Abstract Purpose To validate the predictive impact of a hypoxia gene expression classifier in identifying patients with head and neck squamous cell carcinoma (HNSCC) having benefit from hypoxic ...modification of radiotherapy. Patients and methods Gene expressions were quantified from formalin-fixed, paraffin-embedded tumour biopsies of 323 HNSCC patients randomized for placebo or nimorazole in conjunction with radiotherapy in the DAHANCA 5 study. Tumours were classified as either “more” or “less” hypoxic with a classifier constituting of 15 hypoxia responsive genes. The predictive impact was evaluated by analysing the response to nimorazole vs. placebo in terms of loco-regional tumour control (LRC) and disease-specific survival (DSS) in the two classified groups. Results Hundred and fourteen patients (35%) were classified as having “more” hypoxic tumours. These patients had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC (5-year actuarial values 49% vs. 18%; p = 0.001) and DSS (48% vs. 30%; p = 0.04). “Less” hypoxic tumours had no significant effect of hypoxic modification (LRC: 50% vs. 44%; p = 0.39, DSS: 57% vs. 51%; p = 0.49) and generally an outcome, which was similar to “more” hypoxic tumours treated with nimorazole. In contrast to HPV-negative tumours, HPV-positive tumours had a substantially better outcome in response to radiotherapy, which was irrespective of hypoxic modification. Conclusions A predictive 15-gene hypoxia classifier could identify patients associated with improved outcome after combining radiotherapy with hypoxic modification and underlines the relevance of such therapy. The impact of the classifier was limited to HPV-negative tumours.
Tumour hypoxia in locally advanced squamous cervical cancer (LACC) has been shown to be of substantial prognostic importance. The aims of the present study were therefore to investigate if hypoxia ...could be identified by a newly validated hypoxic gene expression classifier and used as a prognostic factor for disease free survival (DFS).
Paraffin embedded biopsies were obtained from 190 patients with LACC with squamous cell carcinoma treated 2005-2016 with chemo-radiation and image guided adaptive brachytherapy. Analysis of hypoxia was successful in 183 patients (96%). Hypoxic classification of tumours into 'more' or 'less' hypoxic was based on 15 genes using the same method as in a prospective head and neck cancer trial (NCT02661152). HPV was genotyped using INNO-LiPA. Local tumour invasion was evaluated by the T-score. Primary endpoint was DFS analysed by Kaplan-Meier and Cox regression. Events were death of any cause, persistent disease, or recurrence.
The FIGO
2009
stage distribution was IB-IIA 9%, IIB 64%, and III-IVA 27%, and mean T-score was 7.2. Pathological nodes were present in 53%. Median observation time was 5.2 years. Local control rate at 5 years was 96%, and pelvic (loco-regional) control 91%. Overall, 36% of the tumours were classified as 'more' hypoxic. The frequency of 'more' hypoxic tumours increased with local tumour intrusion (30% for T-score 0-9 vs. 55% for T-score ≥10, p = 0.004). Hypoxia was associated with decreased DFS in univariate, HR 1.71 (1.04-2.82), and multivariate analysis, HR 1.75 (1.04-2.92), and the effect was particularly observed among tumours with a T-score ≥10. HPV 16/18 was not associated with improved DFS in neither in univariate nor in multivariate analysis.
Hypoxic gene expression is a prominent prognostic factor for DFS in LACC with SCC histology and should be considered for treatment stratification in clinical trials.
Highlights • Radiogenomics is a scientific field related to radiobiology. • It addresses associations between genetic variants and normal tissue radiosensitivity. • More than 130 original papers have ...been published on this topic. • Several compelling associations have been reported.
Given the poor results using hypofractionated radiotherapy for early breast cancer, a dose of 50 Gy in 25 fractions (fr) has been the standard regimen used by the Danish Breast Cancer Group (DBCG) ...since 1982. Results from more recent trials have stimulated a renewed interest in hypofractionation, and the noninferiority DBCG HYPO trial (ClincalTrials.gov identifier: NCT00909818) was designed to determine whether a dose of 40 Gy in 15 fr does not increase the occurrence of breast induration at 3 years compared with a dose of 50 Gy in 25 fr.
One thousand eight hundred eighty-two patients > 40 years of age who underwent breast-conserving surgery for node-negative breast cancer or ductal carcinoma in situ (DCIS) were randomly assigned to radiotherapy at a dose of either 50 Gy in 25 fr or 40 Gy in 15 fr. The primary end point was 3-year grade 2-3 breast induration assuming noninferiority regarding locoregional recurrence.
A total of 1,854 consenting patients (50 Gy, n = 937; 40 Gy, n = 917) were enrolled from 2009-2014 from eight centers. There were 1,608 patients with adenocarcinoma and 246 patients with DCIS. The 3-year rates of induration were 11.8% (95% CI, 9.7% to 14.1%) in the 50-Gy group and 9.0% (95% CI, 7.2% to 11.1%) in the 40-Gy group (risk difference, -2.7%; 95% CI, -5.6% to 0.2%;
= .07). Systemic therapies and radiotherapy boost did not increase the risk of induration. Telangiectasia, dyspigmentation, scar appearance, edema, and pain were detected at low rates, and cosmetic outcome and patient satisfaction with breast appearance were high with either no difference or better outcome in the 40-Gy cohort compared with the 50-Gy cohort. The 9-year risk of locoregional recurrence was 3.3% (95% CI, 2.0% to 5.0%) in the 50-Gy group and 3.0% (95% CI, 1.9% to 4.5%) in the 40-Gy group (risk difference, -0.3%; 95% CI, -2.3% to 1.7%). The 9-year overall survival was 93.4% (95% CI, 91.1% to 95.1%) in the 50-Gy group and 93.4% (95% CI, 91.0% to 95.2%) in the 40-Gy group. The occurrence of radiation-associated cardiac and lung disease was rare and not influenced by the fractionation regimen.
Moderately hypofractionated breast irradiation of node-negative breast cancer or DCIS did not result in more breast induration compared with standard fractionated therapy. Other normal tissue effects were minimal, with similar or less frequent rates in the 40-Gy group. The 9-year locoregional recurrence risk was low.
Abstract Objective: Reverse transcription quantitative real-time polymerase chain reaction is efficient for quantification of gene expression, but the choice of reference genes is of paramount ...importance as it is essential for correct interpretation of data. This is complicated by the fact that the materials often available are routinely collected formalin-fixed, paraffin-embedded (FFPE) samples in which the mRNA is known to be highly degraded. The purpose of this study was to investigate 22 potential reference genes in sarcoma FFPE samples and to study the variation in expression level within different samples taken from the same tumor and between different histologic types. Methods: Twenty-nine patients treated for sarcoma were enrolled. The samples encompassed 82 (FFPE) specimens. Extraction of total RNA from 7-μm FFPE sections was performed using a fully automated, bead-base RNA isolation procedure, and 22 potential reference genes were analyzed by reverse transcription quantitative real-time polymerase chain reaction. The stability of the genes was analyzed by RealTime Statminer. The intrasamples variation and the interclass correlation coefficients were calculated. The linear regression model was used to calculate the degradation of the mRNA over time. Results: The quality of RNA was sufficient for analysis in 84% of the samples. Recommended reference genes differed with histologic types. However, PPIA, SF3A1 , and MRPL19 were stably expressed regardless of the histologic type included. The variation in ∆Cq value for samples from the same patients was similar to the variation between patients. It was possible to compensate for the time-dependent degradation of the mRNA when normalization was made using the selected reference genes. Conclusion: PPIA, SF3A1 , and MRPL19 are suitable reference genes for normalization in gene expression studies of FFPE samples from sarcoma regardless of the histology.
Hospital-acquired infections are the most frequent adverse events in health care and can be reduced by improving the hand hygiene compliance (HHC) of health care workers (HCWs). We aimed to ...investigate the effect of nudging with sensor lights on HCWs' HHC.
An 11-month intervention study was conducted in 2 inpatient departments at a university hospital. An automated monitoring system (Sani Nudge
) measured the HHC. Reminder and feedback nudges with lights were displayed on alcohol-based hand rub dispensers. We compared the baseline HHC with HHC during periods of nudging and used the follow-up data to establish if a sustained effect had been achieved.
A total of 91 physicians, 135 nurses, and 15 cleaning staff were enrolled in the study. The system registered 274,085 hand hygiene opportunities in patient rooms, staff restrooms, clean rooms, and unclean rooms. Overall, a significant, sustained effect was achieved by nudging with lights in relation to contact with patients and patient-near surroundings for both nurses and physicians. Furthermore, a significant effect was observed on nurses' HHC in restrooms and clean rooms. No significant effect was found for the cleaning staff.
Reminder or feedback nudges with light improved and sustained physicians' and nurses' HHC, and constitute a new way of changing HCWs' hand hygiene behavior.
Blood-based protein biomarkers can be a useful tool as pre-treatment prognostic markers, as they can reflect both variations in the tumor microenvironment and the host immune response. We ...investigated the influence of a panel of plasma proteins for the development of any failure defined as recurrent disease in the T-, N-, or M-site in HNSCC.
We used a multiplex bead-based approach to analyze 19 proteins in 86 HNSCC patients and 15 healthy controls. We evaluated the associations between the biomarkers, loco-regional failure, failure in the T-, N-, or M-site, overall survival (OS), p16 status, and hypoxia.
In 41 p16 positive oropharynx cancer patients we identified a profile of biomarkers consisting of upregulation of IL-2, IL-4, IL-6, IL-8, eotaxin, GRO-a, and VEGF and downregulation of VEGFR-1 and VEGFR-2 with a significantly reduced risk of failure (p<0.01). None of the individual proteins were associated with outcome.
The identified plasma profile potentially reflects an activated immune response in a subgroup of the p16 positive patients.
•We present a comprehensive analysis of the DBCG 82bc randomized trial with a 30-year long-term follow-up.•I am study with 3083 patients did we evaluate the importance of postmastectomy irradiation ...(PMRT) in high-risk pre- and postmenopausal breast cancer patients who also received adjuvant systemic therapy.•We observed that PMRT strongly improved the loco-regional tumor control and subsequent long-term survival.•Such benefit could be achieved without any excess ischemic heart damage or other non-breast cancer related death.•Thus, radiotherapy has an important role in the multidisciplinary treatment of breast cancer.
Between 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (<70 years) breast cancer patients comparing mastectomy plus adjuvant systemic therapy alone versus the same treatment plus postoperative irradiation.
To present a comprehensive analysis of the complete DBCG 82bc study with a 30-year long-term follow-up of the cancer therapeutic effect and survival, together with an additional focus on the potential long-term life-threatening morbidity related to cardiac irradiation and/or the risk of secondary cancer induction.
A total of 3083 patients with pathological stage II and stage III breast cancer were after mastectomy randomly assigned to receive adjuvant systemic therapy and postoperative irradiation to the chestwall and regional lymph nodes (1538 pts), or adjuvant systemic therapy alone (1545 pts). Pre- and menopausal patients (DBCG 82b) received 8–9 cycles of CMF with an interval of 4 weeks, whereas postmenopausal patients (DBCG 82c) received tamoxifen 30 mg daily for one year. The median follow-up time was 34 years. The primary endpoints were loco-regional recurrence (LRR) and overall mortality, and the secondary endpoints were distant metastasis, breast cancer mortality, and irradiation related late morbidity.
Overall the 30-year cumulative incidence of loco-regional recurrence was 9% in irradiated patients versus 37% in non-irradiated patients who received adjuvant systemic therapy alone (HR: 0.21 95% cfl 0.18–0.26). Distant metastasis probability at 30 years was 49% in irradiated patients compared to 60% in non-irradiated (HR: 0.77 0.70–0.84). Consequently, these figures resulted in a reduced breast cancer mortality: 56% vs 67% (HR: 0.75 0.69–0.82, and overall mortality (81% vs 86% at 30 years (p < 0.0001), HR: 0.83 0.77–0.90 in favor of irradiation. Radiotherapy did not result in any significant excess death of other courses, such as ischemic heart disease, HR: 0.82 0.58–1.18; nor secondary lung cancer HR: 1.44 0.92–2.24, or other non-cancer related death HR: 1.15 0.92–1.45.
The study definitely demonstrate that optimal long-term treatment benefit of high-risk breast cancer can only be achieved if both loco-regional and systemic tumor control are aimed for. Therefore, radiotherapy has an important role in the multidisciplinary treatment of breast cancer. The PMRT treatment did not result in excess ischemic heart damage, nor in other non-breast cancer related death.
•Increased risk of coronary artery disease in left-sided versus right-sided breast cancer patients irradiated with non-CT-based techniques was observed in the non-CT-based period within the first ...5 years after radiotherapy and was significant after 10 years.•No increased risk of coronary artery disease in left-sided versus right-sided patients was observed in the CT-based period.•Risk of valvular heart disease was not associated with laterality of radiotherapy the irradiated breast cancer at a median follow-up of 8 years.
Radiotherapy (RT) for early breast cancer (BC) reduces the risk of recurrence and improves overall survival. However, thoracic RT may cause some incidental RT dose to the heart with subsequent risk of heart disease. During 2000–2010, CT-based RT planning was gradually introduced. The aim of this study was to investigate the risk of cardiac events in left-sided compared with right-sided BC patients treated during a non-CT-based (1999–2007) vs a CT-based period (2008–2016).
Information on BC and cardiac events among Danish women was obtained from population-based medical registers. Patients diagnosed with BC during 1999–2016, were included. A cardiac event was defined as coronary artery disease or severe valvular heart disease.
Among 29,662 patients, 22,056 received RT. For those irradiated during the non-CT-based period, the 10-year cumulative risk of cardiac event was 1.7% (95% CI 1.4–2.0) at median follow-up of 11.1 years. The incidence rate ratio (IRR) for cardiac event in left-sided vs right-sided patients was 1.44 (1.07–1.94) and a trend towards worse outcome was seen within the first 10 years after RT and approached statistical significance with longer follow-up. Among patients irradiated during the CT-based period, the 10-year cumulative risk of cardiac event was 2.1% (1.8–2.4) at median 6.8 years follow-up. The IRR for cardiac event in left-sided vs right-sided patients was 0.90 (0.69–1.16) and no trend towards worse outcome within the first 10 years was observed.
This study confirmed a higher risk of cardiac events in left-sided vs right-sided BC patients irradiated during a non-CT-based period. For patients irradiated during a CT-based period, no increased risk of cardiac events in left-sided vs right-sided patients was observed within the first 10 years after RT, whilst information on cardiac events beyond 10 years after RT was limited.
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