Abstract Chronic stress is associated with morbidity and mortality from numerous conditions, many of whose pathogenesis involves persistent inflammation. Here, we examine how chronic stress ...influences signaling pathways that regulate inflammation in monocytes. The sample consisted of 33 adults caring for a family member with glioblastoma and 47 controls whose lives were free of major stressors. The subjects were assessed four times over eight months. Relative to controls, caregivers’ monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys cortisol’s anti-inflammatory signals to monocytes. Transcript origin analyses revealed that CD14+/CD16− cells, a population of immature monocytes, were the predominate source of inflammatory gene expression among caregivers. We considered hormonal, molecular, and functional explanations for caregivers’ decreased glucocorticoid-mediated transcription. Across twelve days, the groups displayed similar diurnal cortisol profiles, suggesting that differential adrenocortical activity was not involved. Moreover, the groups’ monocytes expressed similar amounts of glucocorticoid receptor protein, suggesting that differential receptor availability was not involved. In ex vivo studies, subjects’ monocytes were stimulated with lipopolysaccharide, and caregivers showed greater production of the inflammatory cytokine interleukin-6 relative to controls. However, no group differences in functional glucocorticoid sensitivity were apparent; hydrocortisone was equally effective at inhibiting cytokine production in caregivers and controls. These findings may help shed light on the mechanisms through which caregiving increases vulnerability to inflammation-related diseases.
Caring for a family member with cancer is a psychologically demanding experience. However, it remains unclear whether the distress that caregiving provokes also takes a physiologic toll on the body. ...This study observed familial caregivers of patients with brain cancer for a year after diagnosis and tracked changes in neurohormonal and inflammatory processes.
Eighteen caregivers (age 50.4 +/- 3.5 years) and 19 controls (age 50.2 +/- 2.6 years) were assessed four times during a year (before and after radiotherapy, as well as 6 weeks and 4 months thereafter). Salivary biomarkers of hypothalamus-pituitary-adrenal axis and sympathetic nervous system (SNS) activity were collected, and blood was drawn for assessment of the systemic inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6). Blood was also used to monitor in vitro IL-6 production by endotoxin-stimulated leukocytes and expression of mRNA for pro- and anti-inflammatory signaling molecules.
Caregivers showed marked changes over time in diurnal output of salivary amylase, a marker of SNS activity, whereas secretions in controls were stable during follow-up. Cortisol output was similar in caregivers and controls. During the year, caregivers showed a profound linear increase in systemic inflammation, as indexed by CRP. At the same time, they displayed a linear decline in mRNA for anti-inflammatory signaling molecules and diminished in vitro glucocorticoid sensitivity.
These preliminary data show that familial caregivers of patients with cancer experience marked changes in neurohormonal and inflammatory processes in the year after diagnosis. These changes may place them at risk for morbidity and mortality from diseases fostered by excessive inflammation.
We sought to evaluate overall survival (OS) and local recurrence (LR) in patients with grade 2 meningiomas treated with adjuvant radiotherapy compared to surgery alone at time of diagnosis.
All ...patients at the authors’ institution between 2007 and 2020 were retrospectively reviewed. OS, LR, and treatment toxicities were assessed. Sensitivity analyses were performed for patients with initial gross total resection (GTR) and subtotal resection (STR). Kaplan-Meier analyses and log-rank test for significance were used to compare surgery alone and adjuvant radiotherapy groups.
We included 189 patients with mean age 57.4 ± 14.6 years. Patients were 64% female, and median follow-up was 64 (interquartile range: 20−96) months. At initial treatment, 21 patients received adjuvant radiotherapy and 168 received surgery alone. There was no significant difference for OS (hazard ratio = 1.3 95% confidence interval 0.4−4.5, P = 0.92) overall or when limited to GTR (P = 0.38) or STR (P = 0.85). There was no significant difference in LR overall (P = 0.75) or when restricted to GTR (P = 0.77) or STR (P = 0.20). No patient had radiotherapy stopped or altered because of side effects; however, 71.4% reported tolerable side effects during the treatment period and 14.3% reported chronic side effects persisting longer than 12 months post treatment.
In a large retrospective cohort, we found no survival or local recurrence benefit to adjuvant radiotherapy in treatment of grade 2 meningiomas. Sensitivity analysis limited to initial GTR and STR also failed to demonstrate any OS or LR benefit with adjuvant radiotherapy. In our experience, there is limited utility to upfront adjuvant radiotherapy following initial surgical resection in the treatment of grade 2 meningiomas.
BACKGROUND:Total mesorectal excision has long been the standard of care for patients with rectal cancer. However, in select patients, local excision is an appropriate alternative option. The role of ...adjuvant radiation therapy in patients treated with local excision is controversial and evidence is lacking.
OBJECTIVE:The purpose of this study was to report oncological outcomes of patients with rectal cancer treated with local excision and adjuvant radiation.
DESIGN:This study was a retrospective chart review.
SETTINGS:The study was conducted at the BC Cancer Agency, a tertiary referral hospital.
PATIENTS:A total of 93 patients with node-negative rectal cancer treated with local excision and adjuvant radiotherapy between 2001 and 2010 were included in the study.
MAIN OUTCOME MEASURES:Patient and tumor characteristics are reported. Five-year local control, progression-free survival, and overall survival were analyzed using Kaplan-Meier methods.
RESULTS:Five-year overall survival, local control, and progression-free survival for patients treated with local excision and adjuvant radiotherapy were 78.5%, 86.1%, and 83.8%. In T1 disease, local control was 92.5%.
LIMITATIONS:Referral bias, selection bias, lack of uniform surveillance, and retrospective analysis are the study limitations.
CONCLUSIONS:Local excision with adjuvant radiotherapy provides a good level of local control in T1 disease and remains a good treatment option for patients who are either medically not suitable for a more radical surgical approach or who refuse this procedure. Local excision and radiotherapy should not be advocated in T2/T3 disease; however, it can provide a good alternative in those patients who are not fit enough for a more radical operation.
Volumetric modulated arc therapy (VMAT), the predecessor to Varian's RapidArc, is a novel extension of intensity-modulated radiotherapy (IMRT) wherein the dose is delivered in a single gantry ...rotation while the multileaf collimator leaves are in motion. Leaf positions and the weights of field samples along the arc are directly optimized, and a variable dose rate is used. This planning study compared seven-field coplanar IMRT (cIMRT) with VMAT for high-grade gliomas that had planning target volumes (PTVs) overlapping organs at risk (OARs).
10 previously treated patients were replanned to 60 Gy in 30 fractions with cIMRT and VMAT using the following planning objectives: 98% of PTV covered by 95% isodose without violating OAR and hotspot dose constraints. Mean OAR doses were maximally decreased without reducing PTV coverage or violating hotspot constraints. We compared dose-volume histogram data, monitor units, and treatment times.
There was equivalent PTV coverage, homogeneity, and conformality. VMAT significantly reduced maximum and mean retinal, lens, and contralateral optic nerve doses compared with IMRT (p < 0.05). Brainstem, chiasm, and ipsilateral optic nerve doses were similar. For 2-Gy fractions, mean monitor units were as follows: cIMRT = 789 +/- 112 and VMAT = 363 +/- 45 (relative reduction 54%, p = 0.002), and mean treatment times (min) were as follows: cIMRT = 5.1 +/- 0.4 and VMAT = 1.8 +/- 0.1 (relative reduction 65%, p = 0.002).
Compared with cIMRT, VMAT achieved equal or better PTV coverage and OAR sparing while using fewer monitor units and less time to treat high-grade gliomas.
Interest is growing in treating multiple brain metastases with radiosurgery. We report on the effectiveness and tolerability of volumetric radiosurgery (VRS).
We enrolled patients with a ≥6-month ...estimated life expectancy and 1 to 10 brain metastases with a diameter of ≤3 cm at 5 cancer centers. Volumetric radiosurgery was delivered in 5 fractions with 98% target coverage, prescribed as 95% of 50 Gy (47.5 Gy in 5 fractions) to the metastases with no margin and 95% of 40 Gy (38 Gy in 5 fractions) to their 2-mm planning target volumes, concurrent with 20 Gy to the whole brain planning target volume. The treatment was delivered with daily image guidance using conventional linear accelerators and volumetric modulated arc therapy. A magnetic resonance imaging scan was obtained every 3 months. The primary endpoint was the 3-month objective response in the brain according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The principal secondary endpoint was 1-year actuarial control of treated metastases. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. The present study is registered with ClinicalTrials.gov (clinicaltrials.gov identifier NCT01046123).
From July 2010 to May 2013, 60 patients underwent VRS with 47.5 Gy in 5 fractions for 12 metastases in the thalamus and basal ganglia (deep metastases) and 207 non-deep metastases. The median follow-up period was 30.5 months, and the median survival was 10.1 months. For the 43 patients assessable at 3 months, the objective response in the brain was 56%. The treated metastases were controlled in 88% of patients at 1 year and 84% at 3 years. Overall survival did not differ for patients with 4 to 10 versus 1 to 3 metastases (hazard ratio 1.18, P=.6). The crude incidence of severe radionecrosis (grade 3-5) was 25% (3 of 12) per deep metastasis, 1.9% (4 of 219) per non-deep metastasis, and 10% (6 of 60) per patient.
For non-deep brain metastases, 47.5 Gy in 5 fractions was tolerable. Volumetric radiosurgery was effective for long-term control of treated brain metastases.
Purpose
In this study we present a novel method for re‐calculating a treatment plan on different respiratory phases by accurately modeling the panning and tilting beam motion during DTT (the ...“rotation method”). This method is used to re‐calculate the dose distribution of a plan on multiple breathing phases to accurately assess the dosimetry.
Methods
sIMRT plans were optimized on a breath hold computed tomography (CT) image taken at exhale (BHexhale) for 10 previous liver stereotactic ablative radiotherapy patients. Our method was used to re‐calculate the plan on the inhale (0%) and exhale (50%) phases of the four‐dimensional CT (4DCT) image set. The dose distributions were deformed to the BHexhale CT and summed together with proper weighting calculated from the patient’s breathing trace. Subsequently, the plan was re‐calculated on all ten phases using our method and the dose distributions were deformed to the BHexhale CT and accumulated together. The maximum dose for certain organs at risk (OARs) was compared between calculating on two phases and all ten phases.
Results
In total, 26 OARs were examined from 10 patients. When the dose was calculated on the inhale and exhale phases six OARs exceeded their dose limit, and when all 10 phases were used five OARs exceeded their limit.
Conclusion
Dynamic tumor tracking plans optimized for a single respiratory phase leave an OAR vulnerable to exceeding its dose constraint during other respiratory phases. The rotation method accurately models the beam’s geometry. Using deformable image registration to accumulate dose from all 10 breathing phases provides the most accurate results, however it is a time consuming procedure. Accumulating the dose from two extreme breathing phases (exhale and inhale) and weighting them properly provides accurate results while requiring less time. This approach should be used to confirm the safety of a DTT treatment plan prior to delivery.
•Stereotactic Ablative Radiation Therapy (SABR) is an effective and well tolerated treatment option for selected patients with liver metastases from colorectal cancer.•SABR for colorectal liver ...metastases requires higher biological effective doses to provide adequate local control.•SABR to colorectal liver metastases may provide patients with a delay to starting or recommencing systemic therapy.
Stereotactic Ablative Radiation Therapy (SABR) is a therapeutic option for patients with inoperable oligometastatic colorectal carcinoma (CRC). Given the scarcity of prospective data on outcomes of SABR for metastatic CRC, this study aims to review SABR outcomes and determine predictive factors of local control (LC) and survival in patients with liver metastases from CRC.
A retrospective review of SABR for CRC liver metastases between 2011 and 2019 was undertaken. Endpoints included LC, overall survival (OS), progression-free survival (PFS) and time to restarting systemic therapy. Univariate (UVA) and multivariable analyses (MVA) were performed to identify predictive factors.
Forty-eight patients were identified. The total number of tumors treated was 58. Median follow-up was 26.6 months. LC at 1, 2 and 3 years was 92.7%, 80.0%, and 61.2% respectively. Median time to local failure was 40.0 months (95% CI 31.8-76.1 months). Median OS was 31.9 months (95% CI 20.6-40.0 months). OS at 1, 2, and 3 years was 79.2%, 61.7%, and 44.9% respectively. Thirty-three patients (69%) restarted systemic therapy after completion of SABR. Median time to restarting chemotherapy was 11.0 months (95% CI 7.1-17.6 months). Systemic therapy free survival at 1, 2, and 3 years was 45.7%, 29.6%, and 22.6% respectively. On MVA, inferior LC was influenced by GTV volume ≥40 cm3 (HR: 3.805, 95% CI 1.376-10.521, P = .01) and PTV D100% BED <100 Gy10 (HR 2.971, 95% CI 1.110-7.953; P = .03). Inferior OS was associated with PTV volume ≥200 cm3 (HR 5.679, 95% CI 2.339-13.755; P < .001).
SABR is an effective therapeutic option for selected patients with CRC liver metastases providing acceptable LC within the first 2 years. In many cases, it provides meaningful chemotherapy-free intervals. Higher biological effective doses are required to enhance LC.
This retrospective report of SABR of 58 treated colorectal liver metastases in 48 patients describes local control at 2 years of 80.0%. Median overall survival was 31.9 months. Local control was adversely impacted by larger tumour volumes and lower BED used.
Surgical resection, when feasible, is the standard of care for hepatocellular carcinoma. However, many tumours are not resectable at the time of diagnosis. Recently, stereotactic body radiation ...therapy (SBRT) has emerged as a non-invasive local therapy for both non-resectable primary hepatic malignancies as well as hepatic metastases. Knowledge of the expected hepatic parenchymal appearance post treatment, as well as potential pitfalls and complications, is essential for accurate evaluation of treatment response. This pictorial review provides a fundamental description of the SBRT technique, outlines the expected cross-sectional imaging appearances of tumour response, and highlights potential pitfalls in interpretation. The expected liver parenchymal changes post-SBRT are also reviewed, along with some common radiation-induced complications.
Primary liver cancer, mainly hepatocellular carcinoma, is one of the most common malignancies worldwide. Surgical management, either resection or transplantation, is considered definitive treatment, ...however, less than 20% of patients are ultimately candidates. Thermal ablation modalities such as radiofrequency ablation and microwave ablation have evolved such that these modalities have been applied with curative intent. Moreover, thermal ablation has demonstrated efficacy in treating early-stage tumors and can be offered as first-line treatment in patients with uncomplicated disease. Attributing to refinements in technology and techniques, recent studies evaluating stereotactic ablative body radiotherapy have shown promising results, while irreversible electroporation, an emerging modality, may further expand the role of ablative therapy in treating potentially resectable hepatocellular carcinoma.
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