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OBJECTIVE: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. MATERIAL AND METHODS: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. RESULTS: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). CONCLUSION: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. CLINICAL RELEVANCE STATEMENT: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. KEY POINTS: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules.
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OBJECTIVES: To evaluate the additional diagnostic benefit of diffusion weighted imaging (DWI) and contrast enhanced (CE) images during MR enterography (MRE) of Crohn's disease. METHODS: Datasets from 73 patients (mean age 32; 40 male) (28 new-diagnosis, 45 relapsed) were read independently by two radiologists selected from a pool of 13. Radiologists interpreted datasets using three sequential sequence blocks: (1) T2 weighted and steady state free precession gradient echo (SSFP) images alone (T2^); (2) T2 weighted and SSFP images with DWI (T2 + DWI^) and; (3) T2 weighted images, SSFP, DWI and post-contrast enhanced (CE) T1 images (T2 + DWI + CE^), documenting presence, location, and activity of small bowel disease. For each sequence block, sensitivity and specificity (readers combined) was calculated against an outcome-based construct reference standard. RESULTS: 59/73 patients had small bowel disease. Per-patient sensitivity for disease detection was essentially identical (80 % [95 % CI 72, 86], 81 % [73,87], and 79 % [71,86] for T2^, T2 + DWI^and T2 + DWI + CE^respectively). Specificity was identical (82 % [64 to 92]). Per patient sensitivity for disease extent was 56 % (47,65), 56 % (47,65) and 52 % (43 to 61) respectively, and specificity was 82 % (64 to 92) for all blocks. Sensitivity for active disease was 97 % (90,99), 97 % (90,99) and 98 % (92,99), and specificity was also comparable between all sequence combination reads. Results were consistent across segments and newly diagnosed/relapse patients. CONCLUSION: There is no additional diagnostic benefit of adding either DWI or CE to T2 FSE and SSFP sequences for evaluating small bowel Crohn's disease, suggesting MRE protocols can be simplified safely.
Subject(s)
Contrast Media , Crohn Disease , Diffusion Magnetic Resonance Imaging , Sensitivity and Specificity , Humans , Crohn Disease/diagnostic imaging , Male , Female , Adult , Diffusion Magnetic Resonance Imaging/methods , Middle Aged , Reproducibility of Results , Adolescent , Aged , Young Adult , Image Enhancement/methodsABSTRACT
OBJECTIVES: The simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) are promising intestinal ultrasound (IUS) indices of CD, but studied mainly in small settings with few sonographers. We compared SUS-CD and BUSS against histological and magnetic resonance enterography (MRE) reference standards in a post hoc analysis of a prospective multicentre, multireader trial. METHODS: Participants recruited to the METRIC trial (ISRCTN03982913) were studied, including those with available terminal ileal (TI) biopsies. Sensitivity and specificity of SUS-CD and BUSS for TI CD activity were calculated with 95% confidence intervals (CI), from the prospective observations of the original METRIC trial sonographers against the histological activity index (HAI) and the simplified magnetic resonance index of activity (sMARIA). RESULTS: We included 284 patients (median 31.5 years, IQR 23-46) from 8 centres, who underwent IUS and MRE. Of these, 111 patients had available terminal ileal biopsies with HAI scoring. Against histology, sensitivity and specificity for active disease were 79% (95% CI 69-86%) and 50% (31-69%) for SUS-CD, and 66% (56-75%) and 68% (47-84%) for BUSS, respectively. Compared to sMARIA, the sensitivity and specificity for active CD were 81% (74-86%) and 75% (66-83%) for SUS-CD, and 68% (61-74%) and 85% (76-91%) for BUSS, respectively. The sensitivity of SUS-CD was significantly greater than that of BUSS against HAI and sMARIA (p < 0.001), but its specificity was significantly lower than of BUSS against the MRE reference standard (p = 0.003). CONCLUSIONS: Particularly when compared to MRE activity scoring, SUS-CD and BUSS are promising tools in a real-world clinical setting. CLINICAL RELEVANCE STATEMENT: When tested using data from a multicentre, multireader diagnostic accuracy trial, the simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) were clinically viable intestinal ultrasound indices that were reasonably sensitive and specific for terminal ileal Crohn's disease, especially when compared to a magnetic resonance reference standard. KEY POINTS: The simple ultrasound activity score for Crohn's disease and bowel ultrasound score are promising intestinal ultrasound indices of Crohn's disease but to date studied mainly in small settings with few sonographers. Compared to histology and the magnetic resonance reference standard in a multicentre, multireader setting, the sensitivity of simple ultrasound activity score for Crohn's disease is significantly greater than that of bowel ultrasound score. The specificity of simple ultrasound activity score for Crohn's disease was significantly lower than that of bowel ultrasound score compared to the magnetic resonance enterography reference standard. The specificity of both indices was numerically higher when the magnetic resonance enterography reference standard was adopted.
Subject(s)
Crohn Disease , Adult , Humans , Crohn Disease/pathology , Ileum/diagnostic imaging , Ileum/pathology , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Prospective StudiesABSTRACT
OBJECTIVES: To compare the distention quality and patient experience of oral mannitol and polyethylene glycol (PEG) for MRE. METHODS: This study is a retrospective, observational study of a subset of patients enrolled in a multicentre, prospective trial evaluating the diagnostic accuracy of MRE for small bowel Crohn's. Overall and segmental MRE small bowel distention, from 105 patients (64 F, mean age 37) was scored from 0 = poor to 4 = excellent by two experienced observers (68 [65%] mannitol and 37 [35%] PEG). Additionally, 130 patients (77 F, mean age 34) completed a questionnaire rating tolerability of various symptoms immediately and 2 days after MRE (85 [65%] receiving mannitol 45 [35%] receiving PEG). Distension was compared between agents and between those ingesting ≤ 1 L or > 1 L of mannitol using the test of proportions. Tolerability grades were collapsed into "very tolerable," "moderately tolerable," and "not tolerable." RESULTS: Per patient distension quality was similar between agents ("excellent" or "good" in 54% [37/68] versus 46% [17/37]) with mannitol and PEG respectively. Jejunal distension was significantly better with mannitol compared to PEG (40% [27/68] versus 14% [5/37] rated as excellent or good respectively). There was no significant difference according to the volume of mannitol ingested. Symptom tolerability was comparable between agents, although fullness following MRE was graded as "very tolerable" in 27% (12/45) of patients ingesting PEG, verses 44% (37/84) ingesting mannitol, difference 17% (95% CI 0.6 to 34%). CONCLUSION: Mannitol-based solutions and PEG generally achieve comparable distension quality and side effect profiles, although jejunal distension is better quality with mannitol. Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol. KEY POINTS: ⢠Mannitol-based and PEG-based oral preparation agents generally achieve comparable distension quality for MRE with the exception of the jejunum which is better distended with mannitol. ⢠Mannitol-based and PEG-based oral preparation agents used for MRE have similar side effect profiles. ⢠Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol.
Subject(s)
Crohn Disease , Drug-Related Side Effects and Adverse Reactions , Adult , Contrast Media/pharmacology , Crohn Disease/diagnostic imaging , Humans , Magnetic Resonance Imaging , Mannitol/pharmacology , Patient Outcome Assessment , Polyethylene Glycols , Prospective Studies , Retrospective StudiesABSTRACT
OBJECTIVES: To evaluate interobserver variability for diagnosis of disease presence and extent of small bowel and colonic Crohn's disease using MR enterography (MRE). METHODS: Data from the first 73 consecutive patients (mean age 32, 33F, 28 new diagnosis, 45 suspected relapse) recruited to a multicentre, prospective diagnostic accuracy trial evaluating MRE for small bowel Crohn's disease were each read independently by three (from a pool of 20) radiologists. Radiologists documented presence and segmental location of small bowel Crohn's disease and recorded morphological mural/extramural parameters for involved segments. Per patient percentage agreement for disease presence and extent were calculated against an outcome-based construct reference standard (averaged between pairs of readers). Prevalence-adjusted bias-adjusted κ (PABAK) was calculated. RESULTS: Agreement for small bowel disease presence for new diagnosis/relapsed patients was 68%(κ = 0.36)/ 78% (κ = 0.56) and 43%(κ = 0.14)/ 53% for disease extent (κ = 0.07), respectively. For disease presence, all three radiologists agreed correctly with the reference standard in 41/59 (69%) of patients with small bowel involvement, and in 8/14 (57%) cases of without small bowel disease. Agreement was highest for multisegment disease, greater than 5 cm in length, with mural thickness>6 mm, and increased mural T2 signal. Agreement for colonic disease presence was 61% (κ = 0.21 fair agreement) for new diagnosis/ 60% (κ = 0.20, slight agreement) for relapsed patients. CONCLUSION: There is a reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed Crohn's disease, and patients with suspected relapse, respectively. Agreement is lower for disease extent. ADVANCES IN KNOWLEDGE: There is reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed (68%) Crohn's disease, and patients with suspected relapse (78%). Agreement is lower for disease extent (43% new diagnosis and 53% suspected relapse).
Subject(s)
Crohn Disease , Adult , Clinical Trials as Topic , Crohn Disease/diagnostic imaging , Crohn Disease/pathology , Female , Humans , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Multicenter Studies as Topic , Observer Variation , Prospective Studies , RecurrenceABSTRACT
Whakarongorau Aotearoa/New Zealand Telehealth Services, formerly known as Homecare Medical, is New Zealand's largest digital healthcare service. It originated as a house call doctor service about 20 years ago and now delivers free 24/7 telehealth services to the New Zealand public 365 days a year. Whakarongorau Aotearoa changed its name in April 2021 to reflect the growing kaupapa and was gifted this whakatauki: He reo marohirohi ka taringa rongohia-A brave voice deserves a listening ear. This viewpoint sets out to address a number of public and professional misconceptions about Whakarongorau Aotearoa and provide a more detailed description of the depth, breadth and complexity of the organisation, how it is structured, the range of services available to the public and its clinical governance, leadership and oversight.
Subject(s)
Delivery of Health Care/organization & administration , Leadership , Telemedicine , Humans , New ZealandABSTRACT
Sarcoidosis is a systemic inflammatory condition causing increased immune system activity and manifesting as noncaseating granulomatous disease with the ability to affect multiple organ systems. Neurosarcoidosis is an uncommon presentation, with just 5-10% of patients with sarcoidosis experiencing intracranial disease. The diagnosis of neurosarcoidosis can be difficult, especially given the overlap of imaging findings with more common intracranial lesions. This case presents trigeminal neuralgia as the initial symptom of neurosarcoidosis and emphasizes the importance of a high clinical index of suspicion for neurosarcoidosis in patients with otherwise unexplained neurological symptoms.
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BACKGROUND: Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was compared. OBJECTIVE: To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease. DESIGN: Prospective multicentre cohort study. SETTING: Eight NHS hospitals. PARTICIPANTS: Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse. INTERVENTIONS: Magnetic resonance enterography and ultrasonography. MAIN OUTCOME MEASURES: The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness. RESULTS: Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity [80%, 95% confidence interval (CI) 72% to 86%] was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%; p = 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests. LIMITATIONS: Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice. CONCLUSIONS: Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03982913. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 42. See the NIHR Journals Library website for further project information.
Crohn's disease is a waxing and waning lifelong inflammatory condition that affects the colon (large bowel) and small bowel. Treatment relies on accurately determining disease extent and underlying inflammation. Colonoscopy is very good for examining the colon, but it is invasive and, at best, can only visualise a few centimetres of the small bowel, so radiological imaging is very important. Magnetic resonance enterography (a type of magnetic resonance imaging scan) and ultrasonography are both radiological tests commonly performed in the NHS, and it is unclear which method is better. We performed a study to compare the accuracy of magnetic resonance enterography and ultrasonography for determining the extent of Crohn's disease in the bowel of participants newly diagnosed and in those participants with established Crohn's disease but with suspected deterioration. We also investigated how often radiologists agree with each other during test interpretation, the participant experience of undergoing the tests and their cost-effectiveness. We compared the tests in 284 participants (133 newly diagnosed and 151 with suspected deterioration). We found that both tests were accurate for detecting the presence (97% for magnetic resonance enterography and 92% for ultrasonography) and location (80% for magnetic resonance enterography and 70% for ultrasonography) of disease in the small bowel, but magnetic resonance enterography was better than ultrasonography for both (correctly classifying disease extent in 107 more participants for every 1000 participants with Crohn's disease). Magnetic resonance enterography was similarly better than ultrasonography at determining if the bowel was inflamed. The results were similar in newly diagnosed participants and those participants with suspected deterioration. Agreement between radiologists interpreting the same images was, at best, moderate for both tests. A total of 88% of participants tolerated magnetic resonance enterography well or fairly well, which was less than the percentage (99%) of participants who tolerated ultrasonography well or fairly well. Both tests had a similar effect on the treatment decisions made by doctors. Both tests were also similar in their value for money for the NHS.
Subject(s)
Cost-Benefit Analysis , Crohn Disease/diagnostic imaging , Magnetic Resonance Imaging , Ultrasonography , Adolescent , Adult , Female , Humans , Intestine, Small , Male , Middle Aged , Prospective Studies , Recurrence , Sensitivity and Specificity , United Kingdom , Young AdultABSTRACT
BACKGROUND: While a shift to minimally invasive techniques in rectal cancer surgery has occurred, non-inferiority of laparoscopy in terms of oncological outcomes has not been definitely demonstrated. Transanal total mesorectal excision (TaTME) has been pioneered to potentially overcome difficulties experienced when operating with a pure abdominal approach deep down in the pelvis. This study aimed to compare short-term oncological results of TaTME versus laparoscopic TME (lapTME), based on a strict anatomical definition for low rectal cancer on MRI. METHODS: From June 2013, all consecutive TaTME cases were included and compared to lapTME in a single institution. Propensity score-matching was performed for nine relevant factors. Primary outcome was resection margin involvement (R1), secondary outcomes included intra- and post-operative outcomes. RESULTS: After matching, forty-one patients were included in each group; no significant differences were observed in patient and tumor characteristics. The resection margin was involved in 5 cases (12.2%) in the laparoscopic group, versus 2 (4.9%) TaTME cases (P = 0.432). The TME specimen quality was complete in 84.0% of the laparoscopic cases and in 92.7% of the TaTME cases (P = 0.266). Median distance to the circumferential resection margin (CRM) was 5 mm in lapTME and 10 mm in TaTME (P = 0.065). Significantly more conversions took place in the laparoscopic group, 9 (22.0%) compared to none in the TaTME group (P < 0.001). Other clinical outcomes did not show any significant differences between the two groups. CONCLUSION: This is the first study to compare results of TaTME with lapTME in a highly selected patient group with MRI-defined low rectal tumors. A significant decrease in R1 rate could not be demonstrated, although conversion rate was significantly lower in this TaTME cohort.
Subject(s)
Laparoscopy/methods , Neoplasm Staging/methods , Proctectomy/methods , Propensity Score , Rectal Neoplasms/surgery , Rectum/surgery , Transanal Endoscopic Surgery/methods , Adult , Aged , Aged, 80 and over , Female , Humans , Magnetic Resonance Imaging , Male , Margins of Excision , Middle Aged , Operative Time , Postoperative Complications/surgery , Rectal Neoplasms/diagnosis , Rectum/pathologyABSTRACT
BACKGROUND: Magnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. Therefore, we did a multicentre trial to address this issue. METHODS: We recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed. FINDINGS: 284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% [95% CI 72-86]) and presence (97% [91-99]) were significantly greater than that of ultrasound (70% [62-78] for disease extent, 92% [84-96] for disease presence); a 10% (95% CI 1-18; p=0·027) difference for extent, and 5% (1-9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% [85-98]) was significantly greater than that of ultrasound (81% [64-91]); a difference of 14% (1-27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86-99) with MRE and 84% (65-94) with ultrasound (difference 12% [0-25]; p=0·054). There were no serious adverse events. INTERPRETATION: Both MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly. FUNDING: National Institute of Health and Research Health Technology Assessment.
Subject(s)
Crohn Disease/diagnostic imaging , Intestine, Small/diagnostic imaging , Magnetic Resonance Imaging , Ultrasonography , Adolescent , Adult , Female , Humans , Male , Middle Aged , Prospective Studies , Recurrence , Sensitivity and Specificity , Young AdultABSTRACT
BACKGROUND: There remains a lack of international consensus on the appropriate management of lateral nodal disease. Although the East manages this more aggressively with lateral lymph node dissections, the West aims to eradicate small-volume disease with neoadjuvant chemoradiotherapy and lateral nodal disease is not considered for routine surgical treatment. However, recent studies have shown that, despite neoadjuvant treatment, a significant number of patients with lateral nodal disease develop local recurrence in the lateral compartment after total mesorectal excision. OBJECTIVE: The aim of this study is to assess the role of the pretreatment features of lateral nodes on MRI in regard to local recurrence. DESIGN: All patients operated on for low locally advanced rectal cancer over a 5-year period were evaluated retrospectively. SETTINGS: This study was conducted at a single expert center. PATIENTS: The MRIs of a total of 313 patients were reviewed, and only those with rectal cancers up to 8 cm from the anorectal junction, measured on MRI, were selected. This left 185 patients; of these, 58 patients had clinical T1 or T2 tumors as assessed on MRI, identifying 127 patients who had cT3/T4 tumors that were included in this study. MAIN OUTCOME MEASURES: The primary outcomes measured were lateral local recurrence and multivariate analyses. RESULTS: The lateral local recurrence rate was significantly higher (33.3% 4-year rate) in patients with nodes larger than 10 mm than in patients with smaller nodes (10.1%, p = 0.03), despite patients being irradiated in the lateral compartment. LIMITATIONS: Because this is a relatively uncommon disease, patient numbers are low, and a multicenter study is needed to further address lateral nodal disease in low rectal cancer. CONCLUSIONS: Chemoradiotherapy with total mesorectal excision might not be sufficient in a selected group of patients. Further research is needed about which pretreatment features of the lateral nodes predict local recurrence and what is needed to prevent these from developing. See Video Abstract at http://links.lww.com/DCR/A338.
Subject(s)
Adenocarcinoma/pathology , Adenocarcinoma/therapy , Lymph Nodes/pathology , Neoplasm Recurrence, Local/pathology , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Chemoradiotherapy , Female , Humans , Lymphatic Metastasis , Magnetic Resonance Imaging , Male , Middle Aged , Multivariate Analysis , Rectal Neoplasms/mortality , Retrospective StudiesABSTRACT
SUMMARY: We developed the STOPGAP (Systematic Target OPportunity assessment by Genetic Association Predictions) database, an extensive catalog of human genetic associations mapped to effector gene candidates. STOPGAP draws on a variety of publicly available GWAS associations, linkage disequilibrium (LD) measures, functional genomic and variant annotation sources. Algorithms were developed to merge the association data, partition associations into non-overlapping LD clusters, map variants to genes and produce a variant-to-gene score used to rank the relative confidence among potential effector genes. This database can be used for a multitude of investigations into the genes and genetic mechanisms underlying inter-individual variation in human traits, as well as supporting drug discovery applications. AVAILABILITY AND IMPLEMENTATION: Shell, R, Perl and Python scripts and STOPGAP R data files (version 2.5.1 at publication) are available at https://github.com/StatGenPRD/STOPGAP . Some of the most useful STOPGAP fields can be queried through an R Shiny web application at http://stopgapwebapp.com . CONTACT: matthew.r.nelson@gsk.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Databases, Factual , Genetic Association Studies/methods , Genetic Variation , Linkage Disequilibrium , Algorithms , Humans , Sequence Analysis, DNA/methodsABSTRACT
The Tudor domain of human PHF1 recognizes trimethylated lysine 36 on histone H3 (H3K36me3). PHF1 relies on this interaction to regulate PRC2 methyltransferase activity, localize to DNA double strand breaks and mediate nucleosome accessibility. Here, we investigate the impact of the PHF1 N-terminal domain (NTD) on the Tudor domain interaction with the nucleosome. We show that the NTD is partially ordered when it is natively attached to the Tudor domain. Through a combination of FRET and single molecule studies, we find that the increase of DNA accessibility within the H3K36me3-containing nucleosome, instigated by the Tudor binding to H3K36me3, is dramatically enhanced by the NTD. We demonstrate that this nearly order of magnitude increase is due to preferential binding of PHF1 to partially unwrapped nucleosomes, and that PHF1 alters DNA-protein binding within the nucleosome by decreasing dissociation rates. These results highlight the potency of a PTM-binding protein to regulate DNA accessibility and underscores the role of the novel mechanism by which nucleosomes control DNA-protein binding through increasing protein dissociation rates.
Subject(s)
DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Nucleosomes/metabolism , Polycomb-Group Proteins/chemistry , Polycomb-Group Proteins/metabolism , DNA/metabolism , Histones/metabolism , Humans , Nucleosomes/chemistry , Protein Binding , Protein Domains , Tudor DomainABSTRACT
Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
Subject(s)
Erythrocytes/cytology , Erythropoiesis/genetics , Exome/genetics , Genetic Pleiotropy , Genetic Variation/genetics , Genotype , Black or African American/genetics , Allelic Imbalance , Erythrocyte Indices , Erythrocytes/metabolism , Gene Frequency , Hematocrit , Hemoglobins/genetics , Humans , Quantitative Trait Loci/geneticsABSTRACT
Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
Subject(s)
Blood Platelets/metabolism , Exome/genetics , Genetic Variation/genetics , Female , Genome-Wide Association Study , Humans , Male , Mean Platelet Volume , Platelet CountABSTRACT
Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488-97. ©2016 AACR.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Gene-Environment Interaction , Hypothalamus/metabolism , Melanoma, Experimental/immunology , T-Lymphocyte Subsets/immunology , Adrenergic beta-Antagonists/pharmacology , Animals , Brain-Derived Neurotrophic Factor/deficiency , CD8-Positive T-Lymphocytes/immunology , Housing, Animal , Immunity, Cellular/drug effects , Immunity, Cellular/genetics , Immunity, Cellular/immunology , Immunophenotyping , Male , Melanoma, Experimental/genetics , Melanoma, Experimental/pathology , Mice, Inbred C57BL , Neoplasm Transplantation , Propranolol/pharmacology , Signal Transduction/immunology , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
Environmental enrichment (EE), a housing condition providing complex physical, social, and cognitive stimulation, leads to improved metabolic health and resistance to diet-induced obesity and cancer. One underlying mechanism is the activation of the hypothalamic-sympathoneural-adipocyte axis with hypothalamic brain-derived neurotrophic factor (BDNF) as the key mediator. VGF, a peptide precursor particularly abundant in the hypothalamus, was up-regulated by EE. Overexpressing BDNF or acute injection of BDNF protein to the hypothalamus up-regulated VGF, whereas suppressing BDNF signaling down-regulated VGF expression. Moreover, hypothalamic VGF expression was regulated by leptin, melanocortin receptor agonist, and food deprivation mostly paralleled to BDNF expression. Recombinant adeno-associated virus-mediated gene transfer of Cre recombinase to floxed VGF mice specifically decreased VGF expression in the hypothalamus. In contrast to the lean and hypermetabolic phenotype of homozygous germline VGF knockout mice, specific knockdown of hypothalamic VGF in male adult mice led to increased adiposity, decreased core body temperature, reduced energy expenditure, and impaired glucose tolerance, as well as disturbance of molecular features of brown and white adipose tissues without effects on food intake. However, VGF knockdown failed to block the EE-induced BDNF up-regulation or decrease of adiposity indicating a minor role of VGF in the hypothalamic-sympathoneural-adipocyte axis. Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF.
Subject(s)
Adaptation, Physiological/genetics , Adipocytes/metabolism , Brain-Derived Neurotrophic Factor/genetics , Energy Metabolism/genetics , Environment , Hypothalamus/metabolism , Neuropeptides/genetics , Obesity/genetics , Sympathetic Nervous System/metabolism , Adaptation, Physiological/drug effects , Adipocytes/drug effects , Adiposity , Animals , Blood Glucose/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/pharmacology , Energy Metabolism/drug effects , Food Deprivation , Hypothalamus/drug effects , Leptin , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Growth Factors , Neuropeptides/drug effects , Receptors, Melanocortin/agonists , Social Environment , Sympathetic Nervous System/drug effects , Up-RegulationABSTRACT
Environmental enrichment (EE) is a housing environment for mice that boosts mental and physical health compared to standard laboratory housing. Our recent studies demonstrate that environmental enrichment decreases adiposity, increases energy expenditure, resists diet induced obesity, and causes cancer remission and inhibition in mice. EE typically consists of larger living space, a variety of 'toys' to interact with, running wheels, and can include a number of other novel environmental changes. All of this fosters a more complex social engagement, cognitive and physical stimulations. Importantly, the toy location and type of toy is changed regularly, which encourages the mice to adapt to a frequently changing and novel environment. Many variables can be manipulated in EE to promote health effects in mice. Thus these approaches are difficult to control and must be properly managed to successfully replicate the associated phenotypes. Therefore, the goal of this video is to demonstrate how EE is properly set up and maintained to assure a complex, challenging, and controlled environment so that other researchers can easily reproduce the protective effects of EE against obesity and cancer.