Personal innovative approach in radiation therapy of lung cancer- functional lung avoidance SPECT-guided (ASPECT) radiation therapy: a study protocol for phase II randomised double-blind clinical trial.

BACKGROUND: Radiation therapy (RT) plays a key role in curative-intent treatment for locally advanced lung cancer. Radiation induced pulmonary toxicity can be significant for some patients and becomes a limiting factor for radiation dose, suitability for treatment, as well as post treatment quality of life and suitability for the newly introduced adjuvant immunotherapy. Modern RT techniques aim to minimise the radiation dose to the lungs, without accounting for regional distribution of lung function. Many lung cancer patients have significant regional differences in pulmonary function due to smoking and chronic lung co-morbidity. Even though reduction of dose to functional lung has shown to be feasible, the method of preferential functional lung avoidance has not been investigated in a randomised clinical trial. METHODS: In this study, single photon emission computed tomography (SPECT/CT) imaging technique is used for functional lung definition, in conjunction with advanced radiation dose delivery method in randomised, double-blind trial. The study aims to assess the impact of functional lung avoidance technique on pulmonary toxicity and quality of life in patients receiving chemo-RT for lung cancer. Eligibility criteria are biopsy verified lung cancer, scheduled to receive (chemo)-RT with curative intent. Every patient will undergo a pre-treatment perfusion SPECT/CT to identify functional lung. At radiation dose planning, two plans will be produced for all patients on trial. Standard reference plan, without the use of SPECT imaging data, and functional avoidance plan, will be optimised to reduce the dose to functional lung within the predefined constraints. Both plans will be clinically approved. Patients will then be randomised in a 2:1 ratio to be treated according to either the functional avoidance or the standard plan. This study aims to accrue a total of 200 patients within 3 years. The primary endpoint is symptomatic radiation-induced lung toxicity, measured serially 1-12 months after RT. Secondary endpoints include: a quality of life and patient reported lung symptoms assessment, overall survival, progression-free survival, and loco-regional disease control. DISCUSSION: ASPECT trial will investigate functional avoidance method of radiation delivery in clinical practice, and will establish toxicity outcomes for patients with lung cancer undergoing curative chemo-RT. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04676828 . Registered 1 December 2020.

Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas.

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA's pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.

Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome.

AIMS: Triple-negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non-small-cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC. METHODS AND RESULTS: PDL1 immunohistochemistry was performed on 161 primary TNBCs and assessed in the tumour as well as immune cells in the stromal compartment. PDL1 expression was very common in TNBC, expressed in the tumour cell membrane (64%), cytoplasm (80%) and stromal (93%) cellular compartments. Cytoplasmic tumoral expression of PDL1 was associated with a lower risk of breast cancer-specific death [hazard ratio (HR) 0.45, P = 0.035] while stromal PDL1 expression was associated with a lower rate of deaths from all causes (HR 0.305, P = 0.0042). Membranous expression of PDL1 was not associated with outcome. While both PDL1 expression and tumour-infiltrating lymphocytes were associated with a better outcome, only lymphovascular invasion and high tumour-infiltrating lymphocytes were independently prognostic for breast cancer-specific death. CONCLUSION: While PDL1 expression is frequent in TNBC, it was not independently prognostic. There were differences in outcome depending on the cellular compartment of PDL1 expression. These data provide further impetus for investigating the utility of immune checkpoint therapies in TNBC, given the clinical significance of tumour-infiltrating lymphocytes (TILs) and PDL1 expression in this cohort.

Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers.

BACKGROUND: The rates of oropharyngeal cancers such as tonsil cancers are increasing. The tumour suppressor protein Programmed Cell Death Protein 4 (PDCD4) has been implicated in the development of various human cancers and small RNAs such as microRNAs (miRNAs) can regulate its expression. However the exact regulation of PDCD4 by multiple miRNAs in oropharyngeal squamous cell carcinoma (SCC) is not well understood. RESULTS: Using two independent oropharyngeal SCC cohorts with a focus on the tonsillar region, we identified a miRNA profile differentiating SCC tissue from normal. Both miR-21 and miR-499 were highly expressed in tonsil SCC tissues displaying a loss of PDCD4. Interestingly, expression of the miRNA machinery, Dicer1, Drosha, DDX5 (Dead Box Helicase 5) and DGCR8 (DiGeorge Syndrome Critical Region Gene 8) were all elevated by greater than 2 fold in the tonsil SCC tissue. The 3'UTR of PDCD4 contains three binding-sites for miR-499 and one for miR-21. Using a wild-type and truncated 3'UTR of PDCD4, we demonstrated that the initial suppression of PDCD4 was mediated by miR-21 whilst sustained suppression was mediated by miR-499. Moreover the single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites. CONCLUSION: This study describes the regulation of PDCD4 specifically in tonsil SCC by miR-499 and miR-21 and has documented the loss of PDCD4 in tonsil SCCs. These findings highlight the complex interplay between miRNAs and tumour suppressor gene regulation and suggest that PDCD4 loss may be an important step in tonsillar carcinogenesis.

Radiotherapy Improves Survival in NSCLC After Oligoprogression on Immunotherapy: A Cohort Study.

Introduction: The patterns of oligoprogression after first-line immune checkpoint inhibitors (ICIs) for metastatic NSCLC are yet to be well established. An increasing volume of data suggests that directed radiotherapy improves survival outcomes in patients with progression after ICIs. Methods: A retrospective cohort study was performed on patients with metastatic NSCLC who had completed first-line programmed death-(ligand) 1 inhibitor therapy with or without chemotherapy at two high-volume cancer centers. We sought to characterize the frequency and location of oligoprogression and determine the overall survival (OS) after radiotherapy in this population. Results: A total of 159 patients were included in the study. At first progression, 62 (39.0%) were classified as undergoing oligoprogression. Multivariate analysis confirmed the presence of brain metastases was associated with an increased likelihood of oligoprogression (OR = 2.44, p = 0.04) with most (63.2%) of these patients experiencing progression intracranially. The presence of liver metastases was associated with a decreased likelihood of oligoprogression (OR = 0.17, p < 0.01). For patients with oligoprogression, those who received radiotherapy had a longer median progression-free survival-2 (PFS2) (17 versus 11.5 mo, HR = 0.51, p = 0.02) and a longer median OS (23 versus 13 mo, HR = 0.40, p < 0.001) compared with those who did not receive radiotherapy. No difference in PFS2 or OS outcomes was observed between patients who received radiotherapy versus those who did not for systemic progression. Conclusions: In patients with oligoprogressive metastatic NSCLC after treatment with first-line ICIs, radiotherapy significantly improves OS and PFS2 outcomes. Patients with baseline brain metastases are more likely to experience oligoprogression. Further prospective studies in directed, less heterogeneous populations of patients with metastatic NSCLC will be fundamental to optimize management.

Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy.

Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.

Radiation therapy for ventricular arrhythmias.

Ventricular arrhythmias (VA) can be life-threatening arrhythmias that result in significant morbidity and mortality. Catheter ablation (CA) is an invasive treatment modality that can be effective in the treatment of VA where medications fail. Recurrence occurs commonly following CA due to an inability to deliver lesions of adequate depth to cauterise the electrical circuits that drive VA or reach areas of scar responsible for VA. Stereotactic body radiotherapy is a non-invasive treatment modality that allows volumetric delivery of energy to treat circuits that cannot be reached by CA. It overcomes the weaknesses of CA and has been successfully utilised in small clinical trials to treat refractory VA. This article summarises the current evidence for this novel treatment modality and the steps that will be required to bring it to the forefront of VA treatment.

Chest wall pain after single-fraction thoracic stereotactic ablative Radiotherapy: Dosimetric analysis from the iSABR trial.

BACKGROUND AND PURPOSE: Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk. MATERIALS AND METHODS: This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting. RESULTS: There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V11Gy) and the minimum dose to the hottest 2 cc (D2cc) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D2cc > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V11Gy > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall. CONCLUSION: For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients.

Use of durvalumab in stage III non-small-cell lung cancer based on eligibility for the PACIFIC study.

BACKGROUND: Durvalumab following concurrent chemoradiotherapy is standard treatment for unresectable stage III non-small-cell lung cancer based on the results of the PACIFIC trial. Based on trial criteria, not all patients are eligible for durvalumab in routine clinical practice. METHODS: We evaluated eligibility for durvalumab in a real-world clinical setting and the impact of eligibility on outcomes. Consecutive patients treated with concurrent chemoradiotherapy at two tertiary centers between January 2015 and June 2022 were assessed. Clinical characteristics and outcomes were evaluated based on eligibility criteria for the PACIFIC trial. RESULTS: A total of 126 patients were included. Seventy patients (56%) were eligible for durvalumab. Ineligibility was associated with shorter progression-free survival of 9.7 months versus 18.4 months (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.39-0.95, p = 0.029) and overall survival of 26.4 months versus 58.7 months (HR 0.47, 95% CI 0.28-0.80, p = 0.005). Common reasons for ineligibility were history of previous malignancy (32%) and progressive disease or death during chemoradiotherapy (25%). Ineligible patients who received durvalumab had similar outcomes to eligible patients who received durvalumab. CONCLUSIONS: In a real-world cohort, adjuvant durvalumab is safe and beneficial in a substantial proportion of patients who would not have been eligible for the PACIFIC trial.

SABR for Early Non-Small Cell Lung Cancer: Changes in Pulmonary Function, Dyspnea, and Quality of Life.

PURPOSE: The aim of this study was to report pulmonary function tests (PFTs) and clinician-reported and patient-reported quality-of-life (QoL) outcomes on a cohort of patients with non-small cell lung cancer (NSCLC) treated with SABR. METHODS AND MATERIALS: A total of 119 patients with NSCLC were treated with SABR in the prospective cohort SSBROC study of patients with T1-T2N0M0 NSCLC. PFTs and QoL measures were obtained at baseline pretreatment and at 6-month intervals. Here we report on the 6- to 18-month time points. Analysis of covariance (ANCOVA) methods adjusting for baseline analyzed potential predictors on outcomes of PFTs and patient-reported dyspnea at 18 months. RESULTS: The only statistically significant decline in PFTs was seen in forced expiratory volume in 1 second (FEV1) at 18 months post-SABR, with a decline of -0.11 L (P = .0087; 95% CI, -0.18 to -0.02). Of potential predictors of decline, only a 1-unit increase in smoking pack-years resulted in a -0.12 change in diffusing capacity for carbon monoxide (P = .026; 95% CI, -0.02 to -0.23) and a 0.003 decrease in FEV1 (P = .026; 95% CI, -0.006 to -0.0004). For patient-reported outcomes, statistically significant worsening in both the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (QLQ-C30 Version 3) and the lung module (QLQ-LC13) dyspnea scores occurred at the 18-month time point, but not earlier. No potential predictors of worsening dyspnea were statistically significant. There was no statistically significant decline in clinician-reported outcomes or global QoL scores. CONCLUSIONS: We found a statistically significant decline in FEV1 at 18 months posttreatment. Smoking pack-years was a predictor for decline in diffusing capacity for carbon monoxide and FEV1 at 18 months. Worsening of patient-reported dyspnea scores was observed, consistent with the expected progression of lung comorbid disease.

Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial.

Importance: Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy. Objective: To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control. Design, Setting, and Participants: This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3). Intervention: Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3. Main outcome: Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up. Results: In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01463423.

Impact of DNA damage response defects in cancer cells on response to immunotherapy and radiotherapy.

The DNA damage response (DDR) is a complex set of downstream pathways triggered in response to DNA damage to maintain genomic stability. Many tumours exhibit mutations which inactivate components of the DDR, making them prone to the accumulation of DNA defects. These can both facilitate the development of tumours and provide potential targets for novel therapeutic interventions. The inhibition of the DDR has been shown to induce radiosensitivity in certain cancers, rendering them susceptible to treatment with radiotherapy and improving the therapeutic window. Moreover, DDR defects are a strong predictor of patient response to immune checkpoint inhibition (ICI). The ability to target the DDR selectively has the potential to expand the tumour neoantigen repertoire, thus increasing tumour immunogenicity and facilitating a CD8+ T and NK cell response against cancer cells. Combinatorial approaches, which seek to integrate DDR inhibition with radiotherapy and immunotherapy, have shown promise in early trials. Further studies are necessary to understand these synergies and establish reliable biomarkers.

Radiation therapy in the prevention and management of brain metastases in patients with small cell lung cancer: a narrative review.

OBJECTIVE: The purpose of this narrative review is to survey the current literature and provide treatment recommendations for the management of patients with brain metastases (BMs) from small cell lung cancer (SCLC). BACKGROUND: BMs are very common in patients with SCLC and management has changed significantly in recent years. Radiation techniques and systemic therapies have evolved and this review will highlight these recent studies and implications on clinical practice. METHODS: This narrative review covers prophylaxis and treatment of established BMs in patients with SCLC. Studies included are based on Medline, PubMed, Google scholar searches, abstracts from conference proceedings and references from published papers. CONCLUSIONS: Radiation therapy continue to have an important role in the prophylaxis and treatment of patients with BMs. Radiation technologies have resulted in significant reduction of toxicities and improved quality of life (QoL). There continues to be many unanswered questions and results of currently accruing trials will hopefully fill some of these gaps and refine the role of radiation therapy in the management of this condition.

A Systematic Review Into the Radiologic Features Predicting Local Recurrence After Stereotactic Ablative Body Radiotherapy (SABR) in Patients With Non-Small Cell Lung Cancer (NSCLC).

PURPOSE: Posttreatment surveillance for local recurrence (LR) after stereotactic ablative body radiotherapy (SABR) can include both fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). Radiation-induced lung injury shares a similar appearance to LR after treatment, making the detection of LR on imaging difficult for clinicians. We aimed to summarize radiologic features of CT and FDG-PET predicting LR and to evaluate radiomics as another tool for detecting LR. METHODS AND MATERIALS: We searched MEDLINE, EMBASE, and PubMed databases for published studies and Web of Science, Wiley Online, and Science Direct databases for conference abstracts that had patient populations with non-small cell lung cancer and reported post-SABR radiologic features of FDG-PET or CT and radiomics from either FDG-PET or CT. Studies for inclusion were independently reviewed by 2 authors. RESULTS: Across 32 relevant studies, the incidence of LR was 13% (222/1726). On CT, certain gross radiologic appearances and kinetic features of changes in size, diameter, volume, or 3 consecutive rises in volume of masslike consolidation are suggestive of LR. **Particular regard should be made for the presence of any ≥3 high-risk features on CT or the individual high-risk features of enlarging opacity at ≥12 month's post-SABR as being highly suspicious of LR. On FDG-PET a relative reduction of <5% of maximum standardised uptake value (SUVmax) from baseline in the first 12 months or cut-offs of SUVmax >5 and SUVmean >3.44 after 12 months can indicate LR. There is limited evidence available to corroborate radiomic features suggestive of LR. CONCLUSIONS: This research has identified common features of LR compared with radiation-induced lung injury, which may aid in early and accurate detection of LR post-SABR; further research is required to validate these findings.

MRI radiomics in the prediction of therapeutic response to neoadjuvant therapy for locoregionally advanced rectal cancer: a systematic review.

Introduction: The standard of care for locoregionally advanced rectal cancer is neoadjuvant therapy (NA CRT) prior to surgery, of which 10-30% experience a complete pathologic response (pCR). There has been interest in using imaging features, also known as radiomics features, to predict pCR and potentially avoid surgery. This systematic review aims to describe the spectrum of MRI studies examining high-performing radiomic features that predict NA CRT response.Areas covered: This article reviews the use of pre-therapy MRI in predicting NA CRT response for patients with locoregionally advanced rectal cancer (T3/T4 and/or N1+). The primary outcome was to identify MRI radiomic studies; secondary outcomes included the power and the frequency of use of radiomic features.Expert opinion: Advanced models incorporating multiple radiomics categories appear to be the most promising. However, there is a need for standardization across studies with regards to; the definition of NA CRT response, imaging protocols, and radiomics features incorporated. Further studies are needed to validate current radiomics models and to fully ascertain the value of MRI radiomics in the response prediction for locoregionally advanced rectal cancer.

Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas.

Radiotherapy is the cornerstone of treatment of high-grade gliomas (HGGs). It eradicates tumor cells by inducing oxidative stress and subsequent DNA damage. Unfortunately, almost all HGGs recur locally within several months secondary to radioresistance with intricate molecular mechanisms. Therefore, unravelling specific underlying mechanisms of radioresistance is critical to elucidating novel strategies to improve the radiosensitivity of tumor cells, and enhance the efficacy of radiotherapy. This review addresses our current understanding of how hypoxia and the hypoxia-inducible factor 1 (HIF-1) signaling pathway have a profound impact on the response of HGGs to radiotherapy. In addition, intriguing links between hypoxic signaling, circadian rhythms and cell metabolism have been recently discovered, which may provide insights into our fundamental understanding of radioresistance. Cellular pathways involved in the hypoxic response, DNA repair and metabolism can fluctuate over 24-h periods due to circadian regulation. These oscillatory patterns may have consequences for tumor radioresistance. Timing radiotherapy for specific times of the day (chronoradiotherapy) could be beneficial in patients with HGGs and will be discussed.

Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer.

Radiation therapy (RT) is responsible for at least 40% of cancer cures, however treatment resistance remains a clinical problem. There have been recent advances in understanding the molecular mechanisms of radiation-induced cell death. The type of cell death after radiation depends on a number of factors including cell type, radiation dose and quality, oxygen tension, TP53 status, DNA repair capacity, cell cycle phase at time of radiation exposure, and the microenvironment. Mitotic catastrophe (a pathway preceding cell death that happens in mitosis or as a consequence of aberrant mitotic progression) is the primary context of radiation-induced cell death in solid cancers, although in a small subset of cancers such as haematopoietic malignancies, radiation results in immediate interphase apoptosis, occurring within hours after exposure. There is intense therapeutic interest in using stereotactic ablative body radiotherapy (SABR), a precise, high-dose form of RT given in a small number of fractions, to prime the immune system for cancer cell killing, but the optimal radiation dose and fractionation remain unclear. Additionally, promising novel radiosensitisers targeting the cell cycle and DNA repair pathways are being trialled. In the context of the increasing use of SABR and such novel agents in the clinic, we provide an updated primer on the major types of radiation-induced cell death, focussing on their molecular mechanisms, factors affecting their initiation, and their implications on immunogenicity.

Role of gene signatures combined with pathology in classification of oropharynx head and neck cancer.

Treatment personalisation remains an unmet need in oropharynx cancer (OPC). We aimed to determine whether gene expression signatures improved upon clinico-pathological predictors of outcome in OPC. The clinico-pathological predictors, AJCC version 7 (AJCC 7), AJCC 8, and a clinical algorithm, were assessed in 4 public series of OPC (n = 235). Literature review identified 16 mRNA gene expression signatures of radiosensitivity, HPV status, tumour hypoxia, and microsatellite instability. We quality tested signatures using a novel sigQC methodology, and added signatures to clinico-pathological variables as predictors of survival, in univariate and multivariate analyses. AJCC 7 Stage was not predictive of recurrence-free survival (RFS) or overall survival (OS). AJCC 8 significantly predicted RFS and OS. Gene signature quality was highly variable. Among HPV-positive cases, signatures for radiosensitivity, hypoxia, and microsatellite instability revealed significant underlying inter-tumour biological heterogeneity, but did not show prognostic significance when adjusted for clinical covariates. Surprisingly, among HPV-negative cases, a gene signature for HPV status was predictive of survival, even after adjustment for clinical covariates. Across the whole series, several gene signatures representing HPV and microsatellite instability remained significant in multivariate analysis. However, quality control and independent validation remain to be performed to add prognostic information above recently improved clinico-pathological variables.

Circulating MicroRNAs as Prognostic Molecular Biomarkers in Human Head and Neck Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Circulating microRNAs (miRNAs) are potential molecular biomarkers for cancer detection; however, little is known about their prognostic role in head and neck cancer. This current study is aimed at evaluating the role of novel miRNAs in the survival of head and neck cancer patients. MATERIALS AND METHODS: We performed a systematic literature search using online databases for articles published between December 2006 and February 2019. A meta-analysis was conducted to assess the correlation between miRNA expressions and overall survival (OS) among the selected head and neck cancer studies. After multilevel screening by reviewers, meta-analysis was performed using hazard ratios (HR) and associated 95% confidence interval (CI) of survival to calculate a pooled effect size. RESULT: A total of 1577 patients across 13 studies were included in the literature review, with 18 miRNAs upregulated and 4 miRNAs downregulated predicting a poor overall survival. The forest plot generated using cumulated survival data resulted in a pooled HR value of 2.943 (95% CI: 2.394-3.618) indicating a strong association of dysregulated miRNA expression with a poor outcome. Only 2 miRNAs-low levels of miR-9 and high levels of miR-483-5p-were observed in two studies, both showing a significant association with overall cancer survival. CONCLUSION: To our knowledge, this is the first comprehensive systematic review and meta-analysis that examines the prognostic role of circulating miRNAs from blood in head and neck cancer patients. The combined effect estimates a HR across multiple studies and also supports the previous individual findings that an alteration in miRNA expression is highly associated with poor prognosis. This has the potential to use serum and/or plasma miRNAs as biomarkers and become novel tools for predicting the prognosis of head and neck cancer patients in the near future.