An Affordable Platform for Virtual Reality-Based Patient Education in Radiation Therapy.

PURPOSE: The goal of this study was to develop and assess the effectiveness of an affordable smartphone-based virtual reality (VR) patient education platform with 360-degree videos produced depicting a first-person patient perspective during the radiation therapy (RT) care path to reduce patient anxiety. METHODS AND MATERIALS: Three disease site-specific (breast, pelvis, head and neck) VR videos were filmed using a 360-degree camera to portray the first-person perspective of a patient's standard RT appointments, including a computed tomography simulation and the first RT treatment session. Instruction is given for possible clinical implementation. Patient participation was divided into 2 groups: (1) Group A (n = 28) included patients participating before simulation and later after the first treatment, and (2) Group B (n = 33) included patients participating only while undergoing treatment. Patients viewed their disease site-specific video using an inexpensive cardboard VR viewer and their smartphone, emulating an expensive VR-headset. Surveys were administered assessing patient anxiety, comfort, satisfaction, and knowledge of RT on a 5-point Likert-type scale. RESULTS: Patients in Group A and Group B while undergoing treatment both indicated that their anxiety "decreased a little" in the survey, after watching the VR video (Group A, median on a 5-point Likert-type scale, 4 [IQR, 4-5]; Group B, 4 [IQR, 4-4]). The VR aspect of the videos was especially liked by patients while undergoing treatment, with 96.4% in Group A and 90.9% in Group B reporting that the VR aspect of the videos was helpful. All Group A participants believed that the VR videos would be beneficial to new patients. CONCLUSIONS: Our affordable VR patient education platform effectively immerses a patient in their care path from simulation through initial treatment delivery, reducing anxiety and increasing familiarity with the treatment process.

Improved organ sparing using auto-planned Stanford volumetric modulated arc therapy for total body irradiation technique.

PURPOSE/OBJECTIVES: To evaluate dosimetric differences between auto-planned volumetric modulated arc therapy (VMAT) total body irradiation (TBI) technique and two-dimensional radiotherapy using anterior-posterial/posterio-anterial beams (2D AP/PA) TBI technique. METHODS: Ten pediatric patients treated with VMAT-TBI on Varian c-arm linac were included in this study. VMAT-TBI plans were generated using our in-house developed and publicly shared auto-planning scripts. For each VMAT-TBI plan, a 2D AP/PA plan was created replicating the institution's clinical setup with the patient positioned at extended source to skin distance (SSD) with a compensator to account for differences in patient thickness, 50% transmission daily lung blocks, and electron chest wall boosts prescribed to 50% of the photon prescription. Clinically relevant metrics were analyzed and compared between the VMAT and 2D plans. RESULTS: All VMAT-TBI plans achieved planned target volume (PTV) D90% ≥ 100% of prescription. VMAT-TBI PTV D90% significantly increased (7.1% ± 2.9%, p < .001) compared to the 2D technique, whereas no differences were observed in global Dmax (p < .2) and PTV V110% (p < .4). Compared to the 2D plans, significant decreases in the Dmean to the lungs (-25.6% ± 11.5%, p < .001) and lungs-1 cm (-34.1% ± 10.1%, p < .001) were observed with the VMAT plans. The VMAT technique also enabled decrease of dose to other organs: kidneys Dmean (-32.5% ± 5.0%, p < .001) and lenses Dmax (-5.3% ± 8.1%, p = .03); and in addition, for 2 Gy prescription: testes/ovaries Dmean (-41.5% ± 11.5%, p < .001), brain Dmean (-22.6% ± 5.4%, p = .002), and thyroid Dmean (-18.2% ± 16.0%, p = .03). CONCLUSIONS: Superior lung sparing with improved target coverage and similar global Dmax were observed with the VMAT plans as compared to 2D plans. In addition, VMAT-TBI plans provided greater dose reductions in gonads, kidneys, brain, thyroid, and lenses.

Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience.

Purpose: Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center. Methods and Materials: We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset. Results: Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P = .31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P = .03). Conclusions: Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.

Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma.

Purpose/Objectives Combination BRAF (vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited. We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis. DF was defined as any new intracranial lesions. Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of the diameters of the five largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308, p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients with BRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.

Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Volumetric modulated arc therapy total body irradiation in pediatric and adolescent/young adult patients undergoing stem cell transplantation: Early outcomes and toxicities.

INTRODUCTION: Total body irradiation (TBI) is an important component of many conditioning regimens for hematopoietic stem cell transplantation (HSCT), most commonly used in pediatric and adolescent/young adult (AYA) patients. We aimed to evaluate outcomes and toxicities among pediatric and AYA patients treated with TBI utilizing volumetric modulated arc therapy total body irradiation (VMAT-TBI). METHODS: We reviewed pediatric and AYA patients treated with VMAT-TBI at our institution from 2019 to 2021. Data on patient and disease characteristics, treatment details, outcomes and toxicities were collected. Overall survival (OS) and relapse-free survival (RFS) were analyzed using the Kaplan-Meier method. RESULTS: Among 38 patients, 16 (42.1%) were treated with myeloablative regimens and 22 (57.9%) with nonmyeloablative regimens. Median age was 7.2 years (range: 1-27) and median follow-up was 8.7 months (range: 1-21). Lungs Dmean was 7.3 ± 0.3 Gy for myeloablative regimens (range: 6.8-7.8). Kidneys were spared to average mean dose of 71.4 ± 4.8% of prescription dose. Gonadal sparing was achieved for patients treated for nonmalignant diseases to Dmean of 0.7 ± 0.1 Gy. No patient experienced primary graft failure; one (2.6%) experienced secondary graft failure. The most common grade 1-2 acute toxicities were nausea (68.4%) and fatigue (55.3%). Mucositis was the most common grade 3-4 acute toxicity, affecting 39.5% of patients. There were no cases of pneumonitis or nephrotoxicity attributable to TBI. CONCLUSION: VMAT-TBI offers increased ability to spare organs at risk in pediatric and AYA patients undergoing HSCT, with a favorable acute/subacute toxicity profile and excellent disease control.

Radiotherapy for Brain Metastases from Thyroid Cancer: An Institutional and National Retrospective Cohort Study.

Background: Stereotactic radiosurgery (SRS) is the standard of care for patients with a limited number of brain metastases. Despite the fact that the seminal studies regarding SRS for brain metastases were largely tissue agnostic, several current national guidelines do not uniformly recommend SRS in thyroid cancer. We therefore investigated oncological outcomes in a cohort of patients with brain metastases from thyroid cancer who received radiotherapy (RT) at our institution as well as those in a nationally representative cancer cohort, the National Cancer Database (NCDB). Materials and Methods: We identified patients with thyroid cancer and brain metastases treated with RT at our institution from 2002 through 2020. For the NCDB cohort, the national database of patients with thyroid cancer was screened on the basis of brain-directed RT or brain metastases. For the institutional cohort, the cumulative risk of local failure (LF), distant intracranial failure, and radiation necrosis were calculated, adjusted for the competing risk of death. Overall survival (OS) in both cohorts was analyzed using the Kaplan-Meier method. Univariate analysis was accomplished via clustered competing risks regression. Results: For the institutional cohort, we identified 33 patients with 212 treated brain metastases. OS was 6.6 months. The 1-year cumulative incidences of LF and distant intracranial failures were 7.0% and 38%, respectively. The 1-year risk of radiation necrosis was 3.3%. In the NCDB cohort, there were 289 patients, and the median survival was 10.2 months. NCDB national practice patterns analysis showed an increasing use of SRS over time in both the entire cohort and the subset of anaplastic patients. Univariate analysis was performed for OS, risk of LF, risk of regional intracranial failure, and risk of radiation necrosis. Conclusions: SRS is a safe, effective, and increasingly utilized treatment for thyroid cancer brain metastases of any histology and should be the standard of care treatment.

The Stanford Volumetric Modulated Arc Therapy Total Body Irradiation Technique.

PURPOSE: In this article, we describe the technical aspects of the Stanford volumetric modulated arc therapy (VMAT) total body irradiation (TBI) technique, compare it with other VMAT-TBI techniques, and share our initial experience. METHODS AND MATERIALS: From September 2019 to August 2021, 35 patients were treated with VMAT-TBI at our institution. Treatment planning was performed using in-house developed automated planning scripts. Organ sparing depended on the regimen: myeloablative (lungs, kidneys, and lenses) and nonmyeloablative with benign disease (lungs, kidneys, lenses, gonads, brain, and thyroid). Quality assurance was performed using electronic portal imaging device portal dosimetry and Mobius3D. Robustness was evaluated for the first 10 patients by performing local and global isocenter shifts of 5 mm. Treatment was delivered using image-guided radiation therapy for every isocenter and every fraction. In vivo measurements were performed on the match line between the VMAT and anterior-posterior/posterior-anterior fields and on the testes for the first fraction. RESULTS: The lungs, lungs - 1 cm, and kidneys Dmean were consistently spared to 57.6% ± 4.4%, 40.7% ± 5.5%, and 70.0% ± 9.9% of the prescription dose, respectively. Gonadal sparing (Dmean = 0.69 ± 0.13 Gy) was performed for all patients with benign disease. The average planning target volume (PTV) maximum dose to 1 cubic centimeter (D1cc) was 120.7% ± 6.4% for all patients. The average Gamma passing rate for the VMAT plans was 98.1% ± 1.6% (criterion of 3%/2 mm). Minimal differences were observed between Mobius3D- and Eclipse AAA-calculated PTV Dmean (0.0% ± 0.3%) and lungs Dmean (-2.5% ± 1.2%). Robustness evaluation showed that the PTV Dmax and lungs Dmean were insensitive to small positioning deviations between the VMAT isocenters (1.1% ± 2.4% and 1.2% ± 1.0%, respectively). The average match-line dose measurement indicated patient setup was reproducible (96.1% ± 4.5% relative to prescription dose). Treatment time, including patient setup and beam-on, was 47.5 ± 9.5 min. CONCLUSIONS: The Stanford VMAT-TBI technique, from simulation to treatment delivery, was presented and compared with other VMAT-TBI techniques. Together with publicly shared autoplanning scripts, our technique may provide the gateway for wider adaptation of this technology and the possibility of multi-institutional studies in the cooperative group setting.

Liquid Biopsies for Molecular Biology-Based Radiotherapy.

Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance.

A Preliminary Report of Gonadal-Sparing TBI Using a VMAT Technique.

Reproductive toxicity is common after total body irradiation (TBI) and has major quality of life implications for patients. In that context, this is the first report of gonadal-sparing volumetric-modulated arc therapy (VMAT) TBI, successfully delivered in a boy and a girl with aplastic anemia. Both patients' VMAT TBI plans demonstrated improved gonadal sparing versus simulated conventional 2-dimensional (2D) approach (mean testes dose, 0.45 Gy VMAT vs 0.72 Gy 2D; mean ovary dose, 0.64 Gy VMAT vs 1.47 Gy 2D). Planning target volume coverage was also improved for both cases with the VMAT plan versus conventional 2D plan (2 Gy D90% vs 1.9 Gy D90%, respectively). Given these dosimetric advantages, the present study can serve as a proof-of-concept for further prospective studies evaluating this technique for wider applications in populations receiving TBI.

APC-ß-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.

Sporadic colorectal cancer initiates with mutations in APC or its degradation target ß-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-ß-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-ß-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and ß-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis.

Stereotactic radiosurgery practice patterns for brain metastases in the United States: a national survey.

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 treatment 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 USA (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: One hundred sixteen of the 697 radiation oncologists surveyed completed the questionnaire, representing 51 institutions. Sixty-two percent 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 < 0.0001) and whole brain radiation therapy (WBRT) for > 10 brain metastases (82.5%; p < 0.0001). 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 < 0.0001 compared to 11-15, 16-20 and no limit). The most important criteria for choosing SRS or WBRT were number of lesions (p < 0.0001) and performance status (p = 0.016). The most common margin for SRS was 0 mm (49.1%; p = 0.0021). 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 = 0.23). Most departments do not have a policy for brain metastases treatment (64.9%; p = 0.024). CONCLUSIONS: This is one of the first national surveys assessing the use of SRS for brain metastases in clinical practice. These data highlight some clinical considerations for physicians treating brain metastases with SRS.

Correction to: Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

The fourth author's name was incorrect in the initial online publication. The original article has been corrected.

Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

Bevacizumab failure is a major clinical problem in the management of high grade gliomas (HGG), with a median overall survival (OS) of < 4 months. This study evaluated the feasibility and efficacy of fractionated stereotactic re-irradiation (FSRT) for patients progressed after Bevacizumab treatment. Retrospective review was conducted of 36 patients treated with FSRT after progression on bevacizumab. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. The median time from initial bevacizumab treatment to FSRT was 8.5 months. The median plan target volume for FSRT was 27.5 cc. The median OS from FSRT was 4.8 months. FSRT treatment was well tolerated with no grade 3 or higher toxicity. Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment.

Guanylyl cyclase C signaling axis and colon cancer prevention.

Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C's role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.

Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins.

Enterotoxigenic Escherichia coli (ETEC) causes ∼20% of the acute infectious diarrhea (AID) episodes worldwide, often by producing heat-stable enterotoxins (STs), which are peptides structurally homologous to paracrine hormones of the intestinal guanylate cyclase C (GUCY2C) receptor. While molecular mechanisms mediating ST-induced intestinal secretion have been defined, advancements in therapeutics have been hampered for decades by the paucity of disease models that integrate molecular and functional endpoints amenable to high-throughput screening. Here, we reveal that mouse and human intestinal enteroids in three-dimensional ex vivo cultures express the components of the GUCY2C secretory signaling axis. ST and its structural analog, linaclotide, an FDA-approved oral secretagog, induced fluid accumulation quantified simultaneously in scores of enteroid lumens, recapitulating ETEC-induced intestinal secretion. Enteroid secretion depended on canonical molecular signaling events responsible for ETEC-induced diarrhea, including cyclic GMP (cGMP) produced by GUCY2C, activation of cGMP-dependent protein kinase (PKG), and opening of the cystic fibrosis transmembrane conductance regulator (CFTR). Importantly, pharmacological inhibition of CFTR abrogated enteroid fluid secretion, providing proof of concept for the utility of this model to screen antidiarrheal agents. Intestinal enteroids offer a unique model, integrating the GUCY2C signaling axis and luminal fluid secretion, to explore the pathophysiology of, and develop platforms for, high-throughput drug screening to identify novel compounds to prevent and treat ETEC diarrheal disease.

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer.

Obesity has emerged as a principal cause of mortality worldwide, reflecting comorbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. Guanylyl cyclase C (GUCY2C), a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cGMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer, and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis that activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that diet-induced obesity suppressed guanylin and uroguanylin expression in mice and humans. Hormone loss reflects reversible calorie-induced endoplasmic reticulum stress and the associated unfolded protein response, rather than the endocrine, adipokine, or inflammatory milieu of obesity. Loss of intestinal uroguanylin secretion silences the hypothalamic GUCY2C endocrine axis, creating a feed-forward loop contributing to hyperphagia in obesity. Importantly, calorie-induced guanylin loss silences the GUCY2C-cGMP paracrine axis underlying obesity-induced epithelial dysfunction and colorectal tumorigenesis. Indeed, genetically enforced guanylin replacement eliminated diet-induced intestinal tumorigenesis in mice. Taken together, these observations suggest that GUCY2C hormone axes are at the intersection of obesity and colorectal cancer. Moreover, they suggest that hormone replacement that restores GUCY2C signaling may be a novel therapeutic paradigm to prevent both hyperphagia and intestinal tumorigenesis in obesity.

Role of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease duration and effects of IVIG.

Gastrointestinal dysmotility in systemic sclerosis (SSc) is associated with autoantibodies against muscarinic-3 receptor (M3-R). We investigated the temporal course of the site of action of these autoantibodies at the myenteric neurons (MN) vs. the smooth muscle (SM) M3-R in relation to disease duration, and determined the role of intravenous immunoglobulin (IVIG) in reversing these changes. Immunoglobulins purified from SSc patients (SScIgG) were used to assess their differential binding to MN and SM (from rat colon) employing immunohistochemistry (IHC). Effect of SScIgG on neural and direct muscle contraction was determined by cholinergic nerve stimulation and bethanechol-induced SM contraction. Effects of IVIG and its antigen-binding fragment F(ab')2 on SScIgG binding were studied by enzyme-linked immunosorbent assay (ELISA) of rat colonic longitudinal SM myenteric plexus (LSMMP) lysate and to second extracellular loop peptide of M3-R (M3-RL2). SScIgG from all patients demonstrated significantly higher binding to MN than to SM. With progression of SSc duration, binding at MN and SM increased in a linear fashion with a correlation coefficient of 0.696 and 0.726, respectively (P < 0.05). SScIgG-mediated attenuation of neural and direct SM contraction also increased with disease duration. ELISA analysis revealed that IVIG and F(ab')2 significantly reduced SScIgG binding to LSMMP lysate and M3-RL2. Dysmotility in SSc occurs sequentially, beginning with SScIgG-induced blockage of cholinergic neurotransmission (neuropathy), which progresses to inhibition of acetylcholine action at the SM cell (myopathy). IVIG reverses this cholinergic dysfunction at the neural and myogenic receptors by anti-idiotypic neutralization of SScIgG.

GUCY2C ligand replacement to prevent colorectal cancer.

Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).