Comparing Predicted Toxicities between Hypofractionated Proton and Photon Radiotherapy of Liver Cancer Patients with Different Adaptive Schemes.

With the availability of MRI linacs, online adaptive intensity modulated radiotherapy (IMRT) has become a treatment option for liver cancer patients, often combined with hypofractionation. Intensity modulated proton therapy (IMPT) has the potential to reduce the dose to healthy tissue, but it is particularly sensitive to changes in the beam path and might therefore benefit from online adaptation. This study compares the normal tissue complication probabilities (NTCPs) for liver and duodenal toxicity for adaptive and non-adaptive IMRT and IMPT treatments of liver cancer patients. Adaptive and non-adaptive IMRT and IMPT plans were optimized to 50 Gy (RBE = 1.1 for IMPT) in five fractions for 10 liver cancer patients, using the original MRI linac images and physician-drawn structures. Three liver NTCP models were used to predict radiation-induced liver disease, an increase in albumin-bilirubin level, and a Child-Pugh score increase of more than 2. Additionally, three duodenal NTCP models were used to predict gastric bleeding, gastrointestinal (GI) toxicity with grades >3, and duodenal toxicity grades 2-4. NTCPs were calculated for adaptive and non-adaptive IMRT and IMPT treatments. In general, IMRT showed higher NTCP values than IMPT and the differences were often significant. However, the differences between adaptive and non-adaptive treatment schemes were not significant, indicating that the NTCP benefit of adaptive treatment regimens is expected to be smaller than the expected difference between IMRT and IMPT.

Why are 'suboptimal' temperatures preferred in a tropical intertidal ectotherm?

In thermally extreme environments, it is challenging for organisms to maximize performance due to risks associated with stochastic variation in temperature and, subsequently, over evolutionary time minimizing the exposure to risk can serve as one of the mechanisms that result in organisms preferring suboptimal temperatures. We tested this hypothesis in a slow-moving intertidal snail on tropical rocky shores, where temperature variability increases with time from 30 min to 20 hr when recorded at 30 min intervals (due to short-term environmental autocorrelation where temperatures closer in time are more similar as compared to temperatures over a long period of time). Failure to accommodate temporal variation in thermal stress by selecting cool habitats can result in mortality. Thermal performance curves for different traits (heart rate and locomotion) were measured and compared to the snail's thermal preferences in both the field and laboratory. Predicted performances of the snails were simulated based on thermal performance curves for different traits over multiple time-scales and simulated carryover effects. A strong mismatch was found between physiological and behavioural thermal maxima of the snails (physiological thermal maximum being higher by ~7°C), but the snails avoided these maxima and sought temperatures 7-14°C cooler. Such a risk-averse strategy can be explained by their predicted performances where the snails should make decisions about preferred temperatures based on time periods ≥5 hr to avoid underestimating the temporal variation in body temperature. In extreme and stochastic environments, where the temporal variation in environmental conditions can lead to substantial divergence between instantaneous and time-averaged thermal performances, 'cooler is better' and 'suboptimal' body temperatures are preferred as they provide sufficient buffer to reduce mortality risk from heat stress.

Reduced Levels of NAD in Skeletal Muscle and Increased Physiologic Frailty Are Associated With Viral Coinfection in Asymptomatic Middle-Aged Adults.

BACKGROUND: People living with HIV (PLWH) are disproportionately burdened with multimorbidity and decline in physiologic function compared with their uninfected counterparts, but biological mechanisms that differentially contribute to the decline in muscle function in PLWH compared with uninfected people remain understudied. SETTING: The study site was Brigham and Women's Hospital, Harvard Medical School, Boston, MA. METHODS: We evaluated skeletal muscle tissue for levels of total nicotinamide adenine dinucleotide (NAD), NAD+, and nicotinamide adenine dinucleotide (NADH) in middle-aged asymptomatic PLWH, coinfected with hepatitis C virus and/or cytomegalovirus and compared them with uninfected control participants. RESULTS: Of the 54 persons with muscle biopsy data, the mean age was 57 years with 33% women. Total NAD levels declined in skeletal muscle in association with HIV infection and was exacerbated by hepatitis C virus and cytomegalovirus coinfection, with lowest levels of total NAD, NAD+, and NADH among persons who were coinfected with all 3 viruses (P = 0.015, P = 0.014, and P = 0.076, respectively). Levels of total NAD, NAD+, and NADH in skeletal muscle were inversely associated with inflammation (P = 0.014, P = 0.013, and P = 0.055, respectively). Coinfections were also associated with measures of inflammation (CD4/CD8 ratio: P < 0.001 and sCD163: P < 0.001) and immune activation (CD38 and human leukocyte antigen-DR expression on CD8 T cells: P < 0.001). In addition, coinfection was associated with increased physiologic frailty based on the Veteran Aging Cohort Study 1.0 index assessment (P = 0.001). CONCLUSIONS: Further research is warranted to determine the clinical relevance of preclinical deficits in NAD metabolites in skeletal muscle in association with viral coinfection and inflammation, as well as the observed association between viral coinfection and physiologic frailty.

The risk for developing a secondary cancer after breast radiation therapy: Comparison of photon and proton techniques.

BACKGROUND AND PURPOSE: To compare secondary malignancy risks of modern proton and photon therapy techniques for locally advanced breast cancer. METHODS AND MATERIALS: We utilized dosimetric data from 34 [10 photon-VMAT, 10 photon-3DCRT, 14 pencil beam scanning proton (PBS)] breast cancer patients who received comprehensive nodal irradiation. Employing a model based on organ equivalent dose to account for both inhomogeneous organ dose distributions and non-linear functional dose relationships, we estimated excess absolute risk, excess relative risk, and lifetime attributable risk (LAR) for secondary malignancies. The model uses dose distribution, number of fractions, age at exposure, attained age, the linear-quadratic dose response relationship for cell survival, repopulation factor, as well as gender specific age dependencies, and initial slopes of dose response curves. RESULTS: The LAR for carcinoma at age 70 was estimated to be up to 3.64% for esophagus with an advantage of 3DCRT over PBS and VMAT. For the ipsilateral lung, risks were lowest for PBS (up to 5.56%), followed by 3DCRT (up to 6.54%) and VMAT (up to 7.7%). For the contralateral lung, there is a clear advantage of 3DCRT and PBS techniques (risk <0.86%) over VMAT (up to 4.4%). The risk for the contralateral breast is negligible for 3DCRT and PBS but was estimated as up to 1.2% for VMAT. Risks for the thyroid are overall negligible. Independently performed comparative treatment plans on 10 patients revealed that the risk for the contralateral lung and breast using VMAT can be more than an order of magnitude higher compared to PBS. Sarcoma risks were estimated as well showing similar trends but were overall lower compared to carcinoma. CONCLUSION: Conventional (3DCRT) techniques led to the lowest estimated risks of, thyroid and esophageal secondary cancers while PBS demonstrated a benefit for secondary lung and contralateral breast cancer risks, with the highest risks overall associated with VMAT techniques.

Descemet Stripping Only for a Chronic Descemet Detachment After Cataract Surgery.

PURPOSE: To describe a case of postsurgical corneal decompensation in a patient with Fuchs endothelial dystrophy with a sectoral Descemet detachment and corneal edema that was successfully managed with a targeted Descemet stripping only (DSO) procedure. METHODS: This is a case report and review of the literature. RESULTS: A female patient with Fuchs endothelial dystrophy presented with a 6-month history of a persistent sectoral Descemet membrane detachment after cataract surgery with overlying corneal edema. Specular microscopy demonstrated moderate cell dropout with a cell density of 929 cells/mm in the affected eye. Intracameral air injection was attempted without improvement, and a sectoral DSO procedure was performed. Netarsudil and prednisolone were used postoperatively, and she demonstrated gradual improvement with resolution of the edema by postoperative week 10 and a central endothelial cell density of 675 cells/mm by postoperative month 8. CONCLUSIONS: DSO is a viable therapy in certain cases of postsurgical corneal decompensation.

Individualization of Clinical Target Volume Delineation Based on Stepwise Spread of Nasopharyngeal Carcinoma: Outcome of More Than a Decade of Clinical Experience.

PURPOSE: Radiation-related toxicity in nasopharyngeal carcinoma (NPC) is common. There are no well-established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony landmarks and fixed margins around the gross tumor volume (GTV), an approach used to define fields in the conventional 2- and 3-dimensional radiation therapy era. METHODS AND MATERIALS: We retrospectively evaluated patients with newly diagnosed nonmetastatic NPC treated with definitive radiation therapy using a technique of CTV delineation based on individual tumor extent and the orderly stepwise pattern of tumor spread. Dosimetric comparisons were made between national protocol HN001 and our contouring strategies on a representative early- and advanced-stage NPC. The primary endpoints were patterns of failure and local control; secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. RESULTS: Between 1999 and 2013, 73 patients (88% with stage 3-4 disease) were treated with median follow-up of 90 months for surviving patients. Median dose to GTV was 70 Gy. Four patients developed local recurrence and 1 patient developed regional recurrence. All locoregional recurrences occurred within the high-dose GTV. The 5-year local control, regional control, and overall survival was 94% (95% confidence interval [CI], 85%-98%), 99% (95% CI, 90%-100%), and 84% (95% CI, 73%-91%), respectively. Compared with HN001, our contouring strategy resulted in 62% and 36% reduction in CTV for T1 and T4 disease, respectively. In the T1 tumor, the reduction of doses to the contralateral parotid, optic nerve, and cochlea were 54%, 50%, 34% respectively. In the T4 case, there was a decrease of optic chiasm dose of 46% and contralateral optic nerve of 37%. There were 10 grade 3 toxicities. There was no grade 2 or higher xerostomia and no grade 4/5 toxicity. CONCLUSIONS: Our long-term experience with individualized CTV delineation based on stepwise patterns of spread results in excellent local control, with no recurrence outside the GTV.