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-α 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.

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.

Hsp70 in Liquid Biopsies-A Tumor-Specific Biomarker for Detection and Response Monitoring in Cancer.

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat shock protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane Hsp70-positive tumor cells actively release Hsp70 in small extracellular vesicles with biophysical characteristics of exosomes. Due to conformational changes of Hsp70 in a lipid environment, most commercially available antibodies fail to detect membrane-bound and vesicular Hsp70. To fill this gap and to assess the role of vesicular Hsp70 in circulation as a potential tumor biomarker, we established the novel complete (comp)Hsp70 sandwich ELISA, using two monoclonal antibodies (mAbs), that is able to recognize both free and lipid-associated Hsp70 on the cell surface of viable tumor cells and on small extracellular vesicles. The epitopes of the mAbs cmHsp70.1 (aa 451-461) and cmHsp70.2 (aa 614-623) that are conserved among different species reside in the substrate-binding domain of Hsp70 with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/mL, high recovery rates of spiked liposomal Hsp70 (>84%), comparable values between human serum and plasma samples and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy donors. Hsp70 concentrations dropped concomitantly with a decrease in viable tumor mass upon irradiation of patients with approximately 20 Gy (range 18-22.5 Gy) and after completion of radiotherapy (60-70 Gy). In summary, the compHsp70 ELISA presented herein provides a sensitive and reliable tool for measuring free and vesicular Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a tumor-specific biomarker, for risk assessment (i.e., differentiation of grade III vs. IV adeno NSCLC) and monitoring of therapeutic outcomes.

Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.

Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.

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.

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.

Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis.

BACKGROUND AND AIMS: Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. METHODS: We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. RESULTS: Median OS of SBRT patients was 18.1 (10.3-25.9) months compared to 8.8 (8.2-9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8-23.2) months compared to 9.6 (8.6-10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. CONCLUSIONS: In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.

Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms.

The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1R132H expression were analyzed. The results revealed that IDH1R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments.

HPV, hypoxia and radiation response in head and neck cancer.

Over the last decades, the incidence of human papilloma virus (HPV) positive head and neck squamous-cell carcinoma (HNSCC) has significantly increased. Infection with high-risk HPV types drives tumourigenesis through expression of the oncoproteins E6 and E7. Currently, the primary treatment of HNSCC consists of radiotherapy, often combined with platinum-based chemotherapeutics. One of the common features of HNSCC is the occurrence of tumour hypoxia, which impairs the efficacy of radiotherapy and is a negative prognostic factor. Therefore, it is important to detect and quantify the severity of hypoxia, as well as develop strategies to specifically target hypoxic tumours. HPV-positive tumours are remarkably radiosensitive compared to HPV-negative tumours and consequently the HPV-positive patients have a better prognosis. This provides an opportunity to elucidate mechanisms of radiation sensitivity, which may reveal targets for improved therapy for HPV-negative head and neck cancers. In this review, we will discuss the differences between HPV-positive and HPV-negative head and neck tumours and methods of hypoxia detection and targeting in these disease types. Particular emphasis will be placed on the mechanisms by which HPV infection impacts radiosensitivity.

Predictive and prognostic value of tumor volume and its changes during radical radiotherapy of stage III non-small cell lung cancer : A systematic review.

PURPOSE: Lung cancer remains the leading cause of cancer-related mortality worldwide. Stage III non-small cell lung cancer (NSCLC) includes heterogeneous presentation of the disease including lymph node involvement and large tumour volumes with infiltration of the mediastinum, heart or spine. In the treatment of stage III NSCLC an interdisciplinary approach including radiotherapy is considered standard of care with acceptable toxicity and improved clinical outcome concerning local control. Furthermore, gross tumour volume (GTV) changes during definitive radiotherapy would allow for adaptive replanning which offers normal tissue sparing and dose escalation. METHODS: A literature review was conducted to describe the predictive value of GTV changes during definitive radiotherapy especially focussing on overall survival. The literature search was conducted in a two-step review process using PubMed®/Medline® with the key words "stage III non-small cell lung cancer" and "radiotherapy" and "tumour volume" and "prognostic factors". RESULTS: After final consideration 17, 14 and 9 studies with a total of 2516, 784 and 639 patients on predictive impact of GTV, GTV changes and its impact on overall survival, respectively, for definitive radiotherapy for stage III NSCLC were included in this review. Initial GTV is an important prognostic factor for overall survival in several studies, but the time of evaluation and the value of histology need to be further investigated. GTV changes during RT differ widely, optimal timing for re-evaluation of GTV and their predictive value for prognosis needs to be clarified. The prognostic value of GTV changes is unclear due to varying study qualities, re-evaluation time and conflicting results. CONCLUSION: The main findings were that the clinical impact of GTV changes during definitive radiotherapy is still unclear due to heterogeneous study designs with varying quality. Several potential confounding variables were found and need to be considered for future studies to evaluate GTV changes during definitive radiotherapy with respect to treatment outcome.

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.

Planning benchmark study for SBRT of early stage NSCLC : Results of the DEGRO Working Group Stereotactic Radiotherapy.

PURPOSE: The aim was to evaluate stereotactic body radiation therapy (SBRT) treatment planning variability for early stage nonsmall cell lung cancer (NSCLC) with respect to the published guidelines of the Stereotactic Radiotherapy Working Group of the German Society for Radiation Oncology (DEGRO). MATERIALS AND METHODS: Planning computed tomography (CT) scan and the structure sets (planning target volume, PTV; organs at risk, OARs) of 3 patients with early stage NSCLC were sent to 22 radiotherapy departments with SBRT experience: each department was asked to prepare a treatment plan according to the DEGRO guidelines. The prescription dose was 3 fractions of 15 Gy to the 65% isodose. RESULTS: In all, 87 plans were generated: 36 used intensity-modulated arc therapy (IMAT), 21 used three-dimensional conformal radiation therapy (3DCRT), 6 used static field intensity-modulated radiation therapy (SF-IMRT), 9 used helical radiotherapy and 15 used robotic radiosurgery. PTV dose coverage and simultaneously kept OARs doses were within the clinical limits published in the DEGRO guidelines. However, mean PTV dose (mean 58.0 Gy, range 52.8-66.4 Gy) and dose conformity indices (mean 0.75, range 0.60-1.00) varied between institutions and techniques (p ≤ 0.02). OARs doses varied substantially between institutions, but appeared to be technique independent (p = 0.21). CONCLUSION: All studied treatment techniques are well suited for SBRT of early stage NSCLC according to the DEGRO guidelines. Homogenization of SBRT practice in Germany is possible through the guidelines; however, detailed treatment plan characteristics varied between techniques and institutions and further homogenization is warranted in future studies and recommendations. Optimized treatment planning should always follow the ALARA (as low as reasonably achievable) principle.

Dosimetric comparison of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) in total scalp irradiation: a single institutional experience.

PURPOSE: Total scalp irradiation (TSI) is a rare but challenging indication. We previously reported that non-coplanar intensity-modulated radiotherapy (IMRT) was superior to coplanar IMRT in organ-at-risk (OAR) protection and target dose distribution. This consecutive treatment planning study compared IMRT with volumetric-modulated arc therapy (VMAT). MATERIALS AND METHODS: A retrospective treatment plan databank search was performed and 5 patient cases were randomly selected. Cranial imaging was restored from the initial planning computed tomography (CT) and target volumes and OAR were redelineated. For each patients, three treatment plans were calculated (coplanar/non-coplanar IMRT, VMAT; prescribed dose 50 Gy, single dose 2 Gy). Conformity, homogeneity and dose volume histograms were used for plan. RESULTS: VMAT featured the lowest monitor units and the sharpest dose gradient (1.6 Gy/mm). Planning target volume (PTV) coverage and homogeneity was better in VMAT (coverage, 0.95; homogeneity index [HI], 0.118) compared to IMRT (coverage, 0.94; HI, 0.119) but coplanar IMRT produced the most conformal plans (conformity index [CI], 0.43). Minimum PTV dose range was 66.8% -88.4% in coplanar, 77.5%-88.2% in non-coplanar IMRT and 82.8%-90.3% in VMAT. Mean dose to the brain, brain stem, optic system (maximum dose) and lenses were 18.6, 13.2, 9.1, and 5.2 Gy for VMAT, 21.9, 13.4, 14.5, and 6.3 Gy for non-coplanar and 22.8, 16.5, 11.5, and 5.9 Gy for coplanar IMRT. Maximum optic chiasm dose was 7.7, 8.4, and 11.1 Gy (non-coplanar IMRT, VMAT, and coplanar IMRT). CONCLUSION: Target coverage, homogeneity and OAR protection, was slightly superior in VMAT plans which also produced the sharpest dose gradient towards healthy tissue.

The relationship between tumor volume changes and serial plasma osteopontin detection during radical radiotherapy of non-small-cell lung cancer.

The prognostic quality of increased osteopontin (OPN) plasma levels has been demonstrated for the chemotherapy and surgery of lung cancer. There is also evidence in the literature that tumor volume impacts prognosis in definitive radiotherapy (RT) of (lung) cancer. We previously demonstrated that elevated plasma levels of OPN before, and increasing OPN plasma levels after RT significantly correlate with survival and outcome after curative-intent RT of non-small-cell lung cancer (NSCLC). Tumor volume was also associated with prognosis. The present prospective clinical study investigated the prognostic interrelation of OPN plasma levels and tumor volume and their changes in the radical RT of NSCLC. We evaluated a subset of patients (n=27) with inoperable, non-metastasized NSCLC of the previously published patient collective. Patients were treated with radical radiochemotherapy (2 Gy ad 66 Gy). OPN plasma concentrations were determined by ELISA before (t0), at the end (t1), and 4 weeks after RT (t2). GTV was delineated PET- and CT-correlated before RT (GTV1) and after 40 Gy (GTV2). The course of OPN during and after RT and the change of GTV during RT was monitored over time and correlated with prognosis. Median GTV2 after 40 Gy (63 ml) was significantly lower than pre-RT GTV1 (90 ml, P<0.0001). Median OPN before (t0), at the end of (t1) and four weeks after RT (t2) was 846, 777 and 624 ng/ml and not significantly different. GTV significantly declined by 39 ml during RT (P<0.0001) and OPN non-significantly decreased by 56 ng/ml during (t0 to t1) and by 54 ng/ml after RT (t1 to t2). No correlations were determined between absolute OPN and GTV values or their relative changes during RT. In univariate analysis, only GTV2 significantly predicted overall survival (OS, P=0.03). In multivariate analysis, both OPN t1 (P<0.001) and GTV2 (P=0.001) remained significant predictors of OS. Relative OPN plasma level changes after (t1 to t2) and GTV changes during RT (GTV 1 to GTV 2) significantly predicted OS (P=0.02). The combination of absolute GTV values before RT (GTV1) and GTV changes during RT (GTV1 to 2) were significantly associated with OS in both uni- and multivariate analysis (P=0.03). The combination of absolute OPN plasma levels and their changes with GTV and its changes did not reach statistical significance. The lack of a significant correlation between OPN and GTV together with the finding that OPN and GTV remained independent predictors of survival outcome but were not associated with OS in combination supports the hypothesis that tumor volume (GTV) and OPN plasma levels (both their changes and absolute values) are not interrelated in terms of prognosis but do possess each parameter separately, a prognostic quality in the radical RT of NSCLC which justifies further prospective studies to validate these results.

Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer.

Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after radiochemotherapy (RCT) at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test, which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69(+)/CD94(+) NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that squamous cell NSCLC is more immunogenic than adeno NSCLC.

Malignant melanoma brain metastases: Treatment results and prognostic factors--a single-center retrospective study.

The brain is one of the most frequent locations of metastasis in malignant melanoma. We aimed to identify prognostic factors for overall survival (OS) and local tumor control (LC) in patients with malignant melanoma metastasized to the brain treated by multimodal therapy. All patients diagnosed with malignant melanoma brain metastases between 1992 and 2011 at a single center were registered (n=100, 65% male, 35% female). OS and LC of individual brain metastases were retrospectively analyzed. Subgroup analyses was performed in patients with multiple brain metastasis (n=35) and LC per lesion (n=72) was evaluated in 37 patients. Median age was 57 (27-81) years. Fifty-three percent of patients had 1-2 brain metastases, 47% had >2 and 71% presented with additional extracranial metastases. Primary treatment included systemic therapy alone (temozolomide/fotemustine, 14%), local therapy (surgery and/or stereotactic radiotherapy, 25%), whole-brain radiotherapy (WBRT, 10%), combined WBRT and systemic therapy (18%), local therapy plus WBRT (5%) and combination of local and systemic therapy (8%). Three percent received a tri-modal therapy (WBRT, local and systemic therapy) and 17% refused treatment. Median follow-up in surviving patients was 32 (4-222) months, median OS in all patients 3.9 months (1-year survival 21.4%). Local therapy (p<0.001), systemic therapy (p=0.002), number of brain metastases and primary therapy including a local therapy (p<0.001) were significantly associated with OS. In the subgroup with multiple brain metastases (n=35), a trend (p=0.058) for improved OS after initial treatment with WBRT plus systemic therapy was noted (median OS 3.8 months) and use of these two modalities over the course of the disease was significantly associated with OS (p=0.007). The best LC per single lesion (n=37) could be achieved by combination of local with systemic therapy (p=0.011). Number of brain metastases, extracranial metastases and use of local therapy are independent prognostic factors in melanoma metastatic to the brain. LC and OS can be improved by combining local with systemic treatment. In patients with multiple brain metastases, WBRT plus systemic therapy provides superior OS.

Quality of life in very elderly radiotherapy patients: a prospective pilot study using the EORTC QLQ-ELD14 module.

PURPOSE: In very elderly cancer patients, health-related quality of life (HRQOL) is a particularly important issue but has rarely been studied due to a lack of specific instruments and of reference data. We performed a prospective analysis of HRQOL in patients ≥80 years undergoing radiotherapy with the newly validated elderly-specific HRQOL module EORTC QLQ-ELD14. METHODS: We prospectively assessed HRQOL in n = 50 radiotherapy patients ≥80 years (32% lung, 20% gastrointestinal, 8% each of breast, head and neck, gynecologic cancer) at the start (t1), end (t2), and 6 months after (t3) radiotherapy, using EORTC QLQ-C30 and EORTC QLQ-ELD14. Overall survival was determined in the whole cohort and subgroups. RESULTS: Median overall survival from the start of radiotherapy was 15 months; 1-year and 2-year overall survival rates were 57.1 and 31.0%, respectively. Eastern Cooperative Oncology Group (ECOG) performance status <2, Charlson comorbidity index ≤6, curative treatment intention, local tumor stage Union Internationale Contre le Cancer (UICC I, II), and total dose >45 Gy were associated with prolonged survival. No significant changes in any HRQOL domain were observed during the course of treatment (t1 to t2). Six months after radiotherapy (t3), a significant and clinically relevant deterioration of HRQOL was seen in EORTC QLQ-C30 for physical function and role function and in EORTC QLQ-ELD14 for future worries, burden of illness, and family support. CONCLUSIONS: In radiotherapy patients ≥80 years, HRQOL was maintained until the end of radiotherapy but deteriorated in general and elderly-specific areas thereafter, suggesting a need to develop specific supportive interventions for this age group.

Prognostic information of serial plasma osteopontin measurement in radiotherapy of non-small-cell lung cancer.

BACKGROUND: Circulating baseline levels of the plasma-protein osteopontin (OPN) have been suggested as a prognostic indicator in chemotherapy and surgery for lung cancer. However, the role of this hypoxia-related protein in radiotherapy of lung cancer is unclear. We previously demonstrated the prognostic effect of baseline OPN plasma levels which was increased by co-detection with other hypoxia-related proteins in the radical radiotherapy of non-small-cell lung cancer (NSCLC). This prospective clinical study investigated whether serial OPN measurements during and after curative-intent radiotherapy for NSCLC provide additional or superior prognostic information. METHODS: Sixty-nine patients with inoperable NSCLC were prospectively enrolled (55 M0, 14 M1). OPN plasma levels were measured before (t0), at the end (t1) and four weeks after radiotherapy (t2) by ELISA, compared between M0 and M1 patients and correlated with clinicopathological parameters. OPN levels were monitored over time and correlated with prognosis in M0-stage patients treated by radical 66-Gy radiotherapy ± chemotherapy. RESULTS: Pre-treatment OPN levels were associated with T stage (p = .03), lung function (p = .002), weight loss (p = .01), tumor volume (p = .02) and hemoglobin concentration (p = 04). M1 patients had significantly elevated OPN levels at all time points (p < .001). Patients with increasing OPN levels after radiotherapy had inferior freedom from relapse (p = .008), overall survival (p = .004) and disease-free survival (p = .001) compared to patients with stable or decreasing OPN levels. The risk of relapse in patients with increasing or stable OPN levels after radiotherapy was increased by a factor of 2.9 (p = .01). Patients with increasing post-treatment OPN levels had a 3.1-fold increased risk of death (p = .003). In an exploratory multivariate model, post-treatment OPN level changes but not absolute baseline OPN levels remained an independent prognostic factor for overall survival (p = .002) with a 3.6-fold increased risk of death, as well as N stage (p = .006). CONCLUSIONS: Our results suggest that OPN level changes over time, particularly post-treatment, may yield additional prognostic information in curative-intent radiotherapy of NSCLC.