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GCM2 Silencing in Parathyroid Adenoma Is Associated With Promoter Hypermethylation and Gain of Methylation on Histone 3.
Singh, P, Bhadada, SK, Dahiya, D, Saikia, UN, Arya, AK, Sachdeva, N, Kaur, J, Behera, A, Brandi, ML, Rao, SD
The Journal of clinical endocrinology and metabolism. 2021;(10):e4084-e4096
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Abstract
CONTEXT Glial cells missing 2 (GCM2), a zinc finger-transcription factor, is essentially required for the development of the parathyroid glands. OBJECTIVE We sought to identify whether the epigenetic alterations in GCM2 transcription are involved in the pathogenesis of sporadic parathyroid adenoma. In addition, we examined the association between promoter methylation and histone modifications with disease indices. METHODS Messenger RNA (mRNA) and protein expression of GCM2 were analyzed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in 33 adenomatous and 10 control parathyroid tissues. DNA methylation and histone methylation/acetylation of the GCM2 promoter were measured by bisulfite sequencing and chromatin immunoprecipitation-qPCR. Additionally, we investigated the role of epigenetic modifications on GCM2 and DNA methyltransferase 1 (DNMT1) expression in parathyroid (PTH)-C1 cells by treating with 5-aza-2'-deoxycytidine (DAC) and BRD4770 and assessed for GCM2 mRNA and DNMT1 protein levels. RESULTS mRNA and protein expression of GCM2 were lower in sporadic adenomatous than in control parathyroid tissues. This reduction correlated with hypermethylation (P < .001) and higher H3K9me3 levels in the GCM2 promoter (P < .04) in adenomas. In PTH-C1 cells, DAC treatment resulted in increased GCM2 transcription and decreased DNMT1 protein expression, while cells treated with the BRD4770 showed reduced H3K9me3 levels but a nonsignificant change in GCM2 transcription. CONCLUSION These findings suggest the concurrent association of promoter hypermethylation and higher H3K9me3 with the repression of GCM2 expression in parathyroid adenomas. Treatment with DAC restored GCM2 expression in PTH-C1 cells. Our results showed a possible epigenetic landscape in the tumorigenesis of parathyroid adenoma and also that DAC may be a promising avenue of research for parathyroid adenoma therapeutics.
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The anti-spasmodic effect of peppermint oil during colonoscopy: a systematic review and meta-analysis.
Aziz, M, Sharma, S, Ghazaleh, S, Fatima, R, Acharya, A, Ghanim, M, Sheikh, T, Lee-Smith, W, Hamdani, SU, Nawras, A
Minerva gastroenterologica e dietologica. 2020;(2):164-171
Abstract
INTRODUCTION Multiple pharmacological agents have been studied in literature with antispasmodic effect during colonoscopy. Peppermint oil, with its relaxing effect on colon has demonstrated varying results. We therefore conducted a systematic review and meta-analysis of the available literature to evaluate its role during colonoscopy. EVIDENCE ACQUISITION Literature search of the following databases was undertaken: PubMed\Medline, Embase, Cochrane, Web of Science, and CINAHL. Outcomes that were evaluated included incidence of any spasticity, severe spasticity, and peristalsis during examination. Adenoma detection rate (ADR) was evaluated as a quality outcome metric. Risk ratios (RR), risk difference (RD) and mean difference (MD) were calculated using the DerSimonian-Laird method and random effects where applicable. EVIDENCE SYNTHESIS Overall, six studies (with one abstract) were included in this review. Peppermint oil resulted in overall lower incidence for spasticity (RD: -0.39, P=0.02), severe spasticity (RD: -0.15, P=0.04), and peristalsis (-0.27, P≤0.001) during colonoscopy examination. An improved ADR (RR: 1.31, P=0.01) was also noted, however only two studies evaluated this effect. CONCLUSIONS Peppermint oil resulted in relaxation of colon during colonoscopy with decrease incidence of spasticity, severe spasticity, peristalsis and improved ADR. These results are encouraging however results are limited due to significant heterogeneity found in the outcomes. Larger studies with standardized dosing are needed to evaluate this effect. Furthermore, studies evaluating additional colonoscopy outcomes such as polyp detection rate, advanced adenoma detection rate, and serrated adenoma detection rate are needed.
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High capacity of ultrasound for locating parathyroid adenomas in endocrinology (the ETIEN 4 study).
Carral, F, Ayala, MDC, Jiménez, AI, García, C, Robles, MI, Vega, V
Endocrinologia, diabetes y nutricion. 2020;(4):272-278
Abstract
OBJECTIVE To assess the diagnostic performance of neck ultrasound examination performed by endocrinologists to locate parathyroid adenomas in patients with primary hyperparathyroidism (PHPT). METHODOLOGY A retrospective observational study in 135 patients (mean age, 60.0±12.3 years; 74.8% females) seen at endocrinology for PHPT (mean calcium level, 11.3±1.2mg/dL mean PTH level, 240.4±346.8pg/mL) who underwent neck ultrasound examinations at the endocrinology department. 99mTc-MIBI parathyroid scintigraphy was performed before surgery in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated in surgical patients. RESULTS Ninety-eight patients underwent surgery for PHPT and 97.8% were cured at 6 months. Parathyroid ultrasound had a sensitivity of 85% (95% CI: 75.7%-91.2%) and a positive predictive value (PPV) of 95.2% (95% CI: 87.5%-98.4%) to locate parathyroid adenomas 1.7±0.9cm in maximum diameter (69.4% in smaller glands), showing a high correlation (r=0.661 and r=0.716) with maximum diameter and volume of the excised adenoma. Sixty percent of patients had nodular thyroid disease (64.2% bilateral nodules with mean maximum diameter of 1.5±0.9cm), and thyroidectomy was performed in 31.6%. The highest diagnostic performance was seen with a combination of neck ultrasound and 99mTc-MIBI scintigraphy (sensitivity: 96.8% and PPV: 95.8%). CONCLUSION In our area, parathyroid adenoma localization with ultrasound performed by endocrinologists has a high diagnostic yield and allows for detecting nodular thyroid disease in 60% of patients.
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Immunotherapy and potential molecular targets for the treatment of pituitary adenomas resistant to standard therapy: a critical review of potential therapeutic targets and current developments.
Maghathe, T, Miller, WK, Mugge, L, Mansour, TR, Schroeder, J
Journal of neurosurgical sciences. 2020;(1):71-83
Abstract
INTRODUCTION Pituitary adenomas (PAs) are primary central nervous system (CNS) tumors, accounting for as much as 25% of intracranial neoplasms. Although existing remedies show success in treating most PAs, treatment of invasive and non-functioning PAs, in addition to functioning PAs unresponsive to standard therapy, remains challenging. With the continually increasing understanding of biochemical pathways involved in tumorigenesis, immunotherapy stands as a promising alternative therapy for pituitary tumors that are resistant to standard therapy. EVIDENCE ACQUISITION A literature search was conducted of the PubMed database for immunotherapies of PAs. The search yielded a total of 2621 articles, 26 of which were included in our discussion. EVIDENCE SYNTHESIS Several pathologically expressed molecules could potentially serve as promising targets of current or future immunotherapies for PAs. Programmed death ligand-1, matrix metalloproteinases, EpCAM (Trop1) and Trop2, cancer-testis antigen MAGE-A3, epidermal growth factor receptor (EGFR), folate receptor alpha, vascular endothelial growth factor, and galectin-3 have all been implicated as crucial factors involved with tumor survival and invasion. Inhibition of these pathways may prove efficacious in the management of invasive and treatment-resistant PAs. CONCLUSIONS Rapid advancements in tumor immunology may increase the probability of successful treatment of PAs by exploitation of the normal immune response or by targeting novel proteins. Current research on many of the targets reviewed in this article are successfully being utilized to manage various neoplastic disease including CNS tumors. These therapies may eventually play a key role in the treatment of PAs that do not respond to standard therapy.
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Periodontal Disease, Tooth Loss, and Risk of Serrated Polyps and Conventional Adenomas.
Lo, CH, Nguyen, LH, Wu, K, Ogino, S, Chan, AT, Giovannucci, EL, Song, M
Cancer prevention research (Philadelphia, Pa.). 2020;(8):699-706
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Abstract
Growing data indicate an association between periodontal disease and the development of cancer. However, the evidence for colorectal cancer has been inconsistent and longitudinal study examining its precursor lesions is lacking. We prospectively collected information on periodontal disease and number of tooth loss in the Nurses' Health Study (1992-2002) and the Health Professionals Follow-up Study (1992-2010). Polyp diagnosis was acquired via self-reported questionnaires and confirmed through review of medical records. We used logistic regression to calculate the multivariate-adjusted ORs and 95% confidence intervals (CI) with adjustment for smoking and other known risk factors for periodontal disease and colorectal cancer. In this study, we included 17,904 women and 24,582 men. We documented 2,336 cases of serrated polyps and 4,102 cases of conventional adenomas among 84,714 person-endoscopies throughout follow-up. The ORs of serrated polyps and conventional adenomas comparing individuals with and without periodontal disease were 1.17 (95% CI, 1.06-1.29) and 1.11 (95% CI, 1.02-1.19), respectively. Compared with participants without tooth loss, those who lost ≥4 teeth had 20% (OR, 1.20; 95% CI, 1.03-1.39) greater risk of serrated polyps (P trend 0.01). Among never smokers, similar associations with periodontal disease were observed for both serrated polyps (OR, 1.20; 95% CI, 1.02-1.41) and conventional adenomas (OR, 1.12; 95% CI, 1.00-1.26). History of periodontal disease and possibly higher number of tooth loss may modestly increase the risk of developing colorectal precursor lesions. Our findings advance our understanding of the interplay between oral health, microbiome, and early colorectal carcinogenesis.
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Impact of water exchange colonoscopy on endoscopy room efficiency: a systematic review and meta-analysis.
Cadoni, S, Hassan, C, Frazzoni, L, Ishaq, S, Leung, FW
Gastrointestinal endoscopy. 2019;(1):159-167.e13
Abstract
BACKGROUND AND AIMS Separate randomized controlled trials (RCTs) showed water exchange (WE) colonoscopy outperformed other techniques in minimizing insertion pain and optimizing adenoma detection rate. Longer insertion time required for removal of infused water, residual air, and feces might have hampered its wider adoption. We evaluate the impact of WE compared with air or carbon dioxide insufflation (GAS) on room turnaround efficiency measured by cecal intubation, withdrawal, and total procedure times. METHODS With a systematic search in PubMed, Embase, and Cochrane Library, we identified RCTs (published before March 18, 2018) that compared WE with GAS. We focused on parameters of turnaround efficiency and patient-centered outcomes. RESULTS We analyzed 8371 subjects from 17 studies. Demographics and indications were comparable. Mean cecal intubation time (± standard deviation) was WE 12.5 ± 6.1 minutes versus GAS 11.1 ± 7.0 minutes, with a mean difference of 1.4 ± 3.4 minutes. Six studies showed significant differences in insertion time, with mean cecal intubation times of 11.6 ± 5.1 minutes for WE versus 7.7 ± 5.2 minutes for GAS, with a mean difference of 3.9 ± 1.1 minutes. Mean withdrawal time was similar. Mean total procedure time was WE 26.0 ± 9.7 versus GAS 24.2 ± 9.6, with a mean difference of 1.8 ± 6.2 minutes. All mean procedure times were significantly different. Patient-centered outcomes revealed that patients examined with WE had significantly lower real-time insertion pain score, less need for sedation, and higher willingness to repeat the procedure. CONCLUSIONS Based on parameters of procedural time, the impact of WE colonoscopy on endoscopy room turnaround yields an increase in total procedure time of about 2 minutes and is associated with significant improvement in specific patient-centered outcomes.
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Does Increased Adenoma Detection Reduce the Risk of Colorectal Cancer, and How Good Do We Need to Be?
Dilly, CK, Kahi, CJ
Current gastroenterology reports. 2019;(4):9
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Abstract
PURPOSE OF REVIEW Colorectal cancer (CRC) is largely preventable with colonoscopy and other screening modalities. However, the effectiveness of screening and surveillance depends on the quality of the colonoscopy exam. Adenoma detection rate (ADR) is the best-validated metric by which we measure individual physicians' performance. RECENT FINDINGS Recent evidence suggests that ADR benchmarks may be inappropriately low. There is proof that improving ADR leads to significant reductions in post-colonoscopy CRC (PCCRC). Two studies have demonstrated that when a colonoscopy is performed by physicians with higher ADRs, patients are less likely to have advanced adenomas on surveillance and less likely to develop or die from PCCRC. Finally, there is at least some evidence that higher ADRs do not lead to more cumulative surveillance exams. The ADR is a useful outcome measure that can provide individual endoscopists and their patients with information about the likelihood of developing PCCRC. To achieve the lowest possible PCCRC rate, we should be striving for higher ADRs. While strategies and innovations may help a bit in improving ADRs, our efforts should focus on ensuring a complete mucosal exam for each patient. Behavioral psychology theories may provide useful frameworks for studying motivating factors that drive a careful exam.
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Factors Associated With Adenoma Detection in Propofol-sedated Patients.
Jia, H, Koo, M, Hsieh, YH, Tseng, CW, Hu, CT, Zhang, L, Dong, T, Pan, Y, Leung, FW
Journal of clinical gastroenterology. 2019;(7):523-529
Abstract
GOALS To assess the factors associated with adenoma detection in propofol-sedated patients. BACKGROUNDS Low adenoma detection rate (ADR) are linked to increased risk of interval cancer and related deaths. Compared with air insufflation (AI) colonoscopy, the method of water exchange (WE) significantly decreased insertion pain and increased ADR in unsedated patients. Deep sedation with propofol has been increasingly used in colonoscopy. One report suggested that WE significantly increased ADR in propofol-sedated patients, but the factors associated with adenoma detection were not analyzed. STUDY Post hoc multiple logistic regression analyses were performed based on pooled data from 2 randomized controlled trials to assess the factors associated with adenoma detection in propofol-sedated patients. RESULTS Propofol-sedated patients (n=510) were randomized to AI and WE. The baseline characteristics were comparable. Multiple logistic regression analyses show that age, withdrawal time, indications (screening vs. diagnostic), and WE were significantly and independently associated with higher ADR. WE had fewer patients with inadequate Boston Bowel Preparation Scale score of <6. Despite a significantly shorter inspection time, WE had significantly higher overall ADR than AI, especially in those with adequate Boston Bowel Preparation Scale of ≥6. Right colon ADR (17.5% vs. 10.5%), flat ADR (32.3% vs. 19.4%), combined advanced and sessile serrated ADR (13.1% vs. 7.4%) of WE were significantly higher than those of AI. CONCLUSIONS WE enhanced quality of colonoscopy in propofol-sedated patients by significantly improving colon cleanliness and overall ADR. Colonoscopists with patients under propofol sedation might consider evaluating WE method for performance improvement.
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Reduction of multitasking distractions underlies the higher adenoma detection rate of water exchange compared to air insufflation - blinded analysis of withdrawal phase videos.
Hsieh, YH, Koo, M, Tseng, CW, Yang, HW, Leung, FW
United European gastroenterology journal. 2019;(2):230-238
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BACKGROUND Experts have hypothesized that a reduction of multitasking distractions and improved bowel cleanliness can explain why insertion water exchange enhances adenoma detection rate. OBJECTIVE The purpose of this study was to test the role of both distractions during withdrawal and bowel cleanliness in enhancing adenoma detection rate using coded video records of colonoscopy. METHODS The withdrawal phase of videos of 299 consecutive colonoscopies from two randomized controlled trials comparing water exchange versus air insufflation at a regional hospital in Taiwan were coded. The primary outcome was distractions; activities that preclude full attention being paid to inspection of the mucosa for polyps. A single blinded reviewer collected the data. RESULTS There were significant agreements in inter-rater reliability indexes. Compared to air insufflation, water exchange had significantly fewer distractions; higher diagnostic yield (intervention time and number), adenoma detection rate, and Boston Bowel Preparation Scale score. Water exchange had a higher withdrawal technique score (predominantly adequacy of cleaning). The association between increased adenoma detection rate and water exchange was mediated by the number of distractions and withdrawal time, but not the Boston Bowel Preparation Scale score. CONCLUSION The speculation by experts that a reduction of multitasking distractions underlies the significantly higher adenoma detection rate of water exchange is supported by the current study. Increased bowel cleanliness did not contribute to the increased adenoma detection rate by use of water exchange.
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G-EYE colonoscopy is superior to standard colonoscopy for increasing adenoma detection rate: an international randomized controlled trial (with videos).
Shirin, H, Shpak, B, Epshtein, J, Karstensen, JG, Hoffman, A, de Ridder, R, Testoni, PA, Ishaq, S, Reddy, DN, Gross, SA, et al
Gastrointestinal endoscopy. 2019;(3):545-553
Abstract
BACKGROUND AND AIMS Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR. METHODS In this randomized, controlled, international, multicenter study (11 centers), patients (aged ≥50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR. RESULTS One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026). CONCLUSION Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.).