Lessons learned for spine SABR?

•SABR has shown survival benefits in oligometastatic cases, particularly in low-volume metastatic disease states.•Spine SABR offers potential improvements in local control, and pain response for metastatic spine tumors.•Technical requirements for SABR, like advanced image guidance and immobilization systems, are increasingly available.•Current data suggests high local control rates (75-95%) and variable pain responses (40-90%) with SABR using single or multi-fraction regimens.•Further randomized trials are needed to explore SABR applications in different scenarios and populations, while considering global health aspects for wider accessibility.

Mortality due to cancer treatment delay: systematic review and meta-analysis.

OBJECTIVE: To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Published studies in Medline from 1 January 2000 to 10 April 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models. RESULTS: The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P<0.05) for 13 of 17 indications. Surgery findings were consistent, with a mortality risk for each four week delay of 1.06-1.08 (eg, colectomy 1.06, 95% confidence interval 1.01 to 1.12; breast surgery 1.08, 1.03 to 1.13). Estimates for systemic treatment varied (hazard ratio range 1.01-1.28). Radiotherapy estimates were for radical radiotherapy for head and neck cancer (hazard ratio 1.09, 95% confidence interval 1.05 to 1.14), adjuvant radiotherapy after breast conserving surgery (0.98, 0.88 to 1.09), and cervix cancer adjuvant radiotherapy (1.23, 1.00 to 1.50). A sensitivity analysis of studies that had been excluded because of lack of information on comorbidities or functional status did not change the findings. CONCLUSIONS: Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

Pulmonary Artery Abnormalities in Ex-smokers with and without Airflow Obstruction.

Pulmonary vascular disease is a common complication of chronic obstructive pulmonary disease (COPD), and an important risk factor for COPD exacerbations and death. We explored the relationship between pulmonary artery volumes measured using thoracic computed tomography (CT) and lung structure-function measured using spirometry, CT and magnetic resonance imaging (MRI) in 124 ex-smokers with (n = 68) and without (n = 56) airflow obstruction, and a control group of 35 never-smokers. We observed significantly greater main (p = .01), right (p = .001) and total (p = .003) pulmonary artery volumes in ex-smokers with airflow obstruction as compared to ex-smokers without airflow obstruction. There were also significantly greater pulmonary artery volumes in both ex-smoker subgroups, compared to the never-smoker subgroup (p = .008). For all participants, there were significant correlations for pulmonary artery volumes with the ratio of the forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), the diffusing capacity of the lung for carbon monoxide (DLCO%pred), airway count, MRI ventilation defect percent and MRI apparent diffusion coefficients. In ex-smokers, ventilation defect percent was significantly correlated with right (r = 0.27, p = .02) and total (r = 0.25, p = .03) pulmonary artery volumes. Multivariate zero-inflated Poisson regression analysis showed that FEV1%pred (p = .004), DLCO%pred (p = .03), the six minute walk distance (p = .04) and total pulmonary artery volume (p = .03) were significant predictors of acute exacerbations of COPD, while the number of previous exacerbations was not. In conclusion, pulmonary artery enlargement measured using thoracic CT was observed even in ex-smokers without airflow obstruction and was predictive of COPD exacerbations in ex-smokers with airflow obstruction.

Oscillatory Positive Expiratory Pressure in Chronic Obstructive Pulmonary Disease.

Evidence-based guidance for the use of airway clearance techniques (ACT) in chronic obstructive pulmonary disease (COPD) is lacking in-part because well-established measurements of pulmonary function such as the forced expiratory volume in 1s (FEV1) are relatively insensitive to ACT. The objective of this crossover study was to evaluate daily use of an oscillatory positive expiratory pressure (oPEP) device for 21-28 days in COPD patients who were self-identified as sputum-producers or non-sputum-producers. COPD volunteers provided written informed consent to daily oPEP use in a randomized crossover fashion. Participants completed baseline, crossover and study-end pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ), Patient Evaluation Questionnaire (PEQ), Six-Minute Walk Test and (3)He magnetic resonance imaging (MRI) for the measurement of ventilation abnormalities using the ventilation defect percent (VDP). Fourteen COPD patients, self-identified as sputum-producers and 13 COPD-non-sputum-producers completed the study. Post-oPEP, the PEQ-ease-bringing-up-sputum was improved for sputum-producers (p = 0.005) and non-sputum-producers (p = 0.04), the magnitude of which was greater for sputum-producers (p = 0.03). There were significant post-oPEP improvements for sputum-producers only for FVC (p = 0.01), 6MWD (p = 0.04), SGRQ total score (p = 0.01) as well as PEQ-patient-global-assessment (p = 0.02). Clinically relevant post-oPEP improvements for PEQ-ease-bringing-up-sputum/PEQ-patient-global-assessment/SGRQ/VDP were observed in 8/7/9/6 of 14 sputum-producers and 2/0/3/3 of 13 non-sputum-producers. The post-oPEP change in (3)He MRI VDP was related to the change in PEQ-ease-bringing-up-sputum (r = 0.65, p = 0.0004) and FEV1 (r = -0.50, p = 0.009). In COPD patients with chronic sputum production, PEQ and SGRQ scores, FVC and 6MWD improved post-oPEP. FEV1 and PEQ-ease-bringing-up-sputum improvements were related to improved ventilation providing mechanistic evidence to support oPEP use in COPD. Clinical Trials # NCT02282189 and NCT02282202.

Noninvasive quantification of alveolar morphometry in elderly never- and ex-smokers.

Diffusion-weighted magnetic resonance imaging (MRI) provides a way to generate in vivo lung images with contrast sensitive to the molecular displacement of inhaled gas at subcellular length scales. Here, we aimed to evaluate hyperpolarized (3)He MRI estimates of the alveolar dimensions in 38 healthy elderly never-smokers (73 ± 6 years, 15 males) and 21 elderly ex-smokers (70 ± 10 years, 14 males) with (n = 8, 77 ± 6 years) and without emphysema (n = 13, 65 ± 10 years). The ex-smoker and never-smoker subgroups were significantly different for FEV1/FVC (P = 0.0001) and DLCO (P = 0.009); while ex-smokers with emphysema reported significantly diminished FEV1/FVC (P = 0.02) and a trend toward lower DLCO (P = 0.05) than ex-smokers without emphysema. MRI apparent diffusion coefficients (ADC) and CT measurements of emphysema (relative area-CT density histogram, RA950) were significantly different (P = 0.001 and P = 0.007) for never-smoker and ex-smoker subgroups. In never-smokers, the MRI estimate of mean linear intercept (260 ± 27 µm) was significantly elevated as compared to the results previously reported in younger never-smokers (210 ± 30 µm), and trended smaller than in the age-matched ex-smokers (320 ± 72 µm, P = 0.06) evaluated here. Never-smokers also reported significantly smaller internal (220 ± 24 µm, P = 0.01) acinar radius but greater alveolar sheath thickness (120 ± 4 µm, P < 0.0001) than ex-smokers. Never-smokers were also significantly different than ex-smokers without emphysema for alveolar sheath thickness but not ADC, while ex-smokers with emphysema reported significantly different ADC but not alveolar sheath thickness compared to ex-smokers without CT evidence of emphysema. Differences in alveolar measurements in never- and ex-smokers demonstrate the sensitivity of MRI measurements to the different effects of smoking and aging on acinar morphometry.

Differences in hyperpolarized (3) He ventilation imaging after 4 years in adults with cystic fibrosis.

PURPOSE: To evaluate cystic fibrosis (CF) subjects over 4 years using (3) He magnetic resonance imaging (MRI), pulmonary function tests, and track hospitalization and physician visits. MATERIALS AND METHODS: Five CF adults provided written informed consent to an approved protocol and underwent MRI, spirometry, and plethysmography at baseline, 7 days, and 4 ± 1 years later. (3) He MRI ventilation defect percent (VDP) was generated for all subjects and timepoints. RESULTS: After 4 years, mean forced expiratory volume in 1 second / forced vital capacity (FEV1 /FVC) was lower (P = 0.01) in all subjects and there were no other pulmonary function test changes. Two CF adults showed significantly elevated (worse) (3) He VDP at baseline and after 4 years they had significantly greater (worsened) VDP (P = 0.02), without a significant FEV1 decline (P = 0.06) but with a greater number of exacerbations (P < 0.05). Baseline VDP strongly correlated with FEV1 (r(2) = 0.98, P = 0.0007) at 4-year follow-up. CONCLUSION: For two CF subjects, VDP was significantly worse at baseline and worsened over 4 years, which was in agreement with a greater number of hospitalizations and clinic visits. These results are limited by the very small sample size, but the strong VDP correlation with longitudinal changes in FEV1 generates the hypothesis that abnormal VDP may temporally precede FEV1 decline in CF subjects; this must be tested in a larger CF study.

Pulmonary ventilation defects in older never-smokers.

Hyperpolarized (3)He MRI previously revealed spatially persistent ventilation defects in healthy, older compared with healthy, younger never-smokers. To understand better the physiological consequences and potential relevance of (3)He MRI ventilation defects, we evaluated (3)He-MRI ventilation-defect percent (VDP) and the effect of deep inspiration (DI) and salbutamol on VDP in older never-smokers. To identify the potential determinants of ventilation defects in these subjects, we evaluated dyspnea, pulmonary function, and cardiopulmonary exercise test (CPET) measurements, as well as occupational and second-hand smoke exposure. Fifty-two never-smokers (71 ± 6 yr) with no history of chronic respiratory disease were evaluated. During a single visit, pulmonary function tests, CPET, and (3)He MRI were performed and the Burden of Obstructive Lung Disease questionnaire administered. For eight of 52 subjects, there was spirometry evidence of airflow limitation (Global Initiative for Chronic Obstructive Lung Disease-Unclassified, I, and II), and occupational exposure was reported in 13 of 52 subjects. In 13 of 52 (25%) subjects, there were no ventilation defects and in 39 of 52 (75%) subjects, ventilation defects were observed. For those subjects with ventilation defects, six of 39 showed a VDP response to DI/salbutamol. Ventilation heterogeneity and VDP were significantly greater, and forced expiratory volume in 1 s (FEV1)/forced vital capacity was significantly lower (P < 0.05) for subjects with ventilation defects with a response to DI/salbutamol than subjects with ventilation defects without a response to DI/salbutamol and subjects without ventilation defects. In a step-wise, forward multivariate model, FEV1, inspiratory capacity, and airway resistance significantly predicted VDP (R(2) = 0.45, P < 0.001). In conclusion, most never-smokers had normal spirometry and peripheral ventilation defects not reversed by DI/salbutamol; such ventilation defects were likely related to irreversible airway narrowing/collapse but not to dyspnea and decreased exercise capacity.

What can surrogate tissues tell us about the oxidative stress status of the prostate? A hypothesis-generating in-vivo study.

BACKGROUND: Prostatic oxidative stress (OS) is androgen-regulated and a key event in the development of prostate cancer (PC). Thus, reducing prostatic OS is an attractive target for PC prevention strategies. We sought to determine if the individual's prostatic OS status can be determined by examining the OS in surrogate androgen regulated tissues from the same host. METHODOLOGY/PRINCIPAL FINDINGS: Adult male rats were divided equally into three groups: (A-) underwent bilateral orchiectomy, (A+) received continuous testosterone supplementation or (C) were eugonadal. Serum testosterone, 8-hydroxy-2-deoxyguanosine (8-OHdG) and anti-oxidative capacity (AOC) were determined after 72 hrs and the prostate, salivary glands and the hair follicles' Dermal Papillary Cells (DPC) from each animal were harvested, embedded into tissue microarray and examined for the expression of 8-OHdG by immuno-staining. Multi-variate regression was used to analyze inter-individual differences in OS staining within each androgen group and if there was a correlation between serum testosterone, 8-OHdG or AOC and Prostatic OS in tissues of same host. At the group level, 8-OHdG staining intensity directly correlated with serum testosterone levels in all three target tissues (p>0.01, Mann-Whitney Test). Although different levels of prostatic OS were noted between rats with similar serum testosterone levels and similar systemic OS measurements (p<0.01), there were no intra-individual differences between the OS status of the prostate and DPC (p<0.05). CONCLUSIONS/SIGNIFICANCE: The level of prostatic OS is correlated with the OS of hair follicles and salivary glands, but not systemic OS. Moreover, systemic AOC negatively correlates with both prostatic and hair follicle OS. This suggests that hair follicle and salivary gland OS can serve as surrogate markers for the efficiency of OS reduction. This has tremendous potential for the rational evaluation of patient response to prevention strategies.