prognosis than single marker detection.by Christian Emil Arthur Ostheime

Dynamics of Heat Shock Protein 70 Serum Levels As a Predictor of Clinical Response in Non-Small-Cell Lung Cancer and Correlation with the Hypoxia-Related Marker Osteopontin

Hypoxia mediates resistance to radio(chemo)therapy (RT) by stimulating the synthesis of hypoxia-related genes, such as osteopontin (OPN) and stress proteins, including the major stress-inducible heat shock protein 70 (Hsp70). Apart from its intracellular localization, Hsp70 is also present on the plasma membrane of viable tumor cells that actively release it in lipid vesicles with biophysical characteristics of exosomes. Exosomal Hsp70 contributes to radioresistance while Hsp70 derived from dying tumor cells can serve as a stimulator of immune cells. Given these opposing traits of extracellular Hsp70 and the unsatisfactory outcome of locally advanced lung tumors, we investigated the role of Hsp70 in the plasma of patients with advanced, non-metastasized non-small-cell lung cancer (NSCLC) before (T1) and 4–6 weeks after RT (T2) in relation to OPN as potential biomarkers for clinical response. Plasma levels of Hsp70 correlate with those of OPN at T1, and high OPN levels are significantly associated with a decreased overall survival (OS). Due to a therapy-induced reduction in viable tumor mass after RT Hsp70 plasma levels dropped significantly at T2 (p = 0.016). However, with respect to the immunostimulatory capacity of Hsp70 derived from dying tumor cells, patients with higher post-therapeutic Hsp70 levels showed a significantly better response to RT (p = 0.034) than those with lower levels at T2. In summary, high OPN plasma levels at T1 are indicative for poor OS, whereas elevated post-therapeutic Hsp70 plasma levels together with a drop of Hsp70 between T1 and T2, successfully predict favorable responses to RT. Monitoring the dynamics of Hsp70 in NSCLC patients before and after RT can provide additional predictive information for clinical outcome and therefore might allow a more rapid therapy adaptation

Benefit from surgery with additional radiotherapy in N1 head and neck cancer at the time of IMRT: A population-based study on recent developments.

BACKGROUND:Currently, the role of adjuvant irradiation in head and neck cancer (HNC) patients with N1-lymph node status is not clarified. OBJECTIVES:To assess the population-based effect of recent developments in radiotherapy such as intensity-modulated radiotherapy (IMRT) in relation to overall survival (OS) together with surgery in N1 HNC patients. MATERIALS AND METHODS:We used 9,318 HNC cases with pT1/2 N0/1 disease from German cancer registries. Time of diagnosis ranged from January 2000 to December 2014, which we divided into three periods: (low [LIA] vs intermediate [IA] vs high [HIA] IMRT availability period) based on usage of IMRT in Germany. For each period, we examined a possible association between treatment (surgery vs. surgery and radiotherapy) in terms of OS. Statistical analyses included Kaplan-Meier and multivariate Cox regression (models adjusted for HPV-related cancer site). RESULTS:Temporal analysis revealed increasing usage of IMRT in Germany. In patients with N1 tumours, a comparison of patients treated with and without radiotherapy during the HIA period showed a superiority of the combined treatment as opposed to surgery alone (HR 0.54, 95%CI: 0.35-0.85, p = 0.003). The survival analyses related to treatments in terms of period underlined the superiority of surgery plus radiotherapy between periods IA and HIA (p = 0.03). CONCLUSION:The advent of IMRT, additional radiotherapy may present a survival advantage in patients with N1 HNC when combined with surgery

Correlation of increased soluble tumor necrosis factor receptor 1 with mortality and dependence on treatment in non-small-cell lung cancer patients : a longitudinal cohort study

Background: Tumor necrosis factor (TNF) is a multipotent cytokine involved in inflammation and anti-tumor activity. TNF- exerts its function upon binding to TNF-receptor 1 (TNF-R1) and TNF-receptor 2 (TNF-R2). This study investigates the relationship of soluble (s) TNF-R1 levels in non-small-cell lung cancer (NSCLC) patients with treatment and overall survival. Methods: In total, 134 NSCLC patients treated at the Medical Faculty of Martin Luther University Halle-Wittenberg between 2017 and 2019 were included in this study. Serum levels of sTNF-R1 were measured via ELISA at baseline and during and after treatment. A linear mixed-effects model was used to assess sTNF-R1 changes over time. Linear regression was applied to investigate the association between clinical characteristics and changes in sTNF-R1. Cox regression models were used to estimate associations with overall mortality. Results: The estimated average sTNFR-1 at baseline was 2091.71 pg/mL, with a change of 6.19 pg/mL per day. Cox models revealed that the individual change in sTNF-R1 was more strongly associated with mortality than its baseline value, especially after adjusting for covariates. Conclusions: This study provides evidence that the individual change in sTNF-R1 levels during and after treatment were associated with the risk of mortality, suggesting the use of the sTNF-R1 trajectory as a prognostic marker

Lung cancer attributed mortality among 316,336 early stage breast cancer cases treated by radiotherapy and/or chemotherapy, 2000–2015 : evidence from the SEER database

Objective: To estimate the risk of death from lung cancer in patients treated for breast cancer (BC) in relation to the general population. Methods: BC data, covering 2000 to 2015, were extracted from the Surveillance, Epidemiology and End Results-18 (SEER-18) cancer registry database. A comparison of lung cancer attributed mortality between BC patients and the general population was performed using standardized mortality ratios (SMRs) and SMRs conditional on survival length (cSMRs). Prognostic factors of lung cancer mortality were identified using flexible parametric modelling. Our model adjusts the effect of downstream (histopathological BC tumor grade and hormone receptor status) and upstream (age at diagnosis, ethnicity, and marital status) factors. Results: The median follow-up was 6.4 years (interquartile range, 3.0–10.3 years). BC cases who received only radiotherapy (cSMR = 0.93; 95%CI: 0.77–1.13), only chemotherapy (cSMR = 0.91; 0.62–1.33), and radio-and chemotherapy (cSMR = 1.04; 0.77–1.39) had no evidence of increased lung cancer mortality relative to the general population. The adjusted model identified that lung cancer mortality was higher for women who were older at diagnosis compared to those <50 years (ranging from HR50-59 = 3.41 [95%CI: 2.72–4.28] to HR70-79 = 10.53 [95%CI: 8.44–13.13]) and for cases with negative estrogen and progesterone receptors (HR =1.38; 95% CI: 1.21–1.57). Compared to married cases, widowed, divorced, single or others had a 76%, 45%, and 25% higher hazard of lung cancer mortality, respectively. Lung cancer mortality was lower for American Indian/Alaska Native and Asian/Pacific Islander ethnicities (HR = 0.51; 95% CI: 0.40–0.64) compared to BC cases with white ethnic background. Conclusions: There is no evidence for a higher lung cancer mortality in BC patients when compared to the general population.Publikationsfonds ML

Correlation between Circulating miR-16, miR-29a, miR-144 and miR-150, and the Radiotherapy Response and Survival of Non-Small-Cell Lung Cancer Patients

Despite the success of current therapy concepts, patients with advanced non-small-cell lung cancer (NSCLC) still have a very poor prognosis. Therefore, biological markers are urgently needed, which allow the assessment of prognosis, or prediction of the success of therapy or resistance in this disease. Circulating microRNAs (miRs) have potential as biomarkers for the prognosis and prediction of response to therapy in cancer patients. Based on recent evidence that circulating miR-16, miR-29a, miR-144 and miR-150 can be regulated by ionizing radiation, the concentration of these four miRs was assessed in the plasma of NSCLC patients at different time points of radiotherapy by digital droplet PCR (ddPCR). Furthermore, their impact on patients’ prognosis was evaluated. The mean plasma levels of miR-16, miR-29a, miR-144 and miR-150 significantly differed intra- and inter-individually, and during therapy in NSCLC patients, but showed a strong positive correlation. The individual plasma levels of miR-16, miR-29a and miR-144 had prognostic value in NSCLC patients during or at the end of radiotherapy in Cox’s regression models. NSCLC patients with low levels of these three miRs at the end of radiotherapy had the worst prognosis. However, miR-150 plasma levels and treatment-dependent changes were not predictive. In conclusion, circulating miR-16, miR-29a and miR-144, but not miR-150, have a prognostic value in NSCLC patients undergoing radiotherapy