Colonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) demonstrate nutritional selenium deficiencies and are at greater risk of developing colon cancer. Previously, we determined that global reduction of the secreted antioxidant selenium-containing protein, selenoprotein P (SELENOP), substantially increased tumor development in an experimental colitis-associated cancer (CAC) model. We next sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis and define clinical context. METHODS: Selenop floxed mice crossed with Cre driver lines to delete Selenop from the liver, myeloid lineages, or intestinal epithelium were placed on an azoxymethane/dextran sodium sulfate experimental CAC protocol. SELENOP loss was assessed in human ulcerative colitis (UC) organoids, and expression was queried in human and adult UC samples. RESULTS: Although large sources of SELENOP, both liver- and myeloid-specific Selenop deletion failed to modify azoxymethane/dextran sodium sulfate-mediated tumorigenesis. Instead, epithelial-specific deletion increased CAC tumorigenesis, likely due to elevated oxidative stress with a resulting increase in genomic instability and augmented tumor initiation. SELENOP was down-regulated in UC colon biopsies and levels were inversely correlated with endoscopic disease severity and tissue S100A8 (calprotectin) gene expression. CONCLUSIONS: Although global selenium status is typically assessed by measuring liver-derived plasma SELENOP levels, our results indicate that the peripheral SELENOP pool is dispensable for CAC. Colonic epithelial SELENOP is the main contributor to local antioxidant capabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.

Impact of Tumor-Infiltrating Lymphocytes on Overall Survival in Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. As the clinical course can be variable, prognostic markers are needed to better stratify patients. Prior literature, composed of small series with limited sample size, has demonstrated that tumor-infiltrating lymphocytes (TILs) are an important prognostic marker in MCC. To validate these findings on a population level, we sought to analyze and report the prognostic value of TILs in a large national data set. MATERIALS AND METHODS: A retrospective observational cohort study was conducted of patients with nonmetastatic MCC from 2010 to 2015 using the National Cancer Database. Individual variables trending toward significance using a univariable analysis were included in a multivariable Cox proportional hazards model to assess their independent effect on overall survival (OS). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Propensity score-weighted multivariable analysis (PS MVA) was performed to adjust for additional confounding. RESULTS: A total of 2,182 patients met inclusion criteria: 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602-0.933) and brisk (HR, 0.499; 95% CI, 0.338-0.735) was associated with incrementally improved OS compared with no TILs. The association of nonbrisk and brisk TILs with improved OS was retained on PS MVA (Nonbrisk: HR, 0.720; 95% CI, 0.550-0.944; Brisk: HR, 0.483; 95% CI, 0.286-0.814). CONCLUSION: The presence of nonbrisk and brisk TILs is associated with incrementally improved OS in patients with nonmetastatic MCC in a large national data set. This pathologic feature can aid with risk stratification, estimation of prognosis, and, importantly, decision-making with respect to treatment intensification in high-risk patients. IMPLICATIONS FOR PRACTICE: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy with variable clinical course. Prognostic markers are needed to better risk stratify patients. We present the largest retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database. Our analysis demonstrates an association between increasing degrees of tumor-infiltrating lymphocytes and incrementally improved survival. These conclusions improve pathologic risk stratification, and decision-making with respect to treatment intensification. Intensification may include adjuvant radiation therapy to the primary site after wide excision despite small tumor size, to the nodal basin in sentinel lymph node-negative patients, or offering closer follow-up.

Radiotherapy Remains Underused in the Treatment of Soft-Tissue Sarcomas: Disparities in Practice Patterns in the United States.

BACKGROUND: Practice patterns of radiation therapy (RT) use for soft-tissue sarcoma (STS) remain quite variable, despite clinical practice guidelines recommending the addition of RT to surgery for patients with high-grade STS, particularly for larger tumors. Using the National Cancer Database (NCDB), we assessed patterns of overall RT use, neoadjuvant versus adjuvant treatment, and specific RT modalities in this population. PATIENTS AND METHODS: Patients aged ≥18 years with stage II/III STS in 2004 through 2015 were identified from the NCDB. Patterns of care were assessed using multivariable logistic regression analysis. RESULTS: Of 27,426 total patients, 11,654 (42%) were treated with surgery alone versus 15,772 (58%) with RT in addition to surgery, with no overall increase in RT use over the study period. Notable clinical predictors of receipt of RT included tumor size (>5 cm), grade III, and tumors arising in the extremities. Conversely, female sex, older age (≥70 years), Black race, noncommercial insurance coverage, farther distance to treatment, and poor performance status were negative predictors of RT use. Of those receiving RT, 27% were treated with neoadjuvant RT and 73% with adjuvant RT. The proportion of those receiving neoadjuvant RT increased over time. Relevant factors associated with neoadjuvant RT included treatment at academic centers, larger tumor size, and extremity tumors. Of those who received RT with a modality specified as either intensity-modulated RT (IMRT) or 3D conformal RT (3DCRT), 61% were treated with IMRT and 39% with 3DCRT. The proportion of patients treated with IMRT increased over time. Relevant factors associated with IMRT use included treatment at academic centers, commercial insurance coverage, and larger and nonextremity tumors. CONCLUSIONS: Although use of neoadjuvant RT and IMRT has increased over time, a significant number of patients with STS are not receiving adjuvant or neoadjuvant RT. Our findings also note potential sociodemographic disparities and highlight the concern that not all patients with STS are being equally considered for RT.

BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.

Blood vessel epicardial substance (BVES/Popdc1) is a junctional-associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial-to-mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves(-/-) mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5 compared to wild-type (WT) mice. Intercross with Lgr5-EGFP reporter mice confirmed expansion of the stem cell compartment in Bves(-/-) mice. To examine stem cell function after BVES deletion, we used ex vivo 3D-enteroid cultures. Bves(-/-) enteroids demonstrated increased stemness compared to WT, when examining parameters such as plating efficiency, stem spheroid formation, and retention of peripheral cystic structures. Furthermore, we observed increased proliferation, expression of crypt-base columnar "CBC" and "+4" stem cell markers, amplified Wnt signaling, and responsiveness to Wnt activation in the Bves(-/-) enteroids. Bves expression was downregulated after radiation in WT mice. Moreover, after radiation, Bves(-/-) mice demonstrated significantly greater SI crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves(-/-) mice also demonstrated elevations in Lgr5 and Ascl2 expression, and putative damage-responsive stem cell populations marked by Bmi1 and TERT. Therefore, BVES is a key regulator of intestinal stem cell programs and mucosal homeostasis. Stem Cells 2016;34:1626-1636.

The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.

Notch signaling largely determines intestinal epithelial cell fate. High Notch activity drives progenitors toward absorptive enterocytes by repressing secretory differentiation programs, whereas low Notch permits secretory cell assignment. Myeloid translocation gene-related 1 (MTGR1) is a transcriptional corepressor in the myeloid translocation gene/Eight-Twenty-One family. Given that Mtgr1(-/-) mice have a dramatic reduction of intestinal epithelial secretory cells, we hypothesized that MTGR1 is a key repressor of Notch signaling. In support of this, transcriptome analysis of laser capture microdissected Mtgr1(-/-) intestinal crypts revealed Notch activation, and secretory markers Mucin2, Chromogranin A, and Growth factor-independent 1 (Gfi1) were down-regulated in Mtgr1(-/-) whole intestines and Mtgr1(-/-) enteroids. We demonstrate that MTGR1 is in a complex with Suppressor of Hairless Homolog, a key Notch effector, and represses Notch-induced Hairy/Enhancer of Split 1 activity. Moreover, pharmacologic Notch inhibition using a γ-secretase inhibitor (GSI) rescued the hyperproliferative baseline phenotype in the Mtgr1(-/-) intestine and increased production of goblet and enteroendocrine lineages in Mtgr1(-/-) mice. GSI increased Paneth cell production in wild-type mice but failed to do so in Mtgr1(-/-) mice. We determined that MTGR1 can interact with GFI1, a transcriptional corepressor required for Paneth cell differentiation, and repress GFI1 targets. Overall, the data suggest that MTGR1, a transcriptional corepressor well characterized in hematopoiesis, plays a critical role in intestinal lineage allocation.

Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury.

Myeloid translocation genes (MTGs) are transcriptional corepressors implicated in development, malignancy, differentiation, and stem cell function. While MTG16 loss renders mice sensitive to chemical colitis, the role of MTG16 in the small intestine is unknown. Histological examination revealed that Mtg16(-/-) mice have increased enterocyte proliferation and goblet cell deficiency. After exposure to radiation, Mtg16(-/-) mice exhibited increased crypt viability and decreased apoptosis compared with wild-type (WT) mice. Flow cytometric and immunofluorescence analysis of intestinal epithelial cells for phospho-histone H2A.X also indicated decreased DNA damage and apoptosis in Mtg16(-/-) intestines. To determine if Mtg16 deletion affected epithelial cells in a cell-autonomous fashion, intestinal crypts were isolated from Mtg16(-/-) mice. Mtg16(-/-) and WT intestinal crypts showed similar enterosphere forming efficiencies when cultured in the presence of EGF, Noggin, and R-spondin. However, when Mtg16(-/-) crypts were cultured in the presence of Wnt3a, they demonstrated higher enterosphere forming efficiencies and delayed progression to mature enteroids. Mtg16(-/-) intestinal crypts isolated from irradiated mice exhibited increased survival compared with WT intestinal crypts. Interestingly, Mtg16 expression was reduced in a stem cell-enriched population at the time of crypt regeneration. This is consistent with MTG16 negatively regulating regeneration in vivo. Taken together, our data demonstrate that MTG16 loss promotes radioresistance and impacts intestinal stem cell function, possibly due to shifting cellular response away from DNA damage-induced apoptosis and towards DNA repair after injury.

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and Chemotherapy Use in the National Cancer Database.

PURPOSE: Practice patterns for treatment of localized adult pleomorphic rhabdomyosarcoma (PRMS) remain quite variable given its rarity. Current national guidelines recommend management similar to that of other high-grade soft tissue sarcomas (STS), which include surgery with perioperative radiation (RT) with or without chemotherapy. Using the National Cancer Database (NCDB), we assessed practice patterns and overall outcomes of patients with localized PRMS. Patients and Methods. Patients with stage II/III PRMS treated with surgical resection from 2004 to 2015 were identified from the NCDB. Predictors of RT and chemotherapy use were assessed using multivariable logistic regression analysis. The association of radiation and chemotherapy status on overall survival was assessed using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Of 243 total patients, RT and chemotherapy were not uniformly utilized, with 44% receiving chemotherapy and in those who did not undergo amputation 62% receiving RT. In those who did not undergo amputation, RT was associated with improved survival on both univariate (HR: 0.49, 95% CI 0.32-0.73, P < 0.001) and multivariate analysis (HR: 0.40, 95% CI 0.26-0.62, P < 0.001), corresponding to greater 5-year overall survival (59% vs. 38%, P < 0.001). Chemotherapy was associated with a higher rate of 5-year overall survival (63% vs. 39%, P < 0.001). However, the survival benefit of chemotherapy did not reach statistical significance on multivariate analysis (HR: 0.65, 95% CI 0.41-1.03, P=0.064). Notable predictors of omission of RT included female gender (OR: 0.40, 95% CI 0.22-0.74, P < 0.01) and age ≥ 70 (OR: 0.55, 95% CI 0.30-1.00, P=0.05). Correspondingly, factors associated with omission of chemotherapy included age ≥70 (OR: 0.17, 95% CI 0.08-0.39, P < 0.001). CONCLUSIONS: A significant proportion of patients with localized adult PRMS are not receiving RT. Likewise, use of chemotherapy was heterogeneous. Our findings note potential benefits and underutilization of RT, for which further investigation is warranted.

Definitive Local Therapy Is Associated with Improved Survival in Metastatic Soft Tissue Sarcomas.

Background: Definitive local therapy is often utilized in patients with metastatic soft tissue sarcomas (STS) to reduce morbidity associated with local tumor progression. We hypothesize that it is associated with improved overall survival (OS). Methods: Patients with newly diagnosed metastatic STS treated with chemotherapy were identified from the National Cancer Database and dichotomized into cohorts: 1. definitive local therapy (defined as either definitive dose radiotherapy, definitive surgery, or surgery with perioperative radiotherapy) or 2. conservative therapy (defined as systemic therapy with or without palliative therapy). The association between definitive local therapy and OS, and factors associated with the receipt of definitive local therapy were assessed. Results: Total of 4180 patients were identified. Compared with the conservative therapy, receipt of any definitive local therapy was associated with improved OS (median 17.9 vs. 10.1 months). The survival benefit remained on multivariate analyses and propensity-score matched analyses, with a stepwise improvement with surgery and combined modality local therapy, specifically radiotherapy (HR: 0.77; p < 0.001), surgery (HR: 0.67; p < 0.001), and combined surgery and radiotherapy (HR: 0.42; p < 0.001). Conclusions: Analysis of a large national cancer registry of patients with metastatic STS suggests that chemotherapy plus definitive local therapy is associated with a significant survival benefit compared to the standard chemotherapy alone.

Proton beam re-irradiation for gastrointestinal malignancies: a systematic review.

BACKGROUND: Radiotherapy (RT) is part of the standard of care management of most gastrointestinal (GI) cancers. Even with advanced RT, systemic therapy, and surgical techniques, locoregional recurrences or second primary cancers can still occur within previously irradiated fields, which can present challenges in delivering effective and safe treatment. Options for reirradiation are often limited, but given the favorable dosimetric aspects of proton-beam RT, it may provide an effective and safe re-irradiation option for patients with recurrent or second primary GI cancers. METHODS: We conducted a systematic review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol, assessing for reports of proton-beam reirradiation for recurrent or second primary GI cancers, primarily via PubMed. From the initial 373 articles identified, 7 articles were ultimately included in the analysis. RESULTS: The 7 included studies reported on proton-beam re-irradiation for the following disease sites: esophageal (n=2), pancreas (n=1), liver (n=2), rectal (n=1), and anal (n=1). Study sizes varied from as few as 1 to as many as 83 patients. Across studies, in patients who presented with tumor-related symptoms, palliation (stability/improvement) was achieved in 80-100% of the cases. Local control rates, with variable follow-up, ranged from 36-100%. All median overall survival values, when reported, were greater than 1 year. Across both liver studies, there were no cases of radiation-induced liver disease (RILD) from proton-beam re-irradiation. Across all studies, there were 2 acute (esophagopleural fistula in esophageal cancer, small bowel perforation in pancreatic cancer) and 1 late (esophageal ulcer in esophageal cancer) grade 5 toxicities, all favored to be due to progressive disease, rather than proton-beam re-irradiation. Two studies (1 esophageal, 1 rectal) generated comparison photon plans. One found that proton therapy reduced mean heart and lung doses, spinal cord dose, and lung V5Gy as compared to photon treatment, while resulting in higher lung V20Gy and V30Gy. The other found that protons decreased bowel V10Gy, V20Gy, and the dose to 200 and 150 cc of bowel, as compared to photons. CONCLUSIONS: Based upon the published experiences, proton-beam re-irradiation for recurrent or second primary GI cancers appears effective for palliation, with good disease-control, limited toxicity, favorable dosimetry, and overall compares well with published non-proton-beam experiences. Given short follow-up, additional studies are warranted to determine if dosimetric advantages from proton therapy will translate into comparative toxicity benefits.

Association of Insurance Status With Presentation, Treatment, and Survival in Melanoma in the Era of Immune Checkpoint Inhibitors.

The effect of health insurance on management and outcomes in melanoma is unclear. Using the National Cancer Database (NCDB), we evaluated the effect of insurance on (1) stage at diagnosis, (2) receipt of immunotherapy, and (3) overall survival (OS) among patients with melanoma. We included patients with stage I-IV melanoma diagnosed from 2011 to 2015. Patients were stratified by age (below 65 vs. 65 y or above) and insurance (commercial, Medicare, Medicaid and uninsured). We evaluated the association between insurance and (1) stage at diagnosis (stage I-III vs. IV) and (2) receipt of immunotherapy (stage IV) using multivariable logistic regression. The association of insurance status with OS in metastatic patients who received immunotherapy was assessed using Kaplan-Meier and Cox proportional hazards analyses. The study included 167,130 patients; 52% had commercial insurance, 43% had Medicare, 3% had Medicaid and 2% were uninsured. In patients below 65 years, those with Medicaid and the uninsured had a higher likelihood of presenting with metastatic melanoma and were less likely to receive immunotherapy compared with those with commercial insurance. Further among those who received immunotherapy, patients with Medicaid (hazard ratio: 1.51, P=0.001) and no insurance (hazard ratio: 1.37, P=0.046) had an inferior OS. In patients 65 years or above, whereas Medicare was associated with an increased likelihood of presenting with metastatic disease, there was no significant difference in receipt of immunotherapy or OS as compared with commercial insurance. In this large modern cohort, insurance was associated with stage at diagnosis, receipt of immunotherapy, and OS for patients below 65 years old with melanoma.

BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.

Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves-/- mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves-/- mice inoculated with Citrobacter rodentium had greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves-/- mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. coli showed increased attaching/effacing lesions in the absence of BVES. Finally, BVES mRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.

Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.

Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.

Percutaneous stereotactic radiofrequency lesioning for trigeminal neuralgia: determination of minimum clinically important difference in pain improvement for patient-reported outcomes.

BACKGROUND: The Visual Analog Scale (VAS) and the Barrow Neurological Institute Pain Scale (BNI-PS) are 2 patient-reported outcome (PRO) tools frequently used to rate pain from trigeminal neuralgia (TN). Outcomes studies often use these patient-reported outcomes to assess treatment effectiveness, but it is unknown exactly what degree of change in the numerical scores constitutes the minimum clinically important difference (MCID). MCID remains uninvestigated for percutaneous stereotactic radiofrequency lesioning (RFL), a common surgical procedure for TN. OBJECTIVE: To determine MCID values for the VAS and BNI-PS in patients undergoing RFL. METHODS: Forty-three consecutive patients with TN who underwent RFL by a single surgeon were prospectively assessed with the VAS and BNI-PS preoperatively and 3 years postoperatively. Three anchors were used to assign each patient's outcome: satisfaction, willingness to have the surgery again, and Health Transition Index. We then used 3 well-established, anchor-based methods to calculate MCID: average change, minimum detectable change, and change difference. RESULTS: Patients experienced substantial improvement in both VAS (9.81 vs 3.35; P < .001) and BNI-PS (4.95 vs 2.44; P < .001) after RFL. The 3 MCID calculation methods generated a range of MCID values for each of the PROs (VAS, 4.13-8.20; BNI-PS, 1.03-3.30). The area under the receiver-operating characteristic curve was greater for BNI-PS compared with VAS for all 3 anchors, indicating that BNI-PS is probably better suited for calculating MCID. CONCLUSION: RFL-specific MCID is variable on the basis of the calculation technique. With the use of the minimum detectable change calculation method with the Health Transition Index anchor, the minimum clinically important difference is 4.49 for VAS and 1.16 for BNI-PS after RFL for TN. ABBREVIATIONS: AUC, area under the receiver-operating characteristic curveBNI-PS, Barrow Neurological Institute Pain ScaleHTI, Health Transition IndexMCID, minimum clinically important differenceMDC, minimum detectable changePRO, patient-reported outcomeRFL, percutaneous stereotactic radiofrequency lesioningTN, trigeminal neuralgiaVAS, Visual Analog Scale.

Microvascular decompression for classic trigeminal neuralgia: determination of minimum clinically important difference in pain improvement for patient reported outcomes.

BACKGROUND: Outcomes studies use patient-reported outcome (PRO) measurements to assess treatment effectiveness, but can lack direct clinical meaning. Minimum clinically important difference (MCID) calculation provides a point estimate of the critical threshold needed to achieve clinically relevant treatment effectiveness. MCID remains uninvestigated for microvascular decompression (MVD), a common surgical procedure for trigeminal neuralgia. OBJECTIVE: We aimed to determine MCID for the most commonly used PRO measures of pain after MVD: Visual Analog Scale (VAS) and Barrow Neurological Institute Pain Scale (BNI-PS). METHODS: Sixty consecutive patients with classic trigeminal neuralgia who decided to undergo MVD by a single surgeon were prospectively assessed with VAS and BNI-PS preoperatively and 2 years postoperatively. Three anchors were used to assign each patient's outcome. We then used 3 well-established, anchor-based methods to calculate MCID. RESULTS: Patients experienced significant improvement in both VAS (9.9 vs. 2.0, P < .001) and BNI-PS (5.0 vs. 1.9, P < .001) after MVD. The area under the receiver-operating characteristic curve was greater for BNI-PS than for VAS for all 3 anchors, indicating that BNI-PS is probably better suited for calculating MCID. The 3 MCID calculation methods generated a range of MCID values for each of the PROs (VAS: 1.40-8.87, BNI-PS: 0.95-3.26). CONCLUSION: MVD-specific MCID is highly variable based on calculation technique. Some of these calculations appear to either overestimate or underestimate the patients' preoperative expectations. When the different MCID methods are averaged, the results are clinically appropriate and consistent with preoperative expectations. The average MCID for VAS is 6.25 and for BNI-PS is 2.44.

Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis.

Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-ß pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.