The combination of radiation and immunotherapy is currently an exciting avenue of pre-clinical and clinical investigation. The synergy between these two treatment modalities has the potential to expand the role of radiation from a purely local therapy, to a role in advanced and metastatic disease. Tumor regression outside of the irradiated field, known as the abscopal effect, is a recognized phenomenon mediated by lymphocytes and enhanced by checkpoint blockade. In this review, we summarize the known mechanistic data behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy. We also provide pre-clinical data supporting specific radiation timing and optimal dose/fractionation for induction of a robust anti-tumor immune response with or without checkpoint blockade. Importantly, these data are placed in a larger context of understanding T-cell exhaustion and the impact of immunotherapy on this phenotype. We also include relevant pre-clinical studies done in non-tumor systems. We discuss the published clinical trials and briefly summarize salient case reports evaluating the abscopal effect. Much of the data discussed here remains at the preliminary stage, and a number of interesting avenues of research remain under investigation.
Background Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular-arterial (V-A) coupling in hypertensive HFPEF. Methods and Results Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central BP (via radial arterial tonometry), and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the Parametrized Diastolic Filling formalism, which yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees), and V-A coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs tests were used for pre-post comparisons. The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155±35 to 138±30 and 130±16 to 123±18 mmHg, both p=.02) and central end-systolic pressure trended lower (116±18 to 111±16 mmHg, p=.12). In conjunction, diastolic function improved (c, 24.3±5.3 to 22.7±8.1 s−1;p=.03; k, 252±115 to 170±37 s−1;p=.03), Ea decreased (2.0±0.4 to 1.7±0.4 mmHg/ml;p=.007), and V-A coupling improved (Ees:Ea, 1.5±0.3 to 1.7±0.4;p=.04). Conclusions In hypertensive HFPEF patients, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and V-A coupling.
Purpose: Evaluate clinical outcomes in patients with vestibular schwannoma (VS) treated with fractionated proton therapy (PT) at a single institution. Materials and Methods: We retrospectively reviewed the medical records of patients treated with fractionated PT for definitive management of VS between November 2007 and December 2013 at our institution. No patient had received prior treatment for VS. Patients received 50.4 Gy in 28 fractions using passively scattered PT. Pretreatment and posttreatment hearing status, tumor dimensions, and cranial nerve V and VII function were evaluated. Hearing status was graded as nonserviceable or serviceable, defined as Gardner-Robertson grade I or II and the ability to use a telephone with the treated ear. Toxicities were prospectively evaluated using Common Terminology Criteria for Adverse Events, version 4.0. Results: Fourteen patients with 14 lesions (8 men, 6 women) were included in the analysis. Median age at treatment was 60 years (range, 24-74 years). Median clinical follow-up for living patients was 68 months (range, 36-106 months). Mean maximal tumor dimension was 2.1 cm (range, 0.5-3.8 cm). Mean tumor volume was 6.4 cm 3 (range, 0.3-16.0 cm 3). One patient died of unrelated causes 5 months after treatment, and 2 had subsequent surgical resections due to radiographic and/or clinical progression. The actuarial 3-year local control rate was 85%. There were no cranial nerve V or VII injuries. Two of 6 patients (33%) with serviceable hearing at the time of treatment retained serviceable hearing. Three patients (21%) demonstrated radiographic tumor regression on brain magnetic resonance imaging after a median of 26 months (range, 2-113 months). No acute toxicity of grade 3 or above was reported. Conclusion: Fractionated PT for VS is well tolerated and provides good local control. Improvements in proton delivery techniques and patient selection may enable improved outcomes.
RT continues to result in an excellent prognosis for patients with ABC who receive either RT alone or adjuvant RT after surgery.
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