Chemoradiation with Hypofractionated Proton Therapy in Stage II-III Non-Small Cell Lung Cancer: A Proton Collaborative Group Phase 2 Trial.

PURPOSE: Hypofractionated radiation therapy has been safely implemented in the treatment of early-stage non-small cell lung cancer (NSCLC) but not locally advanced NSCLC owing to prohibitive toxicities with photon therapy. Proton therapy, however, may allow for safe delivery of hypofractionated radiation therapy. We sought to determine whether hypofractionated proton therapy with concurrent chemotherapy improves overall survival. METHODS AND MATERIALS: The Proton Collaborative Group conducted a phase 1/2 single-arm nonrandomized prospective multicenter trial from 2013 through 2018. We received consent from 32 patients, of whom 28 were eligible for on-study treatment. Patients had stage II or III unresectable NSCLC (based on the 7th edition of the American Joint Committee on Cancer's staging manual) and received hypofractionated proton therapy at 2.5 to 4 Gy per fraction to a total 60 Gy with concurrent platin-based doublet chemotherapy. The primary outcome was 1-year overall survival comparable to the 62% reported for the Radiation Therapy Oncology Group (RTOG) 9410 trial. RESULTS: The trial closed early owing to slow accrual, in part, from a competing trial, RTOG 1308. Median patient age was 70 years (range, 50-86 years). Patients were predominantly male (n = 20), White (n = 23), and prior smokers (n = 27). Most had stage III NSCLC (n = 22), 50% of whom had adenocarcinoma. After a median follow-up of 31 months, the 1- and 3-year overall survival rates were 89% and 49%, respectively, and progression-free survival rates were 58% and 32%, respectively. No acute grade ≥3 esophagitis occurred. Only 14% developed a grade ≥3 radiation-related pulmonary toxic effect. CONCLUSIONS: Hypofractionated proton therapy delivered at 2.5 to 3.53 Gy per fraction to a total 60 Gy with concurrent chemotherapy provides promising survival, and additional examination through larger studies may be warranted.

Bilateral dysthyroid compressive optic neuropathy responsive to teprotumumab.

Thyroid eye disease is an auto-immune mediated orbitopathy which can cause dysthyroid compressive optic neuropathy. Traditional management of active thyroid eye disease includes temporizing high-dose steroids, orbital radiation and surgical decompression, which each possess significant limitations and/or side effects. Teprotumumab is an IGF-IR inhibitor recently FDA-approved for active thyroid eye disease. The authors report reversal of bilateral dysthyroid compressive optic neuropathy managed medically utilizing teprotumumab.

Treatment Options for Lower Eyelid Festoons.

Festoons represent a combination of fluid accumulation and soft tissue laxity in the superolateral cheek. They remain a difficult entity to treat. The ideal treatment for festoons would possess minimal invasiveness and recovery time, and predictably improve the condition. No nonsurgical treatment currently meets these criteria, and surgical treatments have significant limitations. Fortunately, a variety of treatment options exist that can benefit each patient and be tailored to their specific needs. Knowledge of the underlying anatomy, clinical characteristics, and clinical evaluation will better equip the treating physician to manage festoons.

Blindness After Filler Injection: Mechanism and Treatment.

Dermal fillers remain popular for facial rejuvenation but with its increasing use, the potential for more complications including blindness is present. This article focuses on the mechanism of filler-associated blindness, possible treatments, and future directions. Unfortunately, to date there is no proven treatment to reverse filler-induced blindness or visual compromise. It is essential for all injectors to discuss the potential ocular risks including blindness with their patients and obtain informed consent before filler injection.

Dimensions, Function and Applications of the Auricular Muscle in Facial Plastic Surgery.

PURPOSE: To determine the dimensions and function of the auricular muscle and to consider applications of this muscle in facial plastic surgery. METHODS: Nonpreserved fresh frozen human cadaver dissections from the (HOSPITAL-Blinded) Body Donation program were dissected. The length and width of the superior auricular muscle were measured. One surgeon performed all dissections and measurements. RESULTS: A total of seven left and five right hemifaces were studied. The average central height of the superior auricular muscle was 4.7 cm, and an average width was 5.0 cm. There was no significant difference between the average values of the left versus the right hemiface measurements. The muscle originated in the fibers of the galea and temporal fascia and inserted into the conchal cartilage in each specimen. Engaging the muscle in its line of action yielded slight elevation of the forehead and prevented movement of the galea along the vertex of the scalp. CONCLUSIONS: The auricular muscle acts as an occipitofrontalis stabilizer and a weak brow elevator. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors - www.springer.com/00266 .

Unilateral Ptosis, Proptosis, and Orbital Myositis After Shingles Vaccination.

Vaccinations for shingles are recommended for most adults over 60 years of age and are typically well tolerated. The present case describes acute onset of unilateral ptosis, proptosis, and orbital myositis developing within days after administration of shingles vaccination. The episode resolved to baseline after 1 week of treatment with steroids. To the authors' knowledge, this is first reported case of orbital inflammation following shingles vaccination. Given the temporal relationship and rapid response to treatment, this may represent an autoimmune reaction to the shingles vaccine.

Long-Term Patient Experience with Tetracycline Injections for Festoons.

BACKGROUND: The purpose of this study was to evaluate the long-term patient experience with tetracycline injections for treatment of festoons. METHODS: Charts of all patients undergoing tetracycline injection for treatment of lower eyelid festoons at the Cole Eye Institute, Cleveland Clinic, between 2008 and 2018 were identified using billing records. Patients were invited to participate in a questionnaire based on the FACE-Q checklist, a previously validated questionnaire for studying cosmetic procedure outcomes. Data from the questionnaire were summarized with size, mean, and frequency. RESULTS: One hundred two patients who received tetracycline injection during the study period were identified and 61 responses were obtained. The average follow-up time after injection was 3.6 years. Of 61 respondents, 36 (59 percent) noted improvement in their festoons after treatment, and 27 of 33 (82 percent) noted that improvement occurred within 2 months of treatment. Overall, 40 of 60 respondents (67 percent) would consider repeating tetracycline treatment. The most common adverse effects included discomfort (18 percent), swelling (15 percent), and bruising (13 percent). There was no statistically significant difference in questionnaire responses between men and women, except that men were more likely to consider repeated injection (92 percent versus 58 percent; p = 0.005). CONCLUSION: Tetracycline injection appears to improve festoons in a majority of patients, with an acceptable side-effect profile, although more data are needed to determine the optimal dose and frequency and to identify possible rare and/or significant side effects.

Development of a Comprehensive, Contour-Based, Peer Review Workflow at a Community Proton Center.

PURPOSE: Quality assurance and continuing quality improvement are integral parts of any radiation oncology practice. With increasingly conformal radiation treatments, it has become critical to focus on every slice of the target contour to ensure adequate tumor coverage and optimal normal tissue sparing. Proton therapy centers open internationally with increasing frequency, and radiation oncologists with varying degrees of subspecialization apply proton therapy in daily practice. Precise treatment with proton therapy allows us to limit toxicity but requires in-depth knowledge of the unique properties of proton beam delivery. To address this need at our proton therapy center, we developed a comprehensive peer review program to help improve the quality of care that we were providing for our patients. MATERIALS AND METHODS: We implemented a policy of comprehensive peer review for all patients treated at our community proton facility starting in January 2013. Peer review begins at the time of referral with prospective cases being reviewed for appropriateness for proton therapy at daily rounds. There is then biweekly review of target contouring and treatment plans. RESULTS: During a 6-month period from June 2013 to November 2013, a total of 223 new patients were treated. Documentation of peer review at chart rounds was completed for 222 of the 223 patients (99.6%). An average of 10.7 cases were reviewed in each biweekly chart rounds session, with a total of 560 case presentations. The average time required for contour review was 145 seconds (±71 seconds) and plan review was 120 seconds (±64 seconds). Modifications were suggested for 21 patients (7.9%) during contour review and for 19 patients (6.4%) during treatment plan review. An average of 4 physicians were present at each session. CONCLUSIONS: We demonstrated that the implementation of a comprehensive, prospective peer review program is feasible in the community setting. This article can serve as a framework for future quality assurance programs.

Hypofractionated Proton Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial from the University of Florida and Proton Collaborative Group.

PURPOSE: We report the safety data from the first multicenter phase 1 trial investigating the use of hypofractionated proton therapy with concurrent chemotherapy for patients with stage II or III non-small cell lung cancer. METHODS AND MATERIALS: From 2013 through 2018, patients with newly diagnosed stage II or III non-small cell lung cancer were enrolled in a multicenter phase 1 clinical trial evaluating concurrent chemotherapy with increasing dose-per-fraction proton therapy. This was a stepwise 5 + 2 dose-intensification protocol with the following dose arms: (1) 2.5 GyRBE per fraction to 60 GyRBE; (2) 3.0 GyRBE per fraction to 60 GyRBE; (3) 3.53 GyRBE per fraction to 60.01 GyRBE; and (4) 4.0 GyRBE per fraction to 60 GyRBE. A dose arm was considered tolerable if no radiation therapy-attributable severe adverse event (SAE) occurred within 90 days of treatment among 5 patients enrolled on the arm or if 1 SAE occurred among 7 patients enrolled. Dose constraints to the heart, brachial plexus, and spinal cord were more conservative at higher doses per fraction. RESULTS: The study closed early because of slow accrual and competing enrollment in NRG 1308 before accrual was met, with no maximum tolerated dose identified. Eighteen patients were treated, including 5 patients on arms 1 and 2, 7 patients on arm 3, and 1 patient on arm 4. Two SAEs occurred among 7 patients treated at 3.53 GyRBE per fraction; however, per outside expert review, both were attributed to chemotherapy and unrelated to radiation therapy. CONCLUSIONS: Hypofractionated proton therapy delivered at 2.5 to 3.53 GyRBE per fraction to a dose of 60 GyRBE with concurrent chemotherapy has an acceptable toxicity profile. Further exploration of this regimen is warranted on a phase 2 clinical trial.

Comparison of Orbital Volume in Young Versus Senescent Human Skulls.

PURPOSE: To compare bony orbital volumes in young skulls with those of older skulls to elucidate aging-associated changes of the orbit. METHODS: One hundred Caucasian male skulls from the Hamann-Todd collection of the Cleveland Museum of Natural History were studied. There were 50 young skulls (age range, 19-33 years) and 50 senescent skulls (age range, 79-96 years). Volcanic sand was used to fill each orbit in an identical fashion and weighed as a proxy for volume. Digital calipers were used to perform linear measurements of the orbit. The relationship between orbit measures and skull size was assessed using Pearson's correlations and 95% CI, and statistical models to compare age groups adjusted for skull size. RESULTS: The volume of the orbits (P < 0.001), the horizontal diameter of the orbit (P = 0.015), and the orbital depth (P < 0.001) were significantly larger in the senescent group of skulls after adjusting for skull surface area. No significant differences were found in the vertical diameters of the orbit between the 2 groups. Skull size did not statistically differ between the age groups. CONCLUSIONS: Increases in the depth and horizontal dimensions of the orbit lead to increasing bony orbital volume with increasing age. These changes in size and shape of the orbit with age may contribute to phenotypic changes of aging and may affect disease processes and management.

Temporal Fat Pad Volume in Patients With Thyroid Eye Disease.

PURPOSE: To determine whether thyroid eye disease (TED) is associated with a change in temporal fossa soft tissue volume. METHODS: CT imaging studies were selected from patients with TED considering orbital decompression surgery and from an age-matched group of controls presenting to the Emergency Department for nontraumatic conditions requiring CT imaging. Measurements of the temporal fossa fat pad and soft tissue thickness were used as a proxy for volume and were performed using the zygomaticotemporal suture as a reference point. Categorical variables were described using frequencies and percentages, while continuous variables were described using medians and standard deviations. Chi-square tests were used to assess the relationship between gender and age group, while t-tests were used to examine the relationship between continuous variables and age group. RESULTS: A total of 56 CT scans were evaluated, including scans from 28 patients with TED and 28 controls. The following measurements were found to be significantly larger in the TED population: left fat pad measured 5 mm above the zygomaticotemporal suture (p = 0.012), right fat pad measured 15 mm above the suture (p = 0.005), right soft tissue measured 15 mm above the suture (p = 0.026), left fat pad measured 15 mm above the suture (p = 0.006), and the left soft tissue measure 15 mm above the suture (p = 0.032). CONCLUSIONS: Thyroid eye disease is associated with an increase in temporal fossa fat pad and soft tissue volume. These findings suggest that TED disease may produce pan-facial changes rather than changes confined to the peri-orbital region.

Bloody Epiphora (Hemolacria) Years After Repair of Orbital Floor Fracture.

Surgical repair of orbital fractures with implants is a widely used treatment modality. While a variety of established complications are associated with this technique, most are directly understood and treated. Bloody epiphora is a finding with potentially ominous causes. The authors present a unique case of bloody epiphora, accompanied by orbital hemorrhage arising several years after orbital floor fracture repair, due to erosion of the nasolacrimal drainage system by a displaced implant combined with anticoagulation. The collection and evaluation of all protected patient health information was compliant with the regulations and conditions set forth in the Health Insurance Portability and Availability Act of 1996.

Association of ocular conditions with narrow angles in different ethnicities.

PURPOSE: To quantify the predictive strength of anterior chamber area (ACA), anterior chamber volume (ACV), anterior chamber width (ACW), lens vault (LV), iris thickness (IT), and iris area (IArea) for 2 angle width parameters, trabecular-iris space area (TISA750) and angle opening distance (AOD750) at 750 µm from the scleral spur, in different ethnicities. DESIGN: Prospective, cross-sectional study. METHODS: Anterior segment optical coherence tomography images for 166 white, 90 African, 75 Hispanic, and 132 Chinese subjects were analyzed. First, ACA, ACV, ACW, LV, IT, and IArea were compared among ethnic groups. Second, associations of TISA750 and AOD750 with ACA, ACV, ACW, LV, IT, and IArea were investigated within each ethnic group using multivariable linear regression models, standardized regression coefficients (ß), and coefficients of determination (R(2)). RESULTS: Significant ethnic differences were observed in ACA, ACV, ACW, LV, IT, and IArea (all P < .05). ACA, ACV, and LV were significant predictors of TISA750 and AOD750 in all ethnic groups (all P < .001). ACW and IT were significant predictors of AOD750 in white and African subjects (all P < .05). ACW and IT were significant predictors of TISA750 in white subjects (all P < .05). IArea was a significant predictor of AOD750 in Chinese (P < .05). ACA, ACV, and LV had the highest predictive strength for both TISA750 and AOD750 in all ethnic groups based on ß and R(2). CONCLUSIONS: Despite ethnic differences in ACA, ACV, ACW, LV, IT, and IArea, the same 3 anterior segment parameters (ACA, ACV, and LV) were the strongest predictors of angle width (TISA750 and AOD750) in all 4 ethnic groups.

Single vs multiple intraocular pressure measurements in glaucoma surgical trials.

IMPORTANCE: Little is known about the necessity of multiple same-day intraocular pressure (IOP) measurements in describing the effect of IOP-lowering surgical procedures, and such evidence could affect surgical trial recruitment and retention of participants. OBJECTIVE: To determine whether a single IOP measurement might adequately approximate the mean of several measurements in glaucoma surgical trials. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, interventional cohort from the prerandomization phase of a randomized clinical trial evaluating use of a supraciliary implant for treatment of IOP was conducted at multiple ophthalmology clinics. A total of 609 patients (609 eyes) with primary open-angle glaucoma and cataract were included. INTERVENTIONS: One IOP measurement was made while patients were receiving their usual medications to lower IOP, and 3 IOP measurements were made at 8 am, 12 pm, and 4 pm after patients underwent washout of all IOP-lowering eyedrops. MAIN OUTCOMES AND MEASURES: The proportion of eyes in which the increase in IOP after washout, using the mean of the 3 measurements, differed by more than 0.5, 1.0, 1.5, or 2.0 mm Hg from the increase in IOP after washout using only 1 of the postwashout measurements. A proportion of 10% or less at the 1.5-mm Hg cutoff was considered clinically acceptable. The hypothesis was formulated after data collection but before the data were examined. RESULTS: The mean (SD) IOP before washout was 18.5 (4.0) mm Hg. The mean increase in IOP after washout, using the mean of the 3 measurements, was 5.3 (4.2) mm Hg. The percentage of eyes in which the increase in IOP using a single postwashout IOP differed from the increase in IOP using the mean of 3 measurements by more than 1.5 mm Hg was 35.1%, 25.6%, 34.2%, 30.0%, and 31.4% when the single measurement was made at 8 am, 12 pm, 4 pm, a randomly chosen single measure of those 3 times, and the time closest to that of the prewashout IOP, respectively. By logistic regression, the 12 pm postwashout IOP had the lowest proportion of eyes differing from the mean (P < .001) and thus most closely approximated the mean diurnal IOP. CONCLUSIONS AND RELEVANCE: Although eliminating multiple IOP measurements would simplify the conduct of surgical trials in glaucoma, our data show that using a single IOP measurement after washout does not adequately approximate the mean of multiple IOP measurements.

Effectiveness of intraocular pressure-lowering medication determined by washout.

IMPORTANCE While medication efficacy is well documented in clinical trials, less is known of medication effectiveness in real-world clinical settings. OBJECTIVE To assess the effectiveness of intraocular pressure (IOP)-lowering medications in patients with open-angle glaucoma. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter, interventional cohort from the prerandomization phase of a randomized clinical trial at multiple ophthalmology clinics. A total of 603 patients (603 eyes) with primary open-angle glaucoma who were using up to 3 glaucoma medications were included. INTERVENTIONS One IOP measurement was made while the patient was using his or her usual medications to lower IOP (ON IOP). Eligible participants underwent washout of all IOP-lowering drops, and the diurnal IOP was measured 2 to 4 weeks later (OFF IOP). MAIN OUTCOMES AND MEASURES Difference between OFF IOP and ON IOP. The hypothesis was formulated after data collection. RESULTS The mean (SD) ON IOPs for participants using 0 (n = 102), 1 (n = 272), 2 (n = 147), or 3 (n = 82) medications were 24.2 (3.2), 17.5 (3.2), 17.2 (3.1), and 17.2 (3.1) mm Hg, respectively. Patients not using medication had a mean (SD) IOP decrease of 0.2 (2.8) mm Hg at the OFF visit. Patients using 1, 2, and 3 medications had mean (SD) IOP increases of 5.4 (3.0), 6.9 (3.3), and 9.0 (3.8) mm Hg, respectively, at the OFF visit. The percentages of patients with less than a 25% increase in IOP were 38%, 21%, and 13% for those using 1, 2, and 3 medications, respectively. CONCLUSIONS AND RELEVANCE Discontinuation of 1, 2, and 3 medications was associated with a clinically significant increase in IOP, although with smaller effects for the second and third medications compared with the first medication. A substantial proportion of patients showed only small changes in IOP after medication washout, suggesting either that they were not using the medication effectively or that the medication itself, although used properly, was not lowering the IOP. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01085357.

Human umbilical cord mesenchymal stromal cells exhibit immature nucleus pulposus cell phenotype in a laminin-rich pseudo-three-dimensional culture system.

INTRODUCTION: Cell supplementation to the herniated or degenerated intervertebral disc (IVD) is a potential strategy to promote tissue regeneration and slow disc pathology. Human umbilical cord mesenchymal stromal cells (HUCMSCs) - originating from the Wharton's jelly - remain an attractive candidate for such endeavors with their ability to differentiate into multiple lineages. Previously, mesenchymal stem cells (MSCs) have been studied as a potential source for disc tissue regeneration. However, no studies have demonstrated that MSCs can regenerate matrix with unique characteristics matching that of immature nucleus pulposus (NP) tissues of the IVD. In our prior work, immature NP cells were found to express specific laminin isoforms and laminin-binding receptors that may serve as phenotypic markers for evaluating MSC differentiation to NP-like cells. The goal of this study is to evaluate these markers and matrix synthesis for HUCMSCs cultured in a laminin-rich pseudo-three-dimensional culture system. METHODS: HUCMSCs were seeded on top of Transwell inserts pre-coated with Matrigel™, which contained mainly laminin-111. Cells were cultured under hypoxia environment with three differentiation conditions: NP differentiation media (containing 2.5% Matrigel™ solution to provide for a pseudo-three-dimensional laminin culture system) with no serum, or the same media supplemented with either insulin-like growth factor-1 (IGF-1) or transforming growth factor-ß1 (TGF-ß1). Cell clustering behavior, matrix production and the expression of NP-specific laminin and laminin-receptors were evaluated at days 1, 7, 13 and 21 of culture. RESULTS: Data show that a pseudo-three-dimensional culture condition (laminin-1 rich) promoted HUCMSC differentiation under no serum conditions. Starting at day 1, HUCMSCs demonstrated a cell clustering morphology similar to that of immature NP cells in situ and that observed for primary immature NP cells within the similar laminin-rich culture system (prior study). Differentiated HUCMSCs under all conditions were found to contain glycosaminoglycan, expressed extracellular matrix proteins of collagen II and laminin α5, and laminin receptors (integrin α3 and ß4 subunits). However, neither growth factor treatment generated distinct differences in NP-like phenotype for HUCMSC as compared with no-serum conditions. CONCLUSIONS: HUCMSCs have the potential to differentiate into cells sharing features with immature NP cells in a laminin-rich culture environment and may be useful for IVD cellular therapy.

Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells.

Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a promising hypoxia-selective cytotoxin that has shown significant activity in advanced clinical trials in combination with radiotherapy and cisplatin. The current study aimed to advance our understanding of tirapazamine-induced lesions and the pathways involved in their repair. We show that homologous recombination plays a critical role in repair of tirapazamine-induced damage because cells defective in homologous recombination proteins XRCC2, XRCC3, Rad51D, BRCA1, or BRCA2 are particularly sensitive to tirapazamine. Consistent with the involvement of homologous recombination repair, we observed extensive sister chromatid exchanges after treatment with tirapazamine. We also show that the nonhomologous end-joining pathway, which predominantly deals with frank double-strand breaks (DSB), is not involved in the repair of tirapazamine-induced DSBs. In addition, we show that tirapazamine preferentially kills mutants both with defects in XPF/ERCC1 (but not in other nucleotide excision repair factors) and with defects in base excision repair. Tirapazamine also induces DNA-protein cross-links, which include stable DNA-topoisomerase I cleavable complexes. We further show that gamma H2AX, an indicator of DNA DSBs, is induced preferentially in cells in the S phase of the cell cycle. These observations lead us to an overall model of tirapazamine damage in which DNA single-strand breaks, base damage, and DNA-protein cross-links (including topoisomerase I and II cleavable complexes) produce stalling and collapse of replication forks, the resolution of which results in DSB intermediates, requiring homologous recombination and XPF/ERCC1 for their repair.

The effect of nonmalignant systemic disease on tolerance to radiation therapy.

PURPOSE: Some patients with nonmalignant systemic diseases, like collagen vascular disease (CVD), hypertension, diabetes mellitus, and inflammatory bowel disease (IBD), tolerate radiation therapy poorly. Although the mechanisms of each of these disease processes are different, they share a common microvessel pathology that is potentially exacerbated by radiotherapy. This article reviews and evaluates available data examining the effects of these benign disease processes on radiation tolerance. METHODS: We conducted a thorough review of the Anglo-American medical literature from 1960 to 2001 on the effects of radiotherapy on CVD, hypertension, diabetes mellitus, and IBD. RESULTS: Fifteen studies were identified that examined the effects of radiation therapy for cancer in patients with CVDs. Thirteen of 15 studies documented greater occurrences of acute and late toxicities (range 7%-100%). Higher rates of complications were noted especially for nonrheumatoid arthritis CVDs. Nine studies evaluated the effects of hypertension and diabetes on radiation tolerance. All nine studies documented higher rates of late toxicities than in a "control" group (range 34%-100%). When patients had both diabetes and hypertension, the risk of late toxicities was even higher. Six studies examined radiation tolerance of patients with IBD irradiated to the abdomen and pelvis. Five of these six studies showed greater occurrences of acute and late toxicities for patients with IBD, even with precautionary measures like reduced fraction size and volume and patient immobilization (13%-29%). CONCLUSION: The majority of published studies documented lower radiation tolerance for patients who have CVD, diabetes mellitus, hypertension, and IBD. This may reflect a publication bias, as the majority of these studies are retrospective with small numbers of patients and use different scoring scales for complications. These factors may contribute to an overestimation of true radiation-induced morbidity. Although the paucity of data makes precise estimates difficult, a subset of patients, in particular, those with active CVD, IBD, or a combination of uncontrolled hypertension with type I diabetes, is likely to be at higher risk. Future prospective trials need to document these disease entities when reporting treatment-related complications and also must monitor toxicities associated with quiescent versus active IBD and CVD, type I versus type II diabetes, and levels of hypertension (controlled versus uncontrolled) matched for radiation-specific treatment sites, field size, fractionation, and total dose.