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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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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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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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Ectopic Parathyroid Adenoma in Piriform Sinus: Case Report and Review of the Literature.
Connolly, MJ, Lazinski, D, Aoki, KA, McLean, L, Torres, C, Dos Santos, MP
Ear, nose, & throat journal. 2019;(1):14-17
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During routine blood work, a 53-year-old female patient was noted to have asymptomatic hypercalcemia and subsequently found to have hyperparathyroidism. Localization studies for a suspected parathyroid adenoma included 99mTc Sestamibi scintigraphy, Single Photon Emission Computed Tomography (SPECT)/computed tomography (CT) study, and ultrasound of the neck, which were initially read as negative for parathyroid adenoma. A contrast-enhanced CT scan of the neck was performed to locate the suspected parathyroid adenoma and demonstrated a soft tissue lesion within the right piriform sinus. Flexible fiber optic nasolaryngoscopy revealed a submucosal lesion in the right piriform sinus. Following these findings, the initial 99mTc Sestamibi scintigraphy and SPECT/CT were reviewed with confirmation of a focal area of increased activity superior to the right thyroid lobe, corresponding to a nodule in the right piriform sinus that demonstrated increased activity on SPECT/CT. The patient was brought to the operating room for surgical management where a laryngoscope and operating microscope were utilized. The encapsulated lesion was dissected and excised in total. The parathyroid hormone and ionized calcium levels normalized postoperatively. Pathology confirmed a parathyroid adenoma. Parathyroid adenomas are the most common cause of primary hyperparathyroidism. Sixteen percent of parathyroid adenomas can be situated in an ectopic location. Ectopic parathyroid adenomas in the piriform sinus are rare with only a few previously documented cases. We document a rare case of ectopic parathyroid adenoma in the piriform sinus overlooked on initial imaging studies. These lesions can be challenging to localize, however, an understanding of embryology, close scrutiny of possible ectopic locations, and the application of complementary imaging techniques may prove useful for surgeons and clinicians.
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[Aspirin and colorectal cancer].
Grancher, A, Michel, P, Di Fiore, F, Sefrioui, D
Bulletin du cancer. 2018;(2):171-180
Abstract
Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation.
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Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma.
Cardoso, L, Stevenson, M, Thakker, RV
Human mutation. 2017;(12):1621-1648
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Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e., non-syndromic) non-hereditary (i.e., sporadic) endocrinopathy. Studies of hereditary and syndromic forms of PC, which include the hyperparathyroidism-jaw tumor syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ∼2% of parathyroid adenomas. Moreover, CDC73 germline mutations occur in 20%-40% of patients with sporadic PC and may reveal unrecognized HPT-JT. This indicates that CDC73 mutations are major driver mutations in the etiology of PCs. However, there is no genotype-phenotype correlation and some CDC73 mutations (e.g., c.679_680insAG) have been reported in patients with sporadic PC, HPT-JT, or FIHP. Other genes involved in sporadic PC include germline MEN1 and rearranged during transfection (RET) mutations and somatic alterations of the retinoblastoma 1 (RB1) and tumor protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA misregulation. This review summarizes the genetics and epigenetics of the familial syndromic and non-syndromic (sporadic) forms of PC.
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Effects of calcium on the incidence of recurrent colorectal adenomas: A systematic review with meta-analysis and trial sequential analysis of randomized controlled trials.
Veettil, SK, Ching, SM, Lim, KG, Saokaew, S, Phisalprapa, P, Chaiyakunapruk, N
Medicine. 2017;(32):e7661
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BACKGROUND Protective effects of calcium supplementation against colorectal adenomas have been documented in systematic reviews; however, the results have not been conclusive. Our objective was to update and systematically evaluate the evidence for calcium supplementation taking into consideration the risks of systematic and random error and to GRADE the evidence. METHODS The study comprised a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials (RCTs). We searched for RCTs published up until September 2016. Retrieved trials were evaluated using risk of bias. Primary outcome measures were the incidences of any recurrent adenomas and of advanced adenomas. Meta-analytic estimates were calculated with the random-effects model and random errors were evaluated with trial sequential analyses (TSAs). RESULTS Five randomized trials (2234 patients with a history of adenomas) were included. Two of the 5 trials showed either unclear or high risks of bias in most criteria. Meta-analysis of good quality RCTs suggest a moderate protective effect of calcium supplementation on recurrence of adenomas (relative risk [RR], 0.88 [95% CI 0.79-0.99]); however, its effects on advanced adenomas did not show statistical significance (RR, 1.02 [95% CI 0.67-1.55]). Subgroup analyses demonstrated a greater protective effect on recurrence of adenomas with elemental calcium dose ≥1600 mg/day (RR, 0.74 [95% CI 0.56-0.97]) compared to ≤1200 mg/day (RR, 0.84 [95% CI 0.73-0.97]). No major serious adverse events were associated with the use of calcium, but there was an increase in the incidence of hypercalcemia (P = .0095). TSA indicated a lack of firm evidence for a beneficial effect. Concerns with directness and imprecision rated down the quality of the evidence to "low." CONCLUSION The available good quality RCTs suggests a possible beneficial effect of calcium supplementation on the recurrence of adenomas; however, TSA indicated that the accumulated evidence is still inconclusive. Using GRADE-methodology, we conclude that the quality of evidence is low. Large well-designed randomized trials with low risk of bias are needed.
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Enhanced instructions improve the quality of bowel preparation for colonoscopy: a meta-analysis of randomized controlled trials.
Guo, X, Yang, Z, Zhao, L, Leung, F, Luo, H, Kang, X, Li, X, Jia, H, Yang, S, Tao, Q, et al
Gastrointestinal endoscopy. 2017;(1):90-97.e6
Abstract
BACKGROUND AND AIMS The success of a colonoscopy is highly dependent on the quality of bowel preparation (BP). Many patients have poor BP due to non-compliance with regular instructions. Reports concerning the effects of enhanced instructions on BP quality are inconsistent. The aim of this meta-analysis was to compare BP quality between patients receiving enhanced instructions in addition to regular instructions and those who received regular instructions only. METHODS MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched to identify relevant studies published for August 2015. The quality of BP (adequate/inadequate), adenoma detection rate, polyp detection rate, willingness to repeat preparation, and adverse events were estimated by using odds ratios (OR) and 95% confidence intervals (CI) with random effects models. RESULTS Eight randomized controlled trials (n = 3795) were included. Patients who received enhanced instructions showed significantly better BP quality than those receiving only regular instructions (OR, 2.35; 95% CI, 1.65-3.35; P < .001). Subgroup analysis showed that the beneficial effects of enhanced instructions on BP quality were consistent among patients receiving different purgative types, administration methods, or diet restriction (all P < .05). Patients in the enhanced instructions group showed more willingness to repeat the preparation (OR, 1.91; 95% CI, 1.20-3.04; P = .006). CONCLUSIONS Enhanced instructions significantly improved the quality of BP and willingness to repeat the preparation in patients undergoing colonoscopy. Factors related to patient instructions appear to be as important as the preparation method itself in improving BP quality.
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AIP and the somatostatin system in pituitary tumours.
Ibáñez-Costa, A, Korbonits, M
The Journal of endocrinology. 2017;(3):R101-R116
Abstract
Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.
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Adult weight gain and colorectal adenomas-a systematic review and meta-analysis.
Schlesinger, S, Aleksandrova, K, Abar, L, Vieria, AR, Vingeliene, S, Polemiti, E, Stevens, CAT, Greenwood, DC, Chan, DSM, Aune, D, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2017;(6):1217-1229
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BACKGROUND Colorectal adenomas are known as precursors for the majority of colorectal carcinomas. While weight gain during adulthood has been identified as a risk factor for colorectal cancer, the association is less clear for colorectal adenomas. We conducted a systematic review and meta-analysis to quantify the evidence on this association. METHODS We searched Medline up to September 2016 to identify observational (prospective, cross-sectional and retrospective) studies on weight gain during adulthood and colorectal adenoma occurrence and recurrence. We conducted meta-analysis on high weight gain versus stable weight, linear and non-linear dose-response meta-analyses to analyze the association. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using a random effects model. RESULTS For colorectal adenoma occurrence, the summary OR was 1.39 (95% CI: 1.17-1.65; I2: 43%, N = 9 studies, cases = 5507) comparing high (midpoint: 17.4 kg) versus stable weight gain during adulthood and with each 5 kg weight gain the odds increased by 7% (2%-11%; I2: 65%, N = 7 studies). Although there was indication of non-linearity (Pnon-linearity < 0.001) there was an increased odds of colorectal adenoma throughout the whole range of weight gain. Three studies were identified investigating the association between weight gain and colorectal adenoma recurrence and data were limited to draw firm conclusions. CONCLUSIONS Even a small amount of adult weight gain was related to a higher odds of colorectal adenoma occurrence. Our findings add to the benefits of weight control in adulthood regarding colorectal adenoma occurrence, which might be relevant for early prevention of colorectal cancer.
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Dietary fibre for the prevention of recurrent colorectal adenomas and carcinomas.
Yao, Y, Suo, T, Andersson, R, Cao, Y, Wang, C, Lu, J, Chui, E
The Cochrane database of systematic reviews. 2017;(1):CD003430
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BACKGROUND This is an update of the Cochrane review published in 2002.Colorectal cancer (CRC) is a major cause of morbidity and mortality in industrialised countries. Experimental evidence has supported the hypothesis that dietary fibre may protect against the development of CRC, although epidemiologic data have been inconclusive. OBJECTIVES To assess the effect of dietary fibre on the recurrence of colorectal adenomatous polyps in people with a known history of adenomatous polyps and on the incidence of CRC compared to placebo. Further, to identify the reported incidence of adverse effects, such as abdominal pain or diarrhoea, that resulted from the fibre intervention. SEARCH METHODS We identified randomised controlled trials (RCTs) from Cochrane Colorectal Cancer's Specialised Register, CENTRAL, MEDLINE and Embase (search date, 4 April 2016). We also searched ClinicalTrials.gov and WHO International Trials Registry Platform on October 2016. SELECTION CRITERIA We included RCTs or quasi-RCTs. The population were those having a history of adenomatous polyps, but no previous history of CRC, and repeated visualisation of the colon/rectum after at least two-years' follow-up. Dietary fibre was the intervention. The primary outcomes were the number of participants with: 1. at least one adenoma, 2. more than one adenoma, 3. at least one adenoma greater than or equal to 1 cm, or 4. a new diagnosis of CRC. The secondary outcome was the number of adverse events. DATA COLLECTION AND ANALYSIS Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. We used risk ratios (RR) and risk difference (RD) with 95% confidence intervals (CI) to measure the effect. If statistical significance was reached, we reported the number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH). We combined the study data using the fixed-effect model if it was clinically, methodologically, and statistically reasonable. MAIN RESULTS We included seven studies, of which five studies with 4798 participants provided data for analyses in this review. The mean ages of the participants ranged from 56 to 66 years. All participants had a history of adenomas, which had been removed to achieve a polyp-free colon at baseline. The interventions were wheat bran fibre, ispaghula husk, or a comprehensive dietary intervention with high fibre whole food sources alone or in combination. The comparators were low-fibre (2 to 3 g per day), placebo, or a regular diet. The combined data showed no statistically significant difference between the intervention and control groups for the number of participants with at least one adenoma (5 RCTs, n = 3641, RR 1.04, 95% CI 0.95 to 1.13, low-quality evidence), more than one adenoma (2 RCTs, n = 2542, RR 1.06, 95% CI 0.94 to 1.20, low-quality evidence), or at least one adenoma 1 cm or greater (4 RCTs, n = 3224, RR 0.99, 95% CI 0.82 to 1.20, low-quality evidence) at three to four years. The results on the number of participants diagnosed with colorectal cancer favoured the control group over the dietary fibre group (2 RCTS, n = 2794, RR 2.70, 95% CI 1.07 to 6.85, low-quality evidence). After 8 years of comprehensive dietary intervention, no statistically significant difference was found in the number of participants with at least one recurrent adenoma (1 RCT, n = 1905, RR 0.97, 95% CI 0.78 to 1.20), or with more than one adenoma (1 RCT, n = 1905, RR 0.89, 95% CI 0.64 to 1.24). More participants given ispaghula husk group had at least one recurrent adenoma than the control group (1 RCT, n = 376, RR 1.45, 95% CI 1.01 to 2.08). Other analyses by types of fibre intervention were not statistically significant. The overall dropout rate was over 16% in these trials with no reasons given for these losses. Sensitivity analysis incorporating these missing data shows that none of the results can be considered as robust; when the large numbers of participants lost to follow-up were assumed to have had an event or not, the results changed sufficiently to alter the conclusions that we would draw. Therefore, the reliability of the findings may have been compromised by these missing data (attrition bias) and should be interpreted with caution. AUTHORS' CONCLUSIONS There is a lack of evidence from existing RCTs to suggest that increased dietary fibre intake will reduce the recurrence of adenomatous polyps in those with a history of adenomatous polyps within a two to eight year period. However, these results may be unreliable and should be interpreted cautiously, not only because of the high rate of loss to follow-up, but also because adenomatous polyp is a surrogate outcome for the unobserved true endpoint CRC. Longer-term trials with higher dietary fibre levels are needed to enable confident conclusion.