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Background: Stereotactic radiosurgery (SRS) has emerged as an important modality for the treatment of intracranial metastases. There are currently few established guidelines delineating indications for SRS use and fewer still regarding plan evaluation in the treat- ment of multiple brain metastases. Methods: An 18 question electronic survey was distributed to radiation oncologists at National Cancer Institute (NCI) designated cancer centers in the US (60). Centers without radiation oncologists were excluded. Physicians who indicated that they do not prescribe SRS were excluded from the remaining survey questions. Sign test and Chi-square test were used to determine if responses differed significantly from random distribution. Results: 116 of the 697 radiation oncologists surveyed completed the questionnaire, representing 51 institutions. 62% reported treating patients with brain metastases using SRS. Radiation oncologists prescribing SRS most commonly treat CNS (66.2%) and lung (49.3%) malignancies. SRS was used more frequently for <10 brain metastases (73.7%; p<.0001) and whole brain radiation therapy (WBRT) for >10 brain metastases (82.5%; p<.0001). The maximum number of lesions physicians were willing to treat with SRS without WBRT was 1-4 (40.4%) and 5-10 (42.4%) (p<.0001 compared to 11-15, 16-20 and no limit). The most important criteria for choosing SRS or WBRT were number of lesions (p<.0001) and performance status (p=.016). The most common margin for SRS was 0 mm (49.1%; p=.0021). The most common dose constraints other than critical structure was conformity index (84.2%) and brain V12 (61.4%). The LINAC was the most common treatment modality (54.4%) and mono-isocenter technique for multiple brain metastases was commonly used (43.9%; p=.23). Most departments do not have a policy for brain metastases treatment (64.9%; p=.024). Conclusions: This is one of the first national surveys assessing the use of SRS for brain metastases in clinical practice. These data h

Colorectal cancer is the second leading cause of cancer death. Intestinal transformation begins ubiquitously with activation of Wnt signaling through mutations in APC (80%) or its degradation target β-catenin (15%). This produces a gain-of-function driving TCF-dependent nuclear transcription underlying epithelial dysfunction and tumorigenesis. While a role for APC and β-catenin in colorectal cancer is well-established, steps leading from gene mutation to tumorigenesis, and their reversibility, remain incompletely defined. Guanylin is the paracrine hormone for the receptor GUCY2C. This hormone is expressed in normal epithelium and is the most commonly lost gene product in colorectal cancer, silencing GUCY2C at the earliest step in neoplasia in a mechanism that is conserved across species. GUCY2C regulates homeostatic mechanisms organizing the intestinal crypt-surface axis, and its silencing through guanylin suppression drives hyperproliferation, DNA damage, metabolic reprogramming and desmoplasia, all contributing to tumorigenesis. Here, we demonstrate that inactivation of APC, or activation of β-catenin, induces TCF-dependent elimination of guanylin transcription and translation in human intestinal cells in vitro and in conditional genetic mouse models in vivo. Importantly, enforced genetic expression of guanylin in intestinal epithelial cells abrogated tumorigenesis in several orthogonal mouse models of colorectal tumorigenesis. These observations reveal for the first time a mechanism through which GUCY2C is silenced in colorectal tumorigenesis, and present a pathophysiologic model in which mutant APC-β-catenin signaling eliminates guanylin expression as an obligatory step in tumorigenesis. In addition to APC/β-catenin-associated tumorigenesis silencing GUCY2C, studies herein have also identified guanylin loss as a causative molecular event in obesity-associated tumorigenesis as well. In that context, caloric intake induces intestinal ER stress and silences guanyli

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.