Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

BODYFAT: a new calculator to determine the risk of being overweight validated in Spanish children between 11 and 17 years of age.

The assessment of body fat of children in primary care requires consideration of the dynamic changes in height, weight, lean mass, and fat mass during childhood growth. To achieve this, we aim to develop a predictive equation based on anthropometric values, with optimal diagnostic utility. This is a cross-sectional observational study, involving schoolgoers aged 11-17 years in the Vigo metropolitan area. Out of 10,747 individuals, 577 were randomly recruited. VARIABLES: age, sex, ethnicity/country of origin, weight, height, 8 skinfolds, 3 diameters, 7 perimeters, and 85% percentile of body fat mass as the gold standard. Generalized additive regression was selected by cross-validation and compared using receiver operating characteristic curves (ROC curves). Sensitivity, specificity, positive and negative predictive values, true positive and true negative values, false positive and false negative values, accuracy, and positive and negative likelihood ratios were calculated. Two models were identified. The optimal model includes sex, weight, height, leg perimeter, and arm perimeter, with sensitivity of 0.93 (0.83-1.00), specificity of 0.91 (0.83-0.96), accuracy of 0.91 (0.84-0.96), and area under the curve (AUC) of 0.957 (0.928-0.986). The second model includes sex, age, and body mass index, with sensitivity of 0.93 (0.81-1.00), specificity of 0.90 (0.80-0.97), accuracy of 0.90 (0.82-0.96), and an AUC of 0.944 (0.903-0.984). CONCLUSION: Two predictive models, with the 85th percentile of fat mass as the gold standard, built with basic anthropometric measures, show very high diagnostic utility parameters. Their calculation is facilitated by a complementary online calculator. WHAT IS KNOWN: • In routine clinical practice, mainly in primary care, BMI is used to determine overweight and obesity. This index has its weaknesses in the assessment of children. WHAT IS NEW: • We provide a calculator whose validated algorithm, through the determination of fat mass by impedanciometry, makes it possible to determine the risk of overweight and obesity in the community setting, through anthropometric measurements, providing a new practical, accessible and reliable model that improves the classification of overweight and obesity in children with respect to that obtained by determining BMI.

Finding a City Name in a Traffic Sign: Effects of Word Case and Visual Motion.

OBJECTIVES: To investigate the word recognition effects of the use of all-uppercase (e.g., VALENCIA) or titled-case (e.g., Valencia) for city names in traffic signs, controlling for word size, and comparing stationary and dynamic viewing situations. BACKGROUND: Prior studies provide mixed evidence regarding the effects of word case on the recognition of city names in traffic signs. Moreover, the evidence on the potential impact of visual motion on these effects is scarce. METHOD: We carried out an experimental study using simulated traffic signs. The task was to indicate, for each sign, whether it contained a given city name or not (word search task, 50% positive trials). Visual motion of signs was manipulated as a between-participants factor: stationary (the sign was still) versus dynamic (the sign expanded as if the participant was approaching to it). Word case was manipulated as a within-participants factor: all-uppercase versus two titled-case conditions varying in font size: width-matched titled-case and point size-matched titled-case. RESULTS: In both the stationary and dynamic conditions, all-uppercase resulted in more incorrect responses and slower latencies than width-matched titled-case. When compared to point size-matched titled-case, all-uppercase produced slower correct responses in the stationary condition, whereas faster in the dynamic condition. CONCLUSION: Other factors being equal, all-uppercase city names will be recognized worse than their titled-case versions in traffic signs, both in stationary and dynamic situations. APPLICATION: Results in the current experimental study would be of interest in the design of traffic signs and other circumstances in which text is presented in motion.

Pan-cancer prediction of radiotherapy benefit using genomic-adjusted radiation dose (GARD): a cohort-based pooled analysis.

BACKGROUND: Despite advances in cancer genomics, radiotherapy is still prescribed on the basis of an empirical one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic-adjusted radiation dose (GARD) model to personalise prescription of radiation dose on the basis of the biological effect of a given physical dose of radiation, calculated using individual tumour genomics. We hypothesise that GARD will reveal interpatient heterogeneity associated with opportunities to improve outcomes compared with physical dose of radiotherapy alone. We aimed to test this hypothesis and investigate the GARD-based radiotherapy dosing paradigm. METHODS: We did a pooled, pan-cancer analysis of 11 previously published clinical cohorts of unique patients with seven different types of cancer, which are all available cohorts with the data required to calculate GARD, together with clinical outcome. The included cancers were breast cancer, head and neck cancer, non-small-cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. Our dataset comprised 1615 unique patients, of whom 1298 (982 with radiotherapy, 316 without radiotherapy) were assessed for time to first recurrence and 677 patients (424 with radiotherapy and 253 without radiotherapy) were assessed for overall survival. We analysed two clinical outcomes of interest: time to first recurrence and overall survival. We used Cox regression, stratified by cohort, to test the association between GARD and outcome with separate models using dose of radiation and sham-GARD (ie, patients treated without radiotherapy, but modelled as having a standard-of-care dose of radiotherapy) for comparison. We did interaction tests between GARD and treatment (with or without radiotherapy) using the Wald statistic. FINDINGS: Pooled analysis of all available data showed that GARD as a continuous variable is associated with time to first recurrence (hazard ratio [HR] 0·98 [95% CI 0·97-0·99]; p=0·0017) and overall survival (0·97 [0·95-0·99]; p=0·0007). The interaction test showed the effect of GARD on overall survival depends on whether or not that patient received radiotherapy (Wald statistic p=0·011). The interaction test for GARD and radiotherapy was not significant for time to first recurrence (Wald statistic p=0·22). The HR for physical dose of radiation was 0·99 (95% CI 0·97-1·01; p=0·53) for time to first recurrence and 1·00 (0·96-1·04; p=0·95) for overall survival. The HR for sham-GARD was 1·00 (0·97-1·03; p=1·00) for time to first recurrence and 1·00 (0·98-1·02; p=0·87) for overall survival. INTERPRETATION: The biological effect of radiotherapy, as quantified by GARD, is significantly associated with time to first recurrence and overall survival for patients with cancer treated with radiation. It is predictive of radiotherapy benefit, and physical dose of radiation is not. We propose integration of genomics into radiation dosing decisions, using a GARD-based framework, as the new paradigm for personalising radiotherapy prescription dose. FUNDING: None. VIDEO ABSTRACT.

Effectiveness and Safety of Prostatic Artery Embolization for the Treatment of Lower Urinary Tract Symptoms from Benign Prostatic Hyperplasia in Men with Concurrent Localized Prostate Cancer.

PURPOSE: To assess the effectiveness and safety of prostatic artery embolization (PAE) on lower urinary tract symptoms (LUTS) in the setting of localized prostate cancer (PCa). MATERIALS AND METHODS: This was a retrospective, single-center, institutional review board-approved study from December 2016 to June 2020 of 21 patients (median age, 72; range, 63-83 years) with moderate LUTS and localized PCa. Clinical effectiveness was evaluated at 6 and 12 weeks using International Prostate Symptom Score (IPSS) and quality of life (QoL) improvement. Seventeen patients were scheduled to receive definitive radiotherapy (RT) after PAE; 13 patients completed RT. Short-term imaging signs of oncologic progression were evaluated at 6 and 12 weeks defined by at least one of the following on magnetic resonance imaging: increased Prostate Imaging-Reporting and Data System score of index lesion(s) to at least 4, new extracapsular extension, seminal vesicle involvement, or pelvic lymphadenopathy. Nonparametric Wilcoxon signed-rank test was used for analysis. RESULTS: IPSS improved by a median of 12 (n = 19, P < .0001) and 14 (n = 14, P < .0001) at 6 and 12 weeks, respectively. QoL improved by a median of 2 (n = 19, P < .0001) and 3 (n = 3, P < .0001) at 6 and 12 weeks. Prostate volume decreased by a median of 24% (n = 19, P < .0001) and 36% (n = 12, P = .015) at 6 and 12 weeks. No patients demonstrated disease progression at 6 (n = 16) or 12 (n = 8) weeks by imaging. No patients experienced increased prostate-specific antigen after RT, grade ≥3 adverse events, or greater genitourinary toxicity. CONCLUSIONS: PAE is effective and safe for the treatment of men with LUTS from benign prostatic hyperplasia in the setting of concomitant, localized, non-obstructive PCa.

Measuring attention and vigilance in the laboratory vs. online: The split-half reliability of the ANTI-Vea.

Over the past few years, there has been growing interest in using online methods for collecting data from large samples. However, only a few studies have administered online behavioral tasks to assess attention outside the lab. In the present study, we assessed the classic attentional functions and two vigilance components using two versions of the Attentional Networks Test for Interactions and Vigilance-executive and arousal vigilance components (ANTI-Vea): (1) a standard version, performed under typical experimental conditions (n = 314), and (2) an online version, completed outside the lab (n = 303). Both versions were equally effective in assessing (1) the main effects and interactions of phasic alertness, orienting, and executive control, and (2) the executive (i.e., a decline in the ability to detect infrequent critical signals) and the arousal (i.e., a progressive slowness and variability in responses to stimuli from the environment) vigilance decrement across time on task. Responses were generally slower in the online than in the standard version. Importantly, the split-half reliability observed for both tasks was (1) higher for executive control (~.67) than for phasic alertness and orienting (< .40), as observed in previous versions of the task, and (2) between .71 and .99 for the executive and arousal vigilance measures. We expect the present study will be of interest to researchers aiming to assess attentional functions with a valid and reliable method that, importantly, is publicly available on an open website ( https://www.ugr.es/~neurocog/ANTI/ ) and is easy to use in applied contexts.

Phase-only modulation with two vertical aligned liquid crystal devices.

Spatial Light Modulators (SLMs) are widely used in several fields of optics such as adaptive optics. SLMs based on Liquid Crystal (LC) devices allow a dynamic and easy representation of two-dimensional phase maps. A drawback of these devices is their elevated cost, preventing a massive use of the technology. We present a more affordable approach based on the serial arrangement of vertical aligned LC devices, with characteristics of phase modulation similar to a widely used parallel aligned LC device. We discuss the peculiarities of the approach, the performance and some potential areas of applications.

Modeling precision genomic-based radiation dose response in rectal cancer.

Aim: Genomic-based risk stratification to personalize radiation dose in rectal cancer. Patients & methods: We modeled genomic-based radiation dose response using the previously validated radiosensitivity index (RSI) and the clinically actionable genomic-adjusted radiation dose. Results: RSI of rectal cancer ranged from 0.19 to 0.81 in a bimodal distribution. A pathologic complete response rate of 21% was achieved in tumors with an RSI <0.31 at a minimal genomic-adjusted radiation dose of 29.76 when modeling RxRSI to the commonly prescribed physical dose of 50 Gy. RxRSI-based dose escalation to 55 Gy in tumors with an RSI of 0.31-0.34 could increase pathologic complete response by 10%. Conclusion: This study provides a theoretical platform for development of an RxRSI-based prospective trial in rectal cancer.

Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both?

BACKGROUND: Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB. METHODS: All patients treated at a single institution for SLNB-positive MCC (1998-2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity. RESULTS: The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients). CONCLUSIONS: Regional failure was infrequent (≤ 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity.

Intrinsic radiosensitivity, genomic-based radiation dose and patterns of failure of penile cancer in response to adjuvant radiation therapy.

PURPOSE: Optimal postoperative radiation therapy (PORT) dose is unclear in penile squamous cell carcinoma (PeSCC). Herein, we characterized the radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) profiles in a cohort of patients with PeSCC, and assessed the application of GARD to personalize PORT. METHODS: A total of 25 PeSCC samples were identified for transcriptomic profiling. The RSI score and GARD were derived for each sample. A cohort of 34 patients was reviewed for clinical correlation. RESULTS: The median RSI for PeSCC was 0.482 (range 0.215-0.682). The majority (n = 21; 84%) of cases were classified as radioresistant. PeSCC GARD ranged from 9.56 to 38.39 (median 18.25), suggesting variable therapeutic effects from PORT. We further determined the optimal GARD-based RT doses to improve locoregional control. We found that therapeutic benefit was only achieved in 52% of PeSCC lesions with PORT of 50 Gy, in contrast to 84% benefit from GARD-modeled PORT of 66 Gy. In the clinical cohort, the majority of patients presented with pathological N2 or N3 disease (n = 31; 91%) and was treated with adjuvant concurrent platinum-based chemoradiotherapy (CRT, n = 30; 88%). Fourteen of the 34 patients (41%) had locoregional recurrence (LRR), of which half had LRR within six months of completion of PORT. CONCLUSIONS: The majority of PeSCC are intrinsically radioresistant with a low GARD-based therapeutic effect from PORT dose of 50 Gy, consistent with the observed high rate of LRR in the clinical cohort. A GARD-based strategy will allow personalizing PORT dose prescription to individual tumor biology and improve outcomes.

Legibility of Text and Pictograms in Variable Message Signs: Can Single-Word Messages Outperform Pictograms?

OBJECTIVE: The current research shows the advantage of single-word messages in the particular case of variable message signs (VMSs) with a high aspect ratio. BACKGROUND: Early studies on traffic sign design proposed that pictorial information would advantage equivalent text messages in static signs. METHOD: We used a driving simulator to present individually 36 VMSs, showing six words (e.g., "congestion") and six danger signs (e.g., congestion traffic sign). In Experiment 1, 18 drivers read aloud the text or orally identified the pictograms as soon as they could correctly do it. In Experiment 2, a different sample of 18 drivers gave a motor response, according to the meaning of the message. We analyzed the legibility distance and accuracy, driving performance (speed variability), and glance behavior. RESULTS: Our results show that single-word messages were associated with better performance (farther reading distances) and required less visual demands (fewer glances and less glancing times) than pictograms. CONCLUSION: As typical configurations of VMSs usually have a high aspect ratio, and thus allow large character heights, single-word messages can outperform the legibility of pictograms. However, the final advantage of text or pictorial messages would depend on several factors, such as the driver's knowledge of the language and the pictogram set, the use of single or multiple words, the particular design and size of critical details in letters and pictograms, environmental factors, and driver age. APPLICATION: Potential applications include the design of VMSs and other devices aimed at displaying text and/or pictograms with a high aspect ratio.

The future of personalised radiotherapy for head and neck cancer.

Radiotherapy has long been the mainstay of treatment for patients with head and neck cancer and has traditionally involved a stage-dependent strategy whereby all patients with the same TNM stage receive the same therapy. We believe there is a substantial opportunity to improve radiotherapy delivery beyond just technological and anatomical precision. In this Series paper, we explore several new ideas that could improve understanding of the phenotypic and genotypic differences that exist between patients and their tumours. We discuss how exploiting these differences and taking advantage of precision medicine tools-such as genomics, radiomics, and mathematical modelling-could open new doors to personalised radiotherapy adaptation and treatment. We propose a new treatment shift that moves away from an era of empirical dosing and fractionation to an era focused on the development of evidence to guide personalisation and biological adaptation of radiotherapy. We believe these approaches offer the potential to improve outcomes and reduce toxicity.

A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study.

BACKGROUND: Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological differences between or within tumours. We aimed to assess whether a patient-specific molecular signature of radiation sensitivity could be used to identify the optimum radiotherapy dose. METHODS: We used the gene-expression-based radiation-sensitivity index and the linear quadratic model to derive the genomic-adjusted radiation dose (GARD). A high GARD value predicts for high therapeutic effect for radiotherapy; which we postulate would relate to clinical outcome. Using data from the prospective, observational Total Cancer Care (TCC) protocol, we calculated GARD for primary tumours from 20 disease sites treated using standard radiotherapy doses for each disease type. We also used multivariable Cox modelling to assess whether GARD was independently associated with clinical outcome in five clinical cohorts: Erasmus Breast Cancer Cohort (n=263); Karolinska Breast Cancer Cohort (n=77); Moffitt Lung Cancer Cohort (n=60); Moffitt Pancreas Cancer Cohort (n=40); and The Cancer Genome Atlas Glioblastoma Patient Cohort (n=98). FINDINGS: We calculated GARD for 8271 tissue samples from the TCC cohort. There was a wide range of GARD values (range 1·66-172·4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types. Median GARD values were lowest for gliomas and sarcomas and highest for cervical cancer and oropharyngeal head and neck cancer. There was a wide range of GARD values within tumour type groups. GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer. In the Erasmus Breast Cancer Cohort, 5-year distant-metastasis-free survival was longer in patients with high GARD values than in those with low GARD values (hazard ratio 2·11, 95% 1·13-3·94, p=0·018). INTERPRETATION: A GARD-based clinical model could allow the individualisation of radiotherapy dose to tumour radiosensitivity and could provide a framework to design genomically-guided clinical trials in radiation oncology. FUNDING: None.

Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma.

Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.

Radiation Therapy is Associated with Improved Outcomes in Merkel Cell Carcinoma.

BACKGROUND: Following wide excision of Merkel cell carcinoma (MCC), postoperative radiation therapy (RT) is typically recommended. Controversy remains as to whether RT can be avoided in selected cases, such as those with negative margins. Additionally, there is evidence that RT can influence survival. METHODS: We included 171 patients treated for non-metastatic MCC from 1994 through 2012 at a single institution. Patients without pathologic nodal evaluation (clinical N0 disease) were excluded to reflect modern treatment practice. The endpoints included local control (LC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS). RESULTS: Median follow-up was 33 months. Treatment with RT was associated with improved 3-year LC (91.2 vs. 76.9 %, respectively; p = 0.01), LRC (79.5 vs. 59.1 %; p = 0.004), DFS (57.0 vs. 30.2 %; p < 0.001), and OS (73 vs. 66 %; p = 0.02), and was associated with improved 3-year DSS among node-positive patients (76.2 vs. 48.1 %; p = 0.035), but not node-negative patients (90.1 vs. 80.8 %; p = 0.79). On multivariate analysis, RT was associated with improved LC [hazard ratio (HR) 0.18, 95 % confidence interval (CI) 0.07-0.46; p < 0.001], LRC (HR 0.28, 95 % CI 0.14-0.56; p < 0.001), DFS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001), OS (HR 0.53, 95 % CI 0.31-0.93; p = 0.03), and DSS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001). Patients with negative margins had significant improvements in 3-year LC (90.1 vs. 75.4 %; p < 0.001) with RT. Deaths not attributable to MCC were relatively evenly distributed between the RT and no RT groups (28.5 and 29.3 % of patients, respectively). CONCLUSIONS: RT for MCC was associated with improved LRC and survival. RT appeared to be beneficial regardless of margin status.

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

NCCN Guidelines Insights: Melanoma, Version 3.2016.

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

Stereotactic Body Radiotherapy in the Management of Oligometastatic Disease.

BACKGROUND: The treatment of oligometastatic disease has become common as imaging techniques have advanced and the management of systemic disease has improved. Use of highly targeted, hypofractionated regimens of stereotactic body radiotherapy (SBRT) is now a primary management option for patients with oligometastatic disease. METHODS: The properties of SBRT are summarized and the results of retrospective and prospective studies of SBRT use in the management of oligometastases are reviewed. Future directions of SBRT, including optimizing dose and fractionation schedules, are also discussed. RESULTS: SBRT can deliver highly conformal, dosed radiation treatments for ablative tumors in a few treatment sessions. Phase 1/2 trials and retrospective institutional results support use of SBRT as a treatment option for oligometastatic disease metastasized to the lung, liver, and spine, and SBRT offers adequate toxicity profiles with good rates of local control. Future directions will involve optimizing dose and fractionation schedules for select histologies to improve rates of local control while limiting toxicity to normal structures. CONCLUSIONS: SBRT offers an excellent management option for patients with oligometastases. However, additional research is still needed to optimize dose and fractionation schedules.

Audiovisual presentation of variable message signs improves message processing in distracted drivers during partially automated driving.

INTRODUCTION: Highly automated driving is expected to reduce the accident risk occurrence by human errors, but it can also increase driver distraction. Previous evidence shows that auditory signals can help drivers take over in critical situations. However, it is still uncertain whether the potential benefit of verbal auditory signals could be generalized to driving situations where drivers are visually and auditorily distracted. METHOD: Our first objective was to compare the effectiveness of complementary audio messages (audio + visual condition) and visual only (visual condition) variable message signs (VMS) messages. The second objective was to explore the potential use of oral messages with traffic information to help highly-automated vehicle drivers identify critical situations. Eye-tracking data were also registered. Twenty-four volunteers participated in a driving simulator study, completing two tasks: (a) a TV series task, where they had to pay attention to an episode of a TV series while traveling along the route; and (b) a VMS task, where they had to recover the manual control of the car if the VMS message was a 'critical message.' RESULTS: General results showed that, when the audio was available, the participants: (a) had a higher ability to discriminate the VMS messages, (b) were less conservative, (c) responded earlier, and (d) their pattern of fixations was more efficient. A complementary analysis showed that the counterbalance order was a moderating factor for the discrimination ability and the response distance measures. This evidence suggests a potential learning effect, not cancelled by counterbalancing the order of the conditions. CONCLUSION: The processing of traffic messages may improve when provided as oral and visual messages. PRACTICAL APPLICATIONS: These results would be of special interest for engineers designing highly automated cars, considering that the design of automated systems must ensure that the driver's attention is sufficient to take over control.