An orthogonal matching pursuit optimization method for solving minimum-monitor-unit problems: Applications to proton IMPT, ARC and FLASH.

BACKGROUND: The intensities (i.e., number of protons in monitor unit [MU]) of deliverable proton spots need to be either zero or meet a minimum-MU (MMU) threshold, which is a nonconvex problem. Since the dose rate is proportionally associated with the MMU threshold, higher-dose-rate proton radiation therapy (RT) (e.g., efficient intensity modulated proton therapy (IMPT) and ARC proton therapy, and high-dose-rate-induced FLASH effect needs to solve the MMU problem with larger MMU threshold, which however makes the nonconvex problem more difficult to solve. PURPOSE: This work will develop a more effective optimization method based on orthogonal matching pursuit (OMP) for solving the MMU problem with large MMU thresholds, compared to state-of-the-art methods, such as alternating direction method of multipliers (ADMM), proximal gradient descent method (PGD), or stochastic coordinate descent method (SCD). METHODS: The new method consists of two essential components. First, the iterative convex relaxation (ICR) method is used to determine the active sets for dose-volume planning constraints and decouple the MMU constraint from the rest. Second, a modified OMP optimization algorithm is used to handle the MMU constraint: the non-zero spots are greedily selected via OMP to form the solution set to be optimized, and then a convex constrained subproblem is formed and can be conveniently solved to optimize the spot weights restricted to this solution set via OMP. During this iterative process, the new non-zero spots localized via OMP will be adaptively added to or removed from the optimization objective. RESULTS: The new method via OMP is validated in comparison with ADMM, PGD and SCD for high-dose-rate IMPT, ARC, and FLASH problems of large MMU thresholds, and the results suggest that OMP substantially improved the plan quality from PGD, ADMM and SCD in terms of both target dose conformality (e.g., quantified by max target dose and conformity index) and normal tissue sparing (e.g., mean and max dose). For example, in the brain case, the max target dose for IMPT/ARC/FLASH was 368.0%/358.3%/283.4% respectively for PGD, 154.4%/179.8%/150.0% for ADMM, 134.5%/130.4%/123.0% for SCD, while it was <120% in all scenarios for OMP; compared to PGD/ADMM/SCD, OMP improved the conformity index from 0.42/0.52/0.33 to 0.65 for IMPT and 0.46/0.60/0.61 to 0.83 for ARC. CONCLUSIONS: A new OMP-based optimization algorithm is developed to solve the MMU problems with large MMU thresholds, and validated using examples of IMPT, ARC, and FLASH with substantially improved plan quality from ADMM, PGD, and SCD.

Auranofin Protects Intestine against Radiation Injury by Modulating p53/p21 Pathway and Radiosensitizes Human Colon Tumor.

PURPOSE: The radiosensitivity of the normal intestinal epithelium is the major limiting factor for definitive radiotherapy against abdominal malignancies. Radiosensitizers, which can be used without augmenting radiation toxicity to normal tissue, are still an unmet need. Inhibition of proteosomal degradation is being developed as a major therapeutic strategy for anticancer therapy as cancer cells are more susceptible to proteasomal inhibition-induced cytotoxicity compared with normal cells. Auranofin, a gold-containing antirheumatoid drug, blocks proteosomal degradation by inhibiting deubiquitinase inhibitors. In this study, we have examined whether auranofin selectively radiosensitizes colon tumors without promoting radiation toxicity in normal intestine. EXPERIMENTAL DESIGN: The effect of auranofin (10 mg/kg i.p.) on the radiation response of subcutaneous CT26 colon tumors and the normal gastrointestinal epithelium was determined using a mouse model of abdominal radiation. The effect of auranofin was also examined in a paired human colonic organoid system using malignant and nonmalignant tissues from the same patient. RESULTS: Both in the mouse model of intestinal injury and in the human nonmalignant colon organoid culture, auranofin pretreatment prevented radiation toxicity and improved survival with the activation of p53/p21-mediated reversible cell-cycle arrest. However, in a mouse model of abdominal tumor and in human malignant colonic organoids, auranofin inhibited malignant tissue growth with inhibition of proteosomal degradation, induction of endoplasmic reticulum stress/unfolded protein response, and apoptosis. CONCLUSIONS: Our data suggest that auranofin is a potential candidate to be considered as a combination therapy with radiation to improve therapeutic efficacy against abdominal malignancies.

Quantitative clinical outcomes of therapy for head and neck lymphedema.

PURPOSE: Head and neck surgery and radiation cause tissue fibrosis that leads to functional limitations and lymphedema. The objective of this study was to determine whether lymphedema therapy after surgery and radiation for head and neck cancer decreases neck circumference, increases cervical range of motion, and improves pain scores. METHODS AND MATERIALS: A retrospective review of all patients with squamous cell carcinoma of the oral cavity, oropharynx, or larynx who were treated with high-dose radiation therapy at a single center between 2011 and 2012 was performed. Patients received definitive or postoperative radiation for squamous cell carcinoma of the oral cavity, oropharynx, or larynx. Patients were referred to a single, certified, lymphedema therapist with specialty training in head and neck cancer after completion of radiation treatment and healing of acute toxicity (typically 1-3 months). Patients underwent at least 3 months of manual lymphatic decongestion and skilled fibrotic techniques. Circumferential neck measurements and cervical range of motion were measured clinically at 1, 3, 6, 9, and 12 months after completion of radiation therapy. Pain scores were also recorded. RESULTS: Thirty-four consecutive patients were eligible and underwent a median of 6 months of lymphedema therapy (Range, 3-12 months). Clinically measured total neck circumference decreased in all patients with 1 month of treatment. Cervical rotation increased by 30.2% on the left and 27.9% on the right at 1 month and continued to improve up to 44.6% and 55.3%, respectively, at 12 months. Patients undergoing therapy had improved pain scores from 4.3 at baseline to 2.0 after 1 month. CONCLUSIONS: Lymphedema therapy is associated with objective improvements in range of motion, neck circumference, and pain scores in the majority of patients.

Development and Characterization of an In Vitro Model for Radiation-Induced Fibrosis.

Radiation-induced fibrosis (RIF) is a major side effect of radiotherapy in cancer patients with no effective therapeutic options. RIF involves excess deposition and aberrant remodeling of the extracellular matrix (ECM) leading to stiffness in tissues and organ failure. Development of preclinical models of RIF is crucial to elucidate the molecular mechanisms regulating fibrosis and to develop therapeutic approaches. In addition to radiation, the main molecular perpetrators of fibrotic reactions are cytokines, including transforming growth factor-ß (TGF-ß). We hypothesized that human oral fibroblasts would develop an in vitro fibrotic reaction in response to radiation and TGF-ß. We demonstrate here that fibroblasts exposed to radiation followed by TGF-ß exhibit a fibrotic phenotype with increased collagen deposition, cell proliferation, migration and invasion. In this in vitro model of RIF (RIFiv), the early biological processes involved in fibrosis are demonstrated, along with increased levels of several molecules including collagen 1α1, collagen XIα1, integrin-α2 and cyclin D1 mRNA in irradiated cells. A clinically relevant antifibrotic agent, pentoxifylline, and a curcumin analogue both mitigated collagen deposition in irradiated fibroblast cultures. In summary, we have established an in vitro model for RIF that facilitates the elucidation of molecular mechanisms in radiation-induced fibrosis and the development of effective therapeutic approaches.

CASTLE Thyroid Tumor: A Case Report and Literature Review.

Carcinoma showing thymus-like differentiation is a rare tumor of the thyroid gland, which is structurally similar to thymic tissue. Overall, it has a favorable prognosis. Radiotherapy has been shown to be an effective local treatment, but there have been reports of distant recurrence. It has been suggested that adding chemotherapy may decrease the risk of recurrence. Here, we present a case report of a patient with a large tumor and extrathyroidal extension. The patient was treated with surgery, radiotherapy, and cisplatin with acceptable toxicity. The patient is free of locally recurrent or distant disease at 3 years.

Radiation-induced fibrosis: mechanisms and implications for therapy.

PURPOSE: Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. METHODS: A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms. RESULTS: RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. CONCLUSION: Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.

Stereotactic body radiotherapy for treatment of squamous cell carcinoma of the tongue associated with human papilloma virus: a case report.

Stereotactic body radiotherapy (SBRT) has emerged as a treatment for recurrent squamous cell carcinoma of the head and neck in the field of prior radiation. We report a case of its use in an human papilloma virus (HPV) positive patient with squamous cell carcinoma of the right base of tongue. The patient had complete response to treatment and modest toxicities were noted. This represents encouraging results that SBRT is also useful for salvage in patients with HPV positive disease.

Stereotactic body radiation therapy for reirradiation of localized adenocarcinoma of the pancreas.

BACKGROUND: Local control rates are poor in the treatment of pancreatic cancer. We investigated the role of hypofractionated stereotactic body radiation therapy (SBRT) for salvage or boost treatment after conventional doses of external beam radiation therapy. METHODS: All patients treated with SBRT for pancreatic adenocarcinoma at Georgetown University from June 2002 through July 2007 were examined. Eligible patients had prior external beam radiation therapy to the pancreas. Treatment parameters and clinical and radiographic follow-up were evaluated. RESULTS: Twenty-eight patients were identified who received SBRT after a median prior external beam radiotherapy dose of 50.4 Gy. The median patient age was 63 years old and the median follow-up was 5.9 months. Twelve of fourteen (85.7%) evaluable patients were free from local progression, with three partial responses and nine patients with stable disease. Toxicity consisted of one case of acute Grade II nausea/vomiting, and two cases of Grade III late GI toxicity. The median overall survival was 5.9 months, with 18% survival and 70% freedom from local progression at one year. CONCLUSIONS: Hypofractionated SBRT reirradiation of localized pancreatic cancer is a well-tolerated treatment. Most patients are free from local progression, albeit with limited follow-up, but overall survival remains poor.

17Alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice.

Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17alpha-estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics.