Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect ...observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits.
ClinicalTrials.gov NCT01129115.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We assess the relationship between temperature and global sea-level (GSL) variability over the Common Era through a statistical metaanalysis of proxy relative sea-level reconstructions and tide-gauge ...data. GSL rose at 0.1 ± 0.1 mm/y (2σ) over 0–700 CE. A GSL fall of 0.2 ± 0.2 mm/y over 1000–1400 CE is associated with ∼0.2 °C global mean cooling. A significant GSL acceleration began in the 19th century and yielded a 20th century rise that is extremely likely (probability P ≥ 0.95) faster than during any of the previous 27 centuries. A semiempirical model calibrated against the GSL reconstruction indicates that, in the absence of anthropogenic climate change, it is extremely likely (P = 0.95) that 20th century GSL would have risen by less than 51% of the observed 13.8 ± 1.5 cm. The new semiempirical model largely reconciles previous differences between semiempirical 21st century GSL projections and the process model-based projections summarized in the Intergovernmental Panel on Climate Change’s Fifth Assessment Report.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Treatment for endometrial cancer (EC) is increasingly guided by molecular risk classifications. Here, we aimed at using machine learning (ML) to incorporate clinical and molecular risk factors to ...optimize risk assessment.
The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (n = 596), Memorial Sloan Kettering-Metastatic Events and Tropisms (n = 1315) and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (n = 4561) datasets were used to identify genetic alterations and clinicopathological features. Software packages including Keras, Pytorch, and Scikit Learn were tested to build artificial neural networks (ANNs) with a binary output as either intra-abdominal metastatic progression (‘1’) vs. non-metastatic (‘0’).
Black patients with EC have worse prognosis than White patients, adjusting for TP53 or POLE mutation status. Over 75% of Black patients carry TP53 mutations as compared to approximately 40% of White patients. Older age is associated with an increasing likelihood of TP53 mutation, high risk histology, and distant metastasis. For patients above age 70, 91% of Black and 60% of White EC patients carry TP53 mutations. A ML-based New Unified classifiCATion Score (NU-CATS) that incorporates age, race, histology, mismatch repair status, and TP53 mutation status showed 75% accuracy in prognosticating intra-abdominal progression. A higher NU-CATS is associated with an increasing risk of having positive pelvic or para-aortic lymph nodes and distant metastasis. NU-CATS was shown to outperform Leiden/TransPORTEC model for estimating risk of FIGO Stage I/II disease progression and survival in Black EC patients.
The NU-CATS, a ML-based, cost-effective algorithm, incorporates diverse clinicopathologic and molecular variables of EC and yields superior prognostication of the risk of nodal involvement, distant metastasis, disease progression, and overall survival.
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•Race is an independent risk factor for endometrial cancer (EC) prognosis.•Over 75% of Black EC patients have TP53 mutations as compared to 40% of White patients.•A machine learning (ML)-based algorithm NU-CATS predicts early-stage and Black EC patients' progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Introduction:
A 53-year-old female presented with a large (945 cc) unresectable leiomyosarcoma of the uterus, with metastasis in the lungs, significant abdominal/pelvic pain and evidence of ...hydronephrosis secondary to obstruction caused by the mass. In an effort to palliate symptoms, radiation was recommended.
Methods:
Given the size of the lesion, the patient was treated with crossfire GRID, a type of spatially fractionated radiotherapy (18 Gy × 1), followed four weeks later by a short course of external beam radiation (4 Gy × 5).
Results:
The patient experienced significant symptom relief. Her abdominal/pelvic pain resolved, and a stent was placed to relieve her hydronephrosis. The tumour volume had decreased significantly (5·5 months post-treatment 276 cc, 8·5 months post-treatment 17 cc). Unfortunately, at 9 months post-treatment, the patient died from progression of her metastatic disease in the lungs.
Conclusions:
The use of GRID radiotherapy resulted in effective and sustained palliation of a large uterine leiomyosarcoma in this patient’s case.
Opinion statement
Oligometastatic breast cancer, typically defined as the presence of 1–5 metastases, represents an intermediate state between locally advanced and widely metastatic disease. Emerging ...research suggests that oligometastatic cancer has a unique molecular signature distinct from widely metastatic disease, and that it carries a superior prognosis. Owing to its more limited capacity for widespread progression, oligometastatic disease may benefit from aggressive ablative therapy to known metastases. Options for ablation include surgical excision, radiofrequency ablation, and hypofractionated image–guided radiotherapy (HIGRT). The phase II SABR-COMET trial, which enrolled patients with oligometastatic disease of multiple histologies and randomized them to HIGRT vs. standard of care, found a notable survival advantage in favor of HIGRT. Other data suggest that HIGRT may synergize with immunotherapy by releasing powerful cytokines that increase anti-tumor immune surveillance and by recruiting tumor infiltrating lymphocytes, helping to overcome resistance to therapy. There are many ongoing trials exploring the role of ablative therapy, most notably HIGRT, with or without immunotherapy, for the treatment of oligometastatic breast cancer.
We believe that patients with oligometastatic breast cancer should be offered enrollment on prospective clinical trials when possible. Outside the context of a clinical trial, we recommend that select patients with oligometastatic breast cancer be offered treatment with a curative approach, including ablative therapy to all sites of disease if it can be safely accomplished. Currently, selection criteria to consider for ablative therapy include longer disease-free interval from diagnosis to metastasis (>2 years), fewer metastases, and fewer involved organs. Undoubtedly, new data will refine or even upend our understanding of the definition and optimal management of oligometastatic disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
The occurrence of upper extremity lymphedema after regional nodal irradiation (RNI) for breast cancer treatment varies significantly based on patient and treatment factors. The relationship between ...the radiation therapy (RT) field design and lymphedema risk is not well-characterized. The present study sought to correlate the variations in RT field design with lymphedema outcomes.
Women with stage II-IV breast cancer receiving RNI after breast surgery that included sentinel lymph node biopsy or axillary dissection were identified. Their arm circumference was measured before RT and at each follow-up visit to assess for lymphedema. Nodal RT fields were defined using a trifurcated system. Group 1 excluded the upper level I and II axilla, defined by the lateral border of the nodal field encompassing less than one-third of the humeral head. Group 2 included the upper level I and II axilla, defined by the lateral border of the nodal field encompassing more than one-third of the humoral head treated with an anterior oblique beam. Group 3 included the upper level I and II axilla the same as for group 2 but with parallel-opposed beams delivering a significant dose to the musculature posterior to the axilla.
From 1999 to 2013, 526 women received RNI. The median post-RT follow-up was 5.5 years. For the 492 women meeting the inclusion criteria, the cumulative incidence of lymphedema was 23.5% at 2 years and 31.8% at 5 years. On univariate analysis, the patients in group 1 had a lower 5-year lymphedema rate (7.7%) than those in group 2 (37.1%) and group 3 (36.7%; P < .0001). On multivariate analysis, inclusion of the upper level I and II axilla (groups 2 and 3) remained significantly associated with increased lymphedema risk.
Variations in the RT field design significantly affect the development of lymphedema after RNI. In particular, the upper level I and II axilla appear to be important regions for lymphedema risk after axillary dissection.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been ...questioned given advances in systemic therapy. The 21-gene recurrence score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT.
An observational cohort study was performed on women with T1-2 N1 estrogen receptor-positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the surveillance, epidemiology, and end results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts.
In both the NCDB (
= 7,332) and SEER (
= 3,087) cohorts, there was a significant interaction of RS and PMRT with OS (
= 0.009 and
= 0.03, respectively). PMRT was associated with longer OS in women with a low RS NCDB: time ratio (TR) = 1.70; 95% CI (confidence interval), 1.30-2.22;
< 0.001; SEER: TR = 1.85; 95% CI, 1.33-2.57;
< 0.001, but not in women with an intermediate RS (NCDB: TR = 0.89; 95% CI, 0.69-1.14;
= 0.35; SEER: TR = 0.84; 95% CI, 0.62-1.14;
= 0.26), or a high RS (NCDB: TR = 1.10; 95% CI, 0.91-1.34;
= 0.33; SEER: TR = 0.79; 95% CI, 0.50-1.23;
= 0.28).
Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at the lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS.
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Lymphedema after regional nodal irradiation is a severe complication that could be minimized without significantly compromising nodal coverage if the anatomic region(s) associated with lymphedema ...were better defined. This study sought to correlate dose-volume relationships within subregions of the axilla with lymphedema outcomes to generate treatment planning guidelines for reducing lymphedema risk.
Women with stage II-III breast cancer who underwent breast surgery with axillary assessment and regional nodal irradiation were identified. Nodal targets were prospectively contoured per Radiation Therapy Oncology Group guidelines for field design. The axilla was divided into 8 distinct subregions that were retrospectively contoured. Lymphedema outcomes were assessed by arm circumferences. Multivariate Cox proportional hazards regression assessed patient, surgical, and dosimetric predictors of lymphedema outcomes.
Treatment planning computed tomography scans for 265 women treated between 2013 and 2017 were identified. Median post-radiation therapy follow-up was 3 years (interquartile range IQR, 1.9-3.6). Dose to the axillary-lateral thoracic vessel juncture (ALTJ; superior to level I) was most associated with lymphedema risk (maximally selected rank statistic = 6.3, P < .001). The optimal metric was ALTJ minimum dose (D
) <38.6 Gy (3-year lymphedema rate 5.7% vs 37.4%, P <.001), although multiple parameters relating to sparing of the ALTJ were highly correlated. Multivariate analysis confirmed ALTJ D
<38.6 Gy (hazard ratio HR, 0.13; P < .001), body mass index (HR, 1.06/unit; P = .002), and number of lymph nodes removed (HR, 1.08/node; P < .001) as significant predictors. Women with ALTJ D
<38.6 Gy maintained median V
of 99% in the supraclavicular (IQR, 94-100%), 100% in level III (IQR, 97%-100%), 98% in level II (IQR, 86%-100%), and 91% in level I (IQR, 75%-98%) nodal basins.
Anatomic studies suggest the ALTJ region is typically traversed by arm lymphatics and appears to be an organ at risk in breast radiation therapy. Ideally, avoidance of the ALTJ may be feasible while simultaneously encompassing breast-draining nodal basins. Confirmation of this finding in future prospective studies is needed.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Regional nodal irradiation for women with breast cancer is known to be an important risk factor for the development of upper extremity lymphedema, but tools to accurately predict lymphedema risks for ...individual patients are lacking. This study sought to develop and validate a nomogram to predict lymphedema risk after axillary surgery and radiation therapy in women with breast cancer.
Data from 1832 women accrued on the MA.20 trial between March 2000 and February 2007 were used to create a prognostic model with National Cancer Institute Common Toxicity Criteria Version 2.0 grade 2 or higher lymphedema as the primary endpoint. Multivariable logistic regression estimated model performance. External validation was performed on data from a single large academic cancer center (N = 785).
In the MA.20 trial cohort, 3 risk factors were predictive of lymphedema risk: body mass index (adjusted odds ratio, 1.05 per unit body mass index; 95% confidence interval CI, 1.03-1.08, P < .001), extent of axillary surgery (adjusted odds radio for 8-11 lymph nodes removed, 3.28 95% CI, 1.53-7.89 P = .004; 12-15 lymph nodes, 4.04 95% CI, 1.76-10.26 P = .002; ≥16 nodes, 5.08 95% CI, 2.26-12.70 P < .001), and extent of nodal irradiation (adjusted odds radio for limited, 1.66 95% CI, 1.08-2.56 P = .02; for extensive, 2.31 95% CI, 1.28-4.10 P = .004). A nomogram was created from these data that predicted lymphedema risk with reasonable accuracy confirmed by both internal (concordance index, 0.69; 95% CI, 0.64-0.74) and external validation (concordance index, 0.71; 95% CI, 0.66-0.76).
The nomogram created from the MA.20 randomized trial data using clinical information may be useful for lymphedema screening and risk stratification for therapeutic intervention trials.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
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