Around 95% of anti-cancer drugs that show promise during preclinical study fail to gain FDA-approval for clinical use. This failure of the preclinical pipeline highlights the need for improved, ...physiologically-relevant in vitro models that can better serve as reliable drug-screening and disease modeling tools. The vascularized micro-tumor (VMT) is a novel three-dimensional model system (tumor-on-a-chip) that recapitulates the complex human tumor microenvironment, including perfused vasculature, within a transparent microfluidic device, allowing real-time study of drug responses and tumor-stromal interactions. Here we have validated this microphysiological system (MPS) platform for the study of colorectal cancer (CRC), the second leading cause of cancer-related deaths, by showing that gene expression, tumor heterogeneity, and treatment responses in the VMT more closely model CRC tumor clinicopathology than current standard drug screening modalities, including 2-dimensional monolayer culture and 3-dimensional spheroids.
OBJECTIVES:Little is known about frailty that develops following critical illness. We sought to describe the prevalence of newly acquired frailty, its clinical course, and the co-occurrence of ...frailty with disability and cognitive impairment in survivors of critical illness.
DESIGN:Longitudinal prospective cohort study.
SETTING:Medical and surgical ICUs at five U.S. centers.
PATIENTS:Adult patients treated for respiratory failure and/or shock.
MEASUREMENTS AND MAIN RESULTS:We measured frailty with the Clinical Frailty Scale at baseline (i.e., study enrollment) and at 3 and 12 months postdischarge. We constructed alluvial diagrams to describe the course of frailty and Venn diagrams to describe the overlap of frailty with disability in activities of daily living and cognitive impairment. We included 567 participants a median (interquartile range) of 61 years old (51–70 yr old) with a high severity of illness (Acute Physiology and Chronic Health Evaluation II of 23). Frailty (Clinical Frailty Scale scores ≥ 5) was present in 135 of 567 (24%) at baseline, 239 of 530 (45%) at 3 months, and 163 of 445 (37%) at 12 months. Of those with frailty at 3- or 12-month follow-up, 61% were not frail at baseline. Transition to a worse frailty state occurred in 242 of 530 of patients (46%) between baseline and 3 months and in 179 of 445 of patients (40%) between baseline and 12 months. There were 376 patients with frailty, disability, or cognitive impairment at 3-month follow-up. Of these, 53 (14%) had frailty alone. At 12 months, 276 patients had frailty, disability, or cognitive impairment, 37 (13%) of whom had frailty alone.
CONCLUSIONS:Frailty is common among survivors of critical illness. In the majority, frailty is newly acquired. Roughly one in seven had frailty without co-occurring disability or cognitive impairment. Studies to understand outcomes of frailty that develops as the result of a critical illness and to identify modifiable risk factors for this potentially reversible syndrome are needed.
Several studies evaluating stereotactic radiosurgery (SRS) for patients with >4 brain metastases (BM) demonstrated similar outcomes after treatment of 1, 2 to 4, and 5 to 15 BM; others found ...clinically significant survival decrements in the latter group. In this review of 8 academic centers, we compared outcomes of patients undergoing initial SRS for 1, 2 to 4, and 5 to 15 BM.
A total of 2089 patients treated with initial SRS for BM were included. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Patient and disease characteristics were evaluated for association with OS and cumulative incidence of distant brain failure (DBF) using stepwise multivariable Cox proportional hazards and competing risk regression modeling.
In this series, 989 (47%) patients had 1 metastasis, 882 (42%) had 2 to 4 metastases, and 212 (10%) had 5 to 15 metastases treated. Median OS for the 1, 2 to 4, and 5 to 15 BM groups was 14.6, 9.5, and 7.5 months, respectively (log-rank P < .01). Univariate and multivariable analyses revealed no difference in survival between 2 to 4 and 5 to 15 BM. DBF at 1 year was 30%, 41%, and 50%, respectively (Gray's P < .01). Two-year cumulative incidence of salvage SRS decreased with increasing number of BM (1: 21% vs 2-4: 19% vs 5-15: 13%; P < .01), but no difference in salvage whole brain radiation therapy was observed (1: 12% vs 2-4: 15% vs 5-15: 16%, P = .10). At the time of DBF, median brain metastasis velocity was 3.9, 6.1, and 11.7 new metastases per year in the 1, 2 to 4, and 5 to 15 BM groups, respectively (P < .01).
Patients treated with initial SRS for 5 to 15 BM experienced survival similar to that in patients with 2 to 4 BM. Lower rates of salvage SRS were observed in the 5 to 15 BM group, with no difference in rates of salvage whole brain radiation therapy.
•Histology was found to be an important prognostic factor for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) of early-stage non-small-cell lung cancer (NSCLC). ...Histology-driven SBRT approach has not been explored in routine clinic practice and histology-dependent fractionation schemes remain unknown.•We analyzed pooled histologic TCP data for early-stage NSCLC patients as a function of biologically effective dose (BED) and determined histology-driven optimal SBRT and hypofrationated radiation therapy schemes of least doses to maximize tumor control in 1–30 fractions for the two predominant histologic subtypes lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC).•The determined SBRT schemes are consistent with clinic practice for ADC, SCC requires substantially higher doses to maximize tumor control than ADC. These histology-driven optimal hypofractionated radiation therapy schemes provide first insights for personalized radiation therapy of two predominant early-stage NSCLC subtypes ADC and SCC.
Histology was found to be an important prognostic factor for local tumor control probability (TCP) after stereotactic body radiotherapy (SBRT) of early-stage non-small-cell lung cancer (NSCLC). A histology-driven SBRT approach has not been explored in routine clinical practice and histology-dependent fractionation schemes remain unknown. Here, we analyzed pooled histologic TCP data as a function of biologically effective dose (BED) to determine histology-driven fractionation schemes for SBRT and hypofractionated radiotherapy of two predominant early-stage NSCLC histologic subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC).
The least-χ2 method was used to fit the collected histologic TCP data of 8510 early-stage NSCLC patients to determine parameters for a well-developed radiobiological model per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative.
A fit to the histologic TCP data yielded independent radiobiological parameter sets for radiotherapy of early-stage lung ADC and SCC. TCP increases steeply with BED and reaches an asymptotic maximal plateau, allowing us to determine model-independent optimal fractionation schemes of least doses in 1–30 fractions to achieve maximal tumor control for early-stage lung ADC and SCC, e.g., 30, 44, 48, and 51 Gy for ADC, and 32, 48, 54, and 58 Gy for SCC in 1, 3, 4, and 5 fractions, respectively.
We presented the first determination of histology-dependent radiobiological parameters and model-independent histology-driven optimal SBRT and hypofractionated radiation therapy schemes for early-stage lung ADC and SCC. SCC requires substantially higher radiation doses to maximize tumor control than ADC, plausibly attributed to tumor genetic diversity and microenvironment. The determined optimal SBRT schemes agree well with clinical practice for early-stage lung ADC. These proposed optimal fractionation schemes provide first insights for histology-based personalized radiotherapy of two predominant early-stage NSCLC subtypes ADC and SCC, which require further validation with large-scale histologic TCP data.
Aim
We investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology.
Materials and Methods
N = 1306 ...participants (Visit 5 mean age = 76.5 standard deviation = 5.4 years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N = 248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and β‐amyloid positivity were regressed on periodontal status in logistic regressions.
Results
Periodontal disease was not associated with brain volumes, microhaemorrhages, or elevated β‐amyloid. Compared with periodontally healthy individuals, odds ratios 95% confidence interval for all‐type infarcts were 0.37 0.20, 0.65 for severe tooth loss and 0.56 0.31, 0.99 for edentulous participants.
Conclusions
Within the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or β‐amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.
Radiotherapy (RT) is commonly used in the treatment of breast cancer and often, despite advances in fractionated dosing schedules, produces undesirable skin toxicity. The purpose of this study was to ...evaluate the feasibility of using a keratin-based topical cream, KeraStat® Cream (KC; KeraNetics, Inc., Winston Salem, NC, USA) to manage the symptoms of radiation dermatitis (RD) in breast cancer patients undergoing RT.
A total of 24 subjects were enrolled on this single-center, randomized, open-label study. Participants were randomly assigned to KC or standard of care (SOC, patient's choice of a variety of readily available creams or moisturizers). Patients were asked to apply the assigned treatment to the irradiated area twice daily, beginning with day 1 of RT, through 30 days post-RT. The primary outcome was compliance of use. Secondary outcomes included safety and tolerability of KC, as well as RD severity assessed using the Radiation Therapy Oncology Group (RTOG) scale and the patient-reported Dermatology Life Quality Index (DLQI).
All subjects in the KC group were assessed as compliant with no adverse events. The rate of RTOG Grade 2 RD was lower in the KC group (30.8%) compared to the SOC group (54.5%,
= .408). At the final RT visit, the mean RTOG RD score was lower in the KC group (1.0) versus the SOC group (1.4). Similarly, patient-reported quality of life measured by the DLQI at the end of RT was improved in the KC group (mean 4.25, small effect) versus the SOC group (mean 6.18, moderate effect,
= .412).
KC was safe and well tolerated with no adverse events. Though efficacy measures were not powered to draw definitive conclusions, trends and clinical assessments suggest that there is a benefit of using KC compared to SOC for breast cancer patients treated with RT, and a larger powered study for efficacy is warranted.
This clinical trial is registered as NCT03374995 titled KeraStat(R) Cream for Radiation Dermatitis.
Abstract
Stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) are effective treatments for management of brain metastases. Prospective trials comparing the 2 modalities in ...patients with fewer than 4 brain metastases demonstrate that overall survival (OS) is similar. Intracranial failure is more common after SRS, while WBRT is associated with neurocognitive decline. As technology has advanced, fewer technical obstacles remain for treating patients with 4 or more brain metastases with SRS, but level I data supporting its use are lacking.
Observational prospective studies and retrospective series indicate that in patients with 4 or more brain metastases, performance status, total volume of intracranial disease, histology, and rate of development of new brain metastases predict outcomes more accurately than the number of brain metastases. It may be reasonable to initially offer SRS to some patients with 4 or more brain metastases. Initiating therapy with SRS avoids the acute and late sequelae of WBRT. Multiple phase III trials of SRS vs WBRT, both currently open or under development, are directly comparing quality of life and OS for patients with 4 or more brain metastases to help answer the question of SRS appropriateness for these patients.
Mean dose (EQD2) to 3-cm shell of lung surrounding the PTV was evaluated for association with distant metastasis and PFS after SBRT for stage I NSCLC. Dose was uniformly above previously determined ...threshold and metastasis was uncommon. An association between outcomes and mean EQD2 could not be confirmed or refuted.
Background
Ipsilateral neck radiotherapy (INRT) is controversial in some patients with oral cavity cancer due to concern for contralateral neck failure (CNF).
Methods
A systematic review was ...performed and data were extracted following PRISMA guidelines. Outcomes were the rate of CNF following INRT and the rates of CNF by AJCC 7th ed. tumor and nodal staging.
Results
Fifteen studies consisting of 1825 patients were identified. Among the 805 patients treated with INRT, the rate of CNF was 5.7%. Patients with T4 tumors constituted 56% of all CNF cases. The rate of CNF increased by N stage (N0: 1.2%; N1: 3.8%; N2‐N3: 17.4%) and was significantly higher for patients with N2‐N3 than N0‐N1 disease (p < 0.001).
Discussion
INRT is associated with an overall low risk of CNF in well‐selected patients with N0‐N1 disease. Patients with N2‐3 and/or T4 disease should receive bilateral RT due to increased risk of CNF following INRT.
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